https://orcid.org/0000-0002-1401-1224
Abstract
Papillary craniopharyngioma (PCP) is a rare type of tumor, comprising ∼20% of all craniopharyngioma (CP) cases. It is now recognized as a separate pathological entity from the adamantinomatous type. PCPs are benign tumors, classified as World Health Organization grade 1, characterized by nonkeratinizing squamous epithelium. They typically grow as solid and round papillomatous masses or as unilocular cysts with a cauliflower-like excrescence. PCPs primarily occur in adults (95%), with increased frequency in males (60%), and predominantly affect the hypothalamus. Over 80% of these tumors are located in the third ventricle, expanding either above an anatomically intact infundibulum (strictly third ventricle tumors) or within the infundibulo-tuberal region of the third ventricle floor. Clinical manifestations commonly include visual deficits and a wide range of psychiatric disturbances (45% of patients), such as memory deficits and odd behavior. Magnetic resonance imaging can identify up to 50% of PCPs by the presence of a basal duct-like recess. Surgical management is challenging, requiring complex approaches to the third ventricle and posing significant risk of hypothalamic injury. The endoscopic endonasal approach allows radical tumor resection and yields more favorable patient outcomes. Of intriguing pathogenesis, over 90% of PCPs harbor the somatic BRAFV600E mutation, which activates the mitogen-activated protein kinase signaling pathway. A phase 2 clinical trial has demonstrated that PCPs respond well to proto-oncogene B-Raf/MAPK/ERK kinase inhibitors. This comprehensive review synthesizes information from a cohort of 560 well-described PCPs and 99 large CP series including PCP cases published from 1856 to 2023 and represents the most extensive collection of knowledge on PCPs to date.
Papillary craniopharyngioma (PCP) is now recognized as a separate craniopharyngioma type based on its distinct histology and proto-oncogene B-Raf (BRAF)V600E mutation.
These tumors affect almost exclusively adult patients and develop primarily within the third ventricle.
PCPs usually grow as round, solid papillomatous masses lacking calcifications and may present a distinctive basal duct-like recess above an intact pituitary stalk.
They cause anatomical distortion to and functional impairment of the hypothalamus, leading to complex psychiatric disturbances, particularly defective memory, and personality changes.
Postoperative hypothalamic injury and tumor recurrence are favored by dense and wide tumor adherences to the third ventricle floor.
The endoscopic endonasal approach generally allows a safe radical removal and more favorable visual outcomes than what has been observed following transcranial routes.
Targeted treatment with BRAF/MAPK/ERK kinase inhibitors has yielded satisfactory preliminary results.
More than a century and a half has passed since the Viennese pathologist Carl von Rokitansky (1804-1878) provided the first description of an epithelial papillomatous tumor in the pituitary infundibulum compatible with a papillary craniopharyngioma (PCP) in 1856 (1, 2). However, from a historical scientific perspective, PCP has remained a somewhat “hidden” pathological entity, both literally and figuratively. Typically located within the third ventricle (3V), PCPs have been an unexpected and rather disconcerting finding in the autopsies of patients with a history of mental alterations mimicking dementia praecox (Fig. 1) (3-5). Once the pathological category of hypophyseal duct tumors, or craniopharyngiomas (CPs), was established by the Austrian pathologist Jakob Erdheim (1874-1937) in 1904, PCPs were thought to share a common pathogenic mechanism with their adamantinomatous counterparts, falling under the broader umbrella of CP diagnosis (6, 7). Despite the distinct histopathological and topographical features that differentiate PCPs from adamantinomatous CPs (ACPs), most clinicopathological studies and surgical series of adult CPs lumped an unidentified number of PCPs together with ACPs, without providing separate analyses for each type (Table 1) (8-109). Adding to the confusion, the presence of squamous epithelium characteristic of PCP intermixed with the classic adamantinomatous or enamel-like pattern within the same tissue sample of ACP led to the merging of both histological types in other studies, a viewpoint supported by many pathologists (8, 12, 18, 110-113). Moreover, the traditional concept of CPs as the paradigm of “suprasellar” tumors, along with diagnostic limitations of early radiological methods, resulted in numerous unsuccessful surgical explorations of the suprasellar area in search of a papillary lesion that remained hidden from the surgeon's view, confined within the 3V (11, 13).
Historical milestones in the definition and treatment of papillary craniopharyngiomas. (A) First accounts of PCPs. (A1) Sir Frederick Walter Mott (1853-1926), the British neuropathologist who first hypothesized the embryological origin of a PCP. Reproduced from the Wellcome Collection (Sir Frederick Walker Mott. Photograph by J. Russell & Sons. Reference: 13259i; https://wellcomecollection.org/works/cpdruawx). Licensed under the Creative Commons Attribution 4.0. (A2) Microscopic sagittal illustration of a truly intraventricular PCP found in a patient with florid psychiatric symptoms (case 8 of the 560c). Note the papillary excrescences at the basal portion of the cyst, above an intact third ventricle floor. From Mott and Barratt (3). Public domain. (A3) Illustrations of the first strict third ventricle PCP to undergo a failed surgical attempt at removal via exploratory trepanation, published by Walter Selke in 1891 (case 5 of the 560c). Note the solid, papillomatous architecture of the tumor, which is wholly confined within the third ventricle. From Selke (114). Public domain. (B) Definition of craniopharyngiomas as a new pathological category of pituitary tumors. (B1) Jakob Erdheim (1847-1937), the Viennese neuropathologist who in 1904 defined the category of “hypophyseal-duct tumors” (craniopharyngiomas), which included a “benign” variant (later named PCPs). From Erdheim's family private collection, courtesy of Maria Ros, Erdheim's grandniece. (B2) Squamous cell nests identified in the pituitary gland specimen of a healthy adult that are accumulated at the dorsal surface of the anterior lobe (aPG, lower arrow) and at the upper junction of the pars tuberalis with the infundibulum (upper arrow). (B3) Basal view of a brain specimen with a PCP replacing the infundibulo-tuberal region (case number 12 of the 560c). This unilocular cystic lesion contains a solid cauliflower-like nodule (white arrow). (B4) Histological section of the previous case. (B2-B4). From Erdheim (8). Public domain. (C) Surgery of third ventricle PCPs. (C1) Harvey Williams Cushing (1869-1939), a pioneer craniopharyngioma surgeon. Reproduced from the Wellcome Collection (Harvey Williams Cushing. Photograph by W.(?)W.B. Reference: 13157i; https://wellcomecollection.org/works/f7x5npfn). Licensed under the Creative Commons Attribution 4.0. (C2) Midsagittal autopsy specimen showing a PCP with a cystic-cauliflower consistency predominantly expanding within the third ventricle (case 21 of the 560c). Note the intact pituitary gland below the tumor. From Walker (115). Public domain. (C3) Cushing's sketches showing the frontal transventricular route he employed in April 1932 to successfully remove a third ventricle PCP (case 62 of the 560c). Reproduced from Cushing's Brain Tumor Registry. Public domain.
Abbreviations: 560c, cohort of 560 well-described individual papillary craniopharyngioma patients; OC, optic chiasm; PCP, papillary craniopharyngioma.
Cohort of large CP series published in the medical literature (1904-2023) including PCP patients (99s): summary of fundamental epidemiological, clinical, topographical, surgical, and prognostic data
| No. | Author Year (Ref) | No. CPs | No. PCPs | Mean age | Psychic symptoms (%) | Topography 3V/SS (%) | Surgical approach TCA/TV/EEA (%) | Gross total removal (%) | Overall survival (%) | Recurrence rate (%) |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Erdheim 1904 (8) | 7 | 2 | 40y | NA | 100/0 | – | – | – | – |
| 2 | Cushing 1932 (9, 10) | 92 | 12 | 40y | 58 | 75/25 | 58/16/25 | 20 | 75 | 33% |
| 3 | Kahn 1973 (11) | 60 | 12 | NA | 25 | NA | 73/17/0 | 50 | 100 | 0% |
| 4 | Petito 1976 (12) | 245 | 81a | NA | NA | NA | – | – | – | – |
| 5 | Giangaspero 1984 (13) | – | 6 | 41y | 33 | 66/33 | 66/0/0 | 25 | 66 | 50% |
| 6 | Adamson/Sartoretti 1990 (14, 15) | 93 | 15 | 41y | 50 | 40/60 | – | – | – | – |
| 7 | Szeifert 1993 (16) | 131 | 34 | 40y | NA | NA | NA | NA | 73 | 0% |
| 8 | Weiner/Miller 1994 (17, 18) | 56 | 8 | 48yb | 20A | NA | 80/3/6b | 63 | 75b | 25% |
| 9 | Inoue 1994 (19) | 53 | 9 | 37y | NA | NA | NA | 0 | 100 | 11% |
| 10 | Crotty 1995 (20) | 240 | 48 | 45y | 22 | 47/53 | 88/0/10 | 35 | 96 | 25% |
| 11 | Eldevik 1996 (21) | 45 | 11a | 30y | NA | 81/19 | NA | 0 | NA | 54% |
| 12 | Duff 2000 (22) | 121 | 30 | NA | 13.5A | NA | 60/-/33b | 57b | 95b | 24%b |
| 13 | Pascual 2004 (23) | 61 | 28 | 49y | 40 | 100/0 | 38/62/0 | 46 | 64 | NA |
| 14 | Tavangar 2004 (24) | 141 | 11 | 34y | 7Ab | NA | NA | 73 | NA | 0% |
| 15 | Ersahin 2005 (25) | 87 | 11 Pe | 10yb | 0 | 25/75b | 87/0/3b | 42b | 89b | 28%b |
| 16 | Minamida 2005 (26) | 37 | 13 | NA | NA | NA | 89/0/11b | 80b | 100 | 23% |
| 17 | Gupta 2006 (27) | 116 | 5 Pe | 11yb | 9b | NA | NA | 26 | NA | 20%b |
| 18 | Shi 2006 (28) | 284 | 103 | NA | NA | 40/60b | 96/4/0b | 83b | 96b | 23.5%b |
| 19 | Xu 2006 (29) | 63 | 31 | NA | NA | NA | NA | NA | NA | 19% |
| 20 | Fahlbusch 2008 (30) | 20 | 4 | 41y | 35 | 45/55 | 65/10/10b | 83b | 100b | 10b |
| 21 | Tena-Suck 2009 (31) | 115 | 15 | 52y | 10b | NA | NA | 62b | 87 | 33% |
| 22 | Jung 2009 (32) | 41 | 11 | 46yb | NA | NA | 79/13/8b | 77b | 98b | 24.5%b |
| 23 | Yalçin 2009 (33) | 47 | 9 | 45y | NA | NA | NA | NA | 89 | 11% |
| 24 | Jane Jr 2010 (34) | 12 | 4 | 55y | 25 | 50/50 | 0/0/100 | 75 | 100 | NA |
| 25 | Pekmezci 2010 (35) | 80 | 9 | 48y | 45 | 33/66 | 100/0/0 | 0 | 89 | 44% |
| 26 | Yamada 2010 (36) | 90 | 44 | 36y | NA | NA | 33/0/77b | 77b | 98b | 8%b |
| 27 | Pan 2011 (37) | 17 | 6 | NA | 47b | 100/0 | 100/0/0 | 76b | 88b | NA |
| 28 | Pascual 2011 (38) | 122 | 26 | NA | NA | 100/0 | – | – | – | – |
| 29 | Han 2012 (39) | 98 | 19 | 44yb | 5b | 95/5 | NA | NA | NA | NA |
| 30 | Kim 2012 (40) | 146 | 44 | 41yb | NA | 60/40b | 88/0/10b | 36b | NAb | 27b |
| 31 | Lopez-Serna 2012 (41) | 153 | 25 | 46y | 9b | 60/40b | 84/0/16 | 20 | 93 | 8% |
| 32 | Zacharia 2012 (42) | 244 | 53 | 48y | NA | NA | NA | 36 | 81 | NA |
| 33 | Ogawa 2014 (43) | 42 | 14 | 51yb | NA | NA | 0/0/100 | 93 | 100 | 16% |
| 34 | Yu 2014 (44) | 24 | 10 | 40yb | 33b | 100/0 | 38/62/0 | 80b | 79b | 25%b |
| 35 | Zygourakis 2014 (45) | 84 | 14 | 44y | 24b | 49/51b | 70/0/30b | 16b | 99b | 45%b |
| 36 | Lee 2015 (46) | 18 | 18 | 46y | NA | 83/17 | NA | 39 | 89 | 81% |
| 37 | Cheng 2016 (47) | 92 | 16 | 9yb | NA | 66/34b | 75/17/7b | 47b | 94 | 6% |
| 38 | Fomichev 2016 (48) | 136 | 27 | 49yb | 21b | 18/82b | 0/0/100 | 72b | 94b | 20%b |
| 39 | Jeswani 2016 (49) | 42 | 14 | 45yb | 17b | 82/18b | 49/15/36b | NA | 95 | 22%b |
| 40 | Kshettry 2016 (50) | 43 | 13 | 42yb | 5b | 88/12b | 0/0/100 | 44b | 100b | 26%b |
| 41 | Lee 2016 (51) | 38 | 8 | 59y | NA | NA | NA | 37.5 | 100 | 50% |
| 42 | Morisako 2016 (52) | 72 | 12 | 40yb | 25 | 87/13 | 100/0/0 | 66b | 100 | 20%b |
| 43 | Pan 2016 (53) | 226 | 28 | 38yb | NA | 82/18 | 100/0/0 | 67 | 96 | 16%b |
| 44 | Prieto 2016 (54) | 500 | 111 | 50y | 50 | 90/10 | 55/15/25b | NA | 95 | NA |
| 45 | Turel 2016 (55) | 42 | 11 | 46yb | NA | 26/74b | 33/0/66b | 86b | 97b | 21%b |
| 46 | Wannemuehler 2016 (56) | 21 | 3 | 50yb | NA | NA | 57/0/43b | 57b | 100b | 10%b |
| 47 | Zoli 2016 (57) | 10 | 5 | 52y | NA | 100/0 | 0/0/100 | 80 | 100 | NA |
| 48 | Chu 2017 (58) | 40 | 9 | 39y | 17b | NA | 87/0/13b | 57 | 100b | 4%b |
| 49 | Guadagno 2017 (59) | 45 | 7 | 47y | NA | NA | 0/0/100 | 51 | NA | 14% |
| 50 | Shi 2017 (60) | 1054 | 205 | 99Ad | NA | NA | 99/1/0 | 90b | 98 | 14.5%b |
| 51 | Tariq 2017 (61) | 13 | 13 | 31y | NA | 40/60 | NA | NA | 43 | 28.5% |
| 52 | Dandurand 2018 (62) | 759 | 156 | 38yb | NA | NA | 27/0/73b | 57b | NA | 26%b |
| 53 | Forbes 2018 (63) | 10 | 3 | 57y | 0 | 100/0 | 0/0/100 | 100 | 100 | 33% |
| 54 | La Corte 2018 (64) | 124 | 16 | 50y | 37.5 | 75/25 | 12.5/0/87.5 | 69 | 100 | 19% |
| 55 | Okada 2018 (65) | 67 | 31 | NA | NA | NA | 100/0/0 | NA | 97b | 22%b |
| 56 | Ordoñez-R 2018 (66) | 54 | 6 | 44yb | 20b | 52/48b | 0/0/100 | 83b | 100b | 7.5%b |
| 57 | Pascual 2018 (67) | 210 | 63 | 44y | 100 | 100/0 | NA | NA | NA | NA |
| 58 | Yue 2018 (68) | 52 | 9 | 48y | NA | 83/17b | NA | NA | NA | NA |
| 59 | Zhang 2018 (69) | 445 | 97 | 50y | NA | NA | NA | 20b | 72b | NA |
| 60 | Apra 2019 (70) | 22 | 5 | 58y | 41b | 20/80b | 0/0/100 | 64b | 81b | 36%b |
| 61 | Cai 2019 (71) | 27 | 8 | 52y | NA | 50/50 | 100/0/0 | 87 | 100 | NA |
| 62 | Feng 2019 (72) | 741 | 119 | 43y | NA | NA | NA | NA | NA | NA |
| 63 | Fujio 2019 (73) | 42 | 15 | 52y | NA | NA | NA | NA | NA | NA |
| 64 | Giese 2019 (74) | 71 | 8 | 49yb | 10b | 62/38b | 71/5/13b | 42 | 100 | NA |
| 65 | Li 2019 (75) | 43 | 19 | 44yb | NA | 56/44b | 58/0/42b | 65b | 100b | NA |
| 66 | Algattas 2020 (76) | 62 | 7 | 41yb | 8b | 100/0 | 0/0/100 | 47b | 100b | 38%b |
| 67 | Mende 2020 (77) | 148 | 19 | 46yb | NA | 37/63b | 56/0/44b | NA | NA | 33% |
| 68 | Park 2020 (78) | 64 | 16 | 46yb | NA | 20/80b | 62/0/38 | 75b | 80b | 40%b |
| 69 | Sadashivam 2020 (79) | 95 | 11 | 38yb | 7b | 81/19b | 96/0/4b | 73b | 97b | 24%b |
| 70 | Yang 2020 (80) | 131 | 10 | NA | NA | 68/32b | 0/0/100 | 91b | 98b | 2%b |
| 71 | Cao 2021 (81) | 8V | 6 | 51y | 17 | 100/0 | 0/0/100 | 100 | 100 | 0% |
| 72 | Duan 2021 (82) | 45 | 7 | 53yb | NA | 66/34 | 52/0/34b | 22b | NA | NA |
| 73 | Fan 2021 (83) | 315 | 77 | NA | NA | NA | 60/0/40b | 90b | 97.5b | 8%b |
| 74 | Fan 2021 (84) | 26 | 5 | 50y | NA | 100/0 | 0/0/100 | 100 | 100 | 0% |
| 75 | Hung 2021 (85) | 5 | 5 | 46y | NA | 100/0 | 20/80/0 | NA | NA | NA |
| 76 | Iglesias 2021 (86) | 53 | 23 | 72yb | 35b | NA | 53/0/47b | 45b | 98b | 8.5% |
| 77 | Momin 2021 (87) | 2901 | 605 | NA | – | – | – | – | – | – |
| 78 | Moreno-Torres 2021 (88) | 52 | 11 | 46y | 8 | NA | NA | 60b | 80 | 18% |
| 79 | Seo 2021 (89) | 76 | 20 | NA | 17b | 100/0 | 0/0/100 | 70b | NA | 13%b |
| 80 | Zhao 2021 (90) | 173 | 42 | 42yb | 16.5 | 63/27b | 0/0/100 | 87b | NA | NA |
| 81 | Cao 2022 (91) | 22 | 12 | 44y | 50 | 100/0 | 0/0/100 | 95 | 100 | NA |
| 82 | Castellanos 2022 (92) | 1761 | 507 | NA | – | – | – | – | – | – |
| 83 | Dogra 2022 (93) | 91 | 13 | 48yb | 10b | 40/60b | NA | 49b | 88b | 26%b |
| 84 | Nie 2022 (94) | 273 | 26 | NA | 9b | NA | 54/0/46 | 87b | 100b | NA |
| 85 | Pascual 2022 (95) | 110 | 110 | 50y | 57 | 100/0 | 13/79/8 | 58 | 84 | NA |
| 86 | Prieto 2022 (96) | 245 | 182 | 42yb | 59b | 100/0 | 41/40/10b | 52b | 87b | 15%b |
| 87 | Prieto 2022 (97) | 350 | 350 | 50y | 50.5 | 90/10 | 30/45/16 | 56 | 89 | NA |
| 88 | Rutenberg 2022 (98) | 49 | 7 | 46yb | 16b | NA | NA | NA | 94b | NA |
| 89 | Wu 2022 (99) | 974 | 205 | 91Ad | NA | NA | NA | 49b | NA | 14% |
| 90 | Wu 2022 (100) | 991 | 129 | NA | NA | NA | NA | 41b | NA | NA |
| 91 | Zhao 2022 (101) | 1032 | 5 Pe | 7y | 0 | 0/100 | 60/0/40 | 20 | 100 | 80% |
| 92 | Zhou 2022 (102) | 14 | 9 | 47y | 22 | 100/0 | 0/0/100 | 100 | 100 | 0% |
| 93 | Zoli 2022 (103) | 50 | 12 | 51yb | NA | 100/0 | 20/8/72b | 92b | 100b | NA |
| 94 | Awad 2023 (104) | 296 | 94 | 51yb | NA | NA | 80/0/20 | 55.5b | NA | NA |
| 95 | Bobeff 2023 (105) | 111 | 16 | NA | NA | >80 3V | 0/0/100 | 87 | 100 | 0% |
| 96 | Chen 2023 (106) | 31 | 20 | 46y | 35 | 100/0 | 75/0/25 | 80 | 95 | 10% |
| 97 | Guo 2023 (107) | 742 | 125 | 42y | 3 | NA | 79/0/21 | 82.5 | NA | 16.5% |
| 98 | Pang 2023 (108) | 4202 | 230 | 45yb | 20 | NA | 46/-/53b | 55b | 94b | 26%b |
| 99 | Jia 2023 (109) | 101 | 101 | 48y | 33 | 64/36 | 0/0/100 | 90 | 100 | 13% |
| Total/average data | 23 360 | 4494 | 46y | 30 | 78 3V | 38/8.5/52.5 | 57 | 92 | 22 | |
| No. | Author Year (Ref) | No. CPs | No. PCPs | Mean age | Psychic symptoms (%) | Topography 3V/SS (%) | Surgical approach TCA/TV/EEA (%) | Gross total removal (%) | Overall survival (%) | Recurrence rate (%) |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Erdheim 1904 (8) | 7 | 2 | 40y | NA | 100/0 | – | – | – | – |
| 2 | Cushing 1932 (9, 10) | 92 | 12 | 40y | 58 | 75/25 | 58/16/25 | 20 | 75 | 33% |
| 3 | Kahn 1973 (11) | 60 | 12 | NA | 25 | NA | 73/17/0 | 50 | 100 | 0% |
| 4 | Petito 1976 (12) | 245 | 81a | NA | NA | NA | – | – | – | – |
| 5 | Giangaspero 1984 (13) | – | 6 | 41y | 33 | 66/33 | 66/0/0 | 25 | 66 | 50% |
| 6 | Adamson/Sartoretti 1990 (14, 15) | 93 | 15 | 41y | 50 | 40/60 | – | – | – | – |
| 7 | Szeifert 1993 (16) | 131 | 34 | 40y | NA | NA | NA | NA | 73 | 0% |
| 8 | Weiner/Miller 1994 (17, 18) | 56 | 8 | 48yb | 20A | NA | 80/3/6b | 63 | 75b | 25% |
| 9 | Inoue 1994 (19) | 53 | 9 | 37y | NA | NA | NA | 0 | 100 | 11% |
| 10 | Crotty 1995 (20) | 240 | 48 | 45y | 22 | 47/53 | 88/0/10 | 35 | 96 | 25% |
| 11 | Eldevik 1996 (21) | 45 | 11a | 30y | NA | 81/19 | NA | 0 | NA | 54% |
| 12 | Duff 2000 (22) | 121 | 30 | NA | 13.5A | NA | 60/-/33b | 57b | 95b | 24%b |
| 13 | Pascual 2004 (23) | 61 | 28 | 49y | 40 | 100/0 | 38/62/0 | 46 | 64 | NA |
| 14 | Tavangar 2004 (24) | 141 | 11 | 34y | 7Ab | NA | NA | 73 | NA | 0% |
| 15 | Ersahin 2005 (25) | 87 | 11 Pe | 10yb | 0 | 25/75b | 87/0/3b | 42b | 89b | 28%b |
| 16 | Minamida 2005 (26) | 37 | 13 | NA | NA | NA | 89/0/11b | 80b | 100 | 23% |
| 17 | Gupta 2006 (27) | 116 | 5 Pe | 11yb | 9b | NA | NA | 26 | NA | 20%b |
| 18 | Shi 2006 (28) | 284 | 103 | NA | NA | 40/60b | 96/4/0b | 83b | 96b | 23.5%b |
| 19 | Xu 2006 (29) | 63 | 31 | NA | NA | NA | NA | NA | NA | 19% |
| 20 | Fahlbusch 2008 (30) | 20 | 4 | 41y | 35 | 45/55 | 65/10/10b | 83b | 100b | 10b |
| 21 | Tena-Suck 2009 (31) | 115 | 15 | 52y | 10b | NA | NA | 62b | 87 | 33% |
| 22 | Jung 2009 (32) | 41 | 11 | 46yb | NA | NA | 79/13/8b | 77b | 98b | 24.5%b |
| 23 | Yalçin 2009 (33) | 47 | 9 | 45y | NA | NA | NA | NA | 89 | 11% |
| 24 | Jane Jr 2010 (34) | 12 | 4 | 55y | 25 | 50/50 | 0/0/100 | 75 | 100 | NA |
| 25 | Pekmezci 2010 (35) | 80 | 9 | 48y | 45 | 33/66 | 100/0/0 | 0 | 89 | 44% |
| 26 | Yamada 2010 (36) | 90 | 44 | 36y | NA | NA | 33/0/77b | 77b | 98b | 8%b |
| 27 | Pan 2011 (37) | 17 | 6 | NA | 47b | 100/0 | 100/0/0 | 76b | 88b | NA |
| 28 | Pascual 2011 (38) | 122 | 26 | NA | NA | 100/0 | – | – | – | – |
| 29 | Han 2012 (39) | 98 | 19 | 44yb | 5b | 95/5 | NA | NA | NA | NA |
| 30 | Kim 2012 (40) | 146 | 44 | 41yb | NA | 60/40b | 88/0/10b | 36b | NAb | 27b |
| 31 | Lopez-Serna 2012 (41) | 153 | 25 | 46y | 9b | 60/40b | 84/0/16 | 20 | 93 | 8% |
| 32 | Zacharia 2012 (42) | 244 | 53 | 48y | NA | NA | NA | 36 | 81 | NA |
| 33 | Ogawa 2014 (43) | 42 | 14 | 51yb | NA | NA | 0/0/100 | 93 | 100 | 16% |
| 34 | Yu 2014 (44) | 24 | 10 | 40yb | 33b | 100/0 | 38/62/0 | 80b | 79b | 25%b |
| 35 | Zygourakis 2014 (45) | 84 | 14 | 44y | 24b | 49/51b | 70/0/30b | 16b | 99b | 45%b |
| 36 | Lee 2015 (46) | 18 | 18 | 46y | NA | 83/17 | NA | 39 | 89 | 81% |
| 37 | Cheng 2016 (47) | 92 | 16 | 9yb | NA | 66/34b | 75/17/7b | 47b | 94 | 6% |
| 38 | Fomichev 2016 (48) | 136 | 27 | 49yb | 21b | 18/82b | 0/0/100 | 72b | 94b | 20%b |
| 39 | Jeswani 2016 (49) | 42 | 14 | 45yb | 17b | 82/18b | 49/15/36b | NA | 95 | 22%b |
| 40 | Kshettry 2016 (50) | 43 | 13 | 42yb | 5b | 88/12b | 0/0/100 | 44b | 100b | 26%b |
| 41 | Lee 2016 (51) | 38 | 8 | 59y | NA | NA | NA | 37.5 | 100 | 50% |
| 42 | Morisako 2016 (52) | 72 | 12 | 40yb | 25 | 87/13 | 100/0/0 | 66b | 100 | 20%b |
| 43 | Pan 2016 (53) | 226 | 28 | 38yb | NA | 82/18 | 100/0/0 | 67 | 96 | 16%b |
| 44 | Prieto 2016 (54) | 500 | 111 | 50y | 50 | 90/10 | 55/15/25b | NA | 95 | NA |
| 45 | Turel 2016 (55) | 42 | 11 | 46yb | NA | 26/74b | 33/0/66b | 86b | 97b | 21%b |
| 46 | Wannemuehler 2016 (56) | 21 | 3 | 50yb | NA | NA | 57/0/43b | 57b | 100b | 10%b |
| 47 | Zoli 2016 (57) | 10 | 5 | 52y | NA | 100/0 | 0/0/100 | 80 | 100 | NA |
| 48 | Chu 2017 (58) | 40 | 9 | 39y | 17b | NA | 87/0/13b | 57 | 100b | 4%b |
| 49 | Guadagno 2017 (59) | 45 | 7 | 47y | NA | NA | 0/0/100 | 51 | NA | 14% |
| 50 | Shi 2017 (60) | 1054 | 205 | 99Ad | NA | NA | 99/1/0 | 90b | 98 | 14.5%b |
| 51 | Tariq 2017 (61) | 13 | 13 | 31y | NA | 40/60 | NA | NA | 43 | 28.5% |
| 52 | Dandurand 2018 (62) | 759 | 156 | 38yb | NA | NA | 27/0/73b | 57b | NA | 26%b |
| 53 | Forbes 2018 (63) | 10 | 3 | 57y | 0 | 100/0 | 0/0/100 | 100 | 100 | 33% |
| 54 | La Corte 2018 (64) | 124 | 16 | 50y | 37.5 | 75/25 | 12.5/0/87.5 | 69 | 100 | 19% |
| 55 | Okada 2018 (65) | 67 | 31 | NA | NA | NA | 100/0/0 | NA | 97b | 22%b |
| 56 | Ordoñez-R 2018 (66) | 54 | 6 | 44yb | 20b | 52/48b | 0/0/100 | 83b | 100b | 7.5%b |
| 57 | Pascual 2018 (67) | 210 | 63 | 44y | 100 | 100/0 | NA | NA | NA | NA |
| 58 | Yue 2018 (68) | 52 | 9 | 48y | NA | 83/17b | NA | NA | NA | NA |
| 59 | Zhang 2018 (69) | 445 | 97 | 50y | NA | NA | NA | 20b | 72b | NA |
| 60 | Apra 2019 (70) | 22 | 5 | 58y | 41b | 20/80b | 0/0/100 | 64b | 81b | 36%b |
| 61 | Cai 2019 (71) | 27 | 8 | 52y | NA | 50/50 | 100/0/0 | 87 | 100 | NA |
| 62 | Feng 2019 (72) | 741 | 119 | 43y | NA | NA | NA | NA | NA | NA |
| 63 | Fujio 2019 (73) | 42 | 15 | 52y | NA | NA | NA | NA | NA | NA |
| 64 | Giese 2019 (74) | 71 | 8 | 49yb | 10b | 62/38b | 71/5/13b | 42 | 100 | NA |
| 65 | Li 2019 (75) | 43 | 19 | 44yb | NA | 56/44b | 58/0/42b | 65b | 100b | NA |
| 66 | Algattas 2020 (76) | 62 | 7 | 41yb | 8b | 100/0 | 0/0/100 | 47b | 100b | 38%b |
| 67 | Mende 2020 (77) | 148 | 19 | 46yb | NA | 37/63b | 56/0/44b | NA | NA | 33% |
| 68 | Park 2020 (78) | 64 | 16 | 46yb | NA | 20/80b | 62/0/38 | 75b | 80b | 40%b |
| 69 | Sadashivam 2020 (79) | 95 | 11 | 38yb | 7b | 81/19b | 96/0/4b | 73b | 97b | 24%b |
| 70 | Yang 2020 (80) | 131 | 10 | NA | NA | 68/32b | 0/0/100 | 91b | 98b | 2%b |
| 71 | Cao 2021 (81) | 8V | 6 | 51y | 17 | 100/0 | 0/0/100 | 100 | 100 | 0% |
| 72 | Duan 2021 (82) | 45 | 7 | 53yb | NA | 66/34 | 52/0/34b | 22b | NA | NA |
| 73 | Fan 2021 (83) | 315 | 77 | NA | NA | NA | 60/0/40b | 90b | 97.5b | 8%b |
| 74 | Fan 2021 (84) | 26 | 5 | 50y | NA | 100/0 | 0/0/100 | 100 | 100 | 0% |
| 75 | Hung 2021 (85) | 5 | 5 | 46y | NA | 100/0 | 20/80/0 | NA | NA | NA |
| 76 | Iglesias 2021 (86) | 53 | 23 | 72yb | 35b | NA | 53/0/47b | 45b | 98b | 8.5% |
| 77 | Momin 2021 (87) | 2901 | 605 | NA | – | – | – | – | – | – |
| 78 | Moreno-Torres 2021 (88) | 52 | 11 | 46y | 8 | NA | NA | 60b | 80 | 18% |
| 79 | Seo 2021 (89) | 76 | 20 | NA | 17b | 100/0 | 0/0/100 | 70b | NA | 13%b |
| 80 | Zhao 2021 (90) | 173 | 42 | 42yb | 16.5 | 63/27b | 0/0/100 | 87b | NA | NA |
| 81 | Cao 2022 (91) | 22 | 12 | 44y | 50 | 100/0 | 0/0/100 | 95 | 100 | NA |
| 82 | Castellanos 2022 (92) | 1761 | 507 | NA | – | – | – | – | – | – |
| 83 | Dogra 2022 (93) | 91 | 13 | 48yb | 10b | 40/60b | NA | 49b | 88b | 26%b |
| 84 | Nie 2022 (94) | 273 | 26 | NA | 9b | NA | 54/0/46 | 87b | 100b | NA |
| 85 | Pascual 2022 (95) | 110 | 110 | 50y | 57 | 100/0 | 13/79/8 | 58 | 84 | NA |
| 86 | Prieto 2022 (96) | 245 | 182 | 42yb | 59b | 100/0 | 41/40/10b | 52b | 87b | 15%b |
| 87 | Prieto 2022 (97) | 350 | 350 | 50y | 50.5 | 90/10 | 30/45/16 | 56 | 89 | NA |
| 88 | Rutenberg 2022 (98) | 49 | 7 | 46yb | 16b | NA | NA | NA | 94b | NA |
| 89 | Wu 2022 (99) | 974 | 205 | 91Ad | NA | NA | NA | 49b | NA | 14% |
| 90 | Wu 2022 (100) | 991 | 129 | NA | NA | NA | NA | 41b | NA | NA |
| 91 | Zhao 2022 (101) | 1032 | 5 Pe | 7y | 0 | 0/100 | 60/0/40 | 20 | 100 | 80% |
| 92 | Zhou 2022 (102) | 14 | 9 | 47y | 22 | 100/0 | 0/0/100 | 100 | 100 | 0% |
| 93 | Zoli 2022 (103) | 50 | 12 | 51yb | NA | 100/0 | 20/8/72b | 92b | 100b | NA |
| 94 | Awad 2023 (104) | 296 | 94 | 51yb | NA | NA | 80/0/20 | 55.5b | NA | NA |
| 95 | Bobeff 2023 (105) | 111 | 16 | NA | NA | >80 3V | 0/0/100 | 87 | 100 | 0% |
| 96 | Chen 2023 (106) | 31 | 20 | 46y | 35 | 100/0 | 75/0/25 | 80 | 95 | 10% |
| 97 | Guo 2023 (107) | 742 | 125 | 42y | 3 | NA | 79/0/21 | 82.5 | NA | 16.5% |
| 98 | Pang 2023 (108) | 4202 | 230 | 45yb | 20 | NA | 46/-/53b | 55b | 94b | 26%b |
| 99 | Jia 2023 (109) | 101 | 101 | 48y | 33 | 64/36 | 0/0/100 | 90 | 100 | 13% |
| Total/average data | 23 360 | 4494 | 46y | 30 | 78 3V | 38/8.5/52.5 | 57 | 92 | 22 | |
Abbreviations: 3V, third ventricle occupation (tumor largely occupying the 3V or is wholly confined into it); 99s, cohort of 99 large craniopharyngioma series containing papillary craniopharyngiomas; A, adult CP patients (rate for the cohort of adult CPs in the series when the specific rate for PCPs is not available); Ad, adults; CP, craniopharyngioma; EEA, endoscopic endonasal approach; hc, historical cohort; hist, histology provided; NA, not available; No., number of cases; PCP, papillary craniopharyngioma; Ref, reference number; SS, tumors primarily originated below the third ventricle floor; TCA, transcranial approach (pterional, subfrontal, or bifrontal interhemispheric with or without trans-lamina terminalis approach); TV, transventricular type of approach (frontal-transcortical transventricular/transcallosal/combined); y, years old.
aCP cases with a significant portion of squamous epithelium in addition to the adamantinomatous one.
bIndicates that the rate corresponds to the whole CP series (separate analysis for the histological papilary type is not available).
Cohort of large CP series published in the medical literature (1904-2023) including PCP patients (99s): summary of fundamental epidemiological, clinical, topographical, surgical, and prognostic data
| No. | Author Year (Ref) | No. CPs | No. PCPs | Mean age | Psychic symptoms (%) | Topography 3V/SS (%) | Surgical approach TCA/TV/EEA (%) | Gross total removal (%) | Overall survival (%) | Recurrence rate (%) |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Erdheim 1904 (8) | 7 | 2 | 40y | NA | 100/0 | – | – | – | – |
| 2 | Cushing 1932 (9, 10) | 92 | 12 | 40y | 58 | 75/25 | 58/16/25 | 20 | 75 | 33% |
| 3 | Kahn 1973 (11) | 60 | 12 | NA | 25 | NA | 73/17/0 | 50 | 100 | 0% |
| 4 | Petito 1976 (12) | 245 | 81a | NA | NA | NA | – | – | – | – |
| 5 | Giangaspero 1984 (13) | – | 6 | 41y | 33 | 66/33 | 66/0/0 | 25 | 66 | 50% |
| 6 | Adamson/Sartoretti 1990 (14, 15) | 93 | 15 | 41y | 50 | 40/60 | – | – | – | – |
| 7 | Szeifert 1993 (16) | 131 | 34 | 40y | NA | NA | NA | NA | 73 | 0% |
| 8 | Weiner/Miller 1994 (17, 18) | 56 | 8 | 48yb | 20A | NA | 80/3/6b | 63 | 75b | 25% |
| 9 | Inoue 1994 (19) | 53 | 9 | 37y | NA | NA | NA | 0 | 100 | 11% |
| 10 | Crotty 1995 (20) | 240 | 48 | 45y | 22 | 47/53 | 88/0/10 | 35 | 96 | 25% |
| 11 | Eldevik 1996 (21) | 45 | 11a | 30y | NA | 81/19 | NA | 0 | NA | 54% |
| 12 | Duff 2000 (22) | 121 | 30 | NA | 13.5A | NA | 60/-/33b | 57b | 95b | 24%b |
| 13 | Pascual 2004 (23) | 61 | 28 | 49y | 40 | 100/0 | 38/62/0 | 46 | 64 | NA |
| 14 | Tavangar 2004 (24) | 141 | 11 | 34y | 7Ab | NA | NA | 73 | NA | 0% |
| 15 | Ersahin 2005 (25) | 87 | 11 Pe | 10yb | 0 | 25/75b | 87/0/3b | 42b | 89b | 28%b |
| 16 | Minamida 2005 (26) | 37 | 13 | NA | NA | NA | 89/0/11b | 80b | 100 | 23% |
| 17 | Gupta 2006 (27) | 116 | 5 Pe | 11yb | 9b | NA | NA | 26 | NA | 20%b |
| 18 | Shi 2006 (28) | 284 | 103 | NA | NA | 40/60b | 96/4/0b | 83b | 96b | 23.5%b |
| 19 | Xu 2006 (29) | 63 | 31 | NA | NA | NA | NA | NA | NA | 19% |
| 20 | Fahlbusch 2008 (30) | 20 | 4 | 41y | 35 | 45/55 | 65/10/10b | 83b | 100b | 10b |
| 21 | Tena-Suck 2009 (31) | 115 | 15 | 52y | 10b | NA | NA | 62b | 87 | 33% |
| 22 | Jung 2009 (32) | 41 | 11 | 46yb | NA | NA | 79/13/8b | 77b | 98b | 24.5%b |
| 23 | Yalçin 2009 (33) | 47 | 9 | 45y | NA | NA | NA | NA | 89 | 11% |
| 24 | Jane Jr 2010 (34) | 12 | 4 | 55y | 25 | 50/50 | 0/0/100 | 75 | 100 | NA |
| 25 | Pekmezci 2010 (35) | 80 | 9 | 48y | 45 | 33/66 | 100/0/0 | 0 | 89 | 44% |
| 26 | Yamada 2010 (36) | 90 | 44 | 36y | NA | NA | 33/0/77b | 77b | 98b | 8%b |
| 27 | Pan 2011 (37) | 17 | 6 | NA | 47b | 100/0 | 100/0/0 | 76b | 88b | NA |
| 28 | Pascual 2011 (38) | 122 | 26 | NA | NA | 100/0 | – | – | – | – |
| 29 | Han 2012 (39) | 98 | 19 | 44yb | 5b | 95/5 | NA | NA | NA | NA |
| 30 | Kim 2012 (40) | 146 | 44 | 41yb | NA | 60/40b | 88/0/10b | 36b | NAb | 27b |
| 31 | Lopez-Serna 2012 (41) | 153 | 25 | 46y | 9b | 60/40b | 84/0/16 | 20 | 93 | 8% |
| 32 | Zacharia 2012 (42) | 244 | 53 | 48y | NA | NA | NA | 36 | 81 | NA |
| 33 | Ogawa 2014 (43) | 42 | 14 | 51yb | NA | NA | 0/0/100 | 93 | 100 | 16% |
| 34 | Yu 2014 (44) | 24 | 10 | 40yb | 33b | 100/0 | 38/62/0 | 80b | 79b | 25%b |
| 35 | Zygourakis 2014 (45) | 84 | 14 | 44y | 24b | 49/51b | 70/0/30b | 16b | 99b | 45%b |
| 36 | Lee 2015 (46) | 18 | 18 | 46y | NA | 83/17 | NA | 39 | 89 | 81% |
| 37 | Cheng 2016 (47) | 92 | 16 | 9yb | NA | 66/34b | 75/17/7b | 47b | 94 | 6% |
| 38 | Fomichev 2016 (48) | 136 | 27 | 49yb | 21b | 18/82b | 0/0/100 | 72b | 94b | 20%b |
| 39 | Jeswani 2016 (49) | 42 | 14 | 45yb | 17b | 82/18b | 49/15/36b | NA | 95 | 22%b |
| 40 | Kshettry 2016 (50) | 43 | 13 | 42yb | 5b | 88/12b | 0/0/100 | 44b | 100b | 26%b |
| 41 | Lee 2016 (51) | 38 | 8 | 59y | NA | NA | NA | 37.5 | 100 | 50% |
| 42 | Morisako 2016 (52) | 72 | 12 | 40yb | 25 | 87/13 | 100/0/0 | 66b | 100 | 20%b |
| 43 | Pan 2016 (53) | 226 | 28 | 38yb | NA | 82/18 | 100/0/0 | 67 | 96 | 16%b |
| 44 | Prieto 2016 (54) | 500 | 111 | 50y | 50 | 90/10 | 55/15/25b | NA | 95 | NA |
| 45 | Turel 2016 (55) | 42 | 11 | 46yb | NA | 26/74b | 33/0/66b | 86b | 97b | 21%b |
| 46 | Wannemuehler 2016 (56) | 21 | 3 | 50yb | NA | NA | 57/0/43b | 57b | 100b | 10%b |
| 47 | Zoli 2016 (57) | 10 | 5 | 52y | NA | 100/0 | 0/0/100 | 80 | 100 | NA |
| 48 | Chu 2017 (58) | 40 | 9 | 39y | 17b | NA | 87/0/13b | 57 | 100b | 4%b |
| 49 | Guadagno 2017 (59) | 45 | 7 | 47y | NA | NA | 0/0/100 | 51 | NA | 14% |
| 50 | Shi 2017 (60) | 1054 | 205 | 99Ad | NA | NA | 99/1/0 | 90b | 98 | 14.5%b |
| 51 | Tariq 2017 (61) | 13 | 13 | 31y | NA | 40/60 | NA | NA | 43 | 28.5% |
| 52 | Dandurand 2018 (62) | 759 | 156 | 38yb | NA | NA | 27/0/73b | 57b | NA | 26%b |
| 53 | Forbes 2018 (63) | 10 | 3 | 57y | 0 | 100/0 | 0/0/100 | 100 | 100 | 33% |
| 54 | La Corte 2018 (64) | 124 | 16 | 50y | 37.5 | 75/25 | 12.5/0/87.5 | 69 | 100 | 19% |
| 55 | Okada 2018 (65) | 67 | 31 | NA | NA | NA | 100/0/0 | NA | 97b | 22%b |
| 56 | Ordoñez-R 2018 (66) | 54 | 6 | 44yb | 20b | 52/48b | 0/0/100 | 83b | 100b | 7.5%b |
| 57 | Pascual 2018 (67) | 210 | 63 | 44y | 100 | 100/0 | NA | NA | NA | NA |
| 58 | Yue 2018 (68) | 52 | 9 | 48y | NA | 83/17b | NA | NA | NA | NA |
| 59 | Zhang 2018 (69) | 445 | 97 | 50y | NA | NA | NA | 20b | 72b | NA |
| 60 | Apra 2019 (70) | 22 | 5 | 58y | 41b | 20/80b | 0/0/100 | 64b | 81b | 36%b |
| 61 | Cai 2019 (71) | 27 | 8 | 52y | NA | 50/50 | 100/0/0 | 87 | 100 | NA |
| 62 | Feng 2019 (72) | 741 | 119 | 43y | NA | NA | NA | NA | NA | NA |
| 63 | Fujio 2019 (73) | 42 | 15 | 52y | NA | NA | NA | NA | NA | NA |
| 64 | Giese 2019 (74) | 71 | 8 | 49yb | 10b | 62/38b | 71/5/13b | 42 | 100 | NA |
| 65 | Li 2019 (75) | 43 | 19 | 44yb | NA | 56/44b | 58/0/42b | 65b | 100b | NA |
| 66 | Algattas 2020 (76) | 62 | 7 | 41yb | 8b | 100/0 | 0/0/100 | 47b | 100b | 38%b |
| 67 | Mende 2020 (77) | 148 | 19 | 46yb | NA | 37/63b | 56/0/44b | NA | NA | 33% |
| 68 | Park 2020 (78) | 64 | 16 | 46yb | NA | 20/80b | 62/0/38 | 75b | 80b | 40%b |
| 69 | Sadashivam 2020 (79) | 95 | 11 | 38yb | 7b | 81/19b | 96/0/4b | 73b | 97b | 24%b |
| 70 | Yang 2020 (80) | 131 | 10 | NA | NA | 68/32b | 0/0/100 | 91b | 98b | 2%b |
| 71 | Cao 2021 (81) | 8V | 6 | 51y | 17 | 100/0 | 0/0/100 | 100 | 100 | 0% |
| 72 | Duan 2021 (82) | 45 | 7 | 53yb | NA | 66/34 | 52/0/34b | 22b | NA | NA |
| 73 | Fan 2021 (83) | 315 | 77 | NA | NA | NA | 60/0/40b | 90b | 97.5b | 8%b |
| 74 | Fan 2021 (84) | 26 | 5 | 50y | NA | 100/0 | 0/0/100 | 100 | 100 | 0% |
| 75 | Hung 2021 (85) | 5 | 5 | 46y | NA | 100/0 | 20/80/0 | NA | NA | NA |
| 76 | Iglesias 2021 (86) | 53 | 23 | 72yb | 35b | NA | 53/0/47b | 45b | 98b | 8.5% |
| 77 | Momin 2021 (87) | 2901 | 605 | NA | – | – | – | – | – | – |
| 78 | Moreno-Torres 2021 (88) | 52 | 11 | 46y | 8 | NA | NA | 60b | 80 | 18% |
| 79 | Seo 2021 (89) | 76 | 20 | NA | 17b | 100/0 | 0/0/100 | 70b | NA | 13%b |
| 80 | Zhao 2021 (90) | 173 | 42 | 42yb | 16.5 | 63/27b | 0/0/100 | 87b | NA | NA |
| 81 | Cao 2022 (91) | 22 | 12 | 44y | 50 | 100/0 | 0/0/100 | 95 | 100 | NA |
| 82 | Castellanos 2022 (92) | 1761 | 507 | NA | – | – | – | – | – | – |
| 83 | Dogra 2022 (93) | 91 | 13 | 48yb | 10b | 40/60b | NA | 49b | 88b | 26%b |
| 84 | Nie 2022 (94) | 273 | 26 | NA | 9b | NA | 54/0/46 | 87b | 100b | NA |
| 85 | Pascual 2022 (95) | 110 | 110 | 50y | 57 | 100/0 | 13/79/8 | 58 | 84 | NA |
| 86 | Prieto 2022 (96) | 245 | 182 | 42yb | 59b | 100/0 | 41/40/10b | 52b | 87b | 15%b |
| 87 | Prieto 2022 (97) | 350 | 350 | 50y | 50.5 | 90/10 | 30/45/16 | 56 | 89 | NA |
| 88 | Rutenberg 2022 (98) | 49 | 7 | 46yb | 16b | NA | NA | NA | 94b | NA |
| 89 | Wu 2022 (99) | 974 | 205 | 91Ad | NA | NA | NA | 49b | NA | 14% |
| 90 | Wu 2022 (100) | 991 | 129 | NA | NA | NA | NA | 41b | NA | NA |
| 91 | Zhao 2022 (101) | 1032 | 5 Pe | 7y | 0 | 0/100 | 60/0/40 | 20 | 100 | 80% |
| 92 | Zhou 2022 (102) | 14 | 9 | 47y | 22 | 100/0 | 0/0/100 | 100 | 100 | 0% |
| 93 | Zoli 2022 (103) | 50 | 12 | 51yb | NA | 100/0 | 20/8/72b | 92b | 100b | NA |
| 94 | Awad 2023 (104) | 296 | 94 | 51yb | NA | NA | 80/0/20 | 55.5b | NA | NA |
| 95 | Bobeff 2023 (105) | 111 | 16 | NA | NA | >80 3V | 0/0/100 | 87 | 100 | 0% |
| 96 | Chen 2023 (106) | 31 | 20 | 46y | 35 | 100/0 | 75/0/25 | 80 | 95 | 10% |
| 97 | Guo 2023 (107) | 742 | 125 | 42y | 3 | NA | 79/0/21 | 82.5 | NA | 16.5% |
| 98 | Pang 2023 (108) | 4202 | 230 | 45yb | 20 | NA | 46/-/53b | 55b | 94b | 26%b |
| 99 | Jia 2023 (109) | 101 | 101 | 48y | 33 | 64/36 | 0/0/100 | 90 | 100 | 13% |
| Total/average data | 23 360 | 4494 | 46y | 30 | 78 3V | 38/8.5/52.5 | 57 | 92 | 22 | |
| No. | Author Year (Ref) | No. CPs | No. PCPs | Mean age | Psychic symptoms (%) | Topography 3V/SS (%) | Surgical approach TCA/TV/EEA (%) | Gross total removal (%) | Overall survival (%) | Recurrence rate (%) |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Erdheim 1904 (8) | 7 | 2 | 40y | NA | 100/0 | – | – | – | – |
| 2 | Cushing 1932 (9, 10) | 92 | 12 | 40y | 58 | 75/25 | 58/16/25 | 20 | 75 | 33% |
| 3 | Kahn 1973 (11) | 60 | 12 | NA | 25 | NA | 73/17/0 | 50 | 100 | 0% |
| 4 | Petito 1976 (12) | 245 | 81a | NA | NA | NA | – | – | – | – |
| 5 | Giangaspero 1984 (13) | – | 6 | 41y | 33 | 66/33 | 66/0/0 | 25 | 66 | 50% |
| 6 | Adamson/Sartoretti 1990 (14, 15) | 93 | 15 | 41y | 50 | 40/60 | – | – | – | – |
| 7 | Szeifert 1993 (16) | 131 | 34 | 40y | NA | NA | NA | NA | 73 | 0% |
| 8 | Weiner/Miller 1994 (17, 18) | 56 | 8 | 48yb | 20A | NA | 80/3/6b | 63 | 75b | 25% |
| 9 | Inoue 1994 (19) | 53 | 9 | 37y | NA | NA | NA | 0 | 100 | 11% |
| 10 | Crotty 1995 (20) | 240 | 48 | 45y | 22 | 47/53 | 88/0/10 | 35 | 96 | 25% |
| 11 | Eldevik 1996 (21) | 45 | 11a | 30y | NA | 81/19 | NA | 0 | NA | 54% |
| 12 | Duff 2000 (22) | 121 | 30 | NA | 13.5A | NA | 60/-/33b | 57b | 95b | 24%b |
| 13 | Pascual 2004 (23) | 61 | 28 | 49y | 40 | 100/0 | 38/62/0 | 46 | 64 | NA |
| 14 | Tavangar 2004 (24) | 141 | 11 | 34y | 7Ab | NA | NA | 73 | NA | 0% |
| 15 | Ersahin 2005 (25) | 87 | 11 Pe | 10yb | 0 | 25/75b | 87/0/3b | 42b | 89b | 28%b |
| 16 | Minamida 2005 (26) | 37 | 13 | NA | NA | NA | 89/0/11b | 80b | 100 | 23% |
| 17 | Gupta 2006 (27) | 116 | 5 Pe | 11yb | 9b | NA | NA | 26 | NA | 20%b |
| 18 | Shi 2006 (28) | 284 | 103 | NA | NA | 40/60b | 96/4/0b | 83b | 96b | 23.5%b |
| 19 | Xu 2006 (29) | 63 | 31 | NA | NA | NA | NA | NA | NA | 19% |
| 20 | Fahlbusch 2008 (30) | 20 | 4 | 41y | 35 | 45/55 | 65/10/10b | 83b | 100b | 10b |
| 21 | Tena-Suck 2009 (31) | 115 | 15 | 52y | 10b | NA | NA | 62b | 87 | 33% |
| 22 | Jung 2009 (32) | 41 | 11 | 46yb | NA | NA | 79/13/8b | 77b | 98b | 24.5%b |
| 23 | Yalçin 2009 (33) | 47 | 9 | 45y | NA | NA | NA | NA | 89 | 11% |
| 24 | Jane Jr 2010 (34) | 12 | 4 | 55y | 25 | 50/50 | 0/0/100 | 75 | 100 | NA |
| 25 | Pekmezci 2010 (35) | 80 | 9 | 48y | 45 | 33/66 | 100/0/0 | 0 | 89 | 44% |
| 26 | Yamada 2010 (36) | 90 | 44 | 36y | NA | NA | 33/0/77b | 77b | 98b | 8%b |
| 27 | Pan 2011 (37) | 17 | 6 | NA | 47b | 100/0 | 100/0/0 | 76b | 88b | NA |
| 28 | Pascual 2011 (38) | 122 | 26 | NA | NA | 100/0 | – | – | – | – |
| 29 | Han 2012 (39) | 98 | 19 | 44yb | 5b | 95/5 | NA | NA | NA | NA |
| 30 | Kim 2012 (40) | 146 | 44 | 41yb | NA | 60/40b | 88/0/10b | 36b | NAb | 27b |
| 31 | Lopez-Serna 2012 (41) | 153 | 25 | 46y | 9b | 60/40b | 84/0/16 | 20 | 93 | 8% |
| 32 | Zacharia 2012 (42) | 244 | 53 | 48y | NA | NA | NA | 36 | 81 | NA |
| 33 | Ogawa 2014 (43) | 42 | 14 | 51yb | NA | NA | 0/0/100 | 93 | 100 | 16% |
| 34 | Yu 2014 (44) | 24 | 10 | 40yb | 33b | 100/0 | 38/62/0 | 80b | 79b | 25%b |
| 35 | Zygourakis 2014 (45) | 84 | 14 | 44y | 24b | 49/51b | 70/0/30b | 16b | 99b | 45%b |
| 36 | Lee 2015 (46) | 18 | 18 | 46y | NA | 83/17 | NA | 39 | 89 | 81% |
| 37 | Cheng 2016 (47) | 92 | 16 | 9yb | NA | 66/34b | 75/17/7b | 47b | 94 | 6% |
| 38 | Fomichev 2016 (48) | 136 | 27 | 49yb | 21b | 18/82b | 0/0/100 | 72b | 94b | 20%b |
| 39 | Jeswani 2016 (49) | 42 | 14 | 45yb | 17b | 82/18b | 49/15/36b | NA | 95 | 22%b |
| 40 | Kshettry 2016 (50) | 43 | 13 | 42yb | 5b | 88/12b | 0/0/100 | 44b | 100b | 26%b |
| 41 | Lee 2016 (51) | 38 | 8 | 59y | NA | NA | NA | 37.5 | 100 | 50% |
| 42 | Morisako 2016 (52) | 72 | 12 | 40yb | 25 | 87/13 | 100/0/0 | 66b | 100 | 20%b |
| 43 | Pan 2016 (53) | 226 | 28 | 38yb | NA | 82/18 | 100/0/0 | 67 | 96 | 16%b |
| 44 | Prieto 2016 (54) | 500 | 111 | 50y | 50 | 90/10 | 55/15/25b | NA | 95 | NA |
| 45 | Turel 2016 (55) | 42 | 11 | 46yb | NA | 26/74b | 33/0/66b | 86b | 97b | 21%b |
| 46 | Wannemuehler 2016 (56) | 21 | 3 | 50yb | NA | NA | 57/0/43b | 57b | 100b | 10%b |
| 47 | Zoli 2016 (57) | 10 | 5 | 52y | NA | 100/0 | 0/0/100 | 80 | 100 | NA |
| 48 | Chu 2017 (58) | 40 | 9 | 39y | 17b | NA | 87/0/13b | 57 | 100b | 4%b |
| 49 | Guadagno 2017 (59) | 45 | 7 | 47y | NA | NA | 0/0/100 | 51 | NA | 14% |
| 50 | Shi 2017 (60) | 1054 | 205 | 99Ad | NA | NA | 99/1/0 | 90b | 98 | 14.5%b |
| 51 | Tariq 2017 (61) | 13 | 13 | 31y | NA | 40/60 | NA | NA | 43 | 28.5% |
| 52 | Dandurand 2018 (62) | 759 | 156 | 38yb | NA | NA | 27/0/73b | 57b | NA | 26%b |
| 53 | Forbes 2018 (63) | 10 | 3 | 57y | 0 | 100/0 | 0/0/100 | 100 | 100 | 33% |
| 54 | La Corte 2018 (64) | 124 | 16 | 50y | 37.5 | 75/25 | 12.5/0/87.5 | 69 | 100 | 19% |
| 55 | Okada 2018 (65) | 67 | 31 | NA | NA | NA | 100/0/0 | NA | 97b | 22%b |
| 56 | Ordoñez-R 2018 (66) | 54 | 6 | 44yb | 20b | 52/48b | 0/0/100 | 83b | 100b | 7.5%b |
| 57 | Pascual 2018 (67) | 210 | 63 | 44y | 100 | 100/0 | NA | NA | NA | NA |
| 58 | Yue 2018 (68) | 52 | 9 | 48y | NA | 83/17b | NA | NA | NA | NA |
| 59 | Zhang 2018 (69) | 445 | 97 | 50y | NA | NA | NA | 20b | 72b | NA |
| 60 | Apra 2019 (70) | 22 | 5 | 58y | 41b | 20/80b | 0/0/100 | 64b | 81b | 36%b |
| 61 | Cai 2019 (71) | 27 | 8 | 52y | NA | 50/50 | 100/0/0 | 87 | 100 | NA |
| 62 | Feng 2019 (72) | 741 | 119 | 43y | NA | NA | NA | NA | NA | NA |
| 63 | Fujio 2019 (73) | 42 | 15 | 52y | NA | NA | NA | NA | NA | NA |
| 64 | Giese 2019 (74) | 71 | 8 | 49yb | 10b | 62/38b | 71/5/13b | 42 | 100 | NA |
| 65 | Li 2019 (75) | 43 | 19 | 44yb | NA | 56/44b | 58/0/42b | 65b | 100b | NA |
| 66 | Algattas 2020 (76) | 62 | 7 | 41yb | 8b | 100/0 | 0/0/100 | 47b | 100b | 38%b |
| 67 | Mende 2020 (77) | 148 | 19 | 46yb | NA | 37/63b | 56/0/44b | NA | NA | 33% |
| 68 | Park 2020 (78) | 64 | 16 | 46yb | NA | 20/80b | 62/0/38 | 75b | 80b | 40%b |
| 69 | Sadashivam 2020 (79) | 95 | 11 | 38yb | 7b | 81/19b | 96/0/4b | 73b | 97b | 24%b |
| 70 | Yang 2020 (80) | 131 | 10 | NA | NA | 68/32b | 0/0/100 | 91b | 98b | 2%b |
| 71 | Cao 2021 (81) | 8V | 6 | 51y | 17 | 100/0 | 0/0/100 | 100 | 100 | 0% |
| 72 | Duan 2021 (82) | 45 | 7 | 53yb | NA | 66/34 | 52/0/34b | 22b | NA | NA |
| 73 | Fan 2021 (83) | 315 | 77 | NA | NA | NA | 60/0/40b | 90b | 97.5b | 8%b |
| 74 | Fan 2021 (84) | 26 | 5 | 50y | NA | 100/0 | 0/0/100 | 100 | 100 | 0% |
| 75 | Hung 2021 (85) | 5 | 5 | 46y | NA | 100/0 | 20/80/0 | NA | NA | NA |
| 76 | Iglesias 2021 (86) | 53 | 23 | 72yb | 35b | NA | 53/0/47b | 45b | 98b | 8.5% |
| 77 | Momin 2021 (87) | 2901 | 605 | NA | – | – | – | – | – | – |
| 78 | Moreno-Torres 2021 (88) | 52 | 11 | 46y | 8 | NA | NA | 60b | 80 | 18% |
| 79 | Seo 2021 (89) | 76 | 20 | NA | 17b | 100/0 | 0/0/100 | 70b | NA | 13%b |
| 80 | Zhao 2021 (90) | 173 | 42 | 42yb | 16.5 | 63/27b | 0/0/100 | 87b | NA | NA |
| 81 | Cao 2022 (91) | 22 | 12 | 44y | 50 | 100/0 | 0/0/100 | 95 | 100 | NA |
| 82 | Castellanos 2022 (92) | 1761 | 507 | NA | – | – | – | – | – | – |
| 83 | Dogra 2022 (93) | 91 | 13 | 48yb | 10b | 40/60b | NA | 49b | 88b | 26%b |
| 84 | Nie 2022 (94) | 273 | 26 | NA | 9b | NA | 54/0/46 | 87b | 100b | NA |
| 85 | Pascual 2022 (95) | 110 | 110 | 50y | 57 | 100/0 | 13/79/8 | 58 | 84 | NA |
| 86 | Prieto 2022 (96) | 245 | 182 | 42yb | 59b | 100/0 | 41/40/10b | 52b | 87b | 15%b |
| 87 | Prieto 2022 (97) | 350 | 350 | 50y | 50.5 | 90/10 | 30/45/16 | 56 | 89 | NA |
| 88 | Rutenberg 2022 (98) | 49 | 7 | 46yb | 16b | NA | NA | NA | 94b | NA |
| 89 | Wu 2022 (99) | 974 | 205 | 91Ad | NA | NA | NA | 49b | NA | 14% |
| 90 | Wu 2022 (100) | 991 | 129 | NA | NA | NA | NA | 41b | NA | NA |
| 91 | Zhao 2022 (101) | 1032 | 5 Pe | 7y | 0 | 0/100 | 60/0/40 | 20 | 100 | 80% |
| 92 | Zhou 2022 (102) | 14 | 9 | 47y | 22 | 100/0 | 0/0/100 | 100 | 100 | 0% |
| 93 | Zoli 2022 (103) | 50 | 12 | 51yb | NA | 100/0 | 20/8/72b | 92b | 100b | NA |
| 94 | Awad 2023 (104) | 296 | 94 | 51yb | NA | NA | 80/0/20 | 55.5b | NA | NA |
| 95 | Bobeff 2023 (105) | 111 | 16 | NA | NA | >80 3V | 0/0/100 | 87 | 100 | 0% |
| 96 | Chen 2023 (106) | 31 | 20 | 46y | 35 | 100/0 | 75/0/25 | 80 | 95 | 10% |
| 97 | Guo 2023 (107) | 742 | 125 | 42y | 3 | NA | 79/0/21 | 82.5 | NA | 16.5% |
| 98 | Pang 2023 (108) | 4202 | 230 | 45yb | 20 | NA | 46/-/53b | 55b | 94b | 26%b |
| 99 | Jia 2023 (109) | 101 | 101 | 48y | 33 | 64/36 | 0/0/100 | 90 | 100 | 13% |
| Total/average data | 23 360 | 4494 | 46y | 30 | 78 3V | 38/8.5/52.5 | 57 | 92 | 22 | |
Abbreviations: 3V, third ventricle occupation (tumor largely occupying the 3V or is wholly confined into it); 99s, cohort of 99 large craniopharyngioma series containing papillary craniopharyngiomas; A, adult CP patients (rate for the cohort of adult CPs in the series when the specific rate for PCPs is not available); Ad, adults; CP, craniopharyngioma; EEA, endoscopic endonasal approach; hc, historical cohort; hist, histology provided; NA, not available; No., number of cases; PCP, papillary craniopharyngioma; Ref, reference number; SS, tumors primarily originated below the third ventricle floor; TCA, transcranial approach (pterional, subfrontal, or bifrontal interhemispheric with or without trans-lamina terminalis approach); TV, transventricular type of approach (frontal-transcortical transventricular/transcallosal/combined); y, years old.
aCP cases with a significant portion of squamous epithelium in addition to the adamantinomatous one.
bIndicates that the rate corresponds to the whole CP series (separate analysis for the histological papilary type is not available).
The advent of modern magnetic resonance imaging (MRI) in the 1990s dramatically increased the recognition of PCPs, prompting specific study of this histological type (15, 20). In the last decade, sophisticated surgical techniques employing the endoscopic endonasal approach (EEA) have been implemented for the removal of PCPs primarily located within the 3V (64, 91, 106, 109). This renewed interest culminated in the genetic and molecular characterization of PCP, with the identification of the oncogenic proto-oncogene B-Raf (BRAF)V600E mutation in 2014 by Priscilla Brastianos et al (116). This study definitively established PCP as a distinct entity and led to the separate categorization of the PCP type and ACP type in the 2021 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (5th edition) (117). However, an extensive body of evidence conceptually links PCPs and ACPs under a common CP diagnosis. Numerous unexplained facts about PCPs and their associated clinical and pathological spectrum continue to make them one of the most intriguing and fascinating intracranial lesions in medicine (110-112).
This monograph presents a comprehensive review of PCPs, prompted by the recent molecular and pathological reclassification of PCPs, and undertakes a systematic reappraisal of all the accumulated knowledge about this complex entity (117). A thorough understanding of this CP type is inherently challenging due to the absence of specific information distinguishing PCPs from ACPs in many historical studies, including large pathological and surgical CP series. As PCPs occur almost exclusively in adult patients, most studies analyzed in the present work correspond to adult CP series (Table 1). Nevertheless, it should be kept in mind that the proportion of ACPs in adults is more than double of PCPs (∼70% vs 30%). Therefore, specific PCP features cannot be directly inferred from the findings reported in adult CP series. Conversely, data regarding the subset of PCPs should be deliberately sought out and separated from the overall published data on adult CPs. A very limited set of papers have been published that explicitly address the PCP type from either clinico-pathological or surgical perspectives, the latest published in October 2023 by Jia et al (13-15, 20, 61, 64, 73, 97, 109). Thus, in the present work we aimed at identifying and compiling the most relevant PCP information, which largely remains hidden in articles and meta-analyses focused on adult CPs. To this purpose, we used 2 data sources and approaches: (1) a systematic and in-depth review of large series of CPs that have been published in the medical literature since these lesions were categorized by Jakob Erdheim in 1904 (period 1904-2023, n = 460 CP series). From this pool, we identified and selected 99 large CP series that contained reliable and valuable information about PCPs (99s). This set comprises a total of 23 360 CPs, 4494 of them PCPs (Table 1) (8-109). (2) A systematic search and compilation of well-described/illustrated individual PCP reports, either published separately or within large CP series (period 1856-2023, n = 560 individual PCPs, Table 560c) (118). This compilation of 560 individual PCP reports (560c) expands and updates our prior review of 350 individual PCPs through the end of 2023 (97). Originating from diverse medical fields, these individual reports provide precise but incomplete data about each tumor/patient that can be complemented with the information available in papers from other disciplines. By combining these 2 primary data sources, the present review assembles the largest body of evidence about PCPs published to date. Based on the thorough analysis of this material, we present a comprehensive and cogent synthesis of the pathological and clinical knowledge accumulated on PCPs during the last century and a half (Table 2). In addition, this review presents the latest developments in diagnostic methodologies, surgical techniques, radiotherapy, and novel precision oncology treatment related to PCPs.
Reappraisal of the major epidemiological, clinical-pathological, surgical, and prognostic data of PCPs from the comprehensive analysis of the 560c and 99s (n = 5054 PCPs)
| Characteristics | Main findings |
|---|---|
| Epidemiology |
|
| Presenting symptoms |
|
| Tumor topography |
|
| Tumor adherence |
|
| Tumor removal |
|
| Patient outcome |
|
| Visual outcome |
|
| Tumor recurrence/regrowth |
|
| Characteristics | Main findings |
|---|---|
| Epidemiology |
|
| Presenting symptoms |
|
| Tumor topography |
|
| Tumor adherence |
|
| Tumor removal |
|
| Patient outcome |
|
| Visual outcome |
|
| Tumor recurrence/regrowth |
|
Abbreviations: 3V, third ventricle; 3VF, third ventricle floor; 560c, cohort of 560 well-described individual papillary craniopharyngioma patients; 99s, cohort of 99 large craniopharyngioma series containing papillary craniopharyngiomas; PCP, papillary craniopharyngioma.
Reappraisal of the major epidemiological, clinical-pathological, surgical, and prognostic data of PCPs from the comprehensive analysis of the 560c and 99s (n = 5054 PCPs)
| Characteristics | Main findings |
|---|---|
| Epidemiology |
|
| Presenting symptoms |
|
| Tumor topography |
|
| Tumor adherence |
|
| Tumor removal |
|
| Patient outcome |
|
| Visual outcome |
|
| Tumor recurrence/regrowth |
|
| Characteristics | Main findings |
|---|---|
| Epidemiology |
|
| Presenting symptoms |
|
| Tumor topography |
|
| Tumor adherence |
|
| Tumor removal |
|
| Patient outcome |
|
| Visual outcome |
|
| Tumor recurrence/regrowth |
|
Abbreviations: 3V, third ventricle; 3VF, third ventricle floor; 560c, cohort of 560 well-described individual papillary craniopharyngioma patients; 99s, cohort of 99 large craniopharyngioma series containing papillary craniopharyngiomas; PCP, papillary craniopharyngioma.
Historical Insights into the Papillary Type of CP
In his Manual of Pathological Anatomy (1856), Carl von Rokitansky (1804-1878) provided the first description of cerebral, intra-third ventricle cysts exhibiting a cauliflower-like epithelial growth from the cyst wall. This seminal text summarizes his findings from 30 000 autopsies performed at the Allgemeines Krankenhaus (Vienna General Hospital) (1, 2). Noteworthy in his description is the anatomical site of origin identified for these epithelial cysts: “According to our observations their usual seat and source of origin is the tuber cinereum, from where they enter after the third ventricle.” Unmistakably, these lesions correspond to PCPs, which Rokitansky did not consider associated with pituitary morbid growths but rather recognized as genuine intracerebral tumors (1). Therefore, this very first pathological PCP report provided the essential topographical concept related to these lesions: their primary location within the 3V and their origin from the infundibulo-tuberal region of the third ventricle floor (3VF), the point of maximal adherence of the tumor to the brain. Rokitansky promoted the creation of a pathological-anatomical museum in which a collection of numerous pituitary and infundibulum tumors was instrumental to Jakob Erdheim's discovery of the new CP entity 80 years later (6, 8, 10).
In 1861, E. Wagner published the first clinico-pathological account of a PCP, including a full histological description, in a succinct report titled “Papilläres Cystoid der Hirnbasis” (Papillary cyst of the brain base) (119). This lesion affected an adult woman who experienced a sudden and pronounced loss of memory accompanied by an apathetic mental status that ultimately led her to death. A thin-walled cyst filled with a yellowish fluid was discovered at the base of her brain, occupying the 3V region above an anatomically intact pituitary gland. The cyst wall exhibited multiple villi-like, papillary excrescences including capillaries covered by a multilayered epithelium, “which resembled the epithelium of the oral cavity.”
William Selke described another interesting PCP case in his 1891 dissertation titled “Über ein epitheliales Papillom des Gehirns” (Epithelial papilloma of the brain). This work includes detailed sketches of a solid tumor wholly confined within the 3V (Fig. 1A3) and provides histological sections of this lesion (114). This was the first patient with this tumor type in whom a surgical intervention (a trepanation) was attempted by the Polish surgeon Jan Mikulicz-Radecki (1850-1905). This cauliflower-like lesion covered by squamous epithelium was thought to have originated from the 3V ependyma.
In 1899, British neuropathologist and psychiatrist Sir Frederick Walker Mott (1853-1926) carefully examined a prime example of a PCP (Fig. 1A1 and 1A2) (3, 5). This cystic lesion with protruding papillomatous, cauliflower-like nodules, was discovered entirely within the 3V during the autopsy of a young man exhibiting severe mental disturbances, including memory failures and recurrent suicidal thoughts. The strong resemblance between the stratified squamous epithelium of the tumor and the epithelium covering the oral mucosa prompted Mott to propose the hypothesis that the embryonic primordium of the pituitary gland might be involved in the lesion's appearance. According to Mott, during the development of the pituitary gland, cells from the oral mucosa of the embryo could attach to Rathke's pouch and migrate toward the inner surface of the infundibulum.
The year 1904 marks the definition of CPs as a new pathological category of pituitary/infundibular tumors. The young Austrian pathologist Jakob Erdheim (1874-1937) reexamined the collection of infundibular tumors stored at the anatomical-pathological museum of Vienna and recognized a new category of lesions he named hypophysenganggeschwülste (hypophyseal duct tumors) (Fig. 1B) (6, 8). This term reflects his presumption that these lesions originated from cell remnants of the hypophyseal duct, the embryological pathway followed by Rathke's pouch to form the adenohypophysis. Among the 7 tumors Erdheim classified under this term, 2 corresponded to a more “benign” type, characterized by a cauliflower-like proliferation of squamous epithelium within a cyst that occupied both the infundibulum and the 3V. One of these lesions, which is still stored in the anatomical pathological museum, dates back to 1868 and represents the oldest preserved whole PCP specimen in the world (2, 6).
Similar to Erdheim's cases, the American neurosurgeon Harvey W. Cushing (1869-1939), encountered 2 “papillary infundibular cysts” during autopsies as described in his 1912 masterpiece on pituitary gland tumors, The Pituitary Body and Its Disorders (Fig. 1C) (120). The papillary structure of these lesions intrigued Cushing, leading him to describe them as a separate pathological category of an uncertain nature, long before he coined the term “craniopharyngioma” in 1929, which highlighted the presumed congenital origin of these lesions from the adenohypophyseal primordium (7, 9, 10). Like Erdheim, Cushing eventually included papillary infundibular cysts within the common category of CPs, a fact that decisively influenced the joint analysis of PCPs and ACPs under the same common CP diagnosis for many decades (113, 121).
In the period between Erdheim's definition of hypophyseal duct tumors and Cushing's account of his surgical experience with these lesions in 1932, numerous reports describing isolated PCPs found in autopsy studies appeared in the medical literature (Table 560c) (9, 118, 122). Usually defined as squamous cysto-papillomas of the infundibulum or 3V, these lesions were recognized as a type of Erdheim's hypophyseal duct tumor, or CP. They shared some clinicopathological features, such as their intra-3V location, their round morphology, and a clinical picture dominated by hypothalamic and psychiatric disturbances (4, 123-127).
In 1973, the American neurosurgeon Edgar A. Kahn (1900-1985) called attention to the existence of an “adult” type of CPs characterized by a squamous-papillary histology resembling the epithelium of the oral mucosa and lacking calcifications (11). This variant shared the macroscopic features observed in the strict 3V papillomatous cysts described in earlier autopsies and largely corresponded to PCPs. Kahn described the presence of the Korsakoff-like syndrome associated with this PCP type in adults, attributing it to mammillary body distortion (11). He noted that these tumors had a reduced tendency to recur, even after incomplete excision, and had a better outcome, which he attributed to their looser adherences and a lower tendency to invade the hypothalamus when compared to the “childhood CP type” (adamantinomatous-like CP or ACP) (11).
The categorization of the papillary squamous epithelioma as a distinct clinico-pathological entity separated from ACPs was first proposed in 1984 by pathologists Felice Giangaspero, Robert Stain, and Peter Burger (13). This proposition was based on the earlier observations of a more favorable outcome for the papillary type, as indicated by the surgical study by Kahn and the pathological review by Carol Petito in 1976 (11, 12). The histological examination of 144 surgically treated CPs by M. Gazi Yaşargil, conducted by the pathologists Tim E. Adamson and Paul Kleihues, identified the squamous papillary variant in 15 lesions, further supporting the categorization by Giangaspero et al (14). Based on these findings, the papillary type was officially recognized as a separate histological CP variant or subtype in the WHO 2nd edition (1993) under the category of “craniopharyngioma” (128). The discovery of the clonal somatic BRAFV600E mutation in PCPs in 2014 by Priscilla K. Brastianos, Sandro Santagata, and colleagues (116) has prompted a recategorization of ACP and PCP as separate and distinct pathological entities in the latest WHO classification (2021) as described by the authors Santagata, Kleinschmidt-DeMasters, Komori, Müller, and Pietsch (117). The chronological sequence of these fundamental contributions to the understanding of the PCP type is detailed in Table 3 (1, 3, 8, 9, 11, 13, 15, 20, 23, 54, 64, 95-97, 109, 114, 117, 119, 126, 128-135).
Chronology of groundbreaking contributions to the understanding and treatment of PCPs
| Author, year (Ref) | Novel concepts and therapeutic progress |
|---|---|
| C. von Rokitansky, 1856 (1) |
|
| Von E. Wagner, 1861 ( 119) |
|
| Walter Selke, 1891 (114) |
|
| F.W. Mott et al, 1899 (3) |
|
| Jakob Erdheim, 1904 (8) |
|
| Harvey Cushing, 1932 (9) |
|
| E.I. Dobos et al, 1953 (126) |
|
| E.A. Kahn et al, 1973 (11) |
|
| T.T. King, 1979 (129) |
|
| Ivan S. Ciric et al, 1980 (130) |
|
| F. Giangaspero et al, 1984 (13) |
|
| C.N. Linden et al, 1989 (131) |
|
| T. Fukushima et al, 1990 (132) |
|
| P. Kleihues et al, 1993 (128) |
|
| M.J. Harrison et al, 1994 (133) |
|
| T.B. Crotty et al, 1995 (20) |
|
| S. Sartoretti-S et al, 1997 (15) |
|
| J.M. Pascual et al, 2004 (23) |
|
| P.K. Brastianos et al, 2014 (116) |
|
| S.J. Aylwin et al, 2016 (134) |
|
| R. Prieto et al, 2016 (54) |
|
| E. La Corte et al, 2018 (64) |
|
| S. Santagata et al, 2021 (117) |
|
| R. Prieto et al, 2022 (96) |
|
| R. Prieto et al, 2022 (97) |
|
| J.M. Pascual et al, 2022 (95) |
|
| Y. Jia et al, 2023 (109) |
|
| P.K. Brastianos et al, 2023 (135) |
|
| Author, year (Ref) | Novel concepts and therapeutic progress |
|---|---|
| C. von Rokitansky, 1856 (1) |
|
| Von E. Wagner, 1861 ( 119) |
|
| Walter Selke, 1891 (114) |
|
| F.W. Mott et al, 1899 (3) |
|
| Jakob Erdheim, 1904 (8) |
|
| Harvey Cushing, 1932 (9) |
|
| E.I. Dobos et al, 1953 (126) |
|
| E.A. Kahn et al, 1973 (11) |
|
| T.T. King, 1979 (129) |
|
| Ivan S. Ciric et al, 1980 (130) |
|
| F. Giangaspero et al, 1984 (13) |
|
| C.N. Linden et al, 1989 (131) |
|
| T. Fukushima et al, 1990 (132) |
|
| P. Kleihues et al, 1993 (128) |
|
| M.J. Harrison et al, 1994 (133) |
|
| T.B. Crotty et al, 1995 (20) |
|
| S. Sartoretti-S et al, 1997 (15) |
|
| J.M. Pascual et al, 2004 (23) |
|
| P.K. Brastianos et al, 2014 (116) |
|
| S.J. Aylwin et al, 2016 (134) |
|
| R. Prieto et al, 2016 (54) |
|
| E. La Corte et al, 2018 (64) |
|
| S. Santagata et al, 2021 (117) |
|
| R. Prieto et al, 2022 (96) |
|
| R. Prieto et al, 2022 (97) |
|
| J.M. Pascual et al, 2022 (95) |
|
| Y. Jia et al, 2023 (109) |
|
| P.K. Brastianos et al, 2023 (135) |
|
Abbreviations: ACP, adamantinomtaous craniopharyngioma; CP, craniopharyngioma; EEA, endoscopic endonasal approach; MRI, magnetic resonance imaging; PCP, papillary craniopharyngioma; WHO, World Health Organization.
Chronology of groundbreaking contributions to the understanding and treatment of PCPs
| Author, year (Ref) | Novel concepts and therapeutic progress |
|---|---|
| C. von Rokitansky, 1856 (1) |
|
| Von E. Wagner, 1861 ( 119) |
|
| Walter Selke, 1891 (114) |
|
| F.W. Mott et al, 1899 (3) |
|
| Jakob Erdheim, 1904 (8) |
|
| Harvey Cushing, 1932 (9) |
|
| E.I. Dobos et al, 1953 (126) |
|
| E.A. Kahn et al, 1973 (11) |
|
| T.T. King, 1979 (129) |
|
| Ivan S. Ciric et al, 1980 (130) |
|
| F. Giangaspero et al, 1984 (13) |
|
| C.N. Linden et al, 1989 (131) |
|
| T. Fukushima et al, 1990 (132) |
|
| P. Kleihues et al, 1993 (128) |
|
| M.J. Harrison et al, 1994 (133) |
|
| T.B. Crotty et al, 1995 (20) |
|
| S. Sartoretti-S et al, 1997 (15) |
|
| J.M. Pascual et al, 2004 (23) |
|
| P.K. Brastianos et al, 2014 (116) |
|
| S.J. Aylwin et al, 2016 (134) |
|
| R. Prieto et al, 2016 (54) |
|
| E. La Corte et al, 2018 (64) |
|
| S. Santagata et al, 2021 (117) |
|
| R. Prieto et al, 2022 (96) |
|
| R. Prieto et al, 2022 (97) |
|
| J.M. Pascual et al, 2022 (95) |
|
| Y. Jia et al, 2023 (109) |
|
| P.K. Brastianos et al, 2023 (135) |
|
| Author, year (Ref) | Novel concepts and therapeutic progress |
|---|---|
| C. von Rokitansky, 1856 (1) |
|
| Von E. Wagner, 1861 ( 119) |
|
| Walter Selke, 1891 (114) |
|
| F.W. Mott et al, 1899 (3) |
|
| Jakob Erdheim, 1904 (8) |
|
| Harvey Cushing, 1932 (9) |
|
| E.I. Dobos et al, 1953 (126) |
|
| E.A. Kahn et al, 1973 (11) |
|
| T.T. King, 1979 (129) |
|
| Ivan S. Ciric et al, 1980 (130) |
|
| F. Giangaspero et al, 1984 (13) |
|
| C.N. Linden et al, 1989 (131) |
|
| T. Fukushima et al, 1990 (132) |
|
| P. Kleihues et al, 1993 (128) |
|
| M.J. Harrison et al, 1994 (133) |
|
| T.B. Crotty et al, 1995 (20) |
|
| S. Sartoretti-S et al, 1997 (15) |
|
| J.M. Pascual et al, 2004 (23) |
|
| P.K. Brastianos et al, 2014 (116) |
|
| S.J. Aylwin et al, 2016 (134) |
|
| R. Prieto et al, 2016 (54) |
|
| E. La Corte et al, 2018 (64) |
|
| S. Santagata et al, 2021 (117) |
|
| R. Prieto et al, 2022 (96) |
|
| R. Prieto et al, 2022 (97) |
|
| J.M. Pascual et al, 2022 (95) |
|
| Y. Jia et al, 2023 (109) |
|
| P.K. Brastianos et al, 2023 (135) |
|
Abbreviations: ACP, adamantinomtaous craniopharyngioma; CP, craniopharyngioma; EEA, endoscopic endonasal approach; MRI, magnetic resonance imaging; PCP, papillary craniopharyngioma; WHO, World Health Organization.
Distinctive Features of PCPs: Epidemiology, Topography, Gross Morphology, and Histology
PCP is a benign WHO grade 1 tumor consisting of well-differentiated squamous, nonkeratinizing epithelium. Unlike ACPs, which commonly affect both children and adults, most PCPs develop in adults, with only a small fraction afflicting the pediatric population. PCPs typically grow at high positions along the hypothalamus-pituitary axis, usually at the infundibulum and/or tuber cinereum regions of the 3VF, or wholly within the 3V (97, 117). At this point, it should be clarified that in a strict anatomical sense, the pituitary stalk (PS) consists of a lower solid portion that runs through the chiasmatic cistern and an upper hollow funnel-like portion, the infundibulum, which delimits the infundibular recess of the 3V. The infundibular portion of the PS is an integral part of the 3VF, together with the median eminence and the tuber cinereum, although the seamless transition between these 3 structures makes it difficult to accurately define their anatomical boundaries. From both embryological and physiological perspectives, the infundibulum can be considered a down-growth expansion of the hypothalamus, a critical node where the hypothalamic neuroendocrine factors governing the pituitary gland function are discharged into the hypophyseal portal system. While the solid portion of the PS is merely a downward stem-like extension of the infundibulum that terminates in a knob-like expansion, the neural lobe of the pituitary gland. Although such a distinction between these 2 PS portions is generally not made explicit in surgical and neuroradiological papers analyzing the PS damage caused by CPs, throughout this monograph we will aim to define, whenever possible, the specific involvement of the infundibulum by PCPs or its injury following PCP removal.
Key features that separate ACP and PCP as different pathological entities include distinct histological features as well as molecular and genetic characteristics (117). In particular, each CP type has specific genetic drivers: PCP is characterized by BRAFV600E mutations that activates the MAPK/MEK pathway, while ACPs have mutations in the CTNNB1 gene, encoding the β-catenin protein, thereby activating WNT/β-catenin signaling (116, 117, 136-139).
Epidemiological Features and Main PCP Topographies
The papillary type accounts for only around 10% to 30% of all CPs, which, in turn, represents just 1% to 4.5% of all intracranial tumors (92, 140, 141). A 2018 meta-analysis of 738 adult CP patients found a slightly higher (34%) PCP rate in adults (62). According to the most recent epidemiological data from the Central Brain Tumor Registry of the United States, Momin et al reported that 21% of the 2901 CP cases recorded between 2004 and 2016 corresponded to PCPs (87). This accounts for around 80 to 120 PCPs among the ∼620 new CP cases diagnosed annually in the United States considering all ages. Using the US National Cancer Database for the same period and considering only adult patients, Castellanos et al reported a higher PCP rate of 29% among 4307 recorded CPs (92). The figures from these modern studies are very similar to the historical PCP rate according to studied CP autopsy specimens. A thorough analysis of medical reports from 1839 to 1932, including a total of 408 CP-brain specimens, allowed us to identify 60 cases with unmistakable gross morphological, topographical, and histological features consistent with the papillary type (15%, unpublished data). Likewise, the PCP rate in Erdheim's pathological series (n = 28 CPs) and the surgical series by Cushing (n = 92), were 32% and 15%, respectively (8, 10).
The demographic features of PCPs from the cases included in the 560c demonstrates a normal age distribution and sex imbalance of PCP patients that is rather different from the bimodal age (half of cases in patients under 18 years old) and the roughly equal male to female distribution of ACPs (87, 140, 141). In agreement with the Central Brain Tumor Registry of the United States data, which reported that PCPs represented only 5.5% of the histologically diagnosed CP patients under 30 years of age (87), in the 560c only 4.6% of PCPs occurred in pediatric patients. In the 560c, the mean age at diagnosis for PCP was 43.5 years old (SD 15.3), with 60.2% of the patients over 40. Median age in the 99s was slightly higher at 46 years old. Nevertheless, despite ∼95% of PCPs occurring in the adult/elderly population, the papillary type constitutes less than one-third of the cases in this demographic group (54, 62, 69, 87, 92, 97, 108). In addition, there is a slight but consistent male predominance among PCP patients (87, 97), with a male/female ratio of 1.69 in the 560c and 1.5 in the 99s (60/40 males/females) (Fig. 2A, Table 4).
Epidemiological, clinical, and pathological characterization of the cohort of 560 well-described individual papillary craniopharyngioma patients. (A) Bar graph showing the age and gender distribution in PCP patients. Note the normal age distribution and the predominance of adult male patients from 30 to 60 years old. (B) Distribution of PCP topography, showing the predominance of the strict third ventricle and not-strict third ventricle (infundibulo-tuberal) categories. (C) Distribution of the 6 fundamental types of psychiatric disturbances manifested by PCP patients.
Abbreviations: PCP, papillary craniopharyngioma; pseudo, sellar-suprasellar pseudointraventricular; S-suprasellar, sellar-suprasellar; secondary 3V, sellar-suprasellar secondary intraventricular.
Epidemiological, clinical, and pathological characteristics of individual well-described 560 PCP cases published in the medical literature between 1856 and 2023 (560c) (118)
| Variable | No. of cases (%) | No. of cases with valid data | |
|---|---|---|---|
| Gender | Male/female | 298 (62.9)/176 (37.1) | 474 |
| Age | ≤17 years | 23 (4.6) | 497 |
| 18-40 years | 175 (35.2) | ||
| 41-60 years | 237 (47.7) | ||
| ≥61 years | 62 (12.5) | ||
| Symptoms | Visual impairment | 263 (60.5) | 435 |
| Headache | 255 (59.3) | 430 | |
| Psychiatric disturbances | 183 (43.4) | 422 | |
| Endocrine deficits | 130 (30.4) | 427 | |
| Hypogonadism | 88 (22.7) | 388 | |
| Somnolence | 79 (18.7) | 422 | |
| AVP deficiency (diabetes insipidus) | 69 (16) | 431 | |
| Gait imbalance | 54 (12.8) | 422 | |
| Weight gain/hyperphagia | 51 (12) | 425 | |
| Incontinence | 32 (7.6) | 422 | |
| Consciousness impairment | 27 (6.4) | 422 | |
| Temperature alterations | 28 (6.6) | 422 | |
| Tumor topography | Strict 3V | 308 (58.2) | 529 |
| Not-strict 3V (infundibulo-tuberal) | 165 (31.2) | ||
| Sellar-suprasellar | 35 (6.6) | ||
| S/SS-Pseudo 3V | 11 (2.1) | ||
| S/SS-Secondary 3V | 7 (1.3) | ||
| Others (nasal, posterior fossa) | 3 (0.6) | ||
| Tumor consistency | Pure solid | 272 (52.1) | 522 |
| Unilocular cyst with a cauliflower-like nodule | 89 (17) | ||
| Pure cystic | 77 (14.8) | ||
| Upper-cystic and basal-solid | 54 (10.3) | ||
| Mixed solid-cystic | 30 (5.7) | ||
| Calcifications | Present | 13 (3.8) | 343 |
| Hydrocephalus | Present | 201 (43) | 467 |
| Hypothalamus edema | Present | 27 (18.9) | 143 |
| Basal duct-like recess | Present | 192 (52.2) | 368 |
| Tumor shape | Round | 326 (70.7) | 461 |
| Elliptical | 121 (26.2) | ||
| Pear-like | 7 (1.5) | ||
| Multilobulated | 4 (0.9) | ||
| Dumbbell | 3 (0.7) | ||
| Tumor size | ≤2.5 cm | 110 (22.8) | 483 |
| 2.6-3.4 cm | 157 (32.5) | ||
| 3.5-4.4 cm | 181 (37.5) | ||
| ≥4.5 cm | 35 (7.2) | ||
| Severity of tumor adhesion to the hypothalamus | 307 | ||
| Low risk | 192 (62.5) | ||
| High risk | 115 (37.5) | ||
| Variable | No. of cases (%) | No. of cases with valid data | |
|---|---|---|---|
| Gender | Male/female | 298 (62.9)/176 (37.1) | 474 |
| Age | ≤17 years | 23 (4.6) | 497 |
| 18-40 years | 175 (35.2) | ||
| 41-60 years | 237 (47.7) | ||
| ≥61 years | 62 (12.5) | ||
| Symptoms | Visual impairment | 263 (60.5) | 435 |
| Headache | 255 (59.3) | 430 | |
| Psychiatric disturbances | 183 (43.4) | 422 | |
| Endocrine deficits | 130 (30.4) | 427 | |
| Hypogonadism | 88 (22.7) | 388 | |
| Somnolence | 79 (18.7) | 422 | |
| AVP deficiency (diabetes insipidus) | 69 (16) | 431 | |
| Gait imbalance | 54 (12.8) | 422 | |
| Weight gain/hyperphagia | 51 (12) | 425 | |
| Incontinence | 32 (7.6) | 422 | |
| Consciousness impairment | 27 (6.4) | 422 | |
| Temperature alterations | 28 (6.6) | 422 | |
| Tumor topography | Strict 3V | 308 (58.2) | 529 |
| Not-strict 3V (infundibulo-tuberal) | 165 (31.2) | ||
| Sellar-suprasellar | 35 (6.6) | ||
| S/SS-Pseudo 3V | 11 (2.1) | ||
| S/SS-Secondary 3V | 7 (1.3) | ||
| Others (nasal, posterior fossa) | 3 (0.6) | ||
| Tumor consistency | Pure solid | 272 (52.1) | 522 |
| Unilocular cyst with a cauliflower-like nodule | 89 (17) | ||
| Pure cystic | 77 (14.8) | ||
| Upper-cystic and basal-solid | 54 (10.3) | ||
| Mixed solid-cystic | 30 (5.7) | ||
| Calcifications | Present | 13 (3.8) | 343 |
| Hydrocephalus | Present | 201 (43) | 467 |
| Hypothalamus edema | Present | 27 (18.9) | 143 |
| Basal duct-like recess | Present | 192 (52.2) | 368 |
| Tumor shape | Round | 326 (70.7) | 461 |
| Elliptical | 121 (26.2) | ||
| Pear-like | 7 (1.5) | ||
| Multilobulated | 4 (0.9) | ||
| Dumbbell | 3 (0.7) | ||
| Tumor size | ≤2.5 cm | 110 (22.8) | 483 |
| 2.6-3.4 cm | 157 (32.5) | ||
| 3.5-4.4 cm | 181 (37.5) | ||
| ≥4.5 cm | 35 (7.2) | ||
| Severity of tumor adhesion to the hypothalamus | 307 | ||
| Low risk | 192 (62.5) | ||
| High risk | 115 (37.5) | ||
Abbreviations: 3V, third ventricle; 560c, cohort of 560 well-described individual papillary craniopharyngioma patients; AVP deficiency, arginine vasopressin deficiency; PCP, papillary craniopharyngioma; S/SS, sellar/suprasellar.
Epidemiological, clinical, and pathological characteristics of individual well-described 560 PCP cases published in the medical literature between 1856 and 2023 (560c) (118)
| Variable | No. of cases (%) | No. of cases with valid data | |
|---|---|---|---|
| Gender | Male/female | 298 (62.9)/176 (37.1) | 474 |
| Age | ≤17 years | 23 (4.6) | 497 |
| 18-40 years | 175 (35.2) | ||
| 41-60 years | 237 (47.7) | ||
| ≥61 years | 62 (12.5) | ||
| Symptoms | Visual impairment | 263 (60.5) | 435 |
| Headache | 255 (59.3) | 430 | |
| Psychiatric disturbances | 183 (43.4) | 422 | |
| Endocrine deficits | 130 (30.4) | 427 | |
| Hypogonadism | 88 (22.7) | 388 | |
| Somnolence | 79 (18.7) | 422 | |
| AVP deficiency (diabetes insipidus) | 69 (16) | 431 | |
| Gait imbalance | 54 (12.8) | 422 | |
| Weight gain/hyperphagia | 51 (12) | 425 | |
| Incontinence | 32 (7.6) | 422 | |
| Consciousness impairment | 27 (6.4) | 422 | |
| Temperature alterations | 28 (6.6) | 422 | |
| Tumor topography | Strict 3V | 308 (58.2) | 529 |
| Not-strict 3V (infundibulo-tuberal) | 165 (31.2) | ||
| Sellar-suprasellar | 35 (6.6) | ||
| S/SS-Pseudo 3V | 11 (2.1) | ||
| S/SS-Secondary 3V | 7 (1.3) | ||
| Others (nasal, posterior fossa) | 3 (0.6) | ||
| Tumor consistency | Pure solid | 272 (52.1) | 522 |
| Unilocular cyst with a cauliflower-like nodule | 89 (17) | ||
| Pure cystic | 77 (14.8) | ||
| Upper-cystic and basal-solid | 54 (10.3) | ||
| Mixed solid-cystic | 30 (5.7) | ||
| Calcifications | Present | 13 (3.8) | 343 |
| Hydrocephalus | Present | 201 (43) | 467 |
| Hypothalamus edema | Present | 27 (18.9) | 143 |
| Basal duct-like recess | Present | 192 (52.2) | 368 |
| Tumor shape | Round | 326 (70.7) | 461 |
| Elliptical | 121 (26.2) | ||
| Pear-like | 7 (1.5) | ||
| Multilobulated | 4 (0.9) | ||
| Dumbbell | 3 (0.7) | ||
| Tumor size | ≤2.5 cm | 110 (22.8) | 483 |
| 2.6-3.4 cm | 157 (32.5) | ||
| 3.5-4.4 cm | 181 (37.5) | ||
| ≥4.5 cm | 35 (7.2) | ||
| Severity of tumor adhesion to the hypothalamus | 307 | ||
| Low risk | 192 (62.5) | ||
| High risk | 115 (37.5) | ||
| Variable | No. of cases (%) | No. of cases with valid data | |
|---|---|---|---|
| Gender | Male/female | 298 (62.9)/176 (37.1) | 474 |
| Age | ≤17 years | 23 (4.6) | 497 |
| 18-40 years | 175 (35.2) | ||
| 41-60 years | 237 (47.7) | ||
| ≥61 years | 62 (12.5) | ||
| Symptoms | Visual impairment | 263 (60.5) | 435 |
| Headache | 255 (59.3) | 430 | |
| Psychiatric disturbances | 183 (43.4) | 422 | |
| Endocrine deficits | 130 (30.4) | 427 | |
| Hypogonadism | 88 (22.7) | 388 | |
| Somnolence | 79 (18.7) | 422 | |
| AVP deficiency (diabetes insipidus) | 69 (16) | 431 | |
| Gait imbalance | 54 (12.8) | 422 | |
| Weight gain/hyperphagia | 51 (12) | 425 | |
| Incontinence | 32 (7.6) | 422 | |
| Consciousness impairment | 27 (6.4) | 422 | |
| Temperature alterations | 28 (6.6) | 422 | |
| Tumor topography | Strict 3V | 308 (58.2) | 529 |
| Not-strict 3V (infundibulo-tuberal) | 165 (31.2) | ||
| Sellar-suprasellar | 35 (6.6) | ||
| S/SS-Pseudo 3V | 11 (2.1) | ||
| S/SS-Secondary 3V | 7 (1.3) | ||
| Others (nasal, posterior fossa) | 3 (0.6) | ||
| Tumor consistency | Pure solid | 272 (52.1) | 522 |
| Unilocular cyst with a cauliflower-like nodule | 89 (17) | ||
| Pure cystic | 77 (14.8) | ||
| Upper-cystic and basal-solid | 54 (10.3) | ||
| Mixed solid-cystic | 30 (5.7) | ||
| Calcifications | Present | 13 (3.8) | 343 |
| Hydrocephalus | Present | 201 (43) | 467 |
| Hypothalamus edema | Present | 27 (18.9) | 143 |
| Basal duct-like recess | Present | 192 (52.2) | 368 |
| Tumor shape | Round | 326 (70.7) | 461 |
| Elliptical | 121 (26.2) | ||
| Pear-like | 7 (1.5) | ||
| Multilobulated | 4 (0.9) | ||
| Dumbbell | 3 (0.7) | ||
| Tumor size | ≤2.5 cm | 110 (22.8) | 483 |
| 2.6-3.4 cm | 157 (32.5) | ||
| 3.5-4.4 cm | 181 (37.5) | ||
| ≥4.5 cm | 35 (7.2) | ||
| Severity of tumor adhesion to the hypothalamus | 307 | ||
| Low risk | 192 (62.5) | ||
| High risk | 115 (37.5) | ||
Abbreviations: 3V, third ventricle; 560c, cohort of 560 well-described individual papillary craniopharyngioma patients; AVP deficiency, arginine vasopressin deficiency; PCP, papillary craniopharyngioma; S/SS, sellar/suprasellar.
While CPs may arise at any site along the hypothalamus-pituitary axis from the pituitary gland to the 3V, marked differences in topographical distribution have been observed between ACP and PCP types. In contrast to ACPs, most of which develop from the solid portion of the PS and expand within the sellar/suprasellar compartments below the 3VF, about 80% of PCPs develop within the upper infundibular portion of the PS and/or tuber cinereum (the components of the 3VF, also known as infundibulo-tuberal region) and subsequently expand into the 3V (13, 23, 97). Depending on the anatomical status of the 3VF at the time of diagnosis, 2 major intra-3V topographies can be distinguished among PCPs: (1) infundibulo-tuberal or not-strict 3V PCPs, which have breached the neural layer of the infundibulum/tuber cinereum and develop intra-3V and extra-3V tumor extensions; and (2) strict 3V PCPs, which remain entirely confined within the 3V above an anatomically intact 3VF (23, 38, 96, 97, 142). In the 99s, 78% of PCPs largely occupied the 3V area, without a precise description of the 3VF's anatomical status. The more detailed information provided by the 560c showed that 31.2% of PCPs had an infundibulo-tuberal topography and 58.2% a strict 3V location (Fig. 2B). By contrast, a primary intra-3V location (infundibulo-tuberal) occurs in 40% of ACPs, with only 9% of this histological type showing a strict 3V topography (38, 54, 96).
PCP Gross Morphology
Macroscopically, PCPs are typically well-circumscribed lesions that usually grow either as compact solid masses or as unilocular cysts with a mural cauliflower-like nodule projecting inwards, adjacent to the infundibulum (hereafter called “cystic cauliflower-like” consistency) (Fig. 3A and 3B) (13, 20, 97, 117). These 2 predominant consistencies represented 52% and 17% of the cases in the 560c, respectively (Table 4). The solid portion of PCPs show a characteristic “berry-like” or papillomatous structure, which differs markedly from the typical heterogeneous mixture of solid and cystic components observed in ACPs. Only 5.7% of PCPs had a similarly intermixed solid-cystic architecture. Moreover, the fluid contained within the cysts differs between both histological types. The cyst contents of PCPs are generally yellowish or xanthocromic and do not contain cholesterol crystals, whereas the contents of ACPs are typically brownish or greenish “machine-oil-like” (Table 5).
Histopathological features of PCPs. (A) Coronal section of an autopsy specimen showing a solid strictly third ventricle PCP growing above an intact third ventricle floor (case number 267 of the 560c). Note the clear separation between the lesion and the third ventricle walls (arrows). Courtesy of Dr. Ronald C. Kim, Department of Pathology/Neuropathology, University of California Irvine, Irvine, CA. (B) Midsagittal brain section of a round solid strict third ventricle PCP (upper border of the tumor within the third ventricle indicated by small white arrows). Note the long, narrow duct-like recess (large white arrow) extending from the bottom of the lesion to its center (case 521 of the 560c). Courtesy of Dr. Charles Chan, Anatomical Pathology Department, NSW Health Pathology Concord Repatriation General Hospital, and Concord Clinical School, the University of Sydney, NSW, Australia (Code T9100 M9351/1). (C) Hematoxylin and eosin-stained microscopic sections. (C1) Low-power image shows pseudopapillary structure surrounding loosely structured connective tissue; scale bar: 1 mm. (C2) Higher-power image shows a well-differentiated nonkeratinizing squamous stratified epithelium with a prominent palisaded peripheral basal layer resting on fibrovascular cores of loose stroma; scale bar: 200 µm. (D) Immunohistochemistry for β-catenin and BRAF p.Val600Glu. (D1) Beta-catenin immunoreactivity is localized entirely to the cytoplasmic membrane of epithelial cells without nuclear localization; scale bar: 50 µm. (D2) Mutant BRAF immunoreactivity is diffuse and strong in the neoplastic squamous epithelial cells; scale bar: 200 µm.
Abbreviations: 560c, cohort of 560 well-described individual papillary craniopharyngioma patients; MB, mammillary body; OC, optic chiasm; PCP, papillary craniopharyngioma.
Comparative clinical, radiological, and pathological features of papillary craniopharyngiomas and related epithelial lesions of the pituitary-hypothalamic axis
| Papillary craniopharyngioma | Adamantinomatous craniopharyngioma | Rathke's cleft cyst | Epidermoid cyst | ||
|---|---|---|---|---|---|
| Epidemiology | Gender | Male predominance | Male = Female | Slight female predominance | Male = Female |
| Age | Adults (mean ∼ 45y) | Bimodal distribution with a large peak at 5-15 y and a smaller peak at 45-60 y | Adults (mean ∼ 45y) | Adults (mean ∼ 40y) | |
| Clinical symptoms | Hypothalamic/psychiatric | Frequent | Rare | Rare but possible in large cysts | Rare |
| Visual | Common | Frequent | Rare | Common | |
| Endocrine | Unusual | Frequent | Common | Rare | |
| Area of origin | Midline at infundibulum—3V floor | Midline at pituitary stalk—infundibulum | Midline between anterior and posterior pituitary lobes | Midline/paramedian—suprasellar | |
| Neuroimaging characteristics | Topographical distribution | Mostly involving the 3V (58% strict-3V) | Children: mostly sellar-SS Adults: mostly Not-Strict 3V | Mostly limited to the sella but 60% with SS expansion | SS—below an intact 3V floor |
| Shape | Mostly round | Typically multilobulated or elliptical | Mostly round or oval | Multilobulated | |
| Consistency | Mostly pure solid, but also cystic-cauliflower | Mostly mixed with solid and cystic components | Cystic | Cystic and solid | |
| Size | Medium (2.5-4.5 cm) | Large (>3-4 cm) | Small (<1.5 cm) | Large (>3-4 cm) | |
| Basal duct-like recess | Half of the cases (pathognomonic sign) | Absent | Absent | Absent | |
| Calcification | Rare | Frequent (90% children and 40% adults) | Absent | Absent | |
| MRI signal | Enhancement of the cyst wall or solid portions | Enhancement of the cyst wall or solid portions | Little or no enhancement | Restricted diffusion on DWI. No enhancement | |
| Other macroscopic features | Tumor-hypothalamus adherence | Usually small, between the tumor's anteroinferior area and the infundibulum | Usually strong and wide to the 3V floor/walls | Absent (most covered by sellar diaphragm) | N/A |
| Cyst content | Clear to yellow (when cystic) | Machinery-oil like rich in cholesterol clefts | Mucoid or serous | Soft creamy material | |
| Microscopic features | Epithelium | Well-differentiated stratified squamous | Odontogenic | Simple columnar or cuboidal | Keratinizing stratified cuboidal squamous |
| Stellate reticulum | Absent | Present | Absent | Absent | |
| Keratinization | Exceptional | Wet nodules | Absent | Dry corneal layers | |
| Keratohyaline granules | Rare | Absent | Absent | Frequent | |
| Goblet/ciliated cells | Rare | Absent | Frequent | Absent | |
| Molecular genetics | BRAF (V600E) gene mutation | Present | Exceptional | Exceptional | Absent |
| ß-catenin (CTNNB1) gene mutation | Exceptional | Present | Absent | Absent |
| Papillary craniopharyngioma | Adamantinomatous craniopharyngioma | Rathke's cleft cyst | Epidermoid cyst | ||
|---|---|---|---|---|---|
| Epidemiology | Gender | Male predominance | Male = Female | Slight female predominance | Male = Female |
| Age | Adults (mean ∼ 45y) | Bimodal distribution with a large peak at 5-15 y and a smaller peak at 45-60 y | Adults (mean ∼ 45y) | Adults (mean ∼ 40y) | |
| Clinical symptoms | Hypothalamic/psychiatric | Frequent | Rare | Rare but possible in large cysts | Rare |
| Visual | Common | Frequent | Rare | Common | |
| Endocrine | Unusual | Frequent | Common | Rare | |
| Area of origin | Midline at infundibulum—3V floor | Midline at pituitary stalk—infundibulum | Midline between anterior and posterior pituitary lobes | Midline/paramedian—suprasellar | |
| Neuroimaging characteristics | Topographical distribution | Mostly involving the 3V (58% strict-3V) | Children: mostly sellar-SS Adults: mostly Not-Strict 3V | Mostly limited to the sella but 60% with SS expansion | SS—below an intact 3V floor |
| Shape | Mostly round | Typically multilobulated or elliptical | Mostly round or oval | Multilobulated | |
| Consistency | Mostly pure solid, but also cystic-cauliflower | Mostly mixed with solid and cystic components | Cystic | Cystic and solid | |
| Size | Medium (2.5-4.5 cm) | Large (>3-4 cm) | Small (<1.5 cm) | Large (>3-4 cm) | |
| Basal duct-like recess | Half of the cases (pathognomonic sign) | Absent | Absent | Absent | |
| Calcification | Rare | Frequent (90% children and 40% adults) | Absent | Absent | |
| MRI signal | Enhancement of the cyst wall or solid portions | Enhancement of the cyst wall or solid portions | Little or no enhancement | Restricted diffusion on DWI. No enhancement | |
| Other macroscopic features | Tumor-hypothalamus adherence | Usually small, between the tumor's anteroinferior area and the infundibulum | Usually strong and wide to the 3V floor/walls | Absent (most covered by sellar diaphragm) | N/A |
| Cyst content | Clear to yellow (when cystic) | Machinery-oil like rich in cholesterol clefts | Mucoid or serous | Soft creamy material | |
| Microscopic features | Epithelium | Well-differentiated stratified squamous | Odontogenic | Simple columnar or cuboidal | Keratinizing stratified cuboidal squamous |
| Stellate reticulum | Absent | Present | Absent | Absent | |
| Keratinization | Exceptional | Wet nodules | Absent | Dry corneal layers | |
| Keratohyaline granules | Rare | Absent | Absent | Frequent | |
| Goblet/ciliated cells | Rare | Absent | Frequent | Absent | |
| Molecular genetics | BRAF (V600E) gene mutation | Present | Exceptional | Exceptional | Absent |
| ß-catenin (CTNNB1) gene mutation | Exceptional | Present | Absent | Absent |
Abbreviations: 3V, third ventricle; DWI, diffusion-weighted imaging; HICP, high intracranial pressure; SS, suprasellar; y, years.
Comparative clinical, radiological, and pathological features of papillary craniopharyngiomas and related epithelial lesions of the pituitary-hypothalamic axis
| Papillary craniopharyngioma | Adamantinomatous craniopharyngioma | Rathke's cleft cyst | Epidermoid cyst | ||
|---|---|---|---|---|---|
| Epidemiology | Gender | Male predominance | Male = Female | Slight female predominance | Male = Female |
| Age | Adults (mean ∼ 45y) | Bimodal distribution with a large peak at 5-15 y and a smaller peak at 45-60 y | Adults (mean ∼ 45y) | Adults (mean ∼ 40y) | |
| Clinical symptoms | Hypothalamic/psychiatric | Frequent | Rare | Rare but possible in large cysts | Rare |
| Visual | Common | Frequent | Rare | Common | |
| Endocrine | Unusual | Frequent | Common | Rare | |
| Area of origin | Midline at infundibulum—3V floor | Midline at pituitary stalk—infundibulum | Midline between anterior and posterior pituitary lobes | Midline/paramedian—suprasellar | |
| Neuroimaging characteristics | Topographical distribution | Mostly involving the 3V (58% strict-3V) | Children: mostly sellar-SS Adults: mostly Not-Strict 3V | Mostly limited to the sella but 60% with SS expansion | SS—below an intact 3V floor |
| Shape | Mostly round | Typically multilobulated or elliptical | Mostly round or oval | Multilobulated | |
| Consistency | Mostly pure solid, but also cystic-cauliflower | Mostly mixed with solid and cystic components | Cystic | Cystic and solid | |
| Size | Medium (2.5-4.5 cm) | Large (>3-4 cm) | Small (<1.5 cm) | Large (>3-4 cm) | |
| Basal duct-like recess | Half of the cases (pathognomonic sign) | Absent | Absent | Absent | |
| Calcification | Rare | Frequent (90% children and 40% adults) | Absent | Absent | |
| MRI signal | Enhancement of the cyst wall or solid portions | Enhancement of the cyst wall or solid portions | Little or no enhancement | Restricted diffusion on DWI. No enhancement | |
| Other macroscopic features | Tumor-hypothalamus adherence | Usually small, between the tumor's anteroinferior area and the infundibulum | Usually strong and wide to the 3V floor/walls | Absent (most covered by sellar diaphragm) | N/A |
| Cyst content | Clear to yellow (when cystic) | Machinery-oil like rich in cholesterol clefts | Mucoid or serous | Soft creamy material | |
| Microscopic features | Epithelium | Well-differentiated stratified squamous | Odontogenic | Simple columnar or cuboidal | Keratinizing stratified cuboidal squamous |
| Stellate reticulum | Absent | Present | Absent | Absent | |
| Keratinization | Exceptional | Wet nodules | Absent | Dry corneal layers | |
| Keratohyaline granules | Rare | Absent | Absent | Frequent | |
| Goblet/ciliated cells | Rare | Absent | Frequent | Absent | |
| Molecular genetics | BRAF (V600E) gene mutation | Present | Exceptional | Exceptional | Absent |
| ß-catenin (CTNNB1) gene mutation | Exceptional | Present | Absent | Absent |
| Papillary craniopharyngioma | Adamantinomatous craniopharyngioma | Rathke's cleft cyst | Epidermoid cyst | ||
|---|---|---|---|---|---|
| Epidemiology | Gender | Male predominance | Male = Female | Slight female predominance | Male = Female |
| Age | Adults (mean ∼ 45y) | Bimodal distribution with a large peak at 5-15 y and a smaller peak at 45-60 y | Adults (mean ∼ 45y) | Adults (mean ∼ 40y) | |
| Clinical symptoms | Hypothalamic/psychiatric | Frequent | Rare | Rare but possible in large cysts | Rare |
| Visual | Common | Frequent | Rare | Common | |
| Endocrine | Unusual | Frequent | Common | Rare | |
| Area of origin | Midline at infundibulum—3V floor | Midline at pituitary stalk—infundibulum | Midline between anterior and posterior pituitary lobes | Midline/paramedian—suprasellar | |
| Neuroimaging characteristics | Topographical distribution | Mostly involving the 3V (58% strict-3V) | Children: mostly sellar-SS Adults: mostly Not-Strict 3V | Mostly limited to the sella but 60% with SS expansion | SS—below an intact 3V floor |
| Shape | Mostly round | Typically multilobulated or elliptical | Mostly round or oval | Multilobulated | |
| Consistency | Mostly pure solid, but also cystic-cauliflower | Mostly mixed with solid and cystic components | Cystic | Cystic and solid | |
| Size | Medium (2.5-4.5 cm) | Large (>3-4 cm) | Small (<1.5 cm) | Large (>3-4 cm) | |
| Basal duct-like recess | Half of the cases (pathognomonic sign) | Absent | Absent | Absent | |
| Calcification | Rare | Frequent (90% children and 40% adults) | Absent | Absent | |
| MRI signal | Enhancement of the cyst wall or solid portions | Enhancement of the cyst wall or solid portions | Little or no enhancement | Restricted diffusion on DWI. No enhancement | |
| Other macroscopic features | Tumor-hypothalamus adherence | Usually small, between the tumor's anteroinferior area and the infundibulum | Usually strong and wide to the 3V floor/walls | Absent (most covered by sellar diaphragm) | N/A |
| Cyst content | Clear to yellow (when cystic) | Machinery-oil like rich in cholesterol clefts | Mucoid or serous | Soft creamy material | |
| Microscopic features | Epithelium | Well-differentiated stratified squamous | Odontogenic | Simple columnar or cuboidal | Keratinizing stratified cuboidal squamous |
| Stellate reticulum | Absent | Present | Absent | Absent | |
| Keratinization | Exceptional | Wet nodules | Absent | Dry corneal layers | |
| Keratohyaline granules | Rare | Absent | Absent | Frequent | |
| Goblet/ciliated cells | Rare | Absent | Frequent | Absent | |
| Molecular genetics | BRAF (V600E) gene mutation | Present | Exceptional | Exceptional | Absent |
| ß-catenin (CTNNB1) gene mutation | Exceptional | Present | Absent | Absent |
Abbreviations: 3V, third ventricle; DWI, diffusion-weighted imaging; HICP, high intracranial pressure; SS, suprasellar; y, years.
Notably, macroscopic calcifications are conspicuously absent in practically all PCPs whereas they are common in ACPs (11, 13, 97). Moreover, in contrast to the usually large and multilobulated morphology observed in ACPs, most PCPs display a smoothly rounded shape molded by the 3V walls (97, 143). None of the PCPs in the 560c exceeded 6 cm in greatest dimension and ∼70% had a medium size ranging from 2.6 to 4.4 cm.
PCP Histological Characterization
Microscopically, PCPs are formed of well-differentiated nonkeratinizing stratified squamous epithelium arranged in anastomosing trabeculae, cords, and sheets. The tumor epithelium envelopes fibrovascular cores that contain loose stroma, comprising fibroblasts, capillaries, and inflammatory cells such as neutrophils, T lymphocytes, and macrophages (111, 112, 117). The basal cells rest directly on these fibrovascular cores and contain the majority of proliferating tumor cells. Unlike the squamous cells in ACP, which undergo keratinization and produce anucleate flaky “dry” keratin, the squamous cells in PCP retain their nuclei throughout the entire thickness of tumor epithelium and do not undergo generalized keratinizing. However, occasional collagenous nodules may be observed (12, 110, 111, 117, 144). PCPs appear to undergo a process of dehiscence between the sheets of squamous epithelium, thought to result from the loosening of tight contacts between outer layer epithelial cells during their maturation. Consequently, shallow cracks and crevices develop across the tumor surface allowing buds of epithelium to form pseudopapillae (Fig. 3C1 and 3C2). This distinctive pseudopapillary pattern generates a “berry-like” appearance in the solid component that can be easily distinguishable on MRI (97, 143, 145).
The 3 defining histological features of ACPs, palisading of basal epithelial cells, stellate reticulum, and nodules of “wet keratin,” are absent in PCPs (20, 117) (Table 5). Spherical conglomerates of flattened epithelial cells arranged in concentric layers are not uncommon in PCPs, but these are distinct from the whorls of wet keratin in ACPs. Small groups or single PAS-positive mucin-producing goblet cells can be observed interspersed within the squamous epithelium of PCPs in up to 30% of cases (20, 146). Focal areas of columnar epithelium with ciliated cells may also be present in around 4% of cases (112, 147, 148). In the 560c, ciliated cells or goblet cells occurred in 4.2% of the cases overall, but this rate increased to 34.8% in pediatric PCPs (P < .001) and to 37% in the topographical categories originating below the 3VF (P < .001). Both types of cells are typical of Rathke's cleft cysts (RCCs), a type of sellar/suprasellar cystic lesion that may show areas of focal squamous metaplasia resembling the PCP epithelium. This makes differentiating PCPs from RCCs particularly challenging in certain cases (20, 148-151). Immunohistochemically, the squamous epithelium in PCPs show a diffuse and strong positive staining for epithelial membrane antigen (EMA) and cytokeratins (CK), including high-molecular-weight cytokeratins (34βE12, CK5/6) and intermediate-molecular-weight keratins (CK7, CK17, CK19) (117). By contrast, most PCP cells lack CK8 and CK20 expression, 2 CKs typical of RCCs, although their value for differentiating between both epithelial lesions in diagnostic practice is still uncertain (152, 153). Unlike the nuclear distribution pattern of β-catenin that occurs in a subset of tumor cells in ACPs (especially those in clusters of cells growing in a whorled pattern and in occasional scattered cells), the β-catenin protein in PCPs is uniformly located to the cell membranes (Fig. 3D1) (136, 139, 141, 147). The proliferating cells restricted to the basal layer of epithelium lining the stroma core can be highlighted using Ki-67 immunohistochemistry, with the proliferative index showing a wide variation between cases (117, 154, 155).
Molecular Genetics of PCPs: The BRAFV600E Mutation
A comprehensive whole-exome sequencing study first demonstrated in 2014 that nearly all PCPs harbored the BRAFV600E mutation, while nearly all ACPs exhibited mutations in exon 3 of the CTNNB1 gene (116). These mutations are mutually exclusive and exhibit clonality within each respective tumor type. Notably, no other recurrent mutations or genomic aberrations have been found, implicating these mutations as the principal respective oncogenic drivers of each CP type (116, 156). Regarding the few PCP cases lacking BRAFV600E mutations (BRAFV600E wild-type, around 5-10%), although underlying technical limitations may be considered, further studies with more comprehensive genomic methods are necessary to explore other BRAF mutations or fusions or mutations in other MAPK genes. The discovery of BRAFV600E mutations in PCPs has had a major impact on both their diagnosis and treatment. Immunohistochemistry using antibodies that specifically recognize the epitope in the mutated BRAF protein containing the Val600Glu substitution but not the wild-type counterpart is useful for confirming a PCP diagnosis. This is particularly helpful in small biopsy specimens, in samples with limited epithelial content, or in cases where it is difficult to confidently distinguish PCP and RCCs with abundant squamous metaplasia based on hematoxylin and eosi-stained sections alone (157-161) (Fig. 3D2).
BRAF is a master regulator of the MAPK/ERK pathway, a critical signaling cascade that participates in cell proliferation and differentiation (Fig. 4). Beyond PCPs, this pathway is involved in numerous types of cancer, including melanoma, hairy-cell leukemia, thyroid cancer, and colorectal cancer (162-164). The direct consequence of BRAFV600E mutation is that the resultant mutant BRAF V600E protein has high intrinsic kinase activity with a particularly noteworthy role in constitutively activating the MAPK/ERK pathway in the absence of upstream signaling (162). First, mutant BRAF protein actives MEK1 and MEK2 (MAPK/ERK kinases), which in turn phosphorylate and activate ERK1 and ERK2 (serine/threonine-specific protein kinases). Then, ERKs can translocate to the nucleus and phosphorylate various transcription factors, leading to changes in gene expression that promote cell proliferation, differentiation, and survival (165). Activation of this pathway results in tumor cell proliferation, which is particularly prominent in the basal layer of epithelial cells lining the fibrovascular cores (155, 166). This basal epithelium coexpresses ERK 1 and ERK2, as well as the stem cell marker sex determining region Y-box2 (SOX2), a transcription factor essential for governing the processes of self-renewal and pluripotency of undifferentiated embryonic stem cells (155, 167). Accordingly, BRAFV600E mutation is thought to trigger the tumorigenic proliferative activity either in a niche of SOX2-positive embryonic pituitary cells precursor or in SOX2-positive adult pituitary stem cells, through the activation of the MAPK/ERK pathway (155, 168). This pathway can be effectively blocked in melanoma (169) and represents a promising target for PCPs treatment (Fig. 4).
MAPK signaling pathway in papillary craniopharyngiomas and the role of BRAF and MEK inhibitors. BRAFV600E mutations lead to the independent activation of downstream signaling cascades, resulting in unlimited cellular proliferation and tumorigenesis.
Abbreviations: ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase; RAS, rat sarcoma guanosine-nucleotide-binding protein; RTK, receptor tyrosine kinase.
PCP Pathogenesis: Morphogenetic, Topographical and Histological Clues for a Puzzling Tumorigenesis
CP pathogenesis is not well understood. Despite the recent recognition of ACPs and PCPs as 2 separate CP types, based on their mutually exclusive mutations BRAFV600E and CTNNβ1, the accumulated data supporting the existence of a common biological origin has yet to be explained (110, 112). Identification of the exact tumorigenic cell and its precise origin also remains unclear. Five different data sources must be addressed to better understand PCP pathogenesis: (1) embryology of the pars tuberalis; (2) squamous metaplasia found in normal pituitary glands and sellar/suprasellar epithelial lesions; (3) topographical segregation of ACPs, PCPs, and other epithelial lesions along the hypothalamus-pituitary axis; (4) histological overlap between CP types and other epithelial lesions; and (5) molecular PCP characterization based on human samples and experimental CP models.
PCPs and Embryological Development of the Pars Tuberalis
The embryonic formation of the pituitary infundibulum-pars tuberalis complex has been linked to PCP origin. Neuropathologist Frederick Mott first proposed that ectodermal cells from the embryo's mouth deposited into the hollow infundibulum during Rathke's pouch migration could represent a plausible mechanism for the development of 3V PCPs (3, 5). By the fourth week of embryonic growth, Rathke's pouch evaginates from an embryo's stomodeum as a sac-like outpouching and meets another diencephalic outpouching, the infundibulum (Fig. 5A1) (170, 171). Then, the epithelial tube-like connection between Rathke's pouch and the stomodeum, known as hypophyseal-buccal or craniopharyngeal duct, is obliterated and involuted (Fig. 5A2) (172). At this point, the lower end of Rathke's pouch that was attached to the stomodeum folds itself upwards against the neural tube and transforms into the pars tuberalis, a thin sheath of adenohypophyseal epithelial tissue covering the infundibulum (Fig. 5A3 and 5A4) (173). Through this process, close contact between the lowest portion of Rathke's pouch originally attached to an embryo's mouth and the 3VF occurs at an early development stage.
Proposed mechanisms for the origin of PCPs. (A) Embryological theory from PCP precursors within the pars tuberalis. (A1) Embryologic progenitors of pituitary gland structures. Rathke's pouch (Rp) arises from an outpocketing of the roof of the embryonic oral cavity (eoc), initially connected by the craniopharyngeal duct (cd). (A2) The lowest pole of Rathke's pouch will give rise to the pars tuberalis (pt), where epithelial cell remnants of the craniopharyngeal duct/oral roof may persist (black circle). (A3) Inward-upward folding of Rathke's pouch, by which epithelial cell inclusions from the embryonic craniopharyngeal duct/oral roof may reach the infundibulum/tuber cinereum. (A4) Ratke's pouch will give rise to the adenohypophysis (aPG) while the pars tuberalis wraps around the pituitary stalk. The embryonic epithelial nests (black circle) contain buccal SOX2+ stem cells that can potentially transform into a PCP. (B) Squamous metaplasia theory. PCPs in adult patients have traditionally been considered to originate from squamous metaplasia of functionally inactive adenohypophyseal cells of the pars tuberalis (pt). Black circles indicate the positions where squamous epithelial cell nests accumulate with age, mainly at the dorsal surface of the aPG and at higher positions at the upper junction of the pars tuberalis with the infundibulum. (C) Embryological theory from the early attachment between the neural tube epithelium and the embryonic oral epithelium. Left and right panels correspond to coronal and sagittal sections, respectively, of the human embryo's head. At an early stage of embryonic development (Carnegie stage 10, 22-23 days of embryonic development), the epithelium of the oral cavity located anterior to the area of origin of the Rathke's pouch is in close anatomical contact with the epithelial cells of the neural tube (squares), before the pia mater formation, allowing for the possibility that stem cells from the embryonic oral cavity become embedded within the diencephalic floor (173, 188-191).
Abbreviations: 3V, third ventricle; 3VF, third ventricle floor; N, neurohypophysis; OC, optic chiasm; PCP, papillary craniopharyngioma; r, remains of craniopharyngeal duct; S, sphenoid bone.
In 1904, Jakob Erdheim proposed that the solid-cystic epithelial tumors developed at the pituitary infundibulum, regardless of the adamantinomatous or papillary architecture they showed, all had a common embryological origin from squamous cell remnants of the hypophyseal or craniopharyngeal duct (6, 8). Accordingly, he named these lesions hypophysenganggeschwülste (hypophyseal duct tumors). Erdheim found nests of squamous epithelium embedded at the swollen top end of the pars tuberalis in 10 out of 20 human pituitary gland specimens and interpreted that they corresponded to tumorigenic cells of CPs (Fig. 1B2). This could also explain the frequent primary development of both CP types within the infundibulo-tuberal region (38).
Metaplastic Theory for PCP Origin: A Confounding Source of Data
Erdheim's embryological interpretation of squamous cell nests as the tumorigenic CP precursors conflicted with the apparent lack of these nests in the pituitary gland of children (8, 174). The systematic study of 1354 pituitary gland specimens by the pathologists Sara Luse and James Kernohan could not identify squamous nests in children under the age of 10 (175). Because the number of squamous cell nests also increased with age, an aging process was invoked for their presence (174). Goldberg et al, however, proved the presence of these nests in the pars tuberalis of 4 premature and full-term newborn infants (176). Nevertheless, the theory of a metaplastic transformation of adenohypophyseal cells into squamous cell nests within the pars tuberalis was considered a more likely pathogenetic mechanism for the origin of adulthood PCPs (Fig. 5B) (177-179). The metaplastic theory received additional support from immunohistochemical studies that evidenced positive staining for gonadotropins and corticotropic hormones in the pars tuberalis squamous cells (180, 181) and for hormones in some CPs (16, 24, 182, 183).
Erdheim's embryological theory fit in nicely with the heterogeneous topographic distribution of CPs along the hypothalamus-pituitary axis, but the metaplastic theory could not explain the histological resemblance of ACPs with odontogenic tumors or the predominant juvenile incidence of ACPs (184). Thus, a conciliatory, dual pathogenetic theory was endorsed by many authors, who proposed an embryological pathogenesis for ACPs developed in the congenital and childhood periods and a metaplastic origin for adult PCPs (112, 141). Moreover, a common link between the metaplastic and the embryological theories was provided by Rathke's cleft cysts (RCCs), a group of benign cystic lesions of the sellar region presumably derived from Rathke's cleft epithelium and characterized by a simple columnar epithelium with ciliated and mucinous goblet cells (133, 185). The presence of squamous metaplasia in 20% to 40% of RCCs, in addition to the stratified squamous epithelium identified in a minority of them, supported a common histogenesis for PCPs and RCCs (185, 186). Furthermore, the fact that a small percentage of PCPs (about 4%) show ciliated epithelium with mucinous goblet cells led pathologists to consider a transitional category of “ciliated CPs” that presumably derived from RCCs after a process of extensive metaplasia (146, 149-151).
Pathogenetic Clues From 3V Topography and a Duct-Like Recess in PCPs
The predominant occurrence of PCPs within the 3V and the infundibulo-tuberal region strongly suggest that the original position of CP tumorigenic cells may significantly influence their final histological differentiation (95-97, 187). A major challenge, however, lies in explaining the development of PCPs that are purely localized to the 3V, given that the craniopharyngeal duct resides outside the hermetically sealed neural tube (96, 130). The fusion between the caudal/lateral extensions of Rathke's pouch (the regions from which the pars tuberalis develops) and the 3VF at the early stages of an embryonic development demonstrates that the inclusion of craniopharyngeal duct vestiges, or Rathke's pouch progenitors, into the neural tube might occur before the formation of the pia mater is finished (130, 173). Indeed, an area of neuroectodermal adhesion between the basal forebrain and the embryo's mouth roof, necessary for inducing the appearance of Rathke's pouch, occurs even earlier, at 22 to 23 days of embryonic development (Carnegie stage 10) (Fig. 5C) (188, 189). This adhesion is especially relevant for understanding strict-3V-PCP pathogenesis, as it could allow the intra-3VF inclusion of multipotential stem cells from the stomodeum at an early stage of pituitary gland development (190, 191).
An important morphological indicator that links 3V PCP development with embryological disorders of the craniopharyngeal duct is the recess (or diverticulum) at the midline base of some PCPs, first described by Pascual et al in 2022 (Fig. 3B) (95, 192). The duct-like shape of these diverticula closely resembles that of the craniopharyngeal duct and follows the same diagonal trajectory as the pituitary stalk (PS), 2 facts suggesting the involvement of pituitary gland embryogenesis in their formation. In fact, incomplete closure of the craniopharyngeal canal has been described in some adults, in whom a free communication between the sella turcica and the pharynx persists (172). A similar duct-like communication between the 3V and the sella turcica has also been described, the persisting embryonal infundibular recess, a rare anomaly thought to result from a failed process of obliteration of the infundibular recess (193, 194). Likewise, an inward extension of the craniopharyngeal duct into the 3V and its persistence as an anomalous duct-like epithelial structure, from which CP precursors can undergo neoplastic transformation in adulthood, might represent a crucial morphological clue for the still unsolved pathogenesis of 3V PCPs (95, 192).
Histological Overlapping Between CP Types and Other Parasellar Cysts
Overlapping histological features among several categories of suprasellar epithelial lesions, mainly PCPs, ACPs, RCCs, and epidermoid/dermoid cysts, strongly points to a common ectodermal precursor for all of them. Plausibly, this could correspond to embryonic cells remaining from the craniopharyngeal duct and/or Rathke's pouch endowed with multipotential capacity for differentiating into a wide spectrum of cystic lesions (146, 149, 195). Transitional or mixed CP lesions showing adamantinomatous and papillary components have been reported in about one-third of the large series in the 99s cohort, representing about 1.5% to 2% of all CPs (62, 99, 196, 197). Nevertheless, several pathological studies have shown strikingly higher rates of mixed or transitional CPs (16, 21, 28, 61). The exemplary study published by neuropathologist Petito in 1976 supports the coexistence of papillary and adamantinomatous histologic features within the same tumor in up to one-third of the 245 CP samples she examined (12). Several reports have shown the coexistence of CTNNB1 and BRAFV600E mutations in rare CP samples, possibly supporting the existence of a transitional CP type (68, 86, 88, 101, 198, 199). However, such findings require further corroboration.
Even more cogent is the proven histological overlapping between CPs and other epithelial lesions developed along the hypothalamus-pituitary axis (133, 195, 200). The 1994 seminal study by Harrison et al showed the existence of overlapping features between PCPs and RCCs or epidermoid cysts, including areas of ciliated columnar epithelium, in over half of sellar/suprasellar cystic lesions (133). In 2019, Manjila et al described a set of 4 transitional or mixed cysts combining cuboidal epithelium typical of RCCs trapped within pituitary adenoma, epidermoid cyst, dermoid cyst, and PCP, respectively (200). These findings supporting the theory of a common origin for these lesions (146, 149), gained credence from experimental research showing how oral-mucosa fragments transplanted into the brain of newborn rats differentiated into a spectrum of tissues, including transitions between stratified squamous epithelium and cuboidal epithelium, as well as cholesterol clefts, calcifications, and bone tissue (133, 201). Thus, stem-cell precursors forming part of embryonic oral mucosa may have the potential to differentiate among the spectrum of histological patterns found in CPs (202).
The histological variety of epithelial cysts in the sellar/suprasellar regions might also be largely influenced by their original site of development along the hypothalamus-pituitary axis. The bottom end of this continuum would be represented by RCCs, which develop preferentially within the sella turcica, and at the top end would be PCPs, lesions that more often grow within the infundibulum and/or the 3V. Noteworthy, in 1959 the neuropathologists Dorothy Russell (1895-1983) and Lucien J. Rubinstein (1924-1990) described the peculiar finding of 2 dumbbell-shaped transitional or mixed sellar-suprasellar cystic lesions showing epithelium compatible with RCCs in the lower intrasellar portion while squamous epithelium typical of PCPs in their upper suprasellar portion (110). It is remarkable that in a genetic analysis of 33 RCCs, BRAFV600E mutation was only found in the 3 RCC specimens with a dumbbell-shaped intra- and suprasellar location showing extensive squamous metaplasia (203). These findings are consistent with the influence that the precise spatial/temporal expression of signaling molecules in the peritumoral milieu has on guiding the differentiation and potential neoplastic transformation of stem cell precursors, the cornerstone of the novel paracrine model of CP oncogenesis defined by Martinez-Barbera et al (166, 204).
Molecular Pathology of PCPs: Key Insights into CP Cytogenesis
The somatic BRAFV600E mutation is the genetic hallmark of human PCPs, detected in up to 95% of these tumors (116, 136, 139). At present, the tumor-initiating cell has not yet been proven conclusively, but the insights from molecular studies in murine models and human PCP samples suggest that these tumors may share with ACPs a similar embryological origin, from a niche of SOX2+ stem cells (139, 141). Undifferentiated pituitary stem cells with clonogenic potential can be identified by the SOX2 and SOX9 expression in the adult pituitary gland. These cells are capable of clonal proliferation and differentiation into hormone-producing cells of the adenohypophysis (167, 205-207). In PCPs, BRAFV600E mutation activates components of the MAPK pathway, including the phosphorylation of ERK1 and ERK2. Their expression is restricted to the small subset of SOX2+ tumor cells within the actively proliferating basal cell row of the squamous epithelium (116, 136). BRAFV600E mutation in embryonic SOX2+ cell murine pituitary precursors triggers the proliferation of this stem cell niche and disrupts their normal differentiation toward hormone-lineage committed pools of adenohypophyseal cells (155). By contrast, the expression of BRAFV600E in SOX2+ pituitary progenitors of adult mice induces cellular senescence and apoptosis (155, 168, 208). Therefore, this mutation has revealed the critical role played by stem cells in PCP tumorigenesis, in agreement with the cancer stem-cell paradigm (147, 167, 204). Independently of the origin of this stem cell pool, either from stomodeal or pituitary progenitors, the inclusion of SOX2+ cells along the craniopharyngeal duct at the early stages of an embryo's development, followed by their aberrant proliferation and differentiation driven by the BRAFV600E mutation, is currently the most plausible pathogenetic explanation for PCPs.
In 2021, Mu et al proposed a novel pathogenic theory that linked PCP origin to the dedifferentiation and proliferation of a pool of specialized 3V ependymoglial cells, the tanycytes (209). These cells contribute to create a physical barrier between the median eminence (ME), which lacks a blood-brain barrier, and the remaining upper portion of the hypothalamus, involved in multiple homeostatic functions (210-213). The subgroup of β2-tanycytes in the ME remains quiescent under physiological conditions but can undergo active proliferation as a response to ischemic or mechanical injuries. The induction of mutant BRAFV600E expression in ME Ras+ β2-tanycytes in adult mice has proven an oncogenic stimulus sufficient to drive the dedifferentiation and proliferation of these cells to form well-circumscribed tumors within the 3VF resembling PCPs (209). The tumor cells within the central portion of these PCP-like tumors expressed stem cells markers such as SOX2 and SOX9 and induced the active proliferation of Ki67+ tumor cells on the periphery. Considering the specific anatomical location of most PCPs within the infundibulo-tuberal region, this study reveals an appealing alternative source of tumorigenic cells for the still inconclusive definition of the cell-of-origin for adult-onset PCPs, a finding that merits further exploration (209).
PCP Topography
The ideal topographical classification of CPs should reflect the primary site of tumor origin along the hypothalamus-pituitary axis, the intracranial compartments occupied by the lesion, and, most importantly, the accurate anatomical relationships of the brain structures that are displaced or invaded by the tumor (142, 214-216). Most PCPs develop primarily at the infundibulo-tuberal region of the 3VF, the thin layer of neural tissue that forms the lower boundary of the 3V cavity. As the tumor grows and progressively occupies this cavity, the 3V walls are pushed apart along with the hypothalamus, which undergoes a gradual anatomical distortion and functional impairment. Accordingly, the hypothalamus is the vital brain region at maximal risk during PCP removal, and it should be the major structure of reference, whose dysfunction critically endangers survival, when considering the PCP topography.
Major Classification Schemes to Predict Surgical Hypothalamic Risk
Table 6 summarizes the most relevant classification schemes for PCP surgery (53, 80, 91, 109, 142, 217-221). In 2004, Pascual et al developed a topographical classification based on the accurate relationship between CPs and the 3VF that includes 5 categories: (1) sellar-suprasellar, comprising those tumors that develop from the lower solid portion of the pituitary stalk (PS) and expand into the sellar and/or suprasellar compartments, below a normal 3VF; (2) suprasellar pseudointraventricular, corresponding to those lesions developed from the lower solid portion of the PS beneath the 3VF, which is pushed upwards mimicking a 3V position; (3) secondary 3V CPs, or suprasellar tumors that invade the 3V after breaking through the 3VF; (4) not strictly intraventricular or infundibulo-tuberal, including CPs primarily developed within the upper infundibular portion of the PS and/or tuber cinereum (infundibulo-tuberal region of the 3VF), structures that eventually ends up replaced by the tumor; and (5) strictly intraventricular, which develop subependymally from the infundibulo-tuberal region and are wholly confined within the 3V above an intact 3VF (23, 142). Contrary to pediatric CPs, approximately half of adult CPs and 66% to 90% of PCPs correspond to tumors largely occupying the 3V cavity (Fig. 6) (37, 38, 44, 57, 64, 97, 109, 187). Clear preoperative differentiation between the infundibulo-tuberal (not-strict) and the strict 3V topographies is not likely in 20% to 30% of cases because of the overlapping continuum of possible 3VF anatomical categories, from a thinning but still recognizable 3VF to several degrees of 3VF breaches by tumor expansion or complete CP replacement of this structure (37, 143, 216, 222, 223). Moreover, lesions larger than 3 cm that developed subpially usually lead to infundibulum/tuber cinereum atrophy and its fusion to the tumor capsule, making this area unrecognizable. Consequently, we consider that the strict 3V category is probably overrepresented in the 560c (58.2% of cases). The importance of establishing the topographical distinction between the infundibulo-tuberal and strictly 3V topographies, however, lies in the different severity of hypothalamic adhesions associated with each category (54, 224, 225). A circumferential or ring-like pattern of strong adhesions between the central portion of the tumor and the adjacent hypothalamus is identified intraoperatively in most infundibulo-tuberal CPs, a type of attachment associated with a high risk of injuring the hypothalamus during surgery (38, 54). In contrast, PCPs with a strict 3V topography usually show small pedicle-like/sessile attachments to the 3VF allowing a safe gross total resection (GTR) (23, 37, 64, 91, 95, 97, 106, 109).
PCP-hypothalamic anatomical relationships in the 2 major topographical categories of papillary craniopharyngiomas. (A) Midsagittal illustration of the hypothalamus-pituitary axis showing the location of the main nuclei and axonal bundles of the hypothalamus around the 3V. Supraoptic-hypophysial tract contains axons bundles running from the SO and PV nuclei that release vasopressin into the pPG. (B1-B3) The strict 3V PCP topography: hypothalamus distortion caused by this tumor location and clinical manifestations derived from the associated hypothalamic functional impairment. (B1) Strict 3V PCPs originate subependymally above an anatomically intact 3VF and intact PS below the tumor. (B2) Coronal scheme showing how the tumor growth within the 3V, pushes against the 3V walls and the hypothalamic nuclei and tracts contained within them, mainly the PV, DM, and VM nuclei, as well as both fornices (F). (B3) Major symptoms of the hypothalamic syndrome derived from the dysfunction of these hypothalamic structures. (C1-C3) The not-strict 3V or infundibulo-tuberal PCP topography: associated hypothalamic distortions and functional impairment. (C1) Not-strict 3V or infundibulo-tuberal PCPs originate within the neural layer of the 3VF, replacing progressively this region. (C2) Coronal scheme showing how the tumor growth primarily damages the arcuate nucleus (infundibularis) and the tubero-mammillary nuclei, as well as the median eminence (the highly vascularized structure of the infundibulum supporting the anatomical-functional link between the hypothalamus and the PG. (C3) Major symptoms of the infundibulo-tuberal syndrome associated with this type of injury.
Abbreviations: 3V, third ventricle; 3VF, third ventricle floor; A, arcuate nucleus (also known in humans as infundibularis nucleus); aPG, anterior lobe of the pituitary gland; AVP deficiency, arginine vasopressin deficiency (diabetes insipidus); DH, dorsal region of the hypothalamus; DM, dorsolmedial nucleus; LHA, lateral hypothalamic area; LT, lamina terminalis; MB, mammillary body; MFB, medial forebrain bundle; OC, optic chiasm; OT, optic tract; PCP, papillary craniopharyngioma; PeV, periventricular nucleus PG, pituitary gland; PL, postero-lateral hypothalamic region; PO, preoptic area; pPG, posterior lobe of the pituitary gland; PS, pituitary stalk; PV, paraventricular nucleus; SC, suprachiasmatic nucleus; SO, supraoptic nucleus; VM, ventromedial nucleus.
Classification schemes for craniopharyngioma topography
| Author, year (Ref) | Based on | Categories | Definition | Relevance for PCP surgery/outcome |
|---|---|---|---|---|
| Sainte-Rose 2005 (217) Puget 2007 (218) | Type of hypothalamus involvement by the tumor | Grade 0 | No hypothalamic involvement | Radical resection of grade 2 tumors associates with postoperative hypothalamic injury and worse outcome |
| Grade 1 | The hypothalamus is visible but distorted | |||
| Grade 2 | The hypothalamus is no longer identifiable | |||
| Pascual 2004, 2008 (23, 142) | Site of tumor origin and type of 3V floor involvement by the tumor | Sellar-suprasellar | Origin at the dorsal surface of the pituitary gland | The not-strict (infundibulotuberal) topography associates with wide and dense attachments to the hypothalamus and a worse surgical outcome |
| Suprasellar-pseudointraventricular | Origin below the 3V floor but mimicking an intraventricular position | |||
| Suprasellar-secondary intraventricular | Origin below the 3V floor and breaking through the 3V floor into the 3V cavity | |||
| Not-strict 3V (infundibulo-tuberal) | Subpial origin within the tissue of the 3V floor | |||
| Strict 3V (purely intraventricular) | Subependymal origin above an anatomically intact 3V floor | |||
| Pan 2016 (53) Qi 2017 (219) | Site of tumor origin and tumor-meningeal relationships | Q—intrasellar/subdiaphragmatic | Origin within the sella below the diaphragm | T-type CPs have more tenacious attachments to the hypothalamus with more significant weight gain following surgery |
| S—subarachnoidal extraventricular | Arises from the middle/inferior part of the stalk and grows freely in the suprasellar subaracnoid cisterns | |||
| T—subpial intraventricular | Origin at the infundibulotuberal region and growing into the 3V surrounded by the 3V floor/walls tissue | |||
| Tang 2018, 2019 (220, 221) Yang 2020 (80) | Relation to pituitary stalk and site of origin along the hypothalamus-pituitary axis | Central–transinfundibular | Midline location within and along the pituitary stalk and 3V, without clear origin | Postoperative bilateral hypothalamic injury is associated with central and peripheral-hypothalamic stalk groups |
| Peripheral-hypothalamic | Origin at the hypothalamus-stalk junction and invading the 3V/hypothalamus | |||
| Peripheral-suprasellar | Origin from the suprasellar-low portion of the stalk with extraventricular growth | |||
| Peripheral-intrasellar | Arises from the bottom part of the stalk under the diaphragma | |||
| Cao 2022 (91) Jia 2023 (109) | Tumor origin and status of the 3V floor | Type I: intra-suprasellar with intact 3V floor | Extraventricular lesion originated from the stalk between diaphragma and infundibulum, MBA > 60° | Type II associates with higher rate of tumor recurrence and lower rate of independent patients |
| Type II: intrasuprasellar with invaded 3V floor | Origin from stalk or infundibulum/median eminence with no clear interface between the tumor and the 3V floor | |||
| Type III: intra-third ventricle | Intraventricular lesion strictly inside the 3V with intact 3V floor below, MBA < 60° |
| Author, year (Ref) | Based on | Categories | Definition | Relevance for PCP surgery/outcome |
|---|---|---|---|---|
| Sainte-Rose 2005 (217) Puget 2007 (218) | Type of hypothalamus involvement by the tumor | Grade 0 | No hypothalamic involvement | Radical resection of grade 2 tumors associates with postoperative hypothalamic injury and worse outcome |
| Grade 1 | The hypothalamus is visible but distorted | |||
| Grade 2 | The hypothalamus is no longer identifiable | |||
| Pascual 2004, 2008 (23, 142) | Site of tumor origin and type of 3V floor involvement by the tumor | Sellar-suprasellar | Origin at the dorsal surface of the pituitary gland | The not-strict (infundibulotuberal) topography associates with wide and dense attachments to the hypothalamus and a worse surgical outcome |
| Suprasellar-pseudointraventricular | Origin below the 3V floor but mimicking an intraventricular position | |||
| Suprasellar-secondary intraventricular | Origin below the 3V floor and breaking through the 3V floor into the 3V cavity | |||
| Not-strict 3V (infundibulo-tuberal) | Subpial origin within the tissue of the 3V floor | |||
| Strict 3V (purely intraventricular) | Subependymal origin above an anatomically intact 3V floor | |||
| Pan 2016 (53) Qi 2017 (219) | Site of tumor origin and tumor-meningeal relationships | Q—intrasellar/subdiaphragmatic | Origin within the sella below the diaphragm | T-type CPs have more tenacious attachments to the hypothalamus with more significant weight gain following surgery |
| S—subarachnoidal extraventricular | Arises from the middle/inferior part of the stalk and grows freely in the suprasellar subaracnoid cisterns | |||
| T—subpial intraventricular | Origin at the infundibulotuberal region and growing into the 3V surrounded by the 3V floor/walls tissue | |||
| Tang 2018, 2019 (220, 221) Yang 2020 (80) | Relation to pituitary stalk and site of origin along the hypothalamus-pituitary axis | Central–transinfundibular | Midline location within and along the pituitary stalk and 3V, without clear origin | Postoperative bilateral hypothalamic injury is associated with central and peripheral-hypothalamic stalk groups |
| Peripheral-hypothalamic | Origin at the hypothalamus-stalk junction and invading the 3V/hypothalamus | |||
| Peripheral-suprasellar | Origin from the suprasellar-low portion of the stalk with extraventricular growth | |||
| Peripheral-intrasellar | Arises from the bottom part of the stalk under the diaphragma | |||
| Cao 2022 (91) Jia 2023 (109) | Tumor origin and status of the 3V floor | Type I: intra-suprasellar with intact 3V floor | Extraventricular lesion originated from the stalk between diaphragma and infundibulum, MBA > 60° | Type II associates with higher rate of tumor recurrence and lower rate of independent patients |
| Type II: intrasuprasellar with invaded 3V floor | Origin from stalk or infundibulum/median eminence with no clear interface between the tumor and the 3V floor | |||
| Type III: intra-third ventricle | Intraventricular lesion strictly inside the 3V with intact 3V floor below, MBA < 60° |
Abbreviations: 3V, third ventricle; GTR, gross total resection; MBA, mammillary body angle; PCP, papillary craniopharyngioma; Ref, reference number; TLT, trans-laminar terminalis.
Classification schemes for craniopharyngioma topography
| Author, year (Ref) | Based on | Categories | Definition | Relevance for PCP surgery/outcome |
|---|---|---|---|---|
| Sainte-Rose 2005 (217) Puget 2007 (218) | Type of hypothalamus involvement by the tumor | Grade 0 | No hypothalamic involvement | Radical resection of grade 2 tumors associates with postoperative hypothalamic injury and worse outcome |
| Grade 1 | The hypothalamus is visible but distorted | |||
| Grade 2 | The hypothalamus is no longer identifiable | |||
| Pascual 2004, 2008 (23, 142) | Site of tumor origin and type of 3V floor involvement by the tumor | Sellar-suprasellar | Origin at the dorsal surface of the pituitary gland | The not-strict (infundibulotuberal) topography associates with wide and dense attachments to the hypothalamus and a worse surgical outcome |
| Suprasellar-pseudointraventricular | Origin below the 3V floor but mimicking an intraventricular position | |||
| Suprasellar-secondary intraventricular | Origin below the 3V floor and breaking through the 3V floor into the 3V cavity | |||
| Not-strict 3V (infundibulo-tuberal) | Subpial origin within the tissue of the 3V floor | |||
| Strict 3V (purely intraventricular) | Subependymal origin above an anatomically intact 3V floor | |||
| Pan 2016 (53) Qi 2017 (219) | Site of tumor origin and tumor-meningeal relationships | Q—intrasellar/subdiaphragmatic | Origin within the sella below the diaphragm | T-type CPs have more tenacious attachments to the hypothalamus with more significant weight gain following surgery |
| S—subarachnoidal extraventricular | Arises from the middle/inferior part of the stalk and grows freely in the suprasellar subaracnoid cisterns | |||
| T—subpial intraventricular | Origin at the infundibulotuberal region and growing into the 3V surrounded by the 3V floor/walls tissue | |||
| Tang 2018, 2019 (220, 221) Yang 2020 (80) | Relation to pituitary stalk and site of origin along the hypothalamus-pituitary axis | Central–transinfundibular | Midline location within and along the pituitary stalk and 3V, without clear origin | Postoperative bilateral hypothalamic injury is associated with central and peripheral-hypothalamic stalk groups |
| Peripheral-hypothalamic | Origin at the hypothalamus-stalk junction and invading the 3V/hypothalamus | |||
| Peripheral-suprasellar | Origin from the suprasellar-low portion of the stalk with extraventricular growth | |||
| Peripheral-intrasellar | Arises from the bottom part of the stalk under the diaphragma | |||
| Cao 2022 (91) Jia 2023 (109) | Tumor origin and status of the 3V floor | Type I: intra-suprasellar with intact 3V floor | Extraventricular lesion originated from the stalk between diaphragma and infundibulum, MBA > 60° | Type II associates with higher rate of tumor recurrence and lower rate of independent patients |
| Type II: intrasuprasellar with invaded 3V floor | Origin from stalk or infundibulum/median eminence with no clear interface between the tumor and the 3V floor | |||
| Type III: intra-third ventricle | Intraventricular lesion strictly inside the 3V with intact 3V floor below, MBA < 60° |
| Author, year (Ref) | Based on | Categories | Definition | Relevance for PCP surgery/outcome |
|---|---|---|---|---|
| Sainte-Rose 2005 (217) Puget 2007 (218) | Type of hypothalamus involvement by the tumor | Grade 0 | No hypothalamic involvement | Radical resection of grade 2 tumors associates with postoperative hypothalamic injury and worse outcome |
| Grade 1 | The hypothalamus is visible but distorted | |||
| Grade 2 | The hypothalamus is no longer identifiable | |||
| Pascual 2004, 2008 (23, 142) | Site of tumor origin and type of 3V floor involvement by the tumor | Sellar-suprasellar | Origin at the dorsal surface of the pituitary gland | The not-strict (infundibulotuberal) topography associates with wide and dense attachments to the hypothalamus and a worse surgical outcome |
| Suprasellar-pseudointraventricular | Origin below the 3V floor but mimicking an intraventricular position | |||
| Suprasellar-secondary intraventricular | Origin below the 3V floor and breaking through the 3V floor into the 3V cavity | |||
| Not-strict 3V (infundibulo-tuberal) | Subpial origin within the tissue of the 3V floor | |||
| Strict 3V (purely intraventricular) | Subependymal origin above an anatomically intact 3V floor | |||
| Pan 2016 (53) Qi 2017 (219) | Site of tumor origin and tumor-meningeal relationships | Q—intrasellar/subdiaphragmatic | Origin within the sella below the diaphragm | T-type CPs have more tenacious attachments to the hypothalamus with more significant weight gain following surgery |
| S—subarachnoidal extraventricular | Arises from the middle/inferior part of the stalk and grows freely in the suprasellar subaracnoid cisterns | |||
| T—subpial intraventricular | Origin at the infundibulotuberal region and growing into the 3V surrounded by the 3V floor/walls tissue | |||
| Tang 2018, 2019 (220, 221) Yang 2020 (80) | Relation to pituitary stalk and site of origin along the hypothalamus-pituitary axis | Central–transinfundibular | Midline location within and along the pituitary stalk and 3V, without clear origin | Postoperative bilateral hypothalamic injury is associated with central and peripheral-hypothalamic stalk groups |
| Peripheral-hypothalamic | Origin at the hypothalamus-stalk junction and invading the 3V/hypothalamus | |||
| Peripheral-suprasellar | Origin from the suprasellar-low portion of the stalk with extraventricular growth | |||
| Peripheral-intrasellar | Arises from the bottom part of the stalk under the diaphragma | |||
| Cao 2022 (91) Jia 2023 (109) | Tumor origin and status of the 3V floor | Type I: intra-suprasellar with intact 3V floor | Extraventricular lesion originated from the stalk between diaphragma and infundibulum, MBA > 60° | Type II associates with higher rate of tumor recurrence and lower rate of independent patients |
| Type II: intrasuprasellar with invaded 3V floor | Origin from stalk or infundibulum/median eminence with no clear interface between the tumor and the 3V floor | |||
| Type III: intra-third ventricle | Intraventricular lesion strictly inside the 3V with intact 3V floor below, MBA < 60° |
Abbreviations: 3V, third ventricle; GTR, gross total resection; MBA, mammillary body angle; PCP, papillary craniopharyngioma; Ref, reference number; TLT, trans-laminar terminalis.
Based on the histological analysis of the meningeal structures interposed between the tumor capsule and the 3VF, Songtao Qi et al, from Nanfang Hospital in Guangzhou, China, proposed the QST classification system, which differentiates 3 topographical categories: type Q, comprising tumors developed beneath the diaphragm sellae and separated from the 3VF by a layer of dura mater; type S, including tumors developed from the PS and separated from the 3VF by an arachnoid layer; and type T, which groups all the tumors developed from the upper portion of the pars tuberalis covering the infundibulum and infiltrating the pia mater of the 3VF (219, 226, 227). According to this scheme, 40 out of 77 PCPs operated through the EEA corresponded to the T type (52%) (83), a rate very close to what was observed for the infundibulo-tuberal category in the Pascual et al classification (42%) (38), supporting the equivalence between both categories.
In 2018, Tang et al, from the First Affiliated Hospital of Nanchang University in China, proposed a novel CP classification differentiating between a “central” or trans-infundibular CP type (35%), which expands within and along the infundibulum and extends into the 3V, and a “peripheral” type (65%). The latter may grow either at the hypothalamus-stalk junction (infundibulum) or at lower positions along the solid portion of the PS beneath the 3VF (220, 221). The importance of this classification is the significant relationship between each topography and the anatomical extension of the surgical injury caused to the hypothalamus following radical CP resection, demonstrated both through endoscopic exploration of the tumor-hypothalamus adhesion plane or on postoperative MRI. The central CP type caused a bilateral and the most severe type of hypothalamic injury in 53% of patients. This rate reduced to 28% in the peripheral-hypothalamic-stalk type and to zero in the peripheral-suprasellar/intrasellar types originating beneath the infundibulum (80).
Controversies Surrounding the Strictly Intraventricular Topography
The existence of true strict intra-3V CPs that develop above an anatomically preserved infundibulum/tuber cinereum (3VF) has been debated for a long time. This is due to the assumed embryological CP origin from Rathke's pouch, an embryological structure outside the neural tube (84, 226, 227). Despite the QST topographical classification does not consider the existence of a separate strictly 3V category, a strict 3V position was previously reported in 2011 by the same authors in 33% of 17 intraventricular CPs (37, 53). An intrinsic or strict 3V topography has been confirmed in numerous PCPs removed either by EEA or transcranial corridors (23, 44, 52, 57, 63, 85, 91, 95, 96, 106, 109, 187, 228-231). Regardless of the presence of a paper-thin nonfunctional gliotic-ependymal layer around the lower CP capsule or the existence of a tumor protrusion through a small 3VF breach, the strict 3V category groups those lesions whose lower pole is covered by the expanded infundibulum/tuber cinereum, above an intact PS and a tumor-free chiasmatic cistern (23, 96, 143, 187, 232).
In a systematic review of autopsied whole specimens, intraoperative anatomical descriptions, and MRI studies, Prieto et al compiled a cohort of 245 CPs that conclusively demonstrated the existence of a strictly 3V topographical CP category (96). A total of 82% of these tumors corresponded to PCPs characterized by looser/smaller adherences to the hypothalamus than those of strict 3V ACPs. The 3 MRI criteria defining this topographical category (tumor-free chiasmatic cistern, entirely visible PS, and hypothalamus positioned below the lower pole of the tumor) were tested in a surgical series of 22 strict 3V CPs removed by EEA (91). The authors confirmed intraoperatively the anatomical integrity of the 3VF under the tumor in 9 of 12 PCPs displaying the 3 MRI features, the other 3 causing a small breach at the infundibulo-tuberal region (91). The association between the strictly 3V topography and the papillary type has also been confirmed in 3 additional surgical series published in 2022 and 2023. Zoli et al classified 9 of 12 PCPs largely developed within the 3V as strictly intraventricular and the remaining 3 as infundibulo-tuberal (103). Zhou et al provided evidence for the integrity of the infundibulo-tuberal region covered by the arachnoid layer beneath 9 PCPs, with these lesions showing a loose, easy-to-dissect adherence to either the infundibulum (2 cases) or the tuber cinereum (7 cases) (102). Finally, Chen et al identified 20 strict or almost strict 3V PCPs in their series, 4 of them pure solid lesions showing a midline basal recess (106).
Clinical Manifestations of PCPs
Visual Deficits in PCPs
Impairment of visual function is a major clinical manifestation of CPs, affecting 60% to 85% of patients overall (20, 62, 77, 86, 93, 105-109, 141, 228). Visual acuity loss is the most common type of alteration in adults (∼80% of patients), followed by field defects (55-70%) either bitemporal/unitemporal hemianopsia or homonymous hemianopsia/quadrantanopsia, and fundoscopic alterations, either optic atrophy (10-40%) or papilledema (8-10%) (40, 77, 79). Presence of visual disturbances, however, depends on the type and severity of the anatomical distortion the tumor causes on the optic chiasm, a variable directly related to the CP origin site and size (79, 233). Accordingly, the surgical series including a greater proportion of adult CPs/PCPs that primarily affect the 3V report a lower rate of visual disturbances in around 40% to 65% of patients (28, 35, 37, 44, 53, 64, 70, 81, 83, 91, 95, 97, 102, 109). In the 560c, with predominantly strictly 3V and infundibulo-tuberal topographies, 60.5% of patients overall had visual disturbances upon diagnosis. This rate diminished to 45.1% in the group of patients with strictly 3V PCPs (P < .001).
The impact of the strict 3V CP topography on a lower incidence of visual symptoms is related to the lesser degree of distortion caused by these lesions to the optic chiasm compared with that caused by CPs developed beneath the 3VF (233). The type of displacement and deformation of the optic chiasm caused by CP growth can be assessed on conventional preoperative MRI and represents the main predictive factor of both, the severity of visual defect upon diagnosis, and its recovery after surgical removal. Suprasellar-subchiasmatic ACPs in the pediatric population typically stretch the optic chiasm upward causing its strangulation against the anterior communicating artery complex and the bony edges of the optic foramina, with this anatomical distortion leading to the most severe visual deficits and worst outcome (233). Conversely, PCPs developing strictly within the 3V either do not distort the optic chiasm or cause a slight downward compression on it, which is the least damaging type of deformity (Table 7). Thus, when PCPs cause visual defects, they have also better chances of improvement after tumor removal. A pattern of optic chiasm distortion of intermediate severity is the forward compression against the tuberculum sellae (prefixed or compressed forward chiasm), which is typically associated with infundibulo-tuberal CPs developed at the 3VF level.
Clinical and diagnostic significant relationships found in the 560c (118)
| Variable | P-value | Type of relationship |
|---|---|---|
| Relationship between epidemiology, clinical presentation, and tumor topography | ||
| Age | <.001 | Pediatric group [0-17 years] associated with highest rate of S-SS topography |
| Hypothalamic symptoms | <.001 | Highest rate in Strict-3V PCPs |
| Psychiatric disturbances | <.001 | Highest rate in Strict-3V and Not-Strict-3V PCPs |
| Infundibulo-tuberal symptoms | <.001 | Highest rate in Not-Strict-3V PCPs |
| Endocrine deficits | <.001 | Highest rate in S-SS and Pseudo-3V PCPs |
| Visual impairment | <.001 | Lowest rate in Strict-3V PCPs |
| Relationship between MRI signs and PCP topography | ||
| Chiasmatic cistern | <.001 | Tumor free associated with Strict-3V PCPs |
| Pituitary appearance | <.001 | Normal (wholly visible) associated with Strict-3V PCPs |
| Chiasm morphology | <.001 | Normal and compressed downward associated with Strict-3V PCPs |
| Hypothalamus position | <.001 | Below lower third associated with Strict-3V PCPs |
| Mammillary body angle | <.001 | Hyperacute (<30°) associated with Not-Strict-3V topography |
| Hydrocephalus | <.001 | If present associated with Strict-3V PCPs |
| Tumor consistency | <.001 | Solid associated with Strict-3V topography |
| Basal duct-like recess | <.001 | If present associated with Strict-3V topography |
| Relationship between tumor pathological features and clinical presentation | ||
| Hydrocephalus | .001 | If present associated with psychiatric disturbances |
| Hypothalamic edema | .043 | If present associated with psychiatric disturbances |
| Presence of ciliated/goblet cells | <.001 | Highest rate in S-SS topographies below an intact 3V floor |
| Tumor consistency | .009 | Cauliflower-like or upper cystic and basal solid with psychiatric disturbances |
| Tumor size | .004 | PCPs ≥3.5 cm associated with psychiatric disturbances |
| Basal duct-like recess | .030 | If present associated with psychiatric symptoms |
| <.001 | If present associated with solid/round PCPs | |
| Clinical, radiological, and pathological factors associated with the severity of PCP adherence to the hypothalamus | ||
| Hypothalamic symptoms | .032 | If present associated with high-risk adhesions to the hypothalamus |
| Infundibulo-tuberal symptoms | .001 | If present associated with high-risk adhesions |
| Visual impairment | <.001 | If present associated with high-risk adhesions |
| Tumor consistency | <.001 | Solid PCPs associated with low-risk adhesions |
| Tumor size | .006 | Tumors ≥3.5 associated with high-risk adhesions |
| Tumor topography | <.001 | Strict-3V and S-SS topographies with low-risk hypothalamic adhesions |
| Pituitary stalk appearance | <.001 | Normal (wholly visible) with low-risk adhesions |
| Hypothalamus position | <.001 | Around middle third associated with high-risk adhesions |
| Hypothalamic edema | .003 | If present associated with high-risk adhesions |
| Basal duct-like recess | <.001 | If present associated with low-risk attachment |
| Variable | P-value | Type of relationship |
|---|---|---|
| Relationship between epidemiology, clinical presentation, and tumor topography | ||
| Age | <.001 | Pediatric group [0-17 years] associated with highest rate of S-SS topography |
| Hypothalamic symptoms | <.001 | Highest rate in Strict-3V PCPs |
| Psychiatric disturbances | <.001 | Highest rate in Strict-3V and Not-Strict-3V PCPs |
| Infundibulo-tuberal symptoms | <.001 | Highest rate in Not-Strict-3V PCPs |
| Endocrine deficits | <.001 | Highest rate in S-SS and Pseudo-3V PCPs |
| Visual impairment | <.001 | Lowest rate in Strict-3V PCPs |
| Relationship between MRI signs and PCP topography | ||
| Chiasmatic cistern | <.001 | Tumor free associated with Strict-3V PCPs |
| Pituitary appearance | <.001 | Normal (wholly visible) associated with Strict-3V PCPs |
| Chiasm morphology | <.001 | Normal and compressed downward associated with Strict-3V PCPs |
| Hypothalamus position | <.001 | Below lower third associated with Strict-3V PCPs |
| Mammillary body angle | <.001 | Hyperacute (<30°) associated with Not-Strict-3V topography |
| Hydrocephalus | <.001 | If present associated with Strict-3V PCPs |
| Tumor consistency | <.001 | Solid associated with Strict-3V topography |
| Basal duct-like recess | <.001 | If present associated with Strict-3V topography |
| Relationship between tumor pathological features and clinical presentation | ||
| Hydrocephalus | .001 | If present associated with psychiatric disturbances |
| Hypothalamic edema | .043 | If present associated with psychiatric disturbances |
| Presence of ciliated/goblet cells | <.001 | Highest rate in S-SS topographies below an intact 3V floor |
| Tumor consistency | .009 | Cauliflower-like or upper cystic and basal solid with psychiatric disturbances |
| Tumor size | .004 | PCPs ≥3.5 cm associated with psychiatric disturbances |
| Basal duct-like recess | .030 | If present associated with psychiatric symptoms |
| <.001 | If present associated with solid/round PCPs | |
| Clinical, radiological, and pathological factors associated with the severity of PCP adherence to the hypothalamus | ||
| Hypothalamic symptoms | .032 | If present associated with high-risk adhesions to the hypothalamus |
| Infundibulo-tuberal symptoms | .001 | If present associated with high-risk adhesions |
| Visual impairment | <.001 | If present associated with high-risk adhesions |
| Tumor consistency | <.001 | Solid PCPs associated with low-risk adhesions |
| Tumor size | .006 | Tumors ≥3.5 associated with high-risk adhesions |
| Tumor topography | <.001 | Strict-3V and S-SS topographies with low-risk hypothalamic adhesions |
| Pituitary stalk appearance | <.001 | Normal (wholly visible) with low-risk adhesions |
| Hypothalamus position | <.001 | Around middle third associated with high-risk adhesions |
| Hypothalamic edema | .003 | If present associated with high-risk adhesions |
| Basal duct-like recess | <.001 | If present associated with low-risk attachment |
Abbreviations: 3V, third ventricle; 560c, cohort of 560 well-described individual papillary craniopharyngioma patients; MRI, magnetic resonance imaging; PCP, papillary craniopharyngioma; S-SS, sellar-suprasellar.
Clinical and diagnostic significant relationships found in the 560c (118)
| Variable | P-value | Type of relationship |
|---|---|---|
| Relationship between epidemiology, clinical presentation, and tumor topography | ||
| Age | <.001 | Pediatric group [0-17 years] associated with highest rate of S-SS topography |
| Hypothalamic symptoms | <.001 | Highest rate in Strict-3V PCPs |
| Psychiatric disturbances | <.001 | Highest rate in Strict-3V and Not-Strict-3V PCPs |
| Infundibulo-tuberal symptoms | <.001 | Highest rate in Not-Strict-3V PCPs |
| Endocrine deficits | <.001 | Highest rate in S-SS and Pseudo-3V PCPs |
| Visual impairment | <.001 | Lowest rate in Strict-3V PCPs |
| Relationship between MRI signs and PCP topography | ||
| Chiasmatic cistern | <.001 | Tumor free associated with Strict-3V PCPs |
| Pituitary appearance | <.001 | Normal (wholly visible) associated with Strict-3V PCPs |
| Chiasm morphology | <.001 | Normal and compressed downward associated with Strict-3V PCPs |
| Hypothalamus position | <.001 | Below lower third associated with Strict-3V PCPs |
| Mammillary body angle | <.001 | Hyperacute (<30°) associated with Not-Strict-3V topography |
| Hydrocephalus | <.001 | If present associated with Strict-3V PCPs |
| Tumor consistency | <.001 | Solid associated with Strict-3V topography |
| Basal duct-like recess | <.001 | If present associated with Strict-3V topography |
| Relationship between tumor pathological features and clinical presentation | ||
| Hydrocephalus | .001 | If present associated with psychiatric disturbances |
| Hypothalamic edema | .043 | If present associated with psychiatric disturbances |
| Presence of ciliated/goblet cells | <.001 | Highest rate in S-SS topographies below an intact 3V floor |
| Tumor consistency | .009 | Cauliflower-like or upper cystic and basal solid with psychiatric disturbances |
| Tumor size | .004 | PCPs ≥3.5 cm associated with psychiatric disturbances |
| Basal duct-like recess | .030 | If present associated with psychiatric symptoms |
| <.001 | If present associated with solid/round PCPs | |
| Clinical, radiological, and pathological factors associated with the severity of PCP adherence to the hypothalamus | ||
| Hypothalamic symptoms | .032 | If present associated with high-risk adhesions to the hypothalamus |
| Infundibulo-tuberal symptoms | .001 | If present associated with high-risk adhesions |
| Visual impairment | <.001 | If present associated with high-risk adhesions |
| Tumor consistency | <.001 | Solid PCPs associated with low-risk adhesions |
| Tumor size | .006 | Tumors ≥3.5 associated with high-risk adhesions |
| Tumor topography | <.001 | Strict-3V and S-SS topographies with low-risk hypothalamic adhesions |
| Pituitary stalk appearance | <.001 | Normal (wholly visible) with low-risk adhesions |
| Hypothalamus position | <.001 | Around middle third associated with high-risk adhesions |
| Hypothalamic edema | .003 | If present associated with high-risk adhesions |
| Basal duct-like recess | <.001 | If present associated with low-risk attachment |
| Variable | P-value | Type of relationship |
|---|---|---|
| Relationship between epidemiology, clinical presentation, and tumor topography | ||
| Age | <.001 | Pediatric group [0-17 years] associated with highest rate of S-SS topography |
| Hypothalamic symptoms | <.001 | Highest rate in Strict-3V PCPs |
| Psychiatric disturbances | <.001 | Highest rate in Strict-3V and Not-Strict-3V PCPs |
| Infundibulo-tuberal symptoms | <.001 | Highest rate in Not-Strict-3V PCPs |
| Endocrine deficits | <.001 | Highest rate in S-SS and Pseudo-3V PCPs |
| Visual impairment | <.001 | Lowest rate in Strict-3V PCPs |
| Relationship between MRI signs and PCP topography | ||
| Chiasmatic cistern | <.001 | Tumor free associated with Strict-3V PCPs |
| Pituitary appearance | <.001 | Normal (wholly visible) associated with Strict-3V PCPs |
| Chiasm morphology | <.001 | Normal and compressed downward associated with Strict-3V PCPs |
| Hypothalamus position | <.001 | Below lower third associated with Strict-3V PCPs |
| Mammillary body angle | <.001 | Hyperacute (<30°) associated with Not-Strict-3V topography |
| Hydrocephalus | <.001 | If present associated with Strict-3V PCPs |
| Tumor consistency | <.001 | Solid associated with Strict-3V topography |
| Basal duct-like recess | <.001 | If present associated with Strict-3V topography |
| Relationship between tumor pathological features and clinical presentation | ||
| Hydrocephalus | .001 | If present associated with psychiatric disturbances |
| Hypothalamic edema | .043 | If present associated with psychiatric disturbances |
| Presence of ciliated/goblet cells | <.001 | Highest rate in S-SS topographies below an intact 3V floor |
| Tumor consistency | .009 | Cauliflower-like or upper cystic and basal solid with psychiatric disturbances |
| Tumor size | .004 | PCPs ≥3.5 cm associated with psychiatric disturbances |
| Basal duct-like recess | .030 | If present associated with psychiatric symptoms |
| <.001 | If present associated with solid/round PCPs | |
| Clinical, radiological, and pathological factors associated with the severity of PCP adherence to the hypothalamus | ||
| Hypothalamic symptoms | .032 | If present associated with high-risk adhesions to the hypothalamus |
| Infundibulo-tuberal symptoms | .001 | If present associated with high-risk adhesions |
| Visual impairment | <.001 | If present associated with high-risk adhesions |
| Tumor consistency | <.001 | Solid PCPs associated with low-risk adhesions |
| Tumor size | .006 | Tumors ≥3.5 associated with high-risk adhesions |
| Tumor topography | <.001 | Strict-3V and S-SS topographies with low-risk hypothalamic adhesions |
| Pituitary stalk appearance | <.001 | Normal (wholly visible) with low-risk adhesions |
| Hypothalamus position | <.001 | Around middle third associated with high-risk adhesions |
| Hypothalamic edema | .003 | If present associated with high-risk adhesions |
| Basal duct-like recess | <.001 | If present associated with low-risk attachment |
Abbreviations: 3V, third ventricle; 560c, cohort of 560 well-described individual papillary craniopharyngioma patients; MRI, magnetic resonance imaging; PCP, papillary craniopharyngioma; S-SS, sellar-suprasellar.
Endocrine Symptoms in PCPs
Endocrine deficits are a primary manifestation of CPs, present at diagnosis in 52% to 87% of patients overall (141). Nevertheless, their incidence is lower in PCPs than in ACPs, occurring in only 10% to 50% of PCP patients (20, 35, 39, 107, 109). Likewise, preoperative endocrine alterations were reported in roughly 30% of PCPs in the 560c. Such a reduced rate can be explained by the anatomical integrity of the pituitary stalk (PS), observed in 69% of CPs with a papillary histology (97). Pituitary gland dysfunction is usually caused by the tumor mass effect on the PS, which blocks the downward blood flow of portal veins along the PS and/or the invasion of the ME, which interrupts the axonal contacts of neuroendocrine hypothalamic cells with the capillary network (234, 235). Both mechanisms prevent the action of the hypothalamic-releasing hormones (GHRH/TRH/CRH and GnRH) that control the synthesis and release of adenohypophyseal hormones (somatotropin/ACTH/TSH and LH/FSH) (234, 235). Endocrine deficits caused by CPs can either be partial, when affecting only some of the pituitary hormonal secretions, or complete, leading to panhypopituitarism. The latter also represents the major sequelae after a radical CP resection, which usually implies the PS severing (including its upper infundibular portion) infiltrated by the tumor (6, 32, 72).
The type of preoperative endocrine deficit also differs between PCP and ACP patients. GH deficiency represents the most common type of endocrine dysfunction found in the pediatric CP population (75%), a finding related to the lower anatomical level of injury caused by ACPs (at the pituitary gland and/or lower portion of the PS). By contrast, hypogonadism of a hypothalamic origin and arginine vasopressin deficiency (AVP-D) predominate in PCP patients due to the frequent primary encroachment of the infundibulum by this histological CP type. The usually preserved pituitary function of the adrenal and thyroid axes among PCPs is probably associated with such a high anatomical position of these lesions, close to the 3V. In agreement, in the series of 226 CPs reported by Pan et al panhypopituitarism was only present preoperatively in 20% of subpial-3V CPs, whereas this rate increased to 40% in children with infradiaphragmatic ACPs (53). Likewise, symptomatic endocrine alterations were also higher in the group of pediatric patients of the 560c (39.5%, P < .001), as half of their tumors originated below the 3VF, within the sellar and suprasellar compartments.
Hypogonadism in PCPs
Hypogonadism (deficit of gonadotropins, LHs/FSHs) leading to amenorrhea, impotence, loss of libido, and infertility represents the main endocrine dysfunction in adult-onset CPs, including PCP patients (72, 107, 141). Hypogonadism was reported in 55% to 70% of the 99s (46, 64, 75, 78, 109). An even higher rate (80%) was observed among CPs developed primarily at the 3VF or within the 3V (37), a fact related to the ME encroachment by the tumor. Gonadal function and fertility depend on the fine-tuned pulsatile activity of a small population of GnRH cells (GnRH neurons) in the medial preoptic area and the infundibular (arcuate) nucleus. From these periventricular hypothalamic structures, both GnRH neurons pools establish a complex network of axonal contacts with fenestrated capillaries, glial cells, and tanycytes in the ME (213, 236-238). Plastic changes in the morphological configuration of the tanycytes’ end-feet engulfing GnRH neuron terminals regulate the release of GnRH into the portal blood circulation (211, 239). This mechanism is irreversibly damaged by PCPs developing at the infundibulo-tuberal region or by those strictly 3V lesions severely compressing the ME (37, 38, 54, 238). Tuber cinereum damage also interrupts the axonal terminals from kisspeptin neurons of the infundibular (arcuate) nucleus. These fiber projections, which form part of the tuberoinfundibular tract, are essential for the proper pulsatile activity of the hypothalamus-pituitary-gonadal axis (212, 236). Surgical injury of this delicate area causes a 3VF breach, an anatomical sequela that can be identified on postoperative MRI scans following radical excision of infundibulo-tuberal PCPs (38, 141, 218, 240).
Hypogonadism of hypothalamic origin secondary to an injury to the infundibulo-tuberal region is often accompanied by hyperprolactinemia, which has been reported in 45% to 47% of adult CPs (93, 107). Postoperatively, no significant change in the rates of hyperprolactinemia were observed in these 2 studies, but the rates of secondary adrenal insufficiency and hypothyroidism dramatically increased (from 6-25% to 65-80%, respectively) owing to the PS sectioning. This finding supports the primary hypothalamic origin of gonadotropin/prolactin alterations in PCPs. Accordingly, in the series by Zhou et al hypogonadism was maintained in 4 out of 9 strict 3V PCPs with an intact PS beneath the lesion (102).
Arginine vasopressin deficiency in PCPs
AVP-D, formerly known as diabetes insipidus, is also an endocrine deficit showing a higher incidence in the papillary CP type, probably due to the anatomical involvement of the infundibulo-tuberal area (38, 241). Both pre- and postoperative AVP-D rates were significantly higher in PCPs (34% and 65%, respectively) than in ACPs in the systematic neuroendocrine assessment of 741 CP patients (119 PCPs) by Feng et al (72). Likewise, in the 2023 analysis of pituitary deficits in a surgical series of 742 CPs by Guo et al, significantly higher rates of AVP-D (37% vs 21%) and hyperprolactinemia (45% vs 33%) occurred in PCPs compared to ACPs (107).
Hypothalamic Syndrome in PCPs
Anatomical Basis and Classification
PCPs specifically affect the hypothalamus, both anatomically and functionally (242). Their usual development at the infundibulo-tuberal region of the 3VF and subsequent expansion within the 3V cavity makes this CP type more prone to inflict severe anatomical distortion and dysfunction on the adjacent hypothalamic nuclei and pathways (23, 37, 38, 62, 84, 96, 97, 106, 109). Widespread functional hypothalamic impairment leads to a complex set of symptoms known collectively as hypothalamic syndrome (242, 243). PCPs may disrupt up to 6 major different categories of homeostatic hypothalamic functions: (1) pituitary-gland endocrine output; (2) autonomic control of body temperature, blood osmolarity, and visceral functions; (3) regulation of body energy status and food intake; (4) circadian control of the sleep-wake cycle; (5) reproductive functions and sexual behavior; (6) primary emotional responses (anger/fear/anxiety/apathy) to stimuli from the outer world and their associated behaviors (aggression vs flight; motivation vs indifference) (234, 244, 245). These functions totally depend on the continuous monitoring of body temperature, blood osmolarity, energy status, and hormonal balance by the circumventricular organs, a set of neurovascular structures around the 3V with capillaries lacking a blood-brain barrier (234, 244-247). Among these organs, the ME, the structure immediately above the infundibulum from where the hypothalamic-releasing neuropeptides governing pituitary function are released into the portal system, is critically impaired by PCPs expanding within the 3VF (210, 248).
Hypothalamic disturbances are highly prevalent among PCP patients, involving 44% of the 99s cohort and 63% of the 560c. Depending on the level of anatomical damage along the hypothalamus-pituitary axis, the symptoms of hypothalamus dysfunction can be grouped into 2 major syndromes (Fig. 6):
Infundibulo-tuberal syndrome (ITSd): includes the hypothalamic dysfunction specifically associated with injury to the ME and adjacent tuber cinereum, structures whose damage prevents them from releasing the peptides that govern pituitary function (GHRH, GnRH, TRH, CRH, somatostatin, and dopamine), leading to excessive fatigue and central hypogonadism, in addition to AVP-D, excessive hunger, weight increase, and disruption of the circadian sleep-wake cycle with abnormal diurnal somnolence (38, 241, 242, 249). Symptoms of ITSd occurred in 38.3% of patients in the 560c, with abnormal diurnal somnolence, AVP-D, and obesity affecting 18.7%, 16%, and 12%, respectively.
Hypothalamic syndrome (HySd): in a restrictive sense, it includes the symptoms associated with a bilateral injury to the hypothalamic regions above the 3VF, among them the preoptic and anterior hypothalamic regions; the ventromedial, dorsomedial, and paraventricular (PV) nuclei; and the lateral and posterior hypothalamus, including the fornices and mammillary bodies (MBs) (241, 242). Characteristic symptoms of this HySd are a multifaceted set of neuropsychological and psychiatric disturbances, observed in 30% and 43.3% of PCP patients in the 99s and 560c cohorts, respectively. Among them, a severe memory deficit is the most frequent alteration, present in 30.6% of patients, followed by a general cognitive impairment mimicking dementia (16%) and a wide range of odd behaviors and personality changes (15%) (Fig. 2C).
The HySd in PCP patients, however, largely depends on tumor topography (P < .001, Table 7). The strictly 3V category shows the highest rate of hypothalamic disturbances (96, 97), particularly the subgroup having a basal duct-like recess (67.5%) (95). Another important variable related to the development of HySd is the presence of high-risk, strong CP adhesions to the 3VF/walls (38, 54, 97). Finally, PCPs at an advanced age may cause a total impairment of hypothalamic functions, including severe amnesia and disorientation (25%), disruption of the sleep-wake cycle (25%), hyperphagia (14%), and hypo/hypernatremia (4%) (86).
Assessment and Grading System of Hypothalamic Disturbances
Historically, the lack of a standardized system for diagnosing and classifying the hypothalamic disturbances associated with CPs has hampered a proper assessment of these symptoms (141, 243). In 2016, Pan et al designed a hypothalamus status score (HSS), which differentiates 4 severity grades of hypothalamic dysfunction: grade 1, normal hypothalamus function; grade 2, overweight with a body mass index (BMI) between 25 and 30 kg/m2; grade 3, obesity (BMI > 30) or overweight without hyperphagia and/or a change in affective behavior or memory; and grade 4, includes obesity and hyperphagia and/or cognitive dysfunction, impaired thirst, disturbed thermoregulation, and sleep-wake cycle disruption (53). This scoring system revealed the existing correlation between CP topography and the degree of hypothalamic injury, the subgroup of 3V CPs with a subpial origin at the 3VF (82% of them PCPs) being the topographical category associating a worse postoperative HSS (HSS grades 3 or 4 in 40%). An ulterior analysis of their series showed a better HSS outcome for those T-type or infundibulo-tuberal PCPs removed through a transcranial approach (HSS 3 or 4 in 38%) than through the EEA (HSS grades 3 or 4 in 60%) (83). The HSS was also employed in the series of 20 3V PCPs by Chen et al in which all but 3 patients presented hypothalamic disturbances of at least grade 2 (55%) or higher (35%) after surgery (GTR 80%) (106). An expansion of the HSS including 6 functional categories has shown a significantly higher incidence of hypothalamic dysfunction after surgery in PCPs (64%) than in ACPs (43%) (72).
A topographical qualitative classification of hypothalamic injury (HI) was designed by Yang et al in 2020 (80). In this scheme, a unilateral or bilateral HI (30%) in PCPs associated higher rates of hypopituitarism (80%) and postoperative hypernatremia (55%) than those observed among cases without HI (20% and 16%, respectively) (80). The postoperative weight gain and abnormal sleepiness were also more severe in patients with a unilateral or bilateral HI. In 2023, Guo et al used a neuroendocrine dysfunction scale, which assesses 10 different hypothalamic-pituitary functions to show that half of PCPs presented hypothalamic disturbances involving 1 to 3 functions, with only 21% having normal hypothalamic function (107). The neuroendocrine dysfunction scale + score increased significantly in most patients after GTR (82.5%), with only 5% of them showing normal hypothalamic function after surgery. Nevertheless, preservation of hypothalamic-pituitary functions postoperatively was more favorable in PCP than ACP patients (107).
Hypothalamic Obesity in PCPs
CPs involving the hypothalamus may cause progressive weight gain from lowered metabolism and dysregulated satiety (234, 243, 250-252). In childhood, obesity and hyperphagia affect 20% to 35% of ACP patients preoperatively and up to 80% after GTR (141, 253, 254). The incidence and outcome of obesity in adult PCP patients have not been thoroughly addressed. In 2010, van Gompel et al observed postoperative obesity in 46% of adult CP patients, an incidence related to the degree of HI (255). This relationship was confirmed in the series by Mende et al (42% of HySd when hypothalamic involvement occurred vs only 27% when the hypothalamus remained anatomically spared) and in the series by Bobeff et al (n = 111 CPs, 16 of them PCPs), which showed that the weight gain significantly depended on the degree of hypothalamus distortion caused by the tumor and on a CP diameter larger than 3.5 cm (77, 105). The 2023 meta-analysis comparing the clinical outcome between pediatric and adult CP patients conducted by Pang et al, which included 4202 cases (230 of them PCPs), showed a significantly higher incidence of postoperative obesity in adults (36%) than in children (11%) (108). This lower obesity rate among children must be related to hypothalamus-sparing surgery protocols in most pediatric centers (141, 218, 254, 256). The long-term weight gain assessment in the series of 91 adult CPs by Dogra et al observed morbid obesity and overweight in 39% in 41% of patients, respectively, but only a minority corresponded to PCPs (14%) (93). The information available in the 99s indicates a lower rate of obesity for PCPs than for pediatric ACPs, in a range between 15% and 30% (64, 77, 79, 86, 97, 107). Nevertheless, in the large PCP series of 101 patients published by Jia et al in 2023, obesity was not clearly observed in any patient, and only moderate weight gain occurred in the subgroup of 3V PCP patients (109).
Anatomical injury to the ME and the adjacent infundibular (arcuate) nucleus is the fundamental causal factor of hypothalamic obesity in both pediatric and adult CP patients (52, 53, 79, 105, 240, 253). These 2 structures monitor the blood levels of nutrients, insulin, and appetite-regulating peptides released by adipose tissue (leptin) and the gastrointestinal tract (ghrelin, cholecystokinin, peptide YY). Through this information the hypothalamus triggers feelings of hunger or satiety, thus influencing food intake and body weight (212, 234, 242, 243, 250-252, 257). CP destruction and replacement of the ME prevents the hypothalamus from activating the satiating signals necessary to keep body weight within normal limits (210, 211, 250, 252, 258). In addition, CPs involving the hypothalamus induce an inflammatory process and the formation of a glial scar at the medio-basal hypothalamus, which has been shown to contribute to obesity (259-261). In support of this primary hypothalamic dysfunction as the origin of the ITSd associated with CPs, the symptoms of obesity, hypogonadism, and AVP-D remained after radical surgery in 50% to 66% of the patients despite PS preservation (32, 66).
Postoperative obesity occurs in 30% to 70% of adult CP patients (77, 80, 105). No significant change in the preoperative obesity has been observed after radical removal of PCPs overall (60, 70). Surprisingly, the preoperative BMI value has shown to be inversely associated with weight gained postoperatively; that is, patients with a normal weight or mildly overweight preoperatively showed a higher BMI increase after tumor removal than those already obese before surgery (82). This has been confirmed in the follow-up assessment of PCP patients (n = 12) conducted by Dogra et al who evidenced a significant postoperative weight increase (BMI increase > 5%) in 60% of them, the risk of weight gain being higher when the patient was of normal weight preoperatively, 20 kg on average vs only 13 kg in previously obese patients (93). CP invasion of the whole hypothalamus, including the region posterior to the MBs, correlates with a higher rate of pre- and postoperative obesity than what is observed for tumors involving only the infundibulo-tuberal region anterior to the MBs (262).
Disruption of the Sleep-wake Circadian Rhythm and Thermoregulatory Dysfunctions
Impaired thermoregulation and alterations of the normal sleep-wake cycle are 2 core symptoms of hypothalamic dysfunction that may affect PCP patients but are often underdiagnosed and undertreated (263-265). The hypothalamus regulates the circadian sleep-wake rhythm through the interactions between two mutually inhibitory regions: (1) a sleep-promoting region in the ventrolateral preoptic (VLPO) nucleus that triggers sleep by inhibiting the ascending arousal system and (2) a wakefulness-promoting area formed of a population of histaminergic neurons in the tubero-mammillary (TM) nucleus of the 3VF, and another population of orexin (or hypocretin) neurons in the lateral hypothalamic area (266, 267). The efferent networks of these 2 neuron populations promote wakefulness through their inhibitory action on the VLPO nucleus and excitatory activation of the cerebral cortex. CPs primarily involving the hypothalamus damage the intrahypothalamic inhibitory axonal networks from both the histaminergic and orexigenic neuronal groups, leading to overactivation of the VLPO nucleus and hypersomnolence, observed in up to 45% of patients (263, 268). Accordingly, the sleep disorder caused by CPs usually manifests as a central hypersomnia, characterized by excessive daily somnolence interspersed with sudden sleep-onset rapid eye movement (REM) episodes associating hypnagogic hallucinations that resemble narcolepsy (265). In the 560c, abnormal diurnal somnolence was reported in 19% of patients, this rate increasing to 25% in elderly patients (86). Polysomnographic analyses of sleep disturbances in some CP patients have revealed a diagnostically challenging form of presentation as seizure-like episodes of psychomotor slowing, temporal/spatial disorientation, chaotic limb movements, and oneiric hallucinatory phenomena, coincident with a sudden activation of sleep-onset non-REM and REM periods (264). Another sleep disorder causing drowsiness and sleep fragmentation in CP patients is the loss of the normal sleep-wake circadian rhythm, which is regulated by the pulsatile action of melatonin released by the pineal gland on the suprachiasmatic nucleus (264, 266, 269). This sleep disorder, known as irregular sleep-wake rhythm disorder, can be associated with the tumor blocking the infundibulo-tuberal region containing neuronal populations rich in melatonin receptors that regulate the sleep-wakefulness circadian rhythm (265, 270).
Body-core temperature (BCT) is held relatively constant through the active monitoring of cold- and warmth-sensing neurons in the median preoptic nucleus, adjacent to the lamina terminalis (234). This nucleus activates autonomic responses that control the blood supply to the subcutaneous vascular bed, sweat gland secretion, piloerection, thermogenesis in brown adipose tissue, as well as shivering. CPs expanding within the 3V may injure the preoptic area leading to central malignant hyperthermia as high as 43 °C and resistant to conventional antipyretic therapy (121, 264, 270-272). Hypothalamic thermoregulatory disturbances have been recorded in 6.6% of the PCP patients in the 560c. Hyperthermia of a hypothalamic origin associated with CPs can be ameliorated with chlorpromazine and bromocriptine (270, 272). The only systematic monitoring of BCT and sleep-wake rhythm disruption in PCP patients has been done by Zoli et al, who identified an abnormal BCT pattern throughout the day in 4 of 5 adult patients (80%), all with strictly 3V CPs (57). Sleep-wake rhythm disturbances associating with an increased number of diurnal naps also occurred in 4 strict 3V PCP patients, with BCT disturbance coexisting in 3 of them. Sleep alterations were also observed in infundibulo-tuberal ACP patients, suggesting that the injury to the 3VF structures implicated in sleep regulation, such as the histaminergic TM nucleus, could be involved in this alteration (57).
Psychiatric Symptoms in PCP Patients
As a group of tumors primarily involving the hypothalamus, PCPs represent a neurobiological model of cognitive and psychiatric disturbances (67, 242). These mental alterations have been repeatedly reported in the medical literature, both in individual CP cases and in large CP series (3, 4, 23, 67, 124-127, 273-280), with an incidence ranging from 10% to 60% of patients overall. Neuropsychological disturbances are especially prominent among PCP patients over 65 years of age, with 35% of them showing cognitive/memory impairment and 23% behavioral/personality changes (86). A 2023 meta-analysis comprising 4202 CPs (230 PCPs) showed that cognitive impairment in adult patients tripled the incidence observed in the pediatric population (19.5% vs 6.5%) (108). Psychiatric disturbances occurred in 30% of patients among the 29 CP series of the 99s including PCP cases. This rate increased to 43% among the individual PCP reports of the 560c.
Clinical Assessment and Classification
In 2018, Pascual et al completed the first systematic analysis of psychiatric disturbances in CP patients in a cohort of 210 well-described cases, including 63 PCPs (38%) (67). The repeated patterns of neuropsychiatric disturbances were classified into 6 major types of disorders: (1) disorders of emotional expression or control, such as irritability states with unmotivated rage fits or apathetic states devoid of emotional expression; (2) mood disorders, from hypomania to depression, including anxiety; (3) personality and/or behavioral changes, including self-indifference, childish and/or moria-like behavior with inappropriate social interactions; (4) memory defects, from short-term amnesia to a severe Korsakoff-like syndrome, characterized by time/place disorientation and confabulation; (5) cognitive impairment, from bradypsychia to a dementia-like status with irrational speech and behavior; and (6) psychotic disturbances, including delusional ideations and visual/auditory hallucinations (67). This classification matched with equivalent categories of psychiatric disturbances defined in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (281). Notably, PCP patients in Pascual et al's cohort associated a significantly higher rate of memory defects (78%) and cognitive impairment (56%) than those manifested by ACP patients, a result plausibly related to the usual 3V location of the former type (67).
For a proper clinical assessment of these neuropsychological/psychiatric disturbances, Zhao et al have proposed a neuropsychiatric inventory questionnaire, which includes 12 symptomatic categories: delusions, hallucinations, agitation, depression, anxiety, elation, apathy, disinhibition, irritability, motor disturbance, night-time behavior, and appetite behavior (90). In their cohort of 173 surgically treated adult CP patients from 2018 to 2020 (including 42 PCPs), psychiatric disturbances affected 14.5% overall (90). This rate was slightly higher among PCPs (16.5%), but the incidence markedly increased in the subgroup of 17 CPs with a strict 3V topography (47%). Irritability was the most frequent alteration, found in 64% of patients, followed by agitation in 36% and delusions in 28%. As in the prior studies, the factors that significantly influenced the manifestation of psychiatric disturbances were a tumor volume larger than 7 cm3 (23%), a strict 3V topography (47%);,CP invasion of the hypothalamus (21%), and radical tumor resection. This study demonstrated that it was not the histological CP type per se but the tumor extension into the 3V/hypothalamus that was the major factor related to the hypothalamus dysfunction causing the appearance of psychiatric alterations in PCP patients (90).
Neurobiological Basis of Psychiatric Disturbances in PCPs
The psychiatric disturbances caused by PCPs involving primarily the 3V provide valuable insights into understanding the neurobiological basis of a model of hypothalamic dysfunction for these disorders (67, 242). This model is based on an impaired integration of hypothalamic-controlled emotional and behavioral responses to potentially harmful situations (273, 282-285). Among them, the disruption of the intricate multisynaptic connections between the hypothalamus and the hippocampus, amygdala, and cingulate cortex, the structures that form the limbic system (the border or limbus around the diencephalon), as well as the medial basal prefrontal cortex, has been shown to greatly contribute to cognitive impairment, mnesic deficits, emotional disorders, and abnormal behaviors observed in PCP patients (283, 284).
Psychiatric disturbances of hypothalamic origin are directly related to the topographical expansion of PCPs within the infundibulo-tuberal region and 3V (96, 97, 187, 242). In a multivariate diagnostic model to accurately predict CP topography, psychiatric disorders represented the only clinical variable relevant to a reliable preoperative prediction of the anatomical CP-hypothalamus relationship (223). Specifically, the highest rate of psychiatric symptoms occurred in the subgroup of PCPs showing a strict 3V topography, in which they affected between 35% and 60% of patients (37, 44, 64, 91, 95-97, 106). Likewise, in the 560c, the rate of psychiatric disturbances was significantly higher in those PCPs with a strict 3V topography (54.7%, P < .001) than in cases with other topographies. As strictly 3V PCPs do not usually infiltrate or invade the hypothalamus, psychiatric disorders must be causally linked to the mechanical distortion of the hypothalamic nuclei and pathways adjacent to the 3V walls and floor, especially the impairment of the Papez circuit, formed by the reciprocal connections between the fornices, MBs, thalamus, and cortical regions of the limbic system (Fig. 7) (23, 54, 67, 95-97, 242). All these structures are involved in processing the 2 main emotional drivers that govern active behaviors: motivation and reward (283-285). The associated peritumoral edema, observed in up to 30% of PCPs, and ischemia derived from the occlusion of perforating vessels supplying the hypothalamus are certainly implicated, given the irreversibility of the symptoms in many patients after seemingly safe surgical resections (199, 286).
Pathogenesis of mental disturbances caused by papillary craniopharyngiomas. (A) The hippocampal formation and cingulate gyrus are 2 structures of the limbic system bidirectionally connected through a loop circuit (Papez circuit), that are involved in memory. The fornices and MBs are critical components involved in the temporary storage of memories linked to emotional experiences. Bilateral damage of these structures may cause a definitive Korsakoff-like memory deficit characterized by anterograde amnesia, disorientation, and confabulation. Injury to the connections between the hypothalamus and the amigdala through the VAF impairs the proper-emotional responses of fear and anxiety, causing chronic anxiety and avoidance of normal social interactions. Irritative activation of the MFB, a bilateral loose axonal bundle running through the LHA that provides the main neuromodulatory dopaminergic input to the hypothalamus, septal region, and medial prefrontal cortex, may lead to psychotic symptoms such as delusions and hallucinations. By contrast, injury or inactivation of this structure gives rise to indifference and apathy. Finally, injury to the stria terminalis, the major axonal output pathway of the amygdala, is related to anxiety responses to acute stress and behavioral disinhibition. (B) Basal view of the brain undersurface (middle panel) and coronal sections of the hypothalamus through the IT (left panel) and MB (right panel) regions, showing the main hypothalamic nuclei and pathways that may result impaired by PCPs and give rise to hypothalamic/psychiatric symptoms. (C) Location and extension of the lesions underlying the major mental symptoms grouped in the IT and the hypothalamic (Hp) syndromes (sd) are indicated by black circles. Somnolence (abnormal diurnal hypersomnia) is related to injuries to the TM (histaminergic) and LHA (orexin/hypocretin neuron population). Rage attacks are related to bilateral damage of the VM. Memory disturbances mimicking Korsakoff syndrome are caused by damage of the MBs and fornices (F). Apathy is caused by injuries to the MFB along the lateral hypothalamic area.
Abbreviations: 3V, third ventricle; AC, anterior commissure; DA, dopaminergic nuclei in the ventral tegmental area; DLF, dorsal longitudinal fasciculus of Schütz; Hy, hypothalamus; IT, infundibulo-tuberal; LHA, lateral hypothalamic area; MB, mammillary body; MBint, intermediate mammillary nucleus; MBlat, lateral mammillary nucleus; MFB, middle forebrain bundle; MTg tract, mammillotegmental tract; MTh, mammillothalamic tract; OT, optic tract; PeV, periventricular nucleus; PH, posterior region of the hypothalamus; PV, paraventricular nucleus; SO, supraoptic nucleus; TM, tuberomammillary nucleus; VAF, ventral amygdalofugal pathway; VM, ventromedial nuclei.
Cognitive impairment
A severe impairment of cognitive abilities is reported in 15% to 33% of adult CP patients (22, 44, 62, 64, 86, 89, 93, 94, 97, 98, 102) and in up to 60% of PCPs developed within the 3V (37, 67, 70, 95, 96, 109). This hypothalamus-related cognitive decline is characterized by deficient self-control and impulsive childish-like behavior resembling what is observed after orbital-medial frontal lobe damage (242, 280). Although the exact neural substrate of these disturbances is unknown, neuroimaging evidence links CP-associated cognitive impairment with a dysfunction of the default mode network (DMN) in the frontal-limbic brain regions, an intrinsic functional cerebral network independent of external stimuli that is active during self-generated thought (287-290). Abnormal overactivity of the DMN contributes to negative self-referential thoughts and chronic mood disturbances observed in depressed patients. PCPs expanding within the 3V may cause demyelination of the fornices and disruption of both the normal hippocampal-medial temporal lobe connections and the amygdalofugal ventral pathway, 2 essential subsystems of the DMN (287, 288). These alterations typically lead to working memory deficits and induce severe chronic mood changes such as depression (291). An injury to the TM nuclei situated in the posterior basal hypothalamus, the source of the histaminergic input to the limbic system and cerebral cortex, can also be involved in the diminished arousal, attention deficit, impaired cognition, and autistic-like behaviors observed in patients with 3V PCPs (292).
Memory deficits
Memory impairment is the most prevalent neuropsychological disturbance observed in PCP patients. Amnesia was a prominent symptom, present in 69% of the patients with mental alterations in the 560c and in 77% of PCP cases in the study by Pascual et al (67). The severity of this symptom may vary from a simple anterograde short-term amnesia, characterized by the inability to recall recent events, to a severe confusional state with temporal-spatial disorientation and confabulation, mimicking Korsakoff syndrome, recorded in 55% of PCP patients in Pascual et al cohort (67, 293, 294). Injuries to the fornices, MBs, and mammillo-thalamic tracts are all involved in the genesis of amnesia in PCP patients (Fig. 7) (67, 274, 295, 296). Among these diencephalic structures, all critical for temporary memories storage and short-term recall, the encroachment on MBs by CPs expanding within the 3VF is considered the main pathological substrate of the Korsakoff-like type of amnesia in these patients (38, 223, 278, 293, 297, 298). Notably, among the 101 PCP cases in the series by Jia et al, tumor topography was the main factor predicting memory alterations, with amnesic deficits increasing from only 8% in the group of sellar-suprasellar tumors to 63% in strict 3V PCPs (109). MBs play a central role in modulating the hippocampal-cortical oscillatory theta activity, which is critical for learning-induced plasticity (299, 300). Damage to MBs specifically impairs the hippocampal-cortical encoding processes needed to contextualize events within their proper spatial-temporal frame, dependent on the individual's subjective point of view (301-303). Therefore, this diencephalic type of amnesia associated with the injury and atrophy of MBs caused by 3V PCPs leads to an inability to recall episodic events while sparing the recognition of familiar contexts (304, 305).
Emotional instability
Emotional lability with abnormal reactions ranging from unpredictable outbursts of rage to a permanent apathetic status are typically associated with PCPs involving the 3V. They occurred in 34% of patients with psychiatric disturbances in the 560c and in 47% of PCPs in the series by Pascual et al (67). Unprovoked fits of rage accompanied by violent behavior, hyperphagia, and obesity can be observed after bilateral lesions of the ventromedial hypothalamic region (67, 285, 306, 307). A specific group of hypothalamic neurons in the ventromedial hypothalamic region has been shown to be essential for the expression of stereotyped instinctive aggressive behaviors in males (308). Opposite from emotional irritability is apathy, the incapacity to react emotionally to stimuli, observed in 25% of PCP patients in the Pascual et al series (67, 242, 309, 310). This symptom is plausibly associated with the functional impairment of the medial forebrain bundle, a bilateral axonal tract crossing the lateral hypothalamic area that includes the mesolimbic and mesocortical pathways and provides dopaminergic input from the midbrain to the accumbens nucleus, septal region, ventral striatum, and orbitomedial prefrontal cortex (Fig. 7) (311). These regions are involved in regulating motivational states and promoting behaviors linked to expected pleasurable experiences and rewards, such as those obtained with food and sex (311, 312). Mesolimbic and mesocortical pathway dysfunction within the hypothalamus can also be implicated in causing psychotic delusions and hallucinations, observed in 10% to 15% of PCP patients with psychiatric disturbances, due to the imbalance or increased activity of dopaminergic and serotonergic inputs to the prefrontal cortex and limbic regions (313).
Mood disturbances
Depression was the most prevalent mood alteration among CPs in patients over 65, affecting 18% in this age group (86). It was also observed in half of the 12 strict 3V PCPs reported by Cao et al, either isolated or accompanied by anxiety (91). Surgery did not resolve depression in most cases. Rather, depression was replaced by manic reactions or even delirium in the postoperative period in half of the patients, suggesting a hypothalamic upregulation of the emotional baseline status, previously decreased or inhibited by the tumor. Mood disorders, in particular episodes of major depression and anxiety, are known to be associated with the dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis (314, 315). HPA dysregulation is characterized by deficient negative feedback of circulating cortisol on the PV nuclei, the hypothalamic sources of CRH, leading to an excessive central secretion of CRH (283, 284, 315, 316). Through a blocking effect on the CRH release into the ME, infundibulo-tuberal CPs stimulates CRH hypersecretion by the PV nuclei and dysregulation of the HPA axis, a mechanism contributing to the appearance of mood disorders in these patients (67, 242).
Personality and behavioral changes
PCPs primarily involving the hypothalamus can cause serious personality changes and behavioral disturbances by interfering with the hypothalamic oxytocin pathway, which releases oxytocin produced by the supraoptic (SO) and PV nuclei into the amygdala, hippocampus, nucleus accumbens, and cerebral cortex (315, 317, 318). This pathway modulates social cognition and behavior through recognizing and expressing emotions, thereby contributing to the regulation of the anxiety associated with the development of social and affective bonds among individuals (319). Hypothalamic oxytocin released into the central nucleus of the amygdala reduces fear responses to threatening stimuli and produces a marked anxiolytic effect to promote sociability (315, 320). Oxytocin pathway dysfunction is associated with defective recognition of facial emotions and has been implicated in causing social anxiety disorder as well as odd, eccentric antisocial behaviors, in which the social cues are interpreted as unsafe (321, 322). Intraventricular PCPs may induce these behavioral disturbances by blocking the inhibitory effect of oxytocin on the release of CRH by the PVN in response to stress (67, 242, 320). A pilot study in 10 pediatric ACPs suggested that intranasal administration of oxytocin might enhance emotion recognition in patients with postoperative hypothalamic lesions limited to the anterior area (323).
PCP Diagnosis: The Revealing MRI Signs
The increasing use of MRI in the 1990s revolutionized CP diagnosis, particularly for the PCP type. The usual lack of calcifications and location within the 3V made these lesions go unnoticed on plain radiographs, a fact largely contributing to them not being recognized during the pre-MRI era (7, 10, 11, 13). Moreover, the ability of MRI to accurately define the anatomical relationships between the tumor and the hypothalamus-pituitary axis in 3 spatial dimensions was fundamental for an accurate topographical diagnosis (324-326). Up to this point, CPs were grouped within the category of “suprasellar lesions,” an imprecise term that dates back to the early 20th century, when the identification of calcifications above the sella turcica on skull radiographs was the only reliable sign for establishing a CP diagnosis (10, 327, 328). Use of the term “suprasellar” blinds us to the true relationship between CPs and the hypothalamus, as it suggests a primarily extra-ventricular location (23, 142, 329). The first MRI study assessing CP topography was published by Charles Raybaud in 1991, who demonstrated that most tumors were centered at the level of the 3VF (infundibulo-tuberal CPs) (330). Subsequent studies showed that over 50% of CPs in adults primarily grow in the 3V, either with an infundibulo-tuberal topography (largely but not strictly intraventricular, originated within the 3VF and replacing this structure while extending both into the 3V and towards the suprasellar cistern), observed in 40% of patients, or developing purely within the 3V, above an intact 3VF (strict 3V CPs), in 5% of cases (38, 53, 84, 96, 105, 219). These represent the 2 most common topographies of the papillary CP type, ranging from between 65% and 90% of cases in the 99s (37, 44, 63, 91, 97, 106, 109). The correct preoperative distinction between the 2 locations is invaluable for adequate surgical planning and patient counseling due to their different relationships to the hypothalamus, which is usually strongly adhered to the tumor or infiltrated by it in not strictly PCPs, while easily dissectible from strict 3V PCPs.
Essential MRI Signs for Accurate PCP Histological Definition
The identification of the canonical V600E mutation in the BRAF gene and its potential use as a precision target for PCPs, has spiked interest in learning more accurate MRI clues to reliably define them. Correct preoperative definition of the CP type may obviate the need for tumor biopsy to confirm the histological diagnosis when surgery should be discarded as a primary treatment option, particularly in the more vulnerable elderly population (116, 135, 331). In 1997, Sartoretti-Schefer et al published the first MRI study specifically focusing on the neuroradiological features differentiating between PCPs and ACPs. This was based on 42 CPs from Yasargil's surgical series diagnosed with MRI, 15 of which corresponded to PCPs (15). The authors noted that ACPs characterized by a multilobulated shape (82%) and predominantly cystic (60%) or a heterogeneous cystic-solid consistency (30%) with nodular calcifications, while PCPs were predominantly solid (47%) and round lesions (73%) that rarely contained calcifications or occupied the sella turcica (13%) and never showed vessel encasement (15). On conventional T1W and T2W MRI sequences, most PCPs (85%) exhibited hypointense and hyperintense signals, respectively (15). Ten years later, and based on a series of 38 CPs, Lee et al identified the following specific features to reliably differentiate between PCPs and ACPs: lack of calcifications on computed tomography (CT) scans (100% in PCPs and 16% in ACPs), bright or hyperintense tumor signal on T1W MRI (20% in PCPs and 73% in ACPs), and the presence of a cystic change on T2W MRI (87% in PCPs and 100% in ACPs) (51). However, the discriminative power of these signs was notably reduced in adults, as ACPs in this age group showed lower rates of calcification (70%) and T1W bright signal (58%) (51). The 560c provides an updated morphological neuroimaging characterization of PCPs based on 301 cases with high-quality MRI studies. Contrary to ACPs, the multilobulated shape (0.9%), mixed consistency (5.7%), and presence of calcifications (3.8%) were exceptionally rare among PCPs (Table 4). Most of these lesions, however, had a round smooth shape (70.7%), which is probably not only related to intrinsic histologic features but also to the tumor growing within the 3V. Most lesions had a pure solid consistency with a corrugated/raspberry-like outline (52.1%), and 17% additional PCPs showed a solid corrugated or cauliflower-like nodule inside a round unilocular cystic component (Fig. 8).
Characteristics of PCPs in MRI. (A) Midsagittal T2W image showing a round solid strictly 3V PCP (case number 556 of the 560c). Note the 3VF as a darker grey layer below the tumor. The optic chiasm (OC) has a normal position and anatomical appearance, and the surrounding chiasmatic cistern (ChC) is tumor-free. The pituitary stalk (PS) and gland (PG) are also intact below the tumor. (B) Coronal T1W image displaying a solid strictly 3V PCP causing hydrocephalus (case 551 of the 560c). Note the round hypointense hole at the center of the tumor (thin arrow), which corresponds to the long basal recess completely identified in (C). The level of the hypothalamus is below the tumor's bottom pole (thick arrows). (C) Midsagittal Gd-T1W scan showing homogeneous tumor enhancement. Note the hypointense long recess that follows the same trajectory as the PS and extends from the suprasellar cistern to the tumor center (long arrow). The corrugated/“raspberry-like” outline can be clearly seen at the top of the tumor (short arrow). The OC is slightly compressed downward. Mammillary body angle (MBA) is 45°. (D) Axial T2W image of a PCP with cystic cauliflower-like consistency (case 560 of the 560c). It has a solid nodule (ts) inside a large unilocular cystic component (tc). Note the surrounding edema involving the hypothalamus and optic tracts (arrows). (E) Coronal Gd-T1W image of a not strictly or infundibulo-tuberal PCP with an elliptical shape and an upper-cystic and basal-solid consistency (case 558 of the 560c). Note the upper infundibular portion of the PS has been amputated by the tumor growth. The ChC is partially occupied by the tumor and the position of the hypothalamus is around the tumor's equator (arrows). (F) Midsagittal T1W image of the same case. Note the OC is compressed and displaced forward by the tumor and the MBA is hyperacute (27°).
Abbreviations: 3V, third ventricle; 3VF, third ventricle floor; 560c, cohort of 560 well-described individual papillary craniopharyngioma patients; ChC, chiasmatic cistern; MBA, mammillary body angle; MRI, magnetic resonance imaging; OC, optic chiasm; PCP, papillary craniopharyngioma; PG, pituitary gland; PS, pituitary stalk.
Some studies have focused on MRI accuracy to preoperatively predict the diagnosis of BRAFV600E-mutant PCPs (68, 73, 145, 332). Specifically, Yue et al, in a series of 52 CPs including 8 PCPs, identified 5 MRI signs that served to differentiate the papillary type: a lack of intrasellar involvement, a spherical shape, a predominantly solid consistency, a gadolinium homogeneous enhancement, and a thickened PS (68). The presence of 3 of these MRI features allowed the diagnosis of a PCP with a 100% sensitivity and 91% specificity. Fujio et al were able to correctly predict the diagnosis of BRAFV600E-PCPs with 83% sensitivity and 93% specificity by combining the patient age (older than 18 years old) with 2 simple radiological features: the absence of calcifications and a tumor location above the sella turcica (73). The critical issue, however, is to differentiate PCPs from ACPs in adult patients when their tumors have originated at the 3VF and predominantly expanded within the 3V (infundibulo-tuberal topography), because the incidence of infundibulo-tuberal ACPs in the adult population is higher than that of PCPs (37, 38, 53, 63, 91, 106). A heuristic assessment of the preoperative MRI studies of a series of 31 3V CPs, including 11 ACPs and 20 PCPs displaying similar morphological characteristics on T1W midsagittal scans, allowed Prieto et al to correctly predict the histology in 24 cases (77%) (145). This rate increased to 90% in the PCP group just by considering 2 major morphological patterns: (1) a pure solid consistency with superficial “berry-like” papillomatous excrescences or (2) a cystic consistency with a basal cauliflower-like protruding nodule at the level of the 3VF. Moreover, all PCPs had a smooth round/spherical shape and were situated above an intact, wholly visible PS (145).
The Basal Duct-like Recess Sign: A Hallmark of PCPs
In 2022, Pascual et al identified on conventional MRI studies a novel morphological sign pathognomonic of PCPs, known as a “basal duct-like recess” or “basal diverticulum.” This is a hollow tubular structure, either a duct-like or a shallow canal-like recess, at the tumor's basal midline just above the contact point between the tumor and the PS that follows the same trajectory as the stalk on sagittal images (Fig. 8C) (95, 333). On axial or coronal MRI T1W scans, the basal-recess sign appears as an hypointense central circular spot within the tumor bulk (Fig. 8B) (132, 334). The exact nature of this tubular structure is currently unknown, although its homogeneous hypointense signal on T1W and hyperintense signal on T2W sequences is identical to the cerebrospinal fluid (CSF), thus its content plausibly corresponding to freely circulating CSF from the chiasmatic cistern. Alternatively, it may be an invagination of variable extension of the infundibular portion of the 3VF, an embryonic vestige of the craniopharyngeal canal that has extended into the ventral region of the neural tube to allow the deposition of embryo's mouth epithelial stem cells into the 3V with the capacity to undergo neoplastic transformation in adulthood (95, 333).
The basal recess sign was identified in 52% of the 368 individual PCP cases (either autopsy specimens or neuroradiological studies) from the 560c in which this sign could be assessed. This valuable sign has been validated as a specific marker of the papillary type in a cohort of 23 PCPs studied with MRI. Authors identified this sign in 5 out of the 23 cases (21%), all of them corresponding to the strictly 3V topography and showing a predominant solid consistency (335). Therefore, the basal recess represents a distinctive signature for diagnosing papillary CPs, with 100% specificity and 33% to 50% sensitivity in the overall CP population (95, 192, 333, 335). This sign also serves to establish the strict 3V topography among PCPs (present in 70% of strict 3V PCPs, P < .001), with 95% to 100% specificity and 42% to 62% sensitivity (333, 335). Accordingly, it is also associated with low-risk severity tumor attachments to the hypothalamus (P < .001) and with PCP patients suffering psychiatric disturbances (P = .030).
MRI Definition of PCP Topography
Accurately defining PCP topography preoperatively was not possible using only CT, which could not optimally differentiate between suprasellar PCPs that displace the 3VF upwards and ones primarily developed at the 3VF. Nor could it reliably define those tumors strictly located within the 3V (142, 336). This shortcoming is evident when analyzing the neuroradiological signs that have been used to define “intraventricular CPs” in the medical literature from 1953 to 2004 (23). Among the 74 CPs assumed to have an intraventricular location on preoperative CT/MRI studies, only 27 corresponded to true 3V tumors. The remaining cases turned out to be either suprasellar CPs, which had pushed the 3VF upward, mimicking an intra-3V position (pseudointraventricular), or had broken through the 3VF and invaded the 3V (secondary 3V tumors), or to infundibulo-tuberal CPs developed primarily within the 3VF. This infundibulo-tuberal concept is similar to the extra-intraventricular CP topographical category established by Juraj Steno (337).
The importance of MRI goes far beyond the simple description of macroscopic tumor characteristics. This technique accurately defines tumor occupation of the compartments along the sella-3V axis and the anatomical distortions caused to the hypothalamus-pituitary structures and the optic chiasm. This information, assessed on conventional midsagittal and coronal T1W/T2W scans, has proven useful to predict the CP topography and tumor-hypothalamus relationship that will be found during surgery (143, 338). Nevertheless, diagnostic accuracy of PCP topography may be significantly improved with high-resolution 3 to 7 T MRI scanners or, particularly, by using T2W and fast-imaging employing steady-state acquisition (143, 338). These sequences offer the highest resolution power to discriminate the position and anatomical status of the optic chiasm, PS, MBs, and 3VF (339-342). The most relevant MRI signs are described next (Fig. 8).
The mammillary body angle
A useful MRI sign to help differentiate between PCPs with a primary suprasellar location and those with a primary 3V development is the mammillary body angle (MBA). This corresponds to the angle formed by the intersection of a plane tangential to the base of the MBs with the plane tangential to the fourth ventricle floor on midsagittal MR images (223). The relevance of the MBA is that the MBs are the only solid structure of the 3VF that remains recognizable on midsagittal MRI scans in over 85% of CPs encroaching upon the 3V. Normal MBA is between 60° and 90°, but when a CP expands beneath the 3VF, the MBs are usually pushed upwards leading to obtuse MBA values (>90°). Conversely, CPs expanding primarily within the 3VF push the MBs backward and strictly 3V CPs push them downward, diminishing the MBA to acute values (<60°) (Fig. 8C and 8F). The MBA value is usually lower in infundibulo-tuberal CPs (range 5-30°) than in strict 3V CPs (range 20-50°). The usefulness of the MBA sign has been validated in several studies analyzing the topographical relationships between CPs and the 3V (91, 231, 294, 343).
Anatomical status of the hypothalamus-pituitary axis
In 2017, Prieto et al, analyzed the accuracy of conventional T1W and T2W MRI sequences to establish the topographical diagnosis in a cohort of 200 CPs (143). Beyond the tumor shape and MBA, the type of anatomic distortion caused by the tumor on the PS and the optic chiasm, in addition to the position of the hypothalamus regarding the tumor and its extension to the chiasmatic cistern, were identified as useful signs for topographical discrimination. The anatomical appearance of the PS can be classified into three categories: (1) normal, an anatomically intact and wholly visible stalk; (2) amputated, the upper infundibular portion of the stalk is not visible due to tumor growth; and (3) not visible, the stalk is unrecognizable due to tumor encroachment. Four categories of chiasm distortion are considered: (1) not distorted, chiasm displaying a normal position and shape; (2) compressed downward, slightly flattened chiasm at the anteroinferior margin of the tumor; (3) compressed forward, chiasm flattened between the tumor and the tuberculum sellae; and (4) stretched, chiasm elongated and thinned along the antero-superior surface of the tumor. The relative position of the hypothalamus regarding the tumor, best assessed on coronal MRI sections, was classified into 3 levels: (1) lower third, hypothalamic position below the tumor's bottom pole; (2) middle third, around the tumor's equator; and (3) upper third, above the tumor's top pole. Finally, occupation of the chiasmatic cistern by the tumor was classified into 3 categories: tumor-free, partially occupied, and wholly occupied.
The strict 3V topography was specifically defined by (1) a PS wholly identifiable beneath the tumor on midsagittal MRI scans (80%), (2) a hypothalamus position around the lower pole of the tumor on coronal MRI scans (82%), (3) a fully patent chiasmatic (suprasellar) cistern (98%), (4) an optic chiasm compressed downward by the tumor (66%), (5) a round, almost spherical tumor shape (76%), and (6) an MBA value between 30° and 60° (55%). By contrast, infundibulo-tuberal or not strictly 3V PCPs primarily develop at the 3VF itself, thus generating a bidirectional tumor growth toward the 3V cavity and the suprasellar cistern (38, 143, 334). This infundibulo-tuberal topography typically associates the following findings: (1) an “amputated” PS, as only its lower solid portion is identifiable, while the upper infundibular portion is replaced by the tumor (68%); (2) a hypothalamus position around the mid-third central portion (equator) of the tumor (91%); (3) a chiasmatic cistern partially occupied by the lower, protruding portion of the tumor (“frog belly” sign, 54%); (4) an optic chiasm compressed forward by the tumor (40%); (5) an elliptical shape (37%); and (6) a “hyperacute” MBA value of <30° (43%) (143).
Multivariate analyses performed on the 560c to identify the main MRI variables to preoperatively differentiate between not-strict and strict 3V PCPs, selected a logistic regression model that included tumor consistency and PS appearance. The percentage of correct classification into one of the 2 major 3V topographical categories was 92.8% overall. The stalk appearance was identified as the fundamental predictor to distinguish between both topographical categories (Fig. 9). An intact PS below the tumor strongly points to strictly 3V PCPs (94.5% of the cases, P < .001), while an amputation of the upper portion of the stalk suggests a not strictly 3V topography (Fig. 9B). A solid tumor consistency also pointed to the strictly 3V group (69% of the cases, P < .001) (Fig. 9C). Conversely, an upper cystic-basal solid consistency, in addition to the presence of visual impairment (73% of the cases, P < .001) suggested a not strictly 3V (infundibulo-tuberal) PCP topography (Fig. 9D). The low rate of visual alterations among strictly 3V PCPs is supported by the lack of anatomical distortions of the optic chiasm (32%) or merely a slight downward compression (54.3%, P < .001) (233). An additional MRI variable indicating a strictly 3V PCP topography was the identification of a basal duct-like recess (70%, P < .001). Hydrocephalus was more common in strict 3V PCPs (53.9%, P < .001), as their expansion inside the 3V may easily obstruct the foramina of Monro.
Major predictors of PCP topography. (A) Multivariate tree classification model to differentiate between the 2 major topographical categories: strictly intraventricular (strict 3V, white) and infundibulo-tuberal (not-strict 3V, black). This model selected the appearance of the pituitary stalk in the first step, followed by tumor consistency and preoperative visual deficits in the next steps. Correct prediction of the strict 3V topography with this model was as high as 88.8%. (B-E) Stacked bars of tumor topography by their major predictors. (B) By pituitary stalk appearance. The pituitary stalk was wholly visible (normal appearance) in 94.5% of strict 3V cases (P < .001). (C) By tumor consistency. A solid consistency occurred in 69% of strict 3V PCPs, while this rate decreases below 32% in the remaining topographies (P < .001). (D) By presence of visual impairment. It was reported in only 45% of patients with strict 3V PCPs while in more than 75% of patients with the remaining topographical categories (P < .001). (E) By presence of a basal duct-like recess. This sign was present in 70% of strict 3V PCPs (P < .001).
Abbreviations: 3V, third ventricle; PCP, papillary craniopharyngioma.
Hypothalamic and Optic Tracts Edema: Significance in PCP Diagnosis
Presence of hyperintensity on T2W and FLAIR sequences on preoperative MRI, compatible with edema, involving the hypothalamus and optic tracts around the tumor, was observed in 18.9% of PCPs in the 560c (Fig 8D). Its rate, however, doubled in PCPs with a cauliflower-like consistency (P = .005). This signal alteration specifically occurs in PCPs that expand within the 3V chamber, particularly when they infiltrate the optic chiasm (344-346). The edema extending along the course of the optic tracts gives a characteristic “moustache”-like appearance on axial images of CT/MRI scans, originally described by Higashi in 1990 (347). It is a rather specific sign of CPs (348). In the 2019 MRI assessment of hypothalamic edema in a series of 52 CPs by Hayashi et al, this sign was more commonly found in adult patients (74%), a third of them with PCPs (349). The importance of this perifocal hypothalamic edema in adult CPs is its correlation with a more severe anatomical distortion of the hypothalamus (Puget grade 2) (217, 218, 255, 349). Moreover, peritumoral edema was associated with clinical symptoms of hypothalamic dysfunction such as AVP-D, obesity and memory loss, both preoperatively and postoperatively (349). Likewise, in the 560c, edema changes in the hypothalamus and optic tracts on preoperative MRI was associated with the presence of psychiatric disturbances. This sign also predicted high-risk severity attachments to the hypothalamus (P = .003).
In 2023, Taguchi et al found in a study including 30 CPs that optic tract edema was associated with BRAFV600E-mutant solid PCPs. It normally vanished within the first postoperative month (199). Perifocal hypothalamic edema in CPs might be related to the expression of the vascular endothelial growth/permeability factor by tumor cells, which has been observed both in cystic 3V/infundibulo-tuberal CPs and solid PCPs (350). Alternatively, the process of reactive gliosis associated with CPs developing at the 3VF and the injury that these lesions cause to tanycytes, the ependymoglial specialized cells contributing to form the blood-brain barrier function between the ME and the adjacent basal hypothalamus, may also be implicated (239, 242).
Patterns of Hypothalamic Adherence in PCPs
Tumor Adhesion: Concepts and Surgical Evidence
As with ACPs, aside from tumor location, the major limiting factor for a safe, radical PCP removal is the type of tumor adherence to the contiguous critical neurovascular structures: the visual pathway, blood vessels, and most importantly, the hypothalamus. GTR is highly risky or simply not feasible when CP tenacious adhesions to the hypothalamus exist. Distinction between those tumors that can be radically removed, and those whose GTR would inevitably damage vital structures are one of the most worrisome aspects of CP surgery, yet the analysis of this fundamental factor for patient outcome has been neglected in most modern surgical series (23, 54). Moreover, a wide range of terms, such as adherence, adhesion, attachment, infiltration, and invasion, have been used interchangeably in CP medical literature. We favor the use of the general term “adherence” as it alludes to the intrinsic sticking quality of the tumor-brain physical union, which, mostly depends on the CP origin site (225). The term “attachment” simply refers to the morphology of this union. On the other hand, the words “invasion” and “infiltration” are used to define the presence of small or microscopic CP projections into the adjacent brain tissue, but they connote an aggressive biological behavior resembling histologically malignant tumors. Nevertheless, it should be noted that the presence of these finger-shaped tumor protrusions into the brain is rather typical of CPs developing primarily within the 3VF/walls and does not correspond, in most cases, to real brain invasion by the tumor (38, 226, 227, 259).
Classification of PCP-Hypothalamus Adherence
It was not until 2016 that Prieto et al presented the first objective classification scheme to define the type of CP adherence, based on the analysis of 500 CPs including brain specimens and surgically treated cases (54). This scheme considers 3 components: the anatomical structures attached, the extent of the attachment, and its strength (54, 224). Taking into account these 3 components, the severity of the PCP attachment to the hypothalamus can be classified into 2 major levels: (1) high-risk adherence, for PCPs developing at the 3VF itself with wide and tenacious adhesions to the 3VF and adjacent walls; and (2) low-risk-adherence, for PCPs growing inside the 3V with loose or small (pedicle-like or sessile) easily detachable attachments to the 3V inner lining, or for the less common group of suprasellar PCPs originated beneath the 3VF and attached to the PS. Removing these low-risk tumors should leave the hypothalamic region completely intact. This adherence classification scheme has proven to correlate with postoperative hypothalamic injury and patient outcome, as worse morbidity rates are associated with CPs presenting high-risk adhesions to the hypothalamus (54, 97, 224). The 560c definitively confirms the predominance of less severe attachments between PCPs and the hypothalamus suggested by previous studies (23, 37, 54, 70, 96). Overall, 62.5% of PCPs in this cohort had low-risk hypothalamic adhesions.
Pathological Features Associated With PCP-Hypothalamic Adherence
Because the type of tumor-hypothalamus adherence is not homogenous among PCPs, accurate preoperative distinction between high-risk and low-risk patterns provides invaluable information to plan individual treatment. Multivariate statistical analyses in the 560c have demonstrated that PCP topography is the major predictor of the tumor attachment severity to the hypothalamus (97). Most not strictly or infundibulo-tuberal 3V PCPs had high-risk adhesions to the hypothalamus (82.4%) while low-risk adhesions predominated in the strictly 3V category (78.5%) and in the minority group of sellar-suprasellar PCPs (100%) (P < .001, Fig. 10A). The second most influential variable in predicting the PCP attachment severity is the position of the hypothalamus regarding the tumor (Fig. 10B). High-risk attachments predominated in PCPs with a hypothalamic position around the tumors’ middle third (73.3%), while most cases with a hypothalamus located either below the tumor's lower third or above its upper third had low-risk attachments (P < .001) (97, 224). The binary logistic regression model with these 2 variables achieved 82% of correct classification into 1 of the 2 major adherence severity groups overall, a rate that increased to 96% in the low-risk adherence group.
Severity of the attachment between PCP and the hypothalamus: major predictive factors. (A-F) Stacked bars of PCP-hypothalamus adherence severity by their major predictors. (A) By tumor topography. High-risk PCP adhesions predominated within the not-strict 3V topographical category (82.4%, P < .001). (B) By the position of the hypothalamus regarding the tumor. High-risk tumor adhesions predominated among PCPs with the hypothalamus at their middle-third (73.3%, P < .001). (C) By presence of hypothalamic edema. High-risk adherences predominated when hypothalamic edema was present (69.2%, P = .003). (D) By pituitary stalk appearance. Note that 86.9% of PCPs with a pituitary stalk wholly visible below had low-risk attachments (P < .001). (E) By tumor consistency. The highest rate of low-risk adherences occurred in solid PCPs (74.4%, P < .001). (F) By tumor size, the larger the tumor, the higher the rate of high-risk adhesions (25% in lesions ≤2.5 cm, 32.2% when 2.6-3.4 cm, 42.5% when 3.5-4.4 cm, and 65% in those ≥4.5 cm, P = .006).
Abbreviations: 3V, third ventricle; PCP, papillary craniopharyngioma.
Additional radiological signs on preoperative MRI scans pointing to the existence of high-risk PCP-hypothalamic adhesions are (1) the presence of hypothalamic edema (P = .003, Fig. 10C); (2) a PS whose upper portion has been amputated by the tumor (P < .001, Fig. 10D); (3) any tumor consistency except solid (P < .001, Fig. 10E); (4) a compressed optic chiasm displaced forward by the tumor (P = .031); and (5) a medium-large size >3.5 cm (P = .006, Fig. 10F) (Table 7D). This MRI information to optimally ascertain the adherence severity risk is of paramount importance for surgical planning and patient counselling. Nevertheless, the definitive decision as to the possibility of GTR not leading to irreversible hypothalamic injury can only be made during the surgical procedure.
Surgical Treatment of PCPs
Historical Background
The history of PCP surgery has been marked by the difficulties in achieving safe access to this type of lesion and avoiding a tragic outcome from irreversible hypothalamic injury (327). Aside from inadequate hormone replacement therapy, poor illumination sources, and a lack of microsurgical techniques, a major factor for the poor outcome of early CP surgical attempts was the inaccurate preoperative radiological definition of tumor topography and its relationship to the hypothalamus. PCPs confined within the 3V could often not be found or were incompletely removed due to the selection of a suboptimal approach (11, 23, 121). Consequently, failed craniotomies and poor outcomes or death secondary to undue surgical maneuvers and hypothalamic damage were a common occurrence. Such frustrating experiences, however, motivated neurosurgeons to design new surgical strategies to overcome these seemingly insurmountable difficulties.
Sir Victor Horsley (1857-1916) pioneered CP surgery through the transcranial subtemporal approach (328), but the significant morbidity caused by forceful brain retractions led to the development of extracranial transsphenoidal approaches in the first decade of the 20th century (327). The sublabial transsphenoidal technique was the route used by the father of neurosurgery, Harvey Cushing (1869-1939), to treat pituitary tumors at the beginning of his career (121). Nevertheless, the high inaccessible position of most CPs led him to discontinue the transsphenoidal route in favor of the transcranial approach (TCA) as of the late 1920s, as the latter allowed a better view and safer dissection maneuvers to remove lesions involving the 3VF. He first employed the subfrontal approach developed by Chales H. Fraizer (1870-1936) but later substituted it for the more lateral pterional (or fronto-temporal) route devised by George Heuer (1882-1950) that involved less damaging retraction (351). Cushing also pioneered the surgical treatment of CPs growing in the 3V that were hardly visible through standard subfrontal/pterional views, either through a basal trans-lamina terminalis (TLT) route of through upper transcortical-transventricular or transcallosal corridors (10, 121). The transcallosal and TLT approaches were refined after the introduction of the surgical microscope at the end of the 1950s, by Willliam H. Sweet (1910-2001) and Donlin M. Long (1934-2023), respectively (352, 353). The importance of opening the lamina terminalis before considering a surgical exploration as negative was highlighted by Edgar A. Kahn (1900-1985), who warned that the papillary CP type of adults predominantly grew within the 3V (11). The TLT route was found to be safer than upper trans-ventricular approaches in a retrospective review of 105 3V CPs (23). The value of the TLT corridor to safely remove 3V PCPs has led to its use even through the extended endoscopic endonasal approach (EEA) in recent years (102, 109).
The key concept of CPs as hypothalamus-centered lesions proposed by Percival Bailey (1892-1973), based on his thorough study of Cushing's collection of CP brain specimens, was fundamental for subsequent surgical advances (113). His colleague Norman M. Dott (1897-1973) was the first to successfully remove CPs growing at the 3V/hypothalamus through a staged combined approach, a surgical strategy that minimized the risk of hypothalamic injury by using first a basal subfrontal route followed by a transfrontal-transventricular corridor (121). Then, the following generation of British neurosurgeons, led by Douglas Northfiled (1902-1976), contributed to emphasize the surgical risk associated with the topographical category of tuberal CPs that had an intrapial origin and replaced the 3VF (354).
The introduction of MRI revolutionized the accurate preoperative definition of CP topography, fundamental to planning the most suitable treatment strategy (336). Another milestone for CP surgery has been the introduction of the endoscope, as the EEA provides direct midline access and a detailed view of the tumor-hypothalamus boundaries, allowing for a safer tumor dissection (34, 300). The EEA has progressively become the preferred corridor for most CPs in adults, even for those PCPs predominantly located in the 3V (64, 80, 84, 91). In October 2023, Jia et al published the largest series of PCP patients (n = 101) that were operated through the EEA from 2019 to 2022 at the Beijing Tiantan Hospital (109). Their favorable results, with an overall GTR and stalk preservation as high as 90% and 91% of the cases, respectively, support the suitability of this technique for PCPs. Nevertheless, the risk of CSF leak remains substantial for the topographical category of strictly 3V PCPs (15% vs 6% overall).
Controversy Regarding Degree of Tumor Removal and Stalk Preservation
Surgical removal remains the gold standard for PCP treatment and histological verification, as it is for ACPs (141, 238, 355). Tumor tissue sampling is still required to confirm the pathologic diagnosis, even though imaging features and radiomics (a novel method to reveal characteristic tumor patterns from medical images using data-characterization algorithms), can show reliable signs for PCP diagnosis (89, 143, 145, 356). Beyond histological confirmation, PCP resection allows rapid improvement of symptoms by directly decompressing the tumor mass effect on the adjacent neurovascular structures. Nevertheless, while decompression can improve visual deficits and relieve obstructive hydrocephalus, it can often result in derangement of endocrinologic and hypothalamic functions. Surgery is also important for obtaining local disease control and for improving patient survival (97, 238, 254).
Decisions regarding degree of tumor removal, PS preservation, and choice of the appropriate surgical corridor are of paramount importance for achieving optimal patient outcomes. GTR decreases the risk of local CP recurrence and can obviate the need for further interventions and/or adjuvant radiotherapy (RT). The intimate tumor position in relation to the hypothalamic nuclei, however, poses a considerable challenge for safe GTR (44, 63, 224, 242, 327, 337). Most studies do not discriminate between patients in whom GTR can clearly be achieved without hypothalamic damage, and those where the tumor is invasive and would therefore be more suitable for subtotal resection (STR) followed by RT (STR + RT). Hypothalamic injury from aggressive resection can result in life-long morbidity in about 20% of patients, a problem that is probably underreported (238, 357, 358). However, while this morbidity is important to avoid, it must be balanced with the fact that the first resection attempt is the patient's best chance for maximal removal, as postsurgical scarring significantly decreases the likelihood of future GTR (62, 105, 228, 359, 360). The promising preliminary results of targeted treatments with BRAF/MEK inhibitors are an additional aspect to consider when pondering the radicality of PCP removal, particularly for tumors with high-risk attachments to the hypothalamus. Considering this preoperatively can help to define the goals of surgery.
Focusing on neuroendocrine outcome, the risk of experiencing any postoperative endocrinopathy seems to be higher following GTR. Schoenfeld et al reported significantly higher rates of AVP-D (56.3% vs 13.3%) and pan-hypopituitarism following GTR (54.8% vs 26.7%) in a large cohort of 122 CP patients, 75 of them adults (361). Likewise, in a 2019 meta-analysis, a significantly higher rate of panhypopituitarism (2-fold increase) and permanent AVP-D (3-fold increase) was observed to be associated with GTR, as compared with STR (362). Nevertheless, most of these studies were conducted during the period when TCA was the mainstay of surgical access. How the rates of endocrinopathy may differ using EEA is still a matter of debate, but some studies suggest lower rates of pituitary dysfunction and higher rates of progression-free survival (PFS) (363).
In many cases, the ability to obtain a GTR can hinge on the involvement of the pituitary infundibulum. A meta-analysis including 420 CP patients demonstrated the obvious conclusion that sacrificing the PS results in significantly higher rates of endocrinopathy including AVP-D and anterior pituitary dysfunction (364). While this association is self-evident, this study did not take into consideration the effect of PS preservation on rates of GTR or whether post-operative RT was administered. According to the experience of Theodore H. Schwartz at Weill Cornell Medical College, New York, PS preservation results in lower rates of GTR compared to stalk sacrifice (73% vs 100%) (66). However, patients who underwent STR or near-total tumor resection with PS preservation were found to have higher rates of CP recurrence and greater need for post-operative RT (66). Moreover, patients with PS preservation frequently experience AVP-D (49%) and anterior pituitary dysfunction (76%). Therefore, stalk preservation does not guarantee a normal pituitary function. Only 12% of patients with PS preservation achieved a GTR and maintained normal pituitary function. Since post-operative pituitary endocrinopathy is common regardless of stalk preservation and can be supplemented medically, we do not believe that preserving the PS should be prioritized above the goal of obtaining a GTR. Thus, there can still be long-term benefits to GTR over STR + RT, with lower rates of recurrence and necessity for radiation (365). Unfortunately, to date there is no comprehensive analysis separating results for PCPs. Nevertheless, the predominant small sessile/pedicle PCP attachment to the hypothalamus may result in lower rates of hypothalamic injury from surgery than those of ACPs (54, 142). The papillary type has been found to independently associate with a lower risk of hypothalamic obesity and weight gain post-operatively (366). Therefore, the goal of achieving GTR when the hypothalamus can be spared seems to be more probable in PCPs.
Operative Corridors for PCPs
A wide range of approaches can be utilized for CP surgery (Table 8). The usual intraventricular location of PCPs (238, 355, 357, 367), accounts for the preferential use of trans-ventricular approaches through either upper (transcortical or transcallosal) or basal (TLT) routes in both the 99s and 560c. Nevertheless, growing experience with endoscope-assisted technology has led the world's foremost CP surgeons to move away from open transcranial procedures towards EEA, even for tumors wholly confined within the boundaries of the 3V chamber (63, 83, 368). EEA was used in 39% of the 560c patients operated on from 2006 to 2023. Ultimately, the surgical approach chosen should maximize the visualization of the planes of adhesion between the tumor and the surrounding neurovascular structures including the hypothalamus, optic complex, and carotid arteries. Usual CP attachments at the basal tumor pole imply that this area remains out of the surgeon's sight until the final resection stages when using transcortical or transcallosal routes, a circumstance that might lead to unintentional injury to the hypothalamic nuclei (23, 38, 54).
Advantages and disadvantages of the major surgical approaches to papillary craniopharyngiomas
| Operative corridor | Advantages | Disadvantages |
|---|---|---|
Transcallosal |
|
|
Pterional trans-lamina terminalis |
|
|
Endoscopic endonasal approach |
|
|
| Operative corridor | Advantages | Disadvantages |
|---|---|---|
| Transcallosal |
|
|
| Pterional trans-lamina terminalis |
|
|
| Endoscopic endonasal approach |
|
|
Abbreviations: 3V, third ventricle; 3VF, third ventricle floor; CSF, cerebrospinal fluid; PCP, papillary craniopharyngioma.
Advantages and disadvantages of the major surgical approaches to papillary craniopharyngiomas
| Operative corridor | Advantages | Disadvantages |
|---|---|---|
| Transcallosal |
|
|
| Pterional trans-lamina terminalis |
|
|
| Endoscopic endonasal approach |
|
|
| Operative corridor | Advantages | Disadvantages |
|---|---|---|
| Transcallosal |
|
|
| Pterional trans-lamina terminalis |
|
|
| Endoscopic endonasal approach |
|
|
Abbreviations: 3V, third ventricle; 3VF, third ventricle floor; CSF, cerebrospinal fluid; PCP, papillary craniopharyngioma.
Transcranial-transventricular approaches
The pterional or fronto-temporal approach is one of the most common corridors used in CP surgery. This route can provide working windows in the pre-chiasmatic space, optic-carotid and carotid-tentorial triangles as well as above the carotid bifurcation and through the lamina terminalis (60, 228, 369). Yasargil et al employed the pterional approach in two-thirds of their 144 CP patients, with 90% of GTR and a recurrence rate as low as 7%. Moreover, 73% of adults were independent as of their last follow-up (228). The pterional approach was also the one most frequently used (39%) by Fahlbusch et al in their series of 168 CPs (369). The authors noted that an anteriorly positioned chiasm limited the working window and that this unilateral approach provided a limited view of the tumor margin adjacent to the ipsilateral hypothalamus. As such, they used the subfrontal, interhemispheric approach in 28 patients (369). A major advantage of this subfrontal corridor is that it allows visualization along the midline, including both 3V walls and without views obstructed by perforating vessels, although requires traversing the frontal sinus as well as significant brain retraction. In Fahlbusch's surgical series, the GTR rate achieved with the bifrontal approach (59%) was higher than the observed with the pterional one (50%), although the former also associated a higher rate of visual deterioration after surgery (20% vs 14%). The transsphenoidal approach yielded the best results in terms of lack of visual deterioration and good functional outcome (91%) postoperatively, but it was only used for ACPs with a subdiaphragmatic position. Tumor location within the 3V in addition to a large size and presence of calcifications and/or hydrocephalus were identified as negative prognostic factors for GTR (369).
Shi et al, reported one of the largest CP series that includes 1054 CPs (205 PCPs, 19%) (60). These authors used primarily a unilateral basal interhemispheric and/or a pterional approach with the goal of aggressive resection. GTR was achieved in 90% of patients, 13% of them showing tumor recurrence during their follow-up. Visual field deficits improved in 67% of patients and worsened in 14%. New postoperative AVP-D occurred in 30% of patients overall, but at a higher rate when the PS was sacrificed. Finally, obesity/eating disorders were observed in 15% of adult patients (60). The authors remarked that a major limitation of the transcranial corridors used was reaching the lower tumor components located within the sella turcica, an aspect typically irrelevant for PCPs as they rarely extend into the sellar compartment.
Using transventricular approaches, either through frontal transcortical, interhemispheric transcallosal or TLT routes, is also favored for PCPs as most are intraventricular lesions. The rarity of pure intraventricular CPs, however, means that single-center case surgical series are quite small. The TLT corridor, either through a unilateral frontotemporal or a bilateral interhemispheric approach, specifically provides direct view and access to the infundibulum/tuber cinereum, where most PCPs are attached (23, 38, 229). Tumor debulking is vital to viewing the lesion's margins and dissecting the attachments to the 3V. Entry through the lamina terminalis, however, theoretically places the optic nerves/chiasm, supraoptic nuclei of the hypothalamus, and columns of the fornix at risk. Maira et al reported a series of 8 intraventricular CPs (2 PCPs) removed through TLT approach (229). GTR was achieved in 7 patients with only one experiencing tumor recurrence. Seven of the patients were able to return to work, but one did have prolonged hypothalamic deficit that led to death. Hormone replacement therapy was required in 62.5% of patients. Pan et al also reported a series 17 intraventricular CPs, 6 of them PCPs, that were approached through the TLT corridor (38). Total resection was achieved in 76% of them, while tight adherences to the 3VF and no clear dissection plane forced the surgeons to leave tumor remnants in the remaining cases. No patients with GTR had recurrence during the reported follow-up period. Two-thirds of the 24 intraventricular CPs reported by Yu et al, were approached through the transcallosal route, while TLT and transcortical transventricular routes were used in 29.2% and 8.3% of the cases, respectively (44). The authors noted that higher attachment severity to the 3VF correlated with worse endocrinologic and functional outcomes. A major disadvantage of the transcallosal corridor is that expanding the opening to the 3V through transforaminal or transchoroidal routes can place the fornix and deep venous structures at risk, but it can be considered for 3V PCPs causing dilated ventricular size and enlarged foramen of Monro.
The endoscopic endonasal transsphenoidal approach
Renaissance of the microscopic transsphenoidal technique occurred in the 1960s. Although the use of this corridor was primarily limited to infradiaphragmatic CPs (228, 369), over time it was expanded to access suprasellar lesions (370). Specific improvements in illumination and visualization with the endoscope provided a panoramic view of the skull base that allowed for expanding the ventral midline approach through trans-tuberculum and transplanum openings (230, 368, 371). This approach offers a clear view of the PS and 3VF and their relationship with the tumor, working along the vertical axis of the tumor (Fig. 11). Through this approach the surgeon can directly dissect the interface between the tumor and the optic chiasm and hypothalamus from below, minimizing the need for brain retraction and preserving tiny hypothalamic perforators and superior hypophyseal artery branches to the chiasm, of vital importance to achieve good visual outcomes. This corridor, however, is less ideal for patients with lateral tumor extension beyond the carotids. Controversy exists regarding which is the best approach for tumors purely within the 3V, with some authors favoring TCA while others prefer EEA (63). Some works suggest that a pre-fixed chiasm and narrow chiasm-pituitary corridor can limit the EEA, but Omay et al demonstrated that this is not, in fact, a contraindication to the approach and had no correlation with patient outcomes (367).
Operative steps involved in resection of intraventricular craniopharyngiomas through the endoscopic endonasal corridor. Bone removal incorporates a portion of the rostral sella just below the superior intercavernous sinus and planum sphenoidale to expose the bottom of the chiasm. The superior intercavernous sinus is isolated, bipolar cauterized, and transected. Fluorescein-stained cerebrospinal fluid clearly delineates the arachnoid space. Following sharp microdissection of the deep arachnoid, the tumor becomes visible. The tumor is internally debulked and removed using extracapsular sharp and blunt dissection. Closure proceeds using the “gasket-seal” technique. With permission of Theodore H. Schwartz, copyright holder.
Cavallo et al reported a series of 103 CP patients treated via EEA (368). GTR was achieved in 68.9% of patients overall and decreased to only 30% when the tumor invaded the hypothalamus. Visual deficits improved in 74% of patients, but new-onset AVP-D and anterior hypopituitarism occurred in 48% and 44% of them, respectively. Significant weight gain was also experienced by 18% of patients. Overall, CSF leak occurred in 15% of patients, but this rate was significantly higher in those cases with ventricular involvement (28%).
Bobeff et al demonstrated in a series of 111 CP patients treated by EEA that GTR was achieved in 89.5% of newly diagnosed patients in whom this was the surgical goal and in 72.4% of recurrent tumors (105). Apart from prior surgical treatment, inability to obtain GTR was correlated with tumor diameter >3.5 cm and encasement of the optic nerves or major arteries. Furthermore, in this series recurrence-free survival significantly correlated with stalk preservation. Among GTR cases, the recurrence rate was significantly higher in patients that had the PS preserved (22.6%) vs only 4.9% when the stalk was sacrificed. CSF leak rates were as low as ∼2% to 4% in this group (371, 372).
Despite early recommendations against the use of the EEA for intraventricular CPs (228, 230), this approach has been described in a few small case series. Specifically, Algattas et al reviewed their single institution series of 62 patients operated on at the University of Pittsburgh from CPs with ventricular involvement, 7 of them PCPs (76). GTR rates were 47% overall, but improved over time, with 77% GTR after 2012, as well as CSF leak rates, which decreased to 10% with the utilization of nasoseptal flaps. Vision was improved or stable in 98% of patients. Forbes et al reported the use of the EEA for resection of 10 intrinsic 3V CPs, including 3 PCPs (63). Through this route, a surgical plane can be developed between the 3VF, which is bowed inferiorly and stretched to a thin membrane by large tumors, or through a small incision in the 3VF (Fig. 12). GTR was obtained in 90% of patients, and vision remained stable or improved in 90%, whereas postoperative panhypopituitarism occurred in 70% of patients. Fan et al evaluated EEA for 26 intraventricular CPs treated at Nanfang Hospital, Guangzhou (84). GTR was achieved in 92% of patients, with near total resection in the remainder. The tumor capsule and a plane separating the ventricular floor and hypothalamus were often identified, but an intact 3VF could only be maintained in 8% of cases. An intact or small opening into 3VF, however, more likely occurred when the tumors had a small size or a papillary histology.
Resection of a third ventricle papillary craniopharyngioma through an endoscopic endonasal approach. (A) Midsagittal T1W, contrast-enhanced MRI. (A1) Preoperative image shows an enhancing solid round lesion arising from the infundibulo-tuberal region. (A2) Postoperative image demonstrates gross total removal. (B) Intraoperative images from an endoscopic endonasal approach. (B1) Note the typical “berry-like” papillomatous architecture (yellow arrow) of the tumor (T), which arises from the infundibulo-tuberal region, extending into the third ventricle and displacing the pituitary stalk (white arrow). (B2) Following total tumor removal the 3V remains open and the pituitary stalk (white arrow) is still anatomically intact.
Abbreviations: 3V, third ventricle; MRI, magnetic resonance imaging; OC, optic chiasm; PG, pituitary gland; S, suction.
Finally, regarding the controversial use of lumbar drainage in EEA, a randomized controlled trial has provided level 1 evidence demonstrating a statistically significant decrease in CSF leak rates with lumbar drainage (373). Nevertheless, the secondary analysis within the trial suggested a greater benefit in anterior and posterior fossa pathologies compared to suprasellar lesions such as CPs. Moreover, lumbar drainage can carry risks such as spinal headaches, tonsillar herniation, hematomas, or infection. As such, using lumbar drainage for pituitary-3V pathologies continues to vary by surgeon and institution. Schwartz's team favors the use of lumbar drainage in higher risk patients such as those with elevated body mass index (374) or with a predominant intraventricular location (63).
Comparative Results Between TCA and EEA Corridors
In a meta-analysis of 3470 CP patients, the EEA was found to have a higher GTR rate compared to TCA, 67% vs 48% (363). Furthermore, vision improved in 56% of EEA patients while in only 33% of patients who underwent TCA. Endocrine outcome was also more favorable in the EEA group and the rates of permanent AVP-D were lower following EEA (28%) than TCA (54%). There were, however, as expected, significantly higher rates of CSF leak in the EEA patients (18% vs 2%). The rates of CSF leak have long been a limiting factor for EEA acceptance, but improvements in multilayer closure with nasoseptal vascularized tissue flaps, and the closure techniques such as the “gasket-seal” or “button” inlay-onlay, have significantly decreased the rate of this complication over time with large series reporting rates as low as ∼2% to 3% (50, 368, 372, 375).
In the comparison of 26 CPs that were deemed equally amenable to resection by either TCA or EEA, Moussazadeh et al found that the EEA group had significantly less radiographic evidence of brain retraction and damage to normal structures with lower volumes of FLAIR hyperintensity and diffuse restriction postoperatively (376). In agreement, TCA patients demonstrated higher rates of postoperative cognitive deficits. GTR rates (90% vs 40%) and visual improvement rates (65% vs 0%) favored the EEA vs TCA in this series as well. Fan et al also compared outcomes for TCA and EEA in a single institution experience that included 315 patients (83). Overall GTR (∼90%) and recurrence (∼7%) rates were not significantly different between both surgical approaches. Nevertheless, visual improvement was significantly more likely in the EEA group (36%) than in the TCA group (1.6%). Moreover, visual decline was less likely in EEA patients (1.6% vs 11.1%). In the subgroup of CPs arising from the top of the stalk (T-type), patients who underwent TCA had a lower postoperative rate of significant hypothalamic dysfunction than those treated by EEA (38.1% vs 59.7%). Finally, the EEA resulted in significantly higher CSF leak rates overall (∼10-13% vs 0.5%), regardless of the tumor topography. In summary, this work demonstrated the significant benefit of the EEA for CPs with regards to visual outcomes, though this must be weighed and balanced against the poorer hypothalamic outcomes reported for the T-type CPs (infundibulo-tuberal topography) (83).
La Corte et al presented the surgical outcome analysis of 16 BRAF-mutant PCPs operated either through a fronto-temporal craniotomy (n = 2) or by the EEA (n = 14) (64). Overall, GTR was achieved in 69% of cases and the PS was sacrificed in 43% of patients. The rate of GTR, however, increased to 79% with the EEA. By contrast, GTR was not achieved in either of the 2 patients operated through a TCA corridor. Postoperatively, 68.7% developed new AVP-D or new hypopituitarism. Nine patients had increased BMI at last follow-up, and cognitive impairment was stable or improved in 81% of patients. Finally, no CSF leaks occurred in this series, although 1 patient required a shunt for hydrocephalus (64).
Even though the selection of surgical approach for PCPs eventually depends on the surgeon's preference and experience, the European Association of Neurosurgical Societies skull base section, based on the current literature evidence and expert recommendations, encourages the use of the EEA as the first-line corridor for midline and retrochiasmatic CPs without lateral extension, while recommending TCA for CPs with lateral extension beyond the internal carotid artery and for 3V tumors not extending into the suprasellar space (357). However, it should be noted that these are the recommendations of 1 group assessing the literature at one moment in time in an ever-evolving field. The traditional paradigm that discouraged the use of EEA for PCPs expanding at the 3VF or wholly confined within the 3V has been challenged in the last decade thanks to the steep surgical learning curve achieved with this approach in a restricted number of pituitary centers of excellence, which have reported successful patient outcomes following radical tumor removal with increasingly lower CSF leak rates (50, 363, 368, 372). This should not preclude the use of TCA employing either TLT or transcallosal corridors by surgeons mastering these equally valid approaches. Dissection of the tumor-hypothalamus cleavage plane under direct view and careful handling of tumor adherences are the crucial factors influencing the success of PCP surgery.
Surgical Results in PCPs
Degree of Tumor Removal: Differences Between PCPs and ACPs
PCPs have historically been considered more amenable to total removal than ACPs based on the former's presumed lower tendency to infiltrate the adjacent hypothalamic tissue and/or to induce a strong gliotic/inflammatory reaction in this vital brain region (11, 12, 14, 17, 20). Nevertheless, objective information calls such concepts into question (Table 9). A meta-analysis of 974 CPs from 13 different studies, including 217 histologically verified ACPs and 69 PCPs, found that despite GTR being higher in PCPs (65.5%) than ACPs (52%), differences did not reach statistical significance (99). Nor were any significant differences in the degree of resection found between the 2 histological types in single-institution surgical series (34, 36). Analysis of the 99s has reached the same conclusions. The mean GTR rate in the 74 large series providing this information was 60%, almost identical to the GTR rate found for PCPs (57%) in the 35 series including this information separately.
Pathological, clinical, and surgical factors related with patient outcome and tumor recurrence in PCPs
| Factor | Findings identified | Studies with a significant correlation (Ref) | |
|---|---|---|---|
| Comparison between PCP and ACP types | Good dissection plane and higher GTR in PCPs | Crotty 1995 (20) | |
| Microscopic brain invasion absent or extremely rare in PCPs | Adamson 1990 (14), Weiner 1994 (17), Miller 1994 (18), Crotty 1995 (20), Shi 2006 (28) | ||
| Higher rate of postoperative hypothalamic injury and AVP-D in PCP patients | Feng 2019 (72) | ||
| Similar patient survival/outcome | Weiner 1994 (17), Miller 1994 (18), Ersahin 2005 (25), Yamada 2010 (36), LopezSerna 2012 (41), Zygourakis 2014 (45), Zhang 2018 (69), Moreno-Torres 2021 (88), Wu 2022 (100), Awad 2023 (104) | ||
| Similar tumor recurrence rate | Crotty 1995 (20), Duff 2000 (22), Gupta 2006 (27), Shi 2006 (28), Pekmezci 2010 (35), Yamada 2010 (36), Park 2020 (78), Guo 2023 (107) | ||
| Increased survival and better outcome in PCPs | Kahn 1973 (11), Petito 1976 (12), Szeifert 1993 (16), Tavangar 2004 (24), Xu 2006 (29), TenaSuck 2009 (31),Yalcin 2009 (33), Cheng 2016 (47), Chu 2017 (58), Iglesias 2021 (86), Bobeff 2023 (105), Guo 2023 (107) | ||
| No recurrence following GTR in PCPs | Adamson 1990 (14), Szeifert 1993 (16), Weiner 1994 (17), Miller 1994 (18), Tavangar 2004 (25), Bobeff 2023 (105) | ||
| Lower PCP recurrence rate | Minamida 2005 (20), Xu 2006 TenaSuck 2009 (31), Yalcin 2009 (33) LopezSerna 2012 (41), Cheng 2016 (47), Chu 2017 (58), Iglesias 2021 (86), Wu 2022 (99) | ||
| Higher PCP recurrence rate | Mende 2020 (77) | ||
| Presenting symptoms | |||
| Hypothalamic | If present | Poor outcome | Prieto 2022 (97) |
| Psychiatric | If present | Poor outcome | Duff 2000a (22), Prieto 2022 (97) |
| Higher rate of postoperative hypothalamic injury | Prieto 2022 (97) | ||
| Poor neuropsychological outcome | Cao 2022a (91) | ||
| Visual | If present | Higher tumor recurrence rate | Sadashivam 2020a (79) |
| Endocrine | If more than 3 axes affected | Not related to postoperative weight gain | Dogra 2022a (93) |
| Higher rate of postoperative weight gain | Duan 2021a (82) | ||
| Weight gain | If absent or small | Higher rate of postoperative weight gain | Duan 2021a (82), Dogra 2022a (93) |
| Tumor features | |||
| Size | No relation with postoperative weight gain | Dogra 2022a (93) | |
| Small <2.5-3 cm | Higher rate of GTR | Bobeff 2023a (105) | |
| Increased survival/better outcome | Petito 1976 (12), Zacharia 2012a (42), Zhang 2018a (69), Wu 2022a (100), Bobeff 2023a (105) | ||
| Large (volume > 7 cm3) | Higher rate of postoperative psychiatric disturbances | Zhao 2021a (90) | |
| Topography | Tumors growing in the 3V floor (infundibulo-tuberal) | Poor outcome and higher rate of postoperative hypothalamic injury | Pan 2016a (53) |
| Higher rate of postoperative obesity | Bobeff 2023a (105) | ||
| Lower GTR rate | Pan 2016a (53), Jia 2023a (109) | ||
| Higher recurrence rate | Jia 2023 (109) | ||
| 3V involvement | Higher rate of postoperative psychiatric disturbances | Zhao 2021a (90) | |
| Strict 3V | Lower recurrence rate | Prieto 2022 (97) | |
| Better outcome | Jia 2023 (109) | ||
| Consistency | Cystic-cauliflower | Higher rate of postoperative hypothalamic injury | Prieto 2022 (97) |
| Macroscopic hypothalamic features | |||
| Hypothalamic edema | If present | Poor outcome | Prieto 2022 (97) |
| Type of tumor-hypothalamic adherence | Wide and dense | Poor outcome, and higher rate of tumor recurrence | Duff 2000a (22), Yu 2014a (44), Pan 2016a (53), Prieto 2016a (54), Prieto 2022 (97) |
| Higher rate of postoperative hypothalamic injury | Prieto 2022 (97) | ||
| Lower GTR rate | Jia 2023 (109) | ||
| Small-pedicle | Good outcome | Pan 2011 (38), Prieto 2016 (54) | |
| Type of hypothalamic involvement by the tumor | If invaded | Higher rate of postoperative psychiatric disturbances | Yang 2020a (80), Zhao 2021a (90) |
| Bilateral | Higher rate of postoperative DI and weight gain | Yang 2020a (80) | |
| Puget's grade | No relation with postoperative weight gain | Dogra 2022a (93) | |
| Treatment | |||
| Treatment modality | RT vs STR + RT vs GTR | Similar patient survival | Zhang 2018a (69) |
| RT | When administrated | Increased patient survival | Wu 2022a (100) |
| Surgical approach | Transcranial vs EEA | No differences in tumor recurrence | Jeswani 2016a (49), Park 2020a (78), Dandurand 2018a (62) |
| Higher rate of GTR with EEA | Nie 2022a (94) | ||
| Lower rate of GTR with EEA | Awad 2023a (104) | ||
| Lower recurrence rate with EEA | Nie 2022a (94) | ||
| Lower postoperative endocrine deficits with EEA | Li 2019a (75) | ||
| Better hypothalamic outcome with transcraneal removal of T-topography | Fan 2021a (83) | ||
| IH-TLT vs EEA | Higher rate of postoperative hypothalamic injury but better visual outcome with EEA | Chen 2023a (106) | |
| Degree of tumor removal | GTR vs STR | Similar patient survival | Wu 2022a (100) |
| Similar neuropsychological outcome | Giese 2019a (74) | ||
| Higher rate of postoperative psychiatric disturbances with GTR | Zhao 2021a (90) | ||
| Higher recurrence rate in STR | Kim 2012a (40), Dandurand 2018a (62), Sadashivam 2020a (79), Wu 2022a (99), Pang 2023a (108) | ||
| GTR vs STR + RT | Similar patient survival | Zhang 2018a (69), Awad 2023a (104) | |
| Similar tumor recurrence | Pang 2023a (108) | ||
| Lower recurrence rate in GTR | Kim 2012a (40), Dandurand 2018a (62), Wu 2022a (99), Bobeff 2023a (105) | ||
| STR vs STR + RT | Similar survival/recurrence | Tariq 2017 (13) | |
| Increased survival in STR + RT | Petito 1976 (12), Crotty 1995 (20), Kim 2012a (40), Zacharia 2012a (42), Dandurand 2018a (62), Zhang 2018a (69) | ||
| Lower recurrence rate in STR + RT | Petito 1976 (12), Crotty 1995 (20), Kim 2012a (40), Zacharia 2012a (42), Dandurand 2018a (62), Zhang 2018a (69), Awad 2023a (104) | ||
| GTR | No relation with postoperative weight gain | Dogra 2022a (93) | |
| Pituitary stalk | When preserved | Higher rate of tumor recurrence | Sadashivam 2020a (79), Bobeff 2023a (105) |
| Factor | Findings identified | Studies with a significant correlation (Ref) | |
|---|---|---|---|
| Comparison between PCP and ACP types | Good dissection plane and higher GTR in PCPs | Crotty 1995 (20) | |
| Microscopic brain invasion absent or extremely rare in PCPs | Adamson 1990 (14), Weiner 1994 (17), Miller 1994 (18), Crotty 1995 (20), Shi 2006 (28) | ||
| Higher rate of postoperative hypothalamic injury and AVP-D in PCP patients | Feng 2019 (72) | ||
| Similar patient survival/outcome | Weiner 1994 (17), Miller 1994 (18), Ersahin 2005 (25), Yamada 2010 (36), LopezSerna 2012 (41), Zygourakis 2014 (45), Zhang 2018 (69), Moreno-Torres 2021 (88), Wu 2022 (100), Awad 2023 (104) | ||
| Similar tumor recurrence rate | Crotty 1995 (20), Duff 2000 (22), Gupta 2006 (27), Shi 2006 (28), Pekmezci 2010 (35), Yamada 2010 (36), Park 2020 (78), Guo 2023 (107) | ||
| Increased survival and better outcome in PCPs | Kahn 1973 (11), Petito 1976 (12), Szeifert 1993 (16), Tavangar 2004 (24), Xu 2006 (29), TenaSuck 2009 (31),Yalcin 2009 (33), Cheng 2016 (47), Chu 2017 (58), Iglesias 2021 (86), Bobeff 2023 (105), Guo 2023 (107) | ||
| No recurrence following GTR in PCPs | Adamson 1990 (14), Szeifert 1993 (16), Weiner 1994 (17), Miller 1994 (18), Tavangar 2004 (25), Bobeff 2023 (105) | ||
| Lower PCP recurrence rate | Minamida 2005 (20), Xu 2006 TenaSuck 2009 (31), Yalcin 2009 (33) LopezSerna 2012 (41), Cheng 2016 (47), Chu 2017 (58), Iglesias 2021 (86), Wu 2022 (99) | ||
| Higher PCP recurrence rate | Mende 2020 (77) | ||
| Presenting symptoms | |||
| Hypothalamic | If present | Poor outcome | Prieto 2022 (97) |
| Psychiatric | If present | Poor outcome | Duff 2000a (22), Prieto 2022 (97) |
| Higher rate of postoperative hypothalamic injury | Prieto 2022 (97) | ||
| Poor neuropsychological outcome | Cao 2022a (91) | ||
| Visual | If present | Higher tumor recurrence rate | Sadashivam 2020a (79) |
| Endocrine | If more than 3 axes affected | Not related to postoperative weight gain | Dogra 2022a (93) |
| Higher rate of postoperative weight gain | Duan 2021a (82) | ||
| Weight gain | If absent or small | Higher rate of postoperative weight gain | Duan 2021a (82), Dogra 2022a (93) |
| Tumor features | |||
| Size | No relation with postoperative weight gain | Dogra 2022a (93) | |
| Small <2.5-3 cm | Higher rate of GTR | Bobeff 2023a (105) | |
| Increased survival/better outcome | Petito 1976 (12), Zacharia 2012a (42), Zhang 2018a (69), Wu 2022a (100), Bobeff 2023a (105) | ||
| Large (volume > 7 cm3) | Higher rate of postoperative psychiatric disturbances | Zhao 2021a (90) | |
| Topography | Tumors growing in the 3V floor (infundibulo-tuberal) | Poor outcome and higher rate of postoperative hypothalamic injury | Pan 2016a (53) |
| Higher rate of postoperative obesity | Bobeff 2023a (105) | ||
| Lower GTR rate | Pan 2016a (53), Jia 2023a (109) | ||
| Higher recurrence rate | Jia 2023 (109) | ||
| 3V involvement | Higher rate of postoperative psychiatric disturbances | Zhao 2021a (90) | |
| Strict 3V | Lower recurrence rate | Prieto 2022 (97) | |
| Better outcome | Jia 2023 (109) | ||
| Consistency | Cystic-cauliflower | Higher rate of postoperative hypothalamic injury | Prieto 2022 (97) |
| Macroscopic hypothalamic features | |||
| Hypothalamic edema | If present | Poor outcome | Prieto 2022 (97) |
| Type of tumor-hypothalamic adherence | Wide and dense | Poor outcome, and higher rate of tumor recurrence | Duff 2000a (22), Yu 2014a (44), Pan 2016a (53), Prieto 2016a (54), Prieto 2022 (97) |
| Higher rate of postoperative hypothalamic injury | Prieto 2022 (97) | ||
| Lower GTR rate | Jia 2023 (109) | ||
| Small-pedicle | Good outcome | Pan 2011 (38), Prieto 2016 (54) | |
| Type of hypothalamic involvement by the tumor | If invaded | Higher rate of postoperative psychiatric disturbances | Yang 2020a (80), Zhao 2021a (90) |
| Bilateral | Higher rate of postoperative DI and weight gain | Yang 2020a (80) | |
| Puget's grade | No relation with postoperative weight gain | Dogra 2022a (93) | |
| Treatment | |||
| Treatment modality | RT vs STR + RT vs GTR | Similar patient survival | Zhang 2018a (69) |
| RT | When administrated | Increased patient survival | Wu 2022a (100) |
| Surgical approach | Transcranial vs EEA | No differences in tumor recurrence | Jeswani 2016a (49), Park 2020a (78), Dandurand 2018a (62) |
| Higher rate of GTR with EEA | Nie 2022a (94) | ||
| Lower rate of GTR with EEA | Awad 2023a (104) | ||
| Lower recurrence rate with EEA | Nie 2022a (94) | ||
| Lower postoperative endocrine deficits with EEA | Li 2019a (75) | ||
| Better hypothalamic outcome with transcraneal removal of T-topography | Fan 2021a (83) | ||
| IH-TLT vs EEA | Higher rate of postoperative hypothalamic injury but better visual outcome with EEA | Chen 2023a (106) | |
| Degree of tumor removal | GTR vs STR | Similar patient survival | Wu 2022a (100) |
| Similar neuropsychological outcome | Giese 2019a (74) | ||
| Higher rate of postoperative psychiatric disturbances with GTR | Zhao 2021a (90) | ||
| Higher recurrence rate in STR | Kim 2012a (40), Dandurand 2018a (62), Sadashivam 2020a (79), Wu 2022a (99), Pang 2023a (108) | ||
| GTR vs STR + RT | Similar patient survival | Zhang 2018a (69), Awad 2023a (104) | |
| Similar tumor recurrence | Pang 2023a (108) | ||
| Lower recurrence rate in GTR | Kim 2012a (40), Dandurand 2018a (62), Wu 2022a (99), Bobeff 2023a (105) | ||
| STR vs STR + RT | Similar survival/recurrence | Tariq 2017 (13) | |
| Increased survival in STR + RT | Petito 1976 (12), Crotty 1995 (20), Kim 2012a (40), Zacharia 2012a (42), Dandurand 2018a (62), Zhang 2018a (69) | ||
| Lower recurrence rate in STR + RT | Petito 1976 (12), Crotty 1995 (20), Kim 2012a (40), Zacharia 2012a (42), Dandurand 2018a (62), Zhang 2018a (69), Awad 2023a (104) | ||
| GTR | No relation with postoperative weight gain | Dogra 2022a (93) | |
| Pituitary stalk | When preserved | Higher rate of tumor recurrence | Sadashivam 2020a (79), Bobeff 2023a (105) |
Abbreviations: ACP, adamantinomtaous craniopharyngioma; AVP-D, arginine vasopressin deficiency (diabetes insipidus); CP, craniopharyngioma; EEA, endoscopic endonasal approach; GTR, gross total resection; IH-TLT, interhemispheric-translamina terminalis; PCP, papillary craniopharyngioma; RT, radiation therapy; Ref, reference number; STR, subtotal resection.
aSeries without separate analysis by histological type.
Pathological, clinical, and surgical factors related with patient outcome and tumor recurrence in PCPs
| Factor | Findings identified | Studies with a significant correlation (Ref) | |
|---|---|---|---|
| Comparison between PCP and ACP types | Good dissection plane and higher GTR in PCPs | Crotty 1995 (20) | |
| Microscopic brain invasion absent or extremely rare in PCPs | Adamson 1990 (14), Weiner 1994 (17), Miller 1994 (18), Crotty 1995 (20), Shi 2006 (28) | ||
| Higher rate of postoperative hypothalamic injury and AVP-D in PCP patients | Feng 2019 (72) | ||
| Similar patient survival/outcome | Weiner 1994 (17), Miller 1994 (18), Ersahin 2005 (25), Yamada 2010 (36), LopezSerna 2012 (41), Zygourakis 2014 (45), Zhang 2018 (69), Moreno-Torres 2021 (88), Wu 2022 (100), Awad 2023 (104) | ||
| Similar tumor recurrence rate | Crotty 1995 (20), Duff 2000 (22), Gupta 2006 (27), Shi 2006 (28), Pekmezci 2010 (35), Yamada 2010 (36), Park 2020 (78), Guo 2023 (107) | ||
| Increased survival and better outcome in PCPs | Kahn 1973 (11), Petito 1976 (12), Szeifert 1993 (16), Tavangar 2004 (24), Xu 2006 (29), TenaSuck 2009 (31),Yalcin 2009 (33), Cheng 2016 (47), Chu 2017 (58), Iglesias 2021 (86), Bobeff 2023 (105), Guo 2023 (107) | ||
| No recurrence following GTR in PCPs | Adamson 1990 (14), Szeifert 1993 (16), Weiner 1994 (17), Miller 1994 (18), Tavangar 2004 (25), Bobeff 2023 (105) | ||
| Lower PCP recurrence rate | Minamida 2005 (20), Xu 2006 TenaSuck 2009 (31), Yalcin 2009 (33) LopezSerna 2012 (41), Cheng 2016 (47), Chu 2017 (58), Iglesias 2021 (86), Wu 2022 (99) | ||
| Higher PCP recurrence rate | Mende 2020 (77) | ||
| Presenting symptoms | |||
| Hypothalamic | If present | Poor outcome | Prieto 2022 (97) |
| Psychiatric | If present | Poor outcome | Duff 2000a (22), Prieto 2022 (97) |
| Higher rate of postoperative hypothalamic injury | Prieto 2022 (97) | ||
| Poor neuropsychological outcome | Cao 2022a (91) | ||
| Visual | If present | Higher tumor recurrence rate | Sadashivam 2020a (79) |
| Endocrine | If more than 3 axes affected | Not related to postoperative weight gain | Dogra 2022a (93) |
| Higher rate of postoperative weight gain | Duan 2021a (82) | ||
| Weight gain | If absent or small | Higher rate of postoperative weight gain | Duan 2021a (82), Dogra 2022a (93) |
| Tumor features | |||
| Size | No relation with postoperative weight gain | Dogra 2022a (93) | |
| Small <2.5-3 cm | Higher rate of GTR | Bobeff 2023a (105) | |
| Increased survival/better outcome | Petito 1976 (12), Zacharia 2012a (42), Zhang 2018a (69), Wu 2022a (100), Bobeff 2023a (105) | ||
| Large (volume > 7 cm3) | Higher rate of postoperative psychiatric disturbances | Zhao 2021a (90) | |
| Topography | Tumors growing in the 3V floor (infundibulo-tuberal) | Poor outcome and higher rate of postoperative hypothalamic injury | Pan 2016a (53) |
| Higher rate of postoperative obesity | Bobeff 2023a (105) | ||
| Lower GTR rate | Pan 2016a (53), Jia 2023a (109) | ||
| Higher recurrence rate | Jia 2023 (109) | ||
| 3V involvement | Higher rate of postoperative psychiatric disturbances | Zhao 2021a (90) | |
| Strict 3V | Lower recurrence rate | Prieto 2022 (97) | |
| Better outcome | Jia 2023 (109) | ||
| Consistency | Cystic-cauliflower | Higher rate of postoperative hypothalamic injury | Prieto 2022 (97) |
| Macroscopic hypothalamic features | |||
| Hypothalamic edema | If present | Poor outcome | Prieto 2022 (97) |
| Type of tumor-hypothalamic adherence | Wide and dense | Poor outcome, and higher rate of tumor recurrence | Duff 2000a (22), Yu 2014a (44), Pan 2016a (53), Prieto 2016a (54), Prieto 2022 (97) |
| Higher rate of postoperative hypothalamic injury | Prieto 2022 (97) | ||
| Lower GTR rate | Jia 2023 (109) | ||
| Small-pedicle | Good outcome | Pan 2011 (38), Prieto 2016 (54) | |
| Type of hypothalamic involvement by the tumor | If invaded | Higher rate of postoperative psychiatric disturbances | Yang 2020a (80), Zhao 2021a (90) |
| Bilateral | Higher rate of postoperative DI and weight gain | Yang 2020a (80) | |
| Puget's grade | No relation with postoperative weight gain | Dogra 2022a (93) | |
| Treatment | |||
| Treatment modality | RT vs STR + RT vs GTR | Similar patient survival | Zhang 2018a (69) |
| RT | When administrated | Increased patient survival | Wu 2022a (100) |
| Surgical approach | Transcranial vs EEA | No differences in tumor recurrence | Jeswani 2016a (49), Park 2020a (78), Dandurand 2018a (62) |
| Higher rate of GTR with EEA | Nie 2022a (94) | ||
| Lower rate of GTR with EEA | Awad 2023a (104) | ||
| Lower recurrence rate with EEA | Nie 2022a (94) | ||
| Lower postoperative endocrine deficits with EEA | Li 2019a (75) | ||
| Better hypothalamic outcome with transcraneal removal of T-topography | Fan 2021a (83) | ||
| IH-TLT vs EEA | Higher rate of postoperative hypothalamic injury but better visual outcome with EEA | Chen 2023a (106) | |
| Degree of tumor removal | GTR vs STR | Similar patient survival | Wu 2022a (100) |
| Similar neuropsychological outcome | Giese 2019a (74) | ||
| Higher rate of postoperative psychiatric disturbances with GTR | Zhao 2021a (90) | ||
| Higher recurrence rate in STR | Kim 2012a (40), Dandurand 2018a (62), Sadashivam 2020a (79), Wu 2022a (99), Pang 2023a (108) | ||
| GTR vs STR + RT | Similar patient survival | Zhang 2018a (69), Awad 2023a (104) | |
| Similar tumor recurrence | Pang 2023a (108) | ||
| Lower recurrence rate in GTR | Kim 2012a (40), Dandurand 2018a (62), Wu 2022a (99), Bobeff 2023a (105) | ||
| STR vs STR + RT | Similar survival/recurrence | Tariq 2017 (13) | |
| Increased survival in STR + RT | Petito 1976 (12), Crotty 1995 (20), Kim 2012a (40), Zacharia 2012a (42), Dandurand 2018a (62), Zhang 2018a (69) | ||
| Lower recurrence rate in STR + RT | Petito 1976 (12), Crotty 1995 (20), Kim 2012a (40), Zacharia 2012a (42), Dandurand 2018a (62), Zhang 2018a (69), Awad 2023a (104) | ||
| GTR | No relation with postoperative weight gain | Dogra 2022a (93) | |
| Pituitary stalk | When preserved | Higher rate of tumor recurrence | Sadashivam 2020a (79), Bobeff 2023a (105) |
| Factor | Findings identified | Studies with a significant correlation (Ref) | |
|---|---|---|---|
| Comparison between PCP and ACP types | Good dissection plane and higher GTR in PCPs | Crotty 1995 (20) | |
| Microscopic brain invasion absent or extremely rare in PCPs | Adamson 1990 (14), Weiner 1994 (17), Miller 1994 (18), Crotty 1995 (20), Shi 2006 (28) | ||
| Higher rate of postoperative hypothalamic injury and AVP-D in PCP patients | Feng 2019 (72) | ||
| Similar patient survival/outcome | Weiner 1994 (17), Miller 1994 (18), Ersahin 2005 (25), Yamada 2010 (36), LopezSerna 2012 (41), Zygourakis 2014 (45), Zhang 2018 (69), Moreno-Torres 2021 (88), Wu 2022 (100), Awad 2023 (104) | ||
| Similar tumor recurrence rate | Crotty 1995 (20), Duff 2000 (22), Gupta 2006 (27), Shi 2006 (28), Pekmezci 2010 (35), Yamada 2010 (36), Park 2020 (78), Guo 2023 (107) | ||
| Increased survival and better outcome in PCPs | Kahn 1973 (11), Petito 1976 (12), Szeifert 1993 (16), Tavangar 2004 (24), Xu 2006 (29), TenaSuck 2009 (31),Yalcin 2009 (33), Cheng 2016 (47), Chu 2017 (58), Iglesias 2021 (86), Bobeff 2023 (105), Guo 2023 (107) | ||
| No recurrence following GTR in PCPs | Adamson 1990 (14), Szeifert 1993 (16), Weiner 1994 (17), Miller 1994 (18), Tavangar 2004 (25), Bobeff 2023 (105) | ||
| Lower PCP recurrence rate | Minamida 2005 (20), Xu 2006 TenaSuck 2009 (31), Yalcin 2009 (33) LopezSerna 2012 (41), Cheng 2016 (47), Chu 2017 (58), Iglesias 2021 (86), Wu 2022 (99) | ||
| Higher PCP recurrence rate | Mende 2020 (77) | ||
| Presenting symptoms | |||
| Hypothalamic | If present | Poor outcome | Prieto 2022 (97) |
| Psychiatric | If present | Poor outcome | Duff 2000a (22), Prieto 2022 (97) |
| Higher rate of postoperative hypothalamic injury | Prieto 2022 (97) | ||
| Poor neuropsychological outcome | Cao 2022a (91) | ||
| Visual | If present | Higher tumor recurrence rate | Sadashivam 2020a (79) |
| Endocrine | If more than 3 axes affected | Not related to postoperative weight gain | Dogra 2022a (93) |
| Higher rate of postoperative weight gain | Duan 2021a (82) | ||
| Weight gain | If absent or small | Higher rate of postoperative weight gain | Duan 2021a (82), Dogra 2022a (93) |
| Tumor features | |||
| Size | No relation with postoperative weight gain | Dogra 2022a (93) | |
| Small <2.5-3 cm | Higher rate of GTR | Bobeff 2023a (105) | |
| Increased survival/better outcome | Petito 1976 (12), Zacharia 2012a (42), Zhang 2018a (69), Wu 2022a (100), Bobeff 2023a (105) | ||
| Large (volume > 7 cm3) | Higher rate of postoperative psychiatric disturbances | Zhao 2021a (90) | |
| Topography | Tumors growing in the 3V floor (infundibulo-tuberal) | Poor outcome and higher rate of postoperative hypothalamic injury | Pan 2016a (53) |
| Higher rate of postoperative obesity | Bobeff 2023a (105) | ||
| Lower GTR rate | Pan 2016a (53), Jia 2023a (109) | ||
| Higher recurrence rate | Jia 2023 (109) | ||
| 3V involvement | Higher rate of postoperative psychiatric disturbances | Zhao 2021a (90) | |
| Strict 3V | Lower recurrence rate | Prieto 2022 (97) | |
| Better outcome | Jia 2023 (109) | ||
| Consistency | Cystic-cauliflower | Higher rate of postoperative hypothalamic injury | Prieto 2022 (97) |
| Macroscopic hypothalamic features | |||
| Hypothalamic edema | If present | Poor outcome | Prieto 2022 (97) |
| Type of tumor-hypothalamic adherence | Wide and dense | Poor outcome, and higher rate of tumor recurrence | Duff 2000a (22), Yu 2014a (44), Pan 2016a (53), Prieto 2016a (54), Prieto 2022 (97) |
| Higher rate of postoperative hypothalamic injury | Prieto 2022 (97) | ||
| Lower GTR rate | Jia 2023 (109) | ||
| Small-pedicle | Good outcome | Pan 2011 (38), Prieto 2016 (54) | |
| Type of hypothalamic involvement by the tumor | If invaded | Higher rate of postoperative psychiatric disturbances | Yang 2020a (80), Zhao 2021a (90) |
| Bilateral | Higher rate of postoperative DI and weight gain | Yang 2020a (80) | |
| Puget's grade | No relation with postoperative weight gain | Dogra 2022a (93) | |
| Treatment | |||
| Treatment modality | RT vs STR + RT vs GTR | Similar patient survival | Zhang 2018a (69) |
| RT | When administrated | Increased patient survival | Wu 2022a (100) |
| Surgical approach | Transcranial vs EEA | No differences in tumor recurrence | Jeswani 2016a (49), Park 2020a (78), Dandurand 2018a (62) |
| Higher rate of GTR with EEA | Nie 2022a (94) | ||
| Lower rate of GTR with EEA | Awad 2023a (104) | ||
| Lower recurrence rate with EEA | Nie 2022a (94) | ||
| Lower postoperative endocrine deficits with EEA | Li 2019a (75) | ||
| Better hypothalamic outcome with transcraneal removal of T-topography | Fan 2021a (83) | ||
| IH-TLT vs EEA | Higher rate of postoperative hypothalamic injury but better visual outcome with EEA | Chen 2023a (106) | |
| Degree of tumor removal | GTR vs STR | Similar patient survival | Wu 2022a (100) |
| Similar neuropsychological outcome | Giese 2019a (74) | ||
| Higher rate of postoperative psychiatric disturbances with GTR | Zhao 2021a (90) | ||
| Higher recurrence rate in STR | Kim 2012a (40), Dandurand 2018a (62), Sadashivam 2020a (79), Wu 2022a (99), Pang 2023a (108) | ||
| GTR vs STR + RT | Similar patient survival | Zhang 2018a (69), Awad 2023a (104) | |
| Similar tumor recurrence | Pang 2023a (108) | ||
| Lower recurrence rate in GTR | Kim 2012a (40), Dandurand 2018a (62), Wu 2022a (99), Bobeff 2023a (105) | ||
| STR vs STR + RT | Similar survival/recurrence | Tariq 2017 (13) | |
| Increased survival in STR + RT | Petito 1976 (12), Crotty 1995 (20), Kim 2012a (40), Zacharia 2012a (42), Dandurand 2018a (62), Zhang 2018a (69) | ||
| Lower recurrence rate in STR + RT | Petito 1976 (12), Crotty 1995 (20), Kim 2012a (40), Zacharia 2012a (42), Dandurand 2018a (62), Zhang 2018a (69), Awad 2023a (104) | ||
| GTR | No relation with postoperative weight gain | Dogra 2022a (93) | |
| Pituitary stalk | When preserved | Higher rate of tumor recurrence | Sadashivam 2020a (79), Bobeff 2023a (105) |
Abbreviations: ACP, adamantinomtaous craniopharyngioma; AVP-D, arginine vasopressin deficiency (diabetes insipidus); CP, craniopharyngioma; EEA, endoscopic endonasal approach; GTR, gross total resection; IH-TLT, interhemispheric-translamina terminalis; PCP, papillary craniopharyngioma; RT, radiation therapy; Ref, reference number; STR, subtotal resection.
aSeries without separate analysis by histological type.
There are, however, intrinsic pathological features that may determine the likelihood of achieving GTR among PCPs. Specifically, in the 560c we identified that a strictly 3V location (69%), a solid consistency (70%), a round morphology (67%), and the lack of surrounding hypothalamic edema (64%) are factors associated with higher GTR rates. A major underlying reason for easing removal under such circumstances is the usually low-risk hypothalamic attachment that PCPs with these features have. Total tumor removal was achieved in 80% of the patients whose tumors had low-risk attachments to the hypothalamus (P = .005) (Fig. 13A). The role that the tumor-hypothalamus relationship plays in determining the degree of tumor removed is supported by the lower total removal (52%) achieved in patients presenting with psychiatric disturbances, as these usually imply anatomical hypothalamic impairment.
Major factors related to the degree of tumor removal and recurrence in the subgroup of PCP patients of the cohort of 560 well-described individual PCP patients treated between 2006 and 2023 (118). (A) Stacked bar of the degree of tumor removal by tumor-hypothalamus adherence severity. Total removal decreased from 80.6% in tumors with low-risk attachment to 57.1% in those with high-risk attachment (P = .008). (B) Stacked bar of the degree of tumor removal by surgical approach. The highest rate of total tumor removal was achieved with the endoscopic endonasal approach (75.4%, P = .041). (C) Stacked bar of tumor recurrence by the degree of tumor removal. Recurrence rate decreased from 49.1% when any tumor remnant was left behind to 12% following total tumor removal (P < .001). (D) Stacked bar of tumor recurrence by tumor topography. The lowest rate of tumor recurrence occurred in strict 3V PCPs (20.3%, P = .003).
Abbreviations: 3V, third ventricle; EEA, endoscopic endonasal approach; PCP, papillary craniopharyngioma; w/FU>1y, with follow-up longer than 1 year.
Ongoing technical improvements have likely contributed to increasing the rates of total PCP removal. Focusing on the patients from the 560c operated between 2006 and 2023, overall GTR was 65% (Table 10). The excellent view provided by endoscopic techniques seems particularly noteworthy for the significantly higher GTR rate (75%) found in the EEA group (P = .041) (Table 11A, Fig. 13B). Beyond simple technical improvements, extensive surgical experience has proven to notably increase GTR, with rates as high as 90% in the largest PCP series treated with EEA (n = 101) that were operated in only 3 years at the Neurosurgical Department of Beijing Tiantan Hospital by Songbai Gui et al (109).
Surgical results and outcomes found in the 560c (118)
| Variable | No. of cases (%) | |||
|---|---|---|---|---|
| Periods of treatment | 1856-1980 | 141 (25.2) | ||
| 1981-2005 | 125 (22.3) | |||
| 2006-2023 | 294 (52.5) | |||
| Type of treatmenta | Overall (n = 499) | 1981-2005 (n = 109) | 2006-2023 (n = 249) | |
| Not treated | 99 (18) | 8 (7.3) | 8 (3.2) | |
| Surgery | 348 (69.7) | 73 (67) | 213 (85.5) | |
| Radiotherapy | 10 (2) | 6 (5.5) | 1 (0.4) | |
| Chemotherapy | 1 (0.2) | 0 (0) | 1 (0.4) | |
| Radiotherapy + Chemotherapy | 1 (0.2) | 0 (0) | 1 (0.4) | |
| Surgery + Radiotherapy | 43 (8.6) | 21 (19.3) | 20 (8) | |
| Surgery + Chemotherapy | 5 (1) | 1 (0.9) | 4 (1.6) | |
| Surgery + RT + Chemotherapy | 1 (0.2) | 0 (0) | 1 (0.4) | |
| Surgical approacha | Overall (n = 340) | 1981-2005 (n = 74) | 2006-2023 (n = 206) | |
| Subfrontal/pterional/interhemispheric | 100 (29.4) | 25 (33.8) | 48 (23.3) | |
| Transcranial_Translamina-terminalis | 54 (16) | 18 (24.3) | 34 (16.5) | |
| FTV/transcallosal | 63 (18.5) | 14 (18.9) | 32 (15.5) | |
| Transsphenoidal/EEA | 89 (26.2) | 5 (6.8) | 81 (39.3) | |
| Combined approaches | 11 (3.2) | 6 (8.1) | 3 (1.4) | |
| Others (Stereotactic biopsy/DC) | 23 (6.7) | 6 (8.1) | 8 (3.9) | |
| Degree of tumor removala | Overall (n = 342) | 1981-2005 (n = 86) | 2006-2023 (n = 197) | |
| None/Biopsy/Cyst drain | 35 (10.2) | 11 (12.8) | 11 (5.6) | |
| Partial | 62 (18.2) | 18 (20.9) | 25 (12.7) | |
| Subtotal | 63 (18.4) | 19 (22.1) | 33 (16.7) | |
| Total | 181 (53.2) | 38 (44.2) | 128 (65) | |
| Patient outcomea | Overall (n = 323) | 1981-2005 (n = 77) | 2006-2023 (n = 183) | |
| Good | 144 (44.5) | 43 (55.8) | 85 (46.4) | |
| Fair | 90 (27.9) | 22 (28.6) | 61 (33.4) | |
| Poor | 61 (18.9) | 9 (11.7) | 36 (19.7) | |
| Death | 28 (8.7) | 3 (3.9) | 1 (0.5) | |
| Postoperative symptoms of hypothalamic injurya | Overall (n = 272) | 1981-2005 (n = 67) | 2006-2023 (n = 155) | |
| 58 (21.3) | 6 (9) | 37 (23.8) | ||
| Postoperative AVP deficiency (diabetes insipidus)a | Overall (n = 98) | 1981-2005 (n = 18) | 2006-2023 (n = 70) | |
| Yes | 74 (75.5) | 10 (55.6) | 59 (84.3) | |
| Visual outcome (in patients with preoperative visual deficits)a | Overall (n = 141) | 1981-2005 (n = 38) | 2006-2023 (n = 81) | |
| Improved | 99 (70.2) | 30 (78.9) | 54 (66.7) | |
| Psychiatric outcome (in patients with preoperative psychiatric symptoms)a | Overall (n = 60) | 1981-2005 (n = 13) | 2006-2023 (n = 30) | |
| Improved | 34 (56.7) | 12 (92.3) | 17 (56.7) | |
| Tumor recurrencea | Overall (n = 253) | 1981-2005 (n = 64) | 2006-2023 (n = 137) | |
| Yes | 68 (26.9) | 14 (21.9) | 42 (30.7) | |
| No (follow-up < 1 year) | 96 (37.9) | 25 (39.1) | 44 (32.1) | |
| No (follow-up ≥ 1 year) | 89 (35.2) | 25 (39.1) | 51 (37.2) | |
| Variable | No. of cases (%) | |||
|---|---|---|---|---|
| Periods of treatment | 1856-1980 | 141 (25.2) | ||
| 1981-2005 | 125 (22.3) | |||
| 2006-2023 | 294 (52.5) | |||
| Type of treatmenta | Overall (n = 499) | 1981-2005 (n = 109) | 2006-2023 (n = 249) | |
| Not treated | 99 (18) | 8 (7.3) | 8 (3.2) | |
| Surgery | 348 (69.7) | 73 (67) | 213 (85.5) | |
| Radiotherapy | 10 (2) | 6 (5.5) | 1 (0.4) | |
| Chemotherapy | 1 (0.2) | 0 (0) | 1 (0.4) | |
| Radiotherapy + Chemotherapy | 1 (0.2) | 0 (0) | 1 (0.4) | |
| Surgery + Radiotherapy | 43 (8.6) | 21 (19.3) | 20 (8) | |
| Surgery + Chemotherapy | 5 (1) | 1 (0.9) | 4 (1.6) | |
| Surgery + RT + Chemotherapy | 1 (0.2) | 0 (0) | 1 (0.4) | |
| Surgical approacha | Overall (n = 340) | 1981-2005 (n = 74) | 2006-2023 (n = 206) | |
| Subfrontal/pterional/interhemispheric | 100 (29.4) | 25 (33.8) | 48 (23.3) | |
| Transcranial_Translamina-terminalis | 54 (16) | 18 (24.3) | 34 (16.5) | |
| FTV/transcallosal | 63 (18.5) | 14 (18.9) | 32 (15.5) | |
| Transsphenoidal/EEA | 89 (26.2) | 5 (6.8) | 81 (39.3) | |
| Combined approaches | 11 (3.2) | 6 (8.1) | 3 (1.4) | |
| Others (Stereotactic biopsy/DC) | 23 (6.7) | 6 (8.1) | 8 (3.9) | |
| Degree of tumor removala | Overall (n = 342) | 1981-2005 (n = 86) | 2006-2023 (n = 197) | |
| None/Biopsy/Cyst drain | 35 (10.2) | 11 (12.8) | 11 (5.6) | |
| Partial | 62 (18.2) | 18 (20.9) | 25 (12.7) | |
| Subtotal | 63 (18.4) | 19 (22.1) | 33 (16.7) | |
| Total | 181 (53.2) | 38 (44.2) | 128 (65) | |
| Patient outcomea | Overall (n = 323) | 1981-2005 (n = 77) | 2006-2023 (n = 183) | |
| Good | 144 (44.5) | 43 (55.8) | 85 (46.4) | |
| Fair | 90 (27.9) | 22 (28.6) | 61 (33.4) | |
| Poor | 61 (18.9) | 9 (11.7) | 36 (19.7) | |
| Death | 28 (8.7) | 3 (3.9) | 1 (0.5) | |
| Postoperative symptoms of hypothalamic injurya | Overall (n = 272) | 1981-2005 (n = 67) | 2006-2023 (n = 155) | |
| 58 (21.3) | 6 (9) | 37 (23.8) | ||
| Postoperative AVP deficiency (diabetes insipidus)a | Overall (n = 98) | 1981-2005 (n = 18) | 2006-2023 (n = 70) | |
| Yes | 74 (75.5) | 10 (55.6) | 59 (84.3) | |
| Visual outcome (in patients with preoperative visual deficits)a | Overall (n = 141) | 1981-2005 (n = 38) | 2006-2023 (n = 81) | |
| Improved | 99 (70.2) | 30 (78.9) | 54 (66.7) | |
| Psychiatric outcome (in patients with preoperative psychiatric symptoms)a | Overall (n = 60) | 1981-2005 (n = 13) | 2006-2023 (n = 30) | |
| Improved | 34 (56.7) | 12 (92.3) | 17 (56.7) | |
| Tumor recurrencea | Overall (n = 253) | 1981-2005 (n = 64) | 2006-2023 (n = 137) | |
| Yes | 68 (26.9) | 14 (21.9) | 42 (30.7) | |
| No (follow-up < 1 year) | 96 (37.9) | 25 (39.1) | 44 (32.1) | |
| No (follow-up ≥ 1 year) | 89 (35.2) | 25 (39.1) | 51 (37.2) | |
Abbreviations: 560c, cohort of 560 well-described individual papillary craniopharyngioma patients; AVP deficiency, arginine vasopressin deficiency; DC, decompressive craniectomy; EEA, endoscopic endonasal approach; FTV, frontal trans-ventricular approach; PCP, papillary craniopharyngioma; RT, radiation therapy; SF, subfrontal approach.
aResults (number of cases and percentages) are shown for the overall cohort and for the 2 most recent periods (1981-2005 and 2006-2023).
Surgical results and outcomes found in the 560c (118)
| Variable | No. of cases (%) | |||
|---|---|---|---|---|
| Periods of treatment | 1856-1980 | 141 (25.2) | ||
| 1981-2005 | 125 (22.3) | |||
| 2006-2023 | 294 (52.5) | |||
| Type of treatmenta | Overall (n = 499) | 1981-2005 (n = 109) | 2006-2023 (n = 249) | |
| Not treated | 99 (18) | 8 (7.3) | 8 (3.2) | |
| Surgery | 348 (69.7) | 73 (67) | 213 (85.5) | |
| Radiotherapy | 10 (2) | 6 (5.5) | 1 (0.4) | |
| Chemotherapy | 1 (0.2) | 0 (0) | 1 (0.4) | |
| Radiotherapy + Chemotherapy | 1 (0.2) | 0 (0) | 1 (0.4) | |
| Surgery + Radiotherapy | 43 (8.6) | 21 (19.3) | 20 (8) | |
| Surgery + Chemotherapy | 5 (1) | 1 (0.9) | 4 (1.6) | |
| Surgery + RT + Chemotherapy | 1 (0.2) | 0 (0) | 1 (0.4) | |
| Surgical approacha | Overall (n = 340) | 1981-2005 (n = 74) | 2006-2023 (n = 206) | |
| Subfrontal/pterional/interhemispheric | 100 (29.4) | 25 (33.8) | 48 (23.3) | |
| Transcranial_Translamina-terminalis | 54 (16) | 18 (24.3) | 34 (16.5) | |
| FTV/transcallosal | 63 (18.5) | 14 (18.9) | 32 (15.5) | |
| Transsphenoidal/EEA | 89 (26.2) | 5 (6.8) | 81 (39.3) | |
| Combined approaches | 11 (3.2) | 6 (8.1) | 3 (1.4) | |
| Others (Stereotactic biopsy/DC) | 23 (6.7) | 6 (8.1) | 8 (3.9) | |
| Degree of tumor removala | Overall (n = 342) | 1981-2005 (n = 86) | 2006-2023 (n = 197) | |
| None/Biopsy/Cyst drain | 35 (10.2) | 11 (12.8) | 11 (5.6) | |
| Partial | 62 (18.2) | 18 (20.9) | 25 (12.7) | |
| Subtotal | 63 (18.4) | 19 (22.1) | 33 (16.7) | |
| Total | 181 (53.2) | 38 (44.2) | 128 (65) | |
| Patient outcomea | Overall (n = 323) | 1981-2005 (n = 77) | 2006-2023 (n = 183) | |
| Good | 144 (44.5) | 43 (55.8) | 85 (46.4) | |
| Fair | 90 (27.9) | 22 (28.6) | 61 (33.4) | |
| Poor | 61 (18.9) | 9 (11.7) | 36 (19.7) | |
| Death | 28 (8.7) | 3 (3.9) | 1 (0.5) | |
| Postoperative symptoms of hypothalamic injurya | Overall (n = 272) | 1981-2005 (n = 67) | 2006-2023 (n = 155) | |
| 58 (21.3) | 6 (9) | 37 (23.8) | ||
| Postoperative AVP deficiency (diabetes insipidus)a | Overall (n = 98) | 1981-2005 (n = 18) | 2006-2023 (n = 70) | |
| Yes | 74 (75.5) | 10 (55.6) | 59 (84.3) | |
| Visual outcome (in patients with preoperative visual deficits)a | Overall (n = 141) | 1981-2005 (n = 38) | 2006-2023 (n = 81) | |
| Improved | 99 (70.2) | 30 (78.9) | 54 (66.7) | |
| Psychiatric outcome (in patients with preoperative psychiatric symptoms)a | Overall (n = 60) | 1981-2005 (n = 13) | 2006-2023 (n = 30) | |
| Improved | 34 (56.7) | 12 (92.3) | 17 (56.7) | |
| Tumor recurrencea | Overall (n = 253) | 1981-2005 (n = 64) | 2006-2023 (n = 137) | |
| Yes | 68 (26.9) | 14 (21.9) | 42 (30.7) | |
| No (follow-up < 1 year) | 96 (37.9) | 25 (39.1) | 44 (32.1) | |
| No (follow-up ≥ 1 year) | 89 (35.2) | 25 (39.1) | 51 (37.2) | |
| Variable | No. of cases (%) | |||
|---|---|---|---|---|
| Periods of treatment | 1856-1980 | 141 (25.2) | ||
| 1981-2005 | 125 (22.3) | |||
| 2006-2023 | 294 (52.5) | |||
| Type of treatmenta | Overall (n = 499) | 1981-2005 (n = 109) | 2006-2023 (n = 249) | |
| Not treated | 99 (18) | 8 (7.3) | 8 (3.2) | |
| Surgery | 348 (69.7) | 73 (67) | 213 (85.5) | |
| Radiotherapy | 10 (2) | 6 (5.5) | 1 (0.4) | |
| Chemotherapy | 1 (0.2) | 0 (0) | 1 (0.4) | |
| Radiotherapy + Chemotherapy | 1 (0.2) | 0 (0) | 1 (0.4) | |
| Surgery + Radiotherapy | 43 (8.6) | 21 (19.3) | 20 (8) | |
| Surgery + Chemotherapy | 5 (1) | 1 (0.9) | 4 (1.6) | |
| Surgery + RT + Chemotherapy | 1 (0.2) | 0 (0) | 1 (0.4) | |
| Surgical approacha | Overall (n = 340) | 1981-2005 (n = 74) | 2006-2023 (n = 206) | |
| Subfrontal/pterional/interhemispheric | 100 (29.4) | 25 (33.8) | 48 (23.3) | |
| Transcranial_Translamina-terminalis | 54 (16) | 18 (24.3) | 34 (16.5) | |
| FTV/transcallosal | 63 (18.5) | 14 (18.9) | 32 (15.5) | |
| Transsphenoidal/EEA | 89 (26.2) | 5 (6.8) | 81 (39.3) | |
| Combined approaches | 11 (3.2) | 6 (8.1) | 3 (1.4) | |
| Others (Stereotactic biopsy/DC) | 23 (6.7) | 6 (8.1) | 8 (3.9) | |
| Degree of tumor removala | Overall (n = 342) | 1981-2005 (n = 86) | 2006-2023 (n = 197) | |
| None/Biopsy/Cyst drain | 35 (10.2) | 11 (12.8) | 11 (5.6) | |
| Partial | 62 (18.2) | 18 (20.9) | 25 (12.7) | |
| Subtotal | 63 (18.4) | 19 (22.1) | 33 (16.7) | |
| Total | 181 (53.2) | 38 (44.2) | 128 (65) | |
| Patient outcomea | Overall (n = 323) | 1981-2005 (n = 77) | 2006-2023 (n = 183) | |
| Good | 144 (44.5) | 43 (55.8) | 85 (46.4) | |
| Fair | 90 (27.9) | 22 (28.6) | 61 (33.4) | |
| Poor | 61 (18.9) | 9 (11.7) | 36 (19.7) | |
| Death | 28 (8.7) | 3 (3.9) | 1 (0.5) | |
| Postoperative symptoms of hypothalamic injurya | Overall (n = 272) | 1981-2005 (n = 67) | 2006-2023 (n = 155) | |
| 58 (21.3) | 6 (9) | 37 (23.8) | ||
| Postoperative AVP deficiency (diabetes insipidus)a | Overall (n = 98) | 1981-2005 (n = 18) | 2006-2023 (n = 70) | |
| Yes | 74 (75.5) | 10 (55.6) | 59 (84.3) | |
| Visual outcome (in patients with preoperative visual deficits)a | Overall (n = 141) | 1981-2005 (n = 38) | 2006-2023 (n = 81) | |
| Improved | 99 (70.2) | 30 (78.9) | 54 (66.7) | |
| Psychiatric outcome (in patients with preoperative psychiatric symptoms)a | Overall (n = 60) | 1981-2005 (n = 13) | 2006-2023 (n = 30) | |
| Improved | 34 (56.7) | 12 (92.3) | 17 (56.7) | |
| Tumor recurrencea | Overall (n = 253) | 1981-2005 (n = 64) | 2006-2023 (n = 137) | |
| Yes | 68 (26.9) | 14 (21.9) | 42 (30.7) | |
| No (follow-up < 1 year) | 96 (37.9) | 25 (39.1) | 44 (32.1) | |
| No (follow-up ≥ 1 year) | 89 (35.2) | 25 (39.1) | 51 (37.2) | |
Abbreviations: 560c, cohort of 560 well-described individual papillary craniopharyngioma patients; AVP deficiency, arginine vasopressin deficiency; DC, decompressive craniectomy; EEA, endoscopic endonasal approach; FTV, frontal trans-ventricular approach; PCP, papillary craniopharyngioma; RT, radiation therapy; SF, subfrontal approach.
aResults (number of cases and percentages) are shown for the overall cohort and for the 2 most recent periods (1981-2005 and 2006-2023).
Surgical and outcome significant relationships found in the 560c (118)
| Variable | P-value | Type of relationshipa |
|---|---|---|
| Factors associated with type of surgical approach and degree of tumor removal | ||
| Surgical approach | <.001 | Strict-3V topography associated with TLT/FTV/Tc approaches |
| Degree of tumor removal | <.001 | Solid consistency associated with complete removal |
| .022 | Hypothalamic edema associated with incomplete removal | |
| <.001 | High-risk adherence associated with incomplete removal | |
| .026 | Higher rate of total removal in the Strict-3V topography | |
| .041 | Highest rate of total removal with EEA in period 2006-2023 | |
| Factors associated with postoperative hypothalamic injury and patient outcome | ||
| Visual impairment | .03 | If present associated with poor outcome/death in period 2006-2023 |
| HICP symptoms | .013 | If present associated with poor outcome/death |
| Endocrine deficits | .015 | If present associated with permanent AVP deficiency (diabetes insipidus) |
| Infundibulotuberal symptoms | .037 | If present with permanent AVP deficiency (diabetes insipidus) in period 2006-2023 |
| Hypogonadism | .02 | If present associated with hypothalamic injury |
| Somnolence | .003 | If present associated with poor outcome/death |
| Hypothalamic symptoms | .012 | If present associated with poor outcome/death |
| .024 | If present associated with hypothalamic injury | |
| Psychiatric alterations | <.001 | If present associated with poor outcome/death |
| .017 | If present associated with hypothalamic injury | |
| Tumor topography | <.001 | Low hormonal replacement therapy in 3V-Strict topography |
| Tumor consistency | .004 | Cauliflower-like associated with hypothalamic injury |
| Hypothalamic edema | .006 | If present associated with poor outcome/death and hypothalamic injury |
| Tumor-hypothalamus adherence | <.001 | High-risk adherence associated with poor outcome/death |
| <.001 | High-risk associated with hypothalamic injury | |
| .029 | High-risk associated with AVP deficiency (diabetes insipidus) | |
| Surgical approach | .046 | EEA associated with good outcome in period 2006-2023 |
| .04 | EEA with higher rate of postoperative visual improvement in period 2006-2023 | |
| Degree of tumor removal | <.001 | Total removal associated with good outcome |
| Factors associated with PCP recurrence | ||
| Hypothalamic symptoms | .033 | If present associated with low rate of recurrence |
| Visual impairment | .03 | If present associated with high rate of recurrence |
| Tumor topography | <.001 | Lowest recurrence rate in Strict-3V PCPs |
| Tumor-hypothalamus adherence | <.001 | High-risk adherence associated with PCP recurrence |
| Degree of tumor removal | <.001 | Total removal associated with lack of PCP recurrence |
| .004 | Total removal associated with longer time to recurrence | |
| Variable | P-value | Type of relationshipa |
|---|---|---|
| Factors associated with type of surgical approach and degree of tumor removal | ||
| Surgical approach | <.001 | Strict-3V topography associated with TLT/FTV/Tc approaches |
| Degree of tumor removal | <.001 | Solid consistency associated with complete removal |
| .022 | Hypothalamic edema associated with incomplete removal | |
| <.001 | High-risk adherence associated with incomplete removal | |
| .026 | Higher rate of total removal in the Strict-3V topography | |
| .041 | Highest rate of total removal with EEA in period 2006-2023 | |
| Factors associated with postoperative hypothalamic injury and patient outcome | ||
| Visual impairment | .03 | If present associated with poor outcome/death in period 2006-2023 |
| HICP symptoms | .013 | If present associated with poor outcome/death |
| Endocrine deficits | .015 | If present associated with permanent AVP deficiency (diabetes insipidus) |
| Infundibulotuberal symptoms | .037 | If present with permanent AVP deficiency (diabetes insipidus) in period 2006-2023 |
| Hypogonadism | .02 | If present associated with hypothalamic injury |
| Somnolence | .003 | If present associated with poor outcome/death |
| Hypothalamic symptoms | .012 | If present associated with poor outcome/death |
| .024 | If present associated with hypothalamic injury | |
| Psychiatric alterations | <.001 | If present associated with poor outcome/death |
| .017 | If present associated with hypothalamic injury | |
| Tumor topography | <.001 | Low hormonal replacement therapy in 3V-Strict topography |
| Tumor consistency | .004 | Cauliflower-like associated with hypothalamic injury |
| Hypothalamic edema | .006 | If present associated with poor outcome/death and hypothalamic injury |
| Tumor-hypothalamus adherence | <.001 | High-risk adherence associated with poor outcome/death |
| <.001 | High-risk associated with hypothalamic injury | |
| .029 | High-risk associated with AVP deficiency (diabetes insipidus) | |
| Surgical approach | .046 | EEA associated with good outcome in period 2006-2023 |
| .04 | EEA with higher rate of postoperative visual improvement in period 2006-2023 | |
| Degree of tumor removal | <.001 | Total removal associated with good outcome |
| Factors associated with PCP recurrence | ||
| Hypothalamic symptoms | .033 | If present associated with low rate of recurrence |
| Visual impairment | .03 | If present associated with high rate of recurrence |
| Tumor topography | <.001 | Lowest recurrence rate in Strict-3V PCPs |
| Tumor-hypothalamus adherence | <.001 | High-risk adherence associated with PCP recurrence |
| Degree of tumor removal | <.001 | Total removal associated with lack of PCP recurrence |
| .004 | Total removal associated with longer time to recurrence | |
Abbreviations: 3V, third ventricle; 560c, cohort of 560 well-described individual papillary craniopharyngioma patients; AVP deficiency, arginine vasopressin deficiency; EEA, endoscopic endonasal approach; FTV, frontal trans-ventricular approach; HICP, high intracranial pressure syndrome; PCP, papillary craniopharyngioma; Tc, transcallosal approach; TLT, trans-lamina terminalis approach.
aThese significant relationships were also confirmed for the subgroup of patients treated in the most recent period 2006-2023.
Surgical and outcome significant relationships found in the 560c (118)
| Variable | P-value | Type of relationshipa |
|---|---|---|
| Factors associated with type of surgical approach and degree of tumor removal | ||
| Surgical approach | <.001 | Strict-3V topography associated with TLT/FTV/Tc approaches |
| Degree of tumor removal | <.001 | Solid consistency associated with complete removal |
| .022 | Hypothalamic edema associated with incomplete removal | |
| <.001 | High-risk adherence associated with incomplete removal | |
| .026 | Higher rate of total removal in the Strict-3V topography | |
| .041 | Highest rate of total removal with EEA in period 2006-2023 | |
| Factors associated with postoperative hypothalamic injury and patient outcome | ||
| Visual impairment | .03 | If present associated with poor outcome/death in period 2006-2023 |
| HICP symptoms | .013 | If present associated with poor outcome/death |
| Endocrine deficits | .015 | If present associated with permanent AVP deficiency (diabetes insipidus) |
| Infundibulotuberal symptoms | .037 | If present with permanent AVP deficiency (diabetes insipidus) in period 2006-2023 |
| Hypogonadism | .02 | If present associated with hypothalamic injury |
| Somnolence | .003 | If present associated with poor outcome/death |
| Hypothalamic symptoms | .012 | If present associated with poor outcome/death |
| .024 | If present associated with hypothalamic injury | |
| Psychiatric alterations | <.001 | If present associated with poor outcome/death |
| .017 | If present associated with hypothalamic injury | |
| Tumor topography | <.001 | Low hormonal replacement therapy in 3V-Strict topography |
| Tumor consistency | .004 | Cauliflower-like associated with hypothalamic injury |
| Hypothalamic edema | .006 | If present associated with poor outcome/death and hypothalamic injury |
| Tumor-hypothalamus adherence | <.001 | High-risk adherence associated with poor outcome/death |
| <.001 | High-risk associated with hypothalamic injury | |
| .029 | High-risk associated with AVP deficiency (diabetes insipidus) | |
| Surgical approach | .046 | EEA associated with good outcome in period 2006-2023 |
| .04 | EEA with higher rate of postoperative visual improvement in period 2006-2023 | |
| Degree of tumor removal | <.001 | Total removal associated with good outcome |
| Factors associated with PCP recurrence | ||
| Hypothalamic symptoms | .033 | If present associated with low rate of recurrence |
| Visual impairment | .03 | If present associated with high rate of recurrence |
| Tumor topography | <.001 | Lowest recurrence rate in Strict-3V PCPs |
| Tumor-hypothalamus adherence | <.001 | High-risk adherence associated with PCP recurrence |
| Degree of tumor removal | <.001 | Total removal associated with lack of PCP recurrence |
| .004 | Total removal associated with longer time to recurrence | |
| Variable | P-value | Type of relationshipa |
|---|---|---|
| Factors associated with type of surgical approach and degree of tumor removal | ||
| Surgical approach | <.001 | Strict-3V topography associated with TLT/FTV/Tc approaches |
| Degree of tumor removal | <.001 | Solid consistency associated with complete removal |
| .022 | Hypothalamic edema associated with incomplete removal | |
| <.001 | High-risk adherence associated with incomplete removal | |
| .026 | Higher rate of total removal in the Strict-3V topography | |
| .041 | Highest rate of total removal with EEA in period 2006-2023 | |
| Factors associated with postoperative hypothalamic injury and patient outcome | ||
| Visual impairment | .03 | If present associated with poor outcome/death in period 2006-2023 |
| HICP symptoms | .013 | If present associated with poor outcome/death |
| Endocrine deficits | .015 | If present associated with permanent AVP deficiency (diabetes insipidus) |
| Infundibulotuberal symptoms | .037 | If present with permanent AVP deficiency (diabetes insipidus) in period 2006-2023 |
| Hypogonadism | .02 | If present associated with hypothalamic injury |
| Somnolence | .003 | If present associated with poor outcome/death |
| Hypothalamic symptoms | .012 | If present associated with poor outcome/death |
| .024 | If present associated with hypothalamic injury | |
| Psychiatric alterations | <.001 | If present associated with poor outcome/death |
| .017 | If present associated with hypothalamic injury | |
| Tumor topography | <.001 | Low hormonal replacement therapy in 3V-Strict topography |
| Tumor consistency | .004 | Cauliflower-like associated with hypothalamic injury |
| Hypothalamic edema | .006 | If present associated with poor outcome/death and hypothalamic injury |
| Tumor-hypothalamus adherence | <.001 | High-risk adherence associated with poor outcome/death |
| <.001 | High-risk associated with hypothalamic injury | |
| .029 | High-risk associated with AVP deficiency (diabetes insipidus) | |
| Surgical approach | .046 | EEA associated with good outcome in period 2006-2023 |
| .04 | EEA with higher rate of postoperative visual improvement in period 2006-2023 | |
| Degree of tumor removal | <.001 | Total removal associated with good outcome |
| Factors associated with PCP recurrence | ||
| Hypothalamic symptoms | .033 | If present associated with low rate of recurrence |
| Visual impairment | .03 | If present associated with high rate of recurrence |
| Tumor topography | <.001 | Lowest recurrence rate in Strict-3V PCPs |
| Tumor-hypothalamus adherence | <.001 | High-risk adherence associated with PCP recurrence |
| Degree of tumor removal | <.001 | Total removal associated with lack of PCP recurrence |
| .004 | Total removal associated with longer time to recurrence | |
Abbreviations: 3V, third ventricle; 560c, cohort of 560 well-described individual papillary craniopharyngioma patients; AVP deficiency, arginine vasopressin deficiency; EEA, endoscopic endonasal approach; FTV, frontal trans-ventricular approach; HICP, high intracranial pressure syndrome; PCP, papillary craniopharyngioma; Tc, transcallosal approach; TLT, trans-lamina terminalis approach.
aThese significant relationships were also confirmed for the subgroup of patients treated in the most recent period 2006-2023.
PCP Surgical Results: Impact of Clinico-pathological and Surgical Factors
Postoperative hypothalamic dysfunction and patient outcome
Medical literature is controversial regarding outcome differences between ACPs and PCPs, with some studies reporting better long-term outcomes for PCPs (11, 12, 16, 24, 31, 33, 47, 58, 86, 97, 105, 107), whereas others have failed to find any prognostic differences between the two histological types (17, 18, 25, 36, 41, 45, 88, 100) (Table 9). Lack of uniformity regarding the treatment strategies and follow-ups (12, 21), along with the intrinsic heterogeneity with regard to tumor consistency, topography, or hypothalamic adhesions, are all factors that work against clarifying this controversial issue. Analysis of the 99s showed that the mean overall survival in the large series providing separate information for the PCP type was 92%, the same rate as that calculated when considering both histological types. Moreover, the mean rates of favorable outcomes were very similar for the total number of CPs in the 99s and only the group of PCPs in this cohort, 81% and 78.5% respectively. This result coincides with the rate of favorable outcomes (80%, sum of cases with good and fair outcomes) found in the subgroup of PCP patients from the 560c operated between 2006 and 2023 (Table 10) (54, 96, 97). The overall surgical-mortality rate in the 560c was 8.7%, which is a figure markedly lower than that observed in a similar historical CP cohort with a majority of ACPs (54). This much better outcome prevails when analysis is restricted to the patients treated in the most recent period (from 2006 to 2023), with a perioperative death rate as low as 0.5%, which is 4 times lower than the average rate reported in modern CP surgical series with the usual ACP dominance (108). The seemingly better outcome of PCP surgery might be related to the predominance of low-risk tumor-hypothalamic adhesions in this histological type (54, 97).
Furthermore, the 560c identified several inherent pathological and clinical factors that decisively affect the individual outcome of PCP patients, particularly the type of tumor consistency, the severity of its attachment to the hypothalamus, and several hypothalamic symptoms (Table 11B, Fig. 14). Focusing on those patients operated between 2006 and 2023, it is worth stressing that when psychiatric disturbances were present, poor outcomes increased from 13% to 31% (P = .045) and postoperative hypothalamic injury rose from 24% to 34% (P = .032) (Fig. 14A). Likewise, more unfavorable outcomes were associated with the presence of other hypothalamic symptoms, such as somnolence, gait imbalance, or urinary incontinence. Such poor outcomes are largely substantiated by the serious impairment of critical hypothalamic areas in these patients (67, 242). Accordingly, the rate of postoperative hypothalamic alterations increased to 50% in those patients showing hypothalamic edema on preoperative MRI scans (P = .021) (Fig. 14B). Less favorable outcomes and a significantly higher rate of postoperative hypothalamic injury (60%) occurred in patients operated on from tumors with cauliflower-like consistencies (P = .003). On the contrary, hypothalamic injury only occurred in 19.5% of patients who had solid PCPs (Fig. 14C). Such a more favorable prognosis of solid PCPs is largely substantiated by the predominance of low-risk hypothalamic adhesions in lesions with this consistency (54).
Major factors related to postoperative hypothalamic injury and patient outcome in the subgroup of patients of the 560c treated between 2006 and 2023. (A-C) Stacked bars of postoperative hypothalamic injury by their major predictors. (A) By psychiatric disturbances. One-third of the patients presenting with mental alterations develop symptoms related to hypothalamic injury following surgery (P = .032). (B) By hypothalamic edema surrounding the tumor. Symptoms related to hypothalamic injury occurred in 50% of patients with hypothalamic edema on preoperative MRI (P = .021). (C) By tumor consistency. Note that 60% of patients with cauliflower-like lesions presented symptoms of hypothalamic injury following surgery (P = .003). (D-F) Stacked bars of patient outcome by their major predictors. (D) By tumor-hypothalamus adherence severity. Poor outcomes occurred in 26.8% of cases with high-risk hypothalamic attachments (P = .001). (E) By the degree of tumor removal. Total tumor removal associated with higher rates of good outcome (56.4%) while only 9.6% of poor outcome (P < .001). (F) By type of surgical approach. Poor outcome decreased from 25% following transcranial approaches to only 8.5% following the endoscopic endonasal approach (P = .046).
Abbreviations: EEA, endoscopic endonasal approach; MRI, magnetic resonance imaging.
The impact of the hypothalamus adhesion severity on the risk of causing hypothalamic injury during PCP removal is particularly striking (97, 377). The rate of postoperative hypothalamic injury was almost double in patients whose tumors had high-risk attachments (42%, P = .049), while good outcome rates were reduced to 31% (P = .001) (Fig. 14D). In agreement, Jia et al found in the largest surgical PCP series to date employing the EEA (n = 101 patients), that patients whose tumors corresponded to the infundibulo-tuberal topographical category, characterized by more dense attachments to the hypothalamus, had the worst functional outcome measured in the Karnofsky scale (29% scoring <70) (109). Accordingly, more cautious tumor handling should be advocated for those PCP patients who present psychic disturbances, particularly when their tumors have any consistency other than solid and when wide and tenacious attachments are found during surgery. The degree of 3VF destruction on postop MRI has been shown to correlate with postoperative development of symptoms related to hypothalamic dysfunction (79).
Finally, the analysis of the 560c also supports the impact that the degree of PCP removal has on patient outcome, as the rate of good outcome increased to 56% following GTR (P < .001) (Fig. 14E). Although a potential selection bias for GTR in tumors with less hypothalamic involvement cannot be ruled out, the contribution of residual tumor to survival shortening is supported by the benefit found with the administration of adjuvant RT following STR (12, 20, 40, 42, 62, 69). Regarding the fear that radical resections might increase surgical hypothalamic injury, contradictory results are found in the medical literature (74, 90). The data from the 560c also supports that patient outcome is influenced by the type of surgical approach used. More favorable outcomes were found in PCP patients operated through EEA than through TCA, and good outcomes decreased from 54% in the former to 37% in the latter (P = .046) (Fig. 14F). The reverse trend occurred for postoperative hypothalamic injury. Moreover, the analysis of the US National Inpatient Sample of 11 166 CPs from 1998 to 2014 found higher mortality and morbidity rates in the CP cohort treated through craniotomy than in the EEA cohort (378). Accordingly, some neurosurgeons with high expertise in EEA argue that GTR represents the key factor that may lead to the most favorable long-term tumor control and patient outcome (83, 109, 364, 368).
Visual and endocrine outcomes
Visual improvement after PCP removal ranges from 40% to 80% (20, 79, 109, 379). In the 560c, vision improved in 70% of patients overall. The rate of postoperative visual improvement, however, was significantly higher in patients operated with EEA (77%) than in those operated through classical TCA (54%, P = .040). Likewise, in a small series of 20 intraventricular PCPs, the greatest visual improvement occurred in those patients operated on with EEA, while the worst visual outcomes occurred with the interhemispheric-TLT approach (106). Several additional studies proved that EEA achieved better recovery of visual function (70-85% of patients) than transcranial routes (32, 40, 48, 49, 70, 76, 77, 83, 97, 106, 109). This better visual outcome with EEA is probably related to the direct view of the tumor-chiasm surgical plane, contributing to a less traumatic tumor dissection and better preservation of the tiny perforating vessels supplying the optic chiasm undersurface, an area usually hidden while using TCA corridors (91, 109, 380).
Nevertheless, the lack of visual recovery after surgery is still considerable among PCPs, ranging from 30% to 50% of patients (72, 91, 103, 105). Moreover, in the meta-analysis by Pang et al, the risk of postoperative visual deterioration was around 11% (108). Visual deterioration after EEA usually had an ischemic etiology, resolving in half of cases with supplemental oxygen and hypervolemic hypertensive therapy (381). Some studies have observed a higher risk of visual deterioration in PCPs than ACPs removed through EEA (77, 105), a finding that might be related to the usual lack of arachnoid layers between infundibulo-tuberal PCPs and the optic chiasm (54, 91, 105, 109). Severe preoperative visual defects, particularly when optic atrophy is present, dense tumor attachments to the optic chiasm, a tumor size larger than 3 cm, and GTR are additional factors that negatively influence visual outcome (79, 97, 232, 378, 380). PCPs infiltrating the optic chiasm and inducing a strong gliotic response and vasogenic edema along the optic pathways are the subgroup associated with the highest risk of chiasm injury during removal (199, 342, 344). Intraoperative monitoring of real-time visual function employing visual evoked potential has proved to be a useful method to predict the likelihood of postoperative visual deterioration, which increases from 10% to 25% when a transient potential decrease is recorded and up to 60% when the decrease is permanent (380).
Panhypopituitarism and AVP-D are 2 endocrine disturbances that invariably occur after radical/GTR of CPs (40, 70, 75, 78, 103). These 2 endocrine sequelae are related, respectively, to the anatomical status of the PS and ME, although their integrity does not guarantee a normal function. Permanent AVP-D and hypopituitarism were reported in 84% and 87.5% of the patients treated between 2006 and 2020 in the 560c. Postoperative permanent AVP-D, however, more commonly occurred among patients with the infundibulo-tuberal syndrome (94%, P = .037), as its presence indicates anatomical impairment of the ME (241, 242). Jung et al first demonstrated that surgical PS sparing partially or totally preserved the pituitary functions in up to 40% of patients (32). Similar results were obtained in the analysis of PS preservation by Ordoñez-Rubiano et al, who could avoid panhypopituitarism and AVP-D in 33% and 50% of patients in whom stalk preservation was achieved (66). In the series of 1054 CPs reported by Shi et al, the stalk remained intact after tumor removal in 49% of the patients, an anatomical status allowing 20% of women with preoperative amenorrhea to regain their normal menstrual cycle and become fertile postoperatively, as well as 16% of men to become sexually active again (60).
In the 2023 study by Bobeff et al, the PS could be preserved in 7 of the 13 totally removed PCPs employing the EEA, an action that reduced the rate of panhypopituitarism to only 35%, without tumor recurrence (105). The preferential 3V topography of PCPs above an intact PS, in addition to their more common loose adherences/small attachments to the infundibulum/tuber cinereum, supports a higher rate of PS preservation in PCPs than ACPs (54% vs 42%) (54). Nevertheless, anatomical stalk preservation did not reduce the rate of postoperative AVP-D in this histological type (105, 106). This finding supports that the main cause of vasopressin insufficiency postoperatively is the injury to the hypothalamic-neurohypophyseal tract (vasopressin pathway) at the infundibulo-tuberal region of 3VF, given the extreme vulnerability of the ME to surgical manipulation (234). Accordingly, Jia et al reported a marked reduction in postoperative AVP-D rate to only 38% of patients in the strictly 3V group, in which the anatomical integrity of the 3VF could be preserved after total removal (109).
Quality of life and neurocognitive outcome
The quality of life (QoL) of CP patients after treatment has become a growing concern in the medical literature, beyond the simple assessment of survival. Many long-term sequelae linked to neuroendocrine deficits and hypothalamic dysfunction such as progressive obesity, disruption of circadian rhythms, cognitive impairment, and personality changes have proved serious issues that significantly impair PCP patients’ QoL (67, 72, 74, 77, 80, 82, 107, 108, 242, 243, 258). A 2022 study found that hypothalamic injury represented the strongest QoL predictor in adult CP patients, at the major expense of fatigue, weight gain, emotional/cognitive deterioration, and sleep disturbances (382). Postoperative improvement of psychiatric symptoms is observed in only half of the PCP patients with preoperative mental disturbances (97). Nevertheless, despite the tremendous impact that neuropsychological and psychiatric disturbances have on the QoL of PCP patients and their relatives, these alterations have not been sufficiently addressed.
The most comprehensive assessment of the long-term neuropsychological and cognitive sequelae in adult CPs, was conducted in 2019 by Giese et al in a cohort of 71 patients (including 8 PCPs). The authors showed the deterioration of multiple neuropsychological functions in up to 75% of patients after surgery, the most prominent being a decreased reaction time, a defective working memory, and/or poor attentiveness (74). Moreover, 60% of patients reported a personality change, either toward more impulsive behaviors (20%) or toward a powerless or apathetic attitude, which had obliged them to change jobs or abandon them. Some CP-related identified factors were associated with a higher risk of postoperative neuropsychological disturbances, also valid for PCPs, were (1) a tumor volume larger than 9 cm3, (2) tumor extension into the 3V, (3) tumor expansion against the brain stem, and (4) tumor compression or invasion of the mammillary bodies and/or the fornices (74). Importantly, the bifrontal approach demonstrated to be a risk factor for a postoperative loss of attention and a worse working memory.
PCP recurrence
The term “recurrence” refers strictly to the reappearance of a tumor following a complete surgical resection, although for the sake of simplicity, in CP literature, it also concerns the regrowth of a known tumor remnant (26, 154). Controversy regarding differences in tumor recurrence between ACPs and PCPs is particularly striking in the medical literature. Numerous studies reported lower recurrence rates for PCPs (26, 29, 31, 33, 41, 47, 86, 99). Some authors even claim that tumor recurrence simply does not occur in the PCP type (24), particularly following GTR (14, 16-18, 105). Nevertheless, several others did not find differences between the 2 histological types (20, 22, 27, 28, 35, 36, 78, 107) (Table 9). Our review, based on data from the 99s and the 560c, makes clear that PCPs may recur just like ACPs (Tables 1 and 10). The mean recurrence rate was 22% both in the 66 large series of the 99s including both histological types and in the 36 ones with separate information for the PCP type. Moreover, the overall recurrence rate in 560c was 27%, and it occurred at a median time of 15 months. We believe that such a figure may certainly underestimate the real recurrence rate because fewer than a quarter of the follow-ups in 560c went beyond 3 years. Interestingly, the recurrence rate was slightly higher in the most recent period, due to complex recurrent PCP cases that have come to light after the recent introduction of therapies targeting BRAF mutations (134, 383, 384).
There is a broad consensus regarding the role played by tumor remnants in CP recurrence and the usefulness of adjuvant RT (Table 9). Prieto et al found that the strongest predictors of recurrence after CP surgery were the following 4 variables: (1) presence of tumor remnants after surgery, (2) lacking adjuvant RT after STR, (3) 3V involvement, and (4) tight CP adherences (154). Many authors have reported lower recurrence rates when RT was administered for the residual tumor (12, 20, 40, 42, 62, 69). In fact, a meta-analysis published in 2023 that compiled 106 large CP series (including 230 PCPs) supports that adjuvant RT following incomplete resections reduces the likelihood of recurrence to the same level as totally removed CPs (108). Additional works, including a meta-analysis of 974 CPs, suggest the superiority of GTR over STR plus RT to reduce tumor recurrence (40, 62, 99, 105). None of these works, however, provided a separate analysis of the PCP type. The 560c shows that PCP recurrence was definitively related to the degree of tumor removal. Focusing on the cases of the 560c operated in the most recent period, it is remarkable that the recurrence rate rose 4-fold from 12% after total removal to 49% when tumor resection was incomplete (P < .001) (Fig. 13C). Moreover, the mean time elapsed until tumor recurrence diagnosis was related with the degree of tumor removal: 2.3 years with incomplete removal vs 4 years following total removal (P = .033).
Beyond incomplete removal, the role of other intrinsic pathological factors as CP recurrence predictors is controversial (154). The analysis of tumor proliferative activity in 37 CP samples (9 PCPs) conducted by Duò et al did not find significant differences between the ACP and PCP types (385). However, the 560c showed some clinical and pathological factors related to PCP recurrence (Table 11C). Specifically, the recurrence rate significantly increased when the patients presented hypothalamic symptoms (P = .03) or visual deficits (P = .03). Likewise, the correlation between visual deficits and a higher recurrence rate was also found in the surgical outcome analysis by Sandashivam et al in a series of 95 adult CP patients (79). The 560c indicates that a plausible underlying reason is that vision impairment most commonly occurs in the not strictly or infundibulo-tuberal topographical category, whose recurrence rate was double (45%) that of 3V-strictly lesions, which rarely distorts the optic chiasm (20%, P = .003). Prieto et al observed that the likelihood of radical CP removal, either in primary or recurrent tumors, largely depended on tumor topography (386). As expected, tumor recurrence was even lower (9.7%) for those strictly 3V PCPs totally removed (Fig. 13D). A significantly higher recurrence rate was also reported for infundibulo-tuberal lesions in the analysis of 101 PCPs removed through the EEA by Jia et al (109). The authors suggested that the higher rate of strong adherence to the hypothalamus of this topographical category supports its higher recurrence. In the 560c, tumor recurrence rate roughly tripled in the subgroup of PCPs showing high-risk tumor-hypothalamic adherences (32%) compared to those cases with low-risk attachments (11%, P = .029). Thus, despite further analysis with longer follow-up periods being necessary, we should advocate a close follow-up of any patient with visual or hypothalamic symptoms, particularly with incompletely removed PCPs and when the tumor corresponds to an infundibulo-tuberal topography with wide and strong adhesions to the 3VF/walls.
Radiotherapy for PCPs
Traditionally, radiotherapy (RT) has been the cornerstone of adjuvant treatment for residual CPs (387, 388). Long-term results, side effects, and differences among RT modalities for the PCP type, however, are not well known, as the available published information regarding this therapy is essentially restricted to a few PCP case reports (389-394). In 1993, Inoue et al drew attention to a set of 3 PCPs that had completely disappeared with adjuvant conventional RT (394). After confirming the successful PCP response to RT in 6 additional cases, these authors coined the term “radiosensitive CP” for this potentially curable histology, encouraging further, in-depth analyses (19). Hitherto, however, no specific prospective study on the efficacy of RT in a cohort of PCPs has been published. Therefore, for the time being, any assumption regarding the indications, application protocols, efficacy, and/or complications derived from the different RT techniques employed for PCP treatment must necessarily be extrapolated and cautiously inferred from cohorts of adult CP patients (395-398). Such an extrapolation represents a serious drawback and evidences the need for further separate prospective studies.
Comparative Results Between GTR and STR Plus RT in PCPs
The optimal treatment of adult CPs remains controversial. Moreover, this is an age group in which RT is underutilized compared with the pediatric population (399). Radical removal has classically been recommended as the gold standard of CP treatment because it has proven to lengthen PFS as compared to STR (42, 62, 228, 361, 369, 400, 401). Nevertheless, when STR is combined with postoperative RT, outcomes and rates of local control have been found to be on par with GTR in several retrospective assessments (62, 218, 361, 397, 402, 403). Based on the Surveillance, Epidemiology and End Results (SEER) database, administration of RT following STR was also found to independently associate with prolonged survival time (42). A meta-analysis including 744 CP patients reported similar 5-year PFS rates (67% vs 69%) and 5-year overall survival rates (98% vs 99%) for GTR and STR + RT, respectively (401). A significantly better overall survival rate for adjuvant RT was also reported in a study with 991 CP patients (including 129 PCPs) from the SEER database published in 2022 (100). Accordingly, several experts have recommended STR + RT as an optimal strategy for long-term tumor control, while preserving pituitary and hypothalamic functions (141, 218). Comparable results between both strategies have also been reported in high-risk CPs, that is, with topographies primarily involving the hypothalamus. The multivariate meta-analysis on epidemiological and pathological factors related to CP outcome in a cohort of 1218 patients (97 PCPs) from the SEER database by Zhang et al did not observe significant differences in overall patient survival between GTR and RT, either as primary therapy or after STR (69).
Regarding tumor recurrence, substantial recurrence rates ranging from 20% to 40% on average (encompassing true recurrence after GTR or regrowth after incomplete resection) have been consistently reported, even after GTR, over a 5-year period (62, 79, 403, 404). A meta-analysis including 759 adult CP patients (including 156 PCPs) comparing the results between GTR, STR + RT, and RT found that the rates of tumor recurrence were 17%, 27%, and 45%, respectively; this trend toward a lower recurrence after GTR, however, did not reach statistical significance (62). In a meta-analysis providing separate data by histological type (749 ACPs and 205 PCPs), Wu et al showed that GTR was the only strategy showing a marked increase in PFS rate among PCP patients (99). By contrast, the comparative analysis conducted by Khriguian et al in a cohort of 24 adult CP patients (including 2 PCPs), showed a 5-year PFS rate of 100% in the group treated with STR + RT (that is, no recurrences), significantly better than the 69% observed for the GTR group (399). Accordingly, the authors advocated for the use of adjuvant RT following STR in both histological CP types in adults.
Nonetheless, it should be noted that most of the studies favoring STR + RT have made comparative analyses among patients treated with transcranial approaches (361, 404). Such conclusions are challenged when considering the latest CP surgical series in which the EEA is employed by surgical teams that have mastered this technique (102, 105, 109, 365). In the comparative analysis of tumor control after GTR through EEA vs STR followed by adjuvant RT within the first 3 months, conducted by Godil et al in a series of 44 adult CPs, the 5-year PFS reached 75% after GTR but only 45% after STR + RT (365). Interestingly, this study also found that a tumor volume smaller than 10 cm3 was a factor highly predictive of GTR, a characteristic present in all PCPs of their series. In the series of 111 CP patients (88 adults) treated with the EEA by the same senior author (Theodore H. Schwartz), GTR was associated with a lower recurrence rate (12.5%) than STR + RT (23.5%), and RT treatment did not significantly change the recurrence rate for not totally resected tumors (105). Thus, GTR through the EEA might yield better long-term results for the PCP histology, at least for small solid tumors confined within the 3V, than the alternative STR + RT strategy (80, 83, 105). Such excellent outcomes after surgical GTR with EEA must be interpreted cautiously in light of the steep learning curve and unparalleled experience gained by the pituitary surgeons involved in these studies (372). In centers with limited surgical experience, primary RT or adjuvant RT following an incomplete hypothalamic-sparing resection may represent judicious alternatives to GTR, particularly in elderly patients (86).
Radiation Modalities for PCPs
Conventional photon beam radiotherapy
Conventional RT of 45 to 55 gray (Gy) administered in fractionated doses of 1.8 to 2 Gy over a period of 5 to 7 weeks has been a standard treatment for residual/recurrent CPs for decades (254, 398). This multifraction RT modality has the objective of reducing the radiation toxicity to the hypothalamus-pituitary axis and optic pathways, but it is time-consuming and often precludes future salvage radiation in the event of tumor progression (398). Technological improvements, with 3D conformal RT and particularly, with the widely spread intensity-modulated photon radiotherapy, have improved the accuracy of radiation to target volumes while sparing critical radiosensitive adjacent structures (405). Alternatively, stereotactic radiotherapy (SRT) is a modality that combines precise focal delivery using an accurate 3D mapping technique and a sophisticated mobilization device that minimizes the marginal dose to normal tissues. Standard SRT is usually fractionated in 2 or more sessions (hypofractionated SRT) (388, 406).
Toxicity caused by RT can be classified as acute (within days), early delayed (within weeks), or late delayed (within months to years). The risk of brain injury depends on either the total dose or the dose per fraction administered, duration of treatment, and volume of normal brain irradiated (398, 407-409). Acute transient cyst enlargement may occur in up to 12% of patients during the initial 3 months post-RT. This may lead to visual deterioration or mass effect symptoms, requiring rapid cyst decompression, or it may go unnoticed, the cyst undergoing spontaneous shrinkage in the first 6 months post-RT (98, 409). Early delayed RT injuries include visual deterioration, hypopituitarism, cognitive impairment, or cerebral infarcts occurring in about 10% to 20% of patients. Late delayed effects of radiation necrosis may occur occasionally, from months to years after the treatment, affecting mainly the hypothalamus and the optic apparatus. The rate of optic neuropathy is below 3% for a total 50 to 55 Gy dose administered in daily doses of 1.8 Gy, but it significantly increased for doses higher than 55 Gy (409). A comprehensive analysis of toxicity associated with conventional RT in a cohort of 22 adult CP patients found no complications when the dose was below 55 Gy (410).
Stereotactic radiosurgery
Stereotactic radiosurgery (SRS) is a modality of SRT delivering a single, large dose of radiation. Compared to classic RT, SRS may reduce collateral radiation injury using a marginal dose of 12 Gy (range 9.5-16 Gy, median isodose line 55%) with 5-year and 10-year CP control rates of 70% and 44%, respectively (254). Two types of equipment, each employing different radiation sources and guiding devices, may be used: linear accelerators (LINAC, CyberKnife®, Novalis TX™, Elekta Synergy™), which employ X-rays, and the most used Gamma Knife® radiosurgery (GK), which utilizes gamma rays. GK minimizes the volume of irradiation to vital adjacent structures and is especially appropriate for well-circumscribed, small, solid PCPs located within the 3V (395, 396, 411, 412). Most series of adult CP patients treated with GK reported tumor control rates between 67% and 86% with a 5-year median follow-up (403, 412-414). In a series of 4 adult patients with solid 3V PCPs treated with a GK boost (10-12 Gy) after partial or STR, all tumors showed a dramatic size reduction (415). GK was also administered to 7 subtotally removed CPs in the series by Pan et al with no recurrence during the 2-year follow-up (53). In the 2021 Albano's meta-analysis including 11 large CP series treated with GK (877 patients, 617 of them adults), the 5-year PFS was 70% (395). Within this meta-analysis, only the studies by Kobayashi et al and Lee et al provided a comparative analysis between ACP and PCP types, none of them finding significant differences in the response to GK (396, 416). Finally, 2 patients in the series by Inoue et al and 7 patients in the 560c were treated with GK as a primary therapy after PCP-type histological confirmation. All correspond to small-medium, round, solid, 3V strict PCPs that showed a marked reduction in size or almost completely disappeared following GK treatment (19, 389, 391-393, 396).
Proton beam therapy
The most advanced and accurate form of SRS is proton-beam therapy, which uses protons instead of photons. In spite of the rapid expansion of proton treatment centers, the cost of this therapy makes it inaccessible for most CP patients. A major advantage of this technique is the improved radiation dose gradient between the tumor boundaries and the surrounding neurovascular structures. Thanks to Bragg's peak effect, a sharp dose reduction with no exit dose occurs, resulting in minimal deposition of radiation in the normal brain tissue surrounding the tumor (398). Proton therapy is considered the best RT modality for pediatric CP patients to spare cognitive function, but very few studies have analyzed its suitability for adults (397). Fitzek et al reported in 2006 the first series of adult CP patients (n = 10) treated with a combination of photon RT and proton therapy after biopsy or STR. The 10-year survival rate was 72% and the 10-year PFS 85%, with all the surviving patients maintaining an unaltered functional status (417). In 2020, Rutenberg et al published the largest series of adult CPs treated with proton therapy. It included 14 patients (2 PCPs), and the protocol applied a median dose of 54 Gy over 30 fractions of 1.8 Gy per fraction (397). All patients survived and were disease-free after 3 years of treatment. These results support the safety and efficacy of proton therapy in adult CPs (397).
PCP radiosensitivity: comparative results of different RT modalities
There is no consensus regarding the optimal timing of RT for residual or recurrent PCPs or the preferred modality, whether fractionated radiotherapy (FRT) or GK. Moreover, the specific PCP radiosensitivity to different RT modalities and protocols has not been analyzed separately from the pool of adult CPs in most studies. Overall, FRT (median total dose 50-55 Gy, 1.2-2 Gy per fraction), employing either photon-beam 3D conformal fractionated RT or intensity-modulated photon radiotherapy, yielded overall survival, progression-free survival (PFS) and local tumor control (LTC) rates of 76%, 83%, and 93%, respectively, at 10 years after treatment (98, 399). None of these studies provided independent analyses for each histological CP type. Meanwhile, a 2021 meta-analysis including 617 adult CPs treated with GK showed median overall survival, 10-year PFS, and 5-year LTC of 87%, 58% and 75%, respectively (395). No definitive conclusions can be drawn by comparing these prognostic results. Nevertheless, 9 case reports support GK as an excellent RT modality for the treatment of primary or recurrent PCPs (19, 389, 391-393, 396). All these lesions particularly radiosensitive to GK were round and pure solid PCPs with a strict 3V topography. Likewise, Albano's 2021 meta-analysis found that pure solid CPs responded much better to GK, with most of these lesions probably corresponding to PCPs (392, 403, 416, 418).
Only a few studies to date have comparatively assessed the therapeutic efficacy of FRT vs GK (419-421). In 2011, Jeon et al could not find any significant difference in CP recurrence (50 patients) between cases treated with adjuvant FRT/GK and salvage FRT/GK, independent of the RT modality employed (419). Similarly inconclusive results were reported by Komogawa et al in 2022 comparing immediate adjuvant RT (9 CPs) to salvage RT (12 CPs) and employing fractionated stereotactic radiotherapy (Novalis, 50 Gy in 30 fractions), hypofractionated stereotactic radiotherapy (GK or Novalis, 19-24 Gy in 3 fractions), or stereotactic radiosurgery (GK, 50% isodose 12-15 Gy) (420). All these RT modalities showed comparable effects in tumor control after STR, around 95%. Poiset et al published in 2024 the first comparative evaluation of CP histological type response to two treatment modalities (GTR vs STR + RT) plus 2 RT modalities (FRT vs GK), in a cohort of 115 adult CPs (including 27 PCPs) (421). This study, with well-matched populations for each CP type and RT modalities, showed no significant differences between treatments (5-year LTC of 72% after GTR vs 88% after STR + RT) or histological types regarding LTC. Concerning the comparison of RT modalities, FRT (54 Gy, 1.8 Gy per fraction) was associated with improved LTC compared to GK (median dose 12 Gy), given that 5 treatment failures were observed with the latter modality. The authors remarked that a majority of these failures occurred in patients who received <14 Gy, a dosage aiming to avoid optic radiation toxicity but weak when compared to the 50 to 54 Gy used with conventional FRT (421). Unfortunately, no independent analyses for the differential effect of each RT modality on the papillary type were performed, a shortcoming probably due to the reduced number of PCPs gathered. Likewise, most of the few studies analyzing proton RT efficacy focus on the pediatric ACP population, thus PCP radiosensitivity to this modality remains currently unknown (397). Proton therapy may be considered for adults not well suited to receive other SRS treatments (linear accelerator/GK), either due to large CP size (>3 cm) or close proximity (<3 mm) between the tumor and the optic pathways. Further prospective studies exclusively focused on PCP cohorts are necessary to discriminate potential differences in effectiveness among the wide spectrum of RT modalities for PCPs.
Targeted Treatment in BRAF V600E-mutant PCPs: A New Therapeutic Paradigm Currently Under Assessment
BRAF/MEK Inhibitors: Agents and Protocols
Inhibitors targeting BRAF (especially V600E mutations) and MEK specifically block the aberrant activation of the MAPK/ERK pathway, leading to reduced tumor growth and proliferation. BRAF/MEK inhibitors have already demonstrated remarkable effectiveness when used for treating patients with metastatic melanoma (169), and they represent a promising therapy for PCPs. BRAF inhibitors, such as vemurafenib and dabrafenib, specifically inhibit the mutated BRAFV600E kinase thus disrupting the MAPK/ERK signaling pathway. For their part, MEK inhibitors, like trametinib and cobimetinib, target MEK1- and MEK2- downstream components of the MAPK/ERK pathway (Fig. 4). BRAF and MEK inhibitors are often used in combination as a dual blockade of the signaling pathway, preventing or delaying the development of resistance that may occur when used as monotherapy (135). The most frequently used combination of drugs and dosages in PCPs have been 150 mg dabrafenib twice daily and 2 mg trametinib daily, or 960 mg vemurafenib twice daily for 28 days and 60 mg cobimetinib daily for 21 days (134, 331, 383, 384, 422-433). Treatment duration varies in all published case reports, often continuing until disease progression or unacceptable toxicity occurs. Despite some patients having durable responses, even after treatment was halted, long-term efficacy and safety data are still emerging. The most common side effects include skin rashes, fatigue, and gastrointestinal disturbances, which require regular monitoring and supportive care. Tumor resistance development, which is the major substantial challenge of this therapy in melanoma patients, however, has not yet been widely reported in PCPs. This could be explained by the comparatively simpler genomic landscape of PCPs, as these tumors have few copy number variations and their only driver mutation is BRAFV600E, as opposed to the more complex genetic alterations observed in melanomas.
Results of Targeted Treatment in Individual PCP Cases
Drawing from the previous insights, the team headed by P. Brastianos, and other groups, have reported on the efficacy of treatment with oral BRAF and/or MEK inhibitors in reducing tumor size and improving clinical outcomes in patients with BRAFV600E-mutant PCPs (134, 331, 383, 384, 422-433). Although the current information available is scarce and limited to individual case reports (Table 12), all authors highlight the benefits of these targeted therapies, suggesting that this treatment strategy can improve long-term QoL for certain PCP patients. Of note, the combined targeted therapy with both BRAF and MEK inhibitors seems to have better efficacy in terms of tumor volume reduction and rapidity of actions than a single BRAF inhibitor. The literature overview includes a report of the successful neo-adjuvant treatment of a 59-year-old male with a BRAFV600E-mutant PCP (433). This suggests that a possible treatment strategy for PCP patients may be biopsy followed by targeted therapy for tumor debulking and control, though histological confirmation might be obviated in the presence of highly reliable MRI signs of the papillary type (Table 13). A major limitation of BRAF/MEK inhibitor therapy, however, may be tumor recurrence when discontinued (134, 429, 432, 434), though Losa et al have demonstrated a similar optimal response to second and third courses with the same targeted treatment administered to a patient with a 3.5-year follow-up (434).
Overview of available and updated information on targeted therapy in patients with BRAFV600E mutant PCPs
| No. | Author, Year (Ref) | Age, Sex | Histology, molecular status | Initial treatment | Agents | Regimen | Response |
|---|---|---|---|---|---|---|---|
| 1 | Brastianos, 2015 (383) | 39 M | rPCP, BRAFV600E mutant | Multiple surgeries | Dabrafenib and Trametinib | 150 mg BID, 2 mg BID | PR (85% decrease) after 1 mo. |
| 2 | Aylwin, 2016 (134) | 57 F | rPCP, BRAFV600E mutant | Multiple surgeries | Vemurafenib | 960 mg BID | Near CR after 3 mo. |
| 3 | Rostami, 2017 (384) | 65 M | rPCP, BRAFV600E mutant | Multiple surgeries | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (91% decrease) after 4 mo. |
| 4 | Roque, 2017 (422) | 47 F | rPCP, BRAFV600E mutant | Surgery and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | CR after 7 mo. |
| 5 | Himes, 2018 (423) | 52 M | rPCP, BRAFV600E mutant | Surgery and RT | Dabrafenib | 150-225 mg QD | CR after 9 mo. |
| 6 | Juratli, 2019 (424) | 21 M | Residual PCP, BRAFV600E mutant | Biopsy | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>80% decrease) after 6 mo. |
| 7 | Calvanese, 2022 (331) | 40 M | rPCP, BRAFV600E mutant | Surgery | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>90% decrease) after 5 mo. |
| 8 | 69 M | Residual PCP, BRAFV600E mutant | Biopsy | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>90% decrease) after 4 mo. | |
| 9 | Bernstein, 2019 (425) | 60 M | rPCP, BRAFV600E mutant | Surgery and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | CR after 3 mo. |
| 10 | Rao, 2019 (426) | 35 M | Residual PCP, BRAFV600E mutant | Surgery | Dabrafenib | 150 mg BID | PR (>90% decrease) after 12 mo. |
| 11 | Di Stefano, 2020 (427) | 55 F | Residual PCP, BRAFV600E mutant | Biopsy | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | Near CR after 3.5 mo. |
| 12 | Khaddour, 2020 (428) | 39 M | rPCP, BRAFV600E mutant | Surgery | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>70% decrease) after 9 mo. |
| 13 | Chik, 2021 (429) | 37 M | rPCP, BRAFV600E mutant | Multiple surgeries | Vemurafenib | 960 mg BID | PR (>55% decrease) after 1.5 mo. |
| 14 | Nussbaum, 2022 (430) | 35 M | Residual PCP, BRAFV600E mutant | Surgery | Dabrafenib and Trametinib | 75 mg BID, 2 mg QD | Near CR after 21 mo. |
| 15 | Fasano, 2022 (431) | 62 M | rPCP, BRAFV600E mutant | Multiple surgeries and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD (reduced due to toxicity to 100 mg BID, 1.5 mg QD) | PR (>35% decrease) after 4 mo. |
| 16 | Wu ZP, 2023 (432) | 63 F | rPCP, BRAFV600E mutant | Multiple surgeries and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | CR after 5 mo. |
| 17 | 75 M | rPCP, BRAFV600E mutant | Surgery | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>40% decrease) after 2 mo. | |
| 18 | Lin, 2023 (433) | 59 M | Newly diagnosed PCP (not verified) | None | Dabrafenib | 150 mg BID | Near CR after 6.5 mo. |
| 19 | Losa, 2024 (434) | 75 M | rPCP, BRAFV600E mutant | Surgeries and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | Near CR after 6 mo. |
| No. | Author, Year (Ref) | Age, Sex | Histology, molecular status | Initial treatment | Agents | Regimen | Response |
|---|---|---|---|---|---|---|---|
| 1 | Brastianos, 2015 (383) | 39 M | rPCP, BRAFV600E mutant | Multiple surgeries | Dabrafenib and Trametinib | 150 mg BID, 2 mg BID | PR (85% decrease) after 1 mo. |
| 2 | Aylwin, 2016 (134) | 57 F | rPCP, BRAFV600E mutant | Multiple surgeries | Vemurafenib | 960 mg BID | Near CR after 3 mo. |
| 3 | Rostami, 2017 (384) | 65 M | rPCP, BRAFV600E mutant | Multiple surgeries | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (91% decrease) after 4 mo. |
| 4 | Roque, 2017 (422) | 47 F | rPCP, BRAFV600E mutant | Surgery and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | CR after 7 mo. |
| 5 | Himes, 2018 (423) | 52 M | rPCP, BRAFV600E mutant | Surgery and RT | Dabrafenib | 150-225 mg QD | CR after 9 mo. |
| 6 | Juratli, 2019 (424) | 21 M | Residual PCP, BRAFV600E mutant | Biopsy | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>80% decrease) after 6 mo. |
| 7 | Calvanese, 2022 (331) | 40 M | rPCP, BRAFV600E mutant | Surgery | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>90% decrease) after 5 mo. |
| 8 | 69 M | Residual PCP, BRAFV600E mutant | Biopsy | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>90% decrease) after 4 mo. | |
| 9 | Bernstein, 2019 (425) | 60 M | rPCP, BRAFV600E mutant | Surgery and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | CR after 3 mo. |
| 10 | Rao, 2019 (426) | 35 M | Residual PCP, BRAFV600E mutant | Surgery | Dabrafenib | 150 mg BID | PR (>90% decrease) after 12 mo. |
| 11 | Di Stefano, 2020 (427) | 55 F | Residual PCP, BRAFV600E mutant | Biopsy | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | Near CR after 3.5 mo. |
| 12 | Khaddour, 2020 (428) | 39 M | rPCP, BRAFV600E mutant | Surgery | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>70% decrease) after 9 mo. |
| 13 | Chik, 2021 (429) | 37 M | rPCP, BRAFV600E mutant | Multiple surgeries | Vemurafenib | 960 mg BID | PR (>55% decrease) after 1.5 mo. |
| 14 | Nussbaum, 2022 (430) | 35 M | Residual PCP, BRAFV600E mutant | Surgery | Dabrafenib and Trametinib | 75 mg BID, 2 mg QD | Near CR after 21 mo. |
| 15 | Fasano, 2022 (431) | 62 M | rPCP, BRAFV600E mutant | Multiple surgeries and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD (reduced due to toxicity to 100 mg BID, 1.5 mg QD) | PR (>35% decrease) after 4 mo. |
| 16 | Wu ZP, 2023 (432) | 63 F | rPCP, BRAFV600E mutant | Multiple surgeries and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | CR after 5 mo. |
| 17 | 75 M | rPCP, BRAFV600E mutant | Surgery | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>40% decrease) after 2 mo. | |
| 18 | Lin, 2023 (433) | 59 M | Newly diagnosed PCP (not verified) | None | Dabrafenib | 150 mg BID | Near CR after 6.5 mo. |
| 19 | Losa, 2024 (434) | 75 M | rPCP, BRAFV600E mutant | Surgeries and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | Near CR after 6 mo. |
BRAF inhibitors: Vemurafenib, Dabrafenib. MEK inhibitor: Trametinib.
Abbreviations: BID, 2 times a day; CR, complete response; mo., months; PCP, papillary craniopharyngioma; PR, partial response; QD, once a day; rPCP, recurrent papillary craniopharyngioma; RT, radiation therapy.
Overview of available and updated information on targeted therapy in patients with BRAFV600E mutant PCPs
| No. | Author, Year (Ref) | Age, Sex | Histology, molecular status | Initial treatment | Agents | Regimen | Response |
|---|---|---|---|---|---|---|---|
| 1 | Brastianos, 2015 (383) | 39 M | rPCP, BRAFV600E mutant | Multiple surgeries | Dabrafenib and Trametinib | 150 mg BID, 2 mg BID | PR (85% decrease) after 1 mo. |
| 2 | Aylwin, 2016 (134) | 57 F | rPCP, BRAFV600E mutant | Multiple surgeries | Vemurafenib | 960 mg BID | Near CR after 3 mo. |
| 3 | Rostami, 2017 (384) | 65 M | rPCP, BRAFV600E mutant | Multiple surgeries | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (91% decrease) after 4 mo. |
| 4 | Roque, 2017 (422) | 47 F | rPCP, BRAFV600E mutant | Surgery and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | CR after 7 mo. |
| 5 | Himes, 2018 (423) | 52 M | rPCP, BRAFV600E mutant | Surgery and RT | Dabrafenib | 150-225 mg QD | CR after 9 mo. |
| 6 | Juratli, 2019 (424) | 21 M | Residual PCP, BRAFV600E mutant | Biopsy | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>80% decrease) after 6 mo. |
| 7 | Calvanese, 2022 (331) | 40 M | rPCP, BRAFV600E mutant | Surgery | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>90% decrease) after 5 mo. |
| 8 | 69 M | Residual PCP, BRAFV600E mutant | Biopsy | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>90% decrease) after 4 mo. | |
| 9 | Bernstein, 2019 (425) | 60 M | rPCP, BRAFV600E mutant | Surgery and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | CR after 3 mo. |
| 10 | Rao, 2019 (426) | 35 M | Residual PCP, BRAFV600E mutant | Surgery | Dabrafenib | 150 mg BID | PR (>90% decrease) after 12 mo. |
| 11 | Di Stefano, 2020 (427) | 55 F | Residual PCP, BRAFV600E mutant | Biopsy | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | Near CR after 3.5 mo. |
| 12 | Khaddour, 2020 (428) | 39 M | rPCP, BRAFV600E mutant | Surgery | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>70% decrease) after 9 mo. |
| 13 | Chik, 2021 (429) | 37 M | rPCP, BRAFV600E mutant | Multiple surgeries | Vemurafenib | 960 mg BID | PR (>55% decrease) after 1.5 mo. |
| 14 | Nussbaum, 2022 (430) | 35 M | Residual PCP, BRAFV600E mutant | Surgery | Dabrafenib and Trametinib | 75 mg BID, 2 mg QD | Near CR after 21 mo. |
| 15 | Fasano, 2022 (431) | 62 M | rPCP, BRAFV600E mutant | Multiple surgeries and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD (reduced due to toxicity to 100 mg BID, 1.5 mg QD) | PR (>35% decrease) after 4 mo. |
| 16 | Wu ZP, 2023 (432) | 63 F | rPCP, BRAFV600E mutant | Multiple surgeries and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | CR after 5 mo. |
| 17 | 75 M | rPCP, BRAFV600E mutant | Surgery | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>40% decrease) after 2 mo. | |
| 18 | Lin, 2023 (433) | 59 M | Newly diagnosed PCP (not verified) | None | Dabrafenib | 150 mg BID | Near CR after 6.5 mo. |
| 19 | Losa, 2024 (434) | 75 M | rPCP, BRAFV600E mutant | Surgeries and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | Near CR after 6 mo. |
| No. | Author, Year (Ref) | Age, Sex | Histology, molecular status | Initial treatment | Agents | Regimen | Response |
|---|---|---|---|---|---|---|---|
| 1 | Brastianos, 2015 (383) | 39 M | rPCP, BRAFV600E mutant | Multiple surgeries | Dabrafenib and Trametinib | 150 mg BID, 2 mg BID | PR (85% decrease) after 1 mo. |
| 2 | Aylwin, 2016 (134) | 57 F | rPCP, BRAFV600E mutant | Multiple surgeries | Vemurafenib | 960 mg BID | Near CR after 3 mo. |
| 3 | Rostami, 2017 (384) | 65 M | rPCP, BRAFV600E mutant | Multiple surgeries | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (91% decrease) after 4 mo. |
| 4 | Roque, 2017 (422) | 47 F | rPCP, BRAFV600E mutant | Surgery and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | CR after 7 mo. |
| 5 | Himes, 2018 (423) | 52 M | rPCP, BRAFV600E mutant | Surgery and RT | Dabrafenib | 150-225 mg QD | CR after 9 mo. |
| 6 | Juratli, 2019 (424) | 21 M | Residual PCP, BRAFV600E mutant | Biopsy | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>80% decrease) after 6 mo. |
| 7 | Calvanese, 2022 (331) | 40 M | rPCP, BRAFV600E mutant | Surgery | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>90% decrease) after 5 mo. |
| 8 | 69 M | Residual PCP, BRAFV600E mutant | Biopsy | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>90% decrease) after 4 mo. | |
| 9 | Bernstein, 2019 (425) | 60 M | rPCP, BRAFV600E mutant | Surgery and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | CR after 3 mo. |
| 10 | Rao, 2019 (426) | 35 M | Residual PCP, BRAFV600E mutant | Surgery | Dabrafenib | 150 mg BID | PR (>90% decrease) after 12 mo. |
| 11 | Di Stefano, 2020 (427) | 55 F | Residual PCP, BRAFV600E mutant | Biopsy | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | Near CR after 3.5 mo. |
| 12 | Khaddour, 2020 (428) | 39 M | rPCP, BRAFV600E mutant | Surgery | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>70% decrease) after 9 mo. |
| 13 | Chik, 2021 (429) | 37 M | rPCP, BRAFV600E mutant | Multiple surgeries | Vemurafenib | 960 mg BID | PR (>55% decrease) after 1.5 mo. |
| 14 | Nussbaum, 2022 (430) | 35 M | Residual PCP, BRAFV600E mutant | Surgery | Dabrafenib and Trametinib | 75 mg BID, 2 mg QD | Near CR after 21 mo. |
| 15 | Fasano, 2022 (431) | 62 M | rPCP, BRAFV600E mutant | Multiple surgeries and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD (reduced due to toxicity to 100 mg BID, 1.5 mg QD) | PR (>35% decrease) after 4 mo. |
| 16 | Wu ZP, 2023 (432) | 63 F | rPCP, BRAFV600E mutant | Multiple surgeries and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | CR after 5 mo. |
| 17 | 75 M | rPCP, BRAFV600E mutant | Surgery | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | PR (>40% decrease) after 2 mo. | |
| 18 | Lin, 2023 (433) | 59 M | Newly diagnosed PCP (not verified) | None | Dabrafenib | 150 mg BID | Near CR after 6.5 mo. |
| 19 | Losa, 2024 (434) | 75 M | rPCP, BRAFV600E mutant | Surgeries and RT | Dabrafenib and Trametinib | 150 mg BID, 2 mg QD | Near CR after 6 mo. |
BRAF inhibitors: Vemurafenib, Dabrafenib. MEK inhibitor: Trametinib.
Abbreviations: BID, 2 times a day; CR, complete response; mo., months; PCP, papillary craniopharyngioma; PR, partial response; QD, once a day; rPCP, recurrent papillary craniopharyngioma; RT, radiation therapy.
Summary of the major neuroradiological signs indicating a papillary CP type as opposed to an adamantinomatous CP
| Variable | Sign | |
|---|---|---|
| Tumor calcification |
|  |
| Tumor shape |
| |
| Tumor consistency |
| |
| Basal duct-like recess |
| |
| Sella |
| |
| Pituitary stalk and gland |
| |
| Chiasmatic cistern |
| |
| Hypothalamus level |
| |
| Thrid ventricle |
| |
| Optic chiasm |
| |
| Hypothalamus/optic tract edema |
| |
| Variable | Sign | |
|---|---|---|
| Tumor calcification |
| |
| Tumor shape |
| |
| Tumor consistency |
| |
| Basal duct-like recess |
| |
| Sella |
| |
| Pituitary stalk and gland |
| |
| Chiasmatic cistern |
| |
| Hypothalamus level |
| |
| Thrid ventricle |
| |
| Optic chiasm |
| |
| Hypothalamus/optic tract edema |
| |
Abbreviations: 3V, third ventricle; CT, computed tomography; MRI, magnetic resonance imaging; t-free, tumor free.
Summary of the major neuroradiological signs indicating a papillary CP type as opposed to an adamantinomatous CP
| Variable | Sign | |
|---|---|---|
| Tumor calcification |
| |
| Tumor shape |
| |
| Tumor consistency |
| |
| Basal duct-like recess |
| |
| Sella |
| |
| Pituitary stalk and gland |
| |
| Chiasmatic cistern |
| |
| Hypothalamus level |
| |
| Thrid ventricle |
| |
| Optic chiasm |
| |
| Hypothalamus/optic tract edema |
| |
| Variable | Sign | |
|---|---|---|
| Tumor calcification |
| |
| Tumor shape |
| |
| Tumor consistency |
| |
| Basal duct-like recess |
| |
| Sella |
| |
| Pituitary stalk and gland |
| |
| Chiasmatic cistern |
| |
| Hypothalamus level |
| |
| Thrid ventricle |
| |
| Optic chiasm |
| |
| Hypothalamus/optic tract edema |
| |
Abbreviations: 3V, third ventricle; CT, computed tomography; MRI, magnetic resonance imaging; t-free, tumor free.
Case reports published between 2020 and 2022 that identified BRAF-mutant PCPs in pediatric patients have sparked a debate regarding the most suitable adjuvant therapy, particularly for those with postoperative residual tumors or progression (161, 430). Management strategies are particularly lacking for this age group, as PCPs are exceedingly rare in children. Nevertheless, concerns regarding the long-term adverse effects of RT on neurocognition, vascular injury, and endocrine dysfunction are significant. Targeted therapy using BRAF inhibitors provides a viable alternative option. However, as of now, there is a lack of data on the efficacy and safety of BRAF and/or MEK inhibition in children with BRAF-mutant PCPs. This gap in knowledge underscores the urgent need to better understand the potential of these targeted therapies in managing this rare and challenging condition in children.
Results From Clinical Trials of BRAF/MEK Inhibition in PCPs
The NCT03224767 phase 2 clinical trial published in 2023 by Brastianos et al evaluated the safety and efficacy of BRAF–MEK inhibition in patients with newly diagnosed PCPs who had not undergone previous RT (135). The study included 16 patients with PCPs that tested positive for BRAF mutations and had measurable tumors. They received the BRAF–MEK inhibitor combination vemurafenib–cobimetinib in 28-day cycles. The primary endpoint of the study was the objective response at 4 months, determined by volumetric data. Targeted therapy with the BRAF–MEK inhibitor combination vemurafenib–cobimetinib led to dramatic tumor responses (Fig. 15). All patients who completed at least 1 therapy cycle responded to treatment within 4 months. Specifically, 94% of the patients had a durable objective partial response or better to the therapy, with a median reduction in tumor volume of 91%. PFS was 87% at 12 months and 58% at 24 months. The treatment also resulted in a substantial decrease in potential radiation volumes among patients who had received a short course of treatment with vemurafenib–cobimetinib, suggesting that targeted treatment may reduce the risk of RT-associated toxic effects. Related adverse events had a similar profile to those reported with other tumors. Twelve patients had severe grade 3 symptoms (most commonly maculopapular rash) and 2 life-threatening grade 4 consequences (increased creatinine kinase level or hyperglycemia). Toxic effects led to treatment discontinuation in only 3 cases.
Sagittal post-gadolinium T1W MRI depicting a third ventricle papillary craniopharyngioma (arrow) at baseline (A), 8 weeks after initiation of therapy with BRAF-MEK inhibitor combination vemurafenib-cobimetinib (B), and with sustained response at 22 months (C). Reproduced with permission from The New England Journal of Medicine, Brastianos et al (135).
This trial has prompted reconsideration of the existing clinical approach for the treatment of newly diagnosed PCPs. Medical caregivers may prioritize targeted therapy (with or without biopsy) followed by definitive surgery or RT. This study also identified circulating mutant BRAF DNA in the blood of a subset of patients, which raises the intriguing possibility of noninvasive genomic diagnostics and monitoring for these patients from blood (135). Nevertheless, this study also highlights the need for additional clinical research to address several outstanding questions, such as the impact on visual, endocrine, and neuropsychological outcome, and to optimize the application of these treatment modalities for improving long-term quality of life for PCP patients. While combining BRAF and MEK inhibitors has demonstrated successful responses in untreated/primary PCPs, another arm of the clinical trial that is currently enrolling patients aims to assess the effect of BRAF and MEK inhibitor combination in PCPs that have progressed after prior RT. Finally, new therapy targets have been recently identified in PCPs such as the high-level expression of the immune checkpoint regulating protein PD-L1, in the proliferating basal compartment of the tumor epithelium (435), immunosuppression via extracellular adenosine signaling by the CD39-CD73 ectoenzymes (436), and expression of multiple targets of available antibody drugs conjugates (437), which offers additional therapy opportunities for patients in whom long-term treatment with BRAF-MEK inhibition is not feasible.
Conclusions
First identified in the mid-19th century, PCPs are now recognized as a separate CP type based on their distinct histology and the presence of the oncogenic BRAFV600E mutation, in contrast to the CTNNB1 mutations of ACPs. The pathogenesis of PCPs remains undefined, but unlike ACPs, most PCPs originally develop at the infundibulo-tuberal region of the 3VF, topographically grow within the 3V, and largely affect the adult/elderly population. Contrary to the mixed solid-cystic multilobulated morphology and calcified content of ACPs, PCPs lack calcifications and usually have a smooth round shape, either with a pure solid consistency or a unilocular cyst with a basal nodule. Over half of PCPs can be differentiated from ACPs by the presence of a basal duct-like recess. This is a pathognomonic MRI sign of the papillary type. As lesions that predominantly expand within the 3V, PCPs inflict both anatomical and functional damage to the hypothalamus. The most noteworthy hypothalamic symptoms are a complex set of psychiatric disturbances, including memory/cognitive deficits, emotional instability, odd behavior, and personality changes. Particularly challenging from a surgical perspective, the dramatic technological progress in endoscope-assisted skull base surgery and the vast expertise gained with the endoscopic endonasal approach in the last 2 decades has allowed a safe radical removal of intra-third ventricle PCPs, which, until recently, were deemed not amenable of resection through this corridor. For lesions tightly adherent to the hypothalamus, GK and proton-beam therapy have proven to be valid adjuvant RT modalities to control tumor progression over the long term. Targeted treatment with BRAF/MEK inhibitors has been effective in reducing tumor size and improving clinical outcomes in BRAFV600E-mutant PCP patients and may represent a new therapeutic paradigm. Questions still remain regarding the optimal duration and timing of treatment with BRAF/MEK inhibitors and warrant further study.
Acknowledgments
The authors wish to especially thank Crystal Smith and Liliya Gusakova, reference librarians at the National Library of Medicine, National Institutes of Health (Bethesda, MD); Lucretia Maclure and Jack Eckert, librarians at the Francis Countway Medical Library at Harvard Medical School (Boston, MA); as well as Melissa Grafe, John R. Bumstead Librarian for Medical History, Head of the Medical Library of the Cushing/Whitney Medical Library and Bill Landis of the Manuscript and Archives Department of the Sterling Memorial Library, Yale University (New Haven, CT) for their invaluable assistance during the process of searching and retrieving the original works used in this study. We are very grateful to Maria Rosdolsky for assisting with the translation of German works. We are also indebted to Eduard Winter and Verena Hofecker from the Pathologisch-anatomische Sammlung im Narrenturm-NHM, Vienna, Austria, for allowing us access to the collection of brain tumor specimens. Finally, we are grateful to George Hamilton for his critical review of the language and style of the manuscript.
Funding
This work did not receive specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Disclosures
R.P., E.D.B., L.B., J.M.P.: none. T.A.J.: Speaker's Honoraria from CSL Behring. S.S.: Research Funding from Merck, Speaker Honarium: Novartis. P.K.B.: Consulted for Angiochem, Advise Connect Inspire, Atavistik Bio, Axiom Healthcare Strategies, CraniUS, Dantari, ElevateBio, Eli Lilly, Genentech, InCephalo Therapeutics, Kazia, Merck, MPM Capital Advisors, Sintetica, SK Life Science, Tesaro, and Voyager Therapeutics; scientific advisory board for Kazia and CraniUS; Speaker's Honoraria from Genentech, Medscape, MPM Capital Advisors, Pfizer, and Merck; and institutional research funding (to M.G.H.) from Mirati, Kinnate, Merck, and Eli Lilly. T.H.S.: MIVI Neuroscience—investor; Precision Neuroscience Scientific Advisory Baird, Stock Options; Serenity Medical—investor; Radical Catheter Technologies—investor; Base Camp Vascular—investor; Bendit—investor; Endostream—investor.
References
Abbreviations
- 3V
third ventricle
- 3VF
third ventricle floor
- 560c
cohort of 560 well-described individual papillary craniopharyngioma patients
- 99s
cohort of 99 large craniopharyngioma series containing papillary craniopharyngiomas
- ACP
adamantinomatous craniopharyngioma
- AVP-D
arginine vasopressin deficiency
- BCT
body-core temperature
- BMI
body mass index
- BRAF
proto-oncogene B-Raf
- CP
craniopharyngioma
- CSF
cerebrospinal fluid
- CT
computed tomography
- DMN
default mode network
- EEA
endoscopic endonasal approach
- FRT
fractionated radiotherapy
- GK
gamma knife radiosurgery
- GnRH neurons
GnRH neuroendocrine cells
- GTR
gross total resection
- Gy
gray (radiation unit)
- HI
hypothalamic injury
- HSS
hypothalamus status score
- HPA
hypothalamus-pituitary-adrenal
- HySd
hypothalamic syndrome
- ITSd
infundibulo-tuberal syndrome
- LTC
local tumor control
- MBA
mammillary body angle
- MBs
mammillary bodies
- ME
median eminence
- MEK
MAPK/ERK kinase
- MRI
magnetic resonance imaging
- PCP
papillary craniopharyngioma
- PFS
progression-free survival
- PS
pituitary stalk
- PV
paraventricular
- QoL
quality of life
- RCC
Rathke's cleft cyst
- REM
rapid eye movement
- RT
radiotherapy
- SD
standard deviation
- SEER
Surveillance, Epidemiology and End Results
- SOX2
sex determining region Y-box2
- SRS
stereotactic radiosurgery
- SRT
stereotactic radiotherapy
- STR
subtotal resection
- STR + RT
subtotal resection followed by radiotherapy
- TCA
transcranial approach
- TLT
trans-lamina terminalis
- TM
tubero-mammillary
- VLPO
ventrolateral preoptic
- WHO
World Health Organization
Author notes
R.P. and J.M.P. contributed equally to this work.
