https://orcid.org/0000-0001-5019-0699
To the Editor,
Pituitary blastoma is a rare CNS entity of the sellar region, initially described by Scheithauer et al in 2008,1,2 with reported cases in the literature currently approaching 20.3,4 The 3 histologic features of pituitary blastoma are (1) a primitive embryonal component, (2) a neuroendocrine component, and (3) a Rathke-type epithelium. Typically occurring in children less than 2 years of age, with Cushing syndrome being a common clinical presentation,4,5 pituitary blastoma is known to occur in association with germline DICER1 mutation.6–8 Given the rarity of this entity, we report the clinical, histologic, and imaging features of an additional patient with a pituitary blastoma, including the novel immunohistochemical finding of concurrent SALL4 and Pit-1 immunostaining within the primitive component of the tumor.
A 2-year-old male child presented with sudden and significant weight gain, advancing from the 28th percentile by weight to over the 97% percentile within 4 months. He also had pronounced left eye ptosis. During that time, he frequently consumed large meals, often asked for additional food soon after completing a meal, became irritable if food was taken away, and always appeared to be hungry. He was found to have elevated cortisol. MRI showed a heterogeneously enhancing sellar/suprasellar mass with left cavernous sinus invasion that measured 3.9 cm × 3.2 cm (Figure 1A). The tumor demonstrated T2 hypointensity and associated diffusion restriction suggesting hypercellularity. After subtotal resection of the pituitary blastoma, the patient was treated with 2 cycles of induction chemotherapy (cyclophosphamide, carboplatin, etoposide) followed by focal radiation therapy (54 CGE proton therapy). Postoperative residual disease diminished significantly with treatment, showing no evidence of residual disease or recurrence by imaging at 1.2 years after surgery (Figure 2I–M).
Pituitary blastoma imaging, histologic features, and molecular findings. (A) Preoperative T1-weighted postcontrast MRI showing the sellar/suprasellar enhancing mass. (B) Histologic features of pituitary blastoma include a primitive embryonal component, occurring in this case as small clusters of primitive cells, as well as scattered undifferentiated embryonal cells, and multilayered rosette-like primitive structures. (C) From a lower power a complex appearance of different elements is appreciated. (D) The neuroendocrine component in some areas formed continuous sheets of cells, similar to what is observed in pituitary adenoma/neuroendocrine tumor; however, most of the tumor showed an admixed combination of embryonal cells, neuroendocrine cells, and Rathke-type epithelium. (E) There were multiple cystic Rathke elements, including some filled with dense myxoid material. (F) Occasional small clusters of multilayered rosette-like primitive structures were a distinctive feature, distinguishing this tumor from other sellar/suprasellar entities. (G) Sequencing analysis of the tumor demonstrated two DICER1 mutations, with the frameshift mutation being germline in origin.
Pituitary blastoma immunostaining and therapeutic response to chemoradiation. (A–C) Within a cluster of primitive cells and rosettes (A), concurrent immunostaining for both SALL4 (B) and Pit-1 (C) was observed. (D) The Ki-67 proliferation index was also increased in this area, consistent with the relative elevation seen in primitive components compared to other areas of the tumor. (E–H) Immunostaining for transcription factors of pituitary lineage differentiation Pit-1 (E), T-pit (F), and SF-1 (G) each showed expression in a small percentage of tumor cells, while ACTH (H) showed the greatest degree of pituitary hormone staining. (I–M) Imaging changes from baseline to most recent follow-up. Baseline (I). Coronal post contrast T1-weighted imaging through the sella demonstrates an enhancing tumor in the sellar and suprasellar regions that invaded the left cavernous sinus. (J) Baseline diffusion-weighted imaging. The apparent diffusion coefficient (ADC) map (left) and the T2-weighted trace diffusion image (right) (asterisk) demonstrate homogenous diffusion restriction of the tumor suggesting hypercellularity. The homogeneous restricted diffusion seen in this pituitary blastoma is absent from other sellar tumors encountered in this age group such as teratomas (which are more heterogeneous and typically have internal fat and calcification). (K) Following surgery, the post contrast T1-weighted imaging through the same plane demonstrates subtotal resection of the tumor with residual tumor in the left side of the sella and suprasellar regions including the left cavernous sinus. The blue arrow points toward circumferential encasement of the cavernous carotid artery by tumor suggesting invasion of the left cavernous sinus. (L) After 2 cycles of chemotherapy, the post contrast T1-weighted imaging through the same plane demonstrates reduction of the volume of the residual tumor at the left sellar wall and left cavernous sinus. (M) Following completion of radiation therapy, the post contrast T1-weighted imaging through the same plane demonstrates significant decrease in the volume of the residual tumor which appears as a thin rim of enhancement along the left sellar wall without any appreciable tumor in the left cavernous sinus. (N) At 14 months after diagnosis, post contrast T1-weighted imaging through the same plane demonstrates further thinning of the residual enhancement, which is a pencil-thin line and is suggestive of no active residual tumor. Arrows point toward the enhancing tissue.
Preoperatively, he was found to have elevated serum ACTH of 78.8 pg/mL (ref range 7.2-63.3) and hypercortisolism, not suppressible by dexamethasone suppression testing in the setting of Cushing syndrome. This was managed initially with metyrapone to reduce signs and symptoms of cortisol excess while awaiting more definitive therapy. Serum ACTH values returned to normal range within 2 months of surgery, likely attributable to successful resection and treatment of the tumor, and he was weaned off metyrapone by the end of radiation therapy. Postsurgical development of central hypothyroidism and persistent cortisol deficiency despite resolution of ACTH excess are being managed by regular endocrinology evaluation, treatment with levothyroxine and hydrocortisone, and ongoing screening for other hypothalamic-pituitary dysfunction.
Histologic evaluation of the tumor revealed a classic appearance for pituitary blastoma (Figure 1B–F). Mitotic activity was generally low, with elevated Ki-67 labeling isolated to the embryonal component. Immunostaining for the transcription factors of pituitary lineage differentiation including Pit-1, T-pit, and SF-1 each showed expression in a small percentage of neuroendocrine tumor cells; however, most tumor cells were negative for these. Potentially reflecting the tumor’s blastomatous nature, this mixture of “null” cells, lacking lineage differentiation, and scattered cells of each lineage is a unique combination. Within the primitive multilayered rosette-like structures, there was clustered positive staining for both Pit-1 and SALL4 (Figure 2). These primitive areas with concurrent SALL4 and Pit-1 staining were negative for prolactin, growth hormone, and TSH. ACTH showed the greatest degree of pituitary hormone immunoreactivity within the tumor; there was also focal expression of growth hormone and prolactin, while tumor cells were immunonegative for TSH. Synaptophysin immunostaining was strongly positive within the neuroendocrine component; CAM 5.2 was positive throughout. OCT 3/4 was immunonegative. Immunostaining for SOX2, an established marker of pituitary stem/progenitor cells,9 was positive in a subset of the scattered undifferentiated embryonal cells and in a subset of the cells forming the multilayered rosette-like primitive structures (not shown).
Combined whole exome and transcriptome sequencing of the tumor with targeted sequencing of the germline demonstrated an inactivating germline DICER1 frameshift mutation, and a somatic DICER1 hotspot mutation within the ribonuclease III domain (Figure 1G). This type of mutational profile, a germline DICER1 loss of function mutation paired with a somatic ribonuclease III domain hotspot mutation, is frequently encountered in DICER1 syndrome-associated tumors.6,8 While germline DICER1 mutation can occur de novo or be inherited, rare cases of DICER1 syndrome have occurred in the setting of somatic mosaicism.10 Parental molecular testing and familial pedigree analysis in this case showed maternal inheritance, with a thyroid nodule recorded for the patient’s mother. Thyroid involvement, including multinodular goiter or thyroid nodules, is a frequent and less specific phenotype for DICER1 syndrome.8,11,12
Pituitary blastoma is known to have a distinctive methylation profile separate from pituitary adenomas and CNS neuroepithelial tumors3; however, clinical methylation profiling of this case did not produce a matching calibrated score as pituitary blastoma is not currently within the reference cohort for this test. The mechanism by which DICER1 mutation promotes tumorigenesis is attributed to dysfunctional miRNA processing, favoring 3p miRNA over 5p miRNA in the RNA-induced silencing complex (RISC) and altering translation within the neoplasm.3,13
As pituitary blastomas are rare, clinical outcome data are limited. Among 17 reported cases with outcomes, 8 patients died, 1 with disease progression, and 7 with early or late complications (including sepsis, second brain tumor/suspected pineoblastoma, catheter complications, or aneurysm). Nine patients survived with either no residual disease or stable residual disease, with median follow-up of 6.7 years and ranging up to 23.5 years.3,4 Five of the 9 surviving patients were managed by resection only, with extent of resection being significantly associated with survival.4 While SALL4 has emerged as a potential therapeutic target in some cancers,14,15 this may be a less likely treatment option for pituitary blastoma given the small percentage of overall SALL4-positive tumor cells observed in this case.
Other instances of SALL4 positivity occurring in primitive or glandular elements of DICER1 malignancies include malignant teratoma-like tumors, embryonal rhabdomyosarcoma, and Sertoli-Leydig cell tumor.16–18 As SALL4 expression is seen in a variety of tumor types from embryonal CNS neoplasms to hepatocellular carcinoma, this is favored to reflect the role of SALL4 in renewal and pluripotency15 rather than a DICER1-specific genetic association.
In conclusion, for a child 2 years of age or less with sudden weight gain and a large hypercellular sellar/suprasellar mass, pituitary blastoma should be considered in the clinicopathologic differential diagnosis and consideration given for germline genetic evaluation. Pituitary blastomas contain primitive embryonal cells, which as demonstrated here can have concurrent positivity for both SALL4 and Pit-1. Prior reports of pituitary blastoma with evaluation of germ cell tumor markers such as PLAP and others,1,2 did not include SALL4 staining results. As SALL4 can be seen to some degree in a variety of embryonal tumors, our findings suggest SALL4 expression may serve as a useful diagnostic method to establish a primitive phenotype in ambiguous cases. Continued reporting of clinical treatment and outcomes for pituitary blastoma patients will add to prognostic and management knowledge for this rare entity, which in this case after subtotal resection showed significant therapeutic response to induction chemotherapy and focal proton radiation.
This case was presented in part at the American Association of Neuropathology (AANP) Diagnostic Slide Session (DSS) in Olympic Valley, California on June 8, 2024.
FUNDING
J.C.L. is supported by St. Jude Children’s Research Hospital faculty appointment. This study was conducted without specific project funding.
Conflicts of interest
The authors declare they have no conflict of interest related to this study.
Compliance with ethical standards
All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards, with Institutional Review Board approval. The patient’s family provided consent for case report publication.
DATA AVAILABILITY
Supporting data available from the corresponding author upon reasonable request.
