https://orcid.org/0000-0002-1596-5599
Abstract
Papillary tumor of the pineal region (PTPR) is a rare entity. Its clinical presentation is diverse, and establishing an accurate and timely diagnosis may be challenging. Treatment recommendations are based on the evidence level of case series. Recently, several key advances have been made for immunohistochemical characterization, molecular diagnostics, and neurosurgical treatment of PTPR. Here, we describe our single-center experience.
Tumors of the pineal region are uncommon, comprising 1% or less of all intracranial neoplasms.1 Among them, germ cell and pineal parenchymal tumors are the most common, but choroid plexus tumors, pineal cysts, papillary metastatic carcinomas, ependymomas, meningiomas, and astrocytomas have also been described.2 Less common is the papillary tumor of the pineal region (PTPR), which was introduced in the 2007 World Health Organization (WHO) classification of tumors of the CNS.3 Owing to their rarity, no WHO grade has been assigned to these tumors. Six cases were first described by Jouvet et al4 in 2003, and a retrospective series of 31 cases followed in 2006.2
The clinical presentation of PTPR is diverse. The age of onset ranges from 5 to 67 years (mean 34 years). Common presenting symptoms are related to occlusive hydrocephalus, for example, headache (79%), visual disturbance (61%), and gait disturbance (27%).5 These symptoms typically evolve slowly, over the course of several weeks to months. Visual disturbance includes blurry vision,6 progressive or intermittent double vision,7 bilateral sixth nerve palsy,8 and Parinaud syndrome9 with Foster Kennedy sign.10 Unilateral hearing loss11 and seizures7 have also been reported.
The histological features of PTPRs are characterized by an epithelial-like growth pattern, with cuboidal and columnar tumor cells forming perivascular pseudorosettes or, rarely, true rosettes.2 Immunoreactivity against cytokeratin, vimentin, and S-100 is typically observed, whereas glial fibrillary acid protein and epithelial membrane antigen are less specific.4 Through the morphofunctional features of PTPRs, they are thought to be derived from ependymal cells of the subcommissural organ.4 Hence, PTPRs include an assortment of epithelial, ependymal, and neuroendocrine features.12 On histological examination they might be mistaken for choroid plexus papillomas, ependymomas, or, if more malignant features are present, choroid plexus carcinomas. Based on the diverse clinical and histological presentation, establishing a diagnosis may be challenging.
Concerning recent key advances, the expression of the sterile alpha motif pointed domain-containing Ets transcription factor (SPDEF) protein was identified as a distinguishing immunohistochemical feature of PTPR.13 Furthermore, DNA methylation-based classification analysis enabled the accurate distinction between PTPR and ependymomas or pineal parenchymal tumors, and differentiates 2 prognostic methylation-based subgroups in PTPR.13 Additionally, phosphatase and tensin homolog (PTEN) alteration and subsequent pathological mammalian target of rapamycin (mTOR) activation were described both as a diagnostic tool and a novel therapeutic target in a recently published case.14
We report here our single-center experience with 4 cases of this rare entity.
Methods
Case 1
A 51-year-old woman presented with acute-onset bifrontal headache, unsteady gait, and altered mental status. MRI revealed an obstructive hydrocephalus due to a mass at the entrance of the Sylvian aqueduct (Figure 1). The radiological differential diagnosis of a colloid cyst was initially considered. For hydrocephalus management, we performed a laser-assisted endoscopic third ventriculocystostomy (ETV) and obtained tumor specimens. On histological examination, we diagnosed a moderately pleomorphic glial tumor with few fibrillary areas, papillary cytoarchitecture, and an epithelial-like growth pattern (Figure 2). We detected ATRX (alpha thalassemia/mental retardation syndrome X-linked) retention and a MIB-1 proliferation index of less than 1%. We observed an intact expression of SMARCB1/INI1, focal or weak reactivity toward synaptophysin, S-100, and cytokeratin (pan-CK, CAM5.2), as well as strong immunoreactivity toward neural cell adhesion molecule (NCAM/CD56) and SPDEF. We further noted an activation of the mTOR pathway, with moderate to strong expression of mTOR and phosphorylated AKT (pAKT) in the majority of tumor cells. We additionally carried out somatic tumor mutation testing through a targeted next-generation sequencing approach. However, we did not identify a druggable target. We subsequently performed endoscopic ultrasound-guided stereotactic resection, and thus achieved gross total resection. On follow-up at 20 months after the initial presentation, the patient continues to be well and without neurological deficit (Table 1).
Overview of All Cases
| Case | Sex | Age, y | Presenting symptoms | MRI | Immunohistochemistry | Extended molecular diagnostics | Therapeutic management | Outcome | Follow-up, mo |
|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 51 | Acute headache, gait disturbance, altered mental status | Obstructive hydrocephalus. Well-marginated small lesion at entrance of the Sylvian aqueduct, only faint contrast enhancement | MIB-1 proliferation index < 1% NCAM, SPDEF, mTOR, pAKTa Synaptophysin, S-100, pan-CKb | Somatic tumor mutation testing: low mutational burden, strong genomic instability, no therapeutic targetc | ETV, biopsy, endoscopic stereotactic resection | KPS 100%, no recurrence | 24 |
| 2 | M | 50 | Chronic dizziness, fatigue | Chronic obstructive hydrocephalus. Tectal contrast-enhancing lesion with multiple small cysts | MIB-1 proliferation index 3% pan-CK, CK8, mTOR, pAKTa MAP2, S-100b | Deletion of chromosome 10 and 22q. Duplications of chromosomes 4, 5, and 8. Diagnosis confirmed by methylation array analysis: PTPR group 1 | ETV, biopsy. Refused further treatment | KPS 80% | 60 |
| 3 | F | 27 | Subacute headache, progressive diplopia, gait disturbance | Acute obstructive hydrocephalus. Large intraluminal mass with only partial contrast enhancement | MIB-1 proliferation index 12% NCAM, mTOR, pAKT, pS6a S-100, AE1/AE3, CK18, Kir 7.1b | Somatic tumor mutation testing: duplications of chromosomes 8 and 19, deletion of chromosomes 22q and 10. PTEN missense mutation (c.116C>T; p.Ala39Val)c | ETV, biopsy, open resection, adjuvant RT | KPS 80%, no recurrence | 24 |
| 4 | M | 59 | Progressive diplopia, gait disturbance, hemihypesthesia, trochlear nerve palsy, Parinaud syndrome | Chronic obstructive hydrocephalus. Contrast- enhancing pineal mass with cystic parts and infiltration in brain parenchyma with surrounding edema | MIB-1 proliferation index 5% to 12% SPDEF, mTOR, pAKT, pS6a pan-CK, GFAPb | Deletion of chromosome 10. Diagnosis confirmed by methylation array analysis: PTPR | ETV, biopsy, open resection, VPS, adjuvant RT, temozolomide, bevacizumab | KPS 70%, recurrence at 17 mo | 80 |
| Case | Sex | Age, y | Presenting symptoms | MRI | Immunohistochemistry | Extended molecular diagnostics | Therapeutic management | Outcome | Follow-up, mo |
|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 51 | Acute headache, gait disturbance, altered mental status | Obstructive hydrocephalus. Well-marginated small lesion at entrance of the Sylvian aqueduct, only faint contrast enhancement | MIB-1 proliferation index < 1% NCAM, SPDEF, mTOR, pAKTa Synaptophysin, S-100, pan-CKb | Somatic tumor mutation testing: low mutational burden, strong genomic instability, no therapeutic targetc | ETV, biopsy, endoscopic stereotactic resection | KPS 100%, no recurrence | 24 |
| 2 | M | 50 | Chronic dizziness, fatigue | Chronic obstructive hydrocephalus. Tectal contrast-enhancing lesion with multiple small cysts | MIB-1 proliferation index 3% pan-CK, CK8, mTOR, pAKTa MAP2, S-100b | Deletion of chromosome 10 and 22q. Duplications of chromosomes 4, 5, and 8. Diagnosis confirmed by methylation array analysis: PTPR group 1 | ETV, biopsy. Refused further treatment | KPS 80% | 60 |
| 3 | F | 27 | Subacute headache, progressive diplopia, gait disturbance | Acute obstructive hydrocephalus. Large intraluminal mass with only partial contrast enhancement | MIB-1 proliferation index 12% NCAM, mTOR, pAKT, pS6a S-100, AE1/AE3, CK18, Kir 7.1b | Somatic tumor mutation testing: duplications of chromosomes 8 and 19, deletion of chromosomes 22q and 10. PTEN missense mutation (c.116C>T; p.Ala39Val)c | ETV, biopsy, open resection, adjuvant RT | KPS 80%, no recurrence | 24 |
| 4 | M | 59 | Progressive diplopia, gait disturbance, hemihypesthesia, trochlear nerve palsy, Parinaud syndrome | Chronic obstructive hydrocephalus. Contrast- enhancing pineal mass with cystic parts and infiltration in brain parenchyma with surrounding edema | MIB-1 proliferation index 5% to 12% SPDEF, mTOR, pAKT, pS6a pan-CK, GFAPb | Deletion of chromosome 10. Diagnosis confirmed by methylation array analysis: PTPR | ETV, biopsy, open resection, VPS, adjuvant RT, temozolomide, bevacizumab | KPS 70%, recurrence at 17 mo | 80 |
Abbreviations: ETV, endoscopic third ventriculostomy; F, female; GFAP, glial fibrillary acid protein; M, male; MAP2, microtubule-associated protein 2; mTOR, mammalian target of rapamycin; NCAM, neural cell adhesion molecule; pAKT, phosphorylated AKT; pan-CK, pan-cytokeratin antibody; pS6, phosphor-S6; PTPR, papillary tumor of the pineal region; RT, radiotherapy; SPDEF, SAM pointed domain-containing Ets transcription factor; VPS, ventriculoperitoneal shunt.
aStrong immunoreactivity.
bLow or focal immunoreactivity.
cAn overview of the molecular profiles is available as Supplementary Table 2.
Overview of All Cases
| Case | Sex | Age, y | Presenting symptoms | MRI | Immunohistochemistry | Extended molecular diagnostics | Therapeutic management | Outcome | Follow-up, mo |
|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 51 | Acute headache, gait disturbance, altered mental status | Obstructive hydrocephalus. Well-marginated small lesion at entrance of the Sylvian aqueduct, only faint contrast enhancement | MIB-1 proliferation index < 1% NCAM, SPDEF, mTOR, pAKTa Synaptophysin, S-100, pan-CKb | Somatic tumor mutation testing: low mutational burden, strong genomic instability, no therapeutic targetc | ETV, biopsy, endoscopic stereotactic resection | KPS 100%, no recurrence | 24 |
| 2 | M | 50 | Chronic dizziness, fatigue | Chronic obstructive hydrocephalus. Tectal contrast-enhancing lesion with multiple small cysts | MIB-1 proliferation index 3% pan-CK, CK8, mTOR, pAKTa MAP2, S-100b | Deletion of chromosome 10 and 22q. Duplications of chromosomes 4, 5, and 8. Diagnosis confirmed by methylation array analysis: PTPR group 1 | ETV, biopsy. Refused further treatment | KPS 80% | 60 |
| 3 | F | 27 | Subacute headache, progressive diplopia, gait disturbance | Acute obstructive hydrocephalus. Large intraluminal mass with only partial contrast enhancement | MIB-1 proliferation index 12% NCAM, mTOR, pAKT, pS6a S-100, AE1/AE3, CK18, Kir 7.1b | Somatic tumor mutation testing: duplications of chromosomes 8 and 19, deletion of chromosomes 22q and 10. PTEN missense mutation (c.116C>T; p.Ala39Val)c | ETV, biopsy, open resection, adjuvant RT | KPS 80%, no recurrence | 24 |
| 4 | M | 59 | Progressive diplopia, gait disturbance, hemihypesthesia, trochlear nerve palsy, Parinaud syndrome | Chronic obstructive hydrocephalus. Contrast- enhancing pineal mass with cystic parts and infiltration in brain parenchyma with surrounding edema | MIB-1 proliferation index 5% to 12% SPDEF, mTOR, pAKT, pS6a pan-CK, GFAPb | Deletion of chromosome 10. Diagnosis confirmed by methylation array analysis: PTPR | ETV, biopsy, open resection, VPS, adjuvant RT, temozolomide, bevacizumab | KPS 70%, recurrence at 17 mo | 80 |
| Case | Sex | Age, y | Presenting symptoms | MRI | Immunohistochemistry | Extended molecular diagnostics | Therapeutic management | Outcome | Follow-up, mo |
|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 51 | Acute headache, gait disturbance, altered mental status | Obstructive hydrocephalus. Well-marginated small lesion at entrance of the Sylvian aqueduct, only faint contrast enhancement | MIB-1 proliferation index < 1% NCAM, SPDEF, mTOR, pAKTa Synaptophysin, S-100, pan-CKb | Somatic tumor mutation testing: low mutational burden, strong genomic instability, no therapeutic targetc | ETV, biopsy, endoscopic stereotactic resection | KPS 100%, no recurrence | 24 |
| 2 | M | 50 | Chronic dizziness, fatigue | Chronic obstructive hydrocephalus. Tectal contrast-enhancing lesion with multiple small cysts | MIB-1 proliferation index 3% pan-CK, CK8, mTOR, pAKTa MAP2, S-100b | Deletion of chromosome 10 and 22q. Duplications of chromosomes 4, 5, and 8. Diagnosis confirmed by methylation array analysis: PTPR group 1 | ETV, biopsy. Refused further treatment | KPS 80% | 60 |
| 3 | F | 27 | Subacute headache, progressive diplopia, gait disturbance | Acute obstructive hydrocephalus. Large intraluminal mass with only partial contrast enhancement | MIB-1 proliferation index 12% NCAM, mTOR, pAKT, pS6a S-100, AE1/AE3, CK18, Kir 7.1b | Somatic tumor mutation testing: duplications of chromosomes 8 and 19, deletion of chromosomes 22q and 10. PTEN missense mutation (c.116C>T; p.Ala39Val)c | ETV, biopsy, open resection, adjuvant RT | KPS 80%, no recurrence | 24 |
| 4 | M | 59 | Progressive diplopia, gait disturbance, hemihypesthesia, trochlear nerve palsy, Parinaud syndrome | Chronic obstructive hydrocephalus. Contrast- enhancing pineal mass with cystic parts and infiltration in brain parenchyma with surrounding edema | MIB-1 proliferation index 5% to 12% SPDEF, mTOR, pAKT, pS6a pan-CK, GFAPb | Deletion of chromosome 10. Diagnosis confirmed by methylation array analysis: PTPR | ETV, biopsy, open resection, VPS, adjuvant RT, temozolomide, bevacizumab | KPS 70%, recurrence at 17 mo | 80 |
Abbreviations: ETV, endoscopic third ventriculostomy; F, female; GFAP, glial fibrillary acid protein; M, male; MAP2, microtubule-associated protein 2; mTOR, mammalian target of rapamycin; NCAM, neural cell adhesion molecule; pAKT, phosphorylated AKT; pan-CK, pan-cytokeratin antibody; pS6, phosphor-S6; PTPR, papillary tumor of the pineal region; RT, radiotherapy; SPDEF, SAM pointed domain-containing Ets transcription factor; VPS, ventriculoperitoneal shunt.
aStrong immunoreactivity.
bLow or focal immunoreactivity.
cAn overview of the molecular profiles is available as Supplementary Table 2.
MRI of cases 1 to 4. Contrast-enhanced T1-weighted sequence, A, C, E, and G, sagittal view, and T2-weighted sequences, B, D, E, and H, axial view. A and B, In case 1, a well-marginated small lesion appears with only faint contrast enhancement. C and D, In case 2, a contrast-enhancing lesion appears with multiple small cysts. E and F, In case 3, a large intraluminal mass appears with only partial contrast enhancement. G and H, In case 4, a contrast-enhancing mass appears with cystic parts and infiltration in the brain parenchyma and surrounding edema.
Histology and immunohistochemical analyses. A, Histological sections of cases 1 to 4 highlight morphological patterns (hematoxylin and eosin, scale 200 µm). B, Representative immunohistochemical stainings (top left: pan cytokeratin, top right: glial fibrillary acid protein) and expression of mammalian target of rapamycin pathway (bottom left: phosphor-mammalian target of rapamycin, bottom right: phosphor-S6) appear in the majority of tumor cells of case 3 with phosphatase and tensin homolog missense mutation (scale 200 µm). Complete immunohistochemical staining profiles of cases 1 to 4 are available as Supplementary Table 1 and Supplementary Figure 1.
Case 2
A 50-year-old man presented with a 1-year history of chronic dizziness and fatigue. MRI revealed chronic obstructive hydrocephalus secondary to a 12-mm mass located at the tectum. We performed ETV and obtained tumor specimens. On histological examination, we observed a MIB-1 proliferation index of 3%, strong immunoreactivity for pan-CK (MNF-116), partial cytoplasmatic expression of MAP2 and S-100, as well as an activation of the mTOR pathway with moderate expression of mTOR and pAKT in the majority of tumor cells. Reference pathology confirmed the diagnosis of PTPR. Methylation array analysis classified the tumor in the molecular group of PTPR, subtype 1. Copy number variation analysis showed deletions of chromosome 10 and 22q, and duplications of chromosomes 4, 5, and 8. To exclude dissemination of tumor cells, we recommended spinal imaging followed by adjuvant radiotherapy. The patient instead chose to seek alternative treatment and, at 56 months, complains of progressive vertigo and Parinaud syndrome.
Case 3
A 27-year-old woman presented with a 1-week history of bilateral headache, progressive diplopia, and unsteady gait. MRI revealed obstructive hydrocephalus secondary to a pineal mass. For resection, we chose an interhemispheric transcallosal and transchoroidal approach. On histological examination, we found the MIB-1 proliferative index in the mainly solid tumor to be 12%. We observed positive staining for NCAM/CD56, whereas few tumor cells expressed S-100, cytokeratin AE1/AE3, and CK18. Less than 5% of the tumor cells showed membranous staining for Kir 7.1. The patient received adjuvant radiotherapy with 30 × 1.8 Gy. On follow-up at 20 months after initial diagnosis, she continues to be well, complaining only of mild dizziness. Meanwhile, we carried out somatic tumor mutation testing, identifying a PTEN missense mutation (c.116C > T; p.Ala39Val). Copy number variation suggested duplications of chromosomes 8 and 19, as well as deletion of chromosomes 22q and 10. On subsequent staining of the mTOR pathway, we observed a strong expression of pAKT, phosphor-S6, and mTOR in the majority of tumor cells. Thus, mTOR inhibition might be a therapeutic strategy for progression.
Case 4
A 59-year-old man presented with a 2-year history of progressive diplopia. MRI revealed obstructive hydrocephalus due to a pineal mass. At another center, open resection in a semi-sitting position had been carried out and the preliminary diagnosis of a “papillary tumor WHO II/III” was made. Postoperatively, recurrent hydrocephalus necessitated a ventriculoperitoneal shunt. The patient received adjuvant radiotherapy. On follow-up at 17 months, tumor recurrence was noted. Chemotherapy was started with temozolomide at 400 mg for 7 days on and 21 days off for 4 months and a further 2 months at 180 mg for 7 days on and 7 days off. The patient was referred to us to evaluate further surgical intervention.
On clinical examination we noted an unsteady gait, hypoesthesia on the right side, right trochlear nerve palsy, and Parinaud syndrome. We performed a microsurgical resection via a left parietal-occipital Dandy approach. On histological examination, we found the MIB-1 proliferation index to be 5% to 12% and observed widespread necrotic areas, moderate nuclear pleomorphism, and perivascular pseudorosettes. Based primarily on a strong membranous expression of Kir 7.1, we made the initial diagnosis of a choroid plexus carcinoma. On repeat examination, however, we could not reliably reproduce Kir 7.1 expression. Reference pathology showed strong staining intensity for SPDEF, which instead suggested PTPR. Accordingly, molecular examination by methylation array analysis classified the tumor into the PTPR group. A loss of chromosome 10 involving PTEN was identified. Subsequent staining of the mTOR pathway showed strong expression of pAKT, phosphor-S6, and mTOR in the majority of tumor cells.
On further follow-up at 31 months after the initial diagnosis, we noted tumor recurrence on MRI. The patient received reirradiation (volumetric modulated arc therapy, 45 Gy) and 6 cycles of bevacizumab. On follow-up at 76 months, he is able to independently carry out all basic activities of daily life.
Results
Obstructive hydrocephalus was the first symptom in all 4 cases detailed earlier. Further symptoms included trochlear nerve palsy, Parinaud syndrome, and progressive diplopia, which likely occur because of tumor-induced compression of mesencephalic structures. In a previous cohort with PTPR, obstructive hydrocephalus was present in 89% of patients and contributed to an early diagnosis.15 ETV effectively treats hydrocephalus and enables specimen collection for histological examination.
The immunohistochemical profile of PTPR is very similar to that of choroid plexus tumors.2 This makes a histological diagnosis especially challenging if extensive immunoreactivity for Kir 7.1 (a marker for plexus epithelial differentiation) and necrotic features on light-field microscopy are present, which led to the false differential diagnosis of choroid plexus carcinoma in case 4. Here, SPDEF staining and methylation array analysis both enable a more accurate discrimination of histopathological mimics of PTPR, such as ependymomas or pineal parenchymal tumors of intermediate differentiation.13
Neurosurgical intervention is the mainstay of therapy in PTPR: In a large retrospective series of 44 patients, gross total resection and younger age were associated with a longer overall survival.16 Given the high risk of local recurrence, Fauchon and colleagues16 placed emphasis on the importance of gross total resection. Conversely, a more recent systematic review of 177 patients found tumor size and surgical treatment to be associated with 36-month survival, whereas gross total resection and adjuvant treatment did not confer additional survival benefit.15 Yamaki et al15 instead advise maximal safe resection, weighing the risks associated with an aggressive surgical strategy close to the brainstem. In our patients, gross total resection was safely achieved through both an endoscopic ultrasound-guided stereotactic resection (case 1) and an interhemispheric transcallosal approach (case 3). In pineal lesions, both suboccipital transtentorial and supracerebellar infratentorial approaches have also been used and offer a safe and effective route.17 Recently, a number of authors have described a purely neuroendoscopic resection for intraventricular tumors in general and pineal region tumors in particular.18,19
Up to 56% of patients will show local recurrence on follow-up. Thus, postoperative treatment might be considered.15 However, randomized clinical trials are not available. A number of case reports describe the use of radiotherapy in PTPR, both as an adjuvant treatment and for tumor recurrence, although the treatment protocols were heterogeneous and nonstandardized. These protocols have recently been systematically reviewed.20 At this point, there are insufficient data to comment on the outcome of radiotherapy in PTPR. Prospective studies are warranted, but might be challenging in this rare entity. Temozolomide monotherapy at a dose of 150 mg/m2/day from days 1 to 5 and 100 mg/m2/day from days 6 to 10 in a case of recurrent PTPR led to progression-free survival of 9 years.21 Furthermore, the combination of temozolomide (150 mg/m2 on days 1 to 5, 28-day cycle, 16 courses) and bevacizumab (7.5 mg/kg, day 0, every 4 weeks, 18 courses) resulted in decreased tumor volume on MRI and a progression-free survival of 1 year.22
Generally, the prognosis of PTPR is favorable, with a 36-month survival rate of 83.5%.15 Increased mitotic and proliferative activity is associated with a higher risk of recurrence and worse outcome, but clear grading criteria have not yet been provided by the WHO and the biologic behavior of PTPR is still rather uncertain.23,24 Beyond histological features, methylation array analysis elucidates 2 different subgroups of PTPR, with hypermethylated group 2 tumors demonstrating a tendency toward a shorter progression-free survival.13 Methylation arrays may also reveal a loss of chromosome 10, which inactivates the PTEN gene, activating the mTOR signaling pathway and yielding positive staining for pAkt.25 This provided diagnostic benefit in all of our cases. Additionally, identification of PTEN alterations or immunohistochemical mTOR pathway activation might suggest the use of mTOR inhibitors, such as everolimus, in recurrent or rapidly progressive cases of PTPR, as demonstrated in a recent case report.14
Conclusions
The diagnostic and therapeutic management of patients suffering from PTPR needs an interdisciplinary center. Given the rare incidence of this entity, collaborative clinical networks might be necessary for establishing consensus guidelines.
Acknowledgments
This study was approved by the ethics committee of the University Hospital Tuebingen (281/2019BO2). Informed consent was waived for this study.
Funding
This work was supported by intramural funding of the Medical Faculty Tübingen (Demonstratorprojekt Personalisierte Medizin).
Conflict of interest statement. Dr Gepfner-Tuma reports a travel grant and speakers fees from Novocure and a grant from Medac. Dr Tabatabai reports personal fees (advisory board, speakers fees) from Bayer, Bristol Myers Squibb, AbbVie, Novocure, and Medac; travel grants from Bristol Myers Squibb; educational and travel grants from Novocure; research grants from Roche Diagnostics; and research and travel grants from Medac. The other authors have nothing to disclose.
