Medulloblastoma case reports
An index case of a child who survived medulloblastoma and developed multifocal bilateral oncocytoid renal cell carcinomas with morphology and immunophenotype compatible with eosinophilic solid and cystic renal cell carcinoma (ESC RCC) and demonstrated that both neoplasms harbored distinctive mutations in the TSC1/TSC2 genes. Remarkably, the child's remaining bilateral multifocal renal neoplasms completely responded to MTOR inhibitor therapy without need for further surgery. To confirm our hypothesis that oncocytoid renal cell carcinomas after childhood cancer represent ESC RCC, we obtained formalin-fixed paraffin-embedded tissue blocks from 2 previously published cases of oncocytoid renal cell carcinoma after neuroblastoma, confirmed that the morphology and immunophenotype was consistent with ESC RCC, and demonstrated that both cases harbored somatic TSC gene mutations. Both expressed markers previously associated with neoplasms harboring TSC gene mutations, glycoprotein nonmetastatic B, and cathepsin K. Of note, one of these patients had 2 ESC RCC which harbored distinctive TSC2 mutations, while the background kidney of the other patient had multiple small cysts lined by similar oncocytoid cells which showed loss of TSC2 protein. We then reviewed 3 of 4 cases from the original 1999 report of oncocytoid renal cell carcinomas after neuroblastoma, found that all 3 demonstrated morphology (including basophilic cytoplasmic stippling) that is characteristic of ESC RCC, showed that all 3 overexpressed glycoprotein nonmetastatic B, and showed that both cases with adequate material demonstrated loss of TSC2 protein and expressed cytokeratin 20 and cathepsin K by immunohistochemistry. In summary, “oncocytoid renal cell carcinomas after neuroblastoma” represent ESC RCC which are often multifocal in patients who have survived childhood cancer, likely representing an incompletely characterized tumor predisposition syndrome. MTOR-targeted therapy represents an effective therapeutic option for such patients to preserve functional nephrons 1)
The mutY DNA glycosylase encoded by the MUTYH gene prevents G:C→T:A transversions through the base excision repair DNA repair system. Germline biallelic pathogenic variants in MUTYH cause an adenomatous polyposis called MUTYH-associated polyposis (MAP), an autosomal recessive disease (OMIM: 608456), with an increased risk of colorectal cancer. Digestive lesions in this context show an excess of G:C→T:A transversions, individualising a specific mutational signature associated with MUTYH deficiency called signature SBS36. Predisposition to other tumours in patients with germline biallelic pathogenic variants in MUTYH is suspected but remains unclear. We report the first case of medulloblastoma in a patient with MAP, carrying the homozygous pathogenic variant c.1227_1228dup, p.(Glu410Glyfs*43) in MUTYH.
Methods: Whole exome sequencing was performed on the medulloblastoma to enlighten single nucleotide variants of interest, microsatellite status and mutational signature. The objective was to determine the involvement of MUTYH deficiency in the oncogenesis of this medulloblastoma.
Results: The medulloblastoma has the mutational signature SBS36 and driver pathogenic variants in CTNNB1, PTCH1 and KDM6A corresponding to G:C→T:A transversions, suggesting a role of MUTYH deficiency in oncogenesis.
Conclusions: Therefore, medulloblastoma could be a rare manifestation associated with germline biallelic pathogenic variants in MUTYH 2)
Hadzipasic M, Karsten MB, Olson H, Rodan L, Lidov H, Prabhu SP, Wright K, Fehnel KP. Medulloblastoma in the setting of megalocephaly polymicrogyria polydactyly hydrocephalus. Am J Med Genet A. 2021 Feb 25. doi: 10.1002/ajmg.a.62125. Epub ahead of print. PMID: 33634562.
A 36-year-old diagnosed with pulmonary sarcoidosis presented with ataxia, bilateral horizontal nystagmus, diplopia, and bilateral upper limb dysmetria was found to have a cerebellar mass on magnetic resonance imaging (MRI). He was initially treated with corticosteroids as a case of neurosarcoidosis. The patient's symptoms worsened, and repeat MRI showed an increase in the tumor's size with hydrocephalus. External ventricular drain (EVD) insertion plus midline suboccipital craniotomy and resection of the tumor was performed. Pathology revealed MB classic type, sonic hedgehog (SHH)-activated. There was no CSF dissemination. He received craniospinal radiation and chemotherapy. Follow up 20 months after radiation revealed residual neurological symptoms and no recurrence on MRI brain.
The exceedingly rare coexistence of adult medulloblastoma and sarcoidosis may have a causal relationship based on specific common molecules. Leukotrienes, stimulation of astrocytes and Purkinje neurons, and the SHH signaling pathway can be considered. Further genetic and molecular studies are merited 3).
A 63-year-old woman with an atypical medulloblastoma in the cerebellum and a lesion in the suprasellar area that did not appear to be a metastases of the medulloblastoma. The patient underwent a subtotal resection of the cerebellar medulloblastoma which was classified histologically as classic subtype and molecularly as non-WNT/non-Sonic hedgehog (SHH) subtype in the World Health Organization Classification of Tumors of the Central Nervous System 2016. Then she underwent postoperative chemotherapy followed by radiotherapy. We administered chemotherapy to facilitate therapeutic diagnosis of the suprasellar lesion. The combination treatment resulted in the disappearance of the cerebellar medulloblastoma with treatment toxicity well tolerated, additionally the suprasellar lesion remains under control.
Even in adults over 60 years of age, medulloblastoma should be included in the differential diagnosis of a cerebellar mass, and chemotherapy for adult medulloblastoma has the potential to be efficacious and tolerable 4).