2021 NPB-13

This case was originally published in 2021. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

A 28-year-old woman presented to the ER with confusion and possible seizures. Imaging studies revealed a large, partially cystic mass in the left temporal lobe. No other lesions were found on systemic exam or imaging. Her past medical history was significant for cutaneous melanomas. Her family history was significant for four first- and second-degree relatives with brain tumors and/or melanomas or worrisome nevi. She underwent resection of the left temporal lobe mass.

Tissue Site
Brain, left temporal lobe mass

The whole slide image provided is an H&E-stained section of the brain tumor.

The diagnosis in the above case is pleomorphic xanthoastrocytoma (PXA), WHO grade 2. The H&E slides (Image A, Image B, and whole slide image) show a neoplasm with scattered markedly pleomorphic tumor cells showing enlarged nuclei and abundant cytoplasm – sometimes with xanthomatous change, admixed with smaller mildly pleomorphic astrocytoma-appearing tumor cells. Occasional lymphocytes are seen. Several areas show eosinophilic granular bodies and Rosenthal fibers (Image B). No mitoses, endothelial proliferation, or necrosis are seen. The large tumor cells, and less often the smaller ones, stain strongly for GFAP (Image C), which can nicely highlight the xanthomatous change seen in the cytoplasm of some cells. All tumor cells are immunoreactive for S100 (Image D), while HMB-45 is negative (Image E). The proliferation rate as estimated by Ki-67 immunostaining is quite low (Image F). This finding, together with the lack of mitoses and necrosis, supports the diagnosis of PXA rather than a higher-grade glioma.

Further molecular workup for this patient and at least one of her relatives with a similar disease revealed deletions in the INK4 locus on chromosome 9p21.3; this locus includes both the CDKN2A and CDKN2B tumor suppressor genes. CDKN2A encodes p16INK4a (a cyclin dependent kinase inhibitor) and p14ARF (an inhibitor of p53 signaling), while CDKN2B encodes p15INK4b (another cyclin dependent kinase inhibitor). Genetic analysis in this case also revealed a p.V600E mutation in BRAF. Various BRAF mutations occur in approximately 50% to 78% of PXA cases in the literature. The V600E mutation is not unique to PXA and can also be seen in pilocytic astrocytomas and gangliogliomas, as well as other non-CNS neoplasms.

In the several families that have been reported to have familial genetic alterations in the INK4 locus, individuals have a predisposition for multiple tumor types, including melanoma, astrocytomas, peripheral nerve sheath tumors, and meningiomas. Several families were first described in the literature in the 1990s as having multiple generations of individuals with astrocytomas, cutaneous malignant melanomas, and nerve sheath tumors. These families were classified with this new melanoma-astrocytoma familial genetic syndrome that is characterized by heterozygous germline CDKN2A inactivation and has been given a distinct designation in the Online Mendelian Inheritance in Man. Several families with this syndrome have since been described, one with features similar to the current case, in which the index patient had synchronous PXA and diffuse astrocytoma in different locations and both showed alterations in the CDKN2A/B genes, as did the patient’s germline DNA.

Another recent investigation of 21 pediatric patients with melanoma uncovered two individuals with melanomas of the scalp who also had a history of a primary brain tumor. The first patient, a 10-year-old girl, had a monozygotic twin sister that also had dysplastic nevi and an untreated cerebral lesion. Both siblings had a large deletion in the CDKN2A/B region of 9p21. The other identified case was a boy with an astrocytoma at age seven and congenital nevi on the head noted at age 17. He died from pleural rhabdomyosarcoma at age 22. He was found to have intact CDKN2A/B and a normal ratio profile at the 9p21.3 region but had other alterations in 4p and 6q. Of interest, these individuals developed scalp melanomas after receiving ionizing radiation for treatment of their primary brain tumors, raising the possibility that increased susceptibility to tumor development after radiation exposure exists for individuals with germline variants in some genes.

Other familial cancer genetic syndromes that typically involve primary brain neoplasms include Gorlin syndrome, Li-Fraumeni syndrome, neurofibromatosis, tuberous sclerosis, and Turcot syndrome. Databases to further investigate these familial syndromes are starting to emerge, and expanded molecular testing is uncovering new familial cancer syndromes such as the melanoma-astrocytoma syndrome described in this case.

• The finding of a familial history of brain tumors with or without melanomas (including gliomas, nerve sheath tumors, and/or meningiomas) should prompt further investigation, genetic counseling, and workup for familial cancer syndromes.
• Two separate astrocytic neoplasms, different in subtype or location, should also prompt molecular profiling to look for common genetic alterations and possible germline changes.
• The typical genetic alterations for the melanoma-astrocytoma syndrome include alterations in the INK4 locus at chromosome 9p21.3, which includes the CDKN2A and CDKN2B genes.

1. Kaufman DK, Kimmel DW, Parisi JE, Michels VV. A familial syndrome with cutaneous malignant melanoma and cerebral astrocytoma. Neurology. 1993;43(9):1728-1731.
2. Chan AK, Han SJ, Choy W, et al. Familial melanoma-astrocytoma syndrome: synchronous diffuse astrocytoma and pleomorphic xanthoastrocytoma in a patient with germline CDKN2A/B deletion and a significant family history. Clin Neuropathol. 2017;36(5):213-221.
3. Frigerio S, Disciglio V, Manoukian S, et al. A large de novo 9p21.3 deletion in a girl affected by astrocytoma and multiple melanoma. BMC Medical Genet. 2014;15:59.