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20 April 2022 - Case of the Month #514

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Thanks to Dr. Chunyu Cai, University of Texas Southwestern Medical Center, Dallas, Texas, USA for contributing this case and discussion and to Dr. Meaghan Morris, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA for reviewing the discussion.

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Case of the Month #514

Clinical history:
A 51 year old man presents with progressive hearing loss in the left ear, intermittent dizziness, difficulty walking and recent onset of severe headaches.

Radiology and histopathology images:

What is your diagnosis?

Click here for diagnosis, test question and discussion:

Diagnosis: Clear cell meningioma

Test question (answer at the end):
Which of the following genetic alterations is characteristic of clear cell meningioma?

A. AKT1 mutation
B. BAP1 mutation
C. NF2 mutation
D. SMARCE1 mutation
E. TRAF7 and KLF4 co-mutations





Clear cell meningioma (CCM) is a rare, WHO grade II, variant of meningioma characterized by sheets of clear cells, abundant blocky collagen and loss of nuclear SMARCE1 protein expression. The clear cell components usually compose 90 - 100% of the tumor, with some cases showing small conventional meningothelial nests at the periphery of the tumor. The clear cytoplasm is due to accumulation of glycogen, however, this feature does not sufficiently differ from microcystic meningioma, atypical meningioma with clear cell components and metastatic clear cell renal cell carcinoma.

SMARCE1 mutation was initially identified in families with multiple spinal meningiomas that lacked clinical symptoms of neurofibromatosis type 2 or schwannomatosis; all tumors with SMARCE1 mutation had diffuse clear cell morphology (Nat Genet 2013;45:295). The finding was later extended to cranial (J Pathol 2014;234:436) and sporadic (Brain Pathol 2018;28:466) CCM. Loss of nuclear SMARCE1 protein expression by immunostain is an excellent surrogate marker for biallelic inactivation of the SMARCE1 gene; however, the IHC is not available in most clinical laboratories. Alternatively, carbonic anhydrase IX (CAIX) has been suggested as a useful alternative when presented with the differential diagnosis of clear cell tumors in this region (J Neuropathol Exp Neurol 2019;78:1081). CAIX is a chronic hypoxia marker and a direct downstream target of HIF1α. HIF1α transcriptional activity is positively regulated by SMARCE1 and the SWI/SNF complex (Breast Cancer Res 2016;18:81); loss of SMARCE1 protein leads to complete absence of CAIX expression in CCM regardless of hypoxic state. As a comparison, CAIX is diffusely positive for metastatic clear cell renal cell carcinoma, microcystic meningioma and angiomatous meningioma; however, other conventional meningioma subtypes without cytoplasmic clearing can also be negative (J Neuropathol Exp Neurol 2019;78:1081). CCM also expresses the general meningioma marker SSTR2A, which can help differentiate CCM from metastatic clear cell tumors.

Test question answer:

D. SMARCE1 mutation. Clear cell meningioma is a rare variant characterized by loss of nuclear SMARCE1 protein expression.

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