Answer: Metastatic clear cell renal cell carcinoma

Histology: The lesion consists of nests of cells with abundant clear cytoplasm, small nuclei with punctate nucleoli, occasional mitotic figures, numerous capillaries, and pseudofollicular areas filled with blood. There is no necrosis. A rim of cortical brain tissue is evident at the periphery of the lesion. Immunostains confirm the lesion to have nuclear labeling for Pax8.

Discussion: This is a metastatic clear cell renal cell carcinoma (RCC) to the brain. The differential diagnosis includes other clear cell tumors, notably primary brain hemangioblastomas, primary brain clear cell meningiomas, and metastatic neuroendocrine tumors with clear cytoplasm (malignant paragangliomas, clear cell neuroendocrine tumors of the pancreas, parathyroid carcinomas, etc). The patient’s history and an immunopanel can help make the final diagnosis. Notably, clear cell RCC are positive for CAIX, Pax8, RCC, and CD10, while hemangioblastomas are positive for inhibin. However, wide range of clear cell tumors can occur in patients with the autosomal dominant von Hippel Lindau (VHL) syndrome, including clear cell renal cell carcinomas, brain hemangioblastomas, and clear cell neuroendocrine tumors of the pancreas. Thus, although a patient might have a clear cell RCC of the kidney, a new clear cell lesion in the brain might actually be a hemangioblastoma. Patients with VHL syndrome have mutations in the VHL gene on chromosome 3. The VHL protein regulates HIF1alpha (hypoxia inducible factor), so HIF1a is usually upregulated in hypoxic states to allow for angiogenesis. Of note, carbonic anhydrase IX (CAIX) is a downstream effector of the hypoxia inducible pathway, which is why CAIX immunohistochemistry is expressed in RCC.

Reference(s):
– Hoang MP1, Amirkhan RH. Inhibin alpha distinguishes hemangioblastoma from clear cell renal cell carcinoma. Am J Surg Pathol. 2003 Aug;27(8):1152-6.