Final Diagnosis
BAP1-mutated clear cell renal cell carcinoma, high-grade (WHO/ISUP Nuclear Grade 3).
Discussion
Clear cell renal cell carcinoma (ccRCC) is the most common malignant renal neoplasm, comprising 60 to 70% of malignant renal tumors in adults, and an advanced clinical stage is associated with poor prognosis 1. ccRCC is caused by von Hippel-Lindau (VHL) gene alteration such as gene mutations, loss of chromosome 3p (in particular at 3p25 where VHL gene is located), and gene promoter hypermethylation 2.
While VHL gene alteration is considered to be an initiating driver of ccRCC development, additional gene mutations, on such as BAP1 (BRCA1-associated protein 1), are required for tumor progression 3, 4. BAP1 gene is located at chromosome 3p21.1 in close proximity to VHL gene, thus both genes are often co-deleted 5. BAP1 gene encodes a ubiquitin carboxy-terminal hydrolase (deubiquitinating enzyme), an enzyme responsible for removing ubiquitin from proteins, and BAP1 functions as a tumor suppressor 6-8. BAP1 mutation is found in approximately 10% of sporadic ccRCC 9, 10. BAP1-mutated ccRCC is associated with advanced tumor stage, higher tumor grade, rhabdoid and spindle morphology and poor prognosis 11-13. The detailed morphology with immunohistochemical profile of BAP1-mutated ccRCC is recently reported 14. BAP1-mutated ccRCC has characteristic (but not specific) histologic findings: tubular or tubulopapillary architecture, eosinophilic cytoplasm with cytoplasmic granules or hyaline globules, frequent lymphovascular invasion and distant metastasis 14. Immunohistochemically, PAX-8, CD10 and CAIX are positive in all cases, P504S racemase is positive in 93% of cases particularly in areas of high-grade morphology, and cytokeratin 7 is positive in a half of cases. Melan-A and HMB-45 are negative.
Mechanistically, the function of BAP1 is widespread and complex. BAP1 utilizes its deubiquitinating and binding activity to regulate different proteins involved in chromatin remodeling, DNA damage repair, cell cycle control and proliferation, regulated cell death and cell differentiation 10, 15. BAP1 removes ubiquitin from histone H2A at lysine 119 residue (H2AK119) and modulates chromatin structure and affects gene expressions 16. BAP1 directly binds to Host Cell Factor 1 (HCF1) and removes ubiquitin from lysine residues on HCF1 17. HCF1 is a transcriptional regulator involved in various processes that promote cell cycle progression and proliferation 18. HCF1 recruits histone-modifying enzymes (methyltransferases, acetyl transferases, and histone deacetylase) to alter chromatin structure at the promotor region of E2F family, key transcription factors regulating cell cycle progression from G1 to S phase 7, 19. BAP1 loss leads to modest accumulation of HCF1, which accelerates the transition from G1 to S phase 17. Interestingly, although BAP1 is a deubiquitinating enzyme, the loss of its enzymatic activity finds to be not essential to promote tumor progression in BAP1-mutated ccRCC, rather disruption of binding capacity to HCF1 is more crucial 20. BAP1 also bind to MCRS1, which is a component of the centrosome proteins, and plays an essential role in spindle assembly 21. Since BAP1 stabilizes MCRS1 by deubiquitination, BAP1 loss is associated with polyubiquitination and degradation of MCRS1, resulting in chromosome instability and aneuploidy 21.
Given the significant overlap of histologic features between BAP1-mutated ccRCC and other high-grade RCC, a wide differential diagnosis must be entertained such as type 2 papillary RCC, fumarate hydratase (FH)-deficient RCC, succinate dehydrogenase (SDH)-deficient RCC and Xp11 translocation RCC 14. Type 2 papillary RCC can show high-grade papillary morphology with eosinophilic tumor cells with prominent nucleoli, and often being P504S racemase positive. However, in typical papillary RCC, no classic ccRCC component is identified in the tumor, and CAIX and CD10 stains are usually negative. FH-deficient RCC can show tubulopapillary structure with eosinophilic cytoplasm and high-grade nuclear features with characteristically strikingly prominent nucleoli. To diagnose FH-deficient RCCs, loss of FH expression by immunohistochemistry is important and family history, hereditary leiomyomatosis and renal cell carcinoma syndrome, can be present clinically. SDH-deficient RCC can show eosinophilic cytoplasm with solid growth pattern. SDH-deficient RCC usually lacks papillary architecture and CAIX and C10 expression, and shows loss of SDH expression by immunohistochemistry. SDH-deficiency can be familial. Xp11 translocation RCC can show high-grade tumor with voluminous pale cytoplasm with papillary, tubulopapillary, or solid pattern. Psammomatous calcifications is characteristic if present, which is not present in BAP1-mutated ccRCC. Strong nuclear TFE3 expression and positive TFE3 fluorescence in situ hybridization are most diagnostic for Xp11 translocation RCC. Xp11 translocation RCC lacks expression of CAIX and is often negative for cytokeratin.
In addition to renal cell carcinoma, BAP1 gene alterations are observed in a variety of malignant tumors such as uveal melanoma, malignant mesothelioma, and cutaneous melanoma 7. Somatic BAP1 mutation is identified in 84% of metastatic uveal melanoma, implicating that loss of BAP1 accelerates metastasis in uveal melanoma 22. In malignant mesothelioma, BAP1 gene is the most commonly mutated gene, and BAP1 gene alteration is found in 63.6% of the mesothelioma cases 23. BAP1 loss is associated with younger age at onset, epithelioid differentiation and improved survival 24. BAP1 loss appears to be beneficial for some tumors and the prognostic significance of BAP1 loss varies across different cancer types. This is likely reflecting that BAP1 has different functions in different cell types. Further studies are warranted.
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