Clinicopathologic characteristics of fumarate hydratase-deficient and hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma: A series of 10 cases

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Conference Proceeding

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Lab Invest


Background: Hereditary leiomyomatosis and renal cell carcinoma associated renal cell carcinoma (HLRCC-RCC) is a rare and recently described entity. We aim to analyze the use of fumarate hydratase immunohistochemistry (FH IHC) in identifying HLRCC-RCC and provide a comprehensive study of renal tumors that are FH-deficient, either by IHC or presence of a germline FH mutation. Design: 20 renal tumors with prominent viral inclusion-like nucleoli and perinucleolar halo were initially identified. FH IHC was performed on all cases. All available clinicopathologic data was recorded. Results: 9 tumors showed complete loss of FH staining (1 had confirmed germline FH mutation), and 1 with retained FH staining had a confirmed germline FH mutation. Of these 10, papillary was the most common pattern (80%), followed by solid (60%), cribriform (40%), tubular (40%), collecting duct carcinoma (CDC)-like (30%), tubulopapillary (30%), tubulocystic (30%), sarcomatoid (10%), and cystic (10%). Papillary was the dominant pattern in 40%, solid was dominant in 30%, and sarcomatoid, cribriform, and tubulopapillary were each dominant in 10%. These cases were consistently negative for CK7 (7/7) and mostly negative for p63 (6/7) and GATA3 (6/7). Clinical data were available for 7 cases. 1 was originally diagnosed as HLRCC-RCC; others were originally diagnosed as unclassified RCC (3), CDC (2), and papillary RCC (1). Patient age ranged from 37 to 65 years (median, 44 years), M: F=4:3, tumor size ranged from 3.6 to 17 cm (median, 5.1 cm), and tumor stage was mostly > pT3a (86%). 57% of patients had a history of early-onset uterine leiomyomas or family history of RCC. After a mean follow-up time of 30 months (range, 1 to 99 months), 29% of patients died of disease, 29% had disease progression, and 42% had no evidence of disease. Conclusions: FH IHC is not 100% sensitive for HLRCC-RCC, as rare cases with confirmed germline FH mutations may show retained FH staining. Thus, even with retained FH staining, genetic counseling and testing for a germline FH mutation may be indicated if the clinical history and morphologic features suggest HLRCC-RCC. FH IHC is also unlikely to be 100% specific for HLRCC-RCC, as sporadic FH-deficiency has been described, although it remains unclear how frequently. Patterns other than papillary may predominate, and FH-deficient/ HLRCC-RCC should be included in the differential diagnosis with CDC and urothelial carcinoma; negative CK7, p63, and GATA3 staining is helpful in distinguishing it from the latter two.



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