An emerging group of high-grade renal cell carcinomas (RCCs), particularly carcinomas arising in the hereditary leiomyomatosis renal cell carcinoma syndrome (HLRCC), show fumarate hydratase (FH) gene mutation and loss of function. On the basis of similar cytomorphology and clinicopathologic features between these tumors and cases described as tubulocystic carcinomas with poorly differentiated foci (TC-PD) of infiltrative adenocarcinoma, we hypothesized a relationship between these entities. First, 29 RCCs with morphology of TC-PD were identified retrospectively and assessed for FH expression and aberrant succination (2SC) by immunohistochemistry (IHC), with targeted next-generation sequencing of 409 genes-including FH-performed on a subset. The 29 TC-PD RCCs included 21 males and 8 females, aged 16 to 86 years (median, 46), with tumors measuring 3 to 21 cm (median, 9) arising in the right (n=16) and left (n=13) kidneys. Family history or stigmata of HLRCC were identifiable only retrospectively in 3 (12%). These tumors were aggressive, with 79% showing perinephric extension, nodal involvement in 41%, and metastasis in 86%. Of these, 16 (55%) demonstrated loss of FH by IHC (14/14 with positive 2SC). In contrast, 5 (17%) showed a wild-type immunoprofile of FH+/2SC-. An intriguing group of 8 (28%) showed variable FH± positivity, but with strong/diffuse 2SC+. Next-generation sequencing revealed 8 cases with FH mutations, including 5 FH-/2SC+ and 3 FH±/2SC+ cases, but none in FH+/2SC- cases. Secondly, we retrospectively reviewed the morphology of 2 well-characterized cohorts of RCCs with FH-deficiency determined by IHC or sequencing (n=23 and n=9), unselected for TC-PD pattern, identifying the TC-PD morphology in 10 (31%). We conclude that RCCs with TC-PD morphology are enriched for FH deficiency, and we recommend additional workup, including referral to genetic counseling, for prospective cases. In addition, based on these and other observations, we propose the term "FH-deficient RCC" as a provisional term for tumors with a combination of suggestive morphology and immunophenotype but where genetic confirmation is unavailable upon diagnosis. This term will serve as a provisional nomenclature that will enable triage of individual cases for genetic counseling and testing, while designating these cases for prospective studies of their relationship to HLRCC.
首先，回顾性复习形态学符合TC-PD特征的29例RCCs，并通过免疫组织化学（IHC）评估FH和异常琥珀酸脂（2SC）的表达，通过新一代测序技术对包括FH在内的409个基因进行靶向测序分析。29例TC-PD RCCs中，男性21例，女性8例；年龄16-86岁(中位年龄46岁)；16例起源于右侧肾脏，13例起源于左侧肾脏；肿瘤大小3-21cm（中位大小9cm）。仅3例（12%）具有HLRCC的皮肤红斑或家族史。肿瘤具有侵袭性，79%显示肾周扩散，41%累及淋巴结，86%出现转移。免疫组化结果，16例（55%）FH缺失（14/14 2SC阳性）；相比之下，5例（17%）显示FH+/2SC-的野生型免疫表型模式；有趣的是，8例（28%）显示不同程度的FH±阳性，但是2SC弥漫强阳性。新一代测序技术显示8例具有FH突变，包括5例FH-/2SC+和3例FH±/2SC+的病例，但是FH+/2SC-的病例均无FH突变。