Veterans Affairs Palo Alto Health Care System, Department of Pathology, Palo Alto.
Department of Pathology, University of California, San Francisco, San Francisco.
Am J Surg Pathol. 2020 Jan;44(1):98-110. doi: 10.1097/PAS.0000000000001372.
Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and recently described entity associated with hereditary leiomyomatosis and RCC syndrome. FH-deficient RCC may show variable clinical and pathologic findings, but commonly presents with locally advanced and metastatic disease and carries a poor prognosis. We identified 32 patients with FH-deficient RCC, confirmed by FH immunohistochemistry (IHC) and/or FH mutation analysis, and performed a retrospective review of the clinical and pathologic features. Median age at presentation was 43 years (range, 18 to 69 y), and the M:F ratio was 2.2:1. Median tumor size was 6.5 cm (range, 2.5 to 28 cm), and 71% presented at stage ≥pT3a. After a median follow-up of 16 months (range, 1 to 118 mo) in 26 patients, 19% showed no evidence of disease, 31% were alive with disease, and 50% were dead of disease. The vast majority of cases showed multiple histologic growth patterns, with papillary (52%) being the most common predominant pattern, followed by solid (21%), cribriform/sieve-like (14%), sarcomatoid (3%), tubular (3%), cystic (3%), and low-grade oncocytic (3%). Viral inclusion-like macronucleoli with perinucleolar clearing were present in almost all cases (96%). All cases were evaluated using FH IHC, and 3 cases (9%) showed retained FH expression. Nineteen cases had germline or tumor mutation analysis confirming a FH mutation, with 79% (11/14) of cases showing mutations within coding regions and 21% (3/14) showing mutations within intronic splice-sites. By IHC, 97% (32/33) of cases were negative for CK7, 93% (27/29) were negative for p63, and 52% (15/29) were negative for GATA3. All cases stained were positive for PAX8 and showed retained succinate dehydrogenase B expression. Our overall findings show that FH-deficient RCC is considerably heterogenous in morphology and frequently behaves aggressively. Suspicion for this entity should be raised even in the absence of predominantly papillary architecture and characteristic nucleolar features. We have included cases with uncommonly seen features, including 4 cases with predominantly cribriform/sieve-like architecture as well as one case with pure low-grade oncocytic morphology (9 y of clinical follow-up without evidence of disease). Although FH IHC is a useful tool for identifying cases of FH-deficient RCC, not all cases of FH-deficient RCC show loss of FH staining, and FH mutation analysis should be considered for patients with suspicious clinical or pathologic features, even in cases with retained FH IHC expression.
乏琥珀酸脱氢酶的肾细胞癌（FH-deficient RCC）是一种罕见的、最近描述的实体，与遗传性平滑肌瘤病和肾细胞癌综合征相关。FH-deficient RCC 可能表现出不同的临床和病理表现，但通常表现为局部晚期和转移性疾病，并预后不良。我们通过 FH 免疫组化（IHC）和/或 FH 突变分析，确定了 32 例 FH-deficient RCC 患者，并对其临床和病理特征进行了回顾性分析。中位发病年龄为 43 岁（范围为 18 至 69 岁），男女比例为 2.2:1。中位肿瘤大小为 6.5cm（范围为 2.5 至 28cm），71%的患者处于≥pT3a 期。在 26 例患者的中位随访 16 个月（范围为 1 至 118 个月）后，19%的患者无疾病证据，31%的患者疾病仍在持续，50%的患者因疾病死亡。绝大多数病例显示出多种组织学生长模式，以乳头状（52%）为最常见的主要模式，其次为实性（21%）、筛状/筛板样（14%）、肉瘤样（3%）、管状（3%）、囊性（3%）和低级别嗜酸细胞瘤（3%）。几乎所有病例（96%）都存在病毒包涵体样大核仁，伴有核周晕。所有病例均进行了 FH IHC 评估，其中 3 例（9%）显示 FH 表达保留。19 例进行了种系或肿瘤突变分析，证实存在 FH 突变，79%（11/14）的病例在编码区存在突变，21%（3/14）的病例在内含子剪接部位存在突变。通过 IHC，33 例中有 97%（27/33）的病例 CK7 阴性，29 例中有 93%（27/29）的病例 p63 阴性，29 例中有 52%（15/29）的病例 GATA3 阴性。所有染色的病例均为 PAX8 阳性，并显示琥珀酸脱氢酶 B 表达保留。我们的总体研究结果表明，FH-deficient RCC 在形态上存在很大的异质性，并且常常表现出侵袭性。即使没有主要的乳头状结构和特征性核仁特征，也应怀疑存在这种实体。我们纳入了一些罕见特征的病例，包括 4 例以筛状/筛板样结构为主的病例和 1 例以纯低级别嗜酸细胞瘤形态为主的病例（9 年的临床随访未见疾病证据）。虽然 FH IHC 是识别 FH-deficient RCC 病例的有用工具，但并非所有 FH-deficient RCC 病例均显示 FH 染色缺失，对于具有可疑临床或病理特征的患者，即使 FH IHC 表达保留，也应考虑进行 FH 突变分析。
