Fumarate Hydratase-deficient Renal Cell Carcinoma Is Strongly Correlated With Fumarate Hydratase Mutation and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome
Fumarate Hydratase-deficient Renal Cell Carcinoma Is Strongly Correlated With Fumarate Hydratase Mutation and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome
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DOI：
10.1097/pas.0000000000000617
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发表时间：
2016-07-01
影响因子：
5.6
通讯作者：
Gill, Anthony J.
中科院分区：
文献类型：
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作者：
Trpkov, Kiril;Hes, Ondrej;Gill, Anthony J.
遗传性平滑肌瘤病和肾细胞癌综合征相关的肾细胞癌（RCC）是很难前瞻性诊断。我们使用免疫组织化学（IHC）来识别来自多个机构的诊断为未分类RCC、高级别或乳头状模式或乳头状RCC 2型的病例中的富马酸水合酶（FH）缺陷型肿瘤（定义为FH阴性，2-琥珀半胱氨酸[2SC]阳性）。通过IHC对FH和2SC共124例肿瘤（来自118例患者）进行了评价。在24/124（19%）例病例中发现FH缺陷。在27/124（22%）例病例中发现不确定结果（仅1个标志物异常）。在776个不同类型的RCC的组织微阵列中，只有2个（0.5%）肿瘤，最初被认为是乳头状2型，是FH缺陷。在19/21例FH缺陷型肿瘤中发现FH突变（9/9例肿瘤中有9例证实了种系突变，其中可以评估种系状态），在1/26例通过IHC鉴定的FH不确定肿瘤中发现FH突变。在2/21例FH缺陷型RCC、25/26例FH不确定型RCC和10/10例IHC显示FH表达的RCC中未发现FH突变。FH缺陷RCC患者的中位年龄为44岁（范围为21至65岁）。平均肿瘤大小为8.2 cm（范围：0.9 - 18 cm）。FH缺陷型RCC的特征是至少有局灶性大核，93%的病例显示2种或2种以上的生长模式。乳头状是最常见（74%）和占主导地位（59%）的模式，而其他常见模式包括：实性（44%），管状囊性（41%），筛状（41%）和囊性（33%）。就诊时，57%为pT 3期，52%有阳性淋巴结，19%有远处转移。在平均随访27个月（范围，1至114个月）后，39%的患者死于疾病，26%的患者疾病进展。我们的结论是，FH和2SC是有用的免疫组化辅助工具，可以识别FH缺陷的RCC。
Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinomas (RCC) are difficult to diagnose prospectively. We used immunohistochemistry (IHC) to identify fumarate hydratase (FH)-deficient tumors (defined as FH negative, 2-succinocysteine [2SC] positive) in cases diagnosed as unclassified RCC, high grade or with papillary pattern, or papillary RCC type 2, from multiple institutions. A total of 124 tumors (from 118 patients) were evaluated by IHC for FH and 2SC. An FH deficiency was found in 24/124 (19%) cases. An indeterminate result (only 1 marker abnormal) was found in 27/124 (22%) cases. In a tissue microarray of 776 RCCs of different types, only 2 (0.5%) tumors, initially considered papillary type 2, were FH deficient. FH mutations were found in 19/21 FH-deficient tumors (with confirmed germline mutations in 9 of 9 tumors in which germline status could be assessed) and in 1/26 FH-indeterminate tumors identified by IHC. No FH mutations were found in 2/21 FH-deficient RCCs, 25/26 FH-indeterminate RCCs, and 10/10 RCCs demonstrating FH expression by IHC. Patients with FH-deficient RCC had a median age of 44 years (range, 21 to 65 y). Average tumor size was 8.2 cm (range, 0.9 to 18 cm). FH-deficient RCCs were characterized by at least focal macronucleoli and demonstrated 2 or more growth patterns in 93% cases. Papillary was the most common (74%) and dominant (59%) pattern, whereas other common patterns included: solid (44%), tubulocystic (41%), cribriform (41%), and cystic (33%). At presentation, 57% were stage pT3, 52% had positive nodes, and 19% had distant metastases. After a mean follow-up of 27 months (range, 1 to 114 mo), 39% of patients were dead of disease, and 26% had disease progression. We conclude that FH and 2SC are useful IHC ancillary tools, which allow recognition of FH-deficient RCC.