Réseau National pour Cancers Rares de l'Adulte PREDIR AP-HP labellisé par l'Institut National du Cancer (INCa), Hôpital de Bicêtre, 94275, Le Kremlin Bicêtre, France.
Département de Médecine Oncologique, Institut de Cancérologie de Lorraine Alexis Vautrin, 54519, Vandœuvre-lès-Nancy, France.
Mod Pathol. 2018 Jun;31(6):974-983. doi: 10.1038/s41379-018-0017-7. Epub 2018 Feb 6.
Hereditary leiomyomatosis and renal cell carcinoma syndrome is characterized by an increased risk of agressive renal cell carcinoma, often of type 2 papillary histology, and is caused by FH germline mutations. A prominent eosinophilic macronucleolus with a perinucleolar clear halo is distinctive of hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinoma according to the 2012 ISUP and 2016 WHO kidney tumor classification. From an immunohistochemistry perspective, tumors are often FH-negative and S-(2-succino)-cysteine (2SC) positive. We performed a pathology review of 24 renal tumors in 23 FH mutation carriers, and compared them to 12 type 2 papillary renal cell carcinomas from FH wild-type patients. Prominent eosinophilic nucleoli with perinucleolar halos were present in almost all FH-deficient renal cell carcinomas (23/24). Unexpectedly, they were also present in 58% of type 2 papillary renal cell carcinomas from wild-type patients. Renal cell carcinoma in mutation carriers displayed a complex architecture with multiple patterns, typically papillary, tubulopapillary, and tubulocystic, but also sarcomatoid and rhabdoid. Such pattern diversity was not seen in non-carriers. FH/2SC immunohistochemistry was informative as all hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinomas were either FH- or 2SC+. For FH and 2SC immunohistochemistries taken separately, sensitivity of negative anti-FH immunohistochemistry was 87.5% and specificity was 100%. For positive anti-2SC immunohistochemistry, sensitivity, and specificity were 91.7% and 91.7%, respectively. All FH wild-type renal cell carcinoma were FH-positive, and all but one were 2SC-negative. In conclusion, multiplicity of architectural patterns, rhabdoid/sarcomatoid components and combined FH/2SC staining, but not prominent eosinophilic nucleoli with perinucleolar halos, differentiate hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma from type 2 papillary renal cell carcinoma with efficient FH gene. Our findings are crucial in identifying who should be referred to Cancer Genetics clinics for genetic counseling and testing.
遗传性平滑肌瘤病和肾细胞癌综合征的特征是侵袭性肾细胞癌风险增加，通常为 2 型乳头状组织学类型，由 FH 种系突变引起。根据 2012 年 ISUP 和 2016 年 WHO 肾脏肿瘤分类，具有特征性的嗜酸性大核仁，核仁周围有清晰的晕环，是遗传性平滑肌瘤病和肾细胞癌综合征相关肾细胞癌的特征。从免疫组织化学的角度来看，肿瘤通常 FH 阴性，S-(2-琥珀酰)-半胱氨酸（2SC）阳性。我们对 23 名 FH 突变携带者的 24 个肾肿瘤进行了病理学复习，并将其与 12 例 FH 野生型患者的 2 型乳头状肾细胞癌进行了比较。几乎所有 FH 缺陷型肾细胞癌（23/24）均存在明显的嗜酸性核仁，核仁周围有晕环。出乎意料的是，FH 野生型患者的 2 型乳头状肾细胞癌中也有 58%存在这种情况。突变携带者的肾细胞癌显示出复杂的结构，具有多种模式，通常为乳头状、管状乳头状和管状囊性，但也有肉瘤样和横纹肌样。这种模式多样性在非携带者中未见。FH/2SC 免疫组织化学是有意义的，因为所有遗传性平滑肌瘤病和肾细胞癌综合征相关的肾细胞癌均为 FH-或 2SC+。对于单独进行的 FH 和 2SC 免疫组织化学检查，阴性抗 FH 免疫组织化学的敏感性为 87.5%，特异性为 100%。对于阳性抗 2SC 免疫组织化学，敏感性和特异性分别为 91.7%和 91.7%。所有 FH 野生型肾细胞癌均为 FH 阳性，除 1 例外均为 2SC 阴性。总之，多种结构模式、横纹肌样/肉瘤样成分以及 FH/2SC 联合染色，但不是具有核仁周围晕环的明显嗜酸性核仁，可将遗传性平滑肌瘤病和肾细胞癌综合征相关的肾细胞癌与具有高效 FH 基因的 2 型乳头状肾细胞癌区分开来。我们的发现对于确定谁应该转介到癌症遗传诊所进行遗传咨询和测试至关重要。
