Furuya Mitsuko, Iribe Yasuhiro, Nagashima Yoji, Kambe Naotomo, Ohe Chisato, Kinoshita Hidefumi, Sato Chika, Kishida Takeshi, Okubo Yoichiro, Numakura Kazuyuki, Nanjo Hiroshi, Nakaigawa Noboru, Makiyama Kazuhide, Hasumi Hisashi, Iwashita Hiromichi, Ohta Junichi, Kitamura Hiroshi, Nakajima Takahiko, Yoshida Takahiro, Nakagawa Masahiro, Tanaka Reiko, Yao Masahiro
Molecular Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
Urology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
J Clin Pathol. 2020 Dec;73(12):819-825. doi: 10.1136/jclinpath-2020-206548. Epub 2020 May 6.
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder caused by germline mutations in fumarate hydratase (FH). Affected families have an increased risk of renal cell carcinoma (RCC). HLRCC-associated RCC (HLRCC-RCC) is highly aggressive. Clinicopathological information of genetically diagnosed patients with HLRCC-RCC contributes to the establishment of effective therapies.
Ten Japanese patients with HLRCC-RCC were enrolled in the study. Genetic testing for was carried out. Somatic mutations in and immunohistochemical analyses of FH and B7 family ligands (PD-L1 and B7-H3) were investigated in 13 tumours. Copy number variations were evaluated in two tumours.
All patients had germline mutations. Regarding histology, most tumours had type 2 papillary architecture or tubulocystic pattern or both. All tumours were FH deficient by immunohistochemistry. Ten tumours were positive for PD-L1, and 12 tumours were positive for B7-H3. Somatic mutation analysis demonstrated loss of heterozygosity of in 10 tumours. Copy number variation analysis revealed uniparental disomy between 1q24.2 and 1q44 encompassing ; gain of chromosome 2 p was also common. All patients had either metastases or residual tumours. Three patients died of HLRCC-RCC and one of colon cancer, whereas the other six are currently alive, including two without recurrence.
HLRCC-RCCs appear to have unique molecular profiles, including PD-L1 expression. One patient had complete response to immunotherapy, which may be an option for HLRCC-RCC.
遗传性平滑肌瘤病和肾细胞癌（HLRCC）是一种常染色体显性疾病，由延胡索酸水合酶（FH）的种系突变引起。患病家族患肾细胞癌（RCC）的风险增加。HLRCC相关肾细胞癌（HLRCC-RCC）具有高度侵袭性。对经基因诊断的HLRCC-RCC患者的临床病理信息进行研究有助于确立有效的治疗方法。
10名日本HLRCC-RCC患者纳入本研究。进行了基因检测。对13个肿瘤进行了体细胞突变检测以及FH和B7家族配体（PD-L1和B7-H3）的免疫组化分析。对2个肿瘤评估了拷贝数变异。
所有患者均有FH种系突变。在组织学方面，大多数肿瘤具有2型乳头结构或小管囊性模式或两者皆有。通过免疫组化分析，所有肿瘤均缺乏FH。10个肿瘤PD-L1呈阳性，12个肿瘤B7-H3呈阳性。体细胞突变分析显示10个肿瘤中FH存在杂合性缺失。拷贝数变异分析显示1q24.2和1q44之间包括FH的单亲二体性；2号染色体p臂增益也很常见。所有患者均有转移灶或残留肿瘤。3例患者死于HLRCC-RCC，1例死于结肠癌，而其他6例目前存活，其中2例无复发。
HLRCC-RCC似乎具有独特的分子特征，包括PD-L1表达。1例患者对免疫治疗完全缓解，这可能是HLRCC-RCC的一种治疗选择。
