延胡索酸水合酶缺陷型肾细胞癌与延胡索酸水合酶突变及遗传性平滑肌瘤病和肾细胞癌综合征密切相关。

Fumarate Hydratase-deficient Renal Cell Carcinoma Is Strongly Correlated With Fumarate Hydratase Mutation and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome.

作者信息

Trpkov Kiril, Hes Ondrej, Agaimy Abbas, Bonert Michael, Martinek Petr, Magi-Galluzzi Cristina, Kristiansen Glen, Lüders Christine, Nesi Gabriella, Compérat Eva, Sibony Mathilde, Berney Daniel M, Mehra Rohit, Brimo Fadi, Hartmann Arndt, Husain Arjumand, Frizzell Norma, Hills Kirsten, Maclean Fiona, Srinivasan Bhuvana, Gill Anthony J

机构信息

*Calgary Laboratory Services and University of Calgary, Calgary, AB, Canada §§McGill University, Montreal, QC, Canada †Charles University, Pilsen, Czech Republic ‡Institute of Pathology, Friedrich-Alexander-University, Erlangen-Nürnberg, Germany ∥University Clinic Bonn, Germany §Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH ‡‡University of Michigan, Ann Arbor, MI ∥∥University of South Carolina School of Medicine, Columbia, SC ¶University of Florence, Florence, Italy #Pitié-Salpêtrière Hospital, Paris, France **Hopital Cochin, APHP, Université Paris Descartes, Paris, France ††Barts Cancer Institute, Queen Mary University of London, London, United Kingdom ¶¶Sullivan Nicolaides Pathology, Gold Coast, Qld, Australia ***Mater Hospital, South Brisbane, Qld, Australia ##Douglass Hanly Moir Pathology, North Ryde, NSW, Australia †††Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia.

出版信息

Am J Surg Pathol. 2016 Jul;40(7):865-75. doi: 10.1097/PAS.0000000000000617.

DOI:10.1097/PAS.0000000000000617

PMID:26900816

Abstract

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.

摘要

遗传性平滑肌瘤病和肾细胞癌综合征相关的肾细胞癌（RCC）很难进行前瞻性诊断。我们运用免疫组织化学（IHC）方法，在多个机构诊断为“未分类RCC、高级别或具有乳头状结构”或“2型乳头状RCC”的病例中，鉴别延胡索酸水合酶（FH）缺陷型肿瘤（定义为FH阴性、2-琥珀酰半胱氨酸[2SC]阳性）。共有124个肿瘤（来自118例患者）接受了针对FH和2SC的IHC评估。在24/124（19%）的病例中发现FH缺陷。在27/124（22%）的病例中发现结果不确定（仅1个标志物异常）。在一个包含776个不同类型RCC的组织芯片中，最初被认为是2型乳头状的肿瘤中，只有2个（0.5%）为FH缺陷型。在19/21个FH缺陷型肿瘤中发现了FH突变（在9个可评估种系状态的肿瘤中，9个肿瘤中有9个证实存在种系突变），在通过IHC鉴定的1/26个FH结果不确定的肿瘤中也发现了FH突变。在2/21个FH缺陷型RCC、25/26个FH结果不确定的RCC以及10/10个通过IHC显示FH表达的RCC中未发现FH突变。FH缺陷型RCC患者的中位年龄为44岁（范围21至65岁）。平均肿瘤大小为8.2厘米（范围0.9至18厘米）。FH缺陷型RCC的特征是至少有局灶性大核仁，93%的病例表现出2种或更多的生长模式。乳头状是最常见（74%）且占主导（59%）的模式，而其他常见模式包括：实性（44%）、小管囊性（41%）、筛状（41%）和囊性（33%）。初诊时，57%为≥pT3期，52%有阳性淋巴结，19%有远处转移。平均随访27个月（范围1至114个月）后，39%的患者死于疾病，26%有疾病进展。我们得出结论，FH和2SC是有用的IHC辅助工具，可用于识别FH缺陷型RCC。