Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Department of Pathology, Lahey Hospital and Medical Center, Burlington, MA, USA.
Mod Pathol. 2017 Oct;30(10):1476-1488. doi: 10.1038/modpathol.2017.56. Epub 2017 Jun 30.
Leiomyomas associated with hereditary leiomyomatosis and renal cell carcinoma syndrome and leiomyomas with bizarre nuclei often show overlapping morphological features, in particular cells with prominent eosinophilic nucleoli, perinucleolar halos, and eosinophilic cytoplasmic inclusions. Although hereditary leiomyomatosis and renal cell carcinoma syndrome is defined by fumarate hydratase (FH) germline mutations, resulting in S-(2-succino)-cysteine (2SC) formation, it is unknown whether leiomyomas with bizarre nuclei show similar alterations. In this study, we evaluated the morphology and FH/2SC immunoprofile of 31 leiomyomas with bizarre nuclei. DNA from tumor and normal tissues from 24 cases was subjected to massively parallel sequencing targeting 410 key cancer genes. Somatic genetic alterations were detected using state-of-the-art bioinformatics algorithms. No patient reported a personal history of renal neoplasia or cutaneous leiomyomas, but one had a family history of renal cell carcinoma while another had a family history of uterine leiomyomas. Aberrant FH/2SC expression was noted in 17 tumors (16 FH-negative/2SC-positive, 1 FH-positive/2SC-positive). On univariate analysis, staghorn vessels, eosinophilic cytoplasmic inclusions, diffuse distribution of prominent eosinophilic nucleoli with perinucleolar halos, and an 'alveolar pattern of edema' were associated with an abnormal immunoprofile, but only staghorn vessels remained significant on multivariate analysis. Massively parallel sequencing analysis (n=24) revealed that 13/14 tumors with aberrant FH/2SC immunoprofile harbored somatic FH somatic genetic alterations, including homozygous deletions (n=9), missense mutations coupled with loss of heterozygosity (n=3), and a splice site mutation (n=1), whereas no somatic FH mutations/deletions were found in tumors with normal immunoprofile (n=10; P<0.0001). Leiomyomas with bizarre nuclei with normal FH/2SC staining pattern more frequently harbored TP53 and/or RB1 alterations than those with aberrant FH/2SC immunoprofile (60 vs 14%; P=0.032). These data demonstrate that leiomyomas with bizarre nuclei are morphologically and genetically heterogeneous and that hereditary leiomyomatosis and renal cell carcinoma syndrome-related morphological features, abnormal FH/2SC staining, and somatic FH mutations/deletions can be seen in a subset of sporadic tumors.
平滑肌瘤伴遗传性平滑肌瘤病和肾细胞癌综合征及奇异核平滑肌瘤通常表现出重叠的形态特征，特别是具有明显嗜酸性核仁、核周晕和嗜酸性细胞质包涵体的细胞。尽管遗传性平滑肌瘤病和肾细胞癌综合征是由延胡索酸水合酶（FH）种系突变定义的，导致 S-（2-琥珀酰）半胱氨酸（2SC）形成，但尚不清楚奇异核平滑肌瘤是否显示出类似的改变。在这项研究中，我们评估了 31 例奇异核平滑肌瘤的形态和 FH/2SC 免疫表型。24 例肿瘤和正常组织的 DNA 采用针对 410 个关键癌症基因的大规模平行测序进行检测。使用最先进的生物信息学算法检测体细胞遗传改变。没有患者报告有肾肿瘤或皮肤平滑肌瘤的个人病史，但有 1 例有肾细胞癌家族史，另 1 例有子宫平滑肌瘤家族史。17 例肿瘤（16 例 FH 阴性/2SC 阳性，1 例 FH 阳性/2SC 阳性）中出现异常 FH/2SC 表达。在单因素分析中，鹿角状血管、嗜酸性细胞质包涵体、弥漫分布的具有核周晕的明显嗜酸性核仁以及“水肿肺泡样模式”与异常免疫表型相关，但只有鹿角状血管在多因素分析中仍然显著。大规模平行测序分析（n=24）显示，13/14 例异常 FH/2SC 免疫组化的肿瘤携带体细胞 FH 体细胞遗传改变，包括纯合缺失（n=9）、错义突变伴杂合性丢失（n=3）和剪接位点突变（n=1），而正常免疫组化的肿瘤中未发现体细胞 FH 突变/缺失（n=10；P<0.0001）。具有正常 FH/2SC 染色模式的奇异核平滑肌瘤比具有异常 FH/2SC 免疫组化的平滑肌瘤更频繁地携带 TP53 和/或 RB1 改变（60%比 14%；P=0.032）。这些数据表明，奇异核平滑肌瘤在形态和遗传上是异质性的，并且遗传性平滑肌瘤病和肾细胞癌综合征相关的形态特征、异常 FH/2SC 染色以及体细胞 FH 突变/缺失可在一部分散发性肿瘤中见到。
