背景:唾液腺导管内癌(IDC)是一种混杂实体,我们对它的理解在不断发展。根据组织形态学至少阐明了四种形式,免疫表型,和分子分布:(1)插层管状,S100/SOX10+与频繁的NCOA4::RET融合;(2)嗜酸性细胞,带有TRIM33::RET的S100/SOX10+,NCOA4::RET,和BRAFV600E;(3)大分泌,AR+有PI3激酶途径突变;和(4)混合/杂种插层导管样/顶腺分泌,与S100/SOX10+和AR+区域和频繁的TRIM27::RET。肌上皮细胞具有与腔细胞相同的融合,这表明融合阳性病例并非先前认为的原位癌。至此,完全在导管内生长的纯分泌性IDC尚未发现有融合,但是很少有病例经过测试。
方法:具有纯顶腺分泌形态的IDCs,完全是导管内生长,从作者的档案中没有发现前兆病变(多形性腺瘤或硬化性多囊腺瘤)。几种免疫染色(S100,SOX10,GCDFP-15,AR,p40/SMA)和靶向下一代测序(NGS)组,包括1425个癌症相关基因。
结果:收集了7个完全具有纯顶腺分泌型的IDC。病例发生在腮腺(平均,1.9厘米),5名男性和2名女性,年龄在51至84岁之间(平均值,69.7年)。组织学上,肿瘤由圆形到成角度的导管囊肿组成,上皮细胞排列有丰富的细颗粒状嗜酸性细胞浆和大细胞核,核仁突出。多形性轻度至中度,有丝分裂率低,无坏死。常规侵入性病灶或插层导管样形态的区域未被识别。在所有情况下,腔细胞对AR和GCDFP-15呈弥漫性阳性,而对S100/SOX10呈阴性,并且导管完全被p40和SMA突出显示的肌上皮细胞包围。6例分子分析成功。三个隐藏的融合:一个与NCOA4::RET,另一个带有STRN::ALK,另一个带有CDKN2A::CNTRL和TANC1::YY1AP1。三个融合阴性病例均带有HRAS突变;其他突变(PIK3CA,SPEN,ATM)在3例中的2例中被发现。所有患者均单独接受手术治疗。其中6人目前无病(随访12-190个月),但该病例包含NCOA4::RET以融合阳性的浸润性唾液导管癌的形式发生淋巴结转移。
结论:纯顶腺分泌型IDC是一种异质性疾病。一个子集似乎在遗传上与唾液导管癌相似,并且确实可能代表原位癌。另一组藏有融合,类似于其他形式的IDC。此外,淋巴结转移的发生否认了任何具有完整肌上皮细胞层的融合阳性IDC没有转移潜力的观点.随着基于RET和ALK的靶向治疗的广泛应用,我们的发现进一步强调了融合分析对IDC的重要性.
BACKGROUND: Intraductal carcinoma (IDC) of the salivary glands is a confounding entity, our understanding of which continues to evolve. At least four forms have been elucidated based on histomorphology, immunophenotype, and molecular profile: (1) intercalated duct-like, S100/SOX10+ with frequent NCOA4::RET fusions; (2) oncocytic, S100/SOX10+ with TRIM33::RET, NCOA4::RET, and BRAF V600E; (3) apocrine, AR+ with PI3 kinase pathway mutations; and (4) mixed/hybrid intercalated duct-like/apocrine, with S100/SOX10+ and AR+ areas and frequent TRIM27::RET. The revelation that myoepithelial cells harbor the same fusion as luminal cells suggested that fusion-positive cases are not in situ carcinomas as previously believed. To this point, purely apocrine IDC with entirely intraductal growth has not been found to harbor fusions, but very few cases have been tested.
METHODS: IDCs with pure apocrine morphology, entirely intraductal growth, and no precursor lesion (pleomorphic adenoma or sclerosing polycystic adenoma) were retrieved from the authors\' archives. Several immunostains (S100, SOX10, GCDFP-15, AR, p40/SMA) and targeted next generation sequencing (NGS) panel including 1425 cancer-related genes were performed.
RESULTS: Seven entirely IDC with pure apocrine type were collected. The cases arose in the parotid glands (mean, 1.9 cm) of 5 men and 2 women ranging from 51 to 84 years (mean, 69.7 years). Histologically, tumors consisted of rounded to angulated ductal cysts lined by epithelial cells with abundant finely granular eosinophilic cytoplasm and large nuclei with prominent nucleoli. Pleomorphism was mild to moderate, the mitotic rate was low, and necrosis was absent. Conventionally invasive foci or areas of intercalated duct-like morphology were not identified. In all cases, luminal cells were diffusely positive for AR and GCDFP-15 while negative for S100/SOX10, and the ducts were completely surrounded by myoepithelial cells highlighted by p40 and SMA. Molecular analysis was successful in 6 cases. Three harbored fusions: one with NCOA4::RET, another with STRN::ALK and one with both CDKN2A::CNTRL and TANC1::YY1AP1. The three fusion-negative cases all harbored HRAS mutations; additional mutations (PIK3CA, SPEN, ATM) were found in 2 of 3 cases. All patients were treated by surgery alone. Six of them are currently free of disease (follow up 12-190 months), but the case harboring NCOA4::RET developed lymph nodes metastasis in the form of a fusion-positive invasive salivary duct carcinoma.
CONCLUSIONS: Purely apocrine IDC is a heterogeneous disease. A subset seems to be genetically similar to salivary duct carcinoma and may indeed represent carcinoma in situ. The other group harbors fusions, similar to other forms of IDC. Moreover, the occurrence of lymph node metastasis discredits the idea that any fusion-positive IDC with a complete myoepithelial cell layer has no metastatic potential. With the wide use of RET-and ALK-based targeted therapies, our findings further underscore the importance of fusion analysis for IDC.