Department of Pathology, UT Southwestern Medical Center, Dallas, TX.
Departments of Pathology.
Am J Surg Pathol. 2021 Apr 1;45(4):507-515. doi: 10.1097/PAS.0000000000001605.
Intraductal carcinoma (IDC) is a salivary gland tumor currently believed to be analogous to breast ductal carcinoma in situ, consisting of a complex neoplastic epithelial proliferation surrounded by a continuous layer of myoepithelial cells presumed to be native and non-neoplastic. Recent molecular insights have shown that there are at least 3 different types of IDC: (1) intercalated duct-like, with frequent NCOA4-RET fusions; (2) apocrine, with multiple mutations similar to salivary duct carcinoma; and (3) mixed intercalated duct-like and apocrine with frequent RET fusions, especially TRIM27-RET. Recent observations (eg, IDC occurring in lymph nodes) have challenged the notion that the myoepithelial cells of IDC are non-neoplastic. Five IDCs with known RET fusions by RNA sequencing were retrieved from the authors' archives, including 4 intercalated duct-like IDCs with NCOA4-RET, and 1 mixed intercalated duct-like/apocrine IDC with TRIM27-RET. A panel of immunohistochemistry antibodies (S100 protein, p63 or p40, mammaglobin, smooth muscle actin, calponin, androgen receptor) was tested. To precisely localize RET split-positive cells, each case was subjected to sequential retrieval of whole-slide imaging data of hematoxylin and eosin (HE) staining, immunofluorescence staining for calponin, and fluorescence in situ hybridization (FISH) for RET. Because NCOA4-RET is an inversion difficult to visualize on conventional RET FISH, a novel 3-color FISH technique was utilized to demonstrate it clearly. In all 5 cases, the proliferative ducts were completely surrounded by a layer of myoepithelial cells that were positive for p63 or p40, smooth muscle actin, and calponin. Using combined HE, calponin immunofluorescence, and RET FISH imaging, the positive signals were unmistakably identified in both calponin-negative ductal cells and peripheral, calponin-positive myoepithelial cells in all 5 cases. Utilizing combined HE, calponin immunofluorescence, and RET FISH imaging, we demonstrated that IDCs with RET fusions harbored this alteration in both the ductal and myoepithelial cells. This is compelling evidence that the myoepithelial cells of IDC are not mere bystanders, but are rather a component of the neoplasm itself, similar to other biphasic salivary gland neoplasms like pleomorphic adenoma and epithelial-myoepithelial carcinoma. This finding raises questions about the appropriate terminology, classification, and staging of IDC.
导管内癌(IDC)是一种唾液腺肿瘤,目前被认为类似于乳腺导管原位癌,由一层连续的肌上皮细胞包围的复杂肿瘤上皮增生组成,这些细胞被认为是原生的、非肿瘤性的。最近的分子研究表明,IDC 至少有 3 种不同类型:(1) 中间导管样,常伴有 NCOA4-RET 融合;(2) 大汗腺样,具有类似于唾液腺癌的多种突变;(3) 混合中间导管样和大汗腺样,常伴有 RET 融合,特别是 TRIM27-RET。最近的观察结果(例如,IDC 发生在淋巴结中)挑战了 IDC 的肌上皮细胞是非肿瘤性的观点。从作者的档案中检索到 5 例已知 RET 融合的 IDC,包括 4 例中间导管样 IDC 伴 NCOA4-RET 融合,1 例混合中间导管样/大汗腺样 IDC 伴 TRIM27-RET 融合。应用了一组免疫组化抗体(S100 蛋白、p63 或 p40、乳球蛋白、平滑肌肌动蛋白、钙调蛋白、雄激素受体)进行检测。为了精确定位 RET 分裂阳性细胞,对每个病例进行了苏木精和伊红(HE)染色的全切片成像数据的连续检索、钙调蛋白免疫荧光染色和 RET 荧光原位杂交(FISH)。由于 NCOA4-RET 是一种难以在常规 RET FISH 上可视化的倒位,因此采用了一种新的 3 色 FISH 技术来清晰地显示它。在所有 5 例中,增生的导管完全被一层肌上皮细胞包围,这些细胞 p63 或 p40、平滑肌肌动蛋白和钙调蛋白阳性。通过结合 HE、钙调蛋白免疫荧光和 RET FISH 成像,在所有 5 例中,在钙调蛋白阴性的导管细胞和周围的钙调蛋白阳性的肌上皮细胞中,都可以明确识别出阳性信号。通过结合 HE、钙调蛋白免疫荧光和 RET FISH 成像,我们证明了伴有 RET 融合的 IDC 在导管和肌上皮细胞中都存在这种改变。这有力地证明了 IDC 的肌上皮细胞不是旁观者,而是肿瘤本身的一部分,类似于其他双相唾液腺肿瘤,如多形性腺瘤和上皮-肌上皮癌。这一发现引发了关于 IDC 的适当术语、分类和分期的问题。