Department of Pathology.
Biopticka Laboratory Ltd.
Am J Surg Pathol. 2020 Oct;44(10):1295-1307. doi: 10.1097/PAS.0000000000001535.
Secretory carcinoma (SC), originally described as mammary analogue SC, is a predominantly low-grade salivary gland neoplasm characterized by a recurrent t(12;15)(p13;q25) translocation, resulting in ETV6-NTRK3 gene fusion. Recently, alternative ETV6-RET, ETV6-MAML3, and ETV6-MET fusions have been found in a subset of SCs lacking the classic ETV6-NTRK3 fusion transcript, but still harboring ETV6 gene rearrangements.
Forty-nine cases of SC revealing typical histomorphology and immunoprofile were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). All 49 cases of SC were also tested for ETV6, RET, and NTRK3 break by fluorescence in situ hybridization and for the common ETV6-NTRK3 fusions using reverse transcription polymerase chain reaction.
Of the 49 cases studied, 37 (76%) occurred in the parotid gland, 7 (14%) in the submandibular gland, 2 (4%) in the minor salivary glands, and 1 (2%) each in the nasal mucosa, facial skin, and thyroid gland. SCs were diagnosed more frequently in males (27/49 cases; 55%). Patients' age at diagnosis varied from 15 to 80 years, with a mean age of 49.9 years. By molecular analysis, 40 cases (82%) presented the classic ETV6-NTRK3 fusion, whereas 9 cases (18%) revealed an alternate fusion. Of the 9 cases negative for the ETV6-NTRK3 fusion, 8 cases presented with ETV6-RET fusion. In the 1 remaining case in the parotid gland, next-generation sequencing analysis identified a novel VIM-RET fusion transcript. In addition, the analysis indicated that 1 recurrent high-grade case in the submandibular gland was positive for both ETV6-NTRK3 and MYB-SMR3B fusion transcripts.
A novel finding in our study was the discovery of a VIM-RET fusion in 1 patient with SC of the parotid gland who could possibly benefit from RET-targeted therapy. In addition, 1 recurrent high-grade case was shown to harbor 2 different fusions, namely, ETV6-NTRK3 and MYB-SMR3B. The expanded molecular spectrum provides a novel insight into SC oncogenesis and carries important implications for molecular diagnostics, as this is the first SC-associated translocation with a non-ETV6 5' fusion partner. This finding further expands the definition of SC while carrying implications for selecting the appropriate targeted therapy.
分泌型癌（SC）最初被描述为乳腺类似物 SC，是一种主要为低级别涎腺肿瘤，其特征是反复发生 t(12;15)(p13;q25)易位，导致 ETV6-NTRK3 基因融合。最近，在缺乏典型 ETV6-NTRK3 融合转录本但仍存在 ETV6 基因重排的一部分 SC 中发现了替代的 ETV6-RET、ETV6-MAML3 和 ETV6-MET 融合。
使用 ArcherDX 的 FusionPlex 固体肿瘤试剂盒对 49 例具有典型组织形态学和免疫表型的 SC 病例进行下一代测序分析。所有 49 例 SC 均通过荧光原位杂交检测 ETV6、RET 和 NTRK3 断裂，并通过逆转录聚合酶链反应检测常见的 ETV6-NTRK3 融合。
在研究的 49 例病例中，37 例（76%）发生在腮腺，7 例（14%）发生在下颌下腺，2 例（4%）发生在小涎腺，1 例（2%）分别发生在鼻黏膜、面部皮肤和甲状腺。SC 更常发生在男性（27/49 例；55%）。患者的诊断年龄为 15 至 80 岁，平均年龄为 49.9 岁。通过分子分析，40 例（82%）呈现经典的 ETV6-NTRK3 融合，而 9 例（18%）显示出替代融合。在 9 例 ETV6-NTRK3 融合阴性的病例中，8 例存在 ETV6-RET 融合。在 1 例发生在腮腺的复发性高级别病例中，下一代测序分析鉴定出一种新的 VIM-RET 融合转录本。此外，分析表明，1 例发生在下颌下腺的复发性高级别病例同时存在 ETV6-NTRK3 和 MYB-SMR3B 融合转录本。
我们研究中的一个新发现是，在 1 例发生在腮腺的 SC 患者中发现了一种 VIM-RET 融合，该患者可能受益于 RET 靶向治疗。此外，1 例复发性高级别病例显示存在 2 种不同的融合，即 ETV6-NTRK3 和 MYB-SMR3B。扩展的分子谱为 SC 发生提供了新的见解，并对分子诊断具有重要意义，因为这是首例与非 ETV6 5'融合伙伴相关的 SC 易位。这一发现进一步扩展了 SC 的定义，同时对选择合适的靶向治疗具有重要意义。
