Departments of Pathology.
Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD.
Am J Surg Pathol. 2023 Feb 1;47(2):224-233. doi: 10.1097/PAS.0000000000001976. Epub 2022 Oct 10.
Sinonasal teratocarcinosarcoma (TCS) is a rare tumor defined by intermixed neuroepithelial, mesenchymal, and epithelial elements. While its etiology was historically ambiguous, we recently reported frequent SMARCA4 loss by immunohistochemistry, suggesting that TCS might be related to SMARCA4-deficient sinonasal carcinomas. However, other molecular alterations including CTNNB1 mutation have been reported in TCS, and its full genetic underpinnings are unclear. Here, we performed the first comprehensive molecular analysis of sinonasal TCS to better understand its pathogenesis and classification. We collected 30 TCS including 22 cases from our initial study. Immunohistochemical loss of SMARCA4 was seen in 22 cases (73%), with total loss in 18 cases (60%). β-catenin showed nuclear localization in 14 cases (64%) of the subset tested. We selected 17 TCS for next-generation sequencing with enrichment for partial or intact SMARCA4 immunoexpression. We identified inactivating SMARCA4 mutations in 11 cases (65%) and activating CTNNB1 mutations in 6 cases (35%), including 5 cases with both. Of 5 cases that lacked SMARCA4 or CTNNB1 mutation, 2 harbored other SWI/SNF complex and Wnt pathway alterations, including 1 with SMARCB1 inactivation and 1 with concomitant APC and ARID1A mutations, and 3 had other findings, including DICER1 hotspot mutation. These findings confirm that SMARCA4 inactivation is the dominant genetic event in sinonasal TCS with frequent simultaneous CTNNB1 mutations. They further underscore a possible relationship between TCS and sinonasal carcinomas with neuroendocrine/neuroectodermal differentiation. However, while SMARCA4 and β-catenin immunohistochemistry may help confirm a challenging diagnosis, TCS should not be regarded as a molecularly defined entity.
鼻腔鼻窦胚胎性横纹肌肉瘤(TCS)是一种罕见的肿瘤,其特征为神经上皮、间叶和上皮成分混合存在。虽然其病因历史上一直不明确,但我们最近通过免疫组化报告了频繁的 SMARCA4 缺失,提示 TCS 可能与 SMARCA4 缺陷型鼻腔鼻窦癌有关。然而,在 TCS 中也报道了其他分子改变,包括 CTNNB1 突变,其完整的遗传基础尚不清楚。在此,我们对鼻腔鼻窦 TCS 进行了首次全面的分子分析,以更好地了解其发病机制和分类。我们收集了 30 例 TCS,包括我们最初研究中的 22 例。在 22 例(73%)中观察到 SMARCA4 的免疫组织化学缺失,在 18 例(60%)中完全缺失。在检测的亚组中,有 14 例(64%)β-连环蛋白显示核定位。我们选择了 17 例 TCS 进行下一代测序,这些 TCS 对部分或完整 SMARCA4 免疫表达进行了富集。我们在 11 例(65%)中发现了失活的 SMARCA4 突变,在 6 例(35%)中发现了激活的 CTNNB1 突变,包括 5 例同时存在这两种突变。在 5 例缺乏 SMARCA4 或 CTNNB1 突变的病例中,有 2 例存在其他 SWI/SNF 复合物和 Wnt 通路改变,包括 1 例存在 SMARCB1 失活,1 例同时存在 APC 和 ARID1A 突变,3 例存在其他发现,包括 DICER1 热点突变。这些发现证实,SMARCA4 失活是鼻腔鼻窦 TCS 的主要遗传事件,常伴有同时发生的 CTNNB1 突变。它们进一步强调了 TCS 与具有神经内分泌/神经外胚层分化的鼻腔鼻窦癌之间可能存在的关系。然而,虽然 SMARCA4 和β-连环蛋白免疫组化可能有助于确认具有挑战性的诊断,但 TCS 不应被视为一种分子定义的实体。