NUT carcinoma (aka NUT midline carcinoma) is a rare, still significantly underrecognized aggressive malignancy. Although historically considered a midline malignancy of children and young adults, NUT carcinoma can originate in almost any body site and in any age group. Beside the classic BRD4-NUTM1 fusion, less common fusion partners include BRD3, NSD3, ZNF532, and ZNF592. Other fusions, including CIC, MGA, MXD4, MXD1, and BCORL1 are associated with sarcomas or cancers of unknown histogenesis. Involvement of the Z4 zinc finger protein (ZNF) family members ZNF532 and ZNF592 is exceedingly rare with only 3 recently reported cases. We herein describe a ZNF532-NUTM1–rearranged NUT carcinoma presenting as a 7.5 cm mass in the left lower lung lobe of a 65-year-old woman. Histology revealed undifferentiated monotonous small round cells with focal epithelioid and rhabdoid elements within a variably myxoid stroma. Immunohistochemistry revealed paucity of keratins and variable p63 combined with extensive CD30 and PLAP expression, leading to initial diagnoses of combined small cell carcinoma, CD30-positive unclassified hematolymphoid malignancy and malignant germ cell neoplasm. Negativity for other more specific germ cell markers justified seeking a fourth opinion, which revealed diffuse expression of the NUT antibody. The diagnosis was then confirmed by fluorescence in situ hybridization. Targeted RNA sequencing revealed the ZNF532-NUTM1 fusion. Screening of 7 NUT carcinomas (5 with BRD4-NUTM1 and 2 with NSD3-NUTM1 fusions) for germ cell markers revealed focal SALL4 reactivity in 3 cases (combined with variable AFP expression in 2), but none expressed CD30 or PLAP. An aberrant germ cell immunophenotype should be considered in NUT carcinoma to avoid misinterpretation as genuine germ cell malignancy as both diseases predominantly affect the young population, frequently involve the mediastinum and can be associated with elevated serum AFP.

NUT 癌（又名 NUT 中线癌）是一种罕见的、仍被严重低估的侵袭性恶性肿瘤。尽管历来被认为是儿童和年轻人的中线恶性肿瘤，但 NUT 癌几乎可以起源于任何身体部位和任何年龄组。除了经典的BRD4-NUTM1融合体之外，不太常见的融合伙伴还包括BRD3、NSD3、ZNF532和ZNF592。其他融合，包括CIC、MGA、MXD4、MXD1和BCORL1与未知组织发生的肉瘤或癌症相关。Z4 锌指蛋白 (ZNF) 家族成员 ZNF532 和 ZNF592 的参与极为罕见，最近仅报告了 3 例。我们在此描述了一名 65 岁女性左下肺叶中的ZNF532-NUTM1重排 NUT 癌，表现为 7.5 厘米肿块。组织学显示未分化的单调小圆形细胞，在不同的粘液样基质内具有局灶性上皮样和横纹肌样成分。免疫组织化学显示角蛋白和可变 p63 缺乏，加上广泛的 CD30 和 PLAP 表达，导致初步诊断为组合性小细胞癌、CD30 阳性未分类的血淋巴恶性肿瘤和恶性生殖细胞肿瘤。其他更具体的生殖细胞标记物呈阴性需要寻求第四种意见，该意见揭示了 NUT 抗体的弥漫性表达。然后通过荧光原位杂交证实了诊断。靶向 RNA 测序揭示了ZNF532-NUTM1融合。对 7 个 NUT 癌（5 个具有BRD4 - NUTM1和 2 个具有NSD3-NUTM1融合）的生殖细胞标记物进行筛查，结果显示 3 个病例中有局灶性 SALL4 反应性（2 个病例中结合了可变的AFP表达），但没有一个表达 CD30 或 PLAP。NUT 癌中应考虑异常的生殖细胞免疫表型，以避免被误解为真正的生殖细胞恶性肿瘤，因为这两种疾病主要影响年轻人，经常累及纵隔，并可能与血清 AFP 升高相关。