Although criteria for malignancy have been established for glomus tumors of soft tissue, there are no accepted criteria for gastroesophageal glomus tumors, the behavior of which is considered to be unpredictable. Recently, both benign and aggressive gastroesophageal glomus tumors have been shown to harbor CARMN::NOTCH2 fusions, but, as yet, there are no described genetic features that predict clinical behavior. Here, we evaluated 26 gastroesophageal glomus tumors to investigate histologic and genetic features that might predict malignant behavior. Seventeen patients (65%) were male. The median age at presentation was 54.5 years (range: 16 to 81 y). Primary sites were stomach (25 tumors) and distal esophagus (1). The median tumor size was 4.05 cm (range: 0.8 to 19.5 cm). Tumors were composed of lobules of rounded cells with sharp borders, palely eosinophilic to clear cytoplasm, and round nuclei. All tumors involved the muscularis propria, and 12 also involved the serosal surface. Mitoses ranged from <1 to 53/10 HPF (median: 5/10 HPF). Sixteen tumors, including all 15 with mitoses ≥2/10 HPF, showed atypia (3 mild, 10 moderate, 3 severe), defined as spindle cell morphology, nuclear irregularity, nuclear size variability, enlarged nuclei, or coarse chromatin. Considering these histologic features and clinical behavior, tumors were classified as malignant (15 tumors) if they measured ≥5 cm or showed both atypia and mitoses ≥2/10 HPF, or benign (11 tumors) if these criteria were not met. Follow-up was available for 19 patients (73%; range: 1 to 15 y; median: 5.8 y), including 7 with benign tumors and 12 with malignant tumors. Two patients with malignant tumors had metastases at presentation, and 7 developed metastases subsequently. Follow-up was available for 8 of 9 patients with metastatic disease. Two were alive with disease at most recent follow-up. One underwent resection of a liver metastasis, with no subsequent metastases in 3 years of follow-up. Five patients died of metastatic disease. By immunohistochemistry, smooth muscle actin was diffusely positive in all evaluated tumors, and caldesmon and synaptophysin were positive in 94% and 73%, respectively. Sequencing identified NOTCH2 alterations in 4 benign tumors (80%) and 8 malignant tumors (80%), including CARMN::NOTCH2 fusions in 2 benign and 5 malignant tumors. All 5 sequenced benign tumors lacked complex copy number alterations (CNAs), whereas all 10 sequenced malignant tumors showed complex CNAs, including recurrent loss of 9p21.3 (4/10, variably including CDKN2A/B and MTAP) and ATRX inactivation (4/10). Complex CNAs were identified in all sequenced tumors that were ≥5 cm, exhibited both cytologic atypia and ≥2 mitoses/10 HPF, involved the serosa or metastasized. We propose that gastroesophageal glomus tumors ≥5 cm or with both atypia and mitoses ≥2/10 HPF should be considered malignant. Copy number analysis might be helpful in borderline cases.

尽管已经为软组织血管球瘤建立了恶性标准，但对于胃食管血管球瘤没有公认的标准，其行为被认为是不可预测的。最近，良性和侵袭性胃食管血管球瘤都被证明含有CARMN :: NOTCH2融合，但到目前为止，还没有描述的遗传特征可以预测临床行为。在这里，我们评估了 26 例胃食管血管球瘤，以研究可能预测恶性行为的组织学和遗传特征。17 名患者 (65%) 为男性。就诊时的中位年龄为 54.5 岁（范围：16 至 81 岁）。主要部位是胃（25 个肿瘤）和远端食管（1 个）。中位肿瘤大小为 4.05 厘米（范围：0.8 至 19.5 厘米）。肿瘤由边界清晰的圆形细胞小叶组成，胞质淡嗜酸性至透明，核圆形。所有肿瘤均累及固有肌层，12 例还累及浆膜表面。有丝分裂的范围从 <1 到 53/10 HPF（中位数：5/10 HPF）。16 个肿瘤，包括所有 15 个有丝分裂≥2/10 HPF 的肿瘤，显示非典型性（3 个轻度，10 个中度，3 个重度），定义为梭形细胞形态、核不规则、核大小可变性、核增大或染色质粗糙。考虑到这些组织学特征和临床行为，如果肿瘤测量 ≥ 5 cm 或显示非典型性和有丝分裂≥ 2/10 HPF，则将肿瘤分类为恶性（15 个肿瘤），如果不符合这些标准，则将其分类为良性（11 个肿瘤）。19 名患者（73%；范围：1 至 15 岁；中位数：5.8 岁）进行了随访，其中良性肿瘤 7 例，恶性肿瘤 12 例。2例恶性肿瘤患者在就诊时发生转移，7例随后发生转移。9 名转移性疾病患者中有 8 名可进行随访。在最近的一次随访中，两人还活着。一名接受了肝转移切除术，在 3 年的随访中没有随后的转移。五名患者死于转移性疾病。通过免疫组织化学，平滑肌肌动蛋白在所有评估的肿瘤中呈弥漫性阳性，caldesmon 和突触素阳性率分别为 94% 和 73%。测序鉴定4 个良性肿瘤 (80%) 和 8 个恶性肿瘤 (80%) 中的 NOTCH2 改变，包括2个良性肿瘤和 5 个恶性肿瘤中的CARMN :: NOTCH2融合。所有 5 个测序的良性肿瘤都缺乏复杂的拷贝数改变 (CNA)，而所有 10 个测序的恶性肿瘤都显示出复杂的 CNA，包括 9p21.3（4/10，可变包括CDKN2A / B和MTAP）和ATRX的反复丢失失活（4/10）。在所有≥5cm、细胞学异型性和≥2个有丝分裂/10 HPF、涉及浆膜或转移的肿瘤中均发现了复杂的CNA。我们建议胃食管球瘤≥5 cm 或异型和有丝分裂≥2/10 HPF 应被视为恶性。拷贝数分析在临界情况下可能会有所帮助。