Atypical endometriosis (A-EMS), defined by cytologic atypia and/or crowded glands resembling endometrial intraepithelial neoplasia, remains poorly understood. We aimed to refine the morphologic, immunohistochemical, and molecular features of A-EMS in an institutional series. Cases were identified through a structured search and reviewed by 2 pathologists. Immunohistochemistry and comprehensive sequencing using a panel 447-gene coverage were performed in suitable cases. A-EMS with synchronous and/or subsequent EMS-related neoplasia were compared with those without. Of 4598 EMS cases over an 11-yr period, 36 A-EMS were identified. The mean age at presentation was 46 (range 26–68) yr. Locations included the ovary (24, 66%), tubo-ovary (6, 17%), fallopian tube (3, 8%), and peritoneum (3, 8%). The mean size was 6.5 (range 0.5–40) mm. Cytologic atypia was mild in 4 (11%), moderate in 21 (58%), and severe in 11 (31%). Most lesions were partially or completely flat (28, 78%); of these, 66% showed hobnail nuclei. Crowded/cribriform and micropapillary/papillary patterns were seen in 11 (31%) and 16 (44%) A-EMS, respectively. Immunohistochemistry, performed in 33 A-EMS, showed wildtype p53 (100%) retained PMS2/MSH6 (100%), and positive estrogen receptor (97%, mean 65% cells), progesterone receptor (76%, mean 30% cells), and Napsin A (39%). Ki67 labelling was <1% to 10% (median 5%). Nine (25%) patients presented with concurrent or subsequent ipsilateral endometrioid, seromucinous, or clear cell neoplasia (4 borderline tumors and 4 carcinomas). The only A-EMS feature statistically more frequent in this subset was crowded/glands (6/9 vs. 2/27 A-EMS without, P=0.001 Fisher exact test). Sequencing showed pathogenic variants in 5 of 6 cases analyzed, involving ATM, BRCA2, KRAS, AKT, CTNNB1, PTEN, and ARID1A among other genes. In 2 cases, synchronous neoplasia showed an accumulation of additional variants. A-EMS is characterized by cytologic atypia and crowded architecture but low proliferation index, positive estrogen receptor, and normal p53 and MMR, which can be helpful in the distinction from malignancy. The prevalence of synchronous/subsequent tubo-ovarian neoplasia in our series was 25%, significantly higher than the reported 1% in conventional EMS. Moreover, A-EMS harbors genomic alterations seen in EMS-related tumors and shares pathogenic variants with synchronous ipsilateral neoplasia. Therefore, it is important to report A-EMS as currently defined and describe its architectural features, especially gland crowding as this appears to increase the risk of EMS-related epithelial neoplasia. Napsin-A is often positive in A-EMS and should be interpreted with caution.

非典型 子宫内膜异位症(A-EMS)，由细胞学异型和/或类似于子宫内膜上皮内瘤变的拥挤腺体定义，仍然知之甚少。我们的目标是在机构系列中完善 A-EMS 的形态学、免疫组织化学和分子特征。病例通过结构化搜索确定，并由 2 名病理学家审查。在合适的病例中使用 panel 447 基因覆盖进行免疫组织化学和综合测序。将具有同步和/或后续 EMS 相关肿瘤的 A-EMS 与没有的进行比较。在 11 年期间的 4598 例 EMS 病例中，确定了 36 例 A-EMS。就诊时的平均年龄为 46 岁（范围 26-68 岁）。位置包括卵巢 (24, 66%)、输卵管卵巢 (6, 17%)、输卵管 (3, 8%) 和腹膜 (3, 8%)。平均尺寸为 6.5（范围 0.5–40）毫米。4 例 (11%) 的细胞学异型性较轻，中度 21 人 (58%)，重度 11 人 (31%)。大多数病变部分或完全平坦 (28, 78%)；其中，66% 显示钉状核。分别在 11 (31%) 和 16 (44%) 个 A-EMS 中观察到拥挤/筛状和微乳头状/乳头状模式。在 33 A-EMS 中进行的免疫组织化学显示野生型 p53 (100%) 保留 PMS2/MSH6 (100%)，雌激素受体阳性（97%，平均 65% 细胞），孕激素受体（76%，平均 30% 细胞）和Napsin A (39%)。Ki67 标记为 <1% 至 10%（中位数 5%）。九名 (25%) 患者出现并发或随后的同侧 在 33 A-EMS 中进行的免疫组织化学显示野生型 p53 (100%) 保留 PMS2/MSH6 (100%)，雌激素受体阳性（97%，平均 65% 细胞），孕激素受体（76%，平均 30% 细胞）和Napsin A (39%)。Ki67 标记为 <1% 至 10%（中位数 5%）。九名 (25%) 患者出现并发或随后的同侧 在 33 A-EMS 中进行的免疫组织化学显示野生型 p53 (100%) 保留 PMS2/MSH6 (100%)，雌激素受体阳性（97%，平均 65% 细胞），孕激素受体（76%，平均 30% 细胞）和Napsin A (39%)。Ki67 标记为 <1% 至 10%（中位数 5%）。九名 (25%) 患者出现并发或随后的同侧子宫内膜样、浆液粘液性或透明细胞瘤（4 例交界性肿瘤和 4 例癌）。唯一在该子集中统计上更频繁的 A-EMS 特征是拥挤/腺体（6/9 对比 2/27 没有 A-EMS，P = 0.001 Fisher 精确检验）。测序显示 6 个分析病例中有 5 个存在致病变异，涉及ATM、BRCA2、KRAS、AKT、CTNNB1、PTEN和ARID1A在其他基因中。在 2 例中，同步性肿瘤显示出额外变异的积累。A-EMS的特点是细胞学异型和拥挤的结构，但增殖指数低，雌激素受体阳性，p53和MMR正常，有助于与恶性肿瘤的鉴别。我们系列中同步/后续输卵管卵巢肿瘤的患病率为 25%，显着高于传统 EMS 报道的 1%。此外，A-EMS 具有在 EMS 相关肿瘤中观察到的基因组改变，并与同步同侧肿瘤共享致病变异。因此，报告当前定义的 A-EMS 并描述其结构特征非常重要，尤其是腺体拥挤，因为这似乎会增加 EMS 相关上皮瘤形成的风险。