Yamada Rin, Kawakami Fumi, Maeda Naoko, Nagao Shoji, Yamamoto Mayuko, Motohara Takeshi, Kondoh Eiji, Mikami Yoshiki, Komohara Yoshihiro
Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Diagnostic Pathology, Kumamoto University Hospital, Kumamoto, Japan.
Department of Diagnostic Pathology, Kumamoto University Hospital, Kumamoto, Japan; Department of Pathology and Cell Biology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
Pathol Res Pract. 2025 Sep;273:156146. doi: 10.1016/j.prp.2025.156146. Epub 2025 Jul 25.
Neuroendocrine neoplasms (NENs) of the uterine cervix are highly malignant tumors associated with a poor prognosis. Human papillomavirus test-based uterine cervical cancer screening methods can detect early-stage uterine cervical NENs, so therapeutic strategies for the earliest stages are urgently needed. This study aimed to investigate and evaluate the prognostic significance of intratumoral and stromal immune cell densities, as well as human leukocyte antigen (HLA) and programmed cell death ligand 1 (PD-L1) expression in stage I uterine cervical NENs. Sixteen NENs were identified, including 8 large cell neuroendocrine carcinomas (LCNECs), 4 small cell neuroendocrine carcinomas (SCNECs), 3 neuroendocrine tumors (NETs), and 1 LCNEC with an SCNEC component. Only 3 cases were pure NENs, while 13 cases included a component of adenocarcinoma or squamous cell carcinoma. Eight of the 16 patients experienced postoperative recurrence. The recurrence-free group exhibited significantly higher densities of intratumoral CD3- and CD8-positive cells compared to the recurrence group (median densities: 136 vs. 48 cells/mm, P = 0.0281 and 91 vs. 27 cells/mm, P = 0.0359, respectively). No significant differences in clinicopathological characteristics, other immune cell densities, or expression of HLA class I, HLA-DR, or PD-L1 were observed between groups. HLA-DR expression was nearly absent in uterine cervical NENs, whereas adjacent non-NEN components displayed varying degrees of HLA-DR expression. PD-L1 expression was observed in 25 % of cases, with CD3- and CD8-positive T-cell-rich stroma. The observed modifications to tumor microenvironments could offer clues to future treatments for uterine cervical NEN. (240/250 words).
子宫颈神经内分泌肿瘤（NENs）是恶性程度很高的肿瘤，预后较差。基于人乳头瘤病毒检测的子宫颈癌筛查方法能够检测出早期子宫颈NENs，因此迫切需要针对最早期阶段的治疗策略。本研究旨在调查和评估肿瘤内及基质免疫细胞密度，以及人类白细胞抗原（HLA）和程序性细胞死亡配体1（PD-L1）在I期子宫颈NENs中的表达的预后意义。共鉴定出16例NENs，包括8例大细胞神经内分泌癌（LCNECs）、4例小细胞神经内分泌癌（SCNECs）、3例神经内分泌肿瘤（NETs），以及1例伴有SCNEC成分的LCNEC。仅3例为纯NENs，而13例包含腺癌或鳞状细胞癌成分。16例患者中有8例术后复发。与复发组相比，无复发组肿瘤内CD3阳性和CD8阳性细胞密度显著更高（中位数密度：分别为136对48个细胞/mm，P = 0.0281；91对27个细胞/mm，P = 0.0359）。两组之间在临床病理特征、其他免疫细胞密度或HLA I类、HLA-DR或PD-L1的表达方面未观察到显著差异。子宫颈NENs中几乎不存在HLA-DR表达，而相邻的非NEN成分显示出不同程度的HLA-DR表达。25%的病例观察到PD-L1表达，伴有富含CD3阳性和CD8阳性T细胞的基质。观察到的肿瘤微环境改变可为子宫颈NENs的未来治疗提供线索。（240/250词）
