Abstract：
A classification system for endocervical adenocarcinoma (ECA) based on high-risk human papillomavirus (HPV) status has been established; however, the immunohistochemical markers distinguishing HPV-independent and HPV-associated ECAs have not been fully described. Here, we aimed to characterize ECA immunopathological features.
We evaluated the immunohistochemical profile of CLDN18, CDX2, PAX8, p16, p53, and CEA in 60 ECAs comprising 10 HPV-independent ECAs and 50 HPV-associated ECAs. Both the membranous and nuclear expression levels of CLDN18 were analyzed.
Membranous CLDN18 (CLDN18 [M]) was found to be expressed in the mucinous epithelium of all HPV-independent ECAs, including eight gastric-type ECAs (G-ECAs), one endometrioid ECA, and one clear cell ECA, but no nuclear CLDN18 (CLDN18 [N]) expression was detected in HPV-independent ECAs. Among HPV-associated ECAs, CLDN18 (M) expression levels in intestinal-type (I-ECAs) and usual-type ECAs (U-ECAs) were significantly different from those in invasive stratified mucin-producing (iSMILE) carcinomas (p = 0.036). Positive CLDN18 (M) staining was present in 55.6% (5/9) of intestinal-type and 39.4% (13/33) of usual-type ECAs and was not present in iSMILE ECAs. Silva pattern C cancers expressed higher levels of CLDN18 (M) than Silva pattern A and B cancers (p = 0.004), whereas the CLDN18 (N) expression levels in cancers showing Silva pattern A were significantly higher than those in cancers exhibiting Silva patterns B and C (p < 0.001).
Membranous CLDN18 is expressed in ECAs and is particularly frequently expressed in HPV-independent ECAs, and membranous CLDN18 expression has potential as a therapeutic target. Nuclear staining of CLDN18 is a new immunohistochemical marker for diagnosing Silva pattern A HPV-associated ECAs and is associated with a good prognosis. Further studies should investigate the therapeutic and prognostic significance of membranous and nuclear CLDN18 expression and develop a related test that can be implemented in the clinical evaluation of ECAs.
We evaluated the immunohistochemical profile of CLDN18, CDX2, PAX8, p16, p53, and CEA in 60 ECAs comprising 10 HPV-independent ECAs and 50 HPV-associated ECAs. Both the membranous and nuclear expression levels of CLDN18 were analyzed.
Membranous CLDN18 (CLDN18 [M]) was found to be expressed in the mucinous epithelium of all HPV-independent ECAs, including eight gastric-type ECAs (G-ECAs), one endometrioid ECA, and one clear cell ECA, but no nuclear CLDN18 (CLDN18 [N]) expression was detected in HPV-independent ECAs. Among HPV-associated ECAs, CLDN18 (M) expression levels in intestinal-type (I-ECAs) and usual-type ECAs (U-ECAs) were significantly different from those in invasive stratified mucin-producing (iSMILE) carcinomas (p = 0.036). Positive CLDN18 (M) staining was present in 55.6% (5/9) of intestinal-type and 39.4% (13/33) of usual-type ECAs and was not present in iSMILE ECAs. Silva pattern C cancers expressed higher levels of CLDN18 (M) than Silva pattern A and B cancers (p = 0.004), whereas the CLDN18 (N) expression levels in cancers showing Silva pattern A were significantly higher than those in cancers exhibiting Silva patterns B and C (p < 0.001).
Membranous CLDN18 is expressed in ECAs and is particularly frequently expressed in HPV-independent ECAs, and membranous CLDN18 expression has potential as a therapeutic target. Nuclear staining of CLDN18 is a new immunohistochemical marker for diagnosing Silva pattern A HPV-associated ECAs and is associated with a good prognosis. Further studies should investigate the therapeutic and prognostic significance of membranous and nuclear CLDN18 expression and develop a related test that can be implemented in the clinical evaluation of ECAs.
摘要：
目的：已经建立了基于高危型人乳头瘤病毒（HPV）状态的宫颈腺癌（ECA）分类系统；但是，区分HPV非依赖性和HPV相关ECA的免疫组织化学标志物尚未得到充分描述.这里,我们旨在表征ECA免疫病理学特征。
方法：我们评估了60个ECA中CLDN18、CDX2、PAX8、p16、p53和CEA的免疫组织化学谱，包括10个不依赖HPV的ECA和50个与HPV相关的ECA。分析了CLDN18的膜和核表达水平。
结果：发现膜CLDN18（CLDN18[M]）在所有不依赖HPV的ECA的粘液上皮中表达，包括八个胃型ECA（G-ECA），一个子宫内膜样ECA，和一个透明细胞ECA，但在不依赖HPV的ECA中未检测到核CLDN18（CLDN18[N]）表达。在HPV相关的ECA中，肠型（I-ECAs）和普通型ECAs（U-ECAs）中的CLDN18（M）表达水平与侵袭性分层产生粘蛋白（iSMILE）癌（p=0.036）。CLDN18（M）阳性染色存在于55.6％（5/9）的肠型ECA和39.4％（13/33）的普通型ECA中，而在iSMILEECA中不存在。席尔瓦模式C癌表达CLDN18（M）的水平高于席尔瓦模式A和B癌（p=0.004），而显示席尔瓦模式A的癌症中的CLDN18(N)表达水平显著高于显示席尔瓦模式B和C的癌症(p<0.001)。
结论：膜性CLDN18在ECA中表达，特别是在不依赖HPV的ECA中表达，膜CLDN18表达具有作为治疗靶标的潜力。CLDN18的核染色是诊断席尔瓦型HPV相关ECA的新的免疫组织化学标记，并与良好的预后相关。进一步的研究应研究膜和核CLDN18表达的治疗和预后意义，并开发可在ECA的临床评估中实施的相关测试。
方法：我们评估了60个ECA中CLDN18、CDX2、PAX8、p16、p53和CEA的免疫组织化学谱，包括10个不依赖HPV的ECA和50个与HPV相关的ECA。分析了CLDN18的膜和核表达水平。
结果：发现膜CLDN18（CLDN18[M]）在所有不依赖HPV的ECA的粘液上皮中表达，包括八个胃型ECA（G-ECA），一个子宫内膜样ECA，和一个透明细胞ECA，但在不依赖HPV的ECA中未检测到核CLDN18（CLDN18[N]）表达。在HPV相关的ECA中，肠型（I-ECAs）和普通型ECAs（U-ECAs）中的CLDN18（M）表达水平与侵袭性分层产生粘蛋白（iSMILE）癌（p=0.036）。CLDN18（M）阳性染色存在于55.6％（5/9）的肠型ECA和39.4％（13/33）的普通型ECA中，而在iSMILEECA中不存在。席尔瓦模式C癌表达CLDN18（M）的水平高于席尔瓦模式A和B癌（p=0.004），而显示席尔瓦模式A的癌症中的CLDN18(N)表达水平显著高于显示席尔瓦模式B和C的癌症(p<0.001)。
结论：膜性CLDN18在ECA中表达，特别是在不依赖HPV的ECA中表达，膜CLDN18表达具有作为治疗靶标的潜力。CLDN18的核染色是诊断席尔瓦型HPV相关ECA的新的免疫组织化学标记，并与良好的预后相关。进一步的研究应研究膜和核CLDN18表达的治疗和预后意义，并开发可在ECA的临床评估中实施的相关测试。
