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HPV-negative Gastric Type Adenocarcinoma In Situ of the Cervix: A Spectrum of Rare Lesions Exhibiting Gastric and Intestinal Differentiation.

HPV阴性的宫颈胃型原位腺癌:一组表现出胃肠分化的少见病变

Talia KL,Stewart CJR,Howitt BE,Nucci MR,McCluggage WG

Abstract

In recent years, a number of benign and malignant cervical glandular lesions exhibiting gastric differentiation have been described but premalignant gastric-type lesions have not been well characterized. We report a series of 9 cases of a rare form of cervical adenocarcinoma in situ (AIS) distinguished by gastric and sometimes intestinal differentiation and lack of association with human papillomavirus (HPV) infection. The lesions occurred in women aged 25 to 73 years (mean age 51 y). All cases were located at (or just proximal to) the cervical transformation zone and there was extension to the lower uterine segment in 3 cases, 2 of which also involved the endometrium. In all cases, the normal cervical glandular architecture was largely preserved but in 5 cases there was a mild degree of increased intraglandular architectural complexity. The glandular epithelium ranged from almost purely gastric in type (4 cases) to mixed gastric and intestinal (5 cases), with varying proportions of intermixed goblet cells. In contrast to the basophilic cytoplasm of normal endocervical glands, the gastric-type epithelium was typically predominantly composed of cells with eosinophilic or pale pink cytoplasm, but conspicuous foamy or clear cell cytoplasm was present in some cases. Nuclear atypia was present in all cases but was considered low-grade in 8. High-grade features such as marked nuclear pleomorphism and hyperchromasia were evident in only 1 case. Mitotic activity and apoptotic bodies were present but both were noted to be less frequent than in usual type (HPV-related) AIS. Immunohistochemically, there was usually positive staining with CK 7 (7/7 cases) and MUC 6 (7/8 cases) and some cases were positive with CK 20 (3/7), CDX2 (5/9), PAX 8 (5/9) and CEA (2/6). Estrogen receptor and progesterone receptor were usually negative, although Estrogen receptor was positive in 3 of 9 cases. p16 was negative or exhibited mosaic-type staining (nonblock staining) in all cases and there was mutation-type p53 staining in 2 of 9 cases. HPV molecular testing was negative in all 4 cases tested. We believe this unusual subtype of AIS, which we term "gastric-type AIS (gAIS)," represents a precursor to gastric-type adenocarcinoma of the cervix and suggest that gAIS and so-called "atypical lobular endocervical glandular hyperplasia" are related entities within a spectrum of premalignant gastric-type lesions for which we propose the umbrella term gAIS. The malignant potential and optimal management of gAIS are currently unknown but in one of our cases a gastric-type adenocarcinoma developed 6 years after removal of a cervical polyp which contained gAIS. The introduction of HPV vaccination will result in a relative increase in incidence of premalignant and malignant cervical glandular lesions exhibiting gastric differentiation and these will not be detected by HPV-based screening programs.

摘要

近年来,陆续报道了一些表现出胃型分化的宫颈良性和恶性腺体病变,但是关于胃型腺体病变的癌前病变尚无定论。我们报道9例罕见的原位腺癌,以胃和肠分化为特征且不伴有HPV感染。这组病例发生于25岁至73岁的女性(平均年龄51岁),所有的病例均发生于或接近宫颈移行区,3例累及子宫下段,其中2例更是累及内膜。所有病例中正常宫颈腺体结构基本保存,其中5例腺体内结构复杂性轻度增加。腺上皮为单纯胃型者5例,混合性胃型和肠型6例(其中混杂有不同比例的杯状细胞)。与正常宫颈腺体的嗜碱性胞质不同,胃型上皮细胞通常胞浆呈嗜酸性或浅粉色,但偶有病例上皮胞质呈现泡沫样或透明。所有病例均可见细胞核的异型性,其中8例为低级别,只有1例为高级别的核表现出显著的核多形性和染色质增粗。核分裂像和凋亡小体可见,但两者均较HPV相关AIS少见。免疫组织化学染色阳性的有CK7(7/7)、MUC6(7/8)、CK20(3/7)、CDX-2(5/9)、PAX8(5/9)和CEA(2/6)。尽管ER在9例中有3例阳性,但ER和PR通常为阴性。P16为阴性或者呈镶嵌式染色。此外9例中有2例突变型P53阳性。4例行HPV检测者均为阴性。我们认为这种不常见的AIS亚型-“胃型”AIS(gAIS)是宫颈胃型腺癌的前驱病变。并且gAIS和所谓的“非典型小叶状宫颈管腺体增生”作为胃型腺癌的癌前期病变是密切相关的,因此我们将其总称为gAIS。对gAIS的恶性潜能和最佳的处理方式仍然不清。我们的一例病例在含有gAIS的宫颈息肉摘除后6年后进展为胃型腺癌。HPV疫苗的引进可能将导致胃型分化的宫颈腺体恶性和癌前病变的发病率相对上升,而基于HPV检测的筛查方案却无法检出。

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