Gastrointestinal immunophenotype in adenocarcinomas of the uterine cervix and related glandular lesions: a possible link between lobular endocervical glandular hyperplasia/pyloric gland metaplasia and ‘adenoma malignum‘

Abstract

Gastrointestinal phenotype in cervical adenocarcinomas was examined by immunohistochemistry and correlated with morphologic features. Antibody panels included anti-MUC2, MUC6, CD10, chromogranin A (CGA) and HIK1083. In addition, expression of p16 INK4 , a cyclin-dependent kinase inhibitor which is expressed in a variety of high-risk HPV-related conditions, was studied. A total of 94 invasive adenocarcinomas including 20 minimal deviation adenocarcinomas (MDAs) and 72 adenocarcinomas in situ (AIS) were examined. MDAs were most frequently positive for HIK1083 and/or MUC6, two representative gastric markers, with a rate of 95%, followed by intestinal-type adenocarcinomas (IAs) with a rate of 85% whereas only 27% of 56 usual endocervical-type adenocarcinomas (UEAs) were positive. MUC2, a goblet cell marker, was positive in 85% and 25% of IAs and MDAs, respectively, while in only 14% of UEAs. CD10 was positive in 15% of IAs, indicating incomplete intestinal differentiation without a brush border in most of the cases. CGA-positive cells were frequently seen in MDAs and IAs with rates of 60% and 62%, respectively. Nuclear and cytoplasmic p16 INK4 positivity was identified in 93% of UEAs, whereas 30% of MDAs were positive for p16 INK4 . Results in AISs were comparable to their invasive counterparts, but morphologically usual-type AISs identified in eight cases of MDA were frequently positive for HIK1083 (75%) and MUC6 (63%), and p16 INK4 . Of note was the existence of lobular endocervical glandular hyperplasia (LEGH) with atypical features including cytologic abnormalities, and/or papillary projection, which were identified in this study in pure form (n ¼ 3) or in association with MDAs (n ¼ 6), but not in cases of other types of adenocarcinomas. These observations indicate that gastrointestinal phenotype is frequently expressed in MDAs and IAs, and there seems to be a possible link between MDA, and LEGH and morphologically usual-type AIS with gastric immunophenotype in histogenesis. Frequent absence of p16 INK4 expression in MDAs suggests a possibility that high-risk HPV does not play a crucial role in development of MDAs, in contrast to the majority of endocervical adenocarcinomas. p16 INK4 immunohisto-

Usefulness of a management protocol for patients with cervical multicystic lesions: A retrospective analysis of 94 cases and the significance of GNAS mutation

“…Therefore, a differential diagnosis between LEGH and MDA is challenging. Although LEGH was first reported as a benign disease, it has been reported as a precursor of MDA, because of frequent association between LEGH and MDA as well as its genetic characteristics 6, 7, 8, 9, 10, 11. We previously reported that some LEGH lesions were a precancerous form of MDA due to the pattern of X chromosome inactivation using the human androgen receptor (HUMARA) method 12.…”

Absence of High-Risk Human Papillomavirus (HPV) Detection in Endocervical Adenocarcinoma with Gastric Morphology and Phenotype

“…19,20 Additionally, both neoplasms can be associated with lobular endocervical glandular hyperplasia (LEGH), 19 which represents a pyloric gland metaplasia 21 and has also been shown to be hr-HPV DNA-negative. 16,22 These facts suggest that the mucinous AC with gastric immunophenotype, incorporating MDA as its well-differentiated form in the morphological spectrum, is a distinct entity arising via a hr-HPV-independent pathway.…”

“…In a previous investigation we demonstrated that mucinous AC with gastric immunophenotype was morphologically distinct with a good interobserver reproducibility, characterized by neoplastic cells with conspicuous cell borders and clear and/or pale eosinophilic voluminous cytoplasm, and aggressive clinical behavior. 20,23 MDA is not a common neoplasm, accounting for 1-3% of all endocervical ACs, but the gastric-type adenocarcinoma (GAC) appears in 10 -30% of all endocervical ACs 19,20 and thus may not be a negligible pitfall of HPV DNA tests and vaccination, and therapeutic strategy.…”

Synchronous cervical minimal deviation adenocarcinoma, gastric type adenocarcinoma and lobular endocervical glandular hyperplasia along with stil in peutz-jeghers syndrome: eliciting oncogenesis pathways

“…Histological changes mimicking clear cell carcinoma have been reported after neoadjuvant therapy but immunohistochemical positive expression of cEa, cytokeratin 7 (diffuse), and cytokeratin 20 (focal), positive HIk1083 stain or negative/focal p16 stain favors gastric-type mucinous adenocarcinoma of the cervix (12). Immunophenotypic overlap with pancreaticobiliary adenocarcinomas exists but PaX8 immunoreactivity may be useful to distinguish them.…”