Endocervical Adenocarcinoma With Morphologic Features of Both Usual and Gastric Types

Abstract

The fourth edition of the World Health Organization classification set up new entities of endocervical adenocarcinoma (ECA), namely the "usual type" and "gastric type." These 2 types are considered to be distinct histogenetically because of their differing immunophenotypes, human papillomavirus (HPV) status, and prognoses. Usual-type ECAs (U-ECAs) are virtually always associated with high-risk human papillomavirus (HR-HPV) infection. Gastric-type ECAs (G-ECAs) are believed not to be associated with HR-HPV infection. Morphologically, U-ECA cells are characterized by mucin-poor and eosinophilic cytoplasm, resembling endometrioid carcinoma (a pseudoendometrioid feature). G-ECA cells are characterized by abundant clear or pale, mucinous cytoplasm and distinct cell borders. However, in routine practice we noticed that some ECAs contain morphologically usual type-like components and gastric type-like components in a single tumor; we have named these "G+U" ECAs. The histogenesis of such tumors has not been investigated. We conducted the present study to clarify the clinicopathologic and immunohistochemical features and HPV status of G+U ECAs, and to determine whether G+U ECAs are genuine G-ECAs mimicking U-ECAs or genuine U-ECAs with gastric type-like morphology. We retrospectively analyzed a series of 70 consecutive cases of ECA diagnosed as mucinous ECA, endocervical type, and we reclassified them on the basis of the latest World Health Organization classification. We identified 48 (69%) pure U-ECAs, 9 pure G-ECAs, and 13 G+U ECAs. Ten of the 13 G+U ECAs (77%) showed no HR-HPV infection by in situ hybridization (HPV-unrelated G+U ECAs) and showed frequent HIK1083 expression and aberrant p53 expression in both usual type-like and gastric type-like components. The other 3 G+U ECAs showed HR-HPV infection (HPV-related G+U EACs) and frequent p16+/p53-/HIK1083- immunophenotype in both usual type-like and gastric type-like components. The U-ECAs were characterized by HR-HPV infection detected by in situ hybridization and frequent p16+/p53-/HIK1083- immunophenotype, similar to that of the HPV-related G+U ECAs. In contrast, the pure G-ECAs were characterized by the absence of HPV infection and frequent HIK1083 expression and aberrant p53 expression, similar to that of HPV-unrelated G+U ECAs. G+U ECAs thus represent a heterogenous group composed of genuine G-ECAs and genuine U-ECAs. Most of the G+U ECAs we examined were genuine HPV-unrelated G-ECAs with usual type-like components showing mucin-poor, eosinophilic cytoplasm (pseudoendometrioid morphology). A small population of G+U ECAs was genuine HPV-related U-ECAs with gastric type-like components showing mucin-rich, voluminous cytoplasm. Thus, both types of ECAs can occasionally display patterns of differentiation suggesting a component of the other type but true mixed tumors do not appear to exist. Ancillary techniques (immunohistochemical analysis of p16, p53, and HPV DNA detection assays) should be used to assure proper classification of tumors with mixed morphologic feat...

Clinicopathological and Molecular Differences Between Gastric-type Mucinous Carcinoma and Usual-type Endocervical Adenocarcinoma of the Uterine Cervix

“…Our findings suggest that immunostaining for p16 and p53 allows distinguishing between UEA and GMC. However, in contrast to our results, diffuse and strong nuclear p16 expression has been reported in a rare subset of GMC despite negative molecular testing for HPV (30)(31)(32). Moreover, not all GMCs display mutant p53 immunostaining patterns.…”

Evaluation of human papillomavirus (HPV) prediction using the International Endocervical Adenocarcinoma Criteria and Classification system, compared to p16 immunohistochemistry and HPV RNA in-situ hybridization

“…Using morphology alone, we have identified one hybrid case with both NHPVA and HPVA features. Like the 13 cases reported by Wada et al [ 33 ], the hybrid case contained features of both gastric and usual-type ECA. However, the cases presented in their study demonstrated either positive HPV or negative HPV in both gastric and usual-type components using HPV DNA ISH.…”

International Endocervical Adenocarcinoma Criteria and Classification (IECC)

“…This case, showing “limited HPVA features,” was both p16- and HPV-positive. The most likely explanation is that this was a mucinous HPVA with cytoplasmic features that suggested gastric-type differentiation (a recently reported phenomenon), 28 or part of a mixed carcinoma, with one component being HPV-positive. 47 An alternative explanation is based on the theoretical coincidence of GNAS mutation with HPV infection, with GNAS underpinning the development of some gastric-type tumors in both the endocervix and extra-gynecologic sites.…”

“…All HPV-negative usual-type ECAs in this study were confirmed as usual-type on re-review. While rare p16-negative/HPV-negative usual-type ECAs may represent unusual morphological variants of gastric-type carcinoma, 28 all 10 p16-negative/HPV-negative usual-type ECAs were negative for HIK1083 (data not shown), making it improbable that these tumors were, in fact, of gastric-type. Another theoretical consideration is that rare HPV types not included in the RNA ISH probe set could be responsible for negative HPV results.…”