Gastric‐type mucinous carcinoma of the cervix and its precursors – historical overview

Abstract

The emerging concept of gastric‐type mucinous carcinoma (GAS) of the uterine cervix has been accepted worldwide because of its aggressive clinical behaviour and the absence of high‐risk human papillomavirus (HPV). GAS is included as a variant of mucinous carcinoma in the 2014 World Health Organization classification, and its recognition has provoked a discussion on endocervical adenocarcinoma as a single entity such that endocervical adenocarcinoma is now divided into HPV‐associated and HPV‐independent groups. This article reviews historical and conceptual aspects of GAS and its precursors, starting with minimal deviation adenocarcinoma (MDA), through the ensuing confusion, up to the recent paradigm shift in cervical adenocarcinoma subclassification. The gastric immunophenotype of MDA was demonstrated by a Japanese group in 1998 using the HIK1083 antibody, which recognises gastric pyloric gland mucin, and this elucidated the pathogenesis of this particular tumour. However, this information resulted in overdiagnosis of lobular endocervical glandular hyperplasia (LEGH), first described in 1999 and which represents pyloric gland metaplasia (PGM), as malignant. In the early 2000s the relationship between MDA and LEGH/PGM became a matter of controversy. In 2007 HIK1083 immunohistochemistry extended the morphological spectrum of endocervical adenocarcinoma showing gastric differentiation beyond MDA, which resulted in the proposal of GAS as a distinct entity including MDA as its very well‐differentiated subtype. GAS is now considered to be an aggressive and chemoresistant neoplasm that is not related to high‐risk HPV. The LEGH/PGM–GAS sequence is currently regarded as an HPV‐independent pathway of carcinogenesis. Understanding the underlying molecular events in this process is key to the development of biomarkers for early detection and molecular targeted therapy.

Impact of Histopathological Risk Factors on the Treatment of Stage IB-IIB Uterine Cervical Cancer

“…In contrast to UEA, GAS is frequently located in the upper endocervix and shows a bulky cervix without well-demarcated mass due to its highly infiltrating pattern of growth. While most UEAs are mostly related to human papillomavirus (HPV), GAS is reported to be unrelated to HPV (Mikami 2020) and importantly is associated with aggressive clinical behavior, and its outcome is worse than UEA (Kojima et al 2007;Kusanagi et al 2010;Houghton et al 2010;Park et al 2011;Karamurzin et al 2015;Nishio et al 2019). Of 328 eligible patients with endocervical adenocarcinoma in the JCOG retrospective study, 95 cases were reclassified as GAS by a central pathological review (Nishio et al 2019).…”

Cytomorphologic Features of Gastric-Type Endocervical Adenocarcinoma in Liquid-Based Preparations

“…In contrast to endocervical adenocarcinoma of usual-type (UEA), GAS is primarily characterized by a human papilloma virus (HPV)-independent etiology, pyloric gland-type mucin production (detectable by immunohistochemistry with HIK1083 and MUC6 antibodies), and unfavorable clinical behavior [1]. GAS manifests as part of a spectrum of endocervical lesions which comprise benign, premalignant, and malignant entities and, in case of the latter, encompass a well-differentiated form historically termed “minimal deviation adenocarcinoma” (MDA, also adenoma malignum) [1, 2]. GAS has recently been confirmed as the major subtype in the HPV-independent category of endocervical adenocarcinomas and requires separation from HPV-related mucinous tumors which encompass signet-ring cell type, intestinal type, invasive stratified mucin-producing, and mucinous carcinoma, not otherwise specified [3].…”

“…This is partly due to the fact that the diagnostic category “endocervical mucinous adenocarcinoma” was used in the past for a heterogeneous group of neoplasms. MDA represents a morphologically challenging diagnosis whose bland features may have been overemphasized in relation to its benign and precursor mimics [2, 4, 5]. On the other hand, the proportion of “overt” adenocarcinoma permissible for MDA subcategorization is not well defined.…”

“…Although early diagnosis and treatment are key to improving the prognosis of GAS, a meta-analysis focused on MDA found low detection rates both by cytology and biopsy, thus often requiring multiple successive sampling procedures [10]. Notably, clinical observation of cervical thickening and radiologic detection of multicystic cervical lesions and/or hypertrophy by ultrasound, computed tomography, or magnetic resonance imaging may aid in case identification but cannot reliably distinguish between benign and early malignant changes [2, 10, 11]. MRI features described as “cosmos” sign (small cysts or solid parts surrounded by larger cysts) may represent lobular endocervical glandular hyperplasia (LEGH), a benign morphologic mimic of MDA and potential precursor lesion (identifiable as “atypical” LEGH) of gastric-type mucinous carcinomas [2, 11, 12].…”

Clinicopathological Characteristics of Gastric-type Endocervical Adenocarcinoma Misdiagnosed as an Endometrial, Ovarian or Extragenital Malignancy, or Mistyped as Usual-type Endocervical Adenocarcinoma

“…However, it has been re-classified as one of the HPV-independent subtypes in the latest 2020 WHO Classification (5). Its recognition has provoked the abovementioned discussion on dividing endocervical adenocarcinomas into two groups according to the association with HPV (6)(7)(8), because GEA presents specific histological features and immunophenotype, as well as aggressive clinical behavior. This tumor is morphologically characterized by irregular and dilated glands; abundant, clear, or pale eosinophilic cytoplasm; distinct cell borders; varying degrees of nuclear pleomorphism; and prominent stromal desmoplasia.…”