Adenocarcinomas exhibiting gastric differentiation represent a recently described and uncommon subtype of non-human papillomavirus (HPV) related cervical adenocarcinoma. They comprise a spectrum from a well differentiated variant (adenoma malignum/mucinous variant of minimal deviation adenocarcinoma) to a more poorly overtly malignant form, generally referred to as gastric-type adenocarcinoma. Rarely, such tumours have also been described as primary vaginal neoplasms. Gastric-type adenocarcinomas exhibit considerable morphological overlap with adenocarcinomas originating outside the female genital tract, especially mucinous adenocarcinomas arising in the pancreas and biliary tract. Moreover they often metastasize to unusual sites, such as the ovary and peritoneum/omentum, where they can be mistaken for metastatic adenocarcinomas from other, non-gynaecological sites. There is little information regarding the immunophenotype of gastric-type adenocarcinomas and knowledge of this is important to aid in the distinction from other adenocarcinomas. In this study, we undertook a detailed immunohistochemical analysis of a large series of cervical (n=45) and vaginal (n=2) gastric-type adenocarcinomas. Markers included were CK7, CK20, CDX2, CEA, CA125, CA19.9, p16, ER, PR, MUC6, PAX8, PAX2, p53, hepatocyte nuclear factor 1 beta (HNF1β), carbonic anhydrase IX (CAIX), HER2 and MMR proteins. All markers were classified as negative, focal (<50% of tumour cells positive) or diffuse (≥50% tumour cells positive) except for p53 (classified as “wild-type” or “mutation-type”), HER2 (scored using the College of American Pathologists guidelines for gastric carcinomas) and MMR proteins (categorised as retained or lost). There was positive staining with CK7 (47/47 – 45 diffuse, 2 focal), MUC6 (17/21 – 6 diffuse, 11 focal), CEA (25/31 – 12 diffuse, 13 focal), CAIX (20/24 – 8 diffuse, 12 focal), PAX8 (32/47 – 20 diffuse, 12 focal), CA125 (36/45 – 5 diffuse, 31 focal), CA19.9 (11/11 – 8 diffuse, 3 focal), HNF1β (13/14 – 12 diffuse, 1 focal), CDX2 (24/47 – 4 diffuse, 20 focal), CK20 (23/47 – 6 diffuse, 17 focal) and p16 (18/47 – 4 diffuse, 14 focal). Most cases were negative with ER (29/31), PR (10/11), PAX2 (18/19) and HER2 (25/26). p53 showed “wild-type” and ”mutation-type” staining in 27/46 and 19/46 cases respectively. MMR protein expression was retained in 19/20 cases with loss of MSH6 staining in one patient with Lynch syndrome. Molecular studies for HPV were undertaken in two tumours which exhibited diffuse” block-type” immunoreactivity with p16 and both were negative. This is the first detailed immunohistochemical study of a large series of gastric-type adenocarcinomas of the lower female genital tract. Our results indicate immunophenotypic overlap with pancreaticobiliary adenocarcinomas but suggest that PAX8 immunoreactivity may be especially useful in distinguishing gastric-type adenocarcinomas from pancreaticobiliary and other non-gynaecological adenocarcinomas which are usually negative. Diffuse “block-type”p16 immunoreactivity ...

Adenocarcinoma of the cervix is less common than squamous cell carcinoma, although its relative prevalence is increasing. Oncogenic (high-risk) human papillomavirus (HPV) infection is implicated in the development of approximately 90% of all cervical adenocarcinomas. Of the remaining non-HPV associated tumours, the most frequent is gastric-type adenocarcinoma (GAS), which is recognised by the World Health Organization as a form of mucinous adenocarcinoma of the cervix. Minimal deviation adenocarcinoma (MDA) of mucinous type (adenoma malignum) is considered an extremely well differentiated variant of GAS and is encompassed within the category of GAS. The concept of gastric-type cervical glandular lesions has emerged over recent decades and our understanding of the full spectrum of benign, premalignant and malignant lesions is still evolving. Established benign lesions, which are rare, include simple gastric metaplasia and lobular endocervical glandular hyperplasia (LEGH) (complex gastric metaplasia). Postulated premalignant lesions comprise atypical LEGH and gastric-type adenocarcinoma in situ (gAIS); these are probably related lesions for which the umbrella term 'gAIS' has been proposed. The term 'gastric-type' derives from the morphological resemblance of the glandular epithelium to that seen in the stomach and pancreaticobiliary tree; intestinal metaplasia with goblet cells and neuroendocrine cells are present in some cases. A gastric immunophenotype has been demonstrated using markers of pyloric gland mucin, MUC6 and HIK1083. Uncommonly, gastric-type cervical glandular lesions involve multiple sites in the female genital tract and it may be problematic to discern whether these represent independent synchronous or metastatic lesions. There is also an association between gastric-type cervical lesions and Peutz-Jeghers syndrome. Awareness of the spectrum of gastric-type lesions is important, as the diagnostic features of both gAIS and GAS, particularly well differentiated examples, may be subtle, and p16 immunohistochemistry is usually negative. GAS has a much poorer prognosis than HPV-associated cervical adenocarcinoma, with propensity for presentation at advanced stage and wide dissemination to unusual sites such as the ovary, omentum and peritoneum. Although uncommon, GAS is likely to increase in relative prevalence with the introduction of HPV vaccination and precursor lesions will not be detected by primary HPV-based screening programs.

With the recent elucidation of gastric-type lesions in the female genital tract (especially in the cervix), occasional cases of endometrial adenocarcinoma displaying gastric (gastrointestinal) differentiation have been reported, but they are currently not recognized as a distinct pathologic entity. We report 9 cases of endometrial mucinous lesions which exhibit gastric (gastrointestinal)-type features by morphology and immunohistochemistry, including 4 adenocarcinomas and 5 benign mucinous lesions, in patients aged 32 to 85. The adenocarcinomas showed gastric-type morphology in all 4 cases and goblet cells in 1, with a component of benign gastric-type mucinous glands in 1 case. Immunohistochemically, the adenocarcinomas were positive for CK7 (4/4), CEA (4/4), MUC6 (3/3), PAX8 (3/4), CK20 (2/4), CDX2 (2/4), and estrogen receptor (1/4). They were negative for Napsin A (0/3), with mutation-type p53 staining in 2/4 cases, block-type p16 positivity in 1/4, and scattered chromogranin-positive cells in 1/2. Targeted next-generation sequencing revealed nonsense mutation in RB1 gene for the case with block-positive p16. Follow-up was available in all adenocarcinoma cases and indicated aggressive behavior; 2 patients were dead of disease at follow-up of 7 months to 3 years, 1 was alive with progression at 9 months, and 1 was alive without disease at 7 months. The benign mucinous lesions (including the benign component in 1 adenocarcinoma) exhibited gastric-type morphologic features in 5/6 cases, goblet cells in 5/6, and Paneth-like neuroendocrine cells in 1/6. These benign mucinous lesions were associated with an endometrial polyp in 5/6 cases. Cytologic atypia was present in 2/6 cases and a lobular architecture resembling cervical lobular endocervical glandular hyperplasia in 4/6. Immunohistochemically, the benign mucinous lesions were positive for CK7 (5/5), CDX2 (5/6), estrogen receptor (4/5), MUC6 (4/5), CK20 (3/5), PAX8 (3/5), and CEA (2/4), with scattered chromogranin-positive cells in 4/4 cases; in all cases tested Napsin A was negative, p53 was wild-type and p16 was negative. We propose the term “endometrial gastric (gastrointestinal)-type adenocarcinoma” for this distinctive group of rare aggressive endometrial carcinomas. We believe that benign or atypical gastric (gastrointestinal)-type mucinous lesions are putative precursors for these adenocarcinomas, comparable to recognized premalignant gastric-type lesions in the cervix and the vagina. Future recognition and reporting of these gastric-type endometrial mucinous lesions will help delineate their pathogenesis and clinical significance.

Gastric-type cervical adenocarcinoma (GCA) is an aggressive type of endocervical adenocarcinoma characterized by mucinous morphology, gastric-type mucin, lack of association with human papillomavirus (HPV) and resistance to chemo/radiotherapy. We characterized the landscape of genetic alterations in a large cohort of GCAs, and compared it with that of usual-type HPV-associated endocervical adenocarcinomas (UEAs), pancreatic adenocarcinomas (PAs) and intestinal-type gastric adenocarcinomas (IGAs). GCAs (n=68) were subjected to massively parallel sequencing targeting 410–468 cancer-related genes. Somatic mutations and copy number alterations (CNAs) were determined using validated bioinformatics methods. Mutational data for UEAs (n=21), PAs (n=178) and IGAs (n=148) from The Cancer Genome Atlas (TCGA) were obtained from cBioPortal. GCAs most frequently harbored somatic mutations in TP53 (41%), CDKN2A (18%), KRAS (18%) and STK11 (10%). Potentially targetable mutations were identified in ERBB3 (10%), ERBB2 (8%) and BRAF (4%). GCAs displayed low levels of CNAs with no recurrent amplifications or homozygous deletions. In contrast to UEAs, GCAs harbored more frequent mutations affecting cell cycle related genes including TP53 (41% vs 5%, p<0.01) and CDKN2A (18% vs 0%, p=0.01), and fewer PIK3CA mutations (7% vs 33%, p=0.01). TP53 mutations were less prevalent in GCAs compared to PAs (41% vs 56%, p<0.05) and IGAs (41% vs 57%, p<0.05). GCAs showed a higher frequency of STK11 mutations than PAs (10% vs 2%, p<0.05) and IGAs (10% vs 1%, p<0.05). GCAs harbored more frequent mutations in ERBB2 and ERBB3 (9% vs 1%, and 10% vs 0.5%, both p<0.01) compared to PAs, and in CDKN2A (18% vs 1%, p<0.05) and KRAS (18% vs 6%, p<0.05) compared to IGAs. GCAs harbor recurrent somatic mutations in cell cycle-related genes and in potentially targetable genes, including ERBB2/3 . Mutations in genes such as STK11 may be used as supportive evidence to help distinguish GCAs from other adenocarcinomas with similar morphology in metastatic sites.

So-called gastric-type adenocarcinoma and related premalignant lesions have been characterized in the cervix, but similar lesions are not widely recognized in the vagina. We report a series of 11 vaginal glandular lesions exhibiting gastric differentiation, comprising 5 cases of adenocarcinoma and 6 of adenosis. All cases occurred in adults (aged 33 to 69) with no known history of diethylstilboestrol exposure. The vaginal adenocarcinomas exhibited morphologic features identical to gastric-type adenocarcinoma of the cervix, but 1 case additionally demonstrated basaloid and sarcomatoid components, which have not been previously reported in cervical gastric-type adenocarcinoma. Immunohistochemically, the adenocarcinomas were positive for MUC6 (4/5), PAX8 (3/5), CK7 (5/5), CK20 (1/5), CDX2 (5/5), CA19.9 (5/5), CEA (4/5), CA125 (5/5), and hepatocyte nuclear factor 1β (5/5). p16, estrogen receptor, and Napsin A were negative in all cases tested, whereas p53 exhibited mutation-type staining in 3/5 cases. In all 5 adenocarcinomas, a component of adenosis with benign or atypical nuclear features was identified; the adenosis displayed gastric morphology in 4 cases and tuboendometrial morphology in 1. The 6 cases of pure vaginal adenosis (without associated adenocarcinoma) all contained gastric-type mucinous glands together with tuboendometrial glands in 2 cases. There was focal intestinal differentiation with goblet cells in all 6 cases and neuroendocrine cells with eosinophilic granules in 3. Cytologic atypia was observed in 4/6 cases of pure vaginal adenosis. Immunohistochemically, the gastric-type adenosis (10 cases) was positive for MUC6 (10/10), estrogen receptor (5/10), PAX8 (8/10), CK7 (9/9), CK20 (2/9), CDX2 (5/9), CA19.9 (8/9), CEA (6/9), CA125 (6/9), hepatocyte nuclear factor 1β (10/10), and Napsin A (1/10). p53 exhibited wild-type immunoreactivity in all 10 cases, whereas p16 was negative in all cases tested. Scattered individual chromogranin-positive cells were present in all 5 cases of pure adenosis tested. Follow-up was available in 4 of the adenocarcinoma cases, with 3 patients dead of disease within 1 to 3 years and 1 patient alive with disease at 1 year. The morphologic and immunohistochemical findings in our study suggest a close relationship between vaginal gastric-type adenocarcinoma and adenosis exhibiting gastric differentiation. This probably represents a distinct pathway of vaginal gastric-type carcinogenesis analogous to that occurring in the cervix. We propose that gastric-type adenocarcinoma be recognized as a distinct histologic subtype of vaginal adenocarcinoma while vaginal adenosis of gastric-type represents a novel subtype of adenosis that requires further study to clarify its biological potential.