title: A Detailed Immunohistochemical Analysis of a Large Series of Cervical and Vaginal Gastric-type Adenocarcinomas.
abstract: 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 differentiated overtly malignant form, generally referred to as gastric-type adenocarcinoma. Rarely, such tumors have also been described as primary vaginal neoplasms. Gastric-type adenocarcinomas exhibit considerable morphologic 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, nongynecologic 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 cytokeratin (CK)7, CK20, CDX2, carcinoembryonic antigen, CA125, CA19.9, p16, estrogen receptor, progesterone receptor, MUC6, PAX8, PAX2, p53, hepatocyte nuclear factor 1 beta, carbonic anhydrase IX, human epidermal receptor 2 (HER2), and mismatch repair (MMR) proteins. All markers were classified as negative, focal (<50% of tumor cells positive), or diffuse (≥50% tumor 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 (categorized as retained or lost). There was positive staining with CK7 (47/47-45 diffuse, 2 focal), MUC6 (17/21-6 diffuse, 11 focal), carcinoembryonic antigen (25/31-12 diffuse, 13 focal), carbonic anhydrase IX (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), hepatocyte nuclear factor 1 beta (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 estrogen receptor (29/31), progesterone receptor (10/11), PAX2 (18/19), and HER2 (25/26). p53 showed "wild-type" and "mutation-type" staining in 27 of 46 and 19 of 46 cases, respectively. MMR protein expression was retained in 19 of 20 cases with loss of MSH6 staining in 1 patient with Lynch syndrome. Molecular studies for HPV were undertaken in 2 tumors, 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 nongynecologic adenocarcinomas, which are usually negative. Diffuse "block-type" p16 immunoreactivity in a cervical adenocarcinoma is not necessarily indicative of a high-risk HPV-associated tumor.
authors.affiliation: *Department of Pathology, Belfast Health and Social Care Trust, Belfast ‡Department of Pathology, UHCW NHS Trust, Coventry, UK †Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY §Department of Pathology, Jikei University School of Medicine, Tokyo, Japan ∥Department of Pathology, North Western State Medical University, St. Petersburg, Russia ¶Department of Pathology, Box Hill Hospital, Melbourne, Vic., Australia.
authors.forename: Claire
authors.initials: C
authors.lastname: Carleton
authors.forename: Lien
authors.initials: L
authors.lastname: Hoang
authors.forename: Shatrughan
authors.initials: S
authors.lastname: Sah
authors.forename: Takako
authors.initials: T
authors.lastname: Kiyokawa
authors.forename: Yevgeniy S
authors.initials: YS
authors.lastname: Karamurzin
authors.forename: Karen L
authors.initials: KL
authors.lastname: Talia
authors.forename: Kay J
authors.initials: KJ
authors.lastname: Park
authors.forename: W Glenn
authors.initials: WG
authors.lastname: McCluggage
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry* / Q000235:genetics / Q000473:pathology / Q000821:virology; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D061809:Human Papillomavirus DNA Tests; D006801:Humans; D007150:Immunohistochemistry; D009518:New York; D009660:Northern Ireland; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000032:analysis; D027383:Papillomaviridae / Q000235:genetics; D010641:Phenotype; D011237:Predictive Value of Tests; D002583:Uterine Cervical Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology / Q000821:virology; D014625:Vaginal Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology / Q000821:virology
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D051761:Paired Box Transcription Factors