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 ...

Gastric type adenocarcinoma of the uterine cervix (GAS) is a rare variant of mucinous endocervical adenocarcinoma not etiologically associated with human papillomavirus (HPV) infection, with minimal deviation adenocarcinoma (MDA) at the well-differentiated end of the morphologic spectrum. These tumors are reported to have worse prognosis than usual HPV-associated endocervical adenocarcinoma (UEA). A retrospective review of GAS was performed from the pathology databases of three institutions spanning 20 years. Stage, metastatic patterns, and overall survival were documented. Forty GAS cases were identified, with clinical follow-up data available for 38. The tumors were subclassified as MDA (n=13) and non-MDA GAS (n=27). Two patients were syndromic (one Li-Fraumeni, one Peutz-Jeghers). At presentation, 59% were advanced stage (FIGO II–IV), 50% had lymph node metastases, 35% had ovarian involvement, 20% had abdominal disease, 39% had at least one site of metastasis at the time of initial surgery, and 12% of patients experienced distant recurrence. The metastatic sites included lymph nodes, adnexa, omentum, bowel, peritoneum, diaphragm, abdominal wall, bladder, vagina, appendix, and brain. Follow-up ranged from 1.4 to 136.0 months (mean, 33.9 months); 20/38 (52.6%) had no evidence of disease, 3/38 (7.9%) were alive with disease, and 15/38 (39.5%) died of disease. Disease specific survival at 5 years was 42% for GAS vs. 91% for UEA. There were no survival differences between MDA and non-MDA GAS. GAS represents a distinct, biologically aggressive type of endocervical adenocarcinoma. The majority of patients present at advanced stage and pelvic, abdominal, and distant metastases are not uncommon.

Rare, sporadic uterine leiomyomas arise in the setting of severe metabolic aberration due to somatic fumarate hydratase mutation. Germline mutations account for the Hereditary Leiomyomatosis and Renal Cell Carcinoma syndrome, which predisposes for cutaneous and uterine leiomyomas and aggressive renal cell carcinomas. Altered fumarate hydratase leads to fumarate accumulates in affected cells with formation of S-(2-succino)-cysteine, which can be detected with polyclonal antibody. High levels of these modified cysteine residues are found characteristically in fumarate hydratase-deficient cells, but not in normal tissues or tumors unassociated with Hereditary Leiomyomatosis and Renal Cell Carcinoma syndrome. We hypothesized that S-(2-succino)-cysteine-positive leiomyomas, indicating fumarate hydratase aberration, have morphologic features that differ from those without S-(2-succino)-cysteine positivity. Hematoxylin and eosin-stained slides of uterine smooth muscle tumors were prospectively analyzed for features suggesting Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome, such as prominent eosinophilic macronucleoli with perinucleolar halos, yielding 9 cases. Germline genetic testing for fumarate hydratase mutations was performed in 3 cases. A detailed morphological analysis was undertaken, and S-(2-succino)-cysteine immunohistochemistry was performed with controls from a tissue microarray [leiomyomas (19), leiomyosarcomas (29), and endometrial stromal tumors (15)]. Of the 9 study cases, 4 had multiple uterine smooth muscle tumors. All cases had increased cellularity, staghorn vasculature, and fibrillary cytoplasm with pink globules. All cases had inclusion-like nucleoli with perinuclear halos (7 diffuse, 1 focal). All showed diffuse granular cytoplasmic labeling with the S-(2-succino)-cysteine antibody. Two of 3 tested patients had germline fumarate hydratase mutations. Only 1 leiomyoma from the tissue microarray controls was immunohistochemically positive, and it showed features similar to other immunohistochemically positive cases. Smooth muscle tumors with fumarate hydratase aberration demonstrate morphological reproducibility across cases and S-(2-succino)-cysteine immuno-positivity. Although the features described are not specific for germline fumarate hydratase mutation or the Hereditary Leiomyomatosis and Renal Cell Carcinoma syndrome, their presence should suggest fumarate hydratase aberration. Identifying these cases is an important step in the diagnostic workup of patients with possible Hereditary Leiomyomatosis and Renal Cell Carcinoma.

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Microsatellite instability (MSI) is the hallmark of a molecular pathway to carcinogenesis due to sporadic or inherited abnormalities of DNA mismatch repair genes. Inherited mutations are seen in hereditary nonpolyposis colorectal cancer syndrome. Endometrial carcinoma shows as high an incidence of MSI as does colorectal carcinoma. This review provides a framework for the gynecologic pathologist to understand the complexities of MSI in endometrial carcinoma, by discussing the basic mechanisms of mismatch repair and carcinogenesis, testing, the morphologic features of MSI endometrial cancer and the contradictory data regarding prognosis.

Women with Lynch syndrome (LS) are at increased risk for endometrial (EC) and ovarian carcinoma (OC). Current surveillance recommendations for detection of EC and OC in LS patients are not effective. Small studies have shown that prophylactic hysterectomy and bilateral salpingo-oophorectomy (P-TH-BSO) are the most effective and least expensive preventive measures in these patients. Data regarding histologic findings in prophylactic specimens in these patients are lacking. All LS patients who underwent P-TH-BSO at the Memorial Sloan-Kettering Cancer Center from 2000 to 2011 were identified. Slides were evaluated for the presence of endometrial hyperplasia (EH), EC, OC, or any other recurrent histologic findings. Twenty-five patients were identified, with an age range of 36 to 61 years. Fifteen patients had a synchronous or prior colorectal carcinoma, and 2 patients had a history of sebaceous carcinoma. Focal FIGO grade 1 endometrioid ECs were detected in 2 patients; 1 was 54 years of age (MSH2 mutation; superficially invasive), and the other was 56 years of age (MLH1 mutation; noninvasive). Focal complex atypical hyperplasia, unassociated with carcinoma, was seen in 3 patients, ages 35 and 45 (MLH1 mutations) and 53 years (MSH2 mutation). One patient (44 y, with MSH2 mutation) was found to have a mixed endometrioid/clear cell OC and simple EH without atypia. The OC was adherent to the colon but did not show distant metastasis. In our study, P-TH-BSOs performed because of the presence of LS revealed incidental EC and/or EH in 24% of cases and OC in 4%. The ECs were low grade, confined to the endometrium, and seen in patients older than 50 years. Prophylactic hysterectomy allows detection of early lesions in LS; these lesions appear to be small and focal. This small series of prophylactic hysterectomies may provide some clues about LS-associated endometrial carcinogenesis.

The characteristic histologic pattern of solitary fibrous tumor can be noted in extrapulmonary locations. Development in the larynx is uncommon, but the tumor presents as a polypoid mass with characteristic histologic and immunophenotypic features. Conservative local excision is the treatment of choice to yield an excellent prognosis.

2. Melodelima D, Chapelon JY, Theillere Y, Cathignol D. Combination of thermal and cavitation effects to generate deep lesions with an endocavitary applicator using a plane transducer: ex vivo studies.