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.

Introduction In pregnancy, the presence of preeclampsia (PEC), systemic lupus erythematosus (SLE), and/or antiphospholipid antibody syndrome (APLS) is characterized by poor obstetric outcomes, with potential adverse effects for both mother and fetus. Although the histopathologic changes observed in these entities have been well established, the pathogenic mediators associated with tissue injury are poorly understood. Methods Forty placentas were evaluated, including 10 patients with preeclampsia, 9 with SLE, 11 with APLS, and 10 disease-free controls. Each case was subjected to a panel of immunohistochemical markers including C3b, C4d, Annexin A5, and C5b-9. Staining was graded on intensity and distribution. Results C4d staining was distinctly different among disease groups and controls. Moreover, 6/10 PEC cases, 3/9 SLE cases, and 4/11 APLS cases showed at least focal staining for C4d. All controls were negative. Annexin A5 (AnxA5) staining showed intrinsic variability in all disease groups, while 10/10 controls showed diffuse, strong staining (2+ or 3+). C3b staining was heterogeneous among groups. Discussion Previously, antiphospholipid antibody (aPLA)-associated pregnancy complications have been thought to be a consequence of a unique aPLA-mediated pathogenic mechanism. However, the immunohistochemical similarity (increased complement and decreased AnxA5 staining) observed in placentas from patients with APLS, PEC, and SLE suggests that aPLA-associated pregnancy complications may reflect a more general autoimmune mechanism.

Context Radial scars are benign sclerosing lesions that are routinely excised when diagnosed in a needle core biopsy. Optimal management for patients with incidental and small (≤5 mm) radial scars is uncertain. Objective To assess pathologic upgrade of radial scars diagnosed in needle core biopsy samples and identify a subset of patients who could benefit from conservative management. Design Patients with a diagnosis of radial scar in a needle core biopsy who underwent excision of the biopsied area were identified. Radial scars greater than 5 mm in size and those with coexisting atypia, carcinoma, and papillary lesions were excluded. After histologic-radiographic correlation, rates of pathologic upgrade were assessed. Results Seventy-seven radial scars diagnosed in 66 patients were included. Overall, 9 of 77 (12%) showed upgrade to a high-risk lesion (6 lobular carcinoma in situ, 2 atypical ductal hyperplasia, 1 atypical lobular hyperplasia), while none (0%) showed upgrade to invasive carcinoma or ductal carcinoma in situ. One of 22 incidental radial scars (4.5%) showed upgrade on excision versus 6 of 36 (16.7%) for radial scars considered to be the radiographic target (P = .23). Older age was associated with upgrade (P &lt; .001). Conclusions No incidental or small (≤5 mm) radial scars excised revealed invasive carcinoma or ductal carcinoma in situ on excision. Provided there is good pathologic-radiologic concordance, it appears reasonable for these patients to be managed conservatively.

Mixed endometrial carcinomas are defined as a combination of 2 or more distinct histologic subtypes, one of which must be a type II tumor comprising at least 5% of the tumor volume. The oncogenesis of these tumors remains unclear, particularly in light of the increasingly appreciated morphologic overlap among subtypes, as well as evolving molecular data. We evaluated 8 cases of mixed endometrial carcinoma, including 4 endometrioid (EC)/serous (SC), 1 SC/clear cell (CC), and 3 EC/CC cases, to study the underlying molecular features and oncogenic mechanisms at play. Each component was analyzed by a targeted next-generation sequencing assay. All tumors shared mutations in both components. In 6 cases, one component showed additional mutations. Two EC/SC cases showed shared mutations and mutations unique to each component. When present, unique mutations were typically seen in the SC component, including variants in POLE and TP53, as well as potentially targetable genes DDR2, MAP2K1, and CCNE1. In EC/SC tumors, ERBB2 abnormalities were seen in 2 cases. EC/CC cases showed FGFR2 activating mutations in the EC component only. No fusion drivers were identified. Our data suggest that the majority of these tumors begin as a single clone and diverge along 2 pathways: (1) tumor progression, with one component showing additional mutations, and (2) tumor divergence, in which tumor components have both shared mutations and mutations unique to each component. In addition, the findings suggest a component of morphologic mimicry in these tumors. Our findings are clinically relevant since targetable mutations may be present in only one component of mixed tumors.

No abstract

Objective To characterize ovarian cancers associated with endometriosis and to evaluate the prognostic impact of endometriosis. Methods Ovarian cancer cases from a single institution diagnosed between 2000 and 2013 were examined and specimens reviewed by two pathologists for the presence of endometriosis. Ovarian cancer cases with and without endometriosis were compared to determine the clinical factors associated with endometriosis and the prognostic significance of endometriosis. Two-sample T-tests, Chi-square tests, multivariable logistic regression, and Cox proportional hazards models were used for statistical analysis. Results Among 139 epithelial ovarian cancers diagnosed between 2000 and 2013, there were 49 (35%) with endometriosis and 90 (65%) without endometriosis. The distribution of histologies of ovarian cancers with endometriosis was 43% endometrioid, 23% clear cell, 20% mixed, 8% mucinous, and 6% serous. Endometriosis associated ovarian cancers were more likely to be confined to the pelvis (54% vs. 9%, p<0.0001) and of lower tumor grade (51% vs. 29%, p=0.014). Younger age and earlier stage independently predicted the presence of endometriosis (p=0.0011 and p<0.0001, respectively). Ovarian cancer patients with endometriosis had improved PFS and OS [(HR=0.20; 95% CI, 0.09–0.43), (HR=0.18; 95% CI, 0.04–0.81)], compared to patients without endometriosis. After controlling for tumor stage and age, endometriosis was not an independent predictor of survival. Conclusions Patients with ovarian cancer and endometriosis are younger with lower stage and grade, and disease confined to the pelvis compared to patients without endometriosis. Ovarian cancers with endometriosis have improved PFS and OS; however endometriosis had no independent prognostic significance in our study.

Myeloid sarcoma (MS) is a rare, extramedullary tumor consisting of immature white blood cells of myeloid lineage. MS is usually associated with the concurrent diagnosis of acute myeloid leukemia (AML) but can also present in the absence of bone marrow disease or at relapse of AML. MS of the gynecologic tract is exceedingly rare; however, it is hypothesized that it is likely more prevalent than previously understood given postmortem findings and persistence in preserved ovarian tissue. There is minimal literature surrounding MS and extramedullary relapse with no clear guidelines. This is a case report of a 48-year-old woman with MS involving the uterine corpus, fallopian tubes, and left ovary followed by a literature review. The overall aim is to review data regarding leukemic immune evasion and sanctuary sites in order to raise awareness as this represents an important and underrecognized hematologic malignancy in an often misdiagnosed, underrecognized site.

Historically, endometrial carcinomas have been classified primarily according to their histology. However, the use of immunohistochemistry has become commonplace in their evaluation, particularly in diagnostically challenging cases. Our objective was to evaluate mixed endometrial carcinomas using a well-established panel of biomarkers to assess the consistency and utility of these stains in clinical diagnosis. Eighteen cases comprised of various combinations of classical serous (SC), endometrioid (EC), and clear cell (CC) morphologies were identified and subjected to a panel of immunohistochemical markers including p53, p16, Ki67, estrogen receptor, progesterone receptor, and Napsin A. Intensity and extent of staining were evaluated on 4-tiered and 5-tiered scales, respectively. The typical immunostaining pattern expected for the individual tumor components was seen in only 3 cases, while in 15 cases an unexpected pattern was observed with at least one immunomarker. By tumor type, the most common unexpected finding in EC/SC carcinoma cases was diffuse positivity for p16 and/or estrogen receptor/progesterone receptor in both components, while in SC/CC, diffuse positivity for p53 in both components was most frequently seen, and in SC/CC/EC, Napsin A negativity was most commonly observed. Despite displaying diagnostic morphology, components of many mixed endometrial carcinomas may not exhibit expected immunohistochemical features. This may be due to the fact that these carcinomas arise from a single clone with subsequent divergence, resulting in a tumor with both mixed histologic and genetic features. It is important to note that these tumors may not demonstrate the immunohistochemical prototype of their constituents and should be approached accordingly from a diagnostic perspective.