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PURPOSE We report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma. METHODS A total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration v time curve 6) and paclitaxel (175 mg/m2) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for BRCA1/2 and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry. RESULTS Median follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8 v 32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for BRCA1/2 mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non- BRCA1/2 HRR, the HR was 0.65 (95% CI, 0.51 to 0.85). BRCA1/2, HRR, and CD31 were not predictive of bevacizumab activity. CONCLUSION No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for BRCA1/2 mutations and homologous recombination deficiency is essential.

Endometrial clear cell carcinoma (ECCC) is an uncommon histotype without unique identified molecular alterations. Recently, The Cancer Genome Atlas molecular subtypes have been reported in ECCC. ECCC cases were collected from 11 institutions with diagnoses confirmed by morphologic review and immunohistochemistry. DNA mismatch repair (MMR) proteins, p53 expression, and ARID1A expression was assessed by immunohistochemistry on tissue microarrays. Targeted next-generation sequencing was completed for POLE, TP53, KRAS, and PIK3CA. Pathogenicity of mutations was determined using MutationTaster and PolyPhen databases. For p53, immunohistochemistry and sequencing were complimentarily used to assess the p53 status. Of 57 cases, 46 were considered prototypical ECCC by morphology and immunohistochemical profile (Napsin A-positive and ER-negative). Three cases were excluded because of insufficient sample for complete immunohistochemical analysis, and 6 had failed sequencing, resulting in 37 cases. Of the 37 remaining cases, 6/37 (16%) had predicted pathogenic mutations in the exonuclease domain of POLE with an allelic frequency >10%; however, no hot-spot mutations were identified. No cases were MMR-deficient. The gene most commonly affected was TP53 (59%, 22/37), followed by KRAS (13%, 2/15) and PIK3CA (13%, 2/15). The current study is the largest molecular analysis of pure ECCC reported to date. When strict classification criteria are applied, MMR-deficient and POLE mutated subtypes are not represented. Further consensus on what represents a deleterious POLE mutations is needed. The findings support separately studying histologically/immunohistochemically defined ECCC to identify characteristic molecular alterations in future studies.

Background. Endometrial clear cell carcinoma (ECCC) represents a rare subtype of endometrial cancer. Recently, immunotherapeutic drugs targeting programmed cell death protein 1 (PD-1)/programmed death ligand-1 (PD-L1) was associated with improved survival in several types of cancer (especially in patients with mismatch-repair (MMR)-deficient status). The aim of this study is to evaluate the correlation between the PD-L1/PD-1 axis and clinical and pathological features in strictly defined ECCC diagnosed at our institution. Design. Review of ECCC (diagnosed in the period of 2000 to 2017) identified 23 cases (n = 23) in our institution. The cases were reviewed by 2 gynecological pathologists. Estrogen receptor, progesterone receptor, napsin A, p16, and p53 were also performed so that only pure CCC cases were included. PD-L1 (SP142), PD-1, and MMR antibodies were performed. PD-L1 and PD-1 were scored in both the tumor and the peritumoral lymphocyte infiltration. Clinical and pathological features were recorded to correlate with the expression of the 2 markers. Results. Among the 23 cases, 20 cases were qualified for pure CCC by histology and immunohistochemistry patterns. Regarding PD-1 expression, 6/20 (30%) patients had positive expression in peritumoral lymphocyte infiltration. While 3/20 (15%) cases had PD-L1 either tumoral or peritumoral lymphocytes expression. Loss of MMR expression was present in 1 (5%) of 20 patients. PD-1 and/or PD-L1 expression cases tended to have deeper myometrial invasion and higher stage at presentation. Conclusions. Our results are suggestive of the roles of both PD-1 and PD-L1 in ECCCs as useful therapeutic biomarkers for immunotherapy.

Differentiated-type vulvar intraepithelial neoplasia (dVIN) is a non–human papilloma virus (HPV)-related precursor lesion to vulvar squamous carcinoma. The terminology has only become recognized clinically and histopathologically in recent years despite being described more than 50 years ago. As opposed to the HPV-related VIN (uVIN), dVIN has different features of histomorphology, risk of progression, and molecular pathogenesis. Notably, dVIN commonly develops in a background of chronic inflammatory dermatoses such as lichen sclerosis and lichen simplex chronicus. The recognition of dVIN remains a challenge owing to lack of accurate and reproducible diagnostic criteria. Morphologically, basal layer atypia, dyskeratosis, and elongation and anastomosis of the rete ridges are regarded as very useful diagnostic features. Ancillary tests can be very helpful to establish a definitive diagnosis in some ambiguous cases. In contrast to uVIN, dVIN is more likely to progress to vulvar squamous carcinoma in a shorter period. The goal of this review is to elaborate on the clinicopathologic characteristics and underline the key histologic features that best facilitate the diagnosis of dVIN.

The peritoneum is a site for diverse nonneoplastic and neoplastic disease processes including those encountered in many other organ systems in the body. Once proposed as part of the secondary Mullerian system, its role in the pathogenesis of primary serous carcinomas has recently been questioned. It has been postulated that primary Mullerian peritoneal/omental serous carcinoma is a metastasis from the similar tumor of the fallopian tubes. This theory, however, applies to serous carcinomas only, not tumors of any other Mullerian cell types. Far from being a mere receptacle for metastasis from other organ sites, the notion that the peritoneum and its derivatives serve as important source of primary peritoneal carcinomas remains a valid concept.

PAX8, a member of the paired-box family of genes, is expressed in many tumors of Müllerian origin. However, it is unclear whether PAX8 is a useful marker in diagnosing endocervical glandular lesions because of limited data.To study the expression of PAX8 in endocervical glandular lesions.We first studied a cohort of 29 cervical cone biopsies, followed by a second cohort of 17 cases of endocervical adenocarcinoma and 20 cases of uterine endometrioid adenocarcinoma.In the first cohort, we found that PAX8 was expressed in 23 of 23 (100%) benign endocervical glandular epithelium, 15 of 16 (94%) adenocarcinoma in situ, and 21 of 26 (81%) invasive endocervical adenocarcinoma specimens. In the second cohort, endocervical adenocarcinomas were positive for PAX8 in 14 of 17 (82%), strongly and diffusely positive for p16 in 14 of 17 (82%), positive for carcinoembryonic antigen in 12 of 17 (71%), positive for vimentin in 2 of 17 (12%), and positive for estrogen receptor in 7 of 17 cases (41%). Uterine endometrioid cancer was positive for PAX8 in 20 of 20 (100%), weakly and/or patchy positive for p16 in 17 of 20 (85%), positive for carcinoembryonic antigen in 2 of 20 (10%), positive for vimentin in 19 of 20 (95%), and positive for estrogen receptor in 20 of 20 cases (100%).PAX8 is expressed in the majority of benign, premalignant, and malignant endocervical glandular lesions. The usefulness of PAX8 in differentiating endocervical from endometrial lesions is limited.

Mucinous adenocarcinoma of the fallopian tube is exceptionally rare and the detailed clinicopathologic features of these tumors have not yet been reported in English literature. Here we report a moderately differentiated mucinous adenocarcinoma arising in the tubal fimbria in a 70-year-old woman. Patient had a history of cholecystectomy for gallstones and gastric banding who presented with gastrointestinal discomfort and was found to have a large adnexal mass on imaging studies. Serum CA-125 was moderately elevated. Recent mammography, upper endoscopy and colonoscopy were completely normal. She underwent surgical staging for the adnexal mass. Frozen section and final pathology diagnosis revealed moderately differentiated adenocarcinoma arising in the left fimbria. Carcinoma had spread to the ipsilateral ovary and pelvic soft tissue at the time of her presentation. Tumor was strongly immunoreactive to CK7 and CEA, and was negative for CK20, CDX-2, PAX-8, WT-1, p16, ER, and vimentin. TP53 showed wild-type phenotype by immunohistochemistry. Molecular studies showed no mutation in codon 12 and 13 of the k-ras gene, and no mutation was detected in the BRAF and EGFR genes. In addition, the non-tumorous fimbria epithelium showed a spectrum of mucinous alterations with variable nuclear atypia: cytologically bland areas that were reminiscent of mucinous metaplasia were positive for p53 and showed minimal proliferation as assessed by Ki-67, and cytologically atypical stratified mucinous epithelium that was positive for p53 and Ki-67. The patient received 3 cycles of Folfox and was regularly followed at a 3–6 month interval. Her carcinoma recurred in abdomen at 32 months post surgery. After excluding the possibility of an extra-gynecologic tract primary through extensive clinical investigations and post-surgical follow-up, we concluded that this tumor most likely represented a mucinous adenocarcinoma of tubal origin.

Clear cell carcinoma is an uncommon histotype of endometrial carcinoma, representing less than 1% of cases (1). Although clear cell carcinoma is generally considered to be a clinically aggressive, “high risk” cancer (2), reported patient outcomes have been markedly variable at every stage of disease (3-8), possibly reflecting an underlying biologic heterogeneity that is inherent to the histotype (9). Indeed, somatic mutation profiling of cases classified as clear cell carcinoma have shown them to be markedly heterogeneous at the molecular level, with subsets resembling serous carcinomas, endometrioid carcinoma, neither, or both (10-12). This article is protected by copyright. All rights reserved.

MicroRNAs have been established as key regulators of tumor gene expression and as prime biomarker candidates for clinical phenotypes in epithelial ovarian cancer (EOC). We analyzed the coexpression and regulatory structure of microRNAs and their co-localized gene targets in primary tumor tissue of 20 patients with advanced EOC in order to construct a regulatory signature for clinical prognosis. We performed an integrative analysis to identify two prognostic microRNA/mRNA coexpression modules, each enriched for consistent biological functions. One module, enriched for malignancy-related functions, was found to be upregulated in malignant versus benign samples. The second module, enriched for immune-related functions, was strongly correlated with imputed intratumoral immune infiltrates of T cells, natural killer cells, cytotoxic lymphocytes, and macrophages. We validated the prognostic relevance of the immunological module microRNAs in the publicly available The Cancer Genome Atlas data set. These findings provide novel functional roles for microRNAs in the progression of advanced EOC and possible prognostic signatures for survival.

Purpose To evaluate risk factors for GI adverse events (AEs) within a phase III trial of bevacizumab in first-line ovarian cancer therapy. Patients and Methods Women with previously untreated advanced disease after surgery were randomly allocated to six cycles of platinum-taxane chemotherapy plus placebo cycles (C)2 to C22 (R1); chemotherapy plus bevacizumab C2 to C6 plus placebo C7 to C22 (R2); or chemotherapy plus bevacizumab C2 to C22 (R3). Patients were evaluated for history or on-study development of potential risk factors for GI AEs defined as grade ≥ 2 perforation, fistula, necrosis, or hemorrhage. Results Of 1,873 patients enrolled, 1,759 (94%) were evaluable, and 2.8% (50 of 1,759) experienced a GI AE: 10 of 587 (1.7%, R1), 20 of 587 (3.4%, R2), and 20 of 585 (3.4%, R3). Univariable analyses indicated that previous treatment of inflammatory bowel disease (IBD; P = .005) and small bowel resection (SBR; P = .032) or large bowel resection (LBR; P = .012) at primary surgery were significantly associated with a GI AE. The multivariable estimated relative odds of a GI AE were 13.4 (95% CI, 3.44 to 52.3; P < .001) for IBD; 2.05 (95% CI, 1.09 to 3.88; P = .026) for LBR; 1.95 (95% CI, 0.894 to 4.25; P = .093) for SBR; and 2.15 for bevacizumab exposure (aggregated 95% CI, 1.05 to 4.40; P = .036). Conclusion History of treatment for IBD, and bowel resection at primary surgery, increase the odds of GI AEs in patients receiving first-line platinum-taxane chemotherapy for advanced ovarian cancer. After accounting for these risk factors, concurrent bevacizumab doubles the odds of a GI AE, but is not appreciably increased by continuation beyond chemotherapy.

The histotyping of high-grade endometrial carcinomas with clear cells may be subject to significant interobserver variability, which suggests that a biomarker that can distinguish endometrial clear cell carcinoma (CCC) from its mimics would be of diagnostic utility. This study assessed the usefulness of napsin A immunohistochemistry in the diagnosis of CCC, on the basis of an analysis of 77 cases diagnosed as such at 9 institutions. After being independently reviewed by a subset of 3 pathologists, cases for which there was diagnostic consensus among all 3 reviewers in agreement with the primary contributor (n=60) were used to establish a "consensus group" that served as a gold standard relative to which napsin A performance was assessed. Duplicate, 1.0-mm-core tissue microarrays were constructed from the 54 cases in the consensus group for which requisite materials were available, as well as from 49 endometrial endometrioid carcinomas (all grades) and 17 endometrial serous carcinomas. Napsin A immunohistochemical analysis was performed on the microarrays and on the 17 cases for which there was no diagnostic consensus, with scoring based on the proportion of immunoreactive cells (0, 1+, 2+, and 3+ indicative of 0, 1% to 25%, 26% to 49%, and ≥50% immunoreactive cells, respectively). The distribution of scores for the 49 CCC cases with evaluable cores was as follows: 0, n=6; 1+, n=6; 2+, n=8; 3+, n=29. Among the evaluable cases, the frequency of ≥1+ napsin A immunoreactivity was significantly higher in CCCs (43/49, 88%) than in endometrial serous carcinomas (1/13, 7.7%; P

The expression of α-methylacyl-coenzyme-A racemase (AMACR) has previously been reported in 75% to 100% of urethral/bladder clear cell carcinomas, tumors that are known to display broad phenotypic overlap with their identically named mullerian counterparts. Herein, we assess the utility of AMACR in distinguishing endometrial clear cell carcinomas (CCCs) from endometrial serous carcinomas (ESCs) and endometrial endometrioid carcinomas (EECs). A total of 111 endometrial carcinomas in a tissue microarray, including 49 CCCs, 13 ESCs, and 49 EECs, were assessed for AMACR immunoreactivity, with results scored semiquantitatively (scores 0, 1+, 2+, 3+ for 0%, 1%-5%, 6%-50%, >50% immunoreactive cells, respectively). Fifty (45%) of the 111 carcinomas were AMACR positive, with the following score distribution: CCC: 0 (n = 12), 1+ (n = 12), 2+ (n = 3), 3+ (n = 22); EEC: 0 (n = 38), 1+ (n = 4), 2+ (n = 4), 3+ (n = 3); ESC: 0 (n = 11), 1+ (n = 1), 2+ (n = 0), 3+ (n = 1). AMACR expression was significantly more frequent in CCC (75%) than in ESC (15%) or EEC (22%); P < .0001. The sensitivity and specificity of AMACR expression in classifying a carcinoma as CCC were 0.75 (95% confidence interval [CI], 0.61-0.86) and 0.79 (95% CI, 0.66-0.88), respectively, with an odds ratio of 11.62 (95% CI, 5-28; P < .001) and an area under the curve of 0.79 (95% CI, 0.68-0.88). These findings indicate that AMACR expression is strongly associated with CCC and displays a relatively robust diagnostic test performance. However, its practical utility may be limited by the focal nature of its expression in 32% of the AMACR-positive CCC cases as well as its expression in 15% to 22% of the non-CCC histotypes.

TP53 mutation (and associated p53 protein overexpression) is probably a negative prognostic marker in endometrial cancers, but its relevance in the rarer histologic subtypes, including clear cell carcinomas, has not been delineated. Preclinical studies suggest functional interactions between p53 and the BAF250a protein, the product of a tumor suppressor gene ARID1A (adenine-thymine (AT)-rich interactive domain containing protein 1A) that is frequently mutated in ovarian clear cell carcinoma. In this study, we evaluated the significance of p53 and BAF250a expression, as assessed by immunohistochemistry, in a group of 50 endometrial clear cell carcinomas. Of 50 cases, 17 (34%) were p53+, and the remaining 33 cases had a p53 wild-type (p53-wt) immunophenotype. Of the 11 relapses/recurrences in the entire data set, 73% were in the p53+ group (P=0.008). On univariate analyses, the median overall survival for the p53-wt patients (83 months) was longer than the p53+ patients (63 months) (P=0.07), and the median progression-free survival for the p53-wt group (88 months) was significantly longer than the p53+ group (56 months) (P=0.01). On multivariate analyses, p53 expression was not associated with reduced overall or progression-free survival. In addition, p53 status was not significantly associated with pathologic stage or morphologic patterns. Of the 50 cases, 10 (20%) showed a complete loss of BAF250a expression. There was no significant correlation between p53 and BAF250a expression. The p53+/BAF250a-, p53+/BAF250a+, p53-wt/BAF250a+ and p53-wt/BAF250a- composite immunophenotypes were identified in 8%, 26%, 54% and 12% of cases, respectively, and neither loss of BAF250a expression nor composite p53/BAF250a expression patterns were associated with reduced overall or progression-free survival. In conclusion, a significant subset of CCC express p53, and these cases are apparently not definable by their morphologic features. P53 expression may be a negative prognostic factor in this histotype, and warrants additional studies. Loss of BAF250a expression has no prognostic significance in endometrial clear cell carcinomas.

Osteoclast-like giant cells (OLGCs) are multinucleated cells of histiocytic lineage and have been identified in a wide array of neoplasms. In the uterus, they have most frequently been reported in association with leiomyosarcomas. This article describes a case of an osteoclast-like giant cell–rich uterine tumor that was essentially indistinguishable at the morphologic and immunophenotypic levels, from typical giant cell tumor of bone. This is the first example of such a case that has been reported in the uterus to the authors’ knowledge.

SWI/SNF chromatin-modification complexes use the energy of ATP hydrolysis to remodel nucleosomes and to affect transcription and several cellular processes. Accordingly, their loss of function has been associated with malignant transformation. ARID1A (the expression of whose product, BAF250a, a key complex component, is lost when mutated) has recently been identified as a tumor suppressor gene that is mutated in 46-57% of ovarian clear cell carcinoma (CCC). The purposes of this study are to assess the frequency of loss of BAF250a expression in endometrial CCC and whether this loss has any discernable clinicopathologic implications. 34 endometrial carcinomas with a CCC component (including 22 pure CCC, 8 mixed carcinomas with a 10% CCC component, and 4 carcinosarcomas with a CCC epithelial component), were evaluated by immunohistochemistry using a monoclonal antibody directed against the human BAF250a protein. 5 (22.7%) of the 22 pure CCC were entirely BAF250a negative, whereas the remainder showed diffuse immunoreactivity. None of 4 carcinosarcomas and only 1 (12.5%) of the 8 mixed carcinomas were BAF250a negative. There was no discernable relationship between BAF250a immunoreactivity status and tumor architectural patterns (solid, papillary or tubulocystic areas) or cell type (flat, hobnail or polygonal). Of the 22 patients with pure CCC, 14, 2, 3, and 3 were International Federation of Gynecology and Obstetrics stages 1, II, III and IV respectively. Interestingly, all 5 BAF250a negative cases were late stage [stages III or IV] as compared with 1 of 17 BAF250a positive cases (p=0.0002). Thus, 83% (5/6) of all late stage cases were BAF250a [-], as compared with 0 (0%) of the 16 early stage (I or II) cases (p=.0002). BAF250a negative and positive cases did not show any statistically significant difference regarding patient age and frequency of lymphovascular invasion or myometrial invasion. As may be anticipated from the concentration of late stage cases in the BAF250a negative group, patient outcomes were worsened in that group on univariate analysis. In conclusion, we found in this pilot assessment that 22.7% of endometrial CCC displays complete loss of BAF250a expression. There was a disproportionate concentration of BAF250a negative cases in the late stage group, with the attendant possibility of an associated worsened prognosis for those CCC patients whose tumors are BAF250a negative. These preliminary findings suggest the need for larger analyses to evaluate the prognostic significance, if any, of the loss of BAF250a expression in this rare histotype of endometrial cancer.

Bone morphogenetic proteins (BMPs) are extracellular, multifunctional growth factors that constitute the largest subset of the transforming growth factor β superfamily. BMP2 is involved in cardiovascular embryogenesis, in addition to a variety of other postnatal functions, such as neovascularization, osteoinduction, tumor signaling, and in the uterus, stromal decidualization at the implantation site. Estrogen receptor signaling is common in smooth muscle tumors of the uterus, and preclinical models suggest significant interactions between BMP2 and estrogen receptor-mediated signaling. The purpose of this study is to define the patterns of BMP2 expression, as assessed by immunohistochemistry, in smooth muscle tumors and other tissues of the uterine corpus, and to establish whether BMP2 expression has any prognostic significance in uterine leiomyosarcomas. BMP2 was positive (cytoplasmic pattern, typically focal) in 24% of leiomyosarcomas and 20.7% of leiomyomata, but was either infrequently expressed or not expressed in all other tissues evaluated, including normal myometrium and endometrium, endometrial stromal tumors, typical adenomyoma, adenomyosis, and serosal endometriosis. The endothelial cells of small, thin-walled vessels were frequently, but not invariably immunoreactive for BMP2. There was no significant difference between BMP2⁺ and BMP⁻ leiomyosarcomas regarding average tumor size, average patient age, microvessel density, and proportions with high tumor grade, advanced stage and frequency of death from disease on follow-up. Two (29%) of 7 BMP2⁺ leiomyosarcomas were estrogen receptor+, compared with 5 (50%) of 10 BMP2⁻ leiomyosarcomas, a statistically insignificant difference (P=0.62). It is concluded that BMP2 is only expressed in a minority of smooth muscle tumors of the uterine corpus, and lacks prognostic significance in leiomyosarcomas. BMP2 is rarely expressed in the other nonendothelial tissues of the human uterine corpus that were evaluated. The significance of frequent BMP2 expression in small vessels of the uterus requires further investigation.

A comparative study between endometrial serous carcinoma (ESC) and endometrial endometrioid carcinoma (EEC) was performed to determine whether a personal history of breast cancer is a risk factor for ESC in women aged ≤ 55 yr. Study subjects consisted of 348 women who were diagnosed with ESC and 830 comparison subjects who had EEC. Variables studied included age at diagnosis, a history of breast cancer, tamoxifen therapy, hormonal replacement therapy and smoking history. Overall, 19.4% of women with ESC had a history of breast cancer, which was significantly higher than that of 3% in comparison subjects. Among the study subjects, the incidence of a prior breast cancer was significantly higher in patients who were 55 yr of age or younger (41.5%) than those who were older than 55 yr (16%). The statistical significance of both of the aforementioned comparisons was independent of tamoxifen usage on multivariate analyses. The mean time interval between prior breast cancer and endometrial cancer was 92.5 mo (range 7-240 mo) in the study group and 79 mo (range 7-192 mo) in the comparison group. For the whole cohort and individual subgroups (ESC, EEC, ≤ 55 yr and55 yr), a personal history of breast cancer did not adversely affect the patient outcomes, which was largely dependent on standard clinicopathologic parameters such as International Federation of Gynecology and Obstetrics stage, as has previously been demonstrated. These findings suggest that a personal history of breast cancer may be a significant risk factor for the development of ESC in women aged ≤ 55 yr. Further studies are needed to clarify the relationship between these two cancers in this age group and whether this increased risk is reflective of a genetic predisposition.

Uterine epithelioid smooth muscle tumors and uterine perivascular epithelioid cell tumors (PEComas) are known to display such a substantial overlap in morphologic and immunophenotypic characteristics that the existence of the latter as a distinct clinicopathologic entity at this location has been called into question. Recent research suggests that the constituent entities of the PEComa family at all anatomical locations, including lymphangioleiomyomatosis of the uterus, uniformly display immunoreactivity for CD1a. The purpose of this study is to determine the proportion of uterine epithelioid smooth muscle tumors that may similarly be CD1a-positive. Representative sections from 18 archived epithelioid smooth muscle tumors of the uterine corpus (6 epithelioid leiomyosarcomas and 12 epithelioid leiomyomas), diagnosed and classified as such based on World Health Organization criteria, were subjected to immunohistochemical stains for CD1a and HMB-45. The epithelioid component of the tissue sections evaluated ranged from 10% to 100% (mean, 70%). Two cases were composed predominantly of cells with overtly clear cytoplasm. All cases were entirely negative for CD1a. Of 18 cases, 1 (5.5%) (an epithelioid leiomyosarcoma) displayed immunoreactivity for HMB-45 in scattered lesional cells that constituted approximately 5% of the overall tumoral volume for the case. All others were HMB-45-negative. Given their rarity, future studies are required to confirm that all PEComas of the uterus are indeed uniformly positive for CD1a. However, if the latter staining pattern is confirmed, our findings herein suggest that CD1a may be a useful immunohistochemical adjunct in distinguishing uterine epithelioid smooth muscle tumors from uterine PEComas.

We report a case of uterine perivascular epithelioid cell tumor (PEComa) with malignant histological features in a 59-year-old woman with tuberous sclerosis (TBS). The patient also had extrapulmonary lymphangioleiomyomatosis involving pelvic lymph nodes, myometrium, cervix, and ovary ("pecomatosis"). The uterine tumor measured 2.6 cm and had marked nuclear pleomorphism, necrosis, and 2 mitoses per 50 high-powered field, with an occasional atypical mitosis and infiltrative borders. The nonneoplastic myometrium, the cervical wall, and the hilum of the ovary had multiple clusters of bland-looking epithelioid clear cells that ranged from 1 to 5 mm (pecomatosis). The uterine tumor cells were positive for HMB-45 (90%), Melan-A (70%), smooth muscle actin (50%), and estrogen receptor (30%). Of the 16 pelvic lymph nodes excised, 3 were involved with lymphangioleiomyomatosis that was positive for HMB-45 and estrogen receptor. This is only the second reported PEComa associated with pecomatosis and the fourth PEComa described in a patient with TBS. The clinical significance of pecomatosis is still uncertain but seems to be seen only in patients with TBS.

Cervical intraepithelial neoplasia is a premalignant (dysplastic) lesion that is characterized by abnormal cellular proliferation, maturation and nuclear atypia. The intraepithelial distribution, density, and nature (typical or atypical) of mitotic figures are routinely utilized diagnostic criteria to grade dysplasia and to distinguish high-grade dysplasia from potential histologic mimics such as transitional metaplasia, atrophy or immature squamous metaplasia. In this study, we evaluated the total mitotic indices of the cervical epithelia in hysterectomy specimens from patients with and without dysplastic lesions and investigated a possible relationship between mitotic index and hormonal status, using the endometrial maturation phase as a surrogate indicator of the latter. Two hundred seventy-four cervices from hysterectomy specimens (135 cases without dysplasia, 33, 35 and 71 cases with grades 1, 2 and 3 cervical intraepithelial neoplasia, respectively) were analyzed. A cervical mitotic index (total mitotic figures/10 high-power fields in the most proliferative area) was determined for each case. The endometrium in each case was classified into atrophic, early proliferative, late proliferative and secretory. For all three dysplasia grades, cases in the proliferative endometrium group always had a higher average mitotic index than those in the secretory and atrophic endometrium groups; this observation also held true for the benign cases. Furthermore, in all three dysplasia grades, the average mitotic index was always lowest in the atrophic endometrium group. Although the mitotic index showed expected patterns of increases with increasing dysplasia grades for most of the endometrial phases, this was not a universal finding. Notably, the average mitotic index for our cervical intraepithelial neoplasia 1 cases with late proliferative endometrium was higher than our cervical intraepithelial neoplasia 2 cases with secretory and atrophic endometrium. It is concluded that hormonal status, as reflected in endometrial maturation, can significantly affect the mitotic index of dysplastic squamous epithelium of the uterine cervix. Our findings confirm that the pathologic grading of dysplasia, especially in equivocal cases such as in metaplastic squamous epithelium, should not be solely dependent on the finding mitoses in the cervical squamous epithelium. The full composite of histopathologic features should form the basis for this determination.

Metastatic lung carcinomas with clear cell morphology can be confused with primary ovarian clear cell carcinomas. We performed immunohistochemical stains in 14 cases of non-small cell lung carcinomas with clear cell features and 14 cases of ovarian clear cell carcinomas using a panel of markers, including thyroid transcription factor 1 (TTF-1), carcinoembryonic antigen (CEA), Wilms tumor gene 1, octamer-binding transcription factor 4 (OCT-4), cancer antigen 125 (CA-125), estrogen receptor, and progesterone receptor. Among non-small cell lung carcinomas with clear cell features, 87.5% of adenocarcinomas (or 50% overall frequency in lung carcinomas) were positive for TTF-1, whereas none of the ovarian clear cell carcinomas were positive (P = 0.002). All 14 ovarian clear cell carcinomas stained for CA-125 as compared with 1 non-small cell lung carcinoma (P < 0.001). On the other hand, 85% of non-small cell lung carcinomas stained for CEA, whereas none of the ovarian clear cell carcinomas did (P < 0.001). Interestingly, 4 ovarian clear cell carcinomas (28%) showed positive staining for the germ cell marker OCT-4. Either lung or ovarian carcinomas stained for Wilms tumor gene 1, estrogen receptor, or progesterone receptor very infrequently; and the difference between the 2 groups was not statistically significant. Our results suggest that an immunohistochemical panel consisting of TTF-1, CEA, CA-125, and OCT-4 is helpful in distinguishing most pulmonary and ovarian carcinomas with clear cell features.

Phenotypic differences between otherwise similar tumors arising from different gynecologic locations may be highly significant in understanding the underlying driver molecular events at each site and may potentially offer insights into differential responses to treatment. In this study, the authors sought to identify and quantify phenotypic differences between ovarian clear cell carcinoma (OCCC) and endometrial clear cell carcinoma (ECCC) using a proteomic approach. Tissue microarrays were constructed from tumor samples of 108 patients (54 ECCCs and 54 OCCCs). Formalin-fixed samples on microarray slides were analyzed by matrix-assisted laser desorption/ionization mass spectrometry, and 730 spectral peaks were generated from the combined data set. A linear mixed-effect model with random intercept was used to generate 93 (12.7%) peaks that were significantly different between OCCCs and ECCCs at the fold cutoffs of 1.5 and 0.667 and an adjusted P value cutoff of 1.0 × 10(-10). Liquid chromatography-tandem mass spectrometry was performed on selected cores from each group, and peptides identified therefrom were compared with lists of statistically significant peaks from the aforementioned linear mixed-effects model to find matches within 0.2 Da. A total of 53 candidate proteins were thus identified as being differentially expressed in OCCCs and ECCCs, 45 (85%) of which were expressed at higher levels in ECCCs than OCCCs. These proteins were functionally diverse and did not highlight a clearly dominant cellular theme or molecular pathway. Although ECCCs and OCCCs are very similar, some phenotypic differences are demonstrable. Additional studies of these differentially expressed proteins may ultimately clarify the significance of these differences.

A 36-year-old gravida 4, para 2 African-American woman, presented at three months postpartum with a right ovarian mass identified on a lumbar spine MRI as part of a neurology workup for persistent lower back pain. A follow-up pelvic ultrasound noted a 7.0 × 6.1 × 3.8 cm septated mixed cystic and solid mass. Exploratory laparoscopy and right ovarian cystectomy yielded a final pathologic diagnosis of intermediate grade myxoid liposarcoma, confirmed with DDIT3 gene rearrangement studies.

Dysplastic epithelium frequently bridges the changes between normal epithelium and noninvasive carcinoma. However, such a dysplastic lesion has not been previously described in the development of uterine papillary serous carcinoma (UPSC) or between resting endometrium and serous endometrial intraepithelial carcinoma (EIC), which is composed of indisputably malignant noninvasive cancer cells. In this study, we hypothesize that there is a lesion bridging benign endometrium and serous EIC. Based on current understanding of carcinogenesis in general, the lesion should exhibit dysplastic features that are more atypical than “resting endometrium” but fall short of serous EIC. If the putative dysplastic endometrial lesion exists, it should be highly associated with UPSC rather than uterine endometrioid carcinoma (UEC). We examined the morphologic appearance of the endometrium from 32 uteri with UPSC, 16 with serous EIC, and 60 with UEC. The endometrial dysplastic lesions were identified and their pathologic features were characterized. Immunohistochemical staining with p53 and MIB-1 were performed in all sections containing endometrial dysplastic lesions, serous EICs, and benign areas. In addition, 25 postmenopausal endometrial biopsies including 6 benign resting endometria, 8 dysplastic lesions, and 11 serous EICs were also compared for the level of p53 overexpression and cellular proliferative activity. We found that endometrial dysplastic lesions do exist in the endometrial specimens we speculated and examined. We designate it as endometrial glandular dysplasia (EmGD). EmGD was present in 17 (53%) uteri with UPSC compared with 1 (1.7%) uterus removed for UEC (p = 0.001). EmGD was identified in 12 (75%) of 16 serous EIC uteri. Areas of both EmGD and serous EIC were found in 15 (47%) of the 32 UPSC uteri. Transitions from either EmGD to serous EIC or serous EIC to UPSC were present in 8 (25%) of the UPSC cases. No transitions from EmGD to UPSC were identified in any hysterectomy specimen. EmGD was frequently found in endometrial polyps. There was no statistically significant difference between EmGD in a polyp (48%) and EmGD in nonpolypoid endometrium (52%). The majority of EmGDs were multifocal and involved superficial endometrial glands. However, single glandular involvement and endometrial surface epithelial involvement were also seen. Immunohistochemically, EmGD lesions mostly showed intermediate scores/indices of p53 and MIB-1 in comparison with serous EIC and resting endometrium. EmGD is a morphologically distinct entity, which is commonly and specifically associated with uterine tumors with serous differentiation. EmGD may represent the earliest identifiable morphologic change in the development of UPSC. Characteristics of p53 and MIB-1 immunostains of EmGD may be of diagnostic usage in surgical pathology practice. Recognition of EmGD may provide an opportunity to improve the management of UPSC.

Varicose veins in the vulvar and perivulvar area are seen in 4% of women. Most of them are secondary to pregnancy and usually regress spontaneously. Vulvar varicose veins are rare in nonpregnant women. When present, they can be seen alone, associated with leg varices or associated with venous malformations of the labia, clitoral area, or vagina with or without arteriovenous malformations on the limbs or trunk (Klippel-Trenaunay-Weber syndrome and Parkes-Weber syndrome). In some cases, vulvar varices are seen as part of the so-called "pelvic congestion syndrome." Clinically, vulvar varices may present as small isolated protrusions, mainly in the labia majora, or as large masses, involving the vulva and even the perivulvar area. The treatment of choice of vulvar varices seen during pregnancy is conservative and symptomatic. Surgical pathologists need to be aware of the existence of vulvar varicose veins and its possible presence in biopsy specimens. Vulvar varicose veins can be misdiagnosed clinically as cysts or masses mainly in the Bartholin gland area. Correct diagnosis of the lesion is important to determine appropriate therapy and to recognize the possibility of associated anatomical or pathological problems.

e17070Background: MicroRNAs (miRNA) have been established as key regulators of tumor gene expression as well as prime biomarker candidates for clinical phenotypes. We analyzed the regulatory structure of miRNAs and their colocalized gene targets in EOC tissue to construct a regulatory signature for clinical prognosis. Methods: FFPE blocks of primary EOC tumor tissue with > 80% tumor cells were selected for 20 patients (stage ≥ IIc) for whom follow up data was available. Expression levels of mRNA and miRNA were assayed separately. An integrated analysis was performed to identify miRNA/mRNA regulatory clusters. Gene set enrichment analysis (GSEA) was carried out on the coexpression of putative miRNA target genes, from the miRTarBase database, with their respective miRNAs, to identify enriched categories for each miRNA. MiRNAs with at least one significantly enriched category from the MSigDB C2 dataset at a false discovery rate of 0.05 were chosen. For each enriched category of each miRNA, a regulon was defi...

To analyze quality of life (QOL) in a randomized, placebo-controlled phase III trial concluding that the addition of concurrent and maintenance bevacizumab (Arm 3) to carboplatin and paclitaxel prolongs progression-free survival in front-line treatment of advanced ovarian cancer compared to chemotherapy alone (Arm 1) or chemotherapy with bevacizumab in cycles 2-6 only (Arm 2).The Trial Outcome Index of the Functional Assessment of Cancer Therapy-Ovary (FACT-O TOI) was used to assess QOL before cycles 1, 4, 7, 13, and 21; and 6months after completing study therapy. Differences in QOL scores were assessed using a linear mixed model, adjusting for baseline score, and age. The significance level was set at 0.0167 to account for multiple comparisons.1693 patients were queried. Arm 2 (p0.001) and Arm 3 (p0.001) reported lower QOL scores than those in Arm 1. The treatment differences were observed mainly at cycle 4, when the patients receiving bevacizumab (Arm 2 and Arm 3) reported 2.72 points (98.3% CI: 0.88-4.57; effect size=0.18) and 2.96 points (98.3% CI: 1.13-4.78; effect size=0.20) lower QOL respectively, than those in Arm 1. The difference in QOL scores between Arm 1 and Arm 3 remained statistically significant up to cycle 7. The percentage of patients who reported abdominal discomfort dropped over time, without significant differences among study arms.The small QOL difference observed during chemotherapy did not persist during maintenance bevacizumab.

Purpose microRNAs have emerged as key regulators of gene expression, and their altered expression has been associated with tumorigenesis and tumor progression. Thus, microRNAs have potential as both cancer biomarkers and/or potential novel therapeutic targets. Although accumulating evidence suggests the role of aberrant microRNA expression in endometrial carcinogenesis, there are still limited data available about the prognostic significance of microRNAs in endometrial cancer. The goal of this study is to investigate the prognostic value of selected key microRNAs in endometrial cancer by the analysis of archival formalin-fixed paraffin-embedded tissues. Experimental Design Total RNAs were extracted from 48 paired normal and endometrial tumor specimens using Trizol based approach. The expression of miR-26a, let-7g, miR-21, miR-181b, miR-200c, miR-192, miR-215, miR-200c, and miR-205 were quantified by real time qRT-PCR expression analysis. Targets of the differentially expressed miRNAs were quantified using immunohistochemistry. Statistical analysis was performed by GraphPad Prism 5.0. Results The expression levels of miR-200c (P

Vascular endothelial growth factor is a key promoter of angiogenesis and disease progression in epithelial ovarian cancer. Bevacizumab, a humanized anti-vascular endothelial growth factor monoclonal antibody, has shown single-agent activity in women with recurrent tumors. Thus, we aimed to evaluate the addition of bevacizumab to standard front-line therapy.In our double-blind, placebo-controlled, phase 3 trial, we randomly assigned eligible patients with newly diagnosed stage III (incompletely resectable) or stage IV epithelial ovarian cancer who had undergone debulking surgery to receive one of three treatments. All three included chemotherapy consisting of intravenous paclitaxel at a dose of 175 mg per square meter of body-surface area, plus carboplatin at an area under the curve of 6, for cycles 1 through 6, plus a study treatment for cycles 2 through 22, each cycle of 3 weeks' duration. The control treatment was chemotherapy with placebo added in cycles 2 through 22; bevacizumab-initiation treatment was chemotherapy with bevacizumab (15 mg per kilogram of body weight) added in cycles 2 through 6 and placebo added in cycles 7 through 22. Bevacizumab-throughout treatment was chemotherapy with bevacizumab added in cycles 2 through 22. The primary end point was progression-free survival.Overall, 1873 women were enrolled. The median progression-free survival was 10.3 months in the control group, 11.2 in the bevacizumab-initiation group, and 14.1 in the bevacizumab-throughout group. Relative to control treatment, the hazard ratio for progression or death was 0.908 (95% confidence interval [CI], 0.795 to 1.040; P=0.16) with bevacizumab initiation and 0.717 (95% CI, 0.625 to 0.824; P0.001) with bevacizumab throughout. At the time of analysis, 76.3% of patients were alive, with no significant differences in overall survival among the three groups. The rate of hypertension requiring medical therapy was higher in the bevacizumab-initiation group (16.5%) and the bevacizumab-throughout group (22.9%) than in the control group (7.2%). Gastrointestinal-wall disruption requiring medical intervention occurred in 1.2%, 2.8%, and 2.6% of patients in the control group, the bevacizumab-initiation group, and the bevacizumab-throughout group, respectively.The use of bevacizumab during and up to 10 months after carboplatin and paclitaxel chemotherapy prolongs the median progression-free survival by about 4 months in patients with advanced epithelial ovarian cancer. (Funded by the National Cancer Institute and Genentech; ClinicalTrials.gov number, NCT00262847.).

Preclinical analyses strongly implicate the phosphatidylinositol 3' kinase-Akt-mammalian target of the rapamycin (P13K-Akt-mTOR) signaling pathway in smooth muscle tumorigenesis and differentiation, indicating that this pathway may be a suitable molecular target for the development of anticancer chemotherapeutic agents. The purpose of this study is to define the frequency and patterns of expression of 3 proteins in this pathway (mTOR, Akt, and PI3-K) in smooth muscle tumors of the uterine corpus, and to establish whether the expression of any of these proteins has independent prognostic significance. The expression patterns of mTOR, pan-Akt, and PI3-K were evaluated by immunohistochemistry in 31 uterine leiomyosarcomas and 10 leiomyomata, and the results were correlated with clinicopathologic parameters. Cases were scored by multiplication of staining intensity (on a 0 to 3 + scale) and the extent/ distribution of immunoreactivity (on a 0 to 4 + scale) for potential scores that ranged from 0 to a maximum of 12. Cases with scores of 4 + to 12 + (moderate, 4 + to 8 + ; high, 9+ to 12+ immunoreactivity) were considered positive. Associated peritumoral normal myometrium was present in 27 cases. All 31 leiomyosarcomas were pan-Akt positive, with 80.6% of the positive cases displaying high scores, whereas all 10 leiomyomata and 27 normal myometria were entirely pan-Akt negative. High pan-Akt scores were associated with high tumor grade but not with advanced stage or outcome. Every tumoral and nontumoral sample that was evaluated showed immunoreactivity for mTOR. PI3-K was positive in 20 (64.5%) of the 31 leiomyosarcomas but in none of the leiomyomata. High scores of PI3-K were associated with late pathologic stage (P=0.0022). High PI3-K scores, high pan-Akt scores, and PI3-K positivity were not independently associated with reduced disease-specific survival on multivariate analysis. Our findings suggest that relative to the normal myometrium, there is indeed dysregulation of the P13K-Akt-mTOR pathway in uterine smooth muscle tumors and especially in uterine leiomyosarcomas. Pan-Akt, mTOR, and PI3-K expression lacked independent prognostic significance in this pilot study, but additional and larger analyses are required. If corroborated in other laboratories, the expression patterns of proteins in this pathway, especially pan-Akt, may be of diagnostic use.

Earlier reports have indicated that patients with endometrial clear cell carcinoma (CCC) may have an increased risk for thromboembolic events. Tissue factor is a 47-Kd transmembrane glycoprotein that plays a critical role in platelet activation, fibrinogenesis, blood clot formation, and as such, general hemostasis. The mammalian heparanase is an endo-β-glucuronidase that can cleave heparan sulfate at specific molecular sites, resulting in structural modification of the extracellular matrix barrier, facilitating cancer cell invasion, and eventual metastasis. Recent reports indicate that heparanase may also induce tissue factor expression. The purpose of this study is to assess the clinicopathologic significance of tissue factor and heparanase expression, especially as they relate to the risk of thromboembolic events, in endometrial CCC and selected other endometrial cancers. Eighty-four endometrial carcinomas, including 17 CCC, 20 endometrial serous carcinomas, 15 grade 1 endometrial endometrioid carcinomas (EEC), 15 grade 2 EEC, 10 grade 3 EEC, and 7 mixed endometrial carcinomas with at least a 10% clear cell component (mixed CCC) were evaluated for the immunophenotypic expression of heparanase and tissue factor, and their associated frequency of thromboembolic events. Seven of the 84 patients experienced 8 thromboembolic events during the follow-up period. By multivariate analysis, the pure CCC histotype [odds ratio 5.2; 95% confidence interval (CI): 2.4523-13.6754; P=0.026] was significantly associated with an elevated risk for thromboembolic events. Tissue factor expression was present in 12 (14.28%) of the 84 endometrial carcinomas, including in 7 (41.17%) of 17 pure CCC, 2 (10%) of 20 endometrial serous carcinomas, 1 (14.3%) of 7 mixed CCC, 2 (13.3%) of 15 grade 1 EEC, and in 0% of grade 2 and 3 EEC. Tissue factor expression was significantly more likely to be seen in pure CCC than in all other cancers as a group (P=0.0018) and in all other high-grade endometrial cancers (P=0.007). By multivariate analysis, tissue factor expression was significantly associated with the risk of thromboembolic events [odds ratio 4.8 (95% CI: 1.9196-11.93), P=0.013]. Tissue factor expression was not associated with patient outcome or any other clinicopathologic parameter. Heparanase expression was present in 57 (67.8%) of the 84 endometrial carcinomas, and was significantly associated with the endometrioid histotype, but not outcome or the risk of thromboembolic events. For the overall group of all cancers, there was no significant correlation between heparanase and tissue factor expression (Spearman rank correlation, r=0.311, P=0.4). In summary, patients with endometrial CCC have an increased risk of developing thromboembolic events compared with patients with the other histotypes. This increased risk may be related, at least partially, to an increased rate of tissue factor expression in endometrial CCC.

The purpose of this study is to investigate the expression patterns and role of Notch signaling in human endometrial cells. Notch receptors, Notch 1-3 were expressed in both endometrial epithelial and stromal cells. Notch ligands, Jag1 and Dll4 and Notch target genes, Hes1 and Hey1 were predominantly expressed in endometrial epithelial cells and scarce in stromal cells. Increased de novo synthesis of Dll4 or Jag1 in stromal cells by retroviral delivery significantly induced Hes1 and Hey1. Evaluations of global gene expression by microarrays revealed that more than 400 genes in stromal cells were significantly regulated by Jag1. Gene annotation-based functional analysis classified these genes into biological processes of cell adhesion, cell structure and motility, cell communication, cell cycle, and angiogenesis. This study provides evidence that Notch ligands control the Notch gene activities and may enhance development of human endometrium.

Alteration of p53 is an early event in the development of endometrial serous carcinoma (ESC). We have recently identified a group of benign-looking endometria with p53 overexpression, designated "p53 signatures." In this study, we investigated these p53 signatures and evaluated whether they represented "latent" precancers for ESC. The p53 signatures were specifically associated with ESC, frequently found in the benign-appearing endometrium adjacent to the ESC and only rarely in either the endometrium adjacent to endometrioid carcinomas or in non-cancerous uteri. Forty-two percent of the p53 signature samples showed at least one p53 gene mutation. There were eight ESC uteri with p53 signatures that revealed p53 gene mutations. In four (50%) of these cases, at least one identical p53 gene mutation was found in the signature glands, precancerous regions, and cancerous areas within the same uterus. We concluded that p53 gene mutations apparently precede the morphological changes in affected endometrial cells. The finding of identical p53 mutations in the p53 signatures, precancerous regions, and ESCs in a subset of the uteri provides further evidence of a probable shared lineage between these lesions and suggests that the epithelia that display these p53 signatures are likely latent ESC precancerous regions. These findings underscore the significance of the p53 signature as a target for further research in the early detection and prevention of ESC.

Lymph node involvement is seen in approximately one quarter of women with surgically staged ovarian serous tumors of low malignant potential (serous borderline tumors), and this finding apparently does not adversely impact their overall survival. To help illuminate some of the pathomechanisms underlying this novel phenomenon, in which a largely noninvasive epithelial neoplasm is able to exit its primary site and be transported to lymph nodes with such a substantial frequency, we investigated whether significant differences in lymphatic vessel density exist between ovarian serous borderline tumors that show lymph node involvement and those that do not. The lymphatic vessel density of 13 conventional ovarian serous borderline tumors (i.e. tumors without stromal microinvasion, micropapillary/cribriform areas, or invasive implants) with at least 1 positive lymph node (study group) was compared with the lymphatic vessel density of an age- and disease extent-matched control group of 13 similarly selected lymph node-negative ovarian serous borderline tumors. Lymphatic vessel density was determined by counting the total number of vascular spaces immunohistochemically stained by the lymphatic endothelium marker D2-40 in 5 consecutive microscopic fields (x 20 objective, field area of 1 microscopic field, 0.95 mm 2 ) in the most vessel-dense areas and calculating the average value per microscopic field. The peritumoral lymphatic vessel density was significantly higher than the intratumoral lymphatic vessel density in both groups. However, no statistically significant differences were found between the study and control groups regarding intratumoral lymphatic vessel density (8.0 vs. 7.61; P=0.77), peritumoral lymphatic vessel density (20.33 vs. 21.0; P=0.79), or combined, that is, peritumoral plus intratumoral lymphatic vessel density (27.81 vs. 28.62; P=0.83). Our findings, in conjunction with others in the medical literature, do not support a role for tumor lymphatics in nodal metastasis in this neoplasm. We discuss the possibility that nodal deposits may represent metastatic disease from secondary tumor implants.

Small cell neuroendocrine carcinoma of the prostate is a rare variant of prostatic cancer that shares morphologic similarity with prostatic adenocarcinoma of Gleason 5 pattern. It has also been considered morphologically and immunohistochemically indistinguishable from small cell neuroendocrine carcinomas of other origins. CD44 is a cell-surface molecule proposed to identify cancer stem/progenitor cells in prostate cancer. We performed immunohistochemical study for CD44 expression in 11 cases of prostatic small cell neuroendocrine carcinoma and compared its patterns of expression with 73 cases of prostatic adenocarcinoma and 47 cases of small cell neuroendocrine carcinomas of other organs. Strong and diffuse membrane staining for CD44 was observed in 100% of the prostatic small cell neuroendocrine carcinomas. In conventional adenocarcinomas of the prostate, positive staining was only seen in rare, scattered tumor cells; and CD44 staining was negative in most of the small cell neuroendocrine carcinomas of nonprostate origin. The difference in CD44 expression between small cell neuroendocrine carcinomas of the prostate and those of other organs are statistically significant (P < .001). Our study demonstrates the utility of immunohistochemical staining for CD44 in distinguishing prostatic small cell neuroendocrine carcinoma from its mimickers including prostatic adenocarcinoma of Gleason 5 pattern and small cell neuroendocrine carcinomas of other organs. CD44 is the first marker that shows a high degree of tissue/organ specificity for small cell neuroendocrine carcinomas. Because CD44 is a putative marker of prostate cancer stem cells, the strong and diffuse expression of CD44 and the lack of expression of prostate luminal differentiation markers androgen receptor and prostatic specific antigen in prostatic small cell neuroendocrine carcinomas suggest that the tumor cells may retain cancer stem cell features.

Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is an oncofetal protein highly expressed in fetal tissue and malignant tumors but rarely found in adult benign tissues. The aim of this study is to determine the expression of IMP3 in benign endometrium, endometrial cancer, and its precursor lesions, trying to see whether IMP3 has any diagnostic usage. Two hundred ninety-eight endometrial samples were examined for IMP3 expression by immunohistochemistry. These included benign endometrium (n=68), atypical hyperplasia or endometrial intraepithelial neoplasia (n=35), endometrial glandular dysplasia (n=21), endometrial intraepithelial carcinoma (n=18), endometrioid carcinoma (n=70), mucinous carcinoma (n=8), serous carcinoma (n=51), clear cell carcinoma (n=12), and other malignancies (n=15). Maturational patterns in the 68 benign endometrial samples included atrophic (n=12), proliferative (n=18), secretory (n=14), menstrual (n=8), and gestational (n=16). Most of the carcinomas were histologically pure; where mixed, the second component constituted

We report a rare case of sertoliform endometrioid carcinoma of the endometrium in a 71-year-old African American woman who presented with postmenopausal bleeding. Her medical condition was remarkable for hypertension, diabetes, and obesity. She underwent total hysterectomy, right salpingo-oophorectomy and lymph node sampling. The endometrium was occupied by a 4.5-cm solid polypoid tumor, which grossly invaded into the myometrium. Microscopically, the tumor consisted of small hollow tubules, anastomosing cords and trabeculae, and tightly packed nests. Microglandular areas mimicking adult granulosa cell tumors were also present. But true Call-Exner bodies were absent. Component of typical endometrioid carcinoma was noted only focally. The uninvolved endometrium demonstrated atypical complex hyperplasia. The tumor cells were diffusely immunoreactive for epithelial membrane antigen, estrogen receptor, and progesterone receptor (PR), and focally for vimentin. The tumor cells were also diffusely positive for inhibin alpha and CD99. Immunostains for other sex cord markers (calretinin, WT-1, and Melan-A) were also positive in approximately 30% to 40% of the tumor cells. Immunostains for CD10, smooth muscle actin, desmin, or HHF35 were negative. Two ovarian sertoliform endometrioid carcinomas from our archived tissue were, however, immunoreactive for epithelial membrane antigen but negative for inhibin alpha. Despite the prominent sertoliform features, both histologically and immunohistochemically, the tumor was of a high-grade endometrial carcinoma and will likely behave as such. As of today, dual differentiation of epithelium and sex cord by immunohistochemical staining has not been demonstrated in sertoliform endometrioid carcinomas of either endometrial or ovarian origin. Our case is the first documentation of such example and suggests that endometrial carcinoma can undergo true sex cord differentiation.

Endometrial glandular dysplasia (EmGD) is a newly defined entity that is commonly and specifically associated with serous endometrial intraepithelial carcinoma and uterine papillary serous carcinoma (UPSC). Endometrial glandular dysplasia has been proposed as a true precancerous lesion of UPSC based on our recent studies showing morphological and molecular linkages between these 2 lesions. The present report is to examine if EmGD occurs before UPSC development and to define the period from the occurrence of EmGD to a full-blown UPSC by studying their clinicopathologic features in a retrospective setting. A total of 250 UPSC and 258 benign cases were used as initial study source. To identify if EmGD existed before the development of UPSC, we blindly reviewed all available endometrial biopsies from a period of 3 months or earlier before hysterectomies. These included an available pool of 27 biopsy specimens from UPSC group and 29 samples from benign control group. Any endometrial abnormalities, which morphologically qualified as EmGD as defined previously in preceding biopsies were recorded. Among all endometrial biopsies before hysterectomies, we morphologically identified a total of 10 EmGD cases; 9 (33%) of 27 were from UPSC group and 1 (3.5%) of 29 were from benign control group. All 10 morphologically diagnosed EmGD cases showed a high p53 staining score (>/=5) except 1 noncontributory from UPSC group and 1 from the benign control group with a score of 0. A high MIB-1 index score was seen in all EmGD cases, whereas low index was found in morphologically benign biopsies. The main purpose of this study is to report these retrospectively identified EmGD cases. The period from identifying EmGD to the presence of either a serous endometrial intraepithelial carcinoma or a full-blown UPSC ranged from 16 to 98 months with an average of 33 months. We conclude that occurrence of EmGD precedes the development of UPSC. The findings support our recently proposed UPSC development model, in which EmGD is likely to be a precursor lesion of UPSC. Further studies are needed to address issues in regard to molecular and cellular mechanisms, reversibility, risk of UPSC development, and clinical management of EmGD.

The recognition of morphologically identifiable lesions which may confer an increased risk for subsequent development of an invasive malignancy offers an opportunity to investigate and better understand the molecular-genetic etiopathogenesis of the well-developed tumor, and potentially, to administer a therapeutic intervention before its development. In contrast to uterine endometrioid and serous carcinomas, very little is known about the potential precursor lesions of endometrial clear cell carcinoma (ECCC). In our routine practice, we have noted the presence of a spectrum of atypical glandular changes in the endometria adjacent to ECCC or endometrial carcinomas with a clear cell component, which on the basis of current criteria, would not qualify for any specific designation. We hypothesize that these lesions represent the earliest morphologically recognizable precursor lesions of ECCC and systematically characterize their clinicopathologic features herein. Thirty archived cases of pure ECCC (n = 14) or mixed endometrial carcinomas with a > 10% clear cell component (n = 16) were retrieved and the "normal" endometria adjacent to the malignancies were evaluated in detail. Thirty-eight benign uteri and 30 uteri with classic endometrial endometrioid carcinoma (EEC) served as controls. All cases were reviewed in a blinded fashion. Putative precursor lesions (PPL) were searched for and identified microscopically. The lesions were typically isolated glands or surface epithelium (within an otherwise normal endometrial region) that displayed cytoplasmic clarity and/or eosinophilia with varying degrees of nuclear atypia. Twenty-seven (90%) of the 30 cases had at least 1 PPL. In contrast, PPL were identified neither in the benign uteri nor in endometrioid carcinoma control groups (P < 0.001). A total of 67 foci of PPL were identified in the 27 cases with an average of 2.5 foci per case. The immunohistochemical expression of p53, mib-1, estrogen receptor (ERs), and progesterone receptor in the benign endometria, ECCC, and the PPL were evaluated on all 27 cases. The mean p53 scores for the benign endometria, PPL, and ECCC were 0, 4.5, and 6.2, respectively. Parallel values for mib-1 were 15%, 45%, and 63%. ER/progesterone receptor indices for benign endometria, PPL, and carcinoma were 90/80, 21.52/ 4.61, and 11/4, respectively. The PPL described herein have a morphologic and immunophenotypic profile which seems to be distinct from both the benign endometria in which they reside and the adjacent areas of ECCC. The high frequency of association of these lesions with ECCC, their frequent occurrence as isolated lesions within otherwise "benign-appearing" endometria, and their continuous spectrum of nuclear atypia from minimum (grade 1, cytologic atypia falls short of ECCC cells) to maximum (grade 3, cytologically identical to ECCC cells), argues in favor of our hypothesis that these may represent precursor lesions of ECCC. Further studies are required to conclusively define the nature of these lesions. However, such studies can only be performed if diagnostic surgical pathologists recognize, highlight, and segregate these lesions for further analysis.

Ectopic human chorionic gonadotropin production has been described in a wide variety of non-germ cell tumors, particularly in epithelial tumors, but rarely in sarcomas. In this report, we describe the case of 49-year-old woman with a history of "uterine fibroids," who presented with vaginal bleeding and a positive urine pregnancy test. After pregnancy was ruled out by ultrasound, the patient underwent a laparotomy and hysterectomy for a presumptive diagnosis of "fibroids" and was found to have carcinomatosis at the time of the surgery. Therefore optimal debulking of tumors was performed. Two weeks later, the patient developed a small bowel obstruction, which apparently was due to rapid recurrence of tumors in the abdomen, and soon afterwards she died. Microscopically, the resected pelvic mass was composed of highly atypical and pleomorphic spindle cells admixed with many multinucleated giant cells. The tumor had a high mitotic rate along with areas of hemorrhage and necrosis. Immunohistochemically, the tumor cells were positive for vimentin, desmin, smooth muscle actin, and beta-human chorionic gonadotropin, and were negative for epithelial membrane antigen, keratin AE1/3, S-100, CD31, CD117, Ber-EP4, WT-1, estrogen and progesterone receptors. The majority of cells, including the multinucleated giant cells, were strongly immunoreactive for beta-human chorionic gonadotropin. Only three cases of leiomyosarcomas with beta/human chorionic gonadotropin production have been described in the literature, and all three cases had extrauterine origin. Our case, to the authors' best knowledge, is the first uterine leiomyosarcoma with prominent beta/human chorionic gonadotropin production.

Endometrial glandular dysplasia (EmGD) may be a newly defined precursor lesion of uterine papillary serous carcinoma (UPSC) by morphology. In this report, we studied molecular changes present in EmGD by the loss of heterozygosity (LOH) approach using laser capture microdissected tissue samples. Nineteen uteri showing at least 1 focus of EmGD by morphology were selected. These cases were 12 UPSC, 2 clear cell carcinomas, 1 mixed uterine papillary serous and endometrioid carcinoma, 1 uterine carcinosarcoma, 1 serous endometrial intraepithelial carcinoma (EIC), and 2 EmGD involving endometrial polyps. Seven microsatellite polymorphic DNA markers (TP53 at 17p, D1S211, and D1S162 at 1p32, D17S1323 at 17q21, D17S1330 at 17q25, D5S346 at 5q, and D2S123 at 2p) were utilized. A total of 123 laser-captured microdissection samples from 19 cases was studied with LOH method. The frequencies and patterns of LOH were analyzed and compared among benign resting endometrium (RE), EmGD, serous EIC, and UPSC. LOH was observed for at least 1 of the 7 markers in all categories of lesions, EmGD, serous EIC, and UPSC. The frequency of LOH for EmGD ranged from 4.2% to 31.3%; the range for serous EIC was 5.9% to 78.6%; and that for UPSC was 7.7% to 62.5%. The most frequent LOH in the 3 above-cited categories of lesions was identified at 17p (TP53) and 1p (D1S162). The frequency of LOH in EmGD with markers of TP53 and D1S162 was significantly higher than in RE (p < 0.05). With markers of D1S211 and D2S123, LOH in EmGD was higher than RE, approaching to a statistically significant level. Compared with foci of serous EIC and UPSC, however, the rate of LOH in EmGD was significantly lower only with TP53 locus (31.3% vs more than 60%, p < 0.05). The difference of LOH frequency with other chromosomal markers between EmGD and serous EIC/UPSC did not reach a statistically significant level. A significantly high concordant LOH pattern was found between foci of EmGD and serous EIC/UPSC (p = 0.05). We conclude that EmGD frequently shows LOH at multiple chromosomal loci, particularly at 17p and 1p. Significantly high concordant LOH frequency between EmGD and paired serous EIC or UPSC strongly suggests that EmGD is a noncancerous precursor lesion of UPSC, probably also of serous EIC. The clinical significance of EmGD needs further studies.

Background: Epithelial ovarian cancer accounts for 90% of all cases of malignant tumors of the ovaries, the majority of patients are diagnosed at stage III disease with 70% of them succumbing to their disease within 5 years. Objectives: We addressed 3 questions 1) are there patterns in the pre-surgical miRNA profiles between survivors of stage III ovarian cancer and patients who do not survive the disease “surviving pattern” (SP) 2) are there changes in the miRNA profiles that occur during or after chemotherapy that convert patients into SP. 3) Do patients with benign ovarian masses have the SP? Methods: Between 2004 and 2011 we investigated in patterns of circulating miRNAs collected before, after surgery, during and after chemotherapy in patients presenting for surgery for ovarian masses. We also collected blood at ovarian cancer relapse and tumor and benign ovary (if available) for miRNA analysis. Raw Ct values obtained from Taqman and software Data Assist. Data were processed via programming language R. Raw data were normalized using the least variable miRNA from dataset. Differential expression was studied using the R/Bioconductor package “limma” using moderated t-statistic allowing both 2 sample comparison and multiple sample comparison. Only results with a p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4150. doi:1538-7445.AM2012-4150

Background: microRNAs (miRNAs) have emerged as key regulators of gene expression, and their altered expression has been associated with tumorigenesis and tumor progression. As a result, miRNAs represent important diagnostic biomarkers for the advancement of cancer and potential therapeutic approaches. They may be up-regulated or down-regulated in various tumor types, thus act as oncogenes or tumor suppressors. Although accumulating evidence suggests the role of aberrant miRNA expression in endometrial carcinogenesis, there is still limited data available about the endrometrial miRNAs. Endometrial cancer is characterized by frequently infiltrating tumors, and one of the most important molecular alterations in this process is through epithelial-mesencymal transition (EMT). Several studies implicated the role of miRNAs targeting the critical players during EMT. The goal of this study is to investigate the clinical utility of selected key miRNAs in archival FFPE tissue samples of patients with endometrial cancer. In this study, the expression of miR-26a, miR-205, miR-200c, miR-192, miR-215, let-7g, miR-21, miR-181b were quantified from 20 stage I, 2 stage II, 5 stage III, 8 stage IV endometrial cancer patients (endometrioid-type endometrial cancer (EEC), endometrial serous carcinoma(ESC), clear cell carcinoma(CCC) undifferentiated carcinoma (UDC), malignant mullerian mixed tumor (MMMT)) with up to 15 years clinical follow up information. Methods: Using archival FFPE tissues, areas of tumor and normal tissues were identified according to the corresponding hematoxylin and eosin stained sections, and cores of 1.5 mm in diameter were extracted. Total RNAs were isolated from 35 paired endometrial tumor and adjacent normal tissue specimens by using Trizol based approach. The expression levels of miRNAs were quantified by using real-time qRT-PCR analysis. Results: The expression of miR-205 (p=0.0002) and miR-200c (p Conclusions: miR-205 holds a great potential as a prognostic biomarker in endometrial cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 158. doi:10.1158/1538-7445.AM2011-158