Data Set for Reporting of Uterine Malignant and Potentially Malignant Mesenchymal Tumors: Recommendations From the International Collaboration on Cancer Reporting (ICCR).

The International Collaboration on Cancer Reporting (ICCR) seeks to produce standardized, evidence-based protocols for the reporting of tumors with the aim of ensuring that all cancer reports generated worldwide will be of similar high quality and record the same elements. Herein, we describe the development of the data set for the reporting of uterine malignant and potentially malignant mesenchymal tumors by a panel of expert pathologists and a single clinician and provide the commentary and rationale for the inclusion of core and noncore elements. This data set, which incorporates the recent updates from the 5th edition of the World Health Organization Classification of Female Genital Tumors, addresses several subjects of debate including which mesenchymal tumors should be graded, how to document extent of invasion, mitotic counts, and the role of ancillary testing in tumor diagnosis and patient management. The inclusion of elements is evidence-based or based on consensus of the expert panel with clinical relevance being the guiding standard.

Data Set for the Reporting of Endometrial Cancer: Recommendations From the International Collaboration on Cancer Reporting (ICCR).

Endometrial cancer is one of the most common cancers among women. The International Collaboration on Cancer Reporting (ICCR) developed a standardized endometrial cancer data set in 2011, which provided detailed recommendations for the reporting of resection specimens of these neoplasms. A new data set has been developed, which incorporates the updated 2020 World Health Organization Classification of Female Genital Tumors, the Cancer Genome Atlas (TCGA) molecular classification of endometrial cancers, and other major advances in endometrial cancer reporting, all of which necessitated a major revision of the data set. This updated data set has been produced by a panel of expert pathologists and an expert clinician and has been subject to international open consultation. The data set includes core elements which are unanimously agreed upon as essential for cancer diagnosis, clinical management, staging, or prognosis and noncore elements which are clinically important, but not essential. Explanatory notes are provided for each element. Adoption of this updated data set will result in improvements in endometrial cancer patient care.

Cervical carcinomas with serous-like papillary and micropapillary components: illustrating the heterogeneity of primary cervical carcinomas.

Recent changes in the classification of cervical adenocarcinomas have re-categorized serous carcinoma as potentially nonexistent. However, clinical and pathological profiles of cervical adenocarcinomas with serous-like morphological features have not been systematically evaluated using the latest taxonomy and biomarkers. We studied 14 cases of primary cervical carcinomas with serous-like morphologies (papillary and micropapillary patterns). None of these cases exhibited evidence of serous carcinoma involving the upper tracts. Patient ages ranged between 34 and 86 years, most presented with abnormal uterine bleeding. Histologically, ten cases were classified as human papillomavirus (HPV)-associated carcinomas (eight usual-type endocervical adenocarcinomas and two adenosquamous carcinomas), of which six exhibited a papillary pattern and four had a micropapillary pattern. The four remaining cases were HPV-independent gastric-type adenocarcinomas, which displayed a papillary pattern in one case and a micropapillary pattern in three others. All ten HPV-associated carcinomas displayed block positive p16 and wild-type p53 by immunohistochemistry, with nine of them confirmed by HPV testing. Two of the four gastric-type adenocarcinomas had mutation-type p53, one of which also being p16 block positive. HER2 overexpression was demonstrated in 3/14 (21.4%) cases (2 HPV-associated and 1 HPV-independent). PD-L1 expression was identified in 4/10 (40%) cases, all HPV-associated. Targeted next-generation sequencing was performed in two cases with a micropapillary pattern, revealing a missense variant in ATM in an HPV-associated tumor and missense variants in TP53 and SMARCB1 in an HPV-independent tumor. The results demonstrated that primary endocervical adenocarcinomas can mimic the appearance of serous carcinoma, while not representing serous carcinoma. Serous-like papillary and micropapillary patterns may be present in both HPV-associated and HPV-independent cervical carcinomas, but none of the cases studied were unequivocally serous upon detailed analysis. Our findings support the exclusion of "cervical serous carcinoma" from existing classifications of cervical adenocarcinoma.

Predictive biomarkers and tumor microenvironment in female genital melanomas: a multi-institutional study of 55 cases.

Female genital melanomas are rare. At diagnosis, most affected patients have advanced disease. Surgery remains the primary treatment, and adjuvant therapy is largely ineffective. Recently, immune checkpoints and the mitogen-activated protein kinase pathway have been explored as treatment targets. However, evaluation of these biomarkers in genital melanomas is limited. We evaluated the clinicopathological features of 20 vulvar, 32 vaginal, and three cervical melanomas and assessed programmed cell death ligand 1 (PD-L1) expression, CD8 tumor-infiltrating lymphocyte density, mismatch repair proteins, VE1 immunohistochemistry, and KIT and BRAF mutations. The median age of the patients was 66 years, and median tumor sizes were 25, 30, and 20 mm for vulvar, vaginal, and cervical tumors, respectively. Mean mitotic figures were 18, 19, and 30 per mm2. Thirty-seven patients (67%) had operable tumors. After a median follow-up of 15 months, only nine patients (16%) were alive. Eight of the nine survivors did not have lymph node metastasis. Using 5% as the threshold, PD-L1 expression was observed in 55%, 50%, and 33% of vulvar, vaginal, and cervical tumors, respectively, when the Roche SP263 antibody was used and 20%, 53%, and 0%, respectively, when the Dako 28-8 antibody was used. The median CD8 tumor-infiltrating lymphocyte density was significantly higher in vulvar/vaginal than cervical melanomas and correlated with PD-L1 expression. No cases exhibited loss of mismatch repair proteins. Five cases harbored KIT mutations, three of which were hotspots. BRAF V600E mutation was not detected. Univariable analysis showed that tumor size greater than or equal to 33 mm, mitotic figures of greater than or equal to 10 per mm2, lymph node metastasis, and low CD8+ tumor-infiltrating lymphocyte density were adverse prognostic factors. Thus, patients with genital melanomas have a poor prognosis, and evaluation of multiple biomarkers is necessary to identify patients who may benefit from immunotherapy or targeted therapy.

Machine Learning Interpretation of Extended Human Papillomavirus Genotyping by Onclarity in an Asian Cervical Cancer Screening Population.

This study aimed (i) to compare the performance of the BD Onclarity human papillomavirus (HPV) assay with the Cobas HPV test in identifying cervical intraepithelial neoplasia 2/3 or above (CIN2/3+) in an Asian screening population and (ii) to explore improving the cervical cancer detection specificity of Onclarity by machine learning. We tested 605 stratified random archived samples of cervical liquid-based cytology samples with both assays. All samples had biopsy diagnosis or repeated negative cytology follow-up. Association rule mining (ARM) was employed to discover coinfection likely to give rise to CIN2/3+. Outcome classifiers interpreting the extended genotyping results of Onclarity were built with different underlying models. The sensitivities (Onclarity, 96.32%; Cobas, 95.71%) and specificities (Onclarity, 46.38%; Cobas, 45.25%) of the high-risk HPV (hrHPV) components of the two tests were not significantly different. When HPV16 and HPV18 were used to further interpret hrHPV-positive cases, Onclarity displayed significantly higher specificity (Onclarity, 87.10%; Cobas, 80.77%). Both hrHPV tests achieved the same sensitivities (Onclarity, 90.91%; Cobas, 90.91%) and similar specificities (Onclarity, 48.46%; Cobas, 51.98%) when used for triaging atypical squamous cells of undetermined significance. Positivity in both HPV16 and HPV33/58 of the Onclarity channels entails the highest probability of developing CIN2/3+. Incorporating other hrHPVs into the outcome classifiers improved the specificity of identifying CIN2/3 to up to 94.32%. The extended genotyping of Onclarity therefore can help to highlight patients having the highest risk of developing CIN2/3+, with the potential to reduce unnecessary colposcopy and negative psychosocial impact on women receiving the reports.

Amyloid Precursor Protein Overexpression in Down Syndrome Trophoblast Reduces Cell Invasiveness and Interferes with Syncytialization.

The placentas of Down syndrome (DS) pregnancies exhibit morphologic and functional abnormalities. Although the increase in dosage of certain genes on chromosome 21 has been associated with the DS phenotype, the effects on placenta have seldom been studied. Herein, we examine the expression of four dosage-sensitive genes (APP, ETS2, SOD1, and HMGN1) in normal and DS placentas. We demonstrated significant overexpression of amyloid precursor protein (APP) in DS placentas at RNA and protein levels by real-time quantitative PCR, Western blot analysis, and immunohistochemistry. Inducible APP overexpression trophoblast cell line models were established using a Tet-On system. APP induction in HTR-8/SVneo dose-dependently decelerated cell growth, enhanced apoptosis, and reduced cell migration and invasion when compared with the uninduced controls. Concomitantly, decreased ß-human chorionic gonadotropin in the culture medium was also detected on induction. Moreover, although forskolin treatment induced α/ß-human chorionic gonadotropin and syncytin expression in BeWo cells, such induction of syncytialization was inhibited by APP overexpression. E-cadherin immunofluorescence also demonstrated a decrease in syncytia formation in forskolin-treated BeWo-overexpressing APP. By liquid chromatography-tandem mass spectrometry, proteins related to cell-cell adhesion, protein translation, processing, and folding were found to be up-regulated in APP-induced HTR-8/SVneo clones. Our data demonstrated, for the first time, the effects of increased APP expression in DS placenta.

The mitosis-specific marker phosphohistone-H3 (PHH3) is an independent prognosticator in uterine smooth muscle tumours: an outcome-based study.

AIMS: Accurate mitosis counting, which is important in the diagnosis of uterine smooth muscle tumours (USMTs), is often difficult and subjective. The mitosis-specific immunohistochemical marker phosphohistone-H3 (PHH3) has been shown to be diagnostically useful, but its expression, in relation to outcome, has not been thoroughly investigated. The aim of this study is to evaluate PHH3 as a diagnostic and prognostic marker in USMTs. METHODS AND RESULTS: PHH3 expression was evaluated in 55 leiomyosarcomas (LMSs), 26 smooth muscle tumours of uncertain malignant potential (STUMPs), 18 leiomyomas with bizarre nuclei (LBN), and 12 leiomyomas (LMs). Scores were expressed as counts per 10 high-power fields (HPFs). Median follow-up durations of patients with LMS, STUMP, LBN and LM were, respectively, 39, 78, 65.5 and 49.5 months. Twenty-eight patients with LMSs (50.9%) died, and two (7.7%) patients with STUMPs experienced recurrence. The median PHH3 scores for LMSs were significantly higher than those for other categories of tumour. A score of ≥29/10 HPFs was also independently associated with a poor outcome. To test whether the PHH3 score could distinguish between benign USMTs with atypical histology and those that were clinically malignant, two biological groups were further delineated. Patients in group 1 (18 LBNs and 24 STUMPs) all had an uneventful outcome, whereas patients in group 2 (two recurrent STUMPs and 32 LMSs) all had a recurrence or tumour-related death. Median PHH3 scores for the two groups were, respectively, 2/10 HPFs and 27/10 HPFs. A PHH3 score of ≥7/10 HPFs was highly associated with malignancy. CONCLUSION: PHH3 is useful in evaluation of the biological behaviour of USMTs, and may serve as a prognostic indicator for LMSs.

Subcutaneous phaeohyphomycotic nodule due to Phialemoniopsis hongkongensis sp. nov.

Phialemoniopsis species are ubiquitous dematiaceous molds associated with a wide variety of superficial and systemic infections in human. In this study, we isolated a mold from the forearm nodule biopsy specimen from a patient with underlying liver cirrhosis, ankylosing spondylosis, and tuberculosis. He was treated with itraconazole, but unfortunately, he succumbed as a result of disseminated tuberculosis with multiorgan failure. The histology results of the skin biopsy showed necrotizing granulomas in which numerous fungal elements were found. On Sabouraud dextrose agar, the fungal isolate grew as white-to-cream and smooth-to-velvety colonies. Microscopically, oval-to-cylindrical conidia were observed from abundant adelophialides, which possessed barely visible parallel collarettes but no basal septa. The azole drugs voriconazole, itraconazole, and posaconazole, as well as amphotericin B, showed high activities against this fungus. Internal transcribed spacer, 28S nuclear ribosomal DNA (nrDNA), and ß-actin and ß-tubulin gene sequencing showed that this fungus is most closely related to but distinct from Phialemonium curvata. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and hierarchical cluster analysis showed that the MALDI-TOF MS spectrum of this fungus is most closely related to that of Phialemonium pluriloculosa. We propose a new species, Phialemoniopsis hongkongensis sp. nov., to describe this fungus.

Inhibition of aberrantly overexpressed Polo-like kinase 4 is a potential effective treatment for DNA damage repair-deficient uterine leiomyosarcoma.

PURPOSE: Uterine leiomyosarcoma (LMS) is an aggressive sarcoma and a subset of which exhibit DNA repair defects. Polo-like kinase 4 (PLK4) precisely modulates mitosis, and its inhibition causes chromosome missegregation and increased DNA damage. We hypothesize that PLK4 inhibition is an effective LMS treatment. EXPERIMENTAL DESIGN: Genomic profiling of clinical uterine LMS samples was performed, and homologous recombination (HR) deficiency scores were calculated. PLK4 inhibitor (CFI-400945) with and without an ataxia telangiectasia mutated (ATM) inhibitor (AZD0156) were tested in vitro on gynecological sarcoma cell lines SK-UT-1, and SKN, and SK-LMS-1. Findings were validated in vivo using the SK-UT-1 xenograft model in Balb/c nude mouse model. The effects of CFI-400945 were also evaluated in a BRCA2 knockout SK-UT-1 cell line. The mechanisms of DNA repair were analyzed using a DNA damage reporter assay. RESULTS: Uterine LMS had a high HR deficiency score, overexpressed PLK4 mRNA, and displayed mutations in genes responsible for DNA repair. CFI-400945 demonstrated effective antitumor activity in vitro and in vivo. The addition of AZD0156 resulted in drug synergism, largely due to a preference for nonhomologous end-joining (NHEJ) DNA repair. Compared to wild-type cells, BRCA2 knockouts were more sensitive to PLK4 inhibition when both HR and NHEJ repairs were impaired. CONCLUSIONS: Uterine LMS with DNA repair defects is sensitive to PLK4 inhibition because of the effects of chromosome missegregation and increased DNA damage. Loss-of-function BRCA2 alterations or pharmacological inhibition of ATM enhanced the efficacy of PLK4 inhibitor. Genomic profiling of an advanced-stage or recurrent uterine LMS may guide therapy.

The Malignant Potential of Ovarian Steroid Cell Tumors Revisited: A Multi-institutional Clinicopathologic Analysis of 115 Cases.

Steroid cell tumors (SCTs) of the ovary are rare and understudied, and as such, uncertainties remain about their malignant potential, as well as clinicopathologic predictors of patient outcome. Based on a multi-institutional cohort of cases, we present findings from the largest study of SCT reported to date. Clinicopathologic data were documented on 115 cases of SCT that were assembled from 17 institutions. The median patient age was 55 years (range: 9 to 84). When measured, preoperative androgen levels were elevated in 84.2% (48/57) of patients. A total of 111 (96.5%) cases were classified as stage I (103 stage IA; 2 stage IB; 6 stage IC). The stage distribution for the remaining 4 patients was as follows: stage II (n = 1), III (n = 3; 1 IIIA, 1 IIIB, 1 IIIC). The median tumor size was 3 cm (range: 0.2 to 22). Cytologic atypia, microscopic tumor necrosis, microscopic tumor hemorrhage, and a mitotic index of >1 mitotic figure/10 high-power fields were present in 52% (60/115), 9.6% (11/115), 37% (43/115), and 19% (22/115) of cases, respectively. Of 115 patients, 7 (6.1%) recurred postexcision, 4 (3.5%) ultimately died of disease, and 10 (8.7%) either recurred, died of disease, or were advanced stage at presentation. The median duration to recurrence postresection was 33 months (range: 23 to 180). Four of the 7 recurrences were stage IA at baseline. Tumor size >4 cm, International Federation of Gynecology and Obstetrics (FIGO) stage ≥IB, tumor necrosis, and tumor hemorrhage were each significantly associated with reduced recurrence-free survival in log-rank tests and univariable Cox models, with age older than 65 years being of marginal significance (hazard ratio [HR]: 5.4, 95% CI: 1.0-30.0, P = 0.05). Multivariable analyses suggested that FIGO stage ≥IB (HR: 27.5, 95% CI: 2.6-290.5), and age older than >65 years (HR: 21.8, 95% CI: 1.6-303.9) were the only parameters that were independently associated with recurrence. Cross-section analyses showed that tumor necrosis, tumor hemorrhage, and larger tumor size were significantly associated with a FIGO stage ≥IB status, which bolstered the conclusion that they are not independent predictors of recurrence. In summary, <10% of SCTs are clinically malignant, a substantially lower frequency than has previously been reported in the literature. Clinicopathologic predictors of patient outcomes that are prospectively applicable in practice could not be definitively established. Recurrences may occur many years (up to 15 y in this study) after primary resection, even in stage IA cases.

Detection rates and factors affecting thereof in endometrial hyperplasia, endometrial carcinoma, and cervical glandular lesions on cervical smear.

INTRODUCTION: Endometrial lesions are morphologically diverse and uncommon on cervical smears, with its detection rate and associated diagnostic categories uncharacterized. In this study, cervical smears matched to histologically proven endometrial hyperplasias and carcinomas were reviewed and compared with cervical in-situ-carcinomas/carcinomas, aiming to detail the diagnostic performance of cervical smears for upper tract and glandular lesions. METHODS: Pathology reports of cervical smears, hysterectomies, endometrial and cervical biopsies from 1995 to 2021 were retrieved. Diagnoses of cervical smears were matched to endometrial hyperplasias and carcinomas, or cervical carcinomas and reviewed. RESULTS: Totally 832 cervical smears (272 cervical carcinomas, 312 endometrial carcinomas, and 248 hyperplasias) were included. Considering all cytologic glandular diagnosis as positive, the detection rate of cervical adenocarcinoma-in-situ was the highest (64.3%), followed by cervical adenocarcinoma (63.8%), endometrial carcinoma (31.7%), and hyperplasia (with atypia-8.5%; without atypia-2.3%) (p < 0.001). Endometrial hyperplasia was most often diagnosed as atypical squamous cells of undetermined significance (ASCUS) (5.0%) or atypical glandular cells, not otherwise specified (3.6%) without indication of endometrial origin. For endometrial carcinomas, higher FIGO grading and endocervical involvement were associated with higher detection rates across all diagnostic categories (p = 0.002-0.028). High FIGO grade was associated with suspicious/favor neoplastic (C4) (31.1%vs10.3%, p < 0.001) and carcinoma (C5) (17.8% vs. 5.6%, p = 0.005) categories, but not for all glandular diagnoses combined (33.3% vs. 31.0%, p = 0.761). CONCLUSION: Detection rates for endometrial lesions are lower than cervical lesions but not insignificant. Endometrial hyperplasia should be recognized as a differential of human papilloma virus-negative ASCUS and prompt consideration of investigation of the upper genital tract.

Clinical Behavior and Molecular Landscape of Stage I p53-Abnormal Low-Grade Endometrioid Endometrial Carcinomas.

PURPOSE: The clinical significance of the p53-abnormal (p53abn) molecular subtype in stage I low-grade endometrioid endometrial carcinoma (EEC) is debated. We aimed to review pathologic and molecular characteristics, and outcomes of stage I low-grade p53abn EEC in a large international cohort. EXPERIMENTAL DESIGN: Previously diagnosed stage I p53abn EC (POLE-wild-type, mismatch repair-proficient) low-grade EEC from Canadian retrospective cohorts and PORTEC-1&2 trials were included. Pathology review was performed by six expert gynecologic pathologists blinded to p53 status. IHC profiling, next-generation sequencing, and shallow whole-genome sequencing was performed. Kaplan-Meier method was used for survival analysis. RESULTS: We identified 55 stage I p53abn low-grade EEC among 3,387 cases (2.5%). On pathology review, 17 cases (31%) were not diagnosed as low-grade EEC by any pathologists, whereas 26 cases (47%) were diagnosed as low-grade EEC by at least three pathologists. The IHC and molecular profile of the latter cases were consistent with low-grade EEC morphology (ER/PR positivity, patchy p16 expression, PIK3CA and PTEN mutations) but they also showed features of p53abn EC (TP53 mutations, many copy-number alterations). These cases had a clinically relevant risk of disease recurrence (5-year recurrence-free survival 77%), with pelvic and/or distant recurrences observed in 12% of the patients. CONCLUSIONS: A subset of p53abn EC is morphologically low-grade EEC and exhibit genomic instability. Even for stage I disease, p53abn low-grade EEC are at substantial risk of disease recurrence. These findings highlight the clinical relevance of universal p53-testing, even in low-grade EEC, to identify women at increased risk of recurrence.

Endometriosis-associated serous borderline tumor and endometrial stromal sarcoma of the ovary: a report of a rare lesion in an infant.

Endometriosis in infancy is most unusual, and associated tumors in this age group are exceptionally rare. We report a case of a serous borderline tumor and endometrial stromal sarcoma arising in an ovarian endometriotic cyst. The patient was an infant of 18 months of age who presented with an incidental abdominal mass. The serum sex hormones were at prepubertal levels. There was no evidence of precocious puberty or any obvious genital anomaly. Intraoperative findings included a solitary solid and multicystic right ovarian mass without evidence of any extraovarian disease. On microscopic examination, the tumor was composed of an intimate mixture of florid papillary and stromal cell proliferation in the wall of an endometriotic cyst. The papillae showed hierarchical branching and had hyalinized and edematous cores with scattered psammoma bodies. The epithelial cells were mildly atypical and mitotically inactive. The underlying endometrial stromal cells were arranged in irregular tongues that permeated the thickened fibrous cyst wall. They were mitotically active and immunoreactive for CD10. There was no evidence of any primitive germ cell tumor. The patient received no adjuvant treatment and had an uneventful postoperative follow-up period of 30 months. To the best of our knowledge, endometriosis associated with this most unusual combination of ovarian tumors has never been reported in an infant.

Endometrial Cancer: An Update on Prognostic Pathologic Features and Clinically Relevant Biomarkers.

The prognosis of endometrial cancers has historically been determined by the evaluation of histologic typing, grading, and staging. Recently, molecular classification, pioneered by the 4 prognostic categories from The Cancer Genome Atlas Research Network, has been shown to independently predict the outcome, correlate with biomarker expression, and predict response to adjuvant chemotherapy. In modern-day pathology practice, it has become necessary to integrate the time-honored prognostic pathologic features with molecular classification to optimize patient management. In this review, the significance of the molecular classification of endometrioid carcinomas, the application of practical diagnostic surrogate algorithms, and interpretation of test results will be addressed. Histologic features and theragnostic biomarkers will also be discussed in relation to the molecular subtypes of endometrial cancers.

Tissue Characteristics of Endometrial Carcinoma Analyzed by Quantitative Synthetic MRI and Diffusion-Weighted Imaging.

BACKGROUND: This study investigates the association of T1, T2, proton density (PD) and the apparent diffusion coefficient (ADC) with histopathologic features of endometrial carcinoma (EC). METHODS: One hundred and nine EC patients were prospectively enrolled from August 2019 to December 2020. Synthetic magnetic resonance imaging (MRI) was acquired through one acquisition, in addition to diffusion-weighted imaging (DWI) and other conventional sequences using 1.5T MRI. T1, T2, PD derived from synthetic MRI and ADC derived from DWI were compared among different histopathologic features, namely the depth of myometrial invasion (MI), tumor grade, cervical stromal invasion (CSI) and lymphovascular invasion (LVSI) of EC by the Mann-Whitney U test. Classification models based on the significant MRI metrics were constructed with their respective receiver operating characteristic (ROC) curves, and their micro-averaged ROC was used to evaluate the overall performance of these significant MRI metrics in determining aggressive histopathologic features of EC. RESULTS: EC with MI had significantly lower T2, PD and ADC than those without MI (p = 0.007, 0.006 and 0.043, respectively). Grade 2-3 EC and EC with LVSI had significantly lower ADC than grade 1 EC and EC without LVSI, respectively (p = 0.005, p = 0.020). There were no differences in the MRI metrics in EC with or without CSI. Micro-averaged ROC of the three models had an area under the curve of 0.83. CONCLUSIONS: Synthetic MRI provided quantitative metrics to characterize EC with one single acquisition. Low T2, PD and ADC were associated with aggressive histopathologic features of EC, offering excellent performance in determining aggressive histopathologic features of EC.

A Selective ß-Catenin-Metadherin/CEACAM1-CCL3 Axis Mediates Metastatic Heterogeneity upon Tumor-Macrophage Interaction.

Tumor heterogeneity plays a key role in cancer relapse and metastasis, however, the distinct cellular behaviors and kinetics of interactions among different cancer cell subclones and the tumor microenvironment are poorly understood. By profiling an isogenic model that resembles spontaneous human ovarian cancer metastasis with an highly metastatic (HM) and non-metastatic (NM) tumor cell pair, one finds an upregulation of Wnt/ß-catenin signaling uniquely in HM. Using humanized immunocompetent mice, one shows for the first time that activated ß-catenin acts nonautonomously to modulate the immune microenvironment by enhancing infiltrating tumor-associated macrophages (TAM) at the metastatic site. Single-cell time-lapse microscopy further reveals that upon contact with macrophages, a significant subset of HM, but not NM, becomes polyploid, a phenotype pivotal for tumor aggressiveness and therapy resistance. Moreover, HM, but not NM, polarizes macrophages to a TAM phenotype. Mechanistically, ß-catenin upregulates cancer cell surface metadherin, which communicates through CEACAM1 expressed on macrophages to produce CCL3. Tumor xenografts in humanized mice and clinical patient samples both corroborate the relevance of enhanced metastasis, TAM activation, and polyploidy in vivo. The results thus suggest that targeting the ß-catenin-metadherin/CEACAM1-CCL3 positive feedback cascade holds great therapeutic potential to disrupt polyploidization of the cancer subclones that drive metastasis.

Solitary Fibrous Tumors of the Female Genital Tract: A Study of 27 Cases Emphasizing Nonvulvar Locations, Variant Histology, and Prognostic Factors.

We report 27 solitary fibrous tumors of the female genital tract emphasizing nonvulvar locations, variant histology, and prognostic factors. The patients ranged from 25 to 78 years (most were over 40), and tumors occurred in the vulva (7), vagina (2), cervix (2), corpus (6), fallopian tube/paratubal soft tissue (5), and ovary (5). They ranged from 1.5 to 39 (mean=10.5) cm and were typically solid, but 4 were predominantly cystic. All had a haphazard arrangement of spindled to ovoid cells, with most demonstrating alternating cellular and hypocellular areas and prominent vessels, but 13 lacked hypocellular areas, and 7 had focal diffuse growth with inconspicuous vasculature. Other patterns included corded (8), fascicular (5), trabecular (1), and nested (1). Microcysts (6), myxoid background (8), hyalinization (8), lipomatous differentiation (2), and multinucleated cells (6) were also present, and 10 tumors had necrosis. Vasculature included thin-walled branching "staghorn" (27), thick-walled (7), and hyalinized vessels (5) or dilated anastomosing vascular channels (3). Nuclear atypia ranged from mild (19), moderate (7), to severe (1), and mitoses from 0 to 24/10 HPF (mean=4). STAT6 was positive in all 25 tumors tested. One tumor showed dedifferentiation; the remainder were classified as benign (19) or malignant (7) based on mitotic rate (univariate stratification model) and as low risk (14), intermediate risk (8), or high risk (4) based on the Demicco multivariate risk stratification score. Follow-up (median=23 mo) was available for 16 patients. Six tumors recurred (2 intermediate risk, 3 high risk, and the dedifferentiated tumor), 5 in the abdomen; the dedifferentiated tumor metastasized to the lung. Multivariate risk stratification was superior to univariate classification, as 5 "benign" tumors were reclassified as intermediate risk using the multivariate model; of these, 2 recurred, and 1 patient died of disease. Upper female genital tract tumors occurred in older patients, were larger, and more frequently classified as high risk compared with those of the lower tract. A trend toward increased cellularity was also seen in the upper tract tumors. Only size (P=0.04), necrosis (P=0.04), and Demicco score (P=0.01) independently correlated with recurrence. Female genital tract solitary fibrous tumors demonstrate a wide range of variant morphologies and occur in diverse sites in addition to the vulva. Tumors were often misdiagnosed as other neoplasms; thus, awareness of solitary fibrous tumors occurring at these sites is crucial in prompting staining for STAT6 to establish this diagnosis. The Demicco risk stratification system effectively predicts behavior.

Uterine smooth muscle tumors other than the ordinary leiomyomas and leiomyosarcomas: a review of selected variants with emphasis on recent advances and unusual morphology that may cause concern for malignancy.

Uterine smooth muscle tumors are classified according to their morphologic features that include architecture, growth pattern, cellular characteristics and constituents of the intercellular stroma. While terminologies used for the pathologic diagnosis of various subtypes may be eloquent and histologically accurate, some of these are confusing for the clinician and may also be open to interpretation by different pathologists: the labeling of atypical leiomyomas epitomizes this intricate system. Clinically, it is probably more useful to classify them as either tumors with or tumors without recurrent and/or metastatic potential. The term "atypical leiomyoma" has been used to label tumors that have a low risk of recurrence and is synonymous with benign tumors. The latter are known variously as leiomyoma with bizarre nuclei, symplastic leiomyoma, or pleomorphic leiomyoma. Variants of benign uterine smooth muscle tumors, such as mitotically active leiomyoma, cellular and highly cellular leiomyoma, epithelioid leiomyoma, and myxoid leiomyoma each have distinctive hallmarks that enable subclassification. Nevertheless, they may occasionally possess one or more unusual features that are cause for alarm. Tumors that have a dissecting growth pattern, with or without extrauterine extension, may mimic malignancy both grossly and microscopically. The current review discusses the pathologic diagnosis of and terminology applied to selected variants of uterine smooth muscle tumors other than the ordinary leiomyomas and leiomyosarcomas with emphasis on unusual reported features that may indicate malignancy. This includes an update on uterine smooth muscle tumor of uncertain malignant potential (STUMP), intravenous leiomyomatosis, benign metastasizing leiomyoma, and diffuse leiomyomatosis. Their clinicopathologic features, differential diagnoses, and management options based on findings in the previously reported cases will also be reviewed.