Cell volume expansion and local contractility drive collective invasion of the basement membrane in breast cancer.

Breast cancer becomes invasive when carcinoma cells invade through the basement membrane (BM)-a nanoporous layer of matrix that physically separates the primary tumour from the stroma. Single cells can invade through nanoporous three-dimensional matrices due to protease-mediated degradation or force-mediated widening of pores via invadopodial protrusions. However, how multiple cells collectively invade through the physiological BM, as they do during breast cancer progression, remains unclear. Here we developed a three-dimensional in vitro model of collective invasion of the BM during breast cancer. We show that cells utilize both proteases and forces-but not invadopodia-to breach the BM. Forces are generated from a combination of global cell volume expansion, which stretches the BM, and local contractile forces that act in the plane of the BM to breach it, allowing invasion. These results uncover a mechanism by which cells collectively interact to overcome a critical barrier to metastasis.

Molecular classification and biomarkers of clinical outcome in breast ductal carcinoma in situ: Analysis of TBCRC 038 and RAHBT cohorts.

Ductal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We perform multiscale, integrated molecular profiling of DCIS with clinical outcomes by analyzing 774 DCIS samples from 542 patients with 7.3 years median follow-up from the Translational Breast Cancer Research Consortium 038 study and the Resource of Archival Breast Tissue cohorts. We identify 812 genes associated with ipsilateral recurrence within 5 years from treatment and develop a classifier that predicts DCIS or IBC recurrence in both cohorts. Pathways associated with recurrence include proliferation, immune response, and metabolism. Distinct stromal expression patterns and immune cell compositions are identified. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome.

Transition to invasive breast cancer is associated with progressive changes in the structure and composition of tumor stroma.

Ductal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor to invasive breast cancer (IBC). To understand the changes in the tumor microenvironment (TME) accompanying transition to IBC, we used multiplexed ion beam imaging by time of flight (MIBI-TOF) and a 37-plex antibody staining panel to interrogate 79 clinically annotated surgical resections using machine learning tools for cell segmentation, pixel-based clustering, and object morphometrics. Comparison of normal breast with patient-matched DCIS and IBC revealed coordinated transitions between four TME states that were delineated based on the location and function of myoepithelium, fibroblasts, and immune cells. Surprisingly, myoepithelial disruption was more advanced in DCIS patients that did not develop IBC, suggesting this process could be protective against recurrence. Taken together, this HTAN Breast PreCancer Atlas study offers insight into drivers of IBC relapse and emphasizes the importance of the TME in regulating these processes.

The endoplasmic reticulum stress marker, glucose-regulated protein-78 (GRP78) in visceral adipocytes predicts endometrial cancer progression and patient survival.

OBJECTIVE: Currently, accurately identifying endometrial cancer patients at high risk for recurrence remains poor. To ascertain if changes in the endoplasmic reticulum (ER) stress marker, glucose-regulated-protein-78 (GRP78) can serve as a prognosticator in endometrial cancer, we examined GRP78 expression in patient samples to determine its association with clinical outcome. METHODS: A retrospective cohort study was conducted in endometrial cancer patients. Archived specimens of visceral adipocytes and paired endometrial tumors were analyzed by immunohistochemistry for GRP78 and another ER stress marker, C/EBP homologous protein (CHOP). Expression of these markers was correlated with clinico-pathological information and outcomes. RESULTS: GRP78 expression in visceral adipocytes was detected in 95% of the 179 endometrial cancer patients with analyzable visceral adipocytes. Within individual samples, 24% of adipocytes (range, 0-90%, interquartile range 18%-38%) exhibited GRP78 expression. High visceral adipocyte GRP78 expression positively correlated with advanced-stage disease (p=0.007) and deep myometrial invasion (p=0.004). High visceral adipocyte GRP78 expression was significantly associated with decreased disease-free survival (DFS) in multivariate analyses (hazard ratio 2.88, 95% CI 1.37-6.04, p=0.005). CHOP expression paralleled the GRP78 expression in adipocytes (r=0.55, p<0.001) and in the tumor (p=0.018). CONCLUSIONS: Our study demonstrates that the ER stress markers, GRP78 and CHOP, are elevated in endometrial cancer patients. Furthermore, GRP78 expression levels in visceral adipocytes from these patients were significantly correlated to disease stage and patient survival. Our results demonstrate, for the first time, that the GRP78 levels in endometrial cancer patients may be a prognosticator and aid with clinical risk stratification and focused surveillance.

Primary clear cell carcinoid tumors of the vulva.

Neuroendocrine tumors are uncommon in the female genital tract and have been described in the ovary, uterus, cervix, and vagina. Primary carcinoid tumors have not been described in the vulva. We report 3 cases in 3 middle-aged women who presented with a solitary vulvar nodule without any other associated symptoms. All were treated with simple local excision. Two tumors were composed exclusively of clear cells arranged in nests separated by fibrovascular septae. The third tumor predominantly exhibited nests of eosinophilic granular cells with scattered areas of cells showing clear cytoplasm. Immunohistochemical staining for chromogranin and neuron-specific enolase confirmed neuroendocrine differentiation in all cases. Follow-up of 5.5 to 16 years showed no evidence of recurrence or metastasis. Primary clear cell carcinoid tumors of the vulva need to be considered in the differential diagnosis of vulvar masses with clear cell features. Immunohistochemistry plays an important role in the diagnosis of these lesions.

Endometriosis in para-aortic lymph nodes during pregnancy: case report and review of literature.

OBJECTIVE: To report a case of endometriosis in para-aortic lymph nodes during pregnancy. DESIGN: Case report. SETTING: Tertiary care center. PATIENT(S): A 25-year-old multipara pregnant woman with a history of chronic pelvic pain and ovarian cystectomies for bilateral endometriomas. INTERVENTION(S): The patient was admitted with a placenta previa and a subchorionic hemorrhage at 24 weeks 5 days' gestation, and subsequently developed uterine contractions. Magnetic resonance imaging revealed a large complex adnexal mass adherent to the uterus and pelvic and para-aortic lymphadenopathy. Tocolysis could not be achieved and the patient underwent cesarean delivery at 26 weeks 3 days. An implant on the uterus and an enlarged para-aortic lymph node were removed surgically at that time. MAIN OUTCOME MEASURE(S): Involvement of lymph node by endometriosis and presence of a recurrent endometrioma. RESULT(S): Endometriosis was confirmed pathologically in para-aortic lymph nodes. Uterine serosal biopsy demonstrated endometriosis, and the large adnexal cyst was grossly consistent with endometrioma. The patient delivered a viable male infant at 26 weeks 3 days. CONCLUSION(S): To our knowledge, this is the first reported case of endometriosis in para-aortic lymph nodes. Its presence supports the hypothesis that endometriosis travels lymphatically, and not simply via locoregional spread. Lymphatic spread also further supports the theory that endometriosis is an aggressive chronic systemic disease.

Synchronous ipsilateral Warthin tumor encased by a separate mucoepidermoid carcinoma of the parotid gland: a case report and review of the literature.

Fine-needle aspiration (FNA) is a cost effective and low morbidity procedure in the initial assessment of salivary gland tumors. However, cytological assessment of ipsilateral synchronous tumors (which make up less than 0.3% of all salivary gland neoplasms) may pose diagnostic challenges. Therefore, a wholesome approach, including FNA with clinical and radiological correlation, is of utmost importance. Here, we report a unique case of Warthin tumor encased by a separate high-grade mucoepidermoid carcinoma that was first diagnosed on FNA. Another striking feature seen was the presence of chronic sialadenitis in the surrounding nonneoplastic salivary gland. The presence of two different neoplasms in the background of chronic sialadenitis raises the question of a possible causal relationship. Traditionally, there has been diagnostic difficulty when dealing with synchronous tumors of the salivary gland and the background of chronic sialadenitis may further complicate the diagnosis. FNA is very helpful and can give important cues to the diagnosis.