Ovarian cancer modulates the immunosuppressive function of CD11b(+)Gr1(+) myeloid cells via glutamine metabolism

OBJECTIVE: Immature CD11b(+)Gr1(+) myeloid cells that acquire immunosuppressive capability, also known as myeloid-derived suppressor cells (MDSCs), are a heterogeneous population of cells that regulate immune responses. Our study\u27s objective was to elucidate the role of ovarian cancer microenvironment in regulating the immunosuppressive function of CD11b(+)Gr1(+) myeloid cells. METHODS: All studies were performed using the intraperitoneal ID8 syngeneic epithelial ovarian cancer mouse model. Myeloid cell depletion and immunotherapy were carried out using anti-Gr1 mAb, gemcitabine treatments, and/or anti PD1 mAb. The treatment effect was assessed by survival curve, in situ luciferase-guided imaging, and histopathologic evaluation. Adoptive transfer assays were carried out between congenic CD45.2 and CD45.1 mice. Immune surface and intracellular markers were assessed by flow cytometry. ELISA, western blot, and RT-PCR techniques were employed to assess protein and RNA expression of various markers. Bone marrow-derived myeloid cells were used for ex-vivo studies. RESULTS: Depletion of Gr1(+) immunosuppressive myeloid cells alone and in combination with anti-PD1 immunotherapy inhibited ovarian cancer growth. These findings, in addition to the adoptive transfer studies, validated the role of immunosuppressive CD11b(+)Gr1(+) myeloid cells in promoting ovarian cancer. Mechanistic investigations showed that ID8 tumor cells and their microenvironment produced both recruitment and regulatory factors for immunosuppressive CD11b(+)Gr1(+) myeloid cells. CD11b(+)Gr1(+) myeloid cells primed by ID8 tumors showed increased immunosuppressive marker expression and acquired an energetic metabolic phenotype promoted mainly by increased oxidative phosphorylation fueled by glutamine. Inhibiting the glutamine metabolic pathway reduced the increased oxidative phosphorylation and decreased immunosuppressive markers expression and function. Dihydrolipoamide succinyl transferase (DLST), a subunit of α-KGDC in the TCA cycle, was found be the most significantly elevated gene in tumor primed myeloid cells. Inhibition of DLST reduced oxidative phosphorylation, immunosuppressive marker expression, and function in myeloid cells. CONCLUSION: Our study shows that the ovarian cancer microenvironment can regulate the metabolism and function of immunosuppressive CD11b(+)Gr1(+) myeloid cells and modulate its immune microenvironment. Targeting glutamine metabolism via DLST in those immunosuppressive myeloid decreased their activity, leading to a reduction in the immunosuppressive tumor microenvironment. Thus, targeting glutamine metabolism has the potential to enhance the success of immunotherapy in ovarian cancer

Multiplicity of benign breast disease lesions and breast cancer risk in African American women

The risk of developing subsequent breast cancer is higher in women diagnosed with benign breast disease (BBD) but these studies were primarily performed in non-Hispanic white populations. Still, these estimates have been used to inform breast cancer risk models that are being used clinically across all racial and ethnic groups. Given the high breast cancer mortality rates among African American (AA) women, it is critical to study BBD in this population, to ensure the risk models that include this information perform adequately. This study utilized data from AA women who underwent benign breast biopsies at a hospital served by the University Pathology Group in Detroit, Michigan, from 1998 to 2010. Patients were followed for subsequent breast cancers through the population-based Metropolitan Detroit Cancer Surveillance System (MDCSS). BBD lesion scores were assigned to represent the severity or extent of benign breast lesions, with higher scores indicating a greater number of distinct lesion types. Of 3,461 eligible AA women with BBD in the cohort, 6.88% (n=238) subsequently developed breast cancer. Examined individually, six of the eleven lesions (apocrine metaplasia, ductal hyperplasia, lobular hyperplasia, intraductal papilloma, sclerosing adenosis, columnar alterations and radial scars) were significantly associated with increased risk of breast cancer after adjustment for age and year of biopsy and were further considered in multiple lesion models. For every different type of benign breast lesion, subsequent risk of breast cancer increased by 25% (RR=1.25, 95% CI: 1.10, 1.42) after adjustment for age at biopsy and proliferative versus non-proliferative disease. In summary, this study affirms the increased breast cancer risk in AA women with BBD, particularly in those with multiple lesions. These findings have implications for the management of breast cancer risk in millions of women affected by BBD, a high risk group that could benefit from personalized surveillance and risk reduction strategies

Exceptional pathologic complete response achieved with androgen deprivation and docetaxel therapy in Gleason 10 prostate cancer

Pathologic complete response is an exceptionally rare occurrence in prostate cancer, especially in the setting of poorly differentiated cancer, with high risk and poor prognostic features. Patient reviewed and signed an informed consent. The case details were collected.Patient had PSA of 52.6 ng/dl and Gleason score 5 + 5 = 10 prostate adenocarcinoma with focal signet ring cell pattern. Genomic testing revealed pathogenic p53 and SPOP mutations. The patient received androgen deprivation therapy and six cycles of docetaxel. His PSA declined to undetectable, and radical prostatectomy (RP) showed no evidence of malignancy. The patient has discontinued all therapy and continues in remission 12 months after surgery

Myxoid dermatofibrosarcoma protruberans of the scrotum: A rare diagnosis in an unreported location

Dermatofibrosarcoma Protuberans (DFSP) represents a low grade, locally aggressive mesenchymal neoplasm with characteristic clinicopathologic, immunohistochemical, and molecular findings. Myxoid DFSP is an uncommon variant, with only few cases reported in the literature and may present a diagnostic challenge on histopathologic examination. We report the first case of myxoid DFSP arising in the scrotum of a 38 year-old man and describe the morphologic and immunohistochemical findings. Recognition of this variant at unusual sites is clinically important because the differential diagnosis includes benign and malignant tumors which could lead to under or over-treatment

Predictive histologic factors in carcinosarcomas of the uterus

Uterine carcinosarcomas are rare aggressive biphasic neoplasms. Because ofits rarity, limited data are available on potential prognostic parameters. While severalstudies support that carcinomatous components predict outcomes, others do not. In thisstudy, we evaluated the clinical and histopathologic features of 196 uterinecarcinosarcomas to identify potential prognostic factors. Patients’ages ranged from 34to 95 yr (median, 68 yr). Seventy-three (38%) patients experienced tumor recurrenceduring follow-up. Tumors≥5 cm, outer half myometrial invasion, lymphovascularinvasion, lymph node metastasis, advanced stage (International Federation ofGynecology and Obstetrics stages III–IV), sarcomatous component on recurrence,sarcoma dominance, and positive cytology were significantly associated with shorterdisease-free interval (Po0.05). In addition, serous histology and rhabdomyoblasticdifferentiation was significantly associated with worse 3-yr overall survival. Our datasupports that both carcinomatous and sarcomatous components play a role in tumorprogression and survival of uterine carcinosarcoma patients, suggesting their equalimportance in guiding management decisions

Myoepithelial carcinoma of the posterior mediastinum: An uncommon site for a rare tumor

Myoepithelial carcinoma (MC) is a rare tumor that arises from myoepithelial cells; most commonly in the salivary glands, but other infrequent body sites such as the breast, lung, lower limb, upper limb, head and neck, vulva, and vagina can be involved. We report the first case of myoepithelial carcinoma arising in the posterior mediastinum of a 51 year-old male who presented with a mediastinal mass and subsequently underwent tumor debulking surgery. Grossly, the specimen consisted of multiple tan–gray firm fragments of tissue with an overall measurement of 7.0 cm in greatest dimension. Histologic examination revealed an ill-defined, infiltrative lesion with a biphasic cell population. The tumor cells were diffusely positive for epithelial and myoepithelial markers, confirming the above diagnosis. Recognition of this entity at an uncommon site may present a diagnostic challenge due to its morphologic heterogeneity and the differential diagnosis includes benign and malignant tumors, which could lead to over or under-treatment, respectively

The Impact of Androgen Receptor Expression on Endometrial Carcinoma Recurrence and Survival

Endometrial carcinomas (ECs) are the most common gynecologic cancers in the western world. The impact of androgen receptor (AR) on clinicopathologic parameters of EC is not well studied. The aim of our study is to assess the role of AR expression in ECs and correlate its expression with estrogen (ER) and progesterone (PR). A retrospective review of 261 EC was conducted. H&E slides were reviewed and clinicopathologic parameters were analyzed. Immunohistochemical stains for AR, ER, and PR were performed on a tissue microarray. The hormonal expression was evaluated and the data were analyzed using the Fisher exact test and Kaplan-Meier survival analysis. Patients\u27 age ranged from 31 to 91 (median=65 y). Type I EC included 202 endometrioid and 7 mucinous carcinoma, whereas type II included 34 serous, 16 carcinosarcoma, and 2 clear cell carcinoma. Although not significant, AR expression showed more frequent association with type I EC, early tumor stage (I-II), and low FIGO grade (1-2) EC. AR expression significantly correlated with absence of lymphovascular invasion (P=0.041) and decreased LN involvement (P=0.048). Patients with AR expression showed increased disease-free survival (208 vs. 165 mo, P=0.008) and late disease recurrence (P=0.009). AR expression had a positive significant correlation with PR (P\u3c0.001) and ER (P=0.037) expression. AR might play a role as a prognostic marker for ECs

Clear Cell Carcinoma of the Endometrium: Evaluation of Prognostic Parameters in a Multi-institutional Cohort of 165 Cases

OBJECTIVES: Clear cell carcinoma (CCC) comprises a rare yet an aggressive subtype, accounting for less than 5% of all uterine carcinomas. Several clinicopathologic features have been predictive of poor prognosis; however, data remain controversial. The aim of this study was to evaluate the clinicopathologic features of a multi-institutional cohort of endometrial CCC in order to identify which, if any, have prognostic significance. METHODS: Retrospective review of endometrial CCC diagnosed between 1995 and 2012 at 3 institutions was conducted to evaluate clinicopathologic parameters: age, race, tumor size, stage, myometrial invasion (MI), lymphovascular invasion, lymph node and adnexal involvement, adjuvant therapy, and outcomes. Data were analyzed using Fisher exact, Cox regression, and Kaplan-Meier analyses. RESULTS: Patients\u27 ages ranged from 36 to 90 years (median, 67 years). The median tumor size was 3.6 cm. Inner-half MI was present in 44%, lymphovascular invasion in 34%, adnexal involvement in 16%, and lymph node metastasis in 30% of cases. Fifty-eight percent of the patients presented with early-stage disease. The 5-year overall survival (OS) was 58%. Shorter disease-free interval (DFI) was significantly associated with older age at diagnosis (\u3e70 years), advanced-stage disease, adnexal involvement, and deep MI (P = 0.005, P = 0.001, P = 0.001, and P = 0.003, respectively). Patients who received adjuvant chemotherapy had a significantly worse DFI and 5-year OS (P = 0.001 and P = 0.001, respectively). A significantly shorter 5-year OS was noted with advanced stage (III-IV) and presence of adnexal involvement (P = 0.001 and P = 0.021, respectively). On Cox regression analysis, advanced-stage disease, older age, and adnexal involvement were significant independent predictors of worse DFI (P = 0.001, P = 0.005, and P = 0.019, respectively), whereas inner-half MI was a significant independent predictor of longer DFI (P = 0.004). Adjuvant radiotherapy alone was a significant independent predictor of better 5-year OS (P = 0.012). CONCLUSIONS: In our series of endometrial CCC, older age at diagnosis, advanced stage, deep MI, and adnexal involvement were independent poor prognostic factors. Adjuvant radiotherapy had a significant positive impact on 5-year OS

Clear Cell Carcinoma of the Endometrium: Evaluation of Prognostic Parameters in a Multi-institutional Cohort of 165 Cases.

OBJECTIVES: Clear cell carcinoma (CCC) comprises a rare yet an aggressive subtype, accounting for less than 5% of all uterine carcinomas. Several clinicopathologic features have been predictive of poor prognosis; however, data remain controversial. The aim of this study was to evaluate the clinicopathologic features of a multi-institutional cohort of endometrial CCC in order to identify which, if any, have prognostic significance. METHODS: Retrospective review of endometrial CCC diagnosed between 1995 and 2012 at 3 institutions was conducted to evaluate clinicopathologic parameters: age, race, tumor size, stage, myometrial invasion (MI), lymphovascular invasion, lymph node and adnexal involvement, adjuvant therapy, and outcomes. Data were analyzed using Fisher exact, Cox regression, and Kaplan-Meier analyses. RESULTS: Patients\u27 ages ranged from 36 to 90 years (median, 67 years). The median tumor size was 3.6 cm. Inner-half MI was present in 44%, lymphovascular invasion in 34%, adnexal involvement in 16%, and lymph node metastasis in 30% of cases. Fifty-eight percent of the patients presented with early-stage disease. The 5-year overall survival (OS) was 58%. Shorter disease-free interval (DFI) was significantly associated with older age at diagnosis (\u3e70 years), advanced-stage disease, adnexal involvement, and deep MI (P = 0.005, P = 0.001, P = 0.001, and P = 0.003, respectively). Patients who received adjuvant chemotherapy had a significantly worse DFI and 5-year OS (P = 0.001 and P = 0.001, respectively). A significantly shorter 5-year OS was noted with advanced stage (III-IV) and presence of adnexal involvement (P = 0.001 and P = 0.021, respectively). On Cox regression analysis, advanced-stage disease, older age, and adnexal involvement were significant independent predictors of worse DFI (P = 0.001, P = 0.005, and P = 0.019, respectively), whereas inner-half MI was a significant independent predictor of longer DFI (P = 0.004). Adjuvant radiotherapy alone was a significant independent predictor of better 5-year OS (P = 0.012). CONCLUSIONS: In our series of endometrial CCC, older age at diagnosis, advanced stage, deep MI, and adnexal involvement were independent poor prognostic factors. Adjuvant radiotherapy had a significant positive impact on 5-year OS