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Histologic transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a well-recognized mechanism of resistance in -mutant adenocarcinoma upon treatment with TKIs, but rarely reported with programmed death1 (PD-1) inhibitors. We report two cases of potential transformation during treatment with PD-1 inhibitors. Case 1, a 65-year-old man was diagnosed with stage IVa lung adenocarcinoma on pleural fluid cytology. He received six cycles of carboplatin and pemetrexed, then maintained on pemetrexed. He had disease progression after nine cycles of pemetrexed and was switched to nivolumab. He progressed after five cycles of nivolumab. Core biopsy of the lung mass revealed SCLC. Case 2, a 68-year-old man was diagnosed with two primary NSCLCs and underwent resection. He had recurrence after several months and was treated with four cycles of carboplatin, paclitaxel, and pembrolizumab on clinical trial, with partial response. He was continued on pembrolizumab and had disease progression after 30 cycles. Biopsy of the new lesions showed SCLC. Histologic transformation from NSCLC to SCLC can be explained by the presence of a common cell precursor. Proposed molecular mechanisms include loss of , mutations, and amplification. The distinction between transformation and mixed histology tumors is challenging, especially when pathologic material used for the initial diagnosis is limited. The possibility of a second metachronous primary lung cancer cannot be excluded in our cases. Histologic transformation with PD-1 inhibitors could be under-recognized. Disease progression should prompt re-biopsy to uncover new histology and change in treatment. Future studies are needed to elucidate mechanisms and predictors of transformation.

Context.— Low interobserver diagnostic agreement exists among high-grade endometrial carcinomas. Objective.— To evaluate diagnostic variability in International Federation of Gynecology and Obstetrics (FIGO) grade 3 endometrioid adenocarcinoma (G3EC) in 2 different sign-out practices. Design.— Sixty-six G3EC cases were identified from pathology archives of Wayne State University (WSU, Detroit, Michigan) (general surgical pathology sign-out) and 65 from Memorial Sloan Kettering Cancer Center (MSK, New York, New York) (gynecologic pathology focused sign-out). Each case was reviewed together by 2 gynecologic pathologists, one from each institution, and classified into the G3EC group or a reclassified group. Clinicopathologic parameters were compared. Results.— Twenty-five WSU cases (38%) were reclassified as undifferentiated (n = 2), serous (n = 4), mixed endometrioid and serous carcinomas (n = 12), and FIGO grade 2 endometrioid adenocarcinomas with focal marked nuclear atypia (n = 7). Eleven MSK cases (17%) were reclassified as undifferentiated (n = 5), serous (n = 1), mixed endometrioid and serous carcinomas (n = 4), and mixed endometrioid and clear cell carcinomas (n = 1). Agreement rate between original and review diagnosis was 83% (54 of 65) at MSK and 62% (41 of 66) at WSU ( P = .01) with an overall rate of 73% (95 of 131). There were more undifferentiated carcinomas at MSK than there were at WSU (45% [5 of 11] versus 8% [2 of 25]; P = .02). There were more grade 2 endometrioid adenocarcinomas with focal, marked nuclear atypia at WSU (28%; 7 of 25) than there were at MSK (0%) ( P = .03). Mixed endometrioid and serous carcinoma was the most common misclassified subtype (44%; 16 of 36). Conclusion.— Moderate interobserver variability exists in the diagnosis of G3EC with a significantly greater diagnostic agreement rate in gynecologic pathology–focused sign-out than in general sign-out practice.

Neuroendocrine transdifferentiation of high-grade prostate cancer (PCA-NT) comprises a morphologic and immunophenotypic transition from conventional adenocarcinoma towards high-grade neuroendocrine/small cell carcinoma. This phenomenon is frequently observed post androgen deprivation and/or radiotherapy, but de novo instances are increasingly recognized. Herein, we report a series of de novo PCA-NT focusing on characteristic morphologic, immunophenotypic and clinical features. Treatment naïve PCA-NT were identified. IHC for PSA, NKX3.1, Chromogranin, Synaptophysin, Cyclin D1, RB and Ki67 were performed. Radiology, treatment and follow-up data were reviewed. Sixteen patients were included. Apart from focal areas of high-grade prostate cancer with acinar features (reminiscent of Grade Group 5 disease), extensive areas with sheets of cells with deep amphophilic/basophilic cytoplasm, enlarged, hyperchromatic nuclei with granular chromatin and inconspicuous to prominent nucleoli with high mitotic activity were identified. Immunohistochemistry showed patchy NKX3.1, patchy PSA, variable Synaptophysin and Chromogranin; RB and CyclinD1 showed loss of expression. Ki67 showed high proliferative index, in most cases. Adverse radiologic findings and metastases were documented in most cases. Two patients died of disease. De novo PCA-NT exhibits high-grade nuclei, high mitotic activity, reduced PSA expression with high Ki67 and functional inactivation of RB1 pathway, suggesting transition from androgen-driven to proliferation-driven phenotype. Most cases presented at advanced stage with adverse radiological findings, metastasis at time of diagnosis, and high mortality. In light of their prognostic and therapeutic implications, pathologists may need to maintain a sensitive threshold for performing immunostains–in particular, Ki67 and CyclinD1–when presented with such cases in their day to day clinical practice.

Background Fibroadenomas are common benign breast lesions, and studies of European American women indicate a persistent, increased risk of breast cancer after diagnosing a fibroadenoma on biopsy. This association has not been independently assessed in African American women, despite reports that these women are more likely to present with fibroadenomas. Methods The study cohort included 3853 African American women with a breast biopsy completed between 1997 and 2010 in metropolitan Detroit. Biopsies were microscopically reviewed for benign breast lesions, including fibroadenoma, proliferative disease, and atypia. Risk of breast cancer within the cohort was estimated using relative risk ratios and 95% CIs calculated using multivariable log-binomial regression. Relative risk of breast cancer in this cohort compared with African American women in the broader metropolitan Detroit population was estimated using standardized incidence ratios (SIRs). Results Fibroadenomas occurred more frequently in biopsies of younger women, and other types of benign breast lesions were less likely to occur when a fibroadenoma was present ( p  = 0.008 for lobular hyperplasia; all other p values < 0.01). Unlike women with other benign lesions (SIR, 1.41; 95% CI, 1.20, 1.66), women with fibroadenomas did not have an increased risk of developing breast cancer compared with the general population (SIR, 0.94; 95% CI, 0.75, 1.18). Biopsies that indicated a fibroadenoma were associated with a reduced risk of breast cancer after adjusting for age at biopsy, proliferation, and atypia (relative risk, 0.67; 95% CI, 0.48, 0.93) compared with biopsies without a fibroadenoma. Conclusions These findings have important implications for breast cancer risk models and clinical assessment, particularly among African American women, in whom fibroadenomas are common.

A variety of glandular and clear cell lesions may be seen in the urinary bladder and/or urethra, ranging from benign to malignant primary and secondary tumors. Lesions with no malignant potential include reactive processes, such as nephrogenic metaplasia, and may show similar morphologic features as an infiltrative neoplasm, particularly in small biopsies. Similarly, ectopic tissues of Müllerian origin may be seen in the lower urinary tract, and their distinction from a true glandular neoplasm is essential to avoid overtreatment. A wide variety of primary and secondary malignant tumors exist with varying degrees of glandular and clear cell features. Therefore, surgical pathologists must be aware of the full scope of possible lesions to avoid misdiagnosis. To provide a practical framework for approaching the diagnosis of clear cell and glandular lesions of the urinary bladder/urethra and prostate, highlighting the strengths and limitations of various diagnostic features and ancillary tests. A review of the current literature was performed to obtain data regarding up-to-date diagnostic features and ancillary studies. In summary, distinct morphologic and immunohistochemical features and clinical and radiologic correlation are essential to establish an accurate diagnosis when such cases with glandular and clear features are encountered in the lower urinary tract.

ObjectivesClear 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.MethodsRetrospective 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.ResultsPatients’ 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 (>70 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).ConclusionsIn 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.

BackgroundSARS-CoV-2 is a highly contagious virus that causes the disease COVID-19. We have recently reported that androgens regulate the expression of SARS-CoV-2 host entry factors ACE2 and TMPRSS2, and androgen receptor (AR) in lung epithelial cells. We also demonstrated that the transcriptional repression of the AR enhanceosome inhibited SARS-CoV-2 infection in vitro.MethodsTo better understand the various sites of SARS-CoV-2 infection, and presence of host entry factors, we extensively characterized the tissue distribution and localization of SARS-CoV-2 virus, viral replication, and host entry factors in various anatomical sites sampled via autopsy. We applied RNA in-situ-hybridization (RNA-ISH), immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) approaches. We also assessed histopathological changes in SARS-CoV-2 infected tissues.ResultsWe detect SARS-CoV-2 virus and viral replication in pulmonary tissues by RNA-ISH and IHC and a variety of non-pulmonary tissues including kidney, heart, liver, spleen, thyroid, lymph node, prostate, uterus, and colon by qRT-PCR. We observe heterogeneity in viral load and viral cytopathic effects among various organ systems, between individuals and within the same patient. In a patient with a history of kidney transplant and under immunosuppressant therapy, we observe an unusually high viral load in lung tissue by RNA-ISH, IHC and qRT-PCR. SARS-CoV-2 virus is also detected in this patent’s kidney, liver and uterus. We find ACE2, TMPRSS2 and AR expression to overlap with the infection sites.ConclusionsThis study portrays the impact of dispersed SARS-CoV-2 infection in diverse organ systems, thereby facilitating avenues for systematic therapeutic approaches.Plain language summaryTo understand SARS-CoV-2 infection of human organs, we characterized the tissue distribution of SARS-CoV-2 virus, and the presence of host factors that enable the virus to enter cells, in postmortem tissues from six patients who had COVID-19. We assessed the presence of SARS-CoV-2 viral RNA and the expression of human genes that facilitate virus entry in host cells, using several techniques. We observed that SARS-CoV-2, and factors that facilitate virus entry in host cells, were present in the same location in pulmonary and multiple nonpulmonary tissues, including lung, bronchus, trachea, kidney, heart, liver, spleen, thyroid, lymph node, prostate, uterus, and colon. We also reported changes in the microscopic appearance of SARS-CoV-2 infected tissues at various sites. Such findings will guide future coronavirus biology studies on patients with advanced disease.