Racial Differences in Androgen Receptor (AR) and AR Splice Variants (AR-SVs) Expression in Treatment-Naïve Androgen-Dependent Prostate Cancer.

Androgen receptor splice variants (AR-SVs) contribute to the aggressive growth of castration-resistant prostate cancer (CRPC). AR-SVs, including AR-V7, are expressed in ~30% of CRPC, but minimally in treatment-naïve primary prostate cancer (PCa). Compared to Caucasian American (CA) men, African American (AA) men are more likely to be diagnosed with aggressive/potentially lethal PCa and have shorter disease-free survival. Expression of a truncated AR in an aggressively growing patient-derived xenograft developed with a primary PCa specimen from an AA patient led us to hypothesize that the expression of AR-SVs could be an indicator of aggressive growth both in PCa progression and at the CRPC stage in AA men. Tissue microarrays (TMAs) were created from formalin-fixed paraffin-embedded (FFPE) prostatectomy tumor blocks from 118 AA and 115 CA treatment-naïve PCa patients. TMAs were stained with AR-V7-speicifc antibody and with antibodies binding to the N-terminus domain (NTD) and ligand-binding domain (LBD) of the AR. Since over 20 AR-SVs have been identified, and most AR-SVs do not as yet have a specific antibody, we considered a 2.0-fold or greater difference in the NTD vs. LBD staining as indication of potential AR-SV expression. Two AA, but no CA, patient tumors stained positively for AR-V7. AR staining with NTD and LBD antibodies was robust in most patients, with 21% of patients staining at least 2-fold more for NTD than LBD, indicating that AR-SVs other than AR-V7 are expressed in primary treatment-naïve PCa. About 24% of the patients were AR-negative, and race differences in AR expression were not statistically significant. These results indicate that AR-SVs are not restricted to CRPC, but also are expressed in primary PCa at higher rate than previously reported. Future investigation of the relative expression of NTD vs. LBD AR-SVs could guide the use of newly developed treatments targeting the NTD earlier in the treatment paradigm.

High grade sarcoma with chondrosarcomatous differentiation in primary uterine leiomyosarcoma; A rare case and review of literature.

Primary uterine leiomyosarcoma (LMS) with chondrosarcomatous differentiation is extremely rare. We report a case of a 68-year-old, African American woman who presented with postmenopausal bleeding. Ultrasonography (USG) revealed multiple uterine fibroids. Total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH/BSO) was performed. Microscopic examination of the largest intramural nodule showed high-grade sarcoma, comprising of LMS with a focal transformation to undifferentiated sarcoma with chondrosarcomatous differentiation. Endometrium was benign excluding carcinosarcoma. Heterologous differentiation has rarely been described in metastatic or recurrent uterine LMS; however, a primary uterine LMS with chondrosarcomatous differentiation has not been reported previously.

HBME1 and CK19 expression in non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) vs other follicular patterned thyroid lesions.

BACKGROUND: Thyroid neoplasms with follicular architecture can have overlapping morphologic features and pose diagnostic confusion among pathologists. Various immunohistochemical stains have been investigated as potential diagnostic markers for PTC, among which HBME1 and CK19 have gained popularity. Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) poses similar diagnostic challenges with interobserver variability and is often misdiagnosed as adenomatoid nodule or follicular adenoma. This study aims to evaluate expression of HBME1 and CK19 in NIFTPs in comparison to other well-differentiated thyroid neoplasms and benign mimickers. METHOD: Seventy-three thyroid cases diagnosed over a period of 3 years at Methodist University Hospital, Memphis, TN, USA, were included in this study: 9 NIFTP; 18 papillary thyroid carcinoma (PTC); 11 follicular variant of papillary thyroid carcinoma, invasive (I-FVPTC); 24 follicular adenomas (FA); and 11 multinodular goiters/adenomatoid nodules (MNG). A tissue microarray (TMA) was constructed and HBME1 and CK19 immunohistochemistry was performed. RESULTS: 77.8% of NIFTPs, 88.9% of PTCs, 81.8% of I-FVPTCs, 16.7% of FAs, and 18.2% of MNGs showed HBME-1 expression. 66.7% of NIFTPs, 83.3% of PTCs, 81.8% of I-FVPTCs, 33.3% of FAs, and 45.4% of MNGs expressed CK19. Difference in expression of HBME1 and CK19 was statistically significant for NIFTP vs FA (qualitative; p < 0.05) and NIFTP vs MNG (p < 0.05). No statistically significant difference was found for HBME1 in NIFTP vs PTC (conventional and FVPTC), p ≥ 0.2. Sensitivity of HBME1 and CK19 for NIFTP were 78% and 67%, ~ 88% each for PTC, and 89% and 100% for FVPTC, respectively, while specificity of HBME1 and CK19 for NIFTP were 53% each, ~ 62% each for PTC, and ~55% each for FVPTC. CONCLUSION: Our study indicated that HBME1 and CK19 are valuable markers in differentiating NIFTPs from morphologic mimics like follicular adenoma and adenomatoid nodules/multinodular goiter. While HBME1 and CK19 are both sensitive in diagnosing lesions with PTC-like nuclear features, CK19 stains a higher number of benign lesions in comparison to HBME1. No increase in sensitivity or specificity in diagnosis of NIFTP, PTC, or FVPTC was noted on combining the two antibodies.

SMARCA4 (BRG1) and SMARCB1 (INI1) expression in TTF-1 negative neuroendocrine carcinomas including merkel cell carcinoma.

SMARCA4 and SMARCB1 loss of function has been implicated in many different tumors. The objective of this study was to investigate the loss of BRG1 and INI1 expression in TTF-1 negative neuroendocrine carcinomas to see if they are analogous to small-cell carcinoma of the ovary, hypercalcemic type. The potential role of these tumor suppressor genes in high-grade neuroendocrine carcinoma largely remains unknown. Cases of previously diagnosed Small cell carcinoma (SmCC), Large cell neuroendocrine carcinoma (LCNEC) and Merkel cell carcinoma (MCC) were selected. Immunohistochemical expression patterns for BRG1 and INI1 were interpreted as: intact, hybrid and complete loss of nuclear staining. SmCC and LCNEC cases were divided as TTF-1 positive and TTF-1 negative subsets. One case of TTF-1 negative SmCC (lung) showed loss of SMARCA4(BRG1) expression. Amongst TTF-1 negative LCNEC, one case (lung) showed complete loss of SMARCA4(BRG1) and partial loss of SMARCB1(INI1) and one case (lymph node) had hybrid expression of SMARCA4(BRG1) with intact SMARCB1(INI1) expression. All TTF-1 positive cases and all MCC cases showed intact expression of SMARCA4(BRG1) and SMARCB1(INI1). Our study highlights that SMARCA4(BRG1) is deficient in a subset of NEC. Inactivation of SMARCA4 in a subset of TTF-1 negative neuroendocrine carcinomas especially of pulmonary site can be further studied for their therapeutic response to targeted therapy e.g. EZH2 inhibitors. In addition, our study is the first to show that BRG1 and INI1 expression are intact in MCC and hence the biology of MCC might be completely exclusive of these two tumor suppressor genes.

Diagnostic Challenges of Dermatofibrosarcoma Protuberans (DFSP), a Rare Spindle Cell Tumor of Breast.

Dermatofibrosarcoma protuberans (DFSP) is a low-grade, fibroblastic tumor that is rarely seen in the breast with only a few cases reported in the literature. DFSP poses a diagnostic challenge as there is significant cytomorphological overlap with other spindle cell lesions. We report a case of a 42-year-old female who presented with a nodule in the right breast. Histology revealed a hypercellular lesion composed of spindle cells infiltrating the fat. A diagnosis of spindle cell lipoma was made. However, two years later, the patient developed a recurrent mass in the right breast that was histologically consistent with DFSP with a predominant myxoid stroma obscuring the characteristic storiform architecture with a focal component of giant cell fibroblastoma. A careful histomorphological examination is warranted as DFSP tends to recur if not completely excised.

Hobnail cells in encapsulated papillary thyroid carcinoma: Report of 2 cases with immunohistochemical and molecular findings and literature analysis.

Papillary thyroid carcinoma (PTC) is the most common malignant tumor of the thyroid gland with most tumors behaving in an indolent fashion. However, morphologic variants have been described, such as tall cell, diffuse sclerosing, columnar cell etc. which are biologically more aggressive. One of these variants includes the more recently described hobnail variant (HVPTC) which shows micropapillae and presence of large cells with apically placed hyperchromatic nuclei, reverse polarity, and eosinophilic cytoplasm, akin to hobnail cells. The presence of >30% hobnail cells in a PTC deserves categorization as a hobnail variant. This variant is usually associated with extra thyroidal extension, lymphovascular invasion and lymph node metastasis. We describe the pathologic and molecular features of two cases of encapsulated PTC with hobnail cells in a 68 year old male and a 22 year old female (30% and 10% hobnail cells respectively). Both cases presented as low stage (pT2) tumors and showed no aggressive features like lymph node metastasis, or extrathyroidal extension (ETE) at the time of presentation. Tumors in both cases showed presence of BRAFV600E mutation, absence of RAS and/or TP53 mutations, and were negative for RET and PAX88/PPARG gene rearrangements.