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A 57-year-old man developed a mesothelial proliferation in the peritoneum, several months after he was diagnosed with biopsy-proven epithelioid mesothelioma of the pleura and having undergone several treatments with checkpoint inhibitor immunotherapy. The differential diagnosis was metastatic mesothelioma from the lung primary, versus a reactive process. A diagnosis of atypical mesothelial proliferation was made. Follow-up CT showed no evidence of abdominal disease 5 months later. The complication of serositis following checkpoint inhibitor therapy is reviewed, as well as the differential diagnosis between reactive mesothelial hyperplasia and epithelioid mesothelioma.

The aim of the review is to provide an update on the current and evolving approaches to diagnosing the challenging clinical entity of renal oncocytoma.Renal oncocytoma is being increasingly recognized among patients with renal masses, and it can be found in up to 50% of benign small renal masses (SRMs) less than 4 cm. Renal oncocytomas have benign clinical biology but distinguishing them from some of the other renal masses with more malignant potential can be challenging due to overlapping imaging, histologic, and immunophenotypic characteristics. Increasing integration of various imaging modalities, histologic characteristics, cytogenetics, and molecular and metabolic signatures is helping better define and characterize renal masses.Evolving and complementary diagnostic approaches, including at the molecular level, are continuing to help refine the classification of renal tumors, with implications on their clinical behavior and ultimately clinical management.

Although uterine leiomyosarcoma (ULMS) is a rare disease, it accounts for a significant proportion uterine cancer-related deaths due to frequent metastasis and chemoresistance. The WHO currently recognizes the conventional (spindle), myxoid, and epithelioid variants of ULMS, the latter of which is the rarest, least understood, and cited as clinically more aggressive than the other variants. Descriptions of the histologic features of epithelioid ULMS are extremely limited, and are absent from the cytology literature which has only published descriptions of conventional ULMS or epithelioid variants of other LMS primaries. Therefore, we present a unique case of metastatic epithelioid ULMS to an unusual location, the pancreas, along with its cytologic features on endoscopic ultrasound-guided fine needle aspiration not previously described including pseudoglandular arrangements, scant cytoplasm, and frequent molding.

Human Immunodeficiency Virus (HIV)-related Opportunistic Infections (OI), including Pneumocystis jiroveci pneumonia (PCP), have become much less commonplace with anti-retroviral therapy (ART). Despite this, OIs are still common and it is important to remain vigilant for their presence and be aware of how ART and OI chemoprophylaxis may lead to atypical disease presentations. We present the case of a 51-year-old woman with HIV and CD4+ T helper lymphocytes cell count > 200 cells/ul on both ART and trimethoprim/sulfamethoxazole prophylaxis who presented with cavitating lung masses, mediastinal lymphadenopathy and pleural effusions. Negative bronchoalveolar lavage (BAL) and transbronchial biopsy (TBBx) prompted a second diagnostic procedure with a transthoracic core needle biopsy; the final diagnosis was granulomatous PCP. This case showcases a very rare presentation of PCP, with both large cavitating lung masses on imaging and granulomatous reaction on pathology, as well as the challenge of a potentially missed diagnosis with negative BAL and TBBx requiring transthoracic core needle biopsy for a final diagnosis.

Prostate biopsy (Bx) sampling-based diagnosis of prostate cancer (PCa) has well-described inaccuracy when compared against whole gland analysis upon prostatectomy. Although upgrading of PCa Grade Group (GG) is often described, the occurrence and prognostic implications of downgrading PCa GG at the time of radical prostatectomy (RP) is less understood. Our objective was to evaluate whether downgrading PCa GG at the time of RP was associated with future tumor behavior.The SEER database was searched from 2010 to 2017 and patients were included if they were assigned pathological grades on both Bx and RP specimen. Patients were stratified into Bx GG RP GG and Bx GG ≤ RP GG groups, and tumor behavior after treatment was examined. Cox regression was used for the survival analysis.Here, 99,835 patients were included in this study. A total of 18,516 (18.5%) patients encountered downgrading from Bx GG to RP GG. A downgrading of 1 grade occurred in 13,969 (75.4%) of these patients and of 2 or more grades occurred in 4547 (24.6%) patients. A history of higher Bx GG compared with RP GG increased the risk of cancer-specific mortality (CSM) for each given RP GG controlling for age, race, preop prostate-specific antigen level, percentage of positive biopsy cores, and pathologic TNM stages. Specifically, a history of high Bx GG conferred a 45% increased risk of CSM for any given RP GG (hazard ratio = 1.45 95% confidence interval = 1.16-1.82, p 0.001).A history of higher Bx GG, and hence downgrading at the time of RP, demonstrates some value as a risk-stratification tool for future cancer outcomes after prostatectomy.

Objectives The nested variant of urothelial carcinoma (NVUC) is a rare bladder tumor that may possess a luminal molecular phenotype. We sought to determine whether a small immunohistochemical (IHC) panel using common surrogates for molecular phenotypes would reliably classify a cohort of pure NVUC cases. Methods IHC staining with a panel composed of markers for basal subtypes (CK5/6, CK14) and luminal subtypes (FOXA1, GATA3) was performed on pure small NVUC cases (n = 23) and 5 large NVUC cases (n = 5). Scoring of IHC stains was performed semiquantitatively. Individual cases were analyzed using previously reported IHC-based surrogates for molecular subtype. Results The phenotype of NVUC was classified as luminal from 60.1% (FOXA1+/CK5/6−) to 100% (GATA3+/CK14−) of cases using composite phenotypes. No cases possessed a basal or squamous cell carcinoma–like phenotype. The majority of small NVUC cases (69.5%) showed subset CK5/6 expression distinctly localized to the basal layers of tumor cell nests. Intratumoral heterogeneity was also noted in CK5/6 (21.7% of small NVUC cases) but no other markers. Conclusions NVUC appears to express markers of both basal and luminal bladder tumors. Definitive gene expression profiling may be valuable to further characterize this unique histologic variant.

Introduction An international panel recently recommended reclassification of non-invasive follicular variant of papillary thyroid carcinoma (PTC) to non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). NIFTPs have little or no risk of recurrence and can be treated with lobectomy alone. Preoperative distinction of NIFTP from PTC will help avoid overtreatment. Materials and Methods All thyroid tumors with a histologic diagnosis of PTC and preceding diagnostic cytology (n = 299) over a 5-year period were identified. Cases meeting criteria for NIFTP were reclassified as such. All NIFTP cases with available cytology (n = 6) and a similar number of randomly selected invasive follicular variant of papillary thyroid carcinoma (IFVPTC; n = 9) and classic PTC (cPTC, n = 11) were evaluated for 18 cytologic features. Results A total of 35 (12%) lesions were reclassified as NIFTP, 194 (65%) were cPTC, and 70 (23%) were IFVPTC. The NIFTPs had a preceding cytologic interpretation of benign (31%), atypia of undetermined significance (34%), follicular neoplasm (9%), suspicious for malignancy (12%), or malignant (14%). Cytologically, NIFTP was distinguished from cPTC by absence of any architectural features in all 6 cases, and by absence of pseudoinclusions ( P P = 0.027) in nearly all. Nuclear pseudoinclusions ( P = 0.001), marginal micronucleoli ( P = 0.018), irregular branching sheets ( P = 0.025), and linear arrangement ( P = 0.025) favored IFVPTC over NIFTP. Conclusions NIFTPs were originally assigned to a variety of cytologic categories. There are several cytologic differences between NIFTP and cPTC or IFVPTC. Our findings support restricting the definitive diagnosis of PTC to cases with architectural features of PTC and/or intranuclear pseudoinclusions.

The TNF receptor superfamily member Fn14 is overexpressed by many solid tumor types, including glioblastoma (GBM), the most common and lethal form of adult brain cancer. GBM is notable for a highly infiltrative growth pattern and several groups have reported that high Fn14 expression levels can increase tumor cell invasiveness. We reported previously that the mesenchymal and proneural GBM transcriptomic subtypes expressed the highest and lowest levels of Fn14 mRNA, respectively. Given the recent histopathological re-classification of human gliomas by the World Health Organization based on isocitrate dehydrogenase 1 (IDH1) gene mutation status, we extended this work by comparing Fn14 gene expression in IDH1 wild-type (WT) and mutant (R132H) gliomas and in cell lines engineered to overexpress the IDH1 R132H enzyme. We found that both low-grade and high-grade (i.e., GBM) IDH1 R132H gliomas exhibit low Fn14 mRNA and protein levels compared to IDH1 WT gliomas. Forced overexpression of the IDH1 R132H protein in glioma cells reduced Fn14 expression, while treatment of IDH1 R132H-overexpressing cells with the IDH1 R132H inhibitor AGI-5198 or the DNA demethylating agent 5-aza-2'-deoxycytidine increased Fn14 expression. These results support a role for Fn14 in the more aggressive and invasive phenotype associated with IDH1 WT tumors and indicate that the low levels of Fn14 gene expression noted in IDH1 R132H mutant gliomas may be due to epigenetic regulation via changes in DNA methylation.

The microtubule-stabilizing agent docetaxel in combination with gemcitabine represents one of the most effective regimens against the aggressive gynecologic tumor leiomyosarcoma (LMS). Upregulation of class III &beta, tubulin has previously been shown to confer taxane resistance in a variety of human cancers. Prostaglandin E2 receptor EP4 is linked to progression of a variety of human cancers and may represent a novel target for tumor inhibition in LMS. We evaluated the hypotheses that EP4 and class III &beta, tubulin have increased expression in LMS in comparison to normal myometrium or benign tumors and that expression of class III &beta, tubulin correlates with resistance to taxanes and poor clinical outcome. Gene expression was examined using TCGA data and correlated with clinicopathologic outcome which demonstrated that class III &beta, tubulin is more highly expressed in more aggressive sarcomas with EP4 being widely expressed in all subtypes of sarcoma. Immunohistochemistry for EP4 and class III &beta, tubulin was performed on patients with LMS, leiomyomatosis/STUMP, leiomyoma, and normal myometrium. Expression of EP4 and class III &beta, tubulin were characterized for cell lines SK-UT-1, SK-UT-1B, and PHM-41 and these cell lines were treated with docetaxel alone and in combination with EP4 inhibitors. In taxane-resistant cell lines that overexpress class III &beta, tubulin and EP4, treatment with EP4 inhibitor resulted in at least 2-fold sensitization to docetaxel. Expression of class III &beta, tubulin and EP4 in LMS may identify patients at risk of resistance to standard chemotherapies and candidates for augmentation of therapy through EP4 inhibition.

Nested variant of urothelial carcinoma is a rare variant of urothelial carcinoma morphologically characterized by infiltrative nests of cytologically bland urothelial cells. It is widely recognized that nested variant of urothelial carcinoma can closely mimic von Brunn nests. However, nested variant of urothelial carcinoma with tubule formation can also resemble nephrogenic adenoma, where immunohistochemical positivity for PAX8 has been used to establish the diagnosis of nephrogenic adenoma. Following anecdotal examples of PAX8 positive nested variant of urothelial carcinoma, we formally evaluated 23 cases of nested variant of urothelial carcinoma from 2011 to 2018. Cases were collected from our institution and evaluated for their architectural pattern and PAX8 expression. Except for 1 case from the renal pelvis, cases were located in the bladder. The majority (14/23 [61%]) showed solid nests with at least focal tubular differentiation. PAX8 immunoreactivity was strong (3+) in 7 (30%), moderate (2+) in 6 (26%), and negative in 10 (44%) cases. Four (57%) of the cases with strong expression and 3 (50%) of those with moderate staining showed diffuse immunoreactivity. Moderate-strong immunoreactivity was seen in 4/6 (66.7%) cases with solid nests, 8/14 (57.1%) with solid nests and tubules, and 1/3 (33.3%) with large nests. In conclusion, PAX8 can be positive in a significant proportion of nested variant of urothelial carcinoma cases, and recognition of this finding is important to avoid misdiagnosis of nested variant of urothelial carcinoma as nephrogenic adenoma based on PAX8 expression, particularly in cases with tubular differentiation and limited sampling.

BACKGROUND Thyroid fine-needle aspiration (FNA) plays a key role in triaging thyroid nodules. Yet many cases are assigned to indeterminate categories. The new category "noninvasive follicular thyroid neoplasm with papillary-like features" (NIFTP) complicates thyroid cytology. Digital image-derived nuclear measurements might objectively distinguish papillary thyroid carcinoma (PTC) from benign nodules and NIFTP. METHODS All thyroid FNAs from 2012 to 2016 of atypia of undetermined significance (A; n = 8) and suspicious for malignancy (S; n = 2) with sufficient cellularity and surgical follow-up, all FNAs preceding NIFTP (n = 6), and a random sample of PTC (n = 9) and benign (n = 10) cytology were studied. A modified Giemsa-stained slide from each case was scanned using the Aperio imaging system, and long (dl ) and short (ds )-axis diameters were measured for 125 nuclei per case. Nuclear area and elongation were calculated. RESULTS Nuclear area was larger in PTC (mean, 77.2 μm2 [range, 70.6-86.0 μm2 ]) than benign (mean, 43.3 μm2 [range 38.2-52.2 μm2 ]) (P

Ovarian cancer has the highest mortality incidence of all gynecologic malignancies in the United States. The majority of ovarian cancer cases lead to recurrent disease that is often incurable and fatal due to innate or acquired chemoresistance; therefore, novel therapeutic interventions are desperately needed. Cyclooxygenases–COX-1 and COX-2–are enzymes that catalyze the production of prostaglandin E2 (PGE2), an important inflammatory lipid mediator that is functionally linked to progression of many cancers, including breast and ovarian cancer. PGE2 is exported from the cell via multidrug resistance-associated protein 4 (MRP4) where it acts in a paracrine and autocrine manner by activating a family of four G-protein coupled receptors (EP1-4) that are linked to different intracellular signaling pathways. EP2 and EP4 can activate PKA/cAMP, PI3K and ERK pathways. We hypothesize that the EP4 receptor has increased expression in ovarian cancer and that binding of its cognate ligand, PGE2, will drive ovarian cancer progression. We also hypothesize that alternation of the tumor microenvironment via MRP4 will also lead to inhibition of EP4-mediated signaling and affect phenotypes associated with ovarian cancer progression. In order to test this hypothesis, we analyzed the expression of the EP4 and MRP4 in a human ovarian cancer tissue microarray (TMA) as well as human ovarian cancer cell lines. Immunohistochemical analysis of EP4 on the TMA composed of varying histologies, including serous, endometrioid, and clear-cell, as well as normal ovarian tissue, revealed that EP4 was expressed in 38.7% of ovarian cancer tissues, whereas EP4 had no or low expression in 10 normal ovarian tissue samples. Immunohistochemistry of MRP4 also revealed increased expression in ovarian cancer histologies compared to normal ovarian tissue. Serous, endometrioid, and clear-cell subtypes presented with a majority of 4+ and 3+ staining intensities compared to normal ovarian tissue, which presented with mostly 2+ and 1+ staining, and none of the normal ovarian tissue presented with 4+ intensity. EP4 and MRP4 also has increased expression in multiple ovarian cancer cells lines including those representing low-grade serous, clear-cell, and high-grade serous ovarian cancer. Treatment of these cell lines with an EP4 antagonist resulted in decreased proliferation and migration compared to vehicle control. Consistent with the pharmacologic data, treatment of ovarian cancer cell lines with siRNA directed against the EP4 receptor led to decreased proliferation and migration. Inhibition of PGE2 export via MRP4 inhibitor Ceefourin and probenecid results in increased sensitization of ovarian cancer cell lines to treatment with paclitaxel. Based on these data, targeting of the PGE2 EP4 receptor and PGE2 export via MRP4 should be investigated further for the treatment of ovarian cancer. Citation Format: Jocelyn Reader, McMillan Ching, Cong (Ava) Fan, Sulan Wu, Paul Staats, Teklu Legesse, Olga Goloubeva, Ningbo Jian, Mark Carey, Amy Fulton, Dana Roque, Gautam Rao. Analysis of function and inhibition of PGE2 pathway members MRP4 and EP4 in treatment of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B67.

BACKGROUND: Glioblastoma (GBM) is a difficult to treat brain cancer that nearly uniformly recurs, and recurrent tumors are largely therapy resistant. Our prior work has demonstrated an important role for the tumor necrosis factor–like weak inducer of apoptosis (TWEAK) receptor fibroblast growth factor–inducible 14 (Fn14) in GBM pathobiology. In this study, we investigated Fn14 expression in recurrent GBM and in the setting of temozolomide (TMZ) resistance. METHODS: Fn14 mRNA expression levels in nonneoplastic brain, primary (newly diagnosed) GBM, and recurrent GBM (post-chemotherapy and radiation) specimens were obtained from The Cancer Genome Atlas data portal. Immunohistochemistry was performed using nonneoplastic brain, patient-matched primary and recurrent GBM, and gliosarcoma (GSM) specimens to examine Fn14 protein levels. Western blot analysis was used to compare Fn14 expression in parental TMZ-sensitive or matched TMZ-resistant patient-derived xenografts (PDXs) established from primary or recurrent tumor samples. The migratory capacity of control and Fn14-depleted TMZ-resistant GBM cells was assessed using the transwell migration assay. RESULTS: We found that Fn14 is more highly expressed in recurrent GBM tumors than their matched primary GBM counterparts. Fn14 expression is also significantly elevated in GSM tumors. GBM PDX cells with acquired TMZ resistance have higher Fn14 levels and greater migratory capacity than their corresponding parental TMZ-sensitive cells, and the migratory difference is due, at least in part, to Fn14 expression in the TMZ-resistant cells. CONCLUSIONS: This study demonstrates that the Fn14 gene is highly expressed in recurrent GBM, GSM, and TMZ-resistant GBM PDX tumors. These findings suggest that Fn14 may be a valuable therapeutic target or drug delivery portal for treatment of recurrent GBM and GSM patients.

Background Knowledge of topographic skin thickness is important to plastic surgery of the face as it may guide resection and restoration in oncologic, aesthetic, and reconstructive procedures. Objective The purpose of this study is to report the relative thickness of the face throughout 39 distinct subunits. Methods Full-thickness punch biopsy samples were obtained at 39 predetermined anatomic locations of the face from 10 human cadaveric heads. Tissue was fixed in paraffin-embedded slides and analyzed using triplicate measurement of dermis and epidermis using computerized measurements. Data were analyzed using univariate statistical analysis and expressed as mean thickness values and relative thickness (RT) values based on the thinnest portion of the face. Results The area of the face with the thickest dermis was the lower nasal sidewall (1969.2 µm, dRT: 2.59), and the thinnest was the upper medial eyelid (758.9 µm, dRT: 1.00). The area with the thickest epidermis was the upper lip (62.6 µm, eRT: 2.12), and the thinnest was the posterior auricular skin (29.6 µm, eRT: 1.00). Our results confirm that eyelid skin is the thinnest in the face. The thickest portions of the skin appeared to be in the lower nasal sidewall, but the measurements are comparable to those in the ala and posterior auricular skin, which are novel findings. Conclusions The greatest epidermal, dermal and total skin thickness are found in the upper lip, right lower nasal sidewall, and left lower nasal sidewall respectively. The least epidermal skin thickness is in the posterior auricular skin. The least dermal skin thickness, and the least total skin thickness, are both in the upper medial eyelid.