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Desmoid fibromatosis (DF) is a locally aggressive soft tissue neoplasm with frequent recurrences. DF is characterized by alterations in the Wnt/β-catenin pathway, with the majority showing sporadic mutations in CTNNB1 , whereas others have germline mutations in APC . Immunohistochemical staining for β-catenin is often difficult to interpret and can be negative in up to 30% of cases. Prior studies have shown that some DFs lacking nuclear expression of β-catenin may carry activating CTNNB1 mutations. Droplet digital polymerase chain reaction (ddPCR) has been used effectively in detecting mutations in formalin-fixed, paraffin-embedded (FFPE) samples of various cancer types. In this study, we assess the diagnostic utility of ddPCR to detect CTNNB1 mutations in DF with β-catenin expression on immunohistochemistry (IHC), as well as in diagnostically challenging cases. Of the 28 DFs with nuclear β-catenin expression by IHC, 24 cases showed a CTNNB1 mutation by ddPCR using primers against the most common point mutations in CTNNB1 . The most frequent mutation was T41A (n=14; 50%), followed by S45F (n=8; 33%) and S45P (n=3;12%). We identified 8 additional (myo)fibroblastic lesions of uncertain classification, which were negative for nuclear β-catenin expression by IHC. We detected CTNNB1 mutations in 3 unknown lesions, including S45F (n=2) and S45P (n=1). ddPCR is a sensitive, rapid and cost-efficient methodology to detect common CTNNB1 mutations in DF, especially in diagnostically challenging cases.

Urothelial carcinoma (UC) is known to encompass a wide spectrum of morphologic features and molecular alterations. Approximately 15% to 25% of invasive UC exhibits histomorphologic features in the form of "divergent differentiation" along other epithelial lineages, or different "subtypes" of urothelial or sarcomatoid differentiation. It is recommended that the percentage of divergent differentiation and or subtype(s) be reported whenever possible. Recent advances in molecular biology have led to a better understanding of the molecular underpinning of these morphologic variations. In this review, we highlight histologic characteristics of the divergent differentiation and subtypes recognized by the latest version of WHO classification, with updates on their molecular and clinical features.

We describe a case of a myoepithelial carcinoma of the superficial parotid gland in a 46-year-old male harboring a novel CTCF::NCOA2 gene fusion. To our knowledge, this novel gene fusion has not been described previously in myoepithelial carcinoma. A 46-year-old male patient presented with a mass involving the superficial left parotid gland with extension into the external auditory canal (EAC) and erosion of the conchal cartilage. Histologically, the neoplasm was composed of uniform spindled, epithelioid/ovoid cells arranged in cords and nests within hyalinized to myxoid stroma. On immunohistochemistry (IHC), the tumor cells demonstrated patchy and variable staining for low molecular weight cytokeratin (CAM5.2), pan-cytokeratin (OSCAR), and S-100. Overall, the morphological and immunohistochemical attributes supported a locally aggressive tumor of myoepithelial differentiation consistent with myoepithelial carcinoma. Molecular analysis using a custom 115-gene gene panel by targeted RNA sequencing, showed an in-frame CTCF::NCOA2 fusion. In addition to reporting this novel fusion in myoepithelial carcinoma, we also discuss relevant differential diagnosis, and provide a brief review of NCOA2 gene function in both normal and neoplastic contexts.

The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and cytokines/chemokines/soluble factors regulating various intracellular signaling pathways (ISP) in tumor cells. TME influences the survival/progression of prostate cancer (PC), enabling tumor cell immune-evasion also through the activation of the PD-1/PD-L1 axis. We have performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs. Tumor immune-escape mechanisms include suppression/exhaustion of tumor infiltrating cytotoxic T lymphocytes, inhibition of tumor suppressive NK cells, increase in immune-suppressive immune cells (regulatory T, M2 macrophagic, myeloid-derived suppressor, dendritic, stromal, and adipocytic cells). IFN-γ (the most investigated factor), TGF-β, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a, and other soluble molecules secreted by TME components (and sometimes increased in patients’ serum), as well as and hypoxia, influenced the regulation of PD-L1. Experimental studies using human and mouse PC cell lines (derived from either androgen-sensitive or androgen-resistant tumors) revealed that the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT pathways were involved in PD-L1 upregulation in PC. Blocking the PD-1/PD-L1 signaling by using immunotherapy drugs can prevent tumor immune-escape, increasing the anti-tumor activity of immune cells.

Immunotherapy targeting the PD-1–PD-L1 axis yielded good results in treating different immunologically ‘‘hot’’ tumors. A phase II study revealed good therapeutic activity of pembrolizumab in selected prostatic carcinoma (PC)-patients. We performed a systematic literature review (PRISMA guidelines), which analyzes the immunohistochemical expression of PD-L1 in human PC samples and highlights the pre-analytical and interpretation variables. Interestingly, 29% acinar PCs, 7% ductal PCs, and 46% neuroendocrine carcinomas/tumors were PD-L1+ on immunohistochemistry. Different scoring methods or cut-off criteria were applied on variable specimen-types, evaluating tumors showing different clinic-pathologic features. The positivity rate of different PD-L1 antibody clones in tumor cells ranged from 3% (SP142) to 50% (ABM4E54), excluding the single case tested for RM-320. The most tested clone was E1L3N, followed by 22C3 (most used for pembrolizumab eligibility), SP263, SP142, and 28-8, which gave the positivity rates of 35%, 11–41% (depending on different scoring systems), 6%, 3%, and 15%, respectively. Other clones were tested in

Prostatic Leiomyosarcoma is a rare tumor with less than 200 cases reported. These are aggressive tumors and treatment guidelines are not well established. In early stages, they usually present with obstructive lower urinary tract symptoms without elevation of serum prostate-specific antigen. They lack specific clinical or imaging characteristics, hence keeping a high degree of skepticism might aid in timely detection. The early-stage disease can be managed with surgery and radiotherapy with relatively modest survival. Here we are reporting a case of primary prostatic leiomyosarcoma with some insight into diagnostic issues and disease biology with basic management principles. We have developed a treatment algorithm based on available literature.

Many studies have investigated the potential prognostic and predictive role of PD-L1 in prostatic carcinoma (PC). We performed a systematic literature review (PRISMA guidelines) to critically evaluate human tissue-based studies (immunohistochemistry, molecular analysis, etc.), experimental research (cell lines, mouse models), and clinical trials. Despite some controversial results and study limitations, PD-L1 expression by tumor cells may be related to clinic–pathologic features of adverse outcome, including advanced tumor stage (high pT, presence of lymph node, and distant metastases), positivity of surgical margins, high Grade Group, and castration resistance. Different PD-L1 positivity rates may be observed in matched primary PCs and various metastatic sites of the same patients. Over-fixation, type/duration of decalcification, and PD-L1 antibody clone may influence the immunohistochemical analysis of PD-L1 on bone metastases. PD-L1 seemed expressed more frequently by castration-resistant PCs (49%) as compared to hormone-sensitive PCs (17%). Some series found that PD-L1 positivity was associated with decreased time to castration resistance. Treatment with ipilimumab, cyclophosphamide/GVAX/degarelix, or degarelix alone may increase PD-L1 expression. Correlation of PD-L1 positivity with overall survival and outcomes related to tumor recurrence were rarely investigated; the few analyzed series produced conflicting results and sometimes showed limitations. Further studies are required. The testing and scoring of PD-L1 should be standardized.

In prostate cancer (PC), the PD-1/PD-L1 axis regulates various signaling pathways and it is influenced by extracellular factors. Pre-clinical experimental studies investigating the effects of various treatments (alone or combined) may discover how to overcome the immunotherapy-resistance in PC-patients. We performed a systematic literature review (PRISMA guidelines) to delineate the landscape of pre-clinical studies (including cell lines and mouse models) that tested treatments with effects on PD-L1 signaling in PC. NF-kB, MEK, JAK, or STAT inhibitors on human/mouse, primary/metastatic PC-cell lines variably down-modulated PD-L1-expression, reducing chemoresistance and tumor cell migration. If PC-cells were co-cultured with NK, CD8+ T-cells or CAR-T cells, the immune cell cytotoxicity increased when PD-L1 was downregulated (opposite effects for PD-L1 upregulation). In mouse models, radiotherapy, CDK4/6-inhibitors, and RB deletion induced PD-L1-upregulation, causing PC-immune-evasion. Epigenetic drugs may reduce PD-L1 expression. In some PC experimental models, blocking only the PD-1/PD-L1 pathway had limited efficacy in reducing the tumor growth. Anti-tumor effects could be increased by combining the PD-1/PD-L1 blockade with other approaches (inhibitors of tyrosine kinase, PI3K/mTOR or JAK/STAT3 pathways, p300/CBP; anti-RANKL and/or anti-CTLA-4 antibodies; cytokines; nitroxoline; DNA/cell vaccines; radiotherapy/Radium-223).

Background: Anemia has a myriad of causes and its prevalence is growing. Anemia is associated with increased all-cause hospitalization and mortality in community-dwelling individuals above age 65 years. Our aim was to determine the prevalence and severity of anemia in adult patients in our primary care office and to determine the relationship between anemia and medical comorbidities. Methods: Electronic medical records of 499 adult patients in our suburban internal medicine office were reviewed who had had at least one hemoglobin value and did not undergo moderate to high-risk surgery in the preceding 30 days. Results: About one-fifth (21.1%) of the patients had anemia. The mean age of patients with anemia was 62.6 years. Among all patients with anemia, 20.3% were males and 79.6% were females. Of these patients, 60.1% had mild anemia (hemoglobin 11 - 12.9 g/dL) and 39.8% had moderate anemia (hemoglobin 8 - 10.9 g/dL). For every year of increase in age, there was 1.8% increased odds of having anemia. African-American race had 5.2 times greater odds of having anemia than the Caucasian race. Hispanic race had 3.2 times greater odds of having anemia compared to the Caucasian race. Patients with anemia had a greater average number of comorbidities compared to patients without anemia (1.74 and 0.96, respectively; P < 0.05). There was a statistically greater percentage of patients with essential hypertension, hypothyroidism, chronic kidney disease, malignancy, rheumatologic disease, congestive heart failure, and coronary artery disease in the anemic population as compared to the non-anemic population. Of the patients, 41% with mild anemia and 62% with moderate anemia underwent additional diagnostic studies. Of the patients, 14.8% had resolution of anemia without therapy in 1 year, 15.7% were on iron replacement therapy, and 6.5% were on cobalamin therapy. No specific etiology of anemia was found in 24% of patients. Conclusion: A higher prevalence of anemia was associated with advancing age, African-American and Hispanic ethnicity, and comorbidities, such as essential hypertension, hypothyroidism, chronic kidney disease, malignancy, rheumatologic disease, congestive heart failure, and coronary artery disease. It is important to be aware of the demographic factors and their relationship to anemia in primary care. J Clin Med Res. 2017;9(12):970-980 doi: https://doi.org/10.14740/jocmr3221w

4526 Background: LNEC is a rare, poorly characterized entity morphologically resembling small cell NEC of the urothelial tract (SNEC). Methods: Pure and partial LNEC and SNEC cases were identified by histopathologic re-review; clinical outcomes were compared. A subset was sequenced with MSK-IMPACT (279-505 genes). Results: Between 1992-2020, 43 patients (pts) with LNEC were identified (42 bladder, 1 upper tract); 19 (44%) had concomitant SNEC. LNEC cases were compared to 192 SNEC without LNEC (SNEC-only) (Table 1). Compared to SNEC-only pts, LNEC pts experienced longer overall survival (OS), adjusting for age and M0 vs M1 (median OS not reached vs 22.4 months [mos]; HR 0.34, 95% CI 0.16-0.74, p =.006). Neoadjuvant chemo (NAC) use increased over time. Pathologic response rate (

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are recently being considered as standard of treatment for patients with peritoneal carcinomatosis of appendiceal or colorectal origin. It is an extensive procedure with high morbidity. Being a newer treatment modality, not much experience has been published from an Indian center about it. All patients of colorectal and appendiceal cancer with peritoneal metastasis from January 2012 to March 2015 who were planned for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) were analyzed with respect to morbidity, mortality, and survival. Thirty-three patients were planned for cytoreductive surgery (CRS)+HIPEC for peritoneal carcinomatosis of colorectal or appendiceal origin. There were 18 males and 15 females and mean age was 48.2 years (21–75 years). Of these, 14 had disease from appendiceal origin and 19 of colorectal origin. Cytoreductive surgery was performed 29 times in 27 patients and was abandoned in 6 patients. Overall morbidity was 55.17% with hematological toxicity being the most common (46.1%) and mortality being 3.4%. Four-year actuarial survival of patients undergoing CRS and HIPEC was 58.39% and 33.33% for patients undergoing CRS alone (p=0.302). Appendiceal primary neoplasms had better overall survival compared to colorectal primary (63.64% vs. 50.68% 4-year actuarial survival). CRS and HIPEC can be performed with acceptable morbidity and mortality in selected patients of colorectal and appendiceal malignancies with peritoneal carcinomatosis. In addition, it is associated with better overall survival. Morbidity profile of Indian subcontinent patients is different from that of western population with hematological toxicity being the most common.

Acute exertional compartment syndrome of the thighs is extremely rare. It should be considered in patients who present with myalgia and swelling after vigorous exercise. We present a case of a 35-year-old female athlete with breast cancer who had received one cycle of chemotherapy. The patient presented with diffuse myalgias in her thighs after an exercise session. She was diagnosed with chemotherapy induced compartment syndrome of the bilateral thighs with resultant rhabdomyolysis and acute kidney injury. She required continuous venovenous hemodialysis. The patient suffered a cardiac arrest and could not be resuscitated. This case draws attention to the potential myotoxocity of certain chemotherapeutic agents. It also demonstrates acute compartment syndrome as a rare but devastating consequence of extreme physical training associated with certain chemotherapeutic agents. As many of our patients are adopting vigorous exercise routines, it is important for physicians to be aware of acute exertional compartment syndrome, as it necessitates a high degree of clinical suspicion.

Primary uterine angiosarcoma is a very rare tumour, with only 23 cases described till now. It is a malignant tumour with cells variably recapitulating the morphologic features of an endothelium and expressing immunohistochemical markers of endothelial cells. In general, it is a bulky neoplasm and frequently is at advance stage of disease at presentation. In general, patients with uterine angiosarcoma tend to have a poorer prognosis, mostly related to the aggressive nature and the metastatic potential of these tumours.We report a rare case of primary uterine angiosarcoma with unusual rhabdoid morphology in a 41-year-old female, who underwent radical hysterectomy and died of disease after 4 months of treatment.We described the differential diagnosis of primary angiosarcoma of the uterus that can pose a diagnostic challenge.