Epithelioid Hemangioendothelioma of the Ulnar Artery Presenting with Neuropathy.

We present a rare case of epithelioid hemangioendothelioma arising from the wall of ulnar artery in distal forearm. The presentation was interesting in a 34-year-old man, with progressively worsening symptoms of ulnar neuropathy. A mass was seen arising from the ulnar artery on imaging with ultrasound and magnetic resonance imaging. Soft tissue epithelioid hemangioendothelioma in extremities almost always arise from the veins. Existing literature do not have elaborated imaging findings of epithelioid hemangioendothelioma arising from the arterial wall. The aim of this paper is to briefly review the interesting presentation and imaging features of this rare entity. Knowledge of such vascular tumor would avoid the mishap during surgery. Our case will add an interesting presentation of such rare pathology to the existing literature.

Papillary Renal Cell Carcinoma (PRCC): An Update.

Papillary renal cell carcinoma (PRCC) is the second most common type of renal carcinoma following clear cell renal cell carcinoma. Papillary renal cell carcinoma is usually divided histologically into 2 types namely, type 1 and type 2. This classification, however, is unsatisfactory as many of papillary carcinoma are unclassifiable by the existing criteria. In recent years there has been a remarkable progress in our understanding of the molecular basis of PRCC. These studies have revealed that type 2 PRCCs represent a heterogenous group which may be subdivided into additional subtypes based on the genetic and molecular make up of these tumors and reflecting different clinical course and prognosis. Some of the molecular features such a hypermethylation of CPG islands in the promotor regions of genes and over expression of the antioxidant pathways within tumor cells have been recognized as markers of poor prognosis. Targeted therapies for papillary carcinoma in the past have been unsuccessful because of lack of clear understanding of the molecular basis of these tumors. It is hoped that recent progress in our understanding of the pathogenesis of various subtypes of PRCC, effective targeted therapies will eventually emerge in due course.

Intrinsic Molecular Subclassification of Urothelial Carcinoma of the Bladder: Are We Finally there?

Bladder cancer is a highly prevalent disease throughout the world usually encountered in older patients, and associated with substantial morbidity, mortality, and cost. The treatment of bladder cancer has remained unchanged for the last several decades. However, in recent years the availability of comprehensive genomic data from The Cancer Genome Atlas and other large projects have considerably improved our understanding of the pathogenesis of these tumors. These studies demonstrated that bladder cancers can be grouped into 2 broad categories namely basal and luminal molecular subtypes with recognizable subgroups in each of these categories. Clinical data suggest that invasive basal cancers are more sensitive to neoadjuvant chemotherapy (NAC), such that most patients with basal cancers who are aggressively managed with NAC have excellent outcomes. Patients with luminal cancers do not appear to derive much clinical benefit from NAC, but some may appear to be sensitive to anti-programmed death-ligand 1 (PDL1) antibodies and possibly other immune checkpoint inhibitors. It is hoped that future studies will also identify biomarkers such as immunohistochemical markers which may be used to predict therapeutic response of these tumors. This will contribute substantially toward efficient and cost-effective diagnosis and management of these neoplasms.

Urothelial Carcinoma In Situ (CIS): New Insights.

Urothelial carcinoma in situ (CIS) is a high-grade noninvasive malignancy with a high tendency of progression. Although it is typically grouped with other nonmuscle invasive bladder cancers, its higher grade and aggressiveness make it a unique clinical entity. Urothelial CIS is histologically characterized by replacement of the urothelium by cells which fulfill the morphologic criteria of malignancy including nuclear pleomorphism, hyperchromasia, prominent nucleoli, and increased numbers of normal and abnormal mitoses. Urothelial CIS may be categorized as primary when it is not associated with any past or present urothelial carcinoma. It is termed as secondary when there is concomitant or previous urothelial carcinoma in the patient. In recent years detailed molecular studies have provided valuable data for intrinsic molecular subclassification of urothelial carcinoma into 2 broad categories namely luminal and basal types with significant implications for prognosis and therapy. Similar studies on urothelial CIS are limited but have provided crucial insight into the molecular basis of CIS. These studies have revealed that urothelial CIS may also be divided into luminal and basal subtypes, but luminal subtype is much more common. It has also been shown that in many cases, luminal type of urothelial CIS may undergo a class switch to basal type during progression to an invasive carcinoma. Additional studies may be required to confirm and further elaborate these findings.

Molecular and Metabolic Basis of Clear Cell Carcinoma of the Kidney.

Renal cell carcinoma (RCC) is a heterogenous group of tumors, >70% of which belong to the category of clear cell carcinoma. In recent years, crucial advances have been made in our understanding of the molecular and metabolic basis of clear cell carcinoma. This tumor manifests significant alterations in the cellular metabolism, so that the tumor cells preferentially induce the hypoxia response pathway using aerobic glycolysis, rather than the normal oxidative phosphorylation for energy. Most of the clear cell carcinomas (sporadic as well as familial) have mutations and deletions in the VHL gene located at 3p (p3.25). Normally, pVHL plays a crucial role in the proteasomal degradation of hypoxia-inducible factors (HIF)1 and HIF2. Lack of a functioning pVHL owing to genetic alterations results in stabilization and accumulation of these factors, which promotes cell growth, cell proliferation, and angiogenesis, contributing to a neoplastic phenotype. Several other genes normally located adjacent to VHL (BAP1, SETD2, PBRM1) may also be lost. These are tumor suppressor genes whose loss not only plays a role in carcinogenesis but may also influence the clinical course of these neoplasms. In addition, interaction among a variety of other genes located at several different chromosomes may also play a role in the genesis and progression of clear cell carcinoma.

Prostate cancer small non-coding RNA transcriptome in Arabs.

BACKGROUND: Prostate cancer (PCa) is a complex disorder resulting from the combined effects of multiple environmental and genetic factors. Small non-coding RNAs (sRNAs), particularly microRNAs (miRNAs), regulate several cellular processes and have an important role in many human malignancies including PCa. We assessed the sRNA profiles associated with PCa in Arabs, a population that has rarely been studied. METHODS: We used next generation sequencing technology to obtain the entire sRNA transcriptome of primary prostate tumor formalin-fixed paraffin-embedded tissues, and their paired non-tumor tissues, collected from Bedouin patients (Qatari and Saudi). The miRNA and the target gene expression were evaluated by real-time quantitative PCR. miRNA KEGG pathway and miRNA target genes were subsequently analyzed by starBase and TargetScan software. RESULTS: Different expression patterns of several sRNA and miRNA editing were revealed between PCa tumor and their paired non-tumor tissues. Our study identified four miRNAs that are strongly associated with prostate cancer, which have not been reported previously. Differentially expressed miRNAs significantly affect various biological pathways, such as cell cycle, endocytosis, adherence junction and pathways involved in cancer. Prediction of potential targets for the identified miRNAs indicates the overexpression of KRAS, BCL2 and down-regulation of PTEN in PCa tumor tissues. CONCLUSION: These miRNAs, newly associated with prostate cancer, may represent not only markers for the increased risk of PCa in Arabs, but may also reflect the clinical and pathological diversity as well as the ethno-specific heterogeneity of prostate cancer.

Prostate carcinoma with amphicrine features: further refining the spectrum of neuroendocrine differentiation in tumours of primary prostatic origin?

AIMS: The current World Health Organization classification categorises high-grade neuroendocrine (NE) carcinomas of the prostate into small-cell and large-cell types. A distinct form of carcinoma showing synchronous dual exocrine and NE differentiation, termed amphicrine carcinoma, has been described at various other sites, primarily within the gastrointestinal tract. The aim of this study was to investigate the clinicopathological features of a series of metastatic prostate carcinoma (PCa) cases with amphicrine features. METHODS AND RESULTS: Five cases of high-grade PCa showing an amphicrine immunohistochemical phenotype were prospectively collected. The serum prostate-specific antigen (PSA) level at diagnosis ranged from 38 ng/ml to 992 ng/ml (median 200 ng/ml). All five patients had metastatic disease, four at initial presentation. Microscopically, the tumours showed a solid/nested growth pattern composed of cells with amphophilic cytoplasm, vesicular nuclei, and macronucleoli. Morphological features of small-cell or large-cell NE carcinoma were absent. As compared with conventional high-grade PCa, the tumour cells showed a higher level of nuclear pleomorphism, brisk mitotic activity, and a high Ki67 proliferation index (median 50%). All cases showed immunohistochemical positivity for PSA, androgen receptor, and prostate-specific acid phosphatase, combined with diffuse or confluent/non-focal positivity for chromogranin-A and synaptophysin. Two hormone-naive cases showed a clinical response to androgen deprivation therapy. CONCLUSION: This series highlights a previously undefined, clinically aggressive variant of PCa showing dual exocrine and NE differentiation, for which we are proposing the term PCa with amphicrine features. Increased recognition of these tumours may lead to a better understanding of their biology, and ultimately improve their clinical management.

CrossLink: a novel method for cross-condition classification of cancer subtypes.

BACKGROUND: We considered the prediction of cancer classes (e.g. subtypes) using patient gene expression profiles that contain both systematic and condition-specific biases when compared with the training reference dataset. The conventional normalization-based approaches cannot guarantee that the gene signatures in the reference and prediction datasets always have the same distribution for all different conditions as the class-specific gene signatures change with the condition. Therefore, the trained classifier would work well under one condition but not under another. METHODS: To address the problem of current normalization approaches, we propose a novel algorithm called CrossLink (CL). CL recognizes that there is no universal, condition-independent normalization mapping of signatures. In contrast, it exploits the fact that the signature is unique to its associated class under any condition and thus employs an unsupervised clustering algorithm to discover this unique signature. RESULTS: We assessed the performance of CL for cross-condition predictions of PAM50 subtypes of breast cancer by using a simulated dataset modeled after TCGA BRCA tumor samples with a cross-validation scheme, and datasets with known and unknown PAM50 classification. CL achieved prediction accuracy >73 %, highest among other methods we evaluated. We also applied the algorithm to a set of breast cancer tumors derived from Arabic population to assign a PAM50 classification to each tumor based on their gene expression profiles. CONCLUSIONS: A novel algorithm CrossLink for cross-condition prediction of cancer classes was proposed. In all test datasets, CL showed robust and consistent improvement in prediction performance over other state-of-the-art normalization and classification algorithms.

Urachal mixed adenocarcinoma and small cell neuroendocrine carcinoma with widespread metastasis and resistance to chemotherapy: a case report.

Neuroendocrine carcinoma arising from the urachus is extremely rare. We describe a case of a 33-year-old gentleman who presented with hematuria and diagnosed to have a composite adenocarcinoma and small cell neuroendocrine carcinoma arising from the urachus. The patient also had widespread metastasis at the time of presentation, therefore, he was referred for chemotherapy. However, the disease showed progression despite treatment. Recognition of neuroendocrine carcinoma component in urachal tumors, although rare, is very essential as this histologic type carries poor prognosis with aggressive clinical outcome.

Genome scan study of prostate cancer in Arabs: identification of three genomic regions with multiple prostate cancer susceptibility loci in Tunisians.

BACKGROUND: Large databases focused on genetic susceptibility to prostate cancer have been accumulated from population studies of different ancestries, including Europeans and African-Americans. Arab populations, however, have been only rarely studied. METHODS: Using Affymetrix Genome-Wide Human SNP Array 6, we conducted a genome-wide association study (GWAS) in which 534,781 single nucleotide polymorphisms (SNPs) were genotyped in 221 Tunisians (90 prostate cancer patients and 131 age-matched healthy controls). TaqMan SNP Genotyping Assays on 11 prostate cancer associated SNPs were performed in a distinct cohort of 337 individuals from Arab ancestry living in Qatar and Saudi Arabia (155 prostate cancer patients and 182 age-matched controls). In-silico expression quantitative trait locus (eQTL) analysis along with mRNA quantification of nearby genes was performed to identify loci potentially cis-regulated by the identified SNPs. RESULTS: Three chromosomal regions, encompassing 14 SNPs, are significantly associated with prostate cancer risk in the Tunisian population (P = 1 × 10-4 to P = 1 × 10-5). In addition to SNPs located on chromosome 17q21, previously found associated with prostate cancer in Western populations, two novel chromosomal regions are revealed on chromosome 9p24 and 22q13. eQTL analysis and mRNA quantification indicate that the prostate cancer associated SNPs of chromosome 17 could enhance the expression of STAT5B gene. CONCLUSION: Our findings, identifying novel GWAS prostate cancer susceptibility loci, indicate that prostate cancer genetic risk factors could be ethnic specific.

The Elusive SLIPPERS Syndrome (Supratentorial Lymphocytic Inflammation with Parenchymal Perivascular Enhancement Responsive to Steroids): A Case Report and Literature Review.

Background: In 2015, the term "SLIPPERS" was created to refer to a rare type of encephalomyelitis called CLIPPERS syndrome that affects the pons and sometimes other nearby structures, but in this case, it primarily affects the supratentorial region. This variation of the condition is responsive to treatment with steroids. Case Description: We report the case of a patient who presented with seizures and visual field deficit and had typical radiological and histopathological characteristics of SLIPPERS syndrome. Conclusion: Although the literature is inundated with CLIPPERS syndrome, its supratentorial variant is extremely rare. To our knowledge, this is fourth case of SLIPPERS syndrome to be reported in literature and serves to enhance clinicopathological understanding of this elusive entity.

Serum immune mediators as novel predictors of response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients with high tissue-PD-L1 expression.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related morbidity and mortality worldwide. Immune checkpoint inhibitors (ICIs) including anti-PD-1 and anti-PD-L1 antibodies, have significantly changed the treatment outcomes with better overall survival, but only 15-40% of the patients respond to ICIs therapy. The search for predictive biomarkers of responses is warranted for better clinical outcomes. We aim here to identify pre-treatment soluble immune molecules as surrogate biomarkers for tissue PD-L1 (TPD-L1) status and as predictors of response to anti-PD-1/PD-L1 therapy in NSCLC patients. Sera from 31 metastatic NSCLC patients, eligible for anti-PD-1/PD-L1 or combined chemoimmunotherapy, were collected prior to treatment. Analysis of soluble biomarkers with TPD-L1 status showed significant up/down regulation of the immune inhibitory checkpoint markers (sSiglec7, sSiglec9, sULBP4 and sPD-L2) in patients with higher TPD-L1 (TPD-L1 >50%) expression. Moreover, correlation analysis showed significant positive linear correlation of soluble PD-L1 (sPD-L1) with higher TPD-L1 expression. Interestingly, only responders in the TPD-L1 >50% group showed significant down regulation of the immune inhibitory markers (sPD-L2, sTIMD4, sNectin2 and CEA). When responders vs. non-responders were compared, significant down regulation of other immune inhibitory biomarkers (sCD80, sTIMD4 and CEA) was recorded only in responding patients. In this, the optimal cut-off values of CD80 <91.7 pg/ml and CEA <1614 pg/ml were found to be significantly associated with better progression free survival (PFS). Indeed, multivariate analysis identified the cutoff-value of CEA <1614 pg/ml as an independent predictor of response in our patients. We identified here novel immune inhibitory/stimulatory soluble mediators as potential surrogate/predictive biomarkers for TPD-L1 status, treatment response and PFS in NSCLC patients treated with anti-PD-1/PD-L1 therapy.

Primary intrapulmonary thymoma a case report.

Primary intrapulmonary thymoma (PIT), defined as the presence of thymoma tissue in the lung without an accompanying mediastinal component, is uncommon and so offers a diagnostic quandary. We describe the case of PIT in an 81-year-old man.

Leptomeningeal Metastatic L858R EGFR-mutant Lung Cancer: Prompt Response to Osimertinib in the Absence of T790M-mutation and Effective Subsequent Pulsed Erlotinib.

Leptomeningeal carcinomatosis (LMC) is a known sequel of metastatic lung cancer and its treatment is challenging. Nevertheless, treatment options for LMC due to metastatic epidermal growth factor receptor-mutant (EGFR-mutant) lung adenocarcinoma are expanding. We present a 52-year-old male patient with metastatic non-small-cell lung cancer (NSCLC). The patient was found to have L858R mutation in exon 21 of the EGFR gene. He was initially treated with erlotinib, followed by afatinib/cetuximab, followed by chemotherapy. Thereafter, his disease progressed to LMC. Although tissue biopsy did not show T790M-mutation, osimertinib (160 mg once daily) promptly induced clinical and radiological response that continued for five months. High dose pulsed erlotinib (1500 mg weekly) improved his quality of life and extended his survival for a further four months.

Circulating exosomal immuno-oncological checkpoints and cytokines are potential biomarkers to monitor tumor response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients.

Immune checkpoint inhibitors (ICIs) including anti-PD-1 and anti-PD-L1 antibodies, have significantly changed the treatment outcomes of NSCLC patients with better overall survival. However, 15-40% of the patients still fail to respond to ICIs therapy. Identification of biomarkers associated with responses are mandated in order to increase the efficacy of such therapy. In this study we evaluated 27 serum-derived exosomal immuno-oncological proteins and 44 cytokines/chemokines before and after ICIs therapy in 17 NSCLC patients to identify surrogate biomarkers for treatment/monitoring patient stratification for maximum therapeutic benefit. We first confirmed the identity of the isolated exosomes to have their specific markers (CD63, CD81, HSP70 and CD91). We have demonstrated that baseline concentration of exosomal-PD-L1 (p<0.0001), exosomal-PD-L2 (p=0.0413) and exosomal-PD-1 (p=0.0131) from NSCLC patients were significantly higher than their soluble-free forms. Furthermore, the exosomal-PD-L1 was present in all the patients (100%), while only 71% of patients expressed tissue PD-L1. This indicates that exosomal-PD-L1 is a more reliable diagnostic biomarker. Interestingly, exosomal-PD-L2 expression was significantly higher (p=0.0193) in tissue PD-L1-negative patients compared to tissue PD-L1-positive patients. We have also shown that immuno-oncological proteins isolated from pre-ICIs treated patients were significantly higher in exosomes compared to their soluble-free counterparts (CD152, p=0.0008; CD80, p=0.0182; IDO, p=0.0443; Arginase, p<0.0001; Nectin-2, p<0.0001; NT5E, p<0.0001; Siglec-7, p<0.0001; Siglec-9, p=0.0335; CD28, p=0.0092; GITR, p<0.0001; MICA, p<0.0001). Finally, the changes in the expression levels of exosomal immuno-oncological proteins/cytokines and their correlation with tumor response to ICIs treatment were assessed. There was a significant downregulation of exosomal PD-L1 (p=0.0156), E-Cadherin (p=0.0312), ULBP1 (p=0.0156), ULBP3 (p=0.0391), MICA (p=0.0391), MICB (p=0.0469), Siglec7 (p=0.0078) and significant upregulation of exosomal PD-1 (p=0.0156) and IFN- γ (p=0.0156) in responding patients. Non-responding patients showed a significant increase in exosomal-PD-L1 (p=0.0078). Furthermore, responding-patients without liver-metastasis showed significant-upregulation of PD-1 (p=0.0070), and downregulation of ULBP1 (p=0.0137) and Siglec-7 (p=0.0037). Non-responding patients had significant-downregulation of ULBP3 (p=0.0317) in patient without brain-metastasis and significant-upregulation/downregulation of PD-L1 and ULBP3 (p=0.0262/0.0286) in patients with pulmonary-metastasis. We demonstrated for the first time that exosomal immuno-oncological proteins/cytokines are potential biomarkers to monitor response to ICIs therapy and can predict the clinical outcomes in NSCLC patients.

Prostate cancer metastases to the rectum: a case report.

Prostate cancer rarely metastasis to the rectum. Findings in the patient reported here emphasize the importance of the relationship between urinary and gastrointestinal symptoms in detecting prostatic neoplasms in older male patients.

PD-L1 immunostaining: what pathologists need to know.

BACKGROUND: Immune checkpoint proteins, especially PD-L1 and PD-1, play a crucial role in controlling the intensity and duration of the immune response, thus preventing the development of autoimmunity. These proteins play a vital role in enabling cancer cells to escape immunity, proliferate and progress. METHODS: This brief review highlights essential points related to testing for immune checkpoint therapy that histopathologists need to know. RESULTS: In recent years, several inhibitors of these proteins have been used to reactivate the immune system to fight cancer. Selection of patients for such therapy requires demonstration of PD-L1 activation on the tumor cells, best done by immunohistochemical staining of the tumor and immune cells using various antibodies with predetermined thresholds. CONCLUSIONS: Immune checkpoint therapy appears to be promising and is rapidly expanding to include a large variety of cancers.

Sclerosing epithelioid fibrosarcoma: in-depth review of a genetically heterogeneous tumor.

First described in 1995 by Meis-Kindbloom et al. as a variant of fibrosarcoma simulating carcinoma, sclerosing epithelioid fibrosarcoma (SEF) is a malignant soft tissue sarcoma characterized by epithelioid cells in dense sclerotic stroma, frequent immunoreactivity for MUC4 and heterogeneous genetic profile with recurrent EWSR1 gene rearrangement. It typically affects middle-age adults with a predilection for the lower extremity. It is believed that SEF is closely related to low-grade fibromyxoid sarcoma (LGFMS), both tumors show overlapping features in morphology, immunophenotype, and molecular profile. In this review, we discuss the clinical, morphologic, and immunohistochemical features of SEF with particular emphasis on its molecular diversity and relation to LGFMS.

Endobronchial metastases secondary to prostate cancer: A case report and literature review.

Metastatic disease from solid extrapulmonary tumours affects the lungs frequently. Endobronchial metastases (EM) however are very rare. Most commonly breast, colorectal and renal carcinomas can result in endobronchial metastases. EM secondary to a prostate primary are even more uncommon. We present an unusual case of a synchronous diagnosis of EM and primary prostate cancer. The diagnosis was confirmed on bronchoscopic endobronchial biopsies and immunohistochemical examination. Just 3 such cases have been reported to the best of our knowledge in the last 15 years. We discuss frequencies, similarities with previously reported cases, possible developmental modes and the diagnosis of EM. We conclude that patients with a current or previous diagnosis of an extrapulmonary malignancy with apparently trivial respiratory symptoms and/or unexplained weight loss should be considered for a bronchoscopy. Bronchoscopy and immunohistochemical profiling is the gold standard for diagnosing EM, as they may not be visible on cross sectional imaging.

Pseudomyogenic hemangioendothelioma of bone with rare WWTR1-FOSB fusion gene: Case report and literature review.

Pseudomyogenic hemangioendothelioma rarely arises in bone. WWTR1-FOSB fusion gene is rarely reported in PMHE of bone. Currently, fusion genes can be used as diagnostic markers in PMHE; however, their prognostic and therapeutic significance is unclear.