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.

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.

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.

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.

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.

Isolated pulmonary cryptococcosis in a patient with Crohn's disease treated with infliximab: A case report and literature review.

Tumor necrosis factor-alpha (TNF-α) inhibitors are widely used to treat various inflammatory conditions, where they have demonstrated excellent efficacy and tolerability. However, increased risk of infections is one of the most important concerns associated with these agents. Reactivation of tuberculosis and fungal infections have emerged as significant infective complications of anti-TNF-α therapy. Cryptococcus infection is an opportunistic fungal infection that can occur in patients receiving anti-TNF-α treatment. We report a rare case of isolated pulmonary cryptococcosis in a patient undergoing anti-TNF-α therapy for Crohn's disease. Our case should alert clinicians to the increased incidence and atypical presentation of pulmonary cryptococcosis in patients receiving anti-TNF-α treatment.

Schistosoma gallbladder polyp masquerading as a neoplasm: Rare case report and literature review.

Schistosomiasis affecting the gastrointestinal tract is common in tropical and subtropical areas but associated polyps presenting as gallbladder pathology are rare clinical entities necessitating high clinical suspicion.

A rare initial presentation of a thymic neuroendocrine tumor as Cushing's syndrome.

While evaluating the cause of Cushing's syndrome, biochemical confirmation should be sought first as imaging studies might misdirect the diagnosis toward the wrong problem. One of the rare secondary causes that should be kept in mind while evaluating Cushing's syndrome is the thymic neuroendocrine tumor.

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.

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.

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.

Purely Suprasellar (Hypothalamic) Atypical Teratoid Rhabdoid Tumor Presenting with Diabetes Insipidus and Panhypopituitarism in an Adult Male: A Case Report and Review of Literature.

Atypical teratoid rhabdoid tumor (ATRT) is a rare primary malignant tumor of the central nervous system. Little knowledge is available about natural history, behavior, prognosis, and best management guidelines of such tumor. Its occurrence in adults is very rare and more predominant in females. Locations in adults are mainly cerebral hemispheres, but recently, more cases are reported in sellar/suprasellar cisterns. We are reporting a case of purely suprasellar ATRT of a middle aged male who presented initially with diabetes insipidus (DI).

Diagnostic performance of multi-parametric MRI to differentiate benign sex cord stromal tumors from malignant (non-stromal and stromal) testicular neoplasms.

PURPOSE: Testicular stromal tumors are uncommon, although mostly benign. The purpose of this study is to assess the role of multi-parametric MRI in differentiating benign testicular stromal tumors from malignant testicular neoplasms (non-stromal and stromal). METHODS: A single-center retrospective study comparing benign stromal tumors (STs) to malignant testicular neoplasms (MTNs) was conducted. MR imaging assessment included tumor size, T2- and T1-weighted signal intensity, T2- and T1-weighted texture pattern, diffusion restriction, presence of hemorrhage and/or necrosis, and measurement of apparent diffusion coefficient and dynamic contrast enhancement (DCE). Inter-observer agreement was assessed using Cohen's kappa and Bland-Altman and data were compared using independent t-tests or χ2. Receiver operating characteristic curve analysis was used to test models incorporating various imaging features. RESULTS: Radical orchiectomy and histopathology revealed 20 testicular neoplasms: seven STs (35%) and thirteen MTNs (65%). MTNs were significantly larger in size than STs (5.1 ± 2.36 cm vs. 1.27 ± 0.56 cm; p-value < 0.001). STs demonstrated more hypointense T2W signal (85.7% vs. 46.2%; p-value < 0.09), less T2W heterogeneous texture (14.3% vs. 61.5%; p-value < 0.04), and less diffusion restriction (16.7% vs. 83.3%; p-value < 0.01) in comparison to MTNs. STs demonstrated mainly homogenous post-contrast enhancement pattern (71.4% vs. 7.7%; p-value < 0.004), while MTNs showed primarily heterogeneous enhancement pattern (77% vs. 14.3%; p-value < 0.02). STs revealed greater corrected venous phase enhancement (STs: 0.59 ± 0.29; MTNs: 0.25 ± 0.25; p-value < 0.03). STs showed higher ADC values, though the difference was not statistically significant (p-value < 0.25). A model combining T2W, DWI, and DCE features showed the best overall diagnostic accuracy with area under ROC curve of 0.99 and confidence interval ranging from 0.94 to 1. CONCLUSION: Multi-parametric MRI can potentially differentiate benign stromal tumors from malignant testicular neoplasms, which can help to avoid radical orchiectomy. However, future studies using larger sample sizes are needed to validate our results.

Pleural effusion as an isolated finding in COVID-19 infection.

Common radiological findings of COVID -19 infection include bilateral ground-glass opacities in lower lobes with a peripheral distribution. Pleural effusion is considered a rare manifestation of COVID -19 infection. We present a 52 years old patient with a three-week history of right-sided pleuritic chest pain, fever, and dyspnea. Laboratory investigations revealed high C-reactive protein and ferritin levels and a positive COVID-polymerase chain reaction (PCR) from a nasopharyngeal swab. Chest X-ray and Computed tomography (CT) identified a moderate right-sided pleural effusion, which was exudative with mixed cellularity and high Lactate dehydrogenase (LDH). Histopathology of thoracoscopic pleural biopsy didn't reveal granulomas, malignancy, or any microbiological growth. We postulate that having ruled out any other cause the effusion was likely related to the Covid-19 infection. Our case highlights that COVID-19 can present with isolated pleural effusions, therefore it should be kept as an etiology of effusions especially if other possible causes have been ruled out.

Rosai-Dorfman disease of cranial and spinal origin - A case series.

BACKGROUND: Rosai-Dorfman disease (RDD) is an idiopathic nonneoplastic lymphadenopathy disorder which is characterized by lymph node enlargement, but it may also presents primarily involving a variety of extranodal sites, including central nerves system and craniospinal axis. This study reports five cases of craniospinal RDD, with review of epidemiology, clinical presentation, imaging, and histopathological features with current management strategies. CASE DESCRIPTION: Five cases of RDD are diagnosed at Hamad General Hospital, Qatar, during 2013-2018. Two cases had dural-based cranial lesions with overlying cranial involvement while three cases were having extradural thoracic spine lesions. All cases underwent surgical intervention and confirmed by histopathology. CONCLUSION: Craniospinal RDD is a rare clinical presentation and poses significant diagnostic challenges preoperatively due to its similarity with other neoplastic or inflammatory diseases. Surgical option to remove compressive neural pathology provides a good clinical outcome with no recurrence in long-term follow-up.

Spinal Metastasis of Cerebral Glioblastoma with Genetic Profile: Case Report and Review of Literature.

BACKGROUND: Spinal metastasis of cerebral glioblastoma (GBM) is rare, with some reports suggesting a prevalence of 1%-2%. CASE DESCRIPTION: Herein, we present 2 unique cases of spinal metastasis of cerebral GBM, 1 of which was histologically proven to be a drop spinal GBM metastasis. The first case was a 25-year-old female who presented with a spinal intradural intramedullary spinal lesion a few months after resection of a left temporal lobe GBM (isocitrate dehydrogenase wild type). The patient underwent surgical resection of the new lesion, and subsequent histopathologic examination proved that the intramedullary spinal lesion was GBM. The patient experienced full recovery postoperatively, and then a few months later, she presented again with widespread drop metastasis of the spinal cord. The second case is a middle-aged male with right temporal GBM who developed spinal metastasis 10 months after his diagnosis. CONCLUSIONS: We are reporting these 2 cases due to the rarity of spinal metastasis in GBM. We reviewed the current literature and included genetic and molecular profiles in the discussion. Currently, there are no established treatment guidelines for GBM spinal metastasis. The Stupp protocol after initial brain surgery for GBM did not appear to have beneficial effects on prolonging survival in these patients with spinal metastasis. The goal of treatment was primarily to alleviate pain and neurologic deficits with no effect on overall outcome. Prognosis following the diagnosis of spinal metastasis is poor.

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.

CK20 and CK5/6 Immunohistochemical Staining of Urothelial Neoplasms: A Perspective.

Cytokeratins belong to the family of intermediate filaments. They are expressed in a highly specific manner in epithelial cells where they play a crucial role in the integrity and mechanical stability of the cells. Several types of cytokeratins have been described in normal as well as neoplastic urothelium. In the case of urothelial neoplasms expression of CK20 and CK5/6 has been shown in several studies to have diagnostic and prognostic implications. Thus, low-grade urothelial carcinoma manifests CK expression limited to the umbrella cells, while high-grade tumors usually have an expression in the entire thickness of the urothelium except for the basal layer. CK5/6 expression on the other hand is expressed in the basal cells in all low-grade and some high-grade urothelial carcinomas. Diffuse CK20 staining accompanied by loss of CK5/6-positive basal layer is usually associated with aggressive clinical behavior. Double staining of the slides for these cytokeratins may facilitate proper interpretation and correlation.

Targeting Wnt/EZH2/microRNA-708 signaling pathway inhibits neuroendocrine differentiation in prostate cancer.

Prostate cancer (PC) castration resistance has been linked to the differentiation of PC luminal cells into hormone-refractory neuroendocrine (NE) cells. However, the molecular mechanisms controlling the emergence of lethal NE prostate cancer (NEPC) remain unclear. The present study aimed to investigate the mechanisms underlying the transition from prostate adenocarcinoma to NEPC. The microRNA miR-708 was involved in NE differentiation and was downregulated in NEPC cells and tumor specimens. miR-708 targeted Sestrin-3 to inhibit Forkhead Box O1 (FOXO1) phosphorylation, resulting in apoptosis of prostate adenocarcinoma cells and AKT-inactivated NEPC cells, the latter of which was consistent with the progression of tumor xenografts in mice under miR-708 treatment. In silico analysis of PC and NEPC tumor specimens suggested that the polycomb repressive complex subunit Enhancer of zeste homolog 2 (EZH2) was particularly overexpressed in NEPC. Notably, EZH2 bound to the miR-708 promoter and induced its silencing in NEPC. Inhibition of EZH2 prevented NE differentiation of PC cells. EZH2 expression was regulated by both Cyclin Dependent Kinase 1 (CDK1) and Wnt signaling. Silencing transcription factor 4 (TCF4), as a key protein in Wnt signaling, prevented NEPC formation. These results provide a molecular basis for the roles of miR-708 and EZH2 in NE differentiation in PC and highlight a new paradigm in NEPC formation and survival.