New insights in diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare epithelial neoplasms derived from pluripotent endocrine cells along the gastrointestinal tract and pancreas. GEP-NENs are classified into well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Despite overlapping morphological features, GEP-NENs vary in molecular biology, epigenetic, clinical behavior, treatment response, and prognosis features and remain an unmet clinical challenge. In this review, we introduce recent updates on the histopathologic classification, including the tumor grading and staging system, molecular genetics, and systemic evaluation of the diagnosis and treatment of GEP-NENs at different anatomic sites, together with some insights into the diagnosis of challenging and unusual cases. We also discuss the application of novel therapeutic approaches for GEP-NENs, including peptide receptor radionuclide therapy, targeted therapy, and immunotherapy with immune checkpoint inhibitors. These findings will help improve patient care with precise diagnosis and individualized treatment of patients with GEP-NENs.

Sulfatase-2 Regulates Liver Fibrosis through the TGF-ß Signaling Pathway.

Transforming growth factor-ß (TGF-ß) activates hepatic stellate cells (HSCs), which drive liver fibrosis via the production and deposition of extracellular matrix (ECM). We aimed to elucidate the mechanistic role of sulfatase-2 (SULF2) in liver fibrosis. To this end, we induced liver fibrosis in wild-type (WT) and SULF2 knockout (Sulf2-KO) mice (6-8 weeks-old) via bile duct ligation (BDL), intraperitoneal injection of carbon tetrachloride (CCl4) or thioacetamide (TAA). The levels of fibrosis in the liver sections were assessed via Sirius red and Masson's trichrome staining, immunohistochemistry and immunoblotting for α-smooth muscle actin (α-SMA) and hydroxyproline. To evaluate the interaction between TGF-ß and SULF2, we transfected human HSCs with scrambled control shRNA and shRNA constructs targeting SULF2 and measured α-SMA expression following treatment with TGF-ß1 ligand. We show here that knockout of SULF2 significantly decreases collagen content, as well as bands of bridging fibrosis, as demonstrated by Sirius red, Masson's trichrome and α-SMA staining after BDL, CCl4 and TAA injection in Sulf2-KO versus WT mice. In all three models of liver fibrosis, we observed significantly lower levels of hydroxyproline in the Sulf2-KO mice compared to the WT mice. HSCs with reduced levels of SULF2 failed to significantly express α-SMA and collagen type I following treatment with TGF-ß1. Furthermore, SULF2 co-localizes with TGFBR3 and the in vitro knockdown of SULF2 in HSCs decreases the release of TGF-ß1 from TGFBR3. Together, these data suggest that SULF2 regulates liver fibrosis via the TGF-ß signaling pathway. Pharmacologic inhibition of SULF2 may represent a novel therapeutic approach to improve liver fibrosis.

Hepatocellular carcinoma in non-cirrhotic liver: A comprehensive review.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, which in turns accounts for the sixth most common cancer worldwide. Despite being the 6th most common cancer it is the second leading cause of cancer related deaths. HCC typically arises in the background of cirrhosis, however, about 20% of cases can develop in a non-cirrhotic liver. This particular subgroup of HCC generally presents at an advanced stage as surveillance is not performed in a non-cirrhotic liver. HCC in non-cirrhotic patients is clinically silent in its early stages because of lack of symptoms and surveillance imaging; and higher hepatic reserve in this population. Interestingly, F3 fibrosis in non-alcoholic fatty liver disease, hepatitis B virus and hepatitis C virus infections are associated with high risk of developing HCC. Even though considerable progress has been made in the management of this entity, there is a dire need for implementation of surveillance strategies in the patient population at risk, to decrease the disease burden at presentation and improve the prognosis of these patients. This comprehensive review details the epidemiology, risk factors, clinical features, diagnosis and management of HCC in non-cirrhotic patients and provides future directions for research.

Autologous Graft-Versus-Host Disease of the Gastrointestinal Tract in Patients With Multiple Myeloma and Hematopoietic Stem Cell Transplantation.

Multiple myeloma (MM) is the most common indication for autologous hematopoietic stem cell transplantation (HSCT) in North America. Despite occurring in up to 50% of patients undergoing allogeneic HSCT, the incidence of graft-versus-host disease (GVHD) after autologous HSCT is reportedly only 5-20%. Gastrointestinal involvement with graft-versus-host disease (GI GVHD) is a common and serious complication of allogeneic HSCT. GI GVHD after autologous transplant, which is referred to as autologous GVHD (auto-GVHD), has also been described. Auto-GVHD is usually less severe than allogeneic GVHD, and it can be one of the manifestations of engraftment syndrome with release of inflammatory cytokines and infiltration of auto-reactive T cells into affected tissue. Seventy-nine percent of patients respond well to corticosteroids without evidence of recurrence. However, cases of severe auto-GVHD lacking good response to corticosteroids have been reported, most notably in MM patients. Here we present two cases of autologous GI GVHD in recipients of autologous HSCT for treatment of MM. Our cases demonstrate two distinct clinical and endoscopic presentations of this uncommon entity. In the first case, the patient had more severe clinical symptoms accompanied by radiographic, endoscopic, and pathologic findings. The hospital course was complicated by cryptosporidium enteritis and acute cholecystitis in the setting of increased immunosuppression with a corticosteroid for presumed auto-GVHD. In contrast, the second case presented a patient with normal radiologic and endoscopic findings. Pathology revealing frequent apoptotic bodies led to auto-GVHD as a diagnosis. Both our patients received similar courses of chemotherapy prior to autologous HSCT (four cycles of a proteasome inhibitor, lenalidomide, and dexamethasone). Our work highlights the importance of maintaining a high level of clinical suspicion for auto-GVHD in patients presenting with GI symptoms after autologous HSCT, as it is a potentially treatable pathology that may be easily confused with other conditions. Health care providers should be aware of the potential complications of auto-GVHD after autologous HSCT and should be suspicious of auto-GVHD if GI symptoms occur, especially in patients receiving immunomodulatory therapy for MM, even in the absence of gross endoscopic findings.

Gastric Spindle Cell Neuroendocrine Tumor Mimicking Gastrointestinal Stromal Tumor: Unique Morphology and Diagnostic Pitfall.

Gastric neuroendocrine tumors (GNETs) with spindle cell morphology are extremely rare. We present a case of a 49-year-old female patient with a history of systemic lupus erythematosus, Sjogren's syndrome, and gastroesophageal reflux disease. She was initially thought to have a spindle cell gastrointestinal stromal tumor per histological studies of the fundic polypectomy samples. Immunohistochemically, the tumor cells were negative for CD117, and CD34, but positive for chromogranin, synaptophysin, and CD56 with a 6% Ki-67 index, consistent with a spindle cell-type well differentiated neuroendocrine tumor, World Health Organization (WHO) Grade 2. To the best of our knowledge, this is the first case report of a gastric spindle cell neuroendocrine tumor in the English literature.

Primary Gastric ALK-negative EBV-negative Anaplastic Large Cell Lymphoma Presenting with Iron Deficiency Anemia.

Anaplastic large cell lymphoma (ALCL) is a rare subtype of non-Hodgkin lymphoma (NHL). Primary gastric anaplastic lymphoma kinase (ALK) negative ALCL is extremely rare. Diagnosis of primary gastric ALK-negative ALCL is difficult to establish and prognosis is worse than ALK-positive ALCL. Here, we report a case of an 82-year-old man with a history of cerebrovascular disease presented with weakness and iron deficiency anemia. He denied any abdominal discomforts. The esophagogastroduodenoscopy revealed a large ulcerated, friable mass in the gastric body which encompassed about 80% of entire stomach. Biopsy showed a high grade malignant tumor composed of undifferentiated epithelioid atypical cells, making it difficult to determine the cell of origin. Immunostains for lymphoma, carcinoma, and sarcoma were performed. The tumor cells were positive for CD30, CD4, and CD43, negative for CD20, CD3, ALK-1 and Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) in situ hybridization, establishing the diagnosis of primary gastric ALK-negative ALCL. The patient is currently undergoing chemotherapy with clinical improvement. To the best of our knowledge, this is the first reported case of primary gastric ALK-negative and EBV-negative anaplastic large T-cell lymphoma that presented without gastroenterological symptoms.

Comparison of endoscopic ultrasound guided fine needle aspiration and PET/CT in preoperative diagnosis of pancreatic adenocarcinoma.

BACKGROUND: Endoscopic ultrasound guided fine needle aspiration (EUS-FNA) is the procedure of choice to investigate and sample pancreatic masses for the preoperative diagnosis of pancreatic ductal adenocarcinoma (PDAC). The role of 18fluoro-deoxyglucose positron emission tomography/computed tomography (PET/CT) in PDAC is debated. This study evaluates the role of EUS-FNA as compared to PET/CT in the preoperative evaluation of PDAC. METHODS: Preoperative evaluation by PET/CT and EUS-FNA was performed on 25 patients with pancreatic solid lesions, who underwent a subsequent Whipple procedure or partial pancreatic resection. RESULTS: This series included 19 PDACs and 6 non-PDACs including 1 metastatic breast ductal adenocarcinoma, 2 low grade neuroendocrine tumors, 2 chronic pancreatitis and 1 gastrointestinal tumor abutting the pancreas. EUS-FNA correctly diagnosed 18 of 19 PDACs, 1 metastatic breast ductal adenocarcinoma and all 5 of the other non-PDAC cases. One case of well differentiated PDAC was negative on EUS-FNA. PET/CT provided excellent size and was positive in 14 of 19 PDACs and the metastatic breast ductal adenocarcinoma. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy for EUS-FNA in diagnosis of selected pancreatic tumors were 91%, 100%, 100%, 50% and 92%, respectively, while they were 65%, 100%, 100%, 20% and 68% for PET/CT, respectively. CONCLUSIONS: Compared to PET/CT, EUS-FNA has a higher sensitivity and accuracy for preoperative diagnosis of PDAC. However, PET/CT provides excellent size, volume and stage information. A combination of both PET/CT and EUS will better help guide diagnosis and treatment of pancreatic adenocarcinoma.

Adipose Triglyceride Lipase (ATGL) Expression Is Associated with Adiposity and Tumor Stromal Proliferation in Patients with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Obesity is an established risk factor for the development of pancreatic ductal adenocarcinoma (PDAC). However, the pathophysiology of how increased adiposity increases the risk for PDAC has not been fully elucidated. Adipose triglyceride lipase (ATGL) is a lipase that catabolizes triglyceride hydrolysis and has been implicated in the development of breast cancer. We hypothesized that overweight patients with PDAC would demonstrate higher tumor ATGL expression compared to non-overweight patients with PDAC. MATERIALS AND METHODS: Immunohistochemical analysis for ATGL expression was performed on PDAC tissues from 44 patients after Whipple procedure or distal pancreatectomy. Correlation of ATGL expression with clinicopathological features was evaluated. RESULTS: A total of 23/44 (52.2%) PDACs showed low level ATGL immunoreactivity, while 21/44 (47.8%) showed a high level, with moderate to strong positive ATGL immunoreactivity in more than 50% of the tumor cells. Chi-squared testing revealed a statistically significant association between high ATGL expression and both BMI >25 kg/m2 (χ2=5.74, p=0.017) and increased tumor stroma (χ2=19.14, p<0.001). Chi-squared testing failed to reveal a statistically significant association when comparing ATGL expression by lymph node metastasis, histological grade, tumor size, patient age, patient sex and presence of fat invasion. CONCLUSION: Our results suggest that increased ATGL expression is associated with increased adiposity and stromal proliferation in patients with PDAC, making it a possible key protein in how obesity increases the risk of PDAC.

Liver Metastasis of Urothelial Carcinoma with Hepatoid Features: An Unusual Morphological Finding.

Bladder cancer comprises of many well-known variants and divergent histologies, both of urothelial and adenocarcinomatous type. Extrahepatic tumors with features that resemble hepatocellular carcinoma, often referred to as hepatoid adenocarcinomas, have been described in many different organs, and are aggressive and prognostically unfavorable. Hepatoid features of bladder cancer are unusual and rarely reported. We report a unique case of a metastatic lesion to the liver consisting of a urothelial carcinoma with hepatoid features, a tumor that likely falls within the hepatoid adenocarcinoma spectrum. It is an unusual morphological finding in urothelial carcinoma and is important to recognize due to its potential for aggressive behavior, particularly when it involves a liver lesion in which hepatocellular carcinoma may be suspected.

The role of computed tomography in following up pediatric skull fractures.

BACKGROUND: Despite the added radiation exposure and costs, the role of computed tomography (CT) in following pediatric skull fractures has not been fully evaluated. METHODS: We reviewed the radiology reports and images of the initial and follow-up head CT examinations of children with skull fractures to determine whether any interval changes in the fracture morphology and associated complications necessitate a change in clinical management. RESULTS: A total of 316 pediatric cases of skull fractures were identified, including 172 patients with and 144 without follow-up scans. At follow-up, 7% of skull fractures were unchanged, 65% healing, and 28% healed. No patient showed findings to cause a change in clinical management or a need for further medical or surgical intervention regardless of the number and patterns of the fractures or the initial intracranial complications such as intracranial hemorrhage, pneumocephalus, and traumatic brain injuries. CONCLUSIONS: Head CT may be unnecessary in following pediatric skull fractures in asymptomatic patients to avoid added radiation exposure and cost.

Idelalisib-induced colitis and skin eruption mimicking graft-versus-host disease.

INTRODUCTION: Idelalisib is a selective inhibitor of the delta isoform of phosphatidylinositol 3-kinase which was approved by the United States Federal Drug Administration in 2014 for the treatment of relapsed chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma. Drug-induced injury of the gastrointestinal tract is a relatively frequent but usually under-recognized disease entity. CASE PRESENTATION: We report the case of a 56-year-old male with a history of relapsed follicular lymphoma status post allogenic bone marrow transplant who developed severe diarrhea with a skin eruption mimicking graft-versus-host disease (GVHD) 6 months after starting idelalisib. He underwent a colonoscopy demonstrating a grossly normal-appearing colon and terminal ileum. Biopsies taken during the procedure revealed mild active ileitis, colitis, and proctitis with frequent epithelial apoptosis, and focal intra-epithelial lymphocytosis. Skin biopsies revealed sub-acute spongiotic dermatitis suggestive of either contact dermatitis or an eczematous drug reaction. Symptoms were attributed to idelalisib given their resolution with withdrawal of the drug in conjunction with the skin and colonic biopsies. CONCLUSION: High clinical suspicion and awareness of the histological features of idelalisib-associated colitis is important to distinguish it from potential mimickers such as GVHD and infectious colitis.

Epstein-Barr Virus-Associated Acute Liver Failure Present in a 67-Year-Old Immunocompetent Female.

Acute liver failure (ALF) is a rare illness with a high mortality rate. The only favorable management is emergent liver transplantation. About 13% of ALF cases have no clear etiology. Epstein-Barr virus (EBV)-associated ALF accounts for less than 1% of all ALF cases, and is seen mostly in adults younger than 40 years. There are only a few cases of EBV-associated ALF in elderly immunocompromised adults. We report a case of ALF in an immunocompetent 67-year-old woman caused by EBV infection that was treated by orthotopic liver transplantation (OLT). The diagnosis of EBV-associated ALF was established by EBV-DNA polymerase chain reaction (PCR) and EBV-encoded RNA (EBER-RNA) in situ hybridization (EBER-RISH). The patient is currently doing well 6 months after transplantation without any evidence of clinical EBV infection. This case illustrates the importance of early recognition and diagnosis of EBV-associated ALF by detection of EBV from liver biopsy, especially when patients are immunocompetent and other causes are excluded. To the best of our knowledge, this is the first case of EBV-associated ALF present in an immunocompetent elderly female.

Oncocytoma of the Submandibular Gland: Diagnosis and Treatment Based on Clinicopathology.

Background. Submandibular oncocytomas are rare benign salivary gland neoplasms. They are typically found in Caucasian patients aged 50-70 years with no gender preference. Due to the overlapping histological and clinical features of head and neck tumors, they are often misdiagnosed. Methods. We report a case of unilateral submandibular gland oncocytoma in a 63-year-old Caucasian man. Results. The patient underwent unilateral submandibular gland resection and histopathologic analysis of the tumor specimen. On follow-up at 2 weeks and 1 year, no recurrence was identified. Conclusion. Submandibular oncocytomas are best diagnosed with preoperative FNA and CT imaging and have distinctive findings on cytology and histology. CT followed by fine-needle aspiration cytology would be the preferred diagnostic modalities. Due to its low rate of malignant transformation and recurrence, the best treatment is local resection with follow-up as necessary.

Synchronous Type 1 Papillary Renal Cell Carcinoma in a Patient with Rectal Adenocarcinoma.

Synchronous colorectal cancer (CRC) and renal cell carcinoma (RCC) is relatively rare, particularly when the synchronous RCC is of papillary subtype, which is exceedingly rare. We report a case of a 63-year-old Caucasian man with synchronous CRC and type 1 papillary RCC. After the patient presented with three episodes of melena, colonoscopy followed by biopsy confirmed rectal adenocarcinoma. The computed tomographic imaging also showed an incidental mass of the upper pole of the left kidney suspicious for RCC. Once chemoradiation therapy was successfully completed, an ultra low anterior resection and partial nephrectomy were performed concurrently. Histological examination showed colorectal adenocarcinoma (ypT1 N0 Mx) and papillary RCC type I (pT1a Nx Mx). Although the exact pathogenesis of synchronous CRC and RCC is unknown, it has been suggested that almost all patients with this entity do not have Lynch syndrome. The majority of these patients usually present with CRC-related symptoms and then, during workup, are subsequently found to have an incidental renal mass that is most often diagnosed as clear cell subtype of RCC. To the best of our knowledge, this is only the second reported case of synchronous CRC and type 1 papillary RCC.

Gastrointestinal Pyogenic Granuloma (Lobular Capillary Hemangioma): An Underrecognized Entity Causing Iron Deficiency Anemia.

Pyogenic granuloma (PG), more accurately known as lobular capillary hemangioma, is a benign vascular tumor that usually occurs in the skin or oral mucosa. This lesion is rarely reported in the gastrointestinal tract but is known to bleed if not resected. We herein describe a case series with the clinical, endoscopic, and histologic findings of four cases of gastrointestinal PG at our institution. In addition, we provide a review of the literature and summation of all reported cases of PG specific to the gastrointestinal tract. Based on our experience, we suggest that the actual incidence of gastrointestinal PG may in fact be higher than reported because PG can be unrecognized or improperly diagnosed. It is important for the clinician to properly recognize this lesion as a source of anemia and its propensity to bleed during biopsy or resection.

Synchronous Quadruple Primary Neoplasms: Colon Adenocarcinoma, Collision Tumor of Neuroendocrine Tumor and Schwann Cell Hamartoma and Sessile Serrated Adenoma of the Appendix.

Quadruple synchronous primary neoplasms are very rare with only three cases reported in the English-speaking literature to date. Collision tumors are also rare entities, especially of the appendix. We herein report a case of synchronous quadruple primary neoplasm in a 95-year-old female. She was diagnosed with colon adenocarcinoma, sessile serrated adenoma of the appendix and a collision tumor composed of a well-differentiated neuroendocrine tumor and Schwann cell hamartoma. Histological examination and immunohistochemistry supported these four lesions as separate entities. This case is unique because we report the diagnosis of quadruple synchronous primary, an extremely rare occurrence, in addition to a collision tumor of the appendix. We also provide a review of the literature for synchronous neoplasms and collision tumors.

Synchronous Ileal Neuroendocrine Tumor and Ovarian Steroid Cell Tumor Present in a Female With Hyperandrogenism.

Well-differentiated neuroendocrine tumors (NET) of the ileum are generally slow-growing tumors with metastatic potential that may cause systemic symptoms from the secretion of serotonin, cortisol, and other biologically active substances. Likewise, steroid cell tumors of the ovary are slow-growing tumors that cause systemic symptoms from the functional production of androgens, estrogens, and other hormones. To the best of our knowledge, synchronous ileal NET and ovarian steroid cell tumors have not been previously reported in the English literature. We present a case of a 59-yr-old woman with 2 primary tumors that were found incidentally: a Stage III (T2N1M0) 1.6 cm well-differentiated NET (NET G2) of the terminal ileum with metastasis to a mesenteric lymph node and a 2.4 cm steroid cell tumor of the left ovary. The patient had suffered from hyperandrogenism for several years before diagnosis of an ovarian steroid cell tumor, but had no symptoms attributable to the NET. From review of the literature, this is the first case description of these 2 primaries arising in the same individual.