Clinicopathological Characteristics of Extrahepatic Biliary Neuroendocrine Neoplasms in the Gallbladder, Extrahepatic Biliary Tract, and Ampulla of Vater: A Single-Center Cross-Sectional Study

BackgroundSignificant changes were made in the grading and staging systems for neuroendocrine neoplasms (NENs) in 2017. Therefore, a clinical report to comprehensively update the clinicopathological characteristics, therapeutic approaches, and prognosis of these patients should be drafted.MethodsWe retrospectively reviewed a database of 16 patients who developed NENs or mixed endocrine non-endocrine neoplasms (MiNENs) after curative resection. Among them, eight had ampulla of Vater (AoV) tumors, and eight had non-AoV tumors. One patient had NEN Grade 1, five had NEN Grade 2, and five had NEN Grade 3 (G3); all had poorly differentiated neuroendocrine carcinoma. Five patients had MiNEN or combined carcinoma.ResultsThe mean age was 57.88 years. The overall survival rates after curative surgery at 1, 3, and 5 years were 87.1, 80.4, and 71.4%, respectively. The 1-, 3-, and 5-year disease-free survival rates were 87.1%, 79.8%, and 71.8%, respectively. In univariate analysis, age >65 years, mitotic count (>20/10 high-power fields), Ki-67 index >20%, and presence of stones were significant prognosticators, whereas only the mitotic count was statistically significant in the multivariate analysis. Age >65 years (p=0.039), a Ki-67 index >20% (p=0.03), presence of stones (p=0.021), G3 stage disease, MiNEN (p=0.002), or perineural invasion (p<0.001) were more frequently observed in the non-AoV group than in the AoV group.ConclusionHigh mitosis count had a greater effect on extrahepatic biliary NEN than the tumor-node-metastasis staging system. Patients with AoV tumors had better prognostic predictor factors compared to those with non-AoV tumors.

Neuroendocrine Tumours of Extrahepatic Biliary Tract: Series of Four Cases with Literature Review

Neuroendocrine tumours (NETs) originating from extrahepatic bile duct are an extremely rare entity. They are typically slow growing tumours with malignant potential. Commonly presenting as obstructive jaundice, preoperative clinico-radiologic differentiation between extrahepatic biliary tract neuroendocrine tumours and cholangiocarcinoma is difficult and the final diagnosis is usually established after surgical histopathology and immunohistochemistry examination. R0 resection offers the only curative option with good long term outcomes for Well differentiated NETs (grade1, grade2 and grade3) whilst the aggressive poorly differentiated Neuroendocrine Carcinoma (NEC) needs multimodality approach. We present our experience of management of four cases including three cases of grade II NET and one case of NEC undergoing surgical resection at a single centre with a short review of available literature.

Tissue Is the Issue - A Case of Malignant Insulinoma

Introduction: Insulinomas are rare, functioning pancreatic neuroendocrine tumors, predominantly benign (90%). Most are sporadic, but they can occur as part of inherited disorders. Large size insulinomas are more likely to be malignant. 68Gallium (Ga)-DOTATATE scan is an essential tool in diagnosis and treatment of pancreatic neuroendocrine tumors. However, tissue diagnosis is the ultimate prognosis predictor and treatment guide. Clinical Case: An 80-year-old man presented with left ankle fracture after a syncopal episode. In the past several months he reported multiple episodes of lightheadedness. He denied history of diabetes. Past medical and surgical history included prostate cancer, gastroesophageal reflux disease and bilateral orchiectomy for undescended testes. His left ankle appeared swollen, otherwise the exam was unremarkable: he was well-nourished, the abdomen was soft and nontender, there were no palpable masses. He was noted to have several episodes of hypoglycemia. Hypoglycemia work up included negative sulfonylurea screen, plasma glucose 51 mg/dl (60-99 mg/dl), insulin of 31 uIU/ml (3-25 uIU/ml), proinsulin 85.4 pmol/L (&lt;8 pmol/L), C peptide 3.4 ng/ml (1.1-4.4 ng/ml). Abdominal Computed Tomography with contrast showed a 4.7 x 3.1 cm exophytic mass in the body of pancreas, a 5.3 x 5 cm mass in the head of pancreas and multiple ill-defined hepatic lesions concerning for metastatic disease. 68Ga-DOTATATE scan revealed an avid pancreatic mass and multiple avid foci throughout the liver suspicious for metastatic disease. Octreotide and intravenous dextrose were started for the treatment of persistent hypoglycemia. He underwent Whipple procedure and resection of the metastatic liver lesions. Postoperatively hypoglycemia resolved. The pathology revealed large cell pancreatic neuroendocrine carcinoma with areas of well differentiated tumor and multiple liver metastatic neuroendocrine carcinoma, Ki-67 of 50-80% was reported in the primary tumor and metastatic lesions. Discussion: Metastatic insulinomas carry a significant morbidity and mortality risk. Surgical resection to decrease tumor burden can reduce the risk of hypoglycemia. Histopathology is essential in treatment decision making. Surprisingly our patient’s pathology revealed poorly differentiated neuroendocrine carcinoma, changing the prognosis and treatment. Treatment with platinum-based chemotherapy and etoposide is the standard of care for aggressive neuroendocrine neoplasms. Despite hypoglycemia resolution following surgery and good DOTATATE uptake by the well differentiated neuroendocrine tumor portion, our patient’s prognosis remained poor in view of the high-grade carcinoma. Due to complicated hospital course, and decreased functional status patient was not a candidate for chemotherapy immediately post hospital discharge.

Comprehensive analysis of mutational and clinicopathologic characteristics of poorly differentiated colorectal neuroendocrine carcinomas

Poorly differentiated neuroendocrine carcinoma (NEC) is a rare subtype of colorectal cancer (CRC). This study aimed to investigate clinicopathologic characteristics of colorectal NECs and elucidate genomic differences and similarities between colorectal NECs and colorectal adenocarcinomas (ACs). A total of 30 colorectal NECs were screened for frequently identified CRC oncogenic driver genes by targeted next-generation sequencing of 382 genes. The median age of the patients was 67 years (range, 44 to 88 years). NECs occurred predominantly in the rectum (47%) and exhibited multiple adverse prognostic pathologic factors, including frequent lymphatic and vascular invasions, high rates of lymph node metastasis and distant metastasis and advanced TNM stage. The 1-, 3-, and 5-year overall survival rates of NEC patients were 46.7%, 36.4%, and 32.7%, respectively, with a median overall survival period of 11.5 months. In a molecular analysis, NECs showed high rates of BRAF mutation (23%), predominantly p.V600E (71%), and alterations in RB1 (47%), particularly deletion (57%). The frequencies and distributions of other genes, such as KRAS, APC, SMAD4, and PIK3CA, and microsatellite instability status were similar to those of ACs. These findings provide beneficial information for selecting therapeutic options, including targeted therapy, and a better understanding of the histogenesis of this tumour.

Clinico-pathologic Features of Esophageal Poorly Differentiated Neuroendocrine Carcinomas, a Case Series and Review of Literature

Introduction/Objective Esophageal neuroendocrine carcinomas (NECs) constitute an extremely rare and distinct group of neoplasms. The clinico-pathologic characteristics are poorly understood and differ starkly from high grade well differentiated neuroendocrine tumors. Only one case series describing clinico-pathologic features of NECs has been described in recent literature. Methods We describe a case series of three patients highlighting the typical presentation, diagnostic techniques and pathologic attributes for this rare disease process. Results All three patients were middle age to elderly with two males (ages 58 and 83) and one female (age 72). The typical presentation was dysphagia (2/3, 66%) followed by severe GERD (1/3, 33%). Typical locations were distal esophagus (2/3, 66%) and gastro-esophageal junction (1/3, 33%). Computed tomography showed bulky masses in all patients (3/3, 100%) with median size of 5.6 cm. PET imaging showed metastatic disease (mediastinal or epigastric lymphadenopathy and lung metastasis) in 2/3, 66% of the patients. All the patients were found to have necrotic masses on EGD with biopsy showing poorly differentiated neuroendocrine carcinoma in all (3/3, 100%). Immuno- histochemical stains revealed Synaptophysin positivity in 3/3, 100%, Chromogranin in 1/3, 33% and CD56 in 1/3, 33% of the patients. Patients with metastatic disease at presentation (2/3, 66%) opted for palliative care while the patient without any evidence of metastasis (1/3, 33%) underwent surgical resection followed by chemotherapy. Conclusion ENCs are an exceedingly rare group of malignant neoplasm with variable presentations posing a diagnostic challenge for the clinician and pathologist alike. Most patients tend to be elderly with advanced disease at presentation and guarded prognosis. This case series underscores the importance of including this entity among the differential diagnosis for poorly differentiated carcinomas of the distal esophagus. IHC with positive neuroendocrine markers particularly Synaptophysin helps make the correct diagnosis when combined with typical morphology.