Metastatic Well-differentiated Neuroendocrine Tumor Research Articles

Urinary Neuroendocrine Neoplasms Treated in the "Modern Era": A Multicenter Retrospective Review.

Primary urinary neuroendocrine neoplasms (U-NENs) are extremely rare thus optimal treatment is unknown. Grading and treatment are typically extrapolated from other primary sites. Since 2010, the clinical landscape for NENs has changed substantially. We performed a retrospective review of U-NENs to assess treatment patterns and oncologic outcomes of patients treated in the recent era of NEN therapy. A multicenter retrospective review of patients diagnosed after 2005 and alive after 2010. Time to treatment failure (TTF) was used to evaluate progression and toxicity for systemic therapy. Tumors were categorized as having either well-differentiated neuroendocrine tumor (WDNET) or poorly differentiated neuroendocrine carcinoma (PDNEC) histology. A total of 134 patients from 6 centers were included in our analysis, including 94 (70%) bladder, 32 (24%) kidney, 2 (1.5%) urethra and 4 other urinary primaries (3.0%). Poorly-differentiated neuroendocrine carcinoma was more common in bladder (92%) than non-bladder tumors (8%). Median Ki-67 available in bladder primary was 90% (n=24), kidney 10% (n=23), ureter 95% (n=1), urethra 54% (n=2), and others 90% (n=3). Patients received a median of 2 therapies (range 0-10). Median time to death was not reached in locoregional WDNETs versus 8.2 years (95% CI, 3.5-noncalculable) in metastatic WDNETs (predominantly renal primary). Median time to death was 3.6 years (95% CI, 2.2-9.2) in locoregional PDNECs versus 1 year (95% CI, 0.8-1.3) in metastatic PDNECs (predominantly bladder primary). This is the most extensive series examining treatment patterns in patients with U-NENs in the recent era of NEN therapy. The apparent inferior survival for bladder NENs is likely due to the preponderance of PDNECs in this group. As predicted, treatments for U-NENs mirrored that of other more common NENs. In our retrospective cohort, we observed that patients with WD-UNETs treated with peptide receptor radionuclide therapy (PRRT) and everolimus suggested potential activity for disease control in WD-UNETs. Prospective studies are needed to assess the activity of new oncology drugs in UNENs.

68Ga-DOTATATE PET/CT Incidentally Detects Relapsed Chronic Lymphocytic Leukemia in Patient With Metastatic Neuroendocrine Tumor.

A 54-year-old man with metastatic well-differentiated neuroendocrine tumor of the pancreas underwent 68Ga-DOTATATE PET/CT scan to evaluate treatment response. Patient was known for remote history of chronic lymphocytic leukemia (CLL), previously treated. Scan revealed diffusely increased abnormal tracer uptake throughout the marrow of the axial and proximal appendicular skeleton. Bone marrow biopsy revealed relapsed CLL. We present a rare case of relapsed CLL incidentally detected on 68Ga-DOTATATE PET/CT.

Role of Resection of the Primary in Metastatic Well-Differentiated Neuroendocrine Tumors.

Resection of the primary (RP) in metastatic neuroendocrine tumor (NET) is controversial. The aim was to evaluate survival outcomes for RP in metastatic NET patients. Data were obtained from US hospitals at the National Cancer Database between 2004 and 2014. χ2, analysis of variance tests, univariate, and multivariate cox proportional hazards models were evaluated. Kaplan-Meier curves and log-rank tests conducted to compare the survival difference of patient characteristics. A total of 2361 patients were identified. The mean age was 62.1 years (standard deviation, 13 years), male-to-female ratio 1:1; 33% were small intestine, 26.3% pancreas, and 24.4% lung; 69.6% were well-differentiated; and 42.5% underwent RP. The 5-year overall survival (OS) was significantly improved for patients who underwent RP in small intestine (5-year OS, 63.9% vs 44.2%), lung (5-year OS, 65.4% vs 20.2%), and pancreas tumors (5-year OS, 75.6% vs 30.6%). On multivariate analysis, RP (hazard ratio, 0.46; 95% confidence interval, 0.29-0.73; P < 0.001), female, year of diagnosis 2010-2014, margin, Charlson-Deyo score less than 2, and age less than 51 years, were associated with better OS. Resection of the primary in metastatic well-differentiated NET is associated with improved OS compared with no RP.

Synchronous Upper Intestinal Neurofibromas and Duodenal Periampullary Well-Differentiated Neuroendocrine Tumor Associated With Neurofibromatosis 1

Neurofibromatosis type I (NF1) is an autosomal dominant genetic disorder associated with characteristic skin findings, as well as a fourfold increase in risk of malignancy. NF1 patient malignancies commonly include the central and peripheral nervous system, but these patients are also at high risk of developing gastrointestinal (GI) tumors. While most often these GI tumors are benign upper GI neurofibromas; clinicians should have a high suspicion for malignant tumors, degeneration into a malignant peripheral nerve sheath tumor or less common associated malignancies such as well-differentiated neuroendocrine tumor (formerly carcinoid tumor), when patients present with multiple GI tumors. Our patient underwent a Whipple for symptomatic neurofibromas associated with NF1 and was unexpectedly discovered to have a metastatic duodenal well-differentiated neuroendocrine tumor. The patient is a 66-year-old man with NF1 who presented with hematemesis and was found to have large gastric neurofibromas and an ampullary neurofibroma based on endoscopy and radiological imaging. Another ostensive neurofibroma was noted distally. A pancreatoduodenectomy was performed. Pathological examination identified the neurofibromas but the tumor measuring 1.4cm and arising from the minor duodenal papilla was, in fact, a synchronous well-differentiated neuroendocrine tumor metastatic to regional lymph nodes, consistent with pT2 pN1, Stage IIIB cancer. NF1 patients with multiple GI tumors are at an increased risk for malignancy. Therefore, a high index of suspicion for malignancy in any patient with NF1 presenting with gastrointestinal symptoms has implications for a surgeon, warranting not only a further diagnostic investigation, but also an appropriate surgical intervention and sampling for nodal spread. Because of the possibility of a simultaneous cancer, it is crucial to assess all suspicious tumors even if the masses appear endoscopically benign.

Pulmonary Embolus of Benign Liver Tissue Following Partial Hepatectomy

Abstract We report the case of a 55-year-old man with metastatic well-differentiated neuroendocrine tumor involving the liver and lung. He underwent a left hepatectomy to resect a large mass in the liver followed by a right lung lower lobectomy 4 months later to resect a smaller mass in the lung. The histologic evaluation of the lung specimen revealed a 0.1-cm nodule of ectopic benign liver tissue within a lumen of a small pulmonary artery. Histochemical and immunohistochemical stains were consistent with benign liver and did not provide support for metastatic well-differentiated hepatocellular carcinoma. To our knowledge, this is the first documented case of pulmonary arterial embolization by benign liver tissue as a complication of hepatectomy.

SAT-115 A Rare Case of Metastatic Insulinoma in a Patient with Huntington’s Disease

A 49-year-old female with past medical history of Huntington’s disease presents to the ED after being found unresponsive at her assisted-living facility. She was noted to be hypoglycemic with a glucose of 21 and responded to dextrose. For the past several months, patient had symptoms of dizziness, tremors. She has no history of diabetes, and only home medication is Zyprexa. Patient required D10 drip to maintain glucose levels. Given patient’s psychiatric history, there was concern for surreptitious use of diabetic medications. Labwork showed an insulin level of 163 and an elevated C-peptide of 7.0 consistent with endogenous insulin secretion. Patient underwent a 72-hour fasting protocol which revealed a glucose of 23, C-peptide of 4.1 and insulin of 101, undetectable beta-hydroxybutyrate levels and pro-insulin level of 782 which is consistent with a diagnosis of insulinoma. She was started on diazoxide, which diminishes insulin secretion, to treat the hypoglycemia. Patient underwent a pancreas CT protocol which showed multiple hypervascular hepatic masses up to 9 cm and one 4 cm mass in pancreatic tail concerning for metastasis. Pathology revealed metastatic well-differentiated neuroendocrine tumor grade 3. She was not a candidate for surgical resection of tumors and she was started on Octreotide 200 mcg TID. Patient underwent two Y90 radioembolization treatments, 2 months apart with improvement of hypoglycemia and discontinuation of diazoxide. Patient remains on Octreotide LAR injection every 4 weeks. Insulinoma, although rare, occurs in 1-4% of the population and is the most common type of functional neuroendocrine tumor of the pancreas. It secretes insulin which results in hyperinsulinemic hypoglycemia. Diagnosis involves persistent hypoglycemia with glucose <50 mg/dL, neuroglycopenic symptoms and prompt relief after glucose administration. Gold standard diagnosis is a 72-hour fast and measurement of plasma insulin, C-peptide and pro-insulin, which detects 99% of insulinomas. After lab confirmation, imaging is necessary with either CT, MRI or EUS. Surgical resection is curative in most patients. Other treatment modalities include injection of octreotide, EUS-aided alcohol ablation, radio-frequency ablation or embolization of insulinoma, as well as targeted therapy with everolimus or sunitinib. Malignant insulinomas are extremely rare and often invade into surrounding soft tissue or have lymph node or liver metastasis. They are usually unresectable and require targeted therapy. We present the case of a 49 YO patient with Huntington’s disease who presented with severe persistent hypoglycemia secondary to metastatic insulinoma. Diagnosis of insulinoma is often delayed or missed as symptoms may be attributed to psychiatric, cardiac or neurological disorders or medication misuse. Clinicians should be aware of insulinoma as a cause of life-threatening hypoglycemia.

Unusual skull base metastasis from neuroendocrine tumor: a case report

BackgroundWith increasing treatment options available, neuroendocrine tumor has become a chronic disease and may present later on with atypical manifestation of disease spread once resistant to treatment.Case presentationA 74-year-old white British woman undergoing treatment for metastatic well-differentiated neuroendocrine tumor for the past 9 years presented with a brief history of mild frontal headache, and progressive left ptosis and ocular palsy. She had no visual loss, and had neither speech nor motor deficit. At the outset, it was crucial to exclude acute or missed stroke. An urgent magnetic resonance imaging of her head revealed an unusual skull base metastasis extending into the cavernous sinus, with no peritumoral edema. Following discussion at a specialist neuro-oncology meeting and a neuroendocrine tumor multidisciplinary team meeting, she proceeded to have conventional fractionated radiotherapy followed by subsequent palliative chemotherapy.ConclusionsIntracranial metastasis is rare in patients with neuroendocrine tumor, particularly in those with well-differentiated histology; skull base metastasis is even more uncommon. Management of intracranial metastasis from a rare tumor should always be discussed in a specialist multidisciplinary meeting. Surgery or radiotherapy, including stereotactic radiosurgery, should be considered in skull base metastases. Hormonal abnormalities may occur following radiotherapy to skull base metastases and should be monitored closely in the first few months post treatment.

Dilemma in Managing Carcinoid Crisis Secondary to a Metastatic Well-differentiated Neuroendocrine Tumor of the Lung

Dilemma in Managing Carcinoid Crisis Secondary to a Metastatic Well-differentiated Neuroendocrine Tumor of the Lung

Liver Transplantation in a Young Patient with Severe and Refractory Carcinoid Syndrome

Objective: To report the role of liver transplantation in the management of refractory carcinoid syndrome. Methods: We describe the clinical course, biochemical, radiographic, and histopathologic features of a patient with severe refractory carcinoid syndrome due to a metastatic well-differentiated enterochromaffin cell neuroendocrine tumor of the jejunum. We also review and summarize the literature on liver transplantation in this setting. Results: An 18-year-old patient presented with a 3-year history of progressive palpitations, flushing, abdominal pain, and diarrhea. Initial imaging studies demonstrated multiple cystic liver lesions; biochemistry confirmed elevated 24-hour urinary 5-hydroxy-indolacetic acid (5-HIAA) levels. She was managed with somatostatin analogues followed by a partial small-bowel resection. Five sessions of liver embolization and escalating somatostatin analogues failed to control her symptoms or normalize urinary 5-HIAA levels. Cross-sectional imaging detected disease only in the...

Course Introduction and Selection of Immunohistochemical Staining Panels

Among the core principles in the practice of immunohistochemistry is the use of carefully chosen marker panels. Choosing an appropriate panel of antibodies is predicated on a sound differential diagnosis that is based on detailed examination of hematoxylin and eosin-stained slides. The panel should contain antibodies designed to be immunoreactive in the most likely disease(s) in the differential as well as selected negative markers. In addition, the importance of detailed historical and clinical information in constructing the differential diagnosis and panel selection cannot be understated. Two cases from the Case Presentation sessions of the 5th Annual Retreat for Applied Immunohistochemistry and Molecular Pathology are summarized to illustrate these points. The first case is that of metastatic well-differentiated neuroendocrine tumor (carcinoid) tumor presenting as a breast mass. The second is that of a squamous cell carcinoma of the lung mimicking a tumor with admixed glandular differentiation by entrapment and disruption of bronchial glands. Application of a select immunohistochemistry panel in light of the differential diagnosis and importance of making a specific diagnosis are discussed.

Metastatic Carcinoid from a Nodule Localized by Complete Double-Balloon Enteroscopy: A Small Lesion with Big Potential

Purpose: Carcinoid tumors are rare, slow growing tumors originating from enterochromaffin cells. They generally do not become symptomatic until already metastasized while the primary tumor is still small with the most common site of origin being the small bowel. Double-balloon enteroscopy (DBE) is increasingly becoming an important part of the diagnostic algorithm of primary small bowel neuroendocrine tumor (NET) localization, especially since their surgical excision leads to a better prognosis, even in metastasized NET. A 55-year-old Caucasian woman was diagnosed as having metastatic well-differentiated neuroendocrine tumor lesions of the liver positive for chromogranin and synaptophysin in 2009 per liver biopsy after initially presenting with unexplained fevers and abdominal pain since 2005 but no carcinoid syndrome symptoms. As part of the search for her primary tumor she underwent endoscopic ultrasound of the pancreas and esophagogastroduodenoscopy at our institution. This demonstrated no pancreatic mass but three hepatic hilar and periportal lymph nodes were consistent with benign lymphoid tissue. A MRI of the abdomen and pelvis revealed innumerable arterial enhancing nodules and masses in all segments of the liver consistent with metastatic disease. The largest lesion was in the dome of the liver at the left hepatic lobe, measuring 3.6 cm x 3.5 cm. Additionally, a wireless capsule enteroscopy (WCE) and CT chest were negative. Of note, chromogranin A, serotonin, pancreastatin, pancreatic polypeptide, and gastrin levels were within normal limits. She then underwent a retrograde DBE to the point of maximal insertion, which was the proximal ileum. At the level of the distal ileum there was a 3 mm yellowish nodule removed in one pass. There were no other lesions seen, and the pathology was consistent with a submucosal carcinoid strongly positive for chromogranin, synaptophysin; histochemical stains were positive for Fontana and Grimelius, consistent with mid-gut origin; and the Ki67 proliferation marker was positive in less than 1% of cells. She then underwent an oral DBE to evaluate for other multifocal carcinoid mid gut lesions and the enteroscope was advanced all the way to the cecum with no other lesions identified. An exploratory laparotomy was subsequently performed in order to evaluate for a possible primary tumor; however, despite the small bowel being run in its entirety four times there was neither a macroscopic nor histologic abnormality identified, including in eight regional lymph nodes. This case highlights the metastatic potential of a smaller ileal lesion than has been previously reported in the literature per DBE despite negative imaging, WCE, and exploratory laparotomy.

Resolution of Hepatic Encephalopathy Following Hepatic Artery Embolization in a Patient with Well-Differentiated Neuroendocrine Tumor Metastatic to the Liver

Hepatic encephalopathy is considered a contraindication to hepatic artery embolization. We describe a patient with a well-differentiated neuroendocrine tumor metastatic to the liver with refractory hepatic encephalopathy and normal liver function tests. The encephalopathy was refractory to standard medical therapy with lactulose. The patient's mental status returned to baseline after three hepatic artery embolization procedures. Arteriography and ultrasound imaging before and after embolization suggest that the encephalopathy was due to arterioportal shunting causing hepatofugal portal venous flow and portosystemic shunting. In patients with a primary or metastatic well-differentiated neuroendocrine tumor whose refractory hepatic encephalopathy is due to portosystemic shunting (rather than global hepatic dysfunction secondary to tumor burden), hepatic artery embolization can be performed safely and effectively.

Thyroid Transcription Factor-1 Is Expressed in Extrapulmonary Small Cell Carcinomas but Not in Other Extrapulmonary Neuroendocrine Tumors

Thyroid transcription factor-1 (TTF-1) is a nuclear homeodomain transcription factor that is expressed in the developing thyroid, respiratory epithelium, and diencephalon. TTF-1 is thought to be expressed specifically in pulmonary or thyroid neoplasms, and it is expressed in a significant subset of pulmonary non–small cell carcinomas, small cell carcinomas, and carcinoids but not in nonpulmonary, non–small cell carcinomas. Neuroendocrine tumors from sites other than the lung have not been evaluated for TTF-1 expression. We examined TTF-1 expression using immunohistochemistry on formalin-fixed, paraffin-embedded sections of 49 gastrointestinal carcinoids; 15 pancreatic islet cell tumors; 21 paragangliomas; 8 medullary thyroid carcinomas; 7 small cell carcinomas of the uterine cervix; 4 prostate, 4 bladder, and 6 Merkel cell (primary cutaneous neuroendocrine) carcinomas; and 1 renal carcinoma. No gastrointestinal carcinoid tumor, pancreatic islet cell tumor, paraganglioma, or Merkel cell carcinoma expressed TTF-1. All of the medullary thyroid carcinomas strongly expressed TTF-1. However, 44% of nonpulmonary small cell carcinomas were also TTF-1 positive, including four of four prostate, two of four bladder, and one of seven cervical small cell carcinomas. We conclude that TTF-1 expression is not specific for small cell carcinomas of pulmonary origin and should not be used to distinguish primary from metastatic small cell carcinomas in extrapulmonary sites. However, TTF-1 expression may be useful in distinguishing Merkel cell carcinomas and cutaneous metastasis of small cell carcinomas. Among well-differentiated neuroendocrine tumors, TTF-1 expression seems to be present only in carcinoid tumors of the lung and medullary carcinomas of the thyroid and may be of differential diagnostic value when dealing with a metastatic well-differentiated neuroendocrine tumor.