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Specialists with the Divisions of Gastroenterology and Renal Electrolyte and Hypertension at Penn Medicine have developed an interdisciplinary approach to the diagnosis, staging and medical and surgical treatment of neuroendocrine tumors (NETs) and paraganglioma/pheochromocytomas (PHEOs).

NETs, PETs and PHEOs

Neuroendocrine tumors (NETs) are a rare (~2 percent of all GI tumors) heterogeneous group of malignancies that originate in neuroendocrine cells. Lesions may occur in a variety of locations, but are most often found in the gastrointestinal tract, lungs and pancreas. Pheochromocytomas (PHEO) and paragangliomas (PGL) are tumors that originate from unregulated growth of neuroendocrine chromaffin cells and can occur either in the adrenal glands (PHEO) or in an extra-adrenal location (PGL). These lesions are rarer (~2-8 per 1,000,000 persons) than carcinoids, and most are unilateral and noncancerous.

Diagnosis

Early diagnosis of NETs and PHEOs depends largely on physician experience and expertise and the presence of advanced imaging and laboratory and genetic testing facilities, a combination of advantages unique in the Philadelphia region to the Neuroendocrine Tumor Program at Penn.

Treatment

Surgery can be curative and is typically the first-line treatment for patients with resectable NETs. Patients with unresectable tumors may benefit from debulking surgery and are candidates for hormone therapy with octreotide, a somatostatin analogue, which is used to inhibit tumor growth. Metaiodobenzylguanidine (MIBG) therapy is particularly suited to patients with malignant, unresectable pheochromocytomas. Advances available at Penn in the near future for the diagnosis and treatment of neuroendocrine disease include: Peptide Receptor Radionuclide Therapy (PRRT), a form of molecular targeted therapy that couples a small peptide (a somatostatin analog) to a radionuclide emitting beta radiation; and PET imaging with gallium-68-DOTA, a radio tracer that allows improved resolution of PET and higher affinity for the new generation of SSTR peptides to significantly improve the quality of NET imaging.

Case Study

Mr. D, a 73-year-old male, was referred to the Penn Neuroendocrine Tumor Program when he was found to have hepatomegaly following several months of unusual symptoms, including prolonged facial flushing, cough, fever, chills, weight loss and lassitude. Mr. D's previous medical history was otherwise unremarkable. 

At Penn, ultrasound of the right upper quadrant and CT scanning of the chest and abdomen revealed multiple metastases in the liver. A urinalysis was negative, and serum calcium, chloride and electrolytes were normal. However, Mr. D's serum albumin was low at 2.9 gm/dL (n = 3.5-5.0), and he demonstrated elevated levels of alkaline phosphatase (197 IU/L; n = 42-121), ALT (96 IU/L; n = 10-60) and AST (57 IU/L; n= 10-42). An assessment of Mr. D's serum chromogranin A, a marker for neuroendocrine tumors, was more than five times the upper limit of normal (275 ng/mL; n = 50).

A transcutaneous liver biopsy was positive for neuroendocrine tumor. The tumor was strongly positive for neuron specific enolase, synaptophysin, insulin, S100 and chromogranin. An OctreoScan showed liver and midline abdominal foci of increased radiotracer uptake compatible with neuroendocrine lesions. A diagnosis of metastatic nonfunctional neuroendocrine tumor was made.

Mr. D received somatostatin maintenance therapy for six months for both tumor and syndromic control, at which point recurrent upper respiratory symptoms and severe abdominal discomfort developed. A CT scan of the abdomen at this time revealed several metastases in the liver (Fig 1A) and increasing adenopathy within the gastrohepatic ligament.

Mr. D was a good candidate for peptide receptor radionuclide therapy (PRRT), a therapy with proven efficacy in late-stage, advanced NETs unamenable to surgery. Because PRRT is not yet available in the United States, he was referred from Penn GI to a center in Switzerland, where he subsequently had 3 cycles of PRRT over a two-month period. At the conclusion of this time, a repeat CT scan (Fig. 1B) found substantial diminishment in tumor size, with central absent enhancement indicating tumor necrosis and treatment response. At six-months post-PRRT, Mr. D remains in stable condition, with no current evidence of tumor progression.

CT scans of a 73-year-old man with multiple hepatic metastatic neuroendocrine tumors
Figure: CT scans of a 73-year-old man with multiple hepatic metastatic neuroendocrine tumors before (A) and after (B) three cycles of PRRT. The dominant lesion (*) shows central absent enhancement after treatment, indicating tumor necrosis and treatment response.

Recent Advances in NET/PHEO Therapy at Penn Medicine

The recently approved targeted molecular therapy everolimus is now available at Penn for patients with progressive, well-differentiated, nonfunctional NETs originating in the GI tract or lung. Everolimus is an mTOR inhibitor that regulates protein synthesis, cell growth and proliferation, angiogenesis and cell metabolism in cancers.

In addition, the multi-targeted tyrosine kinase inhibitor sunitinib is available at Penn for patients with advanced, well-differentiated pancreatic NETS.

Access

The Abramson Cancer Center
The Perelman Center for Advanced Medicine
3400 Civic Center Boulevard
Philadelphia, PA 19104

Penn Presbyterian Medical Center
38th and Market Streets
218 Wright-Saunders Building
Philadelphia, PA 19104

Penn Medicine Radnor
250 King of Prussia Road
Module B
Radnor, PA 19087

Published on: June 9, 2016

Penn Faculty Team

Staci Kallish, DO

Assistant Professor of Clinical Medicine

Assistant Professor of Clinical Medicine in Pediatrics

Katherine L. Nathanson, MD

Deputy Director, Abramson Cancer Center

Pearl Basser Professor for BRCA-Related Research at the Abramson Cancer Center of the University of Pennsylvania

Professor of Genetics

Anastassia Amaro, MD

Medical Director, Penn Metabolic Medicine

Associate Professor of Clinical Medicine

Julia Kharlip, MD

Associate Medical Director, Penn Pituitary Center

Associate Professor of Clinical Medicine

David C. Metz, MD

Co-Director, Esophagology and Swallowing Program

Director, Acid-Peptic Program

Co-Director, Neuroendocrine Tumor Center

Professor of Medicine at the Hospital of the University of Pennsylvania

Bryson Katona, MD, PHD

Director, Gastrointestinal Cancer Genetics Program

Director, Gastrointestinal Cancer Risk Evaluation Program

Member, Abramson Cancer Center

Assistant Professor of Medicine at the Hospital of the University of Pennsylvania

Nevena Damjanov, MD

Section Chief Hematology/Oncology, VA Medical Center

Director of Gastrointestinal Oncology, Abramson Cancer Center, Penn Presbyterian Medical Center

Professor of Clinical Medicine

Peter J. O'Dwyer, MD

Director, Developmental Therapeutics Program, Abramson Cancer Center

Professor of Medicine at the Hospital of the University of Pennsylvania and the Presbyterian Medical Center of Philadelphia

Ursina R. Teitelbaum, MD

Clinical Director, Penn Pancreatic Cancer Research Center

Deenie Greitzer and Daniel G. Haller Associate Professor

Michael C. Soulen, MD

Professor of Radiology at the Hospital of the University of Pennsylvania

Professor of Radiology in Surgery

Daniel Pryma, MD

Chief, DIvision of Nuclear Medicine Imaging and Therapy

Professor of Radiology at the Hospital of the University of Pennsylvania

Michelle Alonso-Basanta, MD, PhD

Vice Chair, Clinical Division, Radiation Oncology

Chief, Central Nervous System Service, Radiation Oncology

Associate Professor of Radiation Oncology at the Hospital of the University of Pennsylvania

Keith Cengel, MD, PhD

Executive Director, Penn Mesothelioma and Pleural Diseases Program

Director, Photodynamic Therapy Program

Associate Professor of Radiation Oncology at the Hospital of the University of Pennsylvania

Debbie Cohen, MD

Clinical Director, Hypertension

Co-Director, Neuroendocrine Tumor Program

Professor of Medicine at the Hospital of the University of Pennsylvania

Douglas L. Fraker, MD

Chief, Division of Endocrine and Oncologic Surgery

Professor of Surgery

Robert E. Roses, MD

Associate Professor of Surgery at the Hospital of the University of Pennsylvania

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