Neuroendocrine tumors

ALSO KNOWN AS: NET, neuroendocrine neoplasms (NENs), carcinoid tumors

RELATED CONDITIONS: Multiple endocrine neoplasia type 1 (MEN-1 or Wermer syndrome), multiple endocrine neoplasia type 2 (MEN-2), MEN-2A (Sipple syndrome), MEN-2B (Wagenmann-Froboese syndrome), carcinoid tumors, islet cell tumors, pheochromocytomas, thyroid carcinomas (medullary), parathyroid carcinomas, Zollinger-Ellison syndrome (gastrinoma), prolactinomas, Cushing syndrome, small-cell lung carcinomas

DEFINITION: Neuroendocrine tumors are a group of rare tumors affecting organs that originate embryologically from the neural crest, the layer that gives rise to the brain, spinal cord, peripheral nerves, and endocrine glands (organs that secrete hormones). These tumors mostly arise from hormone-secreting tissues. However, some tumors may not secrete hormones.

Neuroendocrine tumors may be classified as functional or nonfunctional, or hereditary or nonhereditary. The hereditary MEN syndromes consist of two main variants, MEN-1 and MEN-2. MEN-1 has pituitary, parathyroid, and pancreas involvement. MEN-2A manifests as medullary thyroid cancer (MTC), pheochromocytoma (adrenal medulla tumor), and parathyroid hyperplasia. MEN-2B is essentially type 2A without parathyroid involvement and with the addition of mucosal neuromas and gut ganglioneuromas with a Marfanoid body habitus. Isolated medullary thyroid cancer may also be familial but less aggressive compared to MEN-associated variants of the disease. The nonhereditary tumors include pheochromocytoma, carcinoid tumors, islet cell, small-cell, and nonfamilial medullary thyroid carcinomas.

Risk factors: Although most cases involving a single organ are more sporadic, the most prominent for the development of neuroendocrine tumors is a genetic predisposition. The MEN syndromes are autosomal dominant, implying that every generation has an afflicted individual, with a 50 percent probability of offspring inheriting the disease. Exposure to leuprolide acetate and medroxyprogesterone acetate in female rats was associated with a higher incidence of pancreatic islet cell tumors.

Etiology and the disease process: The genetic etiology of the heritable as well as most sporadic cases of somatic (mature, differentiated cells) cell mutations in parathyroid adenomas, gastrinomas, insulinomas, and bronchial carcinoids most commonly originates from mutations in the tumor-suppressor gene MEN1, with the RETproto-oncogene implicated in sporadic medullary thyroid carcinoma cases. MEN-1 originates from one of two etiologies—a mutation within the embryonic crest cell or inactivation of the MEN1 gene, located on the long arm of chromosome 11 (11q13). In MEN-2A, MEN-2B, and familial medullary thyroid carcinoma, the origin is believed to be a mutation in the RET gene, located on the long arm of chromosome 10 (10q11.2). Gastrinomas originate from ERBB2, the HER2/neu (human epidermal growth factor receptor 2/neu) proto-oncogene.

Incidence: The overall occurrence of neuroendocrine tumors is extremely rare, accounting for only 0.5 percent of all malignant cancers. The gastrointestinal tract has the highest incidence of neuroendocrine tumors, accounting for about 50 percent of all neuroendocrine tumors. About 25 percent of neuroendocrine activity occurs in the lungs, and just under 10 percent occurs in the pancreas. Women are more likely than men to develop these tumors, and the average age of diagnosis is between fifty and sixty.

Symptoms: The symptoms associated with neuroendocrine tumors vary widely and are often insidious in onset. Tumors may be found during an unrelated imaging study. Some neuroendocrine tumor symptoms are related to location rather than the disease entities they mimic. For example, pancreatic tumors may manifest as poorly controlled diabetes in and somatostatinoma; pituitary tumors as amenorrhea in prolactinomas; unintentional skin darkening, high blood pressure, and psychosis in Cushing disease; sudden episodes of high blood pressure, cold sweats, and palpitations in pheochromocytomas; or as a plethora of unrelated signs and symptoms such as flushing, abdominal cramps, diarrhea, or new-onset heart murmur in carcinoid tumors.

Nonfunctioning and bulky functioning tumors can compress or infiltrate surrounding tissue or structures and cause obstructive symptoms.

Screening and diagnosis: Diagnosis of neuroendocrine tumors is often difficult and missed because of misleading disease symptoms. Medullary thyroid cancer, especially when family history is present, should initiate a comprehensive search for high calcitonin, blood and urine calcium (medullary thyroid, parathyroid), adrenocorticotropic hormone (ACTH), growth hormone, thyroid-stimulating hormone (TSH), prolactin levels (pituitary), and twenty-four-hour urine metanephrine (adrenal medulla) levels as well as computed tomography (CT) or magnetic resonance imaging (MRI) of the head, neck, chest, and abdomen, as appropriate, to look for primary as well as metastatic sites. Insulin-to-glucose ratios, chromogranin A, gastrin levels, somatostatin receptor scintigraphy, endoscopy, and CT and MRI imaging studies are useful for aiding in pancreatic tumor diagnosis.

Although neuroendocrine tumors have a clear genetic etiology, genetic testing for RET is reserved for patients presenting with medullary thyroid cancer.

Treatment and therapy: Treatment of neuroendocrine tumors includes surgical removal, radiation therapy, and chemotherapy and is highly dependent on the tumor location and type. Precautions should be taken to stabilize the patient preoperatively for many functioning tumors. Control of blood pressure, high glucose levels, electrolyte imbalances, and gastrin excess are essential. Surgery must be able to remove the entire primary tumor and, if needed, structures susceptible to infiltration. For islet cell tumors, chemotherapy with streptozocin, doxorubicin, and 5-fluorouracil alone or in combination have proved beneficial (54 to 69 percent response rate). Other treatment options include peptide receptor radionuclide therapy (PRRT) and hormone therapy. PRRT uses the tumor's hormone receptors to better target radiation therapy, improving the treatment outcome and lowering the impact on surrounding tissue.

Prognosis, prevention, and outcomes: Most cases of neuroendocrine tumors have a good prognosis with radical surgery, chemotherapy, or radiotherapy. Metastatic disease at the time of diagnosis implies a poor prognosis. Gastrinomas, in particular, have a poorer prognosis, as 60 percent are malignant; associated with MEN-1 syndrome, they have a better prognosis than gastrinoma alone. Medullary thyroid cancer and MEN-2 have a five-year survival rate of 90 percent, attributable to early treatment of medullary thyroid cancer. Observation for recurrence involves periodic clinical examinations, laboratory tests for tumor markers, and CT and MRI. Genetic counseling and testing are helpful in individuals with a strong family history of neuroendocrine tumors.

Bibliography

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Raphael, Michael J., et al. “Principles of Diagnosis and Management of Neuroendocrine Tumours.” CMAJ: Canadian Medical Association journal, vol. 189, no. 10, 2017, pp. E398-E404. doi:10.1503/cmaj.160771.

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