Recognizing the subtleties of this elusive cancer

"I have often seen patients who have been labeled as having IBS, IBD, menopause, or even neuropsychiatric disorders for quite a while before they finally get the correct diagnosis." —Dr David C Metz

NETs are a group of neoplasms that can be a challenge to diagnose. Certain NETs, particularly those arising in the GI tract, can produce nonspecific symptoms (such as diarrhea, abdominal pain, flushing, and hypoglycemia) that are easily mistaken for those of other conditions,1 such as irritable bowel syndrome (IBS)2 and inflammatory bowel disease (IBD).3

NETs can form in multiple locations throughout the body,4 including the lungs, pancreas, and difficult-to-pinpoint areas within the midgut. It is not unusual for patients to suffer for years before a NET is correctly diagnosed. In fact, the estimated time to diagnosis for gastroenteropancreatic NETs is 5 to 7 years5 from initial onset of symptoms.

Pancreatic NETs and bronchial NETs: often overlooked

Pancreatic NETs often elude diagnosis because their clinical syndromes may present nonspecific symptoms, such as glucose intolerance, hypo- or hyperglycemia, ulcers, weight loss, and flushing.6,7 Given the relative rarity of pancreatic NETs and their variable clinical presentation, diagnosis of these neoplasms is often delayed and can require a combination of biochemical, imaging, and histologic analyses.6,7

Similarly, grade 1 (G1) and grade 2 (G2) bronchial NETs, also called typical and atypical carcinoids of the lung, occur less frequently than the better-understood large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC).8,9 Some patients with G1/G2 bronchial NETs are asymptomatic,10 whereas others present with asthma-like symptoms that contribute to their delayed diagnosis.9 Other symptoms include cough, hemoptysis, obstructive pneumonia, pleuritic pain, and atelectasis.10

Bronchial NETs may also lead to the development of clinical syndromes due to ectopic secretion of hormones; in fact, they are the most common cause of ectopic Cushing syndrome and extrapituitary acromegaly.9,11

Possible genetic precursor

A further diagnostic consideration is that multiple endocrine neoplasia syndromes (MEN-1, MEN-2, and von Hippel-Lindau disease) represent the most common inherited predisposing factors for NETs.12 The possible role of these syndromes should be considered in diagnostic workups, especially for pancreatic NETs and bronchial NETs, which can occur as part of MEN-1. 9,11,13 Gastrinomas and well-differentiated nonfunctional pancreatic NETs, for example, occur in more than half of MEN-1 patients.13 Biochemical screening and imaging for pancreatic NETs is recommended in patients with genetically proven MEN-1.13

Difficult to detect prior to metastasis

NETs may be silent for years. They usually metastasize to liver and bone before becoming symptomatic.1 Carcinoid syndrome, for example, occurs most frequently when disease metastasizes to the liver, allowing secreted serotonin and other vasoactive substances to reach the systemic circulation via the hepatic vein.14,15

Some NETs may be discovered incidentally—for example, during apparently routine appendectomy. Physicians may discover a colorectal NET in an asymptomatic patient during a screening colonoscopy, or while managing other diseases. Nonfunctional pancreatic NETs, which can become very large without causing symptoms, also are often discovered incidentally during surgery or abdominal imaging.16,17

Sites of metastatic dissemination of GI NETs18

Adapted from Strosberg J et al. Neuroendocrinology. 2009;89(4):471-476.18

Carcinoid syndrome: The most common clinical manifestation of NETs

Carcinoid syndrome occurs in approximately 8% to 35% of patients with neuroendocrine tumors.19 Like NETs themselves, carcinoid syndrome can be extremely difficult to recognize and diagnose. The most common signs and symptoms of carcinoid syndrome are flushing, diarrhea, abdominal cramping, and cardiac disease caused by valvular heart lesions.20 Because the symptoms of carcinoid syndrome can have a major effect on quality of life,19 earlier diagnosis may help patient outcomes. Learn more about the symptoms of carcinoid syndrome.

A symptom-based checklist

Download this checklist to help consider the possibility of a NET associated with carcinoid syndrome in patients with unresolved GI symptoms1

For symptoms that may raise suspicion of a pancreatic NET, specific hormone tests may be warranted. General tumor biomarkers may be helpful in tentatively identifying the presence of a nonfunctional pancreatic NET, some of which secrete peptides.17

Preliminary biomarker results for all types of NETs should be confirmed with imaging and/or endoscopic techniques, as well as biopsy, when appropriate.7

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Discover tools that may help diagnose neuroendocrine tumors

Even though NETs are not easily detected, there are tools that can help establish a diagnosis, as well as tools to help monitor existing NETs.