Diagnosing Carcinoid Tumors and Carcinoid Syndrome

The Importance of a Correct Diagnosis

Delayed diagnosis, or misdiagnosis, occurs frequently in patients with carcinoid syndrome, as symptoms may be mistaken for other diseases, such as irritable bowel syndrome (IBS) or menopause.1 Typically, patients experience delays in diagnosis of 5 to 7 years from initial onset of symptoms, with 60% to 80% of patients diagnosed at an advanced stage of disease and metastases at initial presentation.2,3 Diagnosis of carcinoid tumors and pancreatic neuroendocrine tumors (PNET) therefore requires collaboration between specialists across multiple disciplines, including nursing, primary care, gastroenterology, surgical and radiation oncology, radiology, endocrinology, endocrine surgery, molecular genetics, clinical immunology, pathology, and nuclear medicine.4,5

Neuroendocrine tumors (NET) present a considerable diagnostic challenge3 , because even small carcinoid tumors and PNET <2 cm can be aggressive and metastasize6,7,8 (Figure 6). Fifty percent of PNET are associated with hepatic metastases at diagnosis.9 This diagnostic challenge requires a greater index of suspicion for NET, and a carcinoid tumor profile screen is warranted for patients for the differential diagnosis of more frequent conditions.10

Figure 6. A Relatively Small Primary Tumor can Present With Extensive Metastases

primary-metastatic-nets.jpg/Primary and Metastatic Neuroendocrine Tumors

Images courtesy of Rodney F. Pommier, MD, Division of Surgical Oncology, Oregon Health & Science University, Portland, OR

Patient History and Differential Diagnosis

Obtaining a thorough patient history is key in the diagnosis of carcinoid tumors and PNET.10

Flushing

While compiling the patient history, the health care professional should ask questions about the characteristics of the flushing.10 Carcinoid tumors and PNET are associated with dry flushing that is intermittent.10 In contrast, constant flushing is associated with alcoholism, and wet flushing is associated with menopause.10 In order to determine the source of flushing, the health care professional can test for prostaglandins, 5-hydroxyindoleacetic acid (5-HIAA), serotonin, chromogranin A (CgA), and follicle-stimulating hormone to rule out pheochromocytoma and menopause.10

Diarrhea

It is key to differentiate the gastrointestinal (GI) symptoms of carcinoid tumors and PNET from the diarrhea, abdominal pain, and dyspepsia of IBS by eliciting a patient history that details age, sleep patterns, and nonspecific symptoms10 (Table 5). The health care professional should ask questions about the frequency and characteristics of diarrhea.10 Diarrhea in patients with NET is secretory with no osmotic gap, compared with malabsorptive diarrhea in other GI diseases.10 It is also important to rule out other causes of secretory diarrhea (eg watery diarrhea, hypokalemia, laxative abuse, and acidosis syndrome).10 Potassium hydroxide stool preparation may distinguish diarrhea caused by laxative abuse.10

IBS often develops in individuals near the age of 35; conversely, carcinoid tumors and PNET are more frequent in patients aged older than 50 years.10,11 Sleep disturbances also occur in patients with NET, although not usually in patients with IBS.10 Rectal bleeding is not common in patients with carcinoid tumors or PNET and is a common sign of ulcerative colitis and Crohn disease.12 Fever, weight loss, and persistent severe abdominal pain are common signs of Crohn disease and ulcerative colitis that are not usually seen with IBS and NET.1,12 Also, IBS includes alternating diarrhea and constipation, which is not consistent with NET.10,12

Table 5. Characteristics of Carcinoid Syndrome, Differential Diagnosis12–26
Carcinoid Syndrome IBD IBS
Crohn Disease Ulcerative Colitis
Description of stool Mostly watery13 Could be watery; could be mixed with blood14 Bloody stools are common in ulcerative colitis15 Frequently watery (small quantity), often with mucus present16 and in 31% of patients blood is present17
Nocturnal diarrhea Occurs18 Common19 Common18 Uncommon20
Rectal bleeding N/A Fairly common12 Very common12 N/A
Constipation N/A May occur14 Infrequent – may occur in 10% of patients21 Common20 (may alternate with diarrhea)
Flushing Common22 N/A N/A N/A
Key describing features of abdominal pain Intermittently occurring in episodes,23 often dull, achy,24 and colicky;22 bloating may occur with mesenteric fibrosis25 Crampy14

Abdominal pain varies12 Recurrent abdominal pain or discomort26 with bloating16,24
Pain relieved upon defecation N/A N/A Usually disappears27 Common26

IBD, irritable bowel disease; IBS, irritable bowel syndrome; N/A, not applicable

Physical Examination

A thorough physical examination is also important to detect clinical signs of carcinoid tumors and PNET.10 Bronchospasm is a common sign in obstructive pulmonary disease and occurs in one-third of patients with carcinoid syndrome.10 Abnormal values of substance P, histamine, or 5-hydroxytryptamine (5-HT) will be present in patients with NET, but not in patients with asthma and chronic obstructive pulmonary disease.10 Pellagra is also often a dermatological sign of NET, due to niacin deficiency and increased production of 5-HT.10

The combination of a complete history and physical examination, biochemical and genetic testing, tumor localization, tissue immunohistochemistry, and radiologic imaging will aid health care providers in obtaining the correct diagnosis of NET.10

A diagnostic algorithm from the North American Neuroendocrine Tumor Society (NANETS) consensus guidelines was developed to help physicians diagnose NET effectively.10 Based on the clinical syndrome suggestive of NET, NANETS recommends specific biochemical tests, tissue staining techniques and imaging modalities to help obtain an accurate diagnosis of NET.10

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References
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