expert roundtables

Diagnosis of Carcinoid Syndrome and Neuroendocrine Tumors

by Lowell B. Anthony, MD, FACP; Timothy J. Hobday, MD; and Jonathan R. Strosberg, MD

Overview

Our featured experts discuss the diagnosis of carcinoid syndrome and the evaluation of neuroendocrine tumors (NETs) that commonly cause this syndrome. Presentations can vary remarkably, as can the circumstances that lead to a diagnosis.

Q:

What are some of the different paths to the diagnosis of NETs and carcinoid syndrome?

Jonathan R. Strosberg, MD

Professor of Gastrointestinal Oncology
Section Head, Neuroendocrine Tumor Division
Chair, Gastrointestinal Department Research Program
Moffitt Cancer Center
Tampa, FL

In some cases, there may be a history of recurrent pain or obstructive symptoms that span years. This might occur if the patient has never been scanned. Or, in those who have been scanned, primary tumors are usually undetectable, and mesenteric involvement may be difficult to recognize.”

Jonathan R. Strosberg, MD

There are many paths that lead to the diagnosis of NETs that are known to cause carcinoid syndrome. There are both symptomatic and incidental presentations, although symptomatic presentations are more common. Patients with midgut NETs often present with symptoms related to their primary tumor or mesenteric disease, and there may be abdominal pain or bowel obstruction. In some cases, there may be a history of recurrent pain or obstructive symptoms that span years. This might occur if the patient has never been scanned. Or, in those who have been scanned, primary tumors are usually undetectable, and mesenteric involvement may be difficult to recognize. Other patients with NETs who have liver metastases can present with pain related to liver disease, and abnormal liver function tests are quite common. However, the hallmark symptoms of carcinoid syndrome result from the NETs that produce hormones such as serotonin and other substances that lead to flushing and/or diarrhea. And many patients do have chronic flushing or diarrhea that eventually leads to a visit with their doctor. 

In terms of the workup, most patients at my institution have a biopsy first, followed by an evaluation for carcinoid syndrome. It is much more common for patients to have either a computed tomography scan or a magnetic resonance imaging scan that identifies an abnormality and leads to the biopsy first. This is then followed by an evaluation of the hormonal syndrome. A diagnostic workup that starts with the hormonal syndrome is rarer. Almost all patients have already had anatomical imaging performed when I see them.

Lowell B. Anthony, MD, FACP

Professor and Chief

Division of Medical Oncology

Department of Medicine

Member, UK Markey Cancer Center

University of Kentucky

Lexington, KY

While presentations are quite varied, a delay in diagnosis is common, given that the early symptoms are vague and nonspecific, with early syndromic symptoms typically being flushing and intermittent diarrhea.”

Lowell B. Anthony, MD, FACP

In some cases, the diagnosis results from an incidental finding on imaging that was performed for other reasons. In other cases, the initial syndromic symptoms are more intermittent and less bothersome, and they may go unnoticed. Or you could have the insidious onset of several different symptoms all at once, such as weight loss and pain or nausea. There is usually more than just 1 symptom by the time these patients are diagnosed. While presentations are quite varied, a delay in diagnosis is common, given that the early symptoms are vague and nonspecific, with early syndromic symptoms typically being flushing and intermittent diarrhea.

Flushing may be confused with the physiologic flushing of perimenopause, as these NETs often begin to become evident from a patient's late 40s to their late 60s. Flushing from carcinoid syndrome is often described as dry, whereas many women with perimenopausal or menopausal flushing also experience sweating. Flushing will sometimes be missed or may go unnoticed because it is intermittent, particularly among men, or it may not be recognized or reported until there are additional symptoms. Diarrhea that becomes more frequent and chronic might parallel or mirror the flushing, but, in some cases, it does not. When the functional symptoms of diarrhea or flushing overlap with the nonfunctional symptoms of pain, weight loss, and nausea, that is going to bring your diagnostic potential for NETs with carcinoid syndrome clearly into focus.

From the perspective of somebody in a very busy internal medicine practice who is listening to a patient describe flushing, the symptoms are going to be put into context, along with the patient’s age, other symptoms, and comorbidities. At some point, these patients will have a computed tomography scan, and they may get a biopsy that identifies NETs before a serotonin level is obtained; that is not an uncommon pathway for diagnosis.

Timothy J. Hobday, MD

Associate Professor of Oncology
Education Chair, Division of Medical Oncology
Program Director, Hematology/Oncology Fellowship
Mayo Clinic College of Medicine and Science
Rochester, MN

Incidental asymptomatic presentations are common, and they are often quite alarming because of the visual burden of the NET, especially metastatic disease to the liver, which can sometimes be striking even though the patient feels quite well.”

Timothy J. Hobday, MD

I agree with my colleagues that the presentations of these NETs are incredibly varied. With the increasing use of diagnostic imaging over the last few decades, there are many patients who present incidentally. For example, a patient might have a scan for a kidney stone that ends up identifying liver metastases; they may have a scan for cholecystitis, during which liver metastases are seen; or they may have brief episodes of abdominal pain, and a workup reveals significant mesenteric adenopathy. Incidental asymptomatic presentations are common, and they are often quite alarming because of the visual burden of the NET, especially metastatic disease to the liver, which can sometimes be striking even though the patient feels quite well. This is a hallmark of slowly growing metastatic tumors, or well-differentiated NETs. 

However, many patients do present with symptoms. Some present with abdominal pain, which is often intermittent and slowly progresses over months or years, leading up to scans. There may be intermittent small intestine obstruction or complete obstruction. Sometimes, mesenteric fibrosis from the metastatic lymph nodes can cause some pseudo-obstruction or even vascular compromise of the intestines. Thus, another common presentation stems from the small bowel primary tumor and the regional lymph node involvement. 

Of course, as mentioned, many patients present with the characteristic symptoms of carcinoid syndrome and some amount of flushing, diarrhea, or both. When the hormonal syndrome does dominate, patients might be evaluated for persistent diarrhea, and, at times, people think about the rare diseases and check the assays or a scan because of these symptoms.

A less-common but important presentation is that of carcinoid heart disease with signs and symptoms of right heart failure. In retrospect, newly diagnosed patients often have had a steady but, perhaps, modest manifestation of carcinoid syndrome over long periods of time; however, their presenting condition is the right heart failure from carcinoid heart disease.

References

Cives M, Strosberg JR. Gastroenteropancreatic neuroendocrine tumors. CA Cancer J Clin. 2018;68(6):471-487. doi:10.3322/caac.21493

de Celis Ferrari ACR, Glasberg J, Riechelmann RP. Carcinoid syndrome: update on the pathophysiology and treatment. Clinics (Sao Paulo). 2018;73(suppl 1):e490s. doi:10.6061/clinics/2018/e490s

Hannah-Shmouni F, Stratakis CA, Koch CA. Flushing in (neuro)endocrinology. Rev Endocr Metab Disord. 2016;17(3):373-380. doi:10.1007/s11154-016-9394-8

Kaltsas G, Caplin M, Davies P, et al; Antibes Consensus Conference Participants. ENETS consensus guidelines for the standards of care in neuroendocrine tumors: pre- and perioperative therapy in patients with neuroendocrine tumors. Neuroendocrinology. 2017;105(3):245-254. doi:10.1159/000461583

Laskaratos F-M, Davar J, Toumpanakis C. Carcinoid heart disease: a review. Curr Oncol Rep. 2021;23(4):48. doi:10.1007/s11912-021-01031-z

Maroun J, Kocha W, Kvols L, et al. Guidelines for the diagnosis and management of carcinoid tumours. Part 1: the gastrointestinal tract. A statement from a Canadian national carcinoid expert group. Curr Oncol. 2006;13(2):67-76.

Pavel M, Öberg K, Falconi M, et al; ESMO Guidelines Committee. Gastroenteropancreatic neuroendocrine neoplasms: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(7):844-860. doi:10.1016/j.annonc.2020.03.304

Strosberg JR, Halfdanarson TR, Bellizzi AM, et al. The North American Neuroendocrine Tumor Society consensus guidelines for surveillance and medical management of midgut neuroendocrine tumors. Pancreas. 2017;46(6):707-714. doi:10.1097/MPA.0000000000000850

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