This week we focus on an unusual class of tumors which, in truth, are not well understood even by most oncologists (and I might include myself in that category). But it is likely that a reader or family member may be diagnosed with one of these tumors, so it is worth addressing the topic.
Neuroendocrine tumors were first appreciated in the small bowel (they are most common there) in 1907, were thought to be relatively indolent, i.e., not to behave like a real cancer, but were also not clearly benign, so they were labeled as carcinoids. However, with the passage of time, it has been recognized that this appellation is inaccurate and that these tumors are indeed malignant and that they represent an unusual and weird subcategory of carcinomas (tumors of epithelial origin). They are apparently derived from endocrine (hormonal) tissue and, indeed, often produce polypeptide hormones. There was also a theory that they were derived from tissue in the neural crest and hence they became known as neuroendocrine tumors. (The neural derivation has since been proved incorrect.)
Neuroendocrine tumors can arise in almost any organ of the body and resemble each other more than they reflect the site of origin, sort of like lymphomas. Thus, it is most reasonable to discuss NETs as a group and recognize that this includes tumors in the stomach, small bowel, pancreas, lung, prostate, endometrium, cervix, etc. Their behavior and response to therapy and prognosis will reflect primarily the grade or degree of differentiation of the tumor.
Basically, NETs are high-grade (poorly differentiated) or low-grade (well differentiated). The former are generally very aggressive and carry a poor prognosis with a high mortality rate. For example, 15% of lung cancers are so-called small-cell lung cancers—small-cell lung cancers are high-grade NETs of the lung. They are highly aggressive, metastasize widely including in the brain, and can produce paraneoplastic hormones. They are typical of high-grade NETs of any site of origin and are generally fatal.
The converse is the low-grade well differentiated NET, still usually referred to as carcinoids. These can still metastasize but that is much less common, and they can usually be resected for cure if diagnosed early.
Over the past five decades, the incidence rate of NETs has climbed more than sixfold in the U.S. (from about 1.1/100,000 to about 7/100,000/year). And it is apparently continuing to increase. A recent study in the U.K. has shown a similar eightfold increase over the past 30 years. The most obvious explanation for this increase is diagnostic bias and surveillance, i.e., the profligate use in medicine of diagnostic studies (CT and MRI scans for multiple reasons) as well as endoscopy (increased use of colonoscopy and gastroscopy) which detects NETs which would otherwise be clinically silent but are detected incidentally. Prostate cancer incidence rates have similarly tripled secondary to the widespread use of PSA testing. while thyroid cancer and renal cell carcinoma rates are likewise skyrocketing as the result of widespread use of chest and abdominal CT scans.
Importantly, however, the overall survival rate for NETs appears to be improving as well. This again reflects the distortion in the diagnosis of these tumors. Since the large increase in the number of these tumors stems from the diagnosis of indolent asymptomatic lesions, their prognosis, when diagnosed, is likely to be excellent, and thus the overall average survival rate is likely to be improved.
One of the characteristics of these tumors is that they may produce polypeptide hormones. So there are NETs that present themselves as insulinomas (secreting insulin which reduces the glucose level), glucagonomas (producing glucagon which increases the glucose level), gastrinomas (secreting gastrin which increases the stomach’s acid levels and causes gastritis and ulcers), and serotonin-secreting tumors which cause so-called carcinoid syndrome (flushing, chronic diarrhea and difficulty breathing).
In terms of management, we already discussed the high-grade NETs and their poor prognosis. For low-grade NETs or carcinoids, the regular array of treatments in oncology can be brought to bear. If caught early, surgery can be curative. Radiation therapy and chemotherapy can be adjuncts to surgery or used for uncontrolled disease. There are also drugs available to control the symptoms or manifestations of the disease, as in the carcinoid syndrome. Octreotide has proved to be particularly useful in this regard.
It is really not clear what causes or raises the risk of NETs. Family history is associated with an increased risk and there are some genetic syndromes associated with an increased risk as well. While there are conflicting studies, it does seem overall that tobacco use and alcohol consumption are also associated with NETs. After that, very little is known.
Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.
This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.
