I was lucky enough to attend the 1987 annual meeting of the American Society of Clinical Oncology when Charles Moertel delivered the annual Karnofsky Memorial Lecture, the highest honor of ASCO. The topic was “An Odyssey in the Land of Small Tumors,” and focused on what was known at that time regarding an uncommon and esoteric class of tumors known as carcinoids.
We have previously discussed carcinoid tumors, but repetition never hurts. They are a subgroup of neuroendocrine tumors that are found in most organs but most prominently in the luminal GI tract. They are most common in the appendix and small bowel. When originally identified and studied, it was uncertain as to their origin and degree of malignancy, and thus they were given the compromise appellation of carcinoids. Carcinoids are actually the low-grade group of neuroendocrine tumors and are generally very indolent and unaggressive, which may have led to this ambiguity. But it is now well recognized that they do indeed spread and metastasize both locally to regional lymph nodes as well as distantly to the usual metastatic sites. Nonetheless, as previously recognized, the low-grade carcinoid neuroendocrine tumors can have very long progression and survival times, even in the absence of treatment.
We should not confuse the low-grade carcinoid tumors with the high-grade variety of the neuroendocrine tumors. The high-grade neuroendocrine tumors are very aggressive, dangerous, and difficult to treat, with poor prognoses.
Neuroendocrine tumors were thought to combine traits of neural and hormone cells, hence the name. However, later studies and developments have clarified that the relationship to neural cells was incorrect; nonetheless, the name has stuck. The endocrine aspect of its nature does remain accurate, however; these tumors do generally secrete polypeptides of one type or another. Sometimes the polypeptides secreted by the tumors are the same or similar to hormones that we normally secrete, such as insulin or glucagon, and we are confronted by insulinomas or glucagonomas and the main symptomatology of neuroendocrine tumors may be the effects of the excess hormones, like hypoglycemia.
Many of the carcinoid tumors will produce hormones, such as serotonin or related bioactive peptides. Thus, one can test a patient’s urine for chemicals, such as 5-HIAA or chromogranin A, the presence of which would indicate that the tumor is hormonally active. If the tumor metastasizes to the liver, then the bioactive peptides (primarily serotonin) can escape into the systemic circulation and cause symptoms. Serotonin is 5-hydroxytryptamine whose main function is to act as a neurotransmitter. However excess serotonin and the other chemicals can induce carcinoid syndrome—flushing in the face and neck, chronic diarrhea, and difficulty breathing.
Moertel and his colleagues were responsible for carefully cataloging much of what was known at the time about the prevalence and natural history of neuroendocrine tumors and carcinoids. They also described the characteristics of carcinoid syndrome and the excellent survival rates associated with these malignancies, thus encouraging observation rather than aggressive approaches to their management; these conservative approaches proved to be successful for the large majority of patients. In addition, they tried various chemotherapy drugs for metastatic neuroendocrine tumors, which had variable success. This mostly proved to be a disappointing exercise at the time of Moertel.
What was important, however, was palliation of the carcinoid syndrome, which was very stressful to those who experienced it and also could cause long-term damage to the heart and other organs. The body has developed inhibitors for various hormones, and thus the body’s feedback hormone for the neuroendocrine hormones is somatostatin. It inhibits many of the protein hormones, most notably growth hormone. It turns out that analogues of somatostatin can inhibit serotonin and the carcinoid syndrome quite effectively. The one that proved to be most popular for this purpose was octreotide, which is generally administered subcutaneously or intramuscularly.
In a 1986 paper in the New England Journal of Medicine, Moertel and his colleague Larry Kvols from the Mayo Clinic treated 25 patients with malignant carcinoid syndrome using subcutaneous octreotide. Of the 25 patients, 22 had relief of their symptoms, while eighteen had a <50% reduction in their 5-HIAA urinary excretion. This effect lasted for 18 months. One can also utilize octreotide to do a special type of scan which will map the distribution of neuroendocrine tumor metastases in the body.
Charles Moertel ultimately died in 1994 at the age of 66. He died from a lymphoma.
Last week, I indicated I would list the five individuals who won the Nobel Prize twice. Interestingly, Albert Einstein was not one of them despite his multiple discoveries. Last week we mentioned Linus Pauling, who won in both Chemistry for his work on the structure of proteins and in Peace for campaigning against nuclear testing. John Bardeen of Bell Labs won two Physics Prizes for inventing the transistor and for developing a theory of superconductivity. Frederick Sanger won twice in Chemistry for elucidating the structure of insulin and for developing methods to sequence DNA. Marie Curie won one Prize in Chemistry and one Prize in Physics, both for her seminal work on radioactivity. Barry Sharpless won two Nobel Prizes in Chemistry, the first for developing chiral catalysts—don’t ask me!—and the second for the development of click chemistry.
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. Email: [email protected].
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.
