MTC derives from the thyroid parafollicular C cells that are able to produce and secrete calcitonin. This thyroid cancer subtype occurs as a sporadic tumor or as part of a hereditary syndrome (multiple endocrine neoplasia (MEN), 2A and 2B, or familial MTC). Sporadic MTC accounts for 75 % of all cases (Table 39.2). Median age at diagnosis occurs during fifth or sixth decade of life and remains slightly more frequent in women [6]. In 35–50 % of patients, lymph node metastases are observed at diagnosis. When MTC metastasizes, the most common distant sites are the liver, lung, bones, and, with less frequency, brain and skin [7].

Their neural crest origin is responsible for the ability of C cells to take up amine precursors as well as the secretion of neuroactive peptides that include calcitonin, CEA, serotonin, ACTH, chromogranin A, somatostatin, neurotensin, pro-opiomelanocortin, prostaglandins, kinins, histaminase, and vasoactive intestinal peptide (VIP) [8]. Serum calcitonin or CEA elevations are almost universal and are key in MTC diagnosis, monitoring the clinical course of disease, and evaluating the response to therapy.

Typically, patients present with a palpable asymptomatic neck mass. However, with the appearance of a thyroid nodule, clinicians should be aware of the presence of an MTC if patients suffer from symptoms such as diarrhea, flushes, weight loss, and, more rarely, Cushing’s syndrome or if it is associated with a familial history of MTC, pheochromocytoma, and hyperparathyroidism. The systemic symptoms may occur due to hormonal excess or to distant metastatic disease.

In case of a large palpable thyroid nodule, local compressive symptoms, such as dysphagia or a choking sensation, may occur. Rarely, the mass can infiltrate the recurrent nerve and cause hoarseness [9].

When faced with a patient with chronic diarrhea, neuroendocrine tumors should always be considered in the differential diagnosis. Clues should be sought in the clinical history, physical examination, complementary studies, and laboratory tests. They can help rule out more common causes of chronic diarrhea such as infections, drug use, chronic inflammatory diseases, cathartic agent use, and diabetic diarrhea.

Diarrhea in MTC is caused by two main pathophysiological mechanisms: the most important one suggests a motor dysfunction diarrhea leading to decreased transit time due to hyperactivity of small intestinal and colonic tone, leading to insufficient absorption. It has been reported in 28–39 % of cases [10]. The second possible mechanism is a secretory impairment as the origin of the diarrhea caused by substances other than calcitonin. This postulated mechanism is based on an increase in fluid and electrolyte secretion induced by prostaglandins (E₂ or F_2α), serotonin, or substance P that worsens the absorptive dysfunction in the intestinal tract caused by increased colonic tone and decreased transit time [11]. Circulating agents enter the intestinal epithelial cells (located in the jejunum and ileum) and reverse the absorption of water and electrolytes into a secretory process. The rapid emptying of the proximal colon may contribute to the increase stool weight in these patients. While sodium plays a key role in the absorption of water and electrolytes, chloride is the most important electrolyte involved in the secretion of ions. Several intracellular pathways result in the output of chloride ions from the intestinal epithelial cells via a specific chloride channel in the luminal membrane. The process can start on the luminal side, as occurs in infections, or on the serosal side, for example, when related to circulating agents such as serotonin or VIP. Thus, elevated circulating concentrations of hormones such as gastrin, somatostatin, and VIP can alter both gastrointestinal motor function and intestinal secretion and contribute to the diarrhea associated with MTC [12].

This phenomenon usually occurs in advanced disease, so patients can suffer from a syndrome similar to the carcinoid syndrome with flushing and/or diarrhea. Because the increased levels of circulating calcitonin or other peptides stimulate secretion by the small intestine mucosa, the diarrhea can be severe with a large volume of watery stools, often exceeding 1 L per day, without any specific treatment [11].