" HISTORICAL OVERVIEW
GASTRO-INTESTINAL CARCINOIDS are slow growing neoplasms as compared with adenocarcinomas, but they can also behave aggressively. They are derived from neoplastic proliferation of enterochromaffin (ECL) or Kulchitsky cells (1).
In 1888, Lubarsch first described a patient with multiple carcinoids of the ileum but regarded them as carcinomas (2). Two years later, Ransom first described the classical symptomatology of the carcinoid syndrome in a patient with an ileal carcinoid tumor and hepatic metastasis (3). However, it was Oberndorfer in 1907, who coined the term "karzinoide" to describe these tumors, which he believed to behave in a more benign fashion than adenocarcinomas (4). In 1963, Williams and Sandler classified carcinoids according to their embryologic site of origin as foregut carcinoids (respiratory tract, stomach, duodenum, biliary system, and pancreas), midgut carcinoids (small intestine, appendix, cecum, and proximal colon), and hindgut carcinoids (distal colon and rectum) (5). However, these lesions exhibit a high degree of morphologic and biologic heterogeneity and a more generic term, neuroendocrine tumor (NET) has been introduced to replace the term carcinoid. Such lesions are currently referred to as gastroenteropancreatic (GEP) NETs (GEP-NETs). According to the WHO classification, distinction was made between well-differentiated NETs (benign behavior or uncertain malignant potential), well-differentiated neuroendocrine carcinomas (low-grade malignancy), and poorly differentiated (usually small cell) neuroendocrine carcinomas of high-grade malignancy. Nevertheless, the term carcinoid was not abandoned and for GEP-NETs, it is used synonymously with the term "well-differentiated NET". The term "malignant carcinoid" is used synonymously with the term well-differentiated neuroendocrine carcinoma (6). The differentiation is based on tumor morphology, tumor size (in general larger tumors are more aggressive), and the presence or absence of local invasion and/or metastasis, thus reflecting biological behavior. Most NETs are well-differentiated tumors that are characterized by a solid trabecular or glandular structure, tumor cell monomorphism with absent or low cytological atypia, and a low mitotic (<> 10 mitoses/mm2) and proliferative status (> 15% Ki-67 positive cells), diffuse reactivity for cytosolic markers, and scant or weak reactivity for granular markers or neurosecretory products (1).
Carcinoid lesions are the most common NETs and compose approximately 50% of all NETs of the gastrointestinal tract. In most instances, they are discovered incidentally at the time of surgery for other abdominal disorders. Their presence may be undetectable for years without obvious signs or symptoms. Evidence for this observation is supported by their relatively high incidence in large autopsy series (7). When symptoms do occur, they are due either to local tumor mass effects, the effects of tumor-engendered fibrosis, or to the secreted bioactive products from the neoplasm. Symptoms caused by local tumor effects include vague abdominal pain (invasion, intussusception, fibrous adhesions, hypermotility), which is often undiagnosed or leads to erroneous diagnoses like irritable bowel syndrome (8,9).
Carcinoids have protean clinical presentations, depending on what combination of bioactive substances is secreted. One of their main characteristics of the enterochromaffin (ECL) or Kulchitsky cells is the synthesis, storage, and secretion of serotonin. Serotonin (5-hydroxytrypamine, 5-HT) is synthesized from tryptophan through its precursor, 5-hydroxy tryptophan (5-HTP), and subsequently metabolized to 5-hydroxyindoleacetic acid (5-HIAA), which is excreted in the urine. In addition to serotonin, carcinoid tumors may also secrete other hormones such as corticotrophin (ACTH), histamine, dopamine, substance P, neurotensin, prostaglandins, kallikrein, and tachykinins. In normal subjects, approximately 99% of tryptophan is used for the synthesis of nicotinic acid (niacin), and 1% or less is converted to 5-HT. In patients with carcinoid tumors, there is a shift toward the production of 5-HT and eventually 5-HIAA. This may lead to tryptophan deficiency and pellagra might ensue as a result of nicotinic acid deficiency (9). When 5-HT and other products are secreted into the portal circulation, they are efficiently metabolized by the liver and do not usually cause any systemic signs or symptoms. However, when liver metastases are present or when the primary lesions are found in the bronchus and/or ovaries, the systemic features of the carcinoid syndrome become more evident. This classical syndrome occurs in fewer than 10% of patients, and its most typical clinical manifestations include cutaneous flushing most commonly of the face, neck, and upper chest and diarrhea, occurring in up to 75%. Less frequent manifestations include cardiac valvular abnormalities (plaque-like, fibrous endocardial thickening that principally involves the right side of the heart (causing tricuspid regurgitation tricuspid stenosis, pulmonary regurgitation, and pulmonary stenosis), bronchoconstriction and (as already mentioned) pellagra. Foregut carcinoids can secrete 5-HTP, histamine and polypeptide hormones like ACTH. The can produce a characteristic clinical syndrome known as "atypical" carcinoid syndrome. Midgut carcinoids release 5-HT and other vasoactive compounds such as kinins, prostaglandins, and substance P and they are more likely to cause the classic carcinoid syndrome with the development of hepatic metastases. Hindgut carcinoid tumors rarely contain 5-HT and usually do not present with the carcinoid syndrome; however. The symptoms of the carcinoid syndrome can be both of variable intensity as well as paroxysmal, responding intermittently to a particular "trigger" agent, such as alcohol, cheese, coffee (these are serotonin-rich foods), or exercise (8,10,11).
Many carcinoid tumors exhibit a significant association with other non-carcinoid tumors of various histological types. A relatively large percentage of carcinoids are multicentric.
Because carcinoid tumors frequently present with obscure clinical manifestations, numerous investigatory procedures are often undertaken prior to establishing the correct diagnosis. Although clinical diagnosis is based on symptoms, biochemical confirmation is necessary. The diagnostic strategies employed usually depend on the individual clinical presentation (8,10,11)."
Fonte Bibliográfica: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0004-27302005000500028&lng=pt&nrm=isso
Com base no artigo, percebe-se a influência da síndrome com a pelagra, pois a secreção liberada pelo tumor, no caso a enterochromaffin (ECL), está associada com a produção de serotonina. Para que ocorra síntese de serotonina, deve-se ter triptofano como substrato, logo o triptofano presente no organismo ao invés de ser convertido a niacina - vitamina anti-pelagra- em grande escala é convertido em serotonina, diminuindo os níveis de niacina provocando a pelagra.
By: Ivana Melo