Neuroendocrine tumors pathophysiology
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Neuroendocrine tumors Microchapters |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [6]
Pathophysiology
The neuroendocrine system
The endocrine system is a communication system in which hormones act as biochemical messengers to regulate physiological events in living organisms. The nervous system performs the same functions using electrical impulses as messengers. The neuroendocrine system is the combination of those two systems, or more specifically, the various interfaces between the two systems. A GEP-NET is a tumor of any such interface.
More specifically, the endocrine system is primarily a network of glands that produce and secrete hormones, usually into the bloodstream. It also includes cells that are not part of glands: the diffuse neuroendocrine system, scattered throughout other organs.
A hormone is a chemical that delivers a particular message to a particular organ, typically remote from the hormone's origin. For example, the hormone insulin, secreted by the pancreas, acts primarily to allow glucose to enter the body's cells for use as fuel. The hormone gastrin is secreted by the stomach to tell the stomach to produce acids to digest food.
Hormones can be divided into subtypes such as peptides, steroids, and neuroamines. For some researchers, there is no clear distinction between peptide hormones and peptides; the hormones are simply longer than other peptides. In the context of GEP-NETs, the terms hormone and peptide are often used interchangeably.
The vast majority of GEP-NETs fall into two nearly distinct categories: carcinoids, and pancreatic endocrine tumors (PETs). Despite great behavioral differences between the two, they are grouped together as GEP-NETs because of similarities in cell structure.
Pancreatic endocrine tumors (PETs) are also known as endocrine pancreatic tumors (EPTs) or islet cell tumors. PETs are assumed to originate generally in the islets of Langerhans within the pancreas – or, Arnold et alia suggest, from endocrine pancreatic precursor cells (Arnold et al. 2004, 199) – though they may originate outside of the pancreas. (The term pancreatic cancer almost always refers to adenopancreatic cancer, also known as exocrine pancreatic cancer. Adenopancreatic cancers are generally very aggressive, and are not a neuroendocrine cancers. About 95 percent of pancreatic tumors are adenopancreatic; about 1 or 2 percent are GEP-NETs.) [2]
PETs may secrete hormones (as a result, perhaps, of impaired storage ability), and those hormones can wreak symptomatic havoc on the body. Those PETs that do not secrete hormones are called nonsecretory or nonfunctioning or nonfunctional tumors. Secretory tumors are classified by the hormone most strongly secreted – for example, insulinoma, which produces excessive insulin, and gastrinoma, which produces excessive gastrin (see more detail in the summary below).
Carcinoid tumors are further classified, depending on the point of origin, as foregut (lung, thymus, stomach, and duodenum) or midgut (distal ileum and proximal colon) or hindgut (distal colon and rectum). Less than one percent of carcinoid tumors originate in the pancreas. But for many tumors, the point of origin is unknown.
Carcinoid tumors, which secrete serotonin tend to grow much more slowly than PETs. Although this serotonin secretion is entirely different from a secretory PET's hormone secretion, carcinoid tumors with carcinoid syndrome are nevertheless sometimes called functioning, adding to the frequent confusion of carcinoids with PETs. Carcinoid syndrome is primarily associated with midgut carcinoids. A severe episode of carcinoid syndrome is called carcinoid crisis; it can be triggered by surgery or chemotherapy, among other factors. [3]
The mildest of the carcinoids are discovered only upon surgery for unrelated causes. These coincidental carcinoids are common; one study found that one person in ten has them. [4]
Neuroendocrine tumors other than coincidental carcinoids are rare. Incidence of PETs is estimated at one new case per 100,000 people per year; incidence of clinically significant carcinoids is twice that. Thus the total incidence of GEP-NETs in the United States would be about 9,000 new cases per year. But researchers differ widely in their estimates of incidence, especially at the level of the secretory subtypes (the various "-omas"). [5]
In addition to the two main categories, there are even rarer forms of GEP-NETs. At least one form – neuroendocrine lung tumors – arises from the respiratory rather than the gastro-entero-pancreatic system.
Non-human animals also suffer from GEP-NETs; for example, neuroendocrine cancer of the liver is a disease of dogs, and Devil facial tumor disease is a neuroendocrine tumor of Tasmanian Devils. [6]
Rufini et alia summarize: "Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms originating from endocrine cells, which are characterized by the presence of secretory granules as well as the ability to produce biogenic amines and polypeptide hormones. These tumors originate from endocrine glands such as the adrenal medulla, the pituitary, and the parathyroids, as well as endocrine islets within the thyroid or the pancreas, and dispersed endocrine cells in the respiratory and gastrointestinal tract. The clinical behavior of NETs is extremely variable; they may be functioning or not functioning, ranging from very slow-growing tumors (well-differentiated NETs), which are the majority, to highly aggressive and very malignant tumors (poorly differentiated NETs).... Classically, NETs of the gastrointestinal tract are classified into 2 main groups: (1) carcinoids, ... and (2) endocrine pancreatic tumors (EPTs)" (Rufini, Calcagni, and Baum 2006). (Note that the definition of well-differentiated may be counterintuitive: a tumor is well-differentiated if its cells are similar to normal cells, which have a well-differentiated structure of nucleus, cytoplasm, membrane, etc.)
Ramage et alia provide a summary that differs somewhat from that of Rufini et alia: "NETs ... originate from pancreatic islet cells, gastroenteric tissue (from diffuse neuroendocrine cells distributed throughout the gut), neuroendocrine cells within the respiratory epithelium, and parafollicullar cells distributed within the thyroid (the tumours being referred to as medullary carcinomas of the thyroid). Pituitary, parathyroid, and adrenomedullary neoplasms have certain common characteristics with these tumours but are considered separately" (Ramage et al. 2005, [7]).
Metastases and malignancy
In the context of GEP-NETs, the terms metastatic and malignant are often used interchangeably.
GEP-NETs are often malignant, since the primary site often eludes detection for years, sometimes decades – during which time the tumor has the opportunity to metastasize. Researchers differ widely in their estimates of malignancy rates, especially at the level of the secretory subtypes (the various "-omas").
The most common metastatic sites are the liver, the lymph nodes, and the bones. Liver metastases are so frequent and so well-fed that for many patients, they dominate the course of the cancer. For a patient with a nonsecretory PET, for example, the primary threat to life may be the sheer bulk of the tumor load in the liver.
References
- ↑
"The main two groups of neuroendocrine GEP tumours are so-called carcinoid tumours and endocrine pancreatic tumours" (Öberg 2005a, 90, ).
"Less than 1% of carcinoids arise in the pancreas" (Warner 2005, 9).
Arnold et alia in effect define carcinoids as "extra-pancreatic endocrine gastronintestinal tumors" (Arnold et al. 2004, 196).
Some doctors believe that there is significant overlap between PETs and carcinoids. For example, endocrine surgeon Rodney Pommier says that "there are pancreatic carcinoids" (Pommier 2003, [1]). However, Pommier made his statement in a talk at a conference on carcinoids, not in a peer-reviewed journal; and in his talk he did not define the word carcinoid.
Another way to classify GEP-NETs is to separate those that begin in the glandular neuroendocrine system from those that begin in the diffuse neuroendocrine system. "Neuroendocrine tumors generally may be classified into two categories. The first category is an organ-specific group arising from neuroendocrine organs such as pituitary gland, thyroid, pancreas, and adrenal gland. The second group arises from the diffuse neuroendocrine cells/Kulchitsky cells that are widely distributed throughout the body and are highly concentrated in the pulmonary and gastrointestinal systems" (Liu et al. 2001, [2]).
- ↑
According to Arnold et alia, "endocrine pancreatic tumors are also called 'islet cell tumors'" (Arnold et al. 2004, 199).
Many web sites state that 95 percent of pancreatic tumors are adenopancreatic, and that the remainder are nearly all neuroendocrine. But Warner states: "Clinically significant PETs ... account for only 1% - 2% of all pancreatic tumors" (Warner 2005, 3).
- ↑ Larry Kvols, of the Moffitt Cancer Center and Research Institute in Tampa, Florida, lists flushing, diarrhea, CHF, and asthma as the four critical characteristics of carcinoid syndrome (Kvols 2002, [3]).
- ↑
"[In] 800 autopsy cases, ... incidence of tumor was 10% (6/60) in individuals having histological studies of all sections of the pancreas" (Kimura, Kuroda, and Morioka 1991, [4]).
Small tumors are not necessarily harmless: Rodney Pommier tells of a "chick pea-sized tumor causing [so much] hormonal effect" that the patient was wheelchair-bound, unable to walk (Pommier 2003, [5]).
- ↑ "The incidence of all noncarcinoid NETs is approximately one half that of all carcinoids. Noncarcinoid NETs have been reported to occur in .4 to 1.5/100,000 of the population.... Clinically significant PETs have been reported to occur in approximately 1 per 100,000 people per year" (Warner 2005, 1). One per 100,000 per year implies 3,000 new PET cases per year for the US population of roughly 300 million. And that, with Warner's other numbers, implies 6,000 new carcinoid cases for a total of 9,000 new GEP-NET cases per year.
- ↑
"The tumors [of Devil facial tumor disease] have been characterized as a neuroendocrine cancer" (Bostanci 2005).
Owen and Pemberton, in their book on Tasmanian Devils, discuss Devil facial tumor disease (DFTD) extensively, describing it as a cancer with possible viral or toxic causes or triggers. They never use the term neuroendocrine. "Although cancer is a major cause of devil mortality, it's usually internal", they report (Owen and Pemberton 2005, 171). They discuss the first "official" case of DFTD, in 1995 (Owen and Pemberton 2005, 187), and quote Loh's description thereof: "subcutaneous lymph nodes enlarged and also scattered dermal and subcutaneous swellings, ... necrotic reactionary lesion in the masseter muscle, ... multifocal dermal leukosis with lymphosarcomatous infiltration of lymph nodes and in the periportal tissues of the liver and interstitially in the adrenal and also through skeletal muscle tissue, ... lymphosarcomatous infiltration of ... the masseter muscle, ... widespread lymphosarcomatous neoplasia, ... [and] occasional, but consistent findings of azurophilic intracytoplasmic material in some cells. Artefact or viral inclusions?" (Loh 2003).