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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [7]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[8]


Neuroendocrine tumors, or more properly gastro-entero-pancreatic or gastroenteropancreatic neuroendocrine tumors (GEP-NETs), are cancers of the interface between the endocrine (hormonal) system and the nervous system.

Historical Perspective

Siegfried Oberndorfer, in 1907, was the first person to distinguish clearly what we now call GEP-NETs from other forms of cancer. He gave the term "carcinoid" to these tumors, because they were so slow-growing that he considered them to be "cancer-like" rather than truly cancerous. In 1929, he reported that some such tumors were not so indolent – these he distinguished as what we now call PETs from what most authorities call carcinoids. Despite the differences between the two categories, some doctors, including oncologists, persist in calling all GEP-NETs "carcinoid", even into the twenty-first century. [1]

The earliest synthetic form of somatostatin used in the treatment of Neuroendocrine tumors was octreotide, first marketed, by Sandoz as Sandostatin, in 1988.

Classification

Human GEP-NETs by Site of Origin and by Symptom

Classification of GEP-NETs by cell characteristics

The diverse and amorphous nature of GEP-NETs has led to a confused, overlapping, and changing terminology. In general, aggressiveness (malignancy), secretion (of hormones), and anaplasia (dissimilarity between tumor cells and normal cells) tend to go together, but there are many exceptions, which have contributed to the confusion in terminology. For example, the term atypical carcinoid is sometimes used to indicate an aggressive tumor without secretions, whether anaplastic or well-differentiated.

In 2000, the World Health Organization (WHO) revised the classification of GEP-NETs, abandoning the term carcinoid in favor of neuroendocrine tumor (NET) and abandoning islet cell tumor or pancreatic endocrine tumor for neuroendocrine carcinoma (NEC). Judging from papers published into 2006, the medical community is accepting this new terminology with great sluggishness. (Perhaps one reason for the resistance is that the WHO chose to label the least aggressive subclass of neuroendocrine neoplasm with the term – neuroendocrine tumor – widely used previously either for the superclass or for the generally aggressive noncarcinoid subclass.)

Klöppel et alia have written an overview that clarifies the WHO classification and bridges the gap to the old terminology (Klöppel, Perren, and Heitz 2004). In this article we conform to the old terminology.

Summary of classification by cell characteristics (the WHO classification)

  • Superclass:
    • Öberg, WHO, Klöppel et alia: Gastro-entero-pancreatic neuroendocrine tumor (GEP-NET)
  • Subclass 1 (less malignant)
    • Öberg: Carcinoid
    • WHO: Neuroendocrine tumor (NET)
    • Klöppel et alia: Well-differentiated neuroendocrine tumor (NET) (carcinoid)
    • this article: Carcinoid
  • Subclass 2 (more malignant)
    • Öberg: Endocrine pancreatic tumor
    • WHO: Neuroendocrine carcinoma (NEC)
    • Klöppel et alia: Well-differentiated neuroendocrine carcinoma (NEC) (malignant carcinoid)
    • this article: Pancreatic endocrine tumor (PET) or endocrine pancreatic tumor (EPT) or islet cell tumor or noncarcinoid GEP-NET
  • Subclass 3 (most malignant)
    • WHO: Poorly-differentiated neuroendocrine carcinoma
    • Klöppel et alia: Poorly-differentiated neuroendocrine carcinoma (high-grade malignant carcinoid)
  • Subclass 4 (mixed)
    • WHO: Mixed endocrine/exocrine tumor
  • Subclass 5 (miscellaneous)
    • WHO: Rare neuroendocrine-like lesions

GEP-NETs are also sometimes called APUDomas, but that term is now considered to be misleading, since it is based on a discredited theory of the development of the tumors. [2]

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.

[3]

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.) [4]

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. [5]

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. [6]

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"). [7]

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. [8]

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, [9]).

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.

Causes

In the normal pancreas, cells called islet cells produce hormones that regulate a variety of bodily functions, such as blood sugar level and the production of stomach acid.

Islet cell tumors include:

  • Gastrinomas (Zollinger-Ellison syndrome)
  • Glucagonomas
  • Insulinomas

Complications

  • Diabetes
  • Hormone crises (if the tumor releases certain types of hormones)
  • Severe low blood sugar (from insulinomas)
  • Severe ulcers in the stomach and small intestine (from gastrinomas)
  • Spread of the tumor to the liver

Prognosis

You may be cured if the tumors are surgically removed before they have spread to other organs. If tumors are cancerous, chemotherapy may be used, but it usually cannot cure patients.

Life-threatening problems (such as very low blood sugar) can occur due to excess hormone production, or if the cancer spreads throughout the body.

Symptoms

According to Arnold et alia, "many tumors are asymptomatic even in the presence of metastases" (Arnold et al. 2004, 197).

A carcinoid tumor may produce serotonin (5-HT), a biogenic amine that causes a specific set of symptoms including

This set of symptoms is called Carcinoid syndrome.

Laboratory Findings

Cells that receive hormonal messages do so through receptors on the surface of the cells. For reasons that are not understood, many neuroendocrine tumor cells possess especially strong receptors; for example, PETs often have strong receptors for somatostatin, a very common hormone in the body. We say that such tumor cells overexpress the somatostatin receptors (SSTRs) and are thus avid for the hormone; their uptake of the hormone is strong. This avidity for somatostatin is a key for diagnosis – and it makes the tumors vulnerable to certain targeted therapies.

The list of potential markers for GEP-NETs is long. Aside from the hormones of secretory tumors, the most important markers are

  • Chromogranin A (CgA)
  • Urine 5-hydroxy indole acetic acid (5-HIAA) (grade C)
  • Neuron-specific enolase (NSE, gamma-gamma dimer)
  • Synaptophysin (P38)

and other markers include

  • Synaptobrevin (VAMP-1)
  • Synapsin (1A, 1B, 2A, 2B)
  • SV2
  • Protein P65
  • Protein S-100
  • Protein gene product (PGP) 9.5
  • Intermediate filaments (cytokeratins, vimentin, neurofilaments)
  • Protein 7B2
  • Chromogranin B (secretogranin I)
  • Chromogranin C (secretogranin II)
  • Pancreastatin
  • Vasostatin
  • Cytochrome b561
  • Leu-7 (HNK-1)
  • Calcitonin
  • Human chorionic gonadotropin-alpha (HCG-α)
  • Human chorionic gonadotropin-beta (HCG-β)
  • Thyroid function tests (TFTs)
  • Parathyroid hormone (PTH)
  • Calcium
  • Prolactin
  • {Alpha}-fetoprotein
  • Carcinoembryonic antigen (CEA)
  • ß-human chorionic gonadotrophin (ß-HCG) (grade D)
  • CGRP
  • GRP
  • PYY
  • hCGα
  • N Peptide K
  • Neurokinin A
  • Serotonin
  • Neurotensin
  • Motilin
  • Substance P
  • Histamine
  • Catecholamines
  • Dopa
  • Various rarer peptide hormones
  • Synaptotagmin
  • HISL-19

and newer (as of 2005) markers include

  • N-terminally truncated variant of heat shock protein 70 (Hsp70)
  • CDX-2, a homeobox gene product
  • Neuroendocrine secretory protein-55

Aside from their use in diagnosis, some markers can track the progress of therapy while the patient avoids the detrimental side-effects of CT-scan contrast.

Overview

CT-scan is a common diagnostic tool in the diagnosis of Neuroendocrine tumors.

CT Scan

CT-scans using contrast medium can detect 95 percent of tumors over 3 cm in size, and no tumors under 1 cm (University of Michigan Medical School n. d., [10]).

PET-CT Scan

A gallium-68 receptor PET-CT, integrating a PET image with a CT image, is much more senstitive than an OctreoScan, and it generates objective (quantified) results in the form of a standardized uptake value (SUV).

Octreoscan

The diagnostic procedure that utilizes a somatostatin analog is the OctreoScan, also called somatostatin receptor scintigraphy (SRS or SSRS): a patient is injected with octreotide chemically bound to a radioactive substance, often indium-111; for those patients whose tumor cells are avid for octreotide, a radiation-sensitive scan can then indicate the locations of the larger lesions.

An OctreoScan is a relatively crude test that generates subjective results.

Images courtesy of RadsWiki

OctreoScan demonstrates abnormal uptake in the liver and abdominal lymph nodes


OctreoScan demonstrates abnormal uptake in the liver and abdominal lymph nodes


OctreoScan demonstrates abnormal uptake in the head of the pancreas


OctreoScan demonstrates abnormal uptake in the head of the pancreas


OctreoScan demonstrates abnormal uptake in the head of the pancreas


Reference

  1. ↑ "The term 'carcinoid' was introduced by S[iegfried] Oberndorfer in 1907 to distinguish carcinoids as less rapidly growing and well-differentiated epithelial tumors of the small intestine from the more aggressively growing adenocarcinoma of the gut.... Strictly speaking ... the term 'carcinoid' [is] reserved for endocrine tumors of the gastrointestinal tract ... and not for those of the pancreas.... The vagueness of the term 'carcinoid' results from its histological features which are almost identical with those of endocrine pancreatic tumors" (Arnold et al. 2004, 195).

    "During his tenure at the Pathological Institute of the University of Munich, Oberndorfer noted in 1907 that the lesions were distinct clinical entities and named them 'karzinoide' ('carcinoma-like'), emphasizing in particular their benign features. In 1929 he amended his classification to include the possibility that these small bowel tumors could be malignant and also metastasize" (Modlin 2004).

    Regarding the persistence of the term carcinoid: on a PET news forum, a patient says "for over 4 yrs I was referred to as carcinoid. In fact even when it was discovered I was actually islet cell and the pathologist was questioned by my doctor (specialist in NET) about this the pathology said we classify all islet cell as carcinoid. Since then no matter how many times I say islet cell to a local doctor - oncologist, gastroendocrineologist, radiologist - you get the idea - they ALL continue to refer to me as carcinoid" (NET_IsletCell 2006).

  2. ↑ "The APUD concept led to the belief that these cells arise from the embryologic neural crest. This hypothesis eventually was found to be incorrect" (Warner 2005, 2).

    "The APUD-concept is currently abandoned" (Öberg 1998, 2, [1]).

  3. ↑ "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, [2]). 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, [3]).

  4. ↑ 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).

  5. ↑ 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, [4]).
  6. ↑ "[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, [5]).

    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, [6]).

  7. ↑ "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.
  8. ↑ "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).

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