Neuroendocrine tumor

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

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 is a communication system in which electrical impulses act as messengers to regulate events in living organisms. 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 cancer of any such interface.

More concretely, the endocrine system is in large part a network of glands that produce and secrete hormones, usually into the bloodstream. But 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, peptides and hormones are not different in kind; hormones are simply longer than peptides. In the context of GEP-NETs, the terms hormone and peptide tend to be interchangeable.

Classification of GEP-NETs by Site of Origin and by Symptom

According to Rufini et al., GEP-NETs "originate from pancreatic islet cells, [from] gastroenteric tissue (from diffuse neuroendocrine cells distributed throughout the gut), [from] neuroendocrine cells within the respiratory epithelium, and [from] 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" (http://pubmed.org; search for 16762613). Some researchers, however, do not consider them separately.

Note that some GEP-NETs do not arise from the gastro-entero-pancreatic system; for example, one type listed above arises from the lungs. Those tumors are included under the GEP-NET label because of their similarity to what we may call "true" GEP-NET tumors.

Subtypes of the GEP-NETs by site of origin include

pancreatic endocrine tumor (PET)
carcinoid
medullary carcinoma of the thyroid
Merkel cell cancer (trabecular cancer)
neuroendocrine lung tumors, including small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma
neuroendocrine carcinoma of the cervix
Multiple Endocrine Neoplasia type 1 (MEN-1 or MEN1)
neuroendocrine cancer of the liver (a disease of dogs)
Devil facial tumor disease (a disease of Tasmanian Devils)
other, rare forms

(see more detail in the summary below).

The vast majority of GEP-NETs are in the first two categories. Originally only the carcinoid category was recognized, and it was given the name carcinoid because the tumors were so slow-growing that they were considered to be "cancer-like" rather than truly cancerous. In 1907, Oberndorfer recognized that some such tumors were not so indolent, and the other categories were then slowly delineated.

Pancreatic endocrine tumors (PETs) are also known as endocrine pancreatic tumors (EPTs) or islet cell tumors. PETs generally originate in the islets of Langerhans within the pancreas, 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 cancer is not a neuroendocrine cancer. About 95 percent of cancers occurring in the pancreas are adenopancreatic; about 1 or 2 percent are PETs.)

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 tend to grow much more slowly than PETs. Both types may secrete hormones. Those hormones can wreak symptomatic havoc on the body. Those GEP-NETs that do not secrete hormones are called nonsecretory or nonfunctioning or nonfunctional tumors.

Secretory tumors are classified by the particular hormone most strongly secreted -- for example, gastrinoma, producing excessive gastrin, and insulinoma, producing excessive insulin (see more detail in the summary below).

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

facial flushing
diarrhea
congestive heart failure (CHF)
asthma
acromegaly
Cushing's syndrome

This set of symptoms is called carcinoid syndrome; it is primarily associated with midgut carcinoids. Carcinoid syndrome is generally not classed among the functioning tumors because of the distinct nature of the symptoms produced.

The mildest of the GEP-NETs are discovered only upon surgery for unrelated causes; these coincidental carcinoids are fairly common: for example, for roughly every 250 appendices removed by surgery for unrelated reasons, one is found.

Neuroendocrine cancers other than coincidental carcinoids are rare. Incidence of noncarcinoid GEP-NETs is 0.4 to 1.5 per 100,000 per year; incidence of carcinoid GEP-NETs is twice that. Thus the total incidence of GEP-NETs in the United States is about 9,000 new cases per year.

Rufini summarizes: "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)". (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.)

Summary of Human GEP-NETs by Site of Origin and by Symptom

carcinoids (more benign) and PETs (more aggressive)
- nonfunctioning
  - with carcinoid syndrome
  - without carcinoid syndrome
- functioning
  - gastrinoma (producing excessive gastrin)
  - insulinoma (producing excessive insulin)
  - glucagonoma (producing excessive glucagon)
  - vasoactive intestinal peptideoma (VIPoma) (producing excessive VIP)
  - PPoma (producing excessive pancreatic polypeptide)
  - somatostatinoma (producing excessive somatostatin)
  - watery diarrhea, hypokalemia-achlorhydria (WDHA)
medullary carcinoma of the thyroid
Merkel cell cancer (trabecular cancer)
small-cell lung cancer (SCLC)
large-cell neuroendocrine carcinoma (of the lung)
neuroendocrine carcinoma of the cervix
Multiple Endocrine Neoplasia type 1 (MEN-1 or MEN1)
neurofibromatosis type 1
tuberous sclerosis
von Hippel-Lindau (VHL) disease
neuroblastoma
pheochromocytoma
neuroendocrine tumor of the anterior pituitary
etc.

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 but nonsecretory tumor, 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 and pancreatic endocrine tumor for neuroendocrine carcinoma (NEC). Judging from papers published into 2006, this new classification is being accepted by the medical community 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" -- previously and widely used either for the superclass or for a fairly aggressive subclass.) The summary by Klöppel et alia clarifies the WHO classification and bridges the gap to the old terminology. In this article we conform to the older terminology.

Summary of Classification by Cell Characteristics

superclass:
- Öberg: gastro-entero-pancreatic neuroendocrine tumor (GEP-NET)
- WHO: gastro-entero-pancreatic neuroendocrine tumor (GEP-NET)
- Klöppel et alia: gastro-entero-pancreatic neuroendocrine tumor (GEP-NET)

less malignant subclass:
- Öberg: carcinoid
- WHO: neuroendocrine tumor (NET)
- Klöppel et alia: well-differentiated neuroendocrine tumor (NET) (carcinoid)
- this article: carcinoid

more malignant subclass:
- Öberg: endocrine pancreatic tumor
- WHO: neuroendocrine carcinoma (NEC)
- Klöeppel 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 NET

most malignant subclass:
- WHO: poorly-differentiated neuroendocrine carcinoma
- Klöppel et alia: poorly-differentiated neuroendocrine carcinoma (high-grade malignant carcinoid)

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.

Metastases of GEP-NETs

Metastases of GEP-NETs are common, since the primary site often eludes detection for years, during which the tumor takes advantage of the opportunity to metastasize.

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.

Diagnosis

CT-scans, MRIs, and ultrasound are common diagnostic tools. Symptoms from hormone secretions or from carcinoid syndrome, or measures of the corresponding hormones in the blood, can aid in diagnosis. Palpation can also be useful.

An OctreoScan is another diagnostic tool: a patient is injected with octreotide chemically bound to radioactive Indium; since, for many patients, the tumor cells are avid for octreotide, a radiation-sensitive scan can then indicate the locations of the tumors, or at least of some of the larger lesions. An OctreoScan is a crude test that generates subjective results; a Gallium-68 receptor PET-CT exam is approximately one thousand times more sensitive than an OctreoScan, and it generates objective (quantified) results.

Synaptophysin, neuron-specific enolase (NSE), and chromogranin may serve as blood-test markers for GEP-NETs. Aside from their use in diagnosis, markers can track the progress of therapy while the patient avoids the detrimental side-effects of CT-scans.

Therapies for GEP-NETs

Surgery and Chemotherapy

Surgery is the only therapy that can cure GEP-NETs. However, the typical delay in diagnosis, giving the tumor the opportunity to metastasize, makes most GEP-NETs ineligible for surgery (non-resectable).

There is no standard therapy for liver metastases of GEP-NETs, according to Sato et al. (http://www.pubmed.org; search for 10791232). The most common therapy is chemotherapy, although chemotherapy is reputed to be largely ineffective for carcinoids and not particularly durable (long-lasting) for PETs. For example, a patient who achieves eighteen months of tumor shrinkage or even tumoristasis from chemotherapy is unusual.

When chemotherapy fails, the most common therapy, in the United States, is more chemotherapy, with a different set of agents. Some studies have shown that the benefit from one agent is not especially predictive of the benefit from another agent, except that the long-term benefit of any agent is likely to be low.

Somatostatin Congeners for Symptomatic Relief

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 receptors and are thus "avid for" the hormone; their "uptake" of the hormone is strong. This avidity for somatostatin makes the tumors vulnerable to certain "targeted" therapies, described below.

Unfortunately, the half-life of somatostatin in circulation is under three minutes, making it difficult to utlize in targeted therapies. For this reason, synthetic forms of somatostatin are used instead; the earliest was octreotide, first marketed, by Sandoz, in 1988. The synthetic forms are typically called somatostatin analogs (somatostatin analogues), but according to the US Food and Drug Administration (FDA), the proper term is somatostatin congeners. The congeners have a much longer half-life than somatostatin, and other properties that make them suitable for targeted therapies.

There are two major somatostatin-congener-based targeted therapies. The first of the two therapies provides symptomatic relief for patients with secretory tumors. In effect, somatostatin given subcutaneously or intramuscularly "clogs up" the receptors, blocking the secretion of hormones from the tumor cells. Thus a patient who might otherwise die from severe diarrhea caused by a secretory tumor can gain additional years of life.

Peptide-delivered Ratiotherapy

The second of the two major somatostatin-congener-based targeted therapies is called peptide receptor radionuclide therapy (PRRT), though we might simply call it "peptide-delivered radiotherapy". In this therapy, which was developed in the 1990s, radioactive substances (called radionuclides or radioligands) are chemically bound to peptides or neuroamines; the combination is given to a patient intravenously. The tumor cells, through their overexpression of peptide receptors or through their mechanisms for uptake of neuroamines, pull the peptide or neuroamine to them, and the attached radiation kills the tumor cells. In patients with strongly overexpressing tumor cells, very little radiation escapes the tumor. In Rufini's words, GEP-NETs "are characterized by the presence of neuroamine uptake mechanisms and/or peptide receptors at the cell membrane, and these features constitute the basis of the clinical use of specific radiolabeled ligands, both for imaging and therapy". (Nonmedullary thyroid tumors -- which are not GEP-NETs -- tend to be avid for iodine, and the iodine-131 isotope is a standard therapy such tumors. The use of PRRT for medullary thyroid tumors and other GEP-NETs is analogous to that use of iodine, with the somatostatin congener playing the role of iodine's uptake properties and the radionuclide playing the role of its tumoricidal properties.)

As of 2006, PRRT is available at twelve institutions in Europe and South America. In the USA it is FDA-approved, and available at the MD Anderson Cancer Center, but using a radionuclide (Indium) that is vastly weaker than the two radionuclides (Lutetium and Yttrium) used in Europe. PRRT with Lutetium or Yttrium is nowhere an "approved" therapy, but the German health insurance system, for example, pays for the therapy for German citizens.

Other Therapies

Another therapy for GEP-NETs is hepatic artery embolization (HAE). According to Dr. Larry Kvols of Lee H. Moffitt Cancer Center, "hepatic artery embolization . . . has been quite successful. During that procedure a catheter is placed in the groin and then threaded up to the hepatic artery that supplies the tumors in the liver. We inject a material called embospheres into the artery and it occludes the blood flow to the tumors, and in more than 80% of patients the tumors will show significant tumor shrinkage". HAE is based on the observation that tumor cells get most of their nutrients from the hepatic artery, while the normal cells of the liver get can most of their nutrients from the portal vein.

Hepatic artery chemoembolization (HACE) is a variation on hepatic artery embolization: the spheres are treated with chemotherapy drugs before administration. The targeting of the hepatic artery allows delivery of a higher effective dose of chemotherapy than systemic chemotherapy would allow.

Radioactive microsphere therapy (RMT) is another variation on hepatic artery embolization: spheres of glass or resin are treated with radionuclides before administration. In contrast with PRRT, there is no requirement for the tumor cells to overexpress peptide receptors; however, the treatment affects liver metastases only, not the primary site or other metastases. RMT is also a targeted therapy; the Yttrium-labeled microspheres "are selectively taken up by the tumors, thus preserving normal liver", according to Salem et al. (http://pubmed.org; search for 12354840).

Radiofrequency ablation (RFA) is used when a patient has relatively few tumor sites, whether original sites or metastases. In RFA, a needle is inserted into the center of the tumor and is vibrated at high frequency to generate heat; the tumor cells are killed by cooking. RFA is especially suited for large tumors, which can be cooked about as easily as small tumors.

Cryoablation is similar to RFA; a endothermic substance is injected into the tumors to kill by freezing.

Interferon is sometimes used to treat GEP-NETs; its use was pioneered by Dr. Kjell Öberg at Uppsala. For GEP-NETs, Interferon is often used at low doses and in combination with other agents (especially somatostatin congeners such as octreotide). But some researchers have published test data indicating little value from Interferon.

As described above, somatostatin congeners have been used for about two decades to alleviate symptoms by blocking the production of hormones from secretory tumors. They are also integral to PRRT. In addition, some doctors claim that, even without radiolabeling, even patients with nonsecretory tumors can benefit from somatostatin congeners, which purportedly can shrink or stabilize GEP-NETs. But some researchers have published test data indicating little value from this "cold" octreotide.

Two tricky issues in evaluating test data are durability and stasis. For example, one trial therapy might give excellent initial results -- but within months the benefit evaporates. And another trial therapy might be disparaged by some for causing very little tumor shrinkage, but be championed by others for causing significant tumoristasis.

Finally, therapies based on growth factor inhibitors are in the experimental stage. These inhibitors of epidermal growth factor receptors (EGFRs), of vascular endothelial growth factor receptors (EGFRs), and of angiopoietin-related growth factor (AGF) include imatinib, sunitinib, temozolide, thalidomide, sorafenib, and panitumumab.