Neuroendocrine tumor


Neuroendocrine tumor
Neuroendocrine tumors
Classification and external resources

Micrograph of a neuroendocrine tumor. H&E stain.
ICD-9 209
ICD-O: M8013/3, M8041/3, M8246/3, M8247/3, M8574/3
MeSH D018358

Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. Many are benign, while some are cancers. They most commonly occur in the intestine, but are also found in the lung and the rest of the body.

Although there are many kinds of NETs, they are treated as a group because the cells of these neoplasms share common features, such as looking similar, having special secretory granules, and often producing biogenic amines and polypeptide hormones.[1]

Contents

Background

Neuroendocrine system

NETs are believed to arise from various neuroendocrine cells whose normal function is to serve at the neuroendocrine interface. Neuroendocrine cells are present not only in endocrine glands throughout the body that produce hormones, but also diffusely in all body tissues.[2]

History

Small intestinal neuroendocrine tumors were first distinguished from other tumors in 1907.[3][4] They were named carcinoid tumors because their slow growth was considered to be "cancer-like" rather than truly cancerous.[4]

However, in 1929 it was recognized that some of these small bowel tumors could be malignant.[3][4] Despite the differences between these two original categories, and further complexities due to subsequent inclusion of other NETs of pancreas and pulmonary origin, all NETs are sometimes (incorrectly) subsumed into the term "carcinoid."

Enterochromaffin cells, which give rise to carcinoid tumors, were identified in 1897 by Kulchitsky[3] and their secretion of serotonin was established in 1953[3] when the “flushing” effect of serotonin had become clinically recognized. Carcinoid heart disease was identified in 1952[3] and carcinoid fibrosis in 1961.[3]

Neuroendocrine tumors were sometimes called APUDomas because these cells often show amine precursor (L-DOPA and 5-hydroxytryptophan) uptake and decarboxylation to produce biogenic amines such as catecholamines and serotonin. Although this behavior was also part of the disproven hypothesis that these cells might all embryologically arise from the neural crest,[5][6][2] neuroendocrine cells sometimes produce various types of hormones and amines,[6] and they can also have strong receptors for other hormones to which they respond.

There have been multiple nomenclature systems for these tumors,[7] and the differences between these schema have often been confusing.[7] Nonetheless, these systems all distinguish between well-differentiated (low and intermediate-grade) and poorly differentiated (high-grade) NETs.[7] Cellular proliferative rate is of considerable significance in this prognostic assessment.[7]

Incidence

Although estimates vary, the annual incidence of clinically significant neuroendocrine tumors is approximately 2.5-5 per 100,000;[8] two thirds are carcinoid tumors and one third are other NETs.

The prevalence has been estimated as 35 per 100,000,[8] and may be considerably higher if clinically silent tumors are included. An autopsy study of the pancreas in people who died from unrelated causes discovered a remarkably high incidence of tiny asymptomatic NETs. Routine microscopic study of three random sections of the pancreas found NETs in 1.6%, and multiple sections identified NETs in 10%.[9] As diagnostic imaging increases in sensitivity, such as endoscopic ultrasonography, very small, clinically insignificant NETs may be coincidentally discovered; being unrelated to symptoms, such neoplasms may not require surgical excision.

Categories

WHO classification

The World Health Organization (WHO) classification scheme places neuroendocrine tumors into three main categories:[7][10]

  • well-differentiated neuroendocrine tumours, further subdivided into tumors with benign and those with uncertain behavior
  • well-differentiated (low grade) neuroendocrine carcinomas with low-grade malignant behavior
  • poorly differentiated (high grade) neuroendocrine carcinomas, which are the large cell neuroendocrine and small cell carcinomas.

Additionally, the WHO scheme recognizes mixed tumors with both neuroendocrine and epithelial carcinoma features, such as goblet cell cancer, a rare gastrointestinal tract tumor.[11]

Placing a given tumor into one of categories depends on well-defined histological features: size, lymphovascular invasion, mitotic counts, Ki-67 labelling index, invasion of adjacent organs, presence of metastases and whether they produce hormones.[7][10]

Anatomic distribution

NETs can arise in many different areas of the body, and are most often located in the intestine or the lungs.

The various kinds of cells that can give rise to NETs are present in endocrine glands and are also diffusely distributed throughout the body, most commonly Kulchitsky cells or similar enterochromaffin-like cells, that are relatively more common in the gastrointestinal and pulmonary systems.[12] NETs include certain tumors of the gastrointestinal tract and of the pancreatic islet cells,[1] certain thymus and lung tumors, and medullary carcinoma of the parafollicular cells of the thyroid.[1] Tumors with similar cellular characteristics in the pituitary, parathyroid, and adrenomedullary glands are sometimes included[13] or excluded.[1]

Within the broad category of neuroendocrine tumors there are many different tumor types:[14] this outline is presented to facilitate retrieving information. It is quite clear that neuroendocrine tumors are uncommon in many of these areas, and frequently represent only a very small proportion of the tumors or cancers at these locations.

  • Pituitary
    • neuroendocrine tumor of the anterior pituitary
  • Thyroid tumors, particularly medullary carcinoma
  • Parathyroid tumors
  • Thymus and mediastinal carcinoid tumors[15][16]
  • Pulmonary neuroendocrine tumors[17][18]
    • bronchus[16]
    • pulmonary carcinoid tumors: typical carcinoid (TC; low-grade); atypical carcinoid (AC; intermediate-grade)
    • small-cell lung cancer (SCLC)
    • large-cell neuroendocrine carcinoma (LCNEC of the lung)[19]
  • Extrapulmonary small cell carcinomas (ESCC or EPSCC)
  • Gastroenteropancreatic neuroendocrine tumors (GEP-NET)[20][21]
    • Foregut GEP-NET (foregut tumors can conceptually encompasses not only NETs of the stomach and proximal duodenum, but also the pancreas, and even thymus, lung and bronchus) 
      • Pancreatic endocrine tumors (if considered separately from foregut GEP-NET)[22]
    • Midgut GEP-NET (from distal half of 2nd part of the duodenum to the proximal two-thirds of the transverse colon)
      • appendix,[23] including well differentiated NETs (benign); well differentiated NETs (uncertain malignant potential); well differentiated neuroendocrine carcinoma (with low malignant potential); mixed exocrine-neuroendocrine carcinoma (goblet cell carcinoma, also called adenocarcinoid and mucous adenocarcinoid)
    • Hindgut GEP-NET[24][25]
  • Liver[26][27][28] and gallbladder[29]
  • Adrenal tumors, particularly adrenomedullary tumors
  • Pheochromocytoma
  • Peripheral nervous system tumors, such as:
  • Breast[30]
  • Genitourinary tract
    • urinary tract carcinoid tumor and neuroendocrine carcinoma[31][32]
    • ovary
    • neuroendocrine tumor of the cervix[33]
    • testes
  • Merkel cell carcinoma of skin (trabecular cancer)
  • Several inherited conditions:[34]

TNM stage

A TNM scheme has been proposed for NETs by the European Neuroendocrine Tumor Society.[10]

Histopathology

Small intestinal neuroendocrine tumor at bottom third of image, showing the typical intramural (within the wall) location, and overlying intact epithelium. H&E stain.

Features in common

Neuroendocrine tumors, despite differing embryological origin, have common phenotypic characteristics.  

NETs show tissue immunoreactivity for markers of neuroendocrine differentiation (pan-neuroendocrine tissue markers) and may secrete various peptides and hormones. There is a lengthy list of potential markers in neuroendocrine tumors; several reviews provide assistance in understanding these markers.[40][41] Widely used neuroendocrine tissue markers are various chromogranins, synaptophysin and PGP9.5. Neuron-specific enolase (NSE) is less specific.[1][12]

NETs are often small, yellow or tan masses, often located in the submucosa or more deeply intramurally, and they can be very firm due to an accompanying intense desmoplastic reaction. The overlying mucosa may be either intact or ulcerated. Some GEP-NETs invade deeply to involve the mesentery.

Histologically, NETs are an example of "small blue cell tumors," showing uniform cells which have a round to oval stippled nucleus and scant, pink granular cytoplasm. The cells may align variously in islands, glands or sheets. High power examination shows bland cytopathology. Electron microscopy can identify secretory granules. There is usually minimal pleomorphism but less commonly there can be anaplasia, mitotic activity, and necrosis.

Some neuroendocrine tumor cells possess especially strong hormone receptors, such as somatostatin receptors and uptake hormones strongly. This avidity can assist in diagnosis and may make some tumors vulnerable to hormone targeted therapies.

Argentaffin and hormone secretion

NETs from a particular anatomical origin often show similar behavior as a group, such as the foregut (which conceptually includes pancreas, and even thymus, airway and lung NETs), midgut and hindgut; individual tumors within these sites can differ from these group benchmarks:

  • Foregut NETs are argentaffin negative. Despite low serotonin content, they often secrete 5-hydroxytryptophan (5-HTP), histamine, and several polypeptide hormones. There may be associated atypical carcinoid syndrome, acromegaly, Cushing disease, other endocrine disorders, telangiectasia, or hypertrophy of the skin in the face and upper neck.[42] These tumors can metastasize to bone.
  • Midgut NETs are argentaffin positive, can produce high levels of serotonin 5-hydroxytryptamine (5-HT), kinins, prostaglandins, substance P (SP), and other vasoactive peptides, and sometimes produce corticotropic hormone (previously adrenocorticotropic hormone [ACTH]). Bone metastasis is uncommon.
  • Hindgut NETs are argentaffin negative and rarely secrete 5-HT, 5-HTP, or any other vasoactive peptides. Bone metastases are not uncommon.

Symptoms

GEP-NET

There are two main types of NET within this category:

Carcinoid tumors

(about two thirds of GEP-NETs)

Carcinoids most commonly affect the small bowel, particularly the ileum, and are the most common malignancy of the appendix. Many carcinoids are asymptomatic and are discovered only upon surgery for unrelated causes. These coincidental carcinoids are common; one study found that one person in ten has them. [43] Many tumors do not cause symptoms even when they have metastasized.[4] Other tumors even if very small can produce adverse effects by secreting hormones.[44]

10%[45] or less of carcinoids, primarily some midgut carcinoids, secrete excessive levels of a range of hormones, most notably serotonin (5-HT) or substance P,[46] causing a constellation of symptoms called carcinoid syndrome:

A carcinoid crisis with profound flushing, bronchospasm, tachycardia, and widely and rapidly fluctuating blood pressure[1] can occur if large amounts of hormone are acutely secreted,[46] which is occasionally triggered by factors such as diet,[46] alcohol,[46] surgery[46][1] chemotherapy,[46] embolization therapy[1] or radiofrequency ablation.[1]

Chronic exposure to high levels of serotonin causes thickening of the heart valves, particularly the tricuspid and the pulmonic valves, and over a long period can lead to congestive heart failure.[46] However, valve replacement is rarely needed.[47] The excessive outflow of serotonin can cause a depletion of tryptophan leading to niacin deficiency, and thus pellagra,[1] which is associated with dermatitis, dementia, and diarrhea.

Many other hormones can be secreted by some of these tumors, most commonly growth hormone that can cause acromegaly, or cortisol, that can cause Cushing's syndrome.

Occasionally, haemorrhage or the effects of tumor bulk are the presenting symptoms. Bowel obstruction can occur, sometimes due to fibrosing effects of NET secretory products[44] with an intense desmoplastic reaction at the tumor site, or of the mesentery.

Pancreatic endocrine tumors (PETs)

(about one third of GEP-NETs)

Pancreatic neuroendocrine tumors (PETs or PNETs; not to be confused with the primitive neuroectodermal PNET) can originate within the pancreas or from similar neuroendocrine cells outside of the pancreas. It is unclear whether pancreatic tumors originate from the usual cells of the islet of Langerhans or from diffuse neuroendocrine pluripotent cells.[4] PNETs are quite distinct from the usual form of pancreatic cancer, adenocarcinoma, which arises in the exocrine pancreas. About 95 percent of pancreatic tumors are adenocarcinoma; only 1 or 2% of clinically significant pancreas neoplasms are GEP-NETs.

Well or intermediately differentiated PNETs are sometimes called islet cell tumors; neuroendocrine cancer (NEC) is more aggressive.

About 70-85% PNETs are functional, secreting hormones that cause symptoms. About 15 to 30 percent of PETs are nonsecretory or nonfunctional, which either don’t secrete, or the quantity or type of products do not cause a clinical syndrome, such as pancreatic polypeptide (PPoma), chromogranin A, and neurotensin[34] although blood levels may be elevated. Functional tumors are often classified by the hormone most strongly secreted, for example:

In these functional tumors, the frequency of malignancy and the survival prognosis have been estimated dissimilarly, but a pertinent accessible summary is available.[1]

Other

In addition to the two main categories, there are rarer forms of GEP-NETs, including neuroendocrine lung, thymus and parathyroid tumors. Bronchial carcinoid can cause airway obstruction, pneumonia, pleurisy, difficulty with breathing, cough, and hemoptysis, or may be associated with weakness, nausea, weight loss, night sweats, neuralgia, and Cushing’s syndrome. Some are asymptomatic.

Animal neuroendocrine tumors include neuroendocrine cancer of the liver in dogs, and Devil facial tumor disease in Tasmanian Devils.[49][50][51]

Diagnosis

Markers

Symptoms from secreted hormones may prompt measurement of the corresponding hormones in the blood or their associated urinary products, for initial diagnosis or to assess the interval change in the tumor. Secretory activity of the tumor cells is sometimes dissimilar to the tissue immunoreactivity to particular hormones.[41]

Given the diverse secretory activity of NETs there are many other potential markers, but a limited panel is usually sufficient for clinical purposes.[1] Aside from the hormones of secretory tumors, the most important markers are :

Newer markers include N-terminally truncated variant of Hsp70 is present in NETs but absent in normal pancreatic islets.[52] High levels of CDX2, a homeobox gene product essential for intestinal development and differentiation, are seen in intestinal NETs.[52] Neuroendocrine secretory protein-55, a member of the chromogranin family, is seen in pancreatic endocrine tumors but not intestinal NETs.[52]

Imaging

Imaging modalities in NETs have been reviewed.[10]

CT-scans, MRIs, sonography (ultrasound), and endoscopy (including endoscopic ultrasound) are common diagnostic tools. CT-scans using contrast medium can detect 95 percent of tumors over 3 cm in size, but generally not tumors under 1 cm.

The half-life of somatostatin in circulation is less than three minutes, too short for diagnosis or targeted therapies. Synthetic modifications of somatostatin with longer half-lives, called somatostatin analogs or congeners, are used instead. The earliest was octreotide, marketed by Sandoz as Sandostatin, in 1988. OctreoScan, also called somatostatin receptor scintigraphy (SRS or SSRS), utilizes intravenously administered octreotide that is chemically bound to a radioactive substance, often indium-111, to detect larger lesions with tumor cells that are avid for octreotide.

Standard PET scans using fluorodeoxyglucose (FDG) are not useful in diagnosis of NETs[5] Gallium-68 receptor PET-CT is much more sensitive than an OctreoScan.[citation needed] C-5-hydroxy-L-tryptophan PET has very high sensitivity.[52]

Genetics

Pancreatic neuroendocrine tumors

DNA mutation analysis in well-differentiated pancreatic neuroendocrine tumors identified four important findings:[53]

  • one in six well-differentiated pancreatic NETs have mutations in mTOR pathway genes, such as TSC2, PTEN and PIK3CA.[53] The sequencing discovery might allow selection of which NETs would benefit from mTOR inhibition such as with everolimus, but this awaits validation in a clinical trial.
  • mutations affecting a new cancer pathway involving ATRX and DAXX genes were found in about 40% of pancreatic NETs.[53] The proteins encoded by ATRX and DAXX participate in chromatin remodeling of telomeres;[56] these mutations are associated with a telomerase-independent maintenance mechanism termed ALT (alternative lengthening of telomeres) that results in abnormally long telomeric ends of chromosomes.[56]

Familial syndromes

Neuroendocrine tumors can be seen in several inherited familial syndromes,[34] including:

Recommendations in NET include family history evaluation, evaluation for second tumors, and in selected circumstances testing for germline mutations such as for MEN1.[1]

Treatment

Overview

Several issues help define appropriate treatment of a neuroendocrine tumor, including its location, invasiveness, hormone secretion, and metastasis. Treatments may be aimed at curing the disease or at relieving symptoms (palliation).

Observation may be feasible for non-functioning low grade neuroendocrine tumors.[citation needed]

If the tumor is locally advanced or has metastasized, but is nonetheless slowly growing, treatment that relieves symptoms may often be preferred over immediate challenging surgeries.[citation needed]

Intermediate and high grade tumors (noncarcinoids) are usually best treated by various early interventions (active therapy) rather than observation (wait-and-see approach).[5]

Treatments have improved over the past several decades, and outcomes are improving.[44] In malignant carcinoid tumors with carcinoid syndrome, the median survival has improved from two years to more than eight years.[6]

Detailed guidelines for managing neuroendocrine tumors are available from ESMO,[57] NCCN[58] and a UK panel.[1] The NCI has guidelines for several categories of NET: islet cell tumors of the pancreas,[59] gastrointestinal carcinoids,[60] Merkel cell tumors[61] and pheochromocytoma and paraganglioma.[62]

Surgery

Surgery is a curative treatment for some neuroendocrine tumors.

Even if the tumor has advanced and metastasized, making curative surgery infeasible, surgery often has a role in neuroendocrine cancers for palliation of symptoms and possibly improved survival.[5]

Symptomatic relief

In secretory tumors, somatostatin analogs given subcutaneously or intramuscularly alleviate symptoms by blocking hormone release. A consensus review has reported on the use of somatostatin analogs for GEP-NETs.[63]

These medications may also anatomically stabilize or shrink tumors, as suggested by the PROMID study (Placebo-controlled prospective randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumors): at least in this subset of NETs, average tumor stabilization was 14.3 months compared to 6 months for placebo.[64]

Other medications that block particular secretory effects can sometimes relieve symptoms.[47]

Chemotherapy

Interferon is sometimes used to treat GEP-NETs.[65] Its effectiveness is somewhat uncertain, but low doses can be titrated within each person, often considering the effect on the blood leukocyte count;[65] interferon is often used in combination with other agents, especially somatostatin analogs such as octreotide.

Gastrointestinal neuroendocrine tumors

Most gastrointestinal carcinoid tumors tend not to respond to chemotherapy agents,[47] showing 10 to 20% response rates that are typically less than 6 months.[47] Combining chemotherapy medications has not usually been of significant improvement[47] showing 25 to 35% response rates that are typically less than 9 months. The exceptions are poorly-differentiated (high-grade or anaplastic) metastatic disease, where cisplatin with etoposide may be used[47] and SSRS[disambiguation needed ] negative tumors which had a response rate in excess of 70% compared to 10% in strongly positive SRSS carcinoid tumors.[1]

Pancreatic endocrine tumors

PETs are more responsive to chemotherapy than are gastroenteric carcinoid tumors. Several agents can shown activity[47] and combining several medicines, particularly doxorubicin with streptozocin, is often more effective.[47] Although marginally effective in well-differentiated PETs, cisplatin with etoposide is active in poorly-differentiated neuroendocrine cancers (PDNECs).[47]

Targeted chemotherapy agents have been approved in PETs by the FDA based on improved progression-free survival (PFS):

  • everolimus (Afinitor) is labeled for treatment of progressive neuroendocrine tumors of pancreatic origin in patients with unresectable, locally advanced or metastatic disease.[66][67] The safety and effectiveness of everolimus in carcinoid tumors have not been established.[66][67]
  • sunitinib (Sutent) is labeled for treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in patients with unresectable locally advanced or metastatic disease.[68][69] Sutent also has approval from the European Commission for the treatment of 'unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors with disease progression in adults'.[70]

Bronchial carcinoids

Pulmonary carcinoids are sometimes given a platinum and etoposide combination.[1]

Hormone-delivered radiotherapy

In this type of radioisotope therapy (RIT)[13] the tumor is treated intravenously with a peptide or hormone conjugated to a radionuclide or radioligand, the peptide or neuroamine hormone previously having shown good uptake of a tracer dose. This kind of RIT may be called peptide receptor radionuclide therapy (PRRT), or hormone-delivered radiotherapy, and can attack all lesions in the body, not just liver metastases. This is typically by radiolabeling octreotate to lutetium-177, ytrium-90 or indium-111. This is a highly targeted and effective therapy with minimal side effects in tumours with high levels of cell surface somatostatin cell surface expression. This is because of the radiation is taken up at sites of tumour or excreted in the urine. The radioactively labelled hormones enter the tumor cells, and these and nearby cells are damaged by the attached radiation. Not all cells are immediately killed; cell death can go on for up to two years. Early referral to a nuclear medicine physician is suggested to assess suitability for this new treatment modality.

Hepatic artery

Metastases to the liver can be treated by several types of hepatic artery treatments based on the observation that tumor cells get nearly all their nutrients from the hepatic artery, while the normal cells of the liver get about 70-80 percent of their nutrients and 50% their oxygen supply from the portal vein, and thus can survive with the hepatic artery effectively blocked. [44][71]

Hepatic artery embolization (HAE) occludes the blood flow to the tumors,[46] achieving significant tumor shrinkage in over 80%.[46]

In hepatic artery chemotherapy, the chemotherapy agents are given into the hepatic artery, often by steady infusion over hours or even days. Compared with systemic chemotherapy, a higher proportion of the chemotherapy agents are (in theory) delivered to the lesions in the liver. [71]

Hepatic artery chemoembolization (HACE), sometimes called transarterial chemoembolization (TACE), combines hepatic artery embolization with hepatic artery chemoinfusion: embospheres bound with chemotherapy agents, injected into the hepatic artery, lodge in downstream capillaries. The spheres not only block blood flow to the lesions, but by halting the chemotherapy agents in the neighborhood of the lesions, they provide a much better targeting leverage than chemoinfusion provides.

Selective internal radiation therapy (SIRT)[72] for neuroendocrine metastases to the liver[73] delivers radioactive microsphere therapy (RMT) by injection into the hepatic artery, lodging (as with HAE and HACE) in downstream capillaries. In contrast to hormone-delivered radiotherapy, the lesions need not overexpress peptide receptors. The mechanical targeting delivers the radiation from the yttrium-labeled microspheres selectively to the tumors without unduly affecting the normal liver.[74] This type of treatment is FDA approved for liver metastases secondary to colorectal carcinoma and is under investigation for treatment of other liver malignancies, including neuroendocrine malignancies.[72]

Other therapies

Radiofrequency ablation (RFA) is used when a patient has relatively few metastases. In RFA, a needle is inserted into the center of the lesion and current is applied to generate heat; the tumor cells are killed by cooking.

Cryoablation is similar to RFA; an endothermic substance is injected into the tumors to kill by freezing. Cryoablation has been considerably less successful for GEP-NETs than RFA.[citation needed]

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