Neuroendocrine tumors

Neuroendocrine tumors Microchapters
Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Epidemiology and Demographics
Risk factors
Natural History, Complications and Prognosis
History and Symptoms
Laboratory Findings
CT scan
PET scan
Medical Therapy
Surgery

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [9] Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[10]

Overview

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

• In 1907, Siegfried Oberndorfer was the first person to clearly distinguish GEP-NETs from other forms of cancer. Since they were so slow-growing, he considered them to be "cancer-like" rather than truly cancerous, and hence, he coined the term "carcinoid" for these tumors.
• In 1929, Siegfried Oberndorfer reported that some such tumors were not so indolent and distinguished them as PETs (mostly called carcinoids). Despite of the differences between the two categories, even in the twenty-first century, some doctors (including oncologists) insist on calling all GEP-NETs "carcinoid".
• In 1988, the earliest synthetic form of somatostatin used in the treatment of neuroendocrine tumors was octreotide, which was first marketed by Sandoz as Sandostatin.
• In 2006 and 2007, the European Neuroendocrine Tumor Society (ENETS) proposed a staging scheme same as for most other types of epithelial neoplasms for GEP NENs, alongwith a histologic grading system applicable to all disease stages. American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) later on endorsed this grading proposal for the tumor, node, metastasis (TNM) staging classification of digestive system NENs, after modifying the staging parameters of the ENETS proposal.
• Th 2010 WHO classification of tumors of the gastrointestinal tract, liver, and pancreas (which was subsequently updated in 2017) also endorsed the ENETS grading scheme for NENs of the digestive tract, separating well-differentiated tumors into low-grade (G1) and intermediate-grade (G2) categories. All poorly differentiated NETs are high-grade (G3) NECs according to this classification scheme.

Classification

Human GEP-NETs by Site of Origin and by Symptom

Human GEP-NETs by Site of Origin and by Symptom		Percentage
Carcinoids (about two thirds of GEP-NETs)	With carcinoid syndrome	About 10 percent of carcinoids
	Without carcinoid syndrome	About 90 percent of carcinoids
PETs (about one third of GEP-NETs)	Nonfunctioning	15 to 30 percent of PETs
	Functioning: Gastrinoma (produces excessive gastrin and causes Zollinger-Ellison Syndrome [ZES]) Insulinoma (produces excessive insulin) Glucagonoma (produces excessive glucagon) Vasoactive intestinal peptideoma (VIPoma) (produces excessive vasoactive intestinal peptide [VIP]) PPoma (produces excessive pancreatic polypeptide [often classed with nonfunctioning PETs]) Somatostatinoma (produces excessive somatostatin) Watery diarrhea, hypokalemia-achlorhydria (WDHA) CRHoma (produces excessive corticotropin-releasing hormones [CRH]) Calcitoninoma (produces excessive calcitonin) GHRHoma (produces excessive growth-hormone-releasing hormone [GHRH]) Neurotensinoma (produces excessive neurotensin) ACTHoma (produces excessive adrenocorticotropic hormone [ACTH]) GRFoma (produces excessive growth hormone release factor [GRF]) Parathyroid hormone-related peptide tumor	70 to 85 percent of PETs
Rare GEP-NETs	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) (usually nonfunctioning) (also causing ZES) Multiple Endocrine Neoplasia type 2 (MEN-2 or MEN2) Neurofibromatosis type 1 Tuberous sclerosis Von Hippel-Lindau disease (VHL) Neuroblastoma Pheochromocytoma (phaeochromocytoma) Paraganglioma Neuroendocrine tumor of the anterior pituitary Carney's complex

Simplified classification according to anatomic distribution

Simplified classification of Neuroendocrine tumors according to anatomic distribution

Involved organ	Name/type of neuroendocrine tumor
Pituitary gland	Neuroendocrine tumor of the anterior pituitary
Thyroid gland	Neuroendocrine thyroid tumors Medullary thyroid carcinoma (particularly)
Parathyroid glands	Parathyroid tumors
Thymus and mediastinum	Thymus and mediastinal carcinoid tumors
Lungs	Pulmonary neuroendocrine tumors Bronchus Pulmonary carcinoid tumors: Typical carcinoid (TC; low-grade) Atypical carcinoid (AC; intermediate-grade) Small-cell lung cancer (SCLC) Large cell neuroendocrine carcinoma of the lung (LCNEC)
Extrapulmonary	Extrapulmonary small cell carcinomas (ESCC or EPSCC)
GIT	Gastroenteropancreatic neuroendocrine tumors (GEP-NET) Foregut GEP-NET (foregut tumors can conceptually encompass 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) Midgut GEP-NET (from distal half of 2nd part of the duodenum to the proximal two-thirds of the transverse colon) Appendix, 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 Liver and gallbladder
Adrenal gland	Adrenal tumors, particularly adrenomedullary tumors Pheochromocytoma
Peripheral nervous system	Peripheral nervous system tumors, such as: Schwannoma Paraganglioma Neuroblastoma
Mammary gland	Breast tumors
Genitourinary tract	Urinary tract carcinoid tumor and neuroendocrine carcinoma Ovary Neuroendocrine tumor of the cervix Testes
Skin	Merkel cell carcinoma of the skin (trabecular cancer)
Multiple organs involvement in inherited conditions	Several inherited conditions: Multiple endocrine neoplasia type 1 (MEN1) Multiple endocrine neoplasia type 2 (MEN2) Von Hippel-Lindau (VHL) disease Neurofibromatosis type 1 Tuberous sclerosis Carney complex

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), this old terminology is given in the table below:

Summary of classification by cell characteristics (the WHO classification)

• This classification was done due to peripheral receptors.
• GEP-NETs receptors (APUDomas) are the main detected receptors.
• That term is now misleading, since it is based on a discredited theory of the development of the tumors.
• It is now known that this receptor may not be indicator of cell origin.

Superclass:Öberg, WHO, Klöppel et alia: Gastro-entero-pancreatic neuroendocrine tumor (GEP-NET)
Subclass 1 (less malignant)	Subclass 2 (more malignant)	Subclass 3 (most malignant)	Subclass 4 (mixed)	Subclass 5 (miscellaneous)
Öberg: Carcinoid WHO: Neuroendocrine tumor (NET) Klöppel et alia: Well-differentiated neuroendocrine tumor (NET) (carcinoid) This article: Carcinoid	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	WHO: Poorly-differentiated neuroendocrine carcinoma Klöppel et alia: Poorly-differentiated neuroendocrine carcinoma (high-grade malignant carcinoid)	WHO: Mixed endocrine/exocrine tumor	WHO: Rare neuroendocrine-like lesions

2010 WHO Classification Of NET

• 2010 WHO Classification of neuroendocrine tumors with their ICD-O-3 codes is given below:

2010 World Health Organization International Classification and Distribution of Diseases for Oncology (3rd Ed. (ICD-O-3) Codes of Neuroendocrine Tumors (NETs) in the Gastrointestinal and Pancreatobiliary Tracts)

NET (Neuroendocrine Tumor) Classification		Location	ICD-O-3 Code
NET G1 (Grade 1)		All organs	8240/3
NET G2 (Grade 2)		All organs	8249/3
Neuroendocrine carcinoma		All organs	8246/3
	Large cell NEC	All organs	8013/3
	Small cell NEC	All organs	8041/3
Enterochromaffin cell serotonin-producing NET		All organs	8241/3
Gastrin-producing NET (gastrinoma)		Stomach, ampulla, small intestine, pancreas	8153/3
Glucagon-producing NET (glucagonoma)		Pancreas	8152/3
Gangliocytic paraganglioma		Ampulla, small intestine	8683/0
Somatostatin-producing NET (somatostatinoma)		Ampulla, small intestine, pancreas	8156/3
Insulin-producing NET (insulinoma)		Pancreas	8151/3
VIPoma		Pancreas	8155/3
L cell, Glucagon-like peptide, and PP/PYY-producing NETs		Small intestine, appendix, colorectum	8152/1
Goblet cell carcinoid		Appendix, extrahepatic bile duct	8241/3
Tubular carcinoid		Appendix, extrahepatic bile duct	8245/1
Mixed adenoneuroendocrine carcinoma (MANEC)		All organs	8244/3
Neuroendocrine microadenoma		Pancreas	8150/0

WHO Grading criteria for neuroendocrine neoplasms

• WHO grading criteria for neuroendocrine neoplasms is based upon histological markers for cellular proliferation (rather than cellular polymorphism)
• Following table shows the currently recommended WHO grading criteria for all gastroenteropancreatic neuroendocrine neoplasms:

2017 World Health Organization Classification of Neuroendocrine Tumors (NETs) in the GIT and Pancreatobiliary Tracts (PanNETs)

Grade/Classification	Mitotic Count/ 10 HPFs (High-Power Field)	Ki-67 Labeling Index, %	Traditional
Neuroendocrine neoplasm GX	Grade cannot be assessed
Well-differentiated GIT NETs & PanNENs: Pancreatic neuroendocrine tumors (PanNETs)
Neuroendocrine tumor, Grade 1 and PanNET G1 (low grade)	<2	<3	Carcinoid tumor Islet cell neuroendocrine tumor Pancreatic neuroendocrine tumor
Neuroendocrine tumor, Grade 2 and PanNET G2 (intermediate grade)	2–20	3–20	Carcinoid tumor Atypical carcinoid tumor (intermediate-grade neuroendocrine tumors of the lung) Islet cell neuroendocrine tumor Pancreatic neuroendocrine tumor
PanNET G3	>20	>20	_
Poorly differentiated PanNENs: Pancreatic neuroendocrine carcinomas (PanNECs)
Neuroendocrine carcinoma, Grade 3 and PanNEC G3 (high grade)	>20	>20	Small cell carcinoma
			Large cell neuroendocrine carcinoma
Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN)

Classification of Gastric Enterochromaffin-Like Cell Histamine-Producing Neuroendocrine Tumors

Classification	I	II	III
Incidence, %	55–88	8–13	12–23
Multifocality	Multiple	Multiple	Single
Peritumoral oxyntic mucosa	Atrophic	Hypertrophic	Normal
Size, cm	0.5–1	<2	>2
Location	Corpus	Corpus	Any
Sex	M < F	M = F	M > F
Hypergastrinemia	Yes	Yes	No
Antral G-cell hyperplasia	Yes	No	No
Associated disease	Chronic atrophic gastritis	Multiple endocrine neoplasia 1 Zollinger–Ellison syndrome	No
Precursor lesion	Yes	Yes	No
WHO 2010 classification	Grade 1	Grades 1 or 2	Grades 1–3
Lymph node metastasis, %	5	30	70

Comparison of the WHO classifications of pancreatic neuroendocrine neoplasms

WHO 1980	WHO 2000/2004	WHO 2010	WHO 2017
Islet cell tumor (adenoma/carcinoma)	Well-differentiated endocrine tumor/carcinoma (WDET/WDEC)	NET G1/G2	NET G1/G2/G3 (well-differentiated NEN)
Poorly differentiated endocrine carcinoma	Poorly differentiated endocrine carcinoma/small cell carcinoma (PDEC)	NEC (G3), large cell or small cell type	NEC (G3), large cell or small cell type (poorly differentiated NEN)
_	Mixed exocrine-endocrine carcinoma (MEEC)	Mixed adenoneuroendocrine carcinoma	Mixed neuroendocrine-non-neuroendocrine neoplasm
Pseudotumor lesions	Tumor-like lesions (TLLs)	Hyperplastic and preneoplastic lesions	_

Pathophysiology

Neuroendocrine system

• Endocrine system is a signaling system made of a network of glands that metabolize hormones.
• It secrete hormones in order to lead a series of intracellular cascade to get an appropriate response .
• Neuroendocrine system is actually a combination of both endocrine and nervous system.
• these two systems have various interfaces in order to control many functions, specially in Gastrointestinal system.
• Gastrointestinal neuroendocrine sustem (GEP-NET) is a tumor of gastrointestinal and neuroendocrine system.
• Some of these malignant cells do not form a gland and are consistent in organ as different cells. (Like G cells in stomach.)
• Hormones are divided into further sub-types based on their chemical structure:
  • Peptides/peptide hormones
  • steroids
  • neuroamines
• The vast majority of GEP-NETs fall are further devided in two distinct categories:
  • carcinoids
  • pancreatic endocrine tumors (PETs).
• Despite great difference in hormone made and the action of these 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.
• further classification of gasterointestinal neuroendocrine tumors is based on:
  • Secretory tumors are classified by the dominant hormone secreted hormone.
  • origin, as foregut (lung, thymus, stomach, and duodenum) or midgut (distal ileum and proximal colon) or hindgut (distal colon and rectum).
• Carcinoid tumors (serotonin secreting) tend to grow much more slowly than PETs.

• 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, islet cells produce hormones that regulate a variety of bodily functions, such as the control of blood sugar level and stomach acid production.
• Islet cell tumors include:
  • Gastrinomas (Zollinger-Ellison syndrome)
  • Glucagonomas
  • Insulinomas
• The exact cause of neuroendocrine tumors is unknown.
• Different DNA mutations in neuroendocrine cells is supposed to be one of the causes of neuroendocrine tumors.
• Various hereditary syndromes associated with GIT and pancreatobiliary tract NETs are mentioned in detail in the table below:

Hereditary Syndromes Associated With Gastrointestinal (GI) and Pancreatobiliary Tract Neuroendocrine Tumors (NETs)

Name of the syndrome	Pattern of inheritance	Chromosomal Band Location	Gene/ Protein Involved	GIT and Pancreatobiliary Tract NETs	Other Tumors of GIT and Pancreatobiliary Tract	Clinical Presentation Outside GIT and Pancreatobiliary Tract
Multiple endocrine neoplasia 1 (MEN 1)	Autosomal Dominant	11q13.1	MEN1/ menin	Nonfunctional Maybe associated with multiple: Gastric NETs (gastrinoma) Duodenal NETs Pancreatic NETs (insulinoma)	Esophageal leiomyoma	More commonly: Pituitary adenoma Parathyroid hyperplasia leading to primary hyperparathyroidism Less commonly: Bronchial NET Thymic NET Adrenal cortical adenoma/tumors Carcinoid tumors Nonmedullary thyroid tumors
von Hippel-Lindau disease/syndrome (VHL)	Autosomal Dominant	3p25.3	VHL/ VHL	Nonfunctional or Pancreatic clear cell NETs	Pancreas serous cyst adenomas	CNS or cerebellar hemangioblastomas Retinal hemangioblastomas Renal clear cell carcinomas Pheochromocytomas (often bilateral) Adrenal cortical adenomas
Neurofibromatosis 1 (von Recklinghausen disease)	Autosomal Dominant	17q11.2	NF1/ neurofibromin	Duodenal somatostatin producing NETs Pancreatic somatostatin producing NETs	Gastrointestinal stromal tumor (GIST) Neurofibromas	Neurofibromatosis Cafe´ au lait spots Optic nerve gliomas Pheochromocytoma
Tuberous sclerosis	Autosomal Dominant	9q34.13	TSC1/ hamartin	Pancreatic insulin producing NETs Pancreatic somatostatin producing NETs	Hamartomatous polyp	Hamartomas involving multiple organs Cardiac rhabdomyomas Angiomyolipomas Renal cysts
		16p13.3	TSC2/ tuberin

Other familial syndromes associated with neuroendocrine neoplasms are:

• Multiple Endocrine Neoplasia type 2 (MEN2)
• Carney complex

Epidemiology and Demographics

Lung NETs

• The portion of lung neuroendocrine tumors (NETs) is approximately 1 to 2% of lung malignancy in adults and 30% of neuroendocrine tumores.
• Annual incidence of lung NETs was 1.49 per 100,000 population between 2000 and 2012 according to the United States Surveillance, Epidemiology, and End Results (SEER) database.
• Lung NETs are considered to be the most common primary lung neoplasm in children with typical presentation in late adolescence.
• Average adult age at the time of diagnosis of a typical lung NET is 45 years, whereas patients with atypical tumors are approximately 10 years older.
• Incidence of lung NETs differs from 0.2 to 2 per 100,000 population per year .
• There's a higher incidence of lung NETs in women as compared to men.
• Lung NET has annual incidence rates of 0.2 and 1.3 per 100,000 population among men and women respectively.
• White people have higher incidence of lung NETs as compared to black people.

Digestive system NETs

• Annual incidence of digestive system NETs is 3.56 per 100,000 in United States approximately.
• Digestive system NENs of the tubular gastrointestinal tract and pancreas are relatively rare with an incidence of ≤1 case per 100,000 individuals per year..
• Pancreatic NETs account for 1 to 2% (<3%) of all primary pancreatic neoplasms.
• Following is a table that shows association of different diseases with the incidence of pancreatic NETs:

Disease/Syndrome	% chance of developing Pancreatic NET
Multiple endocrine neoplasia 1 (MEN 1)	80-100%
von Hippel-Lindau disease/syndrome (VHL)	20%
Neurofibromatosis 1 (von Recklinghausen disease)	10%
Tuberous sclerosis	1%

Risk factors

Few of the risk factors for neuroendocrine tumors include:

• Smoking is a risk factor for both lung and pancreatic NETs especially in case of atypical tumors.
• Inherited predisposition is one of the risk factors especially in the case of lung NETs (not related to MEN syndrome).
• Diabetes is associated with increased risk of pancreatic NETs.
• Chronic pancreatitis is associated with increased risk of pancreatic NETs.
• The inherited genetic syndromes associated with increased risk of causing neuroendocrine tumors include:
  • Multiple Endocrine Neoplasia type 1 (MEN1)
  • Multiple Endocrine Neoplasia type 2 (MEN2)
  • Von Hippel-Lindau syndrome
  • Neurofibromatosis
  • Tuberous sclerosis

Natural History, Complications and Prognosis

• Neuroendocrine tumors are slow growing tumors but they can produce amino acids that can cause severe symptoms.

Complications

• Common complications of neuroendocrine tumors include the following:
  • Diabetes
  • Hormone crisis (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

• Neuroendocrine tumors can be cured if they are removed surgically before their spread to the other organs.
• Chemotherapy can be used in case of cancerous tumors but it usually doesn't cure the patients.
• Life-threatening problems (such as a very low blood sugar level) can occur due to excess hormone production, or if cancer spreads throughout the body.
• Few of the prognostic facts about poorly differentiated pancreatic NEC are given below:
  • 88% of the patients have lymph node or distant metastatic disease at the time of tumor presentation.
  • 7% of the patients subsequently develop metastases.
  • The median survival is 11 months, ranging from 0 to 104 months.
  • The two-year survival rate is 22.5%.
  • The five-year survival rate is 16.1%.

History and Symptoms

• Initially, many of the neuroendocrine tumors mostly remain asymptomatic.
• When they cause symptoms, it is usually due to the following two reasons:
  • Tumor location causing:
    • Feeling of a growing lump under the skin
    • Persistent pain occurring from increasing tumor size during its growth in specific area
    • Unusually tired feeling (fatigue)
    • Unintentional weight loss
    • Loss of appetite
    • Headache
    • Jaundice
    • Changes in bowel or bladder habits
    • Unusual discharge or bleeding
    • Persistent cough or hoarseness
    • Persistent fever or night sweats
  • Particular excessive hormone production by the tumor (functional tumor)

Carcinoid tumor

• Carcinoid tumors may produce serotonin (5-HT), a biogenic amine leading to the following specific set of symptoms which are collectively known as Carcinoid syndrome:
  • Flushing of skin
  • Diarrhea (or increase in the number of bowel movements)
  • Weight loss
  • Weight gain
  • Palpitations
  • Congestive heart failure (CHF)
  • Asthma
  • Acromegaly
  • Cushing's syndrome

Pancreatic NETs

• According to the recent studies, 50 to 85% of the pancreatic NETs are nonfunctioning.
• Functioning pancreatic NETs include the following:
  • Insulinomas with typical presentation of episodic hypoglycemia leading to:
    • Confusion
    • Amnesia (during hypoglycemic phase is common)
    • Visual changes
    • Palpitations
    • Tremulousness
    • Diaphoresis
    • Unusual behavior
  • Gastrinomas with typical presentation of:
    • Peptic ulcer disease
    • Diarrhea (prominent feature too sometimes)
  • Glucagonoma causing classical clinical syndrome which includes:
    • Necrolytic migratory erythema
    • Cheilitis
    • Diabetes mellitus
    • Anemia
    • Weight loss
    • Diarrhea
    • Venous thrombosis
    • Neuropsychiatric symptoms
  • VIPoma syndrome presents with the following main clinical symptoms:
    • Watery diarrhea
    • Hypokalemia
    • Hypochlorhydria

Laboratory Findings

• Many neuroendocrine tumor cells especially possess strong receptors on their surfaces through which they receive hormonal messages such as:
  • PETs often have strong receptors for somatostatin.
  • Such tumor cells overexpress the somatostatin receptors (SSTRs) and are thus considered to be avid for this hormone, hence, their uptake of somatostatin is strong.
  • This avidity for somatostatin is the key factor for the PETs' diagnosis and it also makes the tumors vulnerable to certain targeted therapies.

• Generally, the important common uses of tumor markers include:
  • Helpful in the specific tumor diagnosis.
  • Helpful in tracking the progress of tumor therapy hence, the detrimental side effects of contrast CT scan on the patient can be avoided.

List of potential markers for GEP-NETs apart from hormones of secretory tumors
Most important markers	Other markers		Newer (as of 2005) markers
Chromogranin A (CgA) Urine 5-hydroxy indole acetic acid (5-HIAA) (grade C) Neuron-specific enolase (NSE, gamma-gamma dimer) Synaptophysin (P38)	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	N-terminally truncated variant of heat shock protein 70 (Hsp70) CDX-2, a homeobox gene product Neuroendocrine secretory protein-55

CT Scan

• CT scan is one of the most common diagnostic tool used for diagnosing of Neuroendocrine tumors.
• CT scan with contrast medium can detect 95% of the tumors with size of >3 cm in size, and no tumors under 1 cm (University of Michigan Medical School n. d., [11]).

PET 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

Medical Therapy

Approach

According to Warner, the best care, at least for noncarcinoid GEP-NETs, is provided by "an active [as opposed to wait-and-see] approach using sequential multimodality treatment" delivered by a "multidisciplinary team, which also may include a surgeon, endocrinologist, oncologist, interventional radiologist, and other specialists". This recommendation is based on his view that, except for most insulinomas, "almost all" PETs "have long-term malignant potential" – and in sixty percent of cases, that potential is already manifest. "Indeed, the most common cause of death from PETs is hepatic [that is, liver] failure" (Warner 2005, 4).

Two tricky issues in evaluating therapies are durability (is the therapy long-lasting?) and stasis (are the tumors neither growing nor shrinking?). For example, one therapy might give good initial results – but within months the benefit evaporates. And another therapy might be disparaged by some for causing very little tumor shrinkage, but be championed by others for causing significant tumoristasis.

The half-life of somatostatin in circulation is under three minutes, making it useless for diagnosis and targeted therapies. For this reason, 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. (In this article we conform to the old terminology, as the medical community has been slow to adopt the term congener.) The analogs have a much longer half-life than somatostatin, and other properties that make them more suitable for diagnosis and therapy.

Chemotherapy

The most common nonsurgical therapy for all GEP-NETs is chemotherapy, although chemotherapy is reported to be largely ineffective for carcinoids, not particularly durable (long-lasting) for PETs, and inappropriate for PETs of nonpancreatic origin.

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 highly predictive of the benefit from another agent, except that the long-term benefit of any agent is likely to be low.

Strong uptake of somatostatin analogs is a negative indication for chemo.

Symptomatic relief

There are two major somatostatin-analog-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.

Specific counter-hormones or other hormone-blocking medications are sometimes also used to provide symptomatic relief.

Hormone-delivered radiotherapy – PRRT

The second of the two major somatostatin-analog-based targeted therapies is called peptide receptor radionuclide therapy (PRRT), though we might simply call it hormone-delivered radiotherapy. In this form of radioisotope therapy (RIT), radioactive substances (called radionuclides or radioligands) are chemically conjugated with hormones (peptides or neuroamines); the combination is given intravenously to a patient who has good uptake of the chosen hormone. The radioactive labelled hormones enter the tumor cells, and the attached radiation damages the tumor- and nearby cells. Not all cells are immediately killed this way. The process of tumor cells dying as result of this therapy can go on for several months, even up to two years. In patients with strongly overexpressing tumor cells, nearly all the radiation either gets into the tumors or is excreted in urine. As Rufini et alia say, 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" (Rufini, Calcagni, and Baum 2006, [12]).

The use of PRRT for GEP-NETs is similar to the use of iodine-131 as a standard therapy (in use since 1943) for nonmedullary thyroid tumors (which are not GEP-NETs). Thyroid cells (whether normal or neoplastic) tend to be avid for iodine, and nearby cells are killed when iodine-131 is infused into the bloodstream and is soon attracted to thyroid cells. Similarly, overexpressing GEP-NET cells (neoplastic cells only) are avid for somatostatin analogs, and nearby cells are killed when radionuclides attached to somatostatin analogs are infused into the bloodstream and are soon attracted to the tumor cells. In both therapies, hormonal targeting delivers a much higher dose of radiation than external beam radiation could safely deliver.

As of 2006, PRRT is available in at least dozen medical centers in Europe. In the USA it is FDA-approved, and available at the MD Anderson Cancer Center, but using a radionuclide, indium-111, that is much weaker than the lutetium-177 and the even stronger yttrium-90 used on the European continent. In the UK, only the radionuclide metaiodobenzylguanidine (I-MIBG) is licensed (but GEP-NETs are rarely avid for MIBG). Most patients (from all over the world) are treated (with lutetium-177) in The Netherlands, at the Erasmus Medical Center. PRRT with lutetium or yttrium is nowhere an "approved" therapy, but the German health insurance system, for example, covers the cost for German citizens.

PRRT using yttrium or lutetium was first applied to humans about 1999. Practitioners continue to refine their choices of radionuclides to maximize damage to tumors, of somatostatin analogs to maximize delivery, of chelators to bind the radionuclides with the hormones (and chelators can also increase uptake), and of protective mechanisms to minimize damage to healthy tissues (especially the kidneys).

Hepatic artery-delivered therapies

• One therapy for liver metastases of GEP-NETs is hepatic artery embolization (HAE). Larry Kvols, of the Moffitt Cancer Center and Research Institute in Tampa, Florida, says that "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 [tiny spheres of glass or resin, also called microspheres] 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" (Kvols 2002, [13]). HAE is 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 75 percent of their nutrients (and about half of their oxygen) from the portal vein, and thus can survive with the hepatic artery effectively blocked.

• Another therapy is hepatic artery chemoinfusion, the injection of chemotherapy agents into the hepatic artery. Compared with systemic chemotherapy, a higher proportion of the chemotherapy agents are (in theory) delivered to the lesions in the liver.

• 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.

• Radioactive microsphere therapy (RMT) combines hepatic artery embolization with radiation therapy – microspheres bound with radionuclides, injected into the hepatic artery, lodge (as with HAE and HACE) in downstream capillaries. This therapy is also called selective internal radiation therapy, or SIRT. In contrast with PRRT, the lesions need not overexpress peptide receptors. (But PRRT can attack all lesions in the body, not just liver metastases.) Due to the mechanical targeting, the yttrium-labeled microspheres "are selectively taken up by the tumors, thus preserving normal liver" (Salem et al. 2002, [14]).

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 is vibrated at high frequency 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.

• 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 analogs such as octreotide). But some researchers claim that Interferon provides little value aside from symptom control.

• As described above, somatostatin analogs 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 analogs, which purportedly can shrink or stabilize GEP-NETs. But some researchers claim that this "cold" octreotide provides little value aside from symptom control.

Surgery

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).

Case Studies

Case #1

External links

• National Cancer Institute - General information about Pancreatic Neuroendocrine Tumors

Acknowledgements

The content on this page was first contributed by: C. Michael Gibson, M.S., M.D.

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