NEUROENDOCRINE TUMORS

NEUROENDOCRINE CELLS

Cells that are cross between endocrine and nerve cells. Produces peptides and neuropeptides.

OVERVIEW OF NEUROENDOCRINE TUMORS

Generally characterized by their ability to produce peptides that may lead to associated syndromes (functional vs nonfunctional)

Include a heterogeneous group of neoplasms– Gastroenteropancreatic neuroendocrine tumors

(GEP-NETs)

– Islet cell tumors (pNET)– Pheochromocytoma / paraganglioma

– Lung NET (carcinoid): typical, atypical, poorly differentiated

– Small cell carcinoma of the lung

– Merkel cell carcinoma

– Medullary carcinoma of the thyroid

GI NEUROENDOCRINE TUMORS Majority of NET are carcinoid

tumors May go undetected for years

without obvious signs or symptoms

• NETs can be characterized by their ability to produce peptides that lead to their syndromes2

• NETs can be classified as foregut, midgut, or hindgut depending on their embryonic origin1,3

Pancreatic NETs• Insulinoma• Glucagonoma• VIPoma• Pancreatic polypeptidoma

Foregut• Thymus• Esophagus• Lung• Stomach• Duodenum

Midgut• Appendix• Ileum• Cecum• Ascending colon

Hindgut• Distal large bowel• Rectum

Other NETSOther NETS

References: 1. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Gastroenterology. 2005;128(6):1717-1751. 2. Modlin IM, Oberg K, Chung DC, et al. Lancet Oncol. 2008;9(1):61-72. 3. National Comprehensive Cancer Network. NCCN Practice Guidelines in Oncology: Neuroendocrine Tumors. V.1. 2008.

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INCIDENCE OF NETS INCREASING

INCREASING INCIDENCES OF NET

Increased incidence of carcinoid tumours, US population 1973–2005Overall increase recorded for all primary sites during this period. Data from SEER database, US National Cancer Institute

Modlin et al. Lancet Oncol 2008; 9: 61–72

NETS ARE THE SECOND MOST PREVALENT TYPE OF GI MALIGNANCY

2x more prevalent than pancreatic cancer

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1. National Cancer Institute. SEER Cancer Statistics Review, 1975-2004. http://seer.cancer.gov/csr/1975_2004. 2. Modlin IM, Lye KD, Kidd M. Cancer. 2003;97(4):934-959.

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NET MAY PRESENT LATE

CONSTELLATION OF SYMPTOMS CAN MAKE A DIFFERENTIAL DIAGNOSIS DIFFICULT1,2

Menopause

Irritable Bowel Syndrome

Functional Bowel Disease

Anxiety

Neurosis

Food Allergy

Asthma

Alcoholism

Thyrotoxicosis

Peptic Ulcer

NET

Symptoms• Sweating• Flushing• Diarrhea• Intermittent abdominal pain• Bronchoconstriction• GI bleeding• Cardiac disease

Nonspecific Symptoms Are Common to Multiple Diagnoses

1. Vinik A, Moattari AR. Dig Dis Sci. 1989;34(3)(suppl):14S-27S. 2. Toth-Fejel S, Pommier RF. Am J Surg. 2004;187(5):575-579.

NONSPECIFIC SYMPTOMS OFTEN LEAD TO A DELAYED DIAGNOSIS

1. Modlin IM, Moss SF, Chung DC, Jensen RT, Snyderwine E. J Natl Cancer Inst. 2008;100(18):1282-1289.

Presents to primary care

Vague abdominal

symptoms

• May be diagnosed as IBS

• May be referred to specialists for evaluation when symptoms do not resolve

Presents to primary care

Vague abdominal

symptoms

• May be diagnosed as IBS

• May be referred to specialists for evaluation when symptoms do not resolve

Referred to multiple specialists

Symptomsbecome worse or patientconsultsfor another reason

• Diagnosis remains unclear

Referred to multiple specialists

Symptomsbecome worse or patientconsultsfor another reason

• Diagnosis remains unclear

Seen by gastroenterologist or other specialist who orders imaging

A referral leads to a scan or patientscanned for another reason

• Liver metastasis or primary lesion is visualized

• May be an incidental finding

Seen by gastroenterologist or other specialist who orders imaging

A referral leads to a scan or patientscanned for another reason

• Liver metastasis or primary lesion is visualized

• May be an incidental finding

Surgeon, pathologist perform biopsy or resection

Biopsy provides diagnosis of NET

• Patient is referred to surgical oncologist, medical oncologist, or endocrinologist

• Treatment depends on stage, histology, symptoms

Surgeon, pathologist perform biopsy or resection

Biopsy provides diagnosis of NET

• Patient is referred to surgical oncologist, medical oncologist, or endocrinologist

• Treatment depends on stage, histology, symptoms

Estimated time to diagnosis: 5 to 7 years1

Vague abdominal symptoms

Primary tumor

Flushing

Metastases

Diarrhea

Death

NETS ARE OFTEN DIAGNOSED LATE

Time

Vinik A, Moattari AR. Dig Dis Sci. 1989;34[Suppl]:14S-27S.

DIAGNOSIS

Clinical assessment Clinically directed workup of persistent

symptoms Scans

CT scans, Octreoscans, Galium PET/CT Histopathological diagnosis

TUMOR MARKERS

General NET markers– Chromogranin A

Affected by somatostatin analogues, proton pump inhibitors, kidney function, liver function

– Neuron-specific enolase Midgut (small bowel, appendix,

cecum)– 5 HIAA (24-hr urine collection)– Serotonin (blood, more variable)

5-HIAA = 5-hydroxyindoleacetic acid

OTHER MARKERS IN FUNCTIONAL TUMORS

Gastrinoma

Gastrin

Glucagonoma

Glucagon

Insulinoma

Insulin

Pro-insulin

C-peptide

VIPoma

Vasoactive intestinal peptide

Fasting measurements when possible

CHROMOGRANIN A (CGA): A VALUABLE DIAGNOSTIC AND PROGNOSTIC TOOL

Highly elevated serum CgA and/or immunohistochemical (IHC) staining of tumor for CgA is diagnostic of NETs Offers 85% sensitivity and 96% specificity for

NETs1

CgA can be used to monitor treatment response More sensitive than radiology for measuring

progression2

References: 1. Campana D, Nori F, Piscitelli L, et al. J Clin Oncol. 2007;25(15):1967-1973. 2. Eriksson B, Öberg K, Stridsberg M. Digestion. 2000;62(suppl 1):33-38.

CHALLENGES PRESENT WITH CGA TESTING

Other conditions can cause elevated CgA Risk of false positives Severe hypertension Gastric acid suppression (PPI’s) Renal insufficiency

CgA values vary considerably Between different types of NET

Clinical application of results is challenging

Test kits not universally standardized Different standards, units of measures Different antibodies Different detection system

TREATMENT OPTIONS

Surgery (curative vs debulking) Radiofrequency ablation Chemo-embolization Somatostatin analogue (hormonal

treatment) Chemotherapy or other medical

therapy (targeted kinase inhibitors) Radionuclide therapy

SURGERY

RADIOFREQUENCY ABLATION

CHEMOEMBOLISATION

CHEMOEMBOLISATION

Somatostatin receptors highly expressed by NETs

– Targeting SST receptors can provide symptom and disease control

New targets:– mTOR, PI3K, VEGF

inhibitors Combinations?

TARGETING NETS

PI3K = phosphoinositide 3-kinase; SST = somatostatin; VEGF = vascular endothelial growth factor

PEPTIDE RECEPTOR RADIONUCLIDE THERAPY

Octreotide

111In pentetreotide

DTPA-CO-NH-D-Phe-Cys

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PRINCIPLES OF RADIONUCLIDE THERAPY