Presentation by Dr Lim Hwee Yong, Medical Oncologist, National Cancer Centre Singapore, at a NET cancer awareness seminar in Singapore on 20 November 2010.
2. NEUROENDOCRINE CELLS
Cells that are cross between endocrine and nerve
cells. Produces peptides and neuropeptides.
3. 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
4. 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 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.
6. INCREASING INCIDENCES OF NET
Increased incidence of carcinoid tumours, US population 1973–2005
Overall 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
7. NETS ARE THE SECOND MOST PREVALENT
TYPE OF GI MALIGNANCY
2x more prevalent
than pancreatic cancer
]
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.
]
9. 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.
10. 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
Referred to
multiple
specialists
Symptoms
become worse
or patient
consults
for another
reason
• Diagnosis
remains unclear
Seen by
gastroenterologist
or other specialist
who orders imaging
A referral leads
to a scan or patient
scanned 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
Estimated time to diagnosis: 5 to 7 years1
13. 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
14. OTHER MARKERS IN FUNCTIONAL TUMORS
Gastrinoma
Gastrin
Glucagonoma
Glucagon
Insulinoma
Insulin
Pro-insulin
C-peptide
VIPoma
Vasoactive
intestinal
peptide
Fasting measurements when possible
15. 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.
16. 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
17. TREATMENT OPTIONS
Surgery (curative vs debulking)
Radiofrequency ablation
Chemo-embolization
Somatostatin analogue (hormonal treatment)
Chemotherapy or other medical therapy
(targeted kinase inhibitors)
Radionuclide therapy