Carcinoid TumourBiochemical and Radiological

Testing

Gillian Harris 4th year MBBS

Carcinoid Tumour-background

• Rare, slow growing• Derived from resident neuroendocrine cells• Most often found in GIT (2/3) and lung • Secrete various substances including

-Serotonin -Histamine-Bradykinin -Prostaglandins-Kallikrein -Adrenocorticotropic

hormone-Neuropeptide K -Gastrin-Neurokinins A & B -Calcitonin-Substance P -Growth hormone

• Carcinoid syndrome

Biochemical Markers• 5-hydroxy-indole-acetic acid (5-HIAA)

– End product of serotonin metabolism– Measured in 24 hour urinary collection– Sensitivity 75% Specificity 100%

• Chromogranin A (CgA)– In wall of synaptic vesicles that store

serotonin and glucagons– Levels correlate with tumour bulk– Elevated in 85-100% pts with carcinoid

tumour– Sensitivity 67.9% Specificity 85.7%

5-hydroxy-indole-acetic acid (5-HIAA)

• End product of serotonin metabolism

• Normal rate of excretion 2-8mg/day

• Sensitivity of 73%

• Specificity of 100%

Serotonin overproduction

• Increased values of Urinary 5-HIAA secretion occur with:– Malabsorption syndromes – Ingestion of tryptophan-rich foods (eg

bananas and avocadoes)– Certain drugs

Other methods for measuring serotonin overproduction

• Urinary Serotonin

• Platelet concentration of serotonin

Chromogranin A(CgA)

• Found in the wall of secretory vesicles of neuroendocrine cells

• Widely distributed throughout the neuroendocrine system

• Immunohistochemical staining can detect the presence of CgA in the circulation

• CgA is elevated in 85-100% pts with carcinoid tumour

• Specificity 85.7%

• Sensitivity 67.9%

for neuroendocrine tumours

Other causes of increased serum CgA

• Renal impairment

• Liver Failure

• Atrophic Gastritis

• Irritable bowel disease

• Proton pump inhibitors

• Physical Stress

Diagnostic Imaging• Neuroendocrine tumours express:

– Neuroamine uptake mechanisms– Specific receptors (eg. Somatostatin receptors)

• Radiolabelled amines/peptides bound to suitable ligands target specific cells

• Gamma camera visualises uptake

• Improved localisation with simultaneous conventional imaging (eg. CT/MRI)

111In-Pentetreotide Scintigraphy

• 111In-labelled somatostatin analogue• Concentrates in neuroendocrine and some non-

neuroendocrine tumours containing somatostatin receptor subtypes 2 and 5

• 80-90% sensitivity for carcinoid tumours (10)• Identifies lesions not visualised on conventional

imaging– 1/3-2/3 patients had additional localisations– 65 extra lesions found per 100 patients

(11) Van der Lely; De Herder. Carcinoid Syndrome: diagnosis and medical management Arq Bras Endocrinol Metab. 2005: 49:5

Meta-iodobenzylguanidine (MIBG) Scintigraphy

• Guanidine derivative• Utilises Type 1 amine uptake mechanism of cell• Found in carcinoid and other neuroendocrine

tumours • Uses 123I- or 131I-labelled MIBG• 123I-labelled MIBG has a superior image quality• Useful for tumours which do not have

somatostatin receptors• Select patients for MIBG therapy

Conventional Imaging Modalities

• CT

• MRI

• Transabdominal ultrasound

• Endoscopy

• Endoscopic ultrasound

• Selective mesenteric angiography

Tumour type Imaging (12)

Foregut Chest radiography-occasionally detects lesions

CT/MRI-identification of primary tumour, lymph nodes, facilitates biopsy diagnosis

Octreotide Scintigraphy-negative in 30% but most specific

Midgut Octreotide Scintigraphy-staging and identification of primary lesion. 83% diagnostic accuracy, 100% PPV

Transabdominal Ultrasound-1/3 Small bowel carcinoids, 2/3 liver metastases

CT/MRI-to monitor responsiveness to treatment, only detect 50% primary tumours

Double contrast barium studies-to assess for imminent obstruction

Hindgut Octreotide scintigraphy-highest sensitivity

MIBG-when negative scan

Endoscopic ultrasound-90% accuracy for localisation and staging of colorectal carcinoids

MRI

Positron Emission Tomography (PET)

• Carcinoids are slow growing, well differentiated tumours

• FDG has detection rates 25-73%

• Newer tracers:– 11C-5-HTP– 68Ga coupled to octreotide

• More evidence necessary

Summary

• Biochemical Markers– 5-hydroxy-indole-acetic acid (5-HIAA)– Chromogranin A (CgA)

• Radiological Imaging– 111In-Pentetreotide Scintigraphy– Meta-iodobenzylguanidine (MIBG)

Scintigraphy– Conventional Imaging (CT/MRI/Ultrasound)– PET

References1. Feldman JM Urinary Serotonin in the Diagnosis of Carcinoid Tumors. Clin Chem 1986; 32:8402. Feldman JM, O’Doriso TM. Role of Neuropeoptides and Serotonin in the Diagnosis of Carcinoid Tumors. Am J Med

1986; 81:413. Maroun J, Kocha W et al Guidelines for the diagnosis and management of carcinoid tumours. Current Oncology.

13(2): 67-764. Janson ET, Holmberg L. Carcinoid tumors: Analysis of prognostic factors and survival in 301 patients from a referral

center. Annals of Oncology. 1997; 8:685-6905. Bajetta E, Ferrari L. Chromogranin A, Neuron Specific Enolase, Carcinoembryonic Antigen, and Hydroxyindole Acetic

Acid Evaluation in Patients with Neuroendocrine Tumors. American Cancer Society. 1999; 86(5) 8586. Eriksson B, Oberg K. Tumor Markers in Neuroendocrine Tumors. Digestion 2000; 62(suppl 1):33-387. Nobels FRE et al. Chromogranin A: its clinical value as marker of neuroendocrine tumours. European Journal of

Clinical Investigation. 1998; 28: 431-4408. Stridsberg M, Eriksson B et al. A comparison between three commerical kits for chromogranin A measurements. J of

Endocrinology. 2003; 177: 337-3419. Onaitis MW, Kirshbom PM et al. Gastrointestinal Carcinoids: Characteriszation by Site of Origin and Hormone

Production. Annals of Surgery. 232(4): 549-54610. Kweekeboom DJ, Krenning MD. Somatostatin Receptor Scintigraphy in Patients with Carcinoid tumors. World J Surg.

1996; 20:157-161.11. Van der Lely; De Herder. Carcinoid Syndrome: diagnosis and medical management Arq Bras Endocrinol Metab. 2005;

49:512. Kaltsas G, Besser G. The diagnosis and medical management of Advanced Neuroendocrine Tumours. Endocrine

Reviews 25(3):458-51113. Kaltsas G, Rockall A. Recent advances in radiological and radionuclide imaging and therapy of Neuroendocrine

tumours. European Journal of Endocrinology. 2004; 151:15-27.14. Kaltsas G, Korbonits M. Comparison of Somatostatin Analog and Meta-Iodobenzylguanidine Radionuclides in the

Diagnosis and Localization of Advanced Neuroendocrine Tumors. J Clin Endocrinology and Metab. 2001. 86(2) 895

15. Sitaraman SV, Goldfinger SE. Diagnosis of the carcinoid syndrome. Uptodate. 2007.