Colonic Carcinoids: Recognizing the Signs, Sites, and Treatment Options

Carcinoids are rare neuroendocrine tumors. More than 75% of patients present with cutaneous flushing and diarrhea. About 8% of these tumors occur in the colon. Carcinoid tumors are recognized by their histologic patterns seen on Masson's stain, Grimelius'stain, and immunohistochemistry and in situ hybridization. Evidence of the elevation of 2 biochemical markers?plasma chromogranin A and urinary 5-hydroxyindoleacetic acid?is usually sufficient for diagnosis. This article discusses the diagnosis, localization, and current and investigational treatment options for carcinoids of the colon.

Chitra Sadasiwan, MD

Sajan Thomas, MD

Internal Medicine Residency

Melrose Park, Ill

PRACTICE POINTS

• The average 5-year cancer-specific survival for patients with colonic carcinoids of all stages is about 70%, but drops to about 28% in distant-stage tumors.
• Surgery remains the only potentially curative treatment.

Carcinoids are neuroendocrine tumors thought to arise from amine precursor uptake and decarboxylation cells. These specialized cells accumulate amine precursors (dihydroxyphenylalanine, 5-hydroxytryptophan) and decarboxylate them to produce biogenic amines (catecholamines or serotonin). They also produce peptides stored with the amines in secretory granules. The term "Karzinoide"was introduced in 1907 to describe tumors that behaved more indolently than adenocarcinomas.

Colonic carcinoids constitute an extensive spectrum of disease with significant variations in presentation and management, depending on the site of origin. Carcinoid tumors of the colon are rare entities that are usually diagnosed late in the course of the disease and are generally associated with a poor prognosis.

Epidemiology

Carcinoids account for 50% of all neuroendocrine tumors in the gastrointestinal (GI) tract.¹ From 4% to 7% of colonic tumors are carcinoids.² An analysis of 13,715 carcinoid tumors diagnosed over 50 years showed that 7.84% of the tumors were colonic.³

Approximately 35% of colonic carcinoids are located in the cecum, 6% in the ascending colon, 1% in the transverse colon, 3% in the descending colon, and 21% in the sigmoid colon.³ About 90% of colonic tumors are larger than 2 cm, and 50% are 5 cm or larger. Of these tumors, 61% have nodal metastases, and 53% have liver metastases.⁴ Most patients present in the sixth or seventh decade of life.⁴ An analysis of tumor stage at presentation demonstrated that approximately 46% of colonic carcinoids are local (in situ or confined to the colon), 22% are regional (local invasion), and 33% are distant (metastatic dissemination to other organs).⁵ The average 5-year cancer- specific survival for patients with colonic carcinoids of all stages is about 70% but drops to about 28% in distant-stage tumors.⁵

Classification

Several forms of classification for carcinoid tumors have been proposed, but none is universally accepted. The traditional classification proposed in 1963 is based on topographic location, which includes foregut (GI tract area receiving its blood supply from branches of the celiac artery), midgut (GI tract area receiving its blood supply from the superior mesenteric artery), and hindgut (GI tract area receiving its blood supply from the inferior mesenteric artery),⁶ and is discussed in Table 1.

Colonic carcinoids are located either in the midgut or in the hindgut. About 41% of colonic carcinoids are located in the cecum or the ascending colon; only 21% are found in the sigmoid colon.³

The second type of classification divides tumors by secretory behavior?either functioning or nonfunctioning. Neuroendocrine tumors are known to secrete hormones, including adrenocorticotropic hormone, corticotropin-releasing factor, chromogranin A, antidiuretic hormone, growth hormone-releasing hormone, gastrin, 5-hydroxytryptamine, histamine, serotonin, prostaglandins, polypeptides, and somatostatin.

Tumors can also be segregated according to biologic behavior⁷ or by histology, based on microscopic morphology (Table 2).⁸

Pathology

Carcinoid tumors are recognized by their histologic pattern based on Masson's stain (used to assess serotonin content), Grimelius'stain or immunopositivity for cytosolic vesicle or granule markers, immunohistochemistry, in situ hybridization for specific peptide hormones, or electron microscopy. Before the immunocytochemical era, which began in the 1960s, various silver stains were used to identify and characterize neuroendocrine cells. These stains are still used, often in combination with immunocytochemistry, for demonstrating neuroendocrine cells and corresponding tumors. Cells displaying an argyrophil reaction retain silver ions from the impregnation solution, but viable metallic silver only appears after a subsequent reducing process brought about by an external agent. Cells showing an argentaffin reaction contain 1 or more chemical substances (usually serotonin), which retain silver ions and reduce them to metallic silver. The Grimelius argyrophil reaction demonstrates neurohormonal secretory granules, which are present in most normal GI tract neuroendocrine cell types that store peptide hormones and/or biogenic amines. Colonic carcinoids are argentaffin-positive and argyrophil-positive by the Grimelius method.

Based on histology, neuroendocrine tumors can be divided into well-differentiated carcinoids, atypical carcinoids, and small-cell type. However, since considerable controversy exists regarding the various forms of classification, objective parameters are used to determine prognosis, such as the nucleocytoplasmic ratio, different sets of cell markers, DNA ploidy, or expression of various oncogenes, including p53, bcl-2, and ki-67.⁸

Immunohistochemistry

Immunohistochemistry has become the method of choice for defining the neuroendocrine nature of these tumors. Antibodies against chromogranin A, synaptophysin, and serotonin have been used. All well-differentiated neuroendocrine GI tumors show positivity with chromogranin A, except for some insulinomas, which stain positive for chromogranin B. Neuron-specific enolase is another marker used to demonstrate neuroendocrine nature; however, because it is not very specific it should be used in combination with chromogranin A immunohistochemistry.⁹

Biochemistry

Biochemistry is very helpful in the diagnosis of neuroendocrine carcinoids, and the results are often the impetus for searching for a primary tumor. Various radioimmunoassays have been developed in the past few decades. The most important biochemical markers are chromogranin A and urinary 5-hydroxyindoleacetic acid; the combination of these 2 hormones is usually sufficient to diagnose all clinically significant carcinoids.¹⁰ Most tumors arising from the proximal colon, ileum, and appendix secrete hormones and hence can be easily diagnosed, as opposed to the distal colonic and rectal carcinoids, which rarely secrete hormones.

Localization

Colonic carcinoids are usually localized with GI endoscopy, computed tomography (CT), scintigraphy, or positron emission tomography (PET). Other modalities, including barium radiographs, ultrasound, endoscopic ultrasound, selective venous sampling for various hormones, somatostatin receptor scintigraphy, and metaiodobenzylguanidine scans, have been used to identify the location and extent of the primary tumor. At present, somatostatin receptor scintigraphy and CT scanning are the primary diagnostic modalities for tumor staging. Octreotide acetate (Sandostatin) binds with great affinity to somatostatin receptor subtype 2 and has been approved for localizing carcinoids with radionuclide scanning. False-positive results can occur with granulomas, activated lymphocytes, thyroid diseases, and some endocrine tumors because of their high concentration of somatostatin receptors.¹¹ Data suggest that PET scanning with 5-hydroxy-L-tryptophan is effective in localizing carcinoids as small as 0.5 cm and is also useful for tumor staging.¹²

Clinical Presentation

Fewer than 10% of patients with colonic carcinoids present with the carcinoid syndrome, which is more commonly seen in tumors arising from the ileum and proximal colon.¹ The carcinoid syndrome is characterized by flushing of the skin, diarrhea, abdominal cramps, cardiac manifestations (ie, tricuspid regurgitation and pulmonary stenosis secondary to right-sided endocardial fibroelastosis), wheezing, telangiectasia of the face and neck, arthritis, arthralgias, changes in mental state, and ophthalmic changes. From 75% to 85% of patients with midgut carcinoids exhibit this syndrome.¹³ In addition, there have been reports of noncardiac problems secondary to increased fibrous tissue, including retroperitoneal fibrosis, Peyronie's disease, occlusion of mesenteric arteries and veins, and sexual dysfunction secondary to the vascular effect of serotonin on the pelvic vessels. Table 3 lists the presenting features of the carcinoid tumors according to location, in order of decreasing frequency.

Surgery: The Treatment of Choice

Surgery remains the only potentially curative treatment. Localized tumors should be excised completely. Since the possibility of metastatic disease is directly related to the size of the primary tumor, the extent of surgical resection for possible cure should be determined accordingly. If radical surgery cannot be performed, debulking procedures and bypassing can be performed at any time during the course of treatment.¹⁴ The extent of surgery depends on the size and depth of carcinoid invasion.

Appendiceal carcinoids smaller than 1 cm without metastases can be managed with a simple appendicectomy.¹⁵ Those larger than 2 cm necessitate a right hemicolectomy.¹⁵ Tumors between 1 and 2 cm in size fall in the gray zone, with no certain recommendations regarding the extent of surgery. For rectal carcinoids smaller than 1 cm that are not invading the muscularis propria, local resection is adequate.¹⁶ Larger tumors (>2 cm or those invading the muscularis propria) need to be treated with an abdominoperineal resection or with low anterior resection with primary anastomosis. Midgut carcinoids, including those less than 1 cm in size, have been found to have a higher propensity for metastasis (15%-20%).¹ Hence, a wide en bloc resection of adjacent lymph node-bearing mesentery has been advocated for all midgut carcinoids.¹ Tumors larger than 2 cm are best treated by a standard colon resection in the form of a partial or total colectomy, depending on the location.

Resection of isolated hepatic metastases and hepatic artery ligation may be beneficial in select cases. One study showed a 50% reduction in hormone levels after embolization, and overall growth stabilization was achieved in 38% of patients for a median of 7 months.¹⁷ Liver transplantation for patients with metastatic liver disease is generating considerable interest and may be justified in young patients with only hepatic disease.¹⁸

Favorable prognostic factors include:

• Age younger than 50 years
• Pretransplantation somatostatin therapy.

Adverse prognostic factors are age older than 50 years and transplantation combined with upper abdominal exenteration or Whipple's surgery.¹⁸

Other Treatment Modalities

The use of chemotherapy for malignant carcinoids has produced disappointing results. So far, no study has shown any evidence for the benefit of chemotherapy as a single or a multiagent therapy in the treatment of GI carcinoids. The low response rate of 0% to 30% for multiagent combination chemotherapy using streptozocin (Zanosar), doxorubicin (Adriamycin), and fluorouracil (5-FU; Adrucil) has been sustained for less than 1 year in most studies.¹⁰ One study found that anaplastic neuroendocrine tumors might benefit from treatment with a combination of cisplatin (Platinol-AQ) and etoposide (Toposar, VePesid), with a response rate of about 67%.¹⁹

Teletherapy has not been beneficial for the primary treatment of neuroendocrine tumors, but it is useful in the palliative setting for painful bone, skin, and brain metastases.

Somatostatin inhibits the release of various peptide hormones. In addition to antitumor activities, somatostatin affects the autonomic processes, gut motility, mucosal cell proliferation, vascular smooth-muscle tone, and intestinal absorption of nutrients. The antitumor activity is said to be mediated through the induction of tyrosine phosphatase by somatostatin receptor subtype 2 and the inhibition of calcium flux through receptor type 5.^20,21 Somatostatin analogs also induce apoptosis in tumor cells. The somatostatin analogs that have been developed with long half-lives have poor tumoricidal activity but significant tumoristatic and tumor stabilization activity.²² Octreotide and lanreotide (which has an orphan drug status in United States) are 2 of the commonly used analogs. The dosing schedule for octreotide is 50 to 150 mg, 2 to 3 times daily.⁹ The side effects of somatostatin analog therapy include gall bladder dysfunction, gallstones, and rarely, hyperglycemia and hypocalcemia. Therapy with somatostatin analogs has produced biochemical response rates ranging from 30% to 70% and objective tumor shrinkage rates of 5% to 10%.^20,23

Interferon has more tumoristatic than tumoricidal activity. The recommended dose for treatment of colonic carcinoids is 3 to 9 mIU, 3 to 7 times weekly.¹⁰ Side effects of interferon-alpha therapy include chronic fatigue, flulike symptoms, anemia, and increased liver enzymes. Therapy with interferon has shown a biochemical response rate of 50% and an objective tumor response rate of 15%.²⁴

Conclusion

Considerable enthusiasm exists about novel therapies for carcinoids. The National Cancer Institute is currently conducting several studies on alternative therapies, including epidermal growth factor receptor antagonist gefitinib (Iressa), monoclonal antibodies such as bevacizumab (Avastin), and other anticytokine therapies for the treatment of unresectable and metastatic carcinoids. Agents such as temsirolimus (which has an orphan drug status in the United States), flavopiridol (not available in the United States), depot preparations of octreotide, and pegylated interferons are also under evaluation. Colonic carcinoid is the focus of extensive research at present. Patients should be encouraged to participate in clinical trials whenever feasible.

SELF-ASSESSMENT TEST

1. Which of these statements about colonic carcinoids is NOT true?

• Most are tumors larger than 2 cm
• Most are local stage at diagnosis

2. Midgut tumors describe carcinoids in all the following locations, except:

• Duodenum
• Ileum

3. Which of these features is NOT typical of a carcinoid tumor located in the proximal colon?

• Altered bowel movements
• Hypotension

4. Which of these techniques are most valuable for tumor staging?

• CT and PET
• CT and somatostatin receptor scintigraphy

5. All these statements about the treatment of colonic carcinoids are true, except:

• Multiagent chemotherapy is more effective than single-agent chemotherapy
• Liver transplantation may be considered for young patients with metastases confined to the liver

Gastroenterology

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Cancer

2. Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumors. . 1997;79:813-829.

Cancer

3. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. . 2003;97:934-959.

J Exp Clin Cancer

Res.

4. Soga J. Carcinoids of the colon and ileocecal region: a statistical evaluation of 363 cases collected from the literature. 1998;17:139-148.

Ann Surg

5. Maggard MA, O'Connell JB, Ko CY. Updated population-based review of carcinoid tumors. . 2004;240:117-122.

Lancet

6.Williams ED, Sandler M. The classification of carcinoid tumours. . 1963;1:238-239.

Virchows Arch

7. Capella C, Heitz PU, Hofler H, et al. Revised classification of neuroendocrine tumours of the lung, pancreas and gut. . 1995;425:547-560.

Arch Pathol Lab Med

8. Moyana TN, Xiang J, Senthilselvan A, et al. The spectrum of neuroendocrine differentiation among gastrointestinal carcinoids: importance of histologic grading, MIB-1, p53, and bcl-2 immunoreactivity. . 2000;124:570-576.

Gastroenterol Clin North Am.

9. Solcia E, Capella C, Fiocca R, et al. The gastroenteropancreatic endocrine system and related tumors. 1989;18:671-693.

Oncologist

10. ?berg K. Carcinoid tumors: current concepts in diagnosis and treatment. . 1998;3:339-345.

J Nucl

Med.

11. Gibril F, Reynolds JC, Chen CC, et al. Specificity of somatostatin receptor scintigraphy: a prospective study and effects of false-positive localizations on management in patients with gastrinomas. 1999;40:539-553.

Ann N Y Acad Sci

12. Eriksson B, Lilja A, Ahlstrom H, et al. Positron-emission tomography as a radiological technique in neuroendocrine gastrointestinal tumors. . 1994;733:446-452.

Cancer: Principles and Practice

of Oncology

13. Norton J, Levin B, Jensen R. Cancer of the endocrine system. In DeVita VT, Hellman S, Rosenberg SA, eds. . 4th ed. Philadelphia, Pa: JB Lippincott; 1993:1371-1435.

World J Surg

14. Makridis C, ?berg K, Juhlin C, et al. Surgical treatment of midgut carcinoid tumors. . 1990;14:377-383.

Digestion.

15. Rothmund M, Kisker O. Surgical treatment of carcinoid tumors of small bowel, appendix, colon and rectum. 1994;55 (suppl 3):86-91.

Cancer: Principles and Practice

of Oncology.

16. Jensen RT, Norton JA. Carcinoid tumors and carcinoid syndrome. In: DeVita VT, Hellman S , Rosenberg SA, eds. 5th ed. Philadelphia, Pa: Lippincott-Raven; 1997:1704.

Cancer

17. Eriksson BK, Larsson EG, Skogseid BM, et al. Liver embolizations of patients with malignant neuroendocrine gastrointestinal tumors. . 1998;83:2293-2301.

Transplantation.

18. Lehnert T. Liver transplantation for metastatic neuroendocrine carcinoma: an analysis of 103 patients. 1998;66:1307-1312.

Cancer.

19. Moertel CG, Kvols LK, O'Connell MJ, et al. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. 1991;68:227-232.

Life Sci.

20. Patel YC, Greenwood MT, Panetta R, et al. The somatostatin receptor family. 1995;57:1249-1265.

Proc Natl Acad Sci U S A

21. Buscail L, Esteve JP, Saint-Laurent N, et al. Inhibition of cell proliferation by the somatostatin analogue RC-160 is mediated by somatostatin receptor subtypes SSTR2 and SSTR5 through different mechanisms. . 1995;92:1580-1584.

Cancer

22. Saltz L, Trochanowski B, Buckley M, et al. Octreotide as an antineoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors. . 1993;72:244-248.

Acta Oncol

23. ?berg K, Norheim I, Theodorsson E. Treatment of malignant midgut carcinoid tumours with a long-acting somatostatin analogue octreotide. . 1991;30:503-507.

Acta Oncol

24. ?berg K, Eriksson B. The role of interferons in the management of carcinoid tumors. . 1991;30:519-522.

Answers:

1. A; 2. B; 3. A; 4. D; 5. B