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Carcinoid tumors: an update
Surgical Oncology
Carcinoid Tumors: An Update Guest Reviewers: R. B. Kolachalam, MD, and S. C. Young, MD, MSA, FACS CARCINOID TUMORS.
Kulke MA, Mayer RJ. N Engl J Med 1999;340:856 – 868. Comprehensive review of carcinoid tumors.
Objective
Carcinoid tumors are thought to rise from neuroendocrine cells. They show positive reaction to silver stains and to markers of neuroendocrine tissue including neuron-specific enolase, synaptophysin, and chromogranin.
Biology
Traditionally classified as fore-gut (lungs, bronchi, or stomach), mid-gut (small intestine, appendix, and proximal large bowel), and hind-gut carcinoid tumors (distal colon and rectum).
Classification
Revised system classifies carcinoid tumors as well-differentiated neuroendocrine tumors (typical tumors) and “atypical” or “anaplastic” carcinoids when they show biologically aggressive features such as nuclear atypia, mitotic activity, or areas of necrosis. Estimated to be 1 to 2 cases per 100,000 people in the United States.1,2
Incidence
The appendix was the most common site of the carcinoid tumors, followed by the rectum; ileum; and lungs, bronchi, and stomach.1 They can be separated into three groups: those associated with atrophic gastritis (75%), those associated with Zollinger–Ellison syndrome (5% to 10%), and sporadic tumors (15% to 25%).
Gastric Carcinoid Tumors
In contrast to carcinoids associated with atrophic gastritis, sporadic carcinoid tumors tend to be more aggressive and often metastatic. Because of the aggressive nature of these lesions, most sporadic carcinoids are treated with radical gastrectomy. Small (⬍1 cm) carcinoids associated with atrophic gastritis and Zollinger–Ellison syndrome can be treated endoscopically. They are most frequently located in the distal ileum and are often multicentric. They are thought to arise from serotonin-producing epithelial endocrine cells like the carcinoid tumors of the colon. They generally present in the sixth or seventh decade of life. The majority of patients with small-bowel carcinoids present late with vague symptoms and tumors that are metastatic to the lymph nodes or the liver, and 5% to 7% present with the carcinoid tumors. These tumors can be associated with extensive mesenteric fibrosis or mesenteric angiopathy. Small-bowel resection, together with resection of associated mesentery, is the treatment of choice even in patients with known metastatic disease.
Carcinoid Tumors of the Small Intestine
The 5-year survival rate is 65% among patients with localized or regional disease and 36% among those with distant metastases. The most common site of carcinoid tumors is the appendix, and tumors are the most common cancers of the appendix. In contrast to carcinoids of the small intestine and the colon, appendiceal carcinoids arise from subepithelial endocrine cells. Appendiceal carcinoids are more common in women and most often diagnosed in the fourth or fifth decade of life.2 Most are asymptomatic, and 75% are located in the distal third of the appendix. Less than 10% of the carcinoids are symptomatic and less than 10% are located at the base. CURRENT SURGERY
•
Volume 56 / Number 9 • November/December 1999
Appendiceal Carcinoid Tumors
499
The size of the tumor is the best predictor of prognosis in patients with appendiceal carcinoid tumors. Over 95% are less than 2 cm in diameter, and metastasis in this group of patients is rare. In contrast, approximately one third of the patients with tumors greater than 2 cm in diameter have either nodal or distant metastasis.3 Patients with tumors less than 2 cm in diameter are usually treated by simple appendectomy if there is no gross evidence of local spread. Most tumors greater than 2 cm in diameter are treated with right colectomy.3 Carcinoid Tumors of the Colon
Two thirds of these tumors are found in the right side of the colon, most of them in the cecum. Most patients present late, and over two thirds of patients have either nodal or distant disease at the time of presentation. The 5-year survival rates are 70% for patients with local disease, 44% for those with regional metastasis, and 20% for those with distant metastasis.2
Rectal Carcinoid Tumors
Rectal carcinoids, in contrast to carcinoids of the small intestine and colon, contain gulcagon and glicentin-related peptides rather than serotonin. Tumors less than 1 cm in diameter account for two thirds of rectal carcinoids and are treated with local excision. Less than 5% of these patients have metastasis. The 5-year survival rates are 81% for patients with local disease, 47% for patients with regional disease, and 18% for patients with distant metastasis.2 Tumors greater than 2 cm in diameter have traditionally been treated by low anterior resection or abdominoperineal resection. Muscular invasion, symptoms at diagnosis, and ulceration are poor prognostic factors, and smaller carcinoids with these features may warrant more extensive surgical procedures.
Metastatic Carcinoid Tumors
Patients with suspected metastasis should be evaluated with an abdominal computed tomography scan to rule out liver metastases. Measurement of urinary 5-hydroxyindoleacetic acid may be useful in confirming the diagnosis and in subsequent monitoring of patients with metastatic carcinoid tumors. Elevated plasma chromogranin and positive antibody staining of tumor cells for carcinoembryonic antigen are poor prognostic factors.4,5
Treatment With Somatostatin Analogues
Somatostatin analogues have a central role in both the diagnosis and the treatment of metastatic carcinoid tumors. Somatostatic receptors are expressed on more than 80% of carcinoid tumors. Five subtypes of somastostatin receptors have been identified. Scintigraphy with radiolabeled octretide has been used to localize primary or metastatic lesions with a sensitivity of 89%. Somatostatin analogues are highly effective in relieving the symptoms of the carcinoid tumors, primarily by binding to receptor subtype 2.
Carcinoid Heart Disease
Carcinoid heart disease occurs in two thirds of patients with the carcinoid syndrome. Classically, the right side of the heart is involved and tricuspid regurgitation is the most common manifestation. The preponderance of right-side involvement suggests that factors secreted into the hepatic vein by liver metastasis are responsible for carcinoid heart disease.
Management of Hepatic Metastasis
Surgical resection of liver metastasis may be of benefit in patients with limited hepatic disease. Hepatic artery occlusion or embolization is an alternative for patients who are not candidates for hepatic resection. The response rates seem to be better and the duration of response longer when hepatic artery occlusion is followed by systemic chemotherapy. In highly selected patients, liver transplantation had a 5-year survival rate of 69%.
Metastatic Disease
Interferon-␣ alone or in combination with somatostatin analogues has been effective in controlling the symptoms of patients with carcinoid syndrome. However, interferon use is associated with a high incidence of adverse side effects such as fever, anorexia, and weight loss. Systemic chemotherapy has had only limited success in the treatment of metastatic carcinoid tumors. Recently, the therapeutic use of radiolabeled somatostatin analogues has been reported to result in tumor shrinkage and clinical improvement in a small number of patients with metastatic carcinoid tumors. REVIEWER COMMENTS. This is a timely review of our current understanding of carcinoid tumors. The traditional classification of carcinoid tumors into fore-gut, mid-gut, and hind-gut tumors does not take the site of origin and variations in the histologic characteristics into account. The revised system of classifying carcinoid tumors into the so-called typical tumors and the atypical or anaplastic carcinoids better explains the differences in biologic behavior. This article is a state-of-the-art review of carcinoid tumors and the multimodality treatment available. PROGNOSIS AND SURVIVAL IN PATIENTS WITH GASTROINTESTINAL TRACT CARCINOID TUMORS.
Shebani KO, Souba WW, Finkelstein DM, et al. Ann Surg 229:815– 823.
500
CURRENT SURGERY
•
Volume 56 / Number 9 • November/December 1999
To determine the impact of clinical presentation variables on management and prognosis of the carcinoid tumors.
Objective
Retrospective analysis.
Design
Massachusetts General Hospital, Boston.
Setting
This is a 20-year (1975 to 1995) retrospective analysis of 150 patients with gastrointestinal tract carcinoid tumors in a single institution. Survival estimates for each prognostic factor—namely, age, gender, tumor size, tumor depth of penetration, and liver and lymph node metastasis—were calculated, with death from carcinoid as the outcome.
Participants
Ileojejunal and appendiceal carcinoids account for two thirds of all patients. Mean age at presentation was 55 years, with a slight female predominance. Signs and symptoms of carcinoid tumors were vague and nonspecific and include abdominal pain, nausea and vomiting, and weight and blood loss. Not surprisingly, 40% of patients had their carcinoid tumors discovered incidentally. The appendix was the most common site for incidental carcinoids. There were significantly fewer metastases in this group of patients (21% with incidental carcinoids vs 53% in patients with nonincidental carcinoids). Interestingly, only half of the patients with liver metastasis had the classic symptomatology of carcinoid syndrome. The ileum was the most common site of the primary tumor (9 of 13 patients presenting with carcinoid tumor). None of the stomach- or rectal-site tumors developed carcinoid syndrome, regardless of the metastatic status of the liver. All patients with carcinoid syndrome had elevated levels of 5-hydroxyindoleacetic acid (5-HIAA), but not all patients with elevated 5-HIAA levels had or developed the syndrome. Ten percent of patients had multicentric carcinoid tumors, 22% had synchronous noncarcinoid tumors, and metachronous tumors developed in 10% of patients.
Results
When the primary tumor was greater than 2 cm in diameter, 28% of patients had liver metastasis and 72% had lymph node metastases. In contrast, when the primary tumor was less than 1 cm, no liver metastases were observed and only 10% had lymph node metastases. Ileojejunal carcinoids have the worst prognosis of any subsite. Tumor depth had a linear correlation with metastatic disease. Tumors perforating the visceral peritoneum (T4 lesions) had a 25% rate of liver metastasis (compared with a 9% rate for T1 lesions). Female patients and patients younger than 50 years had significantly fewer metastases. Overall median survival of patients with metastatic disease was still 8 years. Lymph node and liver metastases were less common in incidental carcinoid tumors. Also, surprisingly, multicentricity did not carry adverse prognosis. The fact that a patient with carcinoid tumor has a synchronous (22%) or metachronous (9%) noncarcinoid tumor warrants a thorough exploration and evaluation. Depth of bowel wall penetration, site of tumor, age, gender, and metastatic status predicted survival more accurately than size of the tumor. Tumors arising in the small bowel behave more aggressively. Liver metastases are generally multicentric and not amenable to a curative resection.
Conclusions
REVIEWER COMMENTS. This is a large study from one institution and therefore provides better data on patient demographics, incidence, survival, and clinical correlation of several variables. For instance, in this study patient age was a prognostic factor in a multivariate study. Size was not the best predictor of overall survival in this study: depth of penetration, site of tumor, age, gender, and metastatic status were significantly more accurate. These parameters can better help in the management of lesions of intermediate metastatic risk. For instance, a 25-year-old male with a 1.5-cm T2 tumor (invasion of muscularis propia) of the appendix may be better managed by a complete hemicolectomy. THE MANAGEMENT OF CARCINOID TUMORS.
Halford S, Waxman J. QJM 1998;91:795–798. Minireview.
Objective
The two pharmacologic agents in current use include somatostatin analogues and interferon-␣. Octreotide, a somatostatin analogue, inhibits hormone release and exerts its antitumor effect through somatostatin receptor 2. There is symptomatic improvement in 70% of patients, and 50% to 70% of patients have a greater than 50% reduction in urinary 5-hydroxyindoleacetic acid levels. Eighty percent of carcinoid tumors have somatostatin receptors, and their presence corresponds with the likelihood of response to octreotide. In contrast to octreotide, which must be given 3 times daily by subcutaneous injection, newer slow-release somatostatin analogues such as lanreotide are given once every 2 weeks. Carcinoid tumors are characterized by prolonged periods of stable
Pharmacologic Agents
CURRENT SURGERY
•
Volume 56 / Number 9 • November/December 1999
501
disease, making objective assessment of response rates difficult to interpret, although symptoms are well controlled, with minor side effects. Interferon-␣ causes significant side effects in terms of flulike symptoms and chronic fatigue. These side effects probably outweigh its benefits in controlling the symptoms of carcinoid syndrome. Interferon-␣ was better tolerated when given in combination with octreotide. Radionucleide Therapy
Iodine-131–labeled metaiodobenzylguanidine therapy has been shown to have good short-term response.
Chemotherapy
Response rates to chemotherapy are in the range of 10% to 30%, as defined by a reduction in tumor size by greater than 50%. The best response rates (33%) have been seen with combinations of streptozocin and fluorouracil.
Hepatic Artery Embolization and Ligation
Hepatic artery embolization has been shown to palliate symptoms of carcinoid syndrome for a median of 6 to 12 months. When hepatic artery occlusion is followed by chemotherapy, the response rates are much better.
Conclusions
Endocrine treatment leads to an improvement in up to70% of patients for a median duration of 1 year. Treatment is palliative and does not improve survival. REVIEWER COMMENTS. This is a review of the available treatment modalities for carcinoid tumors. Carcinoid tumors, even when there is metastatic spread, are generally thought to have a good prognosis, although a 5-year survival rate of 18% to 38% belies this perception. Overall chemotherapy leads to an objective response in 30% of patients.
SUMMARY Carcinoid tumors are neuroendocrine tumors. The cells of this tumor are characterized by positive reactions to silver stains and markers of neuroendocrine tissue, including neuron-specific enolase, synaptophysin, and chromogen. Carcinoid tumors secrete a wide variety of products including serotonin, coricotropin, histamine, dopamine, substance P, neurotensin, prostaglandins, and kallikrein. Whereas the carcinoid tumors have been traditionally classified as foregut, mid-gut, and hind-gut tumors, a revised system classifies these tumors as typical neuroendocrine tumors, and atypical carcinoids or neuroendocrine carcinomas. Gastrointesinal tract carcinoid tumors have a nonspecific clinical presentation, except in the case of the carcinoid syndrome. Patients with carcinoid syndrome have the classic manifestations, which include episodic flushing, wheezing, diarrhea, and eventual right-side valvular disease. The release of serotonin and other vasoactive substances into the circulation is thought to be responsible for the syndrome. The ileum and the appendix are the most common sites for carcinoid tumors. More than a third of patients have their carcinoid tumors discovered incidentally. The biologic behavior of these incidental carcinoids seems to be less aggressive. Half of the patients with incidental carcinoids have the primary tumor in the appendix. The biologic behavior of carcinoid tumors seems to be influenced by several variables, such as tumor site, tumor size, depth of penetration, gender, and age. Traditionally, tumors greater than 2 cm in diameter have warranted more aggressive surgical resections. It appears from more recent literature that such decision making should involve other factors listed above. For instance, a 1.5-cm appendiceal carcinoid involving the muscularis in a young male may be better treated by hemicolectomy. Clearly, surgical resection is the treatment of choice for improving survival. Even patients who present late with the
502
carcinoid syndrome secondary to metastasis are better served by resection of the intact primary site. Liver metastases are generally multicentric and not amenable to curative surgical resection. They are amenable to multimodality treatment, including hepatic artery chemoembolization, chemotherapy, and hormonal therapy. The French study6 reported a 5-year survival rate of 69% among selected patients who underwent liver transplantation for metastatic carcinoid tumors. Perhaps the greatest advance in the management of neuroendocrine tumors has been the development of scintigraphic imaging and receptor-targeted therapy. Carcinoid tumors express several receptors. Somatostatin analogues have a central role in both the diagnosis and the treatment of metastatic carcinoid tumors. R. B. KOLACHALAM, MD S. C. YOUNG, MD, MSA, FACS Department of Surgery Providence Hospital and Medical Centers Southfield, Michigan REFERENCES 1. Godwin J. Carcinoid tumors: an analysis of 2837 cases. Cancer 1975;36:560 –569. 2. Modlin M, Sandor A. An analysis of 8305 cases of carcinoid tumors. Cancer 1997;79:813– 829. 3. Moertal CG, Weiland LH, Nagorney DM, Dockerty MB. Carcinoid tumor of the appendix: treatment and prognosis. N Engl J Med 1987;317:1699 –1701. 4. Janson ET, Holmberg L, Stridsberg M, et al. Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center. Ann Oncol 1997;8:685– 690. 5. Bishopric GA Jr, Ordonez NG. Carcininoembryonic antigen in primary carcinoid tumors of the lung. Cancer 1986;58:1316 –1320. 6. Le Treut YP, Delpero JR, Dousset B, et al. Results of liver transplantation in the treatment of metastatic neuroendocrine tumors. Ann Surg 1997;225:355–364.
CURRENT SURGERY
•
Volume 56 / Number 9 • November/December 1999
Carcinoid Tumors: An Update Guest Reviewers: R. B. Kolachalam, MD, and S. C. Young, MD, MSA, FACS CARCINOID TUMORS.
Kulke MA, Mayer RJ. N Engl J Med 1999;340:856 – 868. Comprehensive review of carcinoid tumors.
Objective
Carcinoid tumors are thought to rise from neuroendocrine cells. They show positive reaction to silver stains and to markers of neuroendocrine tissue including neuron-specific enolase, synaptophysin, and chromogranin.
Biology
Traditionally classified as fore-gut (lungs, bronchi, or stomach), mid-gut (small intestine, appendix, and proximal large bowel), and hind-gut carcinoid tumors (distal colon and rectum).
Classification
Revised system classifies carcinoid tumors as well-differentiated neuroendocrine tumors (typical tumors) and “atypical” or “anaplastic” carcinoids when they show biologically aggressive features such as nuclear atypia, mitotic activity, or areas of necrosis. Estimated to be 1 to 2 cases per 100,000 people in the United States.1,2
Incidence
The appendix was the most common site of the carcinoid tumors, followed by the rectum; ileum; and lungs, bronchi, and stomach.1 They can be separated into three groups: those associated with atrophic gastritis (75%), those associated with Zollinger–Ellison syndrome (5% to 10%), and sporadic tumors (15% to 25%).
Gastric Carcinoid Tumors
In contrast to carcinoids associated with atrophic gastritis, sporadic carcinoid tumors tend to be more aggressive and often metastatic. Because of the aggressive nature of these lesions, most sporadic carcinoids are treated with radical gastrectomy. Small (⬍1 cm) carcinoids associated with atrophic gastritis and Zollinger–Ellison syndrome can be treated endoscopically. They are most frequently located in the distal ileum and are often multicentric. They are thought to arise from serotonin-producing epithelial endocrine cells like the carcinoid tumors of the colon. They generally present in the sixth or seventh decade of life. The majority of patients with small-bowel carcinoids present late with vague symptoms and tumors that are metastatic to the lymph nodes or the liver, and 5% to 7% present with the carcinoid tumors. These tumors can be associated with extensive mesenteric fibrosis or mesenteric angiopathy. Small-bowel resection, together with resection of associated mesentery, is the treatment of choice even in patients with known metastatic disease.
Carcinoid Tumors of the Small Intestine
The 5-year survival rate is 65% among patients with localized or regional disease and 36% among those with distant metastases. The most common site of carcinoid tumors is the appendix, and tumors are the most common cancers of the appendix. In contrast to carcinoids of the small intestine and the colon, appendiceal carcinoids arise from subepithelial endocrine cells. Appendiceal carcinoids are more common in women and most often diagnosed in the fourth or fifth decade of life.2 Most are asymptomatic, and 75% are located in the distal third of the appendix. Less than 10% of the carcinoids are symptomatic and less than 10% are located at the base. CURRENT SURGERY
•
Volume 56 / Number 9 • November/December 1999
Appendiceal Carcinoid Tumors
499
The size of the tumor is the best predictor of prognosis in patients with appendiceal carcinoid tumors. Over 95% are less than 2 cm in diameter, and metastasis in this group of patients is rare. In contrast, approximately one third of the patients with tumors greater than 2 cm in diameter have either nodal or distant metastasis.3 Patients with tumors less than 2 cm in diameter are usually treated by simple appendectomy if there is no gross evidence of local spread. Most tumors greater than 2 cm in diameter are treated with right colectomy.3 Carcinoid Tumors of the Colon
Two thirds of these tumors are found in the right side of the colon, most of them in the cecum. Most patients present late, and over two thirds of patients have either nodal or distant disease at the time of presentation. The 5-year survival rates are 70% for patients with local disease, 44% for those with regional metastasis, and 20% for those with distant metastasis.2
Rectal Carcinoid Tumors
Rectal carcinoids, in contrast to carcinoids of the small intestine and colon, contain gulcagon and glicentin-related peptides rather than serotonin. Tumors less than 1 cm in diameter account for two thirds of rectal carcinoids and are treated with local excision. Less than 5% of these patients have metastasis. The 5-year survival rates are 81% for patients with local disease, 47% for patients with regional disease, and 18% for patients with distant metastasis.2 Tumors greater than 2 cm in diameter have traditionally been treated by low anterior resection or abdominoperineal resection. Muscular invasion, symptoms at diagnosis, and ulceration are poor prognostic factors, and smaller carcinoids with these features may warrant more extensive surgical procedures.
Metastatic Carcinoid Tumors
Patients with suspected metastasis should be evaluated with an abdominal computed tomography scan to rule out liver metastases. Measurement of urinary 5-hydroxyindoleacetic acid may be useful in confirming the diagnosis and in subsequent monitoring of patients with metastatic carcinoid tumors. Elevated plasma chromogranin and positive antibody staining of tumor cells for carcinoembryonic antigen are poor prognostic factors.4,5
Treatment With Somatostatin Analogues
Somatostatin analogues have a central role in both the diagnosis and the treatment of metastatic carcinoid tumors. Somatostatic receptors are expressed on more than 80% of carcinoid tumors. Five subtypes of somastostatin receptors have been identified. Scintigraphy with radiolabeled octretide has been used to localize primary or metastatic lesions with a sensitivity of 89%. Somatostatin analogues are highly effective in relieving the symptoms of the carcinoid tumors, primarily by binding to receptor subtype 2.
Carcinoid Heart Disease
Carcinoid heart disease occurs in two thirds of patients with the carcinoid syndrome. Classically, the right side of the heart is involved and tricuspid regurgitation is the most common manifestation. The preponderance of right-side involvement suggests that factors secreted into the hepatic vein by liver metastasis are responsible for carcinoid heart disease.
Management of Hepatic Metastasis
Surgical resection of liver metastasis may be of benefit in patients with limited hepatic disease. Hepatic artery occlusion or embolization is an alternative for patients who are not candidates for hepatic resection. The response rates seem to be better and the duration of response longer when hepatic artery occlusion is followed by systemic chemotherapy. In highly selected patients, liver transplantation had a 5-year survival rate of 69%.
Metastatic Disease
Interferon-␣ alone or in combination with somatostatin analogues has been effective in controlling the symptoms of patients with carcinoid syndrome. However, interferon use is associated with a high incidence of adverse side effects such as fever, anorexia, and weight loss. Systemic chemotherapy has had only limited success in the treatment of metastatic carcinoid tumors. Recently, the therapeutic use of radiolabeled somatostatin analogues has been reported to result in tumor shrinkage and clinical improvement in a small number of patients with metastatic carcinoid tumors. REVIEWER COMMENTS. This is a timely review of our current understanding of carcinoid tumors. The traditional classification of carcinoid tumors into fore-gut, mid-gut, and hind-gut tumors does not take the site of origin and variations in the histologic characteristics into account. The revised system of classifying carcinoid tumors into the so-called typical tumors and the atypical or anaplastic carcinoids better explains the differences in biologic behavior. This article is a state-of-the-art review of carcinoid tumors and the multimodality treatment available. PROGNOSIS AND SURVIVAL IN PATIENTS WITH GASTROINTESTINAL TRACT CARCINOID TUMORS.
Shebani KO, Souba WW, Finkelstein DM, et al. Ann Surg 229:815– 823.
500
CURRENT SURGERY
•
Volume 56 / Number 9 • November/December 1999
To determine the impact of clinical presentation variables on management and prognosis of the carcinoid tumors.
Objective
Retrospective analysis.
Design
Massachusetts General Hospital, Boston.
Setting
This is a 20-year (1975 to 1995) retrospective analysis of 150 patients with gastrointestinal tract carcinoid tumors in a single institution. Survival estimates for each prognostic factor—namely, age, gender, tumor size, tumor depth of penetration, and liver and lymph node metastasis—were calculated, with death from carcinoid as the outcome.
Participants
Ileojejunal and appendiceal carcinoids account for two thirds of all patients. Mean age at presentation was 55 years, with a slight female predominance. Signs and symptoms of carcinoid tumors were vague and nonspecific and include abdominal pain, nausea and vomiting, and weight and blood loss. Not surprisingly, 40% of patients had their carcinoid tumors discovered incidentally. The appendix was the most common site for incidental carcinoids. There were significantly fewer metastases in this group of patients (21% with incidental carcinoids vs 53% in patients with nonincidental carcinoids). Interestingly, only half of the patients with liver metastasis had the classic symptomatology of carcinoid syndrome. The ileum was the most common site of the primary tumor (9 of 13 patients presenting with carcinoid tumor). None of the stomach- or rectal-site tumors developed carcinoid syndrome, regardless of the metastatic status of the liver. All patients with carcinoid syndrome had elevated levels of 5-hydroxyindoleacetic acid (5-HIAA), but not all patients with elevated 5-HIAA levels had or developed the syndrome. Ten percent of patients had multicentric carcinoid tumors, 22% had synchronous noncarcinoid tumors, and metachronous tumors developed in 10% of patients.
Results
When the primary tumor was greater than 2 cm in diameter, 28% of patients had liver metastasis and 72% had lymph node metastases. In contrast, when the primary tumor was less than 1 cm, no liver metastases were observed and only 10% had lymph node metastases. Ileojejunal carcinoids have the worst prognosis of any subsite. Tumor depth had a linear correlation with metastatic disease. Tumors perforating the visceral peritoneum (T4 lesions) had a 25% rate of liver metastasis (compared with a 9% rate for T1 lesions). Female patients and patients younger than 50 years had significantly fewer metastases. Overall median survival of patients with metastatic disease was still 8 years. Lymph node and liver metastases were less common in incidental carcinoid tumors. Also, surprisingly, multicentricity did not carry adverse prognosis. The fact that a patient with carcinoid tumor has a synchronous (22%) or metachronous (9%) noncarcinoid tumor warrants a thorough exploration and evaluation. Depth of bowel wall penetration, site of tumor, age, gender, and metastatic status predicted survival more accurately than size of the tumor. Tumors arising in the small bowel behave more aggressively. Liver metastases are generally multicentric and not amenable to a curative resection.
Conclusions
REVIEWER COMMENTS. This is a large study from one institution and therefore provides better data on patient demographics, incidence, survival, and clinical correlation of several variables. For instance, in this study patient age was a prognostic factor in a multivariate study. Size was not the best predictor of overall survival in this study: depth of penetration, site of tumor, age, gender, and metastatic status were significantly more accurate. These parameters can better help in the management of lesions of intermediate metastatic risk. For instance, a 25-year-old male with a 1.5-cm T2 tumor (invasion of muscularis propia) of the appendix may be better managed by a complete hemicolectomy. THE MANAGEMENT OF CARCINOID TUMORS.
Halford S, Waxman J. QJM 1998;91:795–798. Minireview.
Objective
The two pharmacologic agents in current use include somatostatin analogues and interferon-␣. Octreotide, a somatostatin analogue, inhibits hormone release and exerts its antitumor effect through somatostatin receptor 2. There is symptomatic improvement in 70% of patients, and 50% to 70% of patients have a greater than 50% reduction in urinary 5-hydroxyindoleacetic acid levels. Eighty percent of carcinoid tumors have somatostatin receptors, and their presence corresponds with the likelihood of response to octreotide. In contrast to octreotide, which must be given 3 times daily by subcutaneous injection, newer slow-release somatostatin analogues such as lanreotide are given once every 2 weeks. Carcinoid tumors are characterized by prolonged periods of stable
Pharmacologic Agents
CURRENT SURGERY
•
Volume 56 / Number 9 • November/December 1999
501
disease, making objective assessment of response rates difficult to interpret, although symptoms are well controlled, with minor side effects. Interferon-␣ causes significant side effects in terms of flulike symptoms and chronic fatigue. These side effects probably outweigh its benefits in controlling the symptoms of carcinoid syndrome. Interferon-␣ was better tolerated when given in combination with octreotide. Radionucleide Therapy
Iodine-131–labeled metaiodobenzylguanidine therapy has been shown to have good short-term response.
Chemotherapy
Response rates to chemotherapy are in the range of 10% to 30%, as defined by a reduction in tumor size by greater than 50%. The best response rates (33%) have been seen with combinations of streptozocin and fluorouracil.
Hepatic Artery Embolization and Ligation
Hepatic artery embolization has been shown to palliate symptoms of carcinoid syndrome for a median of 6 to 12 months. When hepatic artery occlusion is followed by chemotherapy, the response rates are much better.
Conclusions
Endocrine treatment leads to an improvement in up to70% of patients for a median duration of 1 year. Treatment is palliative and does not improve survival. REVIEWER COMMENTS. This is a review of the available treatment modalities for carcinoid tumors. Carcinoid tumors, even when there is metastatic spread, are generally thought to have a good prognosis, although a 5-year survival rate of 18% to 38% belies this perception. Overall chemotherapy leads to an objective response in 30% of patients.
SUMMARY Carcinoid tumors are neuroendocrine tumors. The cells of this tumor are characterized by positive reactions to silver stains and markers of neuroendocrine tissue, including neuron-specific enolase, synaptophysin, and chromogen. Carcinoid tumors secrete a wide variety of products including serotonin, coricotropin, histamine, dopamine, substance P, neurotensin, prostaglandins, and kallikrein. Whereas the carcinoid tumors have been traditionally classified as foregut, mid-gut, and hind-gut tumors, a revised system classifies these tumors as typical neuroendocrine tumors, and atypical carcinoids or neuroendocrine carcinomas. Gastrointesinal tract carcinoid tumors have a nonspecific clinical presentation, except in the case of the carcinoid syndrome. Patients with carcinoid syndrome have the classic manifestations, which include episodic flushing, wheezing, diarrhea, and eventual right-side valvular disease. The release of serotonin and other vasoactive substances into the circulation is thought to be responsible for the syndrome. The ileum and the appendix are the most common sites for carcinoid tumors. More than a third of patients have their carcinoid tumors discovered incidentally. The biologic behavior of these incidental carcinoids seems to be less aggressive. Half of the patients with incidental carcinoids have the primary tumor in the appendix. The biologic behavior of carcinoid tumors seems to be influenced by several variables, such as tumor site, tumor size, depth of penetration, gender, and age. Traditionally, tumors greater than 2 cm in diameter have warranted more aggressive surgical resections. It appears from more recent literature that such decision making should involve other factors listed above. For instance, a 1.5-cm appendiceal carcinoid involving the muscularis in a young male may be better treated by hemicolectomy. Clearly, surgical resection is the treatment of choice for improving survival. Even patients who present late with the
502
carcinoid syndrome secondary to metastasis are better served by resection of the intact primary site. Liver metastases are generally multicentric and not amenable to curative surgical resection. They are amenable to multimodality treatment, including hepatic artery chemoembolization, chemotherapy, and hormonal therapy. The French study6 reported a 5-year survival rate of 69% among selected patients who underwent liver transplantation for metastatic carcinoid tumors. Perhaps the greatest advance in the management of neuroendocrine tumors has been the development of scintigraphic imaging and receptor-targeted therapy. Carcinoid tumors express several receptors. Somatostatin analogues have a central role in both the diagnosis and the treatment of metastatic carcinoid tumors. R. B. KOLACHALAM, MD S. C. YOUNG, MD, MSA, FACS Department of Surgery Providence Hospital and Medical Centers Southfield, Michigan REFERENCES 1. Godwin J. Carcinoid tumors: an analysis of 2837 cases. Cancer 1975;36:560 –569. 2. Modlin M, Sandor A. An analysis of 8305 cases of carcinoid tumors. Cancer 1997;79:813– 829. 3. Moertal CG, Weiland LH, Nagorney DM, Dockerty MB. Carcinoid tumor of the appendix: treatment and prognosis. N Engl J Med 1987;317:1699 –1701. 4. Janson ET, Holmberg L, Stridsberg M, et al. Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center. Ann Oncol 1997;8:685– 690. 5. Bishopric GA Jr, Ordonez NG. Carcininoembryonic antigen in primary carcinoid tumors of the lung. Cancer 1986;58:1316 –1320. 6. Le Treut YP, Delpero JR, Dousset B, et al. Results of liver transplantation in the treatment of metastatic neuroendocrine tumors. Ann Surg 1997;225:355–364.
CURRENT SURGERY
•
Volume 56 / Number 9 • November/December 1999