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Carcinoid syndrome

Carcinoid syndrome refers to the array of symptoms that occur secondary to carcinoid tumors. Carcinoid tumors are discrete, yellow, well-circumscribed tumors that can occur anywhere along the gastrointestinal tract (GI). They most commonly affect the appendix, ileum, and rectum. These tumors are unique in that they are endocrine in nature. They secrete hormones into the blood stream, which then travel to end organs and act upon them via appropriate receptors. Although quite rare, 15 cases/1,000,000 population, carcinoid tumors account for 75% of GI endocrine tumors. more...

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Carcinoid tumors secrete vasoactive substances such as serotonin, histamine, catecholamines, and prostaglandins. These hormones acts upon many tissues of the body including the central nervous system, blood vessels of the intestinal tract, and platelets, ultimately altering blood flow. Prior to metastasis, the liver is capable of metabolizing most of the hormones elaborated by such tumors, rendering patients asymptomatic. Only about 5% of patients with carcinoid tumors ever develop symptoms of the carcinoid syndrome which includes, flushing, diarrhea, hypotension, edema, asthma-like bronchoconstriction attacks, and valvular heart disease. The onset of these symptoms suggests that the tumor has metastasized to the liver, allowing serotonin and its various by-products to reach systemic circulation.


With a certain degree of clinical suspicion, diagnosis is made by measuring the 24 hour urine levels of 5-HIAA (5-hydroxyindoleacetic acid), a breakdown product of serotonin. Patients with carcinoid syndrome usually excrete >25 mg of 5-HIAA per day.


For symptomatic relief of carcinoid sydrome:

  • Octreotide (somatostatin analogue- neutralizes serotonin and decreases urinary 5-HIAA)
  • Methysergide maleate (antiserotonin agent but not used because of serious side effect of retroperitoneal fibrosis)
  • Cyproheptadine (antihistamine)

Alternative treatment for qualifying candidates:

  • Surgical resection of tumor and chemotherapy (5-FU and doxorubicin)


Prognosis varies from individual to individual. It ranges from a 95% 5 year survival for localized disease to a 20% 5 year survival for those with liver metastases. However, median survival for patients with carcinoid sydrome is 2.5 years from the first episode of flushing.


Thorson-Bioerck syndrome, argentaffinoma syndrome, Cassidy-Scholte sydrome, flush syndrome


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Metastatic carcinoid to the conducting system--is it rare or merely unrecognized manifestation of carcinoid cardiopathy?: A case report and review of the
From Archives of Pathology & Laboratory Medicine, 12/1/02 by Shehata, Bahig M

* We report a unique case of carcinoid cardiopathy. The patient, a 59-year-old white woman with a known carcinoid tumor of the terminal ileum, presented with complete heart block and subsequently died. Because of her clinical presentation, we examined the conducting system at autopsy. The atrioventricular node was heavily infiltrated by metastatic carcinoid. The tumor was also seen in the surrounding atrial myocardium. No other metastatic lesions were seen in the heart. Carcinoid cardiopathy in the form of right-sided endocardial and valvular thickening has been well documented in the literature, and we found these features in our case as well. To our knowledge, carcinoid has never been documented in the cardiac conducting system until now. We found 2 cases of possible involvement of the conducting system reported in the literature. Unfortunately, the conducting system was not examined postmortem in either of these cases. If conducting system involvement is not unique to the present case, patients with metastatic carcinoid and cardiac problems may require different management. We hope that this case will stimulate further postmortem study of the conducting system in patients with metastatic carcinoid tumor.

(Arch Pathol Lab Med. 2002;126:1538-1540)

Carcinoid cardiopathy is well documented in the literature in the form of right-sided endocardial fibrosis. Associated arrhythmias have also been reported; however, the etiology of these arrhythmias has not been explored. We report here a previously undescribed manifestation of carcinoid involvement of the heart. The patient was a 59-- year-old white woman with a primary carcinoid tumor arising from the terminal ileum with multiple organ system metastases. Her illness was complicated by the development of complete heart block, from which she eventually died. As part of our autopsy, we examined the conducting system and found heavy infiltration of the atrioventricular (AV) node by carcinoid tumor. We report the findings in this case, hoping that future studies might clarify whether our findings are unique or an unrecognized manifestation of carcinoid cardiopathy.


A 59-year-old woman with no significant past medical history sought medical attention because of frequent headaches, hot flashes, diarrhea, weight loss, shortness of breath, and palpitations. Laboratory studies revealed a 24-hour urine 5-hydroxyindoleacetic acid (5-HIAA) level of 102 mg (533 (mu)mol/d) (reference range, 2-10 mg/24 h [10-52 (mu)mol/d ]) and a blood serotonin level of 1263 ng/mL (7.17 [(mu)mol/L) (reference, up to 200 ng/mL [1.14 (mu)mol/L]). A small bowel series, a computed tomography scan, and an abdominal echogram revealed a mass in the terminal ileum along with multiple nodules in the liver. These findings were thought to be consistent with carcinoid tumor with metastases to the liver. The patient received chemotherapy and antiserotonin medication with temporary improvement followed by a downhill course over 10 months. Her terminal events included intermittent syncope, after which she became completely unresponsive. Cardiopulmonary resuscitation was performed, with restoration of a pulse at 50 bpm but no blood pressure. An electrocardiogram showed complete heart block above the bundle of His with a narrow QRS complex. The family declined any life-- sustaining measures, including pacemaker insertion. She died the next day.


Examination of the Conducting System

In addition to performing routine sampling of the myocardium, we examined the conducting system using the method of Anderson et al.1 We obtained 2 sections from the sinoatrial node and 5 sections from the internodal tract in descending order from the superior to the inferior end. Additionally, we examined 3 sections of the AV node.


Gross Pathologic Findings

An autopsy disclosed the presence of a carcinoid tumor 10 cm proximal to the ileocecal valve. The tumor was 2.3 cm in maximum dimension and had central necrosis. Metastases to the liver were multifocal and occupied approximately 20% of the liver parenchyma. Metastatic foci were also seen in the mesenteric lymph nodes, pancreas, stomach, visceral pleura, and bone marrow. Examination of the heart revealed right-sided endocardial thickening. No gross tumor nodules were found.

Microscopic Examination

Sections from the original ileal mass showed marked tumor necrosis. At the periphery of the mass, a few viable nests of carcinoid cells were seen; these cells had mild pleomorphism. The nuclei had speckled chromatin with occasional small nucleoli; the cytoplasm was eosinophilic. Sections from the atrial myocardium contained nests of carcinoid tumor (Figure 1). Additionally, a nerve ganglion was seen next to the tumor nests (Figure 2). Sections of the AV node showed extensive infiltration of the conducting system fibers by nests of tumor (Figures 3 and 4). A section obtained from the primary ileal tumor stained strongly positive for synaptophysin (Figure 5). Small foci of old and recent left ventricular myocardial ischemia were found. The endocardium showed prominent endocardial fibroelastosis, particularly in sections obtained from the right side of the heart.


Carcinoid tumor was first described in an appendix by Merling in 1838.2 Subsequently, Siegfried Oberndorfer3 gave the classical description of carcinoid. Bjork et al4 reported cardiac carcinoid involvement in the form of endocardial fibrosis leading to tricuspid insufficiency. Carcinoid tumors arise from enterochromaffin cells (Kulchitsky cells), which are found throughout the gastrointestinal tract, bronchi, bile duct, and pancreatic ducts. Carcinoid tumors are classified according to their embryologic site of origin as foregut, midgut, or hindgut. The incidence of carcinoid tumor is highest in the appendix and small intestine.5

The malignant potential of carcinoid tumors is nearly impossible to determine histologically.5 Size, invasiveness, and location of the tumor are most important in predicting behavior. Tumors measuring greater than 2.0 cm in maximum dimension have a high probability of metastasizing. Tumors located in the appendix have the least malignant potential, and those in the colon have the greatest.5

Normally, the liver is responsible for deactivating the serotonin, histamine, bradykinin, and other vasoactive amines that may be released from primary carcinoid tumors.6 Carcinoid syndrome is clinically evident once liver metastases are present, or when the tumor venous blood flow bypasses the liver and allows the vasoactive amines to enter the systemic circulation.

The symptoms and manifestations of carcinoid syndrome can include palpitations, cutaneous flushing, diarrhea, tricuspid valve insufficiency, pulmonic valve stenosis, bronchospasm, and right-sided heart failure.7 Diagnosis can be made by demonstrating elevated levels of 5-- HIAA in a 24-hour urine specimen.7

Classic carcinoid heart disease is well documented. In most cases, cardiac carcinoid manifestations are limited to the right side of the heart. The usual pattern of involvement is focal or diffuse plaques of thickened valvular or mural endocardium. These plaques can extend to the great veins, coronary sinus, pulmonary trunk, and main pulmonary arteries. The tricuspid and pulmonic valves are most commonly affected by plaque formation. The left heart, including mitral and aortic valves, is much less frequently affected by carcinoid-induced plaques. The pathogenesis of the endocardial fibrosis is uncertain; however, data indicate that it is a reaction to serotonin or kinin peptide exposure.8 Histologically, the plaques are composed of fibroblasts, myofibroblasts, and smooth muscle cells embedded in a collagenous matrix. The plaque is then covered by a layer of endothelium. No elastic tissue is present within the plaque, making it a different entity than endocardial fibroelastosis.

Metastatic tumors to the heart are 40 times more common than primary cardiac neoplasms.9 The cardiac tissue most frequently affected by metastases is the myocardium, followed by the pericardium and then by the endocardium.9 Metastatic tumors extending into the heart chambers themselves are much less common. Conducting system involvement is even less common. In fact, in our search, only one example of irrefutable conducting system involvement was described by Schnitker and Bailey9 in a patient who had small cell carcinoma of the lung extending to the sinoatrial node. The features of many other cases have suggested tumor metastasis to the conducting system,10 based on the development of an arrhythmia in patients with cancer; however, in these cases, either autopsies were not performed, or the conducting system was not examined. The most common route of metastasis to the heart is through lymphatic spread, followed by hematogenous dissemination. Direct extension is more common with intrathoracic tumors.

In conclusion, the metastatic carcinoid lesions in our case were located specifically in the AV node and the surrounding atrial myocardium, without evidence of metastatic involvement elsewhere in the heart. In presenting this case, we hope to encourage close cardiac monitoring of patients with metastatic carcinoid tumor. Additionally, careful postmortem examination of the conducting system in such patients could help determine if conducting system carcinoid is a prevalent finding. Conducting system carcinoid may be an unusual presentation unique to this case, or a fairly common but unrecognized finding. If further studies confirm a frequent involvement of the conduction system by carcinoid tumor, this could lead to a fuller understanding of carcinoid cardiopathy and possibly alter the clinical management of these patients.

The authors thank Sheree St John for her wonderful support and work, Helena Howe for technical assistance, and Alan Weintraub for medical photography.


1. Anderson RH, Wilcox BR, Becker AE. Anatomy of the normal heart. In: Hurst JW, Anderson RH, Becker AE, Wilcox BR, eds. Atlas of the Heart. New York, NY: McGraw-Hill Book Co, Gower Medical Publishing; 1988:1.14.

2. Merling F. Anatomie pathologique de l'appendice du caecum. Experience, Par. 1838;i:337-343.

3. Oberndorfer S. Karzinoide des Dunnadarms. Frankfurt Zischr Pathol. 1907; 1:426-432.

4. Biorck G, Azen O, Thorson A. Unusual cyanosis in a boy with congenital pulmonary stenosis and tricuspid insufficiency: fatal outcome after angiocardiography. Am Heart J. 1952;44:143-148.

5. Marshall JB, Bondarchuk G. Carcinoid tumors of the gut: our experience over three decades and review of the literature. J Clin Gastroenterol. 1993;16: 123-129.

6. Silverberg SG, DeLellis RA, Frable WJ. Principles and Practice of Surgical Pathology and Cytopathology. Vol 2. 3rd ed. New York, NY: Churchill Livingstone; 1997:1808-1809.

7. Klein I, Ojamaa K. Clinical review 36: cardiovascular manifestations of endocrine disease. J Clin Endocrinol Metab. 1992;75:339-342.

8. Schiller VL, Fishbein MC, Siegel RJ. Unusual cardiac involvement in carcinoid syndrome. Am Heart J. 1986;112:1322-1323.

9. Schnitker MA, Bailey OT. Metastatic tumor of the heart: a case diagnosed during life. JAMA 1937;108(21):1787-1790.

10. Shelburne SA, Aronson HS. Tumors of the heart, II: report of a secondary tumor of the heart involving the pericardium and the bundle of HIS with remission following deep roentgen-ray therapy. Ann Intern Med. 1940;14:728-736.

Bahig M. Shehata, MD; Jean E. Thomas, MD; Irina Doudenko-Rufforny, MD, PhD

Accepted for publication January 2, 2002.

From the Department of Pathology, Egleston Children's Hospital, Emory University, Atlanta, Ga (Dr Shehata) and the Medical College of Ohio, Toledo, Ohio (Drs Thomas and Doudenko-Rufforny).

Reprints: Bahig M. Shehata, MD, Department of Pathology, Egleston Children's Hospital, Emory University, Atlanta, GA 30322 (e-mail:

Copyright College of American Pathologists Dec 2002
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