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Carcinoid Tumors
Carcinoid Tumors FRANCES H. SMITH, M.D. ROSEMARY MURPHY, M.D.
UNTIL the last decade when the syndrome of malignant carcinoidosis began to be intensively investigated and reported with increasing frequency, carcinoid tumors of whatever variety were seldom considered in a differential diagnosis. Now, however, the signs and symptoms of this still uncommon but no longer rare disease can be readily recognized. Although reports of appendiceal and small intestinal tumors, which in retrospect seem to have been carcinoids, have appeared in the literature since the mid-nineteenth century, Lubarsch, in 1888, is generally acknowledged to have been the first to describe two primary tumors of the ileum in such a way as to leave no doubt as to their identity. He stated that these tumors were malignant-an opinion with which Oberndorfer, who was the first to call such tumors "carcinoids," disagreed, unfortunately, since it is now recognized that carcinoids, although slowly growing tumors, are capable of manifesting malignant features at any time. Because this disease has such extensive ramifications, it is of special interest to the gastroenterologist, internist, cardiologist, dermatologist, allergist and surgeon.
PATHOLOGY Carcinoid tumors capable of releasing serotonin (5-hydroxytryptamine [5-HTA]) and possibly other biologically active substances are formed by proliferation of Kulchitsky's cells, which are small cuboidal cells with deeply staining nuclei. Fine granules which lie basal to the nucleus in the cytoplasm are eosinophilic, are capable of reducing ammoniacal silver salts and give a vivid yellow color with bichromate solution. These properties have given rise to the terms "argentaffinoma" and "chromaffinoma," but there seems little likelihood that these names will displace that of "carcinoid," which not only has the virtue of brevity but also is actually more accurate, since tumors that contain high concentrations of 5-HTA but which are nonargentaffine have been reported. Kulchitsky's cells are most numerous in the duodenum,4 but proliferation
465
466
FRANCES
H.
SMITH, ROSEMARY MURPHY
takes place most frequently in the appendix and in the jejuno-ileum. Grossly, the tumors are small, discrete, hard masses varying in size from 0.5 to 2.0 cm. or larger. They lie in the submucosa and extend toward the surface away from the lumen, invade the muscularis and occasionally break through the serosa. Microscopically, there are nests and strands of cells with occasional acinar formation which may contain albumin or mucin. Invasion of lymphatics or blood vessels may be found in cases without demonstrable metastases as well as in those with them. Masson 3 describes three types of cells in carcinoid tumor. Round or polygonal cells with a central, finely reticular nucleus and cytoplasm are the most common. The second type, the "palisade cells," surrounds the cell clumps, and the third type lines the small acini. The difference in these cells lies primarily in the distribution of the granules. Mitoses are rare. Metastases occur by direct extension through lymphatic channels and perineural spaces to regional lymph nodes and the mesentery, as well as by blood vessel invasion. Carcinoids of the terminal ileum, especially when the lesions are multiple, may spread to adjacent lymph nodes to form conglomerate masses which kink and mat together loops of intestine so that a right lower quadrant mass is palpable. The onset of obstruction, when it occurs, is usually insidious; the lumen is occluded by external pressure and only rarely by a lesion which breaks through the mucosa with ulceration, edema and internal occlusion. In some instances, obstruction occurs because of intussusception or volvulus. Metastases occur most frequently in the regional nodes and the liver, but they have been reported in almost every organ in the body, notably the right side of the heart, lungs, ovaries, genitourinary system, skin and bone marrow. The tumor may occur as a solitary nodule or as multiple nodules of varying sizes, particularly in the ileum, where as many as 68 have been reported in one surgical specimen. While the tumors themselves are usually of small size, the metastatic lesions to which they give rise may be many times as large. Carcinoid tumors also have, in rare instances, a large connective tissue element which produces annular constricting lesions. A fourth type of lesion is that of the rectal polyp. In addition to this classification, the tumors may also be described as nodular, polypoid, sessile or plaquelike. Although routine slides showing the characteristics described above are usually sufficient to make the diagnosis, additional help in identification may be obtained if one part of the specimen is fixed in formalin within four to six hours after removal, and the other part frozen. Pearse 7 has pointed out that it is the argentaffine reaction, in which the silver salts are reduced by the tissue itself and not by an added reducing agent, that is suggestive of carcinoid tumor. The granules which do this are produced by formalin fixation. Alcohol in the fixative prevents the reaction. Since autolysis also destroys the ability of the tissue to reduce silver
Carcinoid Tumors
467
salts, positive biopsies are more frequent in surgical than in autopsy material. On the other hand, if serotonin assays are to be carried out, the use of formalin must be scrupulously avoided because tissue serotonin is stable only in the frozen state. It is possible that failure to extract serotonin from some carcinoid tumors has been due to improper fixation. 9 SYMPTOMS
The symptoms of carcinoid tumors are due to mechanical factors or to the action of serotonin; in some instances to both. In carcinoids of the appendix, which are by far the most common, the symptoms and signs are usually those of appendicitis, or vague lower abdominal pain; when appendectomy incidental to other surgery has been performed there may have been no symptoms at all. In patients with tumors limited to the small bowel and adjacent nodes, the symptoms and signs are usually those of varying degrees of obstruction: abdominal pain, distention, visible peristalsis, nausea and vomiting. These and other symptoms may arise from concomitant disease, however, and a carcinoid be discovered fortuitously in the pathologic specimen. Thorsonll points out that patients with cirrhosis or nontropical sprue react with intestinal hyperperistalsis to ingested 5-HTA. Therefore, it may be inferred that liver disease interferes with the inactivation of 5-HTA carried in the portal blood. Because the effects are similar to those seen in patients with metastases outside the portal system, alcoholism may be an important factor in the development of clinical manifestations in carcinoid disease. The malignant carcinoid syndrome is a symptom complex associated with carcinoid tumors with metastases. Its most common component is episodic flushing. Isler and Hedinger, who in 1953 were the first to recognize this syndrome, reported three cases in which telangiectasia of the skin and sclerosis of the tricuspid and pulmonary valves were also present. Since their report other symptoms have been accepted as manifestations of the syndrome: hyperperistalsis with frequent watery stools, episodes of asthma-like bronchoconstriction, edema and ascites. Thorsonl l believes that these manifestations are due to metastases to extraportal sites, large metastatic masses and a slow rate of growth. He points out that in tumors limited to the intestine which is drained by the portal system, flushing rarely occurs, but that when metastases occur in areas drained by the caval system, it is almost always present. Flushing is the most characteristic symptom of the syndrome. It is usually of short duration (five to ten minutes), involves first the face, neck and chest and spreads to the rest of the body. The color is usually dark red, with patches of blue, white and normal color. As the disease progresses flushes may become continuollfl. Sometimes massage over the
468
FRANCES
H.
SMITH, ROSEMARY
M URPHY
liver or other body area above the carcinoid tumor will intensify the flush. This external manifestation reflects the widespread changes that occur throughout the vascular bed-changes in peripheral blood pressure, increased pressure in the pulmonary vessels and changes in heart size which occur during flushing. Intestinal disturbances rank second in frequency; diarrhea, borborygmi, abdominal distention and crampy abdominal pain may precede or follow a flush. It is believed that mechanical obstruction alone does not account for these symptoms but that they are due to the autopharmaco logic action of metabolites produced by the tumor. Because profuse diuresis may follow flushing, a specific antidiuretie action has been postulated for 5-HTA, which could also account for the edema and serous effusion that may be seen in patients with advanced carcinoid disease. The endocardial lesions involving primarily the right side of the heart which occur in a few patients with carcinoidosis are a late manifestation of the disease and directly related to it, although the manner of their production as yet has not been clarified. The systolic murmur appears to be distinctive and is the most important sign. It is reported to be harsh, to have a characteristic length and a rhombic appearance in the phonocardiogram. Asthma-like respiratory distress coinciding with flushing has been widely reported. Because death from bronchoconstriction when traction was applied to the tumor during surgical excision has sometimes occurred, the surgical approach to correction of the cardiac lesions and cardiac catheterization have been considered unwarranted. Skin lesions similar to those seen in pellagra with hyperkeratosis and hyperpigmentation have been reported in some eases of carcinoid disease, but not as constantly as might be expected from the disturbance in niacin formation. The unpredictable pattern of symptoms has been attributed to the slow growth of carcinoid tumors and to the manner of release of serotonin into the blood stream. This release may be intermittent or there may be a constant outflow which may be increased by periodic outbursts. METABOLISM OF SEROTONIN
Serotonin (5-hydroxytryptamine [5-HTA], enteramine) is a neurohumoral substance formed in the brain and in the chromaffin cells of the gastrointestinal tract; it is carried by the blood platelets and destroyed in the liver, kidney, brain, lungs and gastrointestinal mucosa. Its precursor is the amino acid, tryptophan (see Fig. 1), of which normally 1 per cent proceeds to the formation of serotonin and the remaining 99 per cent to the synthesis of niacin and protein (Fig. 1). In the malignant.
469
Carcinoid Tumors
METABOLISM OF SEROTONIN
H
NIACIN PROTEIN
Hydroxylase (Slow reaction)
H O W -CHz-CI H-COOH N H
5-HYDROXYTRYPTAM I NE SEROTONIN 5-HTA
~H2
1 Z
N
5-HYDROXYTRYPTOPHAN 5-HTP
-<<:
-CH -CH-COOH _ _ _ _ _
W
TRYPTOPHAN
1
NH2
Decarboxylase
(Pyridoxine-dependent)
HO~ -CHZ-9-H ~~~R!:!~~P~T!!~A~OTHER INDOLES ~,,)
~
1
NH Z
Monoammeoxidase
(Blocked by IpronooZldl
H O W - C H -CHO 5-HYDROXYINDOLEACETALDEHYDE z 5-HIA N H
1
Dehydrogenase
HO~-CHz-COOH _ _ _ _:. EXCRETED IN URINE 5-HYDROXYINDOLEACETIC ACID 5-HIAA
~I\l) ~
Fig. 1
carcinoid syndrome, on the other hand, as much as 60 per cent may proceed to serotonin with a profound reduction in niacin and protein formation. In each site at which serotonin is found in significant quantities, there are also a decarboxylase which facilitates its production and a monoamine oxidase which controls its destruction_ The end-product of monoamine oxidase activity is 5-hydroxyindoleacetic acid (5-HIAA), which is excreted in the urine. 5-HIAA, however, does not account for the total serotonin breakdown, for which other metabolic pathways have been demonstrated. The widespread distribution of serotonin in the body and its potent pharmacological actions suggest that it may be one of the most important neurohumors. The chief physiological actions consist of stimulation of smooth muscle of the gastrointestinal tract, vasoconstriction or dilatation, vasopressor or depressor effects depending upon the vascular status, bronchoconstriction, renal antidiuresis, stimulation of connective tissue growth, and participation in the function of the central nervous system, especially in the hypothalamus. These pharmacological effects of serotonin play a role in the carcinoid
470
FRANCES
H.
SMITH, ROSEMARY
M URPHY
syndrome and account for the vasodilation with episodes of flushing, the hypermotility of the gastrointestinal tract and the bronchospasm with asthmatic symptoms. The absence of central nervous system effects in the presence of elevated circulating serotonin has been attributed to the inability of the amine to penetrate the bloodbrain barrier. The valvular lesions in the right side of the heart, as well as the development of intraabdominal adhesions, may result from the connective tissue stimulating action of 5-HTA. The fact that the left side of the heart is relatively free of lesions is attributed to the destruction of a significant portion of circulating serotonin by the lung tissue. Edema, when present, may result from right heart failure, from an antidiuretic action of serotonin, from a direct tissue response to serotonin, or from hypoproteinemia which results from a diversion of tryptophan from protein synthesis to the formation of serotonin. This diversion may also give rise to a deficiency of nicotinic acid and the production of pellagra-like skin lesions. Since it is well known that vasomotor and gastrointestinal symptoms are characteristic of pellagra, it is not unlikely that deficiency in nicotinic acid may play an ancillary role in the development of these symptoms in the carcinoid syndrome. The normal serum serotonin level ranges from 0.1 to 0.3 micrograms / ml., whereas values in patients with the malignant carcinoid syndrome vary from 0.5 to 3.0 micrograms/ml. Assays of tumors have shown 1 to 3 mg. of serotonin per gram of tissue. The urinary excretion of 5-HIAA normally varies from 2 to 10 mg. per day.8 In patients with carcinoid syndrome, the urinary excretion of both serotonin and its end-product, 5-HlAA, is greatly increased. The estimation of the latter serves as an important diagnostic tool. Values above 15 mg. per day suggest carcinoid syndrome, while values of 30 mg. or over are probably diagnostic. A qualitative test10 (purple to black color) using I-nitroso-2-naphthol as a reagent is positive for values of 30 mg. or more per day. More exact determinations may be made by paper chromatography or spectrophotDfluorometry. Certain precautions must be followed in testing the urine for 5-HIAA. It is important that the patient should not take any medication for at least 48 hours befme the test is performed. The phenothiazine drugs interfere with the reaction, causing false negative tests. 8 The ingestion of bananas,l which contain large amounts of serotonin, may give a truly false positive test, whereas acetanilid and related drugs may give a false positive test. Current interest in the role of amines in mental disease and in the development of tranquilizing drugs has served to focus attention on serotonin. A number of potent pharmacotherapeutic agents have been found to be true antimetabolites of serotonin, to interfere in some fashion with its activity or to prevent its breakdown. Thus, Medmain and the harmine, yohimbine and ergot alkaloids have been shown to be antimetab-
Carcinoid Tumors
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olites. Of these, lysergic acid diethylamide is the most potent. A synthetic antagonist, I-benzyl-2, 5-dimethyl serotonin (BAS) has had a clinical trial'in the treatment of hypertension and the malignant carcinoid syndrome. Those reserpine alkaloids which have a tranquilizing effect presumably release brain serotonin from the bound to the free state. However, they have so little effect on serotonin in the gastrointestinal tract that urinary 5-HIAA is not significantly changed during reserpine therapy.2 Nevertheless, it has been suggested that if reserpine is given to a patient with carcinoid syndrome, an increase in urinary 5-HIAA may be useful in diagnosis. 6 Chlorpromazine apparently interferes with serotonin action in some manner different from that of the antimetabolites, and it would appear to be the most effective drug to use in an attempt to control the symptoms of the carcinoid syndrome. Iproniazid (Marsilid) and other inhibitors of mono-amine oxidase activity have been shown to increase serotonin levels of the brain by inhibiting the breakdown of serotonin to 5-HIAA. Recently, nicotinamide has been shown to be an antagonist of serotonin, but the mechanism of its action is unknown.1 3 TREATMENT
The treatment in all cases is wide surgical excision. As much of the tumor as possible should be removed, even in patients with extensive metastases. This policy reduces the likelihood of future perforations through tumor tissue and possibly may retard the spread and growth of metastases. The logical assumption that serotonin antagonists would be useful in treating the disease has, with the possible exception of chlorpromazine, been unwarranted. Supportive therapy with special attention to correcting the protein and niacin deficiencies as well as the fluid and electrolyte balance attendant on the diarrhea is of prime importance. X-ray therapy has not been helpful. Antihistamines and chlorpromazine have been helpful to some patients in alleviating flushing. Paregoric, and hydrochloric acid before and during meals, has lessened diarrhea in some cases but not in others. Adrenalin and intravenous aminophylline are useful in chronic recurrent bronchospasm, but all methods may be unavailing in the sudden, acute bronchospasm encountered at surgery. The response of the pellagra-like skin lesions to niacin is less than might be expected. Digitalis is not helpful in most cases of right heart failure and may add to the patient's discomfort by increasing nausea and diarrhea. LAHEY CLINIC CASES
At the Lahey Clinic from 1931 to January 1, 1959, there have been 58 cases of carcinoid tumors; 31 occurred before January 1, 1948, and were
472
FRANCES
Table 1.
H.
SMITH, ROSEMARY MURPHY
Location of Carcinoid Tumors
NONMETASTASIZED
METASTA'lIZED
1931 to Jan. 1, 11)48
1948 to Jan. 1, 1959
1931 to Jan. 1, 11)48
Appendix .. Ileum .. Rectum Stomach. Duodenum .. Ampulla of Vai.er Cecum. Colon .. Rectosigmoid.
16 6
14 1 1
0 6
TOTAL ..
23
LOCATION
1948 to Jan. 1, 1959 0 6* 2
TOTAL
30 19 3
1
1 1
1 1
17
8
10
1 58
* Includes one in which primary tumor was not identified but was probably ileal.
reported by Warren and Coyle. 12 Forty had not metastasized and 18 had. The distribution of these tumors may be seen in Table 1. None of the tumors in the appendix had metastasized, but 12 of 19 tumors in the ileum had. The infrequency of metastases from appendiceal carcinoids has been attributed to the early removal of asymptomatic tumors in incidental appendectomies or to the fact that symptoms may develop in this small organ before spread occurs. In the earlier series, the age of the patients ranged from 20 to 69 years. The age range in the later group extends from 29 to 81 years. The 81 year old patient was operated on for resection of adenocarcinoma of the sigmoid and an incidental carcinoid of the appendix was found. She was living and well at age 88 in 1958. In this later group, three nonmetastasizing lesions other than appendiceal were found in patients aged 29, 53 and 65 years; in the ten patients with metastasized carcinoids the ages ranged from 46 to 74 years. The sex distribution in the cases observed from 1948 to 1959 follow the statistics in most large series. It has been noted that in carcinoids of the appendix the incidence in females is much greater than in males. In this group there were 12 females and two males. Of the three other patients with nonmetastasized carcinoids, two were females and one was male. In the ten patients with carcinoids with metastasis, six were female and four male. In the earlier group of cases (before 1948), there were 21 females and ten males, but further differentiation was not made. In the series studied by Warren and Coyle, 19 patients had carcinoid tumors found at autopsy or removed in a surgical specimen resected for another lesion, of which ten were malignant neoplasms. In the later study, the carcinoids of the appendix were all found incidentally at operation for other conditions. Of these, four were malignant neoplasms involving the cecum, rectum and sigmoid (two cases). Five were found at
Carcinoid Tumors
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hysterectomy, two at cholecystectomy, two at operation for common duct stricture, and one at operation for an obstructed duodenal ulcer. Of the three nonappendiceal, nonmetastasized carcinoids, one involved the duodenum, one the rectum and one the distal ileum and cecum. In this latter group, all had abnormal x-ray findings, but none diagnostic of a particular lesion. In one there was a fistulous tract from the sigmoid to the terminal ileum in the lesion involving the ileum and cecum; in the lesion involving the rectum the splenic flexure appeared to be displaced superiorly; in the duodenal carcinoid a duodenal defect was noted. In the 18 cases in which metastases were found, ten had metastasized to the liver, seven to the regional lymph nodes, five to the mesentery, two to the omentum and two to the pelvis. In one case each there were metastases to each of the following sites: bone, a rare complication; colon; adjacent structures, and the parietal peritoneum. X-ray studies were carried out in 14 of the 18 patients in whom metastases were found. Abnormality related to the disease was found in 12. Six of these showed signs of obstruction; two, dilated loops of ileum; two, a high transverse position of the cecum which proved to be related to extensive fibrosis in the mesentery; one, the stomach was displaced toward the right, and in the case of the carcinoid of the stomach there was mucosal distortion high on the lesser curvature. In one patient an unrelated finding, diverticulitis, was reported, and one patient had a normal gastrointestinal x-ray study. Of the 18 patients with metastases, one (previously reported5) may be considered a proved case of the so-called malignant carcinoid syndrome. Extensive hepatic metastases and intra-abdominal fibrosis were demonstrated at laparotomy and urine examination showed consistently elevated urinary 5-HIAA. Clinically, the patient demonstrated diarrhea, ascites, pleural effusion, peripheral edema, muscular wasting, purplish discoloration of the face with telangiectasia, and deep purplish-brown pigmentation of the lower legs. Two other cases, in retrospect, raise the suspicion of the malignant syndrome. One patient was a 61 year old man with symptoms of an "irritable colon" of 14 years' duration, associated with "severe intractable vasomotor attacks" and episodes of apprehension. At autopsy, a carcinoid of the ileum with extensive hepatic metastases was found. The other patient was a 67 year old woman, operated on because of an acute intestinal obstruction, in whom a rectal carcinoid with local extension and hepatic metastases was discovered. She had a history of severe hot flashes which had persisted long beyond the menopause and which were peculiarly resistant to the usual therapeutic agents. SUMMARY
The general problem of carcinoid tumors has been reviewed with special attention to the action and metabolism of serotonin, a potent neuro-
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FRANCES
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SMITH, ROSEMARY MURPHY
endocrine substance which certain of these tumors secrete in amounts adequate to produce symptoms in many systems. The study includes a brief summary of 58 cases of carcinoid tumors seen at the Lahey Clinic between 1938 and 1959, including one proved case of the malignant carcinoid syndrome and two cases which in retrospect seem to belong to this group. REFERENCES 1. Crout, J. R. and Sjoerdsma, A.: Clinical and laboratory significance of serotonin and catechol amines in bananas. New England J. Med. 261: 23-26 (July 2) 1959. 2. Haverback, B. J., Dutcher, T. F., Shore, P. A., Tomich, E. G., Terry, L. L. and Brodie, B. B.: Serotonin changes in platelets and brain induced by small daily doses of reserpine; lack of effect of depletion of platelet serotonin on hemostatic mechanisms. New England J. Med. 256: 343-345 (Feb. 21) 1957. 3. Masson, P.: Citcd by Ritchie, A. C.: Carcinoid tumors. Am. J. M. Sc. 232: 311328 (Sept.) 1956. 4. Morson, B. C.: Pathology of carcinoid tumors. In: Jones, F. A.: Modern Trends in Gastroenterology. Second Series. London, Butterworth & Company, Ltd., 1958, pp. 107-117. 5. Murphy, R. and Rohart, R. R.: Malignant carcinoid: report of a case. Lahey Clin. Bull. 10: 53-55 (Oct.-Dec.) 1956. 6. Page, I. H.: Serotonin (5-hydroxytryptamine); the last four years. Physiol. Rev. 38: 277-335 (April) 1958. 7. Pearse, A. G. E.: Histochemistry, theoretical and applied. Cited by Ritchie, A. C.: Carcinoid tumors. Am. J. M. Sc. 232: 311-328 (Sept.) 1956. 8. Sjoerdsma, A.: Clinical and laboratory features of malignant carcinoid. A.M.A. Arch. Int. Med. 102: 936-938 (Dec.) 1958. 9. Sjoerdsma, A.: Serotonin. New England J. Med. 261: 181-188 (July 23); 231237 (July 30) 1959. 10. Sjoerd~ma, A., Weissbach, H. and Udenfriend, S.: Simple test for diagnosis of metastatic carcinoid (argentaffinoma). J.A.M.A. 159: 397 (Sept. 24) 1955. 11. Thorson, A. H.: Studies on carcinoid disease. Acta med. scandinav. 161 (Suppl. 334): 1-132, 1958. 12. Warren, K. W. and Coyle, E. B.: Carcinoid tumors of the gastrointestinal tract. Am. J. Surg. 82: 372-377 (Sept.) 1951. 13. Woolley, D. W.: Tranquilizing and antiserotonin activity of nicotinamide. Science 128: 1277-1278 (Nov. 21) 1958.
UNTIL the last decade when the syndrome of malignant carcinoidosis began to be intensively investigated and reported with increasing frequency, carcinoid tumors of whatever variety were seldom considered in a differential diagnosis. Now, however, the signs and symptoms of this still uncommon but no longer rare disease can be readily recognized. Although reports of appendiceal and small intestinal tumors, which in retrospect seem to have been carcinoids, have appeared in the literature since the mid-nineteenth century, Lubarsch, in 1888, is generally acknowledged to have been the first to describe two primary tumors of the ileum in such a way as to leave no doubt as to their identity. He stated that these tumors were malignant-an opinion with which Oberndorfer, who was the first to call such tumors "carcinoids," disagreed, unfortunately, since it is now recognized that carcinoids, although slowly growing tumors, are capable of manifesting malignant features at any time. Because this disease has such extensive ramifications, it is of special interest to the gastroenterologist, internist, cardiologist, dermatologist, allergist and surgeon.
PATHOLOGY Carcinoid tumors capable of releasing serotonin (5-hydroxytryptamine [5-HTA]) and possibly other biologically active substances are formed by proliferation of Kulchitsky's cells, which are small cuboidal cells with deeply staining nuclei. Fine granules which lie basal to the nucleus in the cytoplasm are eosinophilic, are capable of reducing ammoniacal silver salts and give a vivid yellow color with bichromate solution. These properties have given rise to the terms "argentaffinoma" and "chromaffinoma," but there seems little likelihood that these names will displace that of "carcinoid," which not only has the virtue of brevity but also is actually more accurate, since tumors that contain high concentrations of 5-HTA but which are nonargentaffine have been reported. Kulchitsky's cells are most numerous in the duodenum,4 but proliferation
465
466
FRANCES
H.
SMITH, ROSEMARY MURPHY
takes place most frequently in the appendix and in the jejuno-ileum. Grossly, the tumors are small, discrete, hard masses varying in size from 0.5 to 2.0 cm. or larger. They lie in the submucosa and extend toward the surface away from the lumen, invade the muscularis and occasionally break through the serosa. Microscopically, there are nests and strands of cells with occasional acinar formation which may contain albumin or mucin. Invasion of lymphatics or blood vessels may be found in cases without demonstrable metastases as well as in those with them. Masson 3 describes three types of cells in carcinoid tumor. Round or polygonal cells with a central, finely reticular nucleus and cytoplasm are the most common. The second type, the "palisade cells," surrounds the cell clumps, and the third type lines the small acini. The difference in these cells lies primarily in the distribution of the granules. Mitoses are rare. Metastases occur by direct extension through lymphatic channels and perineural spaces to regional lymph nodes and the mesentery, as well as by blood vessel invasion. Carcinoids of the terminal ileum, especially when the lesions are multiple, may spread to adjacent lymph nodes to form conglomerate masses which kink and mat together loops of intestine so that a right lower quadrant mass is palpable. The onset of obstruction, when it occurs, is usually insidious; the lumen is occluded by external pressure and only rarely by a lesion which breaks through the mucosa with ulceration, edema and internal occlusion. In some instances, obstruction occurs because of intussusception or volvulus. Metastases occur most frequently in the regional nodes and the liver, but they have been reported in almost every organ in the body, notably the right side of the heart, lungs, ovaries, genitourinary system, skin and bone marrow. The tumor may occur as a solitary nodule or as multiple nodules of varying sizes, particularly in the ileum, where as many as 68 have been reported in one surgical specimen. While the tumors themselves are usually of small size, the metastatic lesions to which they give rise may be many times as large. Carcinoid tumors also have, in rare instances, a large connective tissue element which produces annular constricting lesions. A fourth type of lesion is that of the rectal polyp. In addition to this classification, the tumors may also be described as nodular, polypoid, sessile or plaquelike. Although routine slides showing the characteristics described above are usually sufficient to make the diagnosis, additional help in identification may be obtained if one part of the specimen is fixed in formalin within four to six hours after removal, and the other part frozen. Pearse 7 has pointed out that it is the argentaffine reaction, in which the silver salts are reduced by the tissue itself and not by an added reducing agent, that is suggestive of carcinoid tumor. The granules which do this are produced by formalin fixation. Alcohol in the fixative prevents the reaction. Since autolysis also destroys the ability of the tissue to reduce silver
Carcinoid Tumors
467
salts, positive biopsies are more frequent in surgical than in autopsy material. On the other hand, if serotonin assays are to be carried out, the use of formalin must be scrupulously avoided because tissue serotonin is stable only in the frozen state. It is possible that failure to extract serotonin from some carcinoid tumors has been due to improper fixation. 9 SYMPTOMS
The symptoms of carcinoid tumors are due to mechanical factors or to the action of serotonin; in some instances to both. In carcinoids of the appendix, which are by far the most common, the symptoms and signs are usually those of appendicitis, or vague lower abdominal pain; when appendectomy incidental to other surgery has been performed there may have been no symptoms at all. In patients with tumors limited to the small bowel and adjacent nodes, the symptoms and signs are usually those of varying degrees of obstruction: abdominal pain, distention, visible peristalsis, nausea and vomiting. These and other symptoms may arise from concomitant disease, however, and a carcinoid be discovered fortuitously in the pathologic specimen. Thorsonll points out that patients with cirrhosis or nontropical sprue react with intestinal hyperperistalsis to ingested 5-HTA. Therefore, it may be inferred that liver disease interferes with the inactivation of 5-HTA carried in the portal blood. Because the effects are similar to those seen in patients with metastases outside the portal system, alcoholism may be an important factor in the development of clinical manifestations in carcinoid disease. The malignant carcinoid syndrome is a symptom complex associated with carcinoid tumors with metastases. Its most common component is episodic flushing. Isler and Hedinger, who in 1953 were the first to recognize this syndrome, reported three cases in which telangiectasia of the skin and sclerosis of the tricuspid and pulmonary valves were also present. Since their report other symptoms have been accepted as manifestations of the syndrome: hyperperistalsis with frequent watery stools, episodes of asthma-like bronchoconstriction, edema and ascites. Thorsonl l believes that these manifestations are due to metastases to extraportal sites, large metastatic masses and a slow rate of growth. He points out that in tumors limited to the intestine which is drained by the portal system, flushing rarely occurs, but that when metastases occur in areas drained by the caval system, it is almost always present. Flushing is the most characteristic symptom of the syndrome. It is usually of short duration (five to ten minutes), involves first the face, neck and chest and spreads to the rest of the body. The color is usually dark red, with patches of blue, white and normal color. As the disease progresses flushes may become continuollfl. Sometimes massage over the
468
FRANCES
H.
SMITH, ROSEMARY
M URPHY
liver or other body area above the carcinoid tumor will intensify the flush. This external manifestation reflects the widespread changes that occur throughout the vascular bed-changes in peripheral blood pressure, increased pressure in the pulmonary vessels and changes in heart size which occur during flushing. Intestinal disturbances rank second in frequency; diarrhea, borborygmi, abdominal distention and crampy abdominal pain may precede or follow a flush. It is believed that mechanical obstruction alone does not account for these symptoms but that they are due to the autopharmaco logic action of metabolites produced by the tumor. Because profuse diuresis may follow flushing, a specific antidiuretie action has been postulated for 5-HTA, which could also account for the edema and serous effusion that may be seen in patients with advanced carcinoid disease. The endocardial lesions involving primarily the right side of the heart which occur in a few patients with carcinoidosis are a late manifestation of the disease and directly related to it, although the manner of their production as yet has not been clarified. The systolic murmur appears to be distinctive and is the most important sign. It is reported to be harsh, to have a characteristic length and a rhombic appearance in the phonocardiogram. Asthma-like respiratory distress coinciding with flushing has been widely reported. Because death from bronchoconstriction when traction was applied to the tumor during surgical excision has sometimes occurred, the surgical approach to correction of the cardiac lesions and cardiac catheterization have been considered unwarranted. Skin lesions similar to those seen in pellagra with hyperkeratosis and hyperpigmentation have been reported in some eases of carcinoid disease, but not as constantly as might be expected from the disturbance in niacin formation. The unpredictable pattern of symptoms has been attributed to the slow growth of carcinoid tumors and to the manner of release of serotonin into the blood stream. This release may be intermittent or there may be a constant outflow which may be increased by periodic outbursts. METABOLISM OF SEROTONIN
Serotonin (5-hydroxytryptamine [5-HTA], enteramine) is a neurohumoral substance formed in the brain and in the chromaffin cells of the gastrointestinal tract; it is carried by the blood platelets and destroyed in the liver, kidney, brain, lungs and gastrointestinal mucosa. Its precursor is the amino acid, tryptophan (see Fig. 1), of which normally 1 per cent proceeds to the formation of serotonin and the remaining 99 per cent to the synthesis of niacin and protein (Fig. 1). In the malignant.
469
Carcinoid Tumors
METABOLISM OF SEROTONIN
H
NIACIN PROTEIN
Hydroxylase (Slow reaction)
H O W -CHz-CI H-COOH N H
5-HYDROXYTRYPTAM I NE SEROTONIN 5-HTA
~H2
1 Z
N
5-HYDROXYTRYPTOPHAN 5-HTP
-<<:
-CH -CH-COOH _ _ _ _ _
W
TRYPTOPHAN
1
NH2
Decarboxylase
(Pyridoxine-dependent)
HO~ -CHZ-9-H ~~~R!:!~~P~T!!~A~OTHER INDOLES ~,,)
~
1
NH Z
Monoammeoxidase
(Blocked by IpronooZldl
H O W - C H -CHO 5-HYDROXYINDOLEACETALDEHYDE z 5-HIA N H
1
Dehydrogenase
HO~-CHz-COOH _ _ _ _:. EXCRETED IN URINE 5-HYDROXYINDOLEACETIC ACID 5-HIAA
~I\l) ~
Fig. 1
carcinoid syndrome, on the other hand, as much as 60 per cent may proceed to serotonin with a profound reduction in niacin and protein formation. In each site at which serotonin is found in significant quantities, there are also a decarboxylase which facilitates its production and a monoamine oxidase which controls its destruction_ The end-product of monoamine oxidase activity is 5-hydroxyindoleacetic acid (5-HIAA), which is excreted in the urine. 5-HIAA, however, does not account for the total serotonin breakdown, for which other metabolic pathways have been demonstrated. The widespread distribution of serotonin in the body and its potent pharmacological actions suggest that it may be one of the most important neurohumors. The chief physiological actions consist of stimulation of smooth muscle of the gastrointestinal tract, vasoconstriction or dilatation, vasopressor or depressor effects depending upon the vascular status, bronchoconstriction, renal antidiuresis, stimulation of connective tissue growth, and participation in the function of the central nervous system, especially in the hypothalamus. These pharmacological effects of serotonin play a role in the carcinoid
470
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H.
SMITH, ROSEMARY
M URPHY
syndrome and account for the vasodilation with episodes of flushing, the hypermotility of the gastrointestinal tract and the bronchospasm with asthmatic symptoms. The absence of central nervous system effects in the presence of elevated circulating serotonin has been attributed to the inability of the amine to penetrate the bloodbrain barrier. The valvular lesions in the right side of the heart, as well as the development of intraabdominal adhesions, may result from the connective tissue stimulating action of 5-HTA. The fact that the left side of the heart is relatively free of lesions is attributed to the destruction of a significant portion of circulating serotonin by the lung tissue. Edema, when present, may result from right heart failure, from an antidiuretic action of serotonin, from a direct tissue response to serotonin, or from hypoproteinemia which results from a diversion of tryptophan from protein synthesis to the formation of serotonin. This diversion may also give rise to a deficiency of nicotinic acid and the production of pellagra-like skin lesions. Since it is well known that vasomotor and gastrointestinal symptoms are characteristic of pellagra, it is not unlikely that deficiency in nicotinic acid may play an ancillary role in the development of these symptoms in the carcinoid syndrome. The normal serum serotonin level ranges from 0.1 to 0.3 micrograms / ml., whereas values in patients with the malignant carcinoid syndrome vary from 0.5 to 3.0 micrograms/ml. Assays of tumors have shown 1 to 3 mg. of serotonin per gram of tissue. The urinary excretion of 5-HIAA normally varies from 2 to 10 mg. per day.8 In patients with carcinoid syndrome, the urinary excretion of both serotonin and its end-product, 5-HlAA, is greatly increased. The estimation of the latter serves as an important diagnostic tool. Values above 15 mg. per day suggest carcinoid syndrome, while values of 30 mg. or over are probably diagnostic. A qualitative test10 (purple to black color) using I-nitroso-2-naphthol as a reagent is positive for values of 30 mg. or more per day. More exact determinations may be made by paper chromatography or spectrophotDfluorometry. Certain precautions must be followed in testing the urine for 5-HIAA. It is important that the patient should not take any medication for at least 48 hours befme the test is performed. The phenothiazine drugs interfere with the reaction, causing false negative tests. 8 The ingestion of bananas,l which contain large amounts of serotonin, may give a truly false positive test, whereas acetanilid and related drugs may give a false positive test. Current interest in the role of amines in mental disease and in the development of tranquilizing drugs has served to focus attention on serotonin. A number of potent pharmacotherapeutic agents have been found to be true antimetabolites of serotonin, to interfere in some fashion with its activity or to prevent its breakdown. Thus, Medmain and the harmine, yohimbine and ergot alkaloids have been shown to be antimetab-
Carcinoid Tumors
471
olites. Of these, lysergic acid diethylamide is the most potent. A synthetic antagonist, I-benzyl-2, 5-dimethyl serotonin (BAS) has had a clinical trial'in the treatment of hypertension and the malignant carcinoid syndrome. Those reserpine alkaloids which have a tranquilizing effect presumably release brain serotonin from the bound to the free state. However, they have so little effect on serotonin in the gastrointestinal tract that urinary 5-HIAA is not significantly changed during reserpine therapy.2 Nevertheless, it has been suggested that if reserpine is given to a patient with carcinoid syndrome, an increase in urinary 5-HIAA may be useful in diagnosis. 6 Chlorpromazine apparently interferes with serotonin action in some manner different from that of the antimetabolites, and it would appear to be the most effective drug to use in an attempt to control the symptoms of the carcinoid syndrome. Iproniazid (Marsilid) and other inhibitors of mono-amine oxidase activity have been shown to increase serotonin levels of the brain by inhibiting the breakdown of serotonin to 5-HIAA. Recently, nicotinamide has been shown to be an antagonist of serotonin, but the mechanism of its action is unknown.1 3 TREATMENT
The treatment in all cases is wide surgical excision. As much of the tumor as possible should be removed, even in patients with extensive metastases. This policy reduces the likelihood of future perforations through tumor tissue and possibly may retard the spread and growth of metastases. The logical assumption that serotonin antagonists would be useful in treating the disease has, with the possible exception of chlorpromazine, been unwarranted. Supportive therapy with special attention to correcting the protein and niacin deficiencies as well as the fluid and electrolyte balance attendant on the diarrhea is of prime importance. X-ray therapy has not been helpful. Antihistamines and chlorpromazine have been helpful to some patients in alleviating flushing. Paregoric, and hydrochloric acid before and during meals, has lessened diarrhea in some cases but not in others. Adrenalin and intravenous aminophylline are useful in chronic recurrent bronchospasm, but all methods may be unavailing in the sudden, acute bronchospasm encountered at surgery. The response of the pellagra-like skin lesions to niacin is less than might be expected. Digitalis is not helpful in most cases of right heart failure and may add to the patient's discomfort by increasing nausea and diarrhea. LAHEY CLINIC CASES
At the Lahey Clinic from 1931 to January 1, 1959, there have been 58 cases of carcinoid tumors; 31 occurred before January 1, 1948, and were
472
FRANCES
Table 1.
H.
SMITH, ROSEMARY MURPHY
Location of Carcinoid Tumors
NONMETASTASIZED
METASTA'lIZED
1931 to Jan. 1, 11)48
1948 to Jan. 1, 1959
1931 to Jan. 1, 11)48
Appendix .. Ileum .. Rectum Stomach. Duodenum .. Ampulla of Vai.er Cecum. Colon .. Rectosigmoid.
16 6
14 1 1
0 6
TOTAL ..
23
LOCATION
1948 to Jan. 1, 1959 0 6* 2
TOTAL
30 19 3
1
1 1
1 1
17
8
10
1 58
* Includes one in which primary tumor was not identified but was probably ileal.
reported by Warren and Coyle. 12 Forty had not metastasized and 18 had. The distribution of these tumors may be seen in Table 1. None of the tumors in the appendix had metastasized, but 12 of 19 tumors in the ileum had. The infrequency of metastases from appendiceal carcinoids has been attributed to the early removal of asymptomatic tumors in incidental appendectomies or to the fact that symptoms may develop in this small organ before spread occurs. In the earlier series, the age of the patients ranged from 20 to 69 years. The age range in the later group extends from 29 to 81 years. The 81 year old patient was operated on for resection of adenocarcinoma of the sigmoid and an incidental carcinoid of the appendix was found. She was living and well at age 88 in 1958. In this later group, three nonmetastasizing lesions other than appendiceal were found in patients aged 29, 53 and 65 years; in the ten patients with metastasized carcinoids the ages ranged from 46 to 74 years. The sex distribution in the cases observed from 1948 to 1959 follow the statistics in most large series. It has been noted that in carcinoids of the appendix the incidence in females is much greater than in males. In this group there were 12 females and two males. Of the three other patients with nonmetastasized carcinoids, two were females and one was male. In the ten patients with carcinoids with metastasis, six were female and four male. In the earlier group of cases (before 1948), there were 21 females and ten males, but further differentiation was not made. In the series studied by Warren and Coyle, 19 patients had carcinoid tumors found at autopsy or removed in a surgical specimen resected for another lesion, of which ten were malignant neoplasms. In the later study, the carcinoids of the appendix were all found incidentally at operation for other conditions. Of these, four were malignant neoplasms involving the cecum, rectum and sigmoid (two cases). Five were found at
Carcinoid Tumors
473
hysterectomy, two at cholecystectomy, two at operation for common duct stricture, and one at operation for an obstructed duodenal ulcer. Of the three nonappendiceal, nonmetastasized carcinoids, one involved the duodenum, one the rectum and one the distal ileum and cecum. In this latter group, all had abnormal x-ray findings, but none diagnostic of a particular lesion. In one there was a fistulous tract from the sigmoid to the terminal ileum in the lesion involving the ileum and cecum; in the lesion involving the rectum the splenic flexure appeared to be displaced superiorly; in the duodenal carcinoid a duodenal defect was noted. In the 18 cases in which metastases were found, ten had metastasized to the liver, seven to the regional lymph nodes, five to the mesentery, two to the omentum and two to the pelvis. In one case each there were metastases to each of the following sites: bone, a rare complication; colon; adjacent structures, and the parietal peritoneum. X-ray studies were carried out in 14 of the 18 patients in whom metastases were found. Abnormality related to the disease was found in 12. Six of these showed signs of obstruction; two, dilated loops of ileum; two, a high transverse position of the cecum which proved to be related to extensive fibrosis in the mesentery; one, the stomach was displaced toward the right, and in the case of the carcinoid of the stomach there was mucosal distortion high on the lesser curvature. In one patient an unrelated finding, diverticulitis, was reported, and one patient had a normal gastrointestinal x-ray study. Of the 18 patients with metastases, one (previously reported5) may be considered a proved case of the so-called malignant carcinoid syndrome. Extensive hepatic metastases and intra-abdominal fibrosis were demonstrated at laparotomy and urine examination showed consistently elevated urinary 5-HIAA. Clinically, the patient demonstrated diarrhea, ascites, pleural effusion, peripheral edema, muscular wasting, purplish discoloration of the face with telangiectasia, and deep purplish-brown pigmentation of the lower legs. Two other cases, in retrospect, raise the suspicion of the malignant syndrome. One patient was a 61 year old man with symptoms of an "irritable colon" of 14 years' duration, associated with "severe intractable vasomotor attacks" and episodes of apprehension. At autopsy, a carcinoid of the ileum with extensive hepatic metastases was found. The other patient was a 67 year old woman, operated on because of an acute intestinal obstruction, in whom a rectal carcinoid with local extension and hepatic metastases was discovered. She had a history of severe hot flashes which had persisted long beyond the menopause and which were peculiarly resistant to the usual therapeutic agents. SUMMARY
The general problem of carcinoid tumors has been reviewed with special attention to the action and metabolism of serotonin, a potent neuro-
474
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SMITH, ROSEMARY MURPHY
endocrine substance which certain of these tumors secrete in amounts adequate to produce symptoms in many systems. The study includes a brief summary of 58 cases of carcinoid tumors seen at the Lahey Clinic between 1938 and 1959, including one proved case of the malignant carcinoid syndrome and two cases which in retrospect seem to belong to this group. REFERENCES 1. Crout, J. R. and Sjoerdsma, A.: Clinical and laboratory significance of serotonin and catechol amines in bananas. New England J. Med. 261: 23-26 (July 2) 1959. 2. Haverback, B. J., Dutcher, T. F., Shore, P. A., Tomich, E. G., Terry, L. L. and Brodie, B. B.: Serotonin changes in platelets and brain induced by small daily doses of reserpine; lack of effect of depletion of platelet serotonin on hemostatic mechanisms. New England J. Med. 256: 343-345 (Feb. 21) 1957. 3. Masson, P.: Citcd by Ritchie, A. C.: Carcinoid tumors. Am. J. M. Sc. 232: 311328 (Sept.) 1956. 4. Morson, B. C.: Pathology of carcinoid tumors. In: Jones, F. A.: Modern Trends in Gastroenterology. Second Series. London, Butterworth & Company, Ltd., 1958, pp. 107-117. 5. Murphy, R. and Rohart, R. R.: Malignant carcinoid: report of a case. Lahey Clin. Bull. 10: 53-55 (Oct.-Dec.) 1956. 6. Page, I. H.: Serotonin (5-hydroxytryptamine); the last four years. Physiol. Rev. 38: 277-335 (April) 1958. 7. Pearse, A. G. E.: Histochemistry, theoretical and applied. Cited by Ritchie, A. C.: Carcinoid tumors. Am. J. M. Sc. 232: 311-328 (Sept.) 1956. 8. Sjoerdsma, A.: Clinical and laboratory features of malignant carcinoid. A.M.A. Arch. Int. Med. 102: 936-938 (Dec.) 1958. 9. Sjoerdsma, A.: Serotonin. New England J. Med. 261: 181-188 (July 23); 231237 (July 30) 1959. 10. Sjoerd~ma, A., Weissbach, H. and Udenfriend, S.: Simple test for diagnosis of metastatic carcinoid (argentaffinoma). J.A.M.A. 159: 397 (Sept. 24) 1955. 11. Thorson, A. H.: Studies on carcinoid disease. Acta med. scandinav. 161 (Suppl. 334): 1-132, 1958. 12. Warren, K. W. and Coyle, E. B.: Carcinoid tumors of the gastrointestinal tract. Am. J. Surg. 82: 372-377 (Sept.) 1951. 13. Woolley, D. W.: Tranquilizing and antiserotonin activity of nicotinamide. Science 128: 1277-1278 (Nov. 21) 1958.