23.1.1 Incidence

Carcinoids arise from neuroectodermal derivatives. The gastrointestinal tract is the most common site and in decreasing order of frequency, the locations of carcinoids are the appendix, ileum, rectum, colon, and stomach. ² Approximately 5% of all carcinoids are located in the colon. ^{2 , 3} In the Connecticut Registry with 54 colonic carcinoids, 48% were in the cecum, 16% in the ascending colon, 6% in the transverse colon, 11% in the descending colon, 13% in the sigmoid colon, and 6% were not assigned. ⁴ The incidence of rectal carcinoids was 1.3% of noncarcinoid neoplasms of the rectum; for the colon, the incidence was 0.3% of noncarcinoid neoplasms of the colon. ⁵ In the Connecticut Registry, the age-adjusted incidence was 0.31 cases per 100,000 population/y. ⁴ Colonic involvement accounted for only 2.5% of all gastrointestinal carcinoids and 2.8% of all carcinoids. ⁶ Rectal carcinoids accounted for 12 to 15% of all carcinoids, and carcinoids of the remainder of the colon accounted for 7% of all carcinoids. ⁷

23.1.2 Clinical Features

Carcinoids most commonly occur in the seventh and eighth decades of life, with a female preponderance of 2:1. ^{1 , 6} Colonic carcinoids may present as a simple polyp or as a gross malignancy that is indistinguishable from carcinoma radiologically and has an “apple core” appearance. These carcinoids may be entirely asymptomatic, found in 0.014% of rectal examinations, or they may produce symptoms indistinguishable from those of carcinoma. Colonic carcinoids are usually symptomatic. ⁶ Once they have been diagnosed, a search for other neoplasms should be made because the incidence of synchronous and metachronous neoplasms has been reported as high as 42%. ⁶ Gastrointestinal carcinoid is associated with a high incidence of second primary malignancy. Gerstle et al ⁸ reviewed their experience with 69 patients with carcinoids of the gastrointestinal tract and found that 42% had second synchronous neoplasms and 4% had a metachronous neoplasm. The gastrointestinal tract was the site of 43% of these additional neoplasms with half of these being carcinomas of the colon and rectum. Tichansky et al ⁹ conducted a search of the National Cancer Institute Surveillance, Epidemiology, and End Results database from 1973 to 1996 and found 2,086 patients with colorectal carcinoids. Patients with colorectal carcinoids had an increased rate of carcinoma in the colon and rectum, small bowel, esophagus/stomach, lung/bronchus, urinary tract, and prostate, when compared with the control population. Most of the gastrointestinal carcinomas were synchronous carcinomas, whereas lesions outside the gastrointestinal tract were mostly metachronous neoplasms. After the diagnosis of colorectal carcinoid neoplasms, patients should undergo appropriate screening and surveillance for carcinoma at these other sites.

Most gastrointestinal carcinoids are incidentally discovered at laparotomy or autopsy. The discovery of an asymptomatic gastrointestinal carcinoid during the operative treatment of another malignancy will usually only require resection and has little effect on the prognosis of the individual. Carcinoids may be associated with multiple endocrine neoplasia, (especially of the parathyroid,) but most of these are associated with carcinoids of foregut origin. ¹⁰ Carcinoids of midgut and hindgut origin occur more frequently and produce significant endocrine relationships other than serotonin production. The diagnosis may be established by demonstrating elevated blood levels of serotonin or elevated urinary levels of 5-hydroxyindoleacetic acid.

In the series reported by Rosenberg and Welch, ⁶ 44% of patients had signs of local spread, while 38% of patients had distant metastases. The liver was involved in 35.5% of the patients and the lung in 8%. In a review by Berardi, ¹¹ 57% of patients with colonic carcinoids already had metastases, and of these, 42% had distant metastases. In the series reported by Gerstle et al, ⁸ the overall incidence of metastatic carcinoid at presentation was 32%. The most common sites of metastatic disease were lymph nodes in 82%, liver in 68%, satellite lesions to adjacent small bowel in 32%, peritoneum in 27%, and omentum in 18%. Only 1 of 18 appendiceal carcinoids metastasized and that only to the local lymph nodes. Four of nine colorectal carcinoids metastasized to the lymph nodes and liver. Other sites of metastatic disease included bone. ¹²

23.1.3 Pathology

Macroscopically, carcinoids may vary in appearance from nodular thickening in the mucosa and submucosa to a sessile or pedunculated polypoid lesion, and they may have a yellowish tinge. Larger lesions may ulcerate and become annular, or they may obstruct and metastasize to regional lymph nodes or the liver (▶ Fig. 23.1). The malignant character of these lesions correlates with size, location, and tissue invasion. Carcinoids of the appendix and rectum rarely metastasize. ⁷ Lesions less than 2 cm rarely metastasize, whereas 80% of lesions greater than 2 cm in diameter do metastasize. Superficially invasive lesions have a better prognosis than do deeply penetrating ones. In his review, Berardi ¹¹ found multiple carcinoids in 4.2% of patients with colonic carcinoids as compared with 30% of patients with ileal carcinoids. Associated malignancy of the colon was found in 2.5% of patients with colonic carcinoids as compared with 30 to 53% of patients with ileal carcinoids.

Microscopically, carcinoids consist of uniform, small, round, or polygonal cells with prominent round nuclei and eosinophilic cytoplasmic granules (▶ Fig. 23.2). They usually demonstrate one of five histologic patterns: insular, trabecular, glandular, undifferentiated, or mixed. In decreasing order of median survival time in years, the growth patterns are ranked as follows: mixed insular plus glandular, 4.4; insular, 2.9; trabecular, 2.5; mixed insular plus trabecular 2.3; mixed growth pattern, 1.4; glandular, 0.9; and undifferentiated, 0.5. ¹³

23.1.4 Imaging Procedures

The hypervascular nature of carcinoids and their metastases allows an aggressive role by the radiologist in diagnosis and interventional management. ¹⁴ Double-contrast studies still best define the primary neoplasms. The “spoke wheel” configuration of the desmoplastic mesenteric masses and lymph node metastases are best seen by CT, whereas hepatic metastases can be demonstrated by CT, CT angioportography, ultrasonography, MRI, and octreotide scintigraphy. Superior mesenteric angiography of the small bowel and cecum is useful when scanning procedures are not revealing. Percutaneous needle biopsy with radiologic guidance may confirm the diagnosis.

Octreotide scintigraphy may have a fourfold impact on patient management. ¹⁵ It may detect resectable lesions that would be unrecognized with conventional imaging techniques, it may prevent operation in patients whose lesions have metastasized to a greater extent than can be detected with conventional imaging, it may direct the choice of therapy in patients with inoperable carcinoids, and, in the future, it may be used to select patients for radionuclide therapy.

23.1.5 Chemical Activity

Carcinoids secrete serotonin, a substance with pronounced pharmacologic effects, including flushing of the face, neck, anterior chest wall, and hands; increased peristalsis leading to diarrhea; constriction of bronchi presenting as wheezing; and cardiac valvular lesions with right-sided heart failure (pulmonary stenosis). Other components of the syndrome include a rise in pulmonary arterial pressure, hypotension, edema, pellagralike skin lesions, peptic ulcers, arthralgia, and weight loss. ¹⁶ This constellation of symptoms, known as the carcinoid syndrome, usually occurs with metastases to the liver. Other products such as bradykinin, histamine, vasoactive intestinal peptide, adrenocorticotropic hormone (ACTH), 5-hydroxytryptophan, and prostaglandins produce part of the syndrome complex. The syndrome occurs primarily with carcinoids of the small bowel but not with those of the colon or rectum.

Foregut carcinoids, which are argentaffin negative and argyrophil positive, produce the serotonin precursor 5-hydroxytryptophan. Midgut carcinoids are usually both argyrophil positive and argentaffin positive, are frequently multicentric in origin, and may be associated with the carcinoid syndrome. Hindgut carcinoids are rarely argyrophil positive or argentaffin positive, are usually unicentric, and are not usually associated with the carcinoid syndrome (▶ Fig. 23.3). The carcinoid syndrome is a rare clinical entity that occurs with a prevalence of 1.6% in patients with carcinoids and almost only if liver metastases are present. ¹⁷ Berardi ¹¹ estimated that less than 5% of colonic carcinoids cause the carcinoid syndrome. In a series by Rosenberg and Welch, ⁶ 4.2% of patients had either symptoms suggestive of the syndrome or elevated 5-hydroxyindoleacetic acid levels.

23.1.6 Treatment

Appendiceal carcinoids less than 1 cm in diameter can be treated adequately by appendectomy, but if they are greater than 2 cm in diameter, a right hemicolectomy should be performed. ² The rationale for the latter recommendation is that the average rate of metastases is 30%. ² For lesions between 1 and 2 cm, in which the risk of metastases is between 0 and 1%, the decision-making process is more difficult. Appendectomy is probably sufficient but additional criteria may be considered, such as extension to the mesoappendix or subserosal lymphatic invasion. ¹⁸ A more aggressive approach may be advised for younger patients. ² Gouzi et al ¹⁹ recommended that other than having a size greater than 2 cm and base location, the presence of mucin production is a further indication for secondary right hemicolectomy.

The recommended treatment for small bowel carcinoids is wide segmental resection. Because the average lymph node involvement is 44%, ² relevant lymph node drainage should be included. Meticulous intraoperative examination is indicated because 20 to 40% of small bowel carcinoids are multicentric and simultaneous adenocarcinomas of other parts of the gastrointestinal tract occur at a rate of 8 to 29%. ² For colonic carcinoids, the standard operation for adenocarcinoma should be performed.

Metastatic disease occurs more frequently with carcinoids of the colon. If there is distant disease, resection of the primary lesion is still recommended to alleviate symptoms (because a long survival period is possible). ⁷ Partial hepatectomy should be considered if technically feasible. ^{16 , 20} Beaton et al ²¹ have shown the value of aggressive operative debulking in reducing and sometimes obliterating the manifestations of the syndrome. For patients with unresectable metastatic carcinoids to the liver, combining either operative hepatic dearterialization or hepatic intra-arterial embolization with chemotherapy has reportedly been effective in inducing regression of the liver metastases. ^{14 , 20 , 22}

Chemotherapeutic agents used have included 5-fluorouracil (5-FU), streptozotocin delivered via hepatic artery or portal vein catheters, or floxuridine (FUDR) and doxorubicin administered systemically. ^{23 , 24 , 25} A number of other pharmacologic and cytotoxic agents have been used to control the carcinoid syndrome. ²⁶ Each is aimed at neutralizing one of the pharmacologically active products released by the carcinoid. Vinik and Moattari ²³ have reported the successful use of somatostatin analog in the management of the carcinoid syndrome. The symptoms of diarrhea, flushing, and wheezing can be dramatically reduced or even abolished. Ahlman et al ²⁰ pursued an aggressive policy in the management of patients with midgut carcinoid syndrome and bilobar disease. After primary operation to relieve symptoms of intestine obstruction and ischemia, the authors performed successful embolizations of hepatic arteries. Patients with remedial disease were treated by octreotide. In a series of 64 patients, the authors obtained a 70% 5-year survival rate.

23.1.7 Results

Five-year survival rates for patients with colonic carcinoids are reported to be 52%. ¹⁵ Survival rates reported by Rosenberg and Welch ⁶ were 51, 25, and 10% at 2, 5, and 10 years, respectively. In the Connecticut Registry, 2- and 5-year survival rates were 56 and 33%, respectively. The 5-year survival by Dukes’ staging was as follows: A, 83%; B, 43%; C, 35%; and metastatic, 21%. In a 25-year population-based study of 36 colonic carcinoids, Spread et al ³ found a perioperative mortality of 22%. Actuarial survival rates at 2 and 5 years were 34 and 26%, respectively. In the authors’ review, the size of the lesion and invasion into muscularis propria, the two major histopathologic prognostic factors for carcinoids, were not found to influence survival significantly. Stage, histologic pattern, differentiation, nuclear grade, and mitotic rate (> 20 mitosis/10 high power fields [hpf]) proved to be prognostic factors. The 5-year survival rate in patients with appendiceal carcinoids was 90 to 100%. ² The overall 5-year survival rate for small bowel carcinoids was 50 to 60%. ² The 5-year survival rate decreases from 75% for local disease to 59% for patients with positive nodes to 20 to 35% if liver metastases are present.

23.2.1 Incidence

Lymphoma may occur as a primary lesion or as part of a generalized malignant process involving the gastrointestinal tract. As a primary lesion, it constitutes only 0.5% of all cases of neoplastic disease of the colon, and yet it is the second most common malignant disease of the colon. Lymphoma comprises 6 to 20% of cases of primary gastrointestinal lymphoma ^{7 , 24 , 25 , 26 , 27} and accounts for 5 to 10% of all non-Hodgkin’s lymphoma. ²⁵ It most commonly involves the cecum (70%), with the rectum and ascending colon next in order of frequency. ^{25 , 27} A more recent publication cited distribution sites of primary large bowel lymphoma as cecum 37.5%, descending colon 25%, ascending colon 25%, and rectum 12.5%. ²⁶ It can occur at any age from 3 to 81 years, but the average age is 50 years. Men are affected twice as often as women, but a recent publication cited the reverse. ²⁶

23.2.2 Pathology

Lymphomas represent a diverse group of neoplasms. At least six major classifications of non-Hodgkin’s lymphoma are in use, but there is no consensus among them. Three macroscopic types are seen. ²⁸ Annular or plaquelike thickenings are the most common type, followed by bulky protuberant growths, and, rarely, thickened and aneurysmal dilatations of the bowel wall. The cut surface has a uniform fleshy appearance (▶ Fig. 23.4). Regional lymph nodes are involved in one-half of all cases, but such involvement is not related to prognosis. Multiple primary foci are quite common. Malignant lymphomas may present as multiple polypoid protrusions of the entire colon and may mimic adenomatosis coli. Roentgenographically, 86% of colonic lymphomas are single lesions, 8% are multiple discrete lesions, and 6% show a diffuse colonic involvement. ¹⁷ Dawson et al ²⁹ presented these criteria for a primary lymphoma of the gastrointestinal tract: (1) no palpable peripheral lymphadenopathy, (2) normal roentgenographic findings except at the primary site, (3) normal white blood cell count and differential, (4) tract lesion with only regional lymph node involvement, and (5) no involvement of the liver or spleen.

The large series of large bowel lymphomas reported by Jinnai et al ²⁵ were classified histologically in order of frequency as follows: histiocytic, lymphocytic, mixed, and Hodgkin’s disease. The incidence of each variety varies from series to series, but in the combined series it was as follows: histiocytic type, 43%; lymphocytic type, 29%; mixed type, 14%; and Hodgkin’s disease, 3.5% (▶ Fig. 23.5). ²⁴ In one series of 15 patients, histologically 40% were classified as high-grade and 60% as intermediate-grade non-Hodgkin’s lymphoma. The neoplasms usually presented at an advanced stage: in 87%, the lymphoma had spread to the adjacent mesentery, the regional lymph nodes, or both when first diagnosed. ²⁷

23.2.3 Clinical Features

Lymphomas of the colon are characterized by abdominal pain in more than 90% of patients. Otherwise, the symptoms may be indistinguishable from those of carcinoma, with changes in bowel habits such as diarrhea or constipation, bleeding, weight loss, weakness, and possibly fever. Tender abdominal masses are present in 80% of patients on initial examination. ²⁴ If ulceration supervenes, bleeding may be more prominent. Obstruction occurs in 20 to 25% of patients, but perforation is infrequent. ²⁴ Multiple lesions constitute 8% of cases. ³⁰

The radiologic signs observed during barium enema studies for non-Hodgkin’s lymphoma are as follows: a small nodular pattern frequently with multiple lesions (45.7%), a diffuse or infiltrating pattern (25.4%), a filling defect (22.9%), endoluminal and exoluminal images (17.8%), ulcerating patterns (3.4%), and a pure mesenteric form (0.8%). ^{31 , 32} Lymphomas of the colon may produce the same radiologic appearance as carcinomas and similarly may be indistinguishable from carcinomas at laparotomy. The colonoscopic appearance of a follicular lymphoma is seen in ▶ Fig. 23.6. Biopsy will clarify the diagnosis, but diagnosis still may be difficult because of the superficial nature of the biopsy.

Once the diagnosis is made, staging should be performed through an adequate history, physical examination, barium enema, complete blood count, liver function tests, chest X-ray films, bone marrow assay, CT scan of the abdomen, and lymphangiography. ⁷