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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 102Neoplasms of the Small Intestine, Vermiform Appendix, and Peritoneum

, MD and , MD.

Tumors of the Small Intestine

Introduction

The small intestine is the site for almost 90% of the alimentary tract’s mucosal surface area, but it is the site of only a small percentage of intestinal neoplasms, and only rarely is a malignancy found.1 The reasons for this may include the rapid transit of content through the small bowel, local protective mechanisms, or the relative lack of carcinogens in contact with the mucosal surface.2,3 Nonetheless, the tumors of the small bowel are among the most interesting and well studied of those in the gastrointestinal (GI) tract. Recent figures4 show that less than 3% of all alimentary tract tumors and less than 1% of all malignancies arise in the small bowel. Despite this relative rarity, 4,800 new small bowel malignancies were predicted for 1999. In comparison with colorectal cancer (139,400 new cases), it appears that small bowel tumors are 30 times less frequent. If mortalities are compared, then colorectal tumors account for 50 times as much loss of life. Because of this rarity, the clinician must become familiar with the signs and symptoms of small bowel cancers.

Neoplasms of the small bowel have been reported for 250 years5,6 and successful resections for 115 years.7–9

Most small bowel tumors are benign. These tumors include leiomyoma, adenoma, and lipoma, with rare tumors including fibromas, fibromyxomas, neurofibromas, ganglioneuromas, hemangiomas, and lymphangiomas. The malignant tumors include adenocarcinoma, carcinoids, lymphomas, sarcomas and their subtypes, and other rare tumor types, such as Kaposi’s sarcoma, seen primarily in patients with end-stage human immunodeficiency virus (HIV) infection.

Many small bowel tumors are asymptomatic until late in their course due to their relatively slow growth and the ease with which the contents of the small bowel can pass even a partially obstructing lesion. Half of small bowel cancers are found only at autopsy. The remainder are usually found as a result of the symptoms of partial obstruction: nausea and vomiting if the lesion is proximal; crampy abdominal pain; or other nonspecific findings such as weight loss. Hemorrhage is frequently found in those tumors that penetrate beyond the submucosa but almost always is occult, presenting as stool that is positive on guaiac testing and microcytic anemia. Eventually, malignant tumors cause enough symptoms for the ensuing medical work-up to reveal the tumor. Unfortunately, some time may pass between the first symptom and diagnosis. In one series, almost one-third of the patients had had symptoms for 5 years or more prior to definitive diagnosis.10 A more recent study demonstrated a median duration of symptoms of 8 months prior to diagnosis.11 Many patients eventually diagnosed with small bowel tumors present as an emergency with either bowel obstruction or perforation.

The diagnosis of these lesions is usually accomplished with the aid of radiographic studies. Only 25% of patients present with a palpable mass; another 25% have the symptom of abdominal distention, secondary to obstruction. Plain films of the abdomen are unlikely to be of use, except to demonstrate the presence of obstruction or perhaps displacement of the bowel by a mass. Contrast studies show about one half of these tumors, although, with retrospective readings, up to 75% of small bowel tumors can be found. Some studies have reported even higher rates of diagnosis by barium study.12 More recently, duodenal tumors have been diagnosed using endoscopy, and the advent of computed tomographic (CT) scanning with oral contrast has led to nearly 100% recognition of small bowel tumors in some series.13 Others disagree with this view and hold that a small bowel series is the best radiographic study.14 Angiography and nuclear scanning may be useful in the case of a bleeding tumor or a suspected hemangioma.

The treatment of small bowel tumors is usually surgical, with simple resection for benign lesions and an aggressive approach for malignant lesions. Overall, the survival for adenocarcinomas, carcinoids, lymphomas, and sarcomas was better in 328 cases from a population-based registry than that for all other organs, except the breast, colon, prostate, and uterus.15 In most cases, the surgical resection must include wide margins, resection of lymph nodes, and removal of the supporting mesentery. Lymphadenectomy is usually not performed for leiomyosarcoma due to its lack of lymphatic metastases. In rare cases, radiation or chemotherapy may precede surgery. Duodenal tumors may require pancreaticoduodenectomy if malignant, whereas tumors of the terminal ileum may require right hemicolectomy to ensure complete resection and adequate margins.

Endocrine tumors of the gut, also known as carcinoid tumors of the gut, may present with their own set of classic symptoms, such as flushing, diarrhea, cyanosis, and intermittent respiratory distress. Only a small proportion of patients with carcinoid tumors have these symptoms, the vast majority being asymptomatic or having symptoms secondary to mass lesion effects.

Benign Tumors

Leiomyoma

The most common benign tumor of the small bowel is the leiomyoma. These tumors are composed of smooth muscle cells arranged into whorls when seen microscopically. In a series of 1,721 collected cases, they accounted for 22% of all benign small bowel tumors. They tend to occur in equal numbers in males and females and increase in occurrence with increasing age.16 They usually present either with obstruction, due to their large size encroaching on the lumen, or with bleeding. In the two largest series to date, bleeding was seen in 40 to 67% and obstruction in 25 to 40%.17,18 Perforation is rare but has been reported.17 The diagnosis of leiomyoma versus leiomyosarcoma may be difficult to make by frozen section owing to nuclear pleomorphism in benign tumors. Thus, treatment should consist of surgical resection with wide margins, generally accepted to be 5 cm.

Lipoma

The second most common benign tumor of the small bowel is the lipoma, which accounts for about 20% of such tumors.18 Lipomas consist of dense masses of adult adipose tissue and may be found throughout the GI tract. Approximately 60% of small bowel lipomas are found in the ileum, with the remainder equally divided between the duodenum and jejunum.19 Lipomas are a frequent point of intussusception, which is the cause of surgical exploration in 50%. Treatment consists of local excision for small tumors and segmental resection for larger tumors.

Adenomas

Adenomas of the small bowel are relatively rare, making up 14% of small bowel benign tumors in the collected series reported by Wilson and colleagues.18 These are surface neoplasms arising from mucosal or glandular cells and are usually found on a stalk. The stalk itself usually contains normal mucosa and submucosa.20 Occasionally, adenomas cause symptoms by acting as the leading point for an intussusception. Both sessile lesions and polypoid lesions on stalks are found more often in the duodenum than in other segments of the small bowel. As upper GI endoscopy becomes more common, both types are more frequently diagnosed. Endoscopy is the preferred diagnostic test due to its sensitivity and the ability to obtain biopsies. Lesions on a stalk may be removed endoscopically or, if surgical exploration becomes necessary, by enterotomy.

Some controversy exists as to whether truly benign villous adenomas exist in the small bowel. Whereas some feel that malignant change is rare in small villous adenomas,21 others believe that all villous adenomas are premalignant and should be treated with surgical resection and wide margins.18 Malignant changes are present in almost all specimens greater than 5 cm in diameter. Small size, on the other hand, does not imply a benign nature. Anemia, jaundice, and duodenal obstruction are highly predictive of malignancy.22 In one recent study, one-third of the lesions found were invasive and more than 80% were periampullary.22 Benign lesions are usually treated by transduodenal submucosal excision, whereas lesions with invasive carcinoma more frequently require pancreatoduodenectomy.23–25

Hemangioma

Hemangiomas represent about 10% of benign small bowel tumors in most collected series.18,26–28 They may be of the capillary, cavernous, or mixed-pattern type. About one half of the lesions are cavernous, with capillary and mixed types each making up about one-quarter of the specimens. Multiple intestinal hemangiomas are much more common than are solitary intestinal lesions. Histologically, these tumors are discrete masses composed of well-developed, thin-walled capillaries and veins. They are usually submucosal. Seventy percent of patients present with bleeding, but intussusception and obstruction also occur.26,29 Treatment consists of resection of the lesion, although in the case of multiple lesions, finding the precise site of bleeding may be difficult. Preoperative angiography may be helpful in localizing briskly bleeding lesions.

Lymphangiomas

Lymphangiomas are malformations of sequestered lymphatic tissue that fail to communicate with the normal lymphatic system. In one large collection of benign small bowel tumors, they represented nearly 4% of the tumors, but in most series, they are less common.20,29–33 They most commonly present with symptoms of obstruction due to their large size, but may also present with GI bleeding.34,35 Resection with adequate margins and primary anastomosis appear to be sufficient treatment, although it is not known whether these lesions can recur in another segment of intestine.

Malignant Neoplasms

Adenocarcinoma

Adenocarcinomas are the most common malignant tumors in the small bowel. They most commonly arise in the seventh decade of life and are seen slightly more often in men than in women. They are found equally in the duodenum and in the jejunum (45% each) and least commonly in the ileum (10%). The reason for this distribution in the proximal small bowel is unknown. Experimental data using the carcinogen azoxymethane have demonstrated a similar excess of tumors of the proximal small bowel. Some have postulated that the richness of IgA-secreting cells in the ileum accounts for its relative sparing from adenocarcinoma by neutralizing luminal carcinogens.3 Others have noted that the abundance of the enzyme benzopyrene hydroxylase may play a protective role by detoxifying potential carcinogens.36 Still others note the alkaline content of the small bowel and the rapid turnover time of cells in the small bowel mucosa.

The etiology of adenocarcinomas of the small intestine is uncertain, although they have been associated with nontropical sprue,37,38 and with regional enteritis.39,40 Despite the well-known correlation of colonic cancer with ulcerative colitis, much less evidence exists to indict Crohn’s disease as a cause of adenocarcinoma of the small bowel. The few reports that are available show a slightly increased risk for tumors associated with Crohn’s disease to occur in the terminal ileum and in other sites where Crohn’s disease is active.41–44 The age at diagnosis is usually 10 years younger for the Crohn’s patients than for the population at large. As with ulcerative colitis, the diagnosis of Crohn’s precedes the tumor by about 10 years. Celiac sprue is known to predispose to intestinal lymphoma; it has also been associated with adenocarcinoma.38 The numbers cited in case reports are few, but the presence of disease in otherwise noncharacteristic locations seems to lend credence to the theory that gluten-mediated jejunoileitis is also an independent risk factor for the development of adenocarcinoma of the small bowel, as well as lymphomas.37,38,45 Adenocarcinoma of the small intestine, often aggressive, can affect children and is usually associated with degeneration of a Peutz-Jeghers hamartoma.46

Symptoms of adenocarcinoma of the small bowel range from obstructive symptoms, such as vomiting and jaundice for those with duodenal tumors, to indistinct abdominal pain, weight loss, and anemia for more distal lesions. The most common complaint is abdominal pain in 30 to 70%. Weight loss is also common, occurring in more than 50%. Obstruction is found in up to 70% prior to presentation. In the collected Mayo series, 71% had either overt or clinical evidence of blood loss.47

Metastasis can occur via lymphatics, by a hematogenous route (liver, lungs, and bone most commonly), or by direct extension through the serosal surfaces and into the peritoneal cavity. Due to the insidious nature of adenocarcinomas, they tend to present late with either lymph node involvement or distant metastases. In one series, up to 70% had spread beyond local sites.48 In another series, there was 67% node involvement and 22% had distant metastases.49

The primary treatment for adenocarcinomas is surgical resection, with removal of lymph nodes and the vascular pedicle. Margins of 5 cm are considered acceptable. Recent reports have indicated that even this treatment does not yield good survival rates for node-positive patients. In patients with involvement of the proximal duodenum, pancreatoduodenectomy may be necessary. In those with disease in the terminal ileum, a right hemicolectomy is indicated. In those with jejunal involvement, wide resection is recommended. In patients deemed resectable, only about 30% can be expected to survive 5 years.49,50 In one series,49 there was a 70% 5-year survival in node-negative patients, but only a 13% 5-year survival in those with positive nodes.

All attempts should be made to resect the primary lesion to prevent mucosal bleeding. For patients deemed unresectable intraoperatively, some have advocated the use of intraoperative radiation therapy.51–53 The lack of clinical trials makes this therapy difficult to recommend in a setting other than centers specialized for it. External beam radiation may be helpful to palliate symptoms, but, once again, there is a lack of published experience with this treatment. Chemotherapy usually incorporates 5-fluorouracil and nitrosoureas. In some settings, these agents have led to tumor regression and apparently increased lengths of survival.54

Carcinoid

The carcinoid is an infrequently seen but well-studied tumor of the small bowel. The first description of a carcinoid was by Lubarsch in 1888.55 The name carcinoid was applied by Obendorfer in 1907,56 but the exact nature of the tumor was not determined until 1928 when Masson described its origin as the chromaffin cell.57 Carcinoids commonly occur in the small intestine, as well as in the appendix, stomach, and rectum. Although they may be seen in any site derived from endoderm (such as lung or gonadal carcinoids) or from a teratoma, 95% are found in the digestive tract. Epidemiologic study failed to detect etiologic factors in the majority of cases.41 Depending on the series, the small intestine or the appendix contains the greatest number of these tumors.58 In contradistinction to adenocarcinoma, the carcinoid tends to arise in the distal small intestine rather than in more proximal sites. In the series reported by Moertel, all surgically confirmed, 3% were in the duodenum, 5% in the jejunum, 32% in the proximal ileum, and 60% in the distal ileum.59 The median age of discovery is 60 years, and males constitute 50 to 60% of patients.15,60

In 1963, Williams and Sandler classified carcinoids according to their embryonic site of origin and their usual histologic type.61 They found that those discovered in the foregut (bronchi, stomach, pancreas, biliary tract, and parts one and two of the duodenum) tended to have a histologic pattern of trabeculae and were occasionally associated with the carcinoid syndrome. Those arising from the midgut, the most common site, had a histologic pattern of nests and invading cords were most commonly associated with the carcinoid syndrome. Finally, those found in the hind gut (descending colon and rectum) had a mixed histologic picture but were infrequently involved with the carcinoid syndrome.62

Due to their slow rate of growth and indolent course, carcinoids tend to remain asymptomatic for long periods, some patients reporting having had symptoms for as long as 20 years prior to diagnosis.59 The most common symptoms caused by these tumors include intermittent abdominal pain in 27%, probably caused by partial bowel obstruction as a result of kinking of the bowel associated with dense mesenteric fibrosis. Also noted was nausea and vomiting in 11%, bleeding in 10%, a mass in 10%, and diarrhea in only 5%.63 It was also found that 26% of patients had metastatic disease at the time of diagnosis. More than 30% of these tumors had metastasized to local lymph nodes or liver prior to their surgical discovery.64,65

The size of the tumor is a good predictor of its metastatic potential. In the Moertel series, there were no metastases in tumors less than 0.5 cm in diameter, 15% in those 0.5 to 0.9 cm in diameter, 72% in those 1.0 to 1.9 cm in diameter, and 95% metastases in those larger than 2 cm. Most series report that 30% of these tumors are multicentric.47,63 The cure rate of patients with multicentric disease in whom all visible tumor was resected remains low. At 5 years of follow-up, 20% have relapsed, but recurrences continue up to 25 years postsurgery.47 Even in light of the natural history of this tumor, aggressive surgical therapy is warranted, including segmental resection of ileal lesions with right hemicolectomy as needed. Jejunal lesions should also be widely resected, and duodenal lesions, although rare, may require a modified Whipple pancreaticoduodenectomy. In the case of advanced disease, there may be some benefit to debulking procedures, but this remains controversial, since the absolute size of the tumor does not correspond well with the degree of symptoms.47,66,67 Some authors recommend aggressive treatment even in patients with widely metastatic disease, including resection of all intra-abdominal tumor deposits, segmental liver resection as needed, and hepatic arterial embolization. Cholecystectomy also has been performed to prevent gallbladder necrosis during hepatic embolization. Pretreatment with the synthetic somatostatin analogue octreotide helps to prevent carcinoid crisis.68 Although it has not been proved whether this aggressive surgical approach increases survival, it has yielded biochemical remission in up to 25% of patients and regression of hepatic metastases for long periods.69

Composite tumors, those that display characteristics of both carcinoid tumors and adenocarcinomas, are well described in the appendix but are less well known in the small intestine. These tumors are relatively rare, with most reports to date encompassing only one or two cases. They are aggressive tumors with a metastatic potential similar to that of adenocarcinoma and should be treated as adenocarcinomas. Lymphatic metastasis appeared histologically to be adenocarcinoma in two cases and carcinoid in one. Thus, it seems that these tumors may arise from cells with pluripotential patterns of differentiation.70

Few of the patients with large tumor burdens and metastatic disease exhibit the carcinoid syndrome. It is believed that the metastatic component is necessary to ensure drainage of the compounds involved in the syndrome into the systemic circulation and to provide an adequate tumor mass to produce large amounts of peptidergic products. However, some patients with the carcinoid syndrome and no known metastasis have been described.71 The vast majority of such patients have an abnormal 5-hydroxyindoleacetic acid excretion in a 24-hour urine collection. The usual symptoms include diarrhea and flushing and, occasionally, asthma or dyspnea. This is believed to be caused by the large amounts of serotonin, histamine, and bradykinin that may be released by these tumors. The carcinoid heart syndrome, caused by fibrosis on the right side of the heart, is a late sign.

Most authors still advise surgery to resect the primary tumor and decrease the tumor burden as much as possible.58 Treatment for the carcinoid syndrome includes antidiarrheals for the intestinal manifestations. Calcium channel blockers have proved useful both experimentally and clinically,72 as has octreotide.73 Chemotherapy is useful in patients with very advanced disease.74,75

Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GIST) is the current nomenclature for a diverse group of benign or malignant gastrointestinal neoplasms derived from embryonic mesoderm that may have smooth muscle or neural differentiation, or may appear as undifferentiated spindle cell lesions. Malignant GIST, also known as sarcomas, constitute 15 to 20% of the malignant tumors found in the small bowel.16 Most present either as an abdominal mass causing bowel obstruction evidenced as nausea and vomiting, as pain, or as GI bleeding. Sarcomas usually grow rapidly. Masses 5 cm in diameter or greater are common.76 This rapid rate of growth explains the propensity for GI blood loss, since these tumors may outgrow their blood supply, become necrotic, and ulcerate. Blood loss is usually chronic, with laboratory studies revealing a microcytic anemia.16,20,27,33,76,77 Fistulas and abscesses are also caused by tumor necrosis. Sarcomas usually occur in patients over the age of 50,77 with similar rates of occurrence in both sexes. These tumors tend to spread by local extension, growing into the mesentery, surrounding serosal surfaces, or omentum. Vascular metastases are common but lymphatic spread is unusual. Histologic types include leiomyosarcoma, which is by far the most common sarcoma of the small bowel.16 Other types include angiosarcomas, a rapidly growing tumor with a poor prognosis; fibrosarcomas and liposarcomas, both of which carry an intermediate prognosis; and neurosarcomas, which are rare, except in patients with Recklinghausen’s disease.

These tumors are usually easy to detect with radiologic examination because of their large size, and CT scanning is also an excellent diagnostic test. In one study, all leiomyosarcomas in the series were detected as mass lesions and had a characteristic appearance.15 For angiosarcomas, angiography may be useful to determine feeding vessels.

As with other tumors of the small bowel, the primary treatment for sarcomas is surgical resection with wide margins. With sarcomas, lymph node dissection is not as critical, however, due to the rarity of lymphatic spread. An aggressive approach for metastatic disease may also be warranted in the case of hepatic metastasis, although data to support this are scanty. The use of adjuvant radiotherapy and chemotherapy has been proposed by some. Sarcomas elsewhere in the body respond to radiotherapy and those of the abdominal cavity would be expected to do the same, although tolerable doses are generally lower than used elsewhere for sarcomas.78 Temporary disease control using radiation therapy following incomplete resection has been reported.78 Chemotherapy, as with sarcomas elsewhere in the body, focuses on doxorubicin-based regimens. These regimens are used primarily when surgical resection is incomplete, in order to slow tumor growth and metastasis.79 Although often used adjuvantly too, few data exist to support this practice.

Lymphoma

Primary lymphomas of the GI tract account for only about 5% of all lymphomas, but approximately 20 to 25% of all primary small bowel tumors found at laparotomy are lymphomas.20,80 There is a slight male predominance of about 1.5 to 1, and the median age is lower than that of persons with other small bowel tumors, about 49 in one large series.20

Symptoms are similar to those found in other small bowel tumors, including abdominal pain, nausea, vomiting, and GI bleeding, which may be occult. Perforation may occur in some patients, causing an acute abdomen.77 Systemic signs of lymphoma, such as lymphadenopathy and fever, may also be present. Radiographic studies are helpful in the diagnosis. A CT scan with oral contrast is of value.81 A mass with bulky adenopathy is highly suggestive of abdominal lymphoma.79

Most practitioners believe that treatment should be surgical, with adjuvant chemotherapy playing a major role. When radiation therapy was used first, high rates of tumor necrosis, perforation, and bleeding were encountered.82 The surgical approach should involve removal of the bowel segments, with wide margins, and the involved mesenteric lymph nodes, if possible. Margins need to be completely clear of tumor since lymphomas may spread for long distances in the submucosal plane. The survival rate following complete resection is 45% in most series.83–85 Although the role of adjuvant chemotherapy in patients after potential curative resection is still unproven, many advocate its use.31,84 In patients with unresectable lymphoma, radiation therapy and chemotherapy are recommended.86

One possible cause of lymphoma is celiac disease, although this disease association is uncommon. Harris and colleagues documented 15 cases in which the diagnosis of celiac sprue was made first and subsequently a lymphoma was diagnosed. They then followed 202 patients with sprue. Eight developed small bowel lymphoma with a mean onset of 22 years.87 Two British reports have substantiated Harris’ and colleagues observation of a 5 to 10% correlation between lymphoma and preceding celiac sprue.88,89 The lymphoma associated with sprue was of the T-cell type in one study.90 All cases of intestinal T-cell lymphoma (ITCL) in the Berlin lymphoma registry were studied to determine immunohistochemical profile. Of the 20 patients, 8 had preceding celiac disease. The characteristic immunohistochemical profile led the authors of that study to conclude that ITCL is derived from an intraepithelial T-cell subset of the small intestine.91

Lymphomas of the small bowel have developed following cyclosporin therapy for organ transplant. These tumors appear on an average of 20 months after the initiation of cyclosporin. Involvement of the small bowel was seen in 28% of the non-Hodgkin’s lymphomas occurring in patients on cyclosporin. All responded well to treatment, including resection, conventional chemotherapy and radiation therapy, acyclovir, and reduction of immunosuppression.92

Small bowel lymphomas also occur in AIDS. In one study of 28 patients with AIDS and GI complaints, 3 were found to have lymphomas of the stomach and duodenum. Other reports of small bowel lymphoma and AIDS represent early case reports.93,94 In one series of 904 patients with AIDS, 36 required surgery for intra-abdominal conditions, one of which was an ileal lymphoma and another a perforated Kaposi’s sarcoma.95

The most common tumor of the small bowel in children is non-Hodgkin’s lymphoma, with the distal ileum the most common site. In a recent study of 47 children with GI lymphoma, 17 (36%) had the small intestine as the primary site. All cases were high grade. Children with colonic lymphomas had significantly better overall survival. Treatment was surgical resection and postoperative chemotherapy, since radiotherapy was found to be of limited use in these rapidly growing tumors.96

Small bowel lymphoma is particularly common in the Middle East, especially in southern Iran, where these tumors are the most familiar neoplasm. This Mediterranean lymphoma is found in children and young adults.97–99 Patients tend to be from lower socioeconomic groups, with a background of malnutrition. The tumor progenitor cell is believed to be the perifollicular B cell, which produces IgA. The tumor releases an excess of alpha-heavy chains, which are detectable in the serum.100 Combination chemotherapy is useful in nonresectable disease, although an optimal regimen has not been defined.101 This lymphoma behaves differently from other small bowel lymphomas and appears to have a worse prognosis.

Tumors of the Appendix

Tumors of the appendix are infrequent, and when they are found, it is almost always during a routine appendectomy. In the classic study of 71,000 specimens taken at appendectomy, Collins found 958 malignant and 3,271 benign tumors, with an overall incidence of 4.6% for benign tumors and 1.35% for the malignant tumors.102 Another large series reported a total of 8,699 appendectomies yielding 101 total tumors and 60 malignant neoplasms, for an incidence of 1.2% overall and 0.7% for malignant tumors.103

Benign tumors of the appendix consist of leiomyomas, neuromas, and lipomas. Malignant tumors of the appendix include carcinoids, mucoceles, and adenocarcinomas. The original classification of these tumors was that of Uihlein and McDonald in 1943, and this classification is still used, but with modifications.104 Despite 50 years of use of this system of classification, some still consider the malignant mucocele and adenocarcinoma to be histologically identical and argue that they should be regarded as the same process. Despite this microscopic similarity, however, the natural histories of the two tumors are distinct and most consider them different disease processes.105 In the series by Collins, the carcinoids made up 51% of the malignant tumors found, mucoceles accounted for 32%, and adenocarcinomas were 6%.104 The remainder consisted of a large number of rare tumors, including sarcomas. A complex tumor bearing some features of carcinoid and some of adenocarcinoma, but distinct from both, exists. For this lesion, the term adenocarcinoid has been coined.29,106

Malignant Tumors

Carcinoids

Carcinoid is the most common tumor of the appendix, and the appendix is the most common site of carcinoid tumors. Whether this represents the fact that the appendix is more frequently subject to histologic examination following appendectomy is uncertain. In the Collins series, carcinoids were found in 0.7% of all appendectomy specimens.102 Most other series report a lower incidence of around 0.2 to 0.3%.107 In most series, there is a preponderance of female patients approaching two or three to one.60 The frequency of metastasis is rare, although with long-term follow-up, one group found the rate of metastasis to be 21% with primary lesions between 2 and 3 cm in diameter and 44% in those with lesions greater than 3 cm in diameter. Other authors have found metastases in tumors less than 2 cm in diameter. Nonetheless, the rarity of these large lesions gives an overall rate of metastasis of only 1.3 to 4.7%.107,108

Since metastases are found even with primary tumors of 1.5 to 2 cm in diameter, it is recommended that patients in this group undergo right hemicolectomy. Others advise that tumors under 2 cm require only an appendectomy as adequate treatment. Despite the frequency with which carcinoids are discovered, few cause metastatic disease. Thirlby and colleagues, in 1984, reported 46 cases of metastatic carcinoid tumor, of which 28 involved only regional lymph node metastasis. Six patients of the remaining 18 developed carcinoid syndrome, and there were four reported deaths.109 All of these patients had a primary tumor larger than 2 cm in diameter. Given the frequency of invasion of the mesoappendix by carcinoid (16%), mesoappendiceal involvement alone does not warrant right hemicolectomy.109

The carcinoid tumor is believed to arise from the argentaffin cell and, as these cells continue to develop throughout life, the number of carcinoids continues to increase. At laparotomy, these tumors appear as small yellow nodules, usually in the distal third of the appendix. In only 5% of patients is there involvement of other portions of the GI tract with other primary carcinoid tumors.107 Moertel estimated the incidence of appendiceal carcinoids in various age groups to be 0.33% in 0 to 19-year-olds, 0.69% in 20- to 39-year-olds, and 0.58% in 40- to 59-year-olds. If this rate of incidence, based on findings from appendectomies, is correct, then carcinoids of the appendix would be the most common tumor in the 20- to 39-year-old age group. However, the existence of a carcinoid in the appendix no doubt increases the likelihood of appendectomy, thereby skewing the results.

Three series have described experiences with carcinoids of the appendix in the pediatric population. The youngest patient reported was 3 years old. In the most recent of the series, the largest tumor found was 1.2 cm. In 65%, there was invasion of the muscularis or of the muscularis and serosal layers, which compares with 77 to 90% in other series. In all cases, the tumor was less than 2 cm in diameter, and only appendectomy was performed. There have been no recurrences.110–113 It appears that appendectomy alone is sufficient treatment in children if the initial lesion is less than 2 cm in diameter.

The role of the carcinoid in causing acute appendicitis is unclear. In most cases, the tumor occupies the distal third of the appendix. Distal location was found in 82% in the series reported by Collins102 and in 71% by Moertel and colleagues.107 Of appendiceal tumors discovered during appendectomy for appendicitis, only 30% were apparently involved in causing the appendicitis due to obstruction of the appendiceal lumen.107,114

The prognosis for carcinoid of the appendix is good. In his series of 2,837 cases, Godwin reported a 99% 5-year survival.65 Although the literature reports at least seven patients with metastatic disease following discovery of a primary lesion 1.5 to 2 cm in size, the standard recommendation is still simple appendectomy for lesions smaller than 2 cm. Given this treatment and the relatively benign course of metastatic carcinoids, even if metastasis were to occur, a good prognosis could be expected following the diagnosis of appendiceal carcinoid tumor.

Mucoceles

A mucocele is any one of a number of lesions of the appendix that share a common feature of a dilated, mucus-filled appendiceal lumen. The underlying pathology may be a hyperplastic polyp, a benign neoplasm, such as cystadenoma; or a malignant tumor, such as cystadenocarcinoma. These lesions are almost always found during appendectomy and complicate about 0.3% of all appendectomies.115 Because these cystic lesions may be due to a hyperplastic or neoplastic process, whether benign or malignant, some authors have advocated a classification system different from that of Uihlein and McDonald. Instead, they support the use of a system based on histologic findings rather than on the presence of a cystic lesion.116 Others have found a continuous spectrum of histologic change in mucoceles, given adequate pathologic study, and defend the use of the descriptive term mucocele as that of a specific neoplastic process.117 In this system, the hyperplastic polyp is considered a precursor lesion, which does not represent a neoplasm but is a common response to inflammation.118 According to this classification, a cystic appendix without neoplastic change would be thought to arise simply due to obstructive changes. In the rare cases of cystadenocarcinoma located near the tip of the appendix where they do not cause luminal obstruction, the histology is almost indistinguishable from that of ordinary colonic carcinoma. One author has found a female-to-male ratio of four to one,119 with a mean age at presentation of 55 years.120 A consequence of mucoceles of the appendix (cystadenomas and cystadenocarcinomas) is pseudomyxoma peritonei. This lesion, characterized by large quantities of mucuslike material in the peritoneal cavity, is considered to represent dissemination of mucinous cystadenocarcinoma within the peritoneal cavity (see Pseudomyxoma Peritonei below).117

A rare lesion of the appendix, intermediate between adenocarcinoma and carcinoid, is the adenocarcinoid. This lesion arises from the base of glands and spares the luminal mucosa; it is composed of slender tuboglandular structures, nests of goblet cells, or a mixture of both.121 The tumor represents, at most, only 5% of all appendiceal neoplasms.122 Despite their small size when found at celiotomy, adenocarcinoids behave quite energetically, with a propensity to metastasize to the ovaries. They should be treated aggressively with right hemicolectomy, which is considered curative if the margins are clear and there are no involved lymph nodes.29

The diagnosis of appendiceal mucocele is almost never made preoperatively and is usually an incidental finding at celiotomy. In some instances, however, the patient may complain of dull abdominal pain or have a mass found at barium enema or colonoscopy. In these cases, the mucocele is well seen by either CT or ultrasonography, although other cystic lesions of the peritoneal cavity, such as ovarian cysts, duplication cysts, mesenteric and omental cysts, or an abscess, may have a similar radiographic appearance.123

Treatment is surgical resection, with the extent of resection dependent on the underlying histology. Conversion of laparoscopic appendectomy to an open procedure is recommended due to the risk of peritoneal implants when an appendiceal mucinous tumor is found.27 In the case of hyperplastic polyps or cystadenoma, a simple appendectomy is considered curative. In the case of cystadenocarcinoma or cystadenocarcinoid, formal right hemicolectomy with removal of draining lymph nodes is mandatory.124

Adenocarcinoma

Primary adenocarcinoma of the appendix is an extraordinarily rare tumor, with fewer than 300 of these lesions described in the collected world literature.125 Further complicating the literature concerning primary adenocarcinoma of the appendix is its frequent histologic similarity to cystadenocarcinoma of the appendix. The incidence of adenocarcinoma varies from 2 in 45,000 appendectomies, a 0.004% incidence,126 to 57 in the 71,000 appendectomies reported by Collins,102 an incidence of 0.08%. This tumor is most common in persons aged 51 to 55, but patients as young as 17 years of age have been reported. Some report no sex bias in the occurrence of this tumor, whereas others note a male predominance of anywhere from 4:1 to 2.8:1.125,127,128 Perforation may complicate the clinical picture, occurring in up to 40% of cases, but perforation alone has little effect on overall survival.129

Adenocarcinomas behave aggressively, with metastatic disease frequently found at the time of celiotomy. The degree of metastatic involvement varies with the histologic grade; about 30% of the well-differentiated tumors are found to have metastasized, whereas nearly 70% of the poorly differentiated tumors are metastatic at the time of laparotomy.125,127 Because these tumors behave in a fashion similar to that of colonic adenocarcinomas, they must also be treated with the same aggressive surgical approach. Right hemicolectomy with resection of draining lymph nodes is advocated for these tumors when they are diagnosed histologically.130 Despite the availability of appropriate treatment, survival remains low: 5-year survival is 18.7% for all patients and 43.3% for those deemed resectable.118,125 The Dukes’ stage is also a good prognostic indicator. In one recent series, the 5-year survival of those with a Dukes’ stage A lesion was 17 of 18 (94%); for stage B, it was 38 of 46 (83%); and for stage C, 7 of 16 survived 5 years (44%).127 In this same series, a second primary tumor at a distant site (colon, cervix, breast, prostate, esophagus, stomach, ovary, or bladder) was found in 11% of patients, and in the series reported by Chang and Attiyeh, 32% had second tumors. This suggests some genetic role, loss of a tumor suppressor gene, or a defect in immunosurveillance.125

Neoplasms of the Peritoneum

Mesotheliomas

Most true mesotheliomas are presumed to be caused by exposure to asbestos. Asbestos is, however, not unique in its ability to induce mesotheliomas, as some autopsy series have been unable to document any asbestos in the tissue of patients dying of mesotheliomas.131,132 The malignant form of the disease, malignant mesothelioma, shows extreme male predominance (93% in one series) and frequently a history of asbestos exposure (83% in this series).133 The microscopic findings include extensive cell vacuolization, rare psammoma bodies, the presence of hyaluronic acid, and a lack of mucin.134 This tumor tends to spread to the pleural space in about 50% of patients and, even with aggressive treatment, the prognosis is poor, with a median survival of 12 to 17 months.107,135–137 Treatment consists primarily of surgical palliation. Chemotherapy and radiation therapy are sometimes used and may cause a partial response.138 If laparoscopy is used to make an initial tissue diagnosis, port sites should be confined to the abdominal midline as port site recurrence has been reported requiring extensive abdominal wall resection.139 Recent chemotherapeutic regimens have shown some activity.140

Two benign variants of peritoneal mesothelioma exist. The first, cystic mesothelioma, is a rare tumor consisting primarily of cysts attached to the peritoneum. This tumor primarily affects young women with a median age of 36 years, and there is usually no history of asbestos exposure. Although the disease tends to recur even with aggressive surgical removal, there have been no deaths attributable to this process in the 21 recorded cases.28 Benign papillary mesothelioma occurs in both men and women and consists of papules lined by a single layer of hyperplastic mesothelium. This lesion is also thought to require only follow-up care after excisional biopsy, as no malignant potential has been reported.141,142

A neoplasm of the peritoneal cavity believed to arise from the serous lining cells of the peritoneal cavity is serous surface carcinoma. This tumor is seen almost exclusively in women and is histologically identical to serous carcinoma of the ovary. However, the tumor does not arise from the ovary because it has been found in women who had a bilateral oophorectomy up to 40 years before its discovery. Instead, it is thought to be derived from a common mullerian stem cell, which also lines the peritoneal cavity.143 Treatment consists of total abdominal hysterectomy and salpingo-oophorectomy as needed, with debulking of the tumor and follow-up chemotherapy. Nonetheless, survival is poor, with nearly 100% mortality and a mean survival of 14 months.143

Another rare tumor of the peritoneum, pseudomyxoma peritonei, is caused by the rupture of a cystadenocarcinoma of the appendix or colon with seeding of these mucin-producing cells across the peritoneal surface.10 Even in female patients with synchronous appendiceal and ovarian mucinous tumors, it appears that the appendiceal tumor is the primary source of the tumor.144 Patients with pseudomyxoma peritonei benefit from debulking procedures, and recent work has shown the benefits of intraperitoneal chemotherapy.145 Two commonly used agents with known effectiveness in both clinical and in vitro settings are 5-fluorouracil and mitomycin C. The usefulness of these intraperitoneally administered agents is limited by their inability to penetrate all areas of the peritoneal cavity. They are of little use in treating distant metastases, such as those to the pleural cavity or liver. Some intraoperative intraperitoneal chemotherapy has been performed with good results, but a single application of the chemotherapeutic agents is not curative. At present, the most effective treatment includes a debulking laparotomy with careful attention to allowing maximum penetration of postoperative intraperitoneal chemotherapy. Following intraperitoneal chemotherapy, a second-look laparotomy may be indicated to further assess therapeutic success, and after lysis of adhesions, to allow better penetration of subsequent chemotherapeutic agents throughout the peritoneal cavity.145 About one-third of patients will have disease recurrence after cytoreductive surgery and intraperitoneal chemotherapy. Recurrences tend to follow the sites of previous surgical removal but may occur in areas explored that did not have tumor at first operation, such as the retroperitoneum.146

Another rare tumor of the peritoneum is angiosarcoma. These tumors may appear benign histologically but usually act aggressively. They may arise following previous radiation treatment to the serous membranes. Treatment should be like that of other sarcomas.147

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Bookshelf ID: NBK20880
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