Aims
To identify neoplasms of the small bowel, and their epidemiology, aetiology and treat- ment.
Introduction
Tumors of the small bowel are rare, accounting for only 1–3% of gastrointestinal neoplasms [1].
The low incidence of tumors in the small bowel is intriguing given the fact that it comprises 75%
of the length of the alimentary tract and 90% of its surface area. Furthermore, the small intes- tine is located between the stomach and the colon, which both have a high incidence of neo- plastic diseases. The diagnosis is relatively dif- ficult because of the rare incidence of the disease and because of the non-specific presentation of small bowel tumors.
The limited ability to obtain good imaging of the small bowel further increases the interval between onset of symptoms and diagnosis [2].
Novel diagnostic techniques such as entero- clysis, magnetic resonance imaging (MRI), and enteroscopy provide better imaging and can provide the clinician with valuable informa- tion [3]. However, most of these diagnostic modalities require special expertise and are rarely applied for the diagnosis of non-specific gastrointestinal symptoms typical to small
bowel tumors. Local excision or segmental resection is the treatment of choice for benign lesions located distal to the ligament of Treitz.
Benign lesions arising in the duodenum, especially periampullary lesions, require more complex surgical intervention in the form of limited resection or pancreaticoduodenctomy (Whipple’s procedure).
The treatment of malignant lesions depends mainly on the histologic type and the stage of disease. Due to the lack of large retrospective or prospective randomized clinical trials, the treatment of small bowel malignancies, such as adenocarcinoma, is based mainly on the extrap- olation of data obtained from studies of malig- nancies with similar biological features. Because the natural history of adenocarcinoma of the duodenum has many similarities with adeno- carcinoma of the stomach, similar treatment guidelines are recommended.
Tumors of the jejunum and ileum, mean- while, resemble adenocarcinoma of the colon and therefore should be treated accordingly.
Surgery remains the mainstay of treatment in all adenocarcinomas of the small bowel regardless of their location. Selection of adjuvant chemo- therapy should be done according to the loca- tion and stage of disease [4]. Chemoradiation might be beneficial for adenocarcinoma of the duodenum, because of its positive effect on gastric cancer and the fixed location of the duo- denum. The role of radiation therapy in adeno- carcinomas arising in the other portions of the small intestine is limited because of its mobility 5
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Neoplasms of the Small Bowel
Aviram Nissan and Martin S. Karpeh
and the high risk of radiation damage to the remaining small bowel.
Epidemiology
The incidence of both benign and malignant small bowel neoplasms is low, and the incidence of neoplasms per surface area is even lower. The majority (two-thirds) of small bowel lesions are malignant with a crude incidence of 0.4 to 1 cases per 100 000 population per year [5]. The incidence varies according to the method of diagnosis: surgery or autopsy. In a comprehen- sive analysis [6], data from cancer registries par- ticipating in the Surveillance, Epidemiology, and End-Results (SEER) Program from 1973 to 1990 were analyzed to determine the incidence of small bowel tumors. An average annual incidence rate of 9.9 per million people was reported, with carcinoid and adenocarcinoma being the most common histological subtypes, followed by lymphomas and sarcomas. Over 90% of cases occurred in people over the age of 40. During the 18-year study period, the inci- dence of small bowel tumors has risen slowly.
In a review of the American National Cancer Database, maintained by the American College of Surgeons and the American Cancer Society, 14 253 cases of small bowel cancer diagnosed between 1985 and 1995 were found [7].
Adenocarcinoma was the most common histo- logic subtype with 4995 (35%) cases followed by 3934 (28%) cases of carcinoid, 2967 (21%) cases of lymphoma, and 1441 (10%) of sarcoma; 55%
of the adenocarcinomas arising in the duode- num, 18% in the jejunum, 13% in the ileum, and the remaining 14% in non-specified sites.
Incidence reports of small bowel neoplasms vary from region to region (Table 14.1). The variance in incidence and breakdown to histo- logic subtypes reflects not only true variability but also the small number of cases in each report.
Aetiology
The low incidence of small bowel neoplasms compared with the neighboring organs, stomach, and colon is intriguing. Both adeno- matous polyps and adenocarcinoma are dis- tributed unevenly, with the vast majority of these neoplasms located in the 25 cm long duo- denum. By contrast, the minority of tumors are located in the remaining 300 cm of jejunum and ileum. Despite its length and relatively large surface area and its exposure to a variety of ingested carcinogens, the small bowel is resis- tant to carcinogenesis. The relative resistance of the small intestine was studied by many investigators [8,9], but neither animal models nor clinical studies provided solid evidence to support one hypothesis or another. Cooper et al [10] compared the Bristol Royal Infirmary experience of treating primary adenoma and adenocarcinoma of the small bowel with the effects of treating 88 rats with intravenous azoxymethane (a known colonic carcinogen). In the patients 40% of the neoplasms were located in the duodenum, 24% in the jejunum, and 36%
in the ileum, whereas in the azoxymethane- treated rats 65% of the neoplasms were located in the duodenum, 32% in the jejunum, and 3% in the ileum. The ratio of small to large bowel neoplasms in their experiment was 1 to 4,
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Author Period Region N Adenocarcinoma Carcinoid Lymphoma Sarcoma Other
(years) (%) (%) (%) (%) (%)
Garcia Marcilla 15 Spain 69 38 10 42 10 0
Frost 30 California 63 6 15 13 3
DiSario 25 Utah 328 24 41 22 11 2
Serour 26 Israel 61 30 10 37 23 0
Ciccarelli – Connecticut 51 33 39 16 12 0
Laws 16 Alabama 45 36 29 11 24 0
Barclay 30 Canada 209 35 45 10* 9 1*
Howe 10 USA (NCDB) 14 253 35 28 21 10 6
*Lymphomas and other tumors are reported together.
NCDB, National Cancer DataBase.
compared with 1 to 50 in reported series in humans.
This observation might imply a connection between bile and carcinogenesis, but the results were the same when the experiment was repeated in rats whose bile was surgically diverted.
Predisposing Factors
The predisposing conditions for small bowel neoplasms can be divided into three groups (Table 14.2): (a) inflammatory disorders such as Crohn’s disease, (b) disorders of the immune system such as AIDS, congenital immunodefi- ciency disorders, or patients receiving immuno- suppressive therapy, and (c) genetic disorders such as familial adenomatous polyposis (FAP) or hereditary non-polyposis colon cancer (HNPCC).
Other factors including occupational hazards and lifestyle factors such as smoking or alcohol intake were investigated in two European mul- ticenter case-control studies [11,12]. A cohort of 70 patients diagnosed with small bowel adeno- carcinoma (SBA) during the study period (1995–1997) were compared with 2070 matched controls. Beer and spirits intake were associated with small bowel adenocarcinoma, with an odds ratio (OR) of 3.5 and 95% confidence intervals (CI) of 1.5–8.0. However, there was no associa- tion between smoking or total alcohol intake and adenocarcinoma of the small bowel. In a
second study of the same group, investigators identified occupational clustering of SBA. The strongest industrial risk factors for SBA were dry cleaning, manufacture of workwear, mixed farming (women), and manufacture of motor vehicles (men). A significantly increased risk of SBA was found among men employed as building caretakers (OR 6.7; CI 1.7 to 26.0) and women employed as housekeepers (OR 2.2; CI 1.1 to 4.9); general farm laborers (OR 4.7; CI 1.8 to 12.2); dockers (OR 2.9; CI 1.0 to 8.2); dry cleaners or launderers (OR 4.1; CI 1.2 to 13.6);
and textile workers (OR 2.6; CI 1.0 to 6.8).
Regional Enteritis (Crohn’s Disease)
Regional enteritis or Crohn’s disease is an inflammatory bowel disease that affects mainly people in their 3rd and 4th decades of life. It has long been associated with a high incidence of adenocarcinoma of the small bowel and colon. The first case of small bowel malignancy identified in a patient with Crohn’s disease was reported by the same group that originally described the disease in 1932. Interestingly, when the surgical approach to the treatment of Crohn’s disease was changed from radical resection to bypass surgery, the same group described a high incidence of adenocarcinoma in the bypassed loop of small bowel. Since then, numerous reports of small bowel neoplasms arising in patients with Crohn’s disease have been published.
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Table 14.2. Predisposing factors for small bowel neoplasms Inflammatory conditions
Regional enteritis (Crohn’s disease) Adenocarcinoma Lymphoma
Celiac sprue Lymphoma
Carcinoid Adenocarcinoma
Tuberculosis Lymphoma
Immune deficiencies
Acquired immune deficiency syndrome Kaposi’s sarcoma, lymphoma Common variable hypogammaglobulinemia Lymphoma
Genetic syndromes
Familial adenomatous polyposis Adenoma, adenocarcinoma
HNPCC Adenoma, adenocarcinoma
Peutz–Jeger Adenocarcinoma
Neurofibromatosis Adenocarcinoma
Coeliac Disease (Non-tropical Sprue)
Celiac disease is associated with an increased risk of certain gastrointestinal malignancies, especially of the small bowel. In addition to lym- phoma, there is an increased incidence of gas- trointestinal adenocarcinoma in patients with malabsorption due to celiac disease. This is fre- quently manifested by a loss of response to gluten withdrawal. Metachronous malignancies are well established in the colon, where adeno- carcinoma is common, but are exceptional in the small intestine. It was suggested that the subgroup of celiac patients unresponsive to gluten-free diet are more prone to develop small bowel malignancies, but this hypothesis was never proven. Cases of carcinoid tumors of the small intestine have been reported in patients with celiac disease. Small bowel lymphoma, both B cell and T cell, is the most common malignancy reported in association with celiac disease, with higher incidences of T-cell lym- phomas reported.
Tuberculosis
Intestinal tuberculosis is a rare disease in indus- trial countries and is often mistaken for Crohn’s disease. However, in Asia where intestinal tuberculosis is more frequently encountered, there are several reports of lymphoma compli- cating intestinal tuberculosis.
Acquired Immunodeficiency Syndrome (AIDS)
Patients with the acquired immunodeficiency syndrome (AIDS) are known to be at increased risk for developing a small bowel malignancy.
The rising incidence of small bowel lymphoma over the past two decades has occurred mainly in patients with immunodeficiency disorders such as AIDS or chronic immunosupression following organ transplantation. Balthazar et al [13] reported finding small bowel lymphoma in 52% of AIDS patients in their study of patients with intestinal lymphomas. Other authors also emphasized the association between AIDS and small bowel lymphoma. Most of the reported cases were diagnosed by laparotomy, presenting with intussusception, perforation, biliary obstruction, or small bowel obstruction.
Kaposi’s sarcoma is a neoplasm arising mainly in immunodeficient patients, The asso- ciation between Kaposi’s sarcoma and AIDS is well known. In fact, about one-third of all patients with AIDS have Kaposi’s sarcoma.
Gastrointestinal involvement has been noted in 50% of homosexual men with cutaneous Kaposi’s sarcoma and AIDS [14]. Numerous reports of Kaposi’s sarcoma of the gastroin- testinal tract in AIDS patients have been pub- lished in the medical literature. Diagnosis is made by small bowel imaging, either by com- puted tomography (CT) scan, MRI or entero- clysis. Recommended treatment depends on the individual patient’s general condition and the symptoms related to the lesion. Surgical resec- tion, if feasible, is the treatment of choice for Kaposi’s sarcoma of the small intestine. Others have suggested using radiation therapy as a single mode therapy or in the adjuvant setting.
Immunosuppression
Patients are at an increased risk for developing malignancies following organ transplantation.
Lymphomas, skin malignancies, Kaposi’s sarco- mas, and cervical/vulvar neoplasms are the most common, but visceral malignancies are also well documented, with a reported frequency ranging from 1% to 6% [15]. These visceral tumors represent a mix of neoplasms that were clinically occult at the time of transplantation and those that arise de novo after transplantation. There are several reports in the literature of small bowel neoplasms, mainly lymphomas, in patients receiving immunosuppressive therapy following solid organ transplant.
Hypogammaglobulinemia
Common variable hypogammaglobulinemia or adult-onset hypogammaglobulinemia are genetic disorders of the immune system. There are several reports describing an association between these rare disorders and lymphoma of the small intestine.
Familial Adenomatous Polyposis (FAP)
FAP is an autosomal dominant syndrome man- ifested by hundreds of adenomas that arise in
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the colon and rectum. It accounts for 0.5% of these cancers and the lifetime incidence of col- orectal cancer is nearly 100%. The adenomatous polyposis coli (APC) gene is located on chro- mosome 5q and well-described germline muta- tions are associated with the different FAP phenotypes.
Patients with FAP are at considerable risk of developing extracolonic manifestations of the disease. Desmoid tumors of the abdominal cavity, and duodenal adenomas and carcinomas are the most serious ones. It is estimated that some 10% of all FAP patients will develop desmoids, whereas 50–90% of FAP patients will suffer from duodenal adenomas predominantly concentrated on or around the major papilla.
Desmoid tumors and duodenal carcinomas are major causes of death in those patients in whom a prophylactic proctocolectomy has been performed. Although some investigators suggest that the adenoma–carcinoma sequence, which is generally accepted for colorectal ade- nomas, also applies for the duodenal adenomas in FAP patients, it is not clear whether these patients should be screened for upper gastroin- testinal adenomas. As these polyps are usually small, multiple, and difficult to remove, the benefit of endoscopic surveillance would be the early detection of cancer. In addition, evidence that screening and early treatment leads to an improvement of the prognosis is not available.
Although the role of (procto)colectomy in the treatment of large-bowel polyps is well estab- lished in FAP patients, the treatment of their duodenal counterparts is still open to debate.
The risk of the development of periampullary cancer is not high enough to warrant an aggres- sive prophylactic surgical approach after the discovery of duodenal adenomas. Some authors suggest intraoperative enteroscopy at the time of proctocolectomy and describe small bowel adenomas in 59% of the patients investigated.
Hereditary Non-polyposis Colorectal Cancer (HNPCC)
HNPCC is an autosomal dominant syndrome first described by Lynch. In HNPCC families colorectal cancers not associated with extensive polyposis are the hallmark of the disease.
Extracolonic neoplasms are also common and include endometrial, ovarian, gastric, hepato- biliary, and urinary tract cancers. Mutations in
DNA mismatch repair genes are found in 30–35% of HNPCC patients. DNA microsatellite instability with replication error-positive phe- notype are present in all HNPCC patients as well as in 15% of sporadic colorectal cancers.
The incidence of small bowel cancer in HNPCC patients was studied by Rodriguez- Bigas et al 16]. Forty-two individuals from 40 HNPCC families developed 42 primary and 7 metachronous small bowel tumors, including 46 adenocarcinomas and 3 carcinoid tumors.
Mismatch repair gene mutations were present in 15 of 42 patients (36%). The small bowel was the first site of carcinoma in 24 patients (57%).
Aarnio et al calculated the lifetime risk of developing various HNPCC-related cancers in a cohort of 414 patients, and found that the life- time risk for small bowel cancer was only 1%, compared with 78% for colorectal cancer.
Peutz–Jeghers Syndrome
Peutz–Jeghers syndrome is an autosomal dom- inant disorder characterized by gastrointestinal hamartomatous polyps and cutaneous pigmen- tation. Although the hamartomas typical of Peutz–Jeghers syndrome are benign in nature, it is has been recognized that Peutz–Jeghers patients are at increased risk for the develop- ment of malignant neoplasms of the small bowel. A molecular locus associated with this syndrome has recently been assigned to chromosomal region19p13.3. The LKB1 gene (GenBank accession number U63333), also referred to as STK11, had previously been iden- tified and is located at that site. This gene, which encodes for a serine threonine kinase, is present as a somatic mutation in most patients with Peutz–Jeghers syndrome. Patients with this mutation can also develop cancers at sites outside of the gastrointestinal tract such as in the cervix and ovaries.
Neurofibromatosis (von Recklinghausen’s Disease)
Neurofibromatosis type 1 (von Reckling- hausen’s disease) is an autosomal dominant genetic disorder characterized by café au lait spots, pigmented hamartomas (Lich nodules) of the iris, and cutaneous neurofibromas. While the association between neurofibromatosis and neuroendocrine tumors is well described, there 111
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are several reports of adenocarcinoma of the small bowel arising in patients with von Recklinghausen’s disease.
Clinical Presentation
In general, small bowel tumors, either benign or malignant, present with non-specific gastroin- testinal symptoms. Symptoms are related to the underlying histology, location of the tumor, and the extent of disease. The main groups of symptoms include pain, obstructive symptoms, symptoms related to bleeding, and symptoms related to effects on adjacent organs such obstructive jaundice secondary to periampul- lary tumors. Other symptoms such as palpable mass, perforation, or weight loss are present less frequently, although in a single report of 58 small bowel tumors, the most frequent symp- toms were weight loss and abdominal lump [17]. A large proportion of patients are asymp- tomatic at diagnosis.
Pain is non-specific, can be related to partial obstruction, stretching of the serosa, or neural invasion of the tumor. Usually it is a dull, inter- mittent pain related to food intake, and it is poorly localized. The non-specific pain that is characterized as varying in location and quality is usually interpreted as a functional disorder and many of the patients are diagnosed with
“irritable bowel syndrome” or their symptoms are attributed to other incidental findings such as gallstones or diverticulosis.
Bleeding is rarely acute; more commonly patients have chronic iron-deficiency anemia with related symptoms of weakness and fatigue.
Intermittent acute bleeding is the exception.
Small bowel obstruction as the presenting symptom of a small bowel tumor may occur as a result of a luminal obstruction related to concentric adenocarcinoma. Intratumoral
hemorrhage in a large leiomyosarcoma or lym- phoma can cause obstruction. A less common reason for small bowel obstruction is intussus- ception (Figure 14.1). In a retrospective series, Eisen et al reported 22 cases of small bowel intussusception. The majority were secondary to benign conditions and in the eight patients with malignant underlying lesions these were all metastatic lesions. Begos et al reported 11 cases of small bowel or ileocolic intussusception; only one case was secondary to primary leiomyosar- coma of the small bowel. Azar et al reported that 48% of 44 enteric intussusceptions studied were associated with malignant underlying lesions.
Only one patient had primary adenocarcinoma of the small bowel and another patient pre- sented with an undifferentiated carcinoma.
Overall it is estimated that the underlying etiol- ogy in 20–50% of adult small bowel intussus- ception is malignant and the vast majority of the cases will be metastatic. A summary of the findings of these three studies is outlined in Table 14.3.
Diagnosis
The non-specific nature of symptoms related to small bowel tumors results in a long interval between the onset of symptoms and diagnosis.
A lag period of up to 3 years for the diagnosis of benign tumors and 18 months for malignant tumors was reported. The diagnostic work-up is usually long, expensive, and involves at least one invasive procedure. The diagnostic work-up of the individual patient depends on the pre- senting symptoms. Patients presenting with pain or mild obstructive symptoms such as cramps, occasional vomiting, or distension are best approached radiologically, whereas patients presenting with bleeding symptoms will benefit from an endoscopic approach.
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Author N Benign tumors Malignant tumors Other benign conditions Primary Metastatic
Eisen 22 5 0 8 9
Begos 11 1 1 2* 7
Azar 44 6 2 19 17
* One patient with carcinomatosis.
Plain Abdominal X-Rays
The work-up of non-specific abdominal pain includes using plain abdominal films as an initial screening tool. The value of plain abdom- inal films in the diagnosis of small bowel tumors is limited to identifying complete or partial obstruction. In most cases, a CT scan of the abdomen and pelvis should be performed.
Computed Tomography of the Abdomen
A CT scan performed with both intravenous and oral contrast material can detect benign and malignant tumors of the small bowel and in many cases differentiate between the two
entities. Leiomyoma, the most common benign lesion of the small bowel, will appear as a round, smoothly outlined, homogeneous soft tissue mass, showing marked contrast enhancement.
In the absence of distant metastasis or clear invasion to adjacent organs, there is not a clear radiologic distinction between leiomy- omas and leiomyosarcomas. However, lesions greater than 6 cm tend to carry higher malig- nant potential. Large adenomatous polyps can be detected by CT scan. The image typically appears as an ill-defined intraluminal soft tissue mass, surrounded by oral contrast. Lipomas show up on the CT scan as a smooth, homoge- neous, ovoid mass, with a density comparable to fat. Intussusception is clearly seen on CT scan as a classic “target” lesion.
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Figure 14.1. Intraoperative photograph of a small bowel intussusception secondary to a primary small bowel gastrointetinal stromal tumor. The patient presented with classic symptoms of a small bowel obstruction.
The value of a CT scan is not only in the diag- nosis of malignant small bowel tumors, but also in the evaluation of the extent of disease and staging. The appearance of adenocarcinoma of the small bowel on CT scan is similar to the appearance of adenocarcinoma of the colon and includes the following radiological appearances:
annular stricture formation, polypoid mass, or other filling defect. Ulceration is frequently seen, either in the form of an ulcerated mass or an ulcer. However, duodenal ulcers are common and the presence of malignancy in these lesions is exceedingly rare. Ulcers located in the distal duodenum or other parts of the small intestine should be viewed as suspicious for malignancy.
Barium Radiology
Most of the small bowel tumor patients pre- senting with pain or partial obstruction will require further radiologic studies to establish the diagnosis. Upper gastrointestinal barium radiology is still the most frequent modality used in the work-ups of these symptoms. The correct diagnosis in symptomatic patients with small bowel tumors is obtained only in 50% of the cases by conventional barium radiology.
The low yield of conventional barium upper gastrointestinal studies results primarily from suboptimal distensibility and the presence of overlapping segments. Strictures, small masses or mural lesions such as leiomyomas may be easily overlooked, especially in the presence of an underlying disease such as Crohn’s disease.
Enteroclysis has an important role in the diagnosis of small bowel tumors. Briefly, a transnasal intubation of an 8F catheter is per- formed and manipulated beyond the ligament of Treitz. Methylcellulose-barium solution is used to distend the small bowel and obtain optimal imaging of the small bowel. Enteroclysis was shown to be effective in the detection of small bowel tumors and other diseases [18].
Magnetic Resonance (MR) Enteroclysis
Enteroclysis provides only indirect informa- tion about the small bowel wall and the sur- rounding tissues. MR enteroclysis, although still investigational, shows great promise in provid- ing accurate information about intraluminal,
mural, and extraluminal lesions of the small bowel. The small bowel is distended with 1500–3000 ml of methylcellulose-water solu- tion. The transit of the water in the small bowel is documented by MR fluoroscopy; the exami- nation is completed when the water reaches the colon in cross-sectional MR images.
Luminal distension by methylcellulose provides the ability to distinguish even small lesions.
Umschaden et al [19] compared conventional barium with MR enteroclysis in 30 patients with symptoms of either inflammatory bowel disease or small bowel obstruction. In 24% of the patients, the MR enteroclysis showed abnor- malities not seen in conventional barium ente- roclysis. Furthermore, extraluminal lesions, such as superior mesenteric vein thrombosis, were seen on the MR enteroclysis. The advan- tage of water as a contrast material is clear. It is well tolerated by the patients and unlike after a barium swallow, a subsequent CT scan or other radiographic examinations can be performed immediately after the MR without delay, and it avoids the problems associated with inspissated barium in patients with partial small bowel obstructions. However, since MRI is performed in a closed space not easily accessible to the medical staff, the risk of vomiting and subse- quent aspiration should be taken into account when MRI of partially obstructed patients is performed.
Small Bowel Endoscopy
The major advances in fiberoptic technology enabled the development of flexible endoscopic instruments for the diagnosis and treatment of gastrointestinal diseases. While esophagogas- troduodenoscopy and colonoscopy became the main diagnostic tools for esophageal, gastric, and duodenal tumors and tumors of the colon and rectum (colonoscopy), small bowel endoscopy (enteroscopy) is limited to very few specialty centers around the world. The main reason for the slow development of enteroscopy is the lack of a driving force. Small bowel pathol- ogy, excluding Crohn’s disease, which can be diagnosed and followed by small bowel barium studies and CT scan, is rare. The length of the small bowel and the technical complexity of passing an endoscopic instrument beyond the ligament of Treitz or retrogradely through the ileocecal valve necessitate the development of
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complex instruments and a long learning curve.
Therefore, developing complex and expensive instruments that require significant expertise and training for an infrequent use is not in the interest of most clinical investigators and indus- trial researchers.
Despite that, major progress in small bowel endoscopy has been made over the past few years. The development of a wireless capsule endoscopy was a major breakthrough in small bowel imaging. Preliminary reports show accu- racy and great promise for this imaging method [20]. Push enteroscopy is practiced in several specialty centers mainly to identify occult gas- trointestinal bleeding. Descamps et al reported that out of 233 such patients, the enteroscope was passed successfully, under sedation, beyond the ligament of Treitz in 229 patients. Pathology was identified in 53% of the patients examined.
Other groups also reported a high yield with minimal complications of enteroscopy. Lewis et al examined 258 patients with obscure gastroin- testinal bleeding using small bowel enteroscopy.
A small bowel tumor was found in 5% of patients. In 50% of patients no diagnosis could be made, but when the cause of obscure bleeding was discovered, small bowel tumors were the single most common lesion in patients younger than 50 years. Intraoperative enteroscopy is a more invasive technique with a high yield of occult bleeding detection.
Management
Benign Epithelial Tumors
Adenomatous Polyps (Adenomas)
Adenomatous polyps are the second most common symptomatic benign tumor of the small bowel, and the most common benign tumors in autopsy studies. The majority of ade- nomas are found in the duodenum, with a decreasing incidence toward the distal ileum.
Villous adenomas of the duodenum usually present with obstructive jaundice, and the diagnosis is easily made by endoscopic biopsy.
The propensity for malignant transformation varies with age, location in the duodenum, and size. Villous adenomas diagnosed over the age of 50 years, larger than 5 cm, and located distally in the duodenum carry the highest risk
of malignant transformation. Although some authors recommend transduodenal excision, the high recurrence rate and the risk of missed diagnosis of adenocarcinoma drive many surgeons toward pancreaticoduodenectomy (Whipple’s procedure). Lesions located distal to the ampulla of Vater can be managed by trans- duodenal excision. The vast majority of patients with FAP have multiple duodenal polyps.
Surgical excision of multiple villous adenomas in the duodenum is not recommended.
Endoscopic follow-up with multiple biopsies is recommended in most cases. If high-grade dys- plasia or malignant transformation identified, radical surgery is the treatment of choice.
Brunner’s Gland Adenoma (Hamartoma)
Brunner’s gland enlargement is sometimes called Brunner’s gland adenoma or hamartoma.
There is controversy as to whether these lesions should be classified as hyperplasias, neoplasia, or hamartoma. Whatever the classification, this type of adenoma rarely undergoes malignant degeneration. Symptoms at presentation depend on the size of the tumor and range from a lack of symptoms to chronic upper gastroin- testinal bleeding and duodenal or biliary obstruction. Treatment involves either endo- scopic removal of pedunculated lesions or sur- gical resection of larger lesions.
Malignant Epithelial Tumors
Adenocarcinoma
Adenocarcinoma is the most common malig- nant tumor of the small bowel. However, because it is an uncommon disease, knowledge of its natural history and prognosis is limited.
Management of gastrointestinal neoplasms such as adenocarcinoma of the colon or gastric adenocarcinoma is based mainly on data obtained from prospective randomized trials.
Since adenocarcinoma of the small bowel is rel- atively uncommon, its management is based on extrapolation of data from gastric and colon cancer trials and retrospective studies that show great variability in the management of duode- nal adenocarcinoma.
Joesting et al [16] reviewed the records of 104 patients with adenocarcinoma of the duode- num. They found that 50% of the lesions were resectable, and the 5-year survival rate for 111
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patients with resectable lesions was 46%. Eight patients treated with segmental resections for lesions in the third and fourth portions of the duodenum were alive for at least 5 years.
Survival was directly related to nodal status, the grade of the lesion, and the ability of the surgeon to minimize or eliminate operative mortality. Rotman et al studied factors influ- encing survival of 46 patients with adenocarci- noma of the duodenum resected with curative intent. They concluded that resection of adenocarcinoma of the duodenum should be performed whenever possible, even in the presence of lymph node metastasis and pancre- atic spread. Barnes et al [22] retrospectively reviewed the hospital records of 67 patients with non-ampullary adenocarcinoma of the duode- num treated at the University of Texas M.D.
Anderson Cancer Center. A curative resection was performed in 36 of the 59 (61%) patients who underwent surgery. The 5-year survival difference between resected and unresected patients was 54% versus 0%, respectively (p < 0.0001). No survival difference was noted between patients who underwent pancreatico- duodenectomy rather than wide local excision.
Other authors showed that resectability was the single most important factor influencing survival of patients with adenocarcinoma of the duodenum.
The role of preoperative chemoradiation in the treatment of adenocarcinoma of the duode- num and pancreas was studied by Coia et al in a prospective non-randomized trial. Radiation was given at a total dose of 50.4 Gy with two cycles of chemotherapy given concurrently (5-fluorouracil and mitomycin-C) with radia- tion. Surgery was performed 4–6 weeks after completion of chemoradiation. Thirty-one patients with a median follow-up of 4.5 years were studied. Twenty-seven patients had pan- creatic cancer and four patients had adenocar- cinoma of the duodenum. Twenty-one patients were initially judged to be unresectable and ten potentially resectable prior to chemoradiation.
All four patients with adenocarcinoma of the duodenum underwent complete resection. A complete pathologic response was seen in all four patients and all were alive at the time of analysis.
In summary, based on these small studies, the treatment recommendations for adeno- carcinoma of the duodenum include surgical
resection for early lesions and preoperative chemoradiation for locally advanced lesions.
Adenocarcinoma of the jejunum and ileum should be managed by surgical resection of the tumor-bearing segment with its lymphatic drainage. Adjuvant chemotherapy utilizing 5-fluorouracil and leucovorin should be added for node-positive patients. A comprehensive analysis of the National Cancer Database was performed by Howe et al [7]. Of the 4995 cases of adenocarcinoma of the small intestine they reviewed, surgery as a single therapy was per- formed in 48%, surgery combined with radio- therapy in 2%, surgery with chemotherapy in 13%, and a combination of all three therapeutic modalities was delivered in 4% of the patients.
Radiation alone was delivered in 2% of the cases, chemotherapy alone in 5%, and chemora- diation in 3%. In 3% of the patients treatment modality was unknown, and the remaining 20%
did not receive any treatment. Median survival was 19.7 months and the 5-year survival was 30.5%. In a multivariate analysis of this group of patients, disease-specific survival was adversely affected by age >75, presence of tumor in the duodenum versus jejunum or ileum, tumor stage, tumor grade, and the non- cancer directed surgery.
Prognosis can be reliably predicted by the American Joint Committee on Cancer (AJCC) TNM staging system [23] as shown in Table 14.4.
Lymphoproliferative Disorders
Lymphoid Hyperplasia
Primary hyperplasia of the intestinal lymphoid tissue is a non-neoplastic change that produces visible lesions. Focal lymphoid hyperplasia typ- ically affects the terminal ileum of children and young adults. It may present as a polypoid lesion up to a size of 5 cm. Diffuse nodular lym- phoid hyperplasia is a rare disorder that may involve the entire small intestine or colon. It might be associated with late onset hypogam- maglobulinemia. Management includes careful follow-up to detect additional lymphomas that can arise in these patients.
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Malignant Lymphomas
Half of non-Hodgkin’s lymphomas (NHL) of the gastrointestinal tract arise in the stomach, 40%
in the small intestine and 10% in the colon.
The diagnosis of primary gastrointestinal lym- phoma requires the absence of superficial pal- pable lymph nodes or radiologically detectable mediastinal lymph nodes, normal white cell count, predominance of the gastrointestinal lesion, and tumor-free liver and spleen. There are several classification systems for lym- phomas: the most popular one is the Revised European-American Lymphoma (REAL) classi- fication.
Immunoproliferative small intestinal disease (IPSID), ␣-heavy chain disease, Mediterranean
lymphoma, or mucosa-associated lymphoid tissue (MALT) lymphoma are all synonyms of the same proliferative disorder of IgA-produc- ing B lymphocytes. It affects children and young adults, primarily in Mediterranean countries.
These lesions commonly affect the duodenum and proximal jejunal mucus or the etiology remains unclear. Diarrhea and weight loss are the main presenting symptoms. Treatment with broad-spectrum antibiotics to prevent its trans- formation into a high-grade lymphoma has been theorized, but chemotherapy is the treat- ment of choice.
Primary T-cell gastrointestinal lymphomas are rare. Enteropathy-associated T-cell lym- phoma (EATL) accounts for about one-third of small intestinal lymphomas and usually affects adults over the age of 60. The disease progress rapidly and might cause small bowel perfora- tion. The prognosis is poor, with an overall 5-year survival of 10%. A number of small intestinal T-cell lymphomas may develop in the absence of celiac disease. Some cases are iden- tical to EATL, but some differ in their molecu- lar or cytologic markers. Several cases of primary Hodgkin’s disease of the gastrointesti- nal tract have been reported in the literature.
Treatment options for localized small intesti- nal lymphomas include surgical resection, which may suffice for disease localized to the bowel wall if 12 or more lymph nodes are removed and prove negative. However, the addition of combination chemotherapy should be considered as well. For extension of disease to the regional lymph nodes, surgical resection at the time of diagnosis followed by combina- tion chemotherapy is the treatment of choice.
For unresectable and extensive disease, combi- nation chemotherapy is the treatment of choice.
In addition, radiation therapy is often used to reduce the risk of recurrence in the tumor bed.
Carcinoid Tumour
The majority of carcinoid tumors arise in the gastrointestinal tract, most frequently in the appendix, followed by the small intestine, rectum, colon, and stomach. In several studies, carcinoid tumors of the small intestine accounted for 18–25% of all carcinoids. Patients with small intestinal carcinoids present in the sixth or seventh decade of life, most commonly with abdominal pain or partial small bowel 111
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Table 14.4. TNM staging Primary tumor (T)
TX: Primary tumor cannot be assessed T0: No evidence of primary tumor Tis: Carcinoma in situ
T1: Tumor invades lamina propria or submucosa T2: Tumor invades muscularis propria
T3: Tumor invades through the muscularis propria into the subserosa or into the non-
peritonealized perimuscular tissue (mesentery or retroperitoneum) with extension 2 cm or less T4: Tumor perforates the visceral peritoneum or
directly invades other organs or structures (includes other loops of the small intestine, mesentery, or retroperitoneum more than 2 cm, and the abdominal wall by way of the serosa; for the duodenum only, includes invasion of the pancreas)
Regional lymph nodes (N)
NX: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Regional lymph node metastasis Distant metastasis (M)
MX: Distant metastasis cannot be assessed M0: No distant metastasis
M1: Distant metastasis AJCC stage groupings Stage 0: Tis, N0, M0 Stage I: T1, N0, M0 T2, N0, M0 Stage II: T3, N0, M0 T4, N0, M0 Stage III: Any T, N1, M0 Stage IV: Any T, Any N, M1
obstruction. The majority present with lymph node or distant metastasis and 5–7% present with carcinoid syndrome. In general tumor size correlates directly with the presence of lymph node metastasis and survival. The risk of metas- tases begins to increase significantly for tumors 2 cm or greater. Five-year survival is estimated to be 65% in patients with locoregional disease and 36% in patients with distant disease.
Segmental resection of the small bowel with draining mesenteric lymph nodes is the treat- ment of choice for locoregional disease. The role of surgery is limited in advanced disease.
Mesenchymal Small Bowel Neoplasms
Gastrointestinal mesenchymal tumors can be divided into two categories: those with distinct histologic features such as lipomas or heman- gioma, and those that do not have clear-cut his- tologic features and cannot be classified into any specific cell lineage. Tumors in the second category are called gastrointestinal stromal tumors (GIST).
The classification of GIST is difficult because these tumors lack differentiated cellular charac- teristics, they might be heterogeneous, and they can share overlapping features of several enti- ties. Assessment of the malignant potential of GIST tumors is done by size (>5 cm) and mitotic count (>10/10 high power field). These parame- ters are not always accurate in predicting the malignant potential of a certain tumor.
Gastrointestinal Stromal Tumors (see Chapter 15)
The cellular morphology of GIST ranges from predominantly spindle-shaped to epithelioid.
Moreover the differentiation pathways can vary from indeterminate to myoid or neural. Recent studies have indicated that the interstitial cells of Cajal, postulated to act as pacemaker cells of the gastrointestinal tract, could be candidates for GIST origin. The c-kit proto-oncogene, which encodes a growth factor receptor with tyrosine kinase activity, has been postulated to play an important role in tumorigenesis.
Monoclonal and polyclonal antibodies directed
at the c-kit gene product expressed on the cell surface (CD117/c-kit) are essential in resolving the histopathological differential diagnosis between GIST and true gastrointestinal smooth muscle neoplasms, schwannomas, and other gastrointestinal mesenchymal tumors. Increas- ing tumor size and mitotic activity favor aggres- sive tumor behavior, whereas the prognostic value of germline and somatic mutations within the c-kit proto-oncogene remains to be further elucidated. In a retrospective review, Clary et al [24] studied the clinical differences between leiomyosarcomas occurring within the abdomen and retroperitoneum and GIST. A total of 561 patients, 239 with GIST and 322 with leiomyosarcoma, were studied. Patients with GIST were older, with a median age of 58 years.
The 5-year disease-specific survival for GIST and leiomyosarcoma were 28% and 29%, respectively. Another study from the same group looked at the clinical patterns of recur- rence of GIST. Of the 200 patients studied, 46%
had primary disease without metastasis, 47%
had metastasis, and 7% had isolated local recur- rence. In patients who underwent complete resection, the 5-year actuarial survival was 54%.
Recurrence of disease after resection was mainly intra-abdominal, affecting the original tumor site, the peritoneum, and the liver.
Treatment of localized disease is by surgical resection. A major development in the treat- ment of metastatic c-kit-positive GIST is the introduction of the selective tyrosine kinase inhibitor STI571. STI-571 has already shown clinical value in BCR-ABL-positive leukemias.
Preliminary results from clinical trials show good response of c-kit-positive GIST to STI- 571[25].
Leiomyomas
Leiomyomas of the small bowel are the most common symptomatic small bowel benign tumors. Leiomyomas account for 20–40% of benign small bowel tumors. In autopsy series, the incidence of small bowel leiomyomas is second only to adenomatous polyps.
Since clinical distinction of benign and malig- nant lesions is extremely difficult, size is an important predictor of malignancy. Histologic criteria for malignancy include mitotic activity, necrosis, and nuclear pleomorphism. Treat- ment includes segmental resection of the small
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bowel loop containing the tumor. Enucleation or local excision can be performed in cases of small leiomyomas of the duodenum.
Leiomyosarcomas
Well-differentiated leiomyosarcomas are hard to distinguish from leiomyomas because both appear as firm, rubbery masses. Some of the leiomyosarcomas are large with areas of hem- orrhage or necrosis and these are obviously malignant. Tumor diameter of more than 5 cm is considered a predictive factor of low- grade malignancy. Factors associated with better outcome are complete surgical resection without violation of the tumor pseudocapsule, a localized growth pattern, low histologic grade, and size <5 cm. Lymphatic invasion and nodal metastases are distinctly uncommon.
Other Benign Tumors
Lipomas of the small bowel are rare tumors presenting with symptoms of abdominal pain consistent with partial small bowel obstruction.
In the case of a single lesion, segmental resec- tion is the proper surgical treatment choice.
However, in the case of multiple lipomas, more complex surgical decision-making is required.
Angiomas of the small bowel are less common, may be multifocal, and usually present as occult gastrointestinal bleeding.
Treatment includes segmental resection of the small bowel after the lesion has been localized either preoperatively or intraoperatively.
Neurofibromas can occur as a single lesion or as part of diffuse neurofibromatosis. Upper digestive tract involvement has been estimated to occur in 2% to 25% of patients with systemic neurofibromatosis. Typically, the involvement is characterized by submucosal neurofibromas originating in the submucosal nerve plexus.
Secondary (Metastatic) Neoplasms of the Small Bowel
Several malignant neoplasms show predilection to metastasize to the small intestine. Metastatic malignant melanoma is the most common,
followed by bronchiogenic carcinoma and breast cancer. A report of 103 cases of malignant melanoma of the small bowel from the Armed Forces Institute of Pathology [26] showed that primary lesions preceded intestinal disease by an average of 5.6 years for cases diagnosed in surgery and 2.1 years if diagnosed by autopsy.
They concluded that small bowel involvement by melanoma, even without a known primary, is probably metastatic. Bender et al reported on 32 patients with malignant melanoma metasta- sis involving the small bowel. The sensitivity of small bowel barium follow-through and CT scan in detection of small bowel metastasis was 58%
and 66%, respectively. Krige et al reported 18 patients with small bowel metastasis of malig- nant melanoma who underwent complete resec- tion with a median survival of 4.5 years. They concluded that surgical resection is indicated both for symptoms relief and for prolongation of life. Other authors reported similar results supporting segmental resection of small bowel involved with metastatic malignant melanoma.
Berger et al reviewed 1544 patients with lung cancer and found 7 patients with small intesti- nal metastasis. In all but one case, patients were diagnosed following resection of lung cancer.
Mosier et al reviewed 37 cases in the literature and 3 cases from their own experience of lung cancer small bowel metastasis.
In summary, metastatic lesions are rarely found in the small intestine, with malignant melanoma being the most common followed by bronchiogenic carcinoma.
Questions
1. What are the most common types of small bowel tumors?
2. What are the methods used for diagno- sis of neoplasms?
3. What are the small bowel features of FAP and what tumors commonly develop in the small bowel after panproctocolec- tomy?
4. What are the conditions that can progress to the development of small bowel neoplasms?
5. Outline the staging system for small bowel neoplasms.
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