Incidence of small-bowel tumors by histologic and anatomical type. The graph shows the relative preference of the histologic tumor types for the segments of the small bowel. Almost half of the adenocarcinomas are found in the duodenum and half of the carcinoids are found in the ileum. GIST indicates gastrointestinal stromal tumor.
Crude incidence rate of small-bowel tumors by race per time period. The graph depicts an increase in the incidence of small-bowel tumors per sequential time periods for the total group and the racial subgroups.
Hatzaras I, Palesty JA, Abir F, Sullivan P, Kozol RA, Dudrick SJ, Longo WE. Small-Bowel TumorsEpidemiologic and Clinical Characteristics of 1260 Cases From the Connecticut Tumor Registry. Arch Surg. 2007;142(3):229-235. doi:10.1001/archsurg.142.3.229
To examine the epidemiology and clinical characteristics of small-bowel cancer.
Patients with small-bowel tumors reported between 1980 and 2000, studied retrospectively.
Data from the Connecticut Tumor Registry.
One thousand sixty small-bowel cancer cases: 628 men (49.84%) and 632 women (50.16%). Mean age at presentation was 65.2 years.
The most common location of small-bowel tumors was the ileum (374 cases; 29.7%), followed by the duodenum (320 cases; 25.4%) and the jejunum (193 cases; 15.3%). In 367 patient cases (29.1%: 192 men [30.6%] and 175 women [27.7%]), a prior or subsequent tumor of the gastrointestinal tract was reported. The most prevalent histologic type was carcinoid (417 cases; 33%), followed by adenocarcinoma (341 cases; 27%) and lymphoma (205 cases; 16.3%). The patient population was predominantly white (1159 patients; 92%), followed by African American patients (91 patients; 7.2%). Stratification by consecutive 7-year intervals showed the following: from 1980 to 1986, there were 10.5 cases per 100 000 individuals; from 1987 to 1993, there were 13.05 cases per 100 000 individuals; and from 1994 to 2000, there were 14.86 cases per 100 000 individuals. Men comprised 44.8% of cases from 1980 to 1986, 50.2% of cases from 1987 to 1993, and 53.3% of cases from 1994 to 2000. African American patients accounted for 7.5% of all cases from 1980 to 1986, 5.8% from 1986 to 1993, and 8.2% of cases from 1994 to 2000. In 1106 patients (87.7%), the primary therapy was surgical, including intestinal bypass, radical excision, excisional biopsy, and subtotal or total excision.
The incidence of small-bowel tumors in Connecticut has increased during the past 2 decades, with the highest rate of increase in men. Carcinoid tumors are the most common small intestinal cancers identified histologically, followed by adenocarcinomas. The former seems to be more frequently seen in the ileum, the latter in the duodenum. Surgery is the treatment of choice for the cure or palliation of small-bowel cancers.
Despite having the greatest epithelial surface area in the gastrointestinal tract, the small bowel rarely develops neoplasms. In fact, small-bowel tumors account for 1% to 2% of all gastrointestinal neoplasms (only 0.3% of all neoplasms) and are usually misdiagnosed on first presentation or diagnosed late.1,2 The rare incidence of small-bowel tumors may contribute to the relatively low index of clinical suspicion for their presence. The majority of these tumors are clinically silent for long periods of time or manifest with nonspecific symptoms, such as dull, crampy abdominal pain, abdominal distention, fecal occult blood, nausea, and/or vomiting. Obstruction is also a common presentation; indeed, small-bowel tumors are the third most common cause of small-bowel obstruction in the United States.3 Obstruction may be the direct result of the narrowing of the bowel lumen by the tumor or the indirect effect of the tumor functioning as a lead point for intussusception. The larger the tumor, the more likely the patient will have symptoms.4 Nonetheless, clinical presentation alone rarely permits the distinction between benign and malignant lesions.
Diagnostic modalities used for assessing the existence of small-bowel tumors include endoscopy (for lesions of the duodenum and proximal jejunum) and radiographic imaging (computer tomography and small-bowel series, or enteroclysis). Lesions located distal to the Treitz ligament pose a unique diagnostic challenge for the endoscopist because of the length of the small bowel. Capsule endoscopy is a recently available clinical technology that has been shown to be safe and effective in the diagnosis of small-bowel abnormalities, including neoplasms.5,6 Nevertheless, experience with this technique is still limited and developing. Urinary excretion of 5-hydroxyindoleacetic acid and radionuclide localization scans can be useful for the diagnosis of carcinoid tumors.7 Elevated carcinogen embryonic antigen may indicate an adenocarcinoma but usually in the presence of liver metastases.8 Often none of the mentioned diagnostic tools are fruitful, and because of progressive symptoms, diagnostic laparoscopy or exploratory laparotomy may be indicated for definitive diagnosis and treatment.9
Because small-bowel tumors are relatively rare compared with other neoplasms of the gastrointestinal tract, the following several factors have been proposed to explain or understand this disparity: (1) a decrease in mechanical and/or chemical inflammation of the mucosa because of the liquidity and alkaline pH of the small-bowel contents; (2) the relatively rapid transit of the small-bowel chyme, thus allowing a shorter contact time of luminal carcinogens with the enterocytes; (3) the rapid turnover of epithelial cells outpacing potential growth and development of neoplastic cells; (4) a lower luminal bacterial load, particularly of anaerobes, which results in less total production of potential carcinogens; (5) the apparent enhanced ability of small-bowel mucosa to metabolize and/or detoxify certain dietary components or breakdown products that may be carcinogenic; and (6) the elaborate lymphoid tissue network surrounding the small bowel, and in particular, its ability to secrete immunoglobulin A, which may confer increased immunologic-related tumor control.2,4
Several environmental as well as genetic syndromes that predispose individuals to developing a malignancy in the small intestine have been described.10 First, patients with familial adenomatous polyposis have multiple adenomas in the colon and, if untreated, have a 100% risk of developing colon cancer.10 Moreover, periampullary adenocarcinoma is the leading cause of death in patients with familial adenomatous polyposis who have had a total colectomy. Second, other primary malignancies, such as melanoma and cancers of the colon, rectum, prostate, lung, and breast, may metastasize to the small bowel.10 Third, patients with Crohn disease have been documented to be at higher risk for developing adenocarcinoma of the small bowel, particularly in the ileum.11 Finally, Helicobacter pylori infections seem to increase patient risk for the development of small-bowel lymphomas, particularly in the duodenum and jejunum.12
The difficulty in establishing early definitive diagnosis and treatment of small-bowel cancers is a challenge that must be met if improved results are to be obtained. Knowledge of the epidemiology of the disease and an increased clinical suspicion can be useful in earlier diagnosis of the disease when it is more amenable to treatment and possible cure. However, information regarding the demographics of this disease in the current literature is scarce and the available epidemiologic data derived primarily from individual hospital series have limitations. For example, these series do not include all the histologic tumor subtypes and are thus of questionable general applicability.4,13- 15
This retrospective study was performed to attempt to clarify the existing information on small-bowel tumors. A population-based registry was used so that all cases in a broad distribution throughout a specified lengthy time period were included. To circumvent an inevitable selection bias inherent to a single institution study, analysis of data from a single individual institution was specifically avoided, and instead, all cases from tertiary care medical centers as well as all cases from community hospitals are included herein. The inherent bias of a single institution analysis is thereby diminished, and the statistical power of the study is increased.
The Department of Public Health of the State of Connecticut maintains an extensive tumor registry whereby obligatorily reported malignancies are assembled into a standardized versatile format, which is available for the examination of disease patterns in the state. The computerized database of the registry includes all reported cancer cases by site diagnosed in Connecticut residents continuously from 1935 to the present. It also includes follow-up and treatment data. Connecticut law requires that all hospitals and pathology laboratories report all cancer cases to the registry.
After Human Investigations Committee approval at our institution, data void of personal identifiers were obtained from the Connecticut Tumor Registry, which is located in the Connecticut Department of Public Health. Review by the Department of Public Health Human Investigations Committee was not required because no personal identifiers were obtained. The authors assume full responsibility for the inclusion of the information that was used for analysis and for subsequent interpretation.
The database of small-bowel tumors in the Connecticut Tumor Registry was analyzed for the time period from 1980 to 2000. The primary focus of this analysis was to examine the incidence and characteristics of small-bowel tumors in a protracted period of time. The study group was divided into 3 distinct 7-year periods to accentuate changes in the incidence of small-bowel tumors by site, race, and sex subgroups. This 7-year interval was used to create 3 distinct, equal, and consecutive time periods to enable the grouping of sufficiently large numbers of cases during each interval to show a potential difference in the incidence. Individual yearly analysis was not performed because the rarity of the tumor precluded generating sufficient numbers to express statistical power. To control the findings for fluctuations in the population, a crude incidence rate per time period was used (incidence per time period multiplied by 100 000 and divided by a calculated estimate of average yearly population per time period). The US decennial census was the source of population data for the state of Connecticut. Mean population for each time period was calculated using the population figures for each year included in the respective time period. The patterns of site and histology, sex, and race incidence, as well as modes of treatment, were also analyzed. Relevant literature was reviewed, and the data therein were used as a guide and comparison for our study.
The Connecticut Tumor Registry tabulated the 1260 small-bowel cancer cases reported from 1980 to 2000. In this group, 628 patients were men (49.8%) and 632 were women (50.2%). Mean age at presentation was 65.2 years (range, 4 to 97 years). The age group that was most affected was the decile of 65- to 74-year-olds (374 cases; 29.7%), followed by the decile of 75- to 84-year-olds (270 cases; 21.4%). In 320 cases (25.4%), the tumor was found in the duodenum; in 193 cases (15.3%), it was found in the jejunum; in 374 cases (29.7%), the tumor was found in the ileum; in 14 cases (1.1%), the tumor was overlapping; in 9 cases, it was found in the Meckel diverticulum; and in 350 cases (27.8%), the location of the small-bowel cancer was not otherwise specified. The stratification of site by sex is presented in Table 1 and by histologic type in Figure 1. In 367 cases of small-bowel cancer (29.1%: 192 men [30.6%] and 175 women [27.7%]), 461 tumors other than a small-bowel tumor were reported, either before diagnosis, after diagnosis, or synchronously. The most common secondary tumor site was the large intestine (157 cases; 34.1%), and the most common age group was the decile of 65- to 74-year-olds, composed of 167 patients (91 men and 76 women).
Histologically, the distribution included 417 carcinoids (33.1%), 379 adenocarcinomas (30.1%), 205 lymphomas (16.3%), and 89 gastrointestinal stromal tumors, formerly classified as leiomyomas and leiomyosarcomas (7.1%).16,17 The remaining 170 specimens (13.5%) were composed of mucinous, fibromatous, myxomatous, and lipomatous tumors. Analysis of the prevalence of each histologic type shows that adenocarcinomas were more prevalent in the duodenum (200 cases; 52.7%), carcinoids were more prevalent in the ileum (209 cases; 50.1%), lymphomas were more prevalent in the ileum (54 cases; 26.3%), and gastrointestinal stromal tumors were more prevalent in the ileum (30 cases; 33.7%) (Table 2 and Figure 1).
Malignancy was categorized as in situ or invasive carcinoma. The vast majority of cases were invasive carcinoma (1248 cases; 99%), equally distributed between men and women. There were 10 tumors diagnosed as in situ and 2 of uncertain malignancy. White patients predominated with 1159 cases: 585 men (50.5%) and 574 women (49.5%). African American patients showed a different sex distribution, with 42.9% men (39 of 91 cases) and 57.1% women (52 of 91 cases). In the African American population, the crude incidence rate rose by 46.4% from the second to the third time period of the study (Table 3 and Figure 2). The racial category defined as “other” included 10 individuals: 4 men and 6 women. An increased incidence was noted in both white and African American patients; the male incidence was noted to have increased more than the female incidence in both races (Table 3).
Surgery was the treatment of choice regardless of the histology of the tumor and was used in 1106 patients (87.7%). Excisional biopsy sufficed in 22 patients (1.7%). Partial or total excision was sufficient in 515 patients (40.9%), whereas 116 patients (9.2%) underwent a radical excision. Tumor-directed surgery, unspecified as to extent, was offered to 340 patients. Noncancer related surgery was not coded after 1997. During the period 1980 through 1997, 113 patients (9.0%) had a palliative procedure such as a bypass, a biopsy, or exploratory surgery only. Surgery was not used in 68 patients, and the treatment status was unknown in 42 patients. Information on chemotherapy and radiotherapy was not evaluated as part of the therapeutic modalities. Data on adjuvant therapy were provided; however, the completeness of the reporting of such data to the registry was uncertain. The reasoning was that although chemotherapy and radiation therapy data reporting is mandatory by the hospitals, the patients often received such treatments in outpatient settings.
The small bowel comprises more than two thirds of the length of the digestive tract and more than 90% of its mucosal surface area; however, it generates barely 1.5% to 2% of gastrointestinal tumors. At the same time, its proximal and distal continuity, namely the stomach and large intestine, are 2 sites of rather prevalent carcinogenesis. Gastric cancer accounts for 22 700 new cases and 11 700 deaths each year in the United States. Similarly, colorectal cancer is the fourth most common malignancy, second only to lung cancer as a cause of cancer deaths nationwide, with an estimated 134 000 new cases and 55 000 deaths expected annually. On the contrary, small-bowel neoplasms are relatively rare, with an estimated 5260 new cases and 1130 patient deaths in the United States during 2004.18
This study reports a series of 1260 cases from the State of Connecticut Tumor Registry through a 21-year time period. By nature, large population-based registries such as the Connecticut Tumor Registry collect data from independent hospitals. Each hospital employs a group of individuals whose main responsibility is to report cancer cases. The quality and accuracy of any registry's data are dependent on the diligence of the employees to accurately report the clinical course of a patient, and their meticulous review of each patient's file and accurate depiction of the clinical course in a uniform, standardized fashion. This represents an enormous undertaking. A patient may have multiple visits to an institution, or he or she may visit different hospitals for the care of his or her disease. In most cases, the uniform, standardized manner of input of data provides for a very high quality collection of information that is an accurate depiction of the clinical course. In some instances, certain data are missed. Incomplete data collection is usually caused by overlooked information or because the information to be added is not available or is not pertinent to a patient. As an example, in this study 42 patients were listed as unknown for therapy, and 62 were listed as not having surgery. The first number represents a possible data collection failure. The second number represents a possible clinical scenario: no surgery does not necessarily mean no treatment; it may indicate that these patients were not candidates for surgery. The exact details of their care after the decision not to operate are unknown. Nonetheless, the issue of data completeness may represent a potential weakness of this study.
In this study we show that men and women overall are equally affected; however, the male incidence seems to be increasing, particularly for the African American population, which had a 103.9% increase in the incidence rate from the second to the third time period of epidemiologic observation. The existing data do not allow for clarification of whether this represents a clear incidence increase (ie, whether more African American men were affected during the last years of this study) or whether this observation represents an underreporting of cases in the early years of the study. It may also be that this population is recently diagnosed more frequently rather than affected more frequently (ie, used the available health services and received treatment more in the third period of the study than the first or second). This may reflect an interesting socioeconomic phenomenon: either this population now uses progressively more or now has more access to adequate health services. It should be noted that with a total of only 91 African American patients for the 21 years of the study, the increase in the African American incidence did not reach statistical significance. Data from future years will help put this trend in better perspective.
The overall increase in the incidence of this type of tumor may also be attributed to an increased rate of immunocompromised patients. The AIDS epidemic began during the early years of this study and rapidly became rampant. In 2003, an AIDS infection rate of 20.3 patients per 100 000 individuals was reported in Connecticut, which is above the national average and is a record high for the state. It is well known that human immunodeficiency virus and AIDS have disproportionately affected the United States' African American and Hispanic communities, and it has been shown consistently that the immunodeficiency that heralds human immunodeficiency virus infection and AIDS is a risk factor for carcinogenesis.19 These factors should be taken into account as potential explanations of the increased incidence; however, no definitive conclusions can be drawn because the extent to which AIDS affected this group of patients is unknown.
Patients with familial adenomatous polyposis should also be kept in mind when examining the incidence rate patterns of small-bowel tumors. These patients have multiple adenomas in their gastrointestinal tracts, and if they are not treated appropriately with a total colectomy, they will die of an aggressive form of colorectal cancer. Periampullary adenocarcinoma is well known to be the leading cause of death in patients with familial adenomatous polyposis who have undergone total colonic resection.10 Patients with familial adenomatous polyposis who were treated for their colon disease were included in the small-bowel group when they developed a small-bowel neoplasm.
This study also shows that men are more prone to develop a second primary tumor outside the small bowel and that almost one third of the patients were reported to have a second primary tumor either before or after manifesting a small-bowel neoplasm. An awareness of this fact when treating small-bowel cancer patients, and a high suspicion for an emerging secondary neoplasm, are mandated if optimal therapeutic outcomes are to be achieved.
The most prevalent anatomical tumor site in this study was the ileum (374 cases; 29.7%), followed by the duodenum (320 cases; 25.4%), and then the jejunum, affected in only 193 cases (15.3%). This site dispersion is particularly interesting and may be explained by the fact that the segments of the small bowel in proximity to the stomach and large bowel are exposed to higher concentrations of carcinogens. In the duodenum, for example, ingested and partially digested carcinogens are likely to be in high concentrations. As they move farther down the gastrointestinal tract, they are diluted by copious secretions prior to contact with jejunal mucosa. Other possible mechanisms for explanation of this phenomenon are that the jejunum may be protected by the continuous and rapid turnover of its epithelial cells (life span range, 2-5 days), which confers a unique resiliency of this part of the bowel and that the jejunal mucosa has an enhanced ability to digest, metabolize, and/or detoxify potential carcinogenic byproducts of dietary ingestion.20
In this group, 99% of cases were reported as invasive carcinoma, equally distributed in men and women. This clearly underscores a late diagnosis pattern for this disease. It has been reported that the nonspecific symptoms, combined with lack of physical findings, usually contributes to a delay in diagnosis of 6 to 8 months.4 Late detection is the probable explanation for advanced disease at the time of operation but also likely accounts for a 50% metastasis rate at presentation, thus leading to an overall poor prognosis.12 This delay is often compounded by the tendency of patients to seek medical advice long after the initial onset of symptoms. Maglinte et al21 challenged this notion by reporting that major delays in diagnosis tended to occur after patients were already under medical care. Failure to obtain a definitive diagnostic test or misinterpretation of the results accounted for diagnostic delays of 8 to 12 months, respectively, whereas delays secondary to patient failure to report symptoms were fewer than 2 months.21 This underscores a possible weakness in the design of this study, which relies only on hospital-reported cases and therefore harbors an inherent bias toward symptomatic patients who are more likely to present with advanced disease. In a large study of 9721 consecutive autopsies, 112 neoplasms of the small bowel were discovered, 72 of which were benign lesions (64.3%).22 This suggests that the prevalence of asymptomatic lesions may be even higher than reported herein.
Histologically, in the present study, carcinoid tumors were the predominant form of small-bowel neoplasms (417 cases; 33%), followed by adenocarcinomas (379 cases; 30.1%). At the 3 principal subsites, all tumors showed a predilection for the ileum, with the exception of adenocarcinoma, for which the highest incidence was in the duodenum and then progressively decreased throughout the rest of the more distal small intestine. Ross et al23 has attributed this prevalence of adenocarcinoma in the duodenum to the early metabolism of ingested carcinogens and the interactions of carcinogens with pancreaticobiliary secretions. Ribeiro et al11 reported a significant exception in patients with long-standing Crohn disease. Seventy percent of the patients that develop a change in their clinical status, such as small-bowel obstruction refractory to usual treatment, were found to have developed an adenocarcinoma of the ileum at the site of the primary inflammatory process. These observations indicate that a correlation may exist between inflammation and adenocarcinoma: in the case of the duodenum, chemical inflammation due to interactions of ingested carcinogens with the acidic environment of the first and second portion of the duodenum as well as with the alkaline pancreaticobiliary secretions in the third and fourth portions; and in the case of the ileum, humoral inflammation due to a faulty immune response.
It is notable that no clear recommendations for optimal treatment of small-bowel cancers can be derived from the literature. Furthermore, leading sources of cancer information, such as the National Comprehensive Cancer Network, have not reported guidelines for the treatment of this disease.24 The rarity of this entity precludes the design of studies with adequate statistical power that will enable development of databased recommendations. Accordingly, the existing data are derived from small-scale series. Surgical management was the overall treatment of choice in this group, regardless of the histology of the tumor. The majority of the existing literature supports this treatment modality for all histologic tumor types.25- 32 Information on chemotherapy and radiotherapy as treatment modalities was not evaluated as part of this study. Nevertheless, the role of chemotherapy and radiotherapy for small-bowel tumors is minor, if not undefined.13,33- 36 The 2 exceptions are the carcinoid syndrome, usually occurring after carcinoid tumor metastasis to the liver, which has been shown to be amenable to octreotide; and small-bowel lymphoma, for which chemotherapy is the mainstay of treatment. However, the combination of chemotherapy and surgery has been shown to be superior to single modality treatment in prolonging survival in this patient population.32,36
This report shows that small-bowel tumors, despite being rare, are increasing in incidence and that the most common histologic type is the carcinoid tumor. It also demonstrates that the most commonly affected segment of the small bowel is the ileum and that patients aged 65 to 74 years are the most affected age group. Additionally, carcinoid tumors occur more frequently in the ileum, whereas adenocarcinomas occur more frequently in the duodenum. The most problematic challenge continues to be earlier unequivocal diagnosis to initiate therapeutic measures in a more timely and effective manner despite the usually nonspecific, vague, and variable initial symptoms and signs. The only definitive treatment of choice for primary tumors of the small bowel is surgery.
Correspondence: Walter E. Longo, MD, Department of Surgery, Yale School of Medicine, 330 Cedar St, LH 118, New Haven, CT 06520 (firstname.lastname@example.org).
Accepted for Publication: June 20, 2006.
Author Contributions:Study concept and design: Hatzaras and Longo. Acquisition of data: Hatzaras, Abir, and Sullivan. Analysis and interpretation of data: Palesty, Abir, Kozol, Dudrick, and Longo. Drafting of the manuscript: Hatzaras, Abir, Kozol, and Longo. Critical revision of the manuscript for important intellectual content: Palesty, Abir, Sullivan, Kozol, Dudrick, and Longo. Administrative, technical, and material support: Hatzaras, Abir, Sullivan, Kozol, and Longo. Study supervision: Palesty, Abir, Kozol, Dudrick, and Longo.
Financial Disclosure: None reported.
Previous Presentation: This paper was presented at the 86th New England Surgical Society Meeting; October 2005; Breton Woods, NH.