Introduction

Cancer of the small intestine is not among the top 25 cancers in the
United States. Approximately 3,600 new cases of small-bowel cancer are
diagnosed each year in the United States, with almost 1,000 deaths.[1]
The rarity of small-bowel cancer is particularly surprising given the location
of the small intestine between two organs with relatively high cancer incidence,
ie, the stomach and the colon. Indeed, the small intestine contains 75%
of the length of the alimentary tract, with 90% of its surface mucosal
area, and yet carcinoma is rare in this organ. It is precisely this relative
paucity that makes the tumor so intriguing.

Little has been published about the clinical features and management
of small bowel cancer. Although there are four major histologic subtypes
of small intestinal cancer (ie, adenocarcinoma, malignant carcinoid, lymphoma,
and leiomyosarcoma), this review focuses on adenocarcinoma, the most common
subtype in the United States, constituting roughly 40% to 50% of small
bowel cancers. A major medical center can expect to see four to eight cases
over the course of a year.

Epidemiology

The incidence of small bowel cancer, particularly adenocarcinoma, tends
to be higher in Western industrialized countries than in countries in the
Far East or Third World.[2,] Differences in access to health care and diagnostic
sophistication do not appear to account for this geographical variation.
Instead, it appears to represent real differences in risk.

Table 1 shows the variation in small-
bowel cancers from a selected number of hospital-based case series.[3-20]
In western countries, adenocarcinomas generally represent the largest fraction
of these series, whereas lymphomas predominate in other countries.

The anatomic distribution of small- bowel cancers also reflects the
histologic distribution. For example, data from the Surveillance, Epidemiology
and End Results (SEER) Program for 1973 to 1982, which generally represents
US rates, indicates that 48.4% of adenocarcinomas of the small bowel are
located in the duodenum, with 32.5% in the jejunum and 19.2% in the ileum.[21]
A recent reanalysis, looking at small-bowel adenocarcinomas from 1973 to
1990, showed a rate of 54% in the duodenum, with 28% in the jejunum and
18% in the ileum.[22] This is true whether one is in a high or a low adenocarcinoma
incidence area, and may reflect the presence of the ampulla of Vater in
the duodenum, and thus, higher concentrations of bile and its metabolites.
Lowenfels and others have related high levels of bile to risk for adenocarcinoma.[23,24]

In general, cancer of the small bowel predominates in males, as compared
with females (see Table 1 ). This is
generally true for adenocarcinoma as well. Studies taken from the SEER
population-based tumor registry indicate a male-female ratio of approximately
1.4:1 for adenocarcinoma.[21, 22]

The racial distribution of small bowel cancer, and adenocarcinoma in
particular, has not been studied to a large degree. A study utilizing SEER
data[22] indicates a higher incidence of adenocarcinoma in blacks than
in whites. This was confirmed by a review of the Los Angeles County Cancer
Surveillance Program.[24]

Etiology and Risk Factors

Relatively little is known about the etiology of adenocarcinoma of the
small bowel. The most important known risk factor, prior Crohn's disease,
was initially reported by Ginsburg et al in 1956.[25] Since then, numerous
studies have confirmed this association in a quantitative fashion. The
relative risk of small-bowel adenocarcinoma in patients with Crohn's disease
has been estimated to be between 15 and more than 100.[26-28]

Lashner[26] suggested that the use of mercaptopurine (Purinethol) for
the treatment of Crohn's disease raised the risk of developing subsequent
cancer, as did significant Crohn's disease in the jejunum. It is notable
that whereas the majority of adenocarcinomas occur in the duodenum, Crohn's-associated
adenocarcinomas generally occur in the ileum, reflecting the distribution
of Crohn's disease. The risk of adenocarcinoma does not begin until at
least 10 years after the onset of Crohn's disease and typically occurs
more than 20 years afterward.

The preponderance of small-bowel adenocarcinoma in the duodenum has
led to speculation that bile plays a role in promoting this tumor.[23,24]
Although the carcinogenic properties of bile and its constituents have
been demonstrated in various animal studies, only one human study has indicated
that previous cholecystectomy may be related to the incidence of adenocarcinoma.[29]
Another study suggested that animal fat intake was correlated with the
incidence of small-bowel carcinoma,[30] while yet another[31] suggested
that consumption of red meat or salt-cured or smoked food raised the risk
of small- bowel cancer.

Other factors that have been associated with cancer of the small bowel
or adenocarcinoma in particular include cigarette smoking, alcohol consumption,
prior peptic ulcer disease, familial adenomatous polyposis, prior colon
cancer, celiac sprue, and cystic fibrosis.[Neugut et al: Epidemiology of
cancer of the small intestine. Submitted for publication]

Relationship to Colon Cancer

Many parallels have been drawn between adenocarcinoma of the small bowel
and adenocarcinoma of the large bowel. The incidence rates of these two
diseases correlate in a linear fashion when compared between countries.[32]
Furthermore, patients with small-bowel adenocarcinoma have an elevated
risk of developing large-bowel adenocarcinoma, and vice versa.[33]

The relationship between the two intestinal malignancies goes even further.
Both types of cancer appear to develop from adenomatous polyps.[34] As
mentioned above, familial adenomatous po-lyposis, which gives rise to a
huge number of adenomatous polyps in both the large and small bowel, raises
the risk for both malignancies. Recent preliminary studies exploring molecular
genetic changes in small-bowel adenocarcinomas have suggested that they
also parallel the molecular genetic changes that occur in colorectal cancer.[Arber
et al: Molecular genetics of small-bowel cancer. Submitted for publication]

Implications for Colon Cancer Prevention

This relationship of small- intestinal adenocarcinoma to colorectal
cancer is surprising given the preponderance of adenocarcinomas in the
duodenum, which is in close proximity to the stomach. Furthermore, it raises
the question of the relative incidence of both diseases. Colorectal cancer
is one of the most common cancers in the United States, while small -bowel
adenocarcinoma is 50 times less frequent (or more). Perhaps an understanding
of why small-bowel cancer is so rare could lead to preventive strategies
for large-bowel cancer.

A number of hypotheses have been proposed to explain the relative rarity
of small-bowel cancer, but none has been well established. The best developed
explanation is the extremely rapid turnover of small-intestinal mucosal
cells,[35] which would tend to eliminate partially transformed intestinal
cells prior to their reaching full carcinogenic development. Other potential
explanations relate to the relative absence of bacteria in the small bowel,
which may be protective,[36] and the rapid transit of small-bowel contents,
which reduces the contact time between potential carcinogens and the small-bowel
mucosa.[32] Its alkaline environment may also play a role.[37]

Clinical Implications

The parallels between smal -bowel and large-bowel adenocarcinomas have
clinical implications as well. Although the rarity of small-bowel cancer
makes extensive clinical trials difficult or impossible, many oncologists
have appreciated its similarity to large-bowel adenocarcinoma and have
adopted the same treatment approach as is employed for smal -bowel cancer,
eg, adjuvant chemotherapy for node-positive smal-bowel adenocarcinomas
and the use of fluorouracil (5-FU)-based regimens.