Diagnosis and staging of small bowel neoplasms

Authors
James C Cusack, Jr, MD
Michael J Overman, MD
Robert A Wolff, MD Section Editor
Richard M Goldberg, MD Deputy Editor
Diane MF Savarese, MD

Last literature review version 17.1: January 2009 | This topic last updated: January 18,
2009 (More)

INTRODUCTION A variety of tumors, both malignant and benign, may arise within the
small intestine. Malignant tumors include adenocarcinomas, carcinoids, stromal tumors,
and lymphomas. Benign lesions that may arise in the small bowel include adenomas,
leiomyomas, fibromas, and lipomas.
The diagnosis and staging of small bowel tumors will be reviewed here. The epidemiology,
clinical manifestations, and treatment of the specific types of tumors are discussed
separately. (See "Epidemiology, clinical features, and types of small bowel neoplasms" and
see "Treatment of small bowel neoplasms").

DIAGNOSTIC EVALUATION The clinical features of small bowel neoplasms may

include one or more of the following: pain, obstruction, bleeding, anorexia, weight loss,
perforation, or in the case of a duodenal primary, jaundice. Malignant tumors are more
likely to be symptomatic as compared to benign lesions. (See "Epidemiology, clinical
features, and types of small bowel neoplasms", section on Clinical presentation).
The variable nature of the presenting symptoms, combined with the lack of physical
findings, can contribute to a delay in diagnosis in many cases [1] . In one study, failure to
obtain a proper diagnostic test or misinterpretation of test results accounted for delays of 8
and 12 months, respectively; by comparison, the estimated diagnostic delay due to the
patient's failure to report symptoms was less than two months [2] . As prognosis is closely
linked to disease extent for all of the major malignant small bowel tumors, early detection
and treatment can contribute to a favorable outcome [2-4] . Because of the vagueness and
nonspecificity of the presenting symptoms, a high index of suspicion is essential for early
diagnosis and treatment [5,6] .

Patients whose symptoms are such that a small bowel tumor is part of the differential
diagnosis should undergo a complete history, physical examination, and screening for fecal
occult blood. A minimum laboratory work-up should include a complete blood count,
measurement of serum electrolytes, and liver function tests.
The specific components of the diagnostic and staging workup are addressed in the
following sections. There is no single method that is best for imaging of the small intestine
in a patient with a suspected small bowel tumor. The choices are radiographic (CT scan,
small bowel series, enteroclysis) or endoscopic (wireless capsule endoscopy, push
enteroscopy, double-balloon endoscopy).
Depending on the clinical scenario, multiple tests may be needed to adequately evaluate
the small intestine. The best testing strategy and sequence of diagnostic tests are not
established, and there is debate as to how much diagnostic workup is adequate to exclude
a small bowel tumor. If the suspicion of a small bowel tumor is high, one school of thought
holds that at least two imaging methods (eg, wireless video capsule endoscopy followed by
double balloon enteroscopy) should be used to exclude a small bowel malignancy.
However, there is no consensus on this issue. (See "Wireless video capsule endoscopy"
and see "Overview of double balloon endoscopy")

Radiographic imaging Multiple radiographic investigations are available for patients

suspected of having a small bowel tumor (show table 1). Plain abdominal films are
generally of limited value unless bowel obstruction is suspected, a condition which is a
nonspecific finding.

UGI/SBFT Upper GI series with small bowel follow through (UGI/SBFT) may show a
mass lesion, mucosal defect, or intussusception. In older series, the sensitivity was
approximately 50 to 60 percent for the detection of advanced small bowel tumors [7-9] . In
one report of 89 patients with small bowel tumors, UGI/SBFT was diagnostic in 57 percent
of malignant tumors but only 25 percent of primary benign tumors.

CT scan Computed tomography (CT) is frequently obtained when evaluating vague or

indeterminate abdominal complaints. CT is able to detect abnormalities in approximately 70
to 80 percent of patients with small bowel tumors (show radiograph 1) [10,11] . Besides
demonstrating the primary tumor, CT scans are of critical importance for appropriate
evaluation of extraintestinal spread to distant sites and involvement of regional lymph
nodes. In addition, specific radiographic features may suggest the histologic diagnosis
[12,13]
As an example, for carcinoid tumors, an abdominal CT with intravenous and oral contrast
has a sensitivity of 87 percent for identifying at least one of the manifestations of a
carcinoid tumor [14-16] . This may be the primary tumor, mesenteric stranding due to tumor
involvement and a fibrotic response (show radiograph 2), liver metastases (which are
invariably present when carcinoid syndrome arises from a gut primary), or mesenteric
lymph node enlargement. Gadolinium-enhanced MRI of the liver is more sensitive than
abdominal CT for evaluating both the presence and extent of liver metastases in patients

with a carcinoid tumor [17] (See "Management of metastatic gastroenteropancreatic

neuroendocrine tumors").

Angiography and radionuclide scanning In patients with active bleeding, angiography

or radionuclide scanning with technetium (99mTc) sulfur colloid or 99mTc pertechnatelabeled autologous red blood cells can help to localize the site of bleeding. In addition, for
certain tumors, most notably carcinoid and leiomyosarcoma, a distinctive tumor blush may
be seen on angiography. However, these tests are rarely indicated in the initial diagnostic
workup. (See "Evaluation of obscure gastrointestinal bleeding").

Enteroclysis Enteroclysis is a double-contrast radiographic study that is performed by

passing a tube into the proximal small bowel and injecting both barium and methylcellulose.
This technique is superior to UGI/SBFT to detect malignant small bowel tumors. As an
example, in one study, the sensitivity of enteroclysis for picking up a malignant small bowel
tumors was 90 percent, versus 33 percent for conventional UGI/SBFT [7] . One potential
downside is that enteroclysis usually fails to detect flat infiltrating lesions.
Newer enteroclysis techniques that are performed in conjunction with CT and/or MRI
appear more promising [5,6,18-23] . CT enteroclysis combines the benefit of crosssectional CT scanning and barium contrast studies. The technique involves infusion of
contrast dye via a nasoenteric tube while obtaining CT images.
In one of the largest series, 219 patients with a clinical suspicion for small bowel neoplasms
and a negative upper and lower endoscopic evaluation underwent contrast and waterenhanced multidetector CT enteroclysis [22] . Positive findings were compared with the
results of surgical exploration or endoscopic procedures, while negative results were
correlated with the results of surgery, intraoperative enteroscopy, capsule endoscopy, or
clinical follow-up. The following findings were noted: CT enteroclysis demonstrated a small
bowel mass in 55 patients. A small bowel tumor was confirmed in 50, and there were five
false-positive studies. These included two masses diagnosed as fold thickening at
intraoperative enteroscopy, two small bowel polyps, and one 18 mm hyperintense mass,
with all three cases confirmed as normal mucosa at surgery or preoperative enteroscopy.
Of the 164 patients with a normal result on CT enteroclysis, a small bowel tumor was later
found in nine. The sensitivity, specificity, negative predictive value, and positive predictive
value were 85, 97, 95, and 91 percent, respectively. Whether similar results can be
achieved at other centers is unclear.

Endoscopic techniques The advantages and disadvantages of several endoscopic

methods for evaluation of the small bowel are outlined in the table (show table 1).

Upper endoscopy Standard upper endoscopy is capable of reaching only the proximal
duodenum. It may be adequate if a proximal small bowel tumor is suspected.

Wireless video capsule endoscopy Wireless video capsule endoscopy (VCE) provides a
noninvasive means of visualizing the entire small bowel. It has become a standard
diagnostic approach for patients with obscure gastrointestinal bleeding. This relatively new
technology has already supplanted some of the older techniques, such as enteroclysis, in
the workup of small bowel tumors. (See "Wireless video capsule endoscopy").
The utility of VCE in diagnosing small bowel tumors was demonstrated in a retrospective
study of 562 patients who underwent the procedure at Mount Sinai Medical Center from
2001 to 2003 [24] . Indications for endoscopy were obscure gastrointestinal bleeding (79
percent), chronic abdominal pain (5 percent), or search for carcinoid primary (4 percent). A
total of 50 patients were diagnosed with small bowel tumors, of which 48 percent were
malignant. Among patients who were younger than 50 years old undergoing VCE for
obscure gastrointestinal bleeding, nine (13 percent) had a small bowel tumor. There was
one false-positive result (which prompted a negative surgical exploration), but the number
of false negative studies could not be ascertained as information on outcomes among
patients who had a negative VCE was not available.
Information on the false negative rate of VCE was provided in a meta-analysis of 310
patients from 24 studies in which VCE was compared prospectively to a standard
diagnostic workup (push enteroscopy in 220 patients, small-bowel series 140 patients, or
colonoscopy with ileoscopy in 90 patients) [25] . A total of 106 neoplasms were diagnosed,
of which VCE missed 20 (false negative rate 19 percent). However, this was lower than the
miss rate for the standard diagnostic workup method (63 percent) [25]
The main disadvantage of wireless video capsule endoscopy is that it does not permit
tissue sampling. It should generally not be performed in patients in whom small bowel
obstruction is suspected since the capsule may become lodged proximal to the obstruction
and may require laparotomy for retrieval.

Enteroscopy Enteroscopy refers to the passage of a colonoscope or special

enteroscope beyond the ligament of Treitz using push, intraoperative, or double-balloon
enteroscopy techniques [26] . The main advantage compared to wireless video capsule
endoscopy (VCE) is the ability to obtain tissue samples and perform therapeutic
interventions.
Enteroscopy can be complementary to VCE by allowing for tissue sampling of lesions
identified during VCE. However, the procedure is invasive, can be technically challenging
(and hence not always successful in visualizing the entire small bowel), and the required
expertise and equipment are not always available. These techniques are all described in
more detail elsewhere. (See "Evaluation of obscure gastrointestinal bleeding" and see
"Overview of double balloon endoscopy").

Other methods A variety of novel endoscopic methods to visualize the small bowel are
in various stages of development or are available on a limited basis. These include a
single-balloon enteroscope (Olympus Optical Co, Ltd, Tokyo) and the Spirus Discovery SB
system (Spirus Medical Inc, Stoughton, MA). (See "Evaluation of obscure gastrointestinal
bleeding").

Tumor markers The role of tumor markers in the evaluation of a suspected small bowel
tumor is unclear. The majority of small bowel adenocarcinomas are positive for
carcinoembryonic antigen (CEA) by immunohistochemistry [27,28] , and serum CEA was
elevated in 44 percent of patients with metastatic or locally advanced small bowel
adenocarcinoma in one report [29] . However, CEA is neither sufficiently sensitive nor
specific to be used for diagnostic purposes.
Measurement of urinary 5-hydroxyindoleacetic acid (5-HIAA) or serum chromogranin A
(CGA) should not be routine but instead, done only if there is a strong clinical suspicion of
carcinoid.

Diagnostic testing for carcinoid Patients with carcinoids often present with symptoms
similar to those of other small bowel tumors. However, they may also become symptomatic
from hormones secreted by the tumor cells. The presence of carcinoid syndrome is usually
suspected because of otherwise unexplained diarrhea or flushing. (See "Diagnosis of the
carcinoid syndrome and tumor localization" and see "Epidemiology, clinical features, and
types of small bowel neoplasms", section on Carcinoid tumors).

Urinary excretion of 5-HIAA The most useful initial diagnostic test in patients with
suspected carcinoid syndrome is to measure 24-hour urinary excretion of 5-HIAA, which is
the end product of serotonin metabolism (show figure 1). This test has a sensitivity of 75
percent and specificity of up to 100 percent [30] , but is fraught with errors that may be
induced by the ingestion of certain drugs and foods (show table 2).
Most patients with the carcinoid syndrome have urinary 5-HIAA excretion above 100
mg/day (523 micromol/day). In one study, for example, urinary 5-HIAA excretion in patients
with the carcinoid syndrome ranged from 99 to 2070 mg/day (518 to 10826 micromol/day)
[31] . Lower, but still elevated values were seen in patients with metastatic carcinoid
tumors, but not carcinoid syndrome (50 to 260 mg/day [262 to 1360 micromol/day]). There
is a good correlation between tumor mass and urinary 5-HIAA levels; the sensitivity of
urinary 5-HIAA is diminished in patients with nonmetastatic or asymptomatic carcinoid
tumors [32] . (See "Diagnosis of the carcinoid syndrome and tumor localization").

Other biochemical tests Other useful initial diagnostic tests are serum chromogranin
and serum 5-hydroxytryptamine (5-HT, serotonin). Serum chromogranin levels above 32
unit/L have a 75 percent sensitivity and 84 percent specificity for the detection of
neuroendocrine tumors [33] . (See "Diagnosis of the carcinoid syndrome and tumor
localization").

Tumor localization by octreotide and MIBG scans Radionuclide imaging using

indium-111 octreotide (Octreoscan) is a useful technique for localization of carcinoids
because the tumor cells almost always contain somatostatin receptors, a property shared
with other neuroendocrine neoplasms, some lymphomas (particularly extragastric marginal
zone lymphomas [34] ) and small cell lung cancers. Octreotide imaging has a greater than
90 percent sensitivity for identifying a carcinoid tumor in patients with carcinoid syndrome

and it is superior to radionuclide imaging using radiolabeled (iodine-131 or 121)

metaiodobenzylguanidine (MIBG) [35,36] . Radiolabeled MIBG, which is taken up by the
tumor and stored in its neurosecretory granules, can identify primary or metastatic carcinoid
tumors approximately 50 to 60 percent of the time [37,38] .
On occasion, a patient may benefit from angiography or selective venous sampling if other
diagnostic maneuvers prove unsuccessful.

Surgical exploration In the past, despite a thorough history, physical examination, and
complete diagnostic workup, the correct diagnosis of small bowel malignancy was
established preoperatively in only 70 percent of cases, with the remainder diagnosed at
laparotomy [39] . However, improvements in cross-sectional imaging and the development
of techniques such as wireless video capsule endoscopy have reduced the need for
diagnostic laparotomy.
Nevertheless, exploratory laparotomy is the most sensitive diagnostic modality in
evaluating a patient with a high suspicion of having a small bowel neoplasm. Exploration
should be considered for a patient with occult GI bleeding, unexplained weight loss, or
vague abdominal pain and an otherwise unrevealing diagnostic evaluation. Laparoscopy
may also be useful for establishing the diagnosis of malignancy when the workup is
otherwise negative and for obtaining adequate tissue samples if a diagnosis of lymphoma
is suspected.

STAGING Staging systems differ according to the primary histology.

Adenocarcinoma The most commonly used staging system for small bowel
adenocarcinomas is the TNM system of the American Joint Committee on Cancer (AJCC,
show table 3) [40] . This schema does not apply to carcinoid tumors, lymphomas, or
sarcomas.

Lymphoma The Ann Arbor staging system developed in 1971 for Hodgkin's disease
(HD) was adapted for staging non-Hodgkin's lymphomas (NHLs). This staging system
focuses on the number of tumor sites (nodal and extranodal), location, and the presence or
absence of systemic ("B") symptoms (show table 4). The staging system used for
lymphoma and the diagnostic/staging tests that are recommended for the evaluation of a
patient with a non-Hodgkin lymphoma are discussed in detail elsewhere. (See "Staging and
prognosis of non-Hodgkin lymphoma").

Sarcoma and carcinoid Visceral leiomyosarcomas are sometimes staged according to

the TNM system for soft tissue sarcomas (show table 5), while neither gastrointestinal
stromal tumors (GISTs) nor carcinoids are typically assigned a tumor stage. (See
"Gastrointestinal stromal tumors; leiomyomas; and leiomyosarcomas of the gastrointestinal
tract").

HISTOLOGY AND DIFFERENTIAL DIAGNOSIS Differentiating the various small bowel

tumors on light microscopy is generally straightforward, and the results of
immunohistochemical and/or cytometric studies are usually confirmatory: The morphologic
appearance of GISTs can be predominantly spindle cell or epithelioid, and these tumors
have a characteristic molecular signature. Over 80 percent of GISTs express the CD117
antigen, in contrast to leiomyomas and other spindle-cell tumors of the gastrointestinal (GI)
tract (eg, leiomyosarcomas), which are typically CD117-negative.
The CD117 antigen, which can be identified by immunohistochemical staining (IHC), is part
of the KIT transmembrane receptor tyrosine kinase, a product of the c-kit (also denoted as
KIT) protooncogene. In more than 80 percent of GIST cases, a mutation in the KIT gene
leads to a structural variant of the KIT protein which is abnormally activated and enables
oncogenic signaling in the cell.
A subset of KIT-negative GISTs have activating mutations in a different receptor tyrosine
kinase, platelet-derived growth factor receptor-alpha, which can only be identified using
molecular techniques. (See "Gastrointestinal stromal tumors, leiomyomas, and
leiomyosarcomas of the gastrointestinal tract", section on Histopathology). Neuroendocrine
differentiation, as is characteristic of a carcinoid or noncarcinoid neuroendocrine tumor, can
be demonstrated by IHC staining for synaptophysin or chromogranin. (See
"Neuroendocrine carcinoma of unknown primary site", section on Low-grade
neuroendocrine carcinoma). IHC or cytometric studies for cell surface antigens typically
identify lymphomas as being of either B-cell or T-cell origin. (See "Classification and
pathology of gastrointestinal lymphomas"). Differentiating an adenocarcinoma of the small
bowel from other bowel adenocarcinomas (particularly in the setting of a locally advanced
lesion) can be challenging. In contrast to colorectal cancers, which are almost always
cytokeratin (CK) 20 positive and CK 7 negative, adenocarcinomas of the small bowel are
less often CK 20 positive (47 to 67 percent) and more often CK7 positive (34 to 100
percent) [41,42] . (See "Pathology and prognostic determinants of colorectal cancer").

SUMMARY A variety of tumors, both malignant and benign, may arise within the small
intestine. Malignant tumors include adenocarcinomas, carcinoids, stromal tumors
(gastrointestinal stromal tumors [GISTs] and non-GIST soft tissue sarcomas), and
lymphomas. Benign lesions that may arise in the small bowel include adenomas,
leiomyomas, fibromas, and lipomas.
The diagnosis of a small bowel tumor is often made late in the course of the disease,
because these are generally rare conditions, and the symptoms are nonspecific (abdominal
pain, weight loss, nausea and vomiting, occult GI tract bleeding). Early diagnosis requires a
high index of suspicion. (See "Epidemiology, clinical features, and types of small bowel
neoplasms", section on Clinical presentation).
There is no single method that is best for imaging of the small intestine in a patient with a
suspected small bowel tumor. The choices are radiographic (CT scan, small bowel series,
enteroclysis) or endoscopic (upper endoscopy, wireless video capsule endoscopy, push
enteroscopy, double-balloon endoscopy). The best testing strategy and sequence of
diagnostic tests are not established, and there is debate as to how much diagnostic workup
is adequate to exclude a small bowel tumor. (See "Diagnostic evaluation" above and see
"Evaluation of obscure gastrointestinal bleeding").

There are no tumor markers that are sufficiently sensitive or specific for the diagnosis of
any small bowel tumor. (See "Tumor markers" above).
The presence of carcinoid syndrome should be considered when the patient has
suggestive symptoms such as otherwise unexplained diarrhea or flushing. In such cases,
additional diagnostic testing may include biochemical tests of urine and/or serum to detect
elevated levels of bioactive amines and other substances such as chromogranin A and
Octreotide scanning. (See "Clinical features of the carcinoid syndrome" and see
"Diagnostic testing for carcinoid" above).

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