t h e s u r g e o n x x x ( 2 0 1 4 ) 1 e8

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The Surgeon, Journal of the Royal Colleges
of Surgeons of Edinburgh and Ireland
www.thesurgeon.net

Review

Malignant tumours of the small intestine

Ian Reynolds, Paul Healy, Deborah A. Mcnamara*

Department of Colorectal Surgery, Beaumont Hospital, Dublin, Ireland

article info abstract

Article history: Adenocarcinoma, neuroendocrine tumours, sarcomas and lymphomas are the four most
Received 6 November 2013 common malignant tumours arising in the small intestine, although over forty different
Accepted 16 February 2014 histological subtypes are described. Collectively these account for only 2% of cancers of the
Available online xxx digestive system. The incidence of small bowel cancer has increased in recent decades
with a four-fold increase in carcinoid tumours. Risk factors for small bowel tumours
Keywords: include coeliac disease, inflammatory bowel disease and a number of genetic abnormal-
Small bowel cancer ities. The non-specific nature of their symptoms and the difficulty in visualising these
Small bowel tumours tumours with normal endoscopic techniques often results in late diagnosis. Furthermore
Adenocarcinoma the paucity of literature on this topic has made it difficult to standardise management.
Carcinoid tumours There has however been marked improvement in imaging methods resulting in earlier
Gastrointestinal stromal tumours diagnosis in many cases. As expected, early detection of localised, well differentiated tu-
Diagnosis of small bowel tumours mours followed by surgical resection with negative margins offers the best chance of long
Management of small bowel term survival. Better adjuvant treatment, notably for gastrointestinal stromal tumours, has
tumours improved 5-year survival rates significantly. Development of surveillance guidelines for at
risk populations may be a valuable way of improving early diagnosis of this challenging
group of conditions.
ª 2014 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and
Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.

malignant small intestinal tumours. Most originate in the

Introduction
Small bowel tumours include a heterogenous group of benign
and malignant lesions. The most common malignant lesions
are adenocarcinoma, neuroendocrine tumours, sarcomas and
lymphomas but more than forty different histological sub-
types are described. Adenocarcinoma of the small bowel,
while infrequently encountered, accounts for 40% of all
duodenum followed by jejunum then ileum with about 10%
having an unknown origin.1 Tumours of the ampulla of Vater
and the periampullary region are generally considered sepa-
rately. Other tumour types arising from small intestine
include, in order of frequency, carcinoid tumours, lymphoma
and sarcoma. The incidence of all malignant tumours of the
small intestine ranges from 0.5 to 1.5/100,000 in males and
0.2e1.0/100,000 in females.2 The incidence appears to be

* Corresponding author. Beaumont Hospital, Suite 18 BPC, Beaumont Road, Dublin 9, Ireland. Tel./fax: þ353 1 857 4885.
E-mail address: reynoli@tcd.ie (D.A. Mcnamara).
http://dx.doi.org/10.1016/j.surge.2014.02.003
1479-666X/ª 2014 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland.
Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Reynolds I, et al., Malignant tumours of the small intestine, The Surgeon (2014), http://
dx.doi.org/10.1016/j.surge.2014.02.003
2 t h e s u r g e o n x x x ( 2 0 1 4 ) 1 e8
higher in North America and Western Europe than in Asia,3
with higher incidence rates in US black populations for both
males and females.
The incidence of small bowel cancer is increasing, partic-
ularly the incidence of carcinoid tumours.4 The mean age at
diagnosis of any small bowel cancer is 65 but sarcoma and
lymphoma tend to present earlier than adenocarcinoma and
carcinoid tumours. The incidence rises after the age of 40
years for all histological subtypes.5 It is not uncommon for the
small bowel to be the site of metastasis from another primary
particularly in advanced peritoneal carcinomatosis, however,
haematogenous spread is rare, most common attributable to
melanoma and breast or lung cancers.6
Predisposing factors
Crohn’s disease
Crohns disease is a risk factor for future small bowel adeno-
carcinoma. A relative risk of 33 (95% CI: 15.9e60.9) was re-
ported in a 2006 meta-analysis.7 Male gender, fistulating
disease, early age at diagnosis, distal jejunal or ileal disease
and extended duration of disease are associated with
increased risk.8
Coeliac disease
Patients with coeliac disease have an increased risk of both T-
cell non-Hodgkin’s lymphoma and adenocarcinoma of the
small intestine9 with the relative risk of the latter reported to
be between 60 and 80 compared to normal populations.10
Small intestine adenomas
The prevalence of adenomas in the small intestine is lower
than in the colon, but similarly appears to be a precursor of
adenocarcinoma.11 Most occur in the duodenum. The risk of
malignant transformation is greatest with villous
morphology, increasing size and higher grade dysplasia.12
Peutz Jeghers syndrome
This autosomal dominant condition is characterised by the
presence of small intestinal polyps with melanin spots on the
lips and buccal mucosa. Polyps are found most commonly in
the jejunum and less frequently in the ileum and duodenum.
The condition is due to a mutation on the serine/threonine
kinase 11 (STK11) gene and carries an increased risk of cancers
including breast, ovarian, testicular, pancreas, stomach,
oesophagus and several others. Meta analysis confirms Peutz
Jeghers syndrome carries a relative risk of small bowel cancer
of 520 compared with the general population.13
Familial adenomatous polyposis (FAP)
This autosomal dominant condition is associated with an
increased risk of small bowel cancer, caused by mutations of
the adenomatous polyposis coli (APC) gene on chromosome
5.14 Most patients with FAP (50e90% depending on series) have
Please cite this article in press as: Reynolds I, et al., Malignant tumours of the small intestine, The Surgeon (2014), http://
dx.doi.org/10.1016/j.surge.2014.02.003
duodenal adenomatosis with 3e5% developing duodenal
cancer.15
Hereditary non-polyposis colorectal cancer
HNPCC, another autosomal dominant condition, is caused by
a germline mutation in the Mut S homologue 2 (hMSH2) or Mut
L homologue 1 (hMLH1) mismatch repair gene.16 Patients with
HNPCC have a relative risk of small bowel cancer of more than
100 compared to the general population, with the risk reported
to be higher in MLH1 mutation carriers than in those with
MSH2 mutations.17
Other familial syndromes
Multiple endocrine neoplasia type 1 (MEN-1), von Hippel Lin-
dau disease and neurofibromatosis type 1 each carry
increased risk of carcinoid tumours.
Sporadic colorectal cancer
Patients with sporadic colorectal cancer (CRC) have a higher
than average risk of developing small bowel cancer, while
those diagnosed with primary small bowel cancer should be
considered at risk of CRC. This relationship suggests shared
risk factors.18
Diet and alcohol consumption
Evidence regarding dietary factors and alcohol consumption is
inconclusive. While some authors report an increased risk of
small bowel adenocarcinoma with greater red meat con-
sumption,19 a larger series did not confirm this association.20
Similar variability is noted in studies linking alcohol use to
small bowel cancer risk.21
Body mass index (BMI)/obesity
Several studies have shown an increased risk of small bowel
cancer in overweight and obese people although most of these
studies involve very few cancers.22 One case control study
showed no association with small bowel cancer and BMI and
another study showed an inverse relationship between BMI
and small bowel cancer.23
Cigarette smoking
Some studies suggest smoking increases small bowel cancer
risk.24,25
Gallstones
A Danish series reports an elevated risk for cancer of the small
intestine, mainly carcinoid tumours, in patients with
gallstones.26
 t h e s u r g e o n x x x ( 2 0 1 4 ) 1 e8
Pathogenesis
The substantially lower incidence of small bowel cancer than
colorectal cancer despite it constituting the majority of the
length of the gastrointestinal tract (roughly 75%) continues to
puzzle researchers. One hypothesis suggests that more rapid
transit times in the small intestine results in a reduced
exposure of small bowel intestinal mucosa to carcinogens.
Another hypothesis suggests that reduced bacterial load in
the small intestine results in reduced formation of carcino-
gens from bile acid breakdown.27 The higher levels of IgA in
the small intestine are thought to be protective against lym-
phoma.28 Like CRC, small bowel adenocarcinoma can arises
from adenomatous polyps and both cancers may share many
of the genetic changes of carcinogenesis. Mutations have been
described in K-ras, E-cadherin, b-catenin and P-53.12 A study
of 21 non-familial, non-ampullary small bowel adenocarci-
nomas screened for RER (replication error) status, mutations
in the APC MCR, and immunostaining of hMLH1, hMSH2, b-
catenin, E-cadherin and p53. Only one of the cancers was
RERþ. There were no mutations in the MCR of the APC gene
but 48% of cancers in this study had decreased membranous
expression of b-catenin and 38% had decreased membranous
expression of E-cadherin. Overexpression of p53 was detected
in the nuclei of 24% of cancers.29
Lymphoma of the small intestine is generally divided into
immunoproliferative small intestinal disease (IPSID) lym-
phoma, enteropathy associated T cell (EATL) lymphoma and
other western-type non-IPSID lymphomas (e.g. diffuse large B
cell lymphoma, mantle cell lymphoma, follicular lym-
phoma).30 Patients with coeliac disease are at increased risk of
enteropathy-associated T-cell lymphoma, possibly due to the
chronic mucosal inflammatory response following gliadin
exposure. Similarly infections with bacteria such as
Helicobacter pylori cause chronic antigenic stimulation, a
possible predisposing factor for lymphoma.
Gastrointestinal stromal tumours (GIST) originate from the
interstitial cells of Cajal in the muscularis propria which are
responsible for gut peristalsis with gain of function mutations
in the KIT proto-oncogene present in most. This oncogene
codes for the c-KIT molecule which acts as a receptor for stem
cell factor. Mutations in the gene result in activation of c-KIT
independent of stem cell factor, which results in uncontrolled
proliferation of cells.
Carcinoid tumours arise from the serotonin producing
enterochromaffin (Kulchitsky) cells, predominantly located in
the ileum. Chromosomal instability, point mutations,
methylation abnormalities and dysfunction of tumour sup-
pressor pathways including p53 are responsible for this
malignancy.31,32
Diagnosis & investigation
The clinical features of small bowel tumours are often non-
specific and common to many other illnesses, especially in
their early stages, frequently resulting in delayed diagnosis.
Presenting symptoms include weight loss, nausea, vomiting,
anaemia and abdominal pain, while patients with more
Please cite this article in press as: Reynolds I, et al., Malignant tumours of the small intestine, The Surgeon (2014), http://
dx.doi.org/10.1016/j.surge.2014.02.003
3
advanced disease may present with small bowel obstruction
or perforation. Gastrointestinal bleeding may also occur.33,34
Duodenal tumours tend to present with intestinal obstruc-
tion less frequently than more distal parts of the small in-
testine due to its larger circumference. Biliary obstruction and
frank or occult blood loss tend to be more common pre-
sentations of duodenal tumours. Tumours of the ileum and
jejunum tend to present with vague symptoms more
commonly than tumours of the duodenum. Any of these tu-
mours may present as a palpable abdominal mass. Small
bowel tumours are often identified incidentally during imag-
ing for other reasons. Lymphomas may present with B
symptoms including fever, weight loss [>10% unintentional
weight loss over 6 months] and drenching night sweats.35 A
small number of patients with carcinoid tumours present
with carcinoid syndrome, characterised by cutaneous flush-
ing, diarrhoea and bronchospasm. Some such patients
develop endocardial thickening and right sided cardiac
valvular lesions.
Diagnosis of small bowel tumours is difficult and the op-
timum technique varies depending on the site and size of the
tumour. Upper gastrointestinal radiographic methods
including small bowel follow through (SBFT), computed to-
mography (CT), enteroclysis & enterography may reveal in-
testinal or lymph node masses, mucosal defects and
sometimes intussusception.36 CT scanning has an important
role in evaluating a primary tumour, determining local inva-
sion of surrounding structures and identifying lymph nodes
and distal metastasis although peritoneal metastases are
sometimes difficult to observe radiologically37 (See Pictures. 1
and 2). Carcinoid tumours may display a desmoplastic reac-
tion and calcification of the mesentery that can be seen on CT.
Positron emission tomography (PET) using radiolabelled 18
fluorodeoxyglucose is valuable to detect adenocarcinoma,
sarcoma and some lymphomas but most carcinoid tumours
are not particularly FDG avid. Standard endoscopic tech-
niques are applicable in certain sites, especially for very
proximal tumours and push- or balloon-enteroscopy
Picture 1 e Adenocarcinoma ct.
4 t h e s u r g e o n x x x ( 2 0 1 4 ) 1 e8

Picture 2 e Lymphoma ct.

increases the range of access and tissue sampling of small

bowel. Wireless video capsule endoscopy offers the advantage
of imaging the entire small bowel but does not yet facilitate
tissue diagnosis.38 Increasingly, laparoscopy plays a key role Picture 3 e Adenocarcinoma of jejunum.
in diagnosis.
If carcinoid syndrome is suspected, measurement of
24 h urinary excretion of 5-hydroxyindoloacetic acid (5-HIAA) lymphoma44 (See Picture 4). The Ann Arbor staging system
may be useful.39 Serum chromogranin A and serum 5- that is used to stage lymphomas does not take depth of
hydroxytryptamine may also be useful in the investigation tumour invasion into account. The Lugano staging system
of a potential neuroendocrine tumour, but blood tests are takes both depth of invasion and spread of disease into ac-
generally unhelpful in diagnosis of other small bowel tu- count and is the most widely used staging system for gastro-
mours. Nuclear imaging can facilitate detection of carcinoid intestinal lymphomas.45
tumours. Octreotide scans use indium-111 octreotide which GIST tumours are classified as either spindle cell type,
binds to the somatostatin receptors found in most carcinoid epithelioid type or mixed type. The vast majority express c-kit,
tumour cells. Meta-iodobenzylguanidine (MIBG) scans use detected by routine immunohistochemistry. Over 80% express
radiolabelled-MIBG, again taken up by carcinoid, although the CD117 antigen, part of the KIT transmembrane receptor
they are less sensitive than octreotide scans. tyrosine kinase, a product of the c-kit proto-oncogene. A small
percentage of these tumours have mutations in the platelet
derived growth factor receptor alpha.46 These tumours can be
Histologic diagnosis and staging quite large, forming solitary, well circumscribed masses
covered by either ulcerated or intact mucosa. When consid-
Differentiating each of the four tumours from each other is ering the prognosis of GISTs, tumour size and mitotic count
usually straightforward; however, it can be difficult to deter- are important factors with smaller tumours and low mitotic
mine the organ of origin in locally advanced adenocarcinomas
(See Picture 3). Intestinal carcinomas are graded as well,
moderately or poorly differentiated.40 Unlike CRC, most small
bowel cancers are villous or tubulovillous in type. They also
differ from colorectal adenocarcinoma in that small bowel
adenocarcinoma is less likely to be cytokeratin (CK) 20 positive
and more likely to be CK 7 positive.41 Adenocarcinoma is
staged using the AJCC TNM system42 and as expected small
bowel carcinomas that are well differentiated with only local
invasion and no lymph node metastasis tend to have the best
prognosis.43
Immunohistochemistry and cytometric studies can
distinguish whether lymphomas are of B-cell or T-Cell origin,
with the former expressing CD19 and CD20. The most com-
mon types of gastrointestinal lymphomas encountered in
small bowel are diffuse large-B-cell lymphoma, enteropathy
associated T-cell lymphoma, extranodal marginal zone B-cell
lymphoma (also known as lymphoma of mucosa associated
lymphoid tissue, MALT), mantle cell lymphoma and Burkitts Picture 4 e Lymphoma.

Please cite this article in press as: Reynolds I, et al., Malignant tumours of the small intestine, The Surgeon (2014), http://
dx.doi.org/10.1016/j.surge.2014.02.003
 t h e s u r g e o n x x x ( 2 0 1 4 ) 1 e8
activity correlating with lower malignant potential.47 Staging
is by an AJCC staging system specific to GIST.
Carcinoid tumours are usually definitively identified by
positive immunohistochemistry (IHC) staining for synapto-
physin or chromogranin.48 Grossly, they appear as yellow or
tan intramural or submucosal polypoid masses. Histologically
they are composed of islands of uniform cells with scant
cytoplasm and a round to oval stippled nucleus. Carcinoid
tumours tend to be more indolent than adenocarcinoma49 and
have a separate TNM staging system.
Treatment
Adenocarcinoma
Currently the only option available when treating patients
with curative intent is surgical resection. Resection removes
both the primary and regional lymph nodes and allows ac-
curate staging and guides to determine the need for adjuvant
therapy. Jejunal and ileal tumours are treated with wide
resection removing both the mesentery and lymphatics up to
the superior mesenteric vessels. Right hemicolectomy should
be performed for tumours of the distal ileum. The treatment
of duodenal tumours is more complex. Some early tumours
may be amenable to endoscopic techniques. Larger tumours
of the first and second parts of the duodenum require pan-
creaticoduodenectomy whereas more distal duodenal tu-
mours may be amenable to pancreas sparing duodenectomy
without reducing survival.50 Limited resection is preferred for
tumours of the third or fourth part of the duodenum, provided
negative margins can be achieved.51 Relapse tends to take the
form of peritoneal carcinomatosis, abdominal wall metastasis
and local recurrence.52
Data regarding the role of adjuvant chemotherapy are
limited, with no evidence of significant benefit in survival in
patients with adenocarcinoma of the small intestine treated
with adjuvant chemotherapy. An attempted Cochrane review
in 2007 failed to find any studies eligible for meta-analysis.53
Despite this, adjuvant chemotherapy is frequently used
because small bowel cancer tends to recur systemically,
similar to CRC, and because colon cancers respond to adju-
vant therapy. A 2009 retrospective multicentre study sug-
gested that an adjuvant FOLFOX regimen prolonged overall
survival by around 5 months compared to patients treated
with other regimens but the findings of this small study were
not statistically significant.54 Neoadjuvant therapy has been
used in a very small number of patients but has an obvious
appeal in treatment of otherwise unresectable small bowel
adenocarcinomas55 and improves survival.56 Targeted treat-
ment with biological agents including the vascular endothelial
growth factor (VEGF) inhibitor bevacizumab is another
possible avenue.57 The role of more radical resections or
metastasectomy for small bowel adenocarcinoma is unclear
but anecdotal reports indicate a possible role for cytoreductive
surgery and hyperthermic intraperitoneal chemotherapy.58,59
Palliative radiotherapy is sometimes an option for duodenal
tumours. Patients with incurable disease may be candidates
for palliative surgery which may take the form of resectional
or bypass procedures. Certain patients may benefit from
Please cite this article in press as: Reynolds I, et al., Malignant tumours of the small intestine, The Surgeon (2014), http://
dx.doi.org/10.1016/j.surge.2014.02.003
5
endoscopic placement of a stent to treat obstruction in
endoscopically accessible lesions.60
Carcinoid
40% of patients with midgut carcinoid tumours have a second
GI tract malignancy so comprehensive evaluation of the entire
small bowel, colon and rectum is warranted prior to surgery.61
Surgical resection of small bowel carcinoids of any size should
include en-bloc resection of adjacent mesentery and lymph
nodes with negative resection margins.62 In metastatic carci-
noid disease, resection of hepatic metastasis prolongs disease
free survival63 with some evidence that patients with isolated
liver metastasis may benefit from orthotopic liver trans-
plantation.64 Surgery is rarely possible in patients with carci-
noid syndrome as it is usually associated with extensive
metastatic disease, but debulking surgery is sometimes
possible and may provide short term relief. Special attention
should be paid in the perioperative period due to the risk of
precipitating carcinoid crisis during induction of anaesthesia
or while mobilising the tumour. Perioperative octreotide can
mitigate this risk. Systemic therapy with traditional chemo-
therapeutic agents for metastatic carcinoid is generally not
undertaken. Somatostatin analogues are used to control the
symptoms of carcinoid tumours although they generally do
not reduce tumour volume. Patients with hepatic metastases
can be considered for hepatic arterial embolization as a
palliative option. Various techniques of embolisation
including chemoembolization or radioembolization with
yttrium-labeled microspheres have been described.65
Sarcoma
It is important to differentiate gastrointestinal stromal tu-
mours (GIST) from leiomyosarcomas as the management of
these tumours is very different. Localized GIST and non-GIST
sarcomas are managed similarly to other tumours with
margin negative surgical resection being the primary goal.
Sarcomas rarely metastasize to lymph nodes so extensive
lymphadenectomy is not necessary. Patients with GISTs
greater than 3 cm in diameter are treated with the oral small
molecule tyrosine kinase inhibitor imatinib which acts
against mutations in KIT and PDGFR-a.66 Tumours that
become resistant to imatinib can be treated with a broader
spectrum tyrosine kinase inhibitor, sunitinib. Non-metastatic,
unresectable or borderline resectable tumours can be treated
with imatinib as a downstaging technique to allow subse-
quent resection.67
Lymphoma
Lymphoma is generally diagnosed on the basis of char-
aceteristic imaging and confirmed with core biopsy. Unlike
most other small bowel tumours, the mainstay of treatment is
chemotherapy and resection can generally be avoided.
Resection may be appropriate for those who present with
perforation, bleeding or obstruction but these patients should
still receive systemic chemotherapy.68 The use of antibiotics
against helicobacter pylori and campylobacter jejuni may
result in regression of early stage immunoproliferative small
6 t h e s u r g e o n x x x ( 2 0 1 4 ) 1 e8
intestinal disease (IPSID), however, most patients relapse with
high grade disease and radiotherapy and/or chemotherapy as
well as nutritional support is the mainstay of treatment.69e71
Enteropathy associated T cell intestinal lymphoma (EATL) is
treated with combination chemotherapy using anthracyclines
such as epirubicin. Autologous haematopoietic cell trans-
plantation (HCT) can be used during the first remission.72 The
non-IPSID tumours are treated using different combinations
of antibiotics chemotherapy, radiotherapy and immuno-
therapy. Regimens involve agents such as rituximab, cyclo-
phosphamide, doxorubicin, vincristine and prednisolone
(ReCHOP).73
Treatment of metastasis to the small intestine
Patients with metastases to the small intestine are usually
diagnosed during surveillance imaging for their primary
diagnosis but may rarely present initially with metastatic
disease. Palliation is generally the goal of therapy and sys-
temic chemotherapy is often considered where possible.
Where symptomatic, surgical resection, bypass or placement
of an endoscopically inserted stent may be considered.
Prognosis
As in most adenocarcinomas, absence of lymph node
involvement is a strong predictor of long term survival in
small bowel carcinoma74; with stage I disease associated with
five year survival of 65% versus 4% in stage IV disease.75 Five
year disease specific survival is poorer for tumours arising in
the duodenum as opposed to in the jejunum or ileum. Other
indicators of poor prognosis include positive resection mar-
gins, lymphovascular involvement, T4 tumour stage, exten-
sive nodal involvement and a poorly differentiated tumour.1,76
The outcome for carcinoid tumours tends to be better due
to their more indolent course with variable 5-year survival
rate of between 52% and 100% depending upon the stage of
disease. Histopathologic markers of a poor prognosis include
the degree of expression of the proliferation protein Ki-67 and
p53 tumour suppressor protein, lymphovascular space inva-
sion and high mitotic index. Adverse clinical indicators
include the presence of carcinoid syndrome, heart disease
secondary to carcinoid and high concentrations of the tumour
markers, urinary 5-HIAA and plasma chromogranin A.77,78
Five year disease specific survivals from a large study of
small bowel sarcomas varied from 72% for local disease to
only 7% for those with distant disease.79 The outcomes for
GISTs are expected to be better than these results, particularly
since the introduction of tyrosine kinase inhibitors. Indicators
of prognosis for GISTs include tumour site, tumour size,
whether the resection margins are negative or not and mitotic
activity.
The prognosis for lymphomas varies depending on the
subtype diagnosed. Survival rates for IPSID treated with
combination chemotherapy and tetracycline are reported as
high as 70% in some series.80 Unfortunately the same cannot
be said for enteropathy-associated T-cell intestinal lymphoma
(EATL) which is almost always high grade histology. With
chemotherapy alone the five-year overall survival rate is
10e20 per cent81,82 with case series demonstrating improved
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dx.doi.org/10.1016/j.surge.2014.02.003
overall survival with the use of autologous haematopoietic
cell transplantation.
Conclusion
Small bowel cancers are a rare but increasing cause of
gastrointestinal malignancy. Increased use of better cross-
sectional imaging techniques may increase the frequency of
diagnosis at an earlier stage. When symptomatic, their non-
specific presentation often results in delayed diagnosis.
Aside from small bowel lymphoma, the goal of treatment is
margin negative surgical resection. Later stage at presentation
makes curative resection difficult. There is however some
hope that the mortality from these tumours may decrease
with the growing armamentarium of adjuvant and neo-
adjuvant therapies available. The elucidation of risk factors
for these tumours should arouse the clinician’s suspicion in
certain high risk individuals, particularly those with familial
syndromes, where strong consideration of the possible role of
screening should take place.
Acknowledgements
We wish to thank Dr Yvonne McCarthy from the Pathology
department in Beaumont Hospital for contributing the gross
specimen image of the jejunal adenocarcinoma.
references
1. Dabaja BS, Suki D, Pro B, Bonnen M, Ajani J. Adenocarcinoma
of the small bowel: presentation, prognosticfactors, and
outcome of 217 patients. Cancer 2004;101(3):518e26.
2. Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J. Cancer
incidence in five continents, vol. 7. IARC Publication, Publication
143.
3. Bilimoria Karl Y, Bentrem David J, Wayne Jeffrey D,
Ko Clifford Y, Bennett Charles L, Talamonti Mark S. Small
bowel cancer in the United States. Changes in epidemiology,
treatment and survival over the last 20 years. Ann Surg
2009;249(1):63e71.
4. Pan Sai Yi, Morrison Howard. Epidemiology of cancer of the
small intestine. WJGO 2011;3(3):33e42.
5. Haselkorn Tmirah, Whittemore Alice S, Lilienfeld David E.
Incidence of small bowel cancer in the United States and
worldwide. Geographic, temporal and racial differences.
Cancer Causes Control 2005;16:781e7.
6. Kadakia SC, Parker A, Canales L. Metastatic tumors to the
upper gastrointestinal tract: endoscopic experience. Am J
Gastroenterol 1992 Oct;87(10):1418e23.
7. Canavan C, Abrams KR, Mayberry J. Meta-analysis: colorectal
and small bowel cancer risk in patients with Crohn’s disease.
Aliment Pharmacol Ther 2006;23:1097e104.
8. Feldstein Richard C, Sood Shivani, Katz Seymour. Small bowel
adenocarcinoma in Crohn’s disease. Inflamm Bowel Dis
2008;14(8):1154e7.
9. Green PH, Cellier C. Celiac disease. N Engl J Med
2007;357:1731e43.
10. Green PHR, Stavropoulos SN, Panagi SG, Goldstein SL,
Mcmahon DJ, Absan H, et al. Characteristics of adult celiac
 t h e s u r g e o n x x x ( 2 0 1 4 ) 1 e8
disease in the USA: results of a national survey. Am J
Gastroenterol 2001 Jan;96(1):126e31.
11. Sellner F. Investigations on the significance of the adenorna-
carcinoma sequence in the small bowel. Cancer
1990;66:702e15.
12. Schottenfeld D, Beebe-Dimmer JL, Vigneau FD. The
epidemiology and pathogenesis of neoplasia in the small
intestine. Ann Epidemiol 2009;19:58e69.
13. Giardiello FM, Brensinger JD, Tersmette AC, Goodman SN,
Petersen GM, Booker SV, et al. Very high risk of cancer in
familial Peutz-Jeghers syndrome. Gastroenterology
2000;119(6):1447e53.
14. Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L,
Albertsen H, et al. Identification and characterization of the
familial adenomatous polyposis coli gene. Cell
1991;66(3):589e600.
15. Kadmon M, Tandara A, Herfarth C. Duodenal adenomatosis
in familial adenomatous polyposis coli. A review of the
literature and results from the Heidelberg Polyposis Register.
Int J Colorectal Dis 2001;16(2):63e75.
16. Chung DC, Rustgi AK. The hereditary nonpolyposis colorectal
cancer syndrome: genetics and clinical implications. Ann
Intern Med 2003;138(7):560e70.
17. Vasen HF, Wijnen JT, Menko FH, Kleibeuker JH, Taal BG,
Griffioen G, et al. Cancer risk in families with hereditary
nonpolyposis colorectal cancer diagnosed by mutation
analysis. Gastroenterology 1996;110(4):1020e7.
18. Neugut AI, Santos J. The association between cancers of the
small and large bowel. Cancer Epidemiol Biomarkers Prev
1993;2(6):551e3.
19. Chow WH, Linet MS, McLaughlin JK, Hsing AW, Chien HT,
Blot WJ. Risk factors for small intestine cancer. Cancer Causes
Control 1993;4(2):163e9.
20. Cross AJ, Leitzmann MF, Subar AF, Thompson FE,
Hollenbeck AR, Schatzkin A. A prospective study of meat and
fat intake in relation to small intestinal cancer. Cancer Res
2008;68(22):9274e9.
21. Kaerlev L, Teglbjaerg PS, Sabroe S, Kolstad HA, Ahrens W,
Eriksson M, et al. Is there an association between alcohol
intake or smoking and small bowel adenocarcinoma? Results
from a European multi-center case-control study. Cancer
Causes Control 2000;11(9):791e7.
22. Bjørge T, Tretli S, Engeland A. Height and body mass index in
relation to cancer of the small intestine in two million
Norwegian men and women. Br J Cancer;93(7):807e810.
23. Hassan MM, Phan A, Li D, Dagohoy CG, Leary C, Yao JC. Risk
factors associated with neuroendocrine tumors: a U.S.-based
case-control study. Int J Cancer;123(4):867e873.
24. Wu AH, Yu MC, Mack TM. Smoking, alcohol use, dietary
factors and risk of small intestinal adenocarcinoma. Int J
Cancer 1997;70(5):512e7.
25. Kaerlev L, Teglbjaerg PS, Sabroe S, Kolstad HA, Ahrens W,
Eriksson M, et al. The importance of smoking and medical
history for development of small bowel carcinoid tumor: a
European population-based case-control study. Cancer Causes
Control 2002 Feb;13(1):27e34.
26. Johansen C, Chow WH, Jørgensen T, Mellemkjaer L,
Engholm G, Olsen JH. Risk of colorectal cancer and other
cancers in patients with gall stones. Gut 1996;39(3):439e43.
27. Arber N, Neugut AI, Weinstein IB, Holt P. Molecular genetics
of small bowel cancer. Cancer Epidemiol Biomarkers Prev
1997;6(9):745e8.
28. Gill SS, Heuman DM, Mihas AA. Small intestinal neoplasms. J
Clin Gastroenterol 2001;33(4):267e82.
29. Wheeler JM, Warren BF, Mortensen NJ, Kim HC, Biddolph SC,
Elia G, et al. An insight into the genetic pathway of
adenocarcinoma of the small intestine. Gut
2002;50(2):218e23.
Please cite this article in press as: Reynolds I, et al., Malignant tumours of the small intestine, The Surgeon (2014), http://
dx.doi.org/10.1016/j.surge.2014.02.003
7
30. Freedman A.S. Clinical presentation and diagnosis of primary
gastrointestinal lymphomas. www.uptodate.com.
31. Arnold CN, Sosnowski A, Blum HE. Analysis of molecular
pathways in neuroendocrine cancers of the
gastroenteropancreatic system. Ann N Y Acad
Sci;1014:218e219.
32. Perren A, Komminoth P, Heitz PU. Molecular genetics of
gastroenteropancreatic endocrine tumors. Ann N Y Acad Sci
2004;1014:199e208.
33. Ciresi DL, Scholten DJ. The continuing clinical dilemma of
primary tumors of the small intestine. Am Surg
1995;61(8):698e702.
34. Minardi Jr AJ, Zibari GB, Aultman DF, McMillan RW,
McDonald JC. Small-bowel tumors. J Am Coll Surg
1998;186(6):664e8.
35. Koch P, del Valle F, Berdel WE, Willich NA, Reers B,
Hiddemann W, et al., German Multicenter Study Group.
Primary gastrointestinal non-Hodgkin’s lymphoma: II.
Combined surgical and conservative or conservative
management only in localized gastric lymphomaeresults of
the prospective German Multicenter Study GIT NHL 01/92. J
Clin Oncol 2001;19(18):3874e83.
36. Weyenberg Van, Meijerink MR, Jacobs MA, Van der Peet DL,
Van Kuijk C, Mulder CJ, et al. MR enteroclysis in the diagnosis
of small-bowel neoplasms. Radiology 2010 Mar;254(3):765e73.
37. Horton KM, Fishman EK. Multidetector-row computed
tomography and 3-dimensional computed tomography
imaging of small bowel neoplasms: current concept in
diagnosis. J Comput Assist Tomogr 2004;28(1):106e16.
38. Cobrin GM, Pittman RH, Lewis BS. Increased diagnostic yield
of small bowel tumors with capsule endoscopy. Cancer
2006;107(1):22e7.
39. Kema IP, de Vries EG, Slooff MJ, Biesma B, Muskiet FA.
Serotonin, catecholamines, histamine, and their metabolites
in urine, platelets, and tumor tissue of patients with carcinoid
tumors. Clin Chem 1994;40(1):86e95.
40. Wu TJ, Yeh CN, Chao TC, Jan YY, Chen MF. Prognostic factors
of primary small bowel adenocarcinoma: univariate and
multivariate analysis. World J Surg 2006;30(3):391e8.
41. Chen ZM, Wang HL. Alteration of cytokeratin 7 and
cytokeratin 20 expression profile is uniquely associated with
tumorigenesis of primary adenocarcinoma of the small
intestine. Am J Surg Pathol 2004;28(10):1352e9.
42. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A,
editors. AJCC cancer staging manual. 7th ed. 2010. pp. 127e32.
43. Abrahams NA, Halverson A, Fazio VW, Rybicki LA,
Goldblum JR. Adenocarcinoma of the small bowel: a study of
37 cases with emphasis on histologic prognostic factors. Dis
Colon Rectum 2002;45(11):1496e502.
44. Bautista-Quach Marnelli A, Ake Christopher D, Chen Mingyi,
Wang Jun. Gastrointestinal lymphomas: morphology,
immunophenotype and molecular features. J Gastrointest
Oncol 2012;3(3):209e25.
45. Rohatiner A, d’Amore F, Coiffier B, Crowther D,
Gospodarowicz M, Isaacson P, et al. Report on a workshop
convened to discuss the pathological and staging
classifications of gastrointestinal tract lymphoma. Ann Oncol
1994;5(5):397e400.
46. Downs-Kelly Erinn, Rubin Brian P. Gastrointestinal stromal
tumors: molecular mechanisms and targeted therapies.
Pathol Res Int 2011;2011:708596.
47. Foo Wai Chin, Liegl-Atzwanger Bernadette, Lazar Alexander J.
Pathology of gastrointestinal stromal tumors. Clin Med Insights
Pathol 2012;5:23e33.
48. Pinchot Scott N, Holen Kyle, Sippel Rebecca S, Chen Herbert.
Carcinoid tumors. Oncologist 2008;13(12):1255e69.
49. Kumar V, Abbas AK, Fausto N, Aster JC. The gastrointestinal
tract. In: Turner JR, editor. Robbins and cotran pathologic basis of
8 t h e s u r g e o n x x x ( 2 0 1 4 ) 1 e8
disease. 1600 John F. Kennedy Blvd, Ste 1800, Philadelphia, PA
19103-2899: Elsevier; 2010. P786e90.
50. Kaklamanos IG, Bathe OF, Franceschi D, Camarda C, Levi J,
Livingstone AS. Extent of resection in the management of
duodenal adenocarcinoma. Am J Surg 2000;179(1):37e41.
51. Bakaeen FG, Murr MM, Sarr MG, Thompson GB, Farnell MB,
Nagorney DM, et al. What prognostic factors are important in
duodenal adenocarcinoma? Arch Surg 2000;135(6):635e41
[discussion 641e2].
52. Agrawal S, McCarron EC, Gibbs JF, Nava HR, Wilding GE,
Rajput A. Surgical management and outcome in primary
adenocarcinoma of the small bowel. Ann Surg Oncol 2007
Aug;14(8):2263e9 [Epub 2007 Jun 5].
53. Singhal N, Singhal D. Adjuvant chemotherapy for small
intestine adenocarcinoma. Cochrane Database Syst Rev 2007 Jul
18;3:CD005202.
54. Zaanan A, Costes L, Gauthier M, Malka D, Locher C, Mitry E,
et al. Chemotherapy of advanced small-bowel
adenocarcinoma: a multicenter AGEO study. Ann Oncol
2010;21(9):1786e93.
55. Kelsey CR, Nelson JW, Willett CG, Chino JP, Clough RW,
Bendell JC, et al. Duodenal adenocarcinoma: patterns of
failure after resection and the role of chemoradiotherapy. Int J
Radiat Oncol Biol Phys 2007 Dec 1;69(5):1436e41 [Epub 2007 Aug
6].
56. Gibson MK, Holcroft CA, Kvols LK, Haller D. Phase II study of
5-fluorouracil, doxorubicin, and mitomycin C for metastatic
small bowel adenocarcinoma. Oncologist 2005 Feb;10(2):132e7.
57. Tsang H, Yau T, Khong PL, Epstein RJ. Bevacizumab-based
therapy for advanced small bowel adenocarcinoma. Oncologist
2005;10(2):132e7.
58. Jacks SP, Hundley JC, Shen P, Russell GB, Levine EA.
Cytoreductive surgery and intraperitoneal hyperthermic
chemotherapy for peritoneal carcinomatosis from small
bowel adenocarcinoma. J Surg Oncol 2005 Aug 1;91(2):112e7
[discussion 118e9].
59. Marchettini P, Sugarbaker PH. Mucinous adenocarcinoma of
the small bowel with peritoneal seeding. Eur J Surg Oncol 2002
Feb;28(1):19e23.
60. Jung GS, Song HY, Kang SG, Huh JD, Park SJ, Koo JY, et al.
Malignant gastroduodenal obstructions: treatment by means
of a covered expandable metallic stent-initial experience.
Radiology 2000 Sep;216(3):758e63.
61. Moertel CG, Sauer WG, Dockerty MB, Baggenstoss AH. Life
history of the carcinoid tumor of the small intestine. Cancer
1961 SepeOct;14:901e12.
62. Pape UF, Perren A, Niederle B, Gross D, Gress T, Costa F, et al.,
Barcelona Consensus Conference Participants. ENETS
consensus guidelines for the management of patients with
neuroendocrine neoplasms from the jejuno-ileum and the
appendix including goblet cell carcinomas. Neuroendocrinology
2012;95(2):135e56.
63. Sarmiento JM, Heywood G, Rubin J, Ilstrup DM, Nagorney DM,
Que FG. Surgical treatment of neuroendocrine metastases to
the liver: a plea for resection to increase survival. J Am Coll
Surg 2003 Jul;197(1):29e37.
64. Olausson M, Friman S, Herlenius G, Cahlin C, Nilsson O,
Jansson S, et al. Orthotopic liver or multivisceral
transplantation as treatment of metastatic neuroendocrine
tumors. Liver Transpl 2007;13(3):327e33.
65. King J, Quinn R, Glenn DM, Janssen J, Tong D, Liaw W, et al.
Radioembolization with selective internal radiation
microspheres for neuroendocrine liver metastases. Cancer
2008 Sep 1;113(5):921e9.
66. Dematteo RP, Ballman KV, Antonescu CR, Maki RG,
Pisters PW, Demetri GD, et al., American College of Surgeons
Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study
Team. Adjuvant imatinib mesylate after resection of
Please cite this article in press as: Reynolds I, et al., Malignant tumours of the small intestine, The Surgeon (2014), http://
dx.doi.org/10.1016/j.surge.2014.02.003
localised, primary gastrointestinal stromal tumour: a
randomised, double-blind, placebo-controlled trial. Lancet
2009 Mar 28;373(9669):1097e104.
67. Eisenberg BL, Harris J, Blanke CD, Demetri GD, Heinrich MC,
Watson JC, et al. Phase II trial of neoadjuvant/adjuvant
imatinib mesylate (IM) for advanced primary and metastatic/
recurrent operable gastrointestinal stromal tumor (GIST):
early results of RTOG 0132/ACRIN 6665. J Surg Oncol 2009 Jan
1;99(1):42e7.
68. Cheung MC, Housri N, Ogilvie MP, Sola JE, Koniaris LG.
Surgery does not adversely affect survival in primary
gastrointestinal lymphoma. J Surg Oncol 2009;100:59.
69. Nagashima R, Takeda H, Maeda K, Ohno S, Takahashi T.
Regression of duodenal mucosa-associated lymphoid tissue
lymphoma after eradication of Helicobacter pylori.
Gastroenterology 1996;111:1674.
70. Lecuit M, Abachin E, Martin A, Poyart C, Pochart P, Suarez F,
et al. Immunoproliferative small intestinal disease associated
with campylobacter jejuni. N Engl J Med 2004;350:239.
71. el Saghir NS, Jessen K, Mass RE, al-Mofleh I, Santhosh-
Kumar CR, Hall AD, et al. Combination chemotherapy for
primary small intestinal lymphoma in the middle East. Eur J
Cancer Clin Oncol 1989;25:851.
72. Sieniawski M, Angamuthu N, Boyd K, Chasty R, Davies J,
Forsyth P, et al. Evaluation of enteropathy-associated T-cell
lymphoma comparing standard therapies with a novel
regimen including autologous stem cell transplantation. Blood
2010;115:3664.
73. Sehn LH, Donaldson J, Chhanabhai M, Fitzgerald C, Gill K,
Klasa R, et al. Introduction of combined CHOP plus rituximab
therapy dramatically improved outcome of diffuse large B-
cell lymphoma in British Columbia. J Clin Oncol
2005;23(22):5027.
74. Contant CM, Damhuis RA, van Geel AN, van Eijck CH,
Wiggers T. Prognostic value of the TNM-classification for
small bowel cancer. Hepatogastroenterology 1997;44(14):430e4.
75. Howe JR, Karnell LH, Menck HR, Scott-Conner C, The
American College of Surgeons Commission on Cancer and the
American Cancer Society. Adenocarcinoma of the small
bowel: review of the National Cancer Data Base, 1985e1995.
Cancer 1999;86(12):2693e706.
76. Brücher BL, Stein HJ, Roder JD, Busch R, Fink U, Werner M,
et al. New aspects of prognostic factors in adenocarcinomas
of the small bowel. Hepatogastroenterology 2001;48(39):727e32.
77. Jann H, Roll S, Couvelard A, Hentic O, Pavel M, Müller-
Nordhorn J, et al. Neuroendocrine tumors of midgut and
hindgut origin: tumor-node-metastasis classification
determines clinical outcome. Cancer 2011 Aug
1;117(15):3332e41.
78. Rorstad O. Prognostic indicators for carcinoid neuroendocrine
tumors of the gastrointestinal tract. J Surg Oncol
2005;89(3):151e60.
79. Howe JR, Karnell LH, Scott-Conner C. Small bowel sarcoma:
analysis of survival from the national cancer data base. Ann
Surg Oncol 2001 Jul;8(6):496e508.
80. Akbulut H, Soykan I, Yakaryilmaz F, Icii F, Aksoy F,
Haznedaroglu S, et al. Five-year results of the treatment of 23
patients with immunoproliferative small intestinal disease: a
Turkish experience. Cancer 1997;80:8.
81. Egan LJ, Walsh SV, Stevens FM, Connolly CE, Egan EL,
McCarthy CF. Celiac-associated lymphoma. A single
institution experience of 30 cases in the combination
chemotherapy era. J Clin Gastroenterol 1995;21(2):123e9.
82. Gale J, Simmonds PD, Mead GM, Sweetenham JW, Wright DH.
Enteropathy-type intestinal T-cell lymphoma: clinical
features and treatment of 31 patients in a single center. J Clin
Oncol 2000;18(4):795e803.