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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.

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 subtypes are described. Adenocarcinoma of the small bowel, while infrequently encountered, accounts for 40% of all

malignant small intestinal tumours. Most originate in the 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 separately. 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: [email protected] (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

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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, particularly 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 adenocarcinoma. A relative risk of 33 (95% CI: 15.9e60.9) was reported 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 Tcell 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

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 Lindau 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 consumption,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

Familial adenomatous polyposis (FAP) Gallstones 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

A Danish series reports an elevated risk for cancer of the small intestine, mainly carcinoid tumours, in patients with gallstones.26

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

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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 carcinogens from bile acid breakdown.27 The higher levels of IgA in the small intestine are thought to be protective against lymphoma.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 adenocarcinomas screened for RER (replication error) status, mutations in the APC MCR, and immunostaining of hMLH1, hMSH2, bcatenin, 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) lymphoma, enteropathy associated T cell (EATL) lymphoma and other western-type non-IPSID lymphomas (e.g. diffuse large B cell lymphoma, mantle cell lymphoma, follicular lymphoma).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 suppressor pathways including p53 are responsible for this malignancy.31,32

advanced disease may present with small bowel obstruction or perforation. Gastrointestinal bleeding may also occur.33,34 Duodenal tumours tend to present with intestinal obstruction less frequently than more distal parts of the small intestine due to its larger circumference. Biliary obstruction and frank or occult blood loss tend to be more common presentations 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 tumours may present as a palpable abdominal mass. Small bowel tumours are often identified incidentally during imaging 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 flushing, diarrhoea and bronchospasm. Some such patients develop endocardial thickening and right sided cardiac valvular lesions. Diagnosis of small bowel tumours is difficult and the optimum technique varies depending on the site and size of the tumour. Upper gastrointestinal radiographic methods including small bowel follow through (SBFT), computed tomography (CT), enteroclysis & enterography may reveal intestinal or lymph node masses, mucosal defects and sometimes intussusception.36 CT scanning has an important role in evaluating a primary tumour, determining local invasion 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 reaction 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 techniques are applicable in certain sites, especially for very proximal tumours and push- or balloon-enteroscopy

Diagnosis & investigation The clinical features of small bowel tumours are often nonspecific 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

Picture 1 e Adenocarcinoma ct.

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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 in diagnosis. If carcinoid syndrome is suspected, measurement of 24 h urinary excretion of 5-hydroxyindoloacetic acid (5-HIAA) may be useful.39 Serum chromogranin A and serum 5hydroxytryptamine may also be useful in the investigation of a potential neuroendocrine tumour, but blood tests are generally unhelpful in diagnosis of other small bowel tumours. Nuclear imaging can facilitate detection of carcinoid tumours. Octreotide scans use indium-111 octreotide which binds to the somatostatin receptors found in most carcinoid tumour cells. Meta-iodobenzylguanidine (MIBG) scans use radiolabelled-MIBG, again taken up by carcinoid, although they are less sensitive than octreotide scans.

Histologic diagnosis and staging Differentiating each of the four tumours from each other is usually straightforward; however, it can be difficult to determine 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 common 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 3 e Adenocarcinoma of jejunum.

lymphoma44 (See Picture 4). The Ann Arbor staging system that is used to stage lymphomas does not take depth of tumour invasion into account. The Lugano staging system takes both depth of invasion and spread of disease into account and is the most widely used staging system for gastrointestinal lymphomas.45 GIST tumours are classified as either spindle cell type, epithelioid type or mixed type. The vast majority express c-kit, detected by routine immunohistochemistry. Over 80% express the CD117 antigen, part of the KIT transmembrane receptor 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 quite large, forming solitary, well circumscribed masses covered by either ulcerated or intact mucosa. When considering the prognosis of GISTs, tumour size and mitotic count are important factors with smaller tumours and low mitotic

Picture 4 e Lymphoma.

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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 synaptophysin 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 accurate 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 pancreaticoduodenectomy whereas more distal duodenal tumours 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 adjuvant therapy. A 2009 retrospective multicentre study suggested 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 treatment 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

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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 carcinoid disease, resection of hepatic metastasis prolongs disease free survival63 with some evidence that patients with isolated liver metastasis may benefit from orthotopic liver transplantation.64 Surgery is rarely possible in patients with carcinoid 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 chemotherapeutic 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 tumours (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 subsequent resection.67

Lymphoma Lymphoma is generally diagnosed on the basis of characeteristic 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

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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 transplantation (HCT) can be used during the first remission.72 The non-IPSID tumours are treated using different combinations of antibiotics chemotherapy, radiotherapy and immunotherapy. Regimens involve agents such as rituximab, cyclophosphamide, 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 systemic chemotherapy is often considered where possible. Where symptomatic, surgical resection, bypass or placement of an endoscopically inserted stent may be considered.

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 crosssectional imaging techniques may increase the frequency of diagnosis at an earlier stage. When symptomatic, their nonspecific 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 neoadjuvant 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.

Prognosis

Acknowledgements 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 margins, lymphovascular involvement, T4 tumour stage, extensive 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 invasion 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

We wish to thank Dr Yvonne McCarthy from the Pathology department in Beaumont Hospital for contributing the gross specimen image of the jejunal adenocarcinoma.

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