State of the Art Oncology in EuropeFont: aaa

Small bowel cancer – 2016

UPDATED SEPTEMBER 2016

1. GENERAL INFORMATION

1.1 Epidemiology

1.1.1 Incidence

In sharp contrast with other parts of the intestinal tract (stomach and colon-rectum), small bowel cancer (SBC) is rare, with about 3,900 new cases each year in Europe (EU28) (RARECAREnet). In 2000-2007, the European incidence was 8 per million persons per year. SBC is very rare under 40 years of age, while in the age-group 65+ years the rate is 30. There are geographical differences in the occurrence of the disease, with the lowest incidence in Eastern Europe (4) and the highest in UK and Ireland (7). During the period 1999-2007, incidence rate increased by 35%: from 6 (1999-2001) to 8 (2005-2007) per million/year. The increase in incidence was more marked in men.

1.1.2 Survival

Survival from SBC in adults diagnosed during 2000-2007 in Europe was moderate: about 51% at one year and 27% at 5 years (RARECAREnet). Survival decreases with age: 5-year survival was about 46% under age 45 at diagnosis, but less than 21% for people aged 65 and more. There has been substantial improvement in European survival figures since the end of 1990s. One- and 5-year survival (age-standardised) slightly improved from 47% to 50%, and 23% to 26%, respectively (RARECAREnet).

1.1.3 Prevalence

In Europe, about 13,300 people live with a diagnosis of epithelial tumours of small intestine (Faivre 2012). They could be cured or under treatment or in clinical follow-up. Long survivors (people still alive 15 years or more after diagnosis), often cured patients, can be estimated to be about 30% of the complete prevalence. By contrast, patients in treatment or in clinical follow-up are 46% of the complete prevalence (Faivre 2012).

1.2 Environmental factors

Some studies reported an increased risk of SBC with alcohol consumption (Wu 1997) and smoking (Kaerlev 2000). Other studies reported an increased risk of SBC among the highest consumers of sugar, refined carbohydrates, red meat or smoked food, while a reduced risk was observed with higher intakes of fish, fruit, and vegetables (Chow 1993; Negri 1999). A recent large prospective study found that BMI and menopausal hormone therapy are positively associated with malignant carcinoids (Cross 2013).
The rarity of SBC compared to colorectal adenocarcinoma suggests different mechanisms of exposure. The first is that the contact time between intestinal cells and xenobiotics or dietary carcinogens is shorter than in the colon, resulting in a shorter transit time. Proximal small intestine contains low concentrations of aerophilic Gram-positive bacteria, which produce xenobiotic transformation during which bile salts are deconjugated and dehydroxylated to form desoxycholic acid, which is a potential tumour promoter (Schottenfeld 2009). Furthermore, the epithelial cells of the small bowel are equipped with a wide range of microsomal enzymes, including the benzopyrene hydroxylase, that may protect them against food-derived carcinogens (Delaunoit 2005).

1.2.1 Genetic and predisposing conditions

A small fraction of SBC are related to genetic predisposition, such as the familial adenomatous polyposis (FAP), Lynch syndrome and the Peutz-Jeghers syndrome. Furthermore, SBC is associated with other predisposing conditions such as Crohn’s disease or coeliac diseases (Aparicio 2014).

1.3 Aetiology and risk factors

1.3.1 Aetiology factors

Despite the fact that the small intestine represents 75% of the total length of the gastrointestinal (GI) tract and more than 90% of the mucosal surface, the small bowel rarely develops malignant tumours. The reason for the low incidence of carcinogenesis, in comparison to the colon, remains unknown. Many mechanisms have been postulated to explain this decreased susceptibility for neoplastic transformation (DeVita 2011; Gill 2001; Chow 1993):

  • High levels of benzopyrene hydroxylase and folate receptors: benzopyrene, a carcinogen contained in various foods, is converted to less toxic metabolites by the enzyme benzopyrene hydroxylase, which is present in much higher concentrations in the small intestine in comparison with other parts of the gastrointestinal tract;
  • High cellular turn-over compared to other parts of the GI tract;
  • Liquid and alkaline contents may cause less mucosal irritation;
  • Stem cells in the small intestine are located deep in the intestinal glandular crypts where they are protected from carcinogenic stimuli;
  • Fast transit of intestinal contents through the small bowel may provide shorter exposure of its mucosa to carcinogenesis;
  • Low bacterial load: anaerobic bacteria are rare in the small bowel and, as a consequence, the conversion of bile acids into potential carcinogens is decreased;
  • Immune protection of the increased lymphoid tissue with a high level of secretory immunoglobulin A (lgA) expression in the small bowel may be protective.

Certain hereditary and autoimmune syndromes are associated with an increased incidence of particular histological types of small intestinal tumours. These include (Chow 1993; Björk 2001; Kawashima 1994):

  • Peutz-Jeghers syndrome (PJS): an autosomal dominant disorder characterized by hamartomatous polyps occurring primarily in the jejunum and ileum in association with mucocutaneous melanocytic macules on the lips and oral mucosa. Patients with PJS have a 15-fold increased risk of development of small as well as large intestinal adenocarcinoma;
  • Familial adenomatous polyposis (FAP): a disorder caused by a germline mutation in the Adenomatous Polyposis Coli (APC) gene. Patients develop hundreds of thousands of adenomatous polyps throughout the colon and the small intestine;
  • Hereditary non-polyposis colorectal cancer (HNPCC): is an inherited condition determined by mutations in the DNA mismatch repair genes. Patients have about 80% lifetime risk for colon cancer and a lifetime risk of 1% to 4% for other malignancies, such as SBC;
  • Other genetic conditions: Gardner syndrome, an autosomal dominant disease characterized by multiple colonic polyps, osteomas and skin and soft tissue tumours; Von Recklinghausen’s disease, where the neurofibromas have the potential of malignant transformation into paragangliomas. Patients with cystic fibrosis have an increased incidence of ileal adenocarcinomas;
  • Chronic inflammatory disorders that predispose to malignancy include Crohn’s disease (adenocarcinoma), celiac disease (lymphoma and less frequently adenocarcinoma), and non-proliferation disease (immunoproliferative small intestinal disease – IPSID – and diffuse intestinal lymphoma).

2. PATHOLOGY AND BIOLOGY

More than 40 different histologically distinct tumours have been described in the small intestine; the most commonly occurring histological subtypes are adenocarcinomas (40%), carcinoid tumours (36%), lymphomas, and sarcomas.
Historically adenocarcinoma has been the most common malignant tumour of the small intestine, representing 30% to 50% of all SBC. More recently, the National Cancer Database indicates that carcinoid have surpassed adenocarcinoma in incidence (44% vs. 33%, respectively) (Bilimoria 2009).
The histogenesis of small bowel adenocarcinoma is probably analogous to the colonic adenoma-carcinoma sequence, through which the vast majority of colorectal cancers are thought to evolve. Thus, the single, most important risk factor for small bowel adenocarcinoma is a pre-existing adenoma, either single or multiple in association with one of the multiple polyposis syndromes (Dabaja 2004; Hong 2009). Adenocarcinoma of the small intestine may be polypoid, ulcerative or simply annular or stenosing. Adenocarcinomas begin in crypt epithelium, rather than villi and, therefore, resemble colorectal cancer.

3. DIAGNOSIS

3.1 Signs and Symptoms

SBCs often present insidiously with non-specific complaints, such as abdominal pain, nausea, vomiting, weight loss, anaemia, or bleeding. Approximately 50% of all SBCs present acutely with an obstruction or perforation. Consequently, they are often overlooked by the physician at initial presentation and the correct diagnosis is delayed (Maglinte 1991). In a large series, the mean time to diagnosis from the onset of the initial complaint in patients with small intestinal tumours was 7 months. While benign small intestinal tumours usually remain asymptomatic, clinical presentation of SBCs can be different with respect to various histologic subtypes: adenocarcinomas tend to be associated with abdominal pain, weight loss and obstruction; sarcomas are associated with haemorrhage, lymphomas are associated with perforation. In addition, adenocarcinomas tend to involve mainly the duodenum, while carcinoids more commonly develop in the ileum. Sarcomas and lymphomas can affect the entire small bowel (Dabaja 2004; Hong 2009).

4. STAGING

4.1 Stage classification

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification to define small intestine cancer.

Table 1. Classification of primary tumours (T). (Edge 2010; reprinted with permission from AJCC).
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ
T1a Tumour invades lamina propria
T1b Tumour invades submucosa*
T2 Tumour invades muscularis propria
T3 Tumour invades through the muscularis propria into the subserosa or into the non-peritonealised perimuscular tissue (mesentery or retroperitoneum) with extension ≤2 cm*
T4 Tumour perforates the visceral peritoneum or directly invades other organs or structures (it includes other loops of small intestine, mesentery, or retroperitoneum >2 cm,
and abdominal wall by way of serosa; for duodenum only, invasion of pancreas or bile duct).
* Non-peritonealised perimuscular tissue is, for jejunum and ileum, part of the mesentery and, for duodenum in areas where serosa is lacking, part of the interface with the pancreas.
Table 2. Classification of regional lymph nodes (N). (Edge 2010; reprinted with permission from AJCC).
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in 1-3 regional lymph nodes
N2 Metastases in ≥4 regional lymph nodes
Table 3. Anatomic stage and prognostic groups. (Edge 2010; reprinted with permission from AJCC).
Stage T N M
0 Tis N0 M0
I T1 N0 M0
T2 N0 M0
IIA T3 N0 M0
IIB T4 N0 M0
IIIA Any T N1 M0
IIIB Any T N2 M0
IV Any T Any N M1

4.2 Staging procedures

4.2.1 Preoperative procedures

No single diagnostic modality has been established as the gold standard. The usual tests used for evaluation of abdominal complaints, including oesophagogastroduodenoscopy, colonoscopy, small bowel series (small bowel follow through – SBFT), and abdominal ultrasound, may be useful, especially in advanced lesions, but they are relatively insensitive for early diagnosis of small intestinal malignancy. The frequent delay in the diagnosis is more likely to be caused by failure in proper diagnostic process or misinterpretation of appropriate diagnostic testing rather than by a patient’s delay in signalling symptoms.
Abdominal radiograph is often the first radiological exam performed, but its role is limited to diagnosis of small bowel obstruction (50% to 60% accuracy). SBFT is used for examination of luminal abnormalities and mucosal morphology, but requires a considerable length of time. Accuracy can be improved to greater than 90% with the addition of enteroclysis. This method produces distension of the bowel and allows the fluoroscopist to follow the movement of the contrast material through the gut. Enteroclysis allows better visualization not only of the intestinal lumen, but also of the mucosal surface.
At present, computed tomography (CT) has a role in detecting the primary lesion, and in the preoperative staging and evaluation of metastases. CT evaluation of small bowel neoplasms revealed certain pathognominc features allowing for their differentiation (Buckley 1998; Horton 2004). Small bowel endoscopy or enteroscopy is a relatively recent development in GI endoscopy. Double-balloon enteroscopy, or push enteroscopy, can be used to examine the jejunum for about 40 to 60 cm beyond the ligament of Treitz; it allows visualization of the entire small bowel with the possibility of taking a biopsy of any suspicious lesions. Another endoscopic exam is the video capsule endoscopy (VCE) which is indicated in the investigation of obscure GI bleeding and prior to presentation with obstructive symptoms. Although VCE does not allow tissue sampling or precise localizations of lesions, it has demonstrated higher sensitivity and specificity than older techniques (upper GI follow through) (Mazzarolo 2007; Horton 2004). Nuclear medicine has an important role in the detection of carcinoids.

4.2.2 Surgical staging

The majority of adenocarcinomas arise from the proximal duodenum and jejunum. Peak incidence is in the 7th decade of life, with a male preponderance and an earlier presentation in patients with predisposing genetic conditions. Small bowel adenocarcinoma is diagnosed at a late stage in 58% of patients; only 50% of patients undergoes surgery with curative intent.

5. PROGNOSIS

Overall 5-year survival rates are reported as 22%-30% with a median survival of 19 months. Several groups have reported better survival rates for duodenal adenocarcinoma. Tumour site, differentiation, pathological stage, presence of vascular invasion and resection margins are all prognostic indicators. Those with an advanced pathological stage and positive lymph node involvement are at a high risk of disease recurrence. Survival by stage is 65% for stage I, 48% for stage II, 35% for stage III and 4 % for stage IV (Bilimoria 2009; Sohn 1998).

6. TREATMENT

Surgery is the treatment of choice and is the only therapeutic modality with curative potential. Duodenal tumours may require pancreaticoduodenectomy; in other locations, simple resection of the involved segment of bowel with accompanying mesentery and wide margins is sufficient. Small adenocarcinomas, especially polypoid lesions with tumour confined to the mucosa and submucosa, sometimes can be cured by endoscopic resection (polypectomy or mucosectomy). In advanced, unresectable disease, options include palliative resection and bypass (Agrawal 2007).
The recurrence pattern for small bowel adenocarcinoma is mainly systemic, but evidence for adjuvant therapy is still lacking. Several series have reported adjuvant chemotherapy for jejunal or ileal adenocarcinoma and adjuvant chemotherapy or radiation for duodenal cancer, but none have shown meaningful improvement in survival. The data however, are limited by small numbers and its reliance on 5-fluorouracil (5-FU) as main chemotherapy (Swartz 2007; Locher 2005). Results on combinations with oxaliplatin in the palliative setting are promising and suggest its use in the adjuvant setting (Fishman 2006). For advanced small bowel adenocarcinoma, different prospective and retrospective reports indicate that the combination regimens with 5-FU and platinum improve response rate (Gibson 2005). Irinotecan has a good response as a second-line agent.

6.1 Neuroendocrine tumours

Neuroendocrine tumours (NET) occur predominantly in white patients (80%, compared to other ethnic groups) and men (52.4%), with a median age of presentation of 66 years. Although they follow an indolent course, a delay in their diagnosis leads to presentation at an advanced stage in more than two-thirds of cases. 29% of small bowel NETs are associated with other non-carcinoid neoplasms.
Such neoplasms arise from the neuroendocrine cells of Kulchitsky in the intestinal tract: they are rare, characterized by a low growth and widespread in the gastrointestinal tract (75% of all cases), followed by the lung and bronchus. The majority of NETs occur in the small intestine (42%; the majority are identified in the ileum, followed by the duodenum and then the jejunum), in the rectum (27%), and in the stomach and appendix (9%) (Maggard 2004; Modlin 2003). In 5-7% of patients with small bowel NETs, the tumour secretes bio-active mediators and gives rise to symptoms characteristics of the carcinoid syndrome: intermittent abdominal cramps, diarrhoea, flushing, bronchospasm, and cyanosis. Symptoms can be precipitated by alcohol ingestion, stress and physician activities.
Despite their advanced presentation, overall 5-year survival is between 52% and 77% (Shebani 1999). Predictors of local-regional and metastatic spread are primarily the size of the lesion and its depth of invasion. In addition to classic radiological findings, octreotide scan can be diagnostic in 90% of cases. Biochemically, urinary 5-hydroxyindoleacetic acid (5-HIAA) levels and chromogranin A levels are used as tumour markers.
Segmental resection of the tumour with draining lymph nodes is the treatment of choice because of its locoregional spread. Five-year survival after resection of localised disease ranges between 50-85%. For appendiceal NETs, management is dictated by size: tumours smaller than 2 cm can be treated with appendicectomy, while larger tumours need a right hemicolectomy plus lymphadenectomy. Pretreatment with octreotide is recommended before surgical resection, because surgery may precipitate a carcinoid crisis.
In the metastatic setting, cytoreductive therapy (such as surgery, local ablative therapy involving hepatic arterial embolization (HAE) with or without chemotherapy and systemic chemotherapy) and resection of the primary lesion can achieve symptom control and improved survival. Liver is the most common site of metastases and its resection with the primary tumour should be attempted with curative intent, if possible. In patients with extensive liver disease, surgical debulking or cytoreductive surgery, such as radiofrequency ablation and cryoablation, provides prolonged disease-free survival. Liver transplantation is considered in very limited subset of cases (Givi 2006; Osborne 2006). The role of systemic chemotherapy in the treatment of metastatic carcinoid is unclear. Different chemotherapeutic agents have been investigated including 5-FU, streptozotocin, and doxorubicin with a response rate of 20%. Interferon-alfa, octreotide and their combination with other chemotherapeutic agents has been examined, but the superiority of these combinations compared to single agent therapy is not clear. Promising results have been shown with everolimus, a molecule inhibiting the mammalian target of rapamycin (mTOR) (DeVita 2011). On the bases of RADIANT 4 study, in 2017 this agent will enter in the field of treatment in cases with well differentiated histology (Yao 2016).

7. LATE SEQUELAE

There are no relevant sequelae of surgery or chemotherapy.

8. FOLLOW-UP

Some of the tests used to diagnose may be repeated during follow-up or in order to see the results of treatment.

INDEX

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Maria Di Bartolomeo (Author)
Italian National Cancer Institute, Milan (Italy)
e-mail address: maria.dibartolomeo@istitutotumori.mi.it

Gemma Gatta (Author)
Italian National Cancer Institute, Milan (Italy)
e-mail address: gemma.gatta@istitutotumori.mi.it