Small Bowel Cancer

Etiology

Despite the wide spectrum of potential risk factors for developing small-intestinal malignancies, the following factors have been considered as definitive risk factors to play a role in the consequent small-intestinal tumors: 1) specific diet, including red meat, and ingestion of smoked or cured foods, 2)chronic inflammatory bowel involvement, including Crohn disease, 3) malabsorptive immune disorders, including celiac sprue, and 4) hereditary intestinal disorders, including nonpolyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), and Peutz-Jeghers syndrome. Over time, national registries have found that the incidence of certain types of malignant SI neoplasms varies based on location. While all of the previously mentioned malignancies can be found throughout the SI, studies have shown that these can be seen in higher incidence in certain portions of the SI. For example, adenocarcinoma is considered the most common neoplasm of the duodenum, while neuroendocrine tumors are more common in the ileum. It appears that sarcomas and lymphomas occur at equal rates throughout the SI.[4] Each type of small bowel cancer has been found to have a particular set of hereditary conditions that pose a higher risk of developing such cancerous processes. The basis for each malignancy is dependent on genetics and mutations that occur, resulting in malignant transformation of the cells.[5] The five main types and cells of origin include:

• Sarcoma - is generally classified as leiomyosarcoma and primarily arises from muscle tissue; and it is most commonly found in the ileum but can be found throughout the SI. 
• GIST or gastrointestinal stromal tumors are thought to arise from the interstitial cells of Cajal. These particular tumors are considered soft tissue sarcomas. 

• Adenocarcinoma - usually develops through the malignant transformation of glandular cells of the SI. 

• Neuroendocrine tumors - Also known as carcinoid tumors and are generally derived from hormone-producing cells and therefore are generally associated with secretory cells that cause particular clinical features. 

• Lymphoma - derived from the lymphatics associated with the small intestine.

Risk Factors

Full details regarding epidemiology and rates of occurrence have been delineated below. Certain cancer syndromes and underlying medical conditions may predispose patients to certain types of small bowel neoplasms. 

Celiac Disease

• Longstanding celiac disease is an independent risk factor for the development of high-grade lymphomas of the small bowel. Primarily noted to consist of non-Hodgkin lymphoma subtypes. Although rare, patients with type 2 refractory celiac disease have been found to have an increased risk of enteropathy-associated T cell lymphoma (often referred to as EATL). A high index of suspicion should be considered for patients with severe Celiac Disease with significant issues consistent with a recurrent obstruction or evidence of steatorrhea. Despite this primarily being noted through observational studies, some suggest that the diagnosis of EATL usually is heralded by a clinical relapse after the patient is found to have an adequate response to abstinence from gluten.  

Inflammatory Bowel Disease

• Most specifically, Crohn disease has been found to carry an increase in small bowel cancer. Studies have shown that patients with Crohn disease can have up to a 60 fold increase in the risk of developing adenocarcinoma of the small bowel.[6] 

Hereditary Cancer Syndromes 

• Cancer syndromes that carry an increased risk of cancer development in the colon can often carry an increased risk of cancer of the small bowel. Examples of such syndromes include familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC/Lynch syndrome), and Peutz-Jeghers syndrome (PJS), MUTYH-associated polyposis, as well as cystic fibrosis. All of the syndromes noted above carry an increased risk of adenocarcinoma. The risk of developing small bowel cancer often carries high mortality rates in patients with such diagnoses despite often undergoing prophylactic colectomy. For example, individuals who have undergone colectomy for colon cancer prevention in the known diagnosis of FAP still require surveillance of the upper GI tract with serial upper endoscopy at intervals that vary depending on polyp burden and initial screening pathology results.[7]

Two well-studied small intestine malignancies considering their molecular pathogenesis are adenocarcinomas and GISTs. However, less significant progress has been reported in exploring the pathogenesis of the other small-intestinal tumors. A similar pathogenesis background to colorectal adenocarcinoma with sequential genetic aberrancies has been attributed to small intestine adenocarcinoma. Villous adenomas with maximal aggressive behavior and a specific tendency to grow exponentially large are mainly found in the second portion of the duodenum, and malignant transformation has been well-documented in almost half of the villous adenomas with histopathological evaluation. Along with the histopathological subtype of small intestine adenomas, family and personal history of hereditary polyposis disorders, including familial adenomatous disease, has a critical role in predicting the potential for malignant transformation. Accordingly, almost all diagnosed duodenal adenomas polyps in the context of FAP will eventually transform into adenocarcinoma, and the duodenal cancer risk in these patients is more than 100-times greater than in the general population. Moreover, hamartomatous polyps in patients with Peutz-Jeghers syndrome might contain adenomatous loci with the potential for malignant transformation. However, pathological sequences of GIST tumors, including mutations with a gain of function tendency of proto-oncogene KIT, with a key role in unopposed cellular growth, have been well identified. The interstitial cells of Cajal have an integral role in the GISTs tumor, and the specific staining for CD117 antigen, the KIT receptor, is present in most GIST tumors.[8]

Epidemiology

Small-intestinal malignancies are mainly diagnosed in the fifth or sixth decade of life. The patients with small bowel adenocarcinoma are significantly younger with more advanced stages of cancer at the time of diagnosis than those with colorectal cancer.[9] The incidence of small intestine cancer is very low in the United States, with SI cancer only accounting for approximately 3 to 5% of all gastrointestinal tract malignancies. The rate of incidence is proportionally shallow when one considers that the SI accounts for about 90% of the surface area of the GI tract as a whole.[10] In contrast, Colon Cancer accounts for the third most common cause of cancer-related death in the USA. The exact epidemiology and rate of incidence vary with each type of malignancy. 

Sarcoma

• The most common type is GIST tumors—higher incidence rates in individuals around age 65 with reported male predominance. Sarcomas overall, however, are most commonly found in children as an oncologic process.[11]

Adenocarcinoma 

• Generally present in patients aged 50 to 70 years old with male predominance identified.[12] Certain conditions such as Inflammatory Bowel Disease, mainly Crohn’s Disease, and hereditary cancer syndromes such as FAP and HNPCC carry higher risk and present at younger ages.[13]

Neuroendocrine Tumors

• Generally present in patients aged 50 to 70, with most cases presenting in patients over 65 years old. Studies have shown no gender predilection for NETs of the small intestine or rectum, but NETs of the stomach, appendix, and colon affected women more commonly than men.[14]

Lymphoma

• Out of all gastrointestinal tract lymphomas, small bowel accounts for approximately 9 to 10% of cases in total. The majority of the patients are between 60 to 70 years of age, with a strong male predominance (60% vs. 40%).[15]

History and Physical

Most small bowel cancers have similar clinical presentations except for neuroendocrine tumors, which can present with symptoms specific to the products secreted from the neurosecretory granules contained within the malignant cells. Nonspecific mid abdominal pain, unexplained weight loss, and gastrointestinal bleeding are three of the most common clinical symptoms. The abdominal pain is generally described as intermittent and crampy, with a small percentage of cases associated with nausea and vomiting. Larger neoplastic lesions can present with more severe conditions such as acute small bowel obstruction or perforation, with obstruction presenting more commonly than perforation.[16] The ambiguity of the presenting symptoms often causes a delay in diagnosis. Physical exam findings are often variable depending on disease involvement or presenting symptoms.[17]

Neuroendocrine tumors that have metastasized to the liver can present with a constellation of symptoms due to the secretion of bioactive products from the primary tumor. Therefore, the workup of such lesions includes testing biomarkers to confirm the etiology of the patient’s nonspecific symptoms. The most common symptoms associated with carcinoid syndrome include cutaneous flushing, diarrhea (which carries a broad differential diagnosis), and less common symptoms such as venous telangiectasias and recurrent respiratory symptoms due to bronchospasms.

Evaluation

The evaluation and diagnostic process of small bowel cancer consist of laboratory, imaging, and endoscopic evaluations. Unfortunately, the diagnosis is often delayed due to the nonspecific nature of presenting symptoms and low suspicion in evaluating generalized abdominal pain for small bowel cancer. 

Laboratory Studies Evaluation

Initial workup generally includes an evaluation with complete blood cell count and differential, chemistry studies, and liver function tests. Depending on the location of the lesion, patients may present with evidence of anemia due to fecal occult blood loss. Neuroendocrine tumors require further workup that includes assessing markers to determine the functionality of such lesions and establish the diagnosis of carcinoid syndrome. Minimum workup to be completed once other common causes of noted symptoms have been ruled out include measuring 4-hour urinary excretion of 5-HIAA, chromogranins level, and blood serotonin level.

Imaging

The pathway to arriving at the diagnosis of small bowel cancer includes significant variability in how tests are completed. There are multiple radiographic as well as endoscopic evaluations that are available to assist in the process of diagnosis, and due to the low incidence of such malignant lesions, patients undergo multiple evaluations and imaging studies before a diagnosis is established. 

Computer Tomography Scan (CT scan): It is estimated that a CT scan can help note abnormalities in about 70 to 80% of patients with small bowel cancer. However, these rates of detection can be quite variable based on the location of the lesion.[18] This modality is often utilized when determining if there is evidence of metastatic spread of disease to distal sites or regional lymph nodes. CT tomography enterography involves evaluating the small bowel with the addition of a contrast agent that enhances images by causing distension of the small bowel and allowing for better visualization of more occult malignant lesions.[19]

Upper GI Series with Small Bowel Follow Through vs. Enteroclysis: Involves barium administration, which coats the lining of the GI tract, and follow-up X-rays are obtained. The contrast allows for an outline of the esophagus, stomach, and small intestines to be visualized, which can assist in evaluating mucosal abnormalities from neoplastic processes.[20] This particular study does not allow for visualization of smaller lesions and does not assist with staging.[21]

Enteroclysis is a similar imaging study that involves X-ray imaging as the main modality. However, it has been found to have higher sensitivity than the standard upper GI series as it involves the administration of barium into the small intestine via a nasogastric tube. While more invasive than an Upper GI series, this particular study does provide higher sensitivity, as mentioned previously. 

Endoscopic Evaluation: Endoscopic evaluation of small bowel cancers helps identify mucosal lesions that may not be identified on routine imaging modalities. It can assist in the diagnosis of lesions that are up to the proximal duodenum. Push enteroscopy can help access the GI tract beyond the ligament of Treitz using push or double-balloon enteroscopy techniques. This allows for the traditional scope to visualize a more extensive portion of the small bowel which can help in identifying more distal lesions. Wireless video capsule endoscopy can also be utilized to evaluate the distal small bowel. However, it only allows for tissue visualization and no tissue sampling, which requires more invasive procedures for final diagnosis to be established.[22]

The followings are specific recommendations for small bowel adenocarcinoma according to the National Comprehensive Cancer Network (NCCN). More than half of small bowel adenocarcinomas originate from the duodenum. The remaining 30 and up to 13% of SBAs arise in the jejunum and ileum, respectively.[23]

Patients who are suspected to be affected by small bowel adenocarcinoma should be exclusively evaluated with comprehensive staging measures, including tissue sampling and pathological examination, CBC, imaging, and endoscopy measures, and specific tumor markers, including carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA). Further evaluations might be requested according to the specific tumor’s location and any history suggestive of a malabsorptive disorder, including celiac disease.[24] Further evaluation to identify the microsatellite instability (MSI) and DNA mismatch repair (MMR) is mandatory in all patients with small bowel adenocarcinoma, mainly because of the prognostic and predictive value of the mentioned markers.  

Specific evaluations with Esophagogastroduodenoscopy (EGD) and endoscopic ultrasound (EUS) should be undertaken in patients with suspicious duodenal adenocarcinoma for both primary stagings, differentiating duodenal from other peri-ampullary tumoral lesions, and tissue sampling purposes. In patients with complicated obstructive duodenal adenocarcinoma, palliative measures with stent placement and surgical diversion might be considered. Further endoscopic measures, including double-balloon and capsule endoscopy, might be indicated in selected patients with small bowel cancers. The mentioned endoscopic methods are specifically advantageous in the diagnostic and therapeutic management of complicated patients with strictures. Despite the plenty of explicit information obtained from performing capsule endoscopy, the inability to proceed with tissue diagnosis with this method should not be underestimated. Moreover, in patients who are complicated with small intestinal strictures and/or obstructions, performing capsule endoscopy is contraindicated, which is typically due to the potential need for a surgical intervention to remove the capsule. 

The local and metastatic tumor burden would be evaluated by performing abdominopelvic CT or MRI. Additional details of the tumor characteristics might be explored by performing CT or MR enterography or enteroclysis, which involve using oral or nasogastric instilled contrast, respectively. A prospective study has demonstrated the superiority of MR enterography in comparison with CT enterography to diagnose neoplastic small bowel lesions accurately. 

Positron emission tomography (PET)-CT scans are rarely indicated to diagnose metastatic disease in the few cases of equivocal CT or MRI findings. 

Treatment / Management

Sarcoma: Small bowel sarcomas include gastrointestinal stromal tumors (GIST) and non-GIST tumors. The management of such lesions varies on the specific type that is identified. GISTs, in particular, have been found to have activating mutations that involve the KIT proto-oncogene, and therefore therapy has been designated to target this pathway. KIT inhibitors have become first-line, most specifically Imatinib.[25] A distinct difference in management for GIST and non-GIST tumors involves node resection, which is not recommended for such lesions as they rarely metastasize to regional lymph nodes. Surgical resection, therefore, involves resection of the primary lesion with particular consideration placed on ensuring there is no spillage of the resected tissue intraoperatively. (A1)

Adenocarcinoma: Localized small bowel adenocarcinoma is primarily managed with wide segmental surgical resection. The involved mesentery is removed at the time of surgical removal of the tumor. At the time of surgical resection, nodes are also resected as this helps determine the need for adjuvant chemotherapy. If the tumor is large and involves the first and second portions of the small bowel, a Whipple procedure may be considered.[26][27](B2)

Neuroendocrine Tumors: It has been previously noted that the majority of NETs arise in the jejunum and ileum and are typically well differentiated. They have been noted to be indolent in nature in most cases. However, they do carry metastasis potential. For this reason, resection of the tumor with resection of the adjacent mesentery and lymph nodes is generally recommended. This applies to patients with localized diseases.[28][29] For patients with evidence of advanced disease (symptoms consistent with carcinoid syndrome), curative surgery is unlikely to be an option. Therefore surgical intervention is generally reserved for debulking/palliative purposes. Adjuvant chemotherapy is generally indicated after surgical resection. However, addressing the obstructive lesion takes priority if chemotherapy has not been started and the patient develops obstructive symptoms first.(B2)

Lymphoma: The majority of lesions in the GI tract that are identified as lymphoma consist of non-Hodgkin lymphoma. The majority of SB lymphoma is managed with surgical resection and adjuvant chemotherapy depending on the histological subtype of NHL. Adjuvant radiation therapy is a less preferred option due to the many complications following radiation to the abdominal cavity. Studies have not proven the benefits outweigh the long-term complications.[30](B3)

Differential Diagnosis

The most common presenting signs and symptoms of different small bowel cancers are generally vague in nature. Most of these neoplastic processes include chronic or recurrent abdominal pain, nausea, vomiting, weight loss, or signs consistent with further complications from the cancerous lesions that may include gastrointestinal bleeding or obstructive-type symptoms. Patients with NETs may have more unique symptoms that may help increase the clinician’s index of suspicion and lead to earlier diagnosis. This is primarily because certain NET tumors are associated with carcinoid syndrome. The associated products of the tumor can cause a series of symptoms that are otherwise not seen with small bowel cancers. Therefore, the differential diagnosis includes irritable bowel syndrome, peptic ulcer disease, esophagitis, inflammatory bowel disease, lipomas, hemangiomas, functional abdominal pain, and adenomas.[31][32][33]

Surgical Oncology

Surgical treatment for localized and locoregional adenocarcinoma of the small bowel is recommended with tumoral surgical resection and en-bloc lymphadenectomy. Delicate intra-procedural staging with specific attention to determine the level of involvement in the mesentery, omentum, and peritoneum is mandatory in all patients with SBA.[34],[35] The exact type of appropriate segmental resection to pursue depends on the anatomical location of the tumor. Accordingly, while segmentectomy might be utilized in Jejuno-ileal adenocarcinoma, pancreaticoduodenectomy or Whipple procedure might be indicated in patients with duodenal adenocarcinoma. The latter procedure is specifically indicated in patients with peri-ampullary adenocarcinoma, either with the second section of the duodenal or Vater ampulla and or pancreatic duct. The laparoscopic Whipple procedure to manage peri-ampullary adenocarcinoma is not contraindicated. However, due to the technical complexity of the procedure, it should be selectively used in high-volume patients centers with experienced surgeons. 

Considering the comparable results with radical and limited segmentectomy in terms of overall and disease-free survival in the third and fourth duodenal sections and antimesenteric side SBA, despite the unfavorable lymph node basin identification, segmentectomy, and similarly limited resections are recommended for less than 2 cm size and mesenteric D1 tumors.[36] A minimal number of eight lymph nodes should be collected for review to accurately predict the patients' prognostic status. 

Up to one-third of patients with small bowel adenocarcinoma present metastatic disease in the peritoneal cavity, liver, etc. The estimated 5-year survival for patients with metastatic small bowel adenocarcinoma is almost half of patients with local and locoregional SBA. Operative management might be considered in patients with stage IV SBA for metastasectomy and to address the resectable peritoneal carcinomatosis. 

Evaluation of a limited number of patients with non-endocrine non-colorectal metastatic liver carcinoma was significant for an improved survival rate following metastasectomy.[37] The median survival for SBA in duodenal adenocarcinoma is significantly lower than all other SBAs, with median survival rates of 34 and 58 months, respectively.[37] Furthermore, in a planned metastasectomy, a multidisciplinary approach to evaluating perioperative chemotherapy should be considered. 

Up to 50% of patients with small bowel adenocarcinoma will have evidence of peritoneal carcinomatosis, which is more common in jejunoileal adenocarcinoma and is accompanied by a poor prognosis. While systemic chemotherapy might be used to manage unresectable peritoneal carcinomatosis to address palliative goals, surgical cytoreduction would be considered in treating resectable peritoneal metastasis.[38][39] The data suggesting the beneficial effects of hyperthermic intraperitoneal chemotherapy (HIPEC) for managing small bowel adenocarcinoma complicated with peritoneal carcinomatosis is still lacking and therefore would not be recommended as the standard of care.[40]

Medical Oncology

Small bowel cancer is one of the least commonly identified cancers of the gastrointestinal tract. Therefore the number of studies completed to guide therapy is overall limited compared to other cancers of the GI tract. Each type and case is evaluated on a case-by-case basis and considers the patient’s comorbidities and limitations to tolerate certain therapeutic agents. Most commonly used agents include capecitabine, oxaliplatin, 5-FU, leucovorin, and irinotecan.[41]

Despite the unclear outcomes of adjuvant medical therapy for small bowel adenocarcinoma, enrollment in the clinical trials for all the patients with locoregional and metastatic adenocarcinoma is recommended. Selected patients with primary unresectable adenocarcinoma might be offered neoadjuvant therapy. The first prospective trial, Trial Investigating the Potential Benefit of Adjuvant Chemotherapy for Small Bowel Adenocarcinoma (BALLAD), in its third phase, is willing to explore the potential effect of adjuvant therapy with either 5-FU/leucovorin or 5-FU/leucovorin accompanied by oxaliplatin with observation in patients with local and locoregional small bowel adenocarcinoma. Former retrospective trials regarding the efficacy of utilizing adjuvant therapy in any form of either chemotherapy or chemoradiation for small bowel adenocarcinoma have demonstrated equivocal results. Specifically, the data supporting the survival benefit of adjuvant chemoradiotherapy in a local and locoregional duodenal adenocarcinoma is lacking, and recommended the adjuvant therapy is only for a limited group of patients.[24]

Staging

The most commonly used staging system for the majority of small bowel cancers is the TNM staging system. Adenocarcinoma, in particular, includes a prognostic stage grouping that is utilized as a part of the staging process. Small bowel lymphoma is further staged using the Ann Arbor staging system, which considers the number of tumor sites and locations.[24] The eighth edition of the American joint committee on Cancer (AJCC) describes the TNM staging for small bowel adenocarcinomas as follows: T1 tumors present with the evidence of the lamina propria or submucosa involvement; T2 tumors invade the muscularis propria; T3 tumors invade the subserosa or even non-peritonealized perimuscular tissue, and T4 tumors reach the visceral peritoneum or directly invade other adjacent organs.

AJCC has defined the lymph node involvement classification in the small bowel cancers as follows; N0 (without evidence of regional lymph node metastasis), N1 ( involvement of 1 to 2 regional lymph nodes), and N2: involvement of equal or greater than 3 lymph nodes. Moreover, in the presence of distant organ involvement with the metastatic disease in the small bowel, adenocarcinoma would be classified as M1. Accordingly, limited tumoral involvement with stage I or II of the small intestine adenocarcinoma is attributed to any size of tumoral presence without evidence of nodal or metastatic involvement (any T, N0, M0). Stage III and stage IV  of intestinal adenocarcinoma refers to the locoregional disease without metastatic involvement and distant metastatic disease, respectively.[42]

Prognosis

Sarcoma: Prognosis is heavily dependent on the tumor's location, size, and resectability based on surrounding structures, with average five-year survival rates of approximately 80% if the lesions are resectable.[43]

Adenocarcinoma: Prognosis is dependent on staging. Overall, small bowel adenocarcinoma has been found to have higher mortality rates than equivalent staged colon cancers.[44] As expected, nodal involvement is one of the most important prognostic factors that should be considered. One particular study noted that node-positive disease vs. node-negative disease carried a difference in approximately 40% percent five-year survival rate.[45] Distant metastasis carries a much higher mortality rate and, therefore, significantly reduced five-year prognostic value. Significantly important factors of prognosis, according to the TNM staging in the small intestine adenocarcinoma, include the original site of tumoral involvement within the small intestine, histopathological characteristics, including 1) tumoral grading, 2) the total number of harvested and examined lymph nodes, 3) microsatellite instability, and DNA mismatch repair scores, and underlying disease including inflammatory bowel disease, and celiac.[24]

Patients with small bowel adenocarcinoma are often complicated with local tumoral effects, including duodenal obstruction and crampy abdominal pain in duodenal and Jujeno-ileal adenocarcinoma, respectively. Another complication in small bowel adenocarcinoma, which occurs in up to one-third of patients, is occult gastrointestinal bleeding.[46]

Neuroendocrine tumors: Prognosis of neuroendocrine tumors is often more complex than other gastrointestinal malignant lesions as it is also dependent on the tumor burden, type of product secreted, evidence of carcinoid syndrome vs. no carcinoid syndrome, and extent of nodal involvement/distal metastasis. Generally, tumors without evidence of carcinoid syndrome carry high survival rates, at times up to 90%.[47]

Lymphoma: Prognosis and evaluation of follow-up and surveillance are generally under the guidance of the Ann Arbor staging scale. Resectable lesions carry high survival rates. However, the overall prognosis is affected and noted to be variable due to high rates of recurrence.

Complications

Due to the delay in diagnosis that occurs with a small bowel cancer diagnosis, patients often present with complications later in the disease for their initial evaluation. The most common complications noted include upper and lower gastrointestinal bleeding, small bowel obstruction, small bowel perforation, and subsequent peritonitis.[48]