Small Bowel Cancer – Causes, Symptoms, Treatment

Small Bowel Cancer encompasses a series of malignant lesions that may be identified throughout the small intestine (SI). The small bowel lies between the stomach and the large intestine (LI/Colon) and is encompassed by three different sections, the duodenum, jejunum, and ileum to the level of the ileocecal valve which provides the terminal transition point between the SI and the LI. While there are both benign and malignant lesions that can be identified throughout the SI, the overall incidence of small bowel neoplasms is extremely low when compared to lesions noted in other portions of the gastrointestinal tract. This article will focus on the overall characteristics, diagnostics, treatment, and prognosis of malignant lesions. The majority of these lesions cause multiple nonspecific symptoms which very often lead to delay in diagnosis and therefore delay in early intervention with available treatment strategies. Common clinical features include abdominal pain, anorexia, gastrointestinal bleeding, and weight loss. More advanced processes can present with perforation, small bowel obstruction, or obstructive jaundice. Diagnosis can be variable based on the location of the lesion under investigation and generally consists of laboratory studies, radiographic imaging, and endoscopic evaluation. Malignant lesions overall include lymphomas, neuroendocrine tumors (carcinoids), adenocarcinomas, and stromal tumors. [rx]

Types of Small Bowel Cancer

There are five major types of small intestine cancer:

• Adenocarcinoma. This form begins in your secretory cells. These cells are in tissues that line your major organs and are responsible for releasing mucus and digestive juices.
• Sarcoma. This type of cancer begins in the bones or soft tissues, including fibrous and connective tissues, muscle, and cartilage.
• Carcinoid tumors. These tumors grow slowly and may spread to the liver or other parts of the body.
• Lymphoma. This cancer, which begins in the cells of the immune system, can be further categorized as either Hodgkin lymphoma or non-Hodgkin lymphoma.
• Gastrointestinal stromal tumors. These form in the walls of the gastrointestinal tract. They can be benign or malignant

Causes of Small Bowel Cancer

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.[rx] 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.[rx] The 5 main types and cells of origin include:

• Sarcoma- 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- 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. There have been certain cancer syndromes and underlying medical conditions that may predispose patients to certain types of small bowel neoplasms.

Celiac Disease

• Longstanding Celiac Disease has been found to be 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 II 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’s Disease has been found to carry an increase of small bowel cancer. Studies have shown that patients with Crohn’s Disease can have up to a 60 fold increase in the risk of developing Adenocarcinoma of the small bowel.[rx]

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), Peutz- Jeghers Syndrome (JPS), 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 setting of known diagnosis of FAP still require surveillance of upper GI tract with serial upper endoscopy at intervals that vary depending on polyp burden and initial screening pathology results.[rx]

The rate of incidence of small intestine cancer is very low in the United States with SI Cancer only accounting for approximately 3-5% of all gastrointestinal tract malignancies. The rate of incidence is proportionally extremely low when one considers that the SI accounts for approximately 90% of the surface area of the GI tract as a whole. [rx] 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. [rx]
• Adenocarcinoma – Generally present in patients ages 50-70 years old with male predominance identified. [rx] Certain conditions such as Inflammatory Bowel Disease, mainly Crohn’s Disease, and hereditary cancer syndromes such as FAP and HNPCC carry higher risk and can present at younger ages. [rx]
• Neuroendocrine tumors – Generally present in patients ages 50-70, with the majority of cases presenting in patients >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. [rx]
• Lymphoma – Out of all Gastrointestinal tract lymphomas, small bowel accounts for approximately 9-10% of cases in total. The majority of the patients are between 60-70 years of age with a strong male predominance (60% vs 40%). [rx]

Diagnosis of Small Bowel Cancer

The majority of small bowel cancers have similar clinical presentations with the exception of neuroendocrine tumors which can present with symptoms that are specific to the products that are 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 presenting clinical symptoms. The abdominal pain is generally described as intermittent and crampy in nature with a small percentage of cases have 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. [rx] The ambiguity of the presenting symptoms often causes a delay in diagnosis. Physical exam findings are often variable depending on the degree of disease involvement or presenting symptoms. [rx]

• Physical exam – An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.

Lab Test and Imaging

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 index of suspicion in the course of evaluation of generalized abdominal pain for small bowel cancer.

• Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.
• Liver function tests: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by the liver. A higher than normal amount of a substance can be a sign of liver disease that may be caused by small intestine cancer.
• Endoscopy: A procedure to look at organs and tissues inside the body to check for abnormal areas. There are different types of endoscopy:
  • Upper endoscopy: A procedure to look at the inside of the esophagus, stomach, and duodenum (first part of the small intestine, near the stomach). An endoscope is inserted through the mouth and into the esophagus, stomach, and duodenum. An endoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue samples, which are checked under a microscope for signs of cancer.
  • Capsule endoscopy: A procedure to look at the inside of the small intestine. A capsule that is about the size of a large pill and contains a light and a tiny wireless camera is swallowed by the patient. The capsule travels through the digestive tract, including the small intestine, and sends many pictures of the inside of the digestive tract to a recorder that is worn around the waist or over the shoulder. The pictures are sent from the recorder to a computer and viewed by the doctor who checks for signs of cancer. The capsule passes out of the body during a bowel movement.
  • Double balloon endoscopy: A procedure to look at the inside of the small intestine. A special instrument made up of two tubes (one inside the other) is inserted through the mouth or rectum and into the small intestine. The inside tube (an endoscope with a light and lens for viewing) is moved through part of the small intestine and a balloon at the end of it is inflated to keep the endoscope in place. Next, the outer tube is moved through the small intestine to reach the end of the endoscope, and a balloon at the end of the outer tube is inflated to keep it in place. Then, the balloon at the end of the endoscope is deflated and the endoscope is moved through the next part of the small intestine. These steps are repeated many times as the tubes move through the small intestine. The doctor is able to see the inside of the small intestine through the endoscope and use a tool to remove samples of abnormal tissue. The tissue samples are checked under a microscope for signs of cancer. This procedure may be done if the results of a capsule endoscopy are abnormal. This procedure is also called double-balloon enteroscopy.
• Laparotomy: A surgical procedure in which an incision (cut) is made in the wall of the abdomen to check the inside of the abdomen for signs of disease. The size of the incision depends on the reason the laparotomy is being done. Sometimes organs or lymph nodes are removed or tissue samples are taken and checked under a microscope for signs of disease.
• Biopsy: The removal of cells or tissues so they can be viewed under a microscope to check for signs of cancer. This may be done during an endoscopy or laparotomy. The sample is checked by a pathologist to see if it contains cancer cells.
• Upper GI series with small bowel follow-through: A series of x-rays of the esophagus, stomach, and small bowel. The patient drinks a liquid that contains barium (a silver-white metallic compound). The liquid coats the esophagus, stomach, and small bowel. X-rays are taken at different times as the barium travels through the upper GI tract and small bowel.
• CAT scan A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
• PET scan – Before having the PET scan you will be injected with a small number of radioactive solutions. You will be asked to sit for 30-90 minutes so the solution can move around your body.  Many cancer cells will show up brighter on the scan. The scan takes around 30 minutes.
• Biopsy – If your doctor sees any abnormal or unusual-looking areas they may remove a small sample of the tissue for closer examination. This is known as a biopsy. A pathologist will look at the sample under a microscope to check for signs of disease or cancer.
• Barium x-ray – For this procedure, you will be given a chalky barium liquid to drink which coats the inside of the bowel and can show any signs of cancer when an x-ray is taken.
• Computer tomography scan (CT scan) – It is estimated that CT scan can help note abnormalities in about 70-80% of patients with small bowel cancer, however, these rates of detection can be quite variable based on the location of the lesion. [rx] 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 evaluation of 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. [rx]
• Upper GI series with Small Bowel follow through vs Enteroclysis – Involves the administration of barium which in turn coats the lining of the GI tract and follow-up XRs are obtained. The contrast allows for an outline of the esophagus, stomach, and small intestines to be visualized which in turn can assist in the evaluation of mucosal abnormalities from neoplastic processes. [rx] This particular study does not allow for visualization of smaller lesions and does not assist with staging. [rx]
• 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 standard upper GI series as it involves the administration of barium into the small intestine via 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 in identifying 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 in turn requires more invasive procedures for final diagnosis to be established. [rx]

Treatment of Small Bowel Cancer

• Sarcoma – Small bowel sarcomas include GIST and non-GIST tumors. The management of such lesions varied 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.[rx] A distinct difference in management for GIST and non-GIST tumors involves node resection which is widely 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.
• 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’s procedure may be considered. [rx][rx]
• 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 disease [rx],[rx]. For patients with evidence of advanced disease (symptoms consistent with carcinoid syndrome), curative surgery is unlikely to be an option and therefore surgical intervention is generally reserved for debulking/palliative purposes.
• 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 depend ending on the histological subtype of NHL. Adjuvant radiation therapy is a less preferred option due to the many complications that follow radiation to the abdominal cavity considering that studies have not proven the benefits to outweigh the long-term complications.

Prognosis

• Sarcoma – Prognosis is heavily dependent on the location of the tumor, size, and resectability when based on surrounding structures with average five-year survival rates of approximately 80% if the lesions are resectable. [rx]
• Adenocarcinoma – Prognosis is dependent on staging. Overall, small bowel adenocarcinoma has been found to have higher mortality rates than equivalent staged colon cancers [rx]. 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 diseased carried a difference in approximately 40% percent five-year survival rate. [rx] Distant metastasis carries a much higher mortality rate and therefore significantly reduced five-year prognostic value.
• 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%. [rx]
• 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, the patient’s often present with complications that occur later in the course of 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.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Prevention

It’s not clear what may help to reduce the risk of small bowel cancer since it’s very uncommon. If you’re interested in reducing your risk of cancer in general, it may help to:

• Eat a variety of fruits, vegetables, and whole grains. Fruits, vegetables and whole grains contain vitamins, minerals, fiber, and antioxidants, which may help reduce your risk of cancer and other diseases. Choose a variety of fruits and vegetables so that you get an array of vitamins and nutrients.
• Drink alcohol in moderation, if at all. If you choose to drink alcohol, limit the amount of alcohol you drink to no more than one drink a day for women of all ages and men older than age 65, and up to two drinks a day for men age 65 and younger.
• Stop smoking. Talk to your doctor about ways to quit that may work for you.
• Exercise most days of the week. Try to get at least 30 minutes of exercise on most days. If you’ve been inactive, start slowly and build up gradually to 30 minutes. Also, talk to your doctor before starting any exercise program.
• Maintain a healthy weight. If you are at a healthy weight, work to maintain your weight by combining a healthy diet with daily exercise. If you need to lose weight, ask your doctor about healthy ways to achieve your goal. Aim to lose weight slowly by increasing the amount of exercise you get and reducing the number of calories you eat.

Treatment Team

Depending on your treatment, your treatment team may consist of a number of different health professionals, such as:

• Cancer nurses – assist with treatment and provide information and support throughout your treatment.
• Medical oncologist – prescribes and coordinates the course of chemotherapy.
• Physiotherapist/occupational therapist – help with physical and practical problems such as restoring movement and mobility after treatment.
• Surgeon – surgically removes tumors and performs some biopsies.
• GP (General Practitioner) – looks after your general health and works with your specialists to coordinate treatment.
• A radiation oncologist – prescribes and coordinates radiation therapy treatment.
• Other allied health professionals – such as social workers, pharmacists, and counselors.
• Dietitian – recommends an eating plan to follow while you are in treatment and recovery.
• Gastroenterologist – specializes in diseases of the digestive system..