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  Disease summary:

  
  
  
  
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    Colorectal cancer remains the second leading cause of cancer deaths in the United States, with an estimated 143,000 new diagnoses anticipated in 2012. The lifetime risk of any individual developing colon cancer is 5.1%. Often, the disease has no presenting symptoms, but can manifest through changes in bowel habits or appetite, vague abdominal pain, overt bleeding, occult blood loss, iron deficiency anemia, weight loss, or obstructive bowel symptoms. A significant number of afflicted individuals demonstrate a family history of colon cancer. Moreover, a small subset of these individuals will present with features of an established familial cancer syndrome. Careful integration of the family and personal history, physical examination findings, and endoscopic findings play a critical role in recognition and management of these high-risk individuals. Small bowel cancers remain rare, and account for less than 0.5% of all new cancers diagnosed. Malignancies of the small bowel include adenocarcinoma, lymphomas, carcinoids, and mesenchymal tumors. On occasion, cancers of the small bowel may also represent as a manifestation of a familial cancer syndrome.

  
  

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  Differential diagnosis:

  
  
  
  
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    In the evaluation of an individual with a familial cancer syndrome, the first consideration should be an assessment of polyp burden. Lynch syndrome is the only defined nonpolyposis syndrome with colon and/or extracolonic cancers. Among those patients with polyposis, the main consideration is whether the polyps are adenomatous or hamartomatous. For those patients with large numbers of tubular adenomas, familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) are in the differential diagnosis. Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome (JPS), and PTEN hamartomatous tumor syndromes (PHTS) are considered for those with hamartomatous polyposis.

  
  

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  Monogenic forms:

  
  
  
  
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    Approximately 5% of colon cancer cases are linked to known familial colon cancer syndromes. Generally, these syndromes are broadly classified into polyposis or nonpolyposis syndromes. The most common nonpolyposis syndrome is Lynch syndrome (hereditary nonpolyposis colon cancer [HNPCC]), which accounts for 3% of all colon cancers. Polyposis syndromes include FAP, MAP, JPS, PJS, and PHTS. Of these polyposis syndromes, the first two are adenomatous polyposis syndromes and the latter three are rare hamartomatous polyposis syndromes. Many of these syndromes may also present with cancers outside of the colon including those of the small bowel, stomach, soft tissues, hepatobiliary system, uterus, ovary, urogenital tissues, skin, and central nervous system.

  
  

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  Family history:

  
  
  
  
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    While only 5% of colon cancers are currently estimated to be linked to established colon cancer syndromes, over 25% of afflicted individuals may demonstrate a family history of colon cancer.

  
  

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  Twin studies:

  
  
  
  
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    Analysis of Nordic twins demonstrates that the average genetic contribution to the risk of developing colon cancer is approximately one-third.

  
  

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  Environmental factors:

  
  
  
  
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    Smoking, diet (red meat consumption), obesity (risk greater for men than women)

  
  

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  Genome-wide associations:

  
  
  
  
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    While several loci have been identified, novel mechanisms and drug targets have yet to be elucidated from genome-wide association studies (GWAS).

  
  

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  Pharmacogenomics:

  
  
  
  
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    Testing for specific, somatic mutations in colon cancers can assist in determining which chemotherapeutic agents to utilize. KRAS mutations in tumors have been associated with resistance to anti-EGFR agents. Individuals with stage II microsatellite instability (MSI)-high tumors may not benefit from chemotherapy.

  
  

Small Bowel Cancers

Diagnostic Criteria

Small bowel cancers include adenocarcinoma, lymphomas, carcinoids, and mesenchymal tumors (including gastrointestinal stromal tumors). Definitive diagnosis is often made by tissue analysis obtained via endoscopy, surgery, or interventional radiology. Carcinoid tumors and gastrointestinal stromal tumors (GISTs) may have suggestive radiographic appearances on computed tomographic (CT) scans, but tissue diagnosis should still be obtained if possible.

Clinical Characteristics

Small bowel cancers remain rare, accounting for only 0.5% of new cancer cases each year. Clinical presentation may include vague, nonspecific abdominal pain, weight loss, obstructive symptoms, bleeding, or changes in bowel habits. Rarely, adenocarcinoma may be associated with a familial cancer syndrome (see later). Diseases of chronic inflammation such as Crohn disease may increase the risk of adenocarcinoma. Celiac disease has been associated with a risk of enteropathic T-cell lymphoma. Individuals with metastatic carcinoid tumors may present with carcinoid syndrome—a constellation of symptoms typically including flushing and diarrhea, but may also include palpitations, hypotension, and bronchoconstriction.

Sporadic Colorectal Cancer

Diagnostic Criteria

Diagnosis of colorectal cancer is often made by tissue obtained from endoscopy, surgery, or interventional radiology.

Clinical Characteristics

Many individuals develop colon cancer without any symptoms. Indicative findings on laboratory studies include iron deficiency anemia. Symptoms range from vague abdominal pain, changes in bowel habits, anorexia, weight loss, occult or overt bleeding. A small percentage of individuals may present with synchronous colon cancers at the time of diagnosis, and complete examination of the colon should be performed if possible. Precursor lesions are thought to occur from adenomatous polyps or sessile serrated polyps, with the exception of inflammatory bowel disease in which dysplasia may be flat.

Lynch Syndrome

Diagnostic Criteria

Please see Table 44-1 for genetic differential diagnosis. Ultimately, diagnosis is established by genetic testing. The Amsterdam II criteria are used to make a clinical diagnosis of Lynch syndrome utilizing personal and family history of colon and extracolonic cancers. Individuals satisfying these criteria should proceed directly to germline testing of Lynch-associated genes. If genetic testing is negative and clinical suspicion remains high, such individuals should undergo similar clinical surveillance strategies as those with Lynch syndrome.

Amsterdam II Criteria

Three relatives with a Lynch-associated cancer (colorectal, endometrial, small bowel, ureter, or renal pelvis) include all of the following:

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   One should be a first-degree relative of the two.

   
   
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   At least two successive generations should be involved.

   
   
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   Cancer in one of the affected individuals should be diagnosed before the age of 50 years.

   
   
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   FAP should be excluded in any cases of colorectal cancer.

   
   
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   Tumors should be verified by pathologic examination.

Individuals who do not satisfy Amsterdam II criteria may still have Lynch syndrome. The Revised Bethesda Guidelines were designed to identify those tumors that should undergo microsatellite instability testing and/or immunohistochemistry staining for loss of mismatch repair genes. If microsatellite instability or immunohistochemical loss is demonstrated, germline testing should be pursued to establish the diagnosis.

Revised Bethesda Guidelines

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   Colorectal cancer diagnosed in a patient who is less than 50 years of age.

   
   
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   Synchronous or metachronous colorectal cancer or other Lynch-related cancer regardless of age.

   
   
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   Colorectal cancer with MSI-H histology (presence of tumor infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous or signet-ring differentiation, or medullary growth pattern) diagnosed in a patient less than 60 years of age.

   
   
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   Colorectal cancer diagnosed in one or more first-degree relatives with a Lynch-related tumor, with one of the cancers being diagnosed under age 50 years.

   
   
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   Colorectal cancer diagnosed in two or more first- or second-degree relatives with Lynch-related tumors, regardless of age.

Clinical Characteristics

Lynch syndrome may be responsible for 1% to 4% of all colon cancers. Patients develop few tubular adenomas that rapidly progress into colon cancer. Metachronous colon cancers can also be observed. The median age of presentation can range from 40 to 60 years depending on the particular Lynch-associated gene. In addition, other tumors such as endometrial, small bowel, ovarian, renal, and pancreatic cancers can be observed. Muir-Torre syndrome and Turcot syndrome are variants of Lynch syndrome in which sebaceous skin tumors and glioblastomas, respectively, are also observed.

Familial Adenomatous Polyposis and MUTYH-Associated Polyposis

Diagnostic Criteria