Colon Cancer Workup

Updated: Apr 24, 2018
  • Author: Tomislav Dragovich, MD, PhD; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Workup

Approach Considerations

Because early-stage colon cancer is typically asymptomatic, screening plays a major role in the diagnosis of curable cancerous lesions, as well as the detection of precancerous lesions (adenomatous colon polyps). The decline in colorectal cancer incidence and death rates over recent decades has largely been attributed to widespread adoption of screening. [36]

Screening guidelines endorse the use of several tests and procedures that either detect adenomatous polyps and cancer or that primarily detect cancer. However, guidelines from the American College of Gastroenterology recommend colonoscopy every 10 years, beginning at age 50 years, as the preferred screening strategy. [37]

A suspicion of colorectal cancer diagnosis warrants rectal examination and colonoscopy with a biopsy of any suspicious lesions. The National Comprehensive Cancer Network recommends that all patients younger than 70 years of age who are diagnosed with colorectal cancer be tested for hereditary nonpolyposis colon cancer syndrome (HNPCC, Lynch syndrome); patients 70 and older should be tested only if they meet the revised Bethesda guidelines for HNPCC. [38, 39]

After tissue diagnosis is confirmed, laboratory studies are done with a goal of assessing patients’ organ function (liver, kidneys) in anticipation of diagnostic and therapeutic procedures and also to estimate tumor burden. Adequate imaging of the chest and abdomen should be obtained for staging purposes, ideally preoperatively.

Further workup is driven by the following:

  • Clinical setting (eg, profuse bleeding and obstruction may require emergency surgery)

  • Patient functional status and comorbidities

  • Presenting symptoms

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Blood Studies

Laboratory studies are done with a goal of assessing patients’ organ function (liver, kidneys) in anticipation of diagnostic and therapeutic procedures and also to estimate tumor burden. Studies may include the following:

  • Complete blood cell count

  • Serum chemistries

  • Liver function tests

  • Renal function tests

  • Serum carcinoembryonic antigen (CEA) level

A baseline CEA level should be obtained preoperatively as it carries prognostic value and when highly elevated may indicate more advanced, disseminated disease. Increased levels of serum CEA have been associated with an adverse prognosis in patients with resectable colorectal cancer; however, this biochemical marker has not as of yet been included in colorectal cancer staging guidelines. [40]

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Imaging Studies

Adequate imaging of the chest and abdomen should be obtained for staging purposes, ideally preoperatively. Abdominal/pelvic computed tomography (CT), contrast ultrasound of the abdomen/liver, and abdominal/pelvic magnetic resonance imaging (MRI) scans are appropriate for imaging the abdomen and liver, for the purpose of staging. Imaging studies may also include a chest radiograph or chest CT scan, and an abdominal barium study to better delineate the primary lesion preoperatively.

Positron emission tomography (PET) scanning is emerging as a very useful modality for staging and assessment of colorectal cancers. The newest addition, a fusion PET-CT scan, allows for detection of metastatic deposits and has the added tissue-based resolution of CT. Of note, some histologies, especially a mucinous signet-ring cell variant of colorectal cancer, may not be well visualized on a PET scan.

For more information, see Imaging in Adenocarcinoma of the Colon.

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Screening

The goal of colorectal cancer screening is to decrease mortality through diagnosis and treatment of precancerous lesions (adenomatous colon polyps) and early curable cancerous lesions. The evidence for the importance of early detection and removal of colorectal polyps in preventing development of invasive cancer is mostly indirect but has been corroborated by data from many trials.

In the United States, a joint guideline was developed by the American Cancer Society, US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. [36] The guideline recommends that screening for colorectal cancer and adenomatous polyps start at age 50 years in asymptomatic men and women. In addition, the guideline lists appropriate screening procedures and their indications and frequency, based on projected individual risks of developing colorectal cancer.

Screening options consist of tests that detect adenomatous polyps and cancer, and tests that primarily detect cancer. Any one of these tests can be used for screening.

Tests that detect adenomatous polyps and cancer, and their recommended frequency, include the following:

  • Flexible sigmoidoscopy every 5 years

  • Colonoscopy every 10 years

  • Double-contrast barium enema every 5 years

  • Computed tomographic (CT) colonography every 5 years

Tests that primarily detect cancer, and their recommended frequency, include the following:

  • Annual guaiac-based fecal occult blood test with high test sensitivity for cancer

  • Annual fecal immunochemical test (FIT) with high test sensitivity for cancer

  • Stool DNA test with high sensitivity for cancer, interval uncertain

A Cochrane Database review of 14 trials found that flexible sigmoidoscopy is more effective at detecting advanced adenoma and carcinoma than stool-based tests. [41]  However, a Norwegian study determined that while the use of flexible sigmoidoscopy for screening reduced the incidence and mortality of colorectal cancer in men, it had little or no effect in women. [164]

A study by Wilschut et al found that FIT should be used at higher hemoglobin cutoff levels when colonoscopy capacity is limited. The findings suggest that FIT is more effective in terms of outcome and cost than fecal occult blood testing at all colonoscopy capacity levels. [42]

A retrospective study in which FIT kits were mailed to patients concluded that this is an effective way to screen for colorectal cancer. In the study, the researchers mailed FIT kits to approximately 670,000 adults aged 50–70 years; 48.2% of those completed the test within 1 year. The patients who responded were mailed kits annually for the next 3 years, with response rates ranging from 75%–86%. [43]

In the study, which comprised 98,678 persons, 20 552 were randomly assigned to screening and 78,126 to no screening. On median follow-up of 14.8 years, the absolute risks for colorectal cancer in women were 1.86% in the screening group and 2.05% in the control group (hazard ratio [HR] 0.92). In men, the corresponding risks were 1.72% and 2.50%, respectively (HR 0.66). The absolute risks for death from colorectal cancer in women were 0.60% in the screening group and 0.59% in the control group (HR 1.01); in men, the corresponding risks were 0.49% and 0.81%, respectively (HR 0.63). [164]

Positive results on FIT screening were highest in the first round and declined in subsequent years. Overall, FIT screening identified 80% of patients with colorectal cancer diagnosed within 1 year of testing. [43]

In a cohort study of 70,124 patients with positive FIT results, Corley et al found that patients who underwent colonoscopy within 9 months showed no increased risk for colorectal cancer or advanced-stage disease, compared with those who had colonoscopy done within a month after the positive FIT result. However, patients who did not have procedures done until 10 months or later were at significantly higher risk for cancer findings. [44]

Patients on clopidogrel therapy are at significantly higher risk for delayed but not immediate bleeding when they have polyps removed during colonoscopy. [45, 46] Because interruption of clopidogrel therapy in patients with coronary artery disease increases the risk of serious ischemic events, elective colonoscopy and polypectomy should be delayed in these patients until cessation of clopidogrel therapy is considered safe. [45, 46]

In 2014, the FDA approved Cologuard, a colorectal cancer screening tool that detects DNA mutations and hemoglobin in stool samples. A positive result should be followed up with colonoscopy. Cologuard is recommended for screening of adults of either sex, aged 50 years or older, who are at average risk for colorectal cancer. It is not a replacement for diagnostic or surveillance colonoscopy for individuals at high risk, and its approval did not change practice guidelines that recommend screening using colonoscopy, sigmoidoscopy, or fecal occult blood testing. [47]

In 2016, the FDA approved the first blood-based colorectal cancer screening test, Epi proColon. This is a qualitative in vitro assay for detecting methylated Septin9 DNA, which has been associated with the occurrence of colorectal cancer, in plasma obtained from whole-blood specimens. It is indicated for use in average-risk patients who have chosen not to undergo other screening methods, such as colonoscopy or stool-based tests. [48]

Screening for colorectal cancer should start at an earlier age and be more frequent and more stringent for individuals who carry an increased or high risk of developing colorectal cancer, such as persons with any of the following:

  • Prior history of polyps

  • Prior history of colorectal cancer

  • Family history of colon cancer

  • History of inflammatory bowel diseases

Those genetically diagnosed or suspected of having hereditary familial syndromes such as hereditary nonpolyposis colon cancer syndrome (HNPCC) or familial adenomatous polyposis (FAP) should be treated as having high risk of developing colon and rectal cancer. These patients should adhere to a more intense surveillance protocol. [49] For more information, see Familial Adenomatous Polyposis and Hereditary Colorectal Cancer.

A French study found that even in patients with no personal or family history of colorectal polyps or cancer, starting colonoscopy screening at age 45 instead of age 50 can be valuable. In a prospective study that included 6027 consecutive screening colonoscopies, Karsenti et al found that for the 515 patients age 45 to 49 years, the average polyp detection rate was 26% and the average neoplasia detection rate was nearly 4%. By comparison, for the 4438 patients older than 50 years, the average polyp detection rate exceeded 35% and the average neoplasia detection rate exceeded 5%. Both rates were markedly lower in the 1076 study patients age 44 years and younger. [50]

Noting the rise in colorectal cancer rates in the under-50 population, Dr. Karsenti recommends showing these data to patients 45 years and older, as part of the discussion on colorectal cancer prevention. [50]

A study by Lasser et al found that in an ethnically diverse patient population, completion of colorectal cancer screening was increased by the use of a patient navigation strategy consisting of an introductory letter from the primary care provider with educational material, followed by telephone calls from a language-concordant navigator. Navigator intervention proved particularly beneficial for patients whose primary language was other than English and for black patients. [51]

Capsule colonoscopy

For capsule colonoscopy, the patient swallows a pill camera that acquires images as peristalsis propels it through the gastrointestinal tract. The images are transmitted to a recording device and then converted to a video format for viewing on a computer.

In 2014, the US Food and Drug Administration approved the PillCam COLON 2 Capsule Endoscopy System (Given Imaging Limited, Yoqneam, Israel) for use in patients in whom conventional colonoscopy with adequate preparation was conducted, but a complete evaluation of the colon was not technically possible. In multicenter trials, capsule colonoscopy has demonstrated a sensitivity of 84-89% for detection of polyps larger than 6 mm. [52]

American College of Gastroenterology guidelines

American College of Gastroenterology (ACG) guidelines for colorectal cancer screening are as follows [37] :

  • Tests that prevent cancer are preferred over those that only detect cancer

  • The preferred colorectal cancer prevention test is colonoscopy every 10 years, beginning at age 50 years, but at age 45 years in African Americans

  • For patients who decline colonoscopy or another cancer prevention test, the preferred cancer detection test is FIT, conducted annually

Alternative cancer detection tests recommended in the ACG guidelines are as follows:

  • Flexible sigmoidoscopy every 5-10 years

  • CT colonography every 5 years, which replaces double contrast barium enema as the radiographic screening alternative for patients who decline colonoscopy

Alternative cancer detection tests in the ACG guidelines are as follows:

  • Annual Hemoccult Sensa

  • Fecal DNA testing every 3 years

For screening purposes, patients with one first-degree relative diagnosed with colorectal cancer or advanced adenoma at age 60 years or older are considered at average risk. For patients with a single first-degree relative diagnosed with colorectal cancer or advanced adenoma before age 60 years, or those with two first-degree relatives with colorectal cancer or advanced adenomas, the guideline recommends colonoscopy every 5 years, beginning at age 40 years or at 10 years younger than the age at diagnosis of the youngest affected relative. [37]

Postpolypectomy surveillance

The ACG has published guidelines for surveillance of patients who have had adenomas detected and removed at colonoscopy. [53] These patients should have more frequent followup, as they are at increased risk for developing metachronous adenomas or colon cancer.

Colonoscopy findings and recommended scheduling of followup colonoscopy are as follows [53] :

  • No polyps – 10 years

  • Small (< 10 mm) hyperplastic polyps in rectum or sigmoid – 10 years

  • 1–2 small (< 10 mm) tubular adenomas – 5- 10 years

  • 3–10 tubular adenomas – 3 years

  • 10 adenomas – < 3 years

  • One or more tubular adenomas ≥10 mm – 3 years

  • One or more villous adenomas – 3 years

  • Adenoma with high-grade dysplasia – 3 years

For serrated lesions, recommended surveillance intervals are as follows [53] :

  • Sessile serrated polyp(s) < 10 mm with no dysplasia – 5 years

  • Sessile serrated polyp(s) ≥ 10 mm with no dysplasia – 3 years

  • Sessile serrated polyp with dysplasia – 1 year

  • Traditional serrated adenoma – 1 year

  • Serrated polyposis syndrome – 1 year

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Molecular Testing

Treatment of metastatic colorectal cancer is increasingly guided by molecular testing of the tumor. In April, 2015, the American Society for Clinical Pathology, the College of American Pathologists (CAP), the Association for Molecular Pathology, and the American Society of Clinical Oncology (ASCO) issued a draft of evidence-based guidelines on colorectal cancer molecular testing. [54] The final guidance document is targeted for publication in late 2015. [55] Among the recommendations are the following [54] :

  • RAS mutational testing of colorectal carcinoma tissue should be performed for patients who are being considered for anti-EGFR therapy; this analysis must include KRAS and NRAS codons 12, 13 of exon 2; 59, 61 of exon 3; and 117 and 146 of exon 4 ("expanded" or "extended" RAS)

  • BRAF V600 mutational analysis should be done in conjunction with deficient mismatch repair (dMMR)/microsatellite instability (MSI) testing for prognostic stratification

  • dMMR/MSI testing must be performed in all colorectal cancers for prognostic stratification and identification of Lynch syndrome patients (BRAF mutation testing is not needed for Lynch syndrome if there is no MSI-H with loss of MLH1)

  • Molecular marker testing (KRAS, extended RAS, BRAF, and dMMR/MSI) of the primary colorectal carcinoma tissue is acceptable; if metastatic tissue is available, that is also acceptable and is preferable in patients with metastatic disease.

  • Formalin-fixed, paraffin-embedded tissue is an acceptable specimen; use of other specimens will require additional adequate validation, as would any changes in tissue processing protocols

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Staging

The TNM staging system has become the international standard for staging of colorectal cancer. It uses the following three descriptors:

  • T for primary tumor

  • N for lymph nodal involvement

  • M for metastasis

See Table 1, below.

Colon tumor categories are as follows [56] :

  • Tx: No description of the tumor's extent is possible because of incomplete information

  • Tis: In situ carcinoma; the tumor involves only the muscularis mucosa

  • T1: The cancer has grown through the muscularis mucosa and extends into the submucosa

  • T2: The cancer has grown through the submucosa and extends into the muscularis propria

  • T3: The cancer has grown through the muscularis propria and into the outermost layers of the colon but not through them; it has not reached any nearby organs or tissues

  • T4a: The cancer has grown through the serosa (visceral peritoneum)

  • T4b: The cancer has grown through the wall of the colon and is attached to or invades nearby tissues or organs

Node categories are as follows:

  • Nx: No description of lymph node involvement is possible because of incomplete information

  • N0: No cancer in nearby lymph nodes

  • N1a: Cancer cells found in one nearby lymph node

  • N1b: Cancer cells found in two to three nearby lymph nodes

  • N1c: Small deposits of cancer cells found in areas of fat near lymph nodes, but not in the lymph nodes themselves.

  • N2a: Cancer cells found in four to six nearby lymph nodes

  • N2b: Cancer cells found in seven or more nearby lymph nodes

Metastasis categories are as follows:

  • M0: No distant spread seen

  • M1a: The cancer has spread to one distant organ or set of distant lymph nodes

  • M1b: The cancer has spread to more than one distant organ or set of distant lymph nodes, or has spread to distant parts of the peritoneum

Table 1. TNM Staging System for Colon Cancer (Open Table in a new window)

Stage

Primary Tumor (T)

Regional Lymph Node (N)

Remote Metastasis (M)

Stage 0

Carcinoma in situ (Tis)

N0

M0

Stage I

Tumor may invade submucosa (T1) or muscularis propria (T2)

N0

M0

Stage II

Tumor invades muscularis (T3) or adjacent organs or structures (T4)

N0

M0

Stage IIA

T3

N0

M0

Stage IIB

T4a

N0

M0

Stage IIC

T4b

N0

M0

Stage IIIA

T1-4

N1-2

M0

Stage IIIB

T1-4

N1-2

M0

Stage IIIC

T3-4

N1-2

M0

Stage IVA

T1-4

N1-3

M1a

Stage IVB

T1-4

N1-3

M1b

For more information, see Colon Cancer Staging.

Prognostic factors associated with staging

Patient prognosis is a function of the clinical and histopathologic stage of colon cancer at diagnosis. In addition to the well-established significance of standard pathologic features such as depth of bowel wall penetration (T), number of locoregional lymph nodes involved (N), and presence of extra-colonic metastases (M), several other factors have been proved to be of importance. These include number of harvested and processed lymph nodes, histologic grade, and evidence of lymphovascular and perineural invasion.

Features that have been shown to be associated with worse prognosis include the following:

  • Bowel obstruction at diagnosis

  • Ulcerative growth pattern

  • Perforation

  • Elevated preoperative CEA level

Molecular prognostic factors that have been investigated but not incorporated into standard clinical practice include the following:

  • p53

  • Loss of heterozygosity for 18q [57]

  • Mutations of deleted in colon cancer gene (DCC)

  • Epidermal growth factor receptor (EGFR) gene amplification

KRAS mutations, which are present in about 40% of colon adenocarcinomas, affect sensitivity to treatment with biologic agents directed against the epithelial growth factor receptor (EGFR). [58] The US Food and Drug Administration (FDA) has approved a qualitative real-time polymerase chain reaction (PCR) assay, the therascreen KRAS RGQ PCR Kit, for the detection of specific KRAS mutations in the KRAS oncogene.

Deficient mismatch repair (dMMR), which is associated with high-frequency microsatellite instability (H-MSI), has been shown to be associated with better clinical outcome for patients with resectable colon cancer, based on a retrospective analysis of several large randomized trials of adjuvant therapy for colon cancer. [59, 60] In addition, patients with dMMR (H-MSI) did not appear to benefit from fluorouracil-based adjuvant therapy. [61]

Testing for dMMR with H-MSI may become useful for prognosis and treatment planning in patients with resectable colon cancer. Some research also emphasizes the role of immune regulation in the development and in the natural course and prognosis of patients with colorectal cancers. [62]

For patients aged 60-69 years with selected stage T3 or T4 colorectal cancer, prognostic factor and 5-year relapse-free survival (based on the Mayo Clinic calculator and numbers of lymph nodes analyzed [63] ) are as follows:

  • T3N0 (11-20 nodes analyzed) – 79%

  • T3N0 low grade – 73%

  • T3N0 (≤ 10 lymph nodes examined) – 72%

  • T3N0 high grade – 65%

  • T4N0 low grade – 60%

  • T4N0 high grade – 51%

  • T3N1 – 49%

  • T3N2 – 15%

A review of Surveillance, Epidemiology, and End Results (SEER) population-based data on colon cancer by the American Joint Committee on Cancer (AJCC) Hindgut Taskforce found the following:

  • T1-2N2 cancers have a better prognosis than T3-4N2 cancers

  • T4bN1 and T4N2 cancers have a similar prognosis

  • T1-2N1, T2N0, and T3N0 cancers have a similar prognosis

  • T1-2N2a, T2N0, T3N0 (T1N2a), and T4aN0 (T2N2a) have a similar prognosis

  • Prognosis for T4a lesions is better than that of T4b by N category

  • The number of positive nodes affects prognosis

The Taskforce proposed the following revisions of the TN categorization for colon cancer [64] :

  • Shift T1-2N2 lesions from IIIC to IIIA/IIIB

  • Shift T4bN1 from IIIB to IIIC

  • Subdivide T4/N1 and T4/N2

  • Revise substaging of stages II/III

Histologic subtype and metastatic patterns

In a retrospective Dutch study of autopsy results from 1675 patients with metastatic colorectal cancer and data from 88 patients with synchronous metastases from the Total Mesorectal Excision (TME) trial, Hugen et al noted that the histologic subtype and the localization of the primary tumor in colorectal cancer has a strong influence on its metastatic pattern. [65, 66] Their findings include the following:

  • Metastatic disease occurred more frequently and more often in multiple sites, in patients with mucinous adenocarcinoma (MC) (respectively, 33.9% and 58.6% of cases) or signet-ring cell carcinoma (SRCC) (61.2% and 70.7%) compared with those with adenocarcinoma (AC) (27.6% and 49.9%) [65, 66]

  • Liver metastases occurred more often in patients with AC (73.0%) or MC (52.2%) than in those with SRCC (31.7%) [66]

  • Peritoneal metastases occurred more often in patients with SRCC (51.2%) or MC (48.2%) than in those with AC (20.1%) [66]

  • Metastases to distant lymph nodes occurred in more SRCC patients (43.9%) than patients with either MC (22.3%) or AC (19.9%) [66]

  • Patients with colon cancer had a higher rate of abdominal metastases relative to those with rectal cancer, who had higher rates of extra-abdominal metastases

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