Colorectal Cancer

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[restab title=”Objectives” active=”active”]

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The following module was designed to supplement medical students’ learning in the clinic. Please take the time to read through each module by clicking the headings below. Information on epidemiology, screening & testing, classification, signs & symptoms, diagnosis, radiology, pathology, staging, management, and treatment of colorectal cancer is provided.

By the end of the tutorial, the following objectives should be addressed:
  1. Discuss dietary factors that may play a role in colon cancer.
  2. Discuss what dietary advice is considered prudent in preventing colon cancer.
  3. Identify the importance of family history as a risk factor for colon cancer.
  4. Discuss the relative roles of genetics (including specific syndromes), inflammatory bowel disease and diet in the etiology of colorectal cancer.
  5. Understand the current recommendations for colorectal cancer screening in British Columbia.
  6. List the histopathological types of colorectal cancer.
  7. Understand the relative frequencies and prognostic significance of each histological type of colorectal cancer.
  8. Understand histologic grading of colorectal cancer.
  9. Describe the common signs and symptoms of colorectal cancer.
  10. Understand the common areas of metastasis.
  11. Understand the general approach to colorectal cancer diagnosis.
  12. Understand the laboratory tests and imaging techniques used in the investigation of colorectal cancer.
  13. Understand the general TNM staging for colorectal cancer.
  14. Be aware of the Dukes and Modified Astler Coller classification systems for staging of colorectal cancer, for historical purposes.
  15. Understand that colorectal cancer treatment is different depending on whether the tumour is primarily located in the colon or rectum.
  16. Describe the modalities used in colon and rectal cancer treatment.
  17. Describe some indications, advantages, and disadvantages of the varying treatment modalities.
  18. Understand the purpose of follow-up after treatment of colorectal cancer.
  19. Describe the frequency of follow-up after treatment of colorectal cancer.
  20. Describe the tasks that should be performed at each follow-up visit.

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[restab title=”Anatomy Review”]

Anatomy Review

layers of bowel wall

Illustration of bowel wall layers
(image from AJCC: Cancer Staging Manual, 7th ed)

Layers of the Bowel Wall

Moving from the internal lumen outwards, the layers of the bowel wall are:

  • Mucosa
    • Surface epithelium
    • Lamina propria
    • Muscularis mucosae
  • Submucosa
  • Muscularis propria
  • Subserosa, which is also sometimes called retroperitoneal fat, or pericolic fat
  • Serosa

The Boundary Between Colon & Rectum

The rectum is approximately 12 cm in length. The upper 1/3 is covered by peritoneum on the anterior and lateral aspects. The middle 1/3 is covered by peritoneum on the anterior aspect only. The peritoneum is reflected laterally to form the perirectal fossa, and anteriorly to form the rectovesicular fold (in men) or rectouterine fold (in women). The lower 1/3 is not covered by peritoneum at all, and is referred to as the rectal ampulla.1

Illustration of the rectum (adapted from [7])

Illustration of the rectum (adapted from [7])

The colon is the peritonealized large colon, and spans from the cecum to the start of the rectum.

The true anatomical boundary between the colon and rectum is the point at which the taenia coli fuse to the circumferential longitudinal muscle of the rectum. For the purpose of determining treatment options, however, the colon ends and rectum begins at the point of peritoneal reflection.2

References:

1) Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC cancer staging manual. 7th ed. New York: Springer-Verlag; 2010.

2) Health professionals info: cancer management guidelines: gastrointestinal: colon [Internet]. BC Cancer Agency; [updated 2008 May 6; cited 2010 Jul 16]. Available from: http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/Gastrointestinal/05.Colon/default.htm[/restab]
[restab title=”Epidemiology”]

Epidemiology

Colorectal cancer is the third most common cancer in men and women, with lung and prostate or breast being the first and second most common. It is the second leading cause of cancer deaths, exceeded only by lung cancer. The risk of being diagnosed with colorectal cancer is equal in men and women. In the US, the lifetime risk developing colorectal cancer is 6%, with an average age at time of diagnosis of 66 2.

Risk Factors

Age

The risk of colorectal cancer significantly increases in the population of age 45 and older.

Lifestyle/Diet

Sedentary lifestyle, diet, and smoking appear to play a role.

Studies have shown that having an obese body mass index may increase the risk of colorectal cancer up to 1.5 times the amount of the non-obese population1. Colorectal cancer has a substantially higher rate of incidence and mortality in the developed Western world as compared to other geographic regions such as Asia and Africa. This is thought to be explained by the increased consumption of meats and sedentary lifestyle of economically privileged nations2. Supporting evidence includes a study that showed that Chinese immigrants to the US subsequently acquired the higher risk of colorectal cancer that exists in the US2.

Foods that are generally accepted to increase the risk of colorectal cancer:

  • Red meat
  • Fried, barbequed, and processed meat
  • High fat content
  • Alcohol has demonstrated a minimal increase in risk for men more than women

Foods/food components that are generally accepted to decrease the risk of colorectal cancer:

  • Fruits and vegetables
  • Calcium1
  • Magnesium1

Foods that have an undetermined effect on colorectal cancer risk:

  • Fibre – varying results from studies, with some claiming a significant decrease in colorectal cancer in populations that consumed high amounts of fibre, where other studies failed to find the same inverse relationship between amount of dietary fibre and risk of colorectal cancer2.
  • Coffee and tea – no association with colorectal cancer found2.
  • Folic acid – some studies have shown an actual increased incidence of colon cancer, whereas others have shown a decrease in incidence1.

Prolonged cigarette smoking (> 35 pack years) is known to be associated with a significant increase in colorectal cancer risk2.

Ethnicity

There is a higher risk of colorectal cancer in certain Ashkenazi Jewish families, and African Americans, due to an increased incidence of genetic mutations that predispose to colorectal cancer.

Genetic Factors

In most cases, patients with colorectal cancer do not have a hereditary component. In fact, only 15-30% of patients with colorectal cancer appear to have a major hereditary component2. It is therefore said that most cases of colorectal cancer are sporadic.

The most prevalent predisposing genetic syndromes for colorectal cancer are familial adenomatous polyposis (FAP), and hereditary non-polyposis colorectal cancer (HNPCC). These are highly penetrant genetic conditions, with definite links to colorectal cancer. However, they only comprise about 5% of the incidence of colorectal cancer2. There are numerous other rarer forms of genetic syndromes that may cause colorectal cancer, such as Peutz-Jeghers syndrome.

An individual that has a first-degree relative with colorectal cancer, not attributed to FAP or HNPCC, has double the risk of developing colorectal cancer within his or her lifetime2.

Familial Adenomatous Polyposis (FAP)

FAP accounts for 1% of all colorectal cancers2. Although FAP is inherited in an autosomal dominant pattern, the development of disease requires both alleles of the adenomatous polyposis coli (APC) gene to be mutated (two hit model) 2. Individuals with FAP will inevitably have up to thousands of adenomatous polyps in their colon by their twenties. Nearly 100% of individuals with FAP will develop colorectal carcinoma between age 20-50 if colectomy is not performed2.

There are some variant forms of FAP. Gardner syndrome is one such variant where the polyposis is accompanied by epidermoid cysts, desmoids tumours, and osteomas. Another variant, known as Turcot syndrome, is characterized by colonic polyposis and brain tumours.

Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

HNPCC, also known as Lynch syndrome, accounts for 3% of all colorectal cancers2. It is inherited in an autosomal dominant pattern, with an 80% penetrance. The disease, like FAP, follows the two hit model, requiring both alleles of a DNA mismatch repair gene to be mutated (3). This subsequently causes contraction or expansion of areas with repetitive nucleotide sequences, known as microsatellites. It is therefore said that the loss of both alleles of a DNA mismatch repair gene causes microsatellite instability.

HNPCC type I is a subtype that is characterized by colorectal cancer only, whereas HNPCC type II is distinguished by colorectal cancer accompanied by extra colonic tumors, including endometrial, ovarian, gastric, small bowel, bile duct, renal pelvis, ureter, bladder, and skin cancers2.

The mean age at diagnosis of colorectal caner for individuals with Lynch syndrome is 43 years old. There is a predilection for involvement of the right side of the colon2.

Unlike FAP, which is characterized by the growth of thousands of polyps, patients with HNPCC may have only up to 100 colonic polyps2. The lack of distinctive clinical features makes it much more difficult to diagnose than FAP.

Peutz-Jeghers Syndrome

Peutz-Jeghers syndrome is the cause of less than 1% of colorectal cancers. It is a rare autosomal dominant disease with high penetrance, characterized by hamartomatous polyposis and skin pigmentation. It confers a 9-13 fold increase in the risk of both GI and non GI cancers2. Hamartomatous polyps are typically large, but few in number2. They may be present in the colon as well as in the small bowel. Hallmark features of Peutz-Jeghers syndrome include freckles on hands, around the lips, in buccal mucosa, and periorbitally2.

Inflammatory Bowel Disease

Chronic, severe colitis increases the lifetime risk of developing colorectal cancer. Pancolitis caused by ulcerative colitis confers up to a 15-fold increase in risk of developing colorectal cancer1. A similar magnitude of increased risk is thought to exist with pancolitis due to Crohn disease1.

Protective Factors

The protective effect of non-steroidal anti-inflammatory drugs (NSAIDs) on colorectal cancer has been demonstrated by numerous studies. Although some ideas including enhanced apoptosis and COX-2 inhibition have been proposed, no concrete mechanism of action has been proven1.

Statins have also been shown by a few studies to be protective against colorectal cancer, but results have not been as conclusive as for NSAIDs2.

Anatomical Site

In the past, colon cancer was believed to almost exclusively affect only the left side of the colon. However, the incidence of right-sided colon cancer appears to be increasing in both North America and Europe2. This trend in anatomical localization of disease affects both screening and treatment considerations.

References:

1) Ahnen DJ, Macrae FA. UpToDate: Colorectal cancer: epidemiology, risk factors and protective factors. 2010. Available at: http://www.uptodate.com Accessed June 2010.

2) DeVita VT, Lawrence TS, Rosenberg SA. Cancer: Principles & Practice of Oncology 8th Edition Vol 1. Lippincott Williams & Wilkins, Philadelphia; 2008.[/restab]
[restab title=”Screening”]

Screening

Most colorectal cancers evolve from pathologically benign adenomatous precursor lesions, known as polyps, although sometimes the benign lesions are sessile (flat). Most colorectal cancer cases can be prevented through regular screening and removal of these precancerous lesions.

Screening guidelines vary according to regional protocols. In BC, the screening protocol is developed by the Guidelines and Protocols Advisory Committee (GPAC), sponsored by the BCMA, Medical Services Commission, and the Government of BC.

According to the GPAC guidelines, patients are stratified into three different groups based on their risk of developing colorectal cancer, and then screened according to which risk group they fall under. These groups include high risk, moderate risk, and average risk patients.1 In addition to the guidelines for their particular risk group, all patients aged 50 and over should have an annual digital rectal examination.1

Table 1: Risk Groups Used for Purpose of Screening
Risk group Criteria
High risk patients
  • Previous colorectal cancer
  • Family history of FAP or HNPCC
Moderate risk patients
  • Previous adenomas
  • Longstanding inflammatory bowel disease
  • Colorectal cancer in first degree relatives
Average risk patients
  • Meet none of the above criteria

High Risk Asymptomatic Patients

FAP & FAP Variants

All 1st degree relatives of individuals with FAP or an FAP variant should be offered genetic counseling and testing.1 This should be carried out through a referral to the Hereditary Cancer Program at the BC Cancer Agency.

If the result of the genetic test for FAP is negative, the individual should continue to be screened under the guidelines for the average-risk population.

If the result of the genetic test for FAP is positive, or indeterminate, the individual should be referred to a specialist for further testing and monitoring. These patients will require flexible sigmoidoscopy1:

  • Every year starting at age 12
  • Every 2 years from age 25
  • Every 3 years from age 35
  • As per guidelines for average-risk individuals at age 50

If polyposis is detected, colectomy should be performed, as the risk of developing colon cancer is 100% if the colon is not removed.2

Upper endoscopy has also been recommended by some sources, due to the increased risk of gastric and duodenal polyps. However, this recommendation has not shown a proven benefit in clinical trials.3

HNPCC

There are two separate sets of criteria for determining individuals who are at high risk of having Lynch syndrome. These are known as the Amsterdam II criteria, and the revised Bethesda guidelines. The Amsterdam criteria have low sensitivity, but high specificity, whereas the Bethesda guidelines have high sensitivity, but low specificity2. As a physician, it is prudent to be aware of both systems.

The Amsterdam II criteria are as follows:

  1. Three (or more) relatives with histologically verified Lynch syndrome associated cancers (colorectal, endometrial, small bowel, or transitional cell carcinoma of the ureter or renal pelvis), one of whom is a first degree relative of the other two, AND
  2. At least two successive generations affected, AND
  3. In at least one of the affected relatives, diagnosis of the cancer occurred prior to age 50, AND
  4. FAP is excluded

The revised Bethesda criteria are as follows:

  1. Colorectal cancer diagnosed in a patient who is less than 50 years of age.
  2. Presence of synchronous, metachronous colorectal or other HNPCC-associated tumors, regardless of age.
  3. Colorectal cancer with “microsatellite instability – high” histology diagnosed in a patient who is less than 60 years of age.
  4. Colorectal cancer diagnosed in a patient with one or more first degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed under age 50 years.
  5. Colorectal cancer diagnosed in a patient with two or more first or second-degree relatives with HNPCC-related tumors, regardless of age.

Individuals that meet the Amsterdam II or revised Bethesda criteria are at high risk of having HNPCC. These at-risk individuals should be offered genetic counseling and testing, through a referral to the Hereditary Cancer Program at the BC Cancer Agency.1 The revised Bethesda guidelines recommend microsatellite instability testing for any individuals meeting the criteria, and subsequent genetic mutation testing for DNA mismatch repair genes if the individual is found to have a microsatellite unstable cancer4.

Individuals with a family history of HNPCC should be screened via colonoscopy starting at age 25, or 10 years less than the age of the earliest case in the family member who had colorectal cancer, whichever comes first. Colonoscopy should be performed1:

  • Every 2 years until age 40
  • Every year thereafter

Moderate Risk Asymptomatic Patients1

Colorectal cancer in 1st degree relative, age 55 or younger; or two or more 1st degree relatives of any age

  • Colonoscopy – every 5 years beginning at age 40 or 10 years before the age of presentation of the youngest case in the family, whichever is lower

Colorectal cancer in 1st degree relative over age 55

  • Colonoscopy – every 10 years beginning at age 40

Personal history of polyp >1cm, or multiple colorectal adenomas of any size

  • Colonoscopy – 3 years after polypectomy and every 5 years thereafter if recurrent adenomas are present; if no further adenomas then every 10 years thereafter

Personal history of 1 or 2 colorectal adenomas <1cm

  • Colonoscopy – 5 years after polypectomy and every 5 years thereafter if recurrent adenomas are present; if no further adenomas then every 10 years thereafter

Inflammatory Bowel Disease involving entire colon (pancolitis) for over eight years or the left colon for over 15 years

  • Colonoscopy every 1-2 years in patients without dysplasia
  • If high-grade dysplasia found, or low-grade dysplasia is persistent in several pathological examinations, colectomy is recommended.2

Patients with primary sclerosing cholangitis represent a population with an even higher risk of developing colorectal cancer than patients with inflammatory bowel disease. Although the GPAC guidelines for colorectal cancer have no mention of this fact, the Canadian Association of Gastroenterology recommends screening these patients with colonoscopy on an annual basis.5

Average Risk Asymptomatic Patients1

No known risk factors

  • Fecal occult blood test (FOBT) – yearly, between age 50 and 75 (recommended)
  • Flexible Sigmoidoscopy – every 5 years, between age 50 and 75 (optional, in addition to FOBT)

Colorectal cancer in 2nd degree relatives of any age

  • Colonoscopy – every 10 years between age 50 and 75, or
  • Double contrast barium enema (DCBE) and flexible sigmoidoscopy – every 5-10 years, between age 50 and 75. See “Diagnosis” section for description on double contrast barium enema

Adenomatous polyp in a 1st degree relative younger than age 60

  • Colonoscopy – every 10 years between age 50 and 75, or
  • DCBE and flexible sigmoidoscopy – every 5-10 years, between age 50 and 75

Summary:

All patients aged 50 and over should have an annual digital rectal examination.

Risk group Recommended screening protocol
High risk patients FAP:
  • Flexible sigmoidoscopy:
    • Every year starting at age 12
    • Every 2 years from age 25
    • Every 3 years from age 35
    • As per guidelines for average-risk individuals at age 50

HNPCC:

  • Colonoscopy:
    • Starting at age 25, or 10 years before the age of the youngest case of CRC in the family
    • Every 2 years until age 40
    • Every year thereafter

Moderate risk patientsCRC in 1st degree relative, age 55 or younger; or two or more 1stdegree relatives of any age

  • Colonoscopy
    • Start at age 40 or 10 years before the age of youngest case in the family, whichever is lower
    • Every 5 years

CRC in 1st degree relative over age 55

  • Colonoscopy
    • Start at age 40
    • Every 10 years

Personal history of polyp >1cm, or multiple colorectal adenomas of any size

  • Colonoscopy
    • Start 3 years after polypectomy
    • Every 5 years if recurrent adenomas are present
    • Every 10 years thereafter if no further adenomas

Personal history of 1 or 2 colorectal adenomas <1cm

  • Colonoscopy
    • Start 5 years after polypectomy
    • Every 5 years if recurrent adenomas are present; Every 10 years if no further adenomas

IBD involving entire colon for over 8 years, or the left colon for over 15 years

  • Colonoscopy
    • Start when over 8 years of pancolitis, or 15 years of left-sided colitis
    • Every 1-2 years in patients without dysplasia

Primary sclerosing cholangitis

  • Colonoscopy
    • Annually5

Average risk patientsNo known risk factors

  • FOBT (recommended)
    • Between age 50 and 75
    • Annually
  • Flexible sigmoidoscopy (optional, in addition to FOBT)
    • Between age 50 and 75
    • Every 5 years

Colorectal cancer in 2nd degree relatives of any age

  • Colonoscopy
    • Between age 50 and 75
    • Every 10 years

OR

  • DCBE and flexible sigmoidoscopy
    • Between age 50 and 75
    • Every 5-10 years

Adenomatous polyp in a 1st degree relative younger than age 60

  • Colonoscopy
    • Between age 50 and 75
    • Every 10 years

OR

  • DCBE and flexible sigmoidoscopy
    • Between age 50 and 75
    • Every 5-10 years

References:

1) Detection of colorectal neoplasms in asymptomatic patients. Victoria: Guidelines and Protocols Advisory Committee; 2004 Mar. 11 p. Available from: http://www.bcguidelines.ca/gpac/pdf/colorectal_det.pdf

2) Health professionals info: cancer management guidelines: gastrointestinal: colon: screening/early detection [Internet]. BC Cancer Agency; [updated 2005 Nov 16; cited 2010 Jul 14]. Available from: http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/Gastrointestinal/05.Colon/5Screening.htm

3) Bonis PA, Ahnen DJ, Axell L. UpToDate: Screening and management strategies for patients and families with familial colon cancer syndromes. 2010. Available at: http://www.uptodate.com Accessed July 2010.

4) Ahnen DJ, Axell L. UpToDate: Clinical features and diagnosis of Lynch syndrome (hereditary nonpolyposis colorectal cancer). 2010. Available at: http://www.uptodate.com Accessed July 2010.

5) Leddin D, Hunt R, Champion M, Cockeram A, et al. Canadian Association of Gastroenterology and the Canadian Digestive Health Foundation: Guidelines on colon cancer screening. Can J Gastroenterol 2004 Feb;18(2):93-9.[/restab]
[restab title=”Classification”]

Classification

While pathological staging offers the best postoperative outlook for colorectal cancer, histopathological typing and grading of the tumour can offer additional valuable prognostic information.2

Histopathological Type

Table 1: WHO Histopathological Classifications of Colorectal Cancer
Histopathological type of colorectal cancer Characteristics of the tumour type
Adenocarcinoma in situ or severe dysplasia
Adenocarcinoma The vast majority of colorectal cancers are adenocarcinomas.
Mucinous adenocarcinoma 11-17% of all colorectal cancers.2

Many tumours produce mucin. The mucin can be intracellular or extracellular. When a tumour produces a large amount of extracellular mucin that comprises ≥ 50% of the tumour mass, it is called a mucinous adenocarcinoma. Mucinous adenocarcinomas of the colon and rectum are associated with poor response to chemotherapy and they tend to present at a more advanced stage.2 However, the overall prognostic significance of colorectal mucinous adenocarcinoma remains controversial.3Signet-ring cell carcinoma1-2% of all colorectal cancers.2

When ≥ 50% of the tumour is made up of cells with large amounts of intracellular mucin, it is classified as a signet-ring cell carcinoma. It is called this name, because the intracellular mucin displaces the nucleus and cytoplasm to the sides of the cell, and the cell subsequently looks like a signet ring on histopathological examination. Colorectal signet-ring cell carcinomas are aggressive, with a high potential for extensive intramural spread and peritoneal carcinomatosis.2 Patients usually present at an advanced stage at the time of diagnosis.Squamous cell (epidermoid) carcinomaExtremely rare. Only 18 cases have been described in the medical literature between 1943 and 2002.5

They present at an advanced stage at diagnosis, behave aggressively, and are associated with a poor prognosis.6Adenosquamous carcinoma0.06% of all colorectal cancers.1

These are adenocarcinomas with areas of squamous differentiation. They present at an advanced stage at diagnosis, behave aggressively, and are associated with a poor prognosis.6Small-cell carcinoma, aka oat-cell carcinomaLess than 1% of all colorectal cancers.4

These tumours have neuroendocrine differentiation. Colorectal small-cell carcinomas have a poor prognosis.4Medullary carcinoma3.6% of all colorectal cancers.8

This colorectal cancer type is associated with high microsatellite instability and HNPCC. It has a more favourable prognosis than other colorectal cancer types.3Undifferentiated carcinomaLess favourable outcome.7

Histologic Grade7

GX – grade cannot be assessed
G1 – Well differentiated
G2 – Moderately differentiated
G3 – Poorly differentiated
G4 – Undifferentiated (corresponds to the histological type “undifferentiated carcinoma”)

The terms “low-grade” and “high-grade” refer to the grades G1-G2 and G3-G4 respectively.

Histologic grading of the tumour is based primarily on the presence or absence of well-formed glands. Tumours that are graded as “low-grade” have glands that are present. Conversely, tumours that are “high-grade” have do not have evidence of well-formed glandular tissue.2

References:

1) Cagir B, Nagy MW, Topham A, Rakinic J, Fry RD. Adenosquamous carcinoma of the colon, rectum, and anus: epidemiology, distribution, and survival characteristics. Dis Colon Rectum 1999 Feb;42(2):258-63.

2) Compton CC. UpToDate: Pathology and prognostic determinants of colorectal cancer. 2010. Available at: http://www.uptodate.com Accessed July 2010.

3) DeVita VT, Lawrence TS, Rosenberg SA. Cancer: Principles & Practice of Oncology 8th Edition Vol 1. Lippincott Williams & Wilkins, Philadelphia; 2008.

4) El Demellawy D, Khalifa MA, Ismiil N, Wong S, Ghorab Z. Primary colorectal small cell carcinoma: a clinicopathological and immunohistochemical study of 10 cases. Diagn Pathol 2007 Sep 5;2:35.

5) Gelas T, Peyrat P, Francois Y, Gerard JP, et al. Primary squamous-cell carcinoma of the rectum: report of six cases and review of the literature. Dis Colon Rectum 2002 Nov;45(11)1535-40.

6) Verma S, Balachandra B, Butts C, Koski S, et al. Squamous and adenosquamous carcinoma of the colon and rectum: Institutional and literature review. Proc Am Soc Clin Concol 22:2003 (abstr 1339).

7) Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC cancer staging manual. 7th ed. New York: Springer-Verlag; 2010.

8) Lanza G, Gafà R, Matteuzzi M, Santini A. Medullary-type poorly differentiated adenocarcinoma of the large bowel: a distinct clinicopathologic entity characterized by microsatellite instability and improved survival. J Clin Oncol 1999 Aug;17(8):2429-38.[/restab]
[restab title=”Signs & Symptoms”]

Signs & Symptoms

Patients with colorectal cancer may present with any number of the symptoms listed in table 1 below, with the most common symptoms being1:

  1. Abdominal pain
  2. Change in bowel habit
  3. Hematochezia or melena

20% of patients with colorectal cancer have metastatic disease at the time of presentation.1 In order to effectively ask the appropriate questions and perform an adequate physical exam, the physician must understand the nature of colorectal cancer, including how the tumour cells tend to spread. There are three main ways that colorectal cancer spreads. These include spreading via local extension, lymphatics, and hematogenously. Rarely, colorectal cancer spreads transperitoneally. The most common sites of spread are regional lymph nodes, the liver, lungs, and peritoneum.1 Since lymphatics and blood vessels are found in the submucosa, tumours confined to the mucosa have a lower risk of metastasizing.

The liver is usually the first site of hematogenous dissemination, because the intestines are drained by the portal vein. The exception to this is cancer in the distal rectum, which is an area that drains into the inferior vena cava via the inferior rectal veins. As such, tumour cells of the distal rectum may spread initially to the lungs.1

One effective approach to thinking about signs and symptoms of colorectal cancer, is to categorize the clinical manifestations according to route of spread (i.e., local invasion, lymphatic invasion, or hematogenous invasion). The table below summarizes this approach.

Table 1: Signs and Symptoms of Colorectal Cancer
Route of spread Signs and symptoms Explanation
Local extension Abdominal pain Caused by partial obstruction, peritoneal spread, or perforation leading to peritonitis.1
Change in bowel habit More common in left-sided colon cancers, because the contents in the right colon are more liquid, and can more readily flow around partial obstructions.1
Hematochezia or melena Hematochezia is more commonly caused by rectal cancer, whereas melena is more commonly caused by cancers in more proximal locations. Also worthy of note is that cecal and ascending colon tumours have a 4-fold higher mean daily blood loss than tumours at other sites of the colon.1
Neuropathic pain May occur if the tumour involves the sciatic or obturator nerve.1
Tenesmus Caused by tumours that are at the distal end of the colon, or in the rectum. The presence of the tumour in this region gives the patient the sensation of needing to defecate, but not being able to do so effectively.2
Microcytic anemia Chronic blood loss will cause iron deficiency anemia, which presents as microcytic anemia.1 Patients may potentially present with secondary fatigue, palpitations, and agina pectoris.
Periumbilical nodules Also called Sister Mary Joseph nodules. While these nodules can be the result of lymphatic or hematogenous spread, the most common route is via contiguous extension from the anterior peritoneal surface.3
Nausea and vomiting Caused by obstruction, and subsequent backing up of bowel contents.2
Narrow stools Stool needs to squeeze past the tumour, and results in a pencil- or ribbon-like stool.2
Lymphatic spread Adenopathy (supraclavicular and periumbilical) These signs and symptoms may be caused by lymph node enlargement, which can subsequently compress the bowels and adjacent nerves.1
Abdominal distention
Pain
Nausea and vomiting
Hematogenous spread Right upper quadrant abdominal pain, jaundice Metastasis to liver.
Respiratory symptoms Metastasis to lungs.

There also exist some additional constitutional symptoms of cancer that should be assessed during the patient interview, including weight loss, anorexia, muscle weakness, and malaise. While these symptoms can be a direct effect of the cancer, they can also be explained as a manifestation of a paraneoplastic syndrome, where the tumour is releasing substances that interact with receptors and result in increased metabolism.4

Impact on Prognosis

Patients who are symptomatic due to obstruction or perforation at the time of diagnosis carry a worse prognosis than patients who are asymptomatic.5 In addition, the presence of signs and symptoms of obstruction or perforation may influence the choice of therapeutic modalities.1

References:

1) Ahnen DJ, Macrae FA. UpToDate: Clinical manifestations, diagnosis, and staging of colorectal cancer. 2010. Available from: http://www.uptodate.com Accessed July 2010.

2) Just the facts: symptoms [Internet]. Colorectal Cancer Association of Canada; [cited 2010 Jul 16]. Available from: http://www.colorectal-cancer.ca/en/just-the-facts/symptoms/

3) Coll DM, Meyer JM, Mader M, Smith RC. Imaging appearances of Sister Mary Joseph nodule. Br J Radiol 1999 Dec;72(864):1230-3.

4) Theologides A. Cancer cachexia. Cancer 1979 May;43(5 Suppl):2004-12.

5) DeVita VT, Lawrence TS, Rosenberg SA. Cancer: Principles & Practice of Oncology 8th Edition Vol 1. Lippincott Williams & Wilkins, Philadelphia; 2008.[/restab]
[restab title=”Diagnosis”]

Diagnosis

History

A complete history should be taken. Symptoms associated with colorectal cancer should be elicited during the patient interview. In addition, taking a detailed family history of disease is essential, due to the possibility of a familial cancer syndrome.

Physical Exam

Possible findings during the physical exam include a palpable abdominal mass, bright red blood per rectum, or melena. Metastatic disease may manifest as adenopathy, hepatomegaly, jaundice, or pulmonary signs.1

If a lesion is palpable on digital rectal exam, the size of the tumour, mobility, and distance from the anal verge should be documented. For female patients, a pelvic and rectovaginal examination should be performed to look for local invasion of the tumour into pelvic structures (e.g., vagina, rectovaginal septum).

Lab Investigations

There are no blood tests that are effective at detecting colorectal cancer.2 However, laboratory investigations that raise suspicion of colorectal cancer include a CBC that shows an iron-deficiency anemia, and a positive fecal occult blood test.

Other tests that are ordered for the workup of colorectal cancer include kidney and liver function tests, ALP, CEA, and genetic testing.

Table 1: Laboratory Investigations for Colorectal Cancer Workup
Test parameter Significance
CBC Iron-deficiency anemia, infection.
Fecal occult blood test Positive result in the absence of gross rectal bleeding may be significant as a sign of ongoing occult bleeding.
Electrolytes, urea, creatinine Assess for acute blood loss, dehydration from diarrhea, kidney function for possibility of future chemotherapy.
Liver function tests Metastases to liver.
Alkaline phosphatase Metastases to bone.
CEA (carcinoembryonic antigen) Useful for post-operative monitoring.1
Genetic testing, if needed Presence of a familial cancer syndrome.

Imaging

Sigmoidoscopy

Sigmoidoscopy

Individuals who are symptomatic or have abnormal test results that warrant suspicion of colorectal cancer will require either a colonoscopy or a double contrast barium enema. Colonoscopy is the most useful test, as the physician can view the lumen of the rectum and colon, and at the same time take biopsies of lesions, remove polyps, and detect synchronous lesions.3 However, approximately 5% of patients will have colon cancers that can not be viewed using colonoscopy, due to an obstruction, tortuous colon, or poor bowel prep.3 In these patients, the best diagnostic imaging is the double contrast barium enema. A double contrast barium enema involves receiving a barium enema followed by injection of air to expand the colon for a better view, followed by multiple X-ray images. In addition, patients with a pre-operative obstruction that prevents full examination of the colon should have a study of the entire colon after the obstruction is removed.

For rectal cancers, endorectal ultrasound (EUS) and pelvic MRI are important for staging purposes. EUS is cheaper, less time-consuming, and more accurate than MRI at predicting T stage and N stage.3 Furthermore, EUS allows simultaneous ultrasound guided biopsies to be taken. It should be noted that although EUS is specific for nodal disease, it has low sensitivity. In other words, negative nodal findings on EUS do not effectively rule out the possibility of nodal disease.

Table 2: Imaging for Colorectal Cancer Workup
Type of imaging Significance
Colonoscopy Viewing of lesions, biopsy, polyp removal, detecting synchronous lesions.
Barium enema If colonoscopy is insufficient for diagnosis.
Endorectal ultrasound (EUS) Required for rectal cancers, for T and N staging.
Abdominal and pelvic CT Assess for lymphadenopathy in internal and external iliac chains, liver, and base of lungs.
MRI Identification of metastasis to liver.Useful for T and N staging.Also useful to view tissue planes for planning of surgery.
Chest x-ray Assess for lung metastases.

Pathology

No diagnosis is complete without a biopsy to confirm malignancy. The biopsy is obtained during colonoscopy. The pathologist will also determine the histopathological type of the cancer (see section on classification of colorectal cancer).

References:

1) DeVita VT, Lawrence TS, Rosenberg SA. Cancer: Principles & Practice of Oncology 8th Edition Vol 1. Lippincott Williams & Wilkins, Philadelphia; 2008.

2) Holleb AI, Fink DJ, Murphy GP. Clinical Oncology 1st Edition. American Cancer Society, Atlanta; 1991.

3) Ahnen DJ, Macrae FA. UpToDate: Clinical manifestations, diagnosis, and staging of colorectal cancer. 2010. Available at: http://www.uptodate.com Accessed July 2010.[/restab]
[restab title=”Staging”]

Staging

There are many factors that influence the prognosis of a case of colorectal cancer, including histological typing of the tumour, and the magnitude of symptoms owing to obstruction and perforation, among other things. However, staging provides the most valuable prognostic information. There are multiple staging classification systems that should be known for colorectal cancer, including the Dukes classification, the modified Astler-Coller (MAC) classification and the TNM classification. The TNM classification system has superior value in terms of determining prognosis, and therefore is now the standard staging system in clinical practice. The Dukes and MAC classifications are of historical importance, and are no longer recommended for use.1

Staging helps in deciding a patient’s treatment plan, understanding prognosis and allowing research comparison. Staging also allows different health care professionals to communicate and provides international standardization.

Staging of colorectal cancer is based on medical history, physical examination, imaging, and pathology.

Dukes and MAC Classification

The Dukes classification system was developed in 1930. The modified Astler-Coller (MAC) system is an enhanced version of the Dukes classification system. The major limitations of the Dukes and MAC classification systems are lack of information regarding adequacy of node sampling, extent of node involvement, and tumour grade.3 As the number of positive nodes is the most significant prognostic factor,3 the Dukes and MAC classification systems have been deemed inadequate, and are no longer recommended.1 However, it is important to be aware of these older classification systems, as historical records may be staged using them. The appropriate mapping from a Dukes/MAC stage to TNM stage is provided in Table 9 below.

Table 1: Dukes Classification3
Stage A Limited to mucosa.
Stage B Penetration through bowel wall. Nodes not involved.
Stage C Spread to local-regional lymph nodes.
Stage D Distant metastasis.
Table 2: MAC Classification4
Stage A Limited to mucosa.
Stage B1 Limited to bowel wall beyond mucosa. Nodes not involved.
Stage B2 Extension beyond bowel wall (includes serosa). Nodes not involved.
Stage B3 Extension beyond bowel wall with adherence to or invasion of surrounding areas. Nodes not involved.
Stage C1 Same as B1, but with positive nodes.
Stage C2 Same as B2, but with positive nodes.
Stage C3 Same as B3, but with positive nodes.
Stage D Distant metastatic spread.

TNM Staging1

Note: the BC Cancer Agency supplies its own staging diagrams, based on the TNM staging system. However, as of the writing of this training module (July 16, 2010), the BCCA staging diagrams are outdated, as they are based on the 2002 AJCC staging guidelines, while the AJCC released new staging guidelines in 2010. Nevertheless, you can download the outdated BCCA staging diagrams for colon cancer and rectal cancer.

Primary Tumor (T)

TX – primary tumour cannot be assessed
T0 – No evidence of primary tumour
Tis – Carcinoma in situ: intraepithelial or invasion of lamina propria. The terms “high grade dysplasia”, and “severe dysplasia” are synonymous with in situ carcinoma and in situ adenocarcinoma.
T1 – Tumour invades submucosa
T2 – Tumour invades muscularis propria
T3 – Tumour invades through the muscularis propria into pericolorectal tissues
T4a – Tumour penetrates to the surface of the visceral peritoneum
T4b – Tumour directly invades or is adherent to other organs or structures

Regional Lymph Nodes (N)

Regional lymph nodes are the nodes along the colon, and the nodes along the blood vessels that supply the colon. The regional lymph nodes are further divided into groups depending on which portion of the colon or rectum is affected. During surgical resection of the colon or rectum, the surgeon must try to attain at least 12 lymph nodes for staging purposes.5 However, this number is quite controversial, and some institutions advocate resecting at least 17 nodes.6 In general, the more nodes attained, the better the prognostic accuracy. For similar reasons, the pathologist must make a note of how many nodes were actually analyzed in the determination of the pathological N-stage of the tumour.3

Table 3: Regional Lymph Nodes

Segment

Regional Lymph Nodes

Cecum Pericolic, anterior cecal, posterior cecal, ileocolic, right colic
Ascending colon Pericolic, ileocolic, right colic, middle colic
Hepatic flexure Pericolic, middle colic, right colic
Transverse colon Pericolic, middle colic
Splenic flexure Pericolic, middle colic, left colic, inferior mesenteric
Descending colon Pericolic, left colic, inferior mesenteric, sigmoid
Sigmoid colon Pericolic, inferior mesenteric, superior rectal, superior hemorrhoidal, sigmoidal, sigmoid mesenteric
Rectosigmoid Perirectal, left colic, sigmoid mesenteric, sigmoidal, inferior mesenteric, superior rectal, superior hemorrhoidal, middle hemorrhoidal
Rectum Perirectal, sigmoid mesenteric, inferior mesenteric, lateral sacral, presacral, internal iliac, sacral promontory (Gerota’s) superior hemorrhoidal, inferior hemorrhoidal
Anus Perirectal, anorectal, superficial inguinal, internal iliac, hypogastric, femoral, lateral sacral

NX – regional lymph nodes cannot be assessed
N0 – no regional lymph node metastasis
N1 – metastasis in 1-3 regional lymph nodes
N1a – metastasis in one regional lymph node
N1b – metastasis in 2-3 regiona lymph nodes
N1c – tumour deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis
N2 – metastasis in four or more regional lymph nodes
N2a – metastasis in 4-6 regional lymph nodes
N2b – metastasis in seven or more regional lymph nodes

Distant Metastasis (M)

M0 – no distant metastasis
M1 – distant metastasis
M1a – metastasis confined to one organ or site (e.g., liver, lung, ovary, nonregional node)
M1b – metastasis in more than one organ/site or the peritoneum

Table 9: TNM stage grouping for colorectal cancer

Stage T N M Dukes MAC
0 Tis N0 M0
I T1 N0 M0 A A
T2 N0 M0 A B1
IIA T3 N0 M0 B B2
IIB T4a N0 M0 B B2
IIC T4b N0 M0 B B3
IIIA T1-2 N1/N1c M0 C C1
T1 N2a M0 C C1
IIIB T3-4a N1/N1c M0 C C2
T2-T3 N2a M0 C C1/C2
T1-T2 N2b M0 C C1
IIIC T4a N2a M0 C C2
T3-T4a N2b M0 C C2
T4b N1-N2 M0 C C3
IVA T any N any M1a
IVB T any N any M1b

Other Prognostic Factors That Are Recommended for Collection1

  • Pre-treatment serum CEA
  • Tumour deposits – the number of satellite tumour deposits that are discontinuous from the leading edge of the tumour, and that lack evidence of a residual lymph node.
  • Circumferential resection margin
  • Perineural invasion – histological evidence of invasion of regional nerves
  • Microsatellite instability
  • Tumour regression grade (with neoadjuvant therapy) – the pathological response to preoperative neoadjuvant therapy. A significant decrease in disease after neoadjuvant therapy is associated with a good prognosis.
  • KRAS gene analysis – presence of mutation in KRAS is associated with a poor response to anti-EGFR antibody therapy.

References:

1) Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC cancer staging manual. 7th ed. New York: Springer-Verlag; 2010.

2) Health professionals info: cancer management guidelines: gastrointestinal: colon [Internet]. BC Cancer Agency; [updated 2008 May 6; cited 2010 Jul 16]. Available from: http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/Gastrointestinal/05.Colon/default.htm

3) DeVita VT, Lawrence TS, Rosenberg SA. Cancer: Principles & Practice of Oncology. 8th ed. Vol 1. Philadelphia: Lippincott Williams & Wilkins; 2008.

4) Lester SG. Radiation therapy in colorectal carcinoma. J Natl Med Assoc. 1988 October; 80(10): 1090–1093.

5) Health professionals info: cancer management guidelines: gastrointestinal: colon: management: curative treatment [Internet]. BC Cancer Agency; [updated 2008 May 6; cited 2010 Jul 16]. Available from: http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/Gastrointestinal/05.Colon/Management/Curative.htm

6) Blackbourne LH. Surgical recall. 5th ed. Baltimore: Lippincott Williams and Wilkins; 2009.

7) Silva AC, Vens EA, Hara AK, Fletcher JG, Fidler JL, Johnson CD. Evaluation of Benign and Malignant Rectal Lesions with CT Colonography and Endoscopic Correlation. RadioGraphics 2006;26: 1085-1099.[/restab]
[restab title=”Management”]

Management

For the purpose of managing colorectal cancer, the division between the colon and rectum is located at the point of the peritoneal reflection.1 The approach to management of colorectal cancer is different depending on whether the tumour is located in the colon, or in the rectum. For instance, adjuvant therapy for colon cancer is mainly achieved through chemotherapy, while for rectal cancer it is achieved through both radiation and chemotherapy. The reasoning behind this is that colon cancer tends to recur as distal metastases, whereas rectal cancer has an equal propensity to recur locally (pelvis) and distally (liver, lung).2 This is attributed to the difficulty in obtaining clear resection margins in the surgical removal of rectal cancers.

As with all other types of cancer, application of general cancer management principles involves consideration of patient, tumour and treatment factors when deciding the best course of treatment for each individual case. Based on these factors, the treatment goal may be either curative or palliative.

Treatment: Colon Cancer
Treatment: Rectal Cancer

References:

1) Health professionals info: cancer management guidelines: gastrointestinal: colon [Internet]. BC Cancer Agency; [updated 2008 May 6; cited 2010 Jul 16]. Available from: http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/Gastrointestinal/05.Colon/default.htm

2) Willett CG. UpToDate: Adjuvant therapy for resected rectal cancer. 2010. Available from: http://www.uptodate.com Accessed July 2010.[/restab]
[restab title=”Follow-up”]

Follow-up

Purpose of Follow-up

  1. To ensure that problems due to primary therapy are found and resolved
  2. To detect and offer therapy for recurrence
  3. To detect new polyps, or second primary neoplasms, which have a higher propensity to occur in individuals that have had prior colorectal cancer
  4. To assess the results of therapy

Frequency and Duration

The schedule for follow-up is every 3 months for 3 years, and then every 6 months for 2 more years.During the course of therapy and recovery, follow-up is coordinated by the care team, which consists of the patient’s family physician, gastroenterologist, surgeon, medical oncologist and radiation oncologist.

Follow-up Tasks

Tasks that may be completed at each follow-up visit include:

  • History
    • Every visit
    • Ask about GI and constitutional symptoms
  • Physical examination
    • Every visit
    • Abdominal exam
    • DRE
    • Lymphadenopathy
      • With particular attention to left supraclavicular fossa (the location of Virchow’s node, a common location for metastases from gastrointestinal cancers).1
  • Lab investigations
    • Every visit
    • Serum CEA
      • If elevated, do additional imaging of thorax and abdomen to rule out recurrence
      • Discontinue if normal for 5 years.1
  • Colonoscopy
    • Every 3 years, until no new adenomas found. Thereafter, repeat colonoscopy every 5 years until detection of new cancers is unlikely to affect patient’s lifespan.2
    • Remove and biopsy suspicious lesions
    • May use double-contrast barium enema with flexible sigmoidoscopy as an alternative if colonoscopy is not available.2
  • Liver imaging
    • Every 6 months for 3 years, and then annually for 2 years
    • Indicated in patients who are candidates for resection of isolated liver metastases

In addition to the above tests, the following recommendations apply to patients with rectal cancer:

  • DRE and proctoscopy or sigmoidoscopy
    • If underwent low anterior resection of rectal cancer, to assess for recurrence at the site of anastomosis.2
    • At 3 months, 6 months, 1 year, and 2 years.2
  • Chest x-ray
    • Every 6-12 months for 5 years.1

References:

1) Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC cancer staging manual. 7th ed. New York: Springer-Verlag; 2010.

2) Health professionals info: cancer management guidelines: gastrointestinal: colon [Internet]. BC Cancer Agency; [updated 2008 May 6; cited 2010 Jul 16]. Available from: http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/Gastrointestinal/05.Colon/default.htm

3) DeVita VT, Lawrence TS, Rosenberg SA. Cancer: Principles & Practice of Oncology. 8th ed. Vol 1. Philadelphia: Lippincott Williams & Wilkins; 2008.

4) Lester SG. Radiation therapy in colorectal carcinoma. J Natl Med Assoc. 1988 October; 80(10): 1090–1093.

5) Health professionals info: cancer management guidelines: gastrointestinal: colon: management: curative treatment [Internet]. BC Cancer Agency; [updated 2008 May 6; cited 2010 Jul 16]. Available from: http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/Gastrointestinal/05.Colon/Management/Curative.htm

6) Blackbourne LH. Surgical recall. 5th ed. Baltimore: Lippincott Williams and Wilkins; 2009.

7) Silva AC, Vens EA, Hara AK, Fletcher JG, Fidler JL, Johnson CD. Evaluation of Benign and Malignant Rectal Lesions with CT Colonography and Endoscopic Correlation. RadioGraphics 2006;26: 1085-1099.[/restab]
[restab title=”Virtual Patient Case”]

Virtual Patient Case

This case study was designed to supplement your knowledge on the workup of colorectal cancer and test what you have learned after going through module. Use your mouse to click through the slides and answer each question in the text box provided.

Note: This case can be completed on an Ipad. To do this download the (free) Articulate Mobile Player for the Ipad by clicking here.

Click here to start the Colorectal Cancer Virtual Patient Case[/restab]
[restab title=”Evaluation”]

Evaluation

Thank you for using Learn Oncology. This website was designed to supplement teaching in oncology. While the material is targeted to medical students it is our hope that a variety of health care professionals can use this site. Feedback on your experience will help us to improve the resources. Responses are anonymous. Thank you.

Click here to fill out the Colorectal Cancer Module Survey[/restab]
[restab title=”Authors”]

Major Contributors:

Leo Lai & Srinivas Raman – Medical Students
Dr. Paris Ann Ingledew – MD, FRCP Radiation Oncologist[/restab][/restabs]


Last Updated: August 2014