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:
Moving from the internal lumen outwards, the layers of the bowel wall are:
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.
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.
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.
The risk of colorectal cancer significantly increases in the population of age 45 and older.
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 population. 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 nations. 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 US.
Foods that are generally accepted to increase the risk of colorectal cancer:
Foods/food components that are generally accepted to decrease the risk of colorectal cancer:
Foods that have an undetermined effect on colorectal cancer risk:
Prolonged cigarette smoking (> 35 pack years) is known to be associated with a significant increase in colorectal cancer risk.
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.
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 component. 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 cancer. 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 lifetime.
FAP accounts for 1% of all colorectal cancers. 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). 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 performed.
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.
HNPCC, also known as Lynch syndrome, accounts for 3% of all colorectal cancers. 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 cancers.
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 colon.
Unlike FAP, which is characterized by the growth of thousands of polyps, patients with HNPCC may have only up to 100 colonic polyps. The lack of distinctive clinical features makes it much more difficult to diagnose than FAP.
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 cancers. Hamartomatous polyps are typically large, but few in number. 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 periorbitally.
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 disease.
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 proven.
Statins have also been shown by a few studies to be protective against colorectal cancer, but results have not been as conclusive as for NSAIDs.
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 Europe. This trend in anatomical localization of disease affects both screening and treatment considerations.
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. In addition to the guidelines for their particular risk group, all patients aged 50 and over should have an annual digital rectal examination.
All 1st degree relatives of individuals with FAP or an FAP variant should be offered genetic counseling and testing. 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 sigmoidoscopy:
If polyposis is detected, colectomy should be performed, as the risk of developing colon cancer is 100% if the colon is not removed.
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.
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 specificity. As a physician, it is prudent to be aware of both systems.
The Amsterdam II criteria are as follows:
The revised Bethesda criteria are as follows:
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. 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 cancer.
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 performed:
Colorectal cancer in 1st degree relative, age 55 or younger; or two or more 1st degree relatives of any age
Colorectal cancer in 1st degree relative over age 55
Personal history of polyp >1cm, or multiple colorectal adenomas of any size
Personal history of 1 or 2 colorectal adenomas <1cm
Inflammatory Bowel Disease involving entire colon (pancolitis) for over eight years or the left colon for over 15 years
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.
All patients aged 50 and over should have an annual digital rectal examination.
Moderate risk patients, CRC in 1st degree relative, age 55 or younger; or two or more 1st degree relatives of any age
While pathological staging offers the best postoperative outlook for colorectal cancer, histopathological typing and grading of the tumour can offer additional valuable prognostic information.
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. However, the overall prognostic significance of colorectal mucinous adenocarcinoma remains controversial.
Signet-ring cell carcinoma counts for 1-2% of all colorectal cancers.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. 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.They present at an advanced stage at diagnosis, behave aggressively, and are associated with a poor prognosis.
Adenosquamous carcinoma is 0.06% of all colorectal cancers. 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.
Small-cell carcinoma, aka oat-cell carcinoma count for less than 1% of all colorectal cancers.These tumous have neuroendocrine differentiation. Colorectal small-cell carcinomas have a poor prognosis.
Medullary carcinoma3.6% of all colorectal cancers. This colorectal cancer type is associated with high microsatellite instability and HNPCC. It has a more favourable prognosis than other colorectal cancer types. Undifferentiated carcinomaLess favourable outcome.7
GX – grade cannot be assessed
G1 – Well differentiatedG2 – 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.
Patients with colorectal cancer may present with any number of the symptoms listed in table 1 below, with the most common symptoms being1:
20% of patients with colorectal cancer have metastatic disease at the time of presentation. 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. 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.
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.
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.
Patients who are symptomatic due to obstruction or perforation at the time of diagnosis carry a worse prognosis than patients who are asymptomatic. In addition, the presence of signs and symptoms of obstruction or perforation may influence the choice of therapeutic modalities.
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.
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.
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).
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.
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. 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. 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. 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.
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).
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.
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.
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. 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. 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.
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.
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 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. However, this number is quite controversial, and some institutions advocate resecting at least 17 nodes. 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.
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
For the purpose of managing colorectal cancer, the division between the colon and rectum is located at the point of the peritoneal reflection. 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). 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.
Surgery is the primary treatment modality when the patient is amenable to curative therapy. The surgeon attempts to achieve wide clearance, with resection margins of 5-10 cm from the cancer, and concurrent removal of a large area of the mesentery that is supplied/drained by common vasculature. The surgeon also obtains at least 12 nodes for pathological evaluation – any less than this number is inadequate, and can result in increased mortality due to inaccurate staging.
Laparoscopic surgery decreases hospitalization time, without compromising outcome. However, the ability to offer laparoscopic surgery is dependent on availability of resources and trained personnel.
Solitary metastatic lesions to the liver and lungs are potentially curable by surgical excision. There are reports of 25-30% disease free survival rates after excision of isolated liver metastases. If such a surgery is to be undertaken, the patient requires a preoperative evaluation to exclude extrahepatic metastases, and a CT or PET scan to assess involvement of intrahepatic vasculature. Similar data are not available for cases of isolated lung metastases, but the potential for curative surgery exists.
Chemotherapy is the choice of therapy for adjuvant treatment of colon cancer. Radiation therapy has a small role in palliative treatment of colon cancer, and a larger role in treatment of rectal cancer.
The decision to give adjuvant chemotherapy is based on the stage of disease. Higher stages of disease are associated with higher risk of recurrence, which can be reduced through the administration of adjuvant chemotherapy. Adjuvant chemotherapy is not indicated in stage I and low-risk stage II disease. It is recommended for stage II disease with high-risk factors, and stage III disease. Factors that are considered high-risk include:
Studies have shown that adjuvant chemotherapy increases the cure rate by 10-15% for stage III disease. The effect of adjuvant therapy is optimal if commenced within 8 weeks post-op. It is administered on an outpatient basis, lasting a duration of approximately 6 months. Note that there are multiple chemotherapy regimens available, and that the frequency of administration varies according to treatment regimen. Treatment route may be oral or intravenous.
Initiation of palliative treatment may be delayed in patients who are asymptomatic, and are not at risk of rapid deterioration, if they have predictors of poor tolerance of chemotherapy such as old age and multiple comorbidities. On the other hand, asymptomatic patients that have good performance status are preferentially treated early, before the development of symptoms.
Chemotherapy is the mainstay treatment modality in palliative treatment of colon cancer. There are multiple agents available for use. These include traditional cytotoxic drugs, as well as more novel biologic agents that target vascular endothelial growth factor (anti-angiogenisis), and epidermal growth factor receptor.
A patient with poor performance status will most likely have overall better quality of life on a single-agent regimen, whereas patients with good performance status will likely benefit from combination therapy.
In patients whose disease progresses after initial treatment, retreatment with different agents may be considered if their condition permits.
Surgical resection, bypass or colostomy may be indicated for palliative treatment in select individuals.
Radiation therapy has a limited role in palliative treatment of colon cancer. Radiation therapy is useful for controlling localized pain and bleeding. External beam radiation therapy can also be used to treat non-resectable liver metastatic lesions.
There is a role for surgery, radiation therapy, as well as chemotherapy in the treatment of rectal cancer, whether the intent is curative or palliative. The final decision on treatment regimen will rest on patient, tumour and treatment factors.
Surgery is the main treatment modality when the intent is curative. There are different techniques when it comes to surgery for rectal cancer, with advantages and disadvantages to each:
It is not important at this stage to know the all specific criteria used to decide the surgical approach, but rather to understand the main factors. These include distance of the distal edge of the tumour from the anal verge, body habitus, tumour size, and patient comorbidity.
The ideal surgery will spare the anal sphincter preserving bowel continence, and spare the nervi erigentes preserving rectal, urinary, and erectile function. The nervi erigentes are the pelvic splanchnic nerves, which arise from S2-4 and provide parasympathetic innervation to structures arising from the hindgut.
Neoadjuvant therapy refers to therapy given before the main treatment modality. Neoadjuvant therapy for rectal cancer may involve radiation ± chemotherapy.
Why give chemoradiation preoperatively, as opposed to postoperatively?
There are different regimens of preoperative radiation therapy:
Adding chemotherapy to the radiation results in higher rate of pathologic complete response, as well as lower local recurrence as compared to radiation alone. However, this benefit must be balanced with the increase in toxicity.
Adjuvant chemotherapy and radiation therapy may be used, and has been shown to improve local control and survival in Stage II and III rectal cancer.7 Studies have shown that adjuvant chemoradiation results in a significant improvement in local control and survival rate as compared to surgery or surgery + radiation alone.
The decision whether to give preoperative or postoperative chemoradiation therapy is dependent on the clinical stage of disease.
Most clinical stage IV disease is considered incurable, and is therefore treated palliatively.
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.
Tasks that may be completed at each follow-up visit include:
In addition to the above tests, the following recommendations apply to patients with rectal cancer:
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.