Saturday, April 20, 2013

Rectal Cancer

Background
Colon and rectal cancer incidence was negligible before 1900. The incidence of colorectal cancer has been rising dramatically following economic development and industrialization. Currently, colorectal cancer is the third leading cause of cancer deaths in both males and females in the United States.[1, 2]Adenocarcinomas comprise the vast majority (98%) of colon and rectal cancers. Other rare rectal cancers, including carcinoid (0.4%), lymphoma (1.3%), and sarcoma (0.3%), are not discussed in this article. Squamous cell carcinomas may develop in the transition area from the rectum to the anal verge and are considered anal carcinomas. Very rare cases of squamous cell carcinoma of the rectum have been reported.[1, 3]Approximately 20% of colon cancers develop in the cecum, another 20% in the rectum, and an additional 10% in the rectosigmoid junction. Approximately 25% of colon cancers develop in the sigmoid colon.[1]The incidence and epidemiology, etiology, pathogenesis, and screening recommendations are common to both colon cancer and rectal cancer. These areas are addressed together.An image depicting the staging and workup of rectal cancer can be seen below.







Pathophysiology:

The mucosa in the large intestine regenerates approximately every 6 days. Crypt cells migrate from the base of the crypt to the surface, where they undergo differentiation and maturation, and ultimately lose the ability to replicate.
The significant portions of colorectal carcinomas are adenocarcinomas. The adenoma-carcinoma sequence is well described in the medical literature.[1, 4] Colonic adenomas precede adenocarcinomas. Approximately 10% of adenomas will eventually develop into adenocarcinomas. This process may take up to 10 years.[1]
Three pathways to colon and rectal carcinoma have been described:
the adenomatous polyposis coli (APC) gene adenoma-carcinoma pathway
the hereditary nonpolyposis colorectal cancer (HNPCC) pathway
ulcerative colitis dysplasia.
The APC adenoma carcinoma pathway involves several genetic mutations, starting with inactivation of the APC gene, which allows unchecked cellular replication at the crypt surface. With the increase in cell division, further mutations occur, resulting in activation of the K-ras oncogene in the early stages and p53 mutations in later stages. These cumulative losses in tumor suppressor gene function prevent apoptosis and prolong the cell's lifespan indefinitely. If the APC mutation is inherited, it will result in familial adenomatous polyposis syndrome.
Histologically, adenomas are classified in three groups: tubular, tubulovillous, and villous adenomas. K-ras mutations and microsatellite instability have been identified in hyperplastic polyps. Therefore, hyperplastic polyps may also have malignant potential in varying degrees.[5]
The other common carcinogenic pathway involves mutation in DNA mismatch repair genes. Many of these mismatched repair genes have been identified, including hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6. Mutation in mismatched repair genes negatively affects the DNA repair. This replication error is found in approximately 90% of HNPCC and 15% of sporadic colon and rectal cancers.[1, 6] A separate carcinogenic pathway is also described in inflammatory bowel disease (IBD). Chronic inflammation such as in ulcerative colitis can result in genetic alterations which then lead into dysplasia and carcinoma formation.





Epidemiology:

United States

Colon and rectal cancer is the third most common cancer in both females and males. The American Cancer Society estimates that 102,900 new cases of colon cancer and 39,670 new cases of rectal cancer will occur in 2010; 72,090 cases of colorectal cancers are expected in men and 70,480, in women.[2] Approximately 51,370 deaths from colorectal cancer are expected to occur in 2010.
Both colon and rectal cancer incidences, as well as mortality rates, have been decreasing for the last two decades, from 66.3 per 100,000 population in 1985 to 45.5 in 2006.[2] The rate of decrease accelerated from 1998-2006 (to 3% per year in men and 2.2% per year in women), in part because of increased screening, allowing the detection and removal of colorectal polyps before they progress to cancer. The lifetime risk of developing a colorectal malignancy is approximately 6% in the general US population. This decrease is due to a declining incidence and improvements in both early detection and treatment.
A study by Mak et al found that despite widespread adoption of preoperative radiation therapy for locally advanced rectal cancer, preoperative radiation therapy may be underused in certain sociodemographic groups.[7]
International

Although the incidence of colon and rectal cancer varies considerably by country, an estimated 944,717 cases were identified worldwide in 2000. High incidences of colon and rectal cancer cases are identified in the US, Canada, Japan, parts of Europe, New Zealand, Israel, and Australia. Low colorectal cancer rates are identified in Algeria and India. The majority of colorectal cancers still occur in industrialized countries. Recent rises in colorectal cancer incidence have been observed in many parts of the Japan, China (Shanghai) and in several Eastern European countries.[1]


History
All patients should undergo a complete history (including a family history) and assessment of risk factors for the development of rectal cancer. Many rectal cancers produce no symptoms and are discovered during digital or proctoscopic screening examinations.
Bleeding is the most common symptom of rectal cancer, occurring in 60% of patients. Bleeding often is attributed to other causes (eg, hemorrhoids), especially if the patient has a history of other rectal problems. Profuse bleeding and anemia are rare. Bleeding may be accompanied by the passage of mucus, which warrants further investigation.
Change in bowel habits is present in 43% of patients; change is not evident in some cases because the capacity of a rectal reservoir can mask the presence of small lesions. When change does occur it is often in the form of diarrhea, particularly if the tumor has a large villous component. These patients may have hypokalemia, as shown in laboratory studies. Some patients experience a change in the caliber of the stool. Large tumors can cause obstructive symptoms. Tumors located low in the rectum can cause a feeling of incomplete evacuation and tenesmus.
Occult bleeding is detected via a fecal occult blood test (FOBT) in 26% of all cases. Abdominal pain is present in 20% of the cases. Partial large-bowel obstruction may cause colicky abdominal pain and bloating. Back pain is usually a late sign caused by a tumor invading or compressing nerve trunks. Urinary symptoms may also occur if the tumor is invading or compressing the bladder or prostate.
Malaise is a nonspecific symptom and present in 9% of rectal cancer cases. Bowel obstruction due to a high-grade rectal lesion is rare, occurring in 9% of all cases. Pelvic pain is a late symptom, usually indicating nerve trunk involvement, and is present in 5% of all cases. Other manifestations include emergencies such as peritonitis from perforation (3%) or jaundice, which may occur with liver metastases (< 1%).




Physical:

Physical examination is performed with specific attention to size and location of rectal cancer in addition to possible metastatic lesions, including enlarged lymph nodes or hepatomegaly. The remainder of the colon is also evaluated.
Digital rectal examination (DRE) provides an opportunity to readily detect abnormal lesions. The average finger can reach approximately 8 cm above the dentate line. Rectal tumors can be assessed for size, ulceration, and presence of any pararectal lymph nodes. Fixation of the tumor to surrounding structures (eg, sphincters, prostate, vagina, coccyx and sacrum) also can be assessed. DRE also permits a cursory evaluation of the patient's sphincter function. This information is necessary when determining whether a patient is a candidate for a sphincter-sparing procedure. Rigid proctoscopy is also performed to identify the exact location of the tumor in relation to the sphincter mechanism.

Causes:

The etiology of colorectal cancer is unknown, but colorectal cancer appears to be multifactorial in origin and includes environmental factors and a genetic component. Diet may have an etiologic role, especially diet with high fat content.
Approximately 75% of colorectal cancers are sporadic and develop in people with no specific risk factors. The remaining 25% of cases occur in people with significant risk factors--most commonly, a family history or personal history of colorectal cancer or polyps, which are present in 15-20% of all cases. Other significant risk factors are certain genetic predispositions, such as hereditary nonpolyposis colorectal cancer (HNPCC; 4-7% of all cases) and familial adenomatous polyposis (FAP, 1%); and inflammatory bowel disease (IBD; 1% of all cases).


Environmental Factors:




Diet:

A high-fat, low-fiber diet is implicated in the development of colorectal cancer. Specifically, people who ingest a diet high in unsaturated animal fats and highly saturated vegetable oils (eg, corn, safflower) have a higher incidence of colorectal cancer. The mechanism by which these substances are related to the development of colorectal cancer is unknown.
Saturated fats from dairy products do not have the same carcinogenic effect, nor do oils containing oleic acid (eg, olive, coconut, fish oils). Omega-3 monounsaturated fatty acids and omega-6 monounsaturated fatty acids also appear to be less carcinogenic than unsaturated or polyunsaturated fats. In fact, recent epidemiologic data suggest that high fish consumption may provide a protective effect against development of colorectal cancer. Long-term diets high in red meat or processed meats appear to increase the risk of distal colon and rectal cancers.[4, 13]
The ingestion of a high-fiber diet may be protective against colorectal cancer. Fiber causes the formation of a soft, bulky stool that dilutes carcinogens; it also decreases colonic transit time, allowing less time for harmful substances to contact the mucosa. The decreased incidence of colorectal cancer in Africans is attributed to their high-fiber, low–animal-fat diet. This favorable statistic is reversed when African people adopt a western diet. Meta-analysis of case-controlled studies found that reduction in colorectal cancer risk occurs with increasing intake of dietary fiber.[4]
Increased dietary intake of calcium appears to have a protective effect on colorectal mucosa by binding with bile acids and fatty acids. The resulting calcium salts may have antiproliferative effects, decreasing crypt cell production in the mucosa. A double-blind placebo-controlled study showed a statistically significant reduction in the incidence of metachronous colorectal adenomas.[14] Other dietary components, such as selenium, carotenoids, and vitamins A, C, and E, may have protective effects by scavenging free-oxygen radicals in the colon.







Hereditary Factors:

The relative risk of developing colorectal cancer is increased in the first-degree relatives of affected patients. For offspring, the relative risk is 2.42 (95% CI: 2.20-2.65); when more than one family member is affected, the relative risk increases to 4.25 (95% CI; 3.01-6.08). If the first-degree family member is younger than 45 years at the time of diagnosis, the risk increase is even higher.[19]
Regarding the personal history of colorectal cancer or polyps: Of patients with colorectal cancer, 30% have synchronous lesions, usually adenomatous polyps. Approximately 40-50% of patients have polyps on a follow-up colonoscopy. Of all patients who have adenomatous polyps discovered via a colonoscopy, 29% of them have additional polyps discovered on a repeat colonoscopy one year later. Malignancy develops in 2-5% of patients. The risk of cancer in people who have had polyps removed is 2.7-7.7 times that of the general population.[20]


Genetic Disorders
Familial adenomatous polyposis (FAP)

FAP is an autosomal dominant inherited syndrome that results in the development of more than 100 adenomatous polyps and a variety of extra-intestinal manifestations. The defect is in the APC gene, which is located on chromosome 5 at locus q21. The disease process causes the formation of hundreds of intestinal polyps, osteomas of bone, desmoid tumors, and, occasionally, brain tumors. Individually, these polyps are no more likely to undergo malignant transformation than are polyps in the general population. The increased number of polyps, however, predisposes patients to a greater risk of cancer. If left untreated, colorectal cancer develops in nearly 100% of these patients by age 40. Whenever the hereditary link is documented, approximately 20% of FAP cases are found to be caused by spontaneous mutation.







Hereditary nonpolyposis colorectal cancer

HNPCC is an autosomal dominant inherited syndrome that occurs because of defective mismatch repair genes located on chromosomes 2, 3, and 7. Patients have the same number of polyps as the general population, but their polyps are more likely to become malignant. These patients also have a higher incidence of endometrial, gastric, thyroid, and brain cancers.The revised Amsterdam criteria are used to select at-risk patients (all criteria must apply):

Three or more relatives who are diagnosed with an HNPCC-associated cancer (colorectal, endometrium, small bowel, ureter, or renal pelvis):

One affected person is a first-degree relative of the other 2
One or more cases of cancer are diagnosed before age 50 years
At least 2 generations are affected
FAP has been excluded











Laboratory Studies:

Routine laboratory studies should include a complete blood count; serum chemistries, including liver and renal function tests; and a carcinoembryonic antigen (CEA) test. A cancer antigen (CA) 19-9 assay, if available, may also be useful to monitor the disease.
Screening CBC may demonstrate a hypochromic, microcytic anemia, suggesting iron deficiency. The combined presence of vitamin B-12 or folate deficiency may result in a normocytic or macrocytic anemia. All men and postmenopausal women with iron deficiency anemia require a GI evaluation.
Liver function tests are usually part of the preoperative workup. The results are often normal, even in patients with metastases to the liver.
Perform a CEA test in all patients with rectal cancer. A baseline level is obtained before surgery and a follow-up level is obtained after surgery. If a previously normalized CEA begins to rise in the postoperative period, this suggests possible recurrence. A CEA level higher than 100 ng/mL usually indicates metastatic disease and warrants a thorough investigation. The steps of the workup are outlined in Figure 1.

Histologic Findings:
Histopathologic features such as poor differentiation, lymphovascular and/or perineural invasion, T4 tumor stage, and clinical findings such as obstruction or perforation, and elevated preoperative CEA levels are all associated with increased recurrence rates and worse survival.


Staging


Dukes Classification

In 1932, Cuthbert E. Dukes, a pathologist at St. Mark Hospital in England, introduced a staging system for rectal cancer.
His system divided tumor classification into 3 stages, as follows:
Those limited to the rectal wall (Dukes A)
Those that extended through the rectal wall into extra-rectal tissue (Dukes B)
Those with metastases to regional lymph nodes (Dukes C).
This system was modified by others to include subdivisions of stages B and C, as follows:
Stage B was divided into B1 (ie, tumor penetration into muscularis propria) and B2 (ie, tumor penetration through muscularis propria).
Stage C was divided into C1 (ie, tumor limited to the rectal wall with nodal involvement) and C2 (ie, tumor penetrating through the rectal wall with nodal involvement).
Stage D was added to indicate distant metastases

This system was introduced in 1954 by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (IUAC). The TNM system is a universal staging system for all solid cancers that is based on clinical and pathologic information. Each category is independent.
Neither the Dukes nor the TNM system includes prognostic information such as histologic grade, vascular or perineural invasion, or tumor DNA ploidy. TNM staging of rectal cancer correlates well with 5-year survival rates of patients with rectal cancer (see the TNM stage-dependent 5-year survival rate for rectal carcinomas).
TNM classification for cancer of the colon and rectum (AJCC)

Primary tumor (T) includes the following:
TX - Primary tumor cannot be assessed or depth of penetration not specified
T0 - No evidence of primary tumor
Tis - Carcinoma in situ (mucosal); intraepithelial or invasion of the lamina propria
T1 - Tumor invades submucosa
T2 - Tumor invades muscularis propria
T3 - Tumor invades through the muscularis propria into the subserosa or into non-peritonealized pericolic or perirectal tissue
T4 - Tumor directly invades other organs or structures and/or perforates the visceral peritoneum


Regional lymph nodes (N) include the following:
NX - Regional lymph nodes cannot be assessed
N0 - No regional lymph node metastasis
N1 - Metastasis in 1-3 pericolic or perirectal lymph nodes
N2 - Metastasis in 4 or more pericolic or perirectal lymph nodes
N3 - Metastasis in any lymph node along the course of a named vascular trunk

Distant metastasis (M) include the following:
MX - Presence of metastasis cannot be assessed
M0 - No distant metastasis
M1 - Distant metastasis