Surgical Care
Removal of the entire colon is the only way to completely prevent the development of colon cancer or to treat an existing cancer. Several different operations are currently available for the treatment of hereditary nonpolyposis colorectal cancer (HNPCC).
The three most commonly performed operations are as follows:
-
Subtotal colectomy with ileorectal anastomosis
-
Total colectomy with ileoanal pull-through (pouch procedure)
-
Total colectomy with ileostomy
Subtotal colectomy with ileorectal anastomosis and postsurgical rectal surveillance are recommended when colorectal cancer develops in patients with HNPCC. This operation may be considered for prophylaxis in selected mismatch repair (MMR) gene mutation carriers (see Prophylactic Colectomy).
Subtotal colectomy with ileorectal anastomosis is preferred over segmental resection or hemicolectomy for HNPCC-associated cancers that arise proximal to the peritoneal reflection. Although total proctocolectomy with ileoanal anastomosis and total proctocolectomy with ileostomy eliminate the need for endoscopic surveillance, these procedures are generally reserved for patients with HNPCC who present with rectal cancers, primarily because of concerns about postoperative morbidity and quality of life.
Postoperative Surveillance
Postoperative surveillance is indicated following curative resection in patients with hereditary nonpolyposis colorectal cancer (HNPCC) because of the high rates of metachronous cancers (estimated as high as 40% at 10 y and 72% at 40 y, depending on the length of colon remaining after surgery). Surveillance sigmoidoscopy is recommended every 1-2 years following subtotal colectomy or surveillance colonoscopy is recommended every 1-2 years following partial colectomy.
Evidence supporting this recommendation is derived from the aforementioned studies demonstrating an accelerated rate of malignant transformation in HNPCC and two postresection surveillance studies demonstrating a high rate of metachronous cancers within 2-5 years. In 1994, Lanspa et al identified 17 patients (8%) (in a cohort of 225 patients with HNPCC) who developed metachronous cancers within 5 years of resection (mean, 26.7 mo; range, 4-58.5 mo). [47] In a Danish study of 110 patients with HNPCC, 8 Dukes A or B cancers and 1 Dukes C cancer were detected within 2 years of negative examination findings. [48]
Table 5. Dukes classification. (Open Table in a new window)
Stage |
Tumor |
Node |
Metastasis |
Dukes |
|
|
|
|
|
Stage 1 |
T1 |
N0 |
M0 |
Dukes A |
|
T2 |
N0 |
M0 |
|
|
|
|
|
|
Stage II |
T3 |
N0 |
M0 |
Dukes B |
|
T4 |
N0 |
M0 |
|
|
|
|
|
|
Stage III |
Any T |
N1 |
M0 |
Dukes C |
|
Any T |
N2, N3 |
Mo |
|
|
|
|
|
|
Stage IV |
Any T |
Any N |
M1 |
Dukes D |
Measures for the primary prevention of familial colorectal cancer are discussed below.
Prophylactic Colectomy
Because of the excessive occurrence of both incident and metachronous colon cancers (MCC), prophylactic subtotal colectomy (SC) or total colectomy (TC) may be an alternative to surveillance colonoscopy for individuals with confirmed mutations. Opponents argue that, because of incomplete penetrance, 15-20% of these colectomies may be unnecessary and that patients undergoing prophylactic SC remain at risk of developing metachronous rectal cancers and extra colonic malignancies.
Syngal et al used a decision-analysis model to evaluate life expectancy and quality-adjusted life expectancy derived from surveillance colonoscopy compared with prophylactic surgery in patients aged 25 years who had a confirmed mutation. [49] The analysis showed that, although both approaches offer a modest survival benefit over no intervention, immediate TC and SC were superior to surveillance, with an expected gain in life expectancy of 15.6 years after immediate TC and 15.3 years after SC, as compared with 13.5 years for surveillance. [49] However, the incremental benefit of surgery compared with surveillance diminished with increasing age. Moreover, quality-of-life adjustments favored surveillance over surgery. [49]
In a prospective cohort study by Stupart et al, 60 patients with proven germline mismatch repair gene defect underwent a resection for adenocarcinoma of the colon with a curative intent. All patients were offered annual endoscopic surveillance. Of the 60 patients included in the study, 39 had TC as their initial surgery and 21 had SC. After 6 years of follow-up, MCC occurred in 8 (21%) patients that had SC and in none of the patients that had TC (p=0.048). The overall survival of the two groups was similar (p=0.29). This study concluded that patients with HNPCC have a significant risk of MCC after SC. This is eliminated by performing TC as the primary operation. [50]
Because no evidence-based data support one approach over another, aggressive surveillance is generally preferred, except in select situations in which surveillance is not technically feasible or in patients with mutations who refuse colonoscopic surveillance but agree to sigmoidoscopic surveillance of the rectal remnant. Regardless, patients should be informed about the advantages and disadvantages of each approach and should be encouraged to participate in the decision-making process. In such cases, because of the high rate of metachronous cancers, the colonic remnant should be examined by sigmoidoscopy every 1-2 years.
Prophylactic Hysterectomy and Bilateral Salpingo-oophorectomy
Women should consider undergoing an annual gynecologic examination, including endometrial screening with biopsy (vacuum curettage or Pipel biopsy should be considered). To help reduce the risk of endometrial and ovarian cancer, some experts recommend discussing prophylactic hysterectomy and bilateral salpingo-oophorectomy with women older than 50 years who have hereditary nonpolyposis colorectal cancer (HNPCC). Counseling should include a discussion of the psychosocial effects of prophylactic surgery and the long-term effects of prolonged estrogen replacement therapy.
Currently, the evidence is insufficient to recommend prophylactic hysterectomy and salpingo–oophorectomy to help reduce cancer risk in women who carry the mismatch repair (MMR) gene. The exception to this rule includes females with MSH6 mutations. Current evidence suggests a higher risk for developing endometrial cancer in these women, therefore, prophylactic hysterectomy is indicated. [35, 36] (See Table 3 under Tumor Testing).
Chemoprevention
Observational studies of persons at average risk have suggested that the use of some medications and supplements (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], aspirin, estrogens, folic acid, calcium), as well as antioxidants (eg, beta carotene, vitamin C, vitamin E), may prevent the development of colorectal cancer. However, randomized controlled trials of the use of chemopreventive agents are limited, and only a few studies have specifically enrolled people with an inherited predisposition for colorectal cancer; therefore, the evidence has not convinced experts to recommend these medications and supplements specifically to prevent colorectal cancer in patients with hereditary nonpolyposis colorectal cancer (HNPCC).
NSAIDs
Randomized controlled trials have shown that NSAIDs (sulindac and celecoxib) induce regression of adenomas in patients with familial adenomatosis polyposis (FAP). [51, 52, 53, 54] A considerable volume of preclinical data support the safety and efficacy of cyclooxygenase-2 (COX-2) inhibitors in patients with FAP; therefore, the US Food and Drug Administration (FDA) has approved the use of celecoxib as an adjunct for the management of colorectal adenomas in patients with FAP. The value of COX-2 inhibitors in the sporadic adenoma population is not known.
Studies have shown that COX-2 expression occurs in patients with colorectal adenomas and cancers. However, the expression may not be as pronounced in colorectal adenomas and cancers in HNPCC as it is in FAP sporadic colorectal cancer.
Polymorphisms in drug-metabolizing genes may contribute to the varied responses to NSAIDs. For example, flavin monooxygenase 3 (FMO3) may reduce the catabolism of sulindac, resulting in an increased efficacy in the prevention of polyps in persons with FAP. NSAIDs carry a small risk of bleeding complications, such as stroke and upper gastrointestinal ulceration and bleeding, which weighs against possible benefits.
Aspirin
Prospective studies have demonstrated a significant reduction in colorectal cancers in healthcare workers who regularly used aspirin. [55] In 2011, the first randomized controlled trial into the effect of aspirin on cancer outcomes found that taking aspirin reduces the long-term risk of bowel cancer in people with a family history of the disease by 60%. The British trial, partly funded by Bayer, studied 861 people with Lynch Syndrome who took 600 mg of aspirin per day for 2 years. At a mean follow-up of 55.7 months, 18 of the 427 patients (4.2%) randomly assigned to aspirin developed colorectal cancer compared to 30 of 434 patients (6.8%) assigned to placebo. Further study is needed to determine ideal dose and duration for different groups of people. [56]
Prior to the CAPP2 study, randomized controlled trials had shown reduced risk of adenomas but none had used prevention of colorectal cancer as a primary endpoint. A randomized, double-blind, placebo-controlled trial in patients with a personal history of colon adenomas demonstrated a modest but statistically significant reduction in the incidence of colonic adenomas with daily aspirin use. In a double-blind placebo study, daily aspirin use was also associated with reduction in the incidence of colorectal adenomas in patients with previous colorectal cancer.
Folic acid
In one observational study, the use of folic acid supplements for more than 15 years was associated with a 75% lower rate of colorectal cancer (relative risk [RR] of 0.25; 95% confidence interval [CI], 0.13–0.51). [57, 58] This study was performed in women with a family history of colon cancer. One hypothesis holds that, because folate is required for DNA synthesis, suboptimal amounts may cause abnormalities in DNA synthesis or repair.
Calcium
Researchers have suggested that calcium binds bile acids in the bowel lumen, inhibiting their carcinogenic effects. [59, 60, 61] A randomized controlled trial of calcium supplementation, with a daily intake of 1200 mg of elemental calcium for 4 years, reduced the risk of recurrent adenomas in presumably average-risk people with adenomas by 19% (adjusted risk ratio of 0.81; 95% CI, 0.67–0.99). This finding may not apply to people with a genetically increased risk of colorectal cancer.
Estrogens
Studies have demonstrated that estrogens are associated with a lower incidence of colorectal cancer; however, this information does not address those with a genetically increased risk of colorectal cancer. [62] In addition, over the long term, the effect of combined estrogen plus progestin on colorectal cancer in postmenopausal women did not support a clinically meaningful benefit. [63]
Modifying Behavioral Risk Factors
Several components of diet and behavior have been suggested as risk factors for colorectal cancer, with various levels of consistency. [64, 65, 66] Modifying these lifestyle factors may work toward prevention of HNPCC. Experts differ on the interpretation of the evidence for some of these components. Little is known about whether these same factors are protective in people with a genetically increased risk of colorectal cancer.
In one case-control study, the lack of physical activity, low intake of high-energy foods, and low intake of vegetables contributed significantly to an increased cancer risk in people with no family history of colorectal cancer; however, in those with a family history of colorectal cancer, activity level and diet were not related to cancer risk, despite adequate statistical power.
-
Hereditary Nonpolyposis Colorectal Cancer. Example of an autosomal dominant pedigree.
-
Hereditary Nonpolyposis Colorectal Cancer. Diagnostic approach for patients with colorectal tumors.
Tables
- Table 1. Seven different genes are known to be associated with HNPCC, and all of them are involved with DNA mismatch repair, identified with the frequencies below.
- Table 2. Incidence of different types of cancers in individuals with Lynch syndrome and those in the general population.
- Table 3. IHC staining findings.
- Table 4. Netherlands surveillance protocol for carriers of an MMR-gene mutation.
- Table 5. Dukes classification.
Mismatch Excision Repaired MMR |
Chromosome Location |
Frequency of HNPCC Cases |
MSH2 |
2p16 |
45-50% |
MLH1 |
3p22.3/A> |
20% |
MSH6 |
2p16 |
10% |
PMS2 |
7p22.1 |
1% |
PMS1 |
2q32.2 |
Rare |
MSH3 |
5q14.1 |
Rare |
EXO1 |
1q43 |
Rare |
Other genes not yet discovered |
|
20-25% |
Type of Cancer |
General Population Risk (by age 70 y) |
Lynch Syndrome Risk (by age 70 y) |
Endometrial |
1.5% |
30-40% |
Ovarian |
1% |
9-12% |
Upper Urinary Tract* |
Less than 1% |
4-10% |
Stomach |
Less than 1% |
13% (higher in Asians) |
Small Bowel |
Less than 1% |
1-3% |
Brain |
Less than 1% |
1-4% |
Biliary Tract |
Less than 1% |
1-5% |
MMR Mutations |
Protein Staining |
|||
MLH1 |
MSH2 |
MSH6 |
PMS2 |
|
MLH1 |
- |
+ |
+ |
+ |
MSH2 |
+ |
- |
- |
+ |
MSH6 |
+ |
+ |
- |
+ |
PMS2 |
+ |
+ |
+ |
- |
Surveillance |
MLH1, MSH2, MSH6 (males) |
MSHG (females) |
Colon |
Colonoscopy, every 1-2 years, starting at age 20-25 years |
Colonoscopy, every 1-2 years, starting at age 30 years |
Endometrium |
|
Ultrasonography and CA-125, every 1-2 years, starting at age 30-35 years; consider hysterectomy after age 50 years |
Upper Urinary Tract* |
Urine cytology analysis, every 1-2 years, starting at age 30-35 years, if it occurs 2 or more times in a family |
Urine cytology analysis, every 1-2 years, starting at age 30-35 years, if it occurs 2 or more times in a family |
Stomach |
Gastroscopy every 1-2 years, starting at age 30-35 years, if it occurs 2 or more times in a family |
Gastroscopy every 1-2 years, starting at age 30-35 years, if it occurs 2 or more times in a family |
Stage |
Tumor |
Node |
Metastasis |
Dukes |
|
|
|
|
|
Stage 1 |
T1 |
N0 |
M0 |
Dukes A |
|
T2 |
N0 |
M0 |
|
|
|
|
|
|
Stage II |
T3 |
N0 |
M0 |
Dukes B |
|
T4 |
N0 |
M0 |
|
|
|
|
|
|
Stage III |
Any T |
N1 |
M0 |
Dukes C |
|
Any T |
N2, N3 |
Mo |
|
|
|
|
|
|
Stage IV |
Any T |
Any N |
M1 |
Dukes D |
