Current controversies in colon and rectal cancer.

Colon and rectal cancer is one of the leading causes of cancer death worldwide. Several areas of uncertainty remain in the screening and treatment of this disease, even though significant advances have already led to decreased rates of incidence and mortality over the last several decades. This review addresses some of the current controversies in screening for and the treatment of colorectal cancer, including specifically looking at issues related to screening modalities, local versus radical resections, protocols for adjuvant therapy and the treatment of stage IV disease.

Familial adenomatous polyposis and extracolonic cancer.

Our purpose is to focus attention on the cancer family history, coupled with an understanding of the natural history and extracolonic tumor spectrum of familial adenomatous polyposis (FAP), through a family study. This family report provides an example of how colorectal cancer (CRC) can be prevented by knowledgeable gastroenterologists and colorectal surgeons who educate and compassionately counsel members of high-risk families so that their compliance with diagnostic screening and, ultimately, with protection through prophylactic colectomy, is achieved. A working pedigree of this extended family was constructed through interviews with the proband, followed by questionnaires sent to all primary and secondary relatives. Appropriately signed permission forms enabled us to secure pertinent medical and pathology records in order to ensure accuracy of historical information. Integral extracolonic tumors included medulloblastoma, papillary thyroid carcinoma, hepatoblastoma, and desmoid tumors. We conclude that, due in part to improved longevity as a result of being spared CRC, several family members have developed certain FAP integral extracolonic cancers.

A prospective evaluation of the value of anorectal physiology in the management of fecal incontinence.

PURPOSE: This study was designed to determine whether anorectal physiology testing significantly altered patient management in the setting of fecal incontinence. METHODS: Patients referred to the anorectal physiology laboratory for evaluation of fecal incontinence were prospectively interviewed and examined by a colon and rectal surgeon. A decision to treat either medically or surgically was reached. The patients underwent physiologic testing with transanal ultrasound, pudendal nerve terminal motor latency, and anorectal manometry. A panel of board-certified colon and rectal surgeons then reviewed the history and physical examination, as well as the anorectal physiology tests, of each patient and reached a consensus on management. Management plans before and after physiologic evaluation were compared. RESULTS: Ninety patients (6 males) were entered into the study. The patients were divided in two groups: those with pretest medical management plans (n = 45) and those with pretest surgical management plans (n = 45). A change in management was noted in nine patients (10 percent). In the medical management group, the management changed from medical to surgical therapy in five patients. Transanal ultrasound detected anal sphincter defects in all patients who changed from medical to surgical management but in only 10 percent of those who remained under medical management (P = 0.0001). In the surgical management group, three patients (7 percent) changed from surgical to medical therapy and one patient (2 percent) changed from sphincteroplasty to neosphincter. Transanal ultrasound detected a limited anal sphincter defect in one patient (33 percent) who changed from surgical to medical management and a significant defect in all 41 patients (100 percent) who remained under surgical management (P = 0.003). CONCLUSIONS: Anorectal physiology testing is useful in the evaluation of patients with fecal incontinence. Without the information obtained from physiologic testing, 11 percent of patients who may have benefited from surgery would not have been given this option, and 7 percent of patients could have potentially undergone unnecessary surgery. Transanal ultrasound is the study most likely to change a patient's management plan.

Mouth to pouch transit after restorative proctocolectomy: hydrogen breath analysis correlates with scintigraphy.

OBJECTIVES: Fast intestinal transit may be responsible for slow adaptation and unacceptable steady-state function after restorative proctocolectomy. Investigation of GI transit time may be valuable in such a setting. We hypothesized that postprandial hydrogen breath tests may yield transit data that correlate with technetium-labeled meal scintigrams. METHODS: This study compared intestinal transit after a lactulose and bean meal via the breath hydrogen and scintigraphy methods in 21 ileoanal pouch subjects. The meal consisted of baked beans (425 g), 30 ml (20 g) lactulose syrup, 1 mCi 99mtechnetium sulfur colloid in finely chopped liver and 170 ml tap water. The meal contained 120 Kcal (70% carbohydrate, 18% protein and 12% fat). RESULTS: Of 21 pouch subjects, 11 (53%) had breath tests and scintigraphy transit studies that differed by 5-21 min. Three of 21 (14%) scintigraphy mouth to pouch transit times were faster than breath test transits by 43-107 min. Seven of 21 (33%) subjects did not have breath test peaks >10 ppm. Mouth to pouch transit for breath hydrogen (104+/-16 min) and scintigraphy (98+/-7 min) tests had significant correlation (r = 0.96, p < 0.0001) among subjects with alveolar hydrogen peaks and accurate scintigrams (n = 11). Scintigrams were five times more expensive than breath tests. CONCLUSIONS: A peaking hydrogen breath test provides an alternative to scintigraphy for estimating intestinal transit after ileoanal pouch.

Familial adenomatous polyposis, hereditary nonpolyposis colon cancer, and familial risk: what are the implications for the surgeon?

Recent advances in the understanding of the molecular biology of colorectal cancer have resulted in many new implications for surgeons. To continue providing sound patient care, surgeons must familiarize themselves with associated issues that include genetic counseling and its role in patient and family management. Issues related to genetic counseling are reviewed in this article. Recommendations for surgical therapy and surveillance methods are summarized for each of the hereditary syndromes. Failure to use these patient management tools in an effective way may be a source of future litigation.

How I do it. Anal stenosis.

BACKGROUND: Anal stenosis represents a technical challenge in terms of surgical management. It is a rare but serious complication of anorectal surgery, most commonly seen after surgical hemorrhoidectomy. However, stenosis can also occur in the absence of an anorectal surgical history. DATA SOURCES: A review of the current surgical literature was performed. The etiology, classification, and diagnostic modalities for anal stenosis were reviewed. A detailed overview of surgical and nonsurgical therapeutic options was developed. CONCLUSIONS: Anal stenosis may be anatomic (stricture) or functional (muscular). Anal stricture is most often a preventable complication. It is most commonly seen after overzealous surgical hemorrhoidectomy. A well-performed hemorrhoidectomy is the best way to avoid anal stricture. Symptomatic mild functional stenosis and stricture may be managed conservatively with diet, fiber supplements, and stool softeners. A program of gradual manual or mechanical dilatation may be required. Sphincterotomy and various techniques of anoplasty have been used successfully in the treatment of symptomatic moderate to severe functional anal stenosis and stricture, respectively.

Safety and efficacy of dynamic graciloplasty for fecal incontinence: report of a prospective, multicenter trial. Dynamic Graciloplasty Therapy Study Group.

PURPOSE: Dynamic graciloplasty has been used for intractable fecal incontinence, and good results have been reported. The aim of this study was to assess prospectively the safety and efficacy of dynamic graciloplasty for intractable fecal incontinence in a prospective, multicenter trial. METHODS: A total of 123 adults were treated with dynamic graciloplasty at 20 institutions. Continence was assessed preoperatively and postoperatively by use of 14-day diaries. RESULTS: There was one treatment-related death. One hundred eighty-nine adverse events occurred in 91 patients (74 percent). Forty-nine patients (40 percent) required one or more operations to treat complications. One hundred seventy (90 percent) events were resolved. Sixty-three percent of patients without pre-existing stomas recorded a 50 percent or greater decrease in incontinent events 12 months after dynamic graciloplasty, and an additional 11 percent experienced lesser degrees of improvement. Twenty-six percent were not improved, worsened, or exited. In patients with pre-existing stomas, 33 percent achieved successful outcomes at 12 months. This number increased to 60 percent at 18 months. Seventy-eight percent of patients had increased enema retention time, and mean anal canal pressures improved significantly at 12 months. Significant changes in quality of life were also observed. CONCLUSIONS: Objective improvement can be demonstrated in the majority of patients with end-stage fecal incontinence treated with dynamic graciloplasty. Reduction in incontinence episodes can be correlated with improved quality of life. Adverse events are frequently encountered, but most resolve with treatment.

Fecal Incontinence Quality of Life Scale: quality of life instrument for patients with fecal incontinence.

PURPOSE: This goal of this research was to develop and evaluate the psychometrics of a health-related quality of life scale developed to address issues related specifically to fecal incontinence, the Fecal Incontinence Quality of Life Scale. METHODS: The Fecal Incontinence Quality of Life Scale is composed of a total of 29 items; these items form four scales: Lifestyle (10 items), Coping/Behavior (9 items), Depression/Self-Perception (7 items), and Embarrassment (3 items). RESULTS: Psychometric evaluation of these scales demonstrates that they are both reliable and valid. Each of the scales demonstrate stability over time (test/retest reliability) and have acceptable internal reliability (Cronbach alpha >0.70). Validity was assessed using discriminate and convergent techniques. Each of the four scales of the Fecal Incontinence Quality of Life Scale was capable of discriminating between patients with fecal incontinence and patients with other gastrointestinal problems. To evaluate convergent validity, the correlation of the scales in the Fecal Incontinence Quality of Life Scale with selected subscales in the SF-36 was analyzed. The scales in the Fecal Incontinence Quality of Life Scale demonstrated significant correlations with the subscales in the SF-36. CONCLUSIONS: The psychometric evaluation of the Fecal Incontinence Quality of Life Scale showed that this fecal incontinence-specific quality of life measure produces both reliable and valid measurement.

Standards for anal sphincter replacement.

PURPOSE: Anal sphincter replacement offers a new treatment option for patients with severe refractory fecal incontinence or for those who require abdominoperineal resection for localized malignancy. The purpose of this study was to review the current status of anal sphincter replacement, formulate a consensus statement regarding its current use, and outline suggestions for future development. METHODS: Four areas of interests were selected: indications for sphincter replacement, continence scoring and quality of life, choice of therapy, and dissemination of new technology. A questionnaire regarding these issues was developed and circulated to working party members; its results served as the basis for this consensus document. RESULTS: Both electrically stimulated skeletal muscle neosphincter and artificial anal sphincter are options for patients with end-stage fecal incontinence. Electrically stimulated skeletal muscle neosphincter is also appropriate for reconstruction after surgical excision of the anorectum in selected cases. Avoidance of complications requires strict attention to sterile technique, prophylactic antibiotics, and deep venous thrombus prophylaxis. A standardized scoring system is proposed that evaluates both continence and evacuation. Quality of life is a critical endpoint for assessing sphincter replacement, and use of The American Society of Colon and Rectal Surgeons incontinence-specific quality-of-life instrument is recommended. As the efficacy of sphincter replacement becomes proven, dissemination of the technique should occur in a controlled manner to ensure adequate surgeon training, minimization of complications, and optimization of results. CONCLUSIONS: Sphincter replacement by electrically stimulated skeletal muscle neosphincter and artificial anal sphincter provide a continent option for patients with end-stage fecal incontinence and those requiring abdominoperineal resection. The guidelines offered in this document are intended to facilitate the controlled and safe development and acceptance of these new techniques.

Clinical use of the self-expanding metallic stent in the management of colorectal cancer.

PURPOSE: This report describes our experience with the use of self-expanding metallic stents (SEMS) in the management of obstructing colorectal cancer. METHODS: A retrospective chart review of all patients undergoing placement of SEMS between May 1997 and January 2000 was performed. RESULTS: Insertion of SEMS was attempted in 12 patients. Successful stent placement was achieved in 10 of the 12 patients. The locations of lesions were hepatic flexure (2), splenic flexure (1), left colon (1), sigmoid colon (4) and rectum (4). The intended uses of SEMS were for palliation in 3 patients and as a bridge to elective surgery in 9. In the latter group, SEMS placement allowed for preoperative bowel preparation in 4 patients and administration of neoadjuvant therapy prior to elective surgery in 2 patients. One patient died prior to definitive surgery. Stent placement was unsuccessful in 2 patients. Three SEMS-related complications occurred; 1 stent migrated and 1 stent obstructed secondary to tumor ingrowth. One patient died 13 days after stent placement and colonic decompression. CONCLUSION: SEMS represent a useful tool in the management of obstructing colorectal neoplasms. As a bridge to surgery, SEMS provide time for a complete preoperative evaluation and a mechanical bowel preparation and may obviate the need for fecal diversion or on-table lavage. It may also allow for time to administer neoadjuvant therapy when indicated. As a palliative measure, SEMS can eliminate the need for an operation.

Patient and surgeon ranking of the severity of symptoms associated with fecal incontinence: the fecal incontinence severity index.

PURPOSE: The purpose of this research was to develop and evaluate a severity rating score for fecal incontinence, the Fecal Incontinence Severity Index. METHODS: The Fecal Incontinence Severity Index is based on a type x frequency matrix. The matrix includes four types of leakage commonly found in the fecal incontinent population: gas, mucus, and liquid and solid stool and five frequencies: one to three times per month, once per week, twice per week, once per day, and twice per day. The Fecal Incontinence Severity Index was developed using both colon and rectal surgeons and patient input for the specification of the weighting scores. RESULTS: Surgeons and patients had very similar weightings for each of the type x frequency combinations; significant differences occurred for only 3 of the 20 different weights. The Fecal Incontinence Severity Index score of a group of patients with fecal incontinence (N = 118) demonstrated significant correlations with three of the four scales found in a fecal incontinence quality-of-life scale. CONCLUSIONS: Evaluation of the Fecal Incontinence Severity Index indicates that the index is a tool that can be used to assess severity of fecal incontinence. Overall, patient and surgeon ratings of severity are similar, with minor differences associated with the accidental loss of solid stool.

Influence of arginine dietary supplementation on healing colonic anastomosis in the rat.

INTRODUCTION: This study sought to determine whether dietary arginine influences colonic anastomotic healing in the rat model. METHODS: Three groups of 42 Sprague-Dawley rats were fed 0, 1, and 3 percent arginine diets for three preoperative and three postoperative days. Animals underwent transection of the transverse colon with hand-sewn anastomosis. Subgroups of 14 animals in each dietary group were killed on postoperative Days 6, 10, or 14, and bursting pressures, histologic inflammation, and collagen content were compared. RESULTS: Mean anastomotic bursting pressures on postoperative Day 6 were lower for the 0 percent arginine group than the 1 and 3 percent arginine groups (mean +/- standard error of the mean = 134+/-6 mm Hg, 164+/-7 mm Hg, and 166+/-7 mm Hg, respectively; P<0.0005). On Days 10 and 14, no significant differences in bursting pressures were noted between arginine diets. Mean bursting pressures on postoperative Day 6 (155+/-4 mm Hg) were significantly lower than on Days 10 (204+/-5 mm Hg) and 14 (217+/-6 mm Hg; P<0.001) for all arginine diets. Microscopic evaluation of the anastomoses did not show significant differences in inflammation or collagen content between arginine diets. Collagen content in all dietary groups peaked at Day 10. CONCLUSIONS: Perioperative arginine deficiency in the rat model is associated with impaired anastomotic healing during the first week, as reflected by lower bursting pressures. Arginine supplementation to 3 percent does not improve bursting pressures above those found in the usual 1 percent arginine diet at 6, 10, or 14 days. Bursting pressures plateau by Day 10 regardless of perioperative dietary arginine, whereas collagen content peaks at Day 10 after six-day perioperative arginine diet manipulation.

Colorectal cancer in hereditary breast cancer kindreds.

PURPOSE: This study compared characteristics of colorectal cancer between families with dominant breast cancer inheritance and the general population. The cumulative incidence of colorectal cancer was also studied in genetically determined breast cancer syndrome subjects with BRCA1 and BRCA2 mutations and compared with the general population. METHODS: Subjects included 42 patients with colorectal cancer from 32 clinically determined hereditary breast cancer kindreds based on the autosomal dominant inheritance of breast cancers and early age of onset. The general population colorectal cancer cohort was composed of 755 patients from a tumor registry. Lifetime risk of colorectal cancer was determined in 164 BRCA1 and 88 BRCA2 gene mutation carriers and compared with the general population. Mean age of colorectal cancer onset, anatomic site distribution, histologic stage at presentation, and five year stage-stratified survival rates were compared between clinically determined hereditary breast cancer family members and the general population. RESULTS: The lifetime risk of colorectal cancer in male BRCA1 and BRCA2 mutation carriers was 5.6 percent, which was not different from 6 percent in males from the general population. Likewise, the lifetime colorectal cancer risk in female BRCA1 and BRCA2 mutation carriers was 3.2 percent, which was not different from 5.9 percent in females from the general population. Mean age of onset +/- standard error for patients with colorectal cancer was 60 +/- 2 years for hereditary breast cancer kindreds compared with 67 +/- 0.4 years for the general population (P = 0.0004). Colorectal cancer site distribution did not vary between hereditary breast cancer and the general population. Overall colorectal cancer stage distribution was significantly different, with more Stage I and fewer Stage IV cancers in subjects with hereditary breast cancer compared with the general population (P = 0.01). Overall five year stage-stratified colorectal cancer survival rate +/- standard error was 66 +/- 8 percent for hereditary breast cancer kindreds and 46 +/- 2 percent for the general population (P = 0.023). CONCLUSION: Lifetime cumulative colorectal cancer incidence in subjects with BRCA1 and BRCA2 gene mutations was not different from the general population. However, significant differences in colorectal cancer were noted between hereditary breast cancer family members and the general population. Hereditary breast cancer-associated colorectal cancer had an earlier age of onset, lower tumor stage, and better survival rate than the general population. Except for age of onset, colorectal cancer in hereditary breast cancer kindreds exhibited more favorable characteristics than colorectal cancer in the general population.

Histologic comparison of hereditary nonpolyposis colorectal cancer associated with MSH2 and MLH1 and colorectal cancer from the general population.

PURPOSE: Hereditary nonpolyposis colorectal cancer is reported to have special histologic features. This study compares the histologic features of hereditary nonpolyposis colorectal cancer to colorectal cancers from the general population when hereditary nonpolyposis colorectal cancer cases are restricted to families with known MSH2 and MLH1 mutations. METHODS: Thirty-seven cancers from kindreds carrying MSH2 mutations, 27 cancers from kindreds carrying MLH1 mutations, and 37 colorectal cancers from the general population were reviewed by a pathologist blinded to hereditary nonpolyposis colorectal cancer gene status. Tumor grade, growth pattern, Crohn's-like lymphoid reaction, mucin production, extent of disease in the bowel wall, and lymph node status were evaluated. RESULTS: Poor differentiation and Crohn's-like reaction were a feature of 44 and 49 percent of hereditary nonpolyposis colorectal cancer compared with 14 percent (P = 0.002) and 27 percent (P = 0.049) of colorectal cancers from the general population, respectively. There was no difference in growth pattern, mucin production, lymph node involvement, or local extent of disease between hereditary nonpolyposis colorectal cancer and colorectal cancers from the general population. Poor differentiation and lymph node metastases were found in 57 and 49 percent of MSH2 compared with 26 percent (P = 0.002) and 10 percent (P = 0.03) of MLH1-associated cancers, respectively. There was no difference in growth pattern, mucin production, Crohn's-like lymphoid reaction, or local extent of disease between subgroups of hereditary nonpolyposis colorectal cancer. CONCLUSIONS: Poor differentiation and Crohn's-like reaction are more common in hereditary nonpolyposis colorectal cancer than colorectal cancers from general population. Poor differentiation and lymph node metastases are more commonly seen in MSH2-associated cancers than MLH1. Evaluation of the natural history, pathogenesis, and prognosis of colorectal cancer in hereditary nonpolyposis colorectal cancer should include consideration of which mismatch repair genes are mutated and what the specific mutations are.

Use of preoperative ultrasound staging for treatment of rectal cancer.

INTRODUCTION: Transrectal ultrasound is the standard method for preoperative staging of rectal cancer. This study reviews the accuracy of transrectal ultrasound staging for T3 disease and its use in the selection of patients for neoadjuvant chemoradiation. METHODS: One hundred seventeen patients underwent preoperative transrectal ultrasound evaluation for rectal cancer. Accuracy of transrectal ultrasound was evaluated among 70 patients not receiving preoperative chemoradiation. Forty-seven patients received neoadjuvant chemoradiation based on transrectal ultrasound results. Tumor downstaging and early recurrence were evaluated among 45 of 47 patients receiving neoadjuvant chemoradiation. RESULTS: Among 70 nonirradiated patients, 19 were pathologic Stage pT3. Transrectal ultrasound correctly identified 18 of 19 patients with Stage pT3 (sensitivity, 94.7 percent). Transrectal ultrasound correctly identified 44 of 51 patients with less than pT3 disease (specificity, 86.3 percent). After preoperative chemoradiation in 45 patients with ultrasound Stage uT3 or uT4 tumors, 56 percent of them experienced a reduction in T stage. Residual nodal disease was found in 31 percent of patients. A complete pathologic response with no residual disease at operation was observed in 22 percent of patients. During a median follow-up period of 21 months after diagnosis, seven patients experienced a recurrence of their disease at a median of 12 months after diagnosis. Five of seven patients with recurrence were among a subgroup of ten patients who both failed to downstage T and had residual nodal disease at operation. CONCLUSION: Transrectal ultrasound is an accurate modality for selecting patients for neoadjuvant treatment. Preoperative chemoradiation produced downstaging in 56 percent of patients. Factors related to early recurrence included residual nodal disease and failure to downstage T after neoadjuvant chemoradiation.

A century of progress in hereditary nonpolyposis colorectal cancer (Lynch syndrome).

One of the earliest references to heredity in colorectal cancer dates to Aldred Warthin's now-famous recollection of his seamstress' distress regarding "cancer excess" in her family history. Her prediction of an early demise secondary to cancer of the female organs, colon, or stomach proved true. The slow, arduous investigation that ensued followed a tortuous route of nearly eight decades before the implications of such family histories were widely acknowledged through the designation of hereditary nonpolyposis colorectal cancer or Lynch Syndrome Variants I and II. The story of hereditary nonpolyposis colorectal cancer is one of chance meetings, the selfless sharing of information, perseverance in the face of adversity, meticulous scientific documentation, and ultimate vindication by a scientific process that yielded molecular genetic evidence through the identification of the culprit mutations (hMSH2, hMLH1, hPMS2, and hMSH6). Our purpose is to provide a brief outline of the course charted by the study of the genetics of hereditary nonpolyposis colorectal cancer. This should be of particular interest to the readers of this Journal as we celebrate 100 years of dedication to the diagnosis and treatment of diseases of the colon, rectum, and anus through the efforts of The American Society of Colon and Rectal Surgeons.

Cumulative incidence of colorectal and extracolonic cancers in MLH1 and MSH2 mutation carriers of hereditary nonpolyposis colorectal cancer.

The extracolonic tumor spectrum of hereditary nonpolyposis colorectal cancer (HNPCC) includes cancer of the endometrium, ovaries, stomach, biliary tract, and urinary tract. This study was designed to determine the penetrance of colorectal and extracolonic tumors in HNPCC mutation carriers. Forty-nine patients (22 females and 27 males) were identified with an MSH2 germline mutation, and 56 patients (28 females and 28 males) were identified with an MLH1 I mutation. Cumulative incidence by age 60 (lifetime risk) and mean age of cancer diagnosis were compared. The lifetime risk of extracolonic cancers in MSH2 and MLH1 carriers was 48% and 11%, respectively (P = 0.016). Extracolonic cancer risk in MSH2 females and males was 69% and 34%, respectively (P = 0.042). Mean age of extracolonic cancer diagnosis was significantly older for MSH2 males than females (55.4 vs. 39.0, P = 0.013). No difference was observed in colorectal cancer risk between MLH1 and MSH2 carriers (84% vs. 71%). Colorectal cancer risk was 96% in MSH2 males compared to 39% in MSH2 females (P = 0.034). No differences in colorectal and extracolonic cancer risks between MLH1 females and males were identified. The risk of extracolonic cancer by age 60 was greater in MSH2 mutation carriers than in MLH1 carriers. Gender differences in colorectal and extracolonic cancer risk were observed for MSH2 carriers only. These phenotypic features of HNPCC genotypes may have clinical significance in the design of genotype-specific screening, surveillance, and follow-up for affected individuals.

Ileoanal pouch function and release of peptide YY.

PURPOSE: This study evaluates peptide tyrosine-tyrosine (PYY), intestinal transit, fecal retention time, and anal sphincter manometry in colectomized patients with ileal pouch-anal anastomosis. METHODS: Plasma and pouch PYY, mouth-to-pouch transit time, fecal retention time, and anal canal pressures were studied in 27 patients with ileoanal pouches a mean of 50 (range, 3-84) months after loop ileostomy closure. RESULTS: Basal and peak postprandial plasma PYY were significantly reduced in patients with pouches compared with controls (P < 0.0001). Pouch PYY was decreased compared with control ileal PYY (P = 0.0003). No significant correlation was noted between intestinal transit and total integrated PYY response in patients with pouches (r=0.36; P=0.06). Fecal retention time was related to postprandial total integrated response of plasma PYY (r=0.43; P=0.02), mouth-to-pouch transit (r=0.87; P < 0.0001), and resting (r=0.44; P=0.02) and squeeze (r=0.62; P=0.0006) anal sphincter pressures. CONCLUSIONS: Colectomized ileoanal patients with pouches showed decreased plasma and pouch PYY compared with controls. Intestinal transit was not significantly related to PYY release. However, prolonged pouch fecal retention was associated with greater PYY release, mouth-to-pouch transit, and anal sphincter pressures.

Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population.

PURPOSE: This clinical case review aimed to identify phenotypic variations in colorectal and extracolonic cancer expression between hereditary nonpolyposis colorectal cancer (HNPCC) families with MLH1 and MSH2 germline mutations and the general population. METHODS: Colorectal cancer onset and site distribution were compared among 67 members of MLH1 kindreds, 45 members of MSH2 kindreds, and 1,189 patients from the general population. Synchronous and metachronous cancer rates, tumor stage, extracolonic cancer incidence, and survival were also compared. RESULTS: Mean ages of colorectal cancer onset were 44, 46, and 69 years for MLH1, MSH2, and the general population, respectively (P < 0.001). More proximal and fewer distal colon cancers were noted in HNPCC than the general population (P < 0.001, P = 0.04). Site distribution showed disparity of rectal cancers (8 percent MLH1 vs. 28 percent MSH2; P = 0.01) based on genotypes. Overall, synchronous colorectal cancer rates were 7.4, 6.7, and 2.4 percent for MLH1, MSH2, and the general population, respectively (P = 0.016). Annual metachronous colorectal cancer rates were 2.1, 1.7, and 0.33 percent for MLH1, MSH2, and the general population, respectively (P = 0.041). Colorectal cancer stage presentation was lower in HNPCC than the general population (P = 0.0028). Extracolonic cancers were noted in 33 percent of MSH2 patients, compared with 12 percent of MLH1 patients and 7.3 percent of the general population with colorectal cancers (P < 0.001). Combined MLH1 and MSH2 ten-year survival was 68.7 percent compared with 47.8 percent for the general population (P = 0.009 stage stratified, hazard ratio 0.57). CONCLUSION: The presence of rectal cancer should not preclude the diagnosis of HNPCC, because the incidence of rectal cancer in MSH2 was comparable with that in the general population. Phenotypic variations, including the preponderance of extracolonic cancers in MSH2 patients, did not result in survival differences between genotypic subgroups. These phenotypic features of HNPCC genotypes may have clinical significance in the design of specific screening, surveillance, and follow-up for affected individuals.