Kevin M. Lin

Colorectal carcinoma survival among hereditary nonpolyposis colorectal carcinoma family members

Patients with hereditary nonpolyposis colorectal carcinoma (HNPCC) reportedly have better prognoses than sporadic colorectal carcinoma (CRC) patients, but it has been unclear whether this could be due to differences in stage at diagnosis. The current study compared stage and survival in a retrospective cohort of HNPCC family members who developed CRC with the same factors in an unselected hospital series of patients with sporadic CRC.

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 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.

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 MLH1vs. 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.

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.

Diagnosing anal sphincter injury with transanal ultrasound and manometry.

PURPOSE: This study was undertaken to evaluate how well anorectal manometry and transanal ultrasonography diagnose anal sphincter injury. METHODS: Anorectal manometry and transanal ultrasonography were performed in 20 asymptomatic nulliparous women and 20 asymptomatic parous women, and the results were compared with those obtained in 31 incontinent women who subsequently underwent sphincteroplasty and, thus, had operatively verified anal sphincter injury. By using computerized manometry analysis, mean maximum resting and squeeze pressures, sphincter length, and vector symmetry were determined in all women. All transanal ultrasounds were interpreted blinded as to the patients history, physical examination, and manometry results. RESULTS: Manometric resting and squeeze pressures were significantly higher in the asymptomatic nulliparous women than in the asymptomatic parous women, and both groups had significantly higher pressures than the incontinent women (P<0.001). Anal sphincter length and vector symmetry index were significantly decreased in incontinent women compared with asymptomatic women (P<0.01). Decreased resting and squeeze pressures suggestive of possible sphincter injury were found in 90 percent of incontinent women with known anal sphincter injury. Decreased anal sphincter length and vector symmetry were found in only 42 percent of women with known anal sphincter injury. Transanal ultrasound was able to identify 100 percent of the known sphincter injuries but also falsely diagnosed injury in 10 percent of the asymptomatic nulliparous women with intact anal sphincters. False identification of sphincter injury increased when transanal ultrasound scanning was performed proximal to the distal 1.5 cm of the anal canal. CONCLUSION: Although nonspecific, decreased resting and squeeze pressures were found in 90 percent of patients with anal sphincter injury. Decreased anal sphincter length or vector symmetry index were present in only 42 percent of patients with known sphincter injury. When limited to the distal 1.5 cm of the anal canal, transanal ultrasound identified all known sphincter injuries but falsely identified injury in 10 percent of women with intact anal sphincters. Transanal ultrasound in combination with decreased anal pressures correctly identified all intact sphincters and 90 percent of known anal sphincter injuries.

Hereditary nonpolyposis colorectal cancer: preventive management.

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common form of hereditary colorectal cancer. Inherited mutations in the mismatch repair genes associated with this syndrome have an approximate 80% lifetime risk of colorectal cancer. Since there are no premonitory signs of susceptibility to HNPCC, family history is the initial method for identifying those at increased risk. At risk individuals should undergo genetic counseling and testing. Although an algorithmic indication for genetic testing in at risk HNPCC patients is yet to be determined, many advocate initial screening for microsatellite instability (MSI) of the cancer specimen in individuals suspected of carrying HNPCC mutations. Those who test positive for MSI can then undergo further testing for mutations in the associated germline mismatch repair genes. Techniques for detecting these mutations currently include in vitro synthesized-protein assay, single-strand conformational polymorphism, and DNA sequencing. Given the aggressive nature of HNPCC adenomas, individuals who test positive for HNPCC mutations are recommended to undergo yearly colonoscopic surveillance starting at the age of 25. A reasonable alternative to lifetime colonoscopic surveillance for the prevention of colorectal cancer in these individuals is prophylactic colectomy. The prevention of colorectal cancer through pharmacological means is under investigation as another option in the management of HNPCC patients. Specifically, chemoprevention trials are currently ongoing to evaluate the efficacy of COX-2 inhibitors in the prevention of colorectal cancer in HNPCC and familial adenomatous polyposis patients.

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, Crohns-like lymphoid reaction, mucin production, extent of disease in the bowel wall, and lymph node status were evaluated. RESULTS: Poor differentiation and Crohns-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, Crohns-like lymphoid reaction, or local extent of disease between subgroups of hereditary nonpolyposis colorectal cancer. CONCLUSIONS: Poor differentiation and Crohns-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.

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.

Laparoscopic colectomy for cancer: an oncologic feasible option

The conventional and accepted treatment for curative resection of colon cancer is laparotomy with hemicolectomy for right or left sided lesions. The technique of colon resection through an open laparotomy incision is well known. Over the past several years, laparoscopically assisted colectomy has been developed and studied, following the explosion of laparoscopic technology from the cholecystectomy experience and with acquisition of advanced general laparoscopic techniques. The right, left or sigmoid colon can be mobilized and regional lymphadenectomy performed using laparoscopic instruments and video-imaging equipment. The advantage of laparoscopic colectomy is the use of small abdominal port site and wound incisions which translate to reduced postoperative pain and analgesic requirement, earlier return of bowel function and normal physical activities, and shorter hospital stay without increasing health care costs. Laparoscopic colectomy compares favorably with open colectomy in terms of surgical morbidity and mortality. The laparoscopic approach has been shown to be technically and oncologically feasible with equivalent lymph node harvest from mesenteric lymphadenectomy and achieves adequate proximal and distal margins of colonic resection. Despite initial early anecdotal reports of port site cancer recurrence in laparoscopically assisted colectomy, port site recurrence is rare and its incidence is similar to incisional recurrences in conventional open colectomy. Recent prospective comparative studies have demonstrated equivalent patient survival and equivalent local or distant colon cancer recurrences for open versus laparoscopic curative resection of colon cancer.

Lymphatic Mapping and Sentinel Node Identification for Colorectal Cancer

The primary treatment of resectable CRC is surgical resection. Postoperative adjuvant therapies are recommended when lymph node metastases are found (stage III). There is evidence that about 20% of node negative CRC cases (stage II) are understaged, i.e., they are actually node positive (stage III). New intraoperative procedures (lymphatic mapping and sentinel node identification) that are able to detect occult macro- and micrometastases. Molecular assessment of nodal disease should improve the current staging criteria for colon cancer and could influence recommendation for adjuvant treatment.