Hereditary Nonpolyposis Colorectal Carcinoma Patients Research Articles

The 21st century hepatologist and a systems biology based approach to liver diseases

It is striking how often it is that a 30- to 50-year-old patient will walk into my office with a seemingly mild yet enigmatic problem such as an abnormal aminotransferase level or epigastric pain that persists despite thorough investigation and treatment from their internist. These patients invariably have complicated family histories of multiple cancers or chronic diseases such as diabetes, rheumatoid arthritis, Alzheimer’s disease, and others. Recently, I began linking some of these clinical findings to potentially dysfunctional genetic pathways to effect a diagnosis, treatment, and management plan, and possibly avert disease escalation. Take one recent example of a patient who presented with abnormal aminotransferases and gastric fundic gland polyps (not on proton pump inhibitors). I noted her family history of hepatocellular carcinoma (HCC) and gastric cancer spanning three generations. Familial adenomatous polyposis coli/Gardner’s syndrome with dysfunctional wnt signaling, epigenetic loss of E-cadherin, and silencing of transforming growth factor β signaling are some of the possibilities.1–3 With the right information at hand, this patient’s management plan could include: a screening strategy for HCC and gastric cancer; identifying mutations in affected family members; examining affected gastric tissue for loss of E-cadherin; instituting simple preventive/disease modifying measures such as vitamin D, calcium, and aspirin that switch off pro-oncogenic activated wnt signaling.4,5 Clearly, many patients will need to be studied carefully with genetic networks and a systems biology approach to identify key modifying factors that will effectively work on an individual basis.6 I have most definitely embarked on a steep learning curve as I continue to manage my patients. Possibly, as in hereditary non-polyposis colorectal carcinoma (HNPCC) studies, this patient and her family will eventually fall into a specific genetic group, and we will be able to look to future prevention of other cancers, such as the uterine cancers by earlier hysterectomies in HNPCC patients.7

Metachronous Small Bowel Adenocarcinomas Detected by Capsule Endoscopy in a Patient with Hereditary Nonpolyposis Colorectal Cancer

Hereditary nonpolyposis colorectal carcinoma (HNPCC) is the most common colorectal cancer susceptibility syndrome, with a lifetime risk of colon cancer of 80% [1]. Affected individuals are at risk for extracolonic malignancies as well. These include (in descending order) endometrial, ovarian, gastric, and transition cell carcinoma of the uroepithelial tract. Other more rare HNPCC-associated extracolonic tumors include pancreas, hepatobiliary, brain, skin, and possibly small bowel. The significance of small bowel tumors in HNPCC remains unclear. Two large studies have assessed the risk of extracolonic cancers in HNPCC patients. Vasen et al. [2] observed a very high relative risk (>100-fold) for small bowel cancer in a cohort of 210 mutation carriers. Aarnio et al. [3], however, reviewed a larger cohort of 360 mutation carriers and found no cases of small bowel cancer. Cohort studies have reviewed the clinical pattern of small bowel cancers in HNPCC patients [4–6]. In addition to these larger series, many isolated case reports describe this association [7, 8].

Survival from Colorectal Carcinoma in HNPCC Families as Compared to the General Population in Lithuania – Initial Results

Colorectal cancer in HNPCC appears to have a better prognosis than sporadic colorectal cancer. Selection bias, screening, early intervention and treatment hamper efforts to confirm such a hypothesis. To evaluate survival rates in Lithuanian HNPCC patients with colorectal cancer and compare them with survival rates of sporadic cases arising from the general population. The study group consisted of 8 patients from 6 Hereditary non-polyposis colorectal carcinoma (HNPCC) families, 3 patients had HMSH2 and 5 patients had HMLH1 mutations, who were diagnosed between 1995 and 1999. HNPCC patients characteristic (age and stage) were used to trace the records of the Cancer Registry at the same period to identify the cases corresponding the required criteria. Above 263 patients were found--106 at stage II and 157 at stage III. The 10-year survival was 87.5% in the HNPCC study group compared with only 44.8% in the general population group. Patients with the MSH2 gene mutation were at a greater risk of developing a second primary cancer independent from any cancer prevention and screening programs. Survival rates were also prolonged even with a greater numbers of extra-colonic cancers diagnosed at different stages. HNPCC patients with confirmed MSH2 or MLH1 mutations diagnosed with stages II and III CRC have a good 10-year survival prognoses compared with those from the general population.

Pathologic features of endometrial carcinoma associated with HNPCC

Endometrial carcinoma is a common malignancy in hereditary nonpolyposis colorectal carcinoma (HNPCC). Like colon carcinoma, endometrial carcinoma is diagnosed at an earlier age in women with HNPCC. In contrast to colon carcinoma, the pathologic features of endometrial carcinoma in HNPCC have not been studied in detail. It was the purpose of this study to pathologically characterize a series of HNPCC associated endometrial carcinomas. Fifty women with HNPCC and endometrial carcinoma were analyzed from four different hereditary cancer registries. H&E stained slides and pathology reports were reviewed for clinically important pathologic features of endometrial carcinoma. These results were compared with those for two different groups of sporadic endometrial carcinoma--women younger than age 50 years (n = 42) and women of all ages with tumors demonstrating microsatellite instability (MSI-high) secondary to methylation of MLH1 (n = 26). Nearly one-fourth of HNPCC patients in this study had endometrial tumors with pathologic features that would require adjuvant therapy after hysterectomy. There was a trend toward the HNPCC patients having more nonendometrioid tumors; all of these patients were carriers of MSH2 mutations. Such nonendometrioid tumors were extremely rare in the MLH1 methylated group. A subset of MLH1 methylated sporadic tumors demonstrated a unique, 'undifferentiated' histology that was not observed in HNPCC or the young group. Data suggest a genotype-phenotype relation in which microsatellite instability resulting from MLH1 methylation is almost exclusively associated with classical or 'undifferentiated' endometrioid tumors, whereas microsatellite instability secondary to MSH2 mutation can result in a more variable histologic spectrum of endometrial carcinoma.

MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas

Microsatellite instability (MSI) has been detected in endometrial carcinomas occurring in women affected by hereditary nonpolyposis colorectal carcinoma (HNPCC) as well as in 20% of presumably sporadic endometrial tumors. While the MSI+ phenotype observed in endometrial tumors from HNPCC patients is attributed to germ line mutations in mismatch repair (MMR) genes, somatic mutations of known MMR genes are infrequent in MSI+ sporadic endometrial carcinomas. Recently, cytosine methylation of the MLH1 promoter region has been identified in a subset of MSI+ colon primary carcinomas and cell lines. We studied the MLH1 and MSH2 promoter methylation status in 29 presumably sporadic uterine endometrioid carcinomas (UECs), which had previously been characterized for the MSI phenotype and a subset for DNA MMR gene mutational status. We found that 13 (45%) of 29 cases of EC were hypermethylated in the 5' CpG island of MLH1. Hypermethylation of MSH2 was not observed. MLH1 was hypermethylated in 12 (92%) of 13 MSI+ tumors, while only 1 (6%) of 16 MSI- tumors (Fischer's exact test P<O.0001). Other tumor types we tested did not demonstrate MLH1 promoter hypermethylation. Our data suggest that hypermethylation of MLH1, but not of MSH2, is associated with the MSI phenotype in sporadic endometrial carcinomas.

Characteristics of small bowel carcinoma in hereditary nonpolyposis colorectal carcinoma. International Collaborative Group on HNPCC.

Small bowel carcinoma is uncommon. However, hereditary nonpolyposis colorectal carcinoma (HNPCC) patients are at increased risk of small bowel carcinoma. The purpose of this study was to characterize small bowel tumors in HNPCC patients. A questionnaire was mailed to the members of International Collaborative Group on HNPCC (ICG-HNPCC) requesting clinicopathologic data in their registries on HNPCC patients with small bowel carcinoma. Survival was estimated utilizing the Kaplan-Meier method. Forty-two individuals from 40 HNPCC families developed 42 primary and 7 metachronous small bowel tumors. There were 46 adenocarcinomas and 3 carcinoid tumors. The median age at diagnosis of the index small bowel tumor was 49 years. Mismatch repair gene mutations were present in 15 of 42 patients (36%). There were nine hMLH1 and six hMSH2 mutations. The small bowel was the first site of carcinoma in 24 patients (57%). The median survival for the 42 patients was 47 months (range, 0-447 months). The overall 5- and 10-year survival rates were 44% and 33%, respectively. Small bowel tumors can be the presenting neoplasms in HNPCC patients. Similar to colorectal carcinoma in HNPCC, small bowel adenocarcinomas in HNPCC patients occur at an earlier age and appear to have a better prognosis than those occurring in the general population.

Colorectal carcinoma survival among hereditary nonpolyposis colorectal carcinoma family members

BACKGROUND 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. METHODS This retrospective cohort study compared HNPCC cases (274 cases from 98 HNPCC families) with an unselected hospital series comprising 820 consecutive CRC cases. All patients were staged according to the TNM system of the American Joint Committee on Cancer and the International Union Against Cancer. Median follow-up among living patients was > 10 years and 8.5 years, respectively, for the two cohorts. Cox regression was used to compare survival in stage-stratified analyses of time from diagnosis to death. RESULTS Compared with the unselected series, the HNPCC cases had lower stage disease (P < 0.001), and fewer had distant metastases at diagnosis (P < 0.001 in an analysis stratified by T classification). In stage-stratified survival analysis, the HNPCC cases had a significant overall survival advantage regardless of adjustment for their younger age. A conservative estimate of the hazard ratio (of HNPCC cases to the unselected series) was 0.67 (P < 0.0012). CONCLUSIONS HNPCC patients had lower stage disease at diagnosis than the unselected CRC cases, mainly due to rarer distant metastases at diagnosis. They survived longer than unselected CRC patients with tumors of the same stage. The estimated death rate for the HNPCC cases, adjusted for stage and age differences, was at most two-thirds of the rate for the hospital series. [See editorial on pages 201-3, this issue.] Cancer 1998;83:259-266. © 1998 American Cancer Society.

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. This retrospective cohort study compared HNPCC cases (274 cases from 98 HNPCC families) with an unselected hospital series comprising 820 consecutive CRC cases. All patients were staged according to the TNM system of the American Joint Committee on Cancer and the International Union Against Cancer. Median follow-up among living patients was > 10 years and 8.5 years, respectively, for the two cohorts. Cox regression was used to compare survival in stage-stratified analyses of time from diagnosis to death. Compared with the unselected series, the HNPCC cases had lower stage disease (P < 0.001), and fewer had distant metastases at diagnosis (P < 0.001 in an analysis stratified by T classification). In stage-stratified survival analysis, the HNPCC cases had a significant overall survival advantage regardless of adjustment for their younger age. A conservative estimate of the hazard ratio (of HNPCC cases to the unselected series) was 0.67 (P < 0.0012). HNPCC patients had lower stage disease at diagnosis than the unselected CRC cases, mainly due to rarer distant metastases at diagnosis. They survived longer than unselected CRC patients with tumors of the same stage. The estimated death rate for the HNPCC cases, adjusted for stage and age differences, was at most two-thirds of the rate for the hospital series.

Flat adenoma as a precursor of colorectal carcinoma in hereditary nonpolyposis colorectal carcinoma.

Because flat adenoma shows a higher malignancy rate compared with other types of polyps, it is considered to play an important role in the carcinogenesis of colorectal carcinoma. In the present study, we examined flat adenomas in hereditary nonpolyposis colorectal carcinoma (HNPCC) patients. Nine HNPCC patients who presented with flat adenomas were examined. All patients underwent either surgery or endoscopic polypectomy for colorectal carcinoma and/or adenoma. In all patients, annual colonoscopy had been performed once a year throughout the follow-up period after the initial treatment. When colorectal polyps were detected during follow-up colonoscopy, all lesions were endoscopically excised. Clinicopathologic features and microsatellite instability of both malignant lesions and adenomas were examined. Thirteen malignant lesions were detected: seven advanced carcinomas and six early carcinomas. Among 4 early carcinomas with submucosal invasion, 3 lesions (75%) were categorized as superficial type, with a configuration similar to flat adenoma. The frequency of flat adenoma was strikingly high in HNPCC patients in the present study. Among 73 polyps detected, 37 (50.7%) were flat adenomas. Both malignant lesions and flat adenomas had proximal predominance, 61.5% and 59.5%, respectively. Eleven of 15 lesions (73.3%) showed replication error. These results suggest the importance of flat adenoma as a precursor of colorectal carcinoma in some groups of HNPCC patients. Further study is essential to elucidate the natural history of flat adenomas in HNPCC patients.

Treatment and follow-up strategies in hereditary nonpolyposis colorectal carcinoma.

The treatment and follow-up strategies of patients with hereditary nonpolyposis colorectal carcinoma (HNPCC) were analyzed in 22 Finnish HNPCC families in systematic follow-up between 1983 and 1990. During the seven-year study period metachronous colorectal neoplasia was diagnosed in 41 percent (15/37) of the patients treated by segmental colonic resection and in 24 percent (4/17) of those treated by subtotal colectomy. Extracolonic carcinoma was diagnosed in 12 (30 percent) of the 40 patients during the long-term follow-up. The most common extracolonic malignancy was biliopancreatic carcinoma which accounted for all five cancer-related deaths in the whole series during the study period. It was concluded that subtotal colectomy is superior to hemicolectomy or segmental resection in HNPCC patients with colorectal carcinoma. A regular annual endoscopic follow-up of the residual rectum is still necessary, and surveillance for extracolonic cancers must be considered.