Comparison of proctocolectomy and ileal pouch-anal anastomosis to colectomy and ileorectal anastomosis in familial adenomatous polyposis.

Prophylactic surgical options for familial adenomatous polyposis (FAP) are either colectomy and ileorectal anastomosis (IRA) or proctocolectomy and ileal pouch-anal anastomosis (IPAA). The aim of this study was to analyse the short-term and long-term outcomes of these two operative techniques. All patients with FAP in Finland have been prospectively recorded in a database since 1963 were retrospectively reviewed in this analysis. Altogether 140 (61%) colectomies with IRA and 88 (39%) proctocolectomies with IPAA have been performed. Complications occurred in 28 (21%) patients after IRA and in 26 (30%) patients after IPAA. There were 15 (11%) severe complications for IRA and 5 (6%) for IPAA. Twenty-one (15%) patients of the IRA group ended up in conventional ileostomy whereas 3 (3.4%) patients of the IPAA group had their ileal reservoir converted to an ileostomy (p = 0.01). Cumulative survival for IRA was lower than for the IPAA (p = 0.03), but if accounting only for operations made after the IPAA era had commenced, there was no significant difference. IPAA was associated with improved long-term survival without an increase in postoperative complications. The risk of death after colectomy and IRA seemed to be predominantly related to the remaining risk of rectal cancer. Therefore, we favour proctocolectomy with IPAA as the prophylactic surgical procedure for FAP with intermediate or severe polyposis.

Risk of cancer and secondary proctectomy after colectomy and ileorectal anastomosis in familial adenomatous polyposis.

PURPOSE: The aim of our retrospective study was to review the outcome of patients undergoing colectomy with ileorectal anastomosis (IRA) due to familial adenomatous polyposis (FAP) in Finland during the last 50 years. METHODS: The cumulative risk of rectal cancer and the rate of anus preservation were analyzed. A total of 140 FAP patients with previous colectomy combined with ileorectal anastomosis were included. Kaplan-Meier analysis was performed to evaluate cumulative risks. RESULTS: Secondary proctectomy was performed for 39 (28 %) of 140 patients. The cumulative risk of secondary proctectomy was 53 % at 30 years after colectomy with IRA. A total of 17 (44 %) secondary proctectomies were performed due to cancer or suspicion of cancer, and another 17 (44 %) secondary proctectomies were performed due to uncontrollable rectal polyposis. During our study, the anus preservation rate in secondary proctectomies was 49 %. The cumulative risk of rectal cancer was 24 % at 30 years after colectomy with IRA. Therefore, the cumulative rectal cancer mortality 30 years after colectomy with IRA was 9 %. CONCLUSIONS: Proctocolectomy and ileal pouch-anal anastomosis (IPAA) should be favored as a primary operation for patients not having technical or medical contraindications for it because colectomy with IRA carried a rectal cancer risk of 13 % with a mortality of 7 % during our study, and because IPAA is likely to succeed better at earlier phase of the disease. Patients with attenuated FAP had no rectal cancer in our study, and they may form a group where IRA should still be the first choice as an exception.

Does preoperative radiotherapy with postoperative chemotherapy increase acute side-effects and postoperative complications of total mesorectal excision? Report of the randomized Finnish rectal cancer trial.

BACKGROUND AND AIMS: In a randomized trial the effect of short-term preoperative radiotherapy and postoperative chemotherapy was studied in patients undergoing total mesorectal excision (TME) for clinically resectable rectal cancer. The primary endpoint was overall survival. The secondary endpoints published herein were the incidence of postoperative complications and adverse events with perioperative adjuvant therapy. MATERIAL AND METHODS: In 1995-2002, 278 eligible patients with stage II and stage III rectal cancer were randomly assigned to TME alone (surgery group) or to preoperative 25 Gy radio-therapy in 5 fractions and postoperative 5-fluorouracil and leucovorin chemotherapy in addition (RT+CT group). RESULTS: Anastomotic leakage rate did not significantly differ between the surgery and the RT + CT group, 20.6% vs. 27.4%. Postoperative infections (15.5 vs. 26.2%, p = 0.037) and perineal wound dehiscence (15.9 vs. 38.5%, p = 0.045) were more common after radiotherapy. Grade 3-5 adverse events were uncommon with preoperative radiotherapy (one, 0.7% with reversible lumbar plexopathy) and postoperative chemotherapy (hematologic in 10.8%, with one septic death, and gastrointestinal in 4.8%). CONCLUSIONS: Perioperative adjuvant therapy was generally well tolerated and did not lead to an increase in serious surgical complications. Wound infections and perineal wound dehiscence were more common in irradiated patients.

Risk of cancer in patients with chronic pouchitis after restorative proctocolectomy for ulcerative colitis.

AIM: The aim of this study was to evaluate the consequences of chronic pouchitis after restorative proctocolectomy for ulcerative colitis. METHOD: Forty-two patients with chronic pouchitis underwent pouch endoscopy with biopsies after a median of 8.3 years of postoperative follow up. The pouchitis disease activity index (PDAI) was calculated. Morphological changes were recorded. Immunohistochemical analyses for cyclooxygenase 2 (COX-2), Ki-67 and p53 were performed, as was DNA flow cytometry. Endoscopy was also carried out in 10 patients without pouchitis and in nine healthy subjects. RESULTS: In patients with chronic pouchitis, the PDAI was 6 (standard error of the mean ± 4). Eighteen (43%) patients used continuous medication. The PDAI correlated positively with villous atrophy (P < 0.05). None of the pouch biopsies showed dysplasia. COX-2 immunostaining was detected in 35 (83.3%) patients with chronic pouchitis, in five (50%) without pouchitis, but in none of the normal controls. COX-2 expression correlated with mucosal atrophy (P < 0.01). In 15 (35.7%) of 42 patients with chronic pouchitis, Ki-67 immunostaining was increased, but no increase was observed in either control group (P < 0.002). No p53 immunopositivity was found, and DNA flow cytometry was normal in all pouches. One of the patients developed adenocarcinoma at the anal anastomosis. CONCLUSION: No dysplastic changes were detected during the first decade after surgery. Routine follow up of patients with chronic pouchitis with a hand-sewn anastomosis may not be necessary, although a small risk of cancer seems to remain at the anal anastomosis. The follow up should be focused on at-risk groups.

Survival of patients with pseudomyxoma peritonei treated by serial debulking.

AIM: We evaluated the outcome of patients with pseudomyxoma peritonei (PMP) after traditional debulking. PMP is a clinical condition characterized by disseminated intraperitoneal mucinous tumours often accompanied by mucinous ascites derived usually from an appendiceal neoplasm. Patients with PMP have traditionally been treated by serial debulking, but aggressive cytoreduction followed by hyperthermic intraperitoneal chemotherapy is now advocated as standard treatment in PMP. METHOD: The analysis included 33 consecutive patients with PMP who underwent traditional debulking surgery between June 1984 and August 2008. The patient characteristics and details of the treatment were analysed retrospectively. The primary end-point was survival. RESULTS: The overall 5- and 10-year survival rates were 67% and 31% respectively. The patients underwent an average of 3.2 +/- 0.4 operations (range 1-10). Of 33 patients, 23 (70%) underwent only 1-3 operations. The 30-day operative mortality rate was 2.7%. However, four patients (12%) seemed to have achieved long-term disease-free survival of more than 5 years. CONCLUSIONS: The 5-year survival is comparable with results achieved in patients receiving a combination of cytoreductive surgery and intraperitoneal chemotherapy, but in the long term, the latter seems superior.

Surveillance and treatment of duodenal adenomatosis in familial adenomatous polyposis.

BACKGROUND AND STUDY AIMS: Patients with familial adenomatous polyposis (FAP) are at increased risk for duodenal cancer whereas colorectal cancer is largely prevented by prophylactic colectomy. We analyzed the results of endoscopic surveillance and different treatment modalities of duodenal adenomatosis in patients with FAP. PATIENTS AND METHODS: Data on endoscopies, histopathological examinations, and surgical therapies were collected from the medical histories of 129 patients with FAP. The cumulative incidences of duodenal adenomatosis and severe dysplasia and cancer were calculated using Kaplan-Meier analysis. RESULTS: By the age of 60 years, the cumulative incidence was 80% for any adenomatosis and 23% for severe dysplasia or cancer. Duodenal cancer was observed in six patients (4.7%). Fifteen endoscopic excisions in 14 patients, and 19 open duodenotomies in 17 patients were carried out. Later, pancreaticoduodenectomy was undertaken in six (35.3%) of these 17 patients. Altogether, 12 patients (9.3%) underwent pancreaticoduodenectomy. Except for one patient, the indication for surgery was based on follow-up endoscopies, and none of these patients died of duodenal cancer. No postoperative deaths occurred. Seven patients (58.3%) had major complications, four (33.3%) of which were surgical. CONCLUSIONS: The high incidence of severe dysplasia and cancer in duodenal polyps suggests that endoscopic surveillance is essential. Endoscopic polypectomies under sedation anesthesia have partly replaced open duodenotomies. High-risk patients with Spigelman IV adenomatosis or adenomas with persisting severe dysplasia should undergo surgery with pylorus-preserving pancreaticoduodenectomy before invasive cancer develops.

Differential cancer predisposition in Lynch syndrome: insights from molecular analysis of brain and urinary tract tumors.

Hereditary non-polyposis colorectal carcinoma (Lynch syndrome) is among the most common hereditary cancers in man and a model of cancers arising through deficient DNA mismatch repair (MMR). Lynch syndrome patients are predisposed to different cancers in a non-random fashion, the basis of which is poorly understood. We addressed this issue by determining the molecular profiles for different tumors from a nationwide cohort of Lynch syndrome families (approximately 150 tumors in total). We focused on some less prevalent cancers, affecting the brain (n = 7) and urinary tract (five bladder and five ureter uroepithelial cancers and four kidney adenocarcinomas), and compared their molecular characteristics to those of the most common cancers, colorectal, gastric and endometrial adenocarcinomas, from the same families. Despite origin from verified MMR gene mutation carriers, the frequency of high-level microsatellite instability in tumors varied between high (100-96% for ureter, stomach and colon), intermediate (63-60% for endometrium and bladder) and low (25-0% for kidney and brain). In contrast to gastrointestinal and endometrial carcinomas, active (nuclear) beta-catenin was rare and KRAS mutations were absent in brain and urological tumors. Compared with other tumors, frequent stabilization of p53 protein characterized urinary tract cancers. Promoter methylation of tumor suppressor genes discriminated the tumors in an organ-specific manner. Our findings suggest that different Lynch syndrome tumors develop along different routes. Uroepithelial cancers of the ureter (and bladder to lesser extent) share many characteristics of MMR deficiency-driven tumorigenesis, whereas brain tumors and kidney adenocarcinomas follow separate pathways.

Direct contact in inviting high-risk members of hereditary colon cancer families to genetic counselling and DNA testing.

BACKGROUND: Identification of hereditary predisposition to cancer has limited significance if not followed by efficient cancer prevention in the family. Probands are traditionally left to inform their relatives about the increased risk, but distant relatives may remain uninformed. An approach to contacting directly at-risk persons assumed to be unaware of their increased cancer risk was taken. With cancer prevention as the ultimate goal, the study was aimed at investigating attitudes towards and psychosocial consequences of this novel strategy. METHODS: In families with hereditary non-polyposis colorectal cancer (Lynch syndrome), 286 healthy adult relatives with a 50% risk of a predisposing mutation were contacted by letter. Of these, 112 participated in counselling and predictive testing. Baseline information and information obtained 1 month after the test for 73 respondents were compared with 299 corresponding subjects, approached via the proband (family-mediated approach in our previous study) in these families. RESULTS: After the contact letter, 51% consented to the study. Of these, 92% approved of the direct contact and 33% had tried to seek information. In 34% of the mutation carriers, neoplasia was identified in the first post-test colonoscopy. Although post-test fear of cancer increased among the mutation carriers and decreased among noncarriers, almost all participants were satisfied with their decision to participate, independently of their test results, parallel to the family-mediated approach. CONCLUSION: In this large-scale study, relatives in cancer families were actively contacted to inform them of the condition and genetic counselling. Their attitudes were encouraging, and the psychosocial consequences were similar to the family-mediated approach. Our results suggest the appropriateness of direct contact as an alternative method of contact in cases of life-threatening treatable disease.

Female fertility and childbirth after ileal pouch-anal anastomosis for ulcerative colitis.

BACKGROUND: The aim of this study was to calculate the probability of becoming pregnant after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis, and to evaluate complications during pregnancy and childbirth. METHODS: A questionnaire was posted to 160 women with an IPAA and to 160 controls. The probability of becoming pregnant after IPAA was calculated by the Kaplan-Meier method. RESULTS: Of 54 women who had undergone IPAA surgery, 36 (67 per cent) succeeded in becoming pregnant naturally, compared with 49 (82 per cent) of 60 controls. The probability of pregnancy after 2 years of trying was 56 per cent in the IPAA group and 91 per cent in the control group (P < 0.001). Women in the IPAA group needed infertility investigations more often (24 versus 10 per cent; P = 0.044). In all, 39 (72 per cent) women in the IPAA group and 53 (88 per cent) in the control group bore a child. Twenty-one of 39 women in the IPAA group and 13 of 53 in the control group had a caesarean section (P = 0.005). Anal incontinence after delivery occurred more often in the control group. CONCLUSION: Women with an IPAA mostly suffer a reduction in the probability of conception rather than complete infertility. Because complications during pregnancy and delivery were rare, caesarean section should be based mainly on obstetric indications.

Is gastric cancer part of the tumour spectrum of hereditary non-polyposis colorectal cancer? A molecular genetic study.

BACKGROUND: Gastric cancer is the second most common extracolonic malignancy in individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome. As gastric cancer is relatively common in the general population as well, it is not clear whether or not gastric cancer is a true HNPCC spectrum malignancy. AIM: To determine whether or not gastric cancer is a true HNPCC spectrum malignancy. SUBJECTS AND METHODS: The molecular and clinicopathological profiles of gastric cancers (n = 13) from HNPCC mutation carriers were evaluated and compared with the profiles of sporadic gastric cancers (n = 46) stratified by histology and microsatellite instability (MSI) status. RESULTS: This study on sporadic and HNPCC gastric cancers revealed several important universal associations. Loss of heterozygosity in the adenomatous polyposis coli (APC) region was associated with intestinal histology regardless of the MSI (p = 0.007). KRAS-mutations (p = 0.019) and frameshift mutations in repeat tracts of growth-regulatory genes (p<0.001) were associated with MSI tumours being absent in microsatellite stable (MSS) tumours. The average number of methylated tumour suppressor gene loci among the 24 genes studied (methylation index) was higher in MSI than in MSS tumours regardless of histology (p<0.001). Gastric cancers from HNPCC mutation carriers resembled sporadic intestinal MSI gastric cancers, except that MLH1 promoter methylation was absent (p<0.001) and the general methylation index was lower (p = 0.038), suggesting similar, but not identical, developmental pathways. All these lacked the mismatch repair protein corresponding to the germline mutation and displayed high MSI. CONCLUSION: The present molecular evidence, combined with the previous demonstration of an increased incidence relative to the general population, justify considering gastric cancers as true HNPCC spectrum malignancies.

The MDM2 promoter polymorphism SNP309T-->G and the risk of uterine leiomyosarcoma, colorectal cancer, and squamous cell carcinoma of the head and neck.

BACKGROUND: MDM2 acts as a principal regulator of the tumour suppressor p53 by targeting its destruction through the ubiquitin pathway. A polymorphism in the MDM2 promoter (SNP309) was recently identified. SNP309 was shown to result, via Sp1, in higher levels of MDM2 RNA and protein, and subsequent attenuation of the p53 pathway. Furthermore, SNP309 was proposed to be associated with accelerated soft tissue sarcoma formation in both hereditary (Li-Fraumeni) and sporadic cases in humans. METHODS: We evaluated the possible contribution of SNP309 to three tumour types known to be linked with the MDM2/p53 pathway, using genomic sequencing or restriction fragment length polymorphism as screening methods. Three separate Finnish tumour materials (population based sets of 68 patients with early onset uterine leiomyosarcomas and 1042 patients with colorectal cancer, and a series of 162 patients with squamous cell carcinoma of the head and neck) and a set of 185 healthy Finnish controls were analysed for SNP309. RESULTS: Frequencies of SNP309 were similar in all four cohorts. In the colorectal cancer series, SNP309 was somewhat more frequent in women and in patients with microsatellite stable tumours. Female SNP309 carriers were diagnosed with colorectal cancer approximately 2.7 years earlier than those carrying the wild type gene. However, no statistically significant association of SNP309 with patients' age at disease onset or to any other clinicopathological parameter was found in these three tumour materials. CONCLUSION: SNP309 had no significant contribution to tumour formation in our materials. Possible associations of SNP309 with microsatellite stable colorectal cancer and with earlier disease onset in female carriers need to be examined in subsequent studies.

Fate of the rectum after colectomy with ileorectal anastomosis in ulcerative colitis.

OBJECTIVE: Aim of the study was to evaluate the cumulative success of colectomy and ileorectal anastomosis in 20 patients with ulcerative colitis. PATIENTS AND METHODS: Data were collected from patient histories and cumulative success was calculated by the Kaplan-Meier method. RESULTS: Seven of 20 (35%) ileorectal anastomoses were lost. Cumulative success rate was 84% at 5 years, 69% at 10 years and 56% at 20 years. Most common indication for proctectomy was disabling proctitis. Other reasons for failure were postoperative ileal necrosis and persisting presacral infection. Patients with advanced colonic cancer managed relatively well with ileorectal anastomosis until death. No cases of rectal cancer were detected during postoperative follow-up but one moderate dysplasia was treated locally. CONCLUSION: Ileorectal anastomosis can be chosen for patients who are not suitable for ileoanal operation. Rectal endoscopies are mandatory postoperatively.

Delayed sphincter repair for obstetric ruptures: analysis of failure.

OBJECTIVE: The aim of this study was to examine the clinical results after anterior anal sphincter repair in patients with obstetric trauma and to evaluate possible risk factors for poor outcome. PATIENTS AND METHODS: In years 1990-99 anterior anal sphincter repair for anal incontinence due to obstetric trauma was performed in 39 patients at Helsinki University Central Hospital. Clinical examination with Parks' classification and patients' questionnaire with endoanal ultrasound (EAUS) were done before and after surgery. Pudendal nerve terminal motor latency (PNTML) was measured postoperatively. The median follow-up time after the operation was 22 months (range 2-99). RESULTS: The follow-up results of the patients' questionnaire for 12 patients (31%) were good, for 15 patients (38%) acceptable and for 12 patients (31%) poor. Postoperative EAUS showed sphincter overlap in 28 (72%) patients but a defect was still found in 11 (28%) patients. A defect found on postoperative EAUS correlated with poor clinical result according to Parks' (R = 0.8, P < 0.01) and patients' questionnaire results (R = 0.7, P < 0.01). Patients with poor clinical results (Parks III/IV) were statistically significantly older (median 63 years, range 26-73) than those with favourable results (Parks I/II) (median 45 years, range 27-79) (P < 0.05). Further, the duration of incontinence symptoms correlated with poor functional results (R=0.4, P < 0.05). CONCLUSION: After obstetric trauma anterior anal repair gives acceptable short-term clinical results. EAUS investigation is easy and harmless to perform and should be used pre- and post-operatively. Advanced age, pre-operative signs of perineal descent, long-lasting severe incontinence symptoms and a persistent defect on postoperative EAUS seem to be related to poor clinical result.

Worldwide survey among polyposis registries of surgical management of severe duodenal adenomatosis in familial adenomatous polyposis.

BACKGROUND: The lifetime risk of developing duodenal cancer in familial adenomatous polyposis (FAP) is about 5 per cent. When and to what extent surgical intervention should be undertaken to prevent death from invasive carcinoma is controversial. The aim of this study was to determine the effectiveness of various surgical treatments for cancer and severe duodenal adenomatosis. METHODS: A questionnaire was mailed to the members of the Leeds Castle Polyposis Group to obtain data on patients with FAP, treated for duodenal cancer or severe duodenal adenomatosis after 1990. RESULTS: Sixty-nine patients were included. The indication for surgery was invasive cancer in 13 patients, of whom six died from metastatic disease. Fifty-six patients were initially treated for severe duodenal adenomatosis, five (9 per cent) of whom died from metastatic disease (P = 0.002). In surviving patients, adenomas recurred after ampullectomy (six of eight, at mean follow-up of 11 months), after duodenotomy with polypectomy (17 of 21, at mean 29 months) and after pancreatoduodenectomy (six of 25, at mean 47 months). None of six patients who underwent a pancreas-sparing duodenectomy had recurrence of adenoma (mean follow-up 11 months). CONCLUSION: Surgery for duodenal adenomatosis should take place before endoscopic biopsy reveals invasive cancer. Even after extensive surgical procedures, small bowel adenomas may occur, emphasizing the need for chemoprevention.

Genetic testing for polyposis: practical and ethical aspects.

The three autosomal dominant inherited polyposis syndromes, familial adenomatous polyposis, juvenile polyposis, and Peutz-Jeghers polyposis predispose to colorectal cancer as does hereditary non-polyposis colorectal cancer syndrome. Uncovering the genetic background of these four cancer traits provides the possibility for genetic testing of the family members of an affected patient. Before testing identification of the underlying family specific pathogenic mutation is mandatory. This is possible in about 60% to 95% of families. Endoscopic surveillance can be safely discontinued in mutation negative family members and surveillance or prophylactic surgery can be targeted to mutation positive members alone. Testing requires genetic counselling and written informed consent to prevent misunderstanding and to minimise untoward effects such as anxiety. Permanent surveillance and adequate prophylactic treatment for all mutation positive subjects and families is best ensured in national or regional polyposis registries with the capacity to take care of long term follow up from generation to generation.

Female fecundity before and after operation for familial adenomatous polyposis.

BACKGROUND: Knowledge about the fertility of women suffering from familial adenomatous polyposis (FAP) is scarce and inconclusive. The purpose of this study was to investigate the fecundity of women with FAP before and after operation, and to compare the findings with those of a general population database and women with ulcerative colitis. METHODS: A questionnaire concerning reproductive experiences and waiting times to pregnancy was sent to all 230 women on the polyposis registers in Denmark, Finland, Sweden and Norway in whom primary surgery had consisted of ileorectal anastomosis or ileal pouch-anal anastomosis. Data on the general population and women with ulcerative colitis came from an existing database. Cox regression and Kaplan-Meier plots were used for analysis. RESULTS: The fecundity of women with FAP before operation and after colectomy with ileorectal anastomosis was similar to that of the general population. However, fecundity dropped to 54 per cent (P = 0.015) following proctocolectomy with ileal pouch-anal anastomosis, although it was greater than the postoperative fecundity of women with ulcerative colitis. CONCLUSION: The significant reduction in female fecundity after ileal pouch-anal anastomosis should be communicated to young women with FAP before it is decided which surgical option to follow.

No support for endoscopic surveillance for gastric cancer in hereditary non-polyposis colorectal cancer.

BACKGROUND: The DNA mismatch repair gene mutations underlying hereditary non-polyposis colorectal cancer syndrome (HNPCC) also predispose, besides colorectal and endometrial cancer, to gastric cancer. usually of the intestinal type. The carcinogenetic pathway behind the elevated gastric cancer risk is largely unknown. METHODS: The aim of this study was to determine whether there are any premalignant lesions to search for in gastric surveillance in HNPCC by comparing gastric histopathology between mutation-positive and mutation-negative family members. We searched for differences in occurrence of Helicobacter pylori, inflammation, atrophy, intestinal metaplasia and dysplastic changes. Upper gastrointestinal endoscopy was performed for 73 mutation-positive and 32 mutation-negative family members. RESULTS: One case of duodenal cancer was detected in the mutation-positive group, but no gastric neoplastic lesions were seen in either group. There were no differences in the occurrence of polyps, H. pylori, inflammation, activity, atrophy nor intestinal metaplasia tested with binaric, logistic, regression analysis. CONCLUSIONS: We conclude that surveillance gastroscopy may not be beneficial in HNPCC, since neither cases of early cancer nor premalignant lesions could be detected in our series of 73 mutation-positive subjects.

The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer.

OBJECTIVE: Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary cancer susceptibility disorder associated with a very high risk for carcinoma of the colon and an elevated risk for certain extracolonic cancers including ovarian cancer. Our aim in this study was to describe the clinicopathologic features of ovarian cancer in HNPCC family members. METHODS: . Members of the International Collaborative Group on HNPCC collected retrospective data on 80 ovarian cancer patients who were members of HNPCC families, including 31 known mutation carriers, 35 presumptive carriers (by colorectal/endometrial cancer status), and 14 at-risk family members. RESULTS: Mean age at diagnosis of ovarian cancer was 42.7. Nonepithelial tumors made up only 6.4% of the cancers, and borderline tumors comprised just 4.1% of the epithelial cancers. Among frankly malignant epithelial cases, most cancers were well or moderately differentiated, and 85% were FIGO stage I or II at diagnosis. Synchronous endometrial cancer was reported in 21.5% of cases. CONCLUSIONS: Ovarian cancer in HNPCC differs from ovarian cancer in the general population in several clinically important respects. It occurs at a markedly earlier age. It is more likely to be epithelial. If it is a frankly invasive epithelial cancer, it is more likely to be well or moderately differentiated. HNPCC patients with ovarian cancer are more likely to have a synchronous endometrial cancer than other ovarian cancer patients and are more likely to be diagnosed at an early stage.