Centralized Registration,Prophylactic Examination,and Treatment Results in Improved Prognosis in Familial Adenomatous Polyposis: Results from the Danish Polyposis Register

Background: Over the last few decades numerous regional and national registers have been established all over the world with the aim of improving survival in familial adenomatous polyposis (FAP). The Danish Polyposis Register was founded in 1971 and coordinates the screening and subsequent prophylactic colectomy of FAP patients. Methods: The crude cumulative survival in 321 patients (205 probands and 116 call-up cases) with verified FAP was calculated in accordance with the life-table method. Results: At the time of diagnosis of FAP only 2 of 116 (2%) had colorectal cancer versus 142 of 205 probands (69%). The 10-year cumulative survival was 94% (95% confidence limits, 89-99) in call-up cases compared with only 41% (34-49) in probands (p < 0.00001), and survival improved significantly (p < 0.00001) after the establishment of the Danish Polyposis Register. Conclusion: The establishment of a centralized polyposis register has resulted in a substantial improvement of the prognosis in FAP.     

Impact of screening examinations on survival in familial adenomatous polyposis

BACKGROUND: Prophylactic family screening and surgery has improved the outcome of patients with familial adenomatous polyposis (FAP) largely preventing deaths due to colorectal cancer. The present study compared the mortality rates and causes of death of FAP patients diagnosed by symptoms (probands) or by family screening (call-up). METHODS: The study comprised all 236 FAP patients registered in the Finnish Polyposis Registry until the end of June 1998. There were 116 probands and 120 call-up patients with a median age of 36.8 and 22.8 at diagnosis and median follow-up times of 6.3 and 9.9 years, respectively. Cumulative crude and relative survival estimates were calculated for each group and the causes of death were determined. RESULTS: The life expectancy was significantly better in the call-up group than in the probands after colectomy (P < 0.001). The survival rates of the call-up group equaled those expected for a comparable group in the general population up to 18 years after colectomy. The main cause of death was colorectal cancer accounting for 54 out of 68 deaths: four in the call-up group (all rectal stump cancer) and 50 in probands. Upper GI-tract cancer caused four deaths (periampullary cancer two, stomach cancer two) and two deaths were due to postoperative pulmonary embolism. CONCLUSION: The survival of FAP patients is significantly improved by prophylactic screening and surgery. Further improvement may be possible by using restorative proctocolectomy instead of colectomy and ileorectal anastomosis and by regular upper GI-tract endoscopic surveillance.     

Impact of Screening Examinations on Survival in Familial Adenomatous Polyposis

Background: Prophylactic family screening and surgery has improved the outcome of patients with familial adenomatous polyposis (FAP) largely preventing deaths due to colorectal cancer. The present study compared the mortality rates and causes of death of FAP patients diagnosed by symptoms (probands) or by family screening (call-up). Methods: The study comprised all 236 FAP patients registered in the Finnish Polyposis Registry until the end of June 1998. There were 116 probands and 120 call-up patients with a median age of 36.8 and 22.8 at diagnosis and median follow-up times of 6.3 and 9.9 years, respectively. Cumulative crude and relative survival estimates were calculated for each group and the causes of death were determined. Results: The life expectancy was significantly better in the call-up group than in the probands after colectomy (P &lt; 0.001). The survival rates of the call-up group equaled those expected for a comparable group in the general population up to 18 years after colectomy. The main cause ofdeath was colorectal cancer accounting for 54 out of 68 deaths: four in the call-up group (all rectal stump cancer) and 50 in probands. Upper GI-tract cancer caused four deaths (periampullary cancer two, stomach cancer two) and two deaths were due to postoperative pulmonary embolism. Conclusion: The survival of FAP patients is significantly improved by prophylactic screening and surgery. Further improvement may be possible by using restorative proctocolectomy instead of colectomy and ileorectal anastomosis and by regular upper GI-tract endoscopic surveillance.     

Causes of death in familial adenomatous polyposis.

BACKGROUND: The prognosis in familial adenomatous polyposis (FAP) has improved over the past decades owing to a reduction in the prevalence of colorectal cancer, resulting from effective early screening. During the same period several polyposis registers have recorded an increasing number of deaths due to duodenal/periampullary cancer and desmoid tumours. The aim of this study was to examine the causes of death with special emphasis on duodenal/periampullary cancer. METHODS: The material consisted of 328 patients (144 females and 184 males) registered from I January 1943 to 31 December 1992 in the Danish Polyposis Register. The standard mortality rate (SMR) was calculated for known major causes of death, using the entire Danish population as background population. The attributable risk was also calculated for selected death causes. RESULTS: One hundred and thirty-three patients had died, SMR being 4.98 (95% confidence limits, 4.17-5.90). There were significantly lower SMRs in the call-up group than in the proband group. The late cohort (1943-1992) had lower SMRs than the early group (1889-1942). SMR was significantly increased for death due to colorectal cancer (145), duodenal cancer (214), and ovarian cancer (30). No deaths due to desmoids were observed in the examination period. The attributable risk for colorectal cancer was 29% and for duodenal cancer only 0.6%. CONCLUSION: Colorectal cancer is the most frequent cause of death in polyposis patients, followed by duodenal/periampullary cancer, but the latter is still a rare cause of death in FAP.     

Clinical features in familial polyposis coli

Three hundred nineteen affected members of 94 Danish families with familial polyposis coli had been registered in the Danish Polyposis Register by the end of 1982. Of the 247 histologically verified cases, 168 were propositi and 79 were call-up patients. The frequency of colorectal cancer at the time of diagnosis of polyposis was 69 percent in propositi vs. 3 percent in call-up patients. The cumulative survival rate after ten years was 97 percent in call-up patients, as compared to 42 percent in propositi. The prognosis of polyposis patients has improved significantly since the establishment of the Danish Polyposis Register in 1971. Supported by grants from the Danish Cancer Society (809/71 and 87/80), “Max og Anna Friedmanns Legat,” “Ferdinand og Ellen Hindsgauls Fond,” and “Arkitekt Holger Hjortenberg og hustru, Dagmar Hjortenbergs Fond.” This work has been carried out with statistical aid from the Danish Medical Research Council (5521363/84).     

Epidemiology of Familial Adenomatous Polyposis in Sweden: Changes over Time and Differences in Phenotype between Males and Females

Background: The Swedish Polyposis Registry was set up in Sweden in the late 1950s to promote screening of familial adenomatous polyposis (FAP). The aim of this study was to examine the epidemiology of FAP in Sweden, including the influence of screening on morbidity and mortality in colorectal cancer (CRC). Methods: Four hundred and thirty-one patients (213 males and 218 females) with FAP from 145 families recorded by the Swedish Polyposis Registry were investigated. The effect of screening on morbidity and mortality in CRC was evaluated by comparing the 216 probands with the 215 call-up patients. Three different periods were studied: the pre-screening period (1912-1956), the first screening period (1957-1976), and the second screening period (1977-1996). Results: The mean annual incidence rates during the three periods were 0.2, 1.38, and 0.86 per million, respectively. The birth frequency was calculated to be 1 in 18,000 between 1947 and 1966, and the prevalence was 32 per million at the end of 1996. The proportion of new mutants among the FAP patients born between 1927 and 1966 was estimated to be 11%. The median age at diagnosis of probands was 39 (range, 11-71) years and did not change over time, although an increase was seen in the subgroup with CRC at diagnosis (P = 0.02). In the call-up group the median age at diagnosis was 22 (range, 3-65) years. Sixty-seven per cent of the probands and 3.3% of the call-up patients had CRC at diagnosis, and the corresponding mortality figures were 44% and 1.9%. The risk among probands of having CRC at diagnosis decreased from 81% to 49% (P = 0.0006). Female probands were diagnosed with symptoms (P = 0.03) and CRC (P = 0.04) earlier than male probands. Conclusions: A nationwide screening program facilitates detection and early diagnosis of FAP. A decrease in CRC morbidity among probands contributed to the improved prognosis. An earlier onset of symptoms and CRC in females indicate that the course of FAP is influenced by sex.     

Epidemiology of familial adenomatous polyposis in Sweden: changes over time and differences in phenotype between males and females

BACKGROUND: The Swedish Polyposis Registry was set up in Sweden in the late 1950s to promote screening of familial adenomatous polyposis (FAP). The aim of this study was to examine the epidemiology of FAP in Sweden, including the influence of screening on morbidity and mortality in colorectal cancer (CRC). METHODS: Four hundred and thirty-one patients (213 males and 218 females) with FAP from 145 families recorded by the Swedish Polyposis Registry were investigated. The effect of screening on morbidity and mortality in CRC was evaluated by comparing the 216 probands with the 215 call-up patients. Three different periods were studied: the pre-screening period (1912-1956), the first screening period (1957-1976), and the second screening period (1977-1996). RESULTS: The mean annual incidence rates during the three periods were 0.2, 1.38, and 0.86 per million, respectively. The birth frequency was calculated to be 1 in 18,000 between 1947 and 1966, and the prevalence was 32 per million at the end of 1996. The proportion of new mutants among the FAP patients born between 1927 and 1966 was estimated to be 11%. The median age at diagnosis of probands was 39 (range, 11-71) years and did not change over time, although an increase was seen in the subgroup with CRC at diagnosis (P = 0.02). In the call-up group the median age at diagnosis was 22 (range, 3-65) years. Sixty-seven per cent of the probands and 3.3% of the call-up patients had CRC at diagnosis, and the corresponding mortality figures were 44% and 1.9%. The risk among probands of having CRC at diagnosis decreased from 81% to 49% (P = 0.0006). Female probands were diagnosed with symptoms (P = 0.03) and CRC (P = 0.04) earlier than male probands. CONCLUSIONS: A nationwide screening program facilitates detection and early diagnosis of FAP. A decrease in CRC morbidity among probands contributed to the improved prognosis. An earlier onset of symptoms and CRC in females indicate that the course of FAP is influenced by sex.     

Clinical analysis of eight kindreds of familial adenomatous polyposis

AIM: To study the early diagnosis and management of familial adenomatous polyposis (FAP). METHODS: Eight pedigrees of FAP were collected and their pedigree trees were protracted. Clinical characteristics and treatment outcomes of FAP patients in these kindreds were analysed. RESULTS: A total of 157 members were investigated in eight kindreds and 25 patients with FAP were diagnosed. The ratio of male patients and female patients was 16:9 and the average age at onset was 38 years. Among them, six patients died of cancer with a mortality rate of 28%, and 36% (9/25) FAP patients were diagnosed as synchronous colorectal cancer on the basis of FAP. A proband was diagnosed as synchronous colorectal cancer with liver metastasis and died 11 mo later after partial colectomy and hepatic metastatic lesion biopsy. The other seven probands received total abdominal colectomy and rectal mucosectomy with ileal pouch-anal anastomosis (IPAA), and one of them was diagnosed as synchronous colon cancer on the basis of FAP and was still alive after 7.5 years follow-up. Among the other seven patients with synchronous colorectal cancer on the basis of FAP underwent total abdominal colectomy with ileorectal anastomosis (IRA), one underwent total remnant rectum resection and ileostomy for recurrent carcinoma in the retained rectum 2.5 years later after the IRA and was still alive, while the others all died of recurrence with a median survival time of 4.6 years. Through close follow-up and termly endoscopic surveillance, three FAP patients were detected before presenting symptoms at the age of 18, 20 and 23 years, respectively. Prophylactic IPAA was performed and results were satisfactory after the patients were followed-up for 6, 1, and 8 years, respectively. CONCLUSION: Pedigree investigation, close follow-up and termly endoscopic surveillance are very important for early detection of FAP. Prophylactic IPAA can give satisfactory results to FAP patients.     

Duodenal adenomatosis in familial adenomatous polyposis coli

Familial adenomatous polyposis coli (FAP) is an autosomal dominant genetic disorder caused by mutations of the APC gene on the long arm of chromosome 5. While multiple colorectal adenomas usually developing in early adolescence represent the most conspicuous phenotypic feature, the disease represents a generalized hyperproliferative disorder with various extracolonic manifestations. Duodenal cancer and desmoids are the leading causes of death in FAP patients after prophylactic colectomy. The prevalence of duodenal adenomatosis among FAP patients varies from 50% to greater than 90%, while only few patients (3-5%) develop duodenal cancer. Periampullary adenomas seem to carry a high risk of malignant transformation. The sensitivity of endoscopic procedures for early detection of severely dysplastic or malignant duodenal lesions is low, and the prognosis of duodenal cancer is poor. Thus the question arises whether it is possible to define a subgroup of high-risk patients for duodenal malignancy, and whether severe duodenal adenomatosis should lead to an aggressive prophylactic surgical approach. This contribution discusses the current literature and presents the experience of the Heidelberg Polyposis Register based on gastroduodenoscopy findings in 231 FAP patients. In 135 cases (58.4%) macroscopic duodenal adenomas were observed. The majority of patients displayed numerous lesions throughout the duodenum, while adenomas were restricted to the periampullary region in ten. Four patients suffered from duodenal cancer. Twenty-two required an endoscopic or operative intervention. Five were treated by laparotomy and duodenotomy, while ampullary excision was indicated in six cases. Eight patients underwent partial pancreaticoduodenectomy for severe duodenal adenomatosis.     

The incidence rate of familial adenomatous polyposis

Based on the Danish Polyposis Register epidemiological calculations on familial adenomatous polyposis (FAP) were carried out. The mean annual incidence was 1.85x10^-6 during the years 1971–1992, and the prevalence increasing to about 32x10^-6 at the end of 1992. FAP patients constituted a decreased percentage of all Danish patients with colorectal cancer (0.07% in 1980–1992). The completeness of registration was 97% in 1983–1992. The results are similar to Finnish estimates based on the same direct method of calculation, and as both series are based on almost complete national polyposis registration in well-registered populations we regard our results to be close to the true incidence rate.

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Résumé En se basant sur le registre danois des polyposes, des calculs épidémiologiques ont été réalisés sur la polypose familiale multiple. L'incidence annuelle moyenne est de 1.85x10^-6 au cours des années 1971 à 1992 et la prévalence augmente à environ 32x10^-6 à la fin de 1992. Les patients porterus d'une polypose familiale constituent un pourcentage en diminution de tous les patients porteurs d'un cancer colo-rectal (0.07% entre 1980 et 1992). L'exactitude du registre était de 97% entre 1983 et 1992. Les résultats sont similaries aux estimations finlandaises basées sur une même méthode de calcul; et étant donné que les deux séries témoignent d'un enregistrement pratiquement complet des polyposes à l'échelon national dans une population correctement enregistrée, nos résultats semblent refléter l'incidence réelle de l'affection. and increasing bias due to the significant improval of the prognosis of familial adenomatous polyposis during the last decades. Moreover, most studies are not based on epidemiologically valid patient series without selection bias. Recent calculations of the incidence rate with a direct method have been published on the basis of the national Danish and Finnish polyposis series, showing an annual incidence rate of 1.3–1.6x10^-6 in the early 1980's [5, 6].The aim of the present study was to reevaluate the occurrence of the disease about 25 years after the establishment of the Danish Polyposis Register by presenting estimates on the incidence rate, the point prevalence rate, and the completeness of registration.

     

Colorectal cancer in familial adenomatous polyposis

PURPOSE: This study was performed to determine the relationship among surgical treatment, colorectal cancer, and outcome in patients with familial adenomatous polyposis (FAP). METHODS: Records of 115 patients with FAP who underwent surgery at The Mount Sinai Medical Center between 1947 and 1994 were retrospectively reviewed. Patients without cancer were compared with those with colorectal cancer at initial surgery and with patients who developed rectal cancer following colectomy. RESULTS: Thirty-one patients (27 percent) had colorectal cancer at the time of initial surgery (colon=24; rectal=7). Another 11 patients (26 percent) developed rectal cancer after colectomy with ileorectal anastomosis (IRA). Mean age of patients with colorectal cancer at initial surgery was significantly higher than those without cancer (P <0.01). Patients who developed rectal cancer after IRA were significantly older than patients with colorectal cancer at initial surgery (P <0.01). All patients with rectal cancer after IRA had advanced disease with either nodal or distant metastases at the time of diagnosis. CONCLUSIONS: Colorectal cancer remains a major problem in the treatment of patients with FAP. Nearly one-fourth of these patients have colorectal cancer at initial operation, and one-fourth of patients with IRA develop rectal cancer after a mean follow-up of 13 years. Patients with rectal cancer following IRA are more likely to have advanced tumors than patients with colorectal cancer at initial operation. The high incidence and late stage of rectal cancer detected while under surveillance after IRA supports excision of the entire colorectal mucosa as the treatment of choice for most patients with FAP.     

Epidemiology of familial adenomatous polyposis in Finland: impact of family screening on the colorectal cancer rate and survival.

The incidence and prevalence rates of familial adenomatous polyposis (FAP) in Finland between 1961 and 1990 were estimated from Finnish polyposis registry data comprising 81 FAP families, including 251 affected patients. In addition, the effect of family screening on the occurrence of colorectal carcinoma was evaluated by comparing the call up and proband groups and calculating the proportion of FAP among all patients with colorectal carcinoma. The incidence of FAP was 0.62 to 2.38 per million and the prevalence increased steadily from 0.88 to 26.3 million during the study period suggesting improving prognosis. Altogether 76 of 116 probands (65.5%) had colorectal carcinoma compared with only five of 76 call up patients (6.6%). Consequently, the life expectancy of the call up patients was significantly better than that of the probands from the age of 31 years and above. However, at most, 0.53% of all colorectal carcinomas were associated with FAP in 1966-70, and the diminishing frequency of this proportion was more a result of an increase in sporadic colorectal carcinomas in Finland than of family screening for FAP. Family screening is very effective in FAP and must always be undertaken when a new proband is diagnosed.     

Familial adenomatous polyposis patients without an identified APC germline mutation have a severe phenotype

BACKGROUND: Development of more than 100 colorectal adenomas is diagnostic of the dominantly inherited autosomal disease familial adenomatous polyposis (FAP). Germline mutations can be identified in the adenomatous polyposis coli (APC) gene in approximately 80% of patients. The APC protein comprises several regions and domains for interaction with other proteins, and specific clinical manifestations are associated with the mutation assignment to one of these regions or domains. AIMS: The phenotype in patients without an identified causative APC mutation was compared with the phenotype in patients with a known APC mutation and with the phenotypes characteristic of patients with mutations in specific APC regions and domains. PATIENTS: Data on 121 FAP probands and 149 call up patients from 70 different families were extracted from the Danish Polyposis register. METHODS: Differences in 16 clinical manifestations were analysed according to the patient's mutational status. Two sided independent t sample test, two sided chi(2) test, and odds ratios were calculated. RESULTS: Patients without identified APC mutations had a unique and severe phenotype, which was roughly described as: young age at diagnosis and subsequent death in spite of development of few colorectal adenomas; low risk of involvement of the upper gastrointestinal tract, as reflected by a low mean Spigelman stage, and a low risk of fundic gland polyposis. Finally, they had significantly fewer affected family members, although they do not themselves more often represent an isolated case. CONCLUSIONS: The severe phenotype should be considered when counselling FAP families in which attenuated FAP is excluded and in which a causative APC mutation has not been identified.     

Changing causes of mortality in patients with familial adenomatous polyposis

Widespread use of prophylactic colectomy has resulted in a reduction in the incidence of colorectal cancer in familial adenomatous polyposis (FAP) patients. A retrospective chart review of families registered at the Steve Atanas Stavro Familial Gastrointestinal Cancer Registry in Toronto was performed to determine whether the decrease in the number of patients developing colorectal cancer implies that causes of mortality in FAP patients are shifting to that of extracolonic manifestations of FAP. Information was available on 140 deaths within 158 families and among 461 individuals with FAP. When stratified by decade, from the 1930s to the 1990s, the ratio of deaths caused by extracolonic manifestations of FAP compared with deaths caused by colorectal cancer was noted to have risen. Even though most deaths in FAP patients are still from colorectal cancer, it appears that screening policies and prophylactic colectomy have resulted in a reduction in the number of FAP patients who develop colorectal cancer. Thus, in recent decades, a greater percentage of deaths in FAP patients appears to be attributable to extracolonic manifestations of the disease.     

符合Amsterdam标准的结肠肿瘤患者异时结直肠肿瘤发病风险研究

目的探讨符合Amsterdam标准的结肠肿瘤患者术后异时结直肠癌及高危腺瘤的发病风险及对生存的影响。 方法回顾分析南京医科大学附属江苏省肿瘤医院收治的34例符合Amsterdam标准的结肠肿瘤患者术后生存与异时结直肠肿瘤发病的随访资料。 结果6例患者接受了结肠全切除治疗,中位随访122个月,无异时结直肠肿瘤发生。28例患者接受了结肠部分切除治疗,中位随访82个月,10例发生了异时结直肠癌,1例发生了需要手术切除的异时结肠腺瘤。结肠部分切除组5年和10年累计异时结直肠肿瘤发病风险分别为24.1%和48.2%,与结肠全切除组相比差异具有统计学意义（P=0.047）。全组总体5年和10年生存率分别为100%和85.6%。结肠部分切除组与结肠全切除组总体生存率差异无统计学意义（P=0.306）。发生异时结直肠肿瘤的患者与没有发生异时结直肠肿瘤的患者相比,总体生存率差异无统计学意义（P=0.901）。结肠部分切除后患者性别、年龄、既往结直肠癌手术史、肿瘤部位、分化程度和分期与异时结直肠肿瘤的发病风险均无显著相关关系。 结论符合Amsterdam标准的结肠肿瘤患者术后发生异时结直肠肿瘤的风险相当高,与结肠部分切除相比,结肠全切除治疗有助于预防异时结直肠肿瘤,但不能显著改善总体生存率。     

Age and Colorectal Cancer With Focus on the Elderly: Trends in Relative Survival and Initial Treatment From a Danish Population-Based Study

PURPOSE Elderly patients with colorectal cancer undergo surgery with curative intent less frequently than younger patients, and survival declines with increasing age. We compared relative survival of colorectal cancer among patients older than 75 years with that of younger patients in Denmark during the period 1977 to 1999. We also examined trends in choice of initial treatment.METHODS From the files of the nationwide population-based Danish Cancer Registry, we identified all cases of colorectal cancer diagnosed between 1977 and 1999. We then linked this data to information on survival obtained from the Danish Register of Causes of Death and from the Central Population Register.RESULTS During the entire study period, short-term and long-term relative survival improved for patients of all ages, but the improvement was more pronounced among elderly patients (>75 years). Radical resection was increasingly chosen as the initial treatment for elderly patients; during the 1995 to 1999 period it was performed on approximately 50 percent of such patients, almost as frequently as among younger patients.CONCLUSIONS Relative survival of elderly colorectal cancer patients (>75 years) improved in Denmark between 1977 and 1999. In the most recent period studied, 1995 to 1997, only minor differences in five-year relative survival were observed among younger, middle-aged, and elderly patients. A simultaneous increase in the rate of radical resection among elderly patients, reflecting more effective treatment, may underlie this finding.Supported by the Western Danish Research Forum for Health Sciences and the Leo and Ingeborg Dannin Foundation for Scientific Research.Presented at the spring meeting of the Danish Society of Surgery, Copenhagen, Denmark, April 7 to 8, 2005.Reprints are not available.     

Hereditary colorectal cancer: keeping it in the family--the bowel cancer story

Up to 20% of colorectal cancers are thought to have a genetic component. Several familial syndromes are known to confer an increased risk for colorectal cancer. Advances in our understanding of these syndromes has improved the care delivered to, and the overall survival of, these patients. Genetic testing has great potential to further improve detection and direct subsequent preventative measures. The diagnosis, management and surveillance issues relating to some of the more commonly encountered syndromes - in particular Familial Adenomatous Polyposis and Hereditary Non-Polyposis Colorectal Cancer - are reviewed.     

Novel findings in Swedish patients with MYH-associated polyposis: mutation detection and clinical characterization.

BACKGROUND & AIMS: Biallelic mutations in the base-excision repair gene MYH have recently been associated with recessive inheritance of multiple colorectal adenomas. An investigation and characterization of MYH mutations in Swedish patients were therefore carried out. METHODS: A set of 15 unrelated adenomatous polyposis coli (APC)-mutation negative patients from the Swedish Polyposis Registry was screened for germline mutations in the MYH gene. The patients were clinically characterized and compared with 43 APC-mutation positive probands diagnosed during the same period. RESULTS: Disease-causing biallelic MYH mutations were identified in 6 patients (40%). The mean age at diagnosis was 47.8 years versus 34.1 years in APC-mutation positive patients (P = .015). Colorectal cancer at diagnosis of polyposis was present in 67% (4/6) of the patients, and all were right-sided, compared with only 19% versus 12.5% right-sided cancer in APC-mutation positive patients. Upper gastrointestinal manifestations were diagnosed in 1 of 5 compared with 23 of 27 in APC-mutation positive patients (odds ratio, 23; 95% confidence interval, 2-263; P = .0086). One family exhibited apparent dominant inheritance of colorectal adenomatous polyposis. Two new pathogenic mutations, MYH p.G175E and p.P391L, were identified. The mutations are argued to introduce profound changes in substrate-recognizing domains of the protein. CONCLUSIONS: Biallelic MYH mutations, including 2 novel mutations, were found in a substantial number of the patients with multiple colorectal adenomas who were negative for APC-mutation. The examined MYH-mutation positive patients were found to have higher risks of colorectal cancer at diagnosis, right-sided location of cancers, and a significantly lower incidence of upper gastrointestinal manifestations, compared with APC-mutation positive patients.     

Education and management of patients with familial adenomatous polyposis. Are we making progress? A case report

A 25-year-old male patient was admitted to our clinic for abdominal pain, diarrhea, intermittent rectal bleeding and weight loss. The family history revealed two deaths due to colorectal cancer (maternal grandmother and patient's mother). The colonoscopy showed hundreds of polyps throughout the colon, and an ulcerative rectosigmoidian tumor. The diagnosis was Familial Adenomatous Polyposis (FAP). Colectomy with ileorectal anastomosis was performed. Histopathological diagnosis revealed moderately differentiated adenocarcinoma. Adjuvant chemotherapy was carried out. The patient had three brothers, without clinical symptoms. They had a colonoscopic examination for screening. Two of them were diagnosed with adenomatous polyposis - the first with classic FAP and the other one with the attenuated type (AFAP). The diagnosis of FAP can be made on the basis of either clinical or genetic criteria. When the family history, clinical features, and pathological findings are classic, the diagnosis is straightforward. Screening and prophylactic surgery are effective to prevent colorectal cancer in patients with FAP. Lifelong regular surveillance is necessary to detect and manage extracolonic lesions.     

Rectal epithelial apoptosis in familial adenomatous polyposis patients treated with sulindac

BACKGROUND: Sulindac regresses colorectal adenomas in patients with familial adenomatous polyposis (FAP), although the mechanism of polyp regression is unclear. AIMS: To determine whether differences occur in alteration of rectal epithelial apoptotic index and expression of apoptosis related proteins in FAP patients treated with sulindac compared with placebo. PATIENTS: Twenty one FAP patients; 12 had not undergone colectomy. METHODS: Patients with FAP were treated with sulindac 150 mg orally twice a day for three months (n=10) or placebo (n=11). Colorectal polyp number was determined and biopsies of the normal rectal mucosa were performed before and after three months of treatment. Response to treatment and alteration of the apoptotic ratio (index in base of crypt divided by index in surface epithelium) were evaluated. Bcl-2, bax, p21/WAF-1, and p53 proteins were assessed semiquantitatively by immunohistochemistry. RESULTS: Significant decreases in polyp number and in the apoptotic ratio were seen in patients treated with sulindac compared with controls. The mean percentage change in polyp number from baseline was -46% in the sulindac group and +13% in the placebo group (p=0.005). Mean percentage change in the apoptotic ratio was -8% and +25% in the sulindac and placebo treated patients, respectively (p=0.004). No differences in expression or compartmentalisation of apoptosis related proteins were noted between treatment groups. CONCLUSIONS: Sulindac regression of colorectal adenomas is accompanied by alteration of the rectal epithelial apoptotic ratio with relative increase in apoptosis in surface cells compared with the deeper crypt. The utility of the apoptotic ratio as an intermediate biomarker for colorectal tumorigenesis deserves further study.