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BACKGROUND: Significant advances in the management of patients with lymphoid and myeloid malignancies entered clinical practice in the early 2000's. The EUROCARE-5 study database provides an opportunity to assess the impact of these changes at the population level by country in Europe. We provide survival estimates for clinically relevant haematological malignancies (HM), using the International Classification of Diseases for Oncology 3, by country, gender and age in Europe. METHODS: We estimated age-standardised relative survival using the complete cohort approach for 625, 000 adult patients diagnosed in 2000-2007 and followed up to 2008. Survival information was provided by 89 participating cancer registries from 29 European countries. Mean survival in Europe was calculated as the population weighted average of country-specific estimates. RESULTS: On average in Europe, 5-year relative survival was highest for Hodgkin lymphoma (81% ; 40, 625 cases), poorest for acute myeloid leukaemia (17% ; 57, 026 cases), and intermediate for non- Hodgkin lymphoma (59% ; 329, 204 cases), chronic myeloid leukaemia (53% ; 17, 713 cases) and plasma cell neoplasms (39% ; 94, 024 cases). Survival was generally lower in Eastern Europe and highest in Central and Northern Europe. Wider between country differences (>10%) were observed for malignancies that benefited from therapeutic advances, such as chronic myeloid leukaemia, chronic lymphocytic leukaemia, follicular lymphoma, diffuse large B-cell lymphoma and multiple myeloma. Lower differences (

Background Primary malignant brain tumours are rare but represent a serious health burden due to their poor survival. This manuscript describes the survival of malignant brain tumours in adults diagnosed 2000–2007 in Europe. Methods For this study we analysed patients archived in 86 European population-based cancer registries, followed up to 31st December 2008. Only primary malignant neuroepithelial brain tumours (with pathological confirmation) and primary malignant unspecified brain tumours without pathological confirmation were included. We estimated 1-year and 5-year relative survival (RS) weighted by age group and country. We also estimated country-specific and age-specific survival, together with survival differences between time periods (for 1999–2001, 2002–2004 and 2005–2007). Results Glioblastoma represents 49% of all brain tumours, followed by other/unspecified astrocytoma (18%), oligodendroglioma/oligoastrocytoma (9%), ependymoma (1.5%) and embryonal tumours (1%). Five-year RS was 20% for all tumours combined, but ranged from 58% for ependymoma to only 6% for glioblastoma and sharply decreased with increasing age. Differences between countries were relatively small, but generally RS in Ireland/United Kingdom (UK) and Eastern Europe was below the average. An increase in 1-year RS (up to 10–12%) was noted over time, being largest in Central and Northern Europe in patients between 45 and 74 years of age. Conclusions Despite an increase in 1-year RS in most European regions, the survival of primary malignant brain tumours is still poor. Disparities between countries were evident, being even larger at the end of the study period than at the beginning, suggesting differences in availability of the latest treatment modalities.

Background Previous population-based studies revealed major variation in survival for patients with colorectal cancer (CRC) in Europe by age and between different countries and regions, but also a sustained improvement in survival for patients with CRC in recent years. This EUROCARE-5 paper aims to update available knowledge from previous studies and to provide the latest survival estimates for CRC patients from Europe. Methods The study analysed data of patients diagnosed with CRC from population-based cancer registries diagnosed in 29 European countries. Estimates of 1-year and 5-year relative survival (RS) were derived for patients diagnosed in 2000–2007 by European region, country and age at diagnosis. Additionally to these cohort estimates, time trends in 5-year RS were obtained for the calendar periods 1999–2001 and 2005–2007, using the period analysis methodology. Results European average 5-year RS for patients diagnosed with colon and rectum cancer was 57% and 56%, respectively. The analyses showed persistent differences in cancer survival across Europe with lowest survival for CRC patients observed in Eastern Europe. The analyses further showed a strong gradient in age-specific survival. Even though the study revealed sustained improvement in patient survival between 1999–2001 and 2005–2007 (absolute increase of 4 and 6 percentage points for colon and rectum, respectively), the differences in the survival for CRC patients observed at the beginning of the millennium persisted over time. Conclusion Although survival for CRC patients in Europe improved markedly in the study period, significant geographic variations and a strong age gradient still persisted. Enhanced access to effective diagnostic procedures and treatment options might be the keys to reducing the existing disparities in the survival of CRC patients across Europe.

BACKGROUND: Survival differences across Europe for patients with cancers of breast, uterus, cervix, ovary, vagina and vulva have been documented by previous EUROCARE studies. In the present EUROCARE-5 study we update survival estimates and investigate changes in country-specific and over time survival, discussing their relationship with incidence and mortality dynamics for cancers for which organised screening programs are ongoing. METHODS: We analysed cases archived in over 80 population-based cancer registries in 29 countries grouped into five European regions. We used the cohort approach to estimate 5-year relative survival (RS) for adult (⩾15years) women diagnosed 2000-2007, by age, country and region ; and the period approach to estimate time trends (1999-2007) in RS for breast and cervical cancers. RESULTS: In 2000-2007, 5-year RS was 57% overall, 82% for women diagnosed with breast, 76% with corpus uteri, 62% with cervical, 38% with ovarian, 40% with vaginal and 62% with vulvar cancer. Survival was low for patients resident in Eastern Europe (34% ovary-74% breast) and Ireland and the United Kingdom [Ireland/UK] (31-79%) and high for those resident in Northern Europe (41-85%) except Denmark. Survival decreased with advancing age: markedly for women with ovarian (71% 15-44years ; 20% ⩾75years) and breast (86% ; 72%) cancers. Survival for patients with breast and cervical cancers increased from 1999-2001 to 2005-2007, remarkably for those resident in countries with initially low survival. CONCLUSIONS: Despite increases over time, survival for women's cancers remained poor in Eastern Europe, likely due to advanced stage at diagnosis and/or suboptimum access to adequate care. Low survival for women living in Ireland/UK and Denmark could indicate late detection, possibly related also to referral delay. Poor survival for ovarian cancer across the continent and over time suggests the need for a major research effort to improve prognosis for this common cancer.

Item does not contain fulltext Familial colorectal cancer (CRC) accounts for 10-15% of all CRCs. In about 5% of all cases, CRC is associated with a highly penetrant dominant inherited syndrome. The most common inherited form of non-polyposis CRC is the Lynch syndrome which is responsible for about 2-4% of all cases. Surveillance of individuals at high risk for CRC prevents the development of advanced CRC. About 1 million individuals in Western Europe are at risk for Lynch syndrome. We performed a survey to evaluate the strategies currently used to identify individuals at high risk for CRC in 14 Western European countries. Questionnaires were distributed amongst members of a European collaborative group of experts that aims to improve the prognosis of families with hereditary CRC. The survey showed that in all countries obtaining a family history followed by referral to clinical genetics centres of suspected cases was the main strategy to identify familial and hereditary CRC. In five out of seven countries with a (regional or national) CRC population screening program, attention was paid in the program to the detection of familial CRC. In only one country were special campaigns organized to increase the awareness of familial CRC among the general population. In almost all countries, the family history is assessed when a patient visits a general practitioner or hospital. However, the quality of family history taking was felt to be rather poor. Microsatellite instability testing (MSI) or immunohistochemical analysis (IHC) of CRC are usually recommended as tools to select high-risk patients for genetic testing and are performed in most countries in patients suspected of Lynch syndrome. In one country, IHC was recommended in all new cases of CRC. In most countries there are no specific programs on cancer genetics in the teaching curriculum for medical doctors. In conclusion, the outcome of this survey and the discussions within an European expert group may be used to improve the strategies to identify individuals at high risk of CRC. More attention should be given to increasing the awareness of the general population of hereditary CRC. Immunohistochemical analysis or MSI-analysis of all CRCs may be an effective tool for identifying all Lynch syndrome families. The cost-effectiveness of this approach should be further evaluated. All countries with a CRC population screening program should obtain a full family history as part of patient assessment. 01 juni 2010

Background In Europe skin melanoma (SM) survival has increased over time. The aims were to evaluate recent trends and differences between countries and regions of Europe.Methods Relative survival (RS) estimates and geographical comparisons were based on 241,485 patients aged 15 years and over with a diagnosis of invasive SM in Europe (2000-2007). Survival time trends during 1999-2007 were estimated using the period approach, for 213,101 patients. Age, gender, sub-sites and morphology subgroups were considered. Results In European patients, estimated 5-year RS was 83% (95% confidence interval, CI 83-84%). The highest values were found for patients resident in Northern (88%; 87-88%) and Central (88%; 87-88%) Europe, followed by Ireland and United Kingdom (UK) (86%; 85-86%) and Southern Europe (83%; 82-83%). The lowest survival was in Eastern Europe (74%; 74-75%). Within regions the intercountry absolute difference in percentage points of RS varied from 4% (North) to 34% (East). RS decreased markedly with patients' age and was higher in women than men. Differences according to SM morphology and skin sub-sites also emerged. Survival has slightly increased from 1999 to 2007, with a small improvement in Northern and the most pronounced improvement in Eastern Europe. Discussion SM survival is high and still increasing in European patients. The gap between Northern and Southern and especially Eastern European countries, although still present, diminished over time. Differences in stage distribution at diagnosis may explain most of the geographical differences. However, part of the improvement in survival may be attributed to overdiagnosis from early diagnosis practices.

Background Survival of patients diagnosed with lung and pleura cancer is a relevant health care indicator which is related to the availability and access to early diagnosis and treatment facilities. Aim of this paper is to update lung and pleural cancer survival patterns and time trends in Europe using the EUROCARE-5 database. Methods Data on adults diagnosed with lung and pleural cancer from 87 European cancer registries in 28 countries were analysed. Relative survival (RS) in 2000–2007 by country/region, age and gender, and over time trends in 1999–2007 were estimated. Results Lung cancer survival is poor everywhere in Europe, with a RS of 39% and 13% at 1 and 5 years since diagnosis, respectively. A geographical variability is present across European areas with a maximum regional difference of 12 and 5 percentage points in 1-year and 5-year RS respectively. Pleural cancer represents 4% of cases included in the present study with 7% 5-year RS overall in Europe. Most pleural cancers (83%) are microscopically verified mesotheliomas. Survival for both cancers decreases with advancing age at diagnosis for both cancers. Slight increasing trends are described for lung cancer. Survival over time is higher for squamous cell carcinoma and adenocarcinomas than for small and large cell carcinoma; and better among women than men. Conclusions Despite the generalised although slight increase, survival of lung and pleural cancer patients still remains poor in European countries. Priority should be given to prevention, with tobacco control policies across Europe for lung cancer and banning asbestos exposure for pleural cancer, and in early diagnosis and better treatment. The management of mesothelioma needs a multidisciplinary team and standardised health care strategies.

Background: Overall survival after cancer is frequently used when assessing a health care service’s performance as a whole. It is mainly used by the public, politicians and the media, and is often dismissed by clinicians because of the heterogeneous mix of different cancers, risk factors and treatment modalities. Here we give survival details for all cancers combined in Europe, correlating it with economic variables to suggest reasons for differences. Methods: We computed age and cancer site case- mix standardised relative survival for all cancers combined (ACRS) for 29 countries participating in the EUROCARE-5 project with data on more than 7.5 million cancer cases from 87 population-based cancer registries, using complete and period approach. Results: Denmark, United Kingdom (UK) and Eastern European countries had lower survival than neighbouring countries. Five-year ACRS has been increasing throughout Europe, and substantial increases, between 1999–2001 and 2005–2007, have been achieved in countries where survival was lower in the past. Five-year ACRS for men and women are positively correlated with macro-economic variables like the Gross Domestic Product (GDP) and Total National Expenditure on Health (TNEH) (R2 about 70%). Countries with recent larger increases in GDP and TNEH had greater increases in cancer survival. Conclusions: ACRS serves to compare all cancer survival in Europe taking account of the geographical variability in case-mixes. The EUROCARE-5 data on ACRS confirm previous EUROCARE findings. Survival appears to correlate with macro-economic determinants, particularly with investments in the health care system.

Background This work presents relative survival estimates regarding urinary tract tumours among adult patients (age ⩾ 15 years) diagnosed in Europe. It reports on survival estimates of cases diagnosed in 2000–2007, and on survival time trends from 1999–2001 to 2005–2007. Methods Data on 677,340 adult urinary tract tumour patients, (429,154 cases of invasive and non-invasive bladder and 248,186 cases of invasive kidney cancers) diagnosed between 2000 and 2007 were provided by 86 population-based cancer registries from 29 European countries. The complete approach was used to estimate survival in 2000–2007; the period approach was used to estimate survival over time. Results The age-standardised 5-year relative survival for patients with kidney tumours diagnosed in Europe during 2000–2007 was 60%. The best prognosis was observed in Southern and Central Europe and prognosis improved in all regions along the time period. For invasive and non-invasive patients with bladder tumours combined the age-standardised 5-year relative survival in Europe was 68%. The best prognosis was observed in Southern and Northern Europe. However, in Scotland and The Netherlands the relative survival was significantly lower, although the survival estimates for these two countries were based on invasive tumours only. Conclusions Differences in registration practices affect comparisons of survival values between European countries, especially in patients with urinary bladder cancers. The between-country variation in survival is influenced by the varying use of diagnostic investigation in urinary tract tumours. Further data on stage at diagnosis can help to elucidate the influence of diagnostic intensity or early diagnosis on the survival patterns.

BACKGROUND: Head and neck (H&N) cancers are a heterogeneous group of malignancies, affecting various sites, with different prognoses. The aims of this study are to analyse survival for patients with H&N cancers in relation to tumour location, to assess the change in survival between European countries, and to investigate whether survival improved over time. METHODS: We analysed about 250, 000 H&N cancer cases from 86 cancer registries (CRs). Relative survival (RS) was estimated by sex, age, country and stage. We described survival time trends over 1999-2007, using the period approach. Model based survival estimates of relative excess risks (RERs) of death were also provided by country, after adjusting for sex, age and sub- site. RESULTS: Five-year RS was the poorest for hypopharynx (25%) and the highest for larynx (59%). Outcome was significantly better in female than in male patients. In Europe, age-standardised 5-year survival remained stable from 1999-2001 to 2005-2007 for laryngeal cancer, while it increased for all the other H&N cancers. Five- year age-standardised RS was low in Eastern countries, 47% for larynx and 28% for all the other H&N cancers combined, and high in Ireland and the United Kingdom (UK), and Northern Europe (62% and 46%). Adjustment for sub-site narrowed the difference between countries. Fifty-four percent of patients was diagnosed at advanced stage (regional or metastatic). Five- year RS for localised cases ranged between 42% (hypopharynx) and 74% (larynx). CONCLUSIONS: This study shows survival progresses during the study period. However, slightly more than half of patients were diagnosed with regional or metastatic disease at diagnosis. Early diagnosis and timely start of treatment are crucial to reduce the European gap to further improve H&N cancers outcome.

Background The EUROCARE study collects and analyses survival data from population-based cancer registries (CRs) in Europe in order to provide data on between-country differences in survival and time trends in survival. Methods This study analyses data on liver cancer, gallbladder and extrahepatic biliary tract cancers (“biliary tract cancers”), and pancreatic cancer diagnosed in 2000–2007 from 88 CRs in 29 countries. Relative survival (RS) was estimated overall, by region, sex, age and period of diagnosis using the complete approach. Time trends in 5-year RS over 1999–2007 were also analysed using the period approach. Results The prognosis of the studied cancers was poor. Age-standardised 5-year RS was 12% for liver cancer, 17% for biliary tract cancers and 7% for pancreatic cancer. There were some between-country differences in survival. In general, RS was low in Eastern Europe and high in Central and Southern Europe. For all sites, 5-year RS was similar in men and women and decreased with advancing age. No substantial changes in survival were reported for pancreatic cancer over the period 1999–2007. On average, there was a crude increase in 5-year RS of 3 percentage points between the periods 1999–2001 and 2005–2007 for liver cancer and biliary tract cancers. Conclusions The major changes in imaging techniques over the study period for the diagnosis of the three studied cancers did not result in an improvement in the prognosis of these cancers. In the near future, new innovative treatments might be the best way to improve the prognosis in these cancers.

Background We provide updated estimates of survival and survival trends of male genital tumours (prostate, testicular and penis cancers), in Europe and across European areas. Methods The complete approach was used to obtain relative survival estimates for patients diagnosed in 2000–2007, and followed up through 2008 in 29 countries. Data came from 87 cancer registries (CRs) for prostate tumours and from 86 CRs for testis and penis tumours. Relative survival time trends in 1999–2007 were estimated by the period approach. Data came from 49 CRs in 25 countries. Results We analysed 1,021,275 male genital cancer cases. Five-year relative survival was high and decreased with increasing age for all tumours considered. We found limited variation in survival between European regions with Eastern Europe countries having lower survival than the others. Survival for penile cancer patients did not improve from 1999 to 2007. Survival for testicular cancer patients remained stable at high levels since 1999. Survival for prostate cancer patients increased over time. Conclusions Treatment standardisation and centralisation for very rare diseases such as penile cancers or advanced testicular tumours should be supported. The high survival of testicular cancer makes long-term monitoring of testicular cancer survivors necessary and CRs can be an important resource. Prostate cancer patients’ survival must be interpreted considering incidence and mortality data. The follow-up of the European Randomised Study of Screening for Prostate Cancer should continue to clarify the impact of screening on prostate cancer mortality together with population based studies including information on stage and treatments.

Background Since 25 years the EUROCARE study monitors the survival of cancer patients in Europe through centralised collection, quality check and statistical analysis of population-based cancer registries (CRs) data. The European population covered by the study increased remarkably in the latest round. The study design and statistical methods were also changed to improve timeliness and comparability of survival estimates. To interpret the EUROCARE-5 results on adult cancer patients better here we assess the impact of these changes on data quality and on survival comparisons. Methods In EUROCARE-5 the survival differences by area were studied applying the complete cohort approach to data on nearly nine million cancer patients diagnosed in 2000–2007 and followed up to 2008. Survival time trends were analysed applying the period approach to data on about 10 million cancer cases diagnosed from 1995 to 2007 and followed up to 2008. Differently from EUROCARE-4, multiple primary cancers were included and relative survival was estimated with the Ederer II method. Results EUROCARE-5 covered a population of 232 million resident persons, corresponding to 50% of the 29 participating countries. The population coverage increased particularly in Eastern Europe. Cases identified from death certificate only (DCO) were on average 2.9%, range 0–12%. Microscopically confirmed cases amounted to over 85% in most CRs. Compared to previous methods, including multiple cancers and using the Ederer II estimator reduced survival estimates by 0.4 and 0.3 absolute percentage points, on average. Conclusions The increased population size and registration coverage of the EUROCARE-5 study ensures more robust and comparable estimates across European countries. This enlargement did not impact on data quality, which was generally satisfactory. Estimates may be slightly inflated in countries with high or null DCO proportions, especially for poor prognosis cancers. The updated methods improved the comparability of survival estimates between recently and long-term established registries and reduced biases due to informative censoring.

Precancerous duodenal lesions in patients with familial adenomatous polyposis can be detected with duodenoscopy and treatment may prevent the development of cancer. We proposed to determine the frequency, natural history, cumulative risk, and risk factors of the precancerous duodenal lesions in a series of patients diagnosed in northern Italy. METHODS: A prospective, endoscopic, follow-up protocol was performed in 50 patients examined by gastroduodenoscopy at two years of interval or less. The presence and severity of precancerous lesions of the duodenal mucosa were evaluated by Spigelman score. Twenty-five patients (50 percent) had proctocolectomy and ileoanal anastomosis, 15 (30 percent) had colectomy and ileorectal anastomosis, and 5 (10 percent) had proctocolectomy and definitive ileostomy from 0 to 3 years before the admission to the surveillance program. All patients showed more than a thousand adenomas in the colorectal mucosa. No patients with attenuated polyposis were found. RESULTS: At the first endoscopy, duodenal adenomas could be detected in 19 of 50 patients (38 percent), whereas at the end of the follow-up, 43 (86 percent) had duodenal lesions. The final mean Spigelman score increased during the follow-up period (P < 0.001 respect to baseline values). No duodenal cancer could be detected. Eleven patients had or developed severe precancerous duodenal lesions (Stage IV) treated with endoscopic or surgical resection. The istribution of patients with Stage IV according to the surgery of the colon was: 2 of 25 treated with ileoanal anastomosis and 8 of 15 with ileorectal anastomosis (P = 0.0024, Fisher_s exact test). CONCLUSIONS: Patients with familial adenomatous polyposis are at risk of significant neoplasia. The natural history of precancerous lesions might be related to surgical treatment of colorectal neoplasms.

Mutation-predicting models can be useful when deciding on the genetic testing of individuals at risk and in determining the cost effectiveness of screening strategies at the population level. The aim of this study was to evaluate the performance of a newly developed genetic model that incorporates tumor microsatellite instability (MSI) information, called the AIFEG model, and in predicting the presence of mutations in MSH2 and MLH1 in probands with suspected hereditary non-polyposis colorectal cancer. The AIFEG model is based on published estimates of mutation frequencies and cancer penetrances in carriers and non-carriers and employs the program MLINK of the FASTLINK package to calculate the proband's carrier probability. Model performance is evaluated in a series of 219 families screened for mutations in both MSH2 and MLH1, in which 68 disease-causing mutations were identified. Predictions are first obtained using family history only and then converted into posterior probabilities using information on MSI. This improves predictions substantially. Using a probability threshold of 10% for mutation analysis, the AIFEG model applied to our series has 100% sensitivity and 71% specificity.

Attenuated familial adenomatous polyposis and Muir-Torre syndrome linked to compound biallelic constitutional MYH gene mutations.Peculiar dermatologic manifestations are present in several heritable gastrointestinal disorders. Muir-Torre syndrome (MTS) is a genodermatosis whose peculiar feature is the presence of sebaceous gland tumors associated with visceral malignancies. We describe one patient in whom multiple sebaceous gland tumors were associated with early onset colon and thyroid cancers and attenuated polyposis coli. Her family history was positive for colonic adenomas. She had a daughter presenting with yellow papules in the forehead region developed in the late infancy. Skin and visceral neoplasms were tested for microsatellite instability and immunohistochemical status of mismatch repair (MMR), APC and MYH proteins. The proband colon and skin tumors were microsatellite stable and showed normal expression of MMR proteins. Cytoplasmic expression of MYH protein was revealed in colonic cancer cells. Compound heterozygosity due to biallelic mutations in MYH, R168H and 379delC, was identified in the proband. The 11-year-old daughter was carrier of the monoallelic constitutional mutation 379delC in the MYH gene; in the sister, the R168H MYH gene mutation was detected. This report presents an interesting case of association between MYH-associated polyposis and sebaceous gland tumors. These findings suggest that patients with MTS phenotype that include colonic polyposis should be screened for MYH gene mutations.

Background: Population based colorectal cancer survival among patients diagnosed in 1985–89 was lower in Europe than in the USA (45% v 59% five year relative survival). Aims: To explain this difference in survival using a new analytic approach for patients diagnosed between 1990 and 1991. Subjects: A total of 2492 European and 11 191 US colorectal adenocarcinoma patients registered by 10 European and nine US cancer registries. Methods: We obtained clinical information on disease stage, number of lymph nodes examined, and surgical treatment. We analysed three year relative survival, calculating relative excess risks of death (RERs, referent category US patients) adjusted for age, sex, site, surgery, stage, and number of nodes examined, using a new multivariable approach. Results: We found that 85% of European patients and 92% of US patients underwent surgical resection. Three year relative survival was 69% for US patients and 57% for European patients. After adjustment for age, sex, and site, the RER was significantly high in all 10 European populations, ranging from 1.07 (95% confidence interval 0.86–1.32) (Modena, Italy) to 2.22 (1.79–2.76) (Thames, UK). After further adjustment for stage, surgical resection, and number of nodes examined (a determinant of stage), RERs ranged from 0.77 (0.62–0.96) to 1.59 (1.28–1.97). For some European registries the excess risk was small and not statistically significant. Conclusions: US-Europe survival differences in colorectal cancer are large but seem to be mostly attributable to differences in stage at diagnosis. There are wide variations in diagnostic and surgical practice between Europe and the USA.

Hereditary nonpolyposis colorectal cancer (HNPCC) is frequently associated with constitutional mutations in a class of genes involved in DNA mismatch repair. We identified 32 kindreds, with germline mutations in one of three genes hMSH2, hMLH1 or hMSH6. In this study, we purposed to evaluate how many high-risk individuals in each family underwent genetic testing: moreover, we assessed how many mutation-positive unaffected individuals accepted colonoscopic surveillance and the main findings of the recommended follow-up. Families were identified through a population-based registry, or referred from other centres. Members of the families were invited for an education session with two members of the staff. When a kindred was consistent with HNPCC, neoplastic tissues were examined for microsatellite instability (MSI) and immunohistochemical expression of MSH2, MLH1 and MSH6 proteins. Moreover, constitutional mutations were searched by SSCP or direct sequencing of the whole genomic region. Of the 164 subjects assessed by genetic testing, 89 were gene carriers (66 affected - that is, with HNPCC-related cancer diagnosis - and 23 unaffected) and 75 tested negative. Among the 23 unaffected gene carriers, 18 (78.3%) underwent colonoscopy and four declined. On a total of 292 first degree at risk of cancer, 194 (66.4%) did not undergo genetic testing. The main reasons for this were: (a) difficulty to reach family members at risk, (b) lack of collaboration, (c) lack of interest in preventive medicine or 'fatalistic' attitude towards cancer occurrence. The number of colorectal lesions detected at endoscopy in gene carriers was significantly (P0.01) higher than in controls (noncarriers). We conclude that a large fraction of high-risk individuals in mutation-positive HNPCC families does not undergo genetic testing, despite the benefits of molecular screening and endoscopic surveillance. This clearly indicates that there are still barriers to genetic testing in HNPCC, and that we are unable to provide adequate protection against cancer development in these families.

Germline mutations in BRCA1 and BRCA2 genes predispose to hereditary breast cancer, whereas carriers of mutations in any of the mismatch repair genes (MMR; hMLH1, hMSH2, hMSH6, hPMS2) are highly susceptible to Lynch syndrome. In the present study, we describe a woman affected by unilateral breast cancer at the age of 35 years. After 4 years, during the follow-up she developed synchronous (and asymptomatic) endometrial cancer, ovarian carcinoma and renal clear cell carcinoma. After 7 years (at age 46), the patient developed an infiltrating carcinoma of the contralateral breast and died in a few months of metastatic disease. Initial investigations led to the detection of a constitutional mutation in the BRCA1 gene. The extended genealogical tree disclosed a suspected history of colorectal carcinoma in the maternal branch. Endometrial cancer of the proband was investigated for microsatellite instability (MSI) and immunohistochemical expression of MLH1, MSH2 and MSH6 proteins. An high MSI status and lack of expression of MLH1 protein were detected. hMLH1 gene sequencing revealed the presence of a constitutional mutation, which was also found in the mother of the proband. Loss of the wild-type hMLH1 allele was detected in both breast tumors, thus suggesting that the MMR defect contributed to the development of the breast cancer.

Few studies have investigated rectal cancer management at the population level. We compared how rectal cancers diagnosed in Italy (2003-2005) and France (2005) were managed, and evaluated the extent to which management adhered to European guidelines.Samples of 3938 Italian and 2287 French colorectal cancer patients were randomly extracted from 8 and 12 cancer registries respectively. Rectal cancer patients (860 Italian, 559 French) were analysed. Logistic regression models estimated odds ratios (ORs) of being treated with curative intent, receiving sphincter-saving surgery, and receiving preoperative radiotherapy.Similar proportions of Italian and French patients were treated with curative intent (70% vs. 67%; OR=0.92 [0.73-1.16]); the respective proportions receiving sphincter-saving surgery were 21% and 33% (OR=1.15 [0.86-1.53]). In about 50% of those treated with curative intent, ≥ 12 lymph nodes were harvested in both countries. The proportion receiving postoperative radiotherapy was higher in Italy than in France (25% vs. 11%, p0.01), but French patients were more likely to receive preoperative radiotherapy (52% vs. 21%; OR=4.06 [2.79-5.91]).The proportions of patients receiving preoperative radiotherapy and the numbers of lymph nodes sampled were low in both countries. Centralising treatment and potentiating screening would be practical ways of improving outcomes and adhering to guidelines.

The earliest phases of colorectal tumourigenesis initiate in the normal mucosa, with a generalised disorder of cell replication, and with the appearance of clusters of enlarged crypts (aberrant crypts) showing proliferative, biochemical and biomolecular abnormalities. The large majority of colorectal malignancies develop from adenomatous polyps. These can be defined as well demarcated masses of epithelial dysplasia, with uncontrolled crypt cell division. An adenoma can be considered malignant when neoplastic cells pass through the muscularis mucosae and infiltrate the submucosa. Definitions like "carcinoma in situ" or "intramucosal carcinoma" should be abandoned, since they lead to confusion. Although several lines of evidence indicate that carcinomas usually originate from pre-existing adenomas, this does not imply that all polyps undergo malignant changes, and does not exclude "de novo" carcinogenesis. Besides adenomas, other types of polypoid lesions include hyperplastic polyps (showing elongated crypts often with cystic dilatation), serrated adenomas (with a serrated glandular pattern], flat adenomas (flat lesions which are difficult to detect in routine lower endoscopy, but may possess malignant potential), hamartomatous polyps (which show a complex branching pattern of smooth muscle supporting normal lamina propria and glands), and inflammatory polyps. Colorectal carcinomas are one of the most frequent neoplasms in Western society; the macroscopic appearance of these lesions may be that of a polypoid vegetating mass or of a flat infiltrating lesion. Most of these tumours are adenocarcinomas (96%), that, in some cases, show a mucinous component. More rare malignancies of the large bowel include signet-ring cell carcinoma, squamous carcinoma, undifferentiated neoplasms and medullary type adenocarcinoma (solid carcinoma with minimal glandular differentiation or slight cellular pleomorphism). Colorectal carcinoma can be graded into well, moderately and poorly differentiated lesions; there is little evidence, however, that grading may be of help in evaluating prognosis of affected patients. In conclusion, colorectal tumours cover a wide range of premalignant and malignant lesions, many of which can easily be removed at endoscopy. It follows that colorectal neoplasms might be prevented by interfering with the various steps of carcinogenesis, which begins with uncontrolled epithelial cell replication, continues with the formation of adenomas of various dimensions, and eventually evolves into malignancy.

Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is an autosomal dominant condition accounting for 2–5% of all colorectal carcinomas as well as a small subset of endometrial, upper urinary tract and other gastrointestinal cancers. An assay to detect the underlying defect in HNPCC, inactivation of a DNA mismatch repair enzyme, would be useful in identifying HNPCC probands. Monoclonal antibodies against hMLH1 and hMSH2, two DNA mismatch repair proteins which account for most HNPCC cancers, are commercially available. This study sought to investigate the potential utility of these antibodies in determining the expression status of these proteins in paraffin-embedded formalin-fixed tissue and to identify key technical protocol components associated with successful staining. A set of 20 colorectal carcinoma cases of known hMLH1 and hMSH2 mutation and expression status underwent immunoperoxidase staining at multiple institutions, each of which used their own technical protocol. Staining for hMSH2 was successful in most laboratories while staining for hMLH1 proved problematic in multiple labs. However, a significant minority of laboratories demonstrated excellent results including high discriminatory power with both monoclonal antibodies. These laboratories appropriately identified hMLH1 or hMSH2 inactivation with high sensitivity and specificity. The key protocol point associated with successful staining was an antigen retrieval step involving heat treatment and either EDTA or citrate buffer. This study demonstrates the potential utility of immunohistochemistry in detecting HNPCC probands and identifies key technical components for successful staining.

Colorectal cancer continues to represent one of the major causes of cancer-related morbidity in all western countries. A review has been made of the main aetiological factors which have been related to colorectal cancer development with particular attention being focused on: a) new advancements in molecular biology, and b) the interaction between genetic predisposition and environmental factors. Worldwide, approximately 900,000 cases of colorectal malignancies have been diagnosed in 1996 and this accounts for 8.5% of all new cases of cancer. Crude incidence rates range from 0.6 – 5.0 cases/100,000/year in Senegal and India to 50–70 cases in developed countries. Environmental factors, such as meat, saturated fat, low physical activity, obesity, smiking, alcoholic beverages, and inflammatory bowel diseases seem to increase the risk of colorectal cancer. In contrast, fruit, vegetables, fibre, antioxidant vitamins, calcium, folate, physical exercise and non-steroidal anti-inflammatory drugs seem to show a orotective effect. For some of these factors, the molecular basis of their mechanism of action begins to be elucidated. Colorectal cancer develops from benign precursors, the adenomatous polyps; there is extensive evidence that polyps transform into cancer in a stepwise manner, and that several molecular abnormalities (mutations of oncogenes, inactivation of tumour suppressor genes and microsatellite instability) accompany and, somehow, determine colorectal tumourigenesis. Two major Hereditary Colorectal Cancer syndromes — Familial Adenomatous Polyposis and Hereditary Non polyposis Colorectal Cancer — have been described and characterized at molecular levels; it is estimated that these inherited conditions might account for up to 5% of all large bowel malignancies. Familial colorectal cancer remains undefined and is presumably due to multifactorial inheritance. Recently, identified germline mutations (such as l1307K in the APC gene) might account for a fraction of these familial cases, at least in some populations. At variance with many other tumours, the aetiology and pathogenesis of colorectal cancer have been partially clarified, so that we are now in the position to take preventive measures and to design surveillance programmes which might lead to a certain reduction in incidence and mortality. However, since many of the aetiological factors are strictly related to modern customs and lifestyle, they will be difficult to eradicate; this awareness should stimulate further investigations in this exciting field of research.

Aberrant crypt foci (ACF) have been identified in the methylene-blue stained mucosa of the human colon. Some lines of evidence suggest that ACF may be precursors of colon cancer. The objective of the present study was to establish morphological criteria able to define and classify ACF in histological sections. Twenty-four colectomy specimens were collected after operation for colorectal cancer and fixed in 10% formalin. Strips of grossly normal mucosa were stained in a 0.2% solution of methylene blue in saline for 5-10 min. The strips were measured, put on a glass slide and observed under a light microscope at x25. One hundred and fourteen ACF identified by topology were sectioned parallel to the muscularis mucosae. Eighty-four ACF were evident at histological examination and could be classified into three main groups: group A (61 ACF, 72.6%) including foci whose epithelial cells had regular nuclei, with only mild or focal crowding but no stratification, no mucin depletion and no dysplasia; group B (16 ACF, 19.1%), in which features of hyperplasia were evident; and group C (seven ACF, 8.3%) including foci with enlarged, crowded and stratified nuclei, mucin depletion, frequent mitoses, and evident dysplasia, diffuse or focal (mild in five cases, moderate in two) representing microadenomas. Finally, hyperplastic foci were significantly larger than foci of group A and C. Group B ACF were also more frequent in the rectum than in the colon. In conclusion, selected histological features allow the definition of groups of ACF, which may represent sequential steps in the development of human colorectal tumours.

Attenuated familial adenomatous polyposis (AFAP) is characterized by the presence of 10–99 colorectal adenomas. The disease may be associated with mutations in either APC or MUTYH genes. We purposed to evaluate the contribution of adenomatous polyposis coli (APC) and MutY homologue (MUTYH) germline alterations to the AFAP phenotype and to identify genotype/phenotype correlations. During counselling for familial adenomatous polyposis (FAP), 91 probands (and 107 affected individuals) who met the criteria of AFAP were identified. Eighty-two families were screened for constitutional mutations of the APC and MUTYH genes. MUTYH mutations were detected in 21 families (25.6 % of the 82 tested), and APC mutations in 7 (8.5 %). Overall, constitutional alterations were found in 34.1 % of the probands. Patients with APC mutations were younger at cancer onset and had a higher mean number of polyps (48.5 ± 33.0 in APC+ individuals vs. 35.7 ± 24.9 in MUTYH+ individuals, and 33.2 ± 18.4 in the “no mutation” group). Clinical features rendered the “no mutation” group closer to MUTYH+ than to the APC+ group. Colorectal cancer at diagnosis was detected in 40 % of AFAP individuals. AFAP is a new clinical entity with its frequency in the general population still undefined. The number of adenomas varies greatly, with an average of 30–40 lesions. The molecular basis of AFAP can be established in approximately 1/3 of the patients. Both MUTYH and APC genes are implicated in AFAP, though the role of MUTYH is of considerably greater relevance.

Dukes' stage is the most powerful indicator of patient outcome for colorectal cancer. Several cancer survival studies have considered other prognostic variables, but results are often conflicting. We sought to assess the independent value of several clinical and morphological variables in defining colorectal cancer specific survival. 397 colorectal cancer patients diagnosed from 1984 to 1986, and registered in a large bowel cancer registry instituted in a local health district of Northern Italy, were actively followed-up until 31 December 1991. Univariate and multivariate survival analyses were carried out in colon and rectal cancer cases, separately, using the actuarial life-table method and Cox proportional hazard regressions. Crude and specific 5-year survival rates were 37.5 and 41.4%. In univariate analysis, TNM (tumour, nodes and metastases) stage was the strongest predictor of prognosis in both sites. Other variables significantly related to survival were age of patient at diagnosis and pattern of tumour growth in colon cancer, type of differentiation and pattern of tumour growth in rectal cancer. In multivariate analyses, after adjusting for stage, age had a weak but significant negative effect on colon cancer survival, whereas rectal tumours with the infiltrating type of growth had a significantly worse prognosis than those with the expanding type. Colorectal cancer survival should be analysed in the main large bowel subsites in order to define high-risk groups within each TNM stage category.

Familial adenomatous polyposis (FAP) is a hereditary disease characterized by more than 100 adenomas scattered in the large bowel and by various extracolonic manifestations. We proposed a) to establish the frequency of the disorder in Northern Italy, b) to describe the most relevant clinical findings, and c) in a subgroup of 21 patients (from 8 families), to evaluate the spectrum of mutations of the APC gene.Patients with FAP diagnosed between 1961 and 1991 were referred to our Study Group from surgery and gastroenterology units of the region Emilia-Romagna. The incidence of FAP was in the order of 1 in 16,500, with about a third of patients being 'single' cases. Colorectal malignancies were present in 75.6% of symptomatic patients but absent in most (93.75%) of the asymptomatic family members ('call-up' individuals). Gastric, duodenal, and jejunal adenomas were found in 8.2%, 30.6% and 53.3% of the investigated patients, respectively. Congenital hypertrophy of the retinal pigment epithelium and occult jaw lesions were seen in 64.7% and 39.5% of FAP patients but only in 0.5% and 2.5% of a matched, by age and sex, control population. These two clinical markers had a specificity of 99% and 97%, although their sensitivity was 64% and 39%. Finally, mutations of the APC gene were detected in 6 families (16 affected individuals) of the 8 families (21 affected individuals) tested; no correlation could be found between genotype and phenotype.This study confirms that early diagnosis is essential for an appropriate management of FAP patients, although this aim remains elusive in single cases. High-risk individuals are ideal candidates for APC gene mutation analysis, which should be offered to all first-degree relatives of affected patients.

Aims The assessment of lymphatic vessel density (LVD) has been suggested as a tool to determine the metastatic risk of neoplasias. On this premise, the authors aimed to verify whether progression risk of stage I colorectal cancer may be related to LVD. The authors also evaluated and correlated vascular endothelial growth factor (VEGF)-A expression with LVD revealed in the same cases in order to investigate its potential lymphangiogenic role in the early stage colorectal cancer. Methods LVD and VEGF immunoexpression were analysed and compared in series of 29 stage I surgically resected colorectal carcinomas obtained from patients showing disease progression and in a cohort of 23 stage I colorectal cancers from patients with no evidence of disease progression. The prognostic value of LVD and of VEGF expression on the progression-free survival to colorectal cancer was investigated. Results A high density of peritumoural lymphatics (P-LVD) was significantly associated with high VEGF expression and disease progression. Moreover, high P-LVD and high VEGF expression were significant negative prognostic parameters associated with a shorter disease-free interval in stage I colorectal cancer. Conclusions If our findings are further confirmed in other studies, the assessment of P-LVD on surgical specimens might be used as a tool to identify patients with stage I colorectal cancer at higher risk of progression in order to submit them to adjuvant therapies. Since P-LVD seems to show a VEGF-A mediated regulation in stage I colorectal cancer, therapies targeting this factor might be exploited to reduce lymphangiogenesis and the progression risk of this neoplasia.

Hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome) is characterized by the early onset of colorectal neoplasms, frequently localized in the right colon, increased occurrence of multiple primaries, vertical transmission and aggregation of tumours in families in accordance to a Mendelian dominant type of inheritance. The syndrome accounts for approximately 5% of all colorectal cancers. The purpose of the present study was to describe the tumour spectrum and the most relevant clinical features of 28 kindreds with HNPCC, classified according to the guidelines of the International Collaborative Study Group, and of 61 "suspected" HNPCC. These families were observed during a 6-year registration of colorectal neoplasms in a health-care district of Northern Italy. Colorectal cancer was by far the most frequent malignancy; gastric cancer was the second. Uterine carcinoma was only slightly more frequent than expected. Lung- and breast-tumour rates were lower than expected. Cancer distribution in the large bowel showed that about two fifths of the tumours developed in the right colon. The occurrence of cancer before the age of 50 to 60 was much more frequent in HNPCC. Multiple tumours developed in 25 patients with HNPCC and in 32 with "suspected" HNPCC. Pancolonoscopy remains the procedure of choice for surveillance; other examinations, such as gastroscopy, gynaecological investigations, urography and cholangiography, are suggested only to selected families. One of the main features of the study was the inclusion of 61 "suspected" HNPCC, a heterogeneous group of families which nonetheless deserves careful follow-up.

Item does not contain fulltext Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype-phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis. 01 juli 2010

AIMS: Peutz-Jeghers Syndrome (PJS) is a rare dominantly inherited disease characterized by hamartomatous small bowel polyposis, mucocutaneous hyperpigmentation, and increased risk of cancer. Differentiated thyroid cancers (DTCs) present mainly as sporadic, but they may have also a familial component. We present a case of PJS in a caucasian 25 years-old woman, who developed a DTC. METHODS: The patient had a palpable nodule in the right side of the thyroid region and an endocrinological evaluation, including hormonal assays, neck ultrasound (US) and fine needle aspiration (FNAB) of the nodule was performed. RESULTS: US confirmed a single nodular lesion in the right thyroid lobe (14 mm). Cytological analysis at FNAB revealed a pattern compatible with papillary thyroid carcinoma. The histological analysis after total thyroidectomy confirmed the diagnosis of a Hurtle cell variant of papillary thyroid carcinoma, with follicular architecture. CONCLUSION: Even though rare, the association between PJS and DTC can be possible. In clinical practice it must be borne in mind that the wide spectrum of possible cancer diseases occurring in PJS could also include DTC, that the latter can occur earlier in life in PJS population and with a more aggressive histological pattern. Furthermore, in patients with PJS, US of the thyroid should be performed whenever thyroid disease is suspected at physical examination or based on patient's medical history. Due to lack of established data allowing for a real esteem of the association between PJS and DTC, US of the thyroid, should not be recommended as a routine screening for all subjects with PJS.

We studied rectal cell proliferation by means of bromodeoxyuridine labelling and ornithine decarboxylase activity assay in 16 patients with colorectal adenoma. In each patient, three rectal biopsy specimens taken from normal-appearing mucosa were incubated with bromodeoxyuridine (BrdU), fixed in ethanol and stained with avidin-biotin peroxidase complex using a monoclonal antibody against BrdU. In addition, two biopsies were homogenized and incubated with [1-14C]-ornithine for ornithine decarboxylase (ODC) assay. A direct, significant correlation was found between BrdU-labelling index and ODC levels in the mucosa (r = 0.6511, P less than 0.01). We conclude that BrdU labelling and ODC activity assay give comparable results in the analysis of cell proliferation rate of rectal mucosa. These methods are useful to investigate rectal cell proliferation pattern of patients with increased risk of colorectal cancer.

The clinical findings of a population-based colorectal tumor registry have been analyzed to determine elements of supporting or not supporting the existence of different types of large bowel cancer. Age-specific incidence rate of the 409 registered patients rose sharply with increasing age in all segments of the large bowel; however, regarding left colon and rectum, the male: female ratio showed a marked male preponderance, more evident in the more advanced age groups. Histopathology, studied in 87% of patients, revealed adenocarcinoma as the most frequent feature; however, adenocarcinoma with concomitant adenoma (i.e., presumably arising in adenoma) was observed in 14.3% of cancers of the left colon, in 17.7% of rectal tumors, but in only 5.7% of neoplasms of the proximal colon (P less than 0.05 and P less than 0.01, respectively, vs. left colon and rectum). Some histological features (carcinoid and mucinous carcinoma) were observed in right-side tumors only. Analysis of the familial occurrence of cancer showed that a significantly larger proportion of patients with neoplasms located in proximal colonic segments had three or more first-degree relatives affected by (or deceased from) cancer of all sites. Similarly, colorectal tumors among relatives were more frequent in patients with right-side cancer. The location of the 793 polyps observed during 3 years of registration showed that more than 70% of adenomas were located beyond the splenic flexure, overlapping the distribution of cancers. In conclusion, the differences of sex ratio at different colonic subsites, the higher fraction of adenocarcinomas with adenomas in cancer of the more distal tracts of the large bowel, and the more marked familial occurrence of colorectal cancer in patients with right-side neoplasms tend to support the view that cancer of the proximal colon, cancer of the distal colon, and cancer of the rectum may actually be three different types of tumors.

Cancer registries can be viewed as one of the main strategies for improving our understanding of cancer, as they may reveal the importance of specific trends in cancer incidence and survival; in addition, the information obtained from the registries can be translated into preventive measures that might lead to a better control of neoplasms. A colorectal cancer registry was instituted in Northern Italy in 1984. The purpose of this study is to provide a description of the main findings observed in a 21-year period of continuous registration. Results: A total of 3951 malignancies of the large bowel were registered in 3817 patients, for a crude incidence rate of 75.1/100 000/year in men and 59.0 in women. Overall incidence (crude and age-adjusted) of colorectal tumours increased remarkably throughout the registration period. This increase was mainly due to early (Stage I and II) tumours and to lesions with lymph nodal involvement (Stage III). There was a tendency over time towards a progressive increase of colonic tumours, whereas the fraction of rectal neoplasms tended to decline. Colorectal cancerspecific survival increased significantly over time in each of the main TNM/Dukes classes (p

A large majority of constitutional mutations in hereditary non-polyposis colorectal cancer (HNPCC) are because of the MHL 1 or MSH 2 genes. In a lower fraction of cases, another gene of the mismatch repair (MMR) machinery, MSH6, may be responsible. Families with MSH6 mutations are difficult to recognize, as microsatellite instability (MSI) may not be detectable and immunohistochemistry (IHC) may give ambiguous results. In the present study, we proposed (i) to determine the frequency of MSH6 mutations in a selected population of colorectal cancer patients obtained from a tumor registry, (ii) to assess whether IHC is a suitable tool for selecting and identifying MSH6 mutation carriers. One hundred neoplasms of the large bowel from suspected HNPCC families were analyzed for MSI (BAT 25 and BAT 26 markers) and immunohistochemical expression of the MSH6 protein. We found on 12 tumors (from different families) showing instability or lack of MSH6 expression. Among these, four potentially pathogenic MSH6 mutations were detected (del A at 2984; del TT at 3119; del AGG cod 385; and del CGT cod 1242) by direct gene sequencing. These represented 12.9% of all families with constitutional mutations of the DNA MMR genes. Thus, some 5% of all HNPCC families are featured by constitutional mutation of the MSH6 gene. This appears, however, as a minimum estimate; routine use of IHC and the study of large numbers of individuals and families with little or no evidence of Lynch syndrome might reveal that mutation of this gene account for a large fraction of HNPCC.

Attenuated familial adenomatous polyposis and Muir-Torre syndrome linked to compound biallelic constitutional MYH gene mutations.Peculiar dermatologic manifestations are present in several heritable gastrointestinal disorders. Muir-Torre syndrome (MTS) is a genodermatosis whose peculiar feature is the presence of sebaceous gland tumors associated with visceral malignancies. We describe one patient in whom multiple sebaceous gland tumors were associated with early onset colon and thyroid cancers and attenuated polyposis coli. Her family history was positive for colonic adenomas. She had a daughter presenting with yellow papules in the forehead region developed in the late infancy. Skin and visceral neoplasms were tested for microsatellite instability and immunohistochemical status of mismatch repair (MMR), APC and MYH proteins. The proband colon and skin tumors were microsatellite stable and showed normal expression of MMR proteins. Cytoplasmic expression of MYH protein was revealed in colonic cancer cells. Compound heterozygosity due to biallelic mutations in MYH, R168H and 379delC, was identified in the proband. The 11-year-old daughter was carrier of the monoallelic constitutional mutation 379delC in the MYH gene; in the sister, the R168H MYH gene mutation was detected. This report presents an interesting case of association between MYH-associated polyposis and sebaceous gland tumors. These findings suggest that patients with MTS phenotype that include colonic polyposis should be screened for MYH gene mutations.

The Muir-Torre syndrome (MTS) is an autosomal dominant genodermatosis characterized by the presence of sebaceous gland tumours, with or without keratoacanthomas, associated with visceral malignancies. We describe and characterize two families in which the ample phenotypic variability of MTS was evident. After clinical evaluation, the skin and visceral tumours of one member of a family with 'classic' MTS and one member of a family with a 'peculiar' MTS phenotype without sebaceous lesions, but with only multiple keratoacanthomas, were analysed for microsatellite instability (MSI) and by immunohistochemistry. Tumours of both individuals showed MSI, with a concomitant lack of MSH2 immunostaining in all evaluated skin and visceral lesions; moreover, in the proband of family 2 a constitutional mutation (C-->T substitution leading to a stop codon) in the MSH2 gene was identified. We conclude that the diagnosis of MTS, which is mainly clinical, should take into account an ample phenotypic variability, which includes both cases with typical cancer aggregation in families and cases characterized by the association of visceral malignancies with multiple keratoacanthomas (without sebaceous lesions), without an apparent family history of cancer.

Background Two-thirds of colorectal malignancies are localised in the left colon and rectum. Recent studies suggest a trend towards an increase of right-sided tumours which might have important implications for screening and surveillance. A colorectal cancer registry was set up in Modena, northern Italy, with the purpose of examining incidence, subsite distribution and staging of colorectal malignancies over a 15-year period. Patients and methods From 1984 to 1998, 2517 tumours in 2462 patients were detected and staged with the tumour node metastasis (TNM) system. The ‘right colon’ was considered from caecum to splenic flexure; the ‘left colon’ included descending and sigmoid colon; and the ‘rectum’ included rectosigmoid junction, ampulla and anus. Results Cancer incidence showed an overall increase. Considering the various subsites, an increase of 33.7% in all colonic segments was shown whereas rectal tumours tended to decline. TNM staging showed a gradual increase of localised lesions (41.2% in 1984 versus 53.3% in 1998), with a proportional reduction of advanced tumours. Conclusions Our study indicates an increase of tumour incidence in all colonic segments more than a shift to the right colon. TNM staging tended to improve with an appreciable increase of localised lesions. These findings could be consequent to a more extensive use of colonoscopy.

Background and aims: Although diet and lifestyle are associated with the development of colorectal malignancies, the only clearly identified aetiological factors in colorectal cancer are inheritance (hereditary non-polyposis colorectal cancer (HNPCC) and familial polyposis), inflammatory bowel diseases, papillomavirus, and acquired immunodeficiency syndrome (AIDS). Our aim was to determine what proportion of colorectal neoplasms could be attributed to these specific factors. Patients and methods: Data from a colorectal cancer registry were analysed over a 15 year period, during which nearly 2500 cases were recorded. In patients with suspected HNPCC, microsatellite instability and immunohistochemical expression of proteins encoded by the main DNA mismatch repair genes were assessed. In families with unstable neoplasms, constitutional mutations of the mismatch repair genes hMSH2 , hMLH1 , and hMSH6 were evaluated by single strand conformation polymorphism analysis and sequencing. Results: Inflammatory bowel diseases, familial polyposis, and AIDS were rare causes of colorectal cancer (three, three, and one case, respectively). Anal squamous carcinoma developed in 27 patients (1.0%) and could be attributed to papillomavirus infection. In 58 patients (from 34 families) a clinical diagnosis of HNPCC was established (2.4%). In total, cases with a known aetiology were 92 (3.7% of all patients). Microsatellite instability was detected in 15 cancers from HNPCC families, and germline mutations in six families (12 patients, 0.5% of the total). Families with unstable tumours, with or without mutations, were clinically similar, suggesting the involvement of the mismatch repair system even when mutations were not detected. Conclusions: The study suggests that the aetiology of colorectal malignancies remains elusive in the large majority of cases. Among specific causes, HNPCC represents the most frequent. However, with a population based approach, constitutional mutations of the main genes involved in HNPCC can be detected in only 20% of cases.

Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is an autosomal dominant condition accounting for 2-5% of all colorectal carcinomas as well as a small subset of endometrial, upper urinary tract and other gastrointestinal cancers. An assay to detect the underlying defect in HNPCC, inactivation of a DNA mismatch repair enzyme, would be useful in identifying HNPCC probands. Monoclonal antibodies against hMLH1 and hMSH2, two DNA mismatch repair proteins which account for most HNPCC cancers, are commercially available. This study sought to investigate the potential utility of these antibodies in determining the expression status of these proteins in paraffin-embedded formalin-fixed tissue and to identify key technical protocol components associated with successful staining. A set of 20 colorectal carcinoma cases of known hMLH1 and hMSH2 mutation and expression status underwent immunoperoxidase staining at multiple institutions, each of which used their own technical protocol. Staining for hMSH2 was successful in most laboratories while staining for hMLH1 proved problematic in multiple labs. However, a significant minority of laboratories demonstrated excellent results including high discriminatory power with both monoclonal antibodies. These laboratories appropriately identified hMLH1 or hMSH2 inactivation with high sensitivity and specificity. The key protocol point associated with successful staining was an antigen retrieval step involving heat treatment and either EDTA or citrate buffer. This study demonstrates the potential utility of immunohistochemistry in detecting HNPCC probands and identifies key technical components for successful staining.

Main purpose of the review is to analyse the impact of the current approaches for colorectal cancer prevention, including chemoprevention. Available evidence does not support the contention that a more appropriate diet can be of great help in the prevention of these neoplasms, either because the scientific evidence is poor and highly controversial, or because changes in diet are difficult to implement, at least in many Western countries. Similarly, a preventive approach based on the modification of lifestyle remains improbable, either in the short --or in the long period of time. Secondary prevention--i.e., the systematic removal of adenomatous polyps--can hardly be applied in the general population, with the exception of individuals at risk because members of families with Adenomatosis coli or Lynch syndrome, or affected by inflammatory bowel diseases. Finally, chemoprevention (i.e., the attempt to prevent tumour development through the administration of drugs or natural compounds that interfere with various phases of carcinogenesis) is still in its infancy Though attractive, this approach requires well-designed studies which should be carried out for years before being evaluated and interpreted; so far most of these investigations gave inconsistent or controversial results. In conclusion, both primary and secondary prevention of colorectal malignancies appear difficult to apply in the general population, and chemoprevention is still at the beginning of a (presumably] long story. The final impression is that notwithstanding the remarkable advancements made in the last two decades in colorectal cancer research, the practical application of these new concepts remains difficult.

The development of colorectal cancer has been viewed as an ordered process in which three main phases can be identified: initiation, promotion and progression. There is definite proof that stable alterations of the structure or sequence of DNA (mutations) represent the initiating event; these are followed by an uncontrolled expansion of the neoplastic clones which characterizes tumoural growth. Several classes of genes have been identified foncogenes, tumour suppressor genes and "mutator" genes) the alterations of which are important in the initiation as well as in the promotion and progression of tumours. Colorectal cancer, therefore, results from a series of genetic changes which lead to the progressive and irreversible loss of normal control of cell growth and differentiation. Available evidence is consistent with the hypothesis that there are several molecular pathways underlying the passage from normal mucosa to colorectal carcinoma, thus explaining the existence of intestinal tumours with a different biological nature, which may represent specific targets for prevention and cure. Well-defined molecular pathways have been identified for: A) sporadic colorectal cancer ("Loss of heterozygosity pathway"); B) familial adenomatous polyposis and related polyposis syndromes; C) hereditary non-polyposis colorectal cancer ("mutator genes/microsatellite instability pathway"); D) cancer developing in inflammatory bowel diseases; E) familial colorectal cancer. Thus, there is consistent and considerable evidence suggesting the existence of several biological pathways leading to the same phenotypical expression (i.e., colorectal cancer), and it is likely that additional pathways will be clarified in the future. From a practical point of view, tumours with a diverse biology might offer different and more effective preventive and curative approaches.

BACKGROUND—Marked differences in population based survival across Europe were found for colorectal cancers diagnosed in 1985-1989. AIMS—To understand the reasons for these differences in survival in a new analysis of colorectal cancers diagnosed between 1988 and 1991. SUBJECTS—A total of 2720 patients with adenocarcinoma of the large bowel from 11 European cancer registries (CRs). METHODS—We obtained information on stage at diagnosis, diagnostic determinants, and surgical treatment (not routinely collected by CRs) and analysed the data in relation to three year observed survival, calculating relative risks (RRs) of death and adjusting for age, sex, site, stage, and determinants of stage. RESULTS—Three year observed survival rates ranged from 25% (Cracow) to 59% (Modena), and were low in the Thames area (UK) (38%). Survival rates between registries for "resected" patients varied less than those for all patients. When age, sex, and site were considered, RRs ranged from 0.7 (95% confidence intervals (CI) 0.6-0.9) (Modena) to 2.3 (95% CI 1.9-2.9) (Cracow). After further adjustment by stage, between registry RR variation was between 0.8 (95% CI 0.6-0.9) and 1.8 (95% CI 1.5-2.2). Inter-registry RR differences were slightly reduced when the determinants of stage (number of nodes examined and liver imaging) were included in the model. The reduction was marked for the UK registries. CONCLUSIONS—The wide differences across Europe in colorectal cancer survival depend to a large extent on differences in stage at diagnosis. There are wide variations in diagnostic and surgical practices. There was a twofold range in the risk of death from colorectal cancer even after adjustment for surgery and disease stage. Keywords: colorectal cancer; population based cancer registries; stage at diagnosis; survival; surgery; Europe

Background and Aims. It is still unclear whether recent advancements in colorectal cancer research have led to an improvement in management and prognosis of the disease. Through the data of a specialized colorectal cancer Registry we aimed at analysing pathological staging and 5-year survival of all patients with malignancies of large bowel diagnosed between 1984 and 1997. Main objective was to ascertain whether or not we are making progress in the control of this common neoplasm. Patients and Methods. During the 14 year period 1984–1997, a total of 2,240 colorectal cancer patients were registered, for a crude incidence rate of 64.5 and 55.2/100,000/year in males and females, respectively. Tumours were staged with “Tumour, Node, Metastasis” system, corresponding to Dukes' classification, into four main groups. Survival was assessed with Life Table analysis, and statistical significance — between various subgroups — evaluated with Log-Rank Test. Results. Crude incidence rates of colorectal neoplasms showed minor fluctuations during initial period of registration, increasing sharply after 1990 mainly due to localized (stage I and II) lesions and, to a lesser degree, to stage III tumours. Number of advanced (stage IV and unstaged) malignancies remained virtually stable. When results were expressed as percent of total cases, the fraction of localized lesions increased from 39% in the biennium 1984–1985 to 51.6% in 1986–1997, and the proportion of advanced tumours fell from 39% to 21.6% (p for trend

Human tumours usually develop due to a close interaction between environmental and genetic factors. This concept applies also to well defined genetic diseases such as Hereditary Nonpolyposis Colorectal Cancer (HNPCC or Lynch syndrome), which is featured by early onset tumours of the large bowel (and other target organs), striking aggregation of neoplasms in families, and vertical transmission consistent with an autosomal dominant pattern of inheritance. As a further example of gene/environment interaction, we report on a Hereditary Nonpolyposis Colorectal Cancer family in which two dizygotic twins were affected by cancer of the large bowel. One of the twins was slightly overweight and showed many common risk factors for colorectal carcinoma; he developed a Dukes' C lesion at the age of 52 years. The other twin was not overweight and was much less exposed to exogenous risk factors; a Dukes' B carcinoma was diagnosed at age 60, during a control endoscopy. This anedoctal report suggests that diet and lifestyle are of relevance also in patients with genetically determined tumours of the large bowel. It follows that the control of these environmental factors might be associated with a delay of tumour occurrence and possibly with a less aggressive tumour behaviour.

In 1984, a specialized colorectal cancer registry was instituted in Modena; aims of the Registry were: the evaluation of incidence and mortality, the study of morphological aspects, staging, survival and familiarity of the registered patients.Purpose of the research was to provide an updated description of the main findings (in particular, incidence, staging, morphology and survival) observed in the 12-year registration period.Between January 1984 and December 1995, 1,899 malignancies of the large bowel in 1,831 patients were registered. Tumours were classified according to the International Classification of the Diseases for Oncology (ICDO) and staged with the TNM system. Cancer specific survival was assessed with life table analysis and Log-Rank tests.Crude incidence rate showed minor fluctuations between 1984 and 1989, but tended to rise in the following years. Tumours were mostly located distal to the splenic flexure (73.3% of the total), with a slight tendency over time to a gradual "shift" to the right colon. Staging became progressively more favourable throughout the registration; in 1984 both stages I, II and stage IV + unstaged lesions represented 40% of the total, but in 1995 the former rose to 50% whereas the latter fell to 21.6% (p0.001). This move to earlier stages resulted in an improved survival of patients registered in 1990-91 versus 1984-85 (Log-Rank 14.3 p0.002). Factors associated with a poor survival were the advanced age of patients at diagnosis (74) and clinical stage.