REPORT SECOND MEETING OF THE ICG-HNPCC
AMSTERDAM, AUGUST 13 AND 14, 1990
1. Introduction
Henry Lynch made some remarks regarding the development of the collaborative group and emphasized the importance of collaboration. Meera Khan gave an explanation of the programme and a description of the aims of the collaborative group which would be discussed at the end of the meeting. Furthermore he stressed the need for formalization of the group.
2. Collaborative studies
2a. Prevalence
J.P. Mecklin summarized the data on the prevalence of HNPCC from the literature: Utsonomiya:
4.5% of the colon cancer cases, Ushio: 5%. Mecklin found 3.8% "real" HNPCC cases and 1.7% "suggestive" cases. He concluded that more critical data are needed. As a possibility for further studies on the prevalence he suggested a prospective multicenter study of family histories of consecutive series of CRC-patients.
At present in Finland 12 hospitals participate in such a study.
2b. Natural History
Henry Lynch summarized the known data on the natural history of HNPCC. He stressed that there is much need to gather the data.
2c. Tumour Spectrum
Patricia Watson reported a study of 23 extended HNPCC families. She compared the incidence of the extracolonic cancer in these families with data from a cancer registry and calculated the ratio of observed to expected number of cases among various cancers. An increased ratio was found for cancer of the stomach (4), ovarium (3.5), kidney (3.2) and small bowel (25), a decreased ratio for lung cancer (0.4).
To get more information on the tumour spectrum, she suggested to collect the following data:
1. Pedigrees.
2. Investigation of all cancer reports regardless of site.
3. Data on all family members: dates of birth and death, sex.
4. Data on cancer diagnosis: site, pathology, year of diagnosis.
5. Incidence table of cancer in the general population.
2d. Cross Cultural Comparison
Joji Utsunomiya reported the characteristics of 49 families (personal and reported series) from Japan. He emphasized that there was a big proportion of stomach cancer cases in the HNPCC-families (as in families with familial adenomatous polyposis) compared with the proportion reported in western countries. He outlined a research project on HNPCC in Japan in which 160 institutions participate. One of the aims of the project is identification, surveillance and management of HNPCC. Joji Utsunomiya said that he can use all advices from the group with respect to the subject of this project.
2e. Surveillance
Hans Vasen reported the results of the Dutch Study Group on HNPCC and summarized the ongoing studies. Concerning surveillance of HNPCC families for CRC he said that the two main problems are the upper age limit of screening and the appropriate frequency of examinations. He proposed to get information on (1) the proportion of patients with their first colorectal cancer diagnosed after the age of 60 and (2) the occurrence of interval cancers. Secondly, he proposed to collect some data to assess the value of periodic examinations for endometrial cancer in HNPCC and to find out the appropriate age limits of examinations for such extracolonic primary cancers.
2f. Mucosal Markers
Lemuel Herrera reported the studies on mucosal markers, done in his center. In addition, he reported the results of a study regarding the familiy history in patients younger than 40 years with adenocarcinoma of the right colon. Twenty-nine out of 2424 CRC-patients met these criteria. The pedigrees of eight patients with colorectal cancer showed an autosomal dominant mendelian form of colon cancer. In the pedigrees of 3 patients there was a hereditary tendency for colon cancer.
Evaluation of the histologic types of colonic cancer showed mucinous features in four of the eight HNPCC-cases. Herrera proposed to collect more data to assess the proportion of mucinous cancers in HNPCC.
2g. Chemoprevention Trials
Martin Lipkin reviewed the present status on chemoprevention trials and called for a need for cooperation between different groups involved.
2h. Molecular Genetics
Linkage studies on HNPCC in informative families were reviewed by Meera Khan. It was felt that no conclusion could be adequate enough to yield significant results. Therefore, he urged for an international coordination and cooperation in these studies.
3. Uniform data collection
4. Consensus management HNPCC
4a. Criteria
Ponz de Leon reported a study performed in the Registry in Modena. The criteria for HNPCC used in this study included: vertical transmission, familial aggregation, early age (< 50), proximal localisation, multiple colorectal cancers and mucinous colorectal cancer. Of all cases of colorectal cancer 47% met none of these criteria, 28% one of these criteria, 9% two criteria, 6% three criteria and 5% four or more criteria. The most common criteria was familial aggregation.
He suggested that further studies should include a search for biochemical and genetic markers and segregation analysis. Henry Lynch stressed that the criteria for diagnosis depend on the studies to be conducted such as (A) early detection, mucosal marker and chemoprevention studies; (B) linkage studies and (C) studies on the natural history and the tumor spectrum. With respect to the type A studies the following criteria minimum criteria should be met:
1. Three or more relatives with one relative being a first degree relative of the other two.
2. At least two of these three relatives with one or more of the following criteria: a. age under 45 years, b. multiple CRC, c. CRC in combination with cancer of the endometrium, ovary, stomach or urinary tract in one individual.
Furthermore Henry Lynch stressed the importance of the pattern of cancer. For linkage studies
(B) in addition to the "minimum criteria" there should be six or more living CRC-patients in extended pedigrees. For studies on the natural history and the tumor spectrum Henry would use the following criteria: the "minimum criteria", three or more relatives with the syndrome cancer of any type and extended pedigrees. Patrick Lynch expressed that as a gastroenterlogist he is mainly interested in surveillance. For linkage studies and studies on the natural history he selects extended pedigrees. Otherwise as "minimum criteria" he suggested:
1. Three or more relatives with CRC with one of these three relatives being a sibling, parent or child of the other two.
2. At least two of the three relatives with one of the following criteria: a. age under 45 years, b. proximal localization, c. multiple CRC, d. associated cancer if under 45 years.
In he general discussion Mecklin stressed that a working definition (that is minimum criteria) of the syndrome is very important. Everybody should know what we are talking about. Vasen summarized that there is an agreement on the main criteria:
1. At least three relatives with CRC with one of the relatives being a first degree relative of the other two.
2. At least two generations affected.
The question is whether additional criteria are needed and which criteria should be used. The reason for using additional c riteria would be to differentiate HNPCC from familial clustering of CRC-cases by chance. Of the proposed criteria (age, multiple CRC and proximal localisation) age appears to be the strongest discriminating factor. Joan Slack stressed that the criteria should be as strict as possible. In studies aimed at natural history, the propositus should be excluded.
Another bias is that we are selecting patients with "young age". Herrera expressed the opinion that the number of relatives ( ò 3), vertical transmission and young age are the most important criteria. All participants agreed upon the following minimum criteria:
1. At least three relatives with histologically verified CRC; one of the relatives should be a first degree relative to the other two. Familial adenomatous polyposis should be excluded.
2. At least two successive generations should be affected.
3. In one of the relatives CRC should be diagnosed under 50 years of age.
For studies on linkage, natural history and tumourspectrum more extended pedigrees should be selected.
4b. Terminology
All participants agreed with the suggestion of Mecklin that the term cancer family syndrome is not practical and that the term Hereditary Nonpolyposis Colorectal Cancer or Lynch-syndrome is preferable. Subdivision into Lynch I and Lynch II syndrome appears to be possible only in extensive pedigrees with multiple affected relatives.
4c. Early Detection
Joan Slack reported a study on the risk of cancer death in first degree relatives of 180 kindreds with HNPCC (Lynch type II). The protocol which she recommends includes colonoscopy every five years for members at risk for colorectal cancer and yearly sonography for pelvic cancer. J.P. Mecklin reported the results of his screening programme in which 137 patients were involved.
This programme comprised colonoscopy or sigmoidoscopy in combination with a barium enema every two years, starting at the age of 25 years for CRC and pelvic examination and VABRA curettage every three years for endometrial cancer starting at the age of 35. In the general discussion the participants agreed on the procedures mentioned regarding screening for CRC but recognized that more studies are needed to assess on the appropriate interval between examinations and the upper age limit of screening. It was generally felt also that the value of surveillance for endometrial cancer was not known.
5. Formalization of the collaborative group
On the following issues agreement was met:
Aims of the group
1. To promote cooperation and establishment of collaborative studies.
2. To develop uniform diagnostic criteria and a data collection form.
Size
The ideal number of the members of the group is about 50.
Membership
1. Any HNPCC or potential HNPCC registry will be entitled to join including the associated critical persons.
2. A limited number of individuals are eligible to apply for membership if they are working in the field.
Council
The tasks of this council are:
1. Organizing meetings.
2. Selecting subjects for study.
3. Being responsible for the membership list.
The following persons were proposed as members of the council and they were unanimous elected by the general body: Bulow (Denmark), Cristofaro (Italy), Hamilton (USA), Mecklin (Finland), Meera Khan (The Netherlands), Utsunomiya (Japan) and Henry Lynch (USA - chairman).
Secretariat
It was decided to have the administrative base of the group at Leiden attached to the office of the Dutch Foundation for the Detection of Hereditary Tumours (FDHT).
The tasks of this secretariat are:
1. Maintaining the membership list.
2. Improvement of the data collection forms.
3. Organization of meetings of the group.
4. Serve as the headquaters for the council.
Furthermore, it was decided that Vasen, the medical director of the FDHT will be an ex-officio member and will serve as the executive secretary of the council.
International Informational Center
There was general agreement that the place for this center should be at the Creighton University in Omaha. Patrick Lynch offered to have the Hereditary Colon Cancer Newsletter (previously the Polyposis Newsletter) serve as a medium for communication re activities of the group.
Cooperative Studies
The following studies were proposed:
- A study on mucinous colorectal cancer in HNPCC by Herrera.
- An inventarisation study on surveillance for CRC by Vasen.
- A study on the incidence of extra-colonic cancer by Watson.
There was general agreement that surveillance in HNPCC should be the main item on the next meeting.
Next Meeting
The next meeting will be held in Brindisi (Italy) preceding the Fifth International Symposium on CRC at Turin. Cristofaro will play host to it.
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