REPORT FIFTH MEETING OF THE ICG-HNPCC 
HOUSTON, 2 NOVEMBER 1993

1. Opening

Henry Lynch opened the meeting and welcomed the participants.

2. Reports of collaborative studies

Risk calculation extracolonic cancer (Patrice Watson, Omaha) Patrice Watson collected data from the HNPCC-registers in Finland, Omaha and Holland. The total number of families registered at these centers is about 100. In a previous collaborative study presented at the Fourth meeting of the ICG-HNPCC in Crete in 1992, Patrice Watson had calculated the cumulative risk of having endometrial cancer in these series. In the present collaborative study she had extended the calculations to other extra-colonic cancers. The preliminary results showed that the cumulative lifetime risk of having ovarian cancer at the age of 70 was 6% for putative gene carriers (PGC) and 1% for the first degree relatives (FDR). The cumulative risk of having other extracolonic cancers at age 85 was: small bowel cancer 3% for PGC and <1% for FDR; gastric cancer 12% for PGC and 3% for FDR; urologic tract cancer 12% for PGC and 2% for FDR: all upper GI tract 22% for PGC and 5% for FDR. One of the questions in the discussion was whether differences were found between the three countries. Patrice Watson answered that she did not analyse the data for differences yet. Another question was whether there was an increased cumulative risk for breast cancer. Patrice said that this was not the case. An important question was whether the results would have consequences for the surveillance protocol. Patrice Watson answered that the value of screening for the extracolonic cancers is not known and that there is only some indirect evidence that screening for colorectal cancer is useful.

Epidemiology of urinary tract cancer (Hans Vasen, The Netherlands) Hans Vasen collected data on urinary tract cancer with the following aims: to assess (1) the distribution of the ages at diagnosis; (2) the location and pathology of the tumors; (3) the occurrence of other primary cancers, and (4) the mortality. Data were collected on 58 patients from 8 countries. The patients belonged to 38 families, meeting the Amsterdam criteria. All cases were confirmed by pathology or medical reports. There was an equal distribution of males and females. The mean age at diagnosis was 57 years (range: 29-84). 15 tumors were located in the kidney, 11 in the renal pelvis, 17 in the ureter and 15 in the bladder. 53 patients werd diagnosed because they had signs or symptoms (mainly hematuria). Only two patients were found by screening (sonography), who had both a T2N0M0 tumor. 11 of the 15 kidney tumors were renal cell cancers; there was one renal sarcoma. The pathology from the renal pelvis, ureter and bladder were transitional cell cancers. A large proportion of the patients (72%) had a second primary cancer, 29% had a third primary cancer. The colorectum was the most frequent site (33 cases), followed by the endometrium (8 cases), skin (4 cases), stomach (3 cases), small bowel (3 cases), and breast (3 cases). Almost 70% of the patients had died. The mean age at death was 61 years. Urinary tract cancer was a less frequent cause of death than colorectal cancer.
Hans Vasen concluded after his presentation that several questions remained to be answered, i.e.
(1) should family members from all HNPCC families be screened for urinary tract cancer, and
(2) which screening procedures should be applied. In the discussion it was questioned whether
the occurrence of urinary tract cancer (UTC) in a family would indicate that the family represents a family with the Muir-Torre syndrome (MTS). Hans Vasen answered that (as far as he is informed) in the present series of 58 cases of UTC 4 came from a family with the MTS. Another question was whether all families should be screened for UTC. Hans Vasen said that he would prefer to screen only the families in which this type of cancer occurs. Jukka-Pekka Mecklin would recommend to screen only the gene carriers (by urinalysis, cytology and sonography).
Stanley Hamilton suggests that DNA-analysis of the urine may be a possibility in the future. Pal M”ller had the opinion that all family members should be screened. Patrice Watson said that the risk in FDR is rather low. In conclusion, there is no consensus regarding screening of HNPCC families for UTC. A prospective study is necessary to evaluate the value of a surveillance program.

New mutation rate of HNPCC (Inge Bernstein)
No abstract available

Surveillance in HNPCC (Patrick Lynch)
No abstract available

3. Linkage studies

Recent results of linkage studies (Paivi Peltomaki)
Are there genes other than COCAI determining HNPCC ( P. Meera Khan) No abstract available .

4. Criteria for HNPCC

James St. John (Melbourne) presented an update on his study of cancer risk in relatives of patients with common colorectal cancer (Ann. Intern. Med 1993;118:785-790). More cases of cancer have occurred in the relatives and additional information about deceased relatives has been obtained since the original data were collected in 1985/1986. As a result, two families almost certainly have HNPCC, despite failing to satisfy the Amsterdam criteria. After their exclusion, features of the colorectal cancers were compared in families with three (or four), two, or just one affected individual. There were no differences in site of cancer (predominantly distal), age, or the proportion with multiple primary cancers between the three groups. Lucio Bertario reported that he has many problems "in clinical practice" using the Amsterdam criteria. In the registry in Milan there are many suspected HNPCC families which do not meet the Amsterdam criteria. 27 families had to be excluded because all cases were older than 50 years at diagnosis. In twelve families there were skipped generations; several families did not meet the criteria because endometrial cancer was not included in the criteria. Especially a great problem is establishing the diagnosis in small families. He suggested to adjust the criteria as follows: (1) one ot the three colorectal cancer cases should be diagnosed below the age of 55 instead of 50; (2) extracolonic cancer should be included in the criteria.
Patrice Watson stressed that the Amsterdam criteria should only be used to select families for multicenter studies. To establish criteria to select families in which surveillance is warranted is extremely difficult. She assessed the influence of changing the age criterium and including also endometrial cancer as one of the criteria in the family material of the Omaha registry. Complete results were to be presented by Dr. Boman at a late session, but that study found no effect of changing the age criterion, but some increase in sensitivity by including endometrial cancer. A discussion about the Amsterdam criteria followed, but it was decided to leave the present criteria unchanged.

5. Proposals for new studies

Dietary intervention in family members at risk for HNPCC (Fokko Nagengast)
Prognosis of colorectal cancer (J.P. Mecklin)
Biological characteristics of HNPCC (Maurizio Ponz de Leon)

The risk of developing rectal cancer after subtotal colectomy (Miquel A. Rodriguez)
As more families are being indentified as HNPCC, more patients are undergoing total abdominal colectomy (TAC) and ileorectal anastomosis at the time of diagnosis of colon cancer. It is unlikely that any single institution has had enough patients to provide meaningful information regarding the fate of the rectum after TAC in HNPCC patients. Therefore a collaborative study is proposed. Methods: A questionnaire will be distributed to each member of the ICG-HNPCC whereby patients who underwent TAC or a lesser procedure will be identified. This patients must be members of families who meet the Amsterdam criteria.
Questions:
1. What is the risk of rectal cancer in these patients who underwent TAC or a lesser procedure?
2. What is the risk of adenomas in those patients who underwent TAC or a lesser procedure?
3. If any of this patients had adenomas in the rectum at the time of TAC, do these disappear after surgery?
4. Possibly integrate M. Ponz de Leon "Biological characteristics of HNPCC" proposal to the rectal tumors and if possible compare these to previous tumors the same patient may have had.

6. ICG-HNPCC Business Meeting

1. Nomination of members
Hans Vasen said that last year 7 specialists (James Church, Frank Kee, Yucun Liu, Kay Macdermot, Miquel Rodriques-Bigas, Klaus Schlaefer, and Hartley Stern) showed interest in joining the group. The group unanimously voted for their membership. The total number of the group, including these new members is 66. Hans Vasen reminded the attendants of the decision made in Torino to keep the number of members low (<50) in order to assure the quality of the (informal) discussions. The group agreed that a balance should be found between keeping the number of participants acceptable in order to maintain the quality of discussions and an open attitude of the group to new enthousiastic and active investigators. Vasen brought into discussion that a further increase of members may require a change of the structure of the meeting. An alternative structure of the meetings would be the structure of the Leeds Castle Polyposis meetings (having 2« days formal presentations including one session in which collaborative studies could be discussed). The group preferred to continue the present format of the meetings (one day informal discussions attached to one day open symposium). James St. John suggests to make the memberschip attached to institutions so that other individuals may represent the formal members if necessary. The group agreed upon this proposal. Henry Lynch was wondering whether yearly meetings are really necessary. The majority of the members had the feeling that because of the fast developments in research yearly meetings are indeed warranted. Hans Vasen said that the increasing number of members of the group had increased the workload at the secretariat of the ICG-HNPCC and also increased the costs of the correspondence. Therefore, he proposed that the members would contribute a small amount of money to meet these costs. There was general agreement about this proposal, although it was stressed that the contribution must be in agreement with the real costs.

2. Special issue Anticancer Research
Hans Vasen reminded the group that last year it was decided to publish the efforts of the ICG-HNPCC in a special issue of Anticancer Research. Vasen said that most of the chapters are completed and that he hoped that it will be submitted for publication by the end of this year.

3. Place and date of the next meeting
Five places were proposed: Milan and Amsterdam (both attached to an international meeting on colorectal cancer) in september and december respectively, K”ln (attached to an international congres on malignancies of the gastrointestinal tract in January 1995), Finland, and Los Angeles, preceding the world congress on gastro-enterology in October 1994. The majority of the members agreed upon Milan as the place of the sixth meeting of the ICG-HNPCC. Lucio Bertario will play the host.

4. Closing remarks
Henry Lynch thanked the organizers and adjourned the meeting.