Giuseppe Cristofaro

Surveillance in hereditary nonpolyposis colorectal cancer: An international cooperative study of 165 families

During its second meeting at Amsterdam in 1990, the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC) decided to carry out a pilot study on colorectal cancer surveillance in HNPCC. The objectives of the study were to ascertain in each of the participating centers the number of HNPCC families, the recommended screening procedures, the age at diagnosis of colorectal cancer (CRC), and the occurrence of interval cancers. Nine centers in seven countries including Denmark, Finland, Italy, Japan, The Netherlands, Switzerland, and the United States participated. Data were derived from a total of 165 families. With respect to screening, half of the centers advise colonoscopy as the only procedure. The interval between the consecutive examinations varies from one to three years. In the majority of the centers, screening begins at 20 to 25 years. Lifelong screening is recommended by three centers, while the rest advise discontinuation at age 60 to 75 years. The family material included 840 patients with colorectal cancer. The mean age at diagnosis was 45 years, and about 15 percent were diagnosed at age 60 or later. A total of 682 high-risk relatives are being followed. After the follow-up of 1 to 10 years in these families, only six cases of interval cancers were encountered.

Differential diagnosis of hereditary nonpolyposis colorectal cancer (Lynch syndrome I and Lynch syndrome II)

Increasing recognition of the statistical burden posed by HNPCC (5 to 6 percent of all colorectal cancer) mandates that physicians have a better understanding of the genetics, natural history, and distinction between the hereditary site-specific variant (Lynch syndrome I) and the Cancer Family Syndrome (Lynch syndrome II). The authors report detailed cancer (all sites) family histories on two prototype families with Lynch syndrome I (Family R) and Lynch syndrome II (Family N), which have been under investigation for more than two decades. Emphasis is placed on shared clinicogenetic features; namely, early age of onset of colonic cancer (approximately age 44), multiple primary colonic cancer (24 percent of cases showed metachronous colonic cancer), predominance of proximal colonic cancer location (approximately 65 percent in the proximal colon), and vertical transmission consonant with an autosomal dominantly inherited factor. An increased predilection for extracolonic cancer, particularly endometrial carcinoma, occurs in Lynch syndrome II and is the primary basis for distinction from Lynch syndrome I. Surveillance and management programs must be wholly responsive to these natural history features.

Adenocarcinoma of the small bowel in Lynch syndrome II

Adenocarcinoma of the small bowel is rare and accounts for about 1% of all gastrointestinal tract cancer. This disorder has been identified in association with Crohns disease, celiac disease, Peutz‐Jeghers syndrome, and familial adenomatous polyposis. We report adenocarcinoma of the small bowel in nine patients from eight Lynch syndrome II extended pedigrees. Each affected patient was in the direct genetic lineage or manifested multiple primary cancers (stomach, colon, endometrium, and ovary) consonant with the tumor spectrum of Lynch syndrome II. The average age of onset for small bowel cancer was 47 years (range 31 to 56 years), versus the general population peak occurrence after the sixth decade. We conclude that small bowel cancer may be an integral component of the tumor spectrum of Lynch syndrome II.

History of the International Collaborative Group on Hereditary NonPolyposis Colorectal Cancer

The International Collaborative Group on Hereditary NonPolyposis Colorectal Cancer (ICG-HNPCC) is 14 years old. It was conceived in Jerusalem in August 1989 during the 2nd International Conference on Gastrointestinal Cancer organized by Paul Rozen. During this meeting, Giuseppe Cristofaro of Brindisi, Italy, proposed to Henry T. Lynch (Figure 1) that they should form a group of interested colleagues throughout the world to study HNPCC and to form multiple collaborations in the interest of investigating the genetic, clinical and pathologic aspects of the disease. Henry T. Lynch, Jane Lynch, Patrick Lynch, Jukka-Pekka Mecklin, Giuseppe Cristofaro, Jim St. John and Hans Vasen then met informally and agreed that this idea was quite logical given the growing interest in HNPCC. We reasoned that the syndrome’s genotypic and phenotypic heterogeneity would require the study of large numbers of families with detailed pedigrees. These studies would involve meticulous clinical histories, molecular genetics, pathology, surveillance, and management concerns, as well as genetic counseling, in order to grasp a better understanding of the disorder and, most importantly, to benefit the high risk patients and families. Further discussion and announcement about the establishment of the ICG-HNPCC took place in November 1989 at a plenary session of an International Meeting on Colorectal Cancer sponsored by Joji Utsunomiya in Kobe, Japan (see Figure 2).

Lynch Syndromes I and II - Natural History, Diagnosis and Control Strategies

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited disorder which often shows a distinctive natural history but which lacks any well-defined phenotypic stigmata or biomarkers of cancer susceptibility. This is in striking contrast to its familial adenomatous polyposis (FAP) counterpart, with its distinguishing phenotype of multiple colonic polyps. In addition, the recent identification and characterisation of the APC gene in this region, and demonstration that FAP is caused by mutations in this gene, will enable studies that will define this disease at the biochemical level [1–4]. This discovery adds an entirely new dimension to FAP and may harbour important pathogenetic implications to cancer in general. In comparison to FAP, an HNPCC diagnosis is wholly dependent upon the recognition of certain salient features of its natural history in concert with a detailed pedigree based upon a family history of cancer of all anatomic sites.

Cost-Benefit Implications in the Surveillance of Lynch Syndrome Subjects

Hereditary diseases, especially tumours of the gastrointestinal (Gl) tract, are gaining interest throughout the world [1,2]. They represent a unique model for the understanding of the aetiology of cancer and its biological behaviour, enabling us to introduce preventive strategies and possibly newer, more sophisticated therapies which are currently being searched for by molecular biologists [3].

Medical/Legal Concerns in the Management of Patients from Lynch Syndromes Kindreds

The management of patients affected or at risk for the Lynch Syndromes must focus upon its natural history, early age of onset, predilection for the proximal Colon, excess of synchronous and metachronous Colon cancer, and autosomal dominant mode of inheritance (Lynch Syndrome I). In addition, predisposition to carcinoma of the endometrium, ovary, stomach, pancreas, and other anatomic sites are integral features of the Lynch Syndrome II counterpart [Lynch H.T., 1985, 1988, 1988a]. The absence of biomarkers for the genotype and/ or premonitory signs, such as multiple colonic adenomatous polyps, as occurs in the familial adenomatous polyposis (FAP) syndrome, makes the job of the diagnostician a vexing one [Cristofaro G., 1988, 1989].

Historical and Natural Cancer History Facets of the Lynch Syndromes

Knowledge of cancer genetics, in concert with a thorough cancer family history, has the potential for providing one of the most powerful tools for the recognition of patients at high risk for cancer of specific anatomic sites. These facts have enabled the collection of a prodigious body of descriptive data dealing with the genetics of colorectal cancer. We shall discuss one facet of this problem; namely, the historical background and characteristics of the natural history, which has led to the recognition of hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II). Since premonitory clinical signs of cancer risk are lacking in this disorder(s), it is clear that priority must now be given to the search for biomolecular markers of cancer risk.

Crypt Atrophy of Colorectal Mucosa in Lynch Syndromes I and II: Its Characteristics and Meaning, Preliminary Observations

In twelve young patients (7 males and 5 females, mean age 30.5 years) with findings of Lynch syndromes, crypt atrophy with macrophage excess in colorectal mucosa have been noted. The authors tried to support the simple subjective observation with morphometrical data. Evaluation of the specimens of colonic mucosa was performed, using a semiautomatic Video-Assistence-Unit attached to a microscope. In our set, the mean of the Volume Fraction of crypts is 37.43 (S.D. 9.6), considerably below the values found in 15 healthy subjects used as control group (Mean = 58.75, S.D. = 12.7). Our results suggest that crypt atrophy in young relatives at risk could be considered a premonitory phenotipic manifestation, advising to put under special control patients who show this pattern and to investigate, whether they are more likely to develop carcinomas than the general population.

Cellular Immune Response in Lynch Syndrome II on Gastrointestinal Biopsy

Immunoregulatory cell interactions between macrophages and T-cell subpopulations suggest the need for evaluation of the cellular immune response in gastrointestinal mucosa of asymptomatic subjects with Lynch Syndrome II. It was observed that macrophages pool coexists with T-cell subsets which had almost the same cellularity. However, an interesting movement of the immune cells distribution correlated to age were observed.