An international group of endoscopists, surgeons, and pathologists gathered in Paris for an intensive workshop designed to explore the utility and clinical relevance of the Japanese endoscopic classification of superficial neoplastic lesions of the GI tract. This report summarizes the conclusions of the workshop and proposes a general framework for the endoscopic classification of superficial lesions of the esophagus, stomach, and colon. The clinical relevance of this classification is demonstrated in tables that show the relative proportion of each subtype in the esophagus, stomach, and colon, assessing the risk of submucosal invasion and the risk of lymph node metastases. In the esophagus, stomach, and colon, neoplastic lesions of the digestive tract are called ‘‘superficial’’ at endoscopy when the endoscopic appearance suggests either a small cancer or a noninvasive neoplastic lesion (dysplasia/adenoma). If invasive, ‘‘superficial’’ tumors correspond to the T1 stage of the TNM classification, in which invasion is limited to the mucosa and submucosa. ‘‘Superficial’’ tumors are nonobstructive, usually are asymptomatic, and often are detected as an incidental finding or by screening. In Japan, neoplastic lesions of the stomach with a ‘‘superficial’’ endoscopic appearance are classified as subtypes of ‘‘type 0.’’ The term ‘‘type 0’’ was chosen to distinguish the classification of ‘‘superficial’’ lesions from the Borrmann classification, proposed in 1926 for ‘‘advanced’’ gastric tumors, which included types 1 to 4. Within type 0, there are polypoid and non-polypoid subtypes. The nonpolypoid subtypes include lesions with a small variation of the surface (slightly elevated, flat, and slightly depressed) and excavated lesions. The Japanese Gastric Cancer Association (JGCA) also added a type 5 for unclassifiable advanced tumors. The complete modification for gastric tumors becomes:

The Paris endoscopic classification of superficial neoplastic lesions : esophagus, stomach and colon.

Colorectal cancer arises through a gradual series of histological changes, each of which is accompanied by a specific genetic alteration. In general, an intestinal cell needs to comply with two essential requirements to develop into a cancer: it must acquire selective advantage to allow for the initial clonal expansion, and genetic instability to allow for multiple hits in other genes that are responsible for tumour progression and malignant transformation. Inactivation of APC — the gene responsible for most cases of colorectal cancer — might fulfil both requirements.

APC , Signal transduction and genetic instability in colorectal cancer

Familial colorectal cancer (CRC) is a major public health problem by virtue of its relatively high frequency. Some 15-20% of all CRCs are familial. Among these, familial adenomatous polyposis (FAP), caused by germline mutations in the APC gene, accounts for less than 1%. Hereditary non-polyposis colorectal cancer (HNPCC), also called Lynch syndrome, accounts for approximately 5-8% of all CRC patients. Among these, some 3% are mutation positive, that is, caused by germline mutations in the DNA mismatch repair genes that have so far been implicated (MLH1, MSH2, MSH6, PMS1, and PMS2). Most of the remaining patients belonging to HNPCC or HNPCC-like families are still molecularly unexplained. Among the remaining familial CRCs, a large proportion is probably caused by gene mutations and polymorphisms of low penetrance, of which the I1307K polymorphism in the APC gene is a prime example. Molecular genetic findings have enabled hereditary CRC to be divided into two groups: (1) tumours that show microsatellite instability (MSI), occur more frequently in the right colon, have diploid DNA, harbour characteristic mutations such as transforming growth factor ‚ type II receptor and BAX, and behave indolently, of which HNPCC is an example; and (2) tumours with chromosomal instability (CIN), which tend to be left sided, show aneuploid DNA, harbour characteristic mutations such as K-ras, APC, and p53, and behave aggressively, of which FAP is an example. This review focuses most heavily on the clinical features, pathology, molecular genetics, surveillance, and management including prophylactic surgery in HNPCC. Because of the diYculty in diagnosing HNPCC, a detailed diVerential diagnosis of the several hereditary CRC variants is provided. The extant genetic and phenotypic heterogeneity in CRC leads to the conclusion that it is no longer appropriate to discuss the genetics of CRC without defining the specific hereditary CRC syndrome of concern. Therefore, it is important to ascertain cancer of all anatomical sites, as well as non-cancer phenotypic stigmata (such as the perioral and mucosal pigmentations in PeutzJeghers syndrome), when taking a family cancer history. (J Med Genet 1999;36:801‐818)

https://jmg.bmj.com/content/jmedgenet/36/11/801.full.pdf

Genetic susceptibility to non-polyposis colorectal cancer

Colorectal cancer is a life-threatening disease that can develop spontaneously or as a complication of inflammatory bowel diseases. Mouse models are essential tools for the preclinical testing of novel therapeutic options in vivo. Here, we provide a highly reliable protocol for an experimental mouse model to study the development of colon cancers. It is based on the mutagenic agent azoxymethane (AOM), which exerts colonotropic carcinogenicity. Repeated intraperitoneal administration of AOM results in the development of spontaneous tumors within 30 weeks. As an alternative option, inflammation-dependent tumor growth can be investigated by combining the administration of AOM with the inflammatory agent dextran sodium sulfate in drinking water, which causes rapid growth of multiple colon tumors per mouse within 10 weeks. Different scoring systems including number of tumors and tumor size identify factors promoting or inhibiting tumor initiation and/or tumor progression, respectively.

An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression

Nonpolypoid neoplastic lesions of the colorectal mucosa.

Background Aberrant crypt foci of the colon are possible precursors of adenoma and cancer, but these lesions have been studied mainly in surgical specimens from patients who already had colon cancer. Methods Using magnifying endoscopy, we studied the prevalence, number, size, and dysplastic features of aberrant crypt foci and their distribution according to age in 171 normal subjects, 131 patients with adenoma, and 48 patients with colorectal cancer. We also prospectively examined the prevalence of aberrant crypt foci in 11 subjects (4 normal subjects, 6 with adenoma, and 1 with cancer) before and after the administration of 100 mg of sulindac three times a day for 8 to 12 months and compared the results with those in 9 untreated subjects (4 normal subjects and 5 with adenoma). All 20 subjects had aberrant crypt foci at base line. Results We identified 3155 aberrant crypt foci, 161 of which were dysplastic; the prevalence and number increased with age. There were significant (P<0.001) correlations between...

https://www.nejm.org/doi/pdf/10.1056/NEJM199810293391803

Aberrant Crypt Foci of the Colon as Precursors of Adenoma and Cancer

Background: Aberrant crypt foci of the colon are possible precursors of adenoma and cancer, but these lesions have been studied mainly in surgical specimens from patients who already had colon cancer. Methods: Using magnifying endoscopy, we studied the prevalence, number, size, and dysplastic features of aberrant crypt foci and their distribution according to age in 171 normal subjects, 131 patients with adenoma, and 48 patients with colorectal cancer. We also prospectively examined the prevalence of aberrant crypt foci in 11 subjects (4 normal subjects, 6 with adenoma, and 1 with cancer) before and after the administration of 100 mg of sulindac three times a day for 8 to 12 months and compared the results with those in 9 untreated subjects (4 normal subjects and 5 with adenoma). All 20 subjects had aberrant crypt foci at base line. Results: We identified 3155 aberrant crypt foci, 161 of which were dysplastic; the prevalence and number increased with age. There were significant (P < 0.001) correlations between the number of aberrant crypt foci, the presence of dysplastic foci, the size of the foci, and the number of adenomas. After sulindac therapy, the number of foci decreased, disappearing in 7 of 11 subjects. In the untreated control group, the number of foci was unchanged in eight subjects and slightly increased in one (P < 0.001 for the difference between the groups). Conclusions: Aberrant crypt foci, particularly those that are large and have dysplastic features, may be precursors of adenoma and cancer.

Aberrant crypt foci of the colon as precursors of adenoma and cancer

Purpose: On the basis of the results of our preliminary trial suggesting that aberrant crypt foci (ACF) could be eradicated by short-term administration of sulindac, in the present study, we explored the feasibility of using ACF as surrogate markers for chemoprevention of colorectal cancer.

Experimental design: Randomly assigned to sulindac (300 mg daily), etodolac (400 mg daily), and placebo groups were 189 subjects without polyps or who had undergone polypectomy. Drugs were administered for 2 months. ACF in the rectal region were counted by magnifying endoscopy. Occurrence of polyps was evaluated at 12 months. A planned interim analysis was conducted.

Results: ACF number at 2 months was significantly suppressed in the sulindac group ( P = 0.0075), but not in the etodolac group ( P = 0.73). In the sulindac group, the numbers of adenomas plus hyperplastic polyps (total polyps) and adenomas at 12 months were significantly ( P = 0.02) and marginally ( P = 0.064) lower, respectively, in comparison with the placebo group; no such difference was observed in the etodolac group. In analysis of only polypectomized subjects, the numbers of total polyps and adenomas in the sulindac group were even more markedly lower, with P values of 0.014 and 0.034, respectively. A similar tendency was confirmed by analyses of the incidence of polyps at 12 months. Suppression rates of total polyps and adenomas in ACF responders to sulindac were significantly greater than in nonresponders. In all groups, compliance was more than 90% and no intolerable adverse effects were observed.

Conclusions: ACF may be useful as surrogate lesions for chemoprevention of colorectal cancer. Clin Cancer Res; 17(11); 3803–11. ©2011 AACR .

See commentary by Thompson and Gerner, [p. 3509][1]

 [1]: /lookup/volpage/17/3509?iss=11

https://clincancerres.aacrjournals.org/content/clincanres/early/2011/03/05/1078-0432.CCR-10-2395.full.pdf

Randomized Double-Blind Trial of Sulindac and Etodolac to Eradicate Aberrant Crypt Foci and to Prevent Sporadic Colorectal Polyps

The effects of Krestin (PSK) on the generation of lymphokine-activated killer (LAK) cells were examined in tumor-bearing mice. BALB/c mice were inoculated subcutaneously with methylcholanthrene-induced fibrosarcoma (Meth A) cells, and PSK was administered intraperitoneally every other day. The reduced LAK activity in tumor-bearing mice was restored by the administration of PSK. Since involvement of the humoral immunosuppressive factor in the impairment of LAK activity has been suggested, the effect of PSK on the impaired LAK activity in the presence of an immunosuppressive factor isolated from the ascites of X5563 (plasmacytoma)-inoculated mice was examined. The activity reduced by the immunosuppressive factor in an in vitro induction of LAK was restored by incubation with PSK. The antimetastatic effect of IL-2 was also augmented by its combined use with PSK. The data provide a rational basis for using PSK in combination with recombinant IL-2 in cancer immunotherapy.

Shuichi Nojiri

Papers

Aberrant Crypt Foci of the Colon as Precursors of Adenoma and Cancer

Aberrant crypt foci of the colon as precursors of adenoma and cancer

Randomized Double-Blind Trial of Sulindac and Etodolac to Eradicate Aberrant Crypt Foci and to Prevent Sporadic Colorectal Polyps

Effect of KrestinR (PSK) on the Induction of IL-2 Activated Killer Cells

The Mechanism of Inhibition of IL-2 Production in Human Cancer Bearers