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The main aim of this paper is to evaluate, by reviewing the most pertinent literature, both the prognostic impact of the mesorectum status in patients with cancer of the rectum and the rationale for mesorectal excision. Recent literature has been considered with special reference to the outcomes of the mesorectal surgical treatment on the relapse rate and survival. The infiltration of the mesorectum adversely affects the prognosis of the patient after a curative operation, whereas it is doubtful whether its excision per se is able to improve the prognosis. Therefore, involvement of the mesorectum may be considered to be an important indicator of already advanced and aggressive malignancy more than the true cause for the relapse. In fact, lately, some authors have pointed out that the extent of the mesorectal excision should be tailored to the specific case in order to achieve adequate and safe surgical margins and have enough prognostic information. Indiscriminate total mesorectal excision in all rectal tumours is not supported by data showing a prognostic improvement. Consequently, surgical management should be carefully planned considering the potential risks and the complications affecting this procedure.

Adenomatous polyposis coli (APC) is an autosomal dominant disease characterized by the development of hundreds of colorectal adenomatous polyps during the first decades of life. The expression of the disease varies, as the age of onset of colonic cancer and the severity of extracolonic manifestations often differ between affected families. An attenuated form of APC has also been described in which a small number of polyps and a later age of onset of colonic cancer is observed. Cloning of the APC gene has allowed disease-causing mutations in APC families to be identified. Here, we report a novel splice site mutation (a G to T transversion at position +5 of the splice donor site in intron 9) in the APC gene of affected individuals in an Italian family. Characterization of the transcription products from this mutant APC allele revealed that normal splicing was disrupted: a shorter mRNA was expressed in which exon 8 was connected directly to exon 10. This created a shift in the reading frame and the introduction of a stop codon at position 1358. In addition, some normal APC transcript was produced from the mutant allele in lymphoblastoid cells. A comparison of the clinical features of affected members of this family with four unrelated Italian APC kindreds, in which the same AAAAG deletion at position 3926 has been found, showed a significant difference in the onset of disease symptoms and in the age of death attributable to colorectal cancer. Inefficient exon skipping may be, at least in part, responsible for the delay in the development of the disease in the reported family.

Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common inherited cancer syndromes, accounting for 3-5% of all cases of colorectal cancer. In most HNPCC families, the disease is caused by a germline mutation in MLH1 or MSH2. In some populations, founder mutations appear to explain a substantial fraction of HNPCC. We report here the identification and preliminary characterization of two putative MLH1 founder mutations. The mutation MLH1c.1831delAT was shown to segregate in two Quebec families of Italian origin who fulfilled the Amsterdam criteria for HNPCC. Haplotype analysis using five intragenic microsatellite/single nucleotide polymorphism markers spanning MLH1 on chromosome 3 showed that these two unrelated families share an identical haplotype. In addition, two other Italian kindred whose affected members carry MLH1g.IVS6 + 3AG also share a common haplotype, suggesting that, similarly, the latter mutation has a common origin. These mutations are the first putative founder MLH1 mutations to be identified in HNPCC kindred of Italian origin.

There is controversy regarding which type of surgical treatment is most appropriate for upper gastric cancer invading the oesophagus.A review of the pertinent literature was carried out regarding oesophageal involvement in gastric cancer.Invasion of the oesophagus occurred in 26-63% of Western surgical series. It was more frequent in Borrmann IV type, linitis plastica, pT3-pT4, diffuse type by Lauren, N+ or tumours exceeding 5 cm in diameter. Lymphatic tumour spread was caudad (coeliac nodes, hepatoduodenal nodes, paraortic nodes) but mediastinal nodes were also involved if tumour growth in the oesophagus exceeded 3 cm or if there was transmural oesophageal infiltration. In Western countries there was less than 30% 5-year survival and no long-term survivors when hepatoduodenal or mediastinal nodes were metastatic. Mediastinal dissection through thoracotomy did not provide any benefit.A rational approach involves total gastrectomy plus partial oesophagectomy. Abdominal transhiatal resection may be performed in the case of a localized, non-infiltrating tumour and oesophageal involvement2 cm. However, infiltrating, poorly differentiated or Borrmann III-IV tumours require a right thoracotomy to achieve a longer margin of clearance. When oesophageal involvement is3 cm, or hepatoduodenal or mediastinal nodes are positive, no surgical procedure is curative and the literature demonstrates that extended aggressive surgery has no benefits.

Colorectal carcinogenesis is a multistep process with an apparently orderly progression from benign tissue to invasive malignancy and metastases. Yet at the genome level, a considerably more chaotic situation exists, with order arising through the process of natural selection in the midst of genomic instability. Major pathways for colorectal carcinogenesis begin with suppressor loss or acquisition of a mutator phenotype, but there are other pathways known and yet to be described. These pathways result in the natural selection of cells with unstable genomes leading to malignancy and metastases.

Germline mutations in the APC gene are responsible for familial adenomatous polyposis (FAP), a dominantly inherited syndrome characterized by the development of hundreds to thousands of polyps in the colon and in the rectum of affected individuals and by variable extracolonic manifestations (gastric and duodenal polyps, osteomas, retinal lesions, and desmoid tumors). Through the combined use of single-strand conformation polymorphism (SSCP) analysis and the protein truncation test (PTT), we have screened 66 Italian FAP patients and found 29 different APC mutations in a total of 34 cases. Of the identified mutations, 15 were nonsense, 12 were 1- to 5-bp deletions or insertions and two were complex rearrangements, all leading to the formation of premature stop codons. Only 10 mutations had been already previously described at the germline level, confirming the high heterogeneity of the APC mutational spectrum. The mean age of diagnosis in mutation positive cases and their affected relatives was significantly lower than in cases without identified mutation (30.6 vs 39.1 years, respectively; p = 0.003). In addition, among patients without a family history of polyposis, all mutation-positive cases displayed at least one of the extracolonic manifestations usually associated with FAP, whereas in one-half of the cases without identified mutation, none of these phenotypes was observed. Although a fraction of apparently mutation-negative cases were likely to be due to limitations of the mutation screening strategy, our results suggest, in agreement with previous reports, that allelic and/or genetic heterogeneity might be responsible for the phenotypic variability observed in FAP patients.

A potential tumor suppressor gene, STK11 , encoding a serine threonine kinase, has recently been identified on chromosome 19p13. Germ-line mutations of this gene have been found in patients with Peutz-Jeghers syndrome (PJS). To further investigate the relevance of STK11 mutations in PJS, we analyzed its coding sequence in nine patients and identified two deletions and three missense mutations. Because intestinal carcinomas have been observed to develop in association with PJS, we analyzed tumors from 71 patients for allelic deletions (loss of heterozygosity) and STK11 gene mutations, to elucidate the etiological role of STK11 gene in sporadic colorectal cancer. Loss of heterozygosity, evaluated using the microsatellite D19S886, was observed in 10 of 52 informative cases. No somatic mutations were detected except for a missense alteration in one tumor. Our data indicate the heterogeneity of PJS and the infrequent involvement of the STK11 gene in colorectal cancer.

Small bowel carcinoma is uncommon. However, hereditary nonpolyposis colorectal carcinoma (HNPCC) patients are at increased risk of small bowel carcinoma. The purpose of this study was to characterize small bowel tumors in HNPCC patients.A questionnaire was mailed to the members of International Collaborative Group on HNPCC (ICG-HNPCC) requesting clinicopathologic data in their registries on HNPCC patients with small bowel carcinoma. Survival was estimated utilizing the Kaplan-Meier method.Forty-two individuals from 40 HNPCC families developed 42 primary and 7 metachronous small bowel tumors. There were 46 adenocarcinomas and 3 carcinoid tumors. The median age at diagnosis of the index small bowel tumor was 49 years. Mismatch repair gene mutations were present in 15 of 42 patients (36%). There were nine hMLH1 and six hMSH2 mutations. The small bowel was the first site of carcinoma in 24 patients (57%). The median survival for the 42 patients was 47 months (range, 0-447 months). The overall 5- and 10-year survival rates were 44% and 33%, respectively.Small bowel tumors can be the presenting neoplasms in HNPCC patients. Similar to colorectal carcinoma in HNPCC, small bowel adenocarcinomas in HNPCC patients occur at an earlier age and appear to have a better prognosis than those occurring in the general population.

Primary melanomas (M) of the rectum and anal canal are a rare pathological event, constituting approximately 1% of all invasive tumors in this site. From January 1973 to December 1990 at the Istituto Nazionale per lo Studio e 1a Cura dei Tumori of Milan, 11 patients were treated for M (5 males and 6 females), with a mean age of 60 years (range 40-80). The site of origin of the M was rectal in four patients, anal in five patients and in the anorectal joint in two patients. The lesion was prevalently polypoid and the average size was 4 cm (1-7.5 cm). Symptoms referred by the patients were rectal bleeding and tenesmus. In one patient the diagnosis was made after biopsy of an inguinal metastatic lymphnode. Of the 11 patients, six underwent curative resection (four Miles' resections and two local excisions). One patient is still alive with no evidence of disease after 120 months. The remaining five patients were submitted to palliative treatment, due to the presence of metastases in four of them and to age and general conditions in one. All of these patients died at 1, 2, 4, 5, and 6 months (median: 4 months). Overall median survival was eight months: 20 months in the radically treated group and four months in the palliatively treated group. Our data are in agreement with those reported in literature and confirm the prognostic severity of anorectal M due both to late diagnosis and the biological aggressiveness of the neoplasm.

The authors report about a survey on the behaviour of 51 departments of surgery in Lazio and Lombardia as to diagnosis, staging and therapy of carcinoma of the medium-lower one-third of the rectum. A set of 722 patients treated in 1993 was considered. A questionnaire was distributed and answers collected about the staging protocols, the therapeutic choices and some details of surgical technique as the ligation of the lower mesenteric artery or the extent of the lymphadenectomy. The results indicate some stable trends as to preoperative study (digital examination and fibre optic endoscopy in almost all cases) and as to the choice of the technique of anastomosis (43.1% of termino-terminal stapled anastomosis). Intrarectal ultrasound gains consensus but is still not much diffuse (18.6% of cases). Almost all of the participating Institutions agreed in joining further prospective studies.

From 1975 to 1993, at the Division of Diagnostics and Endoscopic Surgery of the Istituto Nazionale Tumori in Milan, 191 malignant adenomas of colon-rectum have been endoscopically removed. On the basis of histopathologic criteria, endoscopic treatment has been judged adequate in 102 cases (53%), not adequate in 44 (23%), doubtfully adequate in 45 (24%). In 84 patients (44%) endoscopic polypectomy has been followed by surgical resection of the involved intestinal tract, 107 patients (56%) have been treated only by endoscopy. Results have been evaluated on the basis of surgical specimen, clinical follow-up and survival, showing that criteria we have adopted for the adequacy of the endoscopic treatment have a high negative predictive value (96%) and a low positive predictive value (32%). Actuarial survival of patients treated only endoscopically is 97% at 5 years and 95% at 10 years.

Causes of death were evaluated among 350 deceased patients with familial adenomatous polyposis (FAP) recorded in the Italian Polyposis Registry: 78.1% were due to colorectal cancer, 9.5% to extracolonic cancer (more than half of the upper gastrointestinal tract), 3.6% to desmoid tumors, and 8.8% to other causes. The age at diagnosis among 604 patients was studied in relation to presence of symptoms at presentation and presence of colonic cancer at surgery. In asymptomatic patients younger than 30 years the risk of colonic cancer was 3.3% and in symptomatic patients older than 40 it was 80%. A life-table analysis showed that postsurgical survival among patients without cancer at colectomy was 68% after 30 years, whereas that of patients with cancer was 41% after 10 years. The alternative prophylactic treatments of total colectomy with ileorectal anastomosis versus total proctocolectomy (IRA vs. IAA) were compared in terms of postsurgical survival. Both treatments showed a survival of 83% after 10 years. The risk of cancer in the rectal stump after IRA was 14.5% after 15 years and 25.2% after 25 years; the corresponding risks of dying from it were 4.3% and 9.3%, respectively.

Adenomatous polyposis coli is an autosomal dominant disease characterized by the development of hundreds of colorectal adenomas in young adults. If prophylactic colectomy is not performed, colorectal cancer develops in virtually all affected individuals by the fifth decade of life. All at-risk relatives older than 10 years of age need to be screened regularly by endoscopy. Recently, the gene responsible for the disease, the APC gene, was cloned. The finding of inactivating mutations of the APC gene in Italian APC patients allowed us to offer DNA-based diagnostic tests to these 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.

From 1979 to 1989 at Istituto Nazionale Tumori of Milan, 2,629 individuals at high risk for Family History of Large Bowel Cancer (first degree relatives) were screened by guaiac test combined with endoscopy. The test was positive in 95 patients (3.6%), 88 out of them (92%) and 545 H− (21.5%) accepted the endoscopic examinations. 27 colorectal cancers (21 H+, 6 H−) and 89 patients with adenomas (23 H+, 66 H−), mostly in the left side of bowel, were detected. During the follow-up (median 67 mths) 1,492 individuals (60%) were rescreened: 5 cancers and 50 pts. with adenomas were detected. Instead in the non responders group 3 cancers and 4 adenomas were diagnosed (median interval between cancer, adenoma in H-: 26 mths, 24 mths). The overall prevalence for cancers was 1.3% and 5.5% for adenomas. The sensitivity of the test for cancers and adenomas was calculated in about 77% and 29% with a specificity of 98%. The data confirm the opportunity to screen individuals at high risk for family history suggesting annual rescreening.

Patients with a personal history of rectal cancer are considered at high risk for metachronous large-bowel primaries. Since a malignant growth was the main reason for performing a colostomy in patients followed at the centers of the authors' association (AISTOM), a correct follow-up approach for these patients is very important. A multicentric clinical trial was thus carried out to evaluate the efficacy of transstomal endoscopic exploration (TEE) of the residual colon, and data collection began on May 31, 1984. Nine hundred fifty-seven patients were submitted to TEE after curative abdominoperineal resection (Miles) for rectal cancer. The male-female ratio was 1.3;89.6 percent of the patients were over 50 years of age. A family history of large-bowel cancer was present in 18 percent, and in 23 percent of the patients the cancer was associated with synchronous adenomas. Only 31 percent of the patients had colonoscopy or double-contrast barium enema x-ray beyond the neoplastic area before the surgery. TEE was done in 96.8 percent of the patients; in 3.3 percent the examination was not possible, mainly for stenosis of the stoma (in 2.3 percent). In 82 percent of the patients a complete large-bowel exploration was possible: a new large, bowel cancer was found in 22 patients (2.2 percent) and an adenoma in 183 patients (19.1 percent). These results show that, because it is safe, practical, and effective, endoscopy plays an important role in the follow-up of ostomates.

Nineteen cases of pulmonary carcinoid tumors, three of which showed clinically malignant behavior, are reported. The diagnostic and therapeutic possibilities are discussed. Diagnosis is sometimes possible on radiologic examination, when the clinical behavior is not yet malignant. However, these tumors are frequently mistaken for malignant heteroplasias, during the diagnostic work-up so that the postoperative histologic examination results are sometimes surprising. The clinical postoperative course is favorable in the majority of cases, and in the eight cases, we were able to follow up for more than five years, there was only one recurrence. Although pulmonary carcinoids are histologically similar to intestinal carcinoids, and like the latter are abundantly vascularized, they are only rarely accompanied by the carcinoid syndrome, which is often observed in the intestinal form.

The presence of cellular retinoic acid binding protein (cRABP) was analyzed in 13 consecutive patients with large bowel cancer (one right colon and 12 rectum-sigmoid, classified as three Duke B, eight C, and two D). Specimens of neoplastic tissue and of adjacent mucosa were obtained at surgery, and cRABP was determined by an assay based on incubation of partially purified cytosol with labeled retinoic acid and ultracentrifugation in sucrose density gradients. Sixty-one percent of tumors contained detectable levels of cRABP, whereas 58.3% of normal mucosal specimens were positive for cRABP. Among the positive tumors 62.5% contained cRABP also in the corresponding mucosa; in the group of cRABP-negative tumors, 40% showed cRABP in the adjacent mucosa. No correlation could be established with the grading or the stage of the tumors; however, interestingly, 100% (three cases) of gelatinous carcinomas were cRABP positive. Since cRABP seems to be a character of neoplastic cells contrary to normal ones, it would be interesting to investigate the conditions that influence the presence of this protein in normal appearing mucosa adjacent to carcinoma.

From 1979 to 1982, 1233 symptom-free subjects at high risk for colon cancer because of family history and/or personal history of bowel neoplasia (cancer or adenomatous polyp) were examined with a guaiac test (Hemoccult II) for occult blood in stools. The test was positive (H+) in 98 subjects (7.9%). Endoscopy was subsequently performed on 86% of the H+ and on 64% of the H- subjects. Of 20 in invasive cancers found, 15 had been H+ [75.0%; 95% confidence interval (CI), 54.3-91.0%]. Of 96 patients with adenoma(s), 23 were H+ (24%; 95% CI, 16.0-33.0%). However, the sensitivity for adenomas was higher in patients with multiple adenomas or with a single adenoma measuring 2 cm or more in its largest diameter (37.5%; 95% CI, 21.8-54.7%). Of 699 subjects free of neoplastic lesions at endoscopy, 47 had been H+, ie, false positive (6.7%; 95% CI, 5.0-8.7%). Adjusting for differential compliance of H+ and H- subjects to endoscopy, a corrected estimate for sensitivity would be 69% for cancer and 19% for adenomas; the corrected estimate for the false-positive rate would be 5%.

The radiographic appearance at double contrast enema of 33 cases of invasive cancer on adenomatous polyps (AP) of the colon is reviewed. The radiologic diagnosis of malignancy was prospectively made in 54.5% of the cases. In 45.5% of the cases, malignancy was not suspected at the time of examination. The endoscopic appearance of these lesions was identical to that seen on the barium study. There are no radiologic criteria able to entirely rule out the possibility of a carcinomatous transformation of an AP. However, the radiologic features of malignancy (indentation of the intestinal wall and/or irregular outline of the surface of the polyp) have to be considered quite reliable.