Distinct molecular patterns based on proximal and distal sporadic colorectal cancer: arguments for different mechanisms in the tumorigenesis.

BACKGROUND AND AIMS: Colorectal cancer (CRC) ranks as the fourth most frequently diagnosed cancer worldwide. CRCs that arise proximally or distally to the splenic flexure show differences in epidemiologic incidence, morphology, and molecular alterations, suggesting the existence of two categories of CRC based on the site of origin. The aim of the present work is to investigate the histological and molecular differences between CRCs located proximally and distally to the splenic flexure, and their potential involvement in tumor prognosis and therapeutic strategies. METHODS: We evaluated 120 patients affected by sporadic CRC for clinicopathologic features, microsatellite instability (MSI), loss of heterozygosity (LOH) of chromosomes 18q, 8p, and 4p; they were also investigated for hMlh1, hMsh2, Fhit, p27, and Cox-2 immunostaining. RESULTS: The mucinous histotype was more frequent in the proximal than in the distal CRCs (p<0.004). The frequency of MSI phenotype was higher in proximal than in distal tumors (p<0.001); moreover, reduced or absent hMlh1, Fhit, p27 immunohistochemical expressions were more frequent in proximal than in distal tumors (p<0.001 and 0.01 for p27). In contrast, the frequency of LOH in 18q was higher in distal than in proximal tumors (p=0.002). No significant differences were observed between proximal and distal tumors in the frequency of LOH in 8p and altered expression of hMsh2 and p53 protein. CONCLUSION: These different features may reflect different genetic pathways of carcinogenesis and support the hypothesis of a different mechanism of cancer development between the proximal and the distal colon, with potential implications in the therapeutic approach.

Loss of p27 expression and microsatellite instability in sporadic colorectal cancer.

BACKGROUND: The role of the loss of p27 protein expression in the oncogenesis of colorectal cancer is still in debate. In this study, we prospectively examined the immunohistochemical expression of p27 in 108 consecutive colorectal cancers, and we analysed the relationship with the results, the clinicopathological data, microsatellite instability (MSI) and other genetic alterations of tumours. METHODS: Unselected patients (108) who underwent curative colorectal resection for sporadic colorectal cancer in a three-year period were evaluated for MSI using 6 microsatellite markers, and for the presence of p27, p53, Fhit, Mlh1 and Msh2 proteins by means of immunostaining. The relationships between these markers were analysed. p27 protein expression was examined for association with disease recurrences and survival. RESULTS: Lack of p27 expression was noted in 33 out of 108 (30.5%) colorectal cancer cases (P<0.05). This altered expression was significantly higher in proximal cancers (P<0.05), mucinous tumours (P<0.001), poorly differentiated histology (P<0.01), cancers with MSI (P<0.05), tumours with altered expression of Mlh1 (P<0.01), of Msh2 (P<0.05), and of Fhit (P<0.01). Overall survival was better in the patient group with altered level of phenotypic p27 expression, although the difference does not reach statistical significance (P=0.069). The analysis performed only for patients with tumour at stage II showed significantly better survival when the tumour exhibited altered p27 expression (P<0.02). CONCLUSIONS: The results of the present study support the hypothesis that altered expression of p27 may be part of the genetic pathway involving MSI, which is responsible for the development of some colorectal cancers.

Prospective comparison of laparoscopic left hemicolectomy for colon cancer with laparoscopic left hemicolectomy for benign colorectal disease.

BACKGROUND: Short-term outcome and anorectal function results after laparoscopic hemicolectomy for colon cancer were compared with results after laparoscopic hemicolectomy for benign diseases. METHODS: A total of 108 patients who underwent laparoscopic left colectomy (60 for colon cancer, 48 for diverticulitis or polyposis) were enrolled in the study. Left hemicolectomy in patients affected by cancer was performed by high ligation of the inferior mesenteric artery. A questionnaire concerning anorectal function was mailed to patients 6 months after surgery. RESULTS: Complications were more frequent in the cancer group than in the benign disease group: overall morbidity rate (29.6% versus 8.7%; P = 0.009), diarrhea during the first 6 postoperative months (58.7% versus 34.1%; P = 0.022), and anorectal function problems (fecal incontinence and/or the inability to discriminate between gas and stool, and/or urgency, and/or tenesmus) (65.2% versus 31.7%; P = 0.002). DISCUSSION: The level of ligation of the lower mesenteric artery and damage at the lower mesenteric ganglion could explain the poorer anorectal function outcome in the colon cancer group.