الفهرس 
materials and methodsOnly 14 pages are availabe for public view
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Abstract
This study aims first, at evaluation of Fhit protein in dysplastic and malignant neoplastic colorectal lesions. Second, to compare and correlate the findings with other clinicopathological variants such as age, sex, site, tumor grade and stage, lymph node metastases and distant metastases and mean apoptotic index. Statistical analysis and correlations were made for all of these variants.
This retrospective study was carried upon 60 Egyptian patients with different colorectal lesions. The patients were admitted to Benha University Hospital and El-Maadi Armed Forces Hospital during the years 1998-2001.
These cases included 19 dysplastic colorectal lesions, 30 primary colorectal carcinomas and eleven cases of chronic colitis were taken as control. The selected dysplastic lesions included ulcerative colitis, hyperplastic polyps with dysplasia, adenomas with dysplasia and dysplastic area at a colostomy site. Dysplastic changes were graded into low and high grades.
Malignant colorectal lesions were divided into 21 adenocarcinomas and 9 mucoid carcinomas. The mean age of cancer patients was 49 years old and 73.3% of them aged below 60 years. The incidence of colorectal cancer in both sexes was nearly equal (male to female ratio was 8 :7).
Malignant tumors were graded into 4 well differentiated tumors, 15 moderately differentiated tumors and 11 poorly differentiated tumors. Dukes’ and SEER staging systems were applied for each tumor case. Lymph node metastases and distant metastases were evaluated for every case.
As regarding Dukes’ stage, there were 10 cases of stage B, 15 cases of stage C and 5 cases of stage D. No cases of stage A were recorded. As regarding SEER stage, there were 10 cases of stage I. 15 cases of stage III and 5 cases of stage IV. No cases of stage II were recorded. Among the 30 cases of malignancy, 10 cases had no lymph node metastases (NO), 6 cases
belonged to N1 state, 10 cases to N2 state and 4 to N3 state. There were 25 cases without evident distant metastases and 5 cases with distant metastases.
The mean apoptotic index for every group of cases was detected by counting the number of apoptotic nuclei per 100 cells in 10 high power fields in H&E sections. For control cases, the mean Al was 0.31%, for dysplastic cases, it was 1.04% and for malignant cases it was 4.17%. Al was significantly correlated with histopathological type and grade of colorectal lesions, with both Dukes’ and SEER stages of the tumor and with &mph node and distant metastases of the tumor. however, the mean apoptotic indices for both adenocarcinomas and mucoid carcinoma were nearly equal.
Fhit protein was detected by immunohistochemical staining technique. In all control cases, Fhit was detected as diffuse moderate to strong granular cytoplasmic staining, mainly in the superficial parts of the crypt more than in the basal parts. This was explained by the apoptosis activating function of Fhit protein. Intensity of Fhit staining, percent of positive cells (extent of Fhit staining) and a composite score (0-9) were obtained for each examined colorectal lesion. Cases with score 5. 3 had reduced or negative Fhit expression, while cases with score > 3 were assessed as positive for Fhit.
Among 19 case of dysplasia, 52.6% of cases were positive for Fhit protein, while 47.4% of cases had reduced or neg tive Fhit expression. In cases of low grade dysplasia, reduced or negative Fhit expression was recorded in 40% of cases, while the reduction of expression was increased to be 55.6% in cases of high grade dysplasia. This was explained by loss of tumor suppressor function of Fhit with rising grade of dysplasia.
In malignant cases, reduced or negative Fhit expression was recorded in 47.6% of adenocarcinomas in comparison to 77.8% of mucoid carcinomas. As regarding tumor grade, all well differentiated, tumors were positive for Fhit expression. On the other hand, 53.3% of moderately differentiated tumors and 81.8% of poorly differentiated tumors showed reduced or negative Fhit expression.
Loss of Fhit protein was associated with advanced stage of the disease. As regarding Dukes’ stage of the tror, 50% of cases of stage B showed reduced or negative Fhit expression in comparison to 80% of cases of stage D. When SEER staging system was applied, stage I and III showed nearly equal percent of reduced or negative Fhit expression (50% & 53.3% respectively), while stage IV showed marked reduction of Fhit expression ( in 80% of cases).
Marked reduction of Fhit expression (in 100% of cases) was observed in cases with N3 state. Also marked reduction of Fhit expression (80% of cases) occurred with evidence of distant metastases.
The intensity of Fhit staining was significantly correlated to histopathological type and grade of $e colorectal ’Son, to Dukes’ and SEER stages of the tumor, to lymph node status and to distant metastases. The extent of Fhit staining was insignificantly correlated to all available clinicopathological data. The composite score was significantly correlated with the histopathological type and grade of colorectal lesion and to Dukes’ stage of the tumor.
This study revealed increasing mean Al from dysplastic to malignant neoplastic cases in spite of decreasing Fhit expression. there were a significant correlation between mean Al and intensity of Fhit staining (P value < 0.05). This could be explained by either consumption of Fhit protein molecules in apoptotic cells OR occurrence of mutation in OHIT gene leading to difficult detection by immunohistochemistry which only detects the normal Fhit protein. Extent of Fhit staining and the composite score were insignificantly correlated to mean Al.
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Summary & Conclusion Conclusion
•FHIT is a tumor suppressor gene that is involved in early steps of colorectal tumorigenesis. Reduction of Fhit expression occurs with rising grade of dysplasia and malignancy’.
<Reduction of Fhit expression is also marked with the higher stage of malignant colorectal tumor.
4 Marked reduction of Fhit expression is indicator of positive lymph node metastases along mesentric arteries, even, aorta and indicator of positive distant metastases.
<Detection of Fhit score in colorectal lesions is a time consuming process with a little value obtained as it gave insignificant correlations with most of data collected for each of the studied cases.
4 Intensity of Fhit staining is more accurate in assessment of Fhit protein expression in different colorectal lesions, in Comparison to extent of Fhit staining and the composite scores;.
4 Apoptosis is increased in higher grades of colorectal dysplastic and malignant neoplastic lesions and in advanced stages of colorectal malignancy.
4 Fhit may be considered as apoptotic activator protein which is reduced or negative in advanced tumor stage in spite of increasing mean Al, due to either consumption of Fhit in apoptotic cells OR mutation of FHIT gene which can not be detected by immunohistochemical technique.
A good correlation of Fhit to prognosis is predicted as Fhit is significantly correlated with tumor stage, lymph node metastases and distant metastases
which all have a highly important ptognostic value in colorectal cancer. t•?
4 So, it is recommended to repeat the study with larger number of cases
and to correlate Fhit expression with prognosis and survival of the patients. This step could not be carried out because of lack of data.