Telomere shortening in chronic liver disease and hepatocellular carcinoma
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April 1995 AASLD A1099 • TELOMERE SHORTENING IN CHRONIC LIVER DISEASE AND HEPATOCELLULAR CARCINOMA. T. Kitada, S. Seki, N. Kawakita, H. Sakaguchi, Y. Ichikawa, T. Kuroki, K. Kobayashi, T. Monna Dept, &Public Health and 3rd Dept. of Internal Medicine., Osaka City University, Medical School., Osaka, Japan. The structure of the chromosome ends, called telomere,may play a major role in protecting the chromosome ends from abberant recombination and end to end fusion, l~duction in telomere length can lead to genomic instability and genetic alterations of possible significance of tumor development. Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies in the world. HCC is considered to be caused by genetic alterations which accumulate in the hepatocytos during the chronic liver damage. Thus it is of much interest to examine whether telomere reduction which leads to genomic instability can be detected in chronic liver disease. Herein, we measured telomere length in the livers with chronic liver disease and in normal livers. We also examined whether there was a telomere reduction in HCC. (materials & methods) Twenty-eight patients with liver disease ( 10 with chronic hepatitis, 12 with liver cirrhosis, 6 with HCC) were included in this studyl 5 histologically normal liver tissues were obtained at the time of surgery from patients without chronic liver disease. After DNA preparation, Southern blot analysis was performed using a gigoxigenin-labeled (TrA~) 4 as a probe. (results) We found a significant correlation between age and telomere length. To separate the effect of age on telomere length, we used analysis of covar/ance. The group with normal livers had longer telomere than the group with chronic hepatitis (p=0.002) and than the group with cirrhosis (p<0.001). In chronic liver disease, the telomere length tended to decrease with progression of liver disease.The telomere length in HCC was shorter than that in noncancerous surrounding liver in all cases we examined. (conclusion) We found a significant telomere reduction in the livers with chronic liver disease compared to those in the normal livers as a risk factor for genomic instability for hepatocarcinogenesis. Analysis of proliferative activity in small hepatocellular carcinoma (HCC) (<2 cm) using proliferating cell nuclear antigen (PCNA) immnno-staining --comparison with DNA ploidy study--. M. Kitamoto, T. Nakanishi, R. Nakashio, S. Kira, K. Tsuji, Y. Watanabe, G. Kajiyama. First Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima 734, Japan. We previously described of the significance of proliferative activity in small HCC using PCNA immuno-staining in this association (1993,1994). In this study, we examined the relationship between DNA ploidy study and proliferative activity in 25 small HCC nodules (<2 cm) resected. Method: PCNA immuno-staining was performed and we determined PCNA LI according to our previous report. All nodules were examined by DNA ploidy study using flowcytometry. We investigated the differences between the nodules of DNA diploidy and that ofDNA aneuploidy in view ofhistologicai findings and PCNA LI. Results: Of 18 diploidy nodules, 15 (83%) were well differentiated type, 2 (11%) moderately differentiated type and 1(6%) poorly differentiated type. Of 7 aneuploidy nodules, 2 (29%) were well differentiated type, 2 (29%) moderately differentiated type and 3 (42%) poorly differentiated type. The incidence of microscopic aggressive lesions such as capsule invasion, vascular invasion and intrahepatic metastasis was 17% (3/18) in diploidy nodules and 43% (3/7) in aneuploidy nodules. The PCNA LI of diploidy nodules ranged from 0.2 to 42% (average 7.0%) and that of aneuploidy nodules from 1.3% to 72.5% (average 27.0%), difference that was statistically significant (P<0.05). Conclusion: In small HCC, the diploidy nodules were often well differentiated and had rare microscopic aggressive lesions. The proliferative activity of the diploidy nodules was significantly lower than that of the aneuploidy nodules. Long term prognosis of small hepatocellular carcinoma (HCC) (<2 cm) treated by percutaneous ethanol injection therapy (PEIT). M. Kitamoto, T. Nakanishi, S. Kira, R. Nakashio, K. Tsuji, Y Watanabe, G. Kajiyama. First Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima 734, Japan. Recently, the prognosis of HCC patients improved because of the development of imaging diagnostic techniques such as ultrasonography and computed tomography, the development of safety resection and the development of non surgical treatments especially PEIT. According to The Liver Cancer Study Group of Japan, it was reported that among small HCC (<2 era) 5- year survival rates were 55% in surgical resection cases and 3-year survival rates were 53% in patients treated by PEIT. In this study, we evaluated the prognosis of small HCC treated by PEIT. Patients: We treated 21 patients with solitary small HCC nodule (<2 cm) diagnosed histologically by fine needle biopsy. The tumor size ranged from 10 mm to 20 nun (average 16 mm) in diameter. Histologically, 17 nodules were well differentiated and 4 moderately differentiated. By the classification according to Child grade, 10 patients were in the Child grade A, 10 in the Child grade B and 1 in the Child grade C. Results: The 2- and 4-year survival rates were 92% and 80%. The 2-and 4-year recurrence rates were 38% and 56%. Although transient pain and slight fever elevation were present in most patients, no serious complications were observed. These data revealed that PEIT was associated with fairly good prognosis in solitary small HCC. Conclusion: PEIT facilitated the long term prognosis of solitary small HCC as well as surgical resection. Long term prognosis of small hepatocelular carcinoma (HCC) in view of proliferating cell nuclear antigen (PCNA) labeling index (LI). M. Kitamoto, 17,.Nakashio, S. Kira, K. Tsuji, Y. Watanabe, T. Nakanishi, G. Kajiyama. First Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima 734, Japan. We previously reported that proliferative activity evaluated by PCNA LI closely related the prognosis after resection (Cancer72:1859- 65,1993). In this study, we examined the recurrence period after resection and the histology of recurrent nodules comparing between high LI group and low LI group. Patients: 34 solitary small HCC cases resected(<3 cm) were stained immunohistochemically using anti-PCNA monoclonal antibody (PC 10, Dako,Co). The average PCNA L1 of nodules was 19%, thus we divided all cases into two groups, the high LI group (LI>20%) and the low LI group. Results: The 5-year survival rates were 78% in the low Lt group and 36% in the high LI group. The 4-year recurrent rates were 61% in the low LI group and 81% in the high LI group. Although the difference in prognosis between the two groups was not statistically significant, the prognosis of the low LI group was better than that of the high LI group. The period of recurrence was ranged from 8 months to 36 months (average 26 months) in the low LI group and from 3 months to 36 months (average 15 months) in the high LI group. The recurrent nodules were often well differentiated type in low LI group and moderately or poorly differentiated type in the high LI group. Conclusion: PCNA high LI group might be recurred in the early period aider resection because of its high proliferative activity and metastatic potential. On the other hand in the low LI patients the nodules reseeted proved to have low proliferative activity but another carcinogenesis might occur because of its underlying liver disease such as chronic hepatitis or liver cirrhosis.
Transcript of Telomere shortening in chronic liver disease and hepatocellular carcinoma
April 1995 AASLD A1099
• T E L O M E R E S H O R T E N I N G I N C H R O N I C L I V E R D I S E A S E A N D H E P A T O C E L L U L A R C A R C I N O M A . T. Kitada, S. Seki, N. Kawakita, H. Sakaguchi, Y. Ichikawa, T. Kuroki, K. Kobayashi, T. Monna Dept, &Publ ic Heal th and 3rd Dept. of Internal Medicine., Osaka City University, Medical School., Osaka, Japan.
The s t ructure of the chromosome ends, called telomere,may play a major role in protecting the chromosome ends from abberant recombination and end to end fusion, l~duct ion in telomere length can lead to genomic instabil i ty and genetic alterations of possible significance of tumor development. Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies in the world. HCC is considered to be caused by genetic alterations which accumulate in the hepatocytos dur ing the chronic liver damage. Thus it is of much interest to examine whether telomere reduction which leads to genomic instabili ty can be detected in chronic liver disease. Herein, we measured telomere length in the livers with chronic liver disease and in normal livers. We also examined whether there was a telomere reduction in HCC. ( m a t e r i a l s & methods) Twenty-eight pat ients with liver disease ( 10 with chronic hepatit is , 12 with liver cirrhosis, 6 with HCC) were included in this studyl 5 histologically normal liver t issues were obtained a t the time of surgery from pat ients without chronic liver disease. After DNA preparation, Southern blot analysis was performed us ing a gigoxigenin-labeled ( T r A ~ ) 4 as a probe. ( r e s u l t s ) We found a significant correlation between age and telomere length. To separate the effect of age on telomere length, we used analysis of covar/ance. The group with normal livers had longer telomere t h a n the group with chronic hepati t is (p=0.002) and t h a n the group with cirrhosis (p<0.001). In chronic liver disease, the telomere length tended to decrease with progression of liver disease.The telomere length in HCC was shorter t h a n tha t in noncancerous surrounding liver in all cases we examined. ( c o n c l u s i o n ) We found a significant telomere reduction in the livers with chronic liver disease compared to those in the normal livers as a r isk factor for genomic instabili ty for hepatocarcinogenesis.
Analysis of proliferative activity in small hepatocellular carcinoma (HCC) (<2 cm) using proliferating cell nuclear antigen (PCNA) immnno-staining --comparison with DNA ploidy study--. M. Kitamoto, T. Nakanishi, R. Nakashio, S. Kira, K. Tsuji, Y. Watanabe, G. Kajiyama. First Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima 734, Japan.
We previously described of the significance of proliferative activity in small HCC using PCNA immuno-staining in this association (1993,1994). In this study, we examined the relationship between DNA ploidy study and proliferative activity in 25 small HCC nodules (<2 cm) resected. Method: PCNA immuno-staining was performed and we determined PCNA LI according to our previous report. All nodules were examined by DNA ploidy study using flowcytometry. We investigated the differences between the nodules of DNA diploidy and that ofDNA aneuploidy in view ofhistologicai findings and PCNA LI. Results: Of 18 diploidy nodules, 15 (83%) were well differentiated type, 2 (11%) moderately differentiated type and 1(6%) poorly differentiated type. Of 7 aneuploidy nodules, 2 (29%) were well differentiated type, 2 (29%) moderately differentiated type and 3 (42%) poorly differentiated type. The incidence of microscopic aggressive lesions such as capsule invasion, vascular invasion and intrahepatic metastasis was 17% (3/18) in diploidy nodules and 43% (3/7) in aneuploidy nodules. The PCNA LI of diploidy nodules ranged from 0.2 to 42% (average 7.0%) and that of aneuploidy nodules from 1.3% to 72.5% (average 27.0%), difference that was statistically significant (P<0.05). Conclusion: In small HCC, the diploidy nodules were often well differentiated and had rare microscopic aggressive lesions. The proliferative activity of the diploidy nodules was significantly lower than that of the aneuploidy nodules.
Long term prognosis of small hepatocellular carcinoma (HCC) (<2 cm) treated by percutaneous ethanol injection therapy (PEIT) . M. Kitamoto, T. Nakanishi, S. Kira, R. Nakashio, K. Tsuji, Y Watanabe, G. Kajiyama. First Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima 734, Japan.
Recently, the prognosis of HCC patients improved because of the development of imaging diagnostic techniques such as ultrasonography and computed tomography, the development of safety resection and the development of non surgical treatments especially PEIT. According to The Liver Cancer Study Group of Japan, it was reported that among small HCC (<2 era) 5- year survival rates were 55% in surgical resection cases and 3-year survival rates were 53% in patients treated by PEIT. In this study, we evaluated the prognosis of small HCC treated by PEIT. Patients: We treated 21 patients with solitary small HCC nodule (<2 cm) diagnosed histologically by fine needle biopsy. The tumor size ranged from 10 mm to 20 nun (average 16 mm) in diameter. Histologically, 17 nodules were well differentiated and 4 moderately differentiated. By the classification according to Child grade, 10 patients were in the Child grade A, 10 in the Child grade B and 1 in the Child grade C. Results: The 2- and 4-year survival rates were 92% and 80%. The 2-and 4-year recurrence rates were 38% and 56%. Although transient pain and slight fever elevation were present in most patients, no serious complications were observed. These data revealed that PEIT was associated with fairly good prognosis in solitary small HCC. Conclusion: PEIT facilitated the long term prognosis of solitary small HCC as well as surgical resection.
Long term prognosis of small hepatocelular carcinoma (HCC) in view of proliferating cell nuclear antigen (PCNA) labeling index (LI). M. Kitamoto, 17,. Nakashio, S. Kira, K. Tsuji, Y. Watanabe, T. Nakanishi, G. Kajiyama. First Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima 734, Japan.
We previously reported that proliferative activity evaluated by PCNA LI closely related the prognosis after resection (Cancer72:1859- 65,1993). In this study, we examined the recurrence period after resection and the histology of recurrent nodules comparing between high LI group and low LI group. Patients: 34 solitary small HCC cases resected(<3 cm) were stained immunohistochemically using anti-PCNA monoclonal antibody (PC 10, Dako,Co). The average PCNA L1 of nodules was 19%, thus we divided all cases into two groups, the high LI group (LI>20%) and the low LI group. Results: The 5-year survival rates were 78% in the low Lt group and 36% in the high LI group. The 4-year recurrent rates were 61% in the low LI group and 81% in the high LI group. Although the difference in prognosis between the two groups was not statistically significant, the prognosis of the low LI group was better than that of the high LI group. The period of recurrence was ranged from 8 months to 36 months (average 26 months) in the low LI group and from 3 months to 36 months (average 15 months) in the high LI group. The recurrent nodules were often well differentiated type in low LI group and moderately or poorly differentiated type in the high LI group. Conclusion: PCNA high LI group might be recurred in the early period aider resection because of its high proliferative activity and metastatic potential. On the other hand in the low LI patients the nodules reseeted proved to have low proliferative activity but another carcinogenesis might occur because of its underlying liver disease such as chronic hepatitis or liver cirrhosis.
