Pathology Division

1. Pathology Division

　Research in the Pathology Division is based on a combination of molecular and cellular biological analyses and clinicopathological observations.
Pathology of Multistep Carcinogenesis

　The natural history and post-therapeutic outcome of adenomatous hyperplasia and early hepatocellular carcinoma (HCC) of the liver were analyzed. Progression of adenomatous hyperplasia and early hepatocellular carcinoma was confirmed both clinically and pathologically. Cases with single early HCC were shown to have a good prognosis. The high rate of surgical curability justifies the definition of early HCC clinically.^(1,2) Hyperplastic foci defined as small and monotonous hypercellular areas in non-cancerous liver parenchyma were investigated. Immunohistochemically, hyperplastic foci were masses of proliferative hepatocytes similar to adenomatous hyperplasia and early hepatocellular carcinoma. These results indicated that hyperplastic foci reflect the risk of multicentric hepatocarcinogenesis, and strongly suggested that hyperplastic foci are precursors of adenomatous hyperplasia or hepatocellular carcinoma.⁽³⁾ DNA hypermethylation at the D17S5 locus, at which a candidate tumor suppressor gene HIC-1(hypermethylated in cancer) was identified, was found to be associated with gastric carcinogenesis.⁽⁴⁾The significance of other molecular and genetic events in carcinogenesis was also examined.^(5-8)
Molecular and Cellular Mechanisms of Cancer Invasion and Metastasis

　The first and crucial step in cancer invasion and metastasis is the dissociation of cancer cells from primary cancer nests. Dysfunction of the E-cadherin-mediated cell adhesion system plays an important role on this step.^(9,10)The cytoplasmic localization of phosphotyrosine residues in undifferentiated-type gastric cancers was significantly correlated with k-sam expression and diffuse cytoplasmic staining of E-cadherin and b-catenin. These data indicate that alteration of tyrosine phosphorylation status associated with K-sam expression may cause the cytoplasmic distribution of cadherin-catenin molecules and loose cell-cell adhesion in undifferentiated-type gastric cancers.⁽¹¹⁾Ninety percent (9 of 10) of endometrial carcinoma cases with b-catenin mutation and 30% (20 of 66) of cases without it showed accumulation of b-catenin in the cytoplasm and/or nucleus. These data suggest that stabilization of b-catenin due to mutations in exon 3 of the b-catenin gene may play an important role in development of endometrial carcinoma.⁽¹²⁾Macroscopic features at the cut section in 417 colorectal cancers were divided into two types, streak type and non-streak type, according to the presence or absence of white streak(s) at the advancing margin of tumor invasion. The frequency of liver metastasis in streak type tumors was significantly higher than that in non-streak type tumors. The white streak corresponded histologically with cancer cells showing focal dedifferentiation with marked stromal and perivascular fibrosis.⁽¹³⁾The establishment of an in vitro model for the analysis of laminin-mediated signalling has been developed.⁽¹⁴⁾ We have isolated a cDNA for a novel actin-binding protein, designated actinin-4. The non-nuclear localization of actinin-4 was closely associated with an infiltrative histological phenotype and correlated significantly with a poorer prognosis in breast cancer.⁽¹⁵⁾The promoter activity of b-4 integrin gene was found to be mediated by AP1 and Ets, interacting with other factors.⁽¹⁶⁾These results suggest the involvement of transcriptional dysregulation in carcinogenesis and cancer progression.
Molecular Diagnosis of Biological Aggressiveness of Human Cancers

　Fluorescence in situ hybridization (FISH) was applied for the analysis of chromosomal alterations in breast tumors. An unbalanced chromosome rearrangement, i.e. der(16)t(1;16), was detected in low-grade invasive carcinoma and a case of "marked adenosis with atypia" which was cytopathologically malignant. Detection of der(16)t(1;16)/der(1;16) by FISH was shown to be a supportive diagnostic procedure.⁽¹⁷⁾In patients with node-negative breast cancers, accumulation of gene and chromosome alterations were indicators of poor prognosis.^(18,19) In patients with node-positive breast cancers, the combination of p53 nuclear accumulation and c-erbB-2 amplification was an indicator of poor prognosis.⁽²⁰⁾The phenotype of high-grade atypia and c-erbB-2 alterations were usually determined very early in the process of breast cancer development.⁽²¹⁾ Diagnostic implication of tumor-associated carbohydrate antigens was also studied.^(22,23)
Clinicopathological Studies

　Six cases of rhabdomyosarcoma, a rare second primary malignancy in children with bilateral retinoblastoma after irradiation treatment, were reported.⁽²⁴⁾ Clinicopathological studies were also conducted to promote the diagnosis and treatment of various tumors.^(25-43)




	1. Pathology Division



		Research in the Pathology Division is based on a combination of molecular and cellular biological analyses and clinicopathological observations. Pathology of Multistep Carcinogenesis 　The natural history and post-therapeutic outcome of adenomatous hyperplasia and early hepatocellular carcinoma (HCC) of the liver were analyzed. Progression of adenomatous hyperplasia and early hepatocellular carcinoma was confirmed both clinically and pathologically. Cases with single early HCC were shown to have a good prognosis. The high rate of surgical curability justifies the definition of early HCC clinically.^(1,2) Hyperplastic foci defined as small and monotonous hypercellular areas in non-cancerous liver parenchyma were investigated. Immunohistochemically, hyperplastic foci were masses of proliferative hepatocytes similar to adenomatous hyperplasia and early hepatocellular carcinoma. These results indicated that hyperplastic foci reflect the risk of multicentric hepatocarcinogenesis, and strongly suggested that hyperplastic foci are precursors of adenomatous hyperplasia or hepatocellular carcinoma.⁽³⁾ DNA hypermethylation at the D17S5 locus, at which a candidate tumor suppressor gene HIC-1(hypermethylated in cancer) was identified, was found to be associated with gastric carcinogenesis.⁽⁴⁾The significance of other molecular and genetic events in carcinogenesis was also examined.^(5-8) Molecular and Cellular Mechanisms of Cancer Invasion and Metastasis 　The first and crucial step in cancer invasion and metastasis is the dissociation of cancer cells from primary cancer nests. Dysfunction of the E-cadherin-mediated cell adhesion system plays an important role on this step.^(9,10)The cytoplasmic localization of phosphotyrosine residues in undifferentiated-type gastric cancers was significantly correlated with k-sam expression and diffuse cytoplasmic staining of E-cadherin and b-catenin. These data indicate that alteration of tyrosine phosphorylation status associated with K-sam expression may cause the cytoplasmic distribution of cadherin-catenin molecules and loose cell-cell adhesion in undifferentiated-type gastric cancers.⁽¹¹⁾Ninety percent (9 of 10) of endometrial carcinoma cases with b-catenin mutation and 30% (20 of 66) of cases without it showed accumulation of b-catenin in the cytoplasm and/or nucleus. These data suggest that stabilization of b-catenin due to mutations in exon 3 of the b-catenin gene may play an important role in development of endometrial carcinoma.⁽¹²⁾Macroscopic features at the cut section in 417 colorectal cancers were divided into two types, streak type and non-streak type, according to the presence or absence of white streak(s) at the advancing margin of tumor invasion. The frequency of liver metastasis in streak type tumors was significantly higher than that in non-streak type tumors. The white streak corresponded histologically with cancer cells showing focal dedifferentiation with marked stromal and perivascular fibrosis.⁽¹³⁾The establishment of an in vitro model for the analysis of laminin-mediated signalling has been developed.⁽¹⁴⁾ We have isolated a cDNA for a novel actin-binding protein, designated actinin-4. The non-nuclear localization of actinin-4 was closely associated with an infiltrative histological phenotype and correlated significantly with a poorer prognosis in breast cancer.⁽¹⁵⁾The promoter activity of b-4 integrin gene was found to be mediated by AP1 and Ets, interacting with other factors.⁽¹⁶⁾These results suggest the involvement of transcriptional dysregulation in carcinogenesis and cancer progression. Molecular Diagnosis of Biological Aggressiveness of Human Cancers 　Fluorescence in situ hybridization (FISH) was applied for the analysis of chromosomal alterations in breast tumors. An unbalanced chromosome rearrangement, i.e. der(16)t(1;16), was detected in low-grade invasive carcinoma and a case of "marked adenosis with atypia" which was cytopathologically malignant. Detection of der(16)t(1;16)/der(1;16) by FISH was shown to be a supportive diagnostic procedure.⁽¹⁷⁾In patients with node-negative breast cancers, accumulation of gene and chromosome alterations were indicators of poor prognosis.^(18,19) In patients with node-positive breast cancers, the combination of p53 nuclear accumulation and c-erbB-2 amplification was an indicator of poor prognosis.⁽²⁰⁾The phenotype of high-grade atypia and c-erbB-2 alterations were usually determined very early in the process of breast cancer development.⁽²¹⁾ Diagnostic implication of tumor-associated carbohydrate antigens was also studied.^(22,23) Clinicopathological Studies 　Six cases of rhabdomyosarcoma, a rare second primary malignancy in children with bilateral retinoblastoma after irradiation treatment, were reported.⁽²⁴⁾ Clinicopathological studies were also conducted to promote the diagnosis and treatment of various tumors.^(25-43)