PATHOLOGY DIVISION

17.PATHOLOGY DIVISION

　The research activities of the Pathology Division of the Research Institute East currently concentrate on the application of morphological studies of cancer tissue to clinical diagnosis and treatment. Prognostic factors and other clinicopathological characteristics of various cancers have been studied in collaboration with clinical departments of the National Cancer Center Hospital East.
1. Cancer-Stromal Interactions and Clinical Implications

　Cancer- stromal interaction plays important roles in not only carcinogenesis but also cancer progression such as invasion and metastasis. Cancer stroma consists of various kinds of cells including endothelial cells constituting blood vessels, lymph vessels, fibroblasts and inflammatory cells containing macrophages and lymphocytes. A fibrotic focus is often recognized in primary cancers with high malignant potential such as breast, pancreas and lung cancers. It became apparent that colorectal carcinomas with a fibrotic focus or foci have much higher malignant potential as evidenced by their liver metastatic rate and lower survival rate after surgery ⁽²²⁸⁾ Invasive ductal carcinomas of the breast growing in a strand growth pattern or with a fibrotic focus also demonstrated more frequent bone metastasis. The strand growth pattern was a significant predictor of the initial bone metastasis and fibrotic focus becomes a predictor for osteolytic metastasis by multivariate analysis.⁽²²⁹⁾ In order to optimize the method for evaluating angiogenetic potential of the tumor, microvessel counts according to tumor zone in invasive ductal carcinoma of the breast were investigated, and it was found that microvessel counts of an invasive ductal carcinoma significantly increased from the central to the peripheral zone. On the other hand, angiogenesis in the peripheral zone is significantly associated with clinical outcomes.⁽²³⁰⁾ These results indicate the importance of cancer- stromal interactions in the course of cancer invasion and metastasis in various tumors.
2. Clinicopathological Study of Atypical Adenomatous Hyperplasia (AAH) as a Precancerous Lesion of Lung Adenocarcinoma

　Although atypical adenomatous hyperplasia (AAH)has been thought to be a precursor of lung adenocarcinoma because of the histologically similar growth pattern, there is no clinicopathlogical evidence for this. Clinicopathological studies of lung cancer were performed and demonstrated that AAH of the lung is a precancerous lesion of adenocarcinoma of the lung and does not represent intrapulmonary metastasis. The monoclonal nature of AAH of the lung has been demonstrated by an X- chromosome- linked polymorphic marker, the human androgen receptor gene (HUMARA).⁽²³¹⁾ A careful follow- up study is mandatory in patients possessing multiple AAH with special regard to the further development of lung carcinoma in the future. Considering the frequent K- ras activation in AAH, AAH is thought to be a preneoplastic lesion rather than reactive or hyperplasia. These results strongly support the hypothesis of an AAH- adenocarcinoma sequence in lung carcinogenesis as observed in colon carcinogenesis.
3. Application of Histopatholgical Factors to Surgery for Lung Cancer

　Lung carcinoma has become the most frequent cause of cancer death in Japan and adenocarcinoma is the most predominant histological type. A study of young lung cancer patients less than 40 years of age revealed the clinicopathologic features in young lung cancer patients, less smoking history, frequent adenocarcinoma and more advanced staged cancer.⁽²³²⁾ To apply histopathological factors to the surgery for lung cancer, eighteen conventional clinocopathologic prognostic factors, were reevaluated in srugically resected lung carcinoma. In stage I disease, clinical N status, vascular invasion and curativity of resection become significant prognostic factors, and 4 clinicopathologic factors, histology, pathologic N status, tumor size and curativity of resection, possess prognostic value in the other clinical stages. These results indicated that the prognostic factors should be analyzed separately in each pathologic TNM- stage.⁽²³³⁾
4. Clinicopathogical Studies on Various Cancers

　Cytochrome P450 (CYP), which is important in the metabolism of endogenous and exogenous materials, may be responsible for tumor initiation, promotion, and progression. The expression of CYP 3A4 and CYP2C including 2C8,9,18,19,which were detected in the pleomorphic adenoma, and various carcinomas and 3A4 react with various non- neoplastic mucosal cells including intestinal metaplasia.⁽²³⁴⁾ A rare case of mediastinal,⁽²³⁵⁾ lung,^(236,²³⁷⁾ breast,^(238,²³⁹⁾ esophagus,⁽²⁴⁰⁾ stomach,⁽²⁴¹⁾ and pancreas,⁽²⁴²⁾ has been reported. Other clinicopathological studies were also conducted to promote the diagnosis and treatment of various tumors.^(243-²⁴⁹⁾




17.PATHOLOGY DIVISION



	The research activities of the Pathology Division of the Research Institute East currently concentrate on the application of morphological studies of cancer tissue to clinical diagnosis and treatment. Prognostic factors and other clinicopathological characteristics of various cancers have been studied in collaboration with clinical departments of the National Cancer Center Hospital East. 1. Cancer-Stromal Interactions and Clinical Implications 　Cancer- stromal interaction plays important roles in not only carcinogenesis but also cancer progression such as invasion and metastasis. Cancer stroma consists of various kinds of cells including endothelial cells constituting blood vessels, lymph vessels, fibroblasts and inflammatory cells containing macrophages and lymphocytes. A fibrotic focus is often recognized in primary cancers with high malignant potential such as breast, pancreas and lung cancers. It became apparent that colorectal carcinomas with a fibrotic focus or foci have much higher malignant potential as evidenced by their liver metastatic rate and lower survival rate after surgery ⁽²²⁸⁾ Invasive ductal carcinomas of the breast growing in a strand growth pattern or with a fibrotic focus also demonstrated more frequent bone metastasis. The strand growth pattern was a significant predictor of the initial bone metastasis and fibrotic focus becomes a predictor for osteolytic metastasis by multivariate analysis.⁽²²⁹⁾ In order to optimize the method for evaluating angiogenetic potential of the tumor, microvessel counts according to tumor zone in invasive ductal carcinoma of the breast were investigated, and it was found that microvessel counts of an invasive ductal carcinoma significantly increased from the central to the peripheral zone. On the other hand, angiogenesis in the peripheral zone is significantly associated with clinical outcomes.⁽²³⁰⁾ These results indicate the importance of cancer- stromal interactions in the course of cancer invasion and metastasis in various tumors. 2. Clinicopathological Study of Atypical Adenomatous Hyperplasia (AAH) as a Precancerous Lesion of Lung Adenocarcinoma 　Although atypical adenomatous hyperplasia (AAH)has been thought to be a precursor of lung adenocarcinoma because of the histologically similar growth pattern, there is no clinicopathlogical evidence for this. Clinicopathological studies of lung cancer were performed and demonstrated that AAH of the lung is a precancerous lesion of adenocarcinoma of the lung and does not represent intrapulmonary metastasis. The monoclonal nature of AAH of the lung has been demonstrated by an X- chromosome- linked polymorphic marker, the human androgen receptor gene (HUMARA).⁽²³¹⁾ A careful follow- up study is mandatory in patients possessing multiple AAH with special regard to the further development of lung carcinoma in the future. Considering the frequent K- ras activation in AAH, AAH is thought to be a preneoplastic lesion rather than reactive or hyperplasia. These results strongly support the hypothesis of an AAH- adenocarcinoma sequence in lung carcinogenesis as observed in colon carcinogenesis. 3. Application of Histopatholgical Factors to Surgery for Lung Cancer 　Lung carcinoma has become the most frequent cause of cancer death in Japan and adenocarcinoma is the most predominant histological type. A study of young lung cancer patients less than 40 years of age revealed the clinicopathologic features in young lung cancer patients, less smoking history, frequent adenocarcinoma and more advanced staged cancer.⁽²³²⁾ To apply histopathological factors to the surgery for lung cancer, eighteen conventional clinocopathologic prognostic factors, were reevaluated in srugically resected lung carcinoma. In stage I disease, clinical N status, vascular invasion and curativity of resection become significant prognostic factors, and 4 clinicopathologic factors, histology, pathologic N status, tumor size and curativity of resection, possess prognostic value in the other clinical stages. These results indicated that the prognostic factors should be analyzed separately in each pathologic TNM- stage.⁽²³³⁾ 4. Clinicopathogical Studies on Various Cancers 　Cytochrome P450 (CYP), which is important in the metabolism of endogenous and exogenous materials, may be responsible for tumor initiation, promotion, and progression. The expression of CYP 3A4 and CYP2C including 2C8,9,18,19,which were detected in the pleomorphic adenoma, and various carcinomas and 3A4 react with various non- neoplastic mucosal cells including intestinal metaplasia.⁽²³⁴⁾ A rare case of mediastinal,⁽²³⁵⁾ lung,^(236,²³⁷⁾ breast,^(238,²³⁹⁾ esophagus,⁽²⁴⁰⁾ stomach,⁽²⁴¹⁾ and pancreas,⁽²⁴²⁾ has been reported. Other clinicopathological studies were also conducted to promote the diagnosis and treatment of various tumors.^(243-²⁴⁹⁾