PATHOLOGY DIVISION

22.PATHOLOGY DIVISION

    The research activities of the Pathology Division of the Research Institute East currently concentrate both on the application of the morphological study of cancer tissue to clinical course of patients, in order to understand the biological activity of cancer, to establish a new method to select treatment for patients and to elucidate of the mechanism for cancer metastasis. Prognostic factors and clinicopathological characteristics of various cancers have been studied in collaboration with clinical departments of the National Cancer Center Hospital East.
Cancer-Stromal Interaction and Its Clinical Implication

    Cancer-stromal interaction plays important roles in not only carcinogenesis but also cancer progression such as invasion and metastasis. Fibrotic focus (FF) is a mixture of fibroblasts and various amounts of collagen fibers and has been reported to become a good prognostic marker for poor survival of invasive ductal carcinoma (IDC) of the breast. A prospective observational study was performed and found that FF is a useful parameter predicting tumor recurrence in lymph node-negative IDCs ⁽²⁶³⁾. Cancer cells in lymph vessels usually mean aggressive cancer behaviors indicating frequent lymph node metastasis. No investigation has been undertaken to see if the characteristics of tumor cells in lymph vessels play an important role in tumor progression of IDCs of the breast. More than 4 mitotic figures, and more than 6 apoptotic figures of tumor cells in lymph vessels were associated with the increase hazard rates of tumor recurrence and patient survival ⁽²⁶⁴⁾. These data indicate that the histological characteristics of tumor cells in lymph vessels play an important role in the tumor progression of IDCs of the breast.
    In order to elucidate the mechanisms for the worse prognosis associated with pancreatic cancer, clinicopathological characteristics and morphological features were investigated. The rate of the intraductal carcinoma component was found to be a good prognostic marker for IDCs of the pancreas adenocarcinoma. ICDs of pancreatic carcinoma with more than 10% intraductal carcinoma components were associated with a significant better outcome for patients than those with 10% or less intraductal carcinoma components. ⁽²⁶⁵⁾
    Laminin g2, which is a component of the basement membrane of epithelial cells, is involved in tumor invasion and metastasis in various human cancers. The significance of laminin g2 expression was investigated in human pancreas adenocarcinoma. Overexpression of cytoplasmic laminin g2 chain represents a high invasive potential of the tumor and is correlated with distant metastasis, especially hepatic metastasis and with a poorer prognosis ⁽²⁶⁶⁾.
    The most frequent metastatic site of adenocarcinoma of the prostate is bone with marked forming bone. A new animal model for bone metastasis of human prostatic cancer cells to human bone has been established by using NOD-SCID (non-obese diabetes-severe combined immunodeficient) mice and a model of the osteoplastic metastasis of human prostatic cancer has been established. In order to elucidate the osteoplastic mechanism of metastatic prostate cancer, growth factors secreted by a human cancer cell line, LNcap, were investigated and found that the prostate specific antigen (PSA) plays an important effect on stimulation of osteoplasia at the metastatic site. PSA was first found in 1970 in normal human prostate glands and it has been used as a specific serum tumor marker for prostatic cancer worldwide. Using the model, PSA was confirmed to stimulate osteoblasts activation through the mechanism that PSA plays as a serine protease which activates TGF b by cleaving LAP peptides of the latent form of TGF b secreted by osteoblasts and induces apoptosis of precursor cells of osteoclasts.
Evaluation of Histopathological Factors on the Treatment for Cancer

    The relationships between radiosensitivity and clinicopathological factors were investigated in biopsy specimens from esophageal squamous cell carcinoma patients given chemoradiotherapy and found that microvessel density (MVD) alone had significant predictive power for radiosensitivity in esophageal squamous cell carcinoma after radiotherapy and MVD is a potentially useful clinical factor predicting radiosensitivity ⁽²⁶⁷⁾. These results combined with our previous data that laryngeal squamous cell carcinoma (LSCC) patients given radiotherapy and that MVD alone had significant predictive power for radiosensitivity in early stage LSCCs after radiotherapy indicate that MVD using pretreatment biopsy specimens is a potentially useful prognostic marker of radiotherapy and chemoradiotherapy in patients with laryngeal, pharyngeal and esophageal cancer.
    In order to add to the information on the MVD of human cancer, neovascularization of various cancers were calculated in comparison with that of their normal counter tissues. The MVD in pancreatic adenocarcinoma is lower than that of hypervascular tumors such as islet cell tumors but there was no significant difference in other type adenocarcinomas. In addition, MVD was of value for predicting the extent of liver metastasis. These data indicate that this clinically encountered hypovascularity of the pancreatic tumor is thought to be due mainly to contrast with the hyper-vascular non-cancerous pancreas, since MVD in the cancerous area itself was at the same level as in other adenocarcinomas ⁽²⁶⁸⁾.
Clinicopathological Studies on Various Cancers

    Molecular gene analyses on human tissues were performed on primary thymic extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) ⁽²⁶⁹⁾ and on rare lung cancers based on chromate-exposed workers ⁽²⁷⁰⁾.
    A rare case of liver ⁽²⁷¹⁾, lung ⁽²⁷²⁾, esophagus ⁽²⁷³⁾ and colon ⁽²⁷⁴⁾ cancer has been reported. Other clinicopathological studies were also conducted to promote the diagnosis and treatment of tumors ^(275-²⁷⁷⁾.




22.PATHOLOGY DIVISION



	The research activities of the Pathology Division of the Research Institute East currently concentrate both on the application of the morphological study of cancer tissue to clinical course of patients, in order to understand the biological activity of cancer, to establish a new method to select treatment for patients and to elucidate of the mechanism for cancer metastasis. Prognostic factors and clinicopathological characteristics of various cancers have been studied in collaboration with clinical departments of the National Cancer Center Hospital East. Cancer-Stromal Interaction and Its Clinical Implication Cancer-stromal interaction plays important roles in not only carcinogenesis but also cancer progression such as invasion and metastasis. Fibrotic focus (FF) is a mixture of fibroblasts and various amounts of collagen fibers and has been reported to become a good prognostic marker for poor survival of invasive ductal carcinoma (IDC) of the breast. A prospective observational study was performed and found that FF is a useful parameter predicting tumor recurrence in lymph node-negative IDCs ⁽²⁶³⁾. Cancer cells in lymph vessels usually mean aggressive cancer behaviors indicating frequent lymph node metastasis. No investigation has been undertaken to see if the characteristics of tumor cells in lymph vessels play an important role in tumor progression of IDCs of the breast. More than 4 mitotic figures, and more than 6 apoptotic figures of tumor cells in lymph vessels were associated with the increase hazard rates of tumor recurrence and patient survival ⁽²⁶⁴⁾. These data indicate that the histological characteristics of tumor cells in lymph vessels play an important role in the tumor progression of IDCs of the breast. In order to elucidate the mechanisms for the worse prognosis associated with pancreatic cancer, clinicopathological characteristics and morphological features were investigated. The rate of the intraductal carcinoma component was found to be a good prognostic marker for IDCs of the pancreas adenocarcinoma. ICDs of pancreatic carcinoma with more than 10% intraductal carcinoma components were associated with a significant better outcome for patients than those with 10% or less intraductal carcinoma components. ⁽²⁶⁵⁾ Laminin g2, which is a component of the basement membrane of epithelial cells, is involved in tumor invasion and metastasis in various human cancers. The significance of laminin g2 expression was investigated in human pancreas adenocarcinoma. Overexpression of cytoplasmic laminin g2 chain represents a high invasive potential of the tumor and is correlated with distant metastasis, especially hepatic metastasis and with a poorer prognosis ⁽²⁶⁶⁾. The most frequent metastatic site of adenocarcinoma of the prostate is bone with marked forming bone. A new animal model for bone metastasis of human prostatic cancer cells to human bone has been established by using NOD-SCID (non-obese diabetes-severe combined immunodeficient) mice and a model of the osteoplastic metastasis of human prostatic cancer has been established. In order to elucidate the osteoplastic mechanism of metastatic prostate cancer, growth factors secreted by a human cancer cell line, LNcap, were investigated and found that the prostate specific antigen (PSA) plays an important effect on stimulation of osteoplasia at the metastatic site. PSA was first found in 1970 in normal human prostate glands and it has been used as a specific serum tumor marker for prostatic cancer worldwide. Using the model, PSA was confirmed to stimulate osteoblasts activation through the mechanism that PSA plays as a serine protease which activates TGF b by cleaving LAP peptides of the latent form of TGF b secreted by osteoblasts and induces apoptosis of precursor cells of osteoclasts. Evaluation of Histopathological Factors on the Treatment for Cancer The relationships between radiosensitivity and clinicopathological factors were investigated in biopsy specimens from esophageal squamous cell carcinoma patients given chemoradiotherapy and found that microvessel density (MVD) alone had significant predictive power for radiosensitivity in esophageal squamous cell carcinoma after radiotherapy and MVD is a potentially useful clinical factor predicting radiosensitivity ⁽²⁶⁷⁾. These results combined with our previous data that laryngeal squamous cell carcinoma (LSCC) patients given radiotherapy and that MVD alone had significant predictive power for radiosensitivity in early stage LSCCs after radiotherapy indicate that MVD using pretreatment biopsy specimens is a potentially useful prognostic marker of radiotherapy and chemoradiotherapy in patients with laryngeal, pharyngeal and esophageal cancer. In order to add to the information on the MVD of human cancer, neovascularization of various cancers were calculated in comparison with that of their normal counter tissues. The MVD in pancreatic adenocarcinoma is lower than that of hypervascular tumors such as islet cell tumors but there was no significant difference in other type adenocarcinomas. In addition, MVD was of value for predicting the extent of liver metastasis. These data indicate that this clinically encountered hypovascularity of the pancreatic tumor is thought to be due mainly to contrast with the hyper-vascular non-cancerous pancreas, since MVD in the cancerous area itself was at the same level as in other adenocarcinomas ⁽²⁶⁸⁾. Clinicopathological Studies on Various Cancers Molecular gene analyses on human tissues were performed on primary thymic extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) ⁽²⁶⁹⁾ and on rare lung cancers based on chromate-exposed workers ⁽²⁷⁰⁾. A rare case of liver ⁽²⁷¹⁾, lung ⁽²⁷²⁾, esophagus ⁽²⁷³⁾ and colon ⁽²⁷⁴⁾ cancer has been reported. Other clinicopathological studies were also conducted to promote the diagnosis and treatment of tumors ^(275-²⁷⁷⁾.