Pathology Division

17. Pathology Division

　The research activities of the Pathology Division of the Research Institute East currently concentrate on the application of morphological study 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. Establishment of a New Histo-pathological Classification for Invasive Ductal Carcinoma of the Breast

　A fibrotic focus is often recognized in primary tumors of recurrent breast cancer. It became apparent that invasive ductal carcinomas with a fibrotic focus or foci have much higher malignant potential as evidenced by their lower survival rate for not only short but also long period survey after surgery. An immunohistochemical study of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor (FGFR) was conducted to examine the mechanisms of fibrotic focus formation in invasive duct carcinoma of the breast.⁽²⁰³⁾ In order to establish the histological breast cancer recurrence predictive factor, three histopathological factors, each of which has proven to possess significant correlations with patient survival, nuclear atypical grade (N), fibrotic foci (F) and invasive pattern into surrounding fat tissue (F), were measured semi-quantitatively and scored to test whether this classification could become a significant predictor for breast cancer recurrence and low survival of the patients. This Nucleus-Fibrotic focus-Fat invasion (NFF) classification predicted tumor recurrence and patient survival rate.^(204,205)
2. Clinicopathological Study of Atypical Adenomatous Hyperplasia (AAH) as a Precancerous Lesion of Lung Adenocarcinoma

　Lung carcinoma has become the most frequent cause of cancer death and in Japan with adenocarcinoma being the most predominant histological type. Although atypical adenomatous hyperplasia (AAH) has been thought to be a precursor of lung adenocarcinoma because of the histologically similar growth pattern, there remains no clinicopathological evidence for it. Clinicopathological studies of lung cancer demonstrated that AAH of the lung is probably a precancerous lesion of adenocarcinoma of the lung and does not represent intrapulmonary metastases. Precise histological study of synchronous double primary lung carcinomas associated with multiple AAH indicated the possibility of adenoma-carcinoma sequence of lung cancer.⁽²⁰⁶⁾ Considering the frequent K-ras activation in AAH, AAH is thought to be a preneoplastic lesion rather than reactive or hyperplasia. These results suggest the possibility of an AAH-adenocarcinoma sequence in lung carcinogenesis as observed in colon and liver carcinogenesis.
3. Application of Histopatholgical Factors to Limited Surgery for Early Stage Lung Adenocarcinoma

　The major concern in performing thoracoscopic wedge resection for lung cancer patients is the incidence of local recurrence at the surgical margin. Although segmental and wedge resection has been reported to result in comparable or even better prognosis in comparison with lobectomy, most studies were prospective and not randomized. In an attempt to study the feasibility of limited resection, untreated cN0M0 primary peripheral lung carcinomas 1 cm or less in the maximum dimension were evaluated for histopathological factors which predict the risk of limited resection in patients with over 1000 primary peripheral lung cancer patients.⁽²⁰⁷⁾ Even among the pulmonary peripheral cancers smaller than 1 cm in diameter, more than one third showed an invasive nature including venous invasion and lymph node metastasis. These results indicated that tumor size alone cannot be an indicator for limited resection in lung cancer patients.
4. Clinicopathogical Studies of Various Cancer

　Prognostic factors and other clinicopathological characteristic of various cancers including tongue,⁽²⁰⁸⁾ breast,⁽²⁰⁹⁾ and lung^(210,244) have been evaluated. Immunohistochemical examination of biological markers which predict response to 5-fluorouracil and cis-platinum in unresectable gastric cancer patients were also studied.⁽²¹¹⁾ Cytochrome P450,(CYP) which is important in metabolism of endogenous and exogenous materials, may be responsible for tumor initiation, promotion, and progression. The expression of CYP 3A4, which was detected in the metaplastic glands which are thought to be a precuror of gastric cancer but not in fundic gland mucosa, indicated the possible roles of CYP expression in gastric carcinogenesis.⁽²¹²⁾ Rare cases of tumors of the urinary bladder,⁽²¹³⁾ pancreas,⁽²¹⁴⁾ breast,^(215,216) mediastinum,^(217,218) lymph nodes,^(219,220) spleen,⁽²²¹⁾ testis⁽²²²⁾ and duodenum⁽²²³⁾ have been reported by our institution. Other clinico-pathological studies were also conducted to promote the diagnosis and treatment of various tumors.^(224-228)




	17. Pathology Division



		The research activities of the Pathology Division of the Research Institute East currently concentrate on the application of morphological study 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. Establishment of a New Histo-pathological Classification for Invasive Ductal Carcinoma of the Breast 　A fibrotic focus is often recognized in primary tumors of recurrent breast cancer. It became apparent that invasive ductal carcinomas with a fibrotic focus or foci have much higher malignant potential as evidenced by their lower survival rate for not only short but also long period survey after surgery. An immunohistochemical study of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor (FGFR) was conducted to examine the mechanisms of fibrotic focus formation in invasive duct carcinoma of the breast.⁽²⁰³⁾ In order to establish the histological breast cancer recurrence predictive factor, three histopathological factors, each of which has proven to possess significant correlations with patient survival, nuclear atypical grade (N), fibrotic foci (F) and invasive pattern into surrounding fat tissue (F), were measured semi-quantitatively and scored to test whether this classification could become a significant predictor for breast cancer recurrence and low survival of the patients. This Nucleus-Fibrotic focus-Fat invasion (NFF) classification predicted tumor recurrence and patient survival rate.^(204,205) 2. Clinicopathological Study of Atypical Adenomatous Hyperplasia (AAH) as a Precancerous Lesion of Lung Adenocarcinoma 　Lung carcinoma has become the most frequent cause of cancer death and in Japan with adenocarcinoma being the most predominant histological type. Although atypical adenomatous hyperplasia (AAH) has been thought to be a precursor of lung adenocarcinoma because of the histologically similar growth pattern, there remains no clinicopathological evidence for it. Clinicopathological studies of lung cancer demonstrated that AAH of the lung is probably a precancerous lesion of adenocarcinoma of the lung and does not represent intrapulmonary metastases. Precise histological study of synchronous double primary lung carcinomas associated with multiple AAH indicated the possibility of adenoma-carcinoma sequence of lung cancer.⁽²⁰⁶⁾ Considering the frequent K-ras activation in AAH, AAH is thought to be a preneoplastic lesion rather than reactive or hyperplasia. These results suggest the possibility of an AAH-adenocarcinoma sequence in lung carcinogenesis as observed in colon and liver carcinogenesis. 3. Application of Histopatholgical Factors to Limited Surgery for Early Stage Lung Adenocarcinoma 　The major concern in performing thoracoscopic wedge resection for lung cancer patients is the incidence of local recurrence at the surgical margin. Although segmental and wedge resection has been reported to result in comparable or even better prognosis in comparison with lobectomy, most studies were prospective and not randomized. In an attempt to study the feasibility of limited resection, untreated cN0M0 primary peripheral lung carcinomas 1 cm or less in the maximum dimension were evaluated for histopathological factors which predict the risk of limited resection in patients with over 1000 primary peripheral lung cancer patients.⁽²⁰⁷⁾ Even among the pulmonary peripheral cancers smaller than 1 cm in diameter, more than one third showed an invasive nature including venous invasion and lymph node metastasis. These results indicated that tumor size alone cannot be an indicator for limited resection in lung cancer patients. 4. Clinicopathogical Studies of Various Cancer 　Prognostic factors and other clinicopathological characteristic of various cancers including tongue,⁽²⁰⁸⁾ breast,⁽²⁰⁹⁾ and lung^(210,244) have been evaluated. Immunohistochemical examination of biological markers which predict response to 5-fluorouracil and cis-platinum in unresectable gastric cancer patients were also studied.⁽²¹¹⁾ Cytochrome P450,(CYP) which is important in metabolism of endogenous and exogenous materials, may be responsible for tumor initiation, promotion, and progression. The expression of CYP 3A4, which was detected in the metaplastic glands which are thought to be a precuror of gastric cancer but not in fundic gland mucosa, indicated the possible roles of CYP expression in gastric carcinogenesis.⁽²¹²⁾ Rare cases of tumors of the urinary bladder,⁽²¹³⁾ pancreas,⁽²¹⁴⁾ breast,^(215,216) mediastinum,^(217,218) lymph nodes,^(219,220) spleen,⁽²²¹⁾ testis⁽²²²⁾ and duodenum⁽²²³⁾ have been reported by our institution. Other clinico-pathological studies were also conducted to promote the diagnosis and treatment of various tumors.^(224-228)