Tetsuro Kodama

Prognostic implications of fibrotic focus (scar) in small peripheral lung cancers.

ABSTRACT Peripheral lung cancers frequently possess a fibrotic focus or scar in their center or beneath the pleura. We reexamined 58 cases of peripheral lung cancer of less than 3 cm in diameter (48 adenocarcinomas, two large cell carcinomas and eight squamous cell carcinomas) which were removed surgically between June 1962 and July 1973. Analyses of the cases revealed that in adenocarcinoma with increased collagenization or hyalinization in the fibrotic focus, the degree of pleural invasion and incidence of lymph node metastasis and blood vessel invasion were greater and thus the prognosis of the patient was poorer than in cases with no or slight collagenization. The results also indicate that the characteristics of the central fibrotic focus are probably more important than the size of the tumor for estimating the prognosis of patients with peripheral adenocarcinoma of less than 3 cm in diameter. The same might be said of peripheral large-cell carcinoma. However, the prognostic importance of the fibrotic focus was not confirmed in cases of peripheral squamous-cell carcinoma. Although the central or sub-pleural scar has long been the basis of the scar cancer concept, alternate explanations were considered, namely, that scar formation occurred along with tumor development, rather than before, in the case of adenocarcinomas.

Breast Cancer Resistance Protein Impacts Clinical Outcome in Platinum-Based Chemotherapy for Advanced Non-Small Cell Lung Cancer

Purpose: The purpose of this study was to investigate the relationship between the level of expression of ATP-binding cassette (ABC) transporter proteins, and response to chemotherapy and prognosis in advanced non-small cell lung cancer (NSCLC). Experimental Design: Expression of ABC transporter proteins, including P-glycoprotein, multidrug resistance protein (MRP) 1, MRP2, MRP3, and breast cancer resistance protein (BCRP), was examined immunohistochemically in 72 formalin-fixed tumor samples from untreated stage IIIB or IV NSCLC patients. All of the patients received platinum-based chemotherapy. Response to chemotherapy, progression-free survival (PFS), and overall survival were compared in relation to expression of each of the ABC transporter proteins and clinicopathological factors. Results: Expression of P-glycoprotein, MRP1, and MRP3 was not significantly associated with response to chemotherapy or survival. MRP2 expression was associated with overall survival (P = 0.002) but not with response to chemotherapy and PFS. By contrast, the response rate to chemotherapy of patients with BCRP-negative tumors was 44%, as opposed to 24% in patients with BCRP-positive tumors. Response rate was lower in BCRP-positive tumors, although this difference was not statistically significant (P = 0.08). BCRP-positive patients had also shorter PFS (P = 0.0003) and overall survival (P = 0.004) than BCRP-negative patients. Multivariate analysis confirmed BCRP status as an independent variable related to PFS (P = 0.001). Conclusions: Positive immunostaining for BCRP appears to be a predictor of survival in patients with advanced NSCLC. These findings indicate that BCRP may serve as a molecular target for reducing drug resistance to chemotherapy in advanced NSCLC patients.

Histopathologic prognostic factors in adenocarcinomas of the peripheral lung less than 2 CM in diameter

The histologic prognostic factors of pulmonary adenocarcinomas of the lung less than 2 cm in diameter were analyzed in 75 patients who had undergone surgical resection. The pathologic stage, lymph node involvement, and pleural involvement were found to be the major determinants of prognosis (P < 0.01). In addition, other single factors, such as tumor differentiation (P < 0.01), vascular invasion (P < 0.01), the degree of collagenization in the fibrotic focus (P < 0.01), the standard deviation (SD) of nuclear areas (P < 0.05), and mitotic index (P < 0.05) correlated significantly with prognosis by the log‐rank test on the Kaplan‐Meier survival curves of these factors. Patients with dense infiltration of “T‐zone histiocytes” survived significantly longer than those with less infiltration (P < 0.05). Coxs proportional hazard general linear model analysis showed the importance of factors, such as lymph node or pleural involvement and the SD of nuclear area, when the pathologic stage was excluded, and of the mitotic index when all four factors were excluded to emphasize the cellular characteristics. It is possible to predict the postoperative prognosis of patients with small pulmonary adenocarcinoma more precisely by combination of the above histopathologic factors.

Production of alpha‐fetoprotein, normal serum proteins, and human chorionic gonadotropin in stomach cancer: Histologic and immunohistochemical analyses of 35 cases

By immunoperoxidase histochemical staining of formalin‐fixed paraffin‐embedded sections, the production of alpha‐fetoprotein(AFP), albumin(ALB), transferrin(TF), alpha‐1‐antitrypsin(AAT), and human chorionic gonadotropin(HCG) was examined in 35 operatively resected stomach cancers with elevated serum AFP levels (higher than 20 ng/ml as determined by radioimmunoassay). Cells positive for AFP were found in 19 cases (54%). In 29 cases (83%), some tumor cells contained normal serum proteins (ALB, TF, or AAT). All 19 tumors with AFP‐positive cells also stained positively for two or three kinds of normal serum proteins. In some cases, AFP and normal serum proteins were localized in the same cells. There were two cases in which metastatic tumors produced AFP, whereas the primary sites did not. In nine cases (26%), HCG was present in tumor cells and HCG‐ and AFP‐positive cells were coexistent in six tumors. Histologic examination of AFP‐producing stomach tumors revealed medullary or papillotubular arrangements with marked nuclear atypia and eosinophilic granular or clear cytoplasms containing no glycogen or mucin. Some tumors with medullary patterns resembled liver cell carcinomas. Concordant phenotypic expression of AFP and normal serum protein production appears to be a general feature of AFP‐producing tumors such as liver cell carcinoma, yolk sac tumor, and stomach cancer.

Monoclonality of Atypical Adenomatous Hyperplasia of the Lung

Atypical adenomatous hyperplasia (AAH) of the lung has been postulated as a possible precursor lesion of bronchioloalveolar carcinoma (BAC). The clonality of AAHs from seven female patients was analyzed to determine whether AAH is a monoclonal expansion. All AAHs were identified in lungs surgically resected for BAC. The clonality of the BAC and bronchiolar metaplasia in each case was also analyzed. Approximately 500 cells in each lesion were precisely microdissected from methanol-fixed sections. Adjacent normal lung tissue was collected as a normal control. DNA was extracted for clonal analysis based on an X-chromosome-linked polymorphic marker, the human androgen receptor gene (HUMARA). HUMARA was found to be amplified with or without previous digestion by the methylation-sensitive restriction endonuclease Hpa II. Five cases were informative. All 10 AAHs and 7 BACs obtained from the informative cases showed monoclonality, whereas the control cells showed polyclonality. Three different AAH lesions in a single case showed both possible patterns of monoclonality. BAC and contiguous AAH showed identical monoclonality in two cases. Two lesions of bronchiolar metaplasia, which was considered reactive, were polyclonal. Our results demonstrated the monoclonal nature of AAH, and this finding suggests that AAH is a precursor of BAC or a preneoplastic condition.

Randomized Pharmacokinetic and Pharmacodynamic Study of Docetaxel: Dosing Based on Body-Surface Area Compared With Individualized Dosing Based on Cytochrome P450 Activity Estimated Using a Urinary Metabolite of Exogenous Cortisol

PURPOSE Docetaxel is metabolized by cytochrome P450 (CYP3A4) enzyme, and the area under the concentration-time curve (AUC) is correlated with neutropenia. We developed a novel method for estimating the interpatient variability of CYP3A4 activity by the urinary metabolite of exogenous cortisol (6-beta-hydroxycortisol [6-beta-OHF]). This study was designed to assess whether the application of our method to individualized dosing could decrease pharmacokinetic (PK) and pharmacodynamic (PD) variability compared with body-surface area (BSA) -based dosing. PATIENTS AND METHODS Fifty-nine patients with advanced non-small-cell lung cancer were randomly assigned to either the BSA-based arm or individualized arm. In the BSA-based arm, 60 mg/m(2) of docetaxel was administered. In the individualized arm, individualized doses of docetaxel were calculated from the estimated clearance (estimated clearance = 31.177 + [7.655 x 10(-4) x total 6-beta-OHF] - [4.02 x alpha-1 acid glycoprotein] - [0.172 x AST] - [0.125 x age]) and the target AUC of 2.66 mg/L . h. RESULTS In the individualized arm, individualized doses of docetaxel ranged from 37.4 to 76.4 mg/m(2) (mean, 58.1 mg/m(2)). The mean AUC and standard deviation (SD) were 2.71 (range, 2.02 to 3.40 mg/L . h) and 0.40 mg/L . h in the BSA-based arm, and 2.64 (range, 2.15 to 3.07 mg/L . h) and 0.22 mg/L . h in the individualized arm, respectively. The SD of the AUC was significantly smaller in the individualized arm than in the BSA-based arm (P < .01). The percentage decrease in absolute neutrophil count (ANC) averaged 87.1% (range, 59.0 to 97.7%; SD, 8.7) in the BSA-based arm, and 87.4% (range, 78.0 to 97.2%; SD, 6.1) in the individualized arm, suggesting that the interpatient variability in percent decrease in ANC was slightly smaller in the individualized arm. CONCLUSION The individualized dosing method based on the total amount of urinary 6-beta-OHF after cortisol administration can decrease PK variability of docetaxel.

An immunohistochemical study of thymic epithelial tumors i. epithelial component

Twenty-four cases of thymic epithelial tumors, including 18 cases of thymoma, five cases of squamous cell carcinoma, and one case of undifferentiated carcinoma, were studied immunohistochemically using monoclonal antibody Leu-7 (HNK-1) and antikeratin antibody. Seven cases of non-neoplastic thymic tissues were also studied. Leu-7 antibody stained epithelial cells in the outer cortex of the normal thymus, and antikeratin antibody stained thymic epithelial cells in both cortex and medulla of the normal thymus. Seventeen thymomas and one undifferentiated carcinoma were focally or diffusely stained with Leu-7, some showing cortical and medullary differentiation as seen in the normal thymus. On the other hand, none of the five squamous cell carcinomas were stained with Leu-7. All thymomas stained for keratin in varying degrees, and all squamous cell carcinomas were diffusely and strongly stained with antikeratin antibody. It is concluded that normal thymic epithelial cells showed zonal differentiation, and neoplastic cells were considered to retain these characteristics to some extent; i.e., thymomas had the same phenotype of epithelial cells of the cortex, especially the outer cortex of the thymus in some instances (Leu-7-positive, keratin-positive) and of both cortex and medulla (mixture of Leu-7-positive and -negative cells) with organoid arrangement in other instances, and thymic squamous cell carcinoma had the same phenotype as epithelial cells in the thymic medulla (Leu-7-negative, keratin-positive).

Six cases of well-differentiated adenocarcinoma simulating fetal lung tubules in pseudoglandular stage: comparison with pulmonary blastoma

Six cases of well-differentiated adenocarcinoma resembling fetal lung were studied histologically, immunohistochemically, and ultrastructurally, and compared with three cases of pulmonary blastoma. The six cases had no sarcomatous features, unlike the pulmonary blastoma. Individual tumor cells characteristically possessed clear cytoplasm with plentiful glycogen and were similar to the epithelial cells of the branching tubules in the pseudoglandular stage of the fetal lung, as well as the epithelial component of pulmonary blastoma. They also showed little differentiation toward mucous cells and ciliated cells. Although cells containing endocrine-type granules were not found ultrastructurally, a few tumor cells possessed the characteristics of endocrine cells, i.e., cytoplasm was immunohistochemically reactive with anticalcitonin and antigastrin-releasing peptide. Therefore, this type of adenocarcinoma is considered to have a histogenesis similar to that of pulmonary blastoma and may be a tumor with one-sided development of pulmonary blastoma showing only an epithelial component.

Characteristics of Subsolid Pulmonary Nodules Showing Growth During Follow-up With CT Scanning

OBJECTIVE The positive results of a screening CT scan trial are likely to lead to an increase in the use of CT scanning, and, consequently, an increase in the detection of subsolid nodules. Noninvasive methods including follow-up with CT scanning, to determine which nodules require invasive diagnosis and surgical treatment, should be defined promptly. METHODS Between 2000 and 2008, from our database of . 60,000 examinations with CT scanning, we identified 174 subsolid nodules, which showed a ground-glass opacity area . 20% of the nodule and measured 2 cm in diameter, in 171 patients. We investigated the clinical characteristics and CT images of the subsolid nodules in relation to changes identified during the follow-up period. RESULTS The nodule sizes ranged from 4 mm to 20 mm at the fi rst presentation. Nonsolid nodules numbered 98. During the follow-up period, 18 nodules showed resolution or shrinkage, and 41 showed growth of 2 mm or more in diameter. The time to 2-mm nodule-growth curves calculated by Kaplan-Meier methods indicated that the 2-year and 5-year cumulative percentages of growing nodules were 13% and 23% in patients with nonsolid nodules and 38% and 55% in patients with part-solid nodules, respectively. Multivariate analysis disclosed that a large nodule size ( . 10 mm) and history of lung cancer were significant predictive factors of growth in nonsolid nodules. CONCLUSIONS An effective schedule for follow-up with CT scanning for subsolid nodules should be developed according to the type of subsolid nodule, initial nodule size, and history of lung cancer.

Immunohistochemical Differential Diagnosis Between Large Cell Neuroendocrine Carcinoma and Small Cell Carcinoma by Tissue Microarray Analysis With a Large Antibody Panel

To elucidate additional phenotypic differences between large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC), we performed tissue microarray (TMA) analysis of surgically resected LCNEC and SCLC specimens. Immunostaining with 48 antibodies was scored based on staining intensity and the percentage of cells that stained positively. Four proteins were identified as significantly expressed in LCNEC as compared with SCLC: cytokeratin (CK)7, 113 vs 49 (P < .0301); CK18, 171 vs 60 (P < .0008); E-cadherin, 77 vs 9 (P < .0073); and beta-catenin, 191 vs 120 (P < .0286). Immunostaining of cross-sections containing LCNEC and SCLC components revealed significant expression of CK7, CK18 and beta-catenin in the LCNEC component compared with the SCLC component in 2 of 3 cases. Our results indicate that significant expression of CK7, CK18, E-cadherin, and beta-catenin is more characteristic of LCNEC than of SCLC, and these findings provide further support that these tumor types are separate entities morphologically and immunophenotypically, if not biologically.