Tomoyuki Yokose

Neuroendocrine Neoplasms of the Lung: A Prognostic Spectrum

PURPOSE Neuroendocrine (NE) tumors of the lung include typical carcinoid (TC), atypical carcinoid (AC), large-cell NE carcinoma (LCNEC), and small-cell lung carcinoma (SCLC). Their clinicopathologic profiles and relative grade of malignancy have not been defined. PATIENTS AND METHODS From 10 Japanese institutes, 383 surgically resected pulmonary NE tumors were collected. The histologic diagnosis was determined by the consensus of a pathology panel consisting of six expert pathologists as TC, AC, LCNEC, or SCLC on the basis of the WHO classification, and its relationship to clinicopathologic profiles was analyzed. RESULTS Of the 383 tumors, 18 were excluded because of an improper specimen. The pathology panel reviewed the remaining 366 tumors, and a diagnosis of NE tumor was made in 318 patients (87.4%); 55 patients had TC, nine had AC, 141 had LCNEC, and 113 had SCLC. The 5-year survival rates of patients with all stages were as follows: 96.2% for TC, 77.8% for AC, 40.3% for LCNEC, and 35.7% for SCLC. There was significant prognostic difference between TC and AC as well as between AC and LCNEC+SCLC. However, there was no difference between LCNEC and SCLC, and their survival curves were superimposed. The multivariate analysis indicated that histologic type, completeness of resection, symptoms, nodal involvement, and age were significantly prognostic. CONCLUSION The grade of malignancy of NE tumors was upgraded in the following order: TC, AC, LCNEC, and SCLC. No prognostic difference was noted between LCNEC and SCLC. The high-grade NE histology uniformly indicated poor prognosis regardless of its histologic type.

Prognostic significance of the size of central fibrosis in peripheral adenocarcinoma of the lung

BACKGROUND The prognostic significance of the characteristics of central fibrosis in peripheral adenocarcinoma of the lung has been reported. However, the prognostic significance of the size of central fibrosis has never been evaluated. METHODS A total of 100 consecutive surgically resected peripheral adenocarcinomas of the lung measuring 3.0 cm or less in maximum dimension were reviewed histologically, and the maximum dimension of central fibrosis was measured on conventional hematoxylin and eosin stain. RESULTS Median follow-up for patients alive was 54 months. The overall 5-year survival rate was 75%. Twenty-one patients with adenocarcinoma having central fibrosis 5 mm or smaller in maximum dimension had a 5-year survival rate of 100%, whereas the other 79 patients had a 5-year survival less than 70%. Multivariate analysis showed the size of central fibrosis to be an independent prognostic factor as significant as vascular invasion and locoregional lymph node metastasis (p = 0.010, 0.024, and 0.024, respectively). CONCLUSIONS The size of central fibrosis is an independent prognostic factor in peripheral lung adenocarcinoma, as significant as the well-established prognostic factors vascular invasion and lymph node metastasis.

Increased cyclooxygenase 2 (COX-2) expression occurs frequently in precursor lesions of human adenocarcinoma of the lung.

A low incidence of lung carcinoma has been reported in cases of prolonged use of aspirin. Cyclooxygenase (COX) 2 expression is frequently seen in adenocarcinoma of the lung, but COX-2 expression in atypical adenomatous hyperplasia (AAH), a possible precursor lesion of adenocarcinoma of the lung, is not known. COX-2 expression was immunohistochemically evaluated in a cohort of 20 cuboidal cell hyperplasias (CCH), 81 atypical adenomatous hyperplasias (AAH), 18 bronchioloalveolar carcinomas (BAC), and 88 invasive adenocarcinomas (I-Ad). The relationship between COX-2 expression and clinicopathologic factors and survival was examined. COX-2 overexpression was detected in over 80% of CCH, AAH, BAC, and I-Ad. However, overexpression was diffuse in AAH (71.6%) and BAC (66.7%). No relationship was found between COX-2 expression and clinicopathological factors or survival. COX-2 expression was most frequently detected in AAH. These findings, taken with previous reports that treatment with COX-2 inhibitor suppresses human colon carcinogenesis, suggest that inhibition of COX-2 may reduce the incidence of human adenocarcinoma of the lung.

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.

Favorable and unfavorable morphological prognostic factors in peripheral adenocarcinoma of the lung 3 cm or less in diameter

Many small adenocarcinomas can be detected as a result of recent advances in diagnostic radiology. Since the histological and biological heterogeneity of adenocarcinoma often makes it difficult to predict the outcome of operated patients, clarifying the morphological prognostic factors of the tumor is indispensable to the selection of appropriate treatment. We examined 200 cases of adenocarcinoma of the lung 3 cm or less in diameter (T1). Tumor size, tumor cell characteristics, growth pattern, characteristics of fibrosis, vessel and stromal invasion, and metastasis were evaluated to define favorable and unfavorable morphological prognostic factors by univariate and multivariate statistical analysis. There were no deaths in the 66 cases with more than a 75% of lepidic growth component defined as a region of tumor cells growing along alveolar walls and without stromal invasion, central focus of fibrosis 5 mm or less in maximum diameter, or no elastic fiber framework destruction by tumor cells. Multivariate analysis to investigate unfavorable factors revealed that vascular invasion (P<0.001) and a greater than 25% papillary growth component (P=0.043) were the most significant determinants of an unfavorable outcome. The favorable and unfavorable factors demonstrated in this study will be of great value in selecting the treatment of patients with small peripheral adenocarcinoma of the lung.

Pleomorphic Carcinoma of the Lung: Clinicopathologic Characteristics of 70 Cases

Pleomorphic carcinoma (PC) of the lung is rare, and it is classified as a subtype of sarcomatoid carcinoma of the lung in the World Health Organization histologic classification of lung tumors. In this study, 70 cases of PC surgically resected were reviewed to identify its clinicopathologic characteristics. There were 57 men and 13 women, and their mean age was 66 years (range: 29 to 80 y). Sixty-eight tumors contained identifiable epithelial components, and the other 2 consisted of spindle cells and giant cells alone. An adenocarcinoma component was found in 34 cases, a squamous cell carcinoma component in 13, and a large cell carcinoma component in 40. The overall survival rate and disease-free survival rate were 36.6% and 40.7%, respectively, and both rates were significantly lower than for other nonsmall cell lung carcinomas. When the PC patients were divided into 3 groups according to the predominant epithelial component, an adenocarcinoma group, squamous cell carcinoma group, and large cell carcinoma group, there were no significant differences in the overall survival rate and median survival time between the 3 groups. Univariate analysis revealed that advanced stage (stage III), mediastinal lymph node metastasis, lymphatic permeation, and histologically diagnosed massive coagulation necrosis (>25% of the tumor) predicted poorer disease-free survival. Multivariate analysis showed that massive necrosis alone was an independent prognostic factor. We concluded that PC should be considered as an aggressive disease and massive necrosis should be routinely reported and used as a factor in clinical assessments.

Localized pure ground-glass opacity on high-resolution CT: histologic characteristics.

Purpose The aim of this study is to assess the histologic characteristics in cases of localized pure ground-glass opacity (LPGGO) that do not exhibit consolidation on high-resolution CT (HRCT) images. Method Twenty surgically resected lesions from 20 consecutive cases were retrospectively investigated. Each of the 20 lesions had exhibited LPGGO on HRCT images. The HRCT images and histopathologic findings were examined for correlations. Results The areas of LPGGO had a maximum diameter of 2.0–24 mm on the HRCT images. Histopathology of the LPGGO lesions resulted in diagnosis of fibrosis (n = 3; 15%), atypical adenomatous hyperplasia (n = 5; 25%), bronchioloalveolar carcinoma (n = 10; 50%), and adenocarcinoma with stromal invasion (n = 2; 10%). Nonaerogenous components corresponding to solid components without normal alveolar septal destruction were pathologically observed in 15 of the 20 lesions. The diameter of the nonaerogenous components varied between 0.2 and 2.0 mm. Conclusion Because 10% of LPGGO lesions include invasive disease, patients with LPGGO should undergo pathologic examination for confirmation.

Prognostic Significance of Fibrotic Focus in Invasive Ductal Carcinoma of the Breast: A Prospective Observational Study

We have already reported invasive ductal carcinomas (IDCs) with fibrotic focus (FF) to be associated with significantly poorer survival than IDCs without FF. The purpose of this study was to prospectively investigate the effect of the presence of FF on the outcomes of 439 patients with IDCs to confirm the prognostic significance of FF, by the multivariate analysis, employing the Cox proportional hazard regression model, as compared with well-known clinicopathological parameters. We also precisely evaluated the prognostic significance of FF from the viewpoint of FF characteristics. The present study demonstrated that the presence of FF is a very useful parameter predicting tumor recurrence (TR), as well as initial distant organ metastasis (IDOM), in lymph node–negative IDCs (P = .024 and P = .026) and in IDCs positive for either or both estrogen receptor (ER) or progesterone receptor (PR) (P = .007 and P = .015), respectively. In addition, FF of >8 mm in diameter was found to be an independent prognostic parameter for TR and IDOM in lymph node–negative patients and patients with IDC positive for either or both ER or PR (P = .005 and P = .018). We conclude that the presence of FF is a very important histologic prognostic parameter for patients with IDCs of the breast.

Immunohistochemical study of cytochrome P450 2C and 3A in human non-neoplastic and neoplastic tissues.

Abstract Organ and cellular distribution and expression constancy of microsomal cytochrome P450 (CYP) 2C and 3A in humans were studied with new polyclonal antibodies to CYP2C (MP-1) and 3A (NF-2) active in formalin-fixed, paraffin-embedded tissues. Antibodies were raised against purified human CYP2C9 and CYP3A4. On western blotting, MP-1 reacted with 2C8, 2C9, 2C18 and 2C19, and NF-2 with 3A4. In both frozen and paraffin sections, hepatocytes showed diffuse immunoreactivity with MP-1 and centrilobular staining with NF-2. Inparaffin sections of 40 kinds of nonneoplastic tissues, epithelium of the small and large intestine, bile duct, nasal mucosa, kidney and adrenal cortex stained positively with both MP-1 and NF-2 antibodies. Epithelium of gastric fundic glands, salivary glands, tracheobronchial glands, Brunner’s glands, the prostate, uterine cervix and nasopharynx showed definite reactivity with MP-1. Epithelium of the gastric mucosa with intestinal metaplasia, duodenum, gallbladder and intercalated ducts of the pancreas and chief cells of the parathyroid and the corpus luteum of the ovary reacted with NF-2. Among the neoplastic tissues, MP-1 reacted with pleomorphic adenoma of the salivary gland and carcinomas of six different organs, and NF-2 with those of 7 different organs. These results indicate that CYP2C and CYP3A are distributed widely and organ specifically, as well as being variably expressed in neoplastic and normal states.

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.