Shinsuke Aida

Expression of Hypoxia-Inducible Factor-1α Protein Predicts Survival in Patients with Transitional Cell Carcinoma of the Upper Urinary Tract

Hypoxia-inducible factor-1 (HIF-1), identified as one of the transcription factors, has been found to play an essential role in oxygen homeostasis. HIF-1 is a heterodimer composed of HIF-1α and HIF-1β. Increased levels of HIF-1α have been reported during the carcinogenesis and progress of several tumors. We investigated the prognostic importance of HIF-1α expression in transitional cell carcinoma of the upper urinary tract. In 127 cases of transitional cell carcinoma of the upper urinary tract, we examined its expression (using immunohistochemistry and in situ hybridization), and also its relation to the expression of p53 oncoprotein, as well as to proliferating cell nuclear antigen (PCNA) immunoreactivity, microvessel density, clinicopathologic parameters, and clinical outcome. A positive expression of HIF-1α protein was recognized in 55.1% of samples, the expression being apparent within the nucleus in tumor cells. HIF-1α protein expression correlated with grade, growth pattern, p53 oncoprotein expression, and PCNA index, but not with stage. Furthermore, a significant correlation was found between HIF-1α protein expression and both overall and disease-free survival rates in the univariate and multivariate analyses (in all tumors and in invasive tumors). A positive expression of HIF-1α mRNA was recognized in 69.6% of 125 samples which were available, the expression being apparent within the cytoplasm in tumor cells. The positive expression of HIF-1α mRNA by in situ hybridization correlated significantly with HIF-1α protein expression by immunohistochemistry. HIF-1α mRNA expression only correlated with pattern of growth (P = 0.0078). In conclusion, the detection of HIF-1α protein would seem to be of value in informing the prognosis of transitional cell carcinoma of the upper urinary tract.

A proposal for diagnostically meaningful criteria to classify increased epidermal growth factor receptor and c-erbB-2 gene copy numbers in gastric carcinoma, based on correlation of fluorescence in situ hybridization and immunohistochemical measurements

Amplification of the epidermal growth factor receptor (EGFR) and/or c-erbB-2 oncogenes and overexpression of their proteins are detected in 30% of gastric carcinomas, but there are few reports regarding the correlation between gene amplification and protein overexpression. We examined the correlation between amplification of the EGFR and c-erbB-2 genes, detected using fluorescence in situ hybridization, and overexpression of their proteins, detected using immunohistochemistry, in formalin-fixed tissue sections of 54 surgically resected gastric carcinomas. A mean EGFR copy number per nucleus of four or more and an EGFR/chromosome 7 centromere (CEP7) ratio of 1.7 or more were each detected in 4 specimens (7%). The sensitivity and specificity of both criteria for EGFR protein overexpression were 75% and 92%, respectively. A mean c-erbB-2 copy number per nucleus of 7.0 or more and a c-erbB-2/chromosome 17 centromere (CEP17) ratio of 2.0 or more were detected in six (11%) and eight (15%) specimens, respectively. The sensitivity and specificity of the former criterion to c-erbB-2 overexpression were 83% and 98%, respectively, while those of the latter were 63% and 98%. A mean EGFR gene copy number of 4.0 or more and/or an EGFR/CEP7 ratio of 1.7 and a mean c-erbB-2 gene copy number of 7.0 or more and/or a c-erbB-2/CEP17 ratio of 2.0 or more would be useful in defining increased EGFR and c-erbB-2 gene copy numbers, respectively, in gastric carcinomas.

Expression of LAT1 predicts risk of progression of transitional cell carcinoma of the upper urinary tract

L-type amino acid transporter 1 (LAT1), a neutral amino acid transporter, requires covalent association with the heavy chain of 4F2 cell surface antigen (4F2hc) for its functional form. We investigated the importance of LAT1 and 4F2hc expressions to progression in upper urinary tract cancer. We examined their expressions and their relationships to clinicopathologic parameters and clinical outcome in 124 cases. Positive expressions of LAT1 (protein and messenger ribonucleic acid) and 4F2hc (protein) were recognized in 79.8, 89.5, and 87.9% of tumor samples, respectively. In tumor cells, LAT1 protein was detected either as nodular granules within the cytoplasm or diffusely within the cytoplasm and/or on plasma membrane. In the normal urothelium, its expression was detected as nodular granules within the cytoplasm. A correlation with stage was shown for LAT1 protein expression and for a cooperative expression of LAT1 protein with 4F2hc protein (active form of LAT1 protein). Further, in all tumors, a cooperative expression of LAT1 protein and 4F2hc protein was significantly correlated with both overall and disease-free survival rates in the univariate analysis but not in the multivariate analysis. In conclusion, the detection of the active form of LAT1 protein would appear to be of value in informing the risk of progression in transitional cell carcinoma of the upper urinary tract.

Expression of survivin does not predict survival in patients with transitional cell carcinoma of the upper urinary tract

Abstract. The members of the IAP (inhibitors of apoptosis) family, which includes survivin, have recently emerged as modulators of an evolutionarily conserved step in apoptosis. Survivin is present during embryonic and fetal development, but it is downregulated in normal adult tissues. However, it becomes re-expressed in a variety of cancers. We investigated the prognostic importance of the expression of survivin in transitional cell carcinoma of the upper urinary tract (TCC-UUT). In 126 cases of TCC-UUT, we examined its expression (using immunohistochemistry), and also its relationship with the expressions of bcl-2 oncoprotein, p53 oncoprotein, and proliferating cell nuclear antigen (PCNA) immunoreactivity, clinicopathologic parameters, and clinical outcome. A positive expression of survivin was recognized in 12.7% of samples, a granular pattern being apparent within the cytoplasm of tumor cells. Survivin expression did not correlate with clinicopathologic findings, bcl-2 oncoprotein expression, p53 oncoprotein expression, PCNA index, or prognosis. In the normal urothelium, its expression was not detected. In conclusion, the expression of survivin does not predict prognosis in TCC-UUT.

Primary small cell (oat cell) carcinoma of the breast: Report of a case and review of the literature

A case of primary small cell (oat cell) carcinoma of the breast in a 41‐year‐old woman is presented. The patient was alive and well without disease 16 months after modified radical mastectomy and subsequent chemotherapy. The tumor cells revealed morphologic similarity to oat cell carcinoma of the lung and immunohistochemical expression of neuroendocrine markers. In ultrastructural examination, the tumor cells had neurosecretory granules. Review of nine previously reported cases and this case of primary small cell carcinoma of the breast has revealed that this type of tumor shows prominent vascular invasion, frequent lymph node metastasis, infrequent expression of estrogen receptor, and also very poor prognosis. Immunohistochemical study for the c‐kit proto‐oncogene product, which has been reported to be a specific marker for pulmonary small cell carcinoma, demonstrated positive reactivity in approximately 80% of the tumor cells of this case, which is the first report according to our knowledge. The expression of c‐kit might be some aid to the diagnosis of primary small cell carcinoma of the breast.

Distribution of epidermal growth factor and epidermal growth factor receptor in human lung : immunohistochemical and immunoelectron-microscopic studies

The distribution of epidermal growth factor (EGF) and EGF receptor (EGFR) in adult human lung was examined by immunohistochemistry and immunoelectron microscopy. EGF immunoreactivity was observed in secretory granules and endoplasmic reticulum of serous acinar cells of bronchial glands. EGFR immunoreactivity was detected at the cell membrane of the basal cells and the bronchial surface nonciliated cells (indifferent cells) in the bronchus, the nonciliated bronchiolar cells (Clara cells) and the type II pneumocytes in peripheral lung. These results suggest that EGF is secreted into bronchial surface fluid from the bronchial glands and stimulates proliferation and/or differentiation of basal cells and indifferent cells of the bronchus, although the source of EGF responsive to Clara cells and the type II pneumocytes of peripheral lung was not determined.

Expression of membrane-type-1-matrix metalloproteinase and metalloproteinase-2 in nonsmall cell lung carcinomas

For the metastasis and invasion of cancer cells, destruction of extracellular matrix is essential. In this process, collagen is broken down by some matrix metalloproteinases. Matrix metalloproteinase 2 (MMP2) is able to cleave type IV collagen, and membrane-type-1-matrix metalloproteinase (MT1-MMP) induces activation of proMMP2. We investigated the expressions of MT1-MMP and MMP2 and their relation to both clinicopathologic parameters and clinical outcome in non-small cell lung carcinomas (NSCLC). Eighty-nine specimens of NSCLC were examined using in situ hybridization and immunohistochemistry. Each metalloproteinase was expressed within the cytoplasm of tumor cells with or without stromal cells in NSCLC. Tumors in which tumor cells strongly stained for MT1-MMP mRNA or protein made up more than 50% of the tumor area were found in 44 and 26% of cases, respectively. The corresponding values for MMP-2 mRNA and protein, were 51 and 26%. Our analysis of clinicopathological findings revealed a significant positive relationship between MT1-MMP mRNA and p-M. The correlation between MMP2 protein-staining status and overall survival rate reached significance in the univariate analysis. However, an association was not demonstrated in the multivariate analysis. The detection of MT1-MMP and MMP2 is likely to be of limited value in informing the prognosis in NSCLC.

LAT1 expression in normal lung and in atypical adenomatous hyperplasia and adenocarcinoma of the lung

No previous study has investigated neutral large amino acid transporter type 1 (LAT1) in normal lung cells, or in atypical adenomatous hyperplasia(s) (AAH) and nonmucinous bronchioloalveolar carcinoma(s) (NMBAC) of the lung. The authors examined: (1) the levels of LAT1 mRNA/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA in 41 normal lung tissues and 34 NMBAC using semiquantitative reverse transcription–polymerase chain reaction; (2) LAT1 mRNA and protein expressions in 35 normal lung tissues, 34 AAH (11 lesions were interpreted as low-grade AAH and 23 as high-grade AAH), and 43 NMBAC using in situ hybridization and immunohistochemistry; and (2) the association of the incidences of LAT1 mRNA and protein expressions with cell proliferation in these lesions. The level of LAT1 mRNA/GAPDH mRNA (1) tended to be higher in NMBAC (12.0±8.1) than in normal lung tissues (1.0±0.2), and (2) covered a much wider range (from 0 to 276) in NMBAC than in normal lung tissues (from 0 to 5.8), with six NMBAC having values higher than 7.0, while 5.8 was the highest value detected in normal lung tissues. In peripheral normal lung tissues, LAT1 mRNA and protein were detected in bronchial surface epithelial cells and alveolar macrophages (but not in nonciliated bronchiolar epithelial cells, or in alveolar type I or type II cells). In bronchial surface epithelial cells, LAT1 protein appeared to be of a nodular type, which was considered to be a nonfunctional protein pattern. The incidences of positive expressions for LAT1 mRNA and protein were 54.5 and 27.3% in low-grade AAH, 65.2 and 52.2% in high-grade AAH, and 65.1 and 79.1% in NMBAC, respectively. In the case of LAT1 protein expression, significant differences could be shown between total (low-grade plus high-grade) AAH and NMBAC, and between low-grade AAH and NMBAC. Thus, in terms of the incidence of LAT1 protein expression, high-grade AAH appeared intermediate between low-grade AAH and NMBAC. The Ki-67 labeling index (a cell proliferation score) was significantly higher in those AAH and NMBAC that were LTA1-protein-positive than in their LAT1-protein-negative counterparts. In conclusion, LAT1 expression may increase with the upregulation of metabolic activity and cell proliferation in high-grade AAH and NMBAC.

Solitary peripheral ciliated glandular papillomas of the lung: a report of 3 cases.

We report 3 cases of solitary papillomas located in peripheral regions of the lung that are extremely rare in the literature. The patients were 75-year-old and 72-year-old men and a 53-year-old woman. One patient complained of recurrent hemoptysis. The other 2 had no symptoms, but abnormal nodular shadows were revealed by chest radiographs during a health check. The maximum diameters of the tumors were 1.0, 1.4, and 1.1 cm, respectively. The 3 tumors gave almost the same histologic findings. Papillomatous fronds lined by a stratified columnar epithelium were seen in the lumens of peripheral bronchi, bronchioles, or alveoli. The stratified columnar epithelium consisted of ciliated, mucous, and basal cells. The neoplastic epithelium extended to the alveolar region and showed a similar appearance to bronchioloalveolar or papillary type adenocarcinomas. For differential diagnosis, it is noteworthy that endobronchiolar papillomatous fronds constantly exist and spreading along alveolar walls is limited in adjacent alveoli in peripheral papillomas. The presence of ciliated cells and basal cells is considered an important finding to suggest benign character of the lesion.

Localized malignant peritoneal mesothelioma containing rhabdoid cells

A case Is presented of localized malignant peritoneal mesothelioma appearing as a liver neoplasm. The patient underwent tumor resection but developed a recurrent growth and died 10 months after the Initial surgery. The primary tumor showed sarcomatous features with rhabdoid cells. Examination revealed the presence of hyaluronic acid, co‐Immunoreactivlty for cytokeratln epithelial membrane antigen and vlmentln, cellular contacts with small desmosomes, and intracytoplasmic lumina. These findings supported the mesothelial nature of this tumor. The recurrent tumor was composed of predominantly tubulopaplllary proliferation. It was concluded that the present tumor was a localized malignant mesothelioma of a blphasic type showing a predominantly sarcomatous component in the primary tumor.