Biomedical subjects

Toru Kameya

Publications and source records attributed to Toru Kameya.

At least 19 recordsLinked to original sources

PubMed2006

Primary nasopharyngeal mucoepidermoid carcinoma in Japanese patients: two case reports with histochemical and immunohistochemical analysis and a review of the literature.

Mucoepidermoid carcinoma is a common neoplasm of the salivary glands. Salivary gland-type neoplasms are very rare in the nasopharynx, and there are only few reports on mucoepidermoid carcinoma of the nasopharynx. Two additional cases of mucoepidermoid carcinoma arising from the nasopharynx are reported here. Case 1: the patient was a 57-year-old Japanese woman who had bloody sputum. Case 2: the patient was a 51-year-old Japanese woman who underwent resection of a nasopharyngeal tumor. Histologically, both tumors were also low-grade mucoepidermoid carcinomas with clear cells. Histochemically, the gland-like nests and mucous cells were positive for mucin staining. Immunohistochemically, the lesions were positive for cytokeratins (CKs), p63, and MUC1, but negative for alpha-smooth muscle actin and EBER mRNA. The Ki-67 labeling indices of the two tumors were 10.4% and 4.3%, respectively. The two present cases and a review of the English literature indicate that salivary gland-type neoplasms arising from the nasopahrynx are extremely rare. The prognosis of salivary gland-type carcinomas of the nasopharynx is still unknown.

Biomarkers, Tumor↗

PubMed2006

Telomere length, telomerase activity, and expressions of human telomerase mRNA component (hTERC) and human telomerase reverse transcriptase (hTERT) mRNA in pulmonary neuroendocrine tumors.

BACKGROUND: Telomeres are important for chromosome structure and function, protecting them against degradation. However, few studies have examined telomeres in pulmonary neuroendocrine (NE) tumors. METHODS: We investigated deparaffinized sections obtained from 70 primary NE lung tumors [34 typical carcinoids (TCs), 10 atypical carcinoids (ACs), 16 large cell neuroendocrine carcinoma (LCNECs) and 10 small cell lung carcinomas (SCLCs)]. RESULTS: Positive expressions of human telomerase mRNA component (hTERC) and human telomerase reverse transcriptase (hTERT) mRNA were recognized, respectively, in 58% and 74% of TCs, and in 100% and 100% of ACs, LCNECs and SCLCs. Alteration of telomere length was greater in both LCNECs and SCLCs than in TCs. Telomerase activity was detected in LCNECs, but not in TCs. By the reverse-transcriptase polymerase chain reaction (RT-PCR), hTERC mRNA was detected in 100% of LCNECs and TCs examined, while hTERT mRNA was detected in 67% of LCNECs, but not at all in TCs. CONCLUSIONS: These results suggest that alterations in telomere length, telomerase activity, and the expression of hTERT mRNA may (i) play roles in pathogenesis in pulmonary neuroendocrine tumors, and (ii) be a useful tool for differential diagnosis between TCs and LCNECs.

Carcinoma, Neuroendocrine↗

PubMed2006

Evaluation of lymphatic invasion in primary gastric cancer by a new monoclonal antibody, D2-40.

Lymphatic invasion is known as an independent predictor of lymph node metastasis in gastric cancer. However, the diagnosis of lymphatic invasion is sometimes difficult by hematoxylin-eosin (H&E) staining. Immunostaining using D2-40 was performed to study the distribution of lymphatic vessel and lymphatic invasion in a series of 78 primary gastric cancers. D2-40 showed specific staining for the lymphatic vessels, but not for blood vessels. The lymphatic invasion was most frequently found in the upper half of submucosal layer. Positive rate of lymphatic invasion by H&E staining was 27% (21/78), and that by D2-40 was 44% (34/78). Lymphatic invasion on H&E staining was diagnosed as false negative in 17 (21.8%) of 78 primary gastric cancers and false positive in 4 (5.1%) of 78 primary gastric cancers. Sensitivity for lymph node metastasis by the lymphatic invasion diagnosed by D2-40 was significantly higher (89%, 24/27) than by H&E staining (41%, 11/27). These results suggest that the diagnosis of lymphatic invasion by D2-40 is more sensitive than H&E staining. Sensitivity for the prediction of lymph node metastasis from the lymphatic invasion status in primary tumor by D2-40 was significantly higher than by H&E staining. Based on our results, we recommend the use of D2-40 immunoreactions for the routine evaluation of lymphatic invasion in gastric cancer.

Adenocarcinoma↗

PubMed2006

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.

Carcinoma, Small Cell↗

PubMed2006

Malignant pleural mesothelioma in a 14-year-old boy with right aortic arch.

We report successful surgery for malignant pleural mesothelioma (MPM) in a 14-year-old boy with right aortic arch. Pleural biopsy by video-assisted thoracic surgery yielded a diagnosis of MPM, epithelial type. As the disease was not changed after combination chemotherapy with three cycles of cisplatin and gemcitabine, we performed left extrapleural pneumonectomy, including resection of the pericardium and diaphragm for MPM, and aortopexy for right aortic arch. The postoperative course was uneventful, and the patient has remained alive without disease for 10 months postoperatively.

Adolescent↗

PubMed2006

Gastric large cell neuroendocrine carcinomas: a distinct clinicopathologic entity.

The current histologic classifications of gastric cancers define only carcinoids and small cell carcinomas in the neuroendocrine (NE) category. This study aimed to characterize the histologic and clinical features of high-grade gastric NE carcinomas of nonsmall cell type, tentatively named large cell neuroendocrine carcinoma (LCNEC). Tumors with histologic features suspicious of NE differentiation were selected by a histologic review of 2835 resected gastric cancers, and those with a NE phenotype in > 50% and 1% to approximately 50% tumor cells assessed by expressing chromogranin A and/or synaptophysin were defined as LCNEC and adenocarcinoma with neuroendocrine differentiation (ACNED), respectively. One hundred ninety-nine tumors were selected and of the 109 positive for chromogranin A and/or synaptophysin, 42 and 44 met the criteria for LCNEC and ACNED, respectively. Generally, LCNECs demonstrated less predominant NE morphology than carcinoids, and could be roughly divided into solid (30 cases), tubular (7 cases), and scirrhous (5 cases) subtypes with reference to their main growth pattern. The prognosis of LCNECs was significantly worse than that of conventional adenocarcinomas (P < 0.0001). Thus, this study shows that the spectrum of gastric NE tumors is broader than has previously been recognized and LCNEC is not only a distinct histopathologic entity, but also a distinct clinical entity. Furthermore, the prognosis of ACNEDs was also significantly worse than that of adenocarcinomas (P < 0.0001), and some ACNEDs might actually have been LCNECs, and survival analysis showed that > 20% positivity of NE markers could be enough to characterize LCNEC, as long as light microscopic NE morphology was present in the tumor.

Adenocarcinoma↗

PubMed2006

Primary adenoid squamous cell carcinoma of the oral cavity.

Adenoid squamous cell carcinoma (ASCC) is an uncommon but well-recognized variant of squamous cell carcinoma that was first described by Lever in 1947. ASCC has been reported to originate in the sun-exposed skin of the head and neck and in other sites. An additional case of ASCC is reported here. The patient was a 64-year-old Japanese woman who requested examination of a reddish lesion on the left floor of the mouth. The biopsy material was diagnosed as squamous cell carcinoma. Clinical examination showed a well-circumscribed, 20 x 10 mm-sized lesion, which was categorized as cT2cN0cm 0. Tumor resection was therefore performed. Histologically, most parts of the lesion were conventional squamous cell carcinoma in situ, but the invasive part consisted of ASCC with gland-like or reticular appearance. The latter part was negative for mucin staining. Immunohistochemically, this lesion was positive for pancytokeratin, high-molecular-weight keratin, cytokeratin (CK) 7/8, CK19, E-cadherin and p53, but negative for vimentin, CK20, and S-100 protein. The Ki-67 labeling index was 50.3% in the ASCC part and 34.5% in the carcinoma in situ part. These findings and a review of the literature indicate that a gland-like feature of ASCC is associated with the loss of cell adhesion in the center of the cancer nests, and it can be confirmed simply by mucin staining to be neither an adenosquamous carcinoma nor ductal involvement of conventional squamous cell carcinoma.

Cadherins↗

PubMed2006

Characteristics of loss of heterozygosity in large cell neuroendocrine carcinomas of the lung and small cell lung carcinomas.

Large cell neuroendocrine carcinoma (LCNEC) of the lung is a new entity. Besides morphological characteristics, its molecular biological features have been investigated by many researchers and compared to those of other neuroendocrine carcinomas, small cell lung carcinoma (SCLC) and carcinoid tumor (CT). However, there are few reports that show the significantly different genetic characteristics between them. The purpose of the present paper was to study the frequency of loss of heterozygosity (LOH) at chromosome 3p (3p14.2) in 38 neuroendocrine carcinomas of the lung (13 LCNEC, 11 SCLC and 14 CT) and 10 large cell carcinomas (LCC). The frequencies of LOH at 3p14.2 were 69.2% in LCNEC, 81.8% in SCLC, 50.0% in LCC and 7.14% in CT. Those at 22q13.3 were 30.8% in LCNEC, 72.7% in SCLC, 45.5% in LCC and 7.14% in CT. In particular, the frequency of SCLC with LOH at both 3p14.2 and 22q13.3 (63.6%) was significantly higher than that of LCNEC (15.4%). LCNEC and SCLC had different characteristics of LOH patterns at 3p14.2 and 22q13.3. The combined analysis of the LOH at 3p14.2 and 22q13.3 is thought to be useful for differential diagnosis between LCNEC and SCLC.

Biomarkers, Tumor↗

PubMed2006

Runx2 expression is associated with pathologic new bone formation around radicular cysts: an immunohistochemical demonstration.

BACKGROUND: Radicular cysts are the most common cysts in human jaw bones. These lesions induce bone remodeling of the surrounding alveolar bones, which was termed 'condensing osteitis', and was suggested to be related to cells of the osteoblastic lineage. The Runx2 (core-binding protein [cbfa]1/polyoma enhancer-binding protein [pebp]2alphaA) was shown to be a DNA-binding transcriptional molecule expressed in osteoprogenitor cells. METHODS: We confirmed the specificity of anti-Runx2 antiserum, using Western blotting analysis. We investigated the expression and localization of Runx2 in 32 radicular cyst cases with bone tissue fragments, immunohistochemically. RESULTS: Signals for Runx2 were seen in 18 cases (56.3%) of radicular cysts with bone formation. These signals were immunolocalized in the nuclei of the spindle-shaped osteoprogenitor cells in the cyst walls, whereas only a few signals were seen in the cuboidal osteoblastic cells near the fibrous bones. Signals for type I collagen were immunolocalized in the dense collagen fibers in the cyst walls and in the matrix of the fibrous bone around the radicular cysts, whereas no signals were seen on the inner portions with inflammatory cell infiltration of the cyst walls. Very weak signals for transforming growth factor (TGF)-beta1 were infrequently seen in the osteoblasts of the fibrous bone, whereas signals for TGF-beta2 were observed in young osteocytes in the fibrous bones, in B-cell lymphocytes infiltrating into the inner portions, and on the cellular membranes of the lining epithelium. CONCLUSIONS: The nuclear expression of Runx2 in spindle-shaped cells in the outer portions may play an essential role in the induction of fibrous bone tissue around radicular cysts. TGF-beta2 may play a role in the production of type I collagen, which acts as a template for pathologic new bone formation, in radicular cysts.

Activin Receptors, Type I↗

PubMed2006

Differential expression of N-cadherin and E-cadherin in normal human tissues.

E-cadherin, which expressed in various epithelial tissues, is important for the maintenance of normal epithelial phenotypes. However, the distribution of N-cadherin in normal human tissues has not been defined systemically. In the present study, we employed a sensitive, reliable immunohistochemical detection system for N-cadherin on formalin-fixed, paraffin-embedded tissue sections, and succeeded in demonstrating N- and E-cadherin protein expressions and their distribution in normal human tissues. E-cadherin immunoreactivity was detected in all the epithelial tissues examined, except for the adrenal cortical cells and granulosa cells. N-cadherin was selectively expressed on epithelial cells of the thymus, pituitary, pancreas, liver, adrenal, endometrium of the uterus, ovary, and stomach as well as in neuronal tissues. Double immunostaining revealed that N-cadherin expression was closely associated with the hormone-producing ability of cells in the pancreas and pituitary. Thus, this study indicated the possibility that N-cadherin is selectively expressed in relation to hormonal regulation in some organs and plays different functions in different situations. The method presented here should prove useful for the further investigation of the N-cadherin expression and function in several disease conditions on formalin-fixed, paraffin-embedded archival tissues.

Cadherins↗

PubMed2006

Pituicytoma. Two case reports.

Pituicytoma is a rare tumor in the sellar or suprasellar region with distinct histological characteristics of glial neoplasm. A 42-year-old woman presented with a history of amenorrhea and vertigo, and a 62-year-old woman presented with mild headache. Both patients had mild hyperprolactinemia and one had mild anterior pituitary dysfunction. They underwent transcranial partial resection of a suprasellar tumor. The tumors were characterized by storiform pattern of elongated cells immunoreactive for S-100 protein and glial fibrillary acidic protein. Ultrastructural study showed abundant cytoplasmic intermediate filaments and tumor/blood vessel basal lamina, but no desmosomes between tumor cells. The residual tumors showed no changes in size without adjuvant therapy at 56 and 18 months after surgery. Pituicytoma is a glial neoplasm of adults with low proliferative activity. Patients often present with visual symptoms or anterior pituitary dysfunction. Symptoms and signs of neurohypophysis are rare. Neuroimaging reveals an intra- or suprasellar mass with non-specific features. The prognosis and role of adjuvant therapy remain unclear for this discrete noninfiltrative glioma.

Adult↗

PubMed2005

Rescue from dwarfism by thyroid function compensation in rdw rats.

The rdw rat was initially reported as having hereditary dwarfism caused by pituitary dysfunction. Subsequent studies on the rdw rat, however, have demonstrated that the primary cause of rdw dwarfism is present in the thyroid gland but not in the pituitary gland. The primary cause of rdw rat disorders is a missense mutation of the thyroglobulin (Tg) gene by a one-point mutation. In the present study, we attempted to rescue the dwarfism of the rdw rats using a diet supplemented with thyroid powder (T-powder) and a thyroid graft (T-graft). The infants of the rdw rat were successfully raised to a mature stage body weight, accompanied by elevation of serum growth hormone (GH) and prolactin (PRL), by the T-powder. Furthermore, the T-graft successfully increased the body weight with fertility. The serum GH and PRL levels in the T-graft rdw rat significantly increased. The serum thyroid-stimulating hormone (TSH) levels in the T-graft rdw rat were significantly decreased but were significantly higher than those in the control rat. The GH and PRL mRNA expression in the rdw rat with the T-graft was virtually the same as that of the control, but the TSH beta mRNA differed from that of the control rats. Thus, the dwarfism in the rdw rat is rescued by thyroid function compensation, such as that afforded by T-powder and T-graft.

Animals↗

PubMed2004

hASH1 expression is closely correlated with endocrine phenotype and differentiation extent in pulmonary neuroendocrine tumors.

The human homolog 1 of the Drosophila neurogenic achaete-scute genes, hASH1, is specifically expressed in fetal pulmonary neuroendocrine cells and in some neuroendocrine tumor cell lines. However, no data have been gathered regarding its in vivo expression in tumors. hASH1 mRNA expression was investigated by in situ hybridization in 238 surgically resected lung carcinomas, and the correlations between hASH1 expression status and immunostaining results of neuroendocrine markers chromogranin A, neural cell adhesion molecule, gastrin-releasing peptide and calcitonin, and clinical outcome were analyzed. hASH1 expression was detected in 2/20 (10%) adenocarcinomas, 4/30 (13.3%) typical carcinoids, 11/13 (84.6%) atypical carcinoids, 38/67 (56.7%) large-cell neuroendocrine carcinomas and 56/78 (71.8%) small-cell carcinomas, respectively, but not in any squamous cell carcinoma (0/21) or large-cell carcinoma (0/9). The 2 hASH1+ adenocarcinomas also expressed multiple neuroendocrine markers. Thus, hASH1 expression was restricted to lung cancers with neuroendocrine phenotypes. However, not all neuroendocrine tumors expressed hASH1. Within the entities of large-cell neuroendocrine carcinoma and small-cell carcinoma, hASH1 expression correlated very closely with chromogranin A, gastrin-releasing peptide and calcitonin expression (P<0.0001, r=0.852), but was not related to neural cell adhesion molecule expression (P=0.8892), suggesting that hASH1 expression, at least in lung cancer, is associated with endocrine phenotype expression other than 'neuroendocrine differentiation' in a broad sense. The fact that hASH1 was virtually absent in almost fully differentiated typical carcinoids, but was expressed in most, if not all, less differentiated atypical carcinoids as well as large-cell neuroendocrine carcinomas and small-cell carcinomas, suggests that hASH1 expression in lung cancer imitates its early and transient expression in fetal development, and that hASH1 is instrumental in the establishment, but not in the maintenance, of a cellular endocrine phenotype. Finally, hASH1 expression correlated with a significantly shortened survival in small-cell carcinoma patients (P=0.041).

Adenocarcinoma↗

PubMed2004

Divergent cyclin B1 expression and Rb/p16/cyclin D1 pathway aberrations among pulmonary neuroendocrine tumors.

A total of 111 pulmonary neuroendocrine tumors comprising 13 typical carcinoids, five atypical carcinoids, 44 large-cell neuroendocrine carcinomas and 49 small-cell carcinomas were immunohistochemically studied for dysregulated cyclin B1 expression and disruption of the Rb/p16/cyclin D1 pathway (Rb pathway), and the results were correlated with tumor proliferation activity and clinical outcome. Overexpression of cyclins B1 and D1, respectively, was detected in no and 15% typical carcinoids, 20 and 20% atypical carcinoids, 84 and 32% large-cell neuroendocrine carcinomas, 84 and 10% small-cell carcinomas. Loss of Rb and p16 expression, respectively, was observed in no and 14% typical carcinoids, no and 40% atypical carcinoids, 49 and 18% large-cell neuroendocrine carcinomas, 84 and 8% small-cell carcinomas. In summary, 29% typical carcinoids, 20% atypical carcinoids, 78% large-cell neuroendocrine carcinomas and 93% small-cell carcinomas had Rb pathway aberrations. Rb pathway aberration was mostly attributed to Rb loss in small-cell carcinomas, while p16 loss and/or cyclin D1 overexpression besides Rb loss also played an important role in large-cell neuroendocrine carcinomas, while cyclin D1 overexpression was the only cause of Rb pathway aberration in carcinoid tumors. Thus, both cyclin B1-associated G2/M arrest and Rb-mediated G1 arrest are consistently compromised in high-grade large-cell neuroendocrine carcinoma and small-cell carcinoma, but are generally intact or occasionally altered in carcinoid tumor; the mechanisms involved in Rb pathway aberration among the tumor categories are different, reflecting a genetic divergence among the individual tumor categories. Cyclin B1 expression closely correlated with the Ki-67 labeling index either in the individual tumor categories or overall tumors (P < 0.0001, r = 0.742), suggesting that cyclin B1 is one of the key factors regulating cell proliferation in pulmonary neuroendocrine tumors. Neither cyclins B1 and D1, Rb, p16, nor Ki-67 correlated with patient survival in individual tumor categories, suggesting that the prognostic significance of these factors is tumor-type specific.

Biomarkers, Tumor↗

PubMed2004

Recent advances in MEN1 gene study for pituitary tumor pathogenesis.

Evidence of multiple endocrine neoplasia type 1 (MEN1) is found in approximately 2.7% of patients with pituitary adenomas. The multicentricity of pituitary adenomas has not yet been proved. Prolactinomas are most frequent in MEN1 pituitary tumors. Pituitary tumors with MEN1 are larger in size and more aggressive than without MEN1. Heterozygous germline mutations of MEN1 gene are responsible for MEN1 disorders. Various types of mutations likely causing loss of the gene function have been identified throughout the entire region in patients with MEN1 and related disorders. However, the function of menin, the product of MEN1 gene, remains to be established. Neither mutation hot spot nor phenotype-genotype correlation has been established in classical MEN1. A number of recent studies suggest that somatic mutations in the MEN1 gene do not play prominent role in the pathogenesis of sporadic forms of pituitary adenoma.

Germ-Line Mutation↗

PubMed2004

Severe hypoglycemia and hypokalemia in association with liver metastases of gastric cancer.

We report an 80-year-old man who presented with non-islet cell tumor hypoglycemia (NICTH) in association with hepatic recurrence of gastric cancer. His serum potassium was reduced from 3.9 to 3.1 mmol/l 5 weeks after gastrectomy, and he subsequently developed hypoglycemic coma. He was diagnosed as having NICTH because of the presence of serum big IGF-II and positive staining for IGF-II in gastric cancer cells obtained at surgery. A computed tomography showed multiple liver metastases. His hypoglycemia was refractory to steroid therapy. This case suggested that NICTH could develop in association with hepatic metastases of gastric cancer. Unexpected hypokalemia may be a manifestation of occult NICTH.

Adenocarcinoma↗

PubMed2003

Rapid induction of peroxisome proliferator-activated receptor gamma expression in human monocytes by monosodium urate monohydrate crystals.

OBJECTIVE: Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a member of the nuclear hormone receptor superfamily and functions as a key regulator of lipid and glucose metabolism, atherosclerosis, and inflammatory responses. This study was undertaken to evaluate the biologic role of PPAR gamma in self-limiting episodes of acute gouty arthritis. To do this, we investigated PPAR gamma expression by monosodium urate monohydrate (MSU) crystal-stimulated monocytes, and we studied the effects of PPAR gamma ligands on crystal-induced acute inflammation. METHODS: PPAR gamma expression by MSU crystal-stimulated human peripheral blood mononuclear cells was determined by reverse transcription-polymerase chain reaction and immunostaining. Expression of CD36 on monocytes was detected by flow cytometric analysis. The effects of PPAR gamma ligands on in vitro crystal-induced cytokine production and on in vivo cellular infiltration during crystal-induced acute inflammation were also investigated. RESULTS: MSU crystals rapidly and selectively induced PPAR gamma expression by monocytes. Gene expression was detected as early as 2 hours, and maximum expression was observed at 4 hours after stimulation. The induced PPAR gamma was functional, since a PPAR gamma ligand was able to up-regulate CD36 expression on monocytes. A natural ligand of PPAR gamma, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15deoxy-PGJ(2)), significantly reduced the crystal-induced production of cytokines by monocytes. Indomethacin inhibited cytokine production only at high concentrations, and an antidiabetic thiazolidinedione (troglitazone) failed to exert significant effects. Administration of troglitazone and 15deoxy-PGJ(2) significantly prevented cellular accumulation in a mouse air-pouch model of MSU crystal-induced acute inflammation. CONCLUSION: Rapid induction of PPAR gamma expression on monocytes by MSU crystals may contribute, at least in part, to the spontaneous resolution of acute attacks of gout.

Acute Disease↗

PubMed2003

Diversity in expression and prognostic significance of G1/S cyclins in human primary lung carcinomas.

Expression of cyclin A, cyclin E and cdk2 was examined immunohistochemically in 144 cases of primary non-small cell lung carcinoma to evaluate their prognostic value. Cyclin A was co-expressed with cdk2 in the proliferating cells, ie those showing positive Ki-67 staining. The labelling index (LI) of cyclin A revealed a positive correlation with the S-phase fraction and an inverse correlation with histological differentiation. Furthermore, high cyclin A LIs indicated a poor prognosis in all histological types. Cyclin E exhibited a characteristic staining pattern: in squamous cell carcinoma (SCC), differentiated cells without Ki-67 staining revealed cyclin E positivity with expression of cdk2. Conversely, in adenocarcinoma (AC), proliferating cells revealed cyclin E positivity. Cases of large cell carcinoma showed heterogeneous cyclin E staining patterns, unlike those of SCC or AC. Statistical analyses also revealed a marked contrast between SCC and AC. In AC, the LI of cyclin E was inversely correlated with histological differentiation and a high LI predicted a worse prognosis. In contrast, in SCC, the LI of cyclin E correlated positively with histological differentiation and better prognosis. However, the expression levels of cyclin E mRNA evaluated by quantitative RT-PCR were higher in poorly differentiated SCC and AC, suggesting that protein turnover plays a large role in determining cyclin E protein levels. Although the expression of cyclins was demonstrated to be diversely regulated depending on the histological type, the combined immunohistochemical analyses performed in this study on these proteins could be useful tools for evaluating patient prognosis in lung carcinomas.

Adenocarcinoma↗