Hirofumi Kato

A comparison of epidermal growth factor receptor levels and other prognostic parameters in non-small cell lung cancer

Epidermal growth factor receptor (EGFR) was measured using a competitive radioligand binding assay in membrane preparations from 74 primary human non-small cell lung cancer (NSCLC) tissues and 20 pathologically normal peripheral lung tissues. The mean EGFR level in tumours was 30.38 fmol/mg (+/-41.95 S.D.) of membrane protein (mg.p), significantly higher (P = 0.00016) than in normal tissues (mean, 10.26 +/- 10.02 fmol/mg.p). The mean EGFR concentration was also significantly higher in pathological stage IV tissue than in stages I (P = 0.049) and II (P = 0.040), and the mean EGFR concentration was significantly higher in cases with mediastinal involvement than in cases without it (P = 0.029). The mean EGFR level was higher in DNA aneuploid and multiploid cases than in DNA diploid cases, but there was no significant difference. No significant relationships were found to exist between receptor concentrations and pathological tumour size or histological type, or patient gender or age. From the above findings, a possible prognostic role for EGFR in primary NSCLC should be investigated.

Role of transforming growth factor-β1 and decorin in development of central fibrosis in pulmonary adenocarcinoma

Transforming growth factor-beta1 (TGF-beta1) is known as the growth factor that stimulates the synthesis of extracellular matrix. Recently, TGF-beta has been found to control the growth of cancer cells. Small chondroitin-dermatan sulfate (decorin) is an abundant extracellular matrix component. TGF-beta1 stimulates the synthesis of decorin, and decorin is considered to bind TGF-beta1. The activity of decorin in neutralizing TGF-beta1 activity suggests that decorin serves as a negative-feedback regulator of TGF-beta1 activity. To investigate the role and relationship of TGF-beta1 and decorin in the formation of central fibrosis in pulmonary adenocarcinoma, we performed an immunohistochemical study of TGF-beta1 and decorin in 61 cases of T1 pulmonary adenocarcinoma. Positive stainings for TGF-beta1 were shown in 40 cases and negative in 21 cases. Twenty-seven of 32 cases with central fibrosis were positive for TGF-beta1. Positive staining for TGF-beta1 was significantly related to the appearance of central fibrosis in pulmonary adenocarcinoma. When central fibrosis was composed of proliferative connective tissue with loose staining for decorin, cancer cells showed intense staining for TGF-beta1. When central fibrosis was composed of old fibrotic tissue with dense staining for decorin, cancer cells showed weak staining for TGF-beta1. Our results suggest that TGF-beta1 has an important role in the formation of central fibrosis in pulmonary adenocarcinoma, and decorin may play a role as a negative feedback regulator in the production of TGF-beta1 in pulmonary adenocarcinoma.

Well-differentiated fetal adenocarcinoma of lung

Well-differentiated fetal adenocarcinoma (WDFA) histologically resembles pulmonary blastoma, and is thought to be a subtype of pulmonary blastoma which has differentiated epithelial features resembling the fetal lung among its epithelial features and sarcomatous features. We recently encountered one patient who underwent surgery for WDFA. This case is reported with a discussion of the literature. A 33-year-old woman had a tumor shadow in the lower lobe of the right lung. The tumor was diagnosed as pulmonary blastoma as a result of echographic biopsy, and right total pneumonectomy was performed. No sarcomatous features were observed on postoperative histological assessment, and the patient was diagnosed as having WDFA. Its prognosis is believed to tend to be better than that of biphasic blastoma, in which sarcomatous features are mingled with epithelial features. However, it is reported that chemotherapy or radiotherapy has seldom been effective. Complete surgical resection is essential for long-term survival.

Bernard-Soulier syndrome associated with 22q11.2 microdeletion

We describe a Japanese girl with Bernard-Soulier syndrome and 22q11.2 microdeletion. She had viral infections and recurrent thrombocytopenia and hemorrhagic diathesis after cardiac surgery. As congenital heart defects and abnormal immunity are the most common clinical manifestations associated with 22q11.2 deletion, patients with this association may have a greater risk of developing a severe bleeding disorder.

Hilar and mediastinal invasion of Bronchogenic carcinoma : Evaluation by thin-section electron-beam computed tomography

The diagnostic accuracy of thin-section incremental dynamic computed tomography (IDCT) using an electron-beam scanner in evaluating hilar or mediastinal invasion of bronchogenic carcinoma was assessed. Thirty-seven patients with proven bronchogenic carcinoma, contiguous with hilar or mediastinal structures, underwent IDCT. The area of contact was scanned using 19 contiguous 3-mm thick sections during injection of contrast material. The degree of contact between mass and pulmonary artery or vein and their distortion were recorded. Irregular thickening of the bronchial wall, soft tissue within the lumen, or distortion were used to determine airway involvement. Sixty-nine sites were assessed retrospectively and compared with pathology reports. The accuracy, sensitivity, and specificity in evaluating invasion of the pulmonary artery were 75.0%, 77.8%, and 71.4%, respectively. Limited reliability also was found for invasion of the main bronchus and “secondary” carina, with accuracies of 66.7% and 70.5%, sensitivities of 75.0% and 70.0%, and specificities of 57.1% and 71.4%, respectively. Thin-section IDCT with electron beam scanner is not accurate in the detection of hilar or mediastinal invasion by bronchogenic carcinoma.

Malignant transformation in craniopharyngioma after radiation therapy: a case report and review of the literature.

OBJECTIVE Craniopharyngioma is a benign epithelial tumor that is thought to arise from the remnant of the Rathke pouch. Malignant transformation in craniopharyngioma is extremely rare. Herein, we report a case of malignant transformation in craniopharyngioma after radiation therapy. MATERIALS AND METHODS Histopathological and immunohistochemical analyses were carried out for specimens of the suprasellar tumor (from three resections, with the third surgery performed after radiation therapy). RESULTS The resected tumors from the first and second surgeries comprised islands of loosely cohesive aggregates of epithelial cells, so-called stellate reticulum. At the periphery of the nests, palisaded columnar epithelium was observed. Wet keratins were scattered, and few mitotic figures were seen. The third surgical specimen was composed of irregular large nests of basaloid cells that had large, round to oval nuclei with prominent nucleoli, and mitotic figures were frequently seen (21/10 high power fields). In the center of the nests, eosinophilic ghost cells, resembling wet keratin, were observed. Accordingly, the diagnosis of malignant transformation in craniopharyngioma was made. Immunohistochemical studies revealed that the p53 protein was over-expressed in the malignant component, whereas its expression was much lower in the benign component. CONCLUSIONS Similar to the ten previously reported cases of malignant transformation in craniopharyngioma, the present case occurred after radiation therapy. p53 protein overexpression was also observed in the earlier cases of malignant craniopharyngioma as well as in the present case (6/6 cases). We concluded that radiation therapy and p53 mutations could be involved in malignant transformation in craniopharyngioma.

A patient with Kawasaki disease who developed acute urinary retention due to pelvic neuroblastoma.

Neuroblastoma is one of the common solid tumours in childhood. Kawasaki disease (KD) is not an uncommon acute febrile illness in Japan. There have been only two reports of KD patients having neuroblastoma [1,2]. Nonetheless, there is no reported case of acute KD developing urinary retention due to neuroblastoma. A 4-month-old boy was admitted to our hospital because of KD. He had a fever and skin rash for more than 5 days. Hyperemia of the eyes, oral cavity and tongue, left cervical lymph node swelling (diameter 1 cm) and finger scleroedemas were also observed. CRP was 15.7 mg/dl and blood culture was negative. Three days after admission, he suddenly developed acute urinary retention with urinary bladder distension and a decrease in urinary output. A pelvic echogram and an abdominal CT scan showed a small solid mass behind the bladder. Subsequent determination of urinary vanillylmandelic acid and homovanillic acid excretion revealed elevated levels. Surgical resection of the mass was successful. The histopathological finding on the resected tumour was a stroma poor, undifferentiating neuroblastoma according to the Shimada classification. Swelling of vascular endothelial cells and thromboses with perivascular leucocytic infiltration were observed in the resected tumour specimens. The thrombocyte count was elevated to 74.5·10/ll on the 11th day. He was treated with acetylsalicylic acid and he has been free from the disease for more than 9 years. In addition, no complication of coronary disease was noted. Neuroblastoma complicating KD is extremely rare. The incidence of neuroblastoma in Japan is 12–18/ 100,000 among children of 0 to 4 years of age, while that of KD is about 222/100,000. Previously, Yanagisawa et al. [3] reported a 6-month-old male infant who died of KD and had a small encapsulated mass in the left paravertebral region (T–10) found at necropsy. The histopathological diagnosis was neuroblastoma although he had no clinical signs of neuroblastoma. There was no histopathological documentation about an effect of KD on neuroblastoma. A further KD patient developed a neuroblastoma a few years later [2]. In addition, there have been no reports of symptomatic neuroblastoma complicating an acute phase of KD. Tumour specimens of our case showed vascular endothelial cell swelling and intratumour vessel thrombosis with leucocyte infiltration. These findings were consistent with vasculitis. In KD, inflammatory cytokines such as IL-1 and TNF-alpha play a major role in developing a vasculitis [1]. Unfortunately, determination of IL-1 or TNF-alpha level was not done. Nevertheless, vasculitis due to KD possibly caused the rapid swelling of the hidden tumour and the subsequent acute urinary retention. Paediatricians should look for this type of acute urinary retention in patients with KD.

Intrathoracic fibrin glue for postoperative pleuropulmonary fistula

Twenty cases of persistent pleuropulmonary fistula after a thoracic surgical procedure were successfully treated with fibrin glue injection into the thoracic cavity through a drainage tube. A new technique, the overlying method, which is a modification of the conventional technique of fibrin glue injection, was devised. Each patient received one to four injections (mean number, 1.6). This method resulted in closure of the pleuropulmonary fistula in all but 1 patient. Minor complications included pain in 1 patient and fever in 3 patients. A control study involving 24 patients with pleuropulmonary fistula was performed. Autoblood, OK-432, and tetracycline were used instead of fibrin glue. The fistula resolved in 12 patients. Complications after injection included pain in 15 patients, fever in 10, and occlusion of the chest tube in 4. With our new method, patients rarely exhibited pain and fever, and occlusion of the chest tube did not occur.

Estrogen receptor expression and estrogen receptor-independent cytotoxic effects of tamoxifen on malignant rhabdoid tumor cells in vitro.

Recent studies have shown that the antiestrogen tamoxifen (TAM) can be used in the treatment of malignant neoplasms other than breast cancer. In the present study, we investigated the expression of estrogen receptor (ER) in six malignant rhabdoid tumor (MRT) cell lines. Alterations in MRT cell growth in response to estrogen or antiestrogens (4‐hydroxytamoxifen (4‐OHT), TAM, and ICI 182 780) were also investigated. RT‐PCR and western blotting showed that ER‐a was expressed in three of the six MRT cell lines. While 17‐β‐estradiol (E2) did not significantly alter MRT cell line proliferation, the hydroxylated tamoxifen metabolite 4‐OHT significantly inhibited the growth of all 6 MRT cell lines. However, the steroidal antiestrogen ICI 182 780 did not alter the proliferation of any of the MRT cell lines. 4‐OHT induced apoptosis in both ER‐α‐negative and ER‐α‐positive MRT cell lines, as assessed by nuclear morphology and DNA fragmentation. Neither growth inhibition nor induction of apoptosis due to 4‐OHT was blocked by the addition of excess E2. Our data suggested that 4‐OHT induced cytotoxic effects against MRT cells, and that these effects were independent of ER expression.

Expression of pericyte, mesangium and muscle markers in malignant rhabdoid tumor cell lines: Differentiation‐induction using 5‐azacytidine

Malignant rhabdoid tumor (MRT) has been considered to have multiphenotypic diversity characteristics. Some MRTs exhibit a neural phenotype. However, it is still unclear whether MRT cells can display a skeletal muscle, smooth muscle or smooth muscle‐like cell phenotype, like those of pericytes and mesangial cells. To determine if MRTs exhibit skeletal muscle cell or smooth muscle‐like cell phenotypes, six MRT cell lines (TM87‐16, STM91‐01, TTC549, TTC642, YAM‐RTK1 and TTC1240) were examined for markers of skeletal muscle (MyoD, myogenin, myf‐5, myf‐6, acetylcholine receptor‐α, ‐β and ‐γ), smooth muscle (α‐smooth muscle actin, SM‐1 and SM22), and smooth muscle‐like cells, such as pericytes (angiopoietin‐1 and ‐2) and mesangial cells (megsin), using conventional RT‐PCR, semi‐quantitative PCR, western blotting and immunocytochemistry before and after differentiation‐induction with 5‐azacytidine. α‐Smooth muscle actin and SM22 were detected in all six MRT cell lines, while MyoD and myf‐5, crucial markers for skeletal myogenic determination, were not. The TM87‐16 cell line expressed SM‐1 and angiopoietin‐1. TTC1240 also expressed angiopoietin‐1. Interestingly, STM91‐01 expressed megsin, a novel marker for mesangial cells, in addition to angiopoietin‐1. Our results indicated that some MRTs exhibited smooth muscle and/or smooth muscle‐like cell phenotypes and some renal MRTs might be of mesangial origin. Recently, smooth muscle and also smooth muscle‐like cells have been considered to be of neuroectodermal origin. MRT can thus considered to belong to the category of primitive neuroectodermal tumors (PNETs) in the broad sense.