C.D. Gerharz

Differential response to transforming growth factor (TGF)-α and fibroblast growth factor (FGF) in human renal cell carcinomas of the clear cell and papillary types

The clear cell and the papillary types of human renal cell carcinoma (RCC) are distinct tumour entities with marked differences in their biological properties. Because growth factors are considered to affect profoundly the biological behaviour of malignant tumours, we compared the expression and function of transforming growth factor (TGF)-alpha and fibroblast growth factor (FGF) in both types of RCCs. Both in vivo and in vitro expression of TGF-alpha, epidermal growth factor-receptor (EGF-R), FGF-2 and FGF type 3- and 4-receptors was found in RCCs of both types. However, marked differences between clear cell and papillary RCCs became evident for TGF-alpha secretion, which could be demonstrated in 20 out of 24 (83%) clear cell RCCs but in only two out of four (50%) papillary tumours. Moreover, the mean TGF-alpha secretion rate in clear cell RCCs significantly (P<0. 05) exceeded that of papillary RCCs. Because the expression of growth factor receptors could not prove the corresponding signalling cascades were functional, tumour cell proliferation was tested after exposure to exogenous TGF-alpha or FGF-1. These experiments demonstrated that papillary RCCs did not respond significantly to exogenous TGF-alpha or FGF-1, whereas eight (33%) (TGF-alpha) and 11 (46%) (FGF-1) out of 24 clear cell RCCs responded with significant (P<0.05) growth stimulation. In conclusion, our investigation presents data indicating that TGF-alpha and FGF are functionally involved in the progression of clear cell RCCs, directly stimulating proliferation by autocrine and/or paracrine actions. In contrast, TGF-alpha and FGF did not directly stimulate the proliferation of our papillary RCCs, thereby suggesting functional defects or a blockade in the corresponding signalling cascades. This differential functionality might contribute to the more aggressive behaviour of clear cell RCCs.

FHIT expression in clear cell renal carcinomas: versatility of protein levels and correlation with survival

Clear cell renal cell carcinomas (RCCs) are characterized by a deletion of chromosome 3p, which might result in the inactivation of the FHIT (fragile histidine triad) gene, a putative tumour suppressor gene. To explore the relevance of FHIT aberrations for tumour progression and prognosis in clear cell RCCs, FHIT protein expression was analysed in formalin‐fixed tissue from 149 clear cell RCCs by immunohistochemistry. FHIT protein expression was found to be markedly reduced in all RCCs, when compared with adjacent non‐neoplastic tubule epithelia. Although remaining below the FHIT levels of normal tubule epithelia, a significant increase of FHIT expression became evident from well (G1) to poorly (G3) differentiated clear cell RCCs (p=0.0001) and from low (pT1) to advanced (pT3) tumour stages (p=0.001). The log‐rank test demonstrated a significant inverse correlation (p=0.0074) between FHIT expression and tumour aggressiveness as indicated by patient survival. Cox regression analysis revealed that FHIT expression is an independent prognostic parameter (p=0.0139) in clear cell RCCs. In conclusion, clear cell RCCs show a marked reduction of FHIT protein expression when compared with their putative cells of origin. In contrast to other tumour types, however, loss of FHIT protein expression is significantly less pronounced in poorly differentiated RCCs or advanced tumour stages. This versatility of FHIT expression during tumour progression suggests a role for reversible mechanisms of FHIT inactivation during the initiation and progression of clear cell RCCs. Copyright

Dual-Parameter Immunoflow Cytometry in Diagnosis and Follow-Up of Patients with Bladder Cancer

Objectives: The aim of this study was to evaluate the clinical significance of a dual-parameter immunoflow cytometry (DPI-FCM) assay in the detection of tumor cells in barbotage specimens of bladder cancer patients. Methods: DPI-FCM is an automated method, based on the utilization of two monoclonal antibodies (mAbs) either used for a preselection of urothelial cells (mAb Due AUT 2) or the analysis of the expression of a differentiation antigen within the preselected urothelial cells (mAb Due ABC 3). The ratio of ABC 3-positive urothelial cells was used to discriminate between the normal and malignant state of the urothelium. At the time of examination 40 patients had endoscopically overt bladder tumors. Another 30 patients without endoscopically visible tumors were examined before routine rebiopsy. Thirty barbotage specimens from patients with diseases not related to bladder cancer were examined as controls. Results: Overall, the sensitivity of DPI-FCM in patients with endoscopically overt and invisible residual tumors was 95 and 83%, respectively, regardless of concomitant urinary tract infection. The sensitivity of DPI-FCM for both patient groups was 86, 95 and 94% for tumor grades 1, 2 and 3, respectively. The specificity of the method in 30 patients with no history of bladder cancer was 93%. Conclusions: DPI-FCM appears to be a highly reliable method of recognizing tumor cells in bladder barbotage specimens even in patients with concomitant urinary tract infection. The procedure may be of value in monitoring bladder cancer patients for tumor recurrence.

Analysis of growth factor-dependent signalling in human epithelioid sarcoma cell lines: clues to the role of autocrine, juxtacrine and paracrine interactions in epithelioid sarcoma

Human epithelioid sarcoma (ES) is an extremely aggressive soft tissue tumour of unknown histogenesis. Although growth factor-dependent signalling cascades significantly affect the biological behaviour of malignant tumours, little is known so far about their role in human ES. The present investigation, therefore, analyses the coexpression and function of different growth factors and their receptors in the human ES cell line GRU-1 and its clonal subpopulations (GRU-1A, GRU-1B and GRU-1C). As shown by Northern blot, flow cytometry, immunocytochemistry and MTT assay, all ES cell lines expressed transforming growth factor (TGF)-alpha and the epidermal growth factor receptor (EGF-R). Although no response to exogenous TGF-alpha was observed, antagonistic anti-EGF-R antibodies (at 20 microg/ml) induced significant (P<0.05) growth inhibition in all cell lines. All cell lines showed coexpression of platelet-derived growth factor (PDGF)-A and the corresponding receptors. Neutralisation of ES-derived PDGF by anti-hPDGF antibodies resulted in significant (P<0.05) growth inhibition of all clonal subpopulations. Although all cell lines expressed TGF-beta(1) as well as TGF-beta type I and type II receptors (TGF-BI-R and TGF-BII-R), growth inhibition (P<0.05) by exogenous TGF-beta(1) was achieved in the clonal subpopulations only and not in the parental cell line. No ES cell line expressed acidic fibroblast growth factor (FGF) but stimulation of FGF type 3 and type 4 receptors (FGF-3R and FGF-4R) by exogenous acidic FGF (aFGF) resulted in a marked (P<0.05) acceleration of proliferation in all cell lines. In conclusion, our investigation suggests an intricate network of autocrine, juxtacrine and paracrine signalling between ES tumour cells and adjacent non-neoplastic stromal cells.

Epididymal Metastasis of a Prostatic Carcinoma

We report the case of a 73-year-old patient who presented with a local recurrence of a prostatic carcinoma which had metastasized to the right epididymis. The histopathological examination of the resected tissue after transurethral resection of the prostate 8 years before revealed a pluriformal adenocarcinoma of the prostate, but the patient refused any kind of therapy at that time.

Simultaneous Diagnosis of a Metanephric Adenoma and a Clear Cell Carcinoma of the Contralateral Kidney

Metanephric adenoma of the kidney is a rare, newly recognized entity of a unique benign renal tumor. Clinically, pain, hematuria and palpable mass are the most common presenting signs. Females predominate by well over 2:1. A higher incidence of polycythemia is often found in these patients. Only a few cases of this type of adenoma have been reported in the literature. We report on a 78–year–old female patient with a metanephric adenoma of the left kidney, which showed typical clinical, radiologic, microscopic and immunohistochemical findings. A clear cell carcinoma of the contralateral kidney was also discovered and treated.

Angiocentric Lymphoma of the Kidney in the Acquired Immunodeficiency Syndrome

Angiocentric lymphoma, which is the malignant counterpart of angiocentric immunoproliferative lesions, comprises a rare group of non-Hodgkins lymphomas of T-cell origin. It is characterized by marked invasion and destruction of small vessels by lymphomatoid cells, predominantly in the lungs. The prognosis is poor and many patients die within several months. To our knowledge primary involvement of the genitourinary tract has not been previously reported. We report a case of a solitary primary angiocentric lymphoma of the kidney in a patient with the acquired immunodeficiency syndrome. Therapy consisted of nephrectomy without adjuvant treatment. Histological characteristics as well as diagnostic and therapeutic options are discussed.