Epigenetic modulations and lineage plasticity in advanced prostate cancer.

Prostate cancer is the most common cancer and second leading cause of cancer-related death in American men. Antiandrogen therapies are part of the standard of therapeutic regimen for advanced or metastatic prostate cancers; however, patients who receive these treatments are more likely to develop castration-resistant prostate cancer (CRPC) or neuroendocrine prostate cancer (NEPC). In the development of CRPC or NEPC, numerous genetic signaling pathways have been under preclinical investigations and in clinical trials. Accumulated evidence shows that DNA methylation, chromatin integrity, and accessibility for transcriptional regulation still play key roles in prostate cancer initiation and progression. Better understanding of how epigenetic change regulates the progression of prostate cancer and the interaction between epigenetic and genetic modulators driving NEPC may help develop a better risk stratification and more effective treatment regimens for prostate cancer patients.

Focal laser ablation as clinical treatment of prostate cancer: report from a Delphi consensus project.

PURPOSE: To define the role of focal laser ablation (FLA) as clinical treatment of prostate cancer (PCa) using the Delphi consensus method. METHODS: A panel of international experts in the field of focal therapy (FT) in PCa conducted a collaborative consensus project using the Delphi method. Experts were invited to online questionnaires focusing on patient selection and treatment of PCa with FLA during four subsequent rounds. After each round, outcomes were displayed, and questionnaires were modified based on the comments provided by panelists. Results were finalized and discussed during face-to-face meetings. RESULTS: Thirty-seven experts agreed to participate, and consensus was achieved on 39/43 topics. Clinically significant PCa (csPCa) was defined as any volume Grade Group 2 [Gleason score (GS) 3+4]. Focal therapy was specified as treatment of all csPCa and can be considered primary treatment as an alternative to radical treatment in carefully selected patients. In patients with intermediate-risk PCa (GS 3+4) as well as patients with MRI-visible and biopsy-confirmed local recurrence, FLA is optimal for targeted ablation of a specific magnetic resonance imaging (MRI)-visible focus. However, FLA should not be applied to candidates for active surveillance and close follow-up is required. Suitability for FLA is based on tumor volume, location to vital structures, GS, MRI-visibility, and biopsy confirmation. CONCLUSION: Focal laser ablation is a promising technique for treatment of clinically localized PCa and should ideally be performed within approved clinical trials. So far, only few studies have reported on FLA and further validation with longer follow-up is mandatory before widespread clinical implementation is justified.

[Vancouver classification of renal tumors: Recommendations of the 2012 consensus conference of the International Society of Urological Pathology (ISUP)]. / Vancouver-Klassifikation von Nierentumoren : Empfehlungen der Konsenskonferenz der Internationalen Gesellschaft für Uropathologie (ISUP) 2012.

The 2012 consensus conference of the International Society of Urological Pathology (ISUP) has formulated recommendations on classification, prognostic factors and staging as well as immunohistochemistry and molecular pathology of renal tumors. Agreement was reached on the recognition of five new tumor entities: tubulocystic renal cell carcinoma (RCC), acquired cystic kidney disease-associated RCC, clear cell (tubulo) papillary RCC, microphthalmia transcription factor family RCC, in particular t(6;11) RCC and hereditary leiomyomatosis-associated RCC. In addition three rare forms of carcinoma were considered as emerging or provisional entities: thyroid-like follicular RCC, succinate dehydrogenase B deficiency-associated RCC and anaplastic lymphoma kinase (ALK) translocation RCC. In the new ISUP Vancouver classification, modifications to the existing 2004 World Health Organization (WHO) specifications are also suggested. Tumor morphology, a differentiation between sarcomatoid and rhabdoid and tumor necrosis were emphasized as being significant prognostic parameters for RCC. The consensus ISUP grading system assigns clear cell and papillary RCCs to grades 1-3 due to nucleolar prominence and grade 4 is reserved for cases with extreme nuclear pleomorphism, sarcomatoid and/or rhabdoid differentiation. Furthermore, consensus guidelines were established for the preparation of samples. For example, agreement was also reached that renal sinus invasion is diagnosed when the tumor is in direct contact with the fatty tissue or loose connective tissue of the sinus (intrarenal peripelvic fat) or when endothelialized cavities within the renal sinus are invaded by the tumor, independent of the size. The importance of biomarkers for the diagnostics or prognosis of renal tumors was also emphasized and marker profiles were formulated for use in specific differential diagnostics.

Pathology of upper tract urothelial carcinoma with emphasis on staging.

Classification of upper tract urothelial preneoplastic and neoplastic lesions mirrors that of the urinary bladder, with all lesions of the bladder urothelium being possible in the upper tract and vice versa. There are three major groups of non-invasive urothelial neoplasms: flat, papillary, and inverted. These three groups share a similar morphological spectrum of intraurothelial changes, ranging from hyperplasia to dysplasia to carcinoma in situ. However, they differ in terms of architectural growth pattern compared to the surrounding non-neoplastic mucosal surface. Infiltrating urothelial carcinoma is defined as a urothelial tumor that invades beyond the basement membrane. Unlike in non-invasive papillary urothelial neoplasms (pTa), the role of histologic grade in pT1 and higher stage tumors has been suggested to be of only relative importance. The vast majority of tumors of the upper urinary tract are urothelial carcinoma. More commonly seen, however, are foci of squamous differentiation and, less frequently, glandular differentiation. Pure urothelial carcinomas also display a wide range of variant morphologies, and recognition of these morphologies is important for diagnosis, classification, and prognosis.

Targeting prostate-specific membrane antigen for personalized therapies in prostate cancer: morphologic and molecular backgrounds and future promises.

Prostate-specific membrane antigen (PSMA) is an integral, non-shed membrane glycoprotein that is highly expressed on prostate epithelial cells and strongly upregulated in prostate cancer (PCa). Prostatic neoplastic transformation results in the transfer of PSMA from the apical membrane to the luminal surface of the ducts. However, the role of PSMA in tumor angiogenesis and carcinogenesis is poorly understood. PSMA is characterized by folate hydrolase and carboxypeptidase activity and internalization function, and its levels are directly correlated to androgen independence, metastasis and PCa progression. As largely substantiated by preclinical and clinical findings, PSMA could represent a promising target for Positron Emission Tomography (PET) radiopharmaceuticals for PCa imaging. Furthermore, PSMA could prove an important target for the development of new therapeutic approaches, including PSMA-based aptamers, peptides, antibody-drug conjugated therapy, as well as radiotherapy and immunotherapy. This review will summarize the role of PSMA in PCa development and progression and its potential role in the diagnosis and treatment of patients with initial and advanced PCa.

VEGF and VEGFR polymorphisms affect clinical outcome in advanced renal cell carcinoma patients receiving first-line sunitinib.

BACKGROUND: Currently, sunitinib represents one of the therapeutic strongholds for renal cell carcinoma, but the criteria for treatment selection are lacking. We assessed the role of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) polymorphisms in the prediction of the clinical outcome in metastatic renal cell carcinoma (mRCC) patients. METHODS: A total of 84 tumour samples from mRCC patients receiving first-line sunitinib were tested for VEGF and VEGFR single-nucleotide polymorphisms (SNPs). The SNP results were correlated with progression-free survival (PFS) and overall survival (OS). RESULTS: Median PFS was 8.22 months, although whereas median OS was 32.13 months. The VEGF A rs833061 resulted significant in PFS (17 vs 4 months; P<0.0001) and OS (38 vs 10 months; P<0.0001). The VEGF A rs699947 was significant for PFS (18 vs 4 months; P=0.0001) and OS (37 vs 16 months; P<0.0001). The VEGF A rs2010963 was significant in PFS (18 vs 8 vs 2 months; P=0.0001) and OS (31 vs 36 vs 9 months; P=0.0045). The VEGR3 rs6877011 was significant in PFS (12 vs 4 months; P=0.0075) and OS (36 vs 17 months; P=0.0001). At multivariate analysis, rs833061, rs2010963 and rs68877011 were significant in PFS, and rs833061 and rs68877011 were independent factors in OS. CONCLUSIONS: In our analysis, patients with TT polymorphism of rs833061, CC polymorphism of rs699947, CC polymorphism of rs2010963 and CG polymorphism of rs6877011 seem to have a worse PFS and OS when receiving first-line sunitinib.

Treatment effects in prostate cancer following traditional and emerging therapies.

Treatment options for prostate cancer consist of radical prostatectomy, hormonal therapy and radiation therapy. Hormonal and radiation therapy have well-known, often profound, effects on the histological appearance of benign and malignant prostate tissue. Novel therapies including focal ablative treatments, chemotherapies and targeted molecular therapies are beginning to emerge and pathologists will play a central role in documenting the effects of these treatments at the tissue level. As such, knowledge of treatment-related changes and access to clinical information are essential to ensure accurate interpretation and reporting of post-treatment prostate specimens by pathologists.

Karyometry and quantitative immunohistochemical analysis of the urothelium in tissue sections: a feasibility study based on chromatin remodeler DAXX immunostaining.

The aim of this study was to investigate the feasibility of applying a software traditionally used in the field of engineering to pathology, in particular to tissue sections from normal urothelium (NU) immuno-stained for the chromatin remodeler DAXX (death domain-associated protein). The study included 5 cases of NU. Images were recorded with a Nikon digital camera. The nuclear area and the intensity of nuclear staining were analyzed with a software package developed in LabVIEW environment. The nuclear size is 14.8 plus or minus 6.5 square microns. The nuclei in the cells adjacent to the stroma are slightly smaller than in the intermediate cells by a factor of 0.86. The mean nuclear area of the nuclei in the superficial cell layer in NU is identical to the nuclei in the intermediate cell layers. For each nucleus intensity of nuclear staining is calculated based on the gray value of the individual picture elements in the green color plane. The mean and standard deviation of nuclear gray value are 106 plus or minus 15. The mean value in the nuclei adjacent to the stroma is slightly greater by a factor 1.02 and 1.04 compared to the intermediate and superficial cell layers. In conclusion, this exploratory study shows that karyometry and quantitative immunohistochemical analysis can be done accurately by using a digital camera commonly available to pathologists and an image analysis software routinely used in the field of engineering.

Fluorescence in situ hybridization analysis of CCND3 gene as marker of progression in bladder carcinoma.

The aim of this study was to assess patterns of CCND3 gene amplification in bladder cancer and correlate gene status with recurrence-free and progression-free survival. A sequential cohort series of 102 primary bladder tumor samples in which there was enough tissue material to assess CCND3 gene status by fluorescent in situ hybridization (FISH) was the study group. CCND3 gene FISH amplification present in 31.4 percent of bladder carcinomas, was related to tumor progression (p=0.021) and lower time to progression (mean+-SD; 25.75+-15.25 months) as compared to 33.29+-11.0 months in the CCND3 not amplified group (p=0.05). By immunohistochemistry, Cyclin D3 labeling index was higher in the CCND3 amplified group (mean+-SD, 76.69+-27.51) than in not amplified (mean+-SD, 21.57+-7.02) (p less than 0.0001). The univariate survival analysis showed CCND3 gene amplification to be associated to a shorter progression-free survival (p=0.020) together with WHO histological grade (p=0.001) and pT stage category (p less than 0.0001). Cox’s regression analysis selected CCND3 amplification as an independent predictor of progression-free survival (p= 0.030, RR3.561, 95 percent CI 1.128-11.236) together with pT category (p less than 0.0001, RR5.834, 95 percent CI 2.364-14.395). Our FISH analysis suggests that CCND3 gene amplification is a marker of aggressiveness and might be a predictor of tumor progression in bladder urothelial carcinoma.

Is there a role for prostate tumour overexpressed-1 in the diagnosis of HGPIN and of prostatic adenocarcinoma? A comparison with alpha-methylacyl CoA racemase.

Prostate Tumour Overexpressed-1 (PTOV1) was recently identified as a novel gene and protein during a differential display screening for genes overexpressed in prostate cancer (PCa). Alpha-Methyl-CoA racemase (AMACR) mRNA was identified as being overexpressed in PCa. PTOV1 and racemase were immunohistochemically evaluated in PCa, high-grade prostatic intraepithelial neoplasia (HGPIN), atrophy and normal-looking epithelium (NEp) in 20 radical prostatectomies (RPs) with pT2a Gleason score 6 prostate cancer with the aim of analyzing the differences in marker expression between PTOV1 and AMACR. The level of expression of PTOV1 and AMACR increased from NEp and atrophy through HGPIN, away from and adjacent to prostate cancer, to PCa. With the ROC curve analysis the overall accuracy in distinguishing PCa vs HGPIN away from and adjacent to cancer was higher for AMACR than for PTOV1. In conclusion, AMACR can be considered a more accurate marker than PTOV1 in the identification of HGPIN and of PCa. However, PTOV1 may aid in the diagnosis of PCa, at least to supplement AMACR as another positive marker of carcinoma and to potentially increase diagnostic accuracy.

A contemporary update on pathology reporting for urinary bladder cancer.

Providing the best management for patients with bladder cancer relies on close cooperation among uro-oncologists and pathologists. The pathologist is involved in the diagnosis and assessment of prognostic and therapeutic factors in bladder biopsies, transurethral resection (TUR) and cystectomy specimens. The pathologist must report accurately the key features using terms that are well understood by clinicians. Adequate clinical information is important to pathologists in deciding the best approach in handling and processing the surgical specimens.

Immunohistochemical expression and localization of somatostatin receptors in normal prostate, high grade prostatic intraepithelial neoplasia and prostate cancer and its many faces.

Data on the immunohistochemical expression and localization of the five somatostatin receptors (SSTRs) have been obtained by our group in separate studies concerning the many faces of prostate cancer (PCa), its precursor high grade prostatic intraepithelial neoplasia (HGPIN) and normal epithelium (Nep). This publication highlights the key findings, with special reference to: normal prostate epithelium; untreated HGPIN and PCa, both clinically and incidentally detected; PCa with NE differentiation; HGPIN and PCa following complete androgen ablation (CAA); and hormone refractory (HR) PCa. Taken together, the data obtained in these investigations demonstrate that SSTR profiling in individual patients with HGPIN and the multifaceted PCa is feasible and is of relevance to better tailor the somatostatin analogue-based treatment.

Do DNA-methylation and histone acetylation play a role in clear cell renal carcinoma? Analysis of radical nephrectomy specimens in a long-term follow-up.

We investigated global methylation and histone acetylation in 50 conventional clear cell renal carcinomas (RCC), treated with radical nephrectomy, to assess their possible role as diagnostic biomarkers. The features considered in this study were patient age, tumor size and grade, percentage and intensity of 5-methylcytosine (5mc) and Acetyl-Histone (Lys 9) expression in tumor tissue. All considered parameters were correlated with patient specific survival. The mean percentage of global cellular methylation in tumoral tissue was significantly higher compared to normal peritumoral tissue (p<0.0001), while the intensity of cellular methylation was significantly higher in normal tissue than in tumoral tissue (p=0.001). The mean percentage of histone cellular acetylation in tumoral tissue was significantly lower compared to normal peritumoral tissue (p=0.0005), while the intensity of mean acetylation in neoplastic tissue was similar to the normal tissue. The percentage of global DNA methylation was significantly higher in grades 3 and 4 tumors (p=0.033). Global DNA methylation and histone acetylation in tumoral tissue did not correlate with survival. Fuhrman grade was statistically significant for prognosis (p=0.031). In conclusion, global hypermethylation and histone hypoacetylation play an important role in RCC carcinogenesis; Fuhrman grade is still considered the most important factor for patient survival; 5mc can have a role as markers of aggressiveness.

Global acetylation and methylation changes predict papillary urothelial neoplasia of low malignant potential recurrence: a quantitative analysis.

Papillary urothelial neoplasia of low malignant potential (PUNLMP) recurs in approximately 35% of patients. Conventional histopathological assessment does not distinguish non-recurrent from recurrent PUNLMP. The aim of this study is to explore the differences in global histone acetylation and global DNA methylation between non-recurrent and recurrent PUNLMP. Acetylated histone H3 lysine 9 (AcH3K9) and 5-methylcytosine (5MeC) were investigated by immunohistochemistry (IHC) in 20 PUNLMP cases (10 non-recurrent and 10 recurrent), in 5 cases of normal urothelium (NU) and in 5 cases of muscle invasive pT2 urothelial carcinoma (UC). The total optical density of the nuclear staining was measured photometrically in at least 40 nuclei separately for the basal, intermediate and luminal positions in each case. Concerning the total optical density values for both acetylation and methylation, a decrease in staining is observed from non-recurrent PUNLMP to recurrent PUNLMP, at all nuclear locations. For acetylation the mean value in non-recurrent PUNLMP, intermediate between NU and UC, is closer to the former than to latter. The mean value in recurrent PUNLMP is closer to UC than to NU. In NU, non-recurrent and recurrent PUNLMP, the acetylation to methylation ratio decreased from the nuclei in basal position to those in the surface, the average for the above groups being 1.491, 1.611 and 1.746, respectively. Setting the observed values for NU at each sampling location to unity, acetylation shows a steady decrease, the percentages of changes in this nuclear location compared to NU being -5% in non-recurrent PUNLMP, -15% in recurrent PUNLMP and -24% in UC. Concerning methylation, there is a slight increase in non-recurrent PUNLMP (+5%), a decrease in recurrent PUNLMP (-19%) followed by a sharp rise for the UC (+61%). In conclusion, there are differences in global histone acetylation and DNA methylation patterns between non-recurrent and recurrent PUNLMP. Further studies are needed to elucidate the complex interplay between chromatin structure, its modifications and recurrence of PUNLMP.

Immunohistochemical expression and localization of somatostatin receptor subtypes in prostate cancer with neuroendocrine differentiation.

The aim of the study is to examine the tissue expression and localization of the somatostatin receptors (SSTRs) in prostate cancer (PCa) with neuroendocrine (NE) differentiation. The five SSTR subtypes (SSTR1 to 5) were evaluated immunohistochemically in the secretory cells of normal-looking epithelium (Nep), high-grade prostatic intraepithelial neoplasia (HGPIN) and PCa in 20 radical prostatectomies (RPs) with Gleason score 3+3=6 acinar PCa; 20 RPs with GS 4+4=8 and 4+5=9 PCa; and 20 RPs with PCa with NE differentiation. The basal cells were evaluated in Nep and HGPIN. In all groups the stromal smooth muscle and endothelial cells were also analyzed. Concerning the secretory cells, (i) the greatest mean proportions of cells with strong cytoplasmic staining in PCa were seen for SSTR2, mainly in the group of RP with NE differentiation, and for SSTR4 in all three groups; the mean values in HGPIN were intermediate between Nep and PCa; (ii) Membrane staining was seen for SSTR3 and SSTR4; the mean percentages of positive cells, higher in SSTR3 than in SSTR4, decreased from Nep to HGPIN and PCa in all three RP groups; in the latter two, the mean percentages were similar; and (iii) Nuclear staining was seen with SSTR4 and SSTR5; for SSTR4, the mean percentages in the PCa of the three groups were higher than in HGPIN and Nep, the highest proportion being with PCa with NE differentiation. Concerning the basal cells, in Nep the mean proportions of cells with strong staining intensity were greater for SSTR1 and SSTR3 than for the other subtypes, the lowest being with SSTR2; in HGPIN the highest mean propositions of positive cells was with SSTR3, the proportions in the three RP groups being similar. Concerning the stromal smooth muscle and endothelial cells, the highest mean values being in SSTR1 and the lowest in SSTR5; for the former subtype the highest proportion of endothelial cells with strong intensity was seen in the RP NE group. In conclusion, this immunohistochemical study expands our knowledge on the expression and localization of five SSTRs in the various tissue components in the prostate with PCa with NE differentiation, compared with conventional PCa. Typing somatostatin receptor expression in NE tumours could be of relevance to target somatostatin analogue-based diagnostic approach and treatment.

Pathology without microscope: From a projection screen to a virtual slide.

We have witnessed successive stages since the Seventies in the advancements towards digital pathology. We agree with Dr Pallua et al on the tremendous changes that are taking place in pathology, all leading toward greater role of digitalization in the field of pathology, both in terms of consultation and teaching. In particular, distance teaching using digital pathology will grow into a mainstream mode of pathology teaching, something that has been reinforced by COVID-19.

Prognostic role of global DNA-methylation and histone acetylation in pT1a clear cell renal carcinoma in partial nephrectomy specimens.

Surgery is the main treatment for renal cell carcinoma (RCC); nephron sparing surgery can be performed as a treatment of choice for small peripheral lesions. Epigenetics configures a new entity that regulates gene expression throughout methylation, acetylation and chromatin remodelling. In addition to silencing as a result of mutations, loss of heterozygosity, or classic genetic events, epigenetic modification symbolizes essential events during carcinogenesis and tumour development. We investigated global methylation and histone acetylation expression in a series of small conventional clear cell renal carcinomas (i.e. less than 5 cm) (pT1a) treated with partial nephrectomy, to assess their possible role as diagnostic biomarkers. A total of 54 patients with conventional single RCC were selected and treated with partial nephrectomy; they were followed up to 186 months. Immunohistochemistry was performed on paraffin-embedded sections, using anti-5-methylcytosine (5mc) and anti-Acetyl-Histone H3 (Lys 9). Our results confirm that the mean percentage of global cellular methylation in tumoural tissue was significantly higher compared to healthy peritumoural tissue, whereas the mean percentage of histone cellular acetylation in tumoural tissue was significantly lower. The percentage of methylation was significantly higher in grades 3 and 4 (P = 0.033), whereas the percentage of histone acetylation was significantly lower (P = 0.023), suggesting therefore that these markers could correlate with tumour aggressiveness in pT1a RCC. On univariate analysis of patient survival in relation to the different considered factors, Fuhrman grade was the most important survival factor. These epigenetic markers can give us interesting information about chromatin remodelling in RCCs; the percentage of global methylation increases with increasing Fuhrman grade, whereas histone acetylation decreases with increasing grade in small RCC; our results suggest that global hypermethylation and histone hypoacetylation can be assumed to be an early event in RCC and to correlate with tumour aggressiveness.

Immunohistochemical expression of prostate stem cell antigen in cystoprostatectomies with incidental prostate cancer.

High expression of prostate stem cell antigen (PSCA) has been shown to be associated with adverse prognostic features in clinically-diagnosed prostate cancer. The aim of this study is to analyze PSCA expression in cystoprostatectomies with incidental prostate carcinoma (PCa). PSCA expression was evaluated immunohistochemically in normal-looking epithelium (NEp), high-grade prostatic intraepithelial neoplasia (HGPIN) and pT2a Gleason score 6 acinar adenocarcinoma. The evaluation was carried out on 20 cystoprostatectomies (CyPs) with incidental PCa from men with bladder urothelial carcinoma (UC), and 20 radical prostatectomies (RPs) with hormonally untreated PCa from men with clinically detected PCa. Ki-67 was also investigated. The percentages of PSCA positive cells in HGPIN were significantly higher than in NEp (NEp: CyP, mean 2.92%+/-standard deviation 6.26%; RP, 3.5%+/-6.46%. HGPIN: CyP, 13.67%+/-12.78%; RP, 14.67%+/-11.34%) (p<0.001). The proportions of positive cells in PCa were greater than in HGPIN (CyP, 20.25%+/-15.96%; RP, 22.58%+/-13.67%) (p<0.001). For Ki-67 labeling, the proportions of positive nuclei in the CyPs significantly increased from NEp through HGPIN to PCa. A similar trend was seen in the RPs. In the CyPs the percentages of PSCA and Ki67 positive cells were lower than in the RPs, the differences between the CyP and RP compartments being not statistically significant. Our findings suggest that PSCA is a marker associated with neoplastic transformation of prostate cells, both in CyPs and RPs. However, there are no significant differences between CyPs with incidental prostate carcinoma and RPs with clinically diagnosed cancer.

Expression of basic fibroblast growth factor, its receptors and syndecans in bladder cancer.

Basic fibroblast growth factor (bFGF) is a heparin-binding cationic protein involved in a variety of pathological conditions including angiogenesis and solid tumour growth. The basic fibroblast growth factor receptor (FGFR) family comprises at least 4 high affinity tyrosine kinase receptors that require syndecans for their function. Mounting evidence indicates that syndecans, that bind both bFGF and their FGFRs, will act as stimulators, whereas syndecans that only bind bFGF will act as inhibitors of signaling by sequestering the growth factor. Recent findings have highlighted the importance of syndecans in urological cancers. The aim of this study is to investigate the expression of bFGF, its receptors (R1 and R2) and syndecans (1-4) in invasive urothelial carcinoma and normal-looking urothelium by Western blotting, RT-PCR, and immunohistochemistry analyses. Interestingly, bFGF, FGFR1 and FGFR2 protein levels statistically increased in bladder cancer tissues. mRNA of FGFR1 and syndecans (1-4), showed a statistically significant increase while an mRNA increase in the other molecules analysed was not significant. bFGF, its receptors and syndecan immunostaining were mainly present in the urothelium both in normal-looking tissues and urothelial neoplastic cells. In conclusion, our data report that the bFGF, FGFR and syndecan expressions are altered in bladder tumours.

[Nephrotic proteinuria with type 2 diabetes mellitus and autoimmune thyroiditis]. / Proteinuria nefrosica in paziente con diabete mellito di tipo II e tiroidite autoimmune.

This study reports on a 67-year-old man, suffering from type 2 diabetes mellitus for 11 years along with arterial hypertension and autoimmune thyroiditis, in whom nephrotic proteinuria was detected together with a mild reduction in GFR. No autoantibodies or monoclonal proteins were detected in blood and urine. Renal biopsy material examined by light microscopy, immunofluorescence and electron microscopy showed AL amyloidosis. This case underlines the role of renal biopsy in patients with type 2 diabetes mellitus, in whom renal diseases other than diabetic nephropathy may occur frequently.