Hybrid oncocytic/chromophobe tumors (HOCT) of the kidney have been described in patients with Birt-Hogg-Dubé syndrome (BHD) and in association with renal oncocytosis without BHD. HOCT in patients without evidence of BHD or renal oncocytosis is exceedingly rare, and these cases have been poorly characterized. We have identified and studied 14 cases of HOCT from previously diagnosed renal oncocytomas (398 cases) and chromophobe renal cell carcinomas (351 cases) without evidence of BHD or renal oncocytosis. Immunohistochemical, ultrastructural, and molecular genetic studies analyzing numerical chromosomal changes, loss of heterozygosity for chromosome 3p, and mutation status of VHL, c-kit, PDGFR, and folliculin (FLCN) genes were performed. HOCTs were identified in nine men and five women (age range 40-79 years). The size of tumors ranged from 2 to 11 cm. All tumors displayed a solid alveolar architecture and were composed of cells with abundant granular eosinophilic oncocytic cytoplasm with perinuclear halos. Occasional binucleated neoplastic cells were present, but irregular, hyperchromatic, wrinkled (raisinoid) nuclei were absent. The cytoplasm contained numerous mitochondria of varying sizes, but only sparse microvesicles with amorphic lamellar content were found. Tumors were positive for CK7 (12/14), AE1-AE3 (14/14), anti-mitochondrial antigen (14/14), E-cadherin (11/13), parvalbumin (12/14), and epithelial membrane antigen (14/14). Tumors were generally negative for racemase, CK20, CD10, and carboanhydrase IX. Interphase fluorescence in situ hybridization revealed multiple chromosomal losses and gains with a median of four (range 1-9) chromosomal aberrations per case. Monosomy of chromosome 20 was common and found in 7 of 14 cases. Monosomy of chromosomes 6 and 9 was present in 4 of 14 cases each, of which two cases displayed monosomy for both chromosomes 6 and 9. Polysomy of chromosomes 10, 21, and 22 was found in 4/14 cases each, of which one case displayed polysomy for all these three chromosomes. No pathogenic mutations were found in the VHL, c-kit, PDGFR, and folliculin (FLCN) genes. (1) We have shown that hybrid oncocytic/chromophobe tumors of the kidney do occur, albeit rarely, outside the Birt-Hogg-Dubé syndrome and without associated renal oncocytosis. (2) These tumors constitute a relatively homogenous group with histomorphologic features of both chromophobe renal cell carcinoma and renal oncocytoma. (3) Sporadic hybrid oncocytic/chromophobe renal tumors are characterized by multiple numerical aberrations (both mono- and polysomies) of chromosomes 1, 2, 6, 9, 10, 13, 17, 21, and 22 and lack of mutations in the VHL, c-kit, PDGFRA, and FLCN genes. (4) The tumors seem to behave indolently as no evidence of malignant behavior was documented in our series, although admittedly, the follow-up was too short to fully elucidate the biological nature of this rare neoplasm. At worst, these tumors could have a low malignant potential, which only can be found out with longer follow-up.

We present 11 cases of spindle and cuboidal renal cell carcinoma, which is believed to be a distinctive morphological entity. Our cases were histologically, immunohistochemically and ultrastructurally similar to the previously reported cases of spindle and cuboidal renal cell carcinoma. In contrast to all previously reported cases of spindle and cuboidal renal cell carcinoma, we observed an association with nephrolithiasis in three of our cases; moreover, one of our tumours had a conventional renal cell carcinoma component and another revealed a metastatic focus in a regional lymph node. None of our patients died of the disease. This study confirms that spindle and cuboidal renal cell carcinoma has a low malignant potential.

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Xp11.2-translocation renal carcinoma (TRCC) is suspected when a renal carcinoma occurs in young patients, patients with a prior history of exposure to chemotherapy and when the neoplasm has morphological features suggestive of that entity. We retrieved 20 renal tumours (from 17,500 archival cases) of which morphology arose suspicion for TRCC. In nine cases, TFE3 translocation was confirmed by fluorescence in situ hybridisation analysis. In 9 of the remaining 11 TRCC-like cases (7 male, 4 female, aged 22-84 years), material was available for further study. The morphological spectrum was diverse. Six tumours showed a mixture of cells with eosinophilic or clear cytoplasm in tubular, acinar and papillary architecture. One case was high grade with epithelioid, spindle cell and sarcomatoid areas. Another showed tubular, solid, and papillary areas and foci containing spindle cells reminiscent of mucinous tubular and spindle cell carcinoma. The third showed dyscohesive nests of large epithelioid and histiocytoid cells in a background of dense lymphoplasmacytic infiltrate. By immunohistochemistry, keratin AE1/AE3 was diffusely positive in three tumours, while CK7 strongly stained one tumour and another focally and weakly. CD10 and Pax8 were expressed by eight, AMACR and vimentin by seven, CA-IX by four and TFE3 and cathepsin K by two tumours. Of the two TFE3-positive tumours, one showed polysomy of chromosome 7 and the other of 17; they were VHL normal and diagnosed as unclassifiable RCC. Of the seven TFE3-negative tumours, three showed polysomy of 7/17 and VHL abnormality and were diagnosed as combined clear cell RCC/papillary RCC. One TFE3-negative tumour with normal 7/17 but LOH 3p (VHL abnormality) was diagnosed as clear cell RCC. One TFE3-negative tumour with polysomy 7/17 but normal VHL was diagnosed as papillary RCC, and two with normal chromosomes 7/17 and VHL gene were considered unclassifiable. As morphological features and IHC are heterogeneous, TRCC-like renal tumours can only be sub-classified accurately by multi-parameter molecular-genetic analysis.

In this in vitro study the effects of copper sulphate on the motility, morphology and structural integrity of rabbit spermatozoa were investigated. The spermatozoa motility was evaluated by CASA method and Annexin analysis was used for detection of structural changes. For analysis of morphology samples of rabbit semen were fixed with Hancock's solution and stained with Giemsa, and for each sample at least 500 spermatozoa were evaluated. The concentration of copper in the medium varied from 3.57 to 4.85 microg CuSO4/mL. At Time 0 the highest motility was detected in the control group (57.78 +/- 3.90%). Motility in groups with copper administration was lower in comparison to control. Significant differences were detected in groups with 3.70-4.85 microg CuSO4/mL (P<0.05) at Time 0. After 1 h of incubation with copper sulphate the motility significantly decreased almost in all experimental groups. However, at Time 2 h significant increase of total motility was observed in groups with lower concentrations of copper (3.57 and 3.63 microg CuSO4/mL). After 24 and 48 h of incubation almost all the spermatozoa were dead recording no motility at all concentrations. The concentration- dependent decrease of spermatozoa motility up to 50% of control was detected for the group receiving highest copper administration (4.85 microg CuSO4/mL) at Times 1 and 2 h. Progressive motility had an identical trend to that of motility in all experimental groups, at all culture times and for all concentrations. Evaluation of distance and velocity parameters indicated that a sort of stress tolerance developed in lower concentrations (3.57 and 3.63 microg CuSO4/mL). At lower concentrations, an increase was noted for distance parameter DCL and velocity parameter VCL, indirectly confirming the significant motility and progressive motility increase. Other motility parameters (straightness index, linearity index, wobble and amplitude of lateral head displacement) revealed decrease in the group with the highest copper concentration (4.85 microg CuSO4/mL) in comparison to the control group after 2 h of incubation, only. No significant alteration was noted for these parameters in comparison to control at Times 0 and 1 h. The total percentage of morphologically abnormal spermatozoa was significantly higher (P<0.05) in the group with the highest copper concentration (46.20+/-5.54%) in comparison to control (30.60+/-2.91). Predominant morphological abnormalities were acrosomal changes, knob-twisted flagellum and small heads. Detection of spermatozoa with disordered membrane was carried out for groups with higher copper concentrations and control, using Annexin analysis. Analysis showed higher occurrence of positive spermatozoa in the copper-exposed groups. Some Annexin positive reactions from all spermatozoa were detected in the control group. In copper-exposed groups positive reaction proved alteration in anterior part of head (acrosome) and in connection segment (mid-piece) of spermatozoa. Detected data evidently confirm adverse effects of high copper ...