Age-related schwannomatosis with potential exosome-mediated contribution to prostate hyperplasia: a case report and mini-review.

A 72-year-old Caucasian man incurring a prostate hypertrophy presented with a right forearm nodule, the growth of which appeared to parallel the rise in his blood prostate-specific antigen (PSA) level. Echographic examination was consistent with a median-nerve schwannoma, and was confirmed upon magnetic resonance imaging (MRI). Excision of the nodule was readily performed without significant neural damage, and its schwannoma nature was confirmed upon immunohistochemistry analysis. Importantly, blood PSA dropped abruptly from ≈13 to ≈5 ng/ml within 2 months postschwannoma resection, a swift drastic reduction unachievable with oral dutasteride alone. However, 6 weeks later, a new nodule became apparent on the back of the left knee and was identified as a second schwannoma, thereby suggesting that its growth could have been stimulated by the resection of the first schwannoma, as previously described for vestibular schwannomas. The second schwannoma was in fact two: the bigger one was in the common fibular nerve and the smaller one in the tibial nerve. Both echography and MRI results were confirmed upon surgical resection of the bigger knee schwannoma. Although the third schwannoma has not yet been resected and formally characterized, we face a schwannomatosis case with an unexpected potential exosome-mediated stimulating effect on PSA secretion (PSA immunohistochemistry was negative on both schwannomas). On the other hand, preliminary genomic analysis showed a deficient balance for chromosome 22, the very chromosome carrying the three main genes involved in schwannomatosis. This age-related schwannomatosis case is thus discussed in light of the following: age-related DNA repair deficiency culminating in loss of chromosome/heterozygosity; CpG methylation/demethylation-based epigenetic aging; age-related functional decline of the immune system responsible for inefficient elimination of abnormal cells and subsequent tumorigenic cell turn-over; exosome-mediated pathologic intercellular communications; and prostate-invading brain neural progenitors as pathologic peripheral nervous system (PNS) cells.

Dismantling papillary renal cell carcinoma classification: The heterogeneity of genetic profiles suggests several independent diseases.

Papillary renal cell carcinoma (pRCC) is the second most frequent renal cell carcinoma (RCC) after clear cell RCC. In contrast to clear cell RCC, there is no consensual protocol using targeted therapy for metastatic pRCC. Moreover, diagnosis of some pRCC, especially pRCC of type 2 (pRCC2) may be challenging. Our aim was to identify molecular biomarkers that could be helpful for the diagnosis and treatment of pRCC. We studied the clinical, histological, immunohistological, and comprehensive genetic features of a series of 31 pRCC including 15 pRCC1 and 16 pRCC2. We aimed to determine whether pRCC represents a unique entity or several diseases. In addition, we compared the genetic features of pRCC2 to those of eight RCC showing various degrees of tubulo-papillary architecture, including three TFE-translocation RCC and five unclassified RCC. We demonstrate that pRCC is a heterogeneous group of tumors with distinct evolution. While most pRCC2 had genetic profiles similar to pRCC1, some shared genomic features, such as loss of 3p and loss of chromosome 14, with clear cell RCC, TFE-translocation RCC, and unclassified RCC. We identified variants of the MET gene in three pRCC1. A mutation in the BRAF gene was also identified in one pRCC1. In addition, using next-generation sequencing (NGS), we identified several variant genes. Genomic profiling completed by NGS allowed us to classify pRCC2 in several groups and to identify novel mutations. Our findings provide novel information on the pathogenesis of pRCC that allow insights for personalized treatment.

A renal metanephric adenoma showing both a 2p16e24 deletion and BRAF V600E mutation: a synergistic role for a tumor suppressor gene on chromosome 2p and BRAF activation?

Metanephric adenomas (MAs) are rare benign tumors that may be difficult to recognize. Specific genetic anomalies might aid in diagnosis, but genomic data are limited and conflicting. Consistent mutations of the BRAF gene have been recently reported in MAs and could become useful as a discriminative marker among renal tumors. We report here a case of MA, showing both a BRAF V600E mutation and a segmental loss within bands 2p16 and 2p24 as the sole quantitative genomic anomaly. We compared the borders and size of the deleted region in our case to those of five cases of MAs previously reported. We identified a common minimal region containing 87 genes, among which several tumor suppressor genes could be candidate actors in the pathogenesis of MA. We ruled out MSH2 and MSH6 as target gene candidates, both located in the deleted region, on the basis of preserved expression and microsatellite sequence stability. Our study confirms the recurrence of a BRAF mutation and of 2p alterations in MAs. This first case showing simultaneous presence of a BRAF mutation and a 2p deletion raises the question of a synergistic role for these two anomalies in the pathogenesis of MAs.

Pseudo-tumor of the scrotum, a rare clinical presentation of dirofilariasis: a report of two autochtonous cases due to Dirofilaria repens.

In Europe, human dirofilariasis refers to a group of autochtonous parasitic infections caused by tissue nematodes of the genus Dirofilaria, responsible for two distinct clinical presentations: Dirofilaria immitis usually presenting as pulmonary lesions and Dirofilaria repens as subcutaneous nodules. Rare in humans, genital involvement manifests itself as pseudotumor nodules affecting the scrotum, epididymis, or spermatic cord. We report on two cases of Dirofilaria repens infections, involving the spermatic cord and epididymis.

Renal cell carcinoma and a constitutional t(11;22)(q23;q11.2): case report and review of the potential link between the constitutional t(11;22) and cancer.

We observed a t(11;22)(q23-24;q11.2-12) and monosomy 3 in renal tumor cells from a 72-year-old man. The hypothesis of a primitive peripheral neuroectodermal tumor (PPNET) located in the kidney was promptly excluded: Histologically, the tumor was a clear cell renal cell carcinoma (RCC) and we did not observe an EWSR1 gene rearrangement. The constitutional origin of this alteration was established. We report on the second case of RCC in a patient with a constitutional t(11;22). The t(11;22)(q23;q11.2) is the main recurrent germline translocation in humans. Unbalanced translocation can be transmitted to the progeny and can cause Emanuel syndrome. Our observation alerts cancer cytogeneticists to the fortuitous discovery of the constitutional t(11;22) in tumor cells. This translocation appears grossly similar to the t(11;22)(q24;q12) of PPNET and should be evoked if present in all cells of a tumor other than PPNET. This is important when providing appropriate genetic counseling. Moreover, the potential oncogenic role of the t(11;22) and its predisposing risk of cancer are under debate. The family history of the patient revealed a disabled brother who died at an early age from colon cancer and a sister with breast cancer. This observation reopens the issue of a link between the constitutional t(11;22) and cancer, and the utility of cancer prevention workups for t(11;22) carriers.

Absence of bacterial imprints on struvite-containing kidney stones: a structural investigation at the mesoscopic and atomic scale.

OBJECTIVE: Bacterial imprints are always observed on highly carbonated apatite kidney stones but not struvite kidney stones. Struvite and carbonated apatite stones with a high CO(3)(2-)/PO(4)(3-) rate are believed to develop from infections, but their structural differences at the mesoscopic scale lack explanation. METHODS: We investigated 17 urinary calculi composed mainly of struvite or carbonated apatite by Fourier transform infrared, scanning electron microscopy, and powder neutron diffraction techniques. RESULTS: Carbonated apatite but not struvite stones showed bacterial imprints. If the same stone contained both carbonated apatite and struvite components, bacterial imprints were observed on the carbonated apatite but not the struvite part. Moreover, neutron powder diffraction experiments revealed the crystal size of struvite stones were larger than that of carbonated apatite stones (250 ± 50 vs 50 nm). CONCLUSION: Bacterial imprints may appear more easily on kidney stones with small nanocrystals, such as carbonated apatite than with large nanocrystals, such as struvite. This approach may help identify bacteria contributing to stone formation, perhaps with negative results of urine culture.

High Zn content of Randall's plaque: a µ-X-ray fluorescence investigation.

Kidney stone disease, or nephrolithiasis, is a common ailment. Among the different risk factors usually associated with nephrolithiasis are dehydration, metabolic defects (especially with regard to calcium and oxalate). The presence of a mineral deposit at the surface of the renal papilla (termed Randall's plaque) has all been recently underlined. Of note, Randall's plaque is made of the calcium phosphate, carbapatite, and serves as a nucleus for kidney stone formation. The process by which apatite nanocrystals nucleate and form Randall's plaque remains unclear. This paper deals with the possible relationship between trace elements and the formation of this mineral. The investigation has been performed on a set of Randall's plaques, extracted from human kidney stones, through µ-X-ray diffraction and µ-X-ray fluorescence analyses in order to determine the chemical composition of the plaque as well as the nature and the amount of trace elements. Our data provide evidence that Zn levels are dramatically increased in carbapatite of RP by comparison to carbapatite in kidney stones, suggesting that calcified deposits within the medullar interstitium are a pathological process involving a tissue reaction. Further studies, perhaps including the investigation of biomarkers for inflammation, are necessary for clarifying the role of Zn in Randall's plaque formation.

A novel case of t(X;1)(p11.2;p34) in a renal cell carcinoma with TFE3 rearrangement and favorable outcome in a 57-year-old patient.

Renal cell carcinoma (RCC) with translocation involving Xp11.2 (Xp11.2-RCC) is a rare neoplasm that usually occurs in children and young adults. This incidence is underestimated in adults because its morphological similarities with clear-cell RCC or papillary RCC2,3, as well as immunohistochemical and cytogenetic analyses are not carried out systematically in adults. We present a novel case of Xp11.2-RCC in a 57-year-old woman. The histologic features were those of a clear-cell RCC. Molecular cytogenetic analysis showed an uncommon t(X;1)(p11.2;p34) with TFE3 rearrangement and no alteration of chromosome 3. The immunohistochemical analysis showed expression of the TFE3 protein. Only nine cases of (X;1)(p11.2;p34) have been published, most of them occurring in children or young adults. To our knowledge, this is the second report of such a translocation in a patient older than 55 years. After a follow-up period of 13 months, the patient showed no evidence of disease. The clinical outcome was favorable, indicating that this particular translocation might be associated with a good prognosis. This observation confirms that Xp11.2-RCC are very likely to be underestimated in adults older than 40 years, and it highlights the importance of performing immunohistochemical and cytogenetic analyses in RCC for accurate diagnosis.

Flexible ureterorenoscopy with holmium laser in horseshoe kidneys.

OBJECTIVES: To assess the outcome of flexible ureterorenoscopy (F-URS) with the holmium laser in treating stones in the horseshoe kidney (HSK). METHODS: We retrospectively reviewed the records of 17 patients with a HSK stone (17 renal units) who had undergone F-URS with the holmium laser from December 2004 to May 2009. The presenting symptoms were renal colic, urinary tract infection, or hematuria. F-URS was used in as an alternative after the failure of shock wave lithotripsy in 8 patients (47%) and percutaneous nephrolithotomy failure in 4 patients (23.5%). Follow-up examination was performed after 4-6 weeks with plain radiography and either renal ultrasonography or noncontrast computed tomography. Success was defined as stone-free status or residual fragments <3 mm. The use of auxiliary procedures was considered to indicate treatment failure. RESULTS: A total of 17 patients were included in the present study (3 females and 14 males). Their age was 16-52 years (mean age ± SD 34.7 ± 6.3). The HSK stone location was 7 mixed caliceal, 3 mixed pelvic and caliceal, and 7 pelvic. The average stone burden was 16 mm (range 7-35). The overall number of procedures was 25 (mean 1.5 procedures/patient). Of the 17 patients, 15 (88.2%) were rendered stone free. CONCLUSIONS: The results of our study have shown that F-URS with the holmium laser is an efficient minimal invasive procedure for treating HSK stones.

The pathogenesis of Randall's plaque: a papilla cartography of Ca compounds through an ex vivo investigation based on XANES spectroscopy.

At the surface of attached kidney stones, a particular deposit termed Randall's plaque (RP) serves as a nucleus. This structural particularity as well as other major public health problems such as diabetes type-2 may explain the dramatic increase in urolithiasis now affecting up to 20% of the population in the industrialized countries. Regarding the chemical composition, even if other phosphate phases such as whitlockite or brushite can be found as minor components (less than 5%), calcium phosphate apatite as well as amorphous carbonated calcium phosphate (ACCP) are the major components of most RPs. Through X-ray absorption spectroscopy performed at the Ca K-absorption edge, a technique specific to synchrotron radiation, the presence and crystallinity of the Ca phosphate phases present in RP were determined ex vivo. The sensitivity of the technique was used as well as the fact that the measurements can be performed directly on the papilla. The sample was stored in formol. Moreover, a first mapping of the chemical phase from the top of the papilla to the deep medulla is obtained. Direct structural evidence of the presence of ACCP as a major constituent is given for the first time. This set of data, coherent with previous studies, shows that this chemical phase can be considered as one precursor in the genesis of RP.

Oncologic control obtained after exclusive flexible ureteroscopic management of upper urinary tract urothelial cell carcinoma.

OBJECTIVE: To assess oncological outcome after first-line management of upper urinary tract urothelial cell carcinomas (UUT-UCCs) by exclusive flexible ureteroscopy. MATERIALS AND METHODS: A retrospective review was performed for 35 patients treated between 2003 and 2007. All patients underwent retrograde flexible ureteroscopy for diagnosis, treatment (i.e., holmium:YAG vaporisation), and follow-up. The following data were reviewed: sex, age, ASA score, presence of a solitary kidney, unifocal or multifocal tumour, history of bladder cancer, tumour localisation, tumour size, stage and grade, outcome, recurrence, and progression. RESULTS: The mean age was 67 + or - 13.1 years (range: 38-88). The tumour involved the renal pelvis and the caliceal system in 19 cases (54%), the ureter in 8 cases (23%), and both in 8 cases (23%). Twelve patients (34%) had a history of bladder carcinoma. Tumour stage was superficial in 63% (57% were pTa and 6% were pT1) and not available in 37%. Tumour grade was low, high, and unavailable in 49, 14, and 37%, respectively. The median follow-up was 30 months (range: 12-66), and 21 patients had a recurrence (60%). The median survival rate without recurrence was 10 months (95% CI [5-22]). Four patients underwent nephroureterectomy during follow-up. No patient died of disease progression. The main limitation was the limited length of follow-up. CONCLUSIONS: Flexible endoscopic management can be advocated in selected cases of non-muscle invasive UUT-UCCs as an alternative to nephroureterectomy. Because of a high recurrence rate, long-term and stringent surveillance is needed, including iterative ureteroscopies at least every 3 months for 2 years.

Revisiting the localisation of Zn(2+) cations sorbed on pathological apatite calcifications made through X-ray absorption spectroscopy.

The role of oligo-elements such as Zn in the genesis of pathological calcifications is widely debated in the literature. An essential element of discussion is given by their localisation either at the surface or within the Ca apatite crystalline network. To determine the localisation, X-ray absorption experiments have been performed at SOLEIL. The Exafs results suggest that Zn atoms, present in the Zn(2+) form, are bound to about 4 O atoms at a distance of 2.00 A, while the interatomic distance R(CaO) ranges between 2.35 A and 2.71 A. Taking into account the content of Zn (around 1000 ppm) and the difference in ionic radius between Zn(2+) (0.074 nm) and Ca(2+) (0.099 nm), a significant longer interatomic distance would be expected in the case of Zn replacing Ca within the apatite crystalline network. We thus conclude that Zn atoms are localised at the surface and not in the apatite nanocrystal structure. Such structural result has essential biological implications for at least two reasons. Some oligoelements have a marked effect on the transformation of chemical phases, and may modify the morphology of crystals. These are both major issues because, in the case of kidney stones, the medical treatment depends strongly on the precise chemical phase and on the morphology of the biological entities at both macroscopic and mesoscopic scales.

Relationships between carbonation rate of carbapatite and morphologic characteristics of calcium phosphate stones and etiology.

OBJECTIVES: To examine the significance of the carbonation rate (CR) in carbonated apatite (carbapatite [CA]) stones and its relationships with the morphologic characteristics of CA and etiology. CA stones without struvite can result from metabolic disorders or urinary tract infection, but the latter etiology is still debated. Infection stones caused by urea-splitting bacteria are made of CA admixed with struvite and exhibit a high CO(3)(2-)/PO(4)(3-) ratio (CR). However, little is known as to the significance of the CR of CA in the absence of struvite in idiopathic calcium phosphate stones. METHODS: We studied 39 urinary calculi mainly composed of CA without struvite. Of the 39 patients, 13 had a past or present history of urinary tract infection, 24 had hypercalciuria, and 2 had medullary sponge kidney. The stones were examined by Fourier transform infrared spectroscopy and scanning electron microscopy. The presence of amorphous carbonated calcium phosphate or whitlockite was also considered. RESULTS: The CR of CA was 14% +/- 9%. On scanning electron microscopy, the CA particles appeared as spherules of 4.5 +/- 3.0 mum in diameter and were significantly larger in females than in males. In 16 cases, scanning electron microscopy showed bacterial imprints. In these calculi, the CR was significantly greater (22% +/- 7%) than in those without a visible bacterial imprint (8% +/- 5%, P < .0001). Amorphous carbonated calcium phosphate was found in 15 of 16 stones (93.8%) with imprints and in none of the 23 stones without imprints (P < .0001). CONCLUSIONS: A close relationship was observed between the presence of bacterial imprints, indicative of past or current urinary tract infection, and both the presence of amorphous carbonated calcium phosphate (or whitlockite) and a high CR of CA.

Very first tests on SOLEIL regarding the Zn environment in pathological calcifications made of apatite determined by X-ray absorption spectroscopy.

This very first report of an X-ray absorption spectroscopy experiment at Synchrotron SOLEIL is part of a long-term study dedicated to pathological calcifications. Such biological entities composed of various inorganic and/or organic compounds also contain trace elements. In the case of urinary calculi, different papers already published have pointed out that these oligo-elements may promote or inhibit crystal nucleation as well as growth of mineral. Use of this analytical tool specific to synchrotron radiation, allowing the determination of the local environment of oligo-elements and thus their occupation site, contributes to the understanding of the role of trace elements in pathological calcifications.

Detection of the TMPRSS2-ETS fusion gene in prostate carcinomas: retrospective analysis of 55 formalin-fixed and paraffin-embedded samples with clinical data.

The recent identification of fusion genes involving ETS family members in human prostate adenocarcinoma has confirmed the hypothesis that recurrent specific aberrations such as fusion genes may be as frequent in epithelial tumors as they are in leukemias and sarcomas. However, reciprocal translocations with fusion genes are often not detectable in carcinomas by conventional karyotyping because of additional complex chromosomal abnormalities. We retrospectively analyzed a large series of formalin-fixed, paraffin-embedded samples including 55 prostate carcinomas and 11 benign prostate tumors. We identified the fusion gene TMPRSS2-ERG by reverse-transcriptase polymerase chain reaction (RT-PCR) in 40/55 carcinomas (72%). Our study demonstrates that the detection of ETS fusion gene by RT-PCR is feasible on formalin-fixed and paraffin-embedded samples. No significant association between the presence of the fusion gene and any clinical feature, such as preoperative serum prostate-specific antigen (PSA) level (PSA>20 or PSA< or =20), pTNM stage including capsule invasion, seminal vesicle invasion, and lymph nodes metastases, or recurrence was observed in our series.

A report of unusual crossed fused renal ectopia and minimal invasive management of calculi.

Crossed renal ectopias with fusion are rare anomalies of the kidney. Urinary upper tract anatomy is modified and urinary stones may occur. We report such a case, with precise anatomical description of the kidneys and the successful management of a stone with minimal invasive techniques.