A rare case of cancer-to-cancer metastasis: breast cancer to renal cell cancer : Case report and review of literature.

BACKGROUND: Cancer-to-cancer metastasis is very rare with less than 50 cases described in literature. This article reports a case of breast cancer with synchronous metastasis to clear cell renal cell cancer. CASE DESCRIPTION: A 79-year-old woman was diagnosed with a bilateral breast carcinoma. Sonographic staging investigation of the abdomen revealed a 6 cm wide expansion of the right kidney. Bilateral mastectomy and nephrectomy of the right kidney was performed. The histology revealed a clear cell renal cell carcinoma and in the center of the tumor a 0.5 cm metastasis of the breast cancer. The patient's comorbidities and performance status precluded chemotherapy und she received palliative radiotherapy, targeted monoclonal antibody therapy and antihormonal treatment. CONCLUSIONS: Even if cancer-to-cancer metastasis is a very rare phenomenon, the simultaneous or consecutive finding of a renal tumor in women with breast cancer should be carefully evaluated.

Loss of complex I due to mitochondrial DNA mutations in renal oncocytoma.

PURPOSE: Many solid tumors exhibit abnormal aerobic metabolism characterized by increased glycolytic capacity and decreased cellular respiration. Recently, mutations in the nuclear encoded mitochondrial enzymes fumarate hydratase and succinate dehydrogenase have been identified in certain tumor types, thus demonstrating a direct link between mitochondrial energy metabolism and tumorigenesis. Although mutations in the mitochondrial genome (mitochondrial DNA, mtDNA) also can affect aerobic metabolism and mtDNA alterations are frequently observed in tumor cells, evidence linking respiratory chain deficiency in a specific tumor type to a specific mtDNA mutation has been lacking. EXPERIMENTAL DESIGN: To identify mitochondrial alterations in oncocytomas, we investigated the activities of respiratory chain enzymes and sequenced mtDNA in 15 renal oncocytoma tissues. RESULTS: Here, we show that loss of respiratory chain complex I (NADH/ubiquinone oxidoreductase) is associated with renal oncocytoma. Enzymatic activity of complex I was undetectable or greatly reduced in the tumor samples (n = 15). Blue Native gel electrophoresis of the multisubunit enzyme complex revealed a lack of assembled complex I. Mutation analysis of the mtDNA showed frame-shift mutations in the genes of either subunit ND1, ND4, or ND5 of complex I in 9 of the 15 tumors. CONCLUSION: Our data indicate that isolated loss of complex I is a specific feature of renal oncocytoma and that this deficiency is frequently caused by somatic mtDNA mutations.

Diagnostic yield of touch imprint cytology of prostate core needle biopsies.

Touch imprint cytology may provide additional information to core needle biopsy interpretation according to previous reports. The aim of this study was to investigate the diagnostic yield of this method in the diagnosis of prostate carcinoma. For this purpose, 452 transrectal prostate needle biopsies were evaluated from 56 patients. All patients were clinically suspicious of having prostate carcinoma. Two touch imprints were prepared from each fresh biopsy cylinder. Results of the standard histology and of the touch imprint evaluation were compared. Histologically negative biopsy cylinders were further evaluated for prostate carcinoma by fine step serial sectioning. The standard histological examination showed adenocarcinoma in 27 patients. Touch imprint cytology revealed atypical cells suspicious of carcinoma in 38 patients. This group included all 27 patients with positive standard histology and further 11 patients with initially negative core biopsy. Following serial sectioning, in three out of these 11 samples, histological evidence of a carcinoma could be proven. Fine step serial sectioning of all 29 core biopsies negative for carcinoma by standard histological examination, 26 patients remained negative. All three core biopsies initially negative by standard histology but positive after serial sectioning had cytology findings suspicious of carcinoma. We conclude, that in problematic cases the additional use of touch imprint cytology and serial sectioning of prostate core needle biopsies significantly improve the diagnostic accuracy.

Graft Growth and Podocyte Dedifferentiation in Donor-Recipient Size Mismatch Kidney Transplants.

BACKGROUND: Kidney transplantation is the treatment choice for patients with end-stage renal diseases. Because of good long-term outcome, pediatric kidney grafts are also accepted for transplantation in adult recipients despite a significant mismatch in body size and age between donor and recipient. These grafts show a remarkable ability of adaptation to the recipient body and increase in size in a very short period, presumably as an adaptation to hyperfiltration. METHODS: We investigated renal graft growth as well as glomerular proliferation and differentiation markers Kiel-67, paired box gene 2 and Wilms tumor protein (WT1) expression in control biopsies from different transplant constellations: infant donor for infant recipient, infant donor for child recipient, infant donor for adult recipient, child donor for child recipient, child donor for adult recipient, and adult donor for an adult recipient. RESULTS: We detected a significant increase in kidney graft size after transplantation in all conditions with a body size mismatch, which was most prominent when an infant donated for a child. Podocyte WT1 expression was comparable in different transplant conditions, whereas a significant increase in WT1 expression could be detected in parietal epithelial cells, when a kidney graft from a child was transplanted into an adult. In kidney grafts that were relatively small for the recipients, we could detect reexpression of podocyte paired box gene 2. Moreover, the proliferation marker Kiel-67 was expressed in glomerular cells in grafts that increased in size after transplantation. CONCLUSIONS: Kidney grafts rapidly adapt to the recipient size after transplantation if they are transplanted in a body size mismatch constellation. The increase in transplant size is accompanied by an upregulation of proliferation and dedifferentiation markers in podocytes. The different examined conditions exclude hormonal factors as the key trigger for this growth so that most likely hyperfiltration is the key trigger inducing the rapid growth response.

Gangliocytes in neuroblastic tumors express alarin, a novel peptide derived by differential splicing of the galanin-like peptide gene.

In neuroblastic tumors a relationship of differentiation of the tumor to galanin receptor expression and antiproliferative and apoptotic effects upon activation of galanin receptors in neuroblastoma cells was reported. To elucidate the expression of other components of the galanin peptide family in neuroblastic tumors, RT-PCR analysis of a variety of human neuroblastic tumor tissues was performed. Ganglioneuroma tissues revealed the presence of a splice variant of the galanin-like peptide (GALP) mRNA, which results in exclusion of exon 3 and a frame shift after the signal peptide sequence of GALP. This generates a peptide of 25 amino acids, which we have termed alarin because of the N-terminal alanine and the C-terminal serine. The novel neuropeptide alarin does not reveal significant homology to other peptides. Immunohistochemistry with antibodies directed against synthetic alarin peptide detected specific cytoplasmic granular staining in ganglia of human ganglioneuroma and ganglioneuroblastoma, as well as differentiated tumor cells of neuroblastoma tissues. Undifferentiated neuroblasts of these tumor tissues did not show alarin-like immunoreactivity and alarin-specific mRNA. Our findings indicate that alarin expression is a feature of ganglionic differentiation in neuroblastic tumor tissues.

Huge Congenital Segmental Dilatation of the Sigmoid Colon in a Neonate: A "Rarity to Meet" and a "Challenge to Treat".

Only ten cases of neonatal congenital segmental dilatation (CSD) of the colon have been described so far. We present a full-term female newborn with trisomy 21, ventricular septal defect, and gross abdominal distension. Plain abdominal radiographs revealed a huge cystic lesion occupying the left hemiabdomen. Upon laparotomy on day 4 a CSD of the distal sigmoid and proximal rectum was confirmed and resected. The proximal colon was exteriorized and the distal part closed as a Hartmann pouch. Histology confirmed a huge segmental dilatation of the sigmoid without dysganglionosis or pseudodiverticula, but normal intestinal architecture. After correction of the ventricular septal defect a low rectal end-to-end anastomosis could be performed at an age of 5 months. The postoperative course was uneventful. CSD of the sigmoid colon is extremely "rare to meet" and a "challenge to treat" in the newborn period, but clinical awareness of this entity prompts pediatric surgical success.

Galanin and galanin receptors in human cancers.

The increasing interest in peptides and peptide receptors in cancer is based on the possibility of receptor targeting, because peptide receptors are often expressed in different human tumors. The neuropeptide galanin has also been suggested to be involved in the development of neuroendocrine tumors based on the development of estrogen-induced tumors in estrogen-sensitive rats. This study summarizes our current knowledge on the expression of galanin peptide and galanin receptors in different human neuroendocrine tumors. The expression of both, peptide and corresponding receptor, seems to be a common feature of human gliomas, pheochromocytomas, pituitary and neuroblastic tumors. The co-expression of galanin and its receptors supports a role for galanin in tumor cell pathology via autocrine/paracrine mechanisms.

P63 immunoreactivity distinguishes upper urinary tract transitional-cell carcinoma and renal-cell carcinoma even in poorly differentiated tumors.

P63 is essential for the differentiation of normal urothelium and is also expressed in transitional cell carcinoma (TCC) of the bladder. We investigated p63 immunoreactivity in upper urinary tract TCC (n=53) and in renal-cell carcinoma (RCC; n=188) using a tissue microarray technique. P63 expression was detected in 51/53 (96.2%) TCCs, showing decreased expression in high-stage (pT1 and pT2 100%; pT3 90.9%) and poorly differentiated (G1 and G2 100%; G3 92%) tumors. All RCCs were negative for p63. P63 proved to be a helpful tool, even in poorly differentiated and undifferentiated renal malignancies, to distinguish TCC from RCC.

Clonality and loss of heterozygosity of WT genes are early events in the pathogenesis of nephroblastomas.

Nephrogenic rests (NRs), putative precursor lesions of nephroblastomas (Wilms' tumors), are found in 25% to 40% of kidneys presenting with nephroblastomas. Nephroblastomas are clonal tumors that, according to a genetic multistep model, are thought to arise as subclonal proliferations from NRs by accumulating genetic alterations. Different candidate genes for the pathogenesis of nephroblastomas have been identified, including those at chromosomes 11p13 (WT1 gene), 11p15 (WT2 gene), and 16q (WT3 gene). We investigated clonality and loss of heterozygosity (LOH) at these loci in different subtypes of NR. After microdissection under microscopic control, we analyzed a highly polymorphic locus of the human androgen receptor gene (HUMARA) for nonrandom X-inactivation of genomic DNA using a methylation-sensitive restriction enzyme to investigate clonality. Out of 14 patients, we found that 1 case each of adenomatous and hyperplastic NR and 2 of 7 cases of sclerosing NR were monoclonal. Five patients were noninformative. We assessed LOH at chromosomes 11p13, 11p15, and 16q by analyzing polymorphic gene loci at these regions. One hyperplastic NR and the corresponding tumor showed LOH at 11p13 and 11p15; 1 sclerosing NR and the corresponding tumor exhibited LOH at chromosome 16q. We demonstrate for the first time that sclerosing NRs can exhibit genetic alterations found in nephroblastomas, namely monoclonality and LOH at the WT gene loci. The histological morphology is no different between NRs with these genetic alterations and NRs without them. We conclude that these genetic changes are early events in the multistep genetic pathogenesis of nephroblastomas; however, they do not seem to fully determine a malignant potential of NR.

Comparative genomic hybridization analysis of hepatoblastoma reveals high frequency of X-chromosome gains and similarities between epithelial and stromal components.

Hepatoblastoma (HB) is the most common liver tumor in childhood and differs in its environmental risk factors and genetic background from hepatocellular carcinoma. HB is associated with inherited conditions such as familial adenomatous polyposis and Beckwith-Wiedemann syndrome, suggesting the importance of genetic abnormalities in the pathogenesis and progression of this disease. It has a very polymorphous morphology. A diverse range of cytogenetic alterations has been reported to date, the most frequent being trisomy 2 and trisomy 20. Thirty-five HB specimens from 31 patients (22 purely epithelial, 4 purely mesenchymal, 9 mixed) were examined by comparative genomic hybridization (CGH), a technique that enables us to screen the entire tumor genome for genetic losses and gains. Our aims were as follows: (1) to characterize chromosome abnormalities that appear in this tumor and (2) to identify possible differences between different histologic subtypes of HB. We found significant gains of genetic material, with very little difference in the number and type of alterations between the different histologic components of HB. The most frequent alterations were gains of Xp (15 cases, 43%) and Xq (21 cases, 60%). This finding was also confirmed by fluorescent in situ hybridization performed on nuclei extracted from 6 specimens. Other common alterations were 1p-, 2q+, 2q-, 4q-, and 4q+. We found no difference between different histologic subtypes, a finding that may be in agreement with the hypothesis of a common clonal origin for the different components. An hitherto-unreported high frequency of X chromosome gains may support the assumption that X-linked genes are involved in the development of this neoplasm.

Analysis of insulin-like growth factors and insulin-like growth factor I receptor expression in renal cell carcinoma.

The expression of insulin-like growth factors I (IGF-I) and II (IGF-II) and insulin-like growth factor-I receptor (IGF-IR) was studied in 137 clear cell, 23 chromophobe, and 20 papillary renal cell carcinomas (RCCs) using a tissue microarray technique. IGF-I immunoreactivity was detected in 110 (82.1%) of 134 clear cell, 8 (36%) of 22 chromophobe, and 3 (15%) of 20 papillary RCCs (P < .001). IGF-IR immunoreactivity was detected in 39 (29.5%) of 132 clear cell, 9 (41%) of 22 chromophobe, and 19 (95%) of 20 papillary RCCs (P < .001). In contrast, all tumors lacked IGF-II expression. Expression of IGF-I and IGF-IR was not related to tumor stage, grade, or prognosis. The IGF system is expressed differentially among different tumor types. The expression of IGF-I together with its receptor, IGF-IR, provides evidence for the existence of an autocrine-paracrine loop of tumor cell stimulation in RCC and makes this type of cancer a candidate for therapeutic strategies aimed to interfere with the IGF pathway.

Prognostic value of keratin subtyping in transitional cell carcinoma of the upper urinary tract.

To investigate the prognostic value of keratin subtyping in invasive transitional cell carcinomas (TCCs), we performed a systematic study applying 15 different monoclonal keratin antibodies on 53 upper urinary tract TCCs using a tissue microarray technique. Immunoreactivity was correlated with pT stages and tumour grades using the Fisher's exact test. Impact on disease-free survival was analysed using the Kaplan-Meier method and compared by the log-rank test. Immunoreactivity for keratins 5/6, 6, 7, 8, 13, 14, 17, 18, 19, 20, low molecular weight (LMW) keratins (8, 18) and high molecular weight (HMW) keratins (1, 5, 10, 14) was detected in varying quantities. Regarding semi-quantitative assessment, a prognostic impact was found for keratins 5/6, 7, 8, 13, 17, 20 and HMW keratins, with reduced expression or loss of immunoreactivity being significantly associated with disease progression. With respect to analysis of staining patterns, the retention of a basally accentuated labelling for keratin 5/6 and HMW keratin as well as a superficially accentuated labelling for keratin 20 was significantly associated with a favourable outcome. In conclusion, this investigation is the first to demonstrate a possible prognostic value for keratin subtyping in invasive (upper urinary tract) TCCs with respect to metastasis-free survival. Further studies, however, are needed to substantiate our results.

Biological significance of p27 and Skp2 expression in renal cell carcinoma. A systematic analysis of primary and metastatic tumour tissues using a tissue microarray technique.

p27 (p27/kip1) is involved in cell-cycle control, and loss of p27 expression may result in tumour development and/or progression. Association with Skp2 targets p27 for degradation. Using a tissue microarray technique, 171 primary renal cell carcinomas (RCCs) and 58 RCC metastases were immunostained for p27 and Skp2. p27 Immunoreactivity was noted in 83 of 129 (64%) clear cell, 6 of 22 (27%) chromophobe and 15 of 20 (75%) papillary tumours as well as 44 of 58 (76%) metastases. In clear cell cancers, high p27 expression (> or =50% of tumour cells) decreased with rising tumour stage (50% pT1/pT2 versus 20% pT3; P<0.001) and grade (44% G1/G2 versus 21% G3/G4; P=0.008). None of 22 chromophobe cancers showed high expression in contrast to 46 of 129 (36%) clear cell tumours (P<0.001). Skp2 expression was noted in 8 of 129 (6%) clear cell cancers and 11 of 55 (20%) metastases (P=0.008). Immunoreactivity increased with rising tumour stage (1% pT1/pT2 versus 11% pT3; P=0.03) and grade (1% G1/G2 versus 15% G3/G4; P=0.004) and was associated with sarcomatoid morphology (P<0.001). In multivariate analysis, patients with low p27 expression and Skp2 immunoreactivity in clear cell cancers had a less favourable outcome. In conclusion, p27 and Skp2 proved to be additional biomarkers in renal cancer pathology with both prognostic and diagnostic impact.

Keratin immunohistochemistry in renal cell carcinoma subtypes and renal oncocytomas: a systematic analysis of 233 tumors.

Keratin immunohistochemistry represents a widely applied differential diagnostic tool in surgical pathology. To investigate the value of keratin subtyping for the diagnosis among histological subtypes of renal cell carcinoma and oncocytomas, we performed a detailed immunohistochemical study, applying 22 different monoclonal keratin antibodies on a large series of 233 renal tumors [125 conventional, 22 chromophobe, and 20 papillary (12 type-1, 8 type-2 tumors) cancers and 66 oncocytomas] using a tissue microarray technique. Immunoreactivity for keratin 7, 8, 18, and 19 was present in all tumor entities, albeit in varying quantities. With antibodies directed against keratins 8 and 18, oncocytomas showed a distinct perinuclear and punctate dot-like pattern, which was not observed in renal cancer specimens. The only tumors showing immunoreactivity for keratin 20 were two type-2 papillary cancers. All other monospecific keratin antibodies yielded consistently negative results. Overall, in contrast to some recent publications, keratin subtyping generally appeared to be of additional value only for the differentiation of renal epithelial tumors. Hence, with respect to differential diagnostic value, Hale's colloidal iron stain and vimentin immunostaining are still the most useful tools in renal tumor pathology.

Antioxidant treatment of therapy-resistant idiopathic membranous nephropathy with probucol: a pilot study.

BACKGROUND: Proteinuria in Heymann's nephritis, an experimental rat model disease corresponding to membranous nephropathy, has been shown to be due to lipid peroxidation. Since the pathophysiology might be similar to idiopathic membranous nephropathy in humans, we performed a prospective multicenter trial to investigate the efficacy of the lipid peroxidation scavenger, probucol. METHODS: Fifteen patients with biopsy-proven idiopathic membranous nephropathy resistant to conventional immunosuppressive therapy (n = 7) and/or ACEI treatment (n = 12) were recruited. Probucol (1 g/d orally) was administered for three months, followed by a washout period of four weeks, whereon lovastatin (10-20 mg/d orally) was administered for additional three months. RESULTS: A significant reduction in proteinuria was seen during the probucol treatment (median (range): 6.4 (3.8-9.1) g/d vs. 4.7 (1.3-16) g/d; P < 0.05), with partial remission achieved in four patients. Three of these patients had previously been resistant to immunosuppressive therapy. Median protein excretion increased to pretreatment values during the washout period (6.2 (1.9-15) g/d; P < 0.05) and was not significantly different after the intake of lovastatin (4.9 (1.8-19) g/d; P = NS). None of the patients achieved partial remission during lovastatin therapy (P < 0.05 vs. probucol). CONCLUSION: The present study led us to conclude that proteinuria can be reduced by probucol in some patients with idiopathic membranous nephropathy. A randomized multicenter study to further elucidate the influence of lipid peroxidation scavengers on membranous nephropathy is warranted.

Classification of sudden infant death (SID) cases in a multidisciplinary setting. Ten years experience in Styria (Austria).

OBJECTIVE: Sudden infant death syndrome (SIDS) remains a challenge for health professionals despite decreasing rates in recent years. The figures for different areas and time periods are hardly comparable, because of differences in postmortem investigations and classification criteria. In 1992, the European Society for the Study and Prevention of Infant Deaths (ESPID) proposed a classification for any sudden and unexpected death in infancy. This proposal has been used in our study since 1993 to better classify sudden infant death (SID) cases. METHOD: 56 consecutive SID cases observed between 1993 and 2002 in Styria, the south-eastern province of Austria, were analysed by a multidisciplinary team of health professionals. The study group consisted of pediatricians, forensic pathologists, pathologists, psychologists, nurses, members of the parents' association and health authorities. SID cases were analysed with regard to potential risk factors during pregnancy and early life, the circumstances of death (death scene) and post-mortem findings. From the latter, every SID was classified as either 1) classic SIDS, 2) borderline SIDS, 3) non-autopsied SID or 4) explained death. RESULTS: Of the 56 SID cases, 22 were assigned to category 1, 19 to category 2, four to category 3, and in 11 cases death could be explained by major post-mortem findings. For 17/22 cases in category 1 and 11/19 cases in category 2, the death scene investigation showed the typical risk profile of manner of bedding and/or environmental conditions. In three cases, child abuse or infanticide was considered possible but could not be proven despite careful autopsy. In recent years, SIDS incidence in Styria has decreased to approximately 0.18/1,000 live-born infants, and the few deaths still occurring mainly present with the typical risk profile. CONCLUSION: An extensive analysis of SID events is a prerequisite for reliable and comparable SIDS statistics. Our data show that in several SID cases careful post-mortem examinations led to an explanation of death. In other cases, minor alterations may have contributed to the lethal event. These findings should therefore be considered in the classification of SIDs. The ESPID classification of 1992 appears to be very useful for this purpose and its use may therefore be recommended.