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Aim of study Incidence rates of melanoma, generated by cancer registries (CRs), are susceptible to reporting inconsistencies due to increasing decentralisation of diagnosis. We therefore independently assessed the burden of melanoma in Austria. Methods We collected histopathological reports on melanoma of all patients diagnosed in Austria in 2011. Demographic and clinical characteristics, histopathological tumour stages were assessed. Their regional distributions and incidence rates were analysed and compared with data of national and international CRs. Results A total of 5246 patients were diagnosed with 1951 in-situ and 3295 invasive melanomas in Austria in 2011 (population 8.4 million). Age, sex and anatomic distribution corresponded to findings in other European countries, however, the incidence of 25/100,000 (world age-standardised rate) for invasive melanomas was two-fold higher than published by the Austrian CR (12/100,000). Varying frequencies in diagnosing thin melanomas (≤1 mm; n = 4415) accounted exclusively for significant regional disparities, while advanced tumours (>1 mm; n = 761) were evenly distributed. Western Austria showed the highest rates (36/100,000). Patients from eastern Austria whose melanomas were diagnosed in laboratories in western Austria (n = 76) showed significantly higher proportions of in-situ lesions (n = 43; 57%) compared to those whose tumours were diagnosed in eastern Austria (n = 4014; in-situ = 1369; 34%) (p Conclusions In Austria, the melanoma burden and its potential socio-economic implications are significantly underestimated. Similarities of incidences indicate this could affect other European countries with well-established CRs and compromise international comparability of data. Austrian regional disparities suggest overdiagnosis of thin melanomas due to the variability of pathologists' thresholds for the diagnosis of early stage tumours.

Summary Animal-type melanoma (ATM) represents a rare subtype within the wide spectrum of melanocytic tumors. Clinically, ATM lesions appear as sharply demarcated, brown, black and dark blue pigmented nodules, which show grey-white surface elements on dermatoscopy. The tumor is restricted to the dermis and arranged in irregular fascicles, which are composed of spindle-shaped and epithelioid melanocytes. Moderate tumor cell pleomorphism, mitoses and apoptotic cells all suggest a malignant process. Abundant, finely dispersed melanin pigment within tumor cells as well as numerous melanophages are strongly suggestive of ATM. Even though locoregional lymph node metastases are frequently found at diagnosis, the course of ATM is generally benign. Specific molecular changes may be detected in melanocytes from lesions and lymph nodes on fluorescence in situ hybridization (FISH). Such findings strongly indicate the malignant potential of ATM. The peculiar biology of ATM, as a moderately malignant tumor, is reflected in a new histopathological classification within the spectrum of dermal borderline melanocytic tumors (BMT).

BACKGROUND: Atypical teratoid/rhabdoid tumors are highly malignant embryonal central nervous system (CNS) tumors that were defined as an entity in 1996. As compared with other malignant CNS tumors, their biological behavior is particularly aggressive, but patients may benefit from an intensified treatment. Atypical teratoid/rhabdoid tumors display a complex histomorphology, which renders them prone to misdiagnosis. They occur predominantly in young children, with an estimated prevalence of 1% to 2% among all pediatric CNS tumors. However, population-based data on the incidence of these tumors are not yet available. METHODS: A nation-wide survey of malignant high-grade CNS tumors (World Health Organization grade III/IV), diagnosed in children (aged birth to 14 years) from 1996 to 2006 was conducted by the Austrian Brain Tumor Registry. A central histopathology review was performed including the assessment of SMARCB1 (INI1) protein status. RESULTS: A total of 311 newly diagnosed, malignant CNS tumors were included. Atypical teratoid/rhabdoid tumors constituted the sixth most common entity (6.1%), referring to an age-standardized incidence rate of 1.38 per 1,000,000 person-years in children. Peak incidence was found in the birth to 2 years age group, where they were as common as CNS primitive neuroectodermal tumors and medulloblastomas. A total of 47.4% of atypical teratoid/rhabdoid tumors were initially diagnosed, whereas 52.6% were retrospectively detected by the central review. The 5-year survival of atypical teratoid/rhabdoid tumor patients was 39.5%, with 66.7% in the correctly diagnosed group versus 15.0% in the not recognized group (P = .0469). CONCLUSIONS: Clinicians and pathologists should be aware of the high incidence of atypical teratoid/rhabdoid tumors in young children to optimize diagnostic and therapeutic management of patients with these tumors. Cancer 2010. © 2010 American Cancer Society.

Introduction Metabolic imaging using 18F-fluordeoxyglucose and a ring-positron emission tomography camera is an established method in the differential diagnosis of pancreatic masses. Ring-positron emission tomography cameras, however, are expensive and available in only few specialized centres. The aim of this study was to investigate how far 18F-fluordeoxyglucose scan with a conventional dual-head gamma-camera could differentiate between benign and malign pancreatic masses. Material and methods Forty-one patients (male/female: 25/16; mean age: 64.0 years; range: 41-86 years) with a pancreatic mass detected by ultrasound, computed tomography or MRI were included. In all patients 18F-fluordeoxyglucose scan was performed after overnight fasting and injection of 4 mCi 18F-fluordeoxyglucose using an ADAC Vertex MCD dual head gamma-camera (ADAC; Milpitas, California, USA), equipped with a 5/8-inch NaI-crystal. Images were acquired through a 180 degrees grade rotation in the three dimensional mode. The chosen matrix was 128 x 128 x 16, a Butterworthfilter (ADAC) was used and data were transferred into visible sinograms via Fourier-Rebinning. Coronar, sagittal and transversal slices of 3.9 mm thickness each were acquired. Focal tracer enhancement was suspicious for a malignoma and therefore regarded as positive, diffuse or no tracer uptake was suspicious for a benign process and was regarded as negative for cancer. DEFINITION OF GOLD STANDARDS: A diagnosis of cancer had to be confirmed histologically by specimens obtained by 18G-needle biopsy, surgical resection or at autopsy. A diagnosis of an inflammatory mass was considered proven, if no carcinoma could be found histologically in the surgically resected mass or at autopsy, or if there was no progression of the disease during a follow-up of at least 12 months. Results In 22 patients carcinoma was diagnosed (pancreatic cancer: n=17; endocrine tumour: n=3; carcinoma of the common bile duct: n=2). 18F-fluordeoxyglucose scan showed a focal tracer enhancement in 19 of these 22 patients (sensitivity: 86.4%). False negative results were acquired in two patients with cancer of the common bile duct and in one patient with poorly controlled insulin-dependent diabetes mellitus. In 19 patients the final diagnosis was an inflammatory pancreatic mass. 18F-fluordeoxyglucose scan showed a diffuse tracer enhancement in 15 of these 19 patients (specificity: 78.9%). False positive results were acquired in three patients whose blood tests showed signs of an acute episode of chronic pancreatitis. Positive and negative predictive values of 18F-fluordeoxyglucose scan were 82.6% and 83.3%, respectively. Conclusion 18F-fluordeoxyglucose scan with a conventional dual-head gamma-camera is a highly sensitive and specific method in the differential diagnosis of benign and malign pancreatic masses.

Most colorectal carcinomas develop from preformed adenomas, but only a minority of adenomas undergo malignant transformation. The clinical significance of polyps of size0.5 cm is controversial. The primary goal of this study was to assess the independent risk factors of adenoma and patient characteristics associated with advanced pathological features (APF; i.e. high-grade dysplasia or invasive carcinoma) in colorectal adenomas. A secondary goal was to assess the malignant potential of adenomas with a diameter of0.5 cm.Patients who underwent total colonoscopy at our Medical Department between 1978 and 1996 and had at least one colorectal adenoma were considered for this study. Patients with a history of colorectal cancer, prior polypectomy or colorectal surgery were excluded. A total of 7590 adenomas removed from 4216 patients were included in this analysis. Logistic regression analysis was used to study the impact of different adenoma and patient characteristics on the risk of APF.Size proved to be the most important risk factor for APF. The percentage of adenomas with APF was 3.4%, 13.5% and 38.5% for adenomas of diameter0.5 cm, 0.5-1 cm and1 cm, respectively. Villous or tubulovillous histology, left-sided location and ageor= 60 years were also associated with APF, whereas sex and number of adenomas had no significant impact. Logistic regression analysis revealed that the risk of an adenoma containing APF was best described by a model incorporating the factors size, location, age, and the age by histology interaction. In the class of adenomas with diameter0.5 cm, no invasive carcinoma was found, but 3.4% of adenomas had high-grade dysplasia.The risk of a colorectal adenoma containing APF can be estimated only by a complex model taking into account several adenoma and patient characteristics. Size, histological type, location and age are independent risk factors for APF in colorectal adenomas. As a considerable percentage of adenomas with diameter0.5 cm contain high-grade dysplasia, the clinical conclusion from our study is that all adenomas, including those with diameter0.5 cm, should be removed whenever possible.

BackgroundOvarian carcinoma spreads by implantation of tumor cells onto the peritoneal mesothelium. We established a 3-dimensional coculture model to simulate the interactions of ovarian carcinoma cell aggregates with human peritoneal mesothelial cells (HPMC).MethodsMulticellular tumor spheroids (MCTS) of the human ovarian cancer cell line SK-OV-3 were directly inoculated onto either confluent HPMC monolayers or their submesothelial matrix or were cocultured with mesothelium without direct cellular contact.Results and DiscussionsInoculation of MCTS onto submesothelial matrix resulted in rapid attachment (within 30 minutes) of the tumor cell aggregates followed by rapid dissemination (within 12 hours) and growth of tumor cells. Intact mesothelium increased the time required for MCTS attachment (up to 180 minutes) and led to almost complete inhibition of tumor cell dissemination and to 47% tumor growth suppression. Bromodeoxyuridine incorporation into tumor cell nuclei was almost completely abolished in cocultured MCTS. Growth also was inhibited in MCTS treated with supernatants of HPMC. Analysis of coculture supernatants revealed that HPMC-derived transforming growth factor β (TGF-β) was almost completely bound by MCTS. Addition of a function-blocking anti–TGF-β antibody (30 μg/mL) to the cocultures abrogated the growth inhibitory effect of the mesothelium by 50%.ConclusionsThe present model provides a dynamic system to study the complex interactions of ovarian carcinoma cells with HPMC over extended periods and suggests that the mesothelium constitutes a mechanical and partly TGF-β–mediated paracrine barrier to the progression of ovarian cancer.

Heat shock proteins (HSPs) have been shown to represent potential target molecules for T-cell-mediated allograft rejection in heart and kidney transplants. In the present study, we therefore investigated the expression of HSP subtypes 60, 72, and 73 in normal kidneys and qualitative and/or quantitative changes in rejected renal allografts. Six normal kidney tissue specimens, three biopsies from patients with minimal change nephritis, as well as 37 biopsies and eight transplant nephrectomy specimens of patients with renal allograft rejection were studied. Type and severity of rejection were assessed according to the Banff classification. Immunohistochemical demonstration of HSP expression was performed using specific monoclonal antibodies after wet autoclave antigen retrieval on sections from either Carnoy-fixed (biopsies) or formalin-fixed (transplant nephrectomies) and paraffin-embedded tissue. The expression was scored in a semiquantitative manner. All three subtypes were found to be constitutively expressed in normal kidney tissue and in noninflammatory minimal change nephritis, albeit with a characteristic compartmental and cellular distribution. Rejection resulted in a higher immunohistochemical scoring for all three HSP subtypes in compartments in which they were normally present; in addition, a de novo expression of HSP60 was found in the vascular compartment and, moreover, infiltrating mononuclear cells were strongly immunoreactive for HSP60 and HSP73. Only quantitative differences were observed for HSP72 immunoreactivity. These results indicate that rejection episodes are paralleled by an increased but differential expression of HSPs in the glomerular, tubular, and vascular compartments of the kidney. This enhancement as well as the de novo appearance of HSP60 on vascular endothelial cells might explain the presence of HSP-reactive T lymphocytes in rejected allografts.

Epstein-Barr virus (EBV)-associated smooth muscle tumors following solid organ transplantation are extremely rare, with only 12 cases reported in the literature thus far. The exact pathogenetic role of EBV infection in the oncogenesis of these soft tissue tumors in immunodeficient patients and the biologic behavior of such tumors is still unclear. We report a 26-year-old man in whom multiple smooth muscle tumors developed 36 to 51 months after heart transplantation. All tumors, two synchronous liver nodules, two subsequently occurring paravertebral tumors, and a single tumor in a vein at the left ankle were surgically resected. The tumor tissue was processed for routine histology and immunohistochemical (IHC) stains. Additionally, competitive polymerase-chain-reaction (PCR), reverse-transcriptase PCR (RT-PCR), as well as in situ hybridization (ISH) were used for EBV particle quantification and gene transcription analysis. The histologic features and immunohistochemical profiles were consistent with leiomyosarcoma in all tumor nodules. EBV infection was detected in >95% of tumor cell nuclei by EBER 1/2 ISH. Competitive PCR revealed 3105 EBV particles per milligram of tumor tissue. The EBV gene expression pattern analyzed by RT-PCR and IHC corresponded to the latency type III with specific expression of EBNA1, EBNA2, LMP1, and LMP2A genes. Under continuous antiviral therapy (famcyclovir) the patient currently shows no evidence of disease. Our data indicate that EBV infection plays a causal role in the development of smooth muscle tumors following organ transplantation. A latency type III, identical to EBV-associated posttransplant lymphoproliferative disorders, was identified and suggests a common pathogenetic mechanism in the development of these histogenetically distinct neoplasms. The fact that the patient currently shows no evidence of disease may be the result of the continuous administration of antiviral therapy because the soft tissue recurrences of the leiomyosarcoma occurred while the patient was not receiving antiviral prophylaxis.

Summary Thymic Hodgkin's disease (HD) shows some peculiar histological features different from nodal disease which are a result of the interaction with the specific thymic microenvironment. We describe the histological and immunohistochemical findings in three cases presenting as a primary thymic neoplasm both clinically and radiologically. Histological hallmarks were the prominent formation of epithelium-lined cysts, inflammatory changes, a marked proliferation of thymic epithelium in association with Hodgkin- and Reed-Sternberg (RS) cells and the occurrence of the nodular sclerosing subtype in all cases. The immunophenotype of the neoplastic cells was that of classical HD. They expressed CD30, CD15 and lacked CD45. In two cases CD20 expression was observed. All cases were negative for the latent membrane protein (LMP) of the Epstein-Barr virus (EBV). The accompanying inflammatory infiltrate was rich in mature T-cells, but also showed a significant number of B-cells with frequent formation of follicles and proliferation of follicular dendritic cells. Thymic HD develops in a microenvironment with features of thymic medulla as defined by the morphology and pattern of the proliferating epithelial cells and the mature immunophenotype of the admixed thymocytes. These findings, especially the CD20 positivity in Hodgkin and RS-cells, may point to the possible origin of thymic HD from medullary B-cells.

In a patient with mannose-binding lectin deficiency and metabolic myopathy with recurrent respiratory infections, left ventricular hypertrabeculation/noncompaction was diagnosed by echocardiography and confirmed at autopsy. In contrast with previously described cases, extensive endocardial calcifications were found, possibly as a result of recurrent endomyocarditis during the recurrent infections.

Objectives To report the echocardiographic and autopsy findings of left ventricular hypertrabeculation (LVHT), also known as noncompaction, in a patient with central and peripheral nervous system disease, who died shortly after diagnosing noncompaction. Case report In a 75 year old woman with cognitive decline, Parkinson syndrome, stroke-like-episodes, basal ganglia calcification, neuromuscular disorder, cataract, diabetes, anemia, arterial hypertension, recurrent heart failure, left anterior hemiblock, and right bundle branch block, acute heart failure developed during treatment of a suspected urosepsis. Transthoracic echocardiography revealed severely reduced fractional shortening, valvular vegetations, and LVHT. Endocarditis was suspected. She died shortly afterwards from renal failure and ventricular fibrillation. Endocarditis and LVHT were confirmed at autopsy. Conclusions This case shows that endocarditis may occur together with LVHT and central and peripheral nervous system disease indicative of a mitochondrial disorder. Whether LVHT predisposes for endocarditis remains speculative.

Grundlagen: In tierexperimentellen Studien wurde die mogliche Anwendbarkeit eines freien Transfers des M. latissimus dorsi (LDM) zur Harnblase untersucht. Wir entwickelten Techniken, um die Entleerung eines der Harnblase entsprechenden Reservoirs durch einen quergestreiften Muskel zu verbessern. Durch diese Untersuchungen sollten Grundlagen fur die funktionelle Verwendung des reinnervierten freien LDM-Lappens an der Blase geschaffen werden. Zusatzlich liegen erste klinische Erfahrungen bereits vor.

Left ventricular hypertrabeculation (LVHT) /non-compaction is frequently associated with neuromuscular disorders. Recently, LVHT has been detected in a 28-year patient with Duchenne muscular dystrophy. Here, the patho-anatomic findings of this patient are presented, which showed LVHT located within in the apex and the anterior and lateral wall, being the most demanded segments during systole. The septum and the left ventricular outflow tract were not involved. The patho-anatomic specimen also showed aberrant bands and false tendons, a frequent finding in hearts with LVHT. The patho-anatomic findings were in line with those of LVHT patients with or without neuromuscular disorders.

The histological workup of the myocardium of a patient with Duchenne muscular dystrophy and left ventricular hypertrabeculation/noncompaction (LVHT) revealed an extremely thin left ventricular wall and a noncompacted layer double in size compared to the compacted layer. Within the compacted layer islets of fibrous tissue predominated, surrounded by areas of myxoid appearance hardly producing collagen, and occasionally normal or dystrophic cardiomyocytes. The noncompacted layer consisted largely of intact cardiomyocytes rarely intermingled with collagen-producing, fibrous tissue. This variant appearance of the compacted and noncompacted layer was found in all areas of noncompaction. These histopathological findings suggest that LVHT represents a compensatory attempt to overcome the failing compacted but dystrophic myocardium.

To test a novel technique of processing prostate biopsy specimen by marking the peripheral end (PE) as a predictive tool for positive resection margin after radical prostatectomy (RP) or for locally advanced carcinoma of the prostate (PC). Prospective, multi-institutional study of a consecutive cohort of men who underwent prostate biopsy with marking the peripheral biopsy end and subsequent RP at the same institution. The study cohort comprised 445 men with a mean age of 63 years (40–77 years). Overall, PE-positive cores were found in 174 men (39.1 %) and R1 status was diagnosed in 132 men after RP (29.7 %). In the multivariate analysis, the presence of at least one PE-positive core was correlated with an increased risk of R1 status (OR 2.29, 95 % CI 1.31–4.00, p = 0.003) and was the strongest predictor followed by Gleason score, PSA and percentage of positive cores. Including all predictive parameters, a nomogram with a concordance index of 72.1 % was calculated. In the pT3/pT4 subgroup, PE positivity was the only predictive factor for R1 status (OR 3.03, 95 % CI 1.36–6.75, p = 0.006). In pT2 stage, no single factor was predictive for R1 status. PE-positive biopsies were not predictive for pT3/pT4 stages. PC at the peripheral end of prostate biopsy specimen predicts an increased risk of R1 status in subsequent RP. This simple and cheap technique may contribute to an increased accuracy of risk stratification for curative treatment for PC.

Ovarian cancer arises mostly from the ovarian surface epithelium. The aim of our study was to compare the effects of cytokines in ovarian surface epithelial (OSE) cells and in ovarian carcinoma cells. Proliferation and expression of surface antigens (CA-125 and classes I and II antigens of the major histocompatibility complex [MHC]) were measured in OSE cells obtained from 7 different patients and 7 ovarian carcinoma cell lines. Proliferation of OSE cells remained unaffected by interferon (IFN)-α or IFN-γ, whereas interleukin-I (IL-I) and tumor necrosis factor (TNF) increased cell growth. Proliferation of ovarian carcinoma cells was reduced by both types of IFN as well as TNF but was not affected by IL-I. Expression of the tumor marker CA-125 was increased by IFN-γ in ovarian carcinoma cells but not by any other treatment. None of the cytokines affected CA-125 surface expression in OSE cells. Expression of MHC-I was augmented in OSE and in carcinoma cells by both IFNs but not by the other cytokines. Both types of cell were negative for MHC-II, but IFN-γ induced its expression in both OSE and carcinoma cells. Significant concentrations of the cytokines evaluated here have been measured in blood and follicular fluid by several authors. The different actions of these cytokines in OSE and carcinoma cells could therefore be important in understanding the role of such molecules in the regulation of physiological and pathological processes in the ovary, such as ovulation or malignant proliferation. © 1996 Wiley-Liss, Inc.

We developed refinements in the technique of cystectomy and subsequent intestine to urethra anastomosis to improve postoperative results in women undergoing anterior exenteration and creation of an orthotopic neobladder to the urethra.Anatomical dissection and microdissection studies were performed on formalin-carbol fixed adult cadavers and correlated with previous anatomical and clinical findings. The resulting surgical variations were performed in 5 carefully selected women undergoing lower urinary tract reconstruction.Optimal postoperative results in regard to continence and voiding without compromising oncological outcome may be obtained by preserving the entire lateral vaginal walls, performing nerve sparing dissection of the bladder neck and proximal urethra, removing 1 cm. proximal urethra en bloc with the cystectomy specimen and using additional attachments of the anastomosed intestinal pouch to surrounding pelvic structures. Patients achieved day and night continence after 6 months, mean pouch volume was 580 cc (range 450 to 750) and residual volumes ranged from 0 to 150 cc. No tumor recurred after 6 to 17 months.Refinements in the technique of radical cystectomy and orthotopic neobladder to the urethra in women may improve continence and spontaneous voiding without compromising surgical oncological outcome, and they further justify orthotopic diversion in select women with bladder cancer.

Alpha-1-antitrypsin deficiency is a common autosomal recessive disorder associated with early development of emphysema, liver cirrhosis, and hepatocellular carcinoma. The aim of the present study was to define prognosis and life expectancy in patients with alpha 1-antitrypsin deficiency with and without chronic liver disease.After a follow-up of 15 years the estimated life table analysis of mortality of 160 patients with alpha 1-antitrypsin deficiency was retrospectively calculated. The survival time was estimated using the Kaplan-Meier survival curves and was compared with the life expectancy of the age- and sex-matched population of west Austria.Fifty-four patients with alpha 1-antitrypsin patients had evidence of chronic liver disease; of these, 78% showed positive viral markers. Of the 106 patients with alpha 1-antitrypsin deficiency without chronic liver disease none had evidence of additional viral infection. Life expectancy in patients with alpha-1 antitrypsin deficiency and chronic liver disease was significantly lower than in patients with alpha 1-antitrypsin deficiency without chronic liver disease (p = 0.001). No difference in life expectancy in alpha 1-antitrypsin deficiency without chronic liver disease was found in comparison with that of the normal population.We suggest that in alpha 1-antitrypsin deficiency-associated chronic liver disease it is the high coinfection rather than the inborn error of metabolism itself that is responsible for a deterioration of life expectancy or for the poor prognosis of the disease.

Testicular carcinoma in situ (CIS) is usually diagnosed histologically on surgical biopsies. The present study was performed to test an alternative approch—DNA flow cytometry (FCM) of testicular fine-needle aspirates (FNA)—for the detection of this lesion. FNAs from 18 cases of testicular germ cell tumors (TGCT) and tumor adjacent parenchyma were analysed by DNA FCM. DNA histograms of all cell nuclei and histograms representing selectively the hyperdiploid compatment were analysed. The presence and extention of CIS were determined by histology and immunohistochemistry. In 16 to 18 cases, CIS was histologically present, whereas aneuploid peaks were detected in only 11 cases in DNA histograms of all cell nuclei. In the analysis of the histograms of the hyperdiploid region, 4 additional cases of CIS could be identified increasing the sensitivity to 15/16 cases (93.8%). In all but one case, the DNA indices of CIS and invasive tumors were identical. The study demonstrates that DNA FCM of testicular FNAs using the described data acquisition and analysis could also be applicable for detection of CIS in a clinical situation. © 1994 Wiley-Liss, Inc.

Animal-type melanoma (ATM) represents a rare subtype within the wide spectrum of melanocytic tumors. Clinically, ATM lesions appear as sharply demarcated, brown, black and dark blue pigmented nodules, which show grey-white surface elements on dermatoscopy. The tumor is restricted to the dermis and arranged in irregular fascicles, which are composed of spindle-shaped and epithelioid melanocytes. Moderate tumor cell pleomorphism, mitoses and apoptotic cells all suggest a malignant process. Abundant, finely dispersed melanin pigment within tumor cells as well as numerous melanophages are strongly suggestive of ATM. Even though locoregional lymph node metastases are frequently found at diagnosis, the course of ATM is generally benign. Specific molecular changes may be detected in melanocytes from lesions and lymph nodes on fluorescence in situ hybridization (FISH). Such findings strongly indicate the malignant potential of ATM. The peculiar biology of ATM, as a moderately malignant tumor, is reflected in a new histopathological classification within the spectrum of dermal borderline melanocytic tumors (BMT).

Tumor-cell extravasation involves sequential adhesive interactions with vascular endothelium and the subendothelial basement membrane. We have established a 3-dimensional model in vitro to simulate these events and to elucidate targets of the anti-cell-adhesive synthetic peptide RGDS. Tumor spheroids of the melanoma cell line ST-ML-12 served as models of tumor-cell emboli and were transferred onto human umbilical vein endothelial cells. To imitate the vascular anatomy, the latter were grown on reconstituted basement membranes produced by dextran-stimulated bovine corneal endothelial cells. RGDS did not affect the homotypic aggregation of the tumor cells and only minimally inhibited the attachment of the spheroids to the reconstituted vessel. A short-term (20 min) inhibition of adhesion to denuded basement membranes was observed. The attachment was closely associated with damage to the endothelial cells by oxygen-derived free radicals. RGDS retarded endothelial injury for up to 3 hr. The most prominent effect was observed after penetration of the endothelium. RGDS suppressed the emigration of tumor cells from the attached tumor-cell cluster in a dose- and time-dependent fashion. After 12 hr, the inhibitory effect progressively declined. This was not due to loss of activity of the peptide, indicating a resistance mechanism in the melanoma cells. On purified components of the basement membrane, RGDS effectively inhibited the initial spheroid attachment to fibronectin and collagen IV but had no effect on attachment to laminin. By contrast, subsequent migration was significantly suppressed on all substrata. Our model permits the study of dynamic cell-cell and cell-extracellular-matrix interactions and indicates that RGDS might predominantly act on early tumor-cell locomotion after penetration of the endothelium.

Objective To compare deoxyribonucleic acid (DNA) flow cytometry with a semiquantitative histologic method for the assessment of spermatogenesis and to investigate the influence of various preparative techniques on the results of DNA measurements. Design Testicular tissue from 52 autopsies was examined for spermatogenesis by DNA flow cytometry and by conventional semiquantitative histology. Flow cytometry was performed on single nuclei suspensions from fine needle aspiration biopsies, resuspended imprints, as well as on specimens obtained by mechanical disaggregation of surgical biopsies of the same testis. Results In all cases, flow cytometry revealed a characteristic distribution pattern of haploid (n), diploid (2n), and tetraploid (4n) cells independent of the preparation technique used. The percentage of haploid cells of the testes showed statistically highly significant correlations (P = 0.0002) with the results of semiquantitative histology. Fine needle aspiration biopsy always contained more haploid cells compared with resuspended imprints and mechanically disaggregated samples. Conclusion Our results confirm the suitability of DNA flow cytometry as a fast and reliable quantitative method for the assessment of spermatogenesis and demonstrate its optimal feasibility in combination with fine needle aspiration biopsy.

High-grade malignant nonHodgkin's lymphomas--five lymphoblastic, three pleomorphic, and two immunoblastic--developed in 10/25 cynomolgus monkeys (Macaca fascicularis) followed for up to 746 d after infection with simian immunodeficiency virus, strain SIVsm. These lymphomas were shown to be associated with an Epstein-Barr (EB)-like cynomolgus B-lymphotropic herpesvirus (CBLV) by electron microscopy, by Southern blot hybridization with probes against human EBV, and by the expression of antigens corresponding to EBV-associated nuclear antigens (EBNAs) involved in human B cells transformation. Southern blot demonstration of immunoglobulin gene rearrangements and homogeneous EBV episomes indicated that all the lymphomas were CBLV-associated monoclonal B cell proliferations. Our findings suggest that these tumors correspond to the EBV-associated malignant lymphomas in acquired immunodeficiency syndrome with respect to clinical, morphological, phenotypic, and genotypic characteristics. The particular susceptibility of SIVsm immunodeficient cynomolgus monkeys for CBLV-associated lymphomagenesis appears therefore a useful model for EBV-associated lymphomas in humans.

A patient with painful erosions of the oral cavity and the labia minora developed multifocal blisters in inter-triginous areas. These blisters eroded and evolved into papillomatous erosive vegetations. Histopathology and immunopathological investigations confirmed the diagnosis of pemphigus vegetans, mediated by IgG autoantibodies. The circulating IgG1 and IgG4 autoantibodies were exclusively directed against desmoglein 3, as shown by ELISA and indirect immunofluorescence studies. These IgG1 and IgG4 isotypes were also in vivo bound, as demonstrated with immunoperoxidase staining of perilesional skin. Our clinical, biochemical and immunopathological observations confirm the hypothesis that pemphigus vegetans is a variant of pemphigus vulgaris.

In the present study methods are described for the analysis of the genomic structure of DNA isolated from tissues that have been stored up to several years as air-dried or stained bone marrow smears, bone marrow biopsies in "Histicon", chromosomal preparations in fixative or as formalin fixed tissues embedded in paraffin. By application of the new techniques clonal B- and T-cell disorders, Philadelphia chromosome translocations and ras oncogene mutations in pancreatic carcinomas could be detected. Thus, these DNA extraction procedures may open new avenues to pathological archives and enable the analysis of samples when fresh material is not available.

Somatic mutations in a subset of growth hormone (GH)-secreting pituitary tumors convert the gene for the alpha polypeptide chain (alpha s) of Gs into a putative oncogene, termed gsp. These mutations, which activate alpha s by inhibiting its guanosine triphosphatase (GTPase) activity, are found in codons for either of two amino acids, each of which is completely conserved in all known G protein alpha chains. The likelihood that similar mutations would activate other G proteins prompted a survey of human tumors for mutations that replace either of these two amino acids in other G protein alpha chain genes. The first gene so far tested, which encodes the alpha chain of Gi2, showed mutations that replaced arginine-179 with either cysteine or histidine in 3 of 11 tumors of the adrenal cortex and 3 of 10 endocrine tumors of the ovary. The mutant alpha i2 gene is a putative oncogene, referred to as gip2. In addition, gsp mutations were found in 18 of 42 GH-secreting pituitary tumors and in an autonomously functioning thyroid adenoma. These findings suggest that human tumors may harbor oncogenic mutations in various G protein alpha chain genes.

Objectives The aim of this study was to report the histological findings of a patient with left ventricular hypertrabeculation (LVHT, noncompaction), mannose-binding lectin (MBL) deficiency, and unclassified myopathy in whom also endocardial thickening and calcifications over the compacted and noncompacted layer were found. Case report In a 47-year-old man with left bundle-branch block, ventricular runs, and dilative cardiomyopathy with systolic dysfunction since childhood, LVHT was detected at 40 years of age. At the same time, intracardial calcifications were recognized on a thoracic computed tomographic scan. MBL deficiency was identified as the cause of recurrent respiratory infections since childhood at 45 years of age. Easy fatigability, myalgias, ptosis, and warming-up phenomenon were attributed to an unclassified myopathy at 44 years of age. After death from a sepsis with Staphylococcus aureus , autopsy confirmed LVHT and additionally revealed endocardial thickening, endocardial fibrosis, foci of calcifications within the endocardium, and accumulations of degenerated cardiomyocytes within the calcifications. Endocardial fibrosis and calcifications were located over the compacted as well as noncompacted segments. They were attributed to LVHT rather than the MBL deficiency-triggered infections or the preterminal sepsis. Conclusions LVHT may be associated with MBL deficiency, unclassified myopathy, and endocardial fibrosis with calcifications over the compacted and noncompacted layer. Endocardial fibrosis with prominent calcifications seems to be a rare manifestation of LVHT.

The purpose of this study was to identify melanoma patients with positive sentinel lymph nodes (SLNs) at increased risk for further metastases in this specific lymph node basin. A series of consecutive patients with primary malignant melanoma stage I and II were evaluated retrospectively. The results of SLN biopsy in 26 patients with positive SLNs were compared with those of complete regional lymph node dissection (RLND) using the recently published S-classification of SLNs. The results of S-classification of SLNs were correlated with the outcome of complete RLND. There was a significant correlation between the S stage of positive SLNs and the results of complete RLND (P=0.02). Only patients with SIII stage (n=4) SLNs were found to have further metastases in the residual lymph node basin. The present study indicates that patients with SI stage and SII stage SLNs rarely have further metastases in the specific lymph node basin.

Erdheim-Chester disease is a rare systemic non-Langerhans cell histiocytosis. We report the first case of surgical treatment of severe compression of renal parenchyma by retroperitoneal masses in a 61-year-old male patient with progressing renal failure. After 3 years of follow-up, we have concluded that the open surgical approach is an option in the management of renal complications in Erdheim-Chester disease.

Two cases of infantile liver cirrhosis of unknown origin occurred in a circumscribed rural area of Northern Germany. Both children had increased dietary copper exposure. The search for additional cases of what appeared to be idiopathic copper toxicosis (ICT) revealed a cluster of affected infants in this region, raising questions about the relative importance of genetic and environmental factors that are considered to be etiologic. We gathered clinical and pathologic data concerning the patients, analyzed the pedigrees of affected families, and searched for possible environmental factors contributing to the pathologic process. We encountered 8 cases of infantile liver cirrhosis in 5 families in Emsland, a circumscribed and predominantly rural area of Northern Germany; ICT was definitely proven in 2 cases. Clinical presentation and liver pathology in 6 additional cases were consistent with the diagnosis of ICT. Pedigrees of affected families revealed complex relationships with occasional consanguinity of parents, suggesting autosomal recessive inheritance. The households were served by private wells with water of low pH flowing through copper pipes, suggesting the possibility of increased alimentary copper exposure. These findings support earlier conclusions that ICT develops when an infant with a genetic predisposition is exposed to a copper-enriched diet.

Cancer registration statistics of economically advanced countries indicate that bladder carcinoma incidence ranks fourth in men and eighth in women, but a reliable tumor marker for predicting the disease course is still lacking. We designed an immunohistochemical study to comprehensively assess the trophoblastic hormone production profile of transitional cell carcinoma (TCC) of the bladder. Moreover, we correlated histological differentiation and tumor stages with marker expression and, finally, evaluated a potential tumor origin of hCGbeta core-fragment (hCGbetacf). To this end, formalin-fixed, paraffin-embedded tumor tissues from 104 patients with urothelial neoplasms of various histological grades (23 GI, 24 GII, and 38 GIII) and stage (19pTis, 21pTa, 29pT1, and 35pT2-T4) were analyzed by the immunoperoxidase technique using our own well-characterized monoclonal antibodies against the glycoprotein hormones human chorionic gonadotropin (hCG) and its derivatives hCGalpha, hCGbeta, hCGbetacf, luteinizing hormone (LH, LHbeta), follicle-stimulating hormone (FSH, FSHbeta), and the protein hormones placental lactogen (hPL) and growth hormone (hGH-V/N). Overall, trophoblastic hormone immunoreactivity was found in 36% of TCC. Detailed analysis showed 35% hCGbeta, 17% hCGbetacf, 9% hCGalpha, 4% hCG, and 2% hPL-positive cases. The tumors produced neither GH-N, placental GH-V, nor the pituitary gonadotropins FSH/FSHbeta and LH/LHbeta. Marker positivity significantly increased with high-grade lesions (26% GI- v 55% GIII-TCC) and advanced tumor stages (24% pTa v 63%or = pT2). Hormone immunoreactivity was frequently observed in highly proliferating areas. Our findings, together with recent structural and clinical studies, strongly suggest that these hormones, or derivates thereof, might act as local tumor growth factors. Normal urothelium, urothelial papillomas, and carcinoma in situ showed no positive reactions. All tumors producing hCG-derived molecules were negative for the concommitantly analyzed neuroendocrine markers chromogranin A, synaptophysin, and neuron-specific enolase (NSE). In summary, one third of TCC ectopically produce trophoblastic hormones, which is specifically correlated with stage and grade. Apart from hCGbeta (97% of the marker-positive cases), the intracellular occurrence of hCGbetacf, apparently the second most frequently produced marker, was surprising, and there was also a lesser degree free hCGalpha and intact holo-hormone expression. The placental protein hormones PL and GH-V are not appropriate tumor marker candidates. Finally, our histogenetic findings support a metaplastic origin of the hCG producing choriocarcinomatous phenotype of some TCC.

This study was designed to investigate the ability of the latissimus dorsi muscle in situ to evacuate a bladder reservoir and to study the functional anatomic, and histopathologic results of partial or subtotal bladder reconstruction with an innervated free latissimus dorsi muscle in mongrel dogs. In group I (four dogs), the latissimus dorsi muscle was dissected and tailored in situ. Then the so-formed pedicled latissimus dorsi muscle flap was wrapped around tissue expanders of varying sizes (volumes of 50, 100, and 150 cc, respectively) to form a bladder-like reservoir. Electromyography and intraluminal pressure measurements were done at the time of surgery and 6 months thereafter using a standard electromyograph and a Dantec urodynamic unit. In group II (four dogs), the dome of the bladder wall was removed, with up to 50 percent of the mucosal layer being left intact. The resulting muscular defect was repaired with a free innervated latissimus dorsi muscle flap. The transformed latissimus dorsi muscle was shaped and wrapped around the bladder in a spiral form, with particular attention to the resting tension. The thoracodorsal vessels were anastomosed to the pelvic branches of the hypogastric vessels, and the thoracodorsal nerve was coapted to a pelvic motor nerve that was selected by use of nerve stimulator. Cystography and urodynamic studies were performed after 3, 6, and 9 months. Electromyography was done after 9 months, before sacrifice of the animals, which was followed by regular histologic and electron microscopic examinations. Stimulation of the thoracodorsal nerve of the reconfigured latissimus dorsi muscle reservoirs in situ after 6 months yielded average intraluminal pressures of 190 cmH 2 O at maximum capacity and 35 cmH 2 O at a minimum capacity of 10 to 15 cc. Stimulation of the latissimus dorsi muslce transferred to the bladder resulted in a visible and measurable contraction of the transplanted muscle after 9 months. Urodynamic values preoperatively and postoperatively were basically unchanged. During cystography, the bladder outline was smooth during both filling and voiding. Light and electron microscopic examinations confirmed viable, reinnervated muscle. The reconfigured pedicled latissimus dorsi muscle has the ability to evacuate a bladder-like reservoir after nerve stimulation. A detrusor function of the bladder can be induced through the contractility of a reinnervated free latissimus dorsi muscle that was wrapped around the bladder. An innervated free latissimus dorsi muscle flap does not undergo severe muscle fibrosis, contracture, and atrophy such as occur after transfer of completely or partially denervated, pedicled muscle. This means that a functional bladder reconstruction/augmentation can be achieved by microneurovascular transfer of a latissimus dorsi muscle flap.

Experimental studies were undertaken to investigate the practicability of a microneurovascular transfer of latissimus dorsi muscle to the bladder, and to look for possible techniques enhancing evacuation of a reservoir such as the bladder by striated muscle.Twelve dogs were used for the studies. They were divided into 3 groups. Group I: Evacuation proficiency of a re-configured latissimus dorsi under tension was hydrodynamically tested after 6 months. Group II: Microneurovascular latissimus dorsi transposition anastomosing thoracodorsal vessels and nerve to circumflexa ilium profunda vessels and a lumbar plexus motor nerve, respectively, was performed to cover the bladder devoid of up to 50% of the detrusor muscle. Group III: Microneurovascular latissimus dorsi transposition was used to reconstruct the bladder after supratrigonal cystectomy. Urodynamic and radiographic in vivo studies were done after 6 and 9 months.Stimulation of the thoracodorsal nerve of geometrically reconfigurated non-transposed latissimus dorsi reservoirs after 6 months yielded average intraluminar pressures of 190 cm. H2O at maximum capacity, and 35 cm. H2O at a minimum capacity of 10 to 15 cc. Stimulation of latissimus dorsi transposed to the bladder resulted in a visible and measurable contraction of the transplanted muscle after 9 months. Mean bladder volumes in group II animals pre- and postoperatively were 267.5 and 270 cc, respectively. During cystography the bladder outline was smooth both during filling and voiding. Light and electron microscopic examination confirmed viable, re-innervated muscle.The "tension-torsion" reconfiguration produced intraluminal pressures which should enable stimulated striated muscle to evacuate bladder-like reservoirs successfully. Microneurovascular free transfer of latissimus dorsi muscle resulted in reinnervated, functional muscle in the pelvis. Augmentation cystoplasty using the latissimus dorsi in conjunction with a free omental flap for substitution of an accompanying mucosal defect was unsuccessful. The concept of microneurovascular transfer of latissimus dorsi muscle to the pelvis may be used for complicated fistula of the lower urinary tract, and may be a possible solution for the therapy resistent acontractile bladder.

A 6-year-old girl with acquired immunodeficiency syndrome (AIDS) had extensive alveolar echinococcosis. Diagnosis was proved by needle biopsy of a specimen from affected liver tissue. The case was characterized by the unusually young age of the patient and more specifically by the absence of any detectable parasite-specific humoral and cellular immune response at diagnosis or later. Thus the present case indicates that a marked immunodeficiency caused by AIDS may substantially contribute to the rapid proliferation and early manifestation of the disease. In patients with pediatric AIDS and living in areas endemic for Echinococcus multilocularis, alveolar echinococcosis should be considered in intrahepatic tumor-like lesions even if the result of immunodiagnostic testing is negative.

In testicular germ cell tumors the CD30 antigen has been shown to be regularly expressed in embryonal carcinoma and was thus suggested as a marker for this particular neoplasm. Very recently, it has been proven that the monoclonal antibody Ber-H2 is suitable for the detection of this membrane antigen in paraffin sections. We conducted an immunohistochemical study to investigate the CD30 expression in a large series of different presentations of seminoma (ie, pure, mixed, and spermatocytic) because there is evidence from several sources that embryonal carcinoma is histogenetically closely related to, and probably derives from, seminoma. Sections from formalin-fixed, paraffin-embedded tissue from 38 cases of testicular seminomas were immunostained for the demonstration of the CD30 antigen using the monoclonal antibody Ber-H2, cytokeratins, and placental alkaline phosphatase following an indirect streptavidin-peroxidase regimen. In selected cases, immunostainings were performed on consecutive sections to investigate a possible colocalization of CD30 and cytokeratins in seminoma. Specific immunostaining for CD30 in seminoma cells could be detected in single minute foci in 4 of 21 cases of pure classic seminoma. Seminomatous components of mixed tumors showed CD30 positivity in single, but also multiple, foci in 7 of 14 cases. CD30 immunoreactivity in seminoma cells occurred with and without colocalized expression of cytokeratin. Spermatocytic seminoma (n = 3) as well as intratubular germ cell neoplasia in tumor adjacent parenchyma (n = 36) were negative in all cases investigated. We conclude that in testicular germ cell tumors, the expression of CD30 is not restricted to embryonal carcinoma but can also be found focally in seminoma, adding further evidence for a close relationship between these two tumors. The prevalence of CD30 expression in seminomatous components of mixed tumors, as well as the coexpression with cytokeratins, suggest that CD30 expression in seminomas might indicate their upcoming transformation to embryonal carcinoma. This conclusion coincides with a model featuring seminoma in a central role of germ cell tumor development.

Northern analysis of human multiple tissue blots containing poly A+ RNA from spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes revealed that a prostate specific transcript hybridizes to a tear lipocalin/von Ebner's gland protein (TL/VEGP) gene probe. To characterize this transcript, the corresponding cDNA was amplified by reverse transcription (RT)-PCR. Cloning and sequence analysis showed that it was identical to the tear lipocalin cDNA isolated from human lachrymal glands. Immunohistochemical analysis on thin layer sections of human prostate using a tear lipocalin specific antiserum confirmed the expression of this cDNA in prostate. Thus, our results clearly argue against a unique function of TL/VEGP in human tear fluid or saliva. The human cDNA was expressed in E. coli using the pQE system yielding a recombinant protein which shows biochemical properties identical to the native TL/VEGP.

The aim of the present study was to investigate the extent to which human peritoneal mesothelial cells (HPMCs) are able to participate in the release of tumor marker CA-125 in ovarian cancer and other conditions associated with an involvement of the peritoneum. For this purpose CA-125 shedding was measured in the supernatant culture medium of HPMCs obtained from various donors and seven well-established ovarian cancer cell lines (OVCAR-3, 2780, 2774, SKOV-6, SKOV-8, HOC-7, HTB-77). Furthermore, the influence of inflammatory cytokines [interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma)] on CA-125 release in normal and malignant cells was also studied. Constitutive CA-125 shedding was found to be about five times higher in HPMCs as compared with the investigated ovarian cancer cell lines. IL-1 beta and TNF-alpha treatment of HPMCs resulted in a significant reduction in CA-125 release; however, no consistent pattern in CA-125 secretion was found during incubation with either IL-1 beta or TNF-alpha in the various malignant cell lines. IFN-gamma, on the other hand, induced a highly significant increase in CA-125 secretion in ovarian cancer cells, but did not influence the shedding of CA-125 in HPMCs.