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Primary glandular bladder tumours (bladder adenocarcinoma [BAC], urachal adenocarcinoma [UAC], urothelial carcinoma with glandular differentiation [UCg]) are rare malignancies with histological resemblance to colorectal adenocarcinoma (CORAD) in the majority of this subgroup. Definite case numbers are very low, molecular data are limited and the pathogenesis remains poorly understood. Therefore, this study was designed to complement current knowledge by in depth analysis of BAC (n = 12), UAC (n = 13), UCg (n = 11) and non-invasive glandular lesions (n = 19). In BAC, in addition to known alterations in TP53, Wnt, MAP kinase and MTOR pathway, mutations in SMAD4, ARID1A and BRAF were identified. Compared to published data on muscle invasive bladder cancer (BLCA) and CORAD, UCg exhibited frequent “urothelial” like alterations while BAC and UAC were characterised by a more “colorectal” like mutational pattern. Immunohistochemically, there was no evidence of DNA mismatch repair deficiency or PD-L1 tumour cell positivity in any sample. Depending on the used antibody 0–45% of BAC, 0–30% of UCg and 0% UAC cases exhibited PD-L1 expressing tumour associated immune cells. A single BAC (9%, 1/11) showed evidence of ARID1A protein loss, and two cases of UCg (20%, 2/10) showed loss of SMARCA1 and PBRM1, respectively. Taken together, our data suggest at least in part involvement of similar pathways driving tumourigenesis of adenocarcinomas like BAC, UAC and CORAD independent of their tissue origin. Alterations of TERT and FBXW7 in single cases of intestinal metaplasia further point towards a possible precancerous character in line with previous reports. more...

ZusammenfassungDie Sensitivität der konfokalen Mikroskopie liegt zwischen 80 und 90% und damit über der Sensitivität der Erregeridentifizierung mittels Kultur. Typischerweise kann mittels in vivo konfokaler Mikroskopie bereits am Tag der Aufnahme eine mykotische Keratitis nicht invasiv und atraumatisch diagnostiziert werden. Wir stellen eine Patientin vor mit einem Hornhautulkus im Bereich des Transplantats, ausgeprägter Hornhaut-Endothel-Epithel-Dekompensation (HEED) und retrokornealen Pilzzapfen bei Zustand nach Re-Keratoplastik vor 5 Jahren bei chronischer Transplantatabstoßungsreaktion wegen HEED bei Fuchsʼscher Endotheldystrophie. Klinisch bestand der Verdacht auf eine mykotische Keratitis. Die konventionelle en face konfokale Mikroskopie zeigte initial keine Pilzhyphen. Aufgrund des ausgeprägten Hornhautödems konnten wir erst nach einer Re-Re-Keratoplastik mittels der invertierten in vitro konfokalen Mikroskopie die Pilzhyphen im hinteren Hornhautstroma am Operationstag nachweisen. Die Histologie bestätigte die Diagnose der Keratomykose. more...

Anamnese und klinischer Befund Ein 67-jahriger Patient entwickelte akute Kopfschmerzen, nach 2 Tagen zusatzlich Schuttelfrost und Fieber. Ein Infektfokus konnte nicht gefunden werden, periphere Lymphknoten waren nicht palpabel. Untersuchungen und Diagnose Nach 2 Wochen wurden in einer 18F-FDG-PET-Computertomografie multiple mediastinale, supraklavikulare und axillare Lymphknotenschwellungen gesehen. Histologisch zeigten sich epitheloidzellige Granulome mit zentraler Nekrose. Tuberkulose wurde immunologisch und mikrobiologisch ausgeschlossen. Serologisch wurde eine akute Tularamie diagnostiziert. Therapie und Verlauf Unter der Therapie mit Ciprofloxacin fur 20 Tage kam es zum Abklingen der Kopfschmerzen und Normalisierung der Entzundungsparameter. Folgerung Infektionsquelle war das Einatmen erregerhaltigen Staubs beim Herausreisen einer Efeuhecke 2 Tage vor Symptombeginn. Die Tularamie (Hasenpest) ist eine Zoonose, die direkt von infizierten Tieren oder indirekt uber Zecken und Mucken, inhalativ durch Einatmen von kontaminiertem Staub oder durch Ingestion von kontaminiertem Wasser ubertragen werden kann. Beim histologischen Nachweis epitheloidzelliger Granulome mit Nekrosen ist die Tularamie eine seltene Differenzialdiagnose. History A 67 years old man developed splitting headaches accompanied by chills and fever. No infectious focus was detected, no peripheral lymphadenopathy was found. Findings and diagnosis After 2 weeks, 18F-FDG-PET-computed tomography showed mediastinal, supraclavicular and axillary lymphadenopathy. Histology revealed epithelioid granuloma with central necrosis without evidence of acid-fast bacilli. Serology was positive for tularemia. Therapy and course During antibiotic treatment with ciprofloxacin for 20 days, headache disappeared, and inflammatory parameters normalized. Conclusions The way of infection was the inhalation of dust while tearing out an ivy hedge 2 days before onset of symptoms. Tularemia is a zoonosis transmitted either directly from infected animals or indirectly via tick or mosquito bites, inhalation of contaminated dust or ingestion of contaminated water. Tularemia is a rare cause of epithelioid granuloma with necrosis. more...

Die histopathologische Diagnose des Nierenzellkarzinoms (NZK) ist fur die klinische Vorgehensweise wichtig, aber wenig ist daruber bekannt, welche Bedeutung die WHO-Klassifikation des NZK von 2016 fur die tagliche histopathologische Routinediagnostik hat. Das Ziel der Arbeit ist die retrospektive Aufarbeitung der histopathologischen Diagnosen der NZK der Jahre 1998 bis 2017 im Kontext der WHO-Klassifikation 2016 und Uberlebensanalysen. Es wurde eine retrospektive registerbasierte Analyse des Rostocker Nierentumorkollektivs durchgefuhrt. Uberlebensanalysen wurden angeschlossen. Es waren insgesamt 1440 NZK registriert worden, davon 77,7 % klarzellige NZK und 22,3 % nichtklarzellige NZK. Es fanden sich 2,6 % seltene NZK im Kollektiv. Diese teilten sich weiter auf in 1 % translokationsassoziierte NZK der MiT-Familie (MiT-tNZK), 0,35 % NZK-assoziiert mit erworbener Zystennierenerkrankung, 0,35 % multilokular-zystische Nierenneoplasien mit niedrig malignem Potential, 0,35 % Sammelrohrkarzinome, 0,3 % muzinos tubular spindelzellige NZK, 0,1 % klarzellig papillare NZK und 0,1 % NZK mit (angio)leiomyomatosem Stroma. Cox-Regressionsanalysen zeigten signifikant unterschiedliches Gesamt- und progressionsfreies Uberleben der Subtypen. Die Aufsplittung des NZK in mehrere Entitaten stellt erhohte Anforderungen an die histopathologische Diagnostik. An der Universitatsmedizin Rostock wurden morphologisch distinkte seltene NZK-Entitaten uberwiegend konventionell diagnostiziert; fur molekular definierte Entitaten wie das MiT-tNZK musste die molekulare Diagnostik etabliert werden. Der histologische Subtyp des NZK nach der WHO-Klassifikation 2016 ist prognostisch bedeutsam und kann Basis einer pradiktiven Pathologie sein. more...

Aim: We aimed to explore ceruloplasmin (CP) expression in clear cell renal cell carcinoma (ccRCC). Materials & methods: CP was analyzed in biofluid samples of 63 ccRCC patients, divided into three grading groups, and immunohistochemically, in 308 ccRCC. Results: Significant differences of mean plasma and urine CP levels in different grading groups were found. CP immunoreactivity was significantly linked to high-grade disease. Log rank tests showed a significant shorter overall survival rate in CP-positive cases (all p more...

Papillary fibroelastomas (PFE) are benign neoplasms, mostly located on valvular surfaces with high embolic potential. This study presents a 27-year single institutional experience on surgical treatment of PFE in an adult patient- cohort with long-term follow-up. This study was approved by the institutional review board. Date and number of IRB approval: 11/23/2017, Institutional Review Board approval number A2014-0149. The need for individual patient consent was waived. We retrospectively evaluated all patients who underwent cardiac surgery for suspected space-occupying lesions in the observation period between June 1991 and June 2018 at our hospital. Clinicopathological features, imaging characteristics, surgical procedures and disease outcome were analyzed. 120 patients were diagnosed with various primary/secondary cardiac tumors and histology confirmed 21 PFEs were found in 16 patients. There was no significant age difference between patients with valvular vs nonvalvular PFEs (P = 0.26). Valvular lesions were found in aortic valve (n = 6), mitral valve (n = 2) and tricuspid valve (n = 1). Nonvalvular PFEs were found in right atrium (n = 2), left ventricle (n = 2), left atrial appendage (n = 2) and aortic wall (n = 1). Valvular lesions were significantly smaller in size compared to non-valvular lesions (P = 0.0013). Left-side PFEs were associated with a high embolization episodes (10/13 patients, 77%) not related to the size. One patient died in-hospital. All other patients were discharged out of the hospital postoperative. Follow-up was performed regularly for a median of 2.8 years (range 0.1–11 years) postoperative. Nonvalvular PFE tended to be larger in size and at least when located on the left sided heart had equally high propensity to embolize compared to valvular PFE. We strongly advocate surgical excision in all left-sided PFE. more...

Ureteric stents have become an indispensable tool in the armamentarium of every urologist. However, they carry their own morbidity resulting mostly from infectious or abacterial fouling and biofilm formation, and/or urothelial hyperplastic reaction. All of these may interact and lead to clinical complications. Many different stent designs and coatings have been proposed. In this study, we focused on the effect of paclitaxel-coated stents on hyperplastic proliferation of ureteral tissue, using as example anastomotic strictures after ureteroureterostomy in a rat model. Human urothelial cells (SV-HUC-1) were used to determine paclitaxel dosages in vitro. Polyurethane stents were coated with a paclitaxel containing biodegradable polymer and studied in a ureteroureterostomy rat model. 48 male 9-week-old Sprague–Dawley rats underwent either sham surgery (n = 16) or ureteroureterostomy with sutured anastomosis, and consecutive stenting with either a paclitaxel-coated or an uncoated stent (16 per group), respectively. The animals received daily intraperitoneal injections of 5-bromo-2-deoxyuridine (20 mg/ml, 100 mg/kg body weight) during the first eight postoperative days, and were sacrificed on day 28. Healing of the ureteral anastomosis and proliferation of urothelial cells was examined histologically and immunohistochemically. In vitro, a concentration of 10 ng/mm2 paclitaxel can be considered as non-toxic, while still exerting an anti-proliferative effect on urothelial cells. Histologically, typical wound healing processes were seen at the site of the ureteral anastomosis in vivo. Proliferation of urothelial cells was significantly lower in animals with paclitaxel-coated stents compared to those with uncoated stents (LI 41.27 vs. 51.58, p more...

To evaluate uveal melanoma cell activity and pathologic features after stereotactic CyberKnife radiosurgery in specimens from five patients. Specimens from five patients treated by CyberKnife radiosurgery in three fractions were included in this study. Because of persistent retinal detachment in 3 patients, tumour endoresection was performed at four, seven and ten month after CyberKnife radiosurgery. At nine and twelve months after treatment, enucleation of the eye globe was performed in 2 patients because of secondary tumour bleeding and missing regression. After histomorphological analysis and determination of Ki67-proliferation index, DNA cytophotometry, fluorescence in-situ hybridization evaluation for chromosome 3 loss, GNA11and GNAQ mutation analysis were performed. Four of the five tumours included in this study showed variable radiation-induced morphologic changes in the form of enlargement of cells and nuclei, cytoplasmic vacuolisation and nuclear fragmentation. The DNA content of a large fraction of tumour cells was hypoploid. On the other hand, single strikingly hyperchromatic melanoma cells showed marked aneuploidy. The proliferation fraction in the three endoresected tumours was very low ( more...

Aim: To evaluate the expression and prognostic value of RARRES1 at protein level in renal cell carcinoma (RCC). Materials & methods: Expression profile of RARRES1 was analyzed in 903 documented RCC followed by clinicopathological correlations and survival analysis. Results: RARRES1 expression was seen in 72.5% of RCC. A stronger RARRES1 expression was seen in high grade compared with low grade RCC (p < 0.001). Logrank tests revealed shorter overall survival in RARRES1 positive RCC (p = 0.006) and in pT1/2 tumors with RARRES1 expression (p = 0.002). Conclusion: The variable expression profile in low and high grade RCC may reflect and confirm the differences of previous gene expression analysis. There was a significant prognostic value of RARRES1 expression in patients with RCC, especially in pT1/2 tumors. more...

Zusammenfassung: Primäre T-Zell-Lymphome des zentralen Nervensystems (ZNS) sind selten. Sie müssen differenzialdiagnostisch von reaktiven Läsionen unterschieden werden. Die Diagnosestellung sollte integrativ unter Verwendung von immunhistochemischen, molekulargenetischen und/oder zytogenetischen Methoden erfolgen. Wir beschreiben den Fall eines 50-jährigen Mannes, bei welchem ein primäres zerebelläres T-Zell-Lymphom diagnostiziert und eine klonale T-Zell-Rezeptorgen-Umlagerung nachgewiesen wurde. Nach 2Zyklen Chemotherapie entwickelte der Patient eine Pneumozystis-carinii-Pneumonie und verstarb 10Wochen nach Diagnosestellung. Die Autopsie ergab keinen Residualtumor im ZNS more...

This study is designed to examine the feasibility of diffusion-sensitized multishot split-echo rapid acquisition with relaxation enhancement (RARE) for diffusion-weighted ophthalmic imaging free of geometric distortions at 3.0 and 7.0 T in healthy volunteers and patients with intraocular masses.A diffusion-sensitized multishot split-echo RARE (ms-RARE) variant is proposed as an alternative imaging strategy for diffusion-weighted imaging. It is compared with standard single-shot echo planar imaging (EPI) and readout-segmented EPI in terms of geometric distortions in a structure phantom as well as in vivo at 3.0 and 7.0 T. To quantify geometric distortions, center of gravity analysis was carried out. Apparent diffusion coefficient (ADC) mapping in a diffusion phantom was performed to verify the diffusion sensitization within ms-RARE. An in vivo feasibility study in healthy volunteers (n = 10; mean age, 31 ± 7 years; mean body mass index, 22.6 ± 1.7 kg/m²) was conducted at 3.0 and 7.0 T to evaluate clinical feasibility of ms-RARE. As a precursor to a broader clinical study, patients (n = 6; mean age, 55 ± 12 years; mean body mass index, 27.5 ± 4.7 kg/m²) with an uveal melanoma and/or retinal detachment were examined at 3.0 and 7.0 T. In 1 case, the diseased eye was enucleated as part of the therapy and imaged afterward with magnetic resonance microscopy at 9.4 T. Macrophotography and histological investigation was carried out. For qualitative assessment of the image distortion, 3 independent readers reviewed and scored ms-RARE in vivo images for all subjects in a blinded reading session. Statistical significance in the difference of the scores (a) obtained for the pooled ms-RARE data with b = 0 and 300 s/mm² and (b) for the 3 readers was analyzed using the nonparametric Mann-Whitney test.The assessment of geometric integrity in phantom imaging revealed the ability of ms-RARE to produce distortion-free images. Unlike ms-RARE, modest displacements (2.3 ± 1.4 pixels) from the fast low angle shot imaging reference were observed for readout-segmented EPI, which were aggravated for single-shot EPI (8.3 ± 5.7 pixels). These observations were confirmed in the in vivo feasibility study including distortion-free diffusion-weighted ophthalmic images with a 0.5 × 0.5 × 5 mm³ spatial resolution at 3.0 T and as good as 0.2 × 0.2 × 2 mm³ at 7.0 T. The latter represents a factor of 40 enhancement in spatial resolution versus clinical protocols recently reported for diffusion-weighted imaging of the eye at 1.5 T. Mean ADC values within the vitreous body were (2.91 ± 0.14) × 10⁻³ mm²/s at 3.0 T and (2.93 ± 0.41) × 10⁻³ mm²/s at 7.0 T. Patient data showed severe retinal detachment in the anatomical images. Whereas the tumor remained undetected in T1-weighted and T2-weighted imaging at 3.0/7.0 T, in vivo ADC mapping using ms-RARE revealed the presence of a uveal melanoma with a significant contrast versus the surrounding subretinal hemorrhage. This observation was confirmed by high-resolution ex vivo magnetic resonance microscopy and histology. Qualitative analysis of image distortion in ms-RARE images obtained for all subjects yielded a mean ± SD image quality score of 1.06 ± 0.25 for b = 0 s/mm² and of 1.17 ± 0.49 for b = 300 s/mm². No significant interreader differences were observed for ms-RARE with a diffusion sensitization of b = 0 s/mm² and 300 s/mm².This work demonstrates the capability of diffusion-sensitized ms-RARE to acquire high-contrast, high-spatial resolution, distortion-free images of the eye and the orbit at 3.0 and 7.0 T. Geometric distortions that are observed for EPI-based imaging approaches even at lower field strengths are offset by fast spin-echo-based imaging techniques. The benefits of this improvement can be translated into the assessment of spatial arrangements of the eye segments and their masses with the ultimate goal to provide guidance during diagnostic treatment of ophthalmological diseases. more...

Background The purpose of this report was to describe a single case of recurrent interstitial keratitis in a young patient leading to keratoconus-like corneal changes. Results Over the 2 years follow-up, the patient developed clinical signs of keratoconus with Vogt’s striae, Fleischer Ring and paracentral stromal thinning in the affected eye only. The tomographic measurements revealed a rapid reduction of corneal thickness from 581 to 303 μm and an irregular steepening of the pathological cornea. True net corneal power increased from 42.8 to 48.8 dioptres (D) and maximal power of the anterior surface from 44.9 to 66.9 D. Best-corrected visual acuity (BCVA) decreased from 20/20 to 20/200. A penetrating excimer laser keratoplasty was performed to restore vision and corneal stability. Conclusion Keratoconus-like changes can occur in young patients with recurrent interstitial keratitis and request corneal transplantation. more...

Cystinosis is an autosomal recessive inherited lysosomal storage disease with an incidence of 1:100.000 up to 1:200.000 caused by a gene mutation of a lysosomal transport protein resulting in deposition of cystine in lysosomes in all cells and tissues. In the cornea, crystalline, gold-dust deposition of cystine leads to visual impairment, recurrent erosions, photophobia, epiphora and blepharospasmus. Standard therapy is topical and systemic application of cysteamine which may resolve the accumulated cystine crystals. This is a case report of a thirty-one-year-old patient who already underwent renal transplantation because of nephropathic cystinosis. Visual impairment by cystine crystal deposition was aggravated by a central avascular pannus formation in his right eye. Penetrating keratoplasty was performed in intention to improve the patient’s visual acuity and life quality. After penetrating keratoplasty in the right eye, there was only a slight visual improvement. OCT scans of the macula revealed intraretinal cystine crystals and a cystoid macular edema, which was treated with a bevacizumab injection. Transmission electron microscopy of the excised cornea revealed spiky intracorneal inclusions and confocal in vivo microscopy of the left eye allowed detailed visualization of the cystine crystal deposition. There is a variability of ocular manifestations of nephropathic cystinosis. Ophthalmologists have a central role in the early diagnosis of cystinosis as mostly the first manifestation are cystine crystals in the cornea. Penetrating keratoplasty may be one of the therapeutical options. Nevertheless, the patient has to be informed about the limited prognosis because of the persisting underlying disease. more...

Introduction C-kit overexpression has previously been described in chromophobe renal cell carcinoma (cpRCC) and renal oncocytoma (RO). However, so far no KIT mutations have been found. The objective of our study was to analyse c-kit in a large cohort of renal tumors and to perform KIT mutation analysis in a subset cpRCC and RO cases with overexpression of c-kit. Materials and methods We studied the immunohistochemical expression of c-kit on tissue microarrays containing formalin-fixed, paraffin-embedded samples of 948 patients with renal tumors. CpRCC and RO cases with c-kit overexpression ( n = 23) were analyzed for KIT mutations in exons 9, 11, 13, 14, 15, and 17. Results Expression of c-kit was found in 6/642 (0.9%) clear cell RCC, 3/154 (1.9%) papillary RCC, 54/69 (78.3%) cpRCC, 37/45 (82.2%) RO and 2/30 (6.7%) of other unclassified tumor types. In none of the RO and cpRCC cases analyzed, a KIT gene mutation was found. Conclusion C-kit expression is found in the majority of cpRCC and RO, but these tumors do not harbor the usual c-kit activating mutations. This may have implications for the use of tyrosine kinase inhibitors in patients with advanced cpRCC and c-kit expression. more...

Die Sensitivitat der konfokalen Mikroskopie liegt zwischen 80 und 90% und damit uber der Sensitivitat der Erregeridentifizierung mittels Kultur. Typischerweise kann mittels in vivo konfokaler Mikroskopie bereits am Tag der Aufnahme eine mykotische Keratitis nicht invasiv und atraumatisch diagnostiziert werden. Wir stellen eine Patientin vor mit einem Hornhautulkus im Bereich des Transplantats, ausgepragter Hornhaut-Endothel-Epithel-Dekompensation (HEED) und retrokornealen Pilzzapfen bei Zustand nach Re-Keratoplastik vor 5 Jahren bei chronischer Transplantatabstosungsreaktion wegen HEED bei Fuchsʼscher Endotheldystrophie. Klinisch bestand der Verdacht auf eine mykotische Keratitis. Die konventionelle en face konfokale Mikroskopie zeigte initial keine Pilzhyphen. Aufgrund des ausgepragten Hornhautodems konnten wir erst nach einer Re-Re-Keratoplastik mittels der invertierten in vitro konfokalen Mikroskopie die Pilzhyphen im hinteren Hornhautstroma am Operationstag nachweisen. Die Histologie bestatigte die Diagnose der Keratomykose. more...

To investigate factors that influence graft failure after Descemet membrane endothelial keratoplasty (DMEK) based on transmission electron microscopy results. Retrospective observational case series. This single center study included 16 eyes of 16 patients with penetrating keratoplasty (n = 14) or repeat DMEK (n = 2) following graft failure after DMEK. The main outcome measures were ultrastructural changes in the explanted graft on transmission electron microscopy, best-corrected visual acuity, and central corneal thickness. The mean preoperative and postoperative best-corrected visual acuity was 1.01 ± 0.54 logMAR and 0.56 ± 0.37 logMAR. The mean central corneal preoperative and postoperative thickness was 667 ± 187 μm and 511 ± 42 μm. Visual acuity and central corneal thickness improved significantly (P = .001/P = .003) after repeat surgery. Electron microscopy showed that 3 of 14 corneas showed upside down transplantation, and 3 corneas had pigmented cells or pigment granules at the Descemet–stroma interface. Further, 9 of 16 specimens showed a posterior collagenous layer deposited onto the Descemet membrane (average thickness 5.1 ± 6.2 μm; ranged 0.65–20 μm); this did not correlate significantly with the time between the original and repeat keratoplasty. Of 16 original grafts, 7 showed ultrastructural anomalies of the Descemet membrane, but one excised cornea showed no Descemet membrane pathologies. The majority of eyes with graft failure after DMEK showed ultrastructural changes in the Descemet membrane. It is crucial to assess donor tissue quality and to conduct graft marking before surgery to avoid immediate or delayed graft failure after DMEK. Nevertheless, repeat keratoplasty provided significant improvement in central corneal thickness and visual acuity. more...

Objective To evaluate the expression and prognostic value of epithelial cell adhesion/activating molecule (EpCAM) in a large set of renal cell carcinomas (RCCs) using a tissue microarray (TMA) approach. Material and Methods We studied the immunohistochemical expression and overexpression of EpCAM on TMAs containing formalin-fixed, paraffin-embedded samples of 948 patients with documented renal tumours. EpCAM expression was defined as the presence of a specific membranous staining in >5% of the tumour cells. EpCAM overexpression was specified by calculating a total staining score (score range 0–12) as the product of a proportion score and an intensity score, and defined as a score >4. Results Of 948 cases, 927 (97.8%) were evaluable morphologically (haematoxylin and eosin stain). EpCAM expression was found in 233/642 (36.3%), 126/155 (81.3%), 54/68 (78.3%), 17/45 (37.8%), 13/30 (43.3%) of clear-cell RCC, papillary RCC (pRCC), chromophobe RCC (cpRCC), oncocytomas and other unclassified tumour types, respectively. Log-rank tests showed a significantly longer overall survival (OS [P = 0.047]) and a trend of EpCAM expression to be associated with a longer progression-free survival (PFS) in all RCC entities (P = 0.065). EpCAM overexpression was significantly correlated with a better PFS in all RCC subtypes, cpRCC and pRCC (P = 0.011, 0.043 and 0.025, respectively). In multivariate analysis EpCAM overexpression was an independent marker for longer PFS in all RCC entities as well as in high grade RCC (P = 0.009 and P = 0.010, respectively). Conclusions The histological subtypes associated with a high rate of EpCAM expression were cpRCC and pRCC. This retrospective analysis demonstrated a trend towards longer OS and PFS for all major RCC subtypes. EpCAM expression had significant prognostic value in patients with cpRCC and pRCC. Furthermore, EpCAM overexpression in high grade RCC may be a helpful marker for prognostication. more...

Hintergrund: Es existiert ein breites Spektrum gutartiger und bosartiger Bindehautneubildungen, deren Einordnung spaltlampenmikroskopisch haufig nicht moglich ist. Ziel der Untersuchungen war es, konfokalmikroskopische und histologische Befunde zu vergleichen, um praoperative Aussagen uber den jeweiligen Malignitatsgrad treffen zu konnen. Fallberichte: Der Krankheitsverlauf von 3 Patienten wird dargestellt. 2 Tumoren wurden als gutartig im Sinne einer aktinischen Keratose klassifiziert. Konfokalmikroskopisch stellten sich dicht gelagerte, teils hyperreflektive Bindehautepithelzellen mit multiplen Entzundungszellen und Mikrozysten dar. Histologisch zeigte sich in Korrelation eine Keratinisierung mit entzundlichen Infiltrationen und intrazellularer Odembildung. In den konfokalmikroskopischen Untersuchungen des dritten Patienten fiel eine Unterbrechung der Schichtung mit regularem Bindehautepithel auf der einen und Zellkomplexen aus vergroserten Zellen mit polymorphen Zellkernen auf der anderen Seite auf. Histologisch zeigte sich ebenfalls ein abrupter Ubergang von normaler plattenepithelialer Schleimhaut in ein hyperplastisch verbreitertes dysplastisches Plattenepithel. Die Lasion wurde als Carcinoma in situ klassifiziert. Diskussion: Mittels konfokaler In-vivo-Mikroskopie wurden Korrelationen zum histologischen Bild gefunden. Auch wenn die konfokale Mikroskopie eine nicht invasive Verlaufsuntersuchung ermoglicht, bleibt eine histopathologische Mitbeurteilung aufgrund deren Detailgenauigkeit und zusatzlichen Farbetechniken zur Planung des weiteren Vorgehens sowie zur prognostischen Einschatzung unverzichtbar. more...

Background: Patients with liver cirrhosis have an increased risk of developing hepatocellular carcinoma (HCC). Implantation metastasis following diagnostic biopsy is a well-known complication. Therefore, primary resection of a hypervascularised tumour suspicious for HCC is often performed with curative intent. Case Report: An exophytically growing mass was diagnosed between liver segments III and IVb by means of ultrasound in a 53-year old male patient with decompensated liver cirrhosis. Computed tomography confirmed a 3.5 cm large hypervascularised tumour with given resectability. Intraoperatively, the tumour appeared like a HCC. Thus, an atypical resection was performed. Histopathology revealed ectopic spleen tissue without any signs of malignancy. As enquiries revealed, the patient had undergone splenectomy after a blunt abdominal trauma 9 years prior to admission. Conclusion: In the present patient, hepatic splenosis in a cirrhotic liver was misinterpreted as HCC. In patients with a history of traumatic rupture of the spleen or splenectomy, splenosis has to be considered as a potential differential diagnosis of a hypervascularised tumour. Specific diagnostics should be performed to rule out splenosis. more...

Benign and malignant salivary gland tumours are clinically heterogeneous and show different histology. Little is known about the role of human herpes virus 8 (HHV-8), Epstein-Barr virus (EBV), and human papillomavirus (HPV) infection in salivary gland neoplasms. We investigated the presence of the three viruses in formalin-fixed, paraffin-embedded tissue samples in a cohort of 200 different salivary gland tumours. We performed EBV-LMP-1 and HHV-8 and p16 immunohistochemistry, a specific chip based hybridization assay for detection and typing of HPV and a chromogenic in situ hybridization for EBV analysis. Only one case, a polymorphic low-grade carcinoma, showed HHV-8 expression and one lymphoepithelial carcinoma was infected by EBV. In 17 cases (9%) moderate or strong nuclear and cytoplasmic p16 expression was detected. The HPV type was investigated in all of these cases and additionally in 8 Warthin’s tumours. In 19 cases HPV type 16 was detected, mostly in Warthin’s tumour, adenoid cystic carcinoma, and adenocarcinoma NOS. We concluded that HHV-8 infection and EBV infection are not associated with salivary gland cancer, but HPV infection may play a role in these tumour entities. more...

Background Whipple’s disease is a rare, often multisystemic chronic infectious disease caused by the rod-shaped bacterium Tropheryma whipplei. Very rarely the heart is involved in the process of the disease, leading to culture-negative infective endocarditis. Up to 20 % of all infective endocarditis are blood culture-negative and therefore a diagnostic challenge. We present two unusual cases of culture-negative infective endocarditis encountered in two different patients with prior history of arthralgia. A history of rheumatic arthritis or even a transient arthralgia should put Tropheryma whipplei on the top of differentials in patients of this age group presenting with culture-negative infective endocarditis, especially in cases of therapy resistance to antirheumatic agents. Case presentation The first patient was a 55 year-old Caucasian male with culture-negative Whipple-related adhesive pericarditis and endocarditis of the aortic valve. Importantly, the patient reported a 15-year history of therapy resistant sero-negative migratory polyarthritis. Aortic valve endocarditis developed during treatment with tocilizumab. The second patient was a 65-year-old male patient with no prior history of the classic Whipple’s disease who presented with a culture-negative aortic valve endocarditis. His past medical history revealed episodes of transient arthralgia, which he was not treated for however, due to the self-limiting nature of the symptoms. Both patients underwent aortic valve replacement surgery. During surgery, pericardectomy was necessary in the first patient due to adhesive pericarditis. Post surgery both patients were started on long-term treatment with trimetoprim-sulfamethoxazol. At 1-year follow-up of both patients, echocardiographic and clinical assessment revealed no signs of persistent infection. Both men reported negative history of arthralgia during the one year period post surgery. Conclusion Tropheryma whipplei culture negative-infective endocarditis is an emerging clinical entity, predominantly found in middle-aged and older men with a history of arthralgia. These data highlight the need for ruling out Whipple’s disease in patients with a history of arthralgia prior to initiation of biological agents in treatment of rheumatoid arthritis. There is also a need to assess for Tropheryma whipplei in all patients with culture- negative infective endocarditis. more...

Choroidal melanoma is the most frequently occurring intraocular tumor in adults. The aim of this work is to assess the potential of state-of-the art in-vivo and ex-vivo imaging modalities for the characterization of choroidal melanoma. Multimodal imaging of a choroidal melanoma was performed in a 53-year-old male patient. In-vivo ophthalmoscopy, ultrasound microscopy, duplex ultrasound, and 7.0 T MRI were performed. Ex-vivo examination of the enucleated eye included 7.0 and 9.4 T magnetic resonance microscopy as well as histopathology with hematoxylin and eosin staining. Imaging of choroidal melanoma with ultrahigh field MRI and duplex sonography provides detailed morphologic and functional information of the eye. High-spatial-resolution MRI at 9.4 T shows details of the internal texture of melanoma and other structures of the eye with an in-plane spatial resolution of 32 μm. Ultrahigh field in-vivo MRI at 7.0 T and ex-vivo MRI at 7.0 and 9.4 T correlate well with histologic evaluation. In-vivo ultrahigh field MRI is an emerging technique for the characterization and staging of ocular tumors. The combination of in-vivo ultrahigh-field MRI and duplex sonography has the potential to complement or even substitute complex and invasive biopsies. more...

We report on the case of a 52-year-old male presenting with an extranodal marginal zone lymphoma of the mucosa-associated tissue (MALT lymphoma) in the lung 11 years after radiotherapy for a MALT lymphoma of the lacrimal gland, which was primarily diagnosed as dacryoadenitis. Both tumors were investigated by immunohistochemistry and molecular techniques demonstrating their clonal genetic relationship. Both harbored the t(14;18)(q32;q21) and a trisomy 3 and showed identical immunoglobulin heavy-chain gene rearrangements. At the time of pulmonary relapse, clonal CD20- and CD43-positive bone marrow B lymphocytes were detected as well. The elaboration of this case emphasizes the importance of the combined use of modern diagnostic methods for establishment of correct diagnosis of MALT lymphomas at late relapses, which is essential for proper patient management. more...

Because of marrow fibrosis, bone marrow aspirations are often nonconclusive in patients with hairy cell leukemia (HCL). Therefore, histologic examination is important in HCL but often difficult in cases with low numbers of tumor cells. A combined immunohistochemical positivity for DBA.44 and tartrate-resistant phosphatase was previously found in 100% of HCL and suggested to be specific for this diagnosis. To further assess the diagnostic specificity and sensitivity of this immunohistochemical approach in a higher number of cases, we analyzed 56 HCLs and lymphoma tissue microarrays, including 840 cases of the most frequent non-Hodgkin lymphomas. All HCLs showed combined positivity for these two proteins (100% sensitivity). Both antibodies were often positive in other lymphoma types. DBA.44 reactivity was especially frequent in follicular lymphomas (46%), whereas tartrate-resistant acid phosphatase (TRAP) expression was often seen in mantle cell lymphomas (57%), primary mediastinal large B-cell lymphomas (54%), and chronic lymphocytic leukemia/small lymphocytic lymphoma (41%). A combined DBA.44/TRAP positivity was seen in only 3% of non-HCL non-Hodgkin lymphomas, including cases of diffuse large B-cell lymphomas, follicular lymphomas, chronic lymphatic leukemia/small lymphocytic leukemias, and mantle cell lymphomas. Overall, these data confirm the utility of combined immunohistochemical DBA.44/TRAP expression analysis in confirming the diagnosis of HCL. However, combined positivity for these markers is highly sensitive but not absolutely specific for HCL. more...

Background: Gene expression profiling of diffuse large B cell lymphoma (DLBCL) revealed three disease types: germinal centre B cell-like (GC), activated B cell-like (ABC), and a “third” type. Expression of CD44 variant isoforms (CD44v) is associated with an unfavourable clinical outcome in DLBCL, but previous studies did not consider the clinicopathological heterogeneity of this disease. Aims: To analyse the expression and prognostic significance of CD44 in DLBCL types. Methods: A tissue microarray (TMA) comprising 90 DLBCLs was constructed. CD10, CD20, bcl-2, bcl-6, CD44 standard isoform (CD44s), and CD44v4, CD44v6, and CD44v9 were analysed immunohistochemically and correlated with clinical follow up. Results: TMA expression of CD10, CD20, bcl-2, and bcl-6 showed 100% concordance with results from conventional sections in 60 cases. Samples were segregated into 22 GC (bcl-6+/CD10+/bcl-2−), 25 ABC (bcl-6−/CD10−/bcl-2+), and 35 unclassifiable DLBCLs. Overall survival (OS) at 30 months was 89%, 44%, and 58% in GC, ABC, and unclassified types, respectively. CD44v6 was coexpressed with bcl-2, appeared predominantly on bcl-6 negative cases, and correlated with disease stage. Cases negative for CD44s could be separated into CD44v6 negative (OS, 82% at 70 months) and CD44v6 positive (OS, 58%). Conclusions: TMA technology is useful for immunophenotyping and clinicopathological analysis of large lymphoma populations. The GC phenotype of DLBCL is of independent prognostic significance for OS. Expression of CD44v6 correlates with disease stage, and might contribute to lymphoma dissemination. CD44v6 is expressed predominantly in ABC DLBCL, and in CD44 negative cases is associated with worse OS. more...

Objectives. CD57 is normally found on NK-cells, but little is known about its expression in prostatic tissue.Methods. We investigated CD57 expression by immunohistochemistry using tissue microarrays containing 3262 prostate cancers (PCa), lymph node metastases, and benign prostatic tissue. The results were compared with clinical and pathological parameters.Results. Overall, 87% of PCa showed a moderate or strong expression of CD57. There was no significant difference to corresponding benign prostatic tissue. CD57 was increasingly lost from incidental over clinically manifest cancers to metastases. It correlated significantly with Gleason grade and pT-category, but not with PSA tissue expression. Loss of CD57 expression was an independent risk factor for PSA recurrence after prostatectomy in a multivariate Cox regression analysis. In standard sections, CD57 expression was heterogeneous, especially in large, high-grade PCa.Conclusions. There is a peculiar expression of CD57 in PCa and benign prostatic tissue. CD57 loss is associated with tumor dedifferentiation and tumor size. However, the use of this marker for prognostic purposes is hampered by its heterogeneous expression. more...

Purpose: The case reports presented here were compiled to demonstrate the potential for improved diagnosis and monitoring of disease progress of intraocular lesions using ultrahigh-field magnetic resonance microscopy (MRM) at 7.1 Tesla. Methods: High-resolution ex vivo ocular magnetic resonance (MR) images were acquired on an ultrahigh-field MR system (7.1 Tesla, ClinScan, Bruker BioScan, Germany) using a 2-channel coil with 4 coil elements and T2-weighted turbo spin echo (TSE) sequences of human eyes enucleated because of different intraocular lesions. Imaging parameters were: 40640 mm field of view, 5126512 matrix, and 700 mm slice thickness. The results were correlated with in vivo ultrasound and histology of the enucleated eyes. Results: Imaging was performed in enucleated eyes with choroidal melanoma, malignant melanoma of iris and ciliary body with scleral perforation, ciliary body melanoma, intraocular metastasis of esophageal cancer, subretinal bleeding in the presence of perforated corneal ulcer, hemorrhagic choroidal detachment, and premature retinopathy with phthisis and ossification of bulbar structures. MR imaging allowed differentiation between solid and cystic tumor components. In case of hemorrhage, fluid-fluid levels were identified. Melanin and calcifications caused significant hypointensity. Microstructural features of eye lesions identified by MRM were confirmed by histology. Conclusion: This study demonstrates the potential of MRM for the visualization and differential diagnosis of intraocular lesions. At present, the narrow bore of the magnet still limits the use of this technology in humans in vivo. Further advances in ultrahigh-field MR imaging will permit visualization of tumor extent and evaluation of nonclassified intraocular structures in the near future. more...

Ciprofloxacin is a fluorinated quinolone antibiotic with relatively low occurrence of adverse side effects. However, increasing evidence suggests that ciprofloxacin may cause severe liver damage. Until now, 14 cases of ciprofloxacin-associated liver injuries have been reported. We describe a case of a 22-year-old male who developed hepatic failure after intake of ciprofloxacin. The patient had been treated with 2 x 250 mg ciprofloxacin per day. He presented with symptoms of acute liver failure 14 days later. Liver biopsy revealed extensive hepatocellular necrosis involving zones 3 and 2 of hepatic acini and a mixed inflammatory infiltration containing abundant eosinophils. Symptoms resolved after corticoidsteroid therapy. In the present paper, we report the clinico-pathological characteristics of a case of ciprofloxacin-associated acute hepatic failure and discuss the current literature. more...

Background: The use of tissue microarrays (TMAs) is now a generally accepted method for the investigation of solid tumours. However, little is known about the applicability of the TMA technique for analysis of patients with acute leukaemia. A bone marrow (BM)-TMA analysis with 15 different immunohistochemical markers was performed. The TMA was validated by comparison with the corresponding full tissue sections. Materials and methods: A BM-TMA comprising 148 cases of acute leukaemia, including 115 acute myeloid leukaemia (AML) and 33 acute lymphoblastic leukaemia (ALL) cases, was constructed. Expression of CD3, CD10, CD15, CD20, CD34, CD61, CD68, CD79a, CD99, CD117, CD138, myeloperoxidase, haemoglobin A1, glycophorin and terminal deoxynucleotidyl transferase was immunohistochemically analysed. 50 cases of the TMA were directly compared with the corresponding full tissue section to validate the results. Results: Morphologically and immunohistochemically, 6 (4%) of 148 cases and 765 (11%) cores of 6912 individual analyses were not evaluable. A direct comparison of TMA cases with conventional full sections showed a concordance of the results of 100%. Conclusions: The small size of bone-marrow biopsies and the presence of bony trabeculae do not preclude construction and analysis of acute leukaemia TMAs. Acute leukaemia cases on TMA displayed the characteristic phenotypic profiles expected in different AML and ALL subtypes. Therefore, the TMA technique is also a promising method for high-throughput analysis of combined marker expression and clinicopathological correlations in patients with leukaemia. more...

Aims : Imatinib mesylate specifically inhibits KIT tyrosine kinase activity, and has been proven to be effective in the treatment of gastrointestinal stromal tumours. Because other KIT-expressing malignancies might benefit from Imatinib therapy, we evaluated the distribution and expression of KIT in 1166 cases of malignant lymphoma. Materials and results : Tissue microarrays (TMAs) containing 824 non-Hodgkin's lymphoma (NHL) and 342 Hodgkin's lymphoma (HL) cases were immunohistochemically analysed for the expression of the KIT protein. Two KIT-positive NHLs were sequenced using polymerase chain reaction analysis. One T-cell lymphoma and one follicular lymphoma of the 747 NHL cases (0.3%) were positive for KIT. All HLs were Kit-negative. None of the KIT-positive cases showed a kit gene mutation. Conclusions : KIT expression is a very rare event in NHL and virtually absent in HL. In the few positive cases, the aberrant expression is not caused by a mutation in the ‘hot-spots’ of the kit gene, indicating that treatment of these tumours with Imatinib may be ineffective. more...

Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma arise from B-lymphocytes. However, classical markers of the B-cell phenotype, such as CD20, are present only in about 25% of the cases. The aim of the present study was to assess expression of the B-cell-related antigens CD20, CD79a, and CD138 in classical Hodgkin lymphoma using a tissue microarray consisting of 330 classical Hodgkin lymphoma cases. Expression of CD15, CD20, CD30, CD79a, CD138, and latent membrane protein 1 of Epstein-Barr virus was assessed by immunohistochemistry, and the methodology was validated by direct comparison of CD20 expression on the tissue microarray cores with corresponding large sections. The influence of the number of arrayed sample cores on the obtained expression levels of CD20 was analyzed by comparing the results from single, duplicate, and triplicate cores. Two-hundred fifty-three (77%) of the 330 cases were morphologically representative. CD20 was expressed in 84 cases (33%), CD79a in 26 (10%), and CD138 in 2 (1%), respectively. CD20 and CD79a were co-expressed in 16 cases (P.005), and expression of CD20 correlated inversely with CD15 (P.01). Comparing the tissue microarray results with those from conventional sections for expression of CD20 yielded a concordance of 94% (63/67). Examining one, two, and three cores from individual cases revealed positivity for CD20 at 24% (61/253), 32% (82/253), and 33% (84/253), respectively. We conclude that B-cell markers are expressed in 38% of classical Hodgkin lymphoma in the following rank order: CD20CD79aCD138. The use of two cores per tissue sample renders the tissue microarray technology effectively representative and thus very useful for high-throughput evaluation of heterogeneously expressed markers in classical Hodgkin lymphoma. more...

Background Minichromosome maintenance (MCM) proteins are essential for the initiation of DNA replication and have been found to be relevant markers for prognosis in a variety of tumours. The aim of this study was to assess the proliferative activity of diffuse large B-cell lymphoma (DLBCL) in tissue microarray (TMA) using one of the minichromosome maintenance proteins (Mcm2) and to explore its potential value to predict prognosis. Methods Immunohistochemistry for Mcm2 was performed on TMAs constructed from 302 cases of DLBCL. A monoclonal mouse antibody was used after heat induced antigen retrieval. Mcm2 expression was scored quantitatively. Positivity for Mcm2 was defined as presence of nuclear expression of Mcm2 in greater than or equal to 40 % of tumour cells. A statistical analysis was carried out of the association of Mcm2 and the clinico-pathological characteristics. Results Mcm2 expression was clearly evident in the nuclei of proliferating non-neoplastic cells and tumour cells. Positivity for Mcm2 was found in 46% (98/211) of analysable cases. A significant correlation existed between Mcm2 expression and presence of bulky disease (p = 0.003). Poor disease specific survival was observed in patients with DLBCL positive for Mcm2 expression in the univariate analysis (p = 0.0424). Conclusion Mcm2 expression can be used to assess tumour proliferation and may be useful as an additional prognostic marker to refine the prediction of outcome in DLBCL. more...