[Grading of prostate cancer]. / Grading von Prostatakarzinomen.

The current grading of prostate cancer is based on the classification system of the International Society of Urological Pathology (ISUP) following a consensus conference in Chicago in 2014. The foundations are based on the frequently modified grading system of Gleason. This article presents a brief description of the development to the current ISUP grading system.

[Prostate cancer. Part 2: Review of the various tumor grading systems over the years 1966-2015 and future perspectives of the new grading of the International Society of Urological Pathology (ISUP)]. / Prostatakarzinom. Teil 2: Rückblick über die verschiedenen Tumorgradingverfahren der Jahre 1966-2015 und Zukunftsperspektiven des neuen Gradings der International Society of Urological Pathology (ISUP).

The continued development of methods in needle biopsies and radical prostatectomy for treatment of prostate cancer has given special emphasis to the question of the prognostic relevance of the various systems of grading. The classical purely histological grading system of Gleason has been modified several times in the past decades and cleared the way for a new grading system by the prognostic grading of Epstein. Assessment of the old and also modified combined histological and cytological grading of Mostofi, the World health Organization (WHO) and the urologic-pathological working group of prostate cancer in connection with the Gleason grading (combined Gleason-Helpap grading), has led to considerably improved rates of concordance between biopsy and radical prostatectomy and to improved estimations of prognosis beside its contribution to the development of a more practicable grading system for clinical use.

[Prostate cancer. Part 1: Review of cell kinetics over the years 1966-2015 and future perspectives of the new grading of the International Society of Urological Pathology (ISUP)]. / Prostatakarzinom. Teil 1: Rückblick über Zellkinetik der Jahre 1966-2015 und Zukunftsperspektiven des neuen Gradings der International Society of Urological Pathology (ISUP).

Using tritium-labeled thymidine histoautoradiography, the AgNOR staining technique and Ki67-MIB-1 immunohistochemistry to study cell kinetics, prostate cancer can be subdivided into slowly, moderately and rapidly proliferating tumors. These are important supplementary methods and prerequisites for a grading as low, intermediate and high-grade in addition to classical histology and cytology. Cytometry of DNA can confirm the cell kinetics of prostate cancer by detection of a predominance of diploid or aneuploid cell nuclei but should only be evaluated together with histological investigations. All histology-based analyses of cell kinetics encompass the classical highly and poorly differentiated glandular and cribriform patterns as well as solid undifferentiated structures and the various subcategories. The malignancy grading of prostate cancer can result from the summation of histological grading and cell kinetic analyses, as long as the named investigations are included. The future perspectives of individualized therapy options, including active surveillance in early low-grade and also for high-grade prostate cancer and new antihormonal treatment in advanced disease, may increasingly rely on tissue biomarkers and advanced technologies for whole genome analysis including next generation sequencing.

Improving the reproducibility of the Gleason scores in small foci of prostate cancer--suggestion of diagnostic criteria for glandular fusion.

High upgrading rates of Gleason score 6 to 7 carcinomas between biopsy and radical prostatectomy specimens may be produced by change of fused glands of pattern 3 to pattern 4. Therefore, inter-observer reproducibility of fused and non-fused glands in biopsy specimens was analysed. Images of H&E stained slides of glands of carcinomas with Gleason score 6 and 7 (3 + 4) with and without glandular fusions with different lens magnification were analysed by 4 specialized genitourinary pathologists and 3 non-specialized pathologists. The definition of glandular fusion was a complete lack of any stromal fibres between a minimum of two glands and only one line of nuclei within the area of fusion. Overall agreement and inter-observer reproducibility of fused versus non-fused glands of non- and uro-pathologically specialized pathologists were lower in lens magnification of 50× in contrast to 200×. The inter-observer reproducibility of fused glands by specialized observer was higher than that of non-specialized pathologists. The results support the importance of strict but practicable criteria for the diagnosis of fused tumor glands in order to decrease the interobserver variability of Gleason scores, particularly in non-specialised pathologists.

[Importance of second opinions on histology of prostate biopsy specimens]. / Bedeutung der Zweitmeinung bei Prostatabiopsien.

OBJECTIVE: The significance of a second opinion on the histological findings of prostate carcinomas as well as suspicious lesions on core needle biopsy specimens was studied in cases from the year 2008. STUDY DESIGN: A total of 920 core needle biopsy specimens of the prostate were stained with H & E and when necessary immunohistochemical analyses were performed with basal cell markers p63, 34ßE12, PSA and AMACR (P504 S) and neuroendocrine markers such as synaptophysin and chromogranin. The modified Gleason grading system was used. RESULTS: In 43.5% of suspicious lesions adenocarcinomas of the prostate were found. In 53.2% the findings of atypical small acinar proliferations or high-grade prostatic intraepithelial neoplasia (HGPIN) were confirmed with a recommendation of serum PSA and morphological controls. The suspicion of prostatic carcinoma could be confirmed in 87.2% by the diagnosis of adenocarcinoma. After Gleason grading 82.8% of all diagnosed carcinomas had scores 6 or 7(3 + 4) and belonged to the group of low grade carcinomas. High grade carcinomas were without diagnostic problems. CONCLUSION: A second opinion on the histological analysis of suspicious lesions of the prostate as well as of confirmation of Gleason grading is a very important point of quality management of diagnostic steps of prostate carcinomas and may be helpful for different therapeutic strategies.

[Clinical insignificance of prostate cancer: are there morphological findings?]. / Zur klinischen Insignifikanz des Prostatakarzinoms: Gibt es morphologische Hinweise?

OBJECTIVE: Overdiagnosis and overtreatment of microfocal nonpalpable and early-stage prostatic adenocarcinoma are currently a topic of strong discussion. We tried to find morphological findings of such insignificant carcinomas of the prostate. STUDY DESIGN: More than 1,000 consecutive core needle biopsy specimens of prostate carcinoma taken during 1 year (2007) were graded according to the modified Gleason scoring system. The results were correlated to serum prostate-specific antigen (PSA) and tumor extent in the cores. RESULTS: Cases with PSA <10 ng/ml and tumor extent <20% frequently (up to 55%) had Gleason scores of 6 or 7a. Cases with PSA >10 ng/ml or tumor extent >20% had higher Gleason scores (>7a). Cancers with tumor infiltration of <1 mm in one of up to 12 cores and PSA <10 ng/ml mainly had low Gleason scores (6 and 7a), but only 5% of the carcinomas in the studied specimens corresponded to such a parameter. Only 25% of such patients had a pT2a tumor after radical prostatectomy. CONCLUSION: With a very restricted parameter of a microfocal adenocarcinoma of the prostate with a Gleason score <7a, tumor infiltration of

[The value of the modified Gleason grading system of prostate adenocarcinoma in routine urological diagnostics]. / Die Wertigkeit des 2005 modifizierten Gleason-Gradings in der urologischen Diagnostik von Prostatakarzinomen.

In several consensus conferences of the International Society of Urological Pathology (ISUP), the Gleason grading system of prostatic carcinomas was modified and adapted to the routine histological diagnostics of specimens of core needle biopsies and radical prostatectomies. The main results are the documentation of all histological patterns (primary, secondary, tertiary) and a shifting of the maximal Gleason score of biopsies from 6 to 7a (3+4) and of radical prostatectomies from 6 and 7 to 7a and 7b (4+3). Score 2 to 4 carcinomas do not exist in the peripheral prostate. pT2 prostatic carcinomas with good prognosis have a maximal score of 7a; pT3 carcinomas with poor prognosis have a most frequent score of 7b. The agreement of the Gleason scores of core needle biopsies and radical prostatectomy specimens is more than 80%. Inter- and intraobserver reproducibility is better than after the conventional Gleason grading. The prognostic value of scores 6 and 7a may be similar. The border between low- and high-grade prostatic carcinoma may be probably Gleason score 7a and 7b. The prognostic value of score 6 should be changed to score 7a in the different therapeutic options for prostatic carcinomas.

[Small suggestive lesions of the prostate. Histological and immunohistochemical analyses -- report of the uropathology consultation service]. / Kleine suspekte Prostataläsionen. Histologische und immunhistochemische Untersuchungen -- Bericht aus dem uropathologischen Konsiliardienst.

Punch biopsies have been taken from the prostate with increasing frequency in recent years, with a resulting increase in the number of diagnoses made. To check the diagnosis of "small two- or three-gland carcinoma" we prepared new H and E sections and, when the atypical glands were no longer available, also performed immunohistochemical analyses in 1,041 cases referred to our uropathology consultation service, comparing the diagnoses supplied by the referring doctors with the final diagnoses. In 61.6 of these cases histology confirmed the diagnosis of adenocarcinoma of the prostate; the diagnosis recorded when the basal cell marker was absent and the tumour marker P504S was strongly expressed was atypical microglandular proliferation or suspected carcinoma. Previous diagnoses of prostatic carcinoma were confirmed in 99% of cases. In this way we also confirmed a further 27.9% of cases of prostate carcinoma in the grey area of diagnoses endorsed "suggestive" or "suspected". The patients concerned were thus spared multiple screening biopsies and were assigned for definitive treatment.

[Therapy induced regressive changes of prostate cancer]. / Therapieinduzierte Tumorregression des Prostatakarzinoms.

Regressive changes following pretreatment of prostate cancer may represent a big challenge for the histopathologist not familiar with the assessment of pretreated specimens. Characteristic changes after antiandrogen therapy in non-malignant prostate tissue include glandular atrophy, basal cell prominence and/or basal cell hyperplasia as well as a hypercellular stroma. Morphologic changes in prostate cancer include cytoplasmic clearing and vacuolization, nuclear pyknosis and even complete cell destruction. On the glandular level, changes are characterized by various degrees of involutional changes, ranging from almost non-regressive tumor glands to complete glandular disruption with scattered isolated tumor cells dispersed in the stroma. Knowledge about these changes, the selective use of immunohistochemistry as well as a very thorough histological workup is essential for the correct assessment of these specimens.

[Prostatic adenocarcinoma--still a diagnostic problem]. / Das prostatakarzinom--Immer noch ein diagnostisches problem.

Although the diagnosis of usual prostatic adenocarcinoma is not difficult by itself, problems may occur with diagnosis of small carcinomas in punch biopsies. Often small groups of suspicious glands are found with indistinct basal cell layer and lack of immunohistochemical expression of cytokeratin clone 34betaE12 or p63. Despite disturbed architecture, carcinoma cannot be diagnosed without cytological criteria of malignancy, especially prominent nucleoli. This is not only a frequent problem in routine diagnostic slides but also in consultation cases. The consequence of the diagnosis "suspicious" is repeat biopsy after an interval of 6-12 months. Recently, a new marker for prostatic carcinoma an alpha methyl CoA-racemase (P504S) has been tested. P504S is overexpressed in carcinoma-cells of the prostate. Together with negative basal cell marker P63 and positive reaction of P 504S this imunohistochemical combination confirms the diagnosis in 35-45% of so called suspicious prostate biopsies. Facit: this group of patients have now a distinct diagnosis and must have a definite treatment without repeat biopsy.

[Extreme cardiomegaly]. / Extreme Kardiomegalie.

We report the case of 65 year old male patient with extreme heart enlargement. The patient was admitted to the hospital due to acute bleeding from varicose veins of the cardia. The endoscopic treatment by means of hemostatic clips and fibrine was successful. However the patient died two weeks later without having any complaints. The heart of the patient weighed 1350 g. Multiple coronary bypasses were found. There was also a recent myocardial infarction. The adoptive pathophysiologic changes accompanying extreme cardiomegaly are discussed. Numerous cases have been recorded of unusually large hearts, which in a few instances have even exceeded the one reported here. The analysis of observations reported in the literature reveals that rheumatic myocarditis and syphilitic aortitis were responsible for the majority of cases with extreme cardiac hypertrophy. Valvular deformities were also frequent findings. The occurrence of extreme cardiac enlargement in an elderly patient associated with multiple coronary bypasses has been not described so far.

[Extensive bilateral lower leg muscle necrosis after nasal application of heroin. Macroscopic and histologic findings in a 23-year-old man]. / Ausgedehnte bilaterale Unterschenkelmuskelnekrosen nach nasaler Heroinapplikation. Makroskopische und histologische Befunde bei einem 23-jährigen Mann.

Rhabdomyolysis is one of the less known complications of heroin abuse. A case of lower leg muscle necrosis after nasal application of heroin is reported with repeated resection of the necrotic muscles. Superinfection with a methicillin-resistant Staphylococcus aureus (MRSA) strain was present. After 4 weeks, bilateral amputation could not be avoided. We regard a direct toxic effect of the heroin as the most probable mechanism of the muscular damage, with possible influence of the reduced oxygen delivery due to central respiratory and circulatory depression.

[New WHO classification of urothelial carcinoma of the urinary bladder]. / Zur neuen WHO-Klassifikation urothelialer Harnblasenkarzinome.

The WHO classification of urothelial carcinomas of the urinary bladder (1999) presents the papillary urothelial neoplasia of low malignant potential (PUNLMP) as a new entity in between the papillomas and the papillary urothelial carcinomas. This neoplasia shows a typical basal palisading, a low mitotic rate, and a low MIB-1-proliferation index. The PUNLMP is said to have an increased risk of development of recurrent papillary lesions with the possibility of malignant transformation. At present, there is an intensive discussion on this new entity. The participants of a meeting on the consensus classification on urothelial tumors held in Ancona in 2000 have meanwhile split in two discussion groups. One favors the new WHO classification with the papillary urothelial carcinomas G I, G II, and G III, but without PUNLMP, whereas the other group favors the consensus classification of 1998 with papillomas, papillary urothelial neoplasia of low malignant potential, and non invasive as well as invasive low-grade and high grade papillary urothelial carcinomas. Future long term prospective studies will show the significance of PUNLMP compared to well differentiated non invasive papillary urothelial urinary bladder carcinoma G I (G Ia). Otherwise, there is no significant difference in the classification of carcinomas and non epithelial lesions compared with the previous classification of 1973. The new WHO does however discriminate the minimally invasive papillary urothelial carcinomas in those with infiltration of the lamina propria above the muscularis mucosae (pT1a), the infiltration of the lamina muscularis mucosae (pT1b), and the extension beyond the muscularis mucosae (pT1c). The recurrence rate increases from stage pT1b. This substaging may be of therapeutical relevance.

Nonepithelial neoplasms of the urinary bladder.

Nonepithelial tumors are rare in the urinary bladder, but their exact classification is very important in the differential diagnosis between these tumors and epithelial lesions. In the new WHO classification and in the third series of the Armed Forces Institute of Pathology (AFIP) "Atlas of Tumor Pathology" on urinary bladder tumors, various mesenchymal tumors, mixed epithelial and mesenchymal tumors and myofibroblastic proliferations are summarized. In the following we will describe the histology, immunohistology, and cytogenetics of nonepithelial tumors and lesions.

Neuroendocrine differentiation and short-term neoadjuvant hormonal treatment of prostatic carcinoma with special regard to tumor regression.

OBJECTIVES: Neuroendocrine (NE) differentiation in prostate cancer is believed by some authors to play an important role in the development of androgen resistance. However, there is little knowledge about the impact of short-term neoadjuvant hormonal therapy on NE differentiation and on whether the degree of tumor regression is linked with the extent of NE differentiation. METHODS: NE cells were detected by immunohistochemistry using a chromogranin A antibody. The densities of NE cells in 20 pretreated and 20 nonpretreated radical prostatectomy specimens were compared. Furthermore, we compared the NE cell density in tumors with variable degrees of regression. RESULTS: The median percentage of tumor cells showing NE differentiation did not significantly differ between pretreated and nonpretreated specimens (0.61%, range 0.0-2.4%, vs. 1.47%, range 0.0-6.8%; p = 0.9896). Twelve nonregressive/slightly regressive tumor foci and 12 strongly regressive tumor foci were assessed. The NE cell density did not differ significantly (p = 0.1227). CONCLUSIONS: Short-term neoadjuvant hormonal therapy does not induce relevant clonal propagation of NE cells. The degree of tumor regression following short-term neoadjuvant hormonal therapy does not correlate with the extent of NE differentiation.

Expression of vascular endothelial growth factor (VEGF) and VEGF receptor Flk-1 in benign, premalignant, and malignant prostate tissue.

Vascular endothelial growth factor (VEGF) is one of the most potent mitogenic, highly specific tumor angiogenic factors, which acts via binding to 2 specific tyrosine kinase receptors. There are few studies analyzing VEGF receptor expression in prostate cancer cells, and results are contradictory. In an immunohistochemical study, we analyzed VEGF and VEGF receptor fetal liver kinase (Flk)-1 expression in benign glands, high-grade prostatic intraepithelial neoplasia (HGPIN), and prostatic carcinomas of different Gleason scores, obtained from 21 radical prostatectomy specimens. In all benign glands, VEGF and Flk-1 expression was confined almost exclusively to the basal cell layer (proliferative cell compartment). In HGPIN, labeling was no longer confined to the basal cell layer, but also was seen in all neoplastic secretory cells. All carcinomas stained positive for both markers. There was a trend for increasing labeling intensity with increasing cellular dedifferentiation. We concluded that tumor growth stimulated by the VEGF-Flk-1 system is promoted not only by neoangiogenesis, but also by tumor cell autostimulation. The VEGF-Flk-1 system may have an important role in the process of malignant transformation and tumor progression.

[Sudden cardiac death from unrecognized cardiac sarcoidosis]. / Plötzlicher Herztod durch unerkannte kardiale Sarkoidose.

Sarcoidosis is a systemic disease of young adults. Cardiac involvement is rarely diagnosed clinically. It presents with arrhythmias, conduction disorders, increasing myocardial insufficiency, or sudden death. We report a 42-year-old man with cardiac conduction disturbances of unknown cause who died of sudden cardiac death. Sarcoidosis with prominent cardiac involvement was diagnosed only at autopsy. Cardiac sarcoidosis should be considered in young patients with unexplained conduction disorders.

Limiting the diagnosis of atypical small glandular proliferations in needle biopsies of the prostate by the use of immunohistochemistry.

Prostatic biopsies containing small glandular formations suspicious of, but not diagnostic for, carcinoma represent a diagnostic dilemma, as they cannot be definitely identified as either benign or malignant. The term 'atypical small acinar proliferation' (ASAP) in the differential diagnosis of carcinoma has recently evoked considerable discussion. This study has tried to assess the biological potential of ASAP by further immunohistochemical (IHC) analysis. Biopsy-proven cases of ASAP (n=114) were analysed, in which consecutive sections still contained the suspicious lesion. IHC studies were undertaken with anti-cytokeratin 34betaE12 and the proliferation marker MIB-1. Staining with 34betaE12 revealed a complete basal cell layer in 25 cases (21.9%), a fragmented layer in 58 cases (50.9%), and absence of basal cells in 31 cases (27.2%). MIB-1 labelling indices (LIs) in these three groups were significantly higher than in benign prostatic tissue (p<0.001) and reached the level of low-grade prostatic carcinoma (p>0.05). The suspicious morphology of ASAP on haematoxylin and eosin-stained slides was supported by the finding of elevated proliferative activity. Subgroups were revealed by immunohistochemical assessment of basal cell status and cases without basal cells were diagnosed as carcinoma. Nevertheless, rebiopsy is recommended if radical surgery is planned, to exclude insignificant cancer. Cases with a complete or fragmented basal cell layer were regarded as non-malignant. Whether a fragmented basal cell layer reflects a technical artefact or transition to carcinoma is unknown, but the proliferative activity of both lesions was increased and corresponded to that of low-grade prostatic carcinoma. In these cases, therefore, at least clinical follow-up is strongly recommended and repeat biopsies are encouraged.

Acute measles gastric infection.

We describe the case of a 44-year-old man who was referred for gastroscopy because of abdominal pain. During endoscopy, inflammatory changes of the antrum and corpus mucosa were clearly visible, and biopsy samples from the antrum and corpus mucosa were taken. At histology, routine hematoxylin and eosin staining showed characteristics indicative of so-called ex-Helicobacter pylori-gastritis that had developed after antibiotic treatment 2 years ago. Additional large, bizarre inclusion bodies and clusters of multinucleated giant cells were located in the surface epithelium and within the lamina propria. These giant cells had an appearance similar to that of Warthin-Finkeldey cells, which can be found during the prodromal phase of measles infection. Anti-measles virus immunochemistry showed a strong positivity for measles virus antigen within the giant cells. Based on these results, the final diagnosis of morbilliform gastritis was made. To our knowledge, no case of measles gastritis has been described in the literature. Our case report confirms the systemic character of measles virus infection and confirms that measles viral replication can involve the gastric mucosa in addition to the conjunctiva, lung, and intestina.