[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.

[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.

[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.

[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.

Cell proliferation and growth of gastric carcinoma induced in inbred Wistar rats by N-methyl-N'-nitro-N-nitrosoguanidine.

Gastric carcinoma was induced in inbred Wistar rats by p.o. administration of N-methyl-N'-nitro-N-nitrosoguanidine for 25 weeks, and cell proliferation and growth of the gastric carcinoma in an incipient stage were studied. A microscopic cancer was found by 24 weeks, and macroscopic cancers were found after 27 weeks. All the cancers were a single lesion located at the midpoint of the lesser curvature of the stomach. Histologically, they were tubular adenocarcinomas. The mucosal changes predisposing to the development of carcinomas were focal erosions and dysplasias confined to the midpoint of the lesser curvature. The malignant transformation appeared to occur in the dysplastic cells of the eroded mucosa by 17 to 18 weeks after N-methyl-N'-nitro-N-nitrosoguanidine treatment. Following the malignant change, the labeling indices of the tissues with [3H]thymidine decreased, suggesting an elongation of cell cycle time. By repeated injections of [3H]thymidine, a time required for all the cancer cells to enter S phase (reflecting the maximum cell cycle time) was estimated to be about 3.5 days. This gave a theoretical doubling time for the gastric cancers. On the other hand, from the temporal observations of tumor volumes, it was shown that the gastric cancers in an incipient stage underwent exponential growth with a doubling time of 14 days. The difference between the theoretical and actual doubling time might reflect a cell loss rate in the cancer tissue.

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.

Assessment of basal cell status and proliferative patterns in flat and papillary urothelial lesions: a contribution to the new WHO classification of the urothelial tumors of the urinary bladder.

In 1999, the World Health Organization (WHO) published a new classification of papillary urothelial tumors of the urinary bladder. Intended to represent a reproducible, easy-to-use classification system that better separates patients with true malignancies (bladder cancer) from those patients who are at an increased risk for developing bladder cancer, problems in the differential diagnosis of various lesions remained. Probably the most critical distinction is between papillomas, papillary urothelial neoplasms of low malignant potential (lmp), and grade I papillary carcinomas. Conversely, problems in the distinction between reactive atypia, atypia of unknown significance, and dysplasia, as well as the distinction of dysplasia from carcinoma in situ (CIS), are unresolved. Whether urothelial basal cell status assessment on hematoxylin and eosin-stained slides completed by cytokeratin immunohistochemistry with anticytokeratin clone 34betaE12 may help to improve some of the previously mentioned diagnostic dilemmas was investigated. Basal cell status assessment was helpful in the differentiation between dysplasia and CIS. In dysplasia, CK IHC showed a predominantly basal labeling pattern, whereas in CIS, labeling of all urothelial layers was seen. Basal cell status assessment could separate 2 groups of pTa GIb papillary carcinoma. Group 1 with a continuous basal CK labeling and a low MIB-1 labeling index (LI) was compared with group 2, with a diffuse labeling pattern and a significantly higher MIB-1 LI. Whether group 1 carcinomas should better be assigned to the group of papillary urothelial neoplasms of lmp is discussed.

Proliferative pattern of exophytic and superficially invasive and noninvasive low-grade urothelial carcinomas.

In urothelial low-grade carcinomas of the bladder stage pT1, prognosis in general is good. In a subset of these tumors infiltrating beyond the lamina muscularis mucosae, prognosis clearly worsens. Unfortunately, evaluation of the lamina muscularis mucosae often is very difficult or even impossible because of its incomplete extension. In an immunohistochemical study on 131 pTa and pT1 urothelial tumors without provable lamina muscularis mucosae, we evaluated the proliferative activity with the monoclonal antibody MIB-1 and the expression pattern of cytokeratins of high molecular weight with the monoclonal antibody 34betaE12. The highest proliferative indices were found in tumors with a diffuse expression pattern of MIB-1 and 34betaE12. A preliminary analysis of follow-up data showed that 70.6% of the pT1 GIb-GIa tumors that recurred showed a diffuse expression pattern for both markers. Whether these patients are candidates for a doser follow-up or even for a more radical therapy has to be subject to further follow-up studies.

Histological and immunohistochemical findings of prostatic carcinoma after external or interstitial radiotherapy.

In a retrospective study, the extent of reactions of different types of prostatic carcinomas to external or interstitial radiotherapy was compared with reactions to hormonal therapy. It is shown that prostatic carcinomas of different grades of differentiation can be divided into two main subgroups with distinctly different survival rates; i.e., prostatic carcinomas grades of malignancy Ib/IIa and grades IIb/III. Within an observation time of 10 years, the prostatic carcinoma grade of malignancy Ib/IIa shows a good response to external and interstitial radiotherapy. None of the patients died of the prostatic carcinoma. In the more poorly differentiated prostatic carcinomas, 2 out of 11 patients with external radiotherapy died of the carcinoma. The death rates from disease after hormonal therapy were higher, and the survival times were very short without therapy. Regressive changes are much more distinctly expressed in the better-differentiated carcinoma group. Differential diagnostic difficulties between regressive changes in carcinomatous glands and normal glands could be resolved by immunohistochemical proof of high-molecular-mass cytokeratin in basal cells.

Giant-cell reaction in the small tubular bones. A light- and electron-microscopic study.

Light- and electron-microscopic investigations were performed in a case of cystic soap-bubble-like expansion of the shaft region of the second metatarsal bone. Morphologically, strongly cellular tissue with a closely packed net of osteoid trabeculae containing osteoblasts and a whorl-shaped spindle cell stroma with fibroblasts, fibrocytes, and irregularly scattered multinucleated giant cells of the osteoclast type were observed. After clinical and morphological exclusion of osteosarcoma, enchondroma, non-ossifying fibroma, osteoblastoma, osteoclastoma, and bone cysts the final diagnosis was giant-cell reaction of small tubular bone with unusual marked osteoid formation. As recurrences are possible, block resection appears more appropriate than curettage.

Proliferative pattern of urothelial bladder cancer and urothelial atypias.

For early diagnosis of urinary bladder tumors, autoradiographic, cytological, and impulse cytophotometric examinations were performed on fresh bladder tissue with carcinomas of different grades of malignancy and various depths of infiltration, and also on tissues with concomitant urothelial atypias. Cell kinetic examinations of urothelial atypias of mild, moderate, and severe grade revealed labeling indices comparable to those of urothelial carcinomas grade I, II, and III, respectively. The labeling indices of the carcinomas increased with both the grades of malignancy and the depth of invasion up to factor 5. Cytophotometrically mild atypias showed euploidy, while moderate to severe atypias revealed aneuploidy. By means of cytologic, cytophotometric, and cell kinetic analyses, two subgroups of G I urothelial carcinomas were distinguished. Subgroup I a corresponded to highly differentiated papillary urothelial carcinomas with low labeling indices, pap I-III differentiation, and euploidy. Subgroup I b, on the other hand, revealed pap differentiations of IV-V, aneuploidy, and higher labeling indices. This subgroup seems to be more prone to recurrences and apparently indicates higher grades of malignancy and depths of infiltration. The data presented provide evidence that a combination of these methods is helpful for early recognition of precursors of bladder cancer atypias as well as for exact evaluation of the biological potential of carcinomas.

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.

Differential diagnosis of glandular proliferations in the prostate. A conventional and immunohistochemical approach.

A variety of small acinar lesions of the prostate can mimic prostate cancer in punch biopsies and in transurethral resection material. The first part of this review deals with differential diagnostic problems of the central and transition zone, including atypical adenomatous hyperplasia of the prostate, atrophic processes, sclerosing adenosis, basal cell hyperplasia, and low-grade adenocarcinoma. The second part deals with differential diagnostic problems in the peripheral zone: prostatic intraepithelial neoplasia, postatrophic hyperplasia, Cowper's glands, seminal vesicles, and ductal and intraductal carcinoma. Finally, atypical and small acinar proliferations are described. Diagnostic perspectives are discussed. proliferations (ASAP) that cannot be integrated into any of the well-established diagnostic entities [1, 16, 22, 41]. The relevant glandular proliferations of the central, transitional and peripheral zones of the prostate are discussed here with reference to the related carcinomas.

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.

Undifferentiated carcinoma of the prostate with small cell features: immunohistochemical subtyping and reflections on histogenesis.

To investigate the histogenesis of undifferentiated carcinoma of the prostate with small cell features we analysed the expression of neuroendocrine (NE) markers, the androgen receptor (AR), and prostate-specific antigen (PSA) in 19 undifferentiated carcinomas of the prostate. The proliferative activity (MIB-1/Ki67) of the tumours was examined, and the clinical data reviewed. The results identified two groups: carcinomas in group 1 were positive for PSA and AR and negative for NE markers. The mean MIB-1 labelling index (LI) was 34.8% and the mean serum PSA value 56.4 ng/ml. Two of the 7 patients died within 12 months after tumour diagnosis. The tumours in group 2 were NE differentiated small cell carcinomas (SCC), which were negative for PSA and AR. The mean MIB-1 LI was 82.6% and the mean serum PSA value 7.1 ng/ml. Seven of the 10 patients died between 2 and 12 months after tumour diagnosis. Positive staining for NE markers in combination with negative staining for PSA and AR and a high MIB-1 LI substantiated the diagnosis of a NE-SCC. We suggest that this tumour has a stem cell origin and does not derive from a dedifferentiated adenocarcinoma or from benign NE cells of the prostatic epithelium. This clear distinction of NE-SCC from NE-negative undifferentiated carcinoma is in accordance with the differing biological behaviour and response to therapy of the two tumour entities.

Immunohistochemical analysis of the proliferative activity of neuroendocrine tumors from various organs. Are there indications for a neuroendocrine tumor-carcinoma sequence?

Small-cell neuroendocrine carcinomas (NECs) of the prostate are believed not to derive from benign orthotopic NE epithelial cells. Instead, an origin from a putative stem cell is actually the most favored concept. Whether this concept can also be applied to neuroendocrine tumors (NETs) of other organs, especially whether there are indications for well-differentiated NET-NEC sequence, is subject of the present study. A double-labeling technique for the proliferation marker MIB-1 and the NE markers chromogranin A (ChrA) and synaptophysin (SNP) was used for the immunohistochemical analysis of 45 well-differentiated NETs, 16 well-differentiated (low-grade) NECs, and 63 high-grade NECs of the esophagus, stomach, small intestine, appendix, colon, lung, prostate, and urinary bladder. The lowest proliferative activity was found in NETs (0.85% of tumor cells), and the highest activity was found in high-grade NECs (72.5%). The expression of ChrA was highest in NETs and lowest in high-grade NECs. None of the NETs and only sporadic cells in low-grade NECs showed double labeling (up to 0.05%). Up to 50% of the tumor cells in high-grade NECs were positive for MIB-1 and SNP. The percentage of double-labeled cells ranged between 0.9 and 39.6 (mean 9.7). No double-labeled cells were found in the normal epithelium adjacent to the tumors. Transitions from NET to NEC could not be observed. NETs and low-grade NECs differ in their proliferative activity from high-grade NECs, suggesting that they may arise from different precursor cell populations.

Nucleolar and argyrophilic nucleolar organizer region counts in urothelial carcinomas with special emphasis on grade II tumors.

Prognostic assessment of bladder carcinomas of intermediate differentiation is difficult. This study therefore investigated the prognostic values of nucleolar status and silver staining of argyrophilic nucleolar organizer regions (AgNORs) in grade II bladder carcinomas. In biopsies from 34 grade II transitional cell carcinomas of the urinary bladder the number of nuclei with nucleoli, the location of nucleoli within the nucleus and the number of AgNORs were determined in 1000 or 200 nuclei per section respectively. Ten biopsies showing normal urothelium, 18 cases with mild to severe atypia, 27 grade I, 34 grade II and 12 grade III transitional cell carcinomas were also studied. Significantly differing nucleolar and AgNOR values were found comparing normal urothelium/grade I carcinomas with severe urothelial atypia/grade III carcinomas. Grade II carcinomas, however, were inhomogeneous. One subgroup had nucleolar and AgNOR values resembling grade I carcinomas while the second group had values similar to those of grade III carcinomas. This subdivision of grade II carcinomas correlates with results reported for DNA-cytometry. The results suggest a subdivision of patients with grade II transitional cell carcinomas into a low risk and high risk group.

Osteoclast-like giant cell tumour of the pancreas presenting as a pseudocyst-like lesion.

A 57-year-old male patient presented with a cystic lesion in the tail of the pancreas, which was considered to be a pseudocyst. He was treated by cystojejunostomy but one year later a tumour was found to have invaded the stomach and jejunum. This was an osteoclast-like giant cell tumour containing a small area of typical ductal adenocarcinoma. Immunohistochemical staining revealed that the pleomorphic tumour cells were positive for cytokeratin, epithelial membrane antigen, vimentin and the proliferation marker MIB-1. The osteoclast-like giant cells and some small histiocytic cells stained for leukocyte common antigen and histiocytic markers and were negative for MIB-1. At autopsy, tumour rests were found in the pancreas but there were no metastases. Osteoclast-like giant cell tumours of the pancreas may present as cystic lesions and should be included in the differential diagnosis of pseudocysts.