Biomedical subjects

J Köllermann

Publications and source records attributed to J Köllermann.

At least 19 recordsLinked to original sources

PubMed2006

Methylation of tumour suppressor genes APAF-1 and DAPK-1 and in vitro effects of demethylating agents in bladder and kidney cancer.

To examine the significance of the methylation level of the p53 target and tumour suppressor genes apoptotic protease activating factor-1 (APAF-1) and death-associated protein kinase-1 (DAPK-1) in 80 microdissected tumour samples from transitional cell carcinoma (TCC) of the bladder and 80 tumour samples from clear-cell renal cell carcinoma (RCC) as well as from non-tumourous bladder and kidney tissue. Growth-inhibitory effects of the demethylating agents 5-Aza-2'-deoxycytidine (5-Aza-CdR) and zebularine were investigated in TCC and RCC cell lines. The methylation frequency of APAF-1 (DAPK-1) was 100% (77%) in TCC and 100% (33%) in RCC. The methylation levels of APAF-1 could differentiate between the individual tumour stages in TCC as well as in RCC. The APAF-1 methylation levels in RCC were significantly higher in tumours larger than 4 cm and in high-grade tumours. The methylation frequencies in normal tissue for APAF-1 (DAPK-1) were 11% (8%) in bladder tissue and 9% (5%) in kidney tissue. The growth-inhibitory effect of the demethylating agents in TCC (RT4, T24) and RCC (A498, ClearCa-5) cell lines resulted in a 17-132% prolongation of the doubling time (DT). In RCC cell lines, zebularine was superior to 5-Aza-CdR in achieving a DT prolongation. Quantitative real time RT-PCR detected a re-expression of mRNA transcripts of APAF-1 or DAPK-1. In conclusion, demethylating agents effectively retard growth of TCC and RCC cell lines. Methylation level analysis of specific genes has the potential for further tumour characterisation in TCC and RCC.

Aged↗

PubMed2004

[Therapy induced regressive changes of prostate cancer].

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.

Androgen Antagonists↗

PubMed2001

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.

Antigens, Nuclear↗

PubMed2001

[Sudden cardiac death from unrecognized cardiac sarcoidosis].

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.

Adult↗

PubMed2001

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.

Antigens, Nuclear↗

PubMed2001

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.

Chemotherapy, Adjuvant↗

PubMed2001

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.

Carcinoma↗

PubMed2000

[Revisions in the WHO histological classification of urothelial bladder tumors and flat urothelial lesions].

Recently the World Health Organization published a new classification of urinary bladder tumors which is intended to take into account better the biology of the various lesions and to better distinguish between clearly benign and malignant lesions. We examine the possible diagnostic and clinical impact of the new classification, including recent immunohistochemical findings. Papillary urothelial lesions include papillomas, papillary neoplasms of low malignant potential, and papillary carcinomas. Flat urothelial lesions include hyperplasia, reactive atypia/atypia of unknown significance, dysplasia, and carcinoma in situ. Invasive patterns of papillary carcinomas are discussed, with special emphasis on lamina muscularis mucosae substaging. The most important feature of the new classification is its differentiation of two types of low-grade, noninvasive papillary urothelial lesions: papillary neoplasm of low malignant potential vs. papillary carcinoma. Long-term follow-up studies are needed to determine the clinical significance of this differentiation.

Carcinoma, Transitional Cell↗

PubMed2000

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.

Antigens, Nuclear↗

PubMed2000

Nondetected tumor (pT0) after prolonged, neoadjuvant treatment of localized prostatic carcinoma.

OBJECTIVES: 135 patients with stage T1-3N0M0 prostatic carcinoma were submitted to prolonged PSA-monitored neoadjuvant endocrine treatment (PPNET). The rate of pT0 reports was three times higher (15%) than after the standard 3-month therapy (5%). The present work was done to elucidate the initial characteristics of these tumors, to see if additional workup of these prostatectomy specimens is able to detect tumor vestiges and, if so, to describe their morphology. METHODS: The original clinical and histopathological data of 20 pT0 cases were reviewed and an additional histopathological workup of the prostatectomy specimens was done. RESULTS: The majority of patients had initially small (9 patients cT1, 8 patients cT2, 3 patients cT3) and well-differentiated tumors (18 patients Gleason score <7). Microscopic assessment of 4,503 slides revealed very small tumor remnants (mean volume 0.2 ml) in 13 of the 20 prostatectomy specimens. Severe tumor regression was seen in 3 cases, slight to moderate regression in 10 cases. CONCLUSIONS: A pT0 report following detailed routine histopathological workup has to be regarded as a maximal therapeutic effect, but not as tumor elimination. PPNET clearly increases the rate of pT0 reports, implicating that the conventional 3 months of pretreatment does not exploit the possibilities of neoadjuvant therapy.

Androgen Antagonists↗

PubMed1999

Comparative immunocytochemical assessment of isolated carcinoma cells in lymph nodes and bone marrow of patients with clinically localized prostate cancer.

After radical prostatectomy for clinically localized prostate cancer, biochemical progression is seen in up to 40% of the patients due to persistent local and/or systemic remnants. Isolated disseminated carcinoma cells, undetectable by current staging methods, are of special interest as potential precursors of subsequent overt metastases. In the present study, immunohistochemistry (IHC) was performed to evaluate simultaneously the frequency of occult carcinoma cells in both lymph nodes (LNs) and bone marrow (BM) obtained from the iliac crests of 45 prostate cancer patients with untreated stage T(1-3) pN0 M0 prostatic carcinoma. IHC using monoclonal antibodies (MAbs) against epithelial cytokeratins was performed on 521 paraffin-embedded LNs histopathologically classified as tumorfree (pN0), as well as on BM cytospin preparations. To confirm the prostatic origin of positive cells in LNs, additional IHCs for prostate-specific antigen (PSA) and epithelial glycoproteins were performed. In total, isolated tumor cells in LNs and/or BM were detected in 17 of the 45 patients. Parameters such as tumor stage, grade and volume of the primary tumor as well as blood serum PSA levels could not detect patients harboring disseminated single tumor cells in LNs or BM. Following a median observation time of 24.9 months, no significant correlation between IHC positivity and PSA progression as a measure of early relapse was observed. Although the overall incidence of occult tumor cell spread corresponds to similar incidence of relapses after radical prostatectomy as reported by others, the fate of these cells needs to be evaluated in longer follow-up studies.

Bone Marrow Neoplasms↗

PubMed1999

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.

Adenocarcinoma↗

PubMed1999

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.

Antigens, Nuclear↗

PubMed1999

Atypical acinar proliferations of the prostate.

Small acinar lesions of the prostate may mimic prostate cancer. In the central and transition zone of the prostate, atypical adenomatous hyperplasia (AAH) must be differentiated from low grade carcinoma (Gleason score 2-5). In the dorso-peripheral zone, high grade prostatic intraepithelial neoplasia (PIN) and atypical small acinar proliferations (ASAP) are the most important lesions mimicking carcinoma. Further differentiation is necessary between high grade PIN and intraductal carcinoma. ASAP, on the other hand, may mimic low grade carcinoma. The significance of basal cell type cytokeratin immunohistochemistry (IHC) in the differentiation between ASAP and low grade carcinoma of the prostate was substantiated by additional MIB-1 IHC. The status of the basal cell layer in ASAP was found to be variable (complete, fragmented and absent). Independent of the status of the basal cell layer, the mean MIB-1 proliferation index of ASAP was significantly higher than that of clearly benign lesions and did not differ from that of low grade carcinoma. As carcinoma is frequently detected in rebiopsies, close clinical follow up of patients with ASAP is advisable.

Antigens, Nuclear↗

PubMed1999

Neuroendocrine differentiation in prostatic carcinomas: histogenesis, biology, clinical relevance, and future therapeutical perspectives.

Since the introduction of immunohistochemistry, there is an increasing interest in neuroendocrine (NE) differentiation in prostatic carcinomas. Focal NE differentiation in prostatic adenocarcinomas is a very frequent finding. It is subject of numerous studies, since a negative impact on prognosis and an important role in antiandrogen therapy failure are suspected. NE-differentiated small-cell carcinoma is a very rare tumor comprising 0.5-2% of all prostatic carcinomas. Nevertheless, although very rare, it is of clinical importance because it is one of the most aggressive tumors of the prostate with a very poor prognosis. This review is focused on actual concepts of histogenesis, cell biology, clinical implications, and possible future therapeutic perspectives of these two tumor entities.

Adenocarcinoma↗

PubMed1998

Supersensitive PSA-monitored neoadjuvant hormone treatment of clinically localized prostate cancer: effects on positive margins, tumor detection and epithelial cells in bone marrow.

OBJECTIVE: The present study was done to investigate the effects of supersensitive PSA-controlled inductive treatment on positive margins, detection of tumor and epithelial cells in bone marrow of 101 patients with untreated and clinically localized prostatic carcinoma (cT1-3N0M0). METHODS: Hormonal treatment was given until PSA (DPD Immulite(R) third-generation assay) reached <0.1 ng/ml or the nadir value, as shown by two consecutive measurements at monthly intervals. RESULTS: The resultant median duration of treatment was 6 months (range 3-22). Ninety-three (93%) of our patients reached a PSA value <0.1 ng/ml. The nadir of 6 patients (6%) was between 0.1 and 0.3 ng/ml, and it remained >0.3 ng/ml in only 1 case. Of the 101 patients, 82 had a measurable hypoic lesion on initial transrectal ultrasound. 84% of these became smaller, 7.5% remained unchanged and 8.5% increased. Of the 101 prostatectomy specimens, 20 (20%) were margin-positive. The incidence of affected margins was relatively high (35% from 55 patients) with cT3 tumors, but almost negligible (2% from 46 patients) in cT1-2 tumor. Our pathologists, despite their great experience in evaluating hormonally treated prostates (>500 cases) and using immunohistochemical staining, were unable to detect carcinoma in 15 (15%) specimens. Whereas only 2 (4%) of the 55 cT3 specimens were without detectable tumor, this incidence rised to 28% (13 of 46 prostates) in patients with cT1-2 tumors. Of the initial 29 patients with epithelial cells in bone marrow, only 4 (14%) remained positive after controlled induction and all of them had fewer cells than before. CONCLUSION: Endocrine induction controlled by a supersensitive PSA assay and continued until reaching PSA nadir is highly effective in clearing surgical margins and eliminating tumor cells from bone marrow. It seems to be clearly superior to the conventional 3 months of pretreatment at least in cT1-2 tumors in respect to surgical margins and detectability of tumor in the resected prostate. A definitive statement about the value of endocrine induction can only be given by prospective randomized studies, with optimal drugs, doses and treatment time. But the conventional 3 months of pretreatment are far from exploiting the possibilities of this therapeutic option.

Androgen Antagonists↗

PubMed1997

Immunocytochemical monitoring of micrometastatic disease: reduction of prostate cancer cells in bone marrow by androgen deprivation.

Occult dissemination of tumor cells mainly determines the prognosis of patients with primary prostate cancer. The effect of androgen deprivation on micrometastatic tumor cells in these patients is currently unknown. We therefore used an immunocytochemical assay with monoclonal antibodies (MAbs) directed against epithelial cytoskeleton proteins (i.e., cytokeratins) to monitor the concentration of isolated tumor cells in the bone marrow of 36 prostate cancer patients (stage C), who underwent hormonal androgen deprivation with Flutamide and Leuprorelin acetate. Tumor cells in cytologic bone marrow preparations were detected using an assay that employed the MAb CK2 directed against cytokeratin (CK) 18 and the alkaline anti-alkaline phosphatase staining method. Prior to therapy, we detected between 1 and 38 CK-positive cells per sample of 2 x 10(6) nucleated cells in 21 patients, while the remaining 15 patients displayed tumor-free marrow samples. There was no significant correlation between the concentration of CK-positive cells and the volume of hypo-echogenic lesions as an indicator of the primary tumor volume or the serum level of prostate-specific antigen (PSA). After androgen deprivation, 20 of the 21 initially positive patients either became negative (n = 16) or showed at least a reduction in the concentration of CK-positive cells (n = 4). Moreover, only 2 of the 15 patients with negative pre-treatment findings became positive. All of the 7 patients with remaining tumor cells in the bone marrow after therapy showed no detectable amounts of PSA in their serum. Our findings suggest that serum PSA concentration is no indicator of micrometastatic disease in bone marrow. Neoadjuvant androgen deprivation appears to eliminate disseminated CK-positive tumor cells present in bone marrow, a preferred site of overt metastasis in prostate cancer patients.

Adenocarcinoma↗

PubMed1996

[Experiences from consultation in prostatic diseases].

With the introduction of the terms atypical adenomatous hyperplasia (AAH) and prostatic intraepithelial neoplasia (PIN), the spectrum of prostatic diseases has been distinctly enlarged. With more sophisticated diagnostics, however, diagnostic and differential diagnostic problems grow more important. At the institute of pathology in Singen, this issue is reflected by the increasing use of the uropathologic consultation service since 1989. The purpose of this paper is to demonstrate typical diagnostic and differential diagnostic problems in the pathology of the prostate on the basis of this consultation service. 573 submitted prostatic cases were evaluated and the final diagnoses were compared to the preliminary diagnoses by the primary pathologist. Frequent differences could be detected in the 3 following groups: 1. Differentiation of sclerosing adenosis versus well differentiated adenocarcinoma 2. Differentiation of AAH versus well differentiated adenocarcinoma 3. Differentiation of high grade PIN versus poorly differentiated adenocarcinoma 4. Differentiation of glandular G II a versus G II b carcinomas. Possible decision guidelines are presented.

Biopsy, Needle↗