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H Bonkhoff

Publications and source records attributed to H Bonkhoff.

At least 37 records · Page 2Linked to original sources
PubMed1999

Comparative genomic hybridization reveals DNA copy number gains to frequently occur in human prostate cancer.

BACKGROUND: Despite intensive studies over many years, there is only limited knowledge on the genetic changes underlying the development and progression of prostate cancer. No specific prostate carcinoma-related genetic event has yet been identified. METHODS: In order to gain an overall view of regional chromosome gains and losses, comparative genomic hybridization (CGH) was used on a series of 16 prostate adenocarcinomas. Five benign prostate hyperplasia (BPH) samples were also evaluated. RESULTS: Using CGH, chromosome alterations were observed in 81% of the prostate carcinomas analyzed. Gains of DNA copy numbers were found as the predominant imbalance, with chromosomes 3q (56%), 12q (56%), 8q (50%), Xq (50%), 4 (44%), 6q (44%), 5 (38%), 7q (38%), 9p (38%), and 13q (31%) being most frequently involved. Whereas DNA copy number gains comprised the whole chromosome or almost a whole arm of chromosomes 4, 5, 6, 9, and 13, the minimal overlapping regions on the other chromosomes were mapped to 3q25-q26, 8q21-q22, 12q13-q21, 7q31, and Xq22-q25. High-level amplifications were not found. Other chromosomes with nonrandom gains or losses of DNA sequences were discovered. The five BPH samples were found to be normal. CONCLUSIONS: Amplification events at different chromosomal sites seem important in prostate cancer development. A new chromosome region with DNA copy number gains was identified on 12q, while other regions on 3q, 7q, 8q, and Xq were confirmed or narrowed down, indicating a possible role of known or putative protooncogenes in these regions for prostate cancer growth. Our low detection rate of DNA losses may to some part be explained by CGH immanent technical limitations.

Adenocarcinoma↗
PubMed1999

Simultaneous detection of DNA fragmentation (apoptosis), cell proliferation (MIB-1), and phenotype markers in routinely processed tissue sections.

In situ DNA fragmentation assays have proved to be particularly useful in the detection of apoptosis in routinely processed, paraffin-embedded tissue sections. In the present study, a triple-antigen labelling technique was performed to demonstrate DNA fragmentation (apoptosis), cell proliferation (MIB-1), and phenotypic markers in the same tissue section. The in situ apoptosis assay was conducted with the TUNEL method developed by a avidin-biotin alkaline phosphatase complex (ABcomplex/AP). The proliferation-associated MIB-1 antigen was demonstrated in the second staining sequence by the avidin-biotin peroxidase method (ABC). The phenotypic markers chromogranin A or prostate-specific antigen (PSA) were visualized by the alkaline phosphatase anti-alkaline phosphatase method (APAAP) in the third staining sequence. The feasibility of this triple-labelling technique was tested in formalin-fixed, paraffin-embedded tissue of prostatic adenocarcinomas from 8 patients with recurrent, hormone-refractory disease. Although these tumours revealed marked neuroendocrine differentiation, cell proliferation and apoptosis were detected exclusively in non-endocrine (chromogranin A-negative) tumour cells that expressed PSA variably. The triple-labelling protocol described here allows the phenotypic characterization of proliferating and apoptotic cell populations in the same tissue section. It may be useful in studies of tissue kinetics in physiological and pathological processes.

Antigens, Nuclear↗
PubMed1999

Estrogen receptor expression in prostate cancer and premalignant prostatic lesions.

Estrogens have been implicated in prostatic cancerogenesis and tumor progression. The mechanisms underlying estrogen signaling in human prostate tissue, however, remain poorly understood. Using immunohistochemical and in situ hybridization (ISH) techniques, the present study demonstrates the classical estrogen receptor (ERalpha) in premalignant lesions and prostatic adenocarcinoma through the various stages of the disease. Conversely, the novel characterized ERbeta subtype was undetectable in human prostate tissue. High-grade prostatic intraepithelial neoplasia revealed ERalpha mRNA and protein expression in 28% and 11% of cases evaluated. Focal ER immunoreactivity was detected in a minority of low- to intermediate-grade adenocarcinoma. High-grade (primary Gleason grade 4 and 5) tumors revealed ER protein expression in 43% (62% respectively) of cases. The most significant ERalpha gene expression on mRNA and protein levels was observed in hormone refractory tumors and metastatic lesions, including lymph node and bone metastases. Results of the current study suggest that estrogens can affect prostatic cancerogenesis and neoplastic progression through an ER-mediated process in human prostate tissue.

Adenocarcinoma↗
PubMed1999

Carcinosarcoma, endometrial intraepithelial carcinoma and endometriosis after tamoxifen therapy in breast cancer.

The fourth case of heterologous mesodermal tumour of the uterine corpus, that developed, years following tamoxifen therapy for breast cancer in a postmenopausal woman with no previous pelvic irradiation, is presented with coincidental endometriosis and endometrial intraepithelial carcinoma. This coincidence after tamoxifen treatment appears to be an indication for the possible carcinogenic potency of tamoxifen.

Aged↗
PubMed1999

Focal intratumoral heterogeneity for telomerase activity in human prostate cancer.

PURPOSE: The value of telomerase activity as a marker in clinical decision-making is closely related to how representative the analysis of a small tumor sample is for the whole tumor. We therefore evaluated the intratumoral distribution pattern of telomerase activity in prostatic carcinomas. MATERIALS AND METHODS: From 50 prostate cancer patients treated with radical prostatectomy, telomerase activity was determined using the telomeric repeat amplification protocol (TRAP assay). Comparative analysis of at least two separate cancer areas from a single tumor was performed in 42 cases. RESULTS: Telomerase activation has been demonstrated in 90% of the prostatic carcinomas. Focal intratumoral heterogeneity was found in 38.1% of the tumors with at least two different areas examined. Telomerase positivity of all samples from one given tumor was detected in 50%, telomerase negativity of all samples in 11.9%. A heterogeneous telomerase activity pattern was more frequently detected in tumors with a Gleason score < or = 7 than in those with a Gleason score > 7. Furthermore, there was an increase in the proportion of homogeneously telomerase-positive tumors with increase in severity of the Gleason score. The differences reached statistical significance. Telomerase activity was also detected in non-cancerous prostatic tissue samples. CONCLUSIONS: Telomerase activation is nearly ubiquitous in prostatic carcinomas, although a heterogeneous telomerase activity pattern within tumors might produce a false-negative result in the telomerase activity assay. This limits the value of telomerase activity assays for diagnostic means. There is evidence for a shift from telomerase-negative prostate cancer tissue toward telomerase positivity during the progression process of prostate cancer. The relatively high proportion of telomerase-positive nonmalignant prostatic tissue samples argues against cancer-specificity of telomerase activation.

Humans↗
PubMed1998

In situ hybridization analysis of genes coding collagen IV alpha1 chain, laminin beta1 chain, and S-laminin in prostate tissue and prostate cancer: increased basement membrane gene expression in high-grade and metastatic lesions.

BACKGROUND: Recent immunohistochemical data have shown that invasive prostate cancer cells are separated from the host tissue by basement membranes (BM), and express associated adhesive molecules that bind to these de novo synthesized extracellular matrices. METHODS: In the present study, we used in situ hybridization techniques to determine steady-state levels of genes coding BM components (alpha1 chain of collagen IV, laminin beta1 chain, and S-laminin) in prostate tissue obtained from 15 radical prostatectomy specimens and 5 lymph node metastases of common prostatic adenocarcinomas. RESULTS: In benign prostate tissue, transcripts of these genes were detected predominantly in the basal cell layer, indicating that components of epithelial BMs are synthesized by basal cells and not by stromal cells. The cancerous lesions investigated revealed increasing collagen IV, laminin beta1 chain, and S-laminin mRNA levels when compared with benign prostate tissue. The highest steady-state levels were found in high grade (primary Gleason grade 4 and 5) carcinoma and lymph node metastases, and were predominantly localized in epithelial compartments of the cancerous tissue. CONCLUSIONS: These findings indicate that neoplastic BM in prostatic adenocarcinoma derive from tumor cells and not from the host tissue. Increasing transcriptional activities of genes coding BM components detected in poorly differentiated and metastatic lesions may accelerate the BM-forming process, which probably contributes to the ability of tumor cells to penetrate the extracellular matrix during the process of stromal invasion and metastasis.

Adenocarcinoma↗
PubMed1998

Relation between Bcl-2, cell proliferation, and the androgen receptor status in prostate tissue and precursors of prostate cancer.

BACKGROUND: Several recent studies have suggested an important role of the apoptosis suppressing Bcl-2 gene product in prostate cancer progression to an androgen-insensitive disease. METHODS: Using double-labeling techniques, we have investigated the nuclear androgen receptor (AR) status and the proliferation-associated MIB-1 antigen immunoprofile of Bcl-2 expressing cell types in benign prostate tissue, and high-grade prostatic intraepithelial neoplasia (HGPIN). RESULTS: In the peripheral and transition zone of the prostate gland, 77% of cycling (MIB-1 positive) epithelial cells coexpressed the Bcl-2 product and were phenotypically basal cells. Bcl-2 immunoreactive basal cells showed markedly reduced levels of the nuclear AR. In the central zone of the gland, increasing Bcl-2 immunoreactivity was detected in secretory luminal cell types that expressed the nuclear AR at low levels. 22% of HGPIN lesions (47 of 216 cases) overexpressed Bcl-2 in secretory luminal cell types, while most of HGPIN lesions (78%) showed the normal Bcl-2 phenotype restricted to the basal cell layer. No correlation was found between the Bcl-2 status and proliferative activity (P > 0.05). Conversely, markedly reduced levels of nuclear AR were detected in HGPIN overexpressing the Bcl-2 gene product. CONCLUSIONS: The present data suggest that Bcl-2 prevents the proliferation compartment from apoptotic cell death. The aberrant expression of the Bcl-2 gene product in subsets of HGPIN is associated with decreasing levels of the nuclear AR and may confer resistance to the androgen-dependent apoptotic cell death in the dysplastic epithelium.

Animals↗
PubMed1998

[Benign microglandular prostate lesions. Diagnostic criteria na differential diagnosis].

The scope of the present review is to define diagnostic criteria of benign prostatic lesions causing diagnostic difficulty in surgical pathology. The prostate harbors a variety of small acinar lesions that may mimic prostate cancer in biopsy specimens. Generally, the most important diagnostic clues are obtained on low-power magnification by assessing architectural features. Atypical adenomatous hyperplasia (AAH) is a small acinar proliferation closely related to hyperplastic glands. Diagnostic features of postatrophic hyperplasia include a lobular small acinar proliferation associated with atrophic and dilated acini. Basal cell hyperplasia and sclerosing adenosis show characteristic stromal changes that are uncommon in prostate cancer. Additional cytological features and intraluminal secretions are also important in the diagnostic evaluation of small acinar lesions in biopsy specimens. Negative immunohistochemical results obtained with basal-cell-specific cytokeratins should be evaluated in context with other diagnostic criteria. The unequivocal demonstration of basal cells in small acinar lesions excludes invasive cancer. Other rare small acinar lesions must be recognized when assessing biopsy specimens, including verumontanum-mucosa hyperplasia, Cowper's glands and mesonephroid hyperplasia. The various small acinar lesions discussed in the present review have no clinical significance, except atypical adenomatous hyperplasia (AAH), which may be a precursor of small acinar cancer of the transition zone. The biological and clinical significance of AAH, however, remains to be established.

Atrophy↗
PubMed1998

[Morphogenesis of benign prostatic hyperplasia and prostatic carcinoma].

Enlargement of the prostate is an age-related, physiological process that is unique in human tissue. The prostate gland is the most common site of neoplastic disorders in men. Despite the growing impact of the various prostate diseases in terms of morbidity and mortality, the pathogenesis of benign prostate hyperplasia (BPH) and prostate cancer remains poorly understood. This reflects the complex composition of the gland with different anatomic, cellular and functional compartments that are differentially involved in benign and malignant disease processes. The present review summarizes new concepts on the morphogenesis of normal and abnormal growth in the human prostate. There is increasing evidence that prostatic stem cells are located in the basal cell layer that is basically involved in normal growth and the development of glandular hyperplasia and prostate cancer. High-grade prostatic intraepithelial neoplasia is considered the most likely precursor of clinically important cancer of the peripheral zone. Severe differentiation and proliferation abnormalities occur during malignant transformation of the prostatic epithelium. These premalignant changes are associated with abnormal expression of growth factor receptors, oncogene and suppressor gene products and genetic instability. During the process of stromal invasion the transformed cells lose their basal cell phenotype and produce basement membrane-like matrices. Common prostate cancer is mainly composed of exocrine cell types that remain androgen-responsive even in hormone-independent disease. The frequent occurrence of neuroendocrine differentiation in common prostate cancer reflects the differentiation potency of its stem cells. The endocrine phenotype derives from exocrine tumor cells via intermediate (amphicrine) cell types. Neuroendocrine tumor cells consistently lack the nuclear androgen receptor and represent an androgen-insensitive cell population in prostate cancer.

Cell Transformation, Neoplastic↗
PubMed1998

[Diagnostic criteria of prostatic carcinoma].

The histological diagnosis of prostate cancer relies on a combination of structural and cytological findings. Structural features are assessed at low power magnification. Malignant glands are recognised by their abnormal size, shape and location in relation to the surrounding benign glandular structures. The presence of pathological intraluminal secretions (pink amorphous secretions, crystalloids, blue-tinged mucinous secretions) is always suspicious, but not diagnostic for prostate cancer. Cytological criteria including nuclear and nucleolar enlargement, hyperchromasia and cytoplasmic changes have to be evaluated in comparison with the cytological features of surrounding benign glands. The presence of prominent nucleoli is neither diagnostic for malignancy nor represents an absolute requirement for the diagnosis of prostate cancer. The basal cell layer is absent in invasive adenocarcinoma, an important feature that has to be evaluated with care since benign glands may also lack detectable basal cells. The immunohistochemical demonstration of basal cells with high molecular weight cytokeratins excludes invasive cancer. This article reviews the histological criteria for the diagnosis of prostate cancer, including variants of common adenocarcinoma and therapy-induced changes.

Adenocarcinoma↗
PubMed1998

[Diagnostic criteria and differential diagnosis of prostatic intraepithelial neoplasia].

Prostatic intraepithelial neoplasia (HGPIN) is considered the most likely precursor of clinically significant prostate cancer. Biopsy remains the only definitive method for detecting these premalignant lesions. In this article we review the diagnostic criteria of HGPIN and discuss histological features that allow their distinction from other benign and malignant lesions. PIN is recognised at low power magnification as a thickened, basophilic and hyperchromatic epithelium in pre-existing acinar duct structures. This important histological feature is due to nuclear crowding and stratification. Distinction between HGPIN and low grade PIN (LGPIN), a lesion with little clinical significance, is made mainly on the presence or absence of prominent nucleoli. HGPIN lesions always retain an intact or fragmented basal cell layer. The different growth patterns of HGPIN (tufting, micropapillary, cribriform and flat) have no clinical significance but should be considered in the differential diagnosis together with normal structures, and both benign and malignant lesions. HGPIN has a high predictive value as a marker for prostate cancer but should not influence therapeutic decisions. Its identification in biopsy specimens warrants close surveillance with repeated biopsy.

Biopsy↗
PubMed1998

Morphogenetic concepts of normal and abnormal growth in the human prostate.

Benign prostatic hyperplasia (BPH) and prostate cancer are multifactorial disease processes, involving a growing number of biochemical, genetic and epigenetic factors. Their pathogenesis, however, remains poorly understood. The present review examines current morphogenetic concepts of normal and abnormal growth in the human prostate. This includes the role of basal cells in organogenesis and cancerogenesis, the impact of cell-matrix interactions, and the importance of cellular heterogeneity in tumour progression and hormone-insensitive growth. Knowledge of morphogenesis and morphology is required in any scientific approach to BPH and prostate cancer.

Cell Differentiation↗
PubMed1998

p53 autoantibodies in patients with urological tumours.

OBJECTIVE: To determine the presence of p53 serum antibodies in patients with clinically well-defined urological cancer using a new enzyme-linked immunosorbent assay (ELISA). PATIENTS AND METHODS: The study included 73 patients with prostatic cancer, 72 with transitional cell carcinoma of the urinary tract, 37 with renal cell cancer and 16 controls with a benign disease, all of whom were tested using the ELISA for p53 autoantibodies. The specific reaction of the ELISA (positive p53 antibody titre) was confirmed by Western Blot analysis. RESULTS: Thirteen patients with cancer and one control patient (7.6% overall) were positive for p53 autoantibodies. The sensitivity of the test was low, whereas the specificity was remarkably high. Surprisingly, 9 of the 13 p53-positive patients died within a median of 3.7 months (range 2-6) and the one positive control patient died of undetected lung cancer. There was no significant correlation of p53 antibody positivity with clinical stage or tumour-specific differences. CONCLUSIONS: The expression of p53 autoantibody seems to be a very late but significant event in urological tumour development, with the worst outcome (tumour-specific death) within a few weeks of developing positivity. In histopathologically heterogeneous tumour entities, p53 autoantibodies might be independent prognostic factors in patients with urological cancers.

Autoantibodies↗
PubMed1998

Neuroendocrine cells in benign and malignant prostate tissue: morphogenesis, proliferation, and androgen receptor status.

BACKGROUND: The presence of neuroendocrine (NE) differentiation in benign and neoplastic prostate tissue has attracted increasing attention in contemporary prostate cancer research. METHODS: The present review focuses on the proliferation and androgen receptor (AR) status of NE phenotypes and their morphogenetic origin in benign and malignant prostate tissue. RESULTS: Recent data have documented phenotype relation between NE cells and other cell lineages in benign and malignant prostate tissue indicating their common origin. NE cell types (as defined by the most commonly used endocrine marker, chromogranin A) do not show evidence of cell proliferation and consistently lack the nuclear AR in both benign and malignant conditions. CONCLUSIONS: Prostatic NE cells most likely derive from local stem cells and represent terminally differentiated and androgen-insensitive cell populations in benign prostate tissue. The frequent occurrence of NE differentiation in prostatic adenocarcinoma obviously reflects the differentiation repertoire of its stem cells. Neoplastic NE cells devoid of nuclear AR constitute an androgen-insensitive cell population in prostate cancer. Furthermore, the absence of proliferation activity may endow NE tumor cells with relative resistance toward cytotoxic drugs and radiation therapy.

Adenocarcinoma↗
PubMed1998

Analytical molecular pathology of epithelial-stromal interactions in the normal and neoplastic prostate.

OBJECTIVE: To review recent data on epithelial-stromal interactions, recognized as playing an important role in prostatic growth in vitro. STUDY DESIGN: The present review summarizes recent data on gene expression of basement membrane (BM) components and related integrin receptors reported in human prostate tissue and discusses potential implications of these adhesive elements in prostatic carcinogenesis and tumor progression. RESULTS: Benign glandular structures and premalignant prostatic lesions (prostatic intraepithelial neoplasia, high grade (HGPIN)) are surrounded by BM and form stable hemidesmosomes. Early stromal invasion is associated with the loss of both hemidesmosome-associated adhesive elements (laminin 5, collagen type VII, alpha 6, beta 4 integrins) and basal cell differentiation. Invasive tumor cells produce BM-like matrices and express related integrin receptors. Increasing transcriptional activity of BM encoding genes has been found in poorly differentiated and metastatic lesions. CONCLUSION: The inability of transformed cells to express hemidesmosome structures and related adhesive elements appears to be a crucial event in neoplastic progression of HGPIN to early stromal invasion and may account for the definitive loss of basal cell differentiation during this process. Formation of de novo synthesized BM and adhesion via specific receptors may significantly contribute to the ability of prostate cancer cells to penetrate the extracellular matrix during stromal invasion and metastasis.

Cell Division↗
PubMed1997

[Primary fallopian tube carcinoma. Report of a single case with review of the literature].

With an incidence of 0.1-1.0% of all genital malignancies, primary fallopian tube carcinoma is an extremely uncommon neoplasm of the female genital tract. We report a 58-year-old postmenopausal woman with primary fallopian tube carcinoma confined to the right fallopian tube in primary stage pT2a pN0 G3 M0, who is alive without evidence of disease 2 years after abdominal hysterectomy, bilateral adnexectomy, omentectomy and lymphonodectomy followed by an adjuvant cisplatin (70 mg/m2) and treosulfan (5 g/m2) chemotherapy. An accompanying literature review indicates that clinical signs and symptoms of fallopian tube neoplasms are usually nonspecific and include lower abdominal pain. The primary treatment remains surgical resection followed by adjuvant chemotherapy or radiation. Prognosis is poor, although long-term survivors have been reported.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Relationship between atypical adenomatous hyperplasia (AAH), prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma.

Two histopathologic lesions are considered putative precursors of prostate cancer, but the supportive evidence for one (prostatic intraepithelial neoplasia, or PIN) is much greater than the other (atypical adenomatous hyperplasia, or AAH). High grade PIN is the most likely precursor of carcinoma, arising in the peripheral zone, but probably does not account for well-differentiated cancer arising in the transition zone. The biological significance of atypical adenomatous hyperplasia of the prostate (AAH) is inconclusive at the time. The histological and cytological features of AAH are intermediate between BPH and low grade carcinoma, suggesting that AAH may be a precursor of well differentiated transition; zone carcinoma. In the recent time new findings on morphogenetic aspects of normal and abnormal prostatic growth i.e. stem cell models are discussed and topics about grading and proliferative activities, frequency and histological changes associated with aging as well as clinical relevance of PIN and AAH. This paper reviews the results and discussion at the second international consultation meeting on PIN in Mayo Clinic, Rochester, Nov. 3-4 th. 1995, following the first international consultation meeting of AAH and PIN and origin of the prostatic carcinoma in Ancona, Sept. 11-12 th 1994.

Adenocarcinoma↗