[Implications of estrogens and their receptors for the development and progression of prostate cancer]. / Bedeutung der Ostrogene und ihrer Rezeptoren für die Entstehung und Progression des Prostatakarzinoms.

The recent discovery of the estrogen receptors alpha and beta (ERalpha, ERbeta) and the progesterone receptor (PR) in human prostate tissue offers new insights into the role of estrogens and their receptors in prostate cancer development and tumor progression. The differentiation compartment of the prostatic epithelium (secretory luminal cells) expresses high levels of ERbeta, while the ERalpha is restricted to the proliferation compartment (basal cells). In high grade prostatic intraepithelial neoplasia (HGPIN), ERalpha gene expression extends to luminal cells and thus may mediate cancerogenic effects of estrogens on the dysplastic epithelium. Conversely, the ERbeta is downregulated in HGPIN indicating that the chemopreventive effects of phytoestrogens mediated by the ERbeta are partially lost. Irrespective of grades and stages, prostate cancer retains high levels of the ERbeta which is partially lost in androgen-insensitive stages of the disease. In contrast with breast cancer, the presence of the ERalpha and the PR is a late event in prostate cancer progression. At least 30% of metastatic and androgen-insensitive tumors express high levels of the PR indicating that these tumors harbor a functional ERalpha. The antiestrogen Raloxifene has growth-inhibitory effects on androgen-insensitive prostate cancer cells in vitro and induces the apoptotic cell death in a dose-dependent fashion. These data provide a rational for clinical trials to study the efficiency of antiestrogens in the medical treatment of advanced prostate cancer.

[Gleason grading: diagnostic criteria and clinical implications]. / Gleason-Grading Diagnostische Kriterien und klinische Bedeutung.

Prostate cancer offers a wide spectrum ranging from clinically insignificant to aggressive and fatal disease. The Gleason grade is a powerful prognostic indicator and does influence treatment decision. Educational programs and websites are currently available to improve reproducibility and reliability of Gleason grading. A major problem in reporting of Gleason grading in needle biopsy is undergrading. The Gleason grade 3 is the lowest grade which can be assigned reliably in needle biopsies. The major prognostic shift is between Gleason grades 3 und 4 which is characterized by fusion of the glandular formations. Reporting the proportion of Gleason grades 4 and 5 in needle biopsies may be critical in terms of treatment decisions. The present review deals with diagnostic criteria of the Gleason grades and its clinical implications.

[Neuroendocrine differentiation in prostate cancer: an unrecognized and therapy resistant phenotype]. / Neuroendokrine Differenzierung im Prostatakarzinom. Ein Marker für die Androgen- und Strahlenresistenz.

Neuroendocrine (NE) differentiation frequently occurs in common prostatic malignancies but usually escapes pathological and clinical detection. The present review focuses on biological properties of NE tumor cells making them resistant to androgen deprivation and radiation therapy. Recent data have shown that NE prostate cancer cells (as defined by the most commonly used endocrine marker chromogranin A) are arrested in the G0-phase of the cell cycle and do not undergo apoptosis. This particular phenotype consistently lacks the nuclear androgen receptor in both benign and malignant conditions but produces a series of hormonal growth factors exerting mitogenic stimuli on adjacent, exocrine tumor cells. Neoplastic NE cells devoid of the nuclear androgen receptor constitute an androgen-insensitive cell population in prostate cancer. The absence of proliferative and apoptotic activity makes NE tumor cells particularly resistant towards cytotoxic drugs and radiation therapy. Pathological and clinical detection of NE features is recommended for all prostate cancer patients for whom radiation therapy and androgen deprivation is being considered.

[Differential diagnosis of prostate cancer: impact of pattern analysis and immunohistochemistry]. / Differenzialdiagnose des Prostatakarzinoms. Rolle der Mustererkennung und der Immunhistochemie.

Prostate cancer offers a wide range of growth patterns depicted in the classical Gleason diagram. For each Gleason pattern exist a number of benign and malignant mimickers that can simulate prostatic adenocarcinoma. In the present review, the use of immunohistochemical markers is discussed with emphasis to a pattern-based approach to differential diagnosis in prostate pathology. Basal cell markers (34betaE12 and P63) are very useful to analyze histo-architectural features of small and large glandular lesions. AMACR (P504 s) is helpful not only in identifying small amount of cancer in needle biopsies but also in the diagnosis of high grade prostatic intra epithelial neoplasia (HGPIN). A number of lesions which may be confused with small acinar adenocarcinoma (Cowper's gland, nephrogenic metaplasia, mesonephric glands) and poorly differentiated prostate cancer (urothelial neoplasia, mucinous colon cancer and other metastatic lesions) lacks convincing PSA immunoreactivity. Basal cell markers and the nuclear androgen receptors are important markers to differentiate Gleason grade 5 A und 5 B patterns from prostatic involvement by transitional cell carcinoma. Finally, a selected panel of markers is useful to classify prostatic stromal lesions. In each case, immunohistochemical findings should be interpreted in context with the various patterns on routine microscopy.

[Prognostic factors in prostate cancer]. / Prognosefaktoren des Prostatakarzinoms.

Since several therapeutic options are currently available for clinically organ-confined prostate cancer, morphological parameters have rapidly emerged as prognostic factors to stratify patients into different therapeutic modalities. In addition to the PSA value, pathologic stage, as defined by the TNM system, Gleason grade and the surgical margin status, other markers have prognostic implications. This includes the percent pattern 4/5 cancer, tumor volume, intraductal spread, large volume perineural invasion and molecular markers. This review discusses the methods of sampling and reporting in prostate pathology with an emphasis on well established and new prognostic factors.

Simultaneous tumour-like, atypical basal cell hyperplasia and acinar adenocarcinoma of the prostate: a comparative morphological and genetic approach.

Basal cell tumours of the prostatic gland are rare, and the classification is difficult. In the present case report, a large, tumour-like proliferation of atypical basaloid cells was found incidentally in a prostatectomy specimen that otherwise contained a conventional acinar adenocarcinoma. The basaloid cells displayed a solid or adenoid-cystic growth pattern and strongly expressed high-molecular-weight cytokeratins and bcl-2. A high Ki-67 index was recorded within the atypical basaloid cells, by far exceeding the one counted in the conventional adenocarcinoma. However, there were no definite criteria for a malignant behaviour of the basal cell tumour. Comparative genomic hybridisation from microdissected tumour cells yielded losses at the short arms of chromosomes 8 and 12 in the conventional adenocarcinoma and a normal karyotype in the basal cell tumour. The pathological findings favoured the diagnosis of an atypical basal cell hyperplasia.

[Neuroendocrine differentiation in prostate cancer. An unrecognized and therapy-resistant phenotype]. / Neuroendokrine Differenzierung im Prostatakarzinom. Ein unerkannter und therapierefraktärer Phänotyp.

Neuroendocrine (NE) differentiation frequently occurs in common prostatic malignancies and has attracted increasing attention in contemporary prostate cancer research. This particular phenotype, however, usually escapes pathological and clinical detection in routine practice. The present review focuses on the biological properties of NE tumor cells that make them resistant to androgen deprivation and radiation therapy. NE cells produce a number of hormonal growth factors (e.g., serotonin) that may act through endocrine, paracrine, and autocrine mechanisms. Morphogenetic studies have identified intermediate phenotypes between the three basic cell types of the prostatic epithelium indicating their common origin from stem cells located in the basal cell layer. Virtually all prostatic adenocarcinomas show NE differentiation as defined by the most commonly used endocrine marker chromogranin A. Clinical studies suggest that the extent of NE differentiation increases with tumor progression and the development of androgen insensitivity. NE differentiation exclusively occurs in the G0 phase of the cell cycle in which tumor cells are usually resistant to radiation therapy and cytotoxic drugs. In addition, NE tumor cells also escape programmed cell death. Even under androgen deprivation, only 0.16% of NE tumor cells show apoptotic activity. This indicates that the vast majority of NE tumor cells represent an immortal cell population in prostate cancer. Although NE tumor cells do not proliferate, they produce a number of NE growth factors with mitogenic properties that maintain cell proliferation in adjacent (exocrine) tumor cells through a paracrine mechanism. NE tumor cells consistently lack the androgen receptor and are androgen insensitive in all stages of the disease. They derive through a process of intermediate differentiation from exocrine tumor cells, the most prevalent phenotype in common prostatic adenocarcinoma. Elevated serum levels of chromogranin A in prostate cancer patients correlate with poor prognosis and are scarcely influenced by either androgen deprivation or chemotherapy. Looking for NE differentiation is recommended in the pathological and clinical evaluation of prostate cancer patients for whom radiation and androgen deprivation are therapeutic options.

[New insights into the role of estogens and their receptors in prostate cancer]. / Neue Einblicke in die Rolle der Ostrogene und ihrer Rezeptoren im Prostatakarzinom.

The present review gives a survey on the differential expression of estrogen receptors alpha and beta (ERalpha, ERbeta) and the progesterone receptor (PR) in human prostate tissue and discusses their potential implications for normal and abnormal prostatic growth. The differentiation compartment of the prostatic epithelium (secretory luminal cells) expresses high levels of ERbeta, while the ERalpha is restricted to the proliferation compartment (basal cells). In high-grade prostatic intraepithelial neoplasia (HGPIN), ERalpha gene expression extends to luminal cells and thus may mediate cancerogenic effects of estrogens on the dysplastic epithelium. Conversely, the ERbeta is downregulated in HGPIN indicating that the chemopreventive effects of phytoestrogens mediated by the ERbeta are partially lost. Irrespective of grades and stages, prostate cancer retains high levels of the ERbeta, which is partially lost in androgen-insensitive stages of the disease. In contrast with breast cancer, the presence of the ERalpha and the progesterone receptor (PR) is a late event in prostate cancer progression. At least 30% of metastatic and androgen-insensitive tumors express high levels of the PR indicating that these tumors harbor a functional ERalpha. The antiestrogen raloxifene has growth-inhibitory effects on androgen-insensitive prostate cancer cells in vitro and induces apoptotic cell death in a dose-dependent fashion. These data provide a rationale for clinical trials to study the efficiency of antiestrogens in the medical treatment of advanced prostate cancer.

[Solid-pseudopapillary tumor of the pancreas in a 9-year-old girl]. / Solider-pseudopapillärer Tumor des Pankreas bei einem 9-jährigen Mädchen.

Solid-pseudopapillary tumor of the pancreas constitutes a very rare benign or low-grade malignant lesion occurring most commonly in young women and girls. It was first described by Frantz. Local infiltration, distant metastasis and recurrence are very rare. Until today, the histogenetic origin of the tumor cell remains to be elucidated. In 1996, solid-pseudopapillary tumor of the pancreas was introduced in the World Health Organization (WHO) classification of tumors of the exocrine pancreas. Our case report--like a recently published work by Lange et al.--intends to underline the significance of solid-pseudopapillary tumor in the differential diagnosis of a pancreatic mass.

Progesterone receptor expression in human prostate cancer: correlation with tumor progression.

BACKGROUND: The recent discovery of the classical estrogen receptor alpha (ERalpha) in metastatic and recurrent prostatic adenocarcinoma suggests that estrogens are implicated in prostate cancer progression. METHODS: To get more insight into estrogen signaling in prostate cancer tissue, the current study has examined the immunoprofile of the estrogen-inducible progesterone receptor (PR), and evaluated its relation to ERalpha gene expression. RESULTS: In primary tumors, the PR was detectable in 36% of primary Gleason grade 3 (5 of 14 cases), 33% of primary Gleason grade 4 (5 of 15 cases), and in 58% of primary Gleason grade 5 tumors (7 of 12 cases). None of the 41 primary tumors investigated revealed significant PR expression in more than 50% of tumor cells. Conversely, moderate to strong receptor expression was observed in 60% of metastatic lesions (9 of 15 cases), and in 54% of androgen-insensitive tumors (38 of 71 cases). Irrespective of grades and stages, the presence of the PR was invariably associated with high steady state levels of ERalpha mRNA, whereas the ERalpha protein was undetectable by immunohistochemistry (IHC) in a significant number of cases (58 of 97 cases). CONCLUSIONS: The progressive emergence of the PR during tumor progression obviously reflects the ability of metastatic and androgen-insensitive tumors to use estrogens through a ERalpha-mediated pathway. The present data provide a theoretical background for studying the efficiency of antiestrogens and antigestagens in the medical treatment of advanced prostate cancer.

Expression of CaT-like, a novel calcium-selective channel, correlates with the malignancy of prostate cancer.

The regulation of intracellular Ca(2+) plays a key role in the development and growth of cells. Here we report the cloning and functional expression of a highly calcium-selective channel localized on the human chromosome 7. The sequence of the new channel is structurally related to the gene product of the CaT1 protein cloned from rat duodenum and is therefore called CaT-like (CaT-L). CaT-L is expressed in locally advanced prostate cancer, metastatic and androgen-insensitive prostatic lesions but is undetectable in healthy prostate tissue and benign prostatic hyperplasia. Additionally, CaT-L is expressed in normal placenta, exocrine pancreas, and salivary glands. New markers with well defined biological function that correlate with aberrant cell growth are needed for the molecular staging of cancer and to predict the clinical outcome. The human CaT-L channel represents a marker for prostate cancer progression and may serve as a target for therapeutic strategies.

Neuroendocrine differentiation in human prostate cancer. Morphogenesis, proliferation and androgen receptor status.

BACKGROUND: The frequent occurrence of neuroendocrine (NE) differentiation in common prostatic malignancies has attracted increasing attention in contemporary prostate cancer research. METHODS: The present review focuses on growth properties and the androgen receptor (AR) status of NE phenotypes, and discusses their morphogenetic origin in benign and malignant prostate tissue. RESULTS: Recent data have documented a phenotype link between NE cells and other cell lineages encountered in benign and malignant prostate tissue. NE tumor cells (as defined by the most commonly used endocrine marker chromogranin A) do not proliferate or show apoptotic activity. This particular phenotype also lacks 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. The absence of proliferative and apoptotic activity may endow NE tumor cells with relative resistance towards cytotoxic drugs and radiation therapy.

Novel amplification unit at chromosome 3q25-q27 in human prostate cancer.

BACKGROUND: In prostate carcinoma, amplification of the genes c-MYC, Her2/NEU, and the androgen receptor gene has been documented, with gene amplification being related to progressive tumor growth. Recently, using comparative genomic hybridization (CGH), we provided evidence for DNA copy number gains at chromosome 3q25-q26 in prostate cancer [Sattler et al.: Prostate 39:79-86, 1999]. METHODS: In this study, additional prostatic tumors were evaluated by CGH to determine the frequency of DNA overrepresentation at 3q. Comparative PCR and Southern blot analyses were applied to determine whether known genes are involved in DNA copy number gains. RESULTS: By CGH, DNA copy number gains, all of which involved chromosome region 3q25-q26, were disclosed in 50% of the prostate tumors analyzed. There was no evidence for high-level amplification. The analysis of 12 genes from 3q25-q27 by comparative PCR revealed amplification in 6 (35.3%) of 17 tumors tested. Amplification was detected for the genes IL12A, MDS1, SLC2A2, and SOX2, with coamplification of three genes in two tumors. IL12A was amplified as single gene in three tumors and in a subline of the DU145 cell line, SLC2A2 in one tumor. CONCLUSIONS: Our studies revealed a novel amplification unit at 3q25-q27 in prostate carcinoma, with the genes IL12A, MDS1, SLC2A2, and SOX2 being located within the amplification unit. A common region of amplification was evident spanning the IL12A gene locus at 3q25-q26.2. Possibly, IL12A indicates an adjacent, till now unidentified gene which is important in the development of prostate cancer.

Chondral lesions after arthroscopic meniscus repair using meniscus arrows.

Meniscus repair using bioabsorbable devices has become popular in the last few years. Good clinical results have been reported and few complications have been published. This report describes the case of a 37-year-old male patient with a lateral meniscus repair using 4 Meniscus Arrows (Bionx Implants, Blue Bell, PA). Postoperatively, repeated episodes of intra-articular effusions have occurred. A second-look arthroscopy 8 months after the reconstruction showed that the meniscus tear had not healed and revealed the presence of chondral damage corresponding to the location of the arrows in the posterior area of the lateral femoral condyle. Surgeons using the Meniscus Arrow should be aware of this possible postoperative complication.

Littoral cell angioma of the spleen: CT and MR imaging appearance.

We report a case of littoral cell angioma (LCA) of the spleen, a recently described splenic pathology, which imaging characteristics and pathologic morphology have been discussed only by a few authors. The imaging findings in unenhanced and contrast-enhanced MRI and CT as well as histologic specimen are presented. Diagnosis was made after elective splenectomy. Differential diagnosis of splenic tumors as well as the imaging findings in this particular case are discussed.

Estrogen receptor gene expression and its relation to the estrogen-inducible HSP27 heat shock protein in hormone refractory prostate cancer.

BACKGROUND: The recent discovery of the classical estrogen receptor alpha (ERalpha) in androgen-insensitive prostate cancer has shed new light on the role of estrogens in endocrine therapy failure. To get more information on downstream events of estrogen signaling in these tumors, we investigated the relation between ERalpha gene expression, and the estrogen-inducible heat shock protein HSP27 in recurrent prostatic adenocarcinomas. METHODS: Palliative transurethral resection specimens from 50 patients with androgen-insensitive disease were submitted for study. Messenger RNA in situ hybridization for the ERalpha and immunohistochemistry of the HSP27 protein were performed on adjacent sections of an equal number of prostate cancer tissue with and without ERalpha protein expression. RESULTS: Cancerous lesions lacking the nuclear ERalpha at the protein level revealed ERalpha mRNA expression in 15 of 25 cases (60%). A coordinate expression of ERalpha mRNA and HSP27 was observed in 33 of 40 cases (83%), although a significant correlation between ERalpha protein and HSP27 expression was not obtained. Conversely, 90% of neoplastic lesions without detectable levels of ERalpha mRNA and protein also lacked HSP27 immunoreactivity. CONCLUSIONS: ERalpha gene expression at the mRNA level significantly correlated with the immunoprofile of the estrogen-inducible HSP27 protein in androgen-insensitive prostatic adenocarcinomas. This may indicate that these tumors harbor functional active estrogen receptors promoting transcriptional activity of the HSP27 gene. Determination of the receptor status by immunohistochemistry is unable to identify neoplastic lesions with established ERalpha mRNA expression in a substantial number of cases. HSP27 may be an additional surrogate biomarker for estrogen-regulated growth in androgen-insensitive prostate cancer.

Cellular and molecular pathology of prostate cancer precursors.

Prostate cancer is usually heterogeneous and multifocal, with diverse clinical and morphologic manifestations. Current understanding of the molecular basis for this heterogeneity is limited, particularly for prostatic intraepithelial neoplasia (PIN), the only putative precursor which can be identified according to morphologic criteria. However, it is likely that prostatic adenocarcinoma might arise from precursor lesions other than PIN, although these cannot be recognized with certainty at the present time. In this review, we summarize the current state of knowledge regarding the cell-biological and genetic bases for linking PIN and prostatic adenocarcinoma. It is conceivable that a stem cell of basal phenotype, or an amplifying cell, is the target of prostatic carcinogenesis. Prominent genetic heterogeneity is characteristic of both PIN and carcinoma; and multiple foci of PIN arise independently within the same prostate. This observation suggests that a field effect probably underlies prostatic neoplasia. Multiple foci of cancer also often arise independently, lending additional support to this hypothesis. The strong genetic similarities between PIN and cancer strongly suggest that evolution and clonal expansion of PIN, or other precursor lesions, may account for the multifocal etiology of carcinoma. Uncertainties with respect to identification of those precursor lesions which are most likely to progress to invasive and metastatic prostate cancer reinforce the requirement for objective immunohistochemical or molecular biological markers of the aggressive phenotype.

Expression of the human telomerase reverse transcriptase is not related to telomerase activity in normal and malignant renal tissue.

In this study, the association between telomerase activity and the expression of the human telomerase subunits human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) in paired neoplastic and normal renal tissue samples was investigated. Reverse transcription (RT)-PCR on 20 tumor nephrectomy samples revealed that hTR was constitutively expressed both in cancer and normal tissue samples, independent of the telomerase activity status. Remarkably, using in situ hybridization, the expression levels of hTR were found to be markedly higher in the normal tissue than those in the tumors. Expression of hTERT mRNA by RT-PCR was observed in 90% of the cancer samples and, notably, also in 75% of the corresponding normal renal tissue samples. Because all of the normal tissue samples and some of the tumor samples were shown to be telomerase negative, our findings suggest that hTERT mRNA expression is not sufficient for telomerase enzyme activation. Furthermore, semiquantitative RT-PCR revealed equal or even higher hTERT mRNA expression levels in the telomerase-negative normal samples than in the corresponding cancer samples with telomerase activity, contradicting the assumption that a certain threshold level of hTERT mRNA is required for telomerase activation at least in renal tissue. It seems more likely, that other mechanisms, such as posttranscriptional modification of hTERT or inactivation of telomerase inhibitors, are involved in the acquisition of enzyme activity.

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.