类固醇受体辅活化子-1和核受体辅阻遏子在雄激素非依赖性前列腺癌的表达及临床意义

目的 探讨类固醇受体辅活化子-1（SRC-1）、核受体辅阻遏子（NCoR）在雄激素非依赖性前列腺癌（AIPC）的表达及临床意义。方法 采用免疫组化法检测20例激素依赖性前列腺癌（ADPC）、15例AIPC组织AR、SRC-1及NCoR表达。结果 1例AIPC无AR表达，其余AIPC及ADPC高表达AR。AIPC、ADPC均检测到SRC-1表达。SRC-1在AIPC的阳性率较ADPC组织明显升高（P〈0．01）。NCoR在AIPC、ADPC均有表达，但在AIPC的表达则出现明显降低（P〈0．01）。结论 SRC-1在AIPC表达升高和／或NCoR在AIPC表达降低引起的AR异常活化可能与前列腺癌（Pca）的进展有关。     

Hedgehog signalling in androgen independent prostate cancer

Objectives

Androgen-deprivation therapy effectively shrinks hormone-naïve prostate cancer, both in the prostate and at sites of distant metastasis. However prolonged androgen deprivation generally results in relapse and androgen-independent tumour growth, which is inevitably fatal. The molecular events that enable prostate cancer cells to proliferate in reduced androgen conditions are poorly understood. Here we investigate the role of Hedgehog signalling in androgen-independent prostate cancer (AIPC).

Methods

Activity of the Hedgehog signalling pathway was analysed in cultured prostate cancer cells, and circulating prostate tumour cells were isolated from blood samples of patients with AIPC.

Results

AIPC cells were derived through prolonged culture in reduced androgen conditions, modelling hormone therapy in patients, and expressed increased levels of Hedgehog signalling proteins. Exposure of cultured AIPC cells to cyclopamine, which inhibits Hedgehog signalling, resulted in inhibition of cancer cell growth. The expression of the Hedgehog receptor PTCH and the highly prostate cancer–specific gene DD3^PCA3 was significantly higher in circulating prostate cancer cells isolated from patients with AIPC compared with samples prepared from normal individuals. There was an association between PTCH and DD3^PCA3 expression and the length of androgen-ablation therapy.

Conclusions

Our data are consistent with reports implicating overactivity of Hedgehog signalling in prostate cancer and suggest that Hedgehog signalling contributes to the androgen-independent growth of prostate cancer cells. As systemic anti-Hedgehog medicines are developed, the Hedgehog pathway will become a potential new therapeutic target in advanced prostate cancer.     

Germline CAG repeat length of the androgen receptor and time to progression in patients with prostate cancer treated with androgen deprivation therapy

Study Type – Prognosis (retrospective cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Germline CAG repeat polymorphisms in the androgen receptor (AR‐CAG) have been shown to influence the activity of the androgen receptor, but there has been conflicting data from small retrospective studies evaluating the effect of CAG repeat polymorphisms on response to ADT. This is the largest published study to date investigating the association of germline AR‐CAG repeat lengths and efficacy of ADT in prostate cancer. Germline AR‐CAG repeat lengths do not predict response to ADT.

OBJECTIVES

? Germline CAG repeat polymorphisms in the androgen receptor (AR‐CAG) have been shown to influence the activity of the AR. ? The purpose of the present study was to determine if AR‐CAG repeat length correlates with time to progression on androgen deprivation therapy (ADT).

PATIENTS AND METHODS

? Germline AR‐CAG repeat lengths were determined in a cohort of 480 patients with recurrent or metastatic prostate cancer treated at a single tertiary care institution and correlated to time to progression (TTP) and overall survival.

RESULTS

? There was no significant correlation between differences in the AR‐CAG repeat lengths and TTP or overall survival in patients with prostate cancer receiving ADT. ? AR‐CAG repeat lengths did not significantly correlate with age, prostate‐specific antigen (PSA), Gleason score or clinical stage at diagnosis. ? In patients with metastatic disease, longer AR‐CAG repeat lengths (>23 vs ≤23) were associated with a longer TTP on ADT, but this finding was of borderline significance (median TTP 18.3 vs 15.5 months, P= 0.09; adjusted HR = 0.76, 95% confidence interval = 0.54–1.09).

CONCLUSIONS

? This is the largest published study to date investigating the association of germline AR‐CAG repeat lengths and efficacy of ADT in prostate cancer. ? Germline AR‐CAG repeat lengths do not predict response to ADT.     

Androgen receptor expression is associated with prostate cancer‐specific survival in castrate patients with metastatic disease

Study Type – Aetiology (case series)
Level of Evidence 4

OBJECTIVE

To investigate whether baseline (before treatment) clinical variables and tumour specimen characteristics (including the androgen receptor, AR) from patients with castrate‐resistant metastatic prostate cancer can be used to predict the time to prostate cancer‐specific mortality and overall survival, as AR levels in prostate cancer have been associated with disease progression, including prostate‐specific antigen (PSA) recurrence and systemic metastasis.

PATIENTS AND METHODS

Haematoxylin and eosin (H&E) slides/blocks and outcome data from a 104 castrate patients with metastatic disease (43 prostatectomy and 61 prostate needle biopsy samples), were independently reviewed; H&E morphometry and quantitative immunofluorescence were used to assess the samples. Sections were analysed with a multiplex quantitative immunofluorescence (IF) assay for cytokeratin‐18 (epithelial cells), 4′,6‐diamidino‐2‐phenylindole (nuclei), p63/high molecular weight keratin (basal cells), AR and α‐methyl CoA‐racemase. Images were acquired with spectral imaging software and processed for quantification with IF algorithms.

RESULTS

The median follow‐up was 12 years from diagnosis; 49 men (47%) baseline PSA levels of ≥ 20 ng/mL, 55 (53%) had a Gleason sum of 8, 63 (60%) died from the disease and 40% were alive (censored). In all, 66 patients had evaluable IF features, and the association with outcome was evaluated by univariate Cox modelling and support‐vector regression. PSA was the only clinical variable associated with outcome (concordance index, CoI, 0.41; P < 0.05, log‐rank test). The amount of AR present within tumour nuclei (regardless of tissue provenance and primary treatment) significantly correlated with a greater risk of a shorter time to prostate cancer‐specific mortality (CoI 0.36; P < 0.05 log‐rank test). There were no H&E features that correlated with mortality.

CONCLUSION

By univariate analysis, increased nuclear AR expression in either the diagnostic biopsy and/or radical prostatectomy specimen, from patients with advanced disease, was associated with a reduced time to prostate cancer‐specific mortality.     

Cryoablative response of prostate cancer cells is influenced by androgen receptor expression

OBJECTIVE

To investigate in prostate cancer cells the consequences of androgen‐insensitivity (AI) development on the cellular and molecular responses to freezing, as a challenge in prostate cancer treatment occurs when the androgen‐sensitive (AS) phenotype switches to an AI phenotype, the latter of which is often refractory to many therapies.

MATERIALS AND METHODS

PC‐3 (AI) and LNCaP (AS) were each genetically altered to express the opposite phenotype and subjected to an in vitro freezing model. Viability, caspase inhibitor and Western blot studies were used to determine the basis of the differential responses of AI and AS cells.

RESULTS

LNCaP high‐passage cells, formed by repeated passage of LNCaP (AS) cells, were AI and showed a phenotypic shift to freeze resistance matching the freeze response of PC‐3 cells (AI). While stably transfected androgen receptor (AR)‐transfected cells (PC‐3 AR) had a freezing sensitivity similar to that of the LNCaP (AS) cell line. Importantly, AI cell lines survived and recovered from freezing exposure to temperatures as low as ?40 °C whereas AS cell lines did not. Caspase inhibition studies and related fluorescent probes showed an elevated level of apoptotic involvement in both AS cell lines after freezing compared with their AI counterparts. Western blot analysis showed that AR expression was modified after exposure to freezing.

CONCLUSION

This study suggests that AS cancers may be far more sensitive to a freezing insult and this might be linked to elevated apoptosis and caspase activity. As such, cryoablation may prove most effective in cancer cells that have not yet progressed to a more resistant AI phenotype, but both generic variants can be fully ablated at sufficiently low temperatures.     

Key targets of hormonal treatment of prostate cancer. Part 1: the androgen receptor and steroidogenic pathways

OBJECTIVE

Knowledge of the molecular and cellular changes that occur during the transition of hormone‐naïve to castration‐resistant prostate cancer (CRPC) is increasing rapidly. This might provide a window of opportunity for (future) drug development, and for treating patients with these potential devastating states of disease. The objective of this review is to provide an understanding of the mechanisms that prostate cancer cells use to bypass androgen‐deprived conditions.

METHODS

We searched PubMed for experimental and clinical studies that describe the molecular changes that lead to CRPC.

RESULTS

CRPC remains dependent on a functional androgen receptor (AR), AR‐mediated processes, and on the availability of intraprostatic intracellular androgens. CRPCs might acquire different (molecular) mechanisms that enable them to use intracellular androgens more efficiently (AR amplification, AR protein overexpression, AR hypersensitivity), use alternative splice variants of the AR protein to mediate androgen‐independent AR functioning, and have altered co‐activator and co‐repressor gene and protein expression. Furthermore, CRPCs might have the ability to synthesise androgens de novo from available precursors through a renewed and up‐regulated synthesis of steroid‐hormone converting enzymes. Blocking of enzymes key to de novo androgen synthesis could be an alternative means to treat patients with advanced and/or metastatic disease.

CONCLUSION

In CRPC, prostate cancer cells still rely on intracellular androgens and on an active AR for growth and survival. CRPCs have gained mechanisms that enable them to use steroids from the circulation more efficiently through altered gene expression, and through a renewed and up‐regulated synthesis of steroid hormone‐converting enzymes. Additionally, CRPCs might synthesise AR isoforms that enable AR mediated processes independent from available androgens.     

Key targets of hormonal treatment of prostate cancer. Part 2: the androgen receptor and 5α‐reductase

OBJECTIVE

The inhibition of 5α‐reductase (5AR) blocks the synthesis of the most powerful intracellular androgen, dihydrotestosterone (DHT). The prostate has two 5AR isoenzymes (5AR1 and 5AR2) that change in expression and cellular location during the development of prostate cancer and tumour progression. The objective of this review is to provide an understanding of the pharmacological properties and the potential clinical benefits of 5AR inhibition.

METHODS

We searched Pubmed for data obtained from pharmacological, preclinical and clinical studies.

RESULTS

5AR1 expression increases with increasing aggressiveness and extension of malignant prostatic disease. Conversely, 5AR2 expression decreases from benign prostatic tissue to localized prostate cancer. The efficacy of 5AR2 monotherapy with finasteride alone or in combination with an androgen receptor antagonist on more final outcome measures seems to be limited. Combining an androgen receptor antagonist with a 5AR inhibitor in patients with asymptomatic, locally advanced or recurrent prostate cancer might be a reasonable first therapeutic hormonal approach. As plasma testosterone levels are maintained, beneficial effects on quality of life, potency and sexual function are expected. From studies on the dual 5AR inhibitor dutasteride, the drug produces a biochemical response in some men who progressed under androgen‐deprivation therapy, and is generally well tolerated.

CONCLUSIONS

Achieving more potent suppression of intracellular DHT synthesis by 5AR inhibition is expected to provide clinical benefit to patients. Previous studies have shown that 5AR inhibition, by dutasteride in particular, halts/delays the progression of disease, and might even cause regression of disease in patients with advanced prostate cancer.     

Expression of the tumour antigen T21 is up-regulated in prostate cancer and is associated with tumour stage

What's known on the subject? and What does the study add? T21 is an immunogenic prostate‐associated tumor antigen identified by SEREX expression cloning and shown to have a highly restricted mRNA expression profile. This study shows the expression of T21 at the protein level in a panel of tissues and cell lines and demonstrates increasing levels of T21 protein expression in patients with more advanced stage prostate cancer.

OBJECTIVES

• ? To define the expression pattern of the tumour antigen T21 at the protein level in prostate tissues, prostate cell lines and a panel of normal tissues.
• ? To correlate the expression pattern of T21 in prostate cancer with clinical parameters.

PATIENTS AND METHODS

• ? Tissue samples were collected from 79 patients presenting at clinic with either prostate cancer (63 patients) or benign prostatic hyperplasia (BPH, 16 patients).
• ? A tissue microarray (TMA) was constructed from 44 of the prostate cancer tissues and areas of benign disease (43 patients) from these tissues were also included on the TMA. The remaining tissues (prostate cancer 19 patients and BPH 16 patients) were mounted fresh frozen onto cork boards and sectioned.
• ? Full ethical approval was granted for all aspects of the study and informed patient consent was taken before tissue collection.
• ? Immunohistochemistry was used on the prostate tumour TMA, the normal tissue TMA and the fresh‐frozen prostate tissues. Fluorescent microscopy and flow cytometry was performed on prostate cell lines.

RESULTS

• ? Expression of T21 was highly restricted within normal tissues with only the stomach, ovary, breast and prostate having detectable T21 expression.
• ? T21 was significantly over‐expressed in prostate cancer glands compared with benign tissue and was present in >80% of the malignant specimens analysed.
• ? Increased expression was positively correlated to pathological stage of prostate tumours.
• ? Additionally, T21 was associated with Gleason grade and prostate‐specific antigen recurrence, although statistical significance was not reached in this restricted cohort of patients.

CONCLUSION

• ? Taken together these results show that T21 is a potential new biomarker for advanced disease and that elevated levels of T21 appear relevant to prostate cancer development.

     

Hunterian Lecture. Characterisation of human prostate epithelial progenitor differentiation in response to androgens

INTRODUCTION

A stem cell model of prostate cancer tumourigenesis explains progression to castration resistant prostate cancer (CRPC) and offers novel perspectives in targeting this cancer in its more advanced forms. Androgen receptor (AR) regulated pathways are central mechanisms in progression to CRPC. However, AR was thought to be lacking in prostate stem cell enriched fractions. Potential low levels of AR expression in stem cell enriched cells were investigated and potential direct effects of androgen were examined.

METHODS

Human prostate stem cell enriched populations, based on high α₂β₁ integrin expression (α₂β₁^hi), were selected from primary human prostate tissue in men undergoing transurethral prostatectomy or cystoprostatectomy. Effects on differentiation were assayed with flow cytometry using differentiation-specific markers.

RESULTS

Low levels of AR were demonstrable in α₂β₁^hi cells following inhibition of the proteasome using MG132. Furthermore, a direct effect of androgen was shown in stabilising/inducing AR expression. Androgen treatment of α₂β₁^hi cells was associated with the induction of differentiation using a number of differentiation-specific markers (prostatic acid phosphatase, cytokeratin 18 and AR) with increases ranging from 49% to 67% (p<0.05). These effects were blocked with the AR-specific inhibitor bicalutamide (p<0.05). These data support a role of direct androgen activity on stem cell enriched cells in the prostate and the implications of these findings are discussed.     

Association of the ABCG2 C421A polymorphism with prostate cancer risk and survival

OBJECTIVE

To determine if the C421A single nucleotide polymorphism (SNP) in the ATP‐binding cassette transporter ABCG2 increases prostate cancer risk or affects survival.

PATIENTS, SUBJECTS AND METHODS

Numerous studies have suggested that dietary, hormonal and environmental factors all play a role in the initiation in prostate cancer; among these, the carcinogenic heterocyclic amine 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP), a known substrate of the ABCG2. A SNP of ABCG2, C421A, resulting in a glutamine to lysine change at amino acid 141, has been shown to result in decreased function of the protein. Due to the expression of ABCG2 in the prostate, together with the purported role of dietary carcinogens and steroids in the development and progression of prostate cancer, 311 individuals were genotyped for the ABCG2 C421A SNP, 170 patients with androgen‐independent prostate cancer (AIPC) and 141 ‘healthy’ controls. We also evaluated the effect of this SNP on the intracellular accumulation of PhIP and testosterone in vitro.

RESULTS

There were no significant differences in the prevalence of prostate cancer based on ABCG2 genetic variation in this population. However, survival was significantly longer for individuals with wild‐type ABCG2, as compared with those hetero‐ or homozygous for the C421A SNP (7.4 years vs 5.3 years, P = 0.044). Intracellular accumulation of PhIP was 80% higher in HEK293 cells transfected with Q141K ABCG2 than in wild‐type cells, confirming that this SNP decreases transport of PhIP. In contrast, testosterone was not transported by either wild‐type or variant transfected cells, nor did it act as in inhibitor of ABCG2 in subsequent transport assays.

CONCLUSION

Increased exposure to PhIP may decrease survival, but the ABCG2 C421A polymorphism does not appear to increase the risk of prostate cancer.     

A phase II study of high-dose calcitriol combined with mitoxantrone and prednisone for androgen-independent prostate cancer

OBJECTIVE

To evaluate the preliminary efficacy, safety, and impact on quality of life (QoL) of high‐dose calcitriol (DN‐101) combined with mitoxantrone and glucocorticoids in androgen‐independent prostate cancer (AIPC).

PATIENTS AND METHODS

Nineteen patients with metastatic AIPC and no previous chemotherapy received DN‐101 180 µg orally on day 1 and mitoxantrone 12 mg/m² intravenously on day 2 every 21 days with continuous daily prednisone 10 mg orally for a maximum of 12 cycles. A confirmed decline in prostate‐specific antigen (PSA) levels by half was the primary endpoint. QoL was evaluated using the European Organization for Research and Treatment of Cancer QLQ‐C30 questionnaire, and pain and analgesic use were evaluated.

RESULTS

Five of 19 patients (26%; 95% confidence interval, CI, 9–51) achieved a ≥50% decline in PSA level. The median (95% CI) time to PSA progression was 16 (6–26) weeks. The overall median (95% CI) survival was 16 (6–26) months; 47 (21–73)% of patients achieved an analgesic response. Toxicity was similar to that expected with mitoxantrone and prednisone alone. The QoL analysis suggested a decrease in physical functioning and increase in fatigue, insomnia, and diarrhoea.

CONCLUSIONS

DN‐101 given every 3 weeks does not add significant activity to mitoxantrone and prednisone in AIPC, as measured by the PSA decline. The high rate of analgesic response is encouraging. The addition of DN‐101 does not appear to increase the toxicity of mitoxantrone.     

Activation of the mammalian target of rapamycin signalling pathway in prostate cancer and its association with patient clinicopathological characteristics

OBJECTIVE

To evaluate the activation level of the mammalian target of rapamycin (mTOR) signalling pathway in Chinese patients with prostate cancer, as this pathway is over‐activated in many human cancers and is an attractive target for cancer therapy.

PATIENTS AND METHODS

We used immunohistochemistry to investigate the activation level of five important markers of the mTOR pathway, including PTEN, p‐Akt, p‐mTOR, p‐p70S6K and p‐4E‐BP1, in tissues from 182 patients with prostate cancer, 20 with benign prostatic hyperplasia (BPH) and 10 with high‐grade prostatic intraepithelial neoplasia (HGPIN). The expression levels of these five markers were associated with patient clinical and pathological characteristics.

RESULTS

Expression levels of p‐Akt, p‐mTOR, p‐4E‐BP1 and p‐p70S6K were significantly higher in prostate cancer tissues than in BPH and HGPIN tissues. In 182 patients with prostate cancer the p‐mTOR expression level significantly and positively correlated with its upstream p‐Akt and downstream p‐4E‐BP1 and p‐p70S6K expression levels. The cancer Gleason score was significantly correlated with p‐Akt and p‐mTOR expression level but not with p‐4E‐BP1 and p‐p70S6K expression level. However, the p‐4E‐BP1and p‐p70S6K expression levels in primary cancer lesions were statistically significantly correlated with patient T stage and distant metastases.

CONCLUSIONS

Most patients with prostate cancer have at least one component of the mTOR signalling pathway activated. The activation of the mTOR pathway might be involved in prostate cancer development and progression. The association between activation of mTOR pathway and patient clinicopathological variables suggested that not all patients are equally amenable to treatment strategies targeting the mTOR pathway.     

Patients aged more than 70 had higher risk of locally advanced prostate cancers and biochemical recurrence in Korea

Study Type – Prognosis (cohort series) Level of Evidence 2b What's known on the subject? and What does the study add? This study reports that patients aged 70 years or older have a higher possibility of locally advanced cancer than younger patients. Instead of conservative management, radical eradication of clinically localized prostate cancer should be actively considered in well‐selected healthy patients older than 70 years.

OBJECTIVE

• ? To analyse the differences in the clinicopathological results between two groups of Korean patients aged younger or older than 70 years with clinically localized prostate cancer.

METHODS

• ? A cohort of consecutive male patients who underwent radical prostatectomy was retrospectively analysed. In total, 995 patients (74.6%) were younger than 70 years, and 338 patients (25.4%) were 70 years or older.
• ? Biochemical recurrence (BCR) ‐free survival was evaluated in the patients, who were followed up for more than 24 months.
• ? The Kaplan–Meier method was used to calculate survival estimates for BCR‐free survival. Multivariate Cox proportional hazard regression analysis was performed to predict non‐organ‐confined status and BCR.

RESULTS

• ? Mean preoperative prostate‐specific antigen (PSA) levels and biopsy or pathological Gleason scores showed no differences between the two age groups.
• ? Older patients, aged more than 70 years, displayed significantly higher risk of locally advanced prostate cancer and BCR than younger patients.
• ? Subgroup analysis showed that the risk of the presence of locally advanced disease was significantly increased in patients of 70 years or older when we compared the proportion of locally advanced disease only in patients with PSA <4 ng/mL.
• ? Multivariate analysis showed that old age, high PSA and high Gleason score were significantly associated with non‐organ confined status and BCR.

CONCLUSIONS

• ? Patients aged 70 years or older had a higher possibility of locally advanced cancer than younger patients.
• ? Radical eradication of clinically localized prostate cancer should be actively considered in well‐selected healthy patients older than 70 years.

     

A systems-based modelling approach using transurethral resection of the prostate (TURP) specimens yielded incremental prognostic significance to Gleason when predicting long-term outcome in men with localized prostate cancer

Study Type – Prognosis (individual cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Systems models have been successfully utilised to accurately define risk in men with prostate cancer. This study addresses the challenges when using TURP specimens to yield predictive models.

OBJECTIVE

? To develop a systems‐based model for predicting prostate cancer‐specific survival (PCSS) using a conservatively managed cohort with clinically localized prostate cancer and long‐term follow‐up.

PATIENTS AND METHODS

? Transurethral prostate (TURP) specimens in tissue microarray format and medical records from a 758 patient cohort were obtained. ? Slides were stained with haematoxylin and eosin (H&E), imaged and digitally outlined for invasive tumour. ? Additional sections were analysed with two multiplex quantitative immunofluorescence (IF) assays for cytokeratin‐18 (epithelial cells), 4′‐6‐diamidino‐2‐phenylindole(nuclei), p63/high‐molecular‐weight keratin (basal cells), androgen receptor (AR) and α‐methyl CoA‐racemase, Ki67, phosphorylated AKT (pAKT)and CD34. ? Images were acquired with spectral imaging software. H&E and IF images were evaluated with image analysis algorithms; feature data were integrated with clinical variables to construct prognostic models for outcome.

RESULTS

? Using a training set of 256 patients with 24% events, one clinical variable (Gleason score) and two tissue‐specific characteristics (H&E morphometry and tumour‐specific pAKT levels) were identified (concordance index [CoI] 0.79, sensitivity 76%, specificity 86%, hazard ratio [HR] 6.6) for predicting PCSS. ? Validation on an independent cohort of 269 patients with 29% events yielded a CoI of 0.76, sensitivity 59%, specificity 80% and HR of 3.6. ? Both H&E and IF features were selected in a multivariate setting and added incremental prognostic value to the Gleason score alone (CoI 0.77 to CoI 0.79). ? Furthermore, global Ki67 expression and AR levels in Gleason grade 3 tumours were both univariately associated with outcome; however, neither was selected in the final model.

CONCLUSION

? A previously validated prostate needle‐biopsy systems modelling approach that integrates clinical data with reproducible methods to assess H&E morphometry and biomarker expression, provided incremental benefit to the TURP Gleason score for predicting PCSS. ? Ki67 and AR, known to be associated with outcome in the prostate needle biopsy, were not associated with PCSS in multivariate models using TURP specimens.     

Overexpression of nuclear AR-V7 protein in primary prostate cancer is an independent negative prognostic marker in men with high-risk disease receiving adjuvant therapy

Background

Overexpression of the androgen receptor (AR) splice variant 7 (AR-V7) has recently been reported to be associated with resistance to antihormonal therapy. Herein, we address the question whether tumor cells with AR-V7 expression can be detected at the time of radical prostatectomy, that is, before long-term hormonal manipulation and castration resistance, and what the potential prognostic impact on the biochemical recurrence (BCR)-free survival may be.

Precursor of prostate‐specific antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 90 cases

OBJECTIVE

To assess the expression of the precursor of prostate‐specific antigen (pro‐PSA), a distinct molecular form of serum‐free PSA that includes native and truncated forms, in benign epithelium, high‐grade prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma.

MATERIALS AND METHODS

We immunohistochemically evaluated 90 formalin‐fixed, paraffin‐embedded prostate needle biopsies using monoclonal antibodies against [?2] pro‐PSA, native [?5/?7] pro‐PSA, prostate‐specific membrane antigen (PSMA), PSA and racemase. Staining intensity was recorded using a scale of 0–3 (0, no staining; 3, highest staining). The percentage of immunoreactive cells in benign epithelium, high‐grade PIN and adenocarcinoma was estimated in increments of 10%.

RESULTS

All cases had [?5/?7] pro‐PSA immunoreactivity. There was weak focal perinuclear cytoplasmic immunoreactivity for [?5/?7] pro‐PSA in 62% (range 0–90%) of benign epithelial cells, whereas there was strong diffuse cytoplasmic staining in 83% (range 10–90%) of high‐grade PIN and 87% (range 40–90%) of cancer cells. Almost all (99%) cases were immunoreactive for [?2] pro‐PSA. The median (range) proportion of cells expressing [?2] pro‐PSA was lower in benign epithelium, at 17 (0–80)%, than in high‐grade PIN, at 55 (0–90)% (P < 0.001) and adenocarcinoma, at 55 (0–100)% (P < 0.001). The intensity of immunoreactivity for both isoforms increased from benign to neoplastic (high‐grade PIN and adenocarcinoma) epithelium. A total of 31% of high‐grade PIN and 11% of cancer cases with negative racemase staining showed strong staining for [?5/?7] pro‐PSA.

CONCLUSION

The expression of [?5/?7] pro‐PSA in benign and neoplastic cells might be used in combination with high molecular weight keratin, p63, and racemase to distinguish benign epithelium from high‐grade PIN and adenocarcinoma, particularly when racemase staining is negative. Both isoforms are sensitive markers for prostatic epithelium, making them possible candidates for investigating carcinoma with an unknown primary, particularly in cases in which PSA staining is negative and the level of suspicion is high.