Trends in prostate needle biopsy diagnosis. A ten year experience of a medical center in Taiwan

Prostate cancer has seen a rapid rise in Taiwanese men. The current study was undertaken to evaluate trends of the disease diagnosed on prostate needle biopsy during a ten-year period at the Department of Pathology, Taipei Veterans General Hospital. The study included 8236 men who underwent a total of 9995 prostate needle biopsies at this institute from 1994 to 2003. Pathologic features pertinent to diagnosis of cancer were reviewed and compared for cases diagnosed before and after 1999. There were statistically significant increases of the overall cancer detection rate (from 17.6% to 19.9%), proportion of cases with a Gleason score ≤ 6 (from 16.6% to 40.9%) and focal adenocarcinoma (from 3.0% to 12.8%) in the latter 5 years. The incidence of high-grade prostatic intraepithelial neoplasia (HGPIN) increased from 0.1% to 1.5%. Patients with HGPIN had a significantly higher risk for subsequent cancer discovered on repeat biopsy than did those with a primary benign diagnosis (29.9% versus 13.7%). Despite a relatively lower incidence of cancer and HGPIN in Taiwanese men compared with that reported in Western studies, in recent years we have found an increase of relevant diagnoses, especially cancer of limited extent and lower grade, which may represent the progress in prostate cancer diagnosis.     

Aberrant CpG island hypermethylation of multiple genes in prostate cancer and prostatic intraepithelial neoplasia

To date, several reports have been published about CpG island methylation of various genes in prostate cancer. However, most of these studies have focused on cancer tissue only or a single gene and data about concurrent methylation of multiple genes in prostate cancer or prostatic intraepithelial neoplasia (PIN) are limited. The aim of the present study was to determine the methylation profile of 11 tumour-related genes in prostate cancer and PIN. Seventy-one samples, including 37 prostate cancers, 14 PINs, and 20 normal prostates, were examined for the methylation status of 11 tumour-related genes using methylation-specific PCR. The mean number of genes methylated was significantly higher in prostate cancer and PIN than in non-neoplastic prostate (4.4, 3, and 0.2, respectively; p < 0.001). In prostate cancer, APC, GSTP1, MGMT, and RASSF1A were frequently methylated at a frequency of 56.8%, 86.5%, 75.7%, and 83.8%, respectively. These genes were methylated in more than 30% of PINs. Prostate cancers with high serum prostate-specific antigen (PSA) (more than 8 ng/ml) or a high Gleason score (GS) (3 + 4 or more) showed higher numbers of methylated genes than those with low serum PSA (8 or less) or low GS (3 + 3 or less) (5.4 versus 2.5 and 5.4 versus 3.1, respectively; p < 0.05). The methylation frequency of APC, RASSF1A, and RUNX3 was higher in prostate cancers with high serum PSA or with high GS than in those with low PSA or with low GS, respectively, the differences reaching statistical significance (p < 0.05). A strong association between MGMT methylation and loss of MGMT expression was demonstrated by immunohistochemistry. CpG island methylation is a frequent event, occurs early, and accumulates during multi-step prostatic carcinogenesis. High levels of CpG island hypermethylation might serve as a potential biological marker for aggressive prostate cancer.     

Precursors of prostate cancer

High-grade prostatic intraepithelial neoplasia (PIN) is the only accepted precursor of prostatic adenocarcinoma, according to numerous studies of animal models and man; other proposed precursors include atrophy and malignancy-associated changes (with no morphologic changes). PIN is characterized by progressive abnormalities of phenotype and genotype that are intermediate between benign prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of prostatic carcinogenesis. The only method of detection of PIN is biopsy because it does not significantly elevate serum prostate-specific antigen concentration and cannot be detected by ultrasonography. The mean incidence of PIN in biopsies is 9% (range, 4%-16%), representing about 115,000 new cases of isolated PIN diagnosed each year in the United States. The clinical importance of PIN is its high predictive value as a marker for adenocarcinoma, and its identification warrants repeat biopsy for concurrent or subsequent carcinoma, especially when multifocal or observed in association with atypical small acinar proliferation (ASAP). Carcinoma develops in most patients with PIN within 10 years. Androgen deprivation therapy and radiation therapy decrease the prevalence and extent of PIN, suggesting that these forms of treatment may play a role in prevention of subsequent cancer. Multiple clinical trials to date of men with PIN have had modest success in delaying or preventing subsequent cancer.     

前列腺摘除病检和穿刺活检的形态学差异

目的：探讨前列腺摘除病检和穿刺活检的形态学差异。方法：对340例穿刺标本和280例因良性前列腺增生（BPH）而摘除的前列腺标本进行形态学对比分析。结果：在穿刺活检中,前列腺癌,上皮内新生物（PIN）和非特异性肉芽肿性前列腺炎（NSGP）的检出率明显高于摘除者,在前列腺摘除的标本中,梗死,磷化,间质增生性结节,腺性尿道炎和非典型性腺瘤样增生（AAH）的检出率明显市政地穿刺活检,结论：形态学差异是由于穿刺和摘除标本分别取自前列腺不同解剖并且并且部位所致,对穿刺和摘除前列腺的病理诊断,应该有不同的鉴别诊断思路。     

Effects of radiation on the normal prostate gland

Prostate cancer is one of the commonest tumours of adult males. It shows a range of biological behaviour: many tumours are discovered incidentally; others will kill by producing widespread metastatic disease. Despite the fact that radiation is frequently used in the treatment of a range of pelvic lesions, including adenocarcinoma of the prostate itself, studies on the morphological changes in the normal prostate gland after irradiation are limited. This seems particularly surprising following the increasing use of needle biopsy specimens to assess the prostate. Patients who receive pelvic irradiation often suffer from lower urinary tract symptoms such as frequency and dysuria and it is possible that these may be related to prostatic and/or periprostatic injury. We therefore investigated the prostate glands removed at cystoprostatectomy for transitional cell carcinomas of the bladder which had received radiotherapy pre-operatively. The changes were compared to control prostatic tissue from transurethral resection specimens for benign myoadenomatous hyperplasia. We found a range of inflammatory, fibrotic and reactive cytological features, including many of the changes seen in benign hyperplasia, but these were significantly more exaggerated in the post-radiation group. In addition intraprostatic vascular and neural changes were prominent. This study documents radiation-induced changes throughout the normal prostate gland and neighbouring soft tissue and has particular importance in current pathological practice with the increasing and widespread use of needle biopsies in the diagnosis and follow-up of prostate cancer.     

Ductal (endometrioid) adenocarcinoma of the prostate: a clinicopathological study of 16 cases

Sixteen cases of ductal (endometrioid) carcinoma of the prostate are presented. The tumour presents in elderly men (age range 65–87 years) with haematuria or obstructive symptoms. Serum prostate specific antigen may be normal or raised. On cytoscopy, there is often an exophytic lesion in the region of the verumontanum. Histologically, two variants are recognized: papillary and cribriform, of which there were eight cases each. Eight cases consisted of pure ductal carcinoma and seven were mixed, containing a variable proportion of micro-acinar carcinoma.The associated micro-acinar carcinoma had a Gleason score of at least 5. One case of carcinosarcoma with a ductal epithelial component was also included. All cases displayed positive immunohistochemical staining for prostate specific antigen and prostatic acid phosphatase and but were negative for the basal cell marker MA903. The tumour responds well to orthodox micro-acinar carcinoma therapy and appears notably sensitive to hormonal manipulation. Follow-up of the mixed group is restricted to a maximum of 3 years. Of the eight pure cases, five patients are still alive with survival periods of 11, 8, 7, 3 and 1 years. Three patients died of intercurrent disease of which one patient survived 12 years, having received no treatment. This tumour, therefore, can be regarded as having a good prognosis.     

High-grade Prostatic Intraepithelial Neoplasia of the Prostate: The Precursor Lesion of Prostate Cancer

High-grade intraepithelial neoplasia (HGPIN) is a lesion which is widely believed to be a precursor of prostatic adenocarcinoma. Correct morphologic identification of HGPIN and an understanding of how this diagnosis affects clinical management in the research setting are necessary as HGPIN is a premalignant lesion with many genetic alterations similar to prostate cancer, but is not yet invasive cancer. As such it is critical to differentiate between benign entities, HGPIN, and prostatic adenocarcinoma for experimental design and data interpretation. This review discusses HGPIN, clarifies the terminology used in pathology reports, and describes the clinical and research implications of this entity.     

Detection of prostate cancer by alpha-methylacyl CoA racemase (P504S) in needle biopsy specimens previously reported as negative for malignancy

AIMS : To investigate the possibility of detecting small focal prostatic cancer by alpha-methylacyl CoA racemase (AMACR)/P504S immunohistochemistry on needle biopsy specimens that were previously interpreted as negative for carcinoma on routine haematoxylin and eosin (H&E)-stained sections. METHODS: Prostate needle biopsy specimens (n = 793) previously interpreted as benign prostatic tissue by conventional morphology from 239 patients with prostatic cancer diagnosed in other biopsy cores taken at the same biopsy session were stained with the P504S monoclonal antibody. If a biopsy specimen stained positively, two pathologists independently reviewed the original corresponding H&E-stained sections to establish the malignant diagnosis. RESULTS: Eighty-four of the 793 biopsy specimens showed AMACR immunoreactivity; nine of these (9/793, 1.1%) contained previously unrecognized small focal prostatic carcinoma (Gleason 6, N = 8; Gleason 8, N = 1). Six of nine (67%) carcinomas showed foamy/pseudohyperplastic (N = 3) or atrophic (N = 3) features. Additionally, five biopsy specimens (5/793, 0.6%) with positive AMACR staining that did not meet the criteria for prostatic cancer on the original H&E slides were considered to be atypia. CONCLUSIONS: In this study, we found a 1.1% false-negative rate for carcinoma on routine H&E-stained sections. AMACR immunohistochemical staining has shown the ability to improve detection of small focal prostatic carcinoma that could be missed by conventional histological examination.     

Pathologic findings in patients with targeted magnetic resonance imaging-guided prostate needle core biopsies

In contrast to the routine (non-targeted) sampling approach of transrectal ultrasound guided biopsies (TRUS-GB), targeted magnetic resonance imaging-guided biopsies (TMRI-GB) target regions of the prostate suspicious for prostate cancer (PCa), based on findings on multiparametric MRI. We sought to examine the pathologic findings identified on TMRI-GB, due to the fact that there are limited studies on this in the Pathology literature. A search was made through our Urologic Pathology files for prostate needle core biopsies that were obtained via TMRI-GB. Forty-six patients were identified. Mean patient (PT) age was 62 years (range: 50-78 years). Twenty one of 46 PTs (46%) had a history of PCa, 10/46 PTs (22%) had a history of negative TRUS-GB and rising PSA, and the remaining 15/46 PTs (32%) had never undergone biopsy. Cancer detection rate on TMRI-GB was 57% for PTs with a prior diagnosis of PCa, 50% for PTs with a history of benign biopsy, and 67% who were biopsy naïve. An average of 3.16 cores were sampled from malignant lesions and an average of 2.74 were sampled from benign lesions (P=0.02). TMRI-GB has a higher cancer detection rate than TRUS-GB. TMRI-GB may have a critical role as a tool for active surveillance, tumor mapping, and primary detection of PCa, which will likely evolve as the ability to identify malignant lesions improve. The roles of pathologists and radiologists in the validation of this procedure will continue to be even more vital in the future.     

Expression of prostate stem cell antigen in high-grade prostatic intraepithelial neoplasia and prostate cancer

Barbisan F, Mazzucchelli R, Santinelli A, Scarpelli M, Lopez‐Beltran A, Cheng L & Montironi R (2010) Histopathology 57 , 572–579
Expression of prostate stem cell antigen in high‐grade prostatic intraepithelial neoplasia and prostate cancer Aims: To investigate prostate stem cell antigen (PSCA) and Ki‐67 expression in normal‐looking epithelium (NEp), atrophy, high‐grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma (PCa). Methods and results: PSCA and Ki‐67 were evaluated immunohistochemically in NEp, atrophy, HGPIN and PCa in 20 radical prostatectomies (RPs) and 20 cystoprostatectomies (CyPs). The proportions of PSCA positive cells and of cases with PSCA expression increased from NEp through atrophy and HGPIN to PCa. The differences between NEp and HGPIN and PCa and between atrophy and HGPIN and PCa were statistically significant for the away and adjacent locations, in both the RP and CyP groups. The differences between HGPIN and PCa were statistically significant in the RP group when it was away from PCa and in the CyP group when it was adjacent to and away from PCa. The values in the RPs were slightly greater than in the CyPs, the differences being not statistically significant. The proportions of Ki‐67 positive nuclei increased from atrophy and NEp to HGPIN and PCa. The correlation between the proportion of Ki‐67 positive nuclei and that of PSCA‐positive cells was statistically significant. Conclusions: PSCA expression, deregulated in atrophy and HGPIN, is a marker associated with neoplastic transformation of prostate cells, both in RPs and CyPs.     

Molecular analysis of multifocal prostate cancer lesions

To analyse the origin of multifocal prostate cancer lesions, radical prostatectomy specimens from 17 patients were examined. As a marker of genetic lineage, the allelotype based on 33 microsatellite loci was compared between the different tumours present in a given case. Some results provide evidence suggestive of a clonal origin of multiple tumours in a subset of the prostates. In five cases, for example, comparison of multifocal tumour lesions within a given case revealed at least two concordant changes in allelic imbalance (AI) sequence dosages at different loci. In addition, considerable heterogeneity of allelotype was found within and among tumour foci of a given case. In five of the six tumours analysed for intratumour heterogeneity, for example, more than five discordant AI changes were found in one tumour region but not in the other. Conclusions regarding the clonality of such heterogeneous lesions are difficult to draw. A high frequency of AI changes in four lesions exhibiting prostatic intraepithelial neoplasia (mean 6·5 changes per lesion, range 3–6) was found, compared with eight primary tumours present in the same cases (mean 5·8 changes per lesion, range 3–6). The interpretation of AI associated with clinically detected prostate cancer remains a highly complex issue. The fact that no clear evidence was obtained for either a clonal or a non-clonal origin of multiple lesions in a given prostate indicates that several different mechanisms are likely to operate in establishing the allelotype and that additional evidence from unique mutations or selective gene inactivation may be necessary to obtain definitive results. Copyright © 1999 John Wiley & Sons, Ltd.     

Histopathological approach to prostatic contour alterations with the concept of left-right asymmetry

It has been suggested that prostate cancer spread has predictable patterns, with prostate cancers known to affect the prostatic contours. However, few systematic investigations have documented the associated contour alterations, especially at a clinically localized stage. The purpose of the present paper was to objectively evaluate prostatic contour alterations based on left-right asymmetry, and analyze the histopathological features and prognostic impact. One hundred and sixty-two asymmetrical contours with left-right asymmetry in the length >or=10%, and 278 cancer foci were observed in 114 radical prostatectomy specimens. Of the asymmetrical contours, 55 (34%) were caused by cancer, and of the cancer foci, 55 (20%) generated asymmetrical contours. Cancer-associated asymmetries showed significant correlations with aggressive behaviors such as cancer volume, Gleason score, positive surgical margin, and extraprostatic extension, although these were not significantly associated with unfavorable prognosis. The authors present basic data relating to altered prostatic contours, such as spatial distribution and causative pathological conditions. Clinicopathological characteristics concerning cancer-associated contour alterations, are also presented in detail.     

Anatomy of the prostate revisited: implications for prostate biopsy and zonal origins of prostate cancer

Over the past 25 years, our understanding of prostatic disease has evolved secondary to the increased detection, treatment and study of both benign and neoplastic prostatic lesions. The advent of aggressive prostate-specific antigen screening and standardization of extended transrectal needle biopsy protocols has resulted in significant stage migration and earlier detection of prostate cancers, a growing proportion of which are lower-volume posterior peripheral zone tumours. Consequently, an increased incidence of anterior-predominant prostate cancers has been observed. Given the histomorphological complexity of the prostate, these developments have necessitated a reconsideration of prostatic anatomy, biopsy strategies in the detection of anterior tumours and the determination and relevance of zonal origin in prostate cancer. This review will provide a contemporary update of these topics, while highlighting specific areas in which a keen understanding of prostatic histoanatomy may influence biopsy interpretation.     

Prognostic value of various morphometric measurements of tumour extent in prostate needle core tissue

Aims:  Predicting prostatic cancer patients' outcome is a major objective for clinicians and patients. Several nomograms are currently implemented prior to treatment to help predict clinical and pathological outcome. The aim of this study was to investigate the prognostic significance of morphometric measurements of cancer on the needle biopsy specimen in relation to the final pathological stage or the biochemical failure status following radical prostatectomy, and to determine which measurement of tumour length in cases with discontinuous foci of cancer (DFC) is most reliably reflective of the pathological stage.
Methods and results:  Of the 100 patients included in this study, 34% had high-stage disease (pT ≥ 3 and/or pN1) and 16% experienced biochemical recurrence. The analysis showed that fraction of positive cores, total percentage of cancer and both total and greatest millimetric cancer lengths were the variables most closely associated with pathological stage and biochemical failure status.
Conclusions:  This study confirms the prognostic value of recording tumour extent in prostatic needle biopsy reporting. However, the results are inconclusive in determining the best method to record tumour length in cores with DFC and larger studies are needed to answer this question fully.     

Staging of prostate cancer

Prostatic carcinoma (PCa) is a significant cause of cancer morbidity and mortality worldwide. Accurate staging is critical for prognosis assessment and treatment planning for PCa. Despite the large volume of clinical activity and research, the challenge to define the most appropriate and clinically relevant staging system remains. The pathologically complex and uncertain clinical course of prostate cancer further complicates the design of staging classification and a substaging system suitable for individualized care. This review will focus on recent progress and controversial issues related to prostate cancer staging. The 2010 revision of the American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) tumour, node and metastasis (TNM) system is the most widely used staging system at this time. Despite general acceptance of the system as a whole, there is controversy and uncertainty about its application, particularly for T2 subclassification. The three-tiered T2 classification system for organ-confined prostate cancer is superfluous, considering the biology and anatomy of PCa. A tumour size-based substaging system may be considered in the future TNM subclassification of pT2 cancer. Lymph node status is one of the most important prognostic factors for prostate cancer. Nevertheless, clinical outcomes in patients with positive lymph nodes are variable. Identification of patients at the greatest risk of systemic progression helps in the selection of appropriate therapy. The data suggest that the inherent aggressiveness of metastatic prostate cancer is closely linked to the tumour volume of lymph node metastasis. We recommend that a future TNM staging system should consider subclassification of node-positive cancer on the basis of nodal cancer volume, using the diameter of the largest nodal metastasis and/or the number of positive nodes.     

An update on atypical large glandular proliferations of the prostate

The differential diagnosis of prostatic atypical large gland proliferations includes several benign and malignant entities. This review focusses on issues relevant to the practising pathologist, particularly around areas of controversy such as high-grade prostatic intraepithelial neoplasia (HGPIN) and intraductal carcinoma of the prostate (IDCP). HGPIN is a putative precursor of prostate cancer, but its clinical relevance is as a surrogate marker of unsampled prostate cancer, thereby identifying patients who would benefit from a prompt repeat biopsy. The incidence of missed prostate cancer is much lower in contemporary practice due to pre-biopsy MRI and extended sampling protocols so HGPIN is currently less important. It is however important to distinguish HGPIN from PIN-like carcinoma and IDCP. PIN-like carcinoma is considered a histological subtype/variant of acinar prostate carcinoma and should be graded as Gleason pattern 3. A diagnosis of cribriform HGPIN should not be made in needle biopsies as such a proliferation may represent IDCP. This review discusses controversies related to the diagnosis, reporting and management of IDCP. A personalized approach to management of patients with isolated IDCP in needle biopsies that is based on the histological and radiological features of an individual case is outlined.     

Systematic evaluation of narrow-sense validity of polygenic risk score for prostate cancer in a Chinese prostate biopsy cohort

The aim of this study was to assess the narrow-sense validity of polygenic risk score (PRS) for prostate cancer (PCa) in a Chinese prostate biopsy cohort. We performed an observational prospective study with 2640 men who underwent prostate biopsy. Germline DNA samples were genotyped and PRS was calculated for each subject using 17 PCa risk-associated genetic variants. Additional GWAS data of the ChinaPCa dataset was also used to compliment the evaluation process. The mean PRS was 1.02 in patients with negative biopsy results, which met the baseline benchmark. The mean PRS was significantly higher in the PCa cases (1.32 vs. 1.02, p = 5.56 × 10⁻¹⁷). Significant dose–response associations between PRS values and odds ratios for PCa were observed. However, the raw calibration slope was 0.524 and the average bias score between the observed risk and uncorrected PRS value was 0.307 in the entire biopsy cohort. After applying a correction factor derived from a training set, the corrected calibration slope improved to 1.002 in a testing set. Similar and satisfied results were also seen in the ChinaPCa dataset and two datasets combined, while the calibration results were inaccurate when the calibration process were performed mutually between two different study populations. In conclusion, assessing the narrow-sense validity of PRS is necessary prior to its clinical implementation for accurate individual risk assessment.