Low-grade Prostatic Intraepithelial Neoplasia Research Articles

DIFFERENTIAL EXPRESSION OF C-CAM CELL ADHESION MOLECULE IN PROSTATE CARCINOGENESIS IN A TRANSGENIC MOUSE MODEL

Purpose The transgenic adenocarcinoma of mouse prostate (TRAMP) model, in which various grades of prostate intraepithelial neoplasia (PIN) and prostate cancer with metastases can be reproducibly generated, is a paradigm for prostate disease progression. We have previously shown that C-CAM, an adhesion molecule, can suppress the growth of prostate cancer. In this report, we describe immunohistochemical characterization of differential expression of C-CAM at various stages of prostate tumorigenesis in the TRAMP model. Materials and Methods We sampled prostate specimens and periaortic lymph nodes from TRAMP mice. Indirect immunohistochemical staining with a polyclonal anti-C-CAM antibody was performed on the formalin-fixed, paraffin-embedded specimens. After castration at 12 weeks of age, the TRAMP mice developed androgen-independent prostate cancer (AIPC) and lymph node metastasis at 18 to 24 weeks of age. Samples from these castrated mice were also analyzed. Results C-CAM protein was expressed in the normal prostate epithelia of non-transgenic and TRAMP mice as well as in low-grade PINs in TRAMP mice. Expression was uniform on the luminal surfaces of these epithelia. C-CAM expression was noticeably reduced and the staining pattern heterogeneous in some high-grade PINs. C-CAM staining was generally absent in prostate cancer and metastatic lymph nodes. Androgen independent prostate cancer and its metastatic tumors generated in castrated TRAMP mice were also C-CAM negative. Conclusions C-CAM expression correlates with the differentiation states of prostate epithelia and is down regulated early in prostate tumorigenesis in the TRAMP model.

The association of selected pathological features with prostate cancer in a single-needle biopsy accession

Isolated high-grade prostatic intraepithelial neoplasia (PIN) has been shown to be a positive predictor of prostate cancer (PCa) on follow-up biopsy. However, the incidence of isolated high-grade PIN in needle biopsy specimens has been reported with a highly variable frequency of 1% to 15%. The current study examined the relationship of various pathological features with PCa on a single biopsy accession. A study population of 388 community-based consecutive needle biopsy accessions was prospectively recorded by a single pathologist (T.M.W.). All of the individual biopsy specimens were coded for the presence of PCa, high-grade PIN, low-grade PIN, chronic inflammation (CI), intraluminal prostatic crystalloids (IPC) in benign glands, and mucinous metaplasia (MM). One hundred twenty-nine (33%) of the patients were diagnosed with PCa. The 8% incidence of isolated high-grade PIN was consistent with previous studies. The incidence of other pathological features were as follows: high-grade PIN, 14%; low-grade PIN, 13%; CI, 30%; IPC, 4%; and MM, 8%. Of the patients with high-grade PIN, 47% had PCa on a separate core biopsy, whereas 31% of patients without high-grade PIN were observed to have PCa ( P = .021). Of the patients with CI, 21% were found to have PCa on a separate core, whereas 38% of patients without CI were found to have PCa ( P = .0009). None of the other pathological features surveyed showed any significant association with PCa. High-grade PIN was a relatively common finding (14%) in this study and was positively associated with PCa on a separate core from the same accession biopsy. The negative association of CP with PCa within the same accession has not been reported previously and may be an artifact related to the clinical indications for a prostatic biopsy.

Expression of androgen receptor and growth factors in premalignant lesions of the prostate.

Analysis of growth factors and receptors in putative premalignant lesions of prostatic adenocarcinoma should aid our understanding of their growth pathways. Sixty prostatic TURP (transurethral resection of the prostate) specimens exhibiting atypical adenomatous hyperplasia (AAH) and/or prostatic intraepithelial neoplasia (PIN) lesions were assayed by immunohistochemistry for androgen receptor (AR), epidermal growth factor receptor (EGFR), c-erbB-2, transforming growth factor-alpha (TGF-alpha), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), MIB-1, E-cadherin, and high molecular weight keratin. Expression of these factors in the lesions was compared with that in the co-existing benign prostatic hyperplasia (BPH) or prostatic adenocarcinoma. Strong AR nuclear staining was observed in the luminal cells, but not the basal cells, of BPH and PIN lesions and in all the carcinomas examined. A similar growth factor and receptor profile was demonstrated in the secretory epithelium of high-grade PIN and carcinoma with a tendency to higher expression of membranous EGFR and c-erbB-2 and cytoplasmic TGF-alpha, and lower levels of FGF-2 than in low-grade PIN or BPH glands. Also, increased rates of proliferation, as estimated by MIB-1 stained cells, were observed in high-grade PIN in comparison with low-grade PIN and BPH and were not confined to the basal layer. AAH lesions resembled neither BPH nor carcinoma. Proliferation was virtually absent (MIB-1 expression); both AR and E-cadherin expression was significantly reduced; and, with the exception of FGF-2, all the other growth factors and receptors studied were absent. The results presented would support a premalignant role for high-grade PIN, whilst AAH would appear to represent a quiescent phenotype unlikely to progress to neoplasia.

Ratio of Free to Total Prostate-Specific Antigen in Patients with Prostatic Intraepithelial Neoplasia

Objective: There are many reports about the effects of prostatic intraepithelial neoplasia (PIN) on serum prostate-specific antigen (PSA) level. The aim of this study was to determine the relationship between PIN and serum free PSA/total PSA (fPSA/tPSA) ratios. Methods: We evaluated 46 patients with PIN, 15 patients with benign prostatic hyperplasia (BPH), and 16 patients with localized prostatic carcinoma (CaP) for the amount of fPSA and tPSA with the chemiluminescent enzyme assay. Results: fPSA values from BPH to high-grade PIN (PIN2 and PIN3) was increased, and then a decrease was observed from high-grade PIN to CaP. fPSA was significantly different between BPH and low-grade PIN and high-grade PIN. There was no significant difference observed between BPH and CaP. tPSA values increased from BPH to CaP. tPSA was significantly different between BPH and high-grade PIN and CaP. fPSA/tPSA ratios decreased from BPH to CaP. This ratio was significantly different between CaP and BPH and low-grade PIN. There was no significant difference between CaP and high-grade PIN. Conclusions: Our results confirm that fPSA/tPSA ratio is better at discriminating between patients with CaP and those with BPH, but not between patients with CaP and those with high-grade PIN. Due to similarities between CaP and high-grade PIN, we think that decreased fPSA/tPSA ratio obtained at the time of intial diagnosis of PIN without concurrent carcinoma could be used as predictive factors to distinguish patients in whom carcinoma will be found on subsequent biopsies from those with PIN not associated with cancer on repeat biopsy.

Diagnostic distance of high grade prostatic intraepithelial neoplasia from normal prostate and adenocarcinoma.

OBJECTIVE: To develop a distance measure based methodology to support the morphological evaluation of high grade prostatic intraepithelial neoplasia (PIN), a direct precursor of prostate cancer. METHODS: Eight morphological and...

Incidence of high-grade prostatic intraepithelial neoplasia in sextant needle biopsy specimens

Objectives There is scant literature on the frequency of high-grade prostatic intraepithelial neoplasia (PIN) in needle biopsy specimens. These data have implications as to how often pathologists should be expected to diagnose these lesions on needle biopsy and impact on the feasibility of cancer chemoprevention trials for prostate cancer. Methods We reviewed 439 consecutive 18-gauge sextant needle biopsy specimens from the Johns Hopkins Hospital. Results Based on the pathology reports, high-grade PIN was recorded in 12 (2.7%) of the cases and was confirmed upon review. Following review of the slides, unequivocal high-grade PIN was found in an additional 6 cases. There were 6 other cases where the findings were borderline between high- and low-grade PIN, but which were believed to be more consistent with high-grade PIN. Considering these latter cases in conjunction with the unequivocal cases of high-grade PIN, the incidence of high-grade PIN was 5.5% (24 of 439). Conclusions Recognizing that approximately 50% of men with high-grade PIN on needle biopsy will be found to have carcinoma on repeat biopsy, the management of high-grade PIN on biopsy will only apply to 50% of the men initially discovered with this finding. If only 2.75% of men who are biopsied eventually need therapy for high-grade PIN on needle biopsy, the number of cases needed to study the decrease of high-grade PIN following chemoprevention might be prohibitively high. If the incidence of high-grade PIN on needle biopsy requiring therapy is only 2.75%, it may also not be worthwhile developing large trials to investigate various treatment regimens for high-grade PIN found on biopsy.

Argyrophilic nucleolar organizer regions in atypical adenomatous hyperplasias, prostatic intraepithelial neoplasias and prostatic neoplasms.

Sections from 104 cases of benign, preneoplastic and neoplastic lesions of the prostate were studied for argyrophilic nucleolar organizer regions (AgNORs). The mean NOR counts in normal controls (2.87) and benign prostatic hyperplasia with or without chronic prostatitis (4.90 and 3.84 NORs/nucleus, respectively) were found to be significantly less (p < 0.001) than that in prostatic intraepithelial neoplasia (PIN) and adenocarcinoma of the prostate (5.65 and 5.78 NORs/nucleus, respectively). The mean AgNOR count of a section with atypical adenomatous hyperplasia was significantly lower than that in PIN. No statistically significant difference was observed between AgNOR counts of high-grade PIN and well-differentiated adenocarcinoma (WDAC; 5.67 vs. 5.78 NORs/nucleus, respectively), however the difference between low-grade PIN and WDAC was statistically significant (5.46 vs. 5.78 NORs/nucleus, p < 0.005). The increase in NOR counts occurred concomitantly with the decrease in the degree of differentiation of adenocarcinoma. Thus, NOR was found to be a good adjuvant to the existing diagnostic parameters to pick up more cases at the stage of PIN when prognosis is better.

Results of Rebiopsy for Suspected Prostate Cancer in Symptomatic Men with Elevated PSA Levels

To develop indications for repeat biopsy in patients with suspected prostate cancer and first negative biopsy. 148 consecutive patients, submitted to two or more biopsies for suspected prostate cancer, were extracted from our database on prostatic diseases. Patients were stratified according to the results of the last biopsy (benign or carcinoma) considering the results of the first and of the last biopsy when more than two biopsies had been performed. PSA velocity was calculated when the interval between PSA obtained before the initial and the final biopsy was at least 6 months; PSA velocities were annualized and absolute changes between the two groups were analyzed. Prostatic carcinoma was detected in 60 of the 148 patients (40.5%), including 19 of 41 (46.4%) with prostatic intraepithelial neoplasia (PIN) and 45 of 107 (42.1%) with normal tissue or prostatic epithelial atrophia on initial biopsy. 20% of patients (4 of 20) with low-grade PIN and 71.1% (15 of 21) with high-grade PIN had cancer at repeat biopsy. The mean PSA value of patients with carcinoma on the repeat biopsy was higher than that of patients without carcinoma (13.3 vs. 10.7 ng/ml). However, this difference was not statistically significant (p = 0.37). Mean PSA velocity increased for patients with a final diagnosis of carcinoma versus those without evidence of carcinoma (+0.3 vs. +1.4 ng/ml/year); this difference was statistically significant (p = 0.002). According to these results, patients with either PIN II-III, or high PSA and PIN I on initial biopsy, and/or with elevated PSA velocity (more than 1 ng/ml/year) should undergo repeat prostate needle biopsy, being at high risk of prostate carcinoma.

Prostatic Intraepithelial Neoplasia: Influence of Clinical and Pathological Data on the Detection of Prostate Cancer

Purpose We attempted to characterize patients diagnosed with prostatic intraepithelial neoplasia without concurrent cancer on biopsy who had prostate cancer on subsequent biopsy. Materials and Methods The records of 93 patients with low and high grade prostatic intraepithelial neoplasia without concurrent cancer on initial biopsy were analyzed. The relationships among prostatic intraepithelial neoplasia grades, patient age, digital rectal examination, serum prostate specific antigen (PSA), transrectal ultrasound appearance and final pathological results were investigated. Results Subsequent carcinoma was found on repeat biopsy in 13.3 percent of patients with low grade and 47.9 percent with high grade prostatic intraepithelial neoplasia (p less than 0.001). In the former group digital rectal examination, patient age, serum PSA and transrectal ultrasound were not predictive of cancer. Transrectal ultrasound appearance, digital rectal examination and serum PSA were statistically different between high grade prostatic intraepithelial neoplasia with and without subsequent cancer (p less than 0.001, p = 0.008 and p = 0.016, respectively, univariate analysis). On multivariate analysis of patients with high grade prostatic intraepithelial neoplasia only digital rectal examination and PSA were predictive of subsequent carcinoma. Conclusions High grade prostatic intraepithelial neoplasia is a strong predictor of subsequent cancer, especially in men with abnormal digital rectal examination and elevated serum PSA. Patients with high grade prostatic intraepithelial neoplasia should undergo repeat biopsy to exclude cancer. Further investigations are needed to optimize the treatment of patients with low grade prostatic intraepithelial neoplasia.

Prospective origins of prostate carcinoma. Prostatic intraepithelial neoplasia and atypical adenomatous hyperplasia.

The search for the precursor of prostatic adenocarcinoma has focused in recent years on two histopathologic findings: high grade prostatic intraepithelial neoplasia (PIN) and atypical adenomatous hyperplasia (AAH). This article describes the diagnostic criteria and clinical significance of PIN and AAH. PIN is the most likely precursor of prostate carcinoma. The continuum that culminates in high grade PIN and early invasive carcinoma is characterized by progressive basal cell layer disruption, loss of markers of secretory differentiation, nuclear and nucleolar abnormalities, increasing proliferative potential, increasing microvessel density, variation in DNA content, and allelic loss. Clinical studies suggest that PIN predates carcinoma by 10 years or more, with low grade PIN first appearing in men in their 30s. AAH is usually found in the transition zone, and shows a weak and inconclusive link to well differentiated adenocarcinoma of the transition zone. The significance of recognizing PIN is based on its strong association with prostatic carcinoma. PIN coexists with carcinoma in most cases, but retains an intact or fragmented basal cell layer, unlike carcinoma, which lacks a basal cell layer. High grade PIN in biopsies predicts the presence of carcinoma in subsequent biopsies, and PIN provides the highest risk ratio of all known predictive factors. This finding indicates the need for repeat biopsy and follow-up when PIN is identified in a biopsy, especially in patients with an elevated serum prostate specific antigen concentration. PIN also offers promise as an intermediate endpoint in studies of chemoprevention of prostatic carcinoma. Unlike PIN, AAH is weakly linked to carcinoma, and current data indicate that no follow-up is necessary for patients with this finding.

Immunolocalization of glycoprotein A-80 in prostatic carcinoma and prostatic intraepithelial neoplasia

A-80 is a mucin-like glycoprotein associated with exocrine differentiation that shows little or no expression in normal exocrine cells and typical adenomas, but is upregulated in dysplasia and adenocarcinoma of certain organs. Its expression has not been systematically examined in prostatic adenocarcinoma and its putative precursor, prostatic intraepithelial neoplasia (PIN). The authors applied a mouse monoclonal antibody against A-80 in paraffin-embedded sections from 103 cases of prostatic carcinoma, 26 cases of nodular hyperplasia, 7 autopsy samples from normal young adult prostates, and 12 fetal prostates. All but one cancer reacted, although expression was heterogeneous; 75 of 103 stained extensively (>3+ on a 0 to 5+ scale) and strongly. Staining extent and intensity were independent of tumor grade, and tended to be strong even when focal. Seventy-seven of 84 foci (92%) of high-grade PIN and 38 of 52 foci (73%) of low-grade PIN stained for A-80; reactions were most extensive and intense in high grade PIN. Only 5 of 26 cases (19%) of hyperplasia reacted, and this consisted of weak to moderate staining in sporadic cells; the remainder were negative. Normal adult prostatic epithelium did not express A-80 except for weak and inconsistent staining in foci of inflammation and infarction; atrophic glands were negative. Fetal prostate showed focally strong reactivity. These results indicate that A-80 is selectively expressed in most cases of intraepithelial neoplasia and prostate cancer, but is usually absent in benign and hyperplastic epithelium. The upregulation of glycoprotein A-80 in PIN and adenocarcinoma parallels observations in other organs, such as the breast and colon, suggesting that this is a significant oncodevelopmental molecule with potential clinical applications.

Do prostate specific antigen and prostate specific antigen density enhance the detection of prostate carcinoma after initial diagnosis of prostatic intraepithelial neoplasia without concurrent carcinoma?

Prostatic intraepithelial neoplasia (PIN) is considered to be a precursor of prostate carcinoma in which serum levels of prostate specific antigen (PSA) have been correlated with PIN grades. The aim of this study was to determine whether PSA and prostate specific antigen density (PSAD), obtained at the time of initial diagnosis of PIN without concurrent carcinoma, can be used as predictive factors to discriminate patients with subsequent cancer on repeat biopsy. We studied, retrospectively, the records of 93 patients with PIN (low and high grade) without concurrent carcinoma at the time of their first needle biopsy. We assessed the relationship between initial PIN grade, PSA, and PSAD with later detection of carcinoma on repeat biopsy. Patients were divided into 3 subgroups for analysis according to their initial PSA level (0-4, 4.1-10, >10 ng/mL). Carcinoma detection rate on repeat biopsy was 13.3% for patients with low grade PIN and 47.7% for patients with high grade PIN (P < 0.006). High grade PIN was frequently associated with subsequent carcinoma whatever the PSA level (33.3-61.9%). Low grade PIN was associated with subsequent carcinoma in 42.8% of the cases when PSA was greater than 10 ng/mL. When PSA was between 4 and 10 ng/mL, low grade PIN carcinoma was found on repeat biopsies in only 10.7% of the cases (P = 0.05). In none of the PSA subgroups did PSAD enhance later cancer detection. For patients with high grade PIN, the incidence of subsequent carcinoma is high, whatever the PSA values. For these cases repeat biopsies should be recommended. Patients with low grade PIN and PSA greater than 10 ng/mL should have repeat biopsies because the incidence of subsequent carcinoma is high and comparable to high grade PIN. PSAD did not provide additional information.

Clinical prognostic criteria for later diagnosis of prostate carcinoma in patients with initial isolated prostatic intraepithelial neoplasia.

Prostatic intraepithelial neoplasia (PIN) is considered as a precursor of prostate cancer and is frequently associated with it. Diagnosis of PIN on a prostate needle biopsy without associated carcinoma is a difficult problem since high-grade PIN does not necessarily mean that prostate cancer is always present and low-grade PIN is associated with cancer as well. Definition of parameters predictive of the later finding of prostate cancer on repeat biopsy in patients with PIN is of evident interest and we have reviewed our experience and recent data from the literature on this topic. High grade is a strong predictor of later cancer found on repeat biopsy (50-100%) and in these patients, serum prostate-specific antigen (PSA), digital rectal examination and transrectal ultrasound are predictors of later cancer found on repeat biopsy. High-grade PIN is, however, frequently associated with later cancer whatever PSA, even when < or = ng/ml. Low-grade PIN seems to behave like BPH since the incidence of later cancer is extremely low when PSA is < 4 ng/ml and is high when PSA > 10 ng/ml. Patients with high-grade PIN should systematically be rebiopsied after 3-6 months to exclude cancer because they are likely to have undiagnosed cancer. Patients with low-grade PIN and low PSA seem to have a low risk of later cancer found on repeat biopsy. Patients with low-grade PIN and high serum PSA should have repeat biopsies because the incidence of subsequent cancer is high and comparable to high-grade PIN. Further investigations are needed to optimize the management of patients with low-grade PIN and intermediate PSA level.

Cell Kinetic Studies on Prostatic Intraepithelial Neoplasia (PIN) and Atypical Adenomatous Hyperplasia (AAH) of the Prostate

To investigate possible cell kinetic relations between benign prostatic hyperplasia (BPH), atypical adenomatous hyperplasia (AAH), prostatic intraepithelial neoplasia (PIN) and carcinoma, cell kinetic analyses were performed using radiolabelled DNA-precursors (3H-thymidine autoradiography), immunohistochemistry (proliferation marker Ki67/MIB1 and/or PCNA) and silver staining of nucleolar organizer regions (AgNOR). All methods yielded the lowest values for BPH and AAH, while maximal values were found in carcinoma of high malignancy. PIN was equal to GII-carcinomas, while AAH was between BPH and carcinoma of low malignancy. This investigation ranks BPH, AAH, low grade carcinoma, PIN and high grade carcinoma in order using different methods of cell kinetic analysis. The preneoplastic character of PIN is apparent whereas the character of AAH remains uncertain.

Interobserver reproducibility in the diagnosis of prostatic intraepithelial neoplasia.

To assess interobserver reproducibility in the categorization of prostatic intraepithelial neoplasia (PIN) seven pathologists reviewed 25 lesions. Rather than classic or consecutive examples of PIN, cases were selected to represent the full spectrum of diagnostic issues in this field. Lesions were classified into one of six categories: (a) benign prostate tissue, (b) PIN1, (c) PIN2, (d) PIN3, (e) PIN3 cannot rule out associated cancer, and (f) PIN3 plus cancer. Following evaluation of the slides, data were also analyzed by combining several of the groups into three categories: (a) benign/PIN1; (b) PIN2/PIN3/PIN cannot rule out cancer; and (c) PIN plus cancer. The level of agreement was fair (Kappa = 0.33) for the six categories and substantial (Kappa = 0.61) for the three groups. In no case was there a uniform diagnosis of PIN1; in all cases at least some pathologists considered the biopsies to be normal. This finding provides support for not commenting on PIN1 in biopsy material. In general, there was good distinction between low-grade PIN (PIN1) and high-grade PIN (PIN2-3). Among the seven cases for which there was a consensus that the lesion represented high-grade PIN, there was no case in which there was uniform agreement as to whether the lesion represented PIN2 or PIN3. This finding supports combining PIN2 and PIN3 into high-grade PIN. Cases classified as low-grade PIN by some and as high-grade PIN by others were those with pleomorphism but without prominent nucleoli. Difficulties in distinguishing "high-grade PIN" from "high grade PIN cannot rule out cancer" were those with cribriform glands, glands with necrosis, and where high-grade PIN was associated with only a few adjacent small atypical glands. These same histologies caused the participating pathologists difficulty in distinguishing "high-grade PIN cannot rule cancer" from "high grade PIN plus cancer."

High grade prostatic intraepithelial neoplasia. The most likely precursor of prostate cancer

The search for the precursor of prostatic adenocarcinoma has focused in recent years on the spectrum of histopathologic changes referred to as high grade prostatic intraepithelial neoplasia (PIN). This review describes the diagnostic criteria and clinical significance of PIN. PIN coexists with cancer in more than 85% of cases, but retains an intact or fragmented basal cell layer, unlike cancer, which lacks a basal cell layer. High grade PIN in biopsies predicts the presence of cancer in subsequent biopsies, and PIN provides the highest risk ratio of all known predictive factors (14.93). The continuum that culminates in high grade PIN and early invasive cancer is characterized by progressive basal cell layer disruption, loss of markers of secretory differentiation, nuclear and nucleolar abnormalities, increasing proliferative potential, variation in DNA content, and allelic loss. Clinical studies suggest that PIN predates carcinoma by 10 years or more, with low grade PIN first appearing in men in their thirties. The significance of recognizing PIN is based on its strong association with prostatic carcinoma. This finding indicates the need for repeat biopsy and follow-up when PIN is identified on biopsy, especially in patients with elevated serum prostate specific antigen concentration. PIN also offers promise as an intermediate end point in studies of chemoprevention of prostatic carcinoma. Cancer 1995 ;75 :1823-36.

DNA quantitation of intraepithelial neoplasia and invasive carcinoma of the prostate.

The relation of prostatic intraepithelial neoplasia (PIN) or ductal dysplasia and the development of invasive prostate cancer is not clear. PIN, especially high grade, is usually associated with coexisting invasive cancer. Although some investigators have identified micro foci of invasive cancer evolving from PIN, the two are usually anatomically separated. Because of these distinct anatomic patterns, many investigators have concluded that PIN represents a "field effect" or marker of potential cancer progression, and is not directly involved in or leads to the development of invasive prostate cancer. We measured the DNA content in 49 foci of invasive cancer and 87 foci of PIN identified in 34 radical prostatectomies containing both PIN and invasive cancer. In addition, we examined 13 prostatectomies and 5 TUR specimens containing only PIN. We found that the majority of low grade PIN had normal or diploid range DNA and that approximately half of the high grade PIN were abnormal or aneuploid. Prostates with coexisting diploid range PIN and invasive cancer had an approximately equal number of diploid range and aneuploid invasive cancers. Conversely, almost all of the aneuploid PIN (usually high grade) had coexisting aneuploid invasive cancers. This would support the hypothesis that events in the progression of prostate cancer may be operative in both the development of PIN and invasive cancer.

Prostatic intraepithelial neoplasia (PIN): current concepts.

Prostatic intraepithelial neoplasia (PIN) represents the putative precancerous end of the morphologic continuum of cellular proliferations within prostatic ducts, ductules and acini. Two grades of PIN are identified (low grade and high grade), and high grade PIN is considered to be a precursor to invasive carcinoma. The continuum which culminates in high grade PIN and early invasive cancer is characterized by basal cell layer disruption, basement membrane disruption, progressive loss of secretory differentiation markers, increasing nuclear and nucleolar abnormalities, increasing proliferative potential, and increasing variation in DNA content (aneuploidy). Clinical studies suggest that PIN predates carcinoma by ten years or more, with low grade PIN first emerging in men in the third decade of life. The clinical importance of recognizing PIN is based on its strong association with carcinoma; its identification in biopsy specimens of the prostate warrants further search for concurrent invasive carcinoma.

Gene expression profiling reveals overexpression of TSPAN13 in prostate cancer

Prostate cancer is one of the most frequent malignancies in the Western world. The identification of additional molecular markers is needed to refine the diagnosis of prostate cancer and to develop more effective therapies. In order to identify molecular abnormalities involved in prostate cancer progression, we performed gene expression analysis of prostate cancer samples compared to matched normal tissue from the same patient using a cancer-related microarray. Amplified RNA was hybridized to a cDNA microarray containing 6386 genes and tissue microarrays were used to study protein expression levels. Using significance analysis of microarrays, we identified >1300 genes differentially expressed in prostate cancer compared to normal tissue. Forty-two of these genes were highly upregulated in prostate cancer while 169 were highly repressed. We found that the gene coding for tspan13 was upregulated >2-fold in 75% of the samples analyzed. Immunohistochemistry analysis of prostate cancer tissue microarrays showed that tspan13 is overexpressed in 80% of prostate cancer samples analyzed. We found that tspan13 expression inversely correlates with Gleason score (p=0.01) and PSA preoperative levels (p=0.11) and directly correlates with presence of prostatic intraepithelial neoplasia in tumor tissue (p=0.04). Moreover, we detected tspan13 expression in low-grade prostatic intraepithelial neoplasia. Thus, our results show that tspan13 is overexpressed in prostate cancer and its expression correlates with factors of favourable outcome. Therefore we suggest that tspan13 may have an important role in the progression of prostate cancer.

Correlation of serum free prostate-specific antigen level with histological findings in patients with prostatic disease

Prostate Specific Antigen (PSA) has been widely used in the diagnosis and management of patients with prostate cancer. It may be elevated in other prostatic diseases and surgical procedures. PSA exists in two forms, a major bound form (cPSA) and a free form (fPSA). The objective of the study was to determine the relationship between serum fPSA levels and histologic findings in biopsy specimens of men with prostatic disease. This study includes 91 patients planned for transurethral resection of prostate (TURP). Blood samples were collected before TURP and tested for fPSA. Histology of the tissue samples collected after TURP were studied and the relationship with fPSA analysed using SPSS 11.5. The median values for benign, premalignant and malignant lesions were 1.8 ng/ml, 4.5 ng/ml and 13.20 ng/ml respectively (p<0.001). Most cases of benign prostatic hyperplasia(BPH) without inflammation had fPSA levels <2 ng/ ml, while most with active inflammation had levels >5 ng/ml. Low grade prostatic intraepithelial neoplasia (LGPIN) saw levels <5 ng/ml while high grade intraepithelial neoplasia (HGPIN) and prostate cancer (PCa) had levels > 5 ng/mL (p<0.05). For detection of high grade lesions (HGPIN and PCa), the sensitivity and specificity of fPSA level > 5 ng/ml was found to be 88.8% and 90.2% respectively. Serum fPSA is elevated marginally in patients with BPH without inflammation. Active inflammation and high grade lesions are associated with fPSA level more than 5 ng/ml.