高级别前列腺上皮内瘤变及其他癌前病变的病理特点

研究表明,高级别前列腺上皮内瘤变(HGPIN)是无可置疑的前列腺癌前病变.HGPIN的形态特点是前列腺导管和腺泡的分泌细胞增生,细胞核和核仁肿大与前列腺癌细胞相似,不同的是HGPIN保留有部分基底细胞层.HGPIN与前列腺癌之间有非常密切的关系,因此对HGPIN的诊断和鉴别诊断有重要的临床意义.除了HGPIN以外,目前还提出了一些与前列腺癌的发生可能有关的癌前病变,如:低级别前列腺上皮内瘤变(LGPIN)、增生性炎症性萎缩(PIA)、不典型性腺瘤样增生(AAH).我们旨在对HGPIN及可能为前列腺癌前病变的一些病变的病理形态学、分子学和流行病学研究新进展作一介绍.     

High-grade prostatic intraepithelial neoplasia with adjacent small atypical glands on prostate biopsy

With high-grade prostatic intraepithelial neoplasia with adjacent small atypical glands (PINATYP), the issue is whether the small glands represent budding or tangentially sectioned glands off of adjacent high-grade prostatic intraepithelial neoplasia (PIN) or invasive cancer next to high-grade PIN. The histology and significance of PINATYP on biopsy have not been described. Among 574 cases of high-grade PIN lesions on needle biopsy, we identified 71 cases of PINATYP. Most cases were consultations, and 51 cases were available for histologic review. At least 1 follow-up prostate biopsy was performed in each of 55 cases. Immunohistochemistry for high-molecular-weight cytokeratin (HMWCK) was performed on cases in which material was available. The average patient age at diagnosis was 65.5 years (range, 48 to 103 years). The initial digital rectal examination, transrectal ultrasound, serum prostate-specific antigen (PSA) level, PSA velocity, and family history of prostate cancer did not predict cancer on repeat biopsy. In 39% of cases, high-grade PIN had a predominantly flat pattern, and remaining cases showed a predominance of other patterns (tufting, micropapillary, cribriform). The average number of high-grade PIN glands and adjacent small atypical glands were 11.5 (1 to 60) and 5.3 (1 to 21), respectively. The farthest adjacent small atypical gland averaged 0.12 mm from the high-grade PIN (0.01 mm to 0.4 mm), as measured with an ocular micrometer. The following histologic features did not predict cancer on repeat biopsy: more than 1 core involved by the high-grade PIN; number of high-grade PIN glands; number of small atypical glands; distance of small atypical glands from the high-grade PIN; size and percentage of nucleoli; marked nuclear pleomorphism; and mitoses. Overall, the risk of cancer on repeat biopsy was 46%. Two findings predicted a lower risk of cancer on repeat biopsy: younger age (62.2 years benign v 68.3 years cancer; P =.004) and predominantly flat high-grade PIN (P =.007). In our material, PINATYP appears to be a greater risk factor than high-grade PIN alone in predicting cancer on rebiopsy. Although age and predominant pattern of associated high-grade PIN may be helpful in predicting which men with this lesion will have cancer on rebiopsy, they cannot be used reliably; therefore, all men with PINATYP should undergo repeat biopsy. HUM PATHOL 32:389-395.     

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.     

Intraepithelial prostatic neoplasia: a new dysplastic lesion of the prostate

Prostatic Intraepithelial Neoplasia were studied retrospectively in 455 cases of surgically resected prostates: 387 benign hypertrophies and 68 adenocarcinomas. The frequency of PIN was highest among prostatic adenocarcinomas well differentiated while the benign hypertrophies showed a lower frequency and a moderate increase with age. The prognostic importance of this lesion in prostatic biopsies is discussed on account of its strong predictive value.     

Desquamating apoptotic variant of high-grade prostatic intraepithelial neoplasia: a possible precursor of intraductal prostatic carcinoma

Various patterns of high-grade prostatic intraepithelial neoplasia have been have been described, many of which show morphologic similarity to patterns of prostatic intraductal carcinoma, which is thought to develop either directly from high-grade prostatic intraepithelial neoplasia or by invasion of existing ducts by Gleason pattern 4 or 5 carcinoma. We document a rare and previously unreported "desquamating apoptotic variant" of high-grade prostatic intraepithelial neoplasia where desquamating cells containing apoptotic nuclear material coalesce in the gland lumens to form basophilic intraluminal masses in up to one third of involved acini. This lesion shares features of both high-grade prostatic intraepithelial neoplasia and prostatic intraductal carcinoma and supports the hypothesis that some forms of prostatic intraductal carcinoma evolve directly from high-grade prostatic intraepithelial neoplasia.     

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.     

Central zone histology of the prostate: a mimicker of high-grade prostatic intraepithelial neoplasia

The central zone (CZ) is located at the base of the prostate adjacent to the seminal vesicles. Its histology as a potential mimicker of high-grade prostatic intraepithelial neoplasia (PIN) has not been formally studied. Three groups were evaluated. Group 1 comprised 30 consecutive radical prostatectomy specimens assessed for the extent of CZ and of Roman arch and/or cribriform formation in the CZ. Group 2 comprised 100 consecutive cases of nonconsult prostate needle biopsies, screened in a random blinded fashion to identify CZ histology and the specificity of its identification on biopsy. Group 3 comprised 34 consult cases (1984 to the present) with CZ histology on needle biopsy. For group 1, the average maximum diameter of CZ histology was 5 mm. Two cases (6.7%) did not contain the classic features of CZ histology. The average amount of cribriform and/or Roman arch formation in the areas with CZ histology was 16.5%. In group 2, 10% of prostate needle biopsy cases had CZ histology. Of these, 80% were located on biopsy specimens designated as the base of the prostate, 10% were located in the base and midportion of the prostate, and 10% were located in the midportion of the prostate. For group 3, CZ histology occupied on average 32% of the involved core. The 2 most common histologic features were eosinophilic cytoplasm (97%) and location at the end of a core (97%). Other features were Roman arch formation (59%), a prominent basal cell layer (32%), cribriform formation (26%), and associated thick muscle bundles typical of bladder neck (24%). On average, cribriform and/or Roman arch formation occupied 22% of the CZ area seen on biopsy. Twenty-six of the consult cases were sent in with preliminary outside diagnoses. Of these, 21 (81%) were either PIN or atypical: 11 (42%) high-grade PIN, 7 (27%) PIN, and 3 (12%) atypical glands. Our findings show that CZ histology is distinctive, as seen in radical prostatectomy specimens. Less frequently it is found on needle biopsy, where the presence of Roman arch and/or cribriform formation mimics PIN. Recognition of the distinctive features of CZ histology (i.e., tall columnar cells with eosinophilic cytoplasm, prominent basal cell layer, and lack of cytologic atypia) can help avoid a misdiagnosis of PIN or "atypia" on needle biopsy.     

Intraductal carcinoma of the prostate gland with transmucosal spread to the seminal vesicle: a lesion distinct from high-grade prostatic intraepithelial neoplasia

Intraductal carcinoma of the prostate (IDC-P) gland represents an intraluminal neoplastic proliferation that is distinct from high-grade prostatic intraepithelial neoplasia (HG-PIN) and almost always coexists with large-volume, high-stage, and high-grade invasive carcinoma. We document an unusual presentation of apparently "early" IDC-P without an aggressive invasive element that, despite being confined to the acinar-ductal system, has gained access to the ejaculatory duct and seminal vesicle by transmucosal spread. This finding confirms that IDC-P, in contrast to HG-PIN, is inherently aggressive and has the ability to spread beyond the prostate gland. In this case, the absence of an aggressive invasive element suggests that IDC-P has most likely evolved within the lumens directly from HG-PIN.     

Microvessel density as a molecular marker for identifying high-grade prostatic intraepithelial neoplasia precursors to prostate cancer

BACKGROUND: Existing clinical data have shown that high-grade prostatic intraepithelial neoplasia (HGPIN) is the most likely precursor to prostate cancer (CaP). Criteria to distinguish HGPIN that progress to CaP from those that do not remain poorly defined. Our objective was to evaluate microvessel density as a molecular marker for distinguishing HGPINs that have the potential of progressing to cancer. MATERIALS AND METHODS: Human prostatic tissue samples were collected randomly from 50 prostatectomy and cystoprostatectomy patients. Formalin-fixed and paraffin-embedded sections were used for immunohistochemical localization of rabbit anti-human von Willebrand factor VIII (vWF) IgG, mouse anti-high molecular weight cytokeratin 34BE-12 in basal cells, and mouse anti-heparan sulphate proteoglycan (HSPG) IgGs in basement membranes associated with benign prostatic hyperplasia (BPH), PIN associated with some BPH (isolated PIN), and PIN associated with CaP. RESULTS: Analysis of immunostaining data showed that PINs could be categorized according to their distributions within and outside 2 standard deviations (SD) of the mean for microvessel density. The average number of microvessels was significantly higher (P < 0.0001) in PINs associated with Gleason score 7 tumors than those associated with Gleason scores 4-6 (P < 0.1328) or 8 and 9 tumors (P < 0.1708). Morphologically, PINs within 2 SD were composed of low- and high-grade type, whereas those outside 2 SD of microvessel density were predominantly of high-grade type. Cytokeratin and HSPG localization patterns also showed differences in PINs found within and outside 2 SD of microvessel density. We found localization of cytokeratin 34BE-12 in basal cells of specimens with BPH alone, isolated PIN, and PIN associated with CaP within 2 SD, whereas many PINs outside 2 SD showed disruptions in cytokeratin localization. The basement membranes of PINs within 2 SD of microvessel density were relatively intact, whereas those outside 2 SD were fragmented. CONCLUSIONS: Our immunostaining data indicates that once HGPIN is found in the initial prostatic biopsy, it should be evaluated for microvessel density by localization of vWF. Our data indicate that characteristics of HGPIN can be augmented by evaluations of cytokeratin and HSPG molecular markers to assess the potential of HGPIN progression to malignancy. When biopsy samples show HGPIN with increased microvessel density and disrupted cytokeratin and HSPG markers, the patient may be a candidate for repeat biopsy. Since our study is limited to 50 prostate tissue samples, we emphasize that our conclusion is tentative and ought to be confirmed in a study with a larger sample size. This is the first report to show that microvessel density may distinguish HGPIN that is a precursor to prostate cancer.     

Cytological features of prostatic intraepithelial neoplasia

Fine-needle aspiration cytology (FNAC) is an acknowledged method for diagnosing prostate cancer. False-positive results are uncommon, but concerns have been raised that prostatic intraepithelial neoplasia (PIN) could be misinterpreted as carcinoma. Therefore, we attempted to describe cytological features of PIN. Cells were scraped from macroscopically normal areas of 177 radical prostatectomy specimens, smeared and Giemsa-stained. Histological slides from these areas were reviewed, and 17 samples with high-grade PIN and with no invasive cancer were selected. Smears from 17 invasive cancers were used for comparison. Cancer showed high cellularity and dissociation, while PIN smears only contained a few clusters of atypical cells. Pronounced nuclear atypia, prominent or multiple nucleoli and mucin were more common in cancer, while cytoplasmic granules, crystalloids and cluster size did not distinguish between PIN and cancer. In conclusion, PIN should not be diagnosed by FNAC alone. However, a highly cellular smear with pronounced atypia seems to preclude PIN.     

Nuclear changes in the normal-looking columnar epithelium adjacent to and distant from prostatic intraepithelial neoplasia and prostate cancer

Subtle morphological changes and molecular alterations have been reported in normal-appearing tissue in prostates with high-grade prostatic intraepithelial neoplasia (PIN) and prostate cancer (PCa). The severity and the distribution of these changes and alterations within the prostate gland have not been addressed in previous publications. The aim of this study was to investigate morphometrically the nuclear changes of the normal-looking columnar epithelium adjacent to and distant from high-grade PIN and PCa. Karyometry was performed on the whole-mount histological sections of three radical prostatectomy (RP) specimens. Two concentrical lines, one corresponding to the outer surface (or capsule) of the prostate and the other corresponding to one centimeter towards the center, were drawn with a black pen on each whole-mount section. The part of the prostate tissue between these two boundaries was then divided into twelve equal sectors or regions. The part within the inner line was divided into two regions. The analysis was also performed on the slides of the apex and base of the prostate. One prostate contained normal-looking epithelium only (case no. 1). Another contained both high-grade PIN and PCa, the former occupying larger areas than the latter (case no. 2). Both high-grade PIN and PCa were present in the third sample, in which PCa was more widely distributed than PIN (case no. 3). The lesion measured in each region was always the most severe, e.g., either high-grade PIN or PCa. When neither were identifiable, then the normal-looking columnar epithelium was analyzed. For each sector, the mean and standard deviation of the nuclear area, maximum nuclear diameter, nuclear roundness factor, and nucleolar area were calculated. In normal-looking columnar epithelium, the mean of the mean nuclear area of the sectors of case no. 1 was 35.19 microm2 (SD 4.14). The mean nuclear areas in cases no. 2 and no. 3 were 37.94 microm2 (SD 4.65) and 37.31 microm2 (SD 4.36), respectively. The mean of the mean nuclear area of the sectors with high-grade PIN of case no. 2 was 49.85 microm2 (SD 8.44), whereas it was 54.26 microm2 (SD 2.91) in case no. 3. The mean of the nuclear area values obtained in the sectors of cases no. 2 and no. 3 with PCa was 56.74 microm2 (SD 6.56) and 61.17 microm2 (SD 8.13), respectively. When considering the normal-looking tissue of the second and third case, 79% and 90%, respectively, of the regions showed nuclear area values greater than 34.94 microm2 (e.g., the 50th percentile of the mean nuclear area values of the regions of the first case). Sectors with normal-looking epithelium, whose nuclear area was above this threshold, were both adjacent to and at a distance of more than 1 cm from those with PIN or PCa. The other nuclear features showed a similar trend of value changes. This study demonstrates that the normal-looking ducts and acini from prostate harboring preneoplastic and neoplastic lesions show morphological nuclear abnormalities that are not seen by the human eyes but that can be detected with image analysis. Such changes may be of diagnostic importance, especially in cases where clinical suspicion for cancer prevails after a negative biopsy.     

Morphoproteomic confirmation of a constitutively activated mTOR pathway in high grade prostatic intraepithelial neoplasia and prostate cancer

Preclinical studies have implicated the mammalian target of rapamycin (mTOR) pathway in the cell cycle progression and growth of prostate cancer cells. Downstream signaling from PI3'-K/Akt leads to phosphorylation (p) of mTOR at serine 2448 and to activation of its substrate, p70S6Kinase (p70S6K), phosphorylated on threonine 389. This promotes translation and cell cycle progression. Morphoproteomic analysis, that combines both the application of phosphospecific probes directed against putative sites of activation on protein analytes and cellular compartmentalization [1] was carried out on tissue microarray (TMA) slides from 64 cases of primary, previously untreated adenocarcinomas of the prostate. Gleason scores ranged from 6 to 10. High grade prostatic intraepithelial neoplasia (HGPIN), which accompanied the invasive cancer in 20 cases, and 15 non-neoplastic controls from benign prostatic hypertrophy specimens in a separate TMA were also included. Ninety-three percent (93%) of tumors exhibited moderate to strong cytoplasmic/plasmalemmal expression of p-mTOR and eighty-five percent (85%) showed similar staining intensity for p-p70S6K. HGPIN demonstrated comparable and occasionally, stronger expression levels for these protein analytes. Quantitative digital imaging revealed an overall increase in the mean expression levels in HGPIN, reaching statistical significance for p-mTOR (Ser 2448) at p<0.05. Morphoproteomic analysis confirms the constitutive activation of the mTOR pathway in prostate cancer and HGPIN, with relative overexpression of p-mTOR in HGPIN. These findings coincide with preclinical studies in supporting a role for the mTOR pathway in the biology and development of prostate cancer through its putative precursor lesion, HGPIN and in suggesting a potential therapeutic target.     

Effects of combination endocrine treatment on normal prostate, prostatic intraepithelial neoplasia, and prostatic adenocarcinoma.

AIMS--To investigate the effect of combination endocrine treatment (CET) or luteinising hormone releasing hormone agonist and flutamide on non-neoplastic prostate, prostatic intraepithelial neoplasia, and prostatic adenocarcinoma. METHODS--The morphology, including the mitotic activity, of 12 radical prostatectomies from patients with prostatic adenocarcinoma pretreated for three months with CET was evaluated in haematoxylin and eosin stained sections and compared with an untreated age and stage matched control group. RESULTS--A differential effect on the non-neoplastic prostate was observed. In fact, the transition zone of the treated prostate showed simplification of the glandular lobules: the ducts and acini were small without undulations of the epithelial border and with a prominent basal cell layer. Within the peripheral zone there was inconspicuous branching of the ducts and acini which looked dilatated and lined by flattened atrophic epithelium. Prostatic intraepithelial neoplasia occurred in scattered ducts and acini in the peripheral zone of 10 of the 12 patients. The epithelial cell lining showed a prominent basal cell layer. A certain degree of secretory cell type stratification was always present. However, crowding was less evident than in the untreated prostate because of cytoplasmic clearing and enlargement as a result of coalescence of vacuoles. The treated adenocarcinomas had neoplastic acini which looked small and shrunken, and areas of individual infiltrating tumour cells separated by abundant interglandular connective tissue. The secretory cells of the nonneoplastic, prostatic intraepithelial neoplasia, and prostatic adenocarcinoma lesions had inconspicuous nucleoli, nuclear shrinkage, chromatin condensation, and cytoplasmic clearing. Apoptotic bodies were easily identifiable in all the cell layers. The lumina were rich in macrophages, sloughed secretory cells with degenerative features, and apoptotic bodies. Mitoses were not observed in any of the treated non-neoplastic prostate, prostatic intraepithelial neoplasia, or prostatic adenocarcinomas, whereas the mitotic frequency increased from non-neoplastic prostate through prostatic intraepithelial neoplasia up to prostatic adenocarcinomas in the untreated specimens. CONCLUSIONS--CET before radical prostatectomy causes regressive epithelial changes together with enhanced apoptosis and blocked mitotic activity.     

Recurrent prostatic stromal sarcoma with massive high-grade prostatic intraepithelial neoplasia

A unique case of prostatic stromal sarcoma (PSS) that recurred in the pelvic cavity with massive high-grade prostatic intraepithelial neoplasia is described. A 52-year-old man who presented with urinary retention underwent a radical cystoprostatectomy. Tumour tissues of the prostate showed an admixture of hyperplastic glands and markedly cellular stroma of spindle cells arranged in a fascicular pattern, and the tumour was diagnosed as PSS. 66 months after the operation, CT scans revealed three recurrent tumours around the bilateral obturator and left fore iliopsoas. The recurrent tumours were biphasic neoplasms, as before, but the epithelial component had grown prominent and manifested overt atypia in a manner resembling high-grade prostatic intraepithelial neoplasia. Our findings suggest that not only the stromal component but also and the epithelial components of PSS may have malignant potential.