High-grade prostatic intraepithelial neoplasia

High-grade prostatic intraepithelial neoplasia (HGPIN) has been established as a precursor to prostatic adenocarcinoma. HGPIN shares many morphological, genetic, and molecular signatures with prostate cancer. Its predictive value for the development of future adenocarcinoma during the prostate-specific antigen screening era has decreased, mostly owing to the increase in prostate biopsy cores. Nevertheless, a literature review supports that large-volume HGPIN and multiple cores of involvement at the initial biopsy should prompt a repeat biopsy of the prostate within 1 year. No treatment is recommended for HGPIN to slow its progression to cancer.     

Multilocular prostatic cystadenoma with high-grade prostatic intraepithelial neoplasia

Multilocular prostatic cystadenoma is a rarely encountered neoplasm located in the midline between the bladder and rectum that is either attached to the prostate by a pedicle or separate from the prostate entirely. Histologically and immunohistochemically these lesions resemble benign prostate tissue. We report the first case of this entity for which multifocal high-grade prostatic intraepithelial neoplasia (PIN) is identified. Conceptually, the finding of high-grade PIN in multilocular prostatic cystadenomas provides further evidence that these lesions are fully analogous to the prostate gland not only in their morphology and immunohistochemistry but also in their predilection for the same diseases.     

Developmental estrogenization and prostatic neoplasia

The association of estrogens with benign prostatic hyperplasia and prostatic cancer has been widely studied, but no conclusive evidence exists for a role of estrogens in prostatic disease. This paper reviews the literature and describes studies which have sought to show a correlation of estrogens and alterations in the prostates of humans and experimental animal models. Using the developmentally estrogenized mouse model, we propose an alternative role for estrogens as a predisposing factor for prostatic diseases: estrogen exposure during development may initiate cellular changes in the prostate which would require estrogens and/or androgens later in life for promotion to hyperplasia or neoplasia. Thus, the critical time for estrogen action would be during the development of the prostatic tissue. We further suggest that estrogen-sensitive cells may remain in the prostate and be more responsive to estrogens later in life or less responsive to the normal controlling mechanisms of prostatic growth. © 1994 Wiley-Liss, Inc.     

Foamy gland high-grade prostatic intraepithelial neoplasia

A 60-year-old man underwent radical prostatectomy for biopsy-proved adenocarcinoma of the prostate. Histologic examination of the entirely embedded prostatectomy specimen revealed extensive ordinary adenocarcinoma, Gleason's grade 3 + 3 = 6, involving both sides of the gland, and extending into extraprostatic soft tissue at the left base. Adjacent to the carcinoma, and separately, extensive high-grade prostatic intraepithelial neoplasia (PIN) was identified, much of which showed bland nuclei and abundant xanthomatous cytoplasm, identical morphologically to that seen in foamy gland prostate carcinoma. However, unlike foamy gland carcinoma, the foamy glands in the current patient were large, showed papillary infolding, and were associated with a discontinuous layer of basal cells, demonstrated by immunostaining for high-molecular weight cytokeratin. No invasive foamy gland carcinoma was identified in the prostatectomy specimen. Immunostains for Ki-67 showed an increased proliferation rate in foamy high-grade PIN glands when compared with adjacent benign glands. Review of additional outside biopsy material revealed foamy gland high-grade PIN on four of seven needle cores, two of which showed no carcinoma. This patient demonstrates a new subtype of high-grade PIN that is difficult to recognize on needle biopsy. It is important to distinguish foamy gland high-grade PIN from its infiltrating counterpart, and it is critical to recognize because of the association of high-grade PIN with prostate carcinoma.     

Molecular biology of prostatic intraepithelial neoplasia

High-grade PIN is the most likely precursor of prostatic adenocarcinoma, according to virtually all available evidence to date. The clinical importance of recognizing PIN is based on its strong association with prostatic carcinoma. PIN has a high predictive value as a marker for adenocarcinoma. Its identification in biopsy specimens of the prostate warrants further search for concurrent invasive carcinoma. PIN is associated with progressive abnormalities of phenotype and genotype intermediate between normal prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of prostatic carcinogenesis. There is progressive gain or loss of a wide variety of biomarkers, including morphometric markers, differentiation markers, stromal markers, growth factors and associated receptors, oncogenes, tumor suppressor genes, and chromosomes. Abnormalities in expression of most biomarkers are amplified in the progression from high-grade PIN to localized cancer, metastatic cancer, and hormone-refractory cancer. Oncogenesis of prostatic carcinoma probably occurs through the selection of several genetic changes, each modifying the expression or function of genes controlling cell growth and differentiation. Further studies are needed to evaluate the function and prognostic value of oncogene expression in the normal, preneoplastic, and neoplastic prostate. © 1996 Wiley-Liss, Inc.     

Clinical evolution of prostatic intraepithelial neoplasia.

High-grade prostatic intraepithelial neoplasia (PIN) is most likely a precursor of prostate cancer and is frequently associated with it whereas the direct link between low-grade PIN and cancer is not established. The clinical evolution of isolated high-grade PIN has been the object of much concern because of the possibility of undiagnosed prostate cancer or the evolution of this premalignant lesion in invasive carcinoma. Parameters predictive of the later finding of prostate cancer on repeat biopsy in patients with PIN are of evident interest and we have reviewed our experience and recent data from the literature on this topic as well as on the clinical management of these patients. Low-grade PIN is not by itself a risk of later cancer found on repeat biopsy unless other factors such as PSA increase the cancer suspicion. Patients with low-grade PIN and high serum PSA should therefore undergo repeat biopsies. Patients with low-grade PIN and without additional factors should be followed. Patients with high-grade PIN should systematically be rebiopsied. If a second set is still consistent with PIN, they should undergo additional biopsies again within 3-6 months because they are likely to have an undiagnosed cancer.     

High-grade prostatic intraepithelial neoplasia in dogs.

The dog is the only nonhuman species in which high-grade intraepithelial neoplasia (HGPIN) and invasive carcinoma spontaneously occur. Our work was the first to describe HGPIN in the dog prostate. Canine HGPIN bears remarkable morphologic similarity to its human counterpart. There is also striking similarity between canine and human HGPIN with respect to basal layer disruption, proliferative index, and microvessel density. For each of these parameters, HGPIN is intermediate between benign epithelium and invasive carcinoma, strengthening the hypothesis that HGPIN is an intermediate step on the road to prostate cancer. In another study, we showed that HGPIN is present in the majority (55%) of elderly sexually intact pet dogs without clinical evidence of prostate cancer. These data suggest that the early events of prostate carcinogenesis may occur with high frequency within the prostates of pet dogs sharing the same environment as humans. We are currently conducting a large-scale autopsy-epidemiological study to further characterize the epidemiology of HGPIN and invasive carcinoma in pet dogs. We are also testing the potential utility of pet dogs for the rapid, cost-effective in vivo screening of chemopreventive agents by using the prevalence and extent of HGPIN in the dog prostate as a surrogate endpoint biomarker.     

High prevalence of human cytomegalovirus in prostatic intraepithelial neoplasia and prostatic carcinoma

PURPOSE: Recent epidemiological data indicate that a history of increased exposure to sexually transmitted diseases is associated with an increased risk of prostate cancer. Human cytomegalovirus (HCMV) is a member of the herpesvirus family, is sexually transmitted in adults and can persistently infect prostatic epithelium in non-immunocompromised hosts. Based on increased awareness of the oncogenic potential of this virus, we decided to reexplore the issue of whether HCMV might be involved in prostate cancer pathogenesis. MATERIALS AND METHODS: Paraffin embedded biopsy specimens from 22 randomly selected patients with prostatic intraepithelial neoplasia (PIN) lesions and prostatic carcinoma were analyzed by immunohistochemistry, in situ hybridization, polymerase chain reaction and DNA sequencing to detect HCMV nucleic acids and determine whether HCMV gene products were specifically associated with neoplastic cells. RESULTS: We detected HCMV proteins and/or nucleic acids in all 22 of the 22 preneoplastic and neoplastic prostate lesions evaluated. HCMV proteins were specifically and often highly expressed in basal cell hyperplasia and PIN lesions, and to a lesser degree in carcinoma cells. RESULTS: To our knowledge these data demonstrate for the first time the specific localization of HCMV nucleic acids and proteins in a high percent of PIN and prostate carcinoma lesions, and raise the possibility that HCMV might contribute to the natural history of prostatic cancer.     

High grade prostatic intraepithelial neoplasia is a disease

High grade prostatic intraepithelial neoplasia (PIN) is now widely accepted as the main premalignant lesion that has the potential to progress to prostate adeno-carcinoma. High grade PIN is a standard diagnosis that must be included as part of the reported pathologic evaluation of prostate biopsies. Premalignant lesions that affect other organs have been identified and are treated when diagnosed such that the premalignant lesions itself are a disease ( eg, carcinoma in situ of the bladder, colon polyps, and cervical dysplasia). Urologists should recognize that high grade PIN is a dangerous lesion and that it should be aggressively managed either by saturation biopsies of the prostate following the diagnosis of high grade PIN, or the more common recommendation—repeated prostate biopsies every 3 to 6 months for 2 years, then annually. Treatment of these precancerous lesions would appear to be of clinical benefit notwithstanding the potential for cancer prevention. These clinical benefits would reduce morbidity, enhance the quality of life, delay surgery or radiation, and increase the interval for surveillance requiring invasive procedures.     

Epidemiology and molecular biology of early prostatic neoplasia

This paper provides our institutional data with respect to the prevalence of early neoplastic changes within the prostate gland and the age and race distribution of the patients. The changes examined were prostatic intraepithelial neoplasia (PIN) and preclinical (latent) cancers. The literature on the prevalence of these early lesions among different geographic and ethnic groups is summarized, and an abbreviated review of the more common molecular alterations reported at this early phase of prostatic neoplasia is offered.     

Finasteride decreases the risk of prostatic intraepithelial neoplasia

PURPOSE: High grade prostatic intraepithelial neoplasia is likely a premalignant lesion of the prostate. Decreasing the frequency of high grade PIN may decrease the risk of prostate cancer. In the Prostate Cancer Prevention Trial we evaluated the impact of finasteride on the risk of a needle biopsy diagnosis of high grade prostatic intraepithelial neoplasia. MATERIALS AND METHODS: The Prostate Cancer Prevention Trial was a randomized, placebo controlled clinical trial that enrolled 18,882 men without evidence of prostate cancer, prostate specific antigen less than 3.0 ng/ml and normal digital rectal examination, and randomized them to 5 mg finasteride daily or placebo. Subjects were followed for 7 years with biopsy recommended for prostate specific antigen greater than 4.0 ng/ml, adjusted in the finasteride group to achieve an equal number of biopsy recommendations or for abnormal digital rectal examination. All cancer-free subjects were recommended to undergo biopsy after 7 years on study. We evaluated the diagnosis of high grade prostatic intraepithelial neoplasia with or without concomitant prostate cancer in these 2 study groups. RESULTS: The number of men evaluable for high grade prostatic intraepithelial neoplasia was 4,568 in the finasteride group and 4,886 in the placebo group. High grade prostatic intraepithelial neoplasia alone was diagnosed in 276 men (6.0%) in the finasteride group vs 347 (7.1%) in the placebo group (RR 0.85, 95% CI 0.73-0.99, p=0.04). High grade prostatic intraepithelial neoplasia accompanied by prostate cancer was diagnosed in 144 men (3.2%) in the finasteride group vs 223 (4.6%) in the placebo group (RR 0.69, 95% CI 0.56-0.85, p=0.0004). Finasteride significantly decreased the overall risk of high grade prostatic intraepithelial neoplasia (alone and with cancer) from 570 cases (11.7%) in the placebo group to 420 (9.2%) in the finasteride group (HR 0.79, 95% CI 0.70-0.89, p<0.001). CONCLUSIONS: Finasteride significantly decreased the risk of high grade PIN. This observation may explain how finasteride decreased prostate cancer in the Prostate Cancer Prevention Trial, supporting the notion that high grade prostatic intraepithelial neoplasia is a premalignant lesion of the prostate, and it provides new information relevant to the consideration of finasteride for prostate cancer prevention.     

前列腺癌及前列腺上皮内瘤13号染色体等位基因杂合性缺失分析

目的　探讨原发性前列腺癌及高级别前列腺上皮内肿瘤 (PIN) 13号染色体等位基因杂合性缺失 (LOH)及其意义。　方法　经显微切割技术获取前列腺癌及PIN标本各 10例。提取DNA ,采用PCR及微卫星多态性技术 ,对 13号染色体上 14个微卫星标志位点LOH进行检测。　结果　 10例原发性前列腺癌中 7例 13号染色体上至少有一个位点检测到LOH。 13q14及 13q12～ 13为两个高频LOH区。 10例PIN中 13号染色体的 14个位点均未检测到LOH。　结论　前列腺癌中存在 13号染色体的高频LOH区 ,乳腺癌易感基因 (BRCA2 )、视网膜母细胞瘤基因 (RB1)及位于附近的肿瘤抑制基因可能与前列腺癌的发生发展有关     

High-grade prostatic intraepithelial neoplasia and prostate cancer risk reduction

High-grade prostatic intraepithelial neoplasia (PIN) is the earliest accepted stage in carcinogenesis, possessing most of the phenotypic and biochemical changes in cancer without invasion of the basal membrane of the acini. The support for high-grade PIN as the main premalignant lesion of prostate cancer is based on several lines of evidence derived from prostate cancer animal models, epidemiological, morphological, genetic, and molecular studies. The incidence of high-grade PIN averages 9% (range 4-16%) in prostate biopsies, representing 115,000 new cases of high-grade PIN diagnosed each year in the United States. Performing saturation prostate biopsies to rule out any coexistent prostate cancer followed by every 3-6 month serial repeated prostate biopsies is currently the only way in which to manage patients found to have high-grade PIN. Medical therapy for high-grade PIN may easily become the mainstay treatment for high-grade PIN. Treatment of high-grade PIN appears to be of clinical benefit notwithstanding the potential for prostate cancer risk reduction. These clinical benefits would reduce morbidity, enhance quality of life, delay surgery or radiation, and increase the interval for surveillance requiring invasive procedures.     

MAPK在前列腺上皮内瘤中的表达及其意义

目的：通过研究有丝分裂活化蛋白激酶（MAPK）在前列腺上皮内瘤（PIN）组织中的表达,探讨MAPK在前列腺肿瘤形成过程中的作用。方法：采用免疫组织化学（IHC）方法对12例PIN标本和16例前列腺增生（BPH）标本进行染色检查。结果：12例PIN标本均表现了不同程度的肿瘤细胞染色,其中6例标本肿瘤细胞的细胞质有较强染色。与对照组相比较,PIN中MAPK染色指数增加了1．48倍（P＜0．05）。结论：PIN组织 中MAPLK的活性高于BPH。PIN中MAPK的过度激活可能是促进肿瘤形成的主要信号传递通路。