Prostatic intraepithelial neoplasia: an overview

Prostatic intraepithelial neoplasia (PIN) is the most established precursor of prostatic carcinoma. The presence of prominent nucleoli within an existing duct structure is an easy way to identify the disorder. Four main patterns of high-grade PIN (HGPIN) have been described: tufting, micropapillary, cribriform, and flat. In addition to exhibiting similar cytologic features, both HGPIN and prostatic carcinoma are associated with increased incidence and severity with age, and with high rates of occurrence in the peripheral zone of the prostate. HGPIN and prostate cancer share genetic and molecular markers as well, with PIN representing an intermediate stage between benign epithelium and invasive malignant carcinoma. The clinical significance of HGPIN is that it identifies patients at risk for malignancy. With the increased use of extended biopsy protocols, clinicians are more likely to identify HGPIN and less likely to miss concurrent carcinoma. Androgen deprivation therapy decreases the prevalence and extent of PIN, and may play a role in chemoprevention. Preliminary studies suggest that selective estrogen receptor modulators may also prevent the progression of HGPIN to prostate cancer.     

Nuclear volume estimates in prostatic intraepithelial neoplasia

OBJECTIVE: Prostatic intraepithelial neoplasia (PIN), the most likely precursor of prostatic adenocarcinoma, is divided into two grades, low and high. Pathologists may encounter difficulties in applying these criteria in daily practice. In view of the clinical significance of high grade PIN as strong predictor of carcinoma, the separation of low and high grade PIN plays an important role in patient management. The aim of the present study was to evaluate three-dimensional nuclear size estimation in normal prostatic glands, low and high grade PIN, and prostatic adenocarcinoma as an element in their classification. STUDY DESIGN: We studied 31 formalin-fixed, paraffin-embedded, whole-mounted radical prostastectomy specimens that contained foci of normal prostatic glands, low and high grade PIN, and prostatic adenocarcinoma. Hematoxylin-eosin-stained sections were selected for the stereologic estimation of volume-weighted mean nuclear volume by the "point-sampled intercepts" method. On each focus, an average of six fields of vision were systematically chosen. RESULTS: The quantitative results indicate a significant increase in nuclear volume from normal prostatic glands (mean, 209.0 micron 3; SD, 64.6 micron 3) to low grade PIN, high grade PIN and prostatic adenocarcinoma with increments of 49%, 88% and 109%, respectively (F = 29.1, P < .001). Two-group comparisons (Duncan procedure) showed differences between low and high grade PIN and prostatic adenocarcinoma (P < .01). The difference between high grade PIN and prostatic adenocarcinoma was not significant. CONCLUSION: Three-dimensional estimates of nuclear size discriminate low and high grade PIN. Lack of stereologic differences between high grade PIN and prostatic adenocarcinoma further supports high grade PIN as a precursor of prostatic adenocarcinoma.     

Quantitative analysis of prostatic intraepithelial neoplasia on tissue sections.

The changes in nuclear morphology (karyometry) and DNA content in prostatic intraepithelial neoplasia (PIN) were analyzed on tissue sections. The cases of PIN were subdivided into PIN 1 and PIN 2 based on the degree of proliferation and the anaplasia of the secretory cells lining the ducts and acini. Cases of nodular hyperplasia (NH) and adenocarcinoma were also studied for comparative purposes. Karyometric analysis showed a progression of most values from NH to PIN to carcinoma. The DNA analysis showed a decrease in the frequency of nuclei in the diploid range and an increase in the percentage of nuclei in the other ploidy regions (especially between 2c and 4c and in the tetraploid range) from NH to PIN to carcinoma. Forward stepwise discriminant analysis showed similarities between NH and PIN 1 and between PIN 2 and carcinoma. These findings suggest that the evolution towards adenocarcinoma is characterized by progressive morphologic derangements of the nuclei and by the transformation of the diploid DNA content into a nondiploid one, with the changes taking place at the level of PIN 2.     

Epigenetic heterogeneity of high-grade prostatic intraepithelial neoplasia: clues for clonal progression in prostate carcinogenesis

High-grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of prostate adenocarcinoma, but the frequency and timing of epigenetic changes found in prostate carcinogenesis has not been extensively documented. Thus, the promoters of three genes (APC, GSTP1, and RARbeta2) involved in prostate carcinogenesis were tested by quantitative methylation-specific PCR in tissue DNA from 30 prostate carcinomas, 128 high-grade PIN lesions, and 30 normal prostate tissue samples dissected from 30 radical prostatectomy specimens using laser capture microdissection. The percentage of methylated alleles (PMA) was calculated for each gene, and hierarchical cluster analysis was used to define the degree of similarity of epigenetic alterations among the various samples. We found that PMA values of APC and RARbeta2 were higher than those of GSTP1 in all three types of tissue samples and median PMA values for all three genes were higher in prostate cancer. By cluster analysis, 26 of 30 prostate carcinomas and 82 of 128 high-grade PIN lesions were grouped in the "high methylation" branch, whereas 24 of 30 normal prostate tissue samples were allocated in the "low methylation" branch. Although high-grade PIN lesions are epigenetically more similar to prostate carcinoma than to normal prostate tissue, paired prostate carcinoma and high-grade PIN lesions did not always segregate together. We concluded that APC and RARbeta2 hypermethylation is frequent in normal prostate tissue and the progressive enrichment in cells carrying methylated alleles observed in high-grade PIN and prostate carcinoma is consistent with clonal progression. Because GSTP1 promoter methylation is mainly observed in prostate carcinoma and some high-grade PIN lesions, it represents an important marker for the transition of in situ to invasive neoplasia.     

Transforming growth factor beta 1 and androgen receptors in prostate neoplasia

OBJECTIVE: To investigate the interplay between transforming growth factor (TGF) beta 1, androgen receptors and stromal-epithelial interactions in benign prostatic hyperplasia (BPH), prostate intraepithelial neoplasia (PIN) and prostate carcinoma areas of prostate neoplasia. STUDY DESIGN: In this immunohistochemical study we investigated staining patterns and then determined the correlation between TGF-beta 1 expression and androgen receptor status in the epithelium and stroma of 60 paraffin-embedded tissues from radical prostatectomies. RESULTS: Staining patterns differed in the epithelium and stroma of tumor and peritumor prostatic tissue. TGF-beta 1 immunostaining (H-scores) in the epithelium and stroma increased significantly from BPH to PIN and from BPH to prostate carcinoma in the epithelium (P < .05), whereas androgen receptor (AR) immunoreactivity significantly (P < .05) increased from BPH to PIN to prostatic carcinoma in epithelium and stroma. TGF-beta 1 did not correlate with histologic grade of differentiation, whereas AR proteins were more strongly expressed in Gleason score 5 and 6 than score 7 tumors (P < .05). Nonlinear regression showed a significant correlation (P < .01) between TGF-beta 1 and AR expression only in the stromal compartment of PIN. CONCLUSION: These findings argue in favor of an interaction between TGF-beta 1 and AR in the early stages of prostate carcinogenesis and suggest that TGF-beta 1 plays a central role in stromal-epithelial interactions during the early stages of malignant transformation.     

Expression of prostate specific membrane antigen (PSMA) in prostatic adenocarcinoma and prostatic intraepithelial neoplasia

The prostatic membrane antigen (PSMA) is a protein that is expressed in the prostatic epithelium. We studied the expression of PSMA in a series of 55 patients with different stages of prostate cancer and we compared the PSMA staining in prostate cancer cells, in high-grade prostatic intraepithelial neoplasia (PIN) and in histologically benign prostatic epithelium for the same specimen. For this purpose archival paraffin-embedded specimens were studied by immunohistochemistry with a monoclonal antibody 7E11-C5.3 against PSMA using the streptavidin-biotin method. The mean percentage of PSMA immunoreactivity was 56.67% in prostate cancer (CaP) cells, and 48.6% in PIN cells, which was significantly higher than benign-appearing prostatic epithelium (5.72%) (for each pair, p<0.001). PSMA expression was greater in CaP with a higher Gleason score (p=0.01), but no relationship was found with serum PSA value. We conclude that PSMA overexpression is detected in high-grade PIN and is associated with a higher Gleason score of prostate cancer. It is a potential marker for studying carcinogenesis and progression of prostate cancer.     

高级别前列腺上皮内瘤（HGPIN）的研究新进展

前列腺上皮内瘤（HGPIN）分为低级别上皮内瘤与高级别上皮内瘤,目前高级别前列腺上皮内瘤是公认的前列腺腺癌的癌前病变,在形态学、遗传学和分子生物学特点上和前列腺癌有许多相似之处。其病因仍不明,临床上影像学检查和实验室检查对其诊断帮助不大,其诊断主要依靠病理组织学检查,包括前列腺穿刺活检与手术切除的组织。免疫组织化学染色应用P504S、P63、34茁E12 有助于和前列腺癌相鉴别。而首次穿刺活检诊断为HGPIN 的患者应定期复查血PSA和定期行增加穿刺针数的活检,是否对HGPIN 行前列腺癌的治疗方法尚存在争议,本文对高级别前列腺上皮内瘤的研究进展做综述如下。     

Nuclear DNA analysis of koilocytic and premalignant lesions of the uterine cervix.

Cervical biopsy samples were taken from 79 patients who had various grades of cervical intraepithelial neoplasia or who showed evidence, in the form of koilocytosis, of human papillomavirus infection of the uterine cervix and from 10 women with normal cervices. The DNA content of the cells in the samples was analysed by flow cytometry. Analysis of the data obtained showed that the biopsy samples from women with cervical intraepithelial neoplasia and human papillomavirus lesions contained significantly more dividing cells (31.2% of cells from human papillomavirus lesions with no cervical intraepithelial neoplasia and 33.06%, 29.89%, and 31.76% of cells from cervical intraepithelial neoplasia grades I, II, and III, respectively) than those from women with normal cervices (21.6%). The proportion of aneuploid samples from the group who showed evidence of human papillomavirus infection only (18.2%) did not differ significantly from the group with cervical intraepithelial neoplasia grade III (21.2%). Aneuploidy and an increased rate of cellular proliferation are recognised characteristics of malignancy. These results therefore support the view that human papillomavirus plays an important part in the aetiology of cervical carcinoma and are relevant to the clinical management of patients.     

Neoplastic disorders of prostate glands in the light of synchrotron radiation and multivariate statistical analysis

The prostate gland is the most common site of neoplastic disorders in men. The pathogenesis of inflammatory cells, prostatic intraepithelial neoplasia (PIN) lesions, and prostate cancer is still under investigation. Inflammatory cells by producing free radicals are considered as major and universal contributors to cancerogenesis. PIN is regarded as a precursor lesion to prostate cancer or a marker signaling the vulnerability of the epithelium to neoplastic transformation [1]. Differentiation markers that are frequently changed in early invasive carcinoma are also changed in PIN lesions. In this study, prostate tissue samples obtained during surgical operation and classified as various disease states (inflammation, PIN lesions, and cancer) were examined. The samples were measured by means of microbeam synchrotron-radiation-induced X-ray emission (micro-SRIXE). Special attention was paid to examine the relationship between the earlier-mentioned disorders and changes in relative concentrations of S, K, Ca, Fe, Cu, and Zn. Applying the image-processing program ImageJ enabled us to select the areas of interest from two-dimensional maps of various prostate samples according to the histopathologist’s evaluation. Detailed analysis of micro-SRIXE spectra based on multivariate methods shows significant differences between elemental concentrations in inflammatory cells, PIN lesions, and cancerous tissues, which confirms that this method can be used to distinguish various pathological states in prostate tissues. Information obtained in this way may provide better understanding of the biochemistry of unhealthy prostate tissues, thus opening the way to find new medicines/treatments to prevent or slow down some harmful intracellular processes.     

Observer variation in histopathological diagnosis and grading of cervical intraepithelial neoplasia.

To assess the variability among histopathologists in diagnosing and grading cervical intraepithelial neoplasia eight experienced histopathologists based at different hospitals examined the same set of 100 consecutive colposcopic cervical biopsy specimens and assigned them into one of six diagnostic categories. These were normal squamous epithelium, non-neoplastic squamous proliferations, cervical intraepithelial neoplasia grades I, II, and III, and other. The histopathologists were given currently accepted criteria for diagnosing and grading cervical intraepithelial neoplasia and asked to mark their degree of confidence about their decision on a visual linear analogue scale provided. The degree of agreement between the histopathologists was characterised by kappa statistics, which showed an overall poor agreement (unweighted kappa 0.358). Agreement between observers was excellent for invasive lesions, moderately good for cervical intraepithelial neoplasia grade III, and poor for cervical intraepithelial neoplasia grades I and II (unweighted kappa 0.832, 0.496, 0.172, and 0.175, respectively); the kappa value for all grades of cervical intraepithelial neoplasia taken together was 0.660. The most important source of disagreement lay in the distinction of reactive squamous proliferations from cervical intraepithelial neoplasia grade I. The histopathologists were confident in diagnosing cervical intraepithelial neoplasia grade III and invasive carcinoma (other) but not as confident in diagnosing cervical intraepithelial neoplasia grades I and II and glandular atypia (other). Experienced histopathologists show considerable interobserver variability in grading cervical intraepithelial neoplasia and more importantly in distinguishing between reactive squamous proliferations and cervical intraepithelial neoplasia grade I. It is suggested that the three grade division of cervical intraepithelial neoplasia should be abandoned and a borderline category introduced that entails follow up without treatment.     

Cyclin A and Ki-67 with DNA content in benign and malignant prostatic epithelial lesions.

OBJECTIVE: To evaluate the usefulness of immunohistochemical staining of cyclin A and Ki-67 together with DNA content in the classification of benign prostatic hyperplasia, prostatic intraepithelial neoplasm (PIN) and prostatic carcinoma foci and to compare these parameters with each other and with parameters obtained from conventional histopathology. STUDY DESIGN: We selected 37 carcinoma, 18 PIN and 8 hyperplastic foci from prostatectomies done during 1996 and 1997 at Turku University Central Hospital. Cyclin A and Ki-67 staining was assessed by immunohistochemistry and DNA content by image cytometry. RESULTS: The hyperplastic, PIN and carcinoma foci differed clearly in their 2.5c exceeding rates, image cytometric proliferation indices and staining indices for cyclin A and Ki-67. No significant differences were found between these histologic entities in their modal DNA ploidy values. In carcinomas, cyclin A and Ki-67 indices differed between low, intermediate and high Gleason and World Health Organization grading groups. Diploid and tetraploid carcinomas had similar cyclin A and Ki-67 indices, which differed from those of aneuploid carcinomas. CONCLUSION: The 2.5c exceeding rate and image cytometric proliferation index as well as the cyclin A and Ki-67 indices differed significantly between different types of prostatic lesions. Cyclin A and Ki-67 had good correlations with the histologic grade of carcinoma.     

The Pace of Prostatic Intraepithelial Neoplasia Development Is Determined by the Timing of Pten Tumor Suppressor Gene Excision

Loss of the PTEN tumor suppressor is a common occurrence in human prostate cancer, particularly in advanced disease. In keeping with its role as a pivotal upstream regulator of the phosphatidylinositol 3-kinase signaling pathway, experimentally-induced deletion of Pten in the murine prostate invariably results in neoplasia. However, and unlike humans where prostate tumorigenesis likely evolves over decades, disease progression in the constitutively Pten deficient mouse prostate is relatively rapid, culminating in invasive cancer within several weeks post-puberty. Given that the prostate undergoes rapid androgen-dependent growth at puberty, and that Pten excisions during this time might be especially tumorigenic, we hypothesized that delaying prostate-specific Pten deletions until immediately after puberty might alter the pace of tumorigenesis. To this end we generated mice with a tamoxifen-inducible Cre recombinase transgene enabling temporal control over prostate-specific gene alterations. This line was then interbred with mice carrying floxed Pten alleles. Despite evidence of increased Akt/mTOR/S6K axis activity at early time points in Pten-deficient epithelial cells, excisions induced in the post-pubertal (6 wk-old) prostate yielded gradual acquisition of a range of lesions. These progressed from pre-malignant changes (nuclear atypia, focal hyperplasia) and low grade prostatic intraepithelial neoplasia (PIN) at 16–20 wks post-tamoxifen exposure, to overtly malignant lesions by ∼1 yr of age, characterized by high-grade PIN and microinvasive carcinoma. In contrast, when Pten excisions were triggered in the pre-pubertal (2 week-old) prostate, neoplasia evolved over a more abbreviated time-frame, with a spectrum of premalignant lesions, as well as overt PIN and microinvasive carcinoma by 10–12 wks post-tamoxifen exposure. These results indicate that the developmental stage at which Pten deletions are induced dictates the pace of PIN development.     

Predictors of random sextant biopsy outcome in screened men with PSA > 4 ng/mL and a negative sextant biopsy at previous screening. Experience in a population-based screening program in Florence

The aim of this study was to evaluate possible pedictors of the outcome of repeat random sextant biopsy of the prostate prompted by a rise in prostate-specific antigen (PSA). Random biopsies performed for PSA elevation (>4 ng/mL) in the course of a randomized study of screening efficacy were reviewed, and 87 consecutive biopsies (carcinoma = 13, high-grade prostatic intraepithelial neoplasia = 6, negative = 68) performed in subjects with a negative random biopsy at the previous screening round were considered. Findings at digital rectal examination or transrectal ultrasonography and total PSA value were not useful predictors of repeat biopsy outcome, whereas PSA velocity was significantly associated with biopsy outcome. The positive predictive value for a cancer biopsy was 2.7% (1/36), 28.5% (2/7), and 22.7% (10/44) for PSA velocity values of <0.1, 0.1-0.19, and >0.19 ng/mL/yr, respectively. A cutoff of 0.1 ng/mL/yr for PSA velocity would have allowed to avoid approximately half (35/74 = 47.2%) of the benign biopsies while decreasing the sensitivity by 7.6% (1/13), and is thus suggested as a possible criterion for the indication of repeat random biopsy for persistent PSA elevation.     

Localization of annexins I, II, IV and VII in whole prostate sections from radical prostatectomy patients

Annexins (ANXs) represent a family of calcium and phospholipid binding proteins that are involved in several physiological processes e.g. signal transduction, cellular differentiation and proliferation. Since they are known to be dysregulated in a variety of cancers we investigated the immunolocalization of ANXs in whole prostate sections containing benign prostatic epithelium (BPE), benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN) and prostate cancer (PCa) in order to evaluate their possible role during tumorigenesis. Samples were obtained from 28 patients undergoing radical prostatectomy. Gross sections of whole prostates were examined immunohistochemically for the distribution of ANX I, II, IV and VII. In BPE all ANXs were localized to the cell membranes and the cytoplasm of all gland cells. In BPH the immunoreactivity of ANX I and II was restricted to the basal cells of glands and expression pattern of ANX IV and VII was similar to BPE. In PIN only basal cells expressed ANX II. In PCa ANX II immunoreactivity was absent and weak ANX I and ANX IV immunoreactivity was restricted to the cytoplasm of tumor cells. ANX VII immunoreactivity was seen in some but not all tumor cells. Since ANX IV and VII expression did not show significant changes in PCa compared to non-neoplastic tissue and PIN an essential role during prostate tumourigenesis seems unlikely. In contrast, as progression from PIN to PCa is characterized by a reduction of ANX I and II this suggests that downregulation of these proteins could represent an important event in prostate carcinogenesis.     

Frequent allelic losses in tumor-associated stromal cells and tumor epitelium of prostate cancer

It has become increasingly clear that tumor microenvironment plays a critical role in carcinogenesis. Accumulation of genetic alterations is typical not only for cancer epithelial cells but tumor-associated fibroblasts as well. Tumor epithelia, tumor-associated stroma from prostatectomy specimens of patients with prostate cancer and cells from prostatic intraepithelial neoplasia (PIN) and adjacent stroma from males with PIN were isolated by using laser capture microdissection. Microsatellite allelotyping was evaluated using 4 highly polymorphic markers for chromosomal regions 8p22, 16q23-24 and 13q14. Incidences of alterations (loss of heterozygosity or allelic imbalance) were 48% for region 8p22, 72% for 16q23 and 37% for 13q14. The LOH frequencies in tumor-associated stroma cells were very similar. Alterations at chromosome 13q were significantly associated with advanced tumor stage, whereas AI at 16q was also associated with high Gleason score and lymph node metastasis. We find some incidences of allelic imbalance in premalignant lesions in epithelial (16-27%) and stromal (7-22%) components. Our results show that the frequencies of genetic aberrations are as high in stromal cells as in tumor cells.     

A study to determine the underlying reason for abnormal glandular cytology and the formulation of a management protocol

A retrospective review is presented of 89 patients with glandular dyskaryosis in order to formulate a management protocol. Fifteen patients had cervical intraepithelial neoplasia (CIN) without glandular abnormality (17%). One patient had adenocarcinoma in situ of the cervix and one patient had vaginal intraepithelial neoplasia (VAIN) grade III. Twenty‐two patients had endometrial carcinoma (24.5%) and 11 patients had cervical carcinoma (12.5%). Of the patients presenting with post‐menopausal bleeding as well as having glandular dyskaryosis, 69% had a gynaecological malignancy. In conclusion, colposcopy and out‐patient endometrial sampling are recommended in all cases. Patients with abnormal endometrial sampling require hysteroscopy. Cone biopsy is necessary to exclude occult glandular disease if cytology remains abnormal despite negative colposcopy and sampling.     

Prostaglandin E(2) stimulates prostatic intraepithelial neoplasia cell growth through activation of the interleukin-6/GP130/STAT-3 signaling pathway.

Cyclooxygenase (COX)-2 expression and prostaglandin E(2) (PGE(2)) secretion are increased in prostatic intraepithelial neoplasia (PIN) and prostate cancer. PGE(2) biosynthesis by cyclooxygenase (COX)-2 plays a pivotal role in inflammation and carcinogenesis. One of the critical proinflammatory cytokines in the prostate is interleukin-6 (IL-6). We hypothesized that increased expression of COX-2, with resultant increased levels of PGE(2) in human PIN cells, activates the IL-6 signaling pathway. We demonstrate an autocrine upregulation of PGE(2) mediated by IL-6 in a human PIN cell line. We further demonstrate that PGE(2) stimulates soluble IL-6 receptor (sIL-6R) release, gp130 dimerization, Stat-3 protein phosphorylation, and DNA binding activity. These events, induced by PGE(2), lead to increased PIN cell growth. Treatment of PIN cells with a selective COX-2 inhibitor decreases cell growth. Finally, PGE(2)-stimulated PIN cell growth was abrogated by the addition of IL-6 neutralizing antibodies. These data provide mechanistic evidence that increased expression of COX-2/PGE(2) contributes to prostate cancer development and progression via activation of the IL-6 signaling pathway.     

Isolation and characterization of the major form of human MUC18 cDNA gene and correlation of MUC18 over-expression in prostate cancer cell lines and tissues with malignant progression.

Ectopical expression of huMUC18, a cell adhesion molecule in the immunoglobulin gene superfamily, causes a non-metastatic human melanoma cell line to become metastatic in a nude mouse system. To determine if MUC18 expression correlates with the development and malignant progression of prostate cancer, we investigated differential expression of human MUC18 (huMUC18) in normal prostate epithelial cells, prostate cancer cell lines, and prostatic normal and cancer tissues. We cloned and characterized the human MUC18 (huMUC18) cDNA gene from three human prostate cancer cell lines and three human melanoma cell lines. The cDNA sequences from the six human cancer cell lines were identical except differences in one to five nucleotides. The deduced amino acid sequences of the longest ORF were 646 amino acids that were identical in these cDNAs except for one to three amino acid residues. The amino acid sequences of all our huMUC18 cDNA genes are similar to that cloned by other group (GenBank access #M28882) except differences in the same seven amino acids. We conclude that huMUC18 cDNA gene reported here represents the gene product from a major allele. The MUC18 mRNA and protein was expressed in three metastatic prostate cancer cell lines (TSU-PR1, DU145, and PC-3), but not in one non-metastatic prostate cancer cell line (LNCaP.FGC). The expression of huMUC18 in these four cell lines is positively related to their extent of in vitro motility and invasiveness and in vivo metastasis in nude mice. HuMUC18 protein was also expressed at high levels in extracts prepared from tissue sample sections containing high grade prostatic intraepithelial neoplasia (PIN), but weakly expressed in extracts prepared from cultured primary normal prostatic epithelial cells and the normal prostate gland. Immunohistochemical analysis showed that huMUC18 was expressed at higher levels in the epithelial cells of high-grade PIN and prostatic carcinomas, and in cells of a perineural invasion, a lymph node, and a lung metastases compared to that in normal or benign hyperplastic epithelium (BPH). We therefore conclude that MUC18 expression is increased during prostate cancer initiation (high grade PIN) and progression to carcinoma, and in metastatic cell lines and metastatic carcinoma. Increased expression of MUC18 is implicated to play an important role in developing and malignant progression of human prostate cancer. Furthermore, the lacking of predominant cytoplasmic membrane expression of MUC18 appeared to correlate with malignant progression of prostate cancer.     

Human papillomavirus infection of the uterine cervix of women without cytological signs of neoplasia.

One hundred and six patients were studied whose cervical smears showed only non-specific inflammatory changes. Screening for genital pathogens yielded only a few positive cases. Histological examination of biopsy specimens taken by colposcopically directed tissue sampling showed cervical intraepithelial neoplasia in 13 of the women (12.3%). Deoxyribonucleic acid (DNA) hybridisation techniques were used to detect human papillomavirus, which was found in 24 patients (22.6%). In a second group of 104 patients with normal cervical cytology tissue biopsy samples were obtained and examined histologically but in no case was cervical intraepithelial neoplasia found. On DNA hybridisation, however, 12 patients (11.5%) were found to be positive for human papillomavirus. In this group finding human papillomavirus DNA was usually associated with a columnar ectopy. An association between human papillomavirus type 16 DNA and both cervical intraepithelial neoplasia and cervical cancer is well established. In this study it was type 16 which occurred most frequently in both groups.