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.     

DNA methylation changes in atypical adenomatous hyperplasia, adenocarcinoma in situ, and lung adenocarcinoma

Background

Aberrant DNA methylation is common in lung adenocarcinoma, but its timing in the phases of tumor development is largely unknown. Delineating when abnormal DNA methylation arises may provide insight into the natural history of lung adenocarcinoma and the role that DNA methylation alterations play in tumor formation.

Methodology/Principal Findings

We used MethyLight, a sensitive real-time PCR-based quantitative method, to analyze DNA methylation levels at 15 CpG islands that are frequently methylated in lung adenocarcinoma and that we had flagged as potential markers for non-invasive detection. We also used two repeat probes as indicators of global DNA hypomethylation. We examined DNA methylation in 249 tissue samples from 93 subjects, spanning the putative spectrum of peripheral lung adenocarcinoma development: histologically normal adjacent non-tumor lung, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS, formerly known as bronchioloalveolar carcinoma), and invasive lung adenocarcinoma. Comparison of DNA methylation levels between the lesion types suggests that DNA hypermethylation of distinct loci occurs at different time points during the development of lung adenocarcinoma. DNA methylation at CDKN2A ex2 and PTPRN2 is already significantly elevated in AAH, while CpG islands at 2C35, EYA4, HOXA1, HOXA11, NEUROD1, NEUROD2 and TMEFF2 are significantly hypermethylated in AIS. In contrast, hypermethylation at CDH13, CDX2, OPCML, RASSF1, SFRP1 and TWIST1 and global DNA hypomethylation appear to be present predominantly in invasive cancer.

Conclusions/Significance

The gradual increase in DNA methylation seen for numerous loci in progressively more transformed lesions supports the model in which AAH and AIS are sequential stages in the development of lung adenocarcinoma. The demarcation of DNA methylation changes characteristic for AAH, AIS and adenocarcinoma begins to lay out a possible roadmap for aberrant DNA methylation events in tumor development. In addition, it identifies which DNA methylation changes might be used as molecular markers for the detection of preinvasive lesions.     

Role of inflammation in benign prostatic hyperplasia

Inflammation of the prostate may represent a mechanism for hyperplastic changes to occur in the prostate. There are a variety of growth factors and cytokines that may lead to a proinflammatory process within the prostate. There are several proposed mechanisms that lead to both the intrinsic and extrinsic basis of inflammation. Prostatic inflammation may represent an important factor in influencing prostatic growth and progression of symptoms. This article reviews the recent literature on inflammation leading to chronic prostatic diseases, such as benign prostatic hyperplasia.     

Urinary hormone excretion in benign prostatic hyperplasia

The urinary excretion of LH, low polar oestrogens (oestrone + oestradiol-17β), dehydroepiandrosterone, androsteone, aetiocholanolone, pregnanediol and total 17-keto-and 17-ketogenic steroids has been determined in 30 men aged 60–84 years with benign prostatic hyperplasia and in 39 healthy men aged 60–79 years. The results show a significantly elevated oestrogen excretion in benign prostatic hyperplasia as compared with the control group. No other significant differences were found in the urinary hormone excretion. It is speculated that the increased oestrogen levels might stimulate the prostate growth mainly by facilitating the transport of peripheral testosterone into prostate cell.     

Pharmacotherapy for benign prostatic hyperplasia.

Benign prostatic hyperplasia is a benign neoplasm of the prostate seen in men of advancing age. Microscopic evidence of the disorder is seen in about 70% of men by 70 years of age, whereas symptoms requiring some form of surgical intervention occur in 30% of men during their lifetime. Although the exact cause of benign prostatic hyperplasia is not clear, it is well recognized that high levels of intraprostatic androgens are required for the maintenance of prostatic growth. In recent years, extensive surveys of patients undergoing transurethral resection of the prostate reveal an 18% incidence of morbidity that has essentially not changed in the past 30 years. This procedure is also the second highest reimbursed surgical therapy under Medicare. These findings have resulted in an intensive search for alternative therapies for prostatic hyperplasia. An alternative that has now been well defined is the use of alpha-adrenergic blockers to relax the prostatic urethra. This is based on findings that a major component of benign prostatic hyperplasia symptoms is spasm of the prostatic urethra and bladder neck, which is mediated by the alpha-adrenergic nerves. A second approach is to block androgens involved in maintaining prostate growth. Several such drugs are now available for clinical use, and we discuss their side effects and use. We also include the newer recommendations on evaluating benign prostatic hyperplasia that are cost-effective yet comprehensive.     

Evaluating men with benign prostatic hyperplasia

The clinical manifestations of benign prostatic hyperplasia (BPH) include lower urinary tract symptoms (LUTS), poor bladder emptying, urinary retention, detrusor instability, urinary tract infection, hematuria, and renal insufficiency. However, the majority of men with BPH present with LUTS only. Because LUTS can indicate a variety of conditions, evaluation of symptomatic men must first aim to identify or exclude BPH and, if present, assess its severity. It is important to assess symptom severity at baseline and during follow-up, using the American Urological Association Symptom Index or the International Prostate Symptom Score. Further testing can then be tailored to narrow the diagnosis and guide treatment decisions. Factors such as patient age and concomitant malignancy will also affect management, but the main goal of treatment remains the improvement of quality of life for the patient.     

Medical treatment of benign prostatic hyperplasia

Medical therapy for the treatment of benign prostatic hyperplasia (BPH) became an accepted standard of care in the 1990s following the reports of randomized, double-blind, placebo-controlled studies showing that finasteride, a 5-α reductase inhibitor, and terazosin, an α-blocker, significantly improved lower urinary tract symptoms and increased peak urinary flow rates in men with BPH. This article reviews novel approaches to the pharmacological treatment of BPH.