Inflammation and preneoplastic lesions in benign prostate as risk factors for prostate cancer

Benign changes ranging from atrophy and inflammation to high-grade prostatic intraepithelial neoplasia (HGPIN) are common findings on prostate core needle biopsies. Although atrophy and inflammation may be precursors of prostate cancer, only HGPIN is currently recommended to be included in surgical pathology reports. To determine whether these benign findings increase prostate cancer risk, we conducted a case-control study nested within a historical cohort of 6692 men with a benign prostate specimen collected between 1990 and 2002. The analytic sample included 574 case-control pairs comprised of cases diagnosed with prostate cancer a minimum of 1 year after cohort entry and controls matched to cases on date and age at cohort entry, race, and type of specimen. The initial benign specimen was reviewed for presence of HGPIN, atrophy (simple, lobular, and partial) and inflammation (glandular and/or stromal). HGPIN significantly increased risk for prostate cancer (odds ratio (OR)=2.00; 95% confidence interval (CI)=1.25-3.20). Inflammation within the stromal compartment was associated with decreased risk (OR=0.66; CI=0.52-0.84), and diffuse stromal inflammation of severe grade had the strongest inverse association with risk (OR=0.21; CI=0.07-0.62). In a model adjusted for prostate-specific antigen (PSA) level at cohort entry and inflammation, simple atrophy was associated with a 33% increased prostate cancer risk that was marginally significant (P=0.03). Clinicians should consider patterns and extent of inflammation when managing high-risk patients with negative biopsy results. Identifying benign inflammatory processes that underlie high PSA levels would help to reduce the number of unnecessary repeated prostate biopsies.     

Mergence of partial and complete atrophy in prostate needle biopsies: a morphologic and immunohistochemical study

Partial atrophy is the most common benign lesion that causes difficulty in the differential diagnosis with adenocarcinoma of the prostate. Very few studies described, illustrated, and discussed the concomitance of partial atrophy with complete atrophy in prostatic needle biopsies. The study group comprised 75 needle prostatic biopsies corresponding to 67 patients. Focal prostatic atrophy was present in all biopsies. Complete atrophy was subtyped into simple atrophy, sclerotic atrophy, and hyperplastic atrophy (or postatrophic hyperplasia). We analyzed the presence of inflammation in the atrophic foci and immunohistochemistry was performed for p63, 34βE12, and PSA. Partial atrophy and complete atrophy were present concomitantly in 47/75 (63%) biopsies. In 20/75 (27%) biopsies, there were areas with mergence of partial atrophy and complete atrophy. We illustrate morphologic transitions between these lesions in the same gland. Using immunohistochemistry, the aberrant phenotypic expression in the secretory compartment in all subtypes of complete atrophy highlighted the morphologic transitions between partial and complete atrophies in the same gland. An intriguing finding was the absence of chronic inflammation in partial atrophy foci as well as in areas of mergence between these lesions. Inflammation was present only in isolated complete focal atrophy foci. Partial atrophy seems to be part of a morphologic spectrum of focal prostatic atrophy and probably precedes complete atrophy. The question of whether the inflammation produces tissue damage and prostatic atrophy or whether some other insults like ischemia induces the tissue damage and atrophy directly, with inflammation occurring secondarily, is still unsettled.     

Urethral adenocarcinoma associated with intestinal-type metaplasia,case report and literature review

The presence of glandular epithelium in urinary tract biopsies poses a diagnostic challenge. Intestinal metaplasia of the urethra may be seen in many congenital, iatrogenic, and reactive conditions, as well as in association with malignant conditions such as urethral adenocarcinoma. We present a case of a 61 year-old woman presenting with microscopic hematuria. Successive biopsies showed glandular epithelium with focal atypia in close association with inflammation, but no overt malignancy. Only on surgical resection was the associated high grade adenocarcinoma revealed. When intestinal-type mucosa is present within a urinary tract biopsy, associated malignancy may be present only focally. Thorough sampling and consideration of the differential diagnosis is imperative.     

IL-17 Expression by macrophages is associated with proliferative inflammatory atrophy lesions in prostate cancer patients

Intraprostatic leukocyte function may vary depending on local inflammatory or malignant cell microenvironment. Interleukin (IL)-17 producing cells play key roles in chronic inflammation and autoimmunity. Little is known about the relevance of IL-17 producing cells at sites of prostate tissue inflammation and/or prostate adenocarcinoma. In this study, we analyzed thirty formalin-fixed paraffin-embedded whole-mount radical prostatectomy specimens of prostate cancer patients. Immunohistochemistry was employed to identify IL-17 producing cells in all sites of mononuclear cell accumulation, noting their relationships to areas of prostate cancer, proliferative inflammatory atrophy (PIA), or hyperplastic benign tissue. Levels of IL-17 producing cells were similar in zones of benign prostate tissue and areas of prostate cancer. Pronounced intraluminal and peri-glandular IL-17 producing cell accumulations were identified in the mononuclear cell infiltrates associated with PIA lesions. Glandular and peri-glandular CD68+ macrophages and neutrophils were the predominant IL-17 producing cells in PIA lesions. The accumulation of IL-17 expressing cells in PIA lesions presents direct evidence of an inflammatory microenvironment that may support the development of prostate cancer.     

Malignant lesions in the ventral prostate of alloxan-induced diabetic rats

The aim of this study was to evaluate the changes caused by chronic diabetes in the rat ventral prostate and to establish a correlation between diabetes and the development of prostatic lesions. Male rats received alloxan (42 mg/kg b.w.) to induce diabetes. Ninety days after diabetes diagnosis, animals were sacrificed and the ventral prostate was removed and prepared for general and immunohistochemical analyses. The total area showing different types of lesions was estimated. Diabetes led to a decrease in the body and prostatic weights, as well as in testosterone levels. The prostate morphology and stereology showed high variation in the diabetic group. Some animals had light changes; the great majority had an intense epithelial atrophy; and other rats showed premalignant and malignant lesions in the prostate. Such epithelial atrophy was, in some samples, combined with chronic inflammation, similar to proliferative inflammatory atrophy (PIA). The diabetic group also presented high incidence of prostatitis, adenocarcinoma and prostatic intra-epithelial neoplasia (PIN). Samples with adenocarcinoma had poorly differentiated acini with high levels of cellular proliferation and nuclear atypia. These lesions exhibited an invasive feature showing Bcl-2-positive cells and interruptions in the basement membrane. An association of PIA, PIN and adenocarcinoma was detected in one sample. Reduced androgen levels have a synergic effect to insulin dysfunction promoting negative effects in the rat prostate. Diabetic individuals had a high incidence of prostatitis, and this inflammation could stimulate the incidence of other forms of prostatic pathology.     

Interobserver variation in the histopathological scoring of Helicobacter pylori related gastritis

AIM: To test the reproducibility between two histopathologists of features of Helicobacter pylori gastritis, using the updated Sydney classification. METHODS: 290 dyspeptic Dutch patients with biopsy proven H pylori infection were enrolled in the study. Gastric antral mucosal biopsy specimens were analysed before and after H pylori eradication treatment. The biopsies were scored semi-quantitatively by two histopathologists, according to the updated Sydney classification system. Variables analysed included the density of H pylori infection, the degree of chronic inflammation, inflammatory activity, atrophy, intestinal metaplasia, and surface epithelial damage. Before grading biopsy specimens, both pathologists reached a consensus on the scoring of gastritis through interactive sessions using a multiheaded microscope. Subsequently all biopsy specimens were graded. Interobserver variability was also analysed using weighted kappa scores. RESULTS: For interobserver agreement on scoring the various gastritis features a high degree of reproducibility was reached overall. Agreement on grading of atrophy was the lowest; however, moderate to good reproducibility was achieved, with weighted kappa values of 0.49 in the pretreatment biopsies and 0.52 in the post-treatment biopsies. Disagreement was most common in biopsy specimens with lesser degrees of atrophy. A high degree of agreement was obtained for intestinal metaplasia, with weighted kappa values of 0.72 in the pretreatment biopsies and 0.73 in the post-treatment biopsies. The best agreement was reached in the assessment of the density of H pylori both before and after H pylori eradication treatment, with excellent weighted kappa values of 0.76 and 0.95, respectively. The grade of reproducibility of inflammatory activity, superficial epithelial damage, and chronic inflammation was high, with weighted kappa values varying from 0.60 to 0.76 and 0.62 to 0.83 before and after eradication, respectively. CONCLUSIONS: Reproducibility of grading H pylori related gastritis is high using the updated Sydney system. Despite the novel criteria for scoring atrophy, there was imperfect agreement on this feature between two independent histopathologists.     

Prostate needle biopsy examination by means of virtual microscopy

This study aimed at determining whether virtual microscopy improves the accuracy in the pathological examination of prostate needle biopsies regarding maximum tumor length, percentage of positive cores, and Gleason grading.We assessed a series of 816 prostate needle biopsy cores in 68 consecutive patients with prostate adenocarcinoma. Biopsy specimens were reviewed using conventional examination. Then, slides were converted to whole slide imaging (Olympus BX51). Tumor was measured, and Gleason score was assigned using the OlyVia software. Optically evaluated pathological features were compared with digital findings to determine whether one of these two methods for the assignment of a preoperative Gleason score is appropriate for predicting the definitive Gleason score of radical prostatectomy.When comparing optical and digital measurements, maximum tumor length in biopsy cores and percent prostate needle biopsy with cancer showed no significant difference. The mean variation in the measurement of tumor length was 2.65 mm per biopsy. Among 240 biopsy cores involved with cancer, the concordance rate for Gleason score assignment was 75.8% (κ = 0.49, good agreement). When considering the higher Gleason score assignment as the score for the entire case (ISUP 2005), the concordance rate was 69.1% (κ = 0.46, good agreement). When comparing the biopsy scores with the definitive score of radical prostatectomy, the concordance rate was significantly increased from 54.4% for conventional examination (κ = 0.23, marginal agreement) to 66.2% for virtual slide examination (κ = 0.42, good agreement).Virtual microscopy does not compromise, but might improve, the accuracy of grading in prostate needle biopsies. This requires further assessment.     

Accumulation of p53 protein in normal,dysplastic, and neoplastic Barrett's oesophagus

Accumulation of p53 protein was determined by immunohistochemisty in archival material of biopsy specimens from 102 patients with Barrett's oesophagus with different grades of dysplasia, in 24 oesophageal adenocarcinomas associated with Barrett's oesophagus, and in 23 cases of metaplatic epithelium adjacent to these carcinomas. Immunostaining for the p53 protein was found in 23/102 (23 per cent) cases of the Barrett's oesophagus biopsies and in 12/23 (52 per cent) cases of Barrett's oesophagus adjacent to adenocarcinoma. Significant correlations were found between the grade of dysplasia and p53 immunoreactivity in both Barrett's biopsies without adenocarcinoma (P<0.001) and Barrett's oesophagus adjacent to adenocarcinoma (P<0.05). In the adenocarcinomas, intense nuclear immunohistochemical staining for p53 was diffusely or focally present in 20/24 (83 per cent) of the specimens. In Barrett's oesophagus, p53 is a progression marker with high expression in high-grade dysplasia (89 per cent) and adenocarcinoma (83 per cent).     

Prostate cancer and inflammation: the evidence

Chronic inflammation is now known to contribute to several forms of human cancer, with an estimated 20% of adult cancers attributable to chronic inflammatory conditions caused by infectious agents, chronic non-infectious inflammatory diseases and/or other environmental factors. Indeed, chronic inflammation is now regarded as an 'enabling characteristic' of human cancer. The aim of this review is to summarize the current literature on the evidence for a role for chronic inflammation in prostate cancer aetiology, with a specific focus on recent advances regarding the following: (i) potential stimuli for prostatic inflammation; (ii) prostate cancer immunobiology; (iii) inflammatory pathways and cytokines in prostate cancer risk and development; (iv) proliferative inflammatory atrophy (PIA) as a risk factor lesion to prostate cancer development; and (v) the role of nutritional or other anti-inflammatory compounds in reducing prostate cancer risk.     

Discontinuous unilateral involvement of 12 part core biopsies by adenocarcinoma predicts bilateral involvement of subsequent radical prostatectomy

At our institution, percent tumor burden in prostate core biopsies is quantified using variations of one of two methods. Measurement by the Aggregate method reports only adenocarcinoma and omits intervening stroma and benign prostatic glands while the Discontinuous method includes the intervening stroma and benign glands between distinct foci of adenocarcinoma. In this study, we selected cases with 12‐part core biopsies that were followed by a radical prostatectomy within two years. Interestingly, we found that when adenocarcinoma involved prostate 12‐part core biopsies and subsequent resection unilaterally, there is no significant difference in absolute percentage of tumor using either measuring method (P = 0.4). In contrast, when adenocarcinoma involved the biopsies unilaterally and subsequent prostatectomy bilaterally, the two measurement methods had a statistically significant difference in percentage scores (P = 0.002). In the study cohort, other factors including Gleason score (P = 0.88) and total number of adenocarcinoma‐involved cores (P = 0.27) did not introduce any significant correlation with bilateral involvement. In this study, we found that biopsies that discontinuously and unilaterally involve half of a prostate are much more likely to involve both lobes than those that are unilateral and present in nodular aggregates.     

Apoptosis markers in liver biopsy of nonalcoholic steatohepatitis in pediatric patients

The natural history of pediatric nonalcoholic steatohepatitis is still unknown; however, there are differences between adult and pediatric presentation. Apoptosis may play an important role in pathophysiologic pathways involved in liver damage and progression. Our aim was to detect early apoptosis markers, activated caspase-3 and cleaved cytokeratin-18, in hepatocytes and to correlate their presence with clinical, serologic, and histologic characteristics in pediatric nonalcoholic steatohepatitis. Twenty-five pediatric nonalcoholic steatohepatitis liver biopsies were evaluated by immunohistochemistry for presence of activated caspase-3 and cleaved cytokeratin-18. Biopsy specimens were semiquantitatively graded for activity (steatosis, inflammation, and ballooning) and fibrosis. Records were reviewed for serum aspartate aminotransferase, alanine aminotransferase, cholesterol, triglycerides, and body mass index, which was elevated in 92% of cases. Serum aspartate aminotransferase and alanine aminotransferase were elevated in 32% and 68% of cases, respectively. Sixty percent of biopsies exhibited lobular steatosis grade 3, 84% lobular inflammatory activity grade 1, 72% ballooning grade 1, and 76% fibrosis stage 3. Cleaved cytokeratin-18 was associated with milder fibrosis (P = .02) and inflammation (P = .07), although there was no association with steatosis grade. Activated caspase-3 detection was also associated with low inflammatory grade (P = .03) but not with fibrosis and steatosis. This study reveals interesting differential features concerning nonalcoholic steatohepatitis histologic characteristics and apoptosis markers compared with adult cases. Because, in this pediatric series, apoptosis seemed to be an early event in the cascade of liver injury steps, it would be useful to consider caspase inhibitors as potential therapeutic strategies to prevent liver damage progression.     

Observer agreement on the grading of gastric atrophy

AIMS: Assessment of lesser or doubtful degrees of gastric atrophy can be difficult, especially in the antrum, since well established criteria are lacking. At the Houston Working Party on Gastritis in 1994 a visual analogue scale was designed for the grading of histopathological parameters. This was done to promote uniformity in grading by acting as a reference. The purpose of the present study was to measure interobserver variation between pathologists familiar with the Houston visual analogue scale in a specifically selected set of biopsies from patients with lesser or doubtful degrees of atrophy. METHODS AND RESULTS: Thirty cases with biopsies of the antrum and corpus from a long-term follow-up study on Helicobacter pylori gastritis comprised the current study material. The cases were selected from that study because there had been uncertainty or disagreement on the presence of gastric atrophy. The study set of haematoxylin and eosin (H & E) slides was circulated amongst gastrointestinal pathologists familiar with the visual analogue scale who were unaware of the source of the study set nor had any other clinical information. Interobserver variability was analysed using kappa statistics. The overall agreement for the grade of atrophy in antral biopsies was 0.461; the kappa value was 0.18 (95% confidence limits 0.12-0.24), which is considered poor agreement. The kappa value was nevertheless statistically significant (P < 0. 01). The overall agreement on the grade of atrophy in the corpus biopsies was apparently good (0.833), but the kappa which adjusts for chance agreement was only moderate (0.48; 95% confidence limits 0.42-0.55; P < 0.001). CONCLUSION: The studied series comprised a self-selected sample in which there was doubt about the grade of atrophy and such a sample will produce lower kappa values than a random sample of gastric biopsies. The results nevertheless confirm that better guidelines and firm criteria are needed to properly diagnose and grade gastric atrophy. It is suggested that the use of two grades, low- and high-grade atrophy, akin to that in use for grading inflammatory bowel disorder (IBD)- associated dysplasia, could improve agreement. Furthermore optimal biopsy quality with full thickness mucosa and proper orientation appears important for grading gastric atrophy.     

HISTOLOGICAL GRADE HETEROGENEITY IN MULTIFOCAL PROSTATE CANCER. BIOLOGICAL AND CLINICAL IMPLICATIONS

In order to understand the clinical and biological implications of prostate cancer multifocality and heterogeneity, we investigated their occurrence in relation to variables such as tumour volume, local invasion, and biopsy findings. In a series of 61 completely sectioned whole-mount radical prostatectomy specimens with clinical stage T2 prostate cancer, we mapped histological grade heterogeneity and tumour multifocality. We also evaluated 55 prostate biopsy cases to assess the accuracy of pre-operative grading. Among all of the prostates, only 28 per cent had a single tumour and in 16 per cent one histological grade of cancer was evident. Extracapsular invasion was not restricted to the largest tumour in each case, but also occurred in tumours of relatively small volume and low histological grade. Variability of histological grade was directly proportional to tumour volume. Both grade heterogeneity and tumour multifocality of the prostatectomy specimen showed no significant relationship to the grade accuracy of biopsies. Biopsy grading error proved greatest among small, well-differentiated tumours. Whole-mount sectioning of prostatectomy specimens in patients with clinically localized adenocarcinoma demonstrates that grade heterogeneity is most closely related to tumour volume; that the largest (index) tumour lesion may not be representative of the pathological stage; and that grading error in prostate needle biopsies can be only partly explained by grade heterogeneity or tumour multifocality.     

IMP3 expression in biopsy specimens of colorectal cancer predicts lymph node metastasis and TNM stage

IMP3 is associated with lymph node metastasis and TNM stage and is a good independent prognostic biomarker for colorectal cancer (CRC). However, the expression status and clinical implication of IMP3 in biopsy specimens have not yet been studied. We aim to address whether the presence of IMP3 expression in preoperative biopsies of CRC could predict lymph node metastasis and TNM stage. In this study, we examined IMP3 expression in paired biopsy and resection specimens of 71 CRC and analyzed the correlation of IMP3 expression with clinicopathological parameters. In the biopsy specimens, IMP3 positive expression was observed in 56 of 71 cases (78.9%) whereas negative expression was observed in 15 of 71 cases (21.1%). In the resection specimens, IMP3 positive expression was detected in 83.1% cases (59/71) whereas negative expression was detected in 16.9% cases (12/71). The absolute concordance rate between biopsy and resection specimens was 90.1% (64/71). The Spearman correlation test documented the existence of a strong linear correlation between the percentage of IMP3-positive cells in the biopsy and resection specimen (r = 0.629; P < 0.001). IMP3 expression in resection specimens was significantly related to histological grade (P = 0.043), T classification (P = 0.035), lymph node metastasis (P = 0.023), TNM stage (P = 0.007), tumor border (P = 0.049) and tumor budding (P = 0.012). IMP3 expression in biopsy specimens was significantly related to lymph node metastasis (P = 0.004), TNM stage (P = 0.005) and tumor budding (P = 0.001). In conclusion, IMP3 expression in biopsy specimens could be used to predict lymph node metastasis and TNM stage in CRC patients.     

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.     

FGFR2, HER2 and cMet in gastric adenocarcinoma: detection,prognostic significance and assessment of downstream pathway activation

Receptor tyrosine kinase pathways are potential therapeutic targets in gastric adenocarcinoma patients. We evaluated HER2 and cMet protein expression, and FGFR2 gene amplification to assess their prognostic significance, and downstream mediators pS6 and pERK for their potential utility as pharmacodynamic biomarkers in patients with gastric adenocarcinoma. Tissue microarrays were constructed from resection samples of 184 patients who underwent surgery for gastric/gastro-oesophageal junction adenocarcinoma. Tissue cores were obtained from the tumour body (TB), luminal surface (LS) and invasive edge (IE), and immunohistochemical and fluorescence in situ hybridisation (FGFR2) analysis was performed. FGFR2 amplification was identified in 2 % of cases and associated with worse survival (P?=?0.005). HER2 overexpression was observed in 10 % of cases and associated with increased survival (P?=?0.041). cMet overexpression was observed in 4 % of cases and associated with worse survival (P?<?0.001). On multivariate analysis, only cMet retained significance (P?=?0.006). pS6 and pERK expression were observed in 73 % and 30 % of tumours, respectively, with no association with survival. HER2 (P?=?0.004) and pERK (P?=?0.001) expression differed between tumour regions with HER2 expression increased in the LS compared with the TB and IE. These findings confirm subpopulations in gastric adenocarcinoma with poor outcome that may benefit from specific therapeutic strategies. However, we found heterogeneous HER2, pS6 and pERK overexpression, which presents challenges for their use as predictive biomarkers in gastric biopsies. The potential downstream pharmacodynamic markers pS6 and pERK were expressed across tumour regions, providing evidence that resections and biopsies would yield comparative results in clinical trials.