Roberta Mazzucchelli

Nonapical and Cytoplasmic Expression of Interleukin-8, CXCR1, and CXCR2 Correlates with Cell Proliferation and Microvessel Density in Prostate Cancer

Purpose: We characterized interleukin-8 (IL-8) and IL-8 receptor expression (CXCR1 and CXCR2) in prostate cancer to address their significance to this disease. Experimental Design: Immunohistochemistry was conducted on 40 cases of human prostate biopsy containing histologically normal and neoplastic tissue, excised from patients with locally confined or invasive androgen-dependent prostate cancer, and 10 cases of transurethral resection of the prostate material from patients with androgen-independent disease. Results: Weak to moderate IL-8 expression was strictly localized to the apical membrane of normal prostate epithelium. In contrast, membranous expression of IL-8, CXCR1, and CXCR2 was nonapical in cancer cells of Gleason pattern 3 and 4, whereas circumferential expression was present in Gleason pattern 5 and androgen-independent prostate cancer. Each of IL-8, CXCR1, and CXCR2 were also increasingly localized to the cytoplasm of cancer cells in correlation with advancing stage of disease. Cytoplasmic expression (but not apical membrane expression) of IL-8 in Gleason pattern 3 and 4 cancer correlated with Ki-67 expression (R = 0.79; P < 0.001), cyclin D1 expression (R = 0.79; P < 0.001), and microvessel density (R = 0.81; P < 0.001). In vitro studies on androgen-independent PC3 cells confirmed the mitogenic activity of IL-8, increasing the rate of cell proliferation through activation of both CXCR1 and CXCR2 receptors. Conclusions: We propose that the concurrent increase in IL-8 and IL-8 receptor expression in human prostate cancer induces autocrine signaling that may be functionally significant in initiating and promoting the progression of prostate cancer by underpinning cell proliferation and angiogenesis.

Vascular endothelial growth factor expression and capillary architecture in high-grade PIN and prostate cancer in untreated and androgen-ablated patients.

Recent studies have demonstrated that angiogenesis is a potent prognostic indicator for patients with prostate cancer (PCa) and have pointed out that the evaluation of vascular endothelial growth factor (VEGF) is useful in assessing the angiogenic phenotype in PCa. The aim of the study was to investigate immunohistochemically the expression of VEGF and its correlation with the pattern of capillary architecture in prostate cancer and high‐grade prostatic intraepithelial neoplasia (PIN), in untreated and androgen‐ablated patients.

A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer

Here we report an integrated analysis that leverages data from treatment of genetic mouse models of prostate cancer along with clinical data from patients to elucidate new mechanisms of castration resistance. We show that castration counteracts tumor progression in a Pten loss–driven mouse model of prostate cancer through the induction of apoptosis and proliferation block. Conversely, this response is bypassed with deletion of either Trp53 or Zbtb7a together with Pten, leading to the development of castration-resistant prostate cancer (CRPC). Mechanistically, the integrated acquisition of data from mouse models and patients identifies the expression patterns of XAF1, XIAP and SRD5A1 as a predictive and actionable signature for CRPC. Notably, we show that combined inhibition of XIAP, SRD5A1 and AR pathways overcomes castration resistance. Thus, our co-clinical approach facilitates the stratification of patients and the development of tailored and innovative therapeutic treatments.

Mechanisms of Disease: high-grade prostatic intraepithelial neoplasia and other proposed preneoplastic lesions in the prostate

High-grade prostatic intraepithelial neoplasia (HGPIN) is the most likely precursor of prostatic adenocarcinoma according to virtually all available evidence. This lesion is characterized by cellular proliferations within pre-existing ducts and acini, with nuclear and nucleolar enlargements similar to those seen in prostate cancer, although unlike cancer HGPIN retains a basal-cell layer. The recognition of HGPIN is clinically important because of the strong association between this disease and prostatic carcinoma. The predictive value for cancer of an initial diagnosis of HGPIN on needle biopsy has substantially declined, with values falling from 36% to 21%. A major factor contributing to this decline is related to increased use of needle biopsy core sampling, which has provided the means for many cancers associated with HGPIN to be detected on initial biopsy; repeat biopsy, even with good sampling, does not detect many additional cancers. Other possible findings in the prostate might indicate premalignant disease (low-grade prostatic intraepithelial neoplasia, atrophy, malignancy-associated changes, and atypical adenomatous hyperplasia or adenosis), but the data for these premalignant diseases are much less convincing than those for HGPIN.

Current practice of Gleason grading of prostate carcinoma.

The Gleason grading system remains one of the most powerful prognostic factors in prostate cancer and is the dominant method around the world in daily practice. It is based solely on the glandular architecture performed at low magnification. The Gleason grading system should be performed in needle core biopsies and radical prostatectomy specimens where it shows a reasonable degree of correlation between both specimens, and most importantly, it remains vital in the treatment decision-making process. This review summarizes the current status of Gleason grading in prostate cancer, incorporating recent proposals for the best contemporary practice of prostate cancer grading.

Morphological diagnosis of urothelial neoplasms

The morphological classification and diagnosis of bladder neoplasms is summarised, with specific focus on histological typing, grading and staging. Four diagnostic categories are described on the basis of the pattern of growth of the urothelial lesions and tumours (flat, exophytic or papillary, endophytic, and invasive). The WHO 2004 classification is currently used. However, the WHO 1973 classification is still considered by many urologists and oncologists as the international standard in patient management.

Classification and grading of the non-invasive urothelial neoplasms: recent advances and controversies

The classification and grading of the non-invasive, intraepithelial neoplasms of the urothelium are based on the morphological pattern of growth—that is, papillary or flat (and endophytic)—and on their degree of architectural and cytological abnormalities. Recent advances in the morphological, molecular, and quantitative evaluation of these lesions have contributed to the refinement of the current classification and grading schemes. However, some controversies on the precise criteria and terminology, especially when the papillary lesions are concerned, are still present.

Changes produced in the urothelium by traditional and newer therapeutic procedures for bladder cancer

A handful of traditional and newer therapeutic procedures, such as chemotherapy, immunotherapy, radiotherapy, photodynamic and laser treatment, and gene therapy, are used to treat epithelial malignancies of bladder origin. These treatment modalities, used either intravesically or systemically, produce morphological changes in the urothelial mucosa that can be mistaken for carcinoma. The pathologist must be able to separate toxic and drug related alterations from tumour related changes. The clinical history is usually invaluable in this assessment.

Precancerous lesions and conditions of the prostate: from morphological and biological characterization to chemoprevention.

Abstract: Prostatic intraepithelial neoplasia (PIN) is composed of dysplastic cells with a luminal cell phenotype, expressing the androgen receptor as well as prostate‐specific antigen. PIN is characterized by progressive abnormalities of phenotype that are intermediate between normal prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of carcinogenesis. High‐grade PIN is considered the most likely precursor of prostatic carcinoma, according to virtually all available evidence. Androgen deprivation decreases the prevalence and extent of PIN and the degree of capillary vascularization (e.g., angiogenesis) in the surrounding stroma via suppression of vascular endothelial growth factor production. Prostatic carcinoma is also likely to arise from precursor lesions other than high‐grade PIN such as low‐grade PIN, atypical adenomatous hyperplasia, malignancy‐associated foci, and atrophy.

Is incidentally detected prostate cancer in patients undergoing radical cystoprostatectomy clinically significant

Cystoprostatectomy specimens obtained from patients with bladder cancer provide a unique opportunity to assess the features of silent prostate adenocarcinoma (PCa). The whole-mount prostate sections of 248 totally embedded and consecutively examined radical cystoprostatectomy (RCP) specimens were reviewed to determine the incidence and features of incidentally detected PCa. PCa was considered clinically significant if any of the following criteria were present: total tumor volume, 0.5 cc or more; Gleason grade, 4 or more; extraprostatic extension; seminal vesicle invasion; lymph node metastasis (of PCa); or positive surgical margins. PCa was present in 123 (49.6%) of 248 specimens. Features were as follows: acinar adenocarcinoma, 123 (100.0%); peripheral zone location, 98 (79.7%); pT2a, 96 (78.0%); pT2b, 11 (8.9%); pT2c, 9 (7.3%); pT3a, 5 (4.1%); pT3b, 2 (1.6%); pT4, 0 (0.0%); Gleason score 6 or less, 107 (87.0%); negative margins, 119 (96.7%); pN0 for PCa, 123 (100.0%); and tumor volume less than 0.5 cc, 116 (94.3%). Of the 123 incidentally detected cases of PCa, 100 (81.3%) were considered clinically insignificant. Incidentally detected PCa is frequently observed in RCP. The majority are clinically insignificant.