Section 1 -

Introduction Dr. John R. Srigley Department of Pathology and Molecular Medicine McMaster University Hamilton, Ontario, Canada Dr. Rodolfo Montironi Institute of Pathological Anatomy and Histopathology, School of Medicine Polytechnic University of the Marche Region (Ancona) Ancona, Italy

INTRODUCTION The incidence of prostate cancer has tripled during the past decade, chiefly because of the widespread use of serum prostate-specific antigen testing, digital rectal examination and transrectal ultrasound. Needle biopsy of the prostate plays a central role in the morphologic evaluation of prostate cancer [1]. The increase in prostate cancer detection has induced a sharp increase in the number of radical prostatectomies [3]. The pathologist has a fundamental and challenging role in the evaluation of tissue specimens and has to define a series of lesions such as cancer, its mimics, and its well known precursor high-grade prostatic intraepithelial neoplasia. In difficult cases when a specific cancer diagnosis is not feasible for a host of reasons, a term indicating diagnostic uncertainty needs to be used. The diagnostic features of adenocarcinoma of the prostate have been dealt with in recent studies and reviews. Architectural and cytological features suggestive of carcinoma have been defined. The list includes features such as small glands infiltrating in between larger benign glands, lack of basal cells, and nuclear enlargement and nucleolar prominence. There are also a number of adjunctive findings that are seen with carcinoma, some of them almost pathognomic for prostate cancer: mucinous fibroplasia (collagenous micronodules) and glomeruloid structures. There are also features that should make pathologists hesitate in diagnosing carcinoma. The list of such features is quite long and includes small glands with minimal atypia merging in with similar glands which seem more recognizably benign. Many histological benign mimickers of cancer can lead to misdiagnosis of cancer. One distinguishing feature is that benign glands contain basal cells, which are absent in cancer, and pathologists have used immunohistological markers to label basal cells. cDNA microarrays have also identified markers specific for prostate cancer. These markers, although improving the accuracy of diagnosis, have their limitations, and this technique should be used in conjunction with sections stained routinely. a-methylacyl-CoA racemase (AMACR) is a marker that is substantially upregulated in prostate cancer. Because negative staining for basal cell markers, especially in a small focus of atypical glands, is not always diagnostic of prostate cancer, positive staining for AMACR can increase confidence in a diagnosis of malignant disease. This procedure has some pitfalls in diagnostic use. Pseudohyperplastic, atrophic, and foamy gland adenocarcinoma of the prostate, variants that are especially difficult to diagnose, are positive for AMACR in only 62–77% of cases. Up to 20% of small foci of adenocarcinoma on needle biopsy can be negative for AMACR. AMACR also labels high-grade prostatic intraepithelial neoplasia glands and occasional benign glands. In prostatic needle biopsies, two histologic entities are predictive of subsequent prostatic adenocarcinoma [4]. High-grade prostatic intraepithelial neoplasia (PIN) is an isolated finding in less than 1% to greater than 20% of needle biopsies and has long been known to be a significant risk factor for PCa. Repeat biopsies for high-grade PIN detected PCa in 21% to 48% of men in most pre-year 2000 studies. The identification of high-grade PIN without concurrent PCa generally warrants follow-up with repeat biopsy. Between 1% and 5.3% of contemporary needle biopsies contain a minute collection of small acini that raises the suspicion of carcinoma, but which falls below the diagnostic threshold. These cases are reported under different terms such as atypical glands suspicious but not diagnostic of malignancy or atypical small acinar proliferation suspicious for but not diagnostic of malignancy (or ASAP) or atypical foci suspicious for carcinoma [6]. The histologic finding of atypical foci is a strong predictor of PCa on repeat biopsy. Therefore, its isolated histologic identification also warrants repeat biopsy. Based on repeat biopsy, about half of atypical foci cases prove to be marginally sampled carcinoma, whereas half represent benign reactive or atrophic acini with sufficient atypia or confounding findings that carcinoma cannot be definitely excluded. PIN and atypical foci may occur together within a biopsy set in the absence of prostate cancer. Substantial effort has been expended in the recent years in describing the available factors and determining their predictive value for staging, cancer recurrence, and patient survival in prostate carcinoma [7]. A wealth of clinical information is available in even the smallest tissue specimens of the prostate, such as biopsies. This includes information on histologic type, Gleason score, extent of involvement, local invasion (extraprostatic extension and seminal vesicle involvement), perineural invasion (focal vs. multifocal, and diameter of nerve bundles), lymphovascular invasion, and location and distribution of tumor [5]. The Gleason score of adenocarcinoma of the prostate is the quintessential prognostic factor. The Gleason grading system is recommended as the international standard for grading prostate cancer. The Gleason score is a scalar measurement that combines discrete primary and secondary groups (patterns or grades) into nine groups (scores 2 to 10). Gleason score should be reported as the composite score and its component patterns, e.g., Gleason 7 = 4 + 3. The method of reporting needle biopsies needed clarification of a few issues including some not addressed in the original Gleason system. A recent consensus conference organized by the members of the International Society of Urological Pathology (ISUP) has dealt with the current application of the Gleason system [2]. Molecular knowledge of prostate cancer can improve prediction of prognosis, but has not yet yielded information that is ready to be routinely incorporated into clinical practice [1, 3, 5]. Among the risk factors for prostate cancer are inherited susceptibility and diet. At the cellular and molecular level, genetic aberrations drive the formation and aggressiveness of prostate cancer. Every carcinoma focus is presumed to arise from a single cell that accumulates genomic changes affecting regulatory genes resulting in a growth or survival advantage. Additional changes lead to local invasion and metastasis. Mutations in classic oncogenes or tumour suppressor genes are uncommon in primary prostate cancer, and mutations specific for prostate cancer (eg, prostate gatekeeper genes) have not been identified. However, several molecular or genetic changes have been found. Although none of them are unequivocally linked to prostate cancer initiation or progression, some are directly involved in prostatic carcinogenesis. In summary, while the prime goal of the needle biopsy is to diagnose prostatic adenocarcinoma, once carcinoma is detected further descriptive information regarding the type, amount of cancer and grade forms the cornerstone for contemporary management of the patient and to assess potential for local cure and the risk for distant metastasis. P roper examination of radical prostatectomy (RP) specimens by the pathologist is critical in accurately determining the prediction of patient outcome. The pathology report should include relevant clinical information as well as provide prognostically useful data derived from the evaluation of the RP specimen [7]. Since the yearly incidence of prostate cancer greatly exceeds the death rate, and since clinically apparent prostate cancers can have a widely variable course, finding genes that control aggressiveness is of particular interest. The 2006 Prostate Cancer Long Course will provide a state-of-the-art update on the pathology of prostate cancer. The global scope of the prostate cancer problem will be presented along with epidemiological considerations. Theoretical aspects including models of cellular and molecular pathogenesis will be discussed. The pragmatic aspects of diagnosing precursor lesions such as prostatic intraepithelial neoplasia (PIN) will be reviewed. The morphological diagnosis of adenocarcinoma in needle biopsies will be emphasized along with the reporting of prognostic factors, especially Gleason grade in needle biopsies and radical prostatectomy specimens. The use of ancillary technologies including immunohistochemistry and molecular pathology will be integrated in the program. While the emphasis will be on prostatic adenocarcinoma, other types of carcinoma affecting prostatic tissue will also be reviewed. Finally, we will look at some futuristic considerations utilizing molecular and bioinformatic technology. At the end of the program, attendees should have a reasonable understanding of the current scope of prostate cancer pathology. References: Amin MB, Boccon-Gibod L, Egevad L, Epstein JI, Humphrey PA, Mikuz G, Newling D, Nilsson S, Sakr W, Srigley JR, Wheeler TM, Montironi R. Prognostic and predictive factors and reporting of prostate carcinoma in prostate needle biopsy specimens. Scan J Urol Nephrol Suppl 2005;216: 20-33 Epstein JI, Allsbrook WCJ, Amin MB , Egevad LL, and The ISUP Grading Committee (2005a) The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason grading of prostatic carcinoma. Am J Surg Pathol 2005;29:1228-1242. Epstein JI, Amin M, Boccon-Gibod L, Egevad L, Humphrey PA, Mikuz G, Newling D, Nilsson S, Sakr W, Srigley JR, Wheeler TM, Montironi R. Prognostic factors and reporting of prostate carcinoma in radical prostatectomy and pelvic lymphadenectomy specimens. Scand J Urol Nephrol Suppl 2005;216:34-63. Herawi M, Kahane H, Cavallo C, Epstein JI. Risk of prostate cancer on first re-biopsy within 1 year following a diagnosis of high grade prostatic intraepithelial neoplasia is related to the number of cores sampled. J Urol 2006;175:121–4. Montironi R, Vela-Navarrete R, Lopez-Beltran A, Mazzucchelli R, Bono A. 2005 Update on pathology of prostate biopsies with cancer. Eur Urol 2006;49:241–47. Schlesinger C, Bostwick DG, Iczkowski KA. High grade prostatic intraepithelial neoplasia and atypical small acinar proliferation: predictive value for cancer in current practice. Am J Surg Pathol 2005;29:1201–7. Srigley JR, Amin M, Boccon-Gibod L, Egevad L, Epstein JI, Humphrey PA, Mikuz G, Newling D, Nilsson S, Sakr W, Wheeler TM, Montironi R. Prognostic and predictive factors in prostate cancer: historical perspectives and recent international consensus initiatives. Scan J Urol Nephrol Suppl 2005;216:8-19