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Immunohistochemical Staining of Precursor Forms of Prostate-specific Antigen (proPSA) in Metastatic Prostate Cancer Anil V. Parwani, MD, PhD,* Cameron Marlow, BS, Angelo M. Demarzo, MD, PhD, Stephen D. Mikolajczyk, PhD, Harry G. Rittenhouse, PhD, Robert W. Veltri, MD, and Theresa Y. Chan Am J Surg Pathol 2006;30:1231–1236 指導老師:陳志榮老師 報告者:Intern 陳嘉哲 Introduction Prostate carcinoma: ＊most common carcinoma in American man. ＊second leading cancer-related deaths in the United States. ＊In the year 2005 in the United States 230,000 new cases of prostate cancer 30,000 deaths due to prostate cancer Introduction Prostate-specific antigen (PSA) ＊ As a tumor marker for prostate cancer ＊ a serine protease produced by both prostate epithelial and cancer cells. ＊normal function: liquify gelatinous semen after ejaculation, allowing spermatazoa to more easily "swim" through the uterine cervix. Introduction Precursors of prostate-specific antigens: ＊ 244-amino acid proenzyme ＊ more concentrated in prostate cancer than in benign tissue ＊ a more cancer-specific marker Introduction Authors’ previous studies: ＊Immunohistochemical staining (IHS) : monoclonal antibodies (mABs) against proPSA with a truncated proleader peptide containing 2 amino acids ([-2]pPSA), and against native proPSA ([-5/-7]pPSA). 2 aa = serine, arginine ＊mABs to proPSA are specific for benign and malignant prostatic tissue. Introduction ＊ProPSA remained uniform among the different tumor grade. ＊PSA staining intensities and Gleason score had a strong inverse correlation. ＊Metastatic prostate carcinoma may show negative PSA staining. Introduction The objective of this study: ＊compare the IHS patterns of proPSA with that of PSA and prostatic acid phosphate (PAP) on a series of metastatic prostate carcinoma cases. ＊Find the utility of proPSA in these lesion Materials and Methods Tissue Microarray (TMA) Design: ＊ 74 cases( metastatic prostate carcinoma): Soft tissue / bone N= 40 lymph node N= 34 from the surgical pathology files of The Johns Hopkins Hospital. (nonhormone refractory tumors) ＊ 3 cores of each specimen - TMA Tissue Microarray (TMA) Design All the metastatic tumors: higher grade, poorly differentiated carcinomas. Control tissues: ＊primary prostate adenocarcinoma with Gleason scores ranging from 6 to 7 (n=20) ＊normal prostatic tissue (n=20) ＊normal tissue from brain, skin, colon, and other 14 tissues to the TMA. Immunohistochemistry IHS: deparaffinized TMA slides using a standard streptavidin horseradishperoxidase conjugate. A purified mouse immunoglobulin G mAB, PS2P446 proPSA with both the 7 aa and 5 aa leader peptides ([-5/-7]pPSA, Beckman Coulter, San Diego, CA). Immunohistochemistry A purified mouse immunoglobulin G mAB, PS2373.3, which recognizes proPSA with a 2 aa leader peptide ([-2]pPSA, Beckman Coulter). pPSA form These proPSA mABs had less than 0.2% cross-reactivity to PSA or to each other. These proPSA mABs: research use. Immunohistochemistry Evaluation of metastatic prostate carcinomas: intensity and extent of IHS. ＊controlled by human eye The intensity of staining was categorized as weak, moderate, or strong. A numerical score assigned to each spot on the TMA. 0 for negative ; 1 for weak ; 2 for moderate ; 3 for strong Immunohistochemistry a mean score was calculated for each sample present in triplicate. The mean score : 0 to 0.5 = negative ; 0.5 to 1.5= weak, 1.5 to 2.5 = moderate ; 2.5 or greater = strong. Immunohistochemistry Extent of staining: diffuse ( more than 50% of cells) patchy ( less than 50% of cells) 5 cases : insufficient tissue on more than 2 of the 3 spots can’t be evaluated. 9 cases : lack of tissue on PSA and PAP stains only ProPSA. Total 60 cases all 4 mABs were evaluated. Results Results There were minor differences between the 4 antibodies in extent of staining. ＊[-5/-7]pPSA and PSA : the most number of cases with diffuse staining (75%, 69%), the least number of cases with patchy staining (25% and 31%). Results [-5/-7]pPSA showed the most number of positive cases (98%) compared with [-2] pPSA (80%), PSA (81%), PAP (83%). strong or moderate staining was seen in 82%, [-5/-7] pPSA, 76% PSA, 39% PAP, and 29% [-2] pPSA. Seven cases (12%) were negative for both PSA and PAP, but showed staining with [-5/-7]pPSA and/or [-2]pPSA. Result Only 3 case (5%): [-5/-7]pPSA was the only positive marker; 2 moderate, and 1 weak. Only 1 case (2%): [-2]pPSA was the only positive marker; the intensity of this one weak. Result There was no staining in prostatic stromal and vascular tissue. No other tumor types was in this study. Only focal weak cytoplasmic staining with both the proPSA mABs to control thyroid and kidney tissues. Discussion In this article, authors evaluated: proPSA as a diagnostic markers in the detection of metastatic prostatic adenocarcinoma versus PSA and PAP. PSA shows a decrease in expression from benign epithelium to HGPIN and adenocarcinoma. (Urology 49: 857–862, 1997.) Discussion A strong inverse correlation between PSA staining intensities and Gleason scores. (Am J Clin Pathol 117: 471–477, 2002.) The immunoreactivity for pro-PSA appears to remain uniform among the different tumor grades. [-2] proPSA appeared to be preferentially more concentrated in cancer tissue than in benign glands. (Urology. 2003;62:177–181.) Discussion In current study, no difference in the staining pattern of benign gland for 4mABs. In this study, proPSA [-5/-7] showed the most number of cases with moderate or strong staining (76%) as compared with PSA (56%), PAP (43%) and proPSA [-2] (55%). Discussion a case of poorly differentiated carcinoma from an unknown primary. using PSA or PAP as a diagnostic marker? In this study, -5/-7 proPSA (native proPSA) may be a better marker than PSA and PAP in metastatic prostate adenocarcinoma, only 2 cases (3%) being negative for the marker. Discussion PSA is a serine protease, and a major protein in seminal fluid. PSA is produced by both prostate epithelial cells and prostate cancer and is secreted into prostatic ducts as an inactive 244-amino acid proenzyme (proPSA) which is activated by cleavage of 7 N-terminal amino acids. (Cancer. 2004;101:894–904.) Discussion PSA either as the free “non-complexed” form or as a complex with alpha1antichymotrypsin. Ratio of free to total serum PSA ＊ lower percent free PSA levels correlating with a higher risk of prostate cancer. (JAMA 297: 1542–1547, 1998) Discussion Normally proPSA with a seven amino acid (aa) proleader peptide ([-7]pPSA). Pro PSA (pPSA), precursor form of PSA, is a component of free PSA in the serum of PCa patients. ProPSA is differentially elevated in PZ-C, but is largely undetectable in TZ . (Cancer Res 60: 756–769, 2000.) Discussion 1. 2. ProPSA: ↑ specificity for prostate carcinoma, particularly in the 2 to 4 ng/mL PSA range. (J Urol. 2003;170:2181–2185) Catalona et al indicated: Percent proPSA better than percent free and calculated complexed PSA for detecting prostate carcinoma in the PSA range of 2 to 10 ng/mL. Selectivity for detecting more aggressive cancers (Gleason score 7 or greater and/or extracapsular tumor extension.) (J Urol. 2004; 71:2239–2244.) Discussion In the diagnostic range of 4 to 10 ng/mL, PSA has limited specificity for distinguishing early prostatic adenocarcinoma from benign prostatic hyperplasia. (Cancer. 2004;101:894–904.) Discussion Further ideas: use of proPSA as an immunohistochemical marker in amount of specimens from variety of sources including cytology specimen. A Truncated Precursor Form of Prostatespecific Antigen Is a More Specific Serum Marker of Prostate Cancer (CANCER RESEARCH 61, 6958–6963, September 15, 2001) HK2 and trypsin can activate [-5/-7]pPSA to mature PSA UROLOGY 62: 177–181, 2003. © 2003 UROLOGY 62: 177–181, 2003. © 2003 SERUM PRO-PROSTATE SPECIFIC ANTIGEN PREFERENTIALLY DETECTS AGGRESSIVE PROSTATE CANCERS IN MEN WITH 2 TO 4 NG/ML PROSTATE SPECIFIC ANTIGEN Urology Vol. 171, 2239–2244, June 2004 Discussion Why does proPSA show greater staining than [-2] proPSA in metastatic cancer? Why should we find a better diagnostic marker for malignant prostate cancer? Maybe we can evaluate proPSA in the serum to detect prostate cancer.