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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.