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The Prostate 31:91–97 (1997)
Characterization of Residual Tumor Cells
Following Radical Radiation Therapy for Prostatic
Adenocarcinoma; Immunohistochemical
Expression of Prostate-Specific Antigen, Prostatic
Acid Phosphatase, and Cytokeratin 8
Gunilla Ljung,1,5* Mona Norberg,2 Lars Holmberg,3 Christer Busch,4 and
Sten Nilsson1
1
Department of Oncology, Akademiska Hospital, University of Uppsala, Uppsala, Sweden
2
Department of Diagnostic Radiology, Akademiska Hospital, University of Uppsala,
Uppsala, Sweden
3
Department of Surgery, Akademiska Hospital, University of Uppsala, Uppsala, Sweden
4
Department of Pathology, Akademiska Hospital, University of Uppsala, Uppsala, Sweden
5
Department of Oncology, Mälar Hospital Eskilstuna, Sweden
BACKGROUND. Our knowledge about the nature and biological activity of tumor cells
residing in the prostate gland after radical radiotherapy (RRT) is limited.
METHODS. In the present study, residual tumor in core biopsies taken from 37 patients
after an average of 6.8 years follow-up after radiation, were investigated with immunohistochemistry for the biochemical markers prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), and the epithelial marker, cytokeratin 8 (CK8).
RESULTS. Tumor cells were cytokeratin-positive in 33 of 34 evaluable specimens (97%). PSA
and PAP were expressed in the tumor cells in 94% (34/36) and 81% (30/37) of cases, respectively. No significant correlation was observed between PSA/PAP expression and tumor
grade after treatment. Endocrine treatment administered in addition to RRT in 12 of the 37
patients did not affect the expression of PSA or PAP. The expression of both biochemical
markers was reduced after radiotherapy in 10 of the 12 cases for which pre- and posttreatment specimens were available.
CONCLUSIONS. Tumor cells retain their epithelial characteristics immunohistochemically
after radiation, though their morphology sometimes suggests an altered phenotype after
treatment. PSA and PAP reactivity was demonstrated in tumor cells nearly 7 years after
radiotherapy, which indicates that these cells maintain their biochemical integrity and protein synthesis to a certain extent. Furthermore, endocrine treatment did not abolish PSA or
PAP expression in the tumor cells. Whether PSA and PAP immunoexpression provides
independent prognostic information needs to be further investigated. Prostate 31:91–97,
1997. © 1997 Wiley-Liss, Inc.
KEY WORDS:
prostatic adenocarcinoma; radiation therapy; endocrine treatment; core
biopsy; PSA; PAP; cytokeratin 8
INTRODUCTION
If systematic mapping biopsies are performed, residual local tumor in the prostate gland has been detected in a high percentage of cases after radical
© 1997 Wiley-Liss, Inc.
*Correspondence to: Dr. Gunilla Ljung, The Mälar Hospital, S-631
88 Eskilstuna, Sweden.
Received 6 November 1995; Accepted 1 March 1996
92
Ljung et al.
radiation therapy (RRT) [1,2]. Very little is known
about those residual tumor cells, but immunohistochemical staining techniques permit the possibility of
obtaining further information about these cells. A
previous report from our institute demonstrated residual tumor cells in 67% of patients in a long-term
follow-up after radical radiation therapy [3]. In 94%
and 64% of these cases, respectively, proliferative activity could be demonstrated by the presence of the
proliferation markers PCNA and Ki-67 [4].
Morphologically, tumor cells have been observed
to lose their epithelial characteristics after radiation
and, sometimes come to resemble sarcoma cells [5].
Therefore, a study aimed at investigating whether,
and to what degree, residual tumor cells maintained
their epithelial characteristics after RRT was constructed; furthermore, it was considered of interest to
determine whether, and to what extent, the tumor
cells retained prostate-specific protein synthesis after
high doses of radiation therapy.
Prostate-specific antigen (PSA) is a 33-kDa glycoprotein specific to prostatic duct and acinar epithelial
cells [6–8]. It is produced in benign and malignant
cells [9–12] and acts as a neutral protease for liquifying the seminal coagulum [13]. Prostatic acid phosphatase (PAP), a glycoprotein of approximately 100
kDa and immunologically different from PSA, is
found not only in benign and malignant prostatic epithelial cells but also in other tissues [14–17]. The
physiological role of PAP remains obscure [18]. Cytokeratin 8 (CK8), an intermediate filament and epithelial marker, has been identified in ductal and glandular benign and malignant prostatic epithelia [19,20]
and constitutes a component of the cytoskeleton in
cells, stabilizing the cell structure and junctions between cells [21–23].
The aim of the present study was to investigate
some of the functional and structural characteristics
of residual tumor cells following RRT. For this purpose, immunohistochemical stainings for the two important prostate markers, PSA and PAP, as well as
for the epithelial marker, CK8, were undertaken.
MATERIALS AND METHODS
Patients and Specimens
Fifty-five patients treated with radical external
beam irradiation for localized prostatic adenocarcinoma underwent transrectal ultrasonically (TRUS)guided sextant core biopsies to assess the histopathological local cure, after an average of 6.8 years after
RRT [3]. In 37 cases (67%), residual tumor was found
in one or several biopsies. Tumor stage (UICC 1987)
[24] at initial diagnosis was T1 in 4, T2 in 26, and T3
in 7 of these 37 patients and initial G1, G2, and G3
tumor grades [5,25] were present in 3, 19, and 15
patients, respectively. Endocrine treatment (estrogen
treatment in three cases, orchiectomy in nine cases)
had been administered in 12 patients, at an average of
38 months (range 8–90) prior to the biopsy investigation. In each of the 37 cases in which residual tumor
was found after RRT, one representative core biopsy
was examined immunohistochemically for the expression of PSA, PAP, and CK8.
To estimate the individual variation of PSA and
PAP expression, all biopsies in which residual tumor
was found [average three biopsies per patient (range
1–7) and 126 biopsies in total] were investigated. Pretreatment TURP specimens were available in 12 of the
37 cases; an average of three blocks per patient (range
2–4) and 17 chips (range 9–28) per block were examined.
Staining Methods
Stainings were performed according to the ABC
method [26,27]. Specimens were de-paraffinated with
xylene and rehydrated with graded ethanols. Endogenous peroxidase activity was blocked with H2O2, and
nonspecific protein binding was blocked by bovine
serum albumin (BSA). Specimens were then incubated with the primary PSA, PAP, and CK8 antibodies
(PSA: A562, 1/200, polyclonal rabbit antisera [Dakopatts, Glostrup, Denmark]; PAP: A627, 1/600, polyclonal rabbit antisera [Dakopatts]; CK8: 6D7, undiluted monoclonal mouse antibody [Immuno Develop
Lab. Sweden]; specimens were pretreated with 0.1%
protease before incubation with this antibody). In a
second step, tissue sections were incubated with the
biotinylated second antibody (DAKO, Glostrup, Denmark E353: 1/200, swine antirabbit antisera for PSA/
PAP; DAKO E0354: 1/200, rabbit antimouse antibody
for CK8) and, finally, sections were incubated with the
ABC-horseradish-peroxidase (HRP) complex in BSA
and developed with ethylcarbazole (AEC) in DMSO
and H2O2. Slides were counterstained with MayersHtx, rinsed in water, and mounted in glycerin/gelatin.
All stainings were performed at room temperature;
incubation lasted 30 min. All incubation steps were
followed by rinsing in phosphate-buffered saline
(PBS). As positive control for PSA and PAP (untreated), TURP specimens with benign prostatic hyperplasia (BPH) and foci of invasive carcinoma were
used, while intestinal mucosa was used as positive
control for CK8. Appropriate negative controls were
included. In addition to the histopathological distinction between invasive carcinoma, PIN and radiationinduced atypia in the post-RRT biopsies, a mouse
monoclonal antibody reactive with human cytokeratin
of high molecular weight and specific for basal cells
was also used (DAKO, 34BE12) [11] (Fig. 1a,b).
PSA, PAP, CK8 in Residual Tumor Cells After Radiation Therapy
93
Fig. 1. a: Immunostaining for high density cytokeratin, labeling basal cells present in nonmalignant
epithelial tissue. Most cells in the biopsy lack a basal cell layer and represent adenocarcinoma. ×100.
b: Same case as in Fig. a. ×250.
Grading and Scoring of Stainings
Statistics
The extent of the stainings was registered on a
semiquantitative scale of 0–3, using the following criteria: 0, no detectable staining; 1, <25% stained cells;
2, $25%<50% stained cells; and 3, staining in >50%
of cells. The intensity of the stainings was registered
according to the following criteria: 0, no detectable
staining; 1, weakly stained cells; 2, moderately
stained cells; and 3, strongly stained cells. A system
for evaluation of the immunostaining pattern with
the multiple of extent × intensity to give scores of
0–9 was used [28]; the possible scores obtained (0, 1,
2, 3, 4, 6, 9) were further denoted negative (score 0),
low (scores 1 and 2), intermediate (scores 3 and 4),
and high (scores 6 and 9). Each sample was quantitated on two separate occasions by one investigator
(G.L.) in a blinded manner, in an effort to test the
reproducibility of the method and minimize bias.
Fisher’s exact test and Pearson correlation coefficients were used. P-values of #0.05 were considered
statistically significant.
RESULTS
In most cases, or 97% (33 of 34 evaluable specimens), positive immunostaining with CK8 was observed in the tumor cells. PSA and PAP were expressed in tumor cells in 94% (34/36) and 81% (30/37)
of evaluable cases, respectively. The distribution of
staining scores is illustrated in Table I; low, intermediate, and high PSA scores were observed in 29%,
21%, and 50% of the positive stainings, respectively.
The corresponding PAP scores were found in 50%,
23% and 27% of positive cases, respectively. The intraobserver reproducibility of the method was 81%
94
Ljung et al.
Fig. 2. PSA immunostaining of poorly differentiated adenocarcinoma. Almost general positivity,
but with heterogeneous intensity. ×250.
Fig. 3. PAP immunostaining in the same case as Fig. 2. Incomplete weak positivity and heterogeneous intensity. ×250.
Fig. 4. High magnification (×400) of PSA immunostaining of poorly differentiated adenocarcinoma.
(29/36) for the PSA stainings and 86% (32/37) for the
PAP stainings. The PSA and PAP expression was heterogeneous between individuals, a phenomenon that
was most marked in G3 tumors. Heterogeneity was
also observed in the individual patient; between tumor cells in the individual biopsy (Figs. 2, 3), as well
as between different parts of the gland where tumor
was found at biopsy. A difference of >2 scores between tumor lesions from different biopsy locations in
the individual case, was observed in 51% (19/37) of
cases as regards to the PSA stainings and 43% (16/37)
of cases as regards to the PAP stainings. A correlation
between the tissue expression of PSA and PAP was
observed, although tumor cells generally expressed
PSA more strongly than PAP (r= 0.6; P=0.0002) (Figs.
2, 3, 4; Table 1).
There was no apparent correlation between the expression of the biochemical markers and the tumor
grade after treatment (Fisher’s exact two-tailed test, P
$0.5). Endocrine treatment in addition to RRT had
PSA, PAP, CK8 in Residual Tumor Cells After Radiation Therapy
TABLE I. PSA and PAP Staining Results and Scores
Score
N (%)
Low
Intermediate
High
PSA
Neg. 2/36 (6%)
Pos. 34/36 (94%) 10/34 (29%) 7/34 (21%) 17/34 (50%)
PAP
Neg. 7/37 (19%)
Pos. 30/37 (81%) 15/30 (50%) 7/30 (23%) 8/30 (27%)
Low, immunohistochemical scores 1 and 2; intermediate, scores 3
and 4; high, scores 6 and 9.
been administered in 12 of the 37 patients and did not
affect PSA or PAP immunoexpression (Fisher’s exact
two-tailed test, P $0.5). In 12 patients, comparisons
of PSA and PAP expression in pretreatment TURP
specimens and post-treatment core biopsies were
possible. PSA and PAP were expressed in all pretreatment specimens, and a reduction of >2 scores of PSA
as well as PAP was demonstrated in 83% (10/12) of
the cases after RRT. PAP expression was enhanced in
1 of 12 patients while, in the remaining cases, both
biochemical markers remained unchanged after treatment.
DISCUSSION
CK8 was expressed in the vast majority of cases
(97%), indicating that tumor cells present after RRT
retain their epithelial characteristics. PSA and PAP
immunostainings were positive in 94% and 81% of
cases, respectively, which confirms that the cells
were not ‘‘sterilized’’ after radiation but capable of
protein synthesis and biochemical activity. This is in
agreement with the few studies previously performed [11,29,30]. While none of the data presented
here was new, further information was gained, in
that the number of patients, the sampling technique,
and follow-up exceeded the data from previous reports.
In the 12 cases of the present series, where preand post-RRT immunoreactivity for PSA and PAP
were available, a reduced expression of both biochemical markers was observed in 83% of cases after
treatment. This may reflect radiation injury to the
cells, but also a dedifferentiation of the cells over time
(observed in 51% of cases [3]), with a loss or impairment of specialized cell functions. Furthermore,
these results must be interpreted with caution because the pretreatment TURP specimens and posttreatment core biopsies reflect different parts of the
prostate gland and may not be readily compared due
95
to the notorious heterogeneity of prostatic adenocarcinoma.
A correlation between tissue PSA and PAP expression in untreated prostatic adenocarcinoma has been
reported [31–33]; the present study demonstrates the
same results in the post-treatment situation. In the
present study, PSA expression was generally stronger than the expression of PAP. However, conflicting
data concerning whether PSA or PAP is the more
sensitive method when labeling prostatic adenocarcinoma cells has been reported [34–36] and, as a consequence, the use of both markers has been recommended [37].
PSA and PAP tissue expression was heterogenous
in the irradiated tumor cells, both in the individual
tumor and between patients. This finding is in accordance with the observations of Brawer et al. [11] in
the post-treatment situation, as well as in untreated
prostatic tumors, of which the majority have been
reported to exhibit a heterogeneous PSA and PAP
immunoreactivity [7,12,15,16,29,30,32,34,35,38–41].
We could see no apparent correlation between PSA
and PAP tissue expression and tumor grade after
treatment, as opposed to the results reported by several investigators who demonstrate an inverse correlation between PSA/PAP immunoexpression and
tumor grade in the pretreatment situation [31–33,35,
38,41–44]. Data regarding PSA and PAP expression
viz. tumor grade post-RRT must, however, be interpreted with caution, due to the difficulties involved
in tumor grading after radiation [2].
In the present study, the expression of PSA and
PAP in tumor cells after RRT did not correlate to disease progression in terms of distant metastases at biopsy control (Fisher’s extact two-tailed test, P >0.2,
data not shown). However, due to the unknown regional lymph node status at initial diagnosis, conclusive data viz. progression of disease cannot be obtained from the present series. An adverse prognosis
for tumors with poor PSA and/or PAP immunoreactivity has been reported [33,38,44–48], but whether
these markers provide independent prognostic information requires further investigation.
The expression of PSA/PAP in tumor cells was not
abolished or decreased when assessed three years after androgen withdrawal or suppression. Contradictory results have been reported [16,43], but our results are in line with other reports [29,49] (Magnus
Hellstrom, Christer Busch, personal communication)
and may suggest altered regulatory mechanisms for
PSA/PAP production in tumor cells after androgen
depletion. Furthermore, the addition of endocrine
manipulation to radiation therapy may not improve
long-term local cure in prostatic adenocarcinoma.
Owing to the low number of cases, the statistical
96
Ljung et al.
power of this study is limited. However, the number
of cases presented exceed the numbers of patients
reported in previous studies on this subject [11,29,
30]. Despite the fact that the interpretation of immunohistochemical stainings is subjective, the staining
results obtained in the present study were highly reproducible. Whether immunohistochemistry adequately reflects the PSA and PAP tissue expression is
unknown, but a close correlation of PSA content assessed by immunohistochemistry and mRNA in situ
hybridization [31,41] and Northern blot techniques
[31] has been demonstrated.
10.
CONCLUSIONS
11.
Residual tumor cells retain their epithelial characteristics immunohistochemically after high doses of
radiation. The biochemical markers PSA and PAP
were expressed in the tumor cells in the majority of
cases, which demonstrates a biological and functional
capacity in residual tumor cells several years after radiation treatment. These results imply that radiation
therapy for prostatic adenocarcinoma must be substantially altered and improved if local cure is to be
achieved.
ACKNOWLEDGMENTS
This study was supported by grants from the Lions
Cancer Research Fund Uppsala, the Swedish Cancer
Research Fund, and the Research Fund of Sörmlands
Country Council, Sweden. Our thanks to Frank Bittkowski for pleasant and skillful cooperation at the
photomicroscope.
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