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Clinical Cancer Research Vol. 6, 160-165, January 2000
© 2000 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Prognostic Significance of Tissue Prostate-specific Antigen in Endocrine-treated Prostate Carcinomas1

Reinhard Stege2, Mirtha Grande, Kjell Carlström, Bernhard Tribukait and Åke Pousette

Departments of Urology [R. S.] and Obstetrics and Gynecology [K. C.], Karolinska Institutet, Huddinge University Hospital, S-146 86 Huddinge, and the Departments of Woman and Child Health [M. G., Å. P.] and Medical Radiobiology [B. T.], Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Fine-needle aspiration biopsy is a minimally invasive technique for obtaining sample material suitable not only for cytological grading but also for flow cytometry and for biochemical analyses. The prognostic value of tissue prostate-specific antigen (T-PSA) from fine-needle aspiration biopsies was compared with serum total and free prostate-specific antigen, the ratio of free:total serum prostate-specific antigen, tumor stage, cytological grade, and DNA ploidy in 179 patients with stage T2–T4 prostate cancer (CAP). The patients, who were free from bone metastases at the time of diagnosis, were treated by either orchidectomy or medical castration with GnRH analogues or high-dose parenteral depot estrogens. They were followed for at least for 71 months or until death, and the different variables were correlated to time to progression and time to death from CAP. Using Cox univariate analysis, T-PSA was shown to be the most important factor in predicting time to progression and time to death. When the patients were divided into three groups with respect to T-PSA, 56 of 60 (93%) of the patients with low T-PSA levels developed progressive disease, and 52 of 60 (87%) died of CAP. For patients with intermediate T-PSA levels, the corresponding figures were 9 of 60 (15%) and 6 of 60 (10%). None of the 59 patients with high T-PSA values developed progressive disease. Similar but less pronounced relationships were found between tumor progress and CAP-specific death on the one hand and clinical stage, cytological grade, and DNA ploidy on the other. In a Cox multivariate stepwise analysis, T-PSA was the only important factor for time to progression and death. This was also true for the subgroup of patients with stages T2 and T3 disease only. The study shows that T-PSA is superior to other hitherto routinely used markers for the prediction of outcome of hormone-treated patients with newly diagnosed CAP.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Many efforts have focused on identifying factors that can predict the clinical behavior of CAP3 and aid the clinician in optimal treatment of the patient. This would be especially valuable for patients without metastases at the time of diagnosis because cancer in these patients may develop very slowly or very rapidly. S-PSA has been established as the most valuable biochemical marker for residual disease and recurrence of CAP. However, studies to evaluate this marker for predicting the clinical outcome of the disease have shown it to be of limited use in this respect (1, 2, 3) .

During recent years, it has been shown that in addition to its monomeric free form, the major fraction of circulating PSA is bound to {alpha}1-antichymotrypsin (4) . Determination of free PSA and ratios of free:total PSA have been shown to be useful in differentiating between CAP and benign prostatic hyperplasia (5 , 6) . Data on the prognostic value of free PSA is scarce. In a retrospective study on limited clinical material, Carter et al. (7) demonstrated a significantly lower percentage of free PSA in serum samples taken 10 years before diagnosis in patients with aggressive CAP compared with samples from patients with a less aggressive disease.

Based on our studies on the hormone-sensitive LNCaP and the hormone-resistant LNCaP-r CAP cell lines, we developed a method for quantitation of PSA (T-PSA) in fine-needle aspiration biopsies from patients with prostate disease. T-PSA was shown to correlate negatively to clinical stage and cytological grade; thus, highly malignant tumors have low tissue concentrations of PSA (8, 9, 10) . Low tissue concentrations of PSA were also found in tetraploid/aneuploid tumors as compared to diploid tumors (9 , 10) . In a 2-year follow-up study of hormonally treated CAP patients, we showed that T-PSA appeared to be a valuable adjunct to cytological grading for predicting progressive disease (10) .

The present study was performed on patients without metastases at the time of diagnosis because the clinical outcome is less predictable in this group than in patients with metastatic disease. The aim was to compare the prognostic value of T-PSA with total and free S-PSA, cytological grade, T stage, and DNA ploidy determined before initiation of treatment. These variables were correlated with time to progression and time to disease-specific death. The observation period covered the time to death or a follow-up period of at least 10 years.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients.
The study material comprised 179 consecutive patients ages 51–82 years (median age, 72.5 years) with histologically and/or cytologically confirmed CAP who were diagnosed and treated at the Department of Urology at Huddinge University Hospital. When this study was initiated in 1986, the patients were scanned only for bone metastases. All patients had M0 disease at the time of diagnosis. Lymph node dissection and/or abdominal/pelvic computed tomography scan were not routine in our department in this group of elderly patients at that time. The presence of N1 disease in our clinical material could therefore not be excluded. With the exception of their specific disease, all subjects were ambulatory, apparently healthy, and previously untreated for CAP.

The patients were treated surgically with bilateral orchidectomy (92 patients) or medically by GnRH analogues [3.6 mg of goserelin acetate (Zoladex) s.c. every fourth week; 14 patients] or parenteral depot estrogens [240 mg of polyestradiol phosphate (Estradurin) i.m. per month; 73 patients). Both regimens of medical treatment suppressed circulating testosterone to castration levels (11) .

Follow-Up and Survival.
The patients were followed and evaluated according to the recommendations of the European Organization for Research on Treatment of Cancer. Clinical examinations were performed every 12 weeks, including an assessment of prostate dimension by digital rectal examination and control of location and dimension of soft tissue metastases. Bone scan and/or conventional X-ray for assessment of bone metastases were performed every 24 weeks.

Objective progression of the disease was defined as an increase of T stage by two steps or more compared to the lowest T stage recorded previously. The appearance of skeletal or nonskeletal metastases was also recorded as objective progression. All patients were followed until the end of the observation period or until death. Time to progression and time to death from CAP (disease-specific death) were calculated.

T Staging.
Ultrasound equipment for transrectal investigation of the prostate was not available at our department when this study was initiated. T staging was therefore performed exclusively by digital rectal examination throughout the entire period of the investigation by the senior urologist of the author group (R. S.) according to the International Union Against Cancer guidelines. In stage T2, the tumor is confined to the gland and corresponds to stage B. Stages T3 and T4 describe tumors extending beyond the capsule, corresponding to stage C (12) .

Fine-Needle Aspiration Biopsies.
Fine-needle aspiration biopsies were obtained during routine examination of the patients according to the method of Franzén (13) . All biopsies were taken by the same pathologist. Five biopsies were obtained from the same tumor area. Two were prepared for morphological analyses, two were prepared for determination of T-PSA, and one was prepared for DNA flow cytometric analysis as described previously (9) . Since the pioneer work of Franzén in 1960, fine-needle aspiration biopsy is an established method in Scandinavia. It is selective for tumor cells, and the number of tumor cells in the samples varies between 65% and 85% in samples from well-differentiated and poorly differentiated tumors (14) . The remaining part of the aspirate consists mainly of benign epithelial prostate cells. In the present study, aspirates with excessive amounts of inflammatory cells (>10%) were excluded.

Blood Sampling.
Venous blood samples were obtained immediately before the biopsy procedure. Serum was separated by centrifugation and stored at -70°C until analysis. Analyses of free and total S-PSA for comparative purposes were performed later on serum aliquots.

Cytology.
Cytological grading of the aspirates was performed by the same senior pathologist without knowledge of biochemical or flow cytometry data. Three grades of malignancy were defined, based on six cellular properties: (a) average nuclear size; (b) average nucleolar size; (c) variability in nuclear size; (d) disturbance of nuclear arrangement; and (e) cellular/nuclear dissociation (15) .

Biochemical Analyses.
Cytosols were prepared by sonication of the biopsy samples, followed by centrifugation at 105,000 x g. Determination of cytosolic T-PSA by RIA and determination of the DNA in the biopsy material by fluorometry were performed as described previously (8) . The tissue content of PSA in the aspirates is given as µg PSA/µg DNA. Levels of total and free S-PSA were measured by chemiluminescence enzyme immunoassay using commercial kits (Immulite PSA and Immulite Free PSA; Diagnostic Products Corp., Los Angeles, CA). The detection limits and intra- and interassay coefficients of variation were 0.04 µg/liter, 4.4–8.1%, and 9.8–11.5% for total S-PSA and 0.008 µg/liter, 1.8–5.6%, and 4.4–8.7% for free S-PSA, respectively.

Flow Cytometry.
After digestion of the ethanol-fixed biopsy sample with RNase A and pepsin, followed by staining with ethidium bromide, the DNA content of the nuclei was measured in a rapid flow cytometer as described in detail in previous studies (9 , 16) .

Statistical Methods.
Differences between two unpaired groups of values were tested with the Mann-Whitney U test. When more than two groups were compared, the Kruskal-Wallis test was used. The impact of different factors on time to progression and time to disease-specific death was analyzed using the life table technique and using Cox univariate and stepwise regression analyses with regard to clinical stage, cytological grade, flow cytometric data, and biochemical data (17 , 18) . Data are presented as the mean ± SE or the median and range according to distribution.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
T Stage, Cytological Grade, and DNA Ploidy.
After cytological examination, the tumors were graded: (a) 35 tumors were graded as well-differentiated carcinomas (G1); (b) 78 were graded as moderately differentiated carcinomas (G2); and (c) 66 were graded as poorly differentiated carcinomas (G3). Twenty-four patients had T2 tumors, 130 patients had T3 tumors, and 25 patients had T4 tumors. Tumors with a high malignancy grade were more frequent in stages T3 and T4 (Table 1)Citation . A total of 113 tumors were diploid, and 66 tumors were tetraploid or aneuploid. A shift from diploid to tetraploid/aneuploid tumors was associated with increasing cytological grade and T stage. Tetraploid/aneuploid tumors were found in 17% of G1 tumors, 26% of G2 tumors, and 61% of G3 tumors. For T2, T3, and T4 tumors, corresponding figures were 4%, 38%, and 60%, respectively.


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  		Table 1 Relationships between cytological grade, palpatory diagnosis (stages T2 to T4), and DNA ploidy in 179 CAP patients with M0 disease at the time of diagnosis. Figures indicate numbers of patients.

 
Tissue and S-PSA.
T-PSA and total and free S-PSA values in relation to cytological grade, clinical stage, and DNA ploidy are shown in Table 2Citation . Due to a lack of serum, retrospective analysis of S-PSA could not be carried out in all patients. T-PSA values decreased, and total as well as free S-PSA value increased significantly with increasing cytological grade, T stage with a less favorable DNA ploidy pattern (all P < 0.001). It should be noted that the changes in T-PSA with increasing cytological grade, T stage, and more unfavorable DNA ploidy pattern were far more pronounced than the corresponding changes in total or free S-PSA.


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  		Table 2 Relationships between T-PSA (µg PSA/µg DNA) and total and free S-PSA (µg/liter), and cytological grade, clinical stage, and DNA ploidy in 179 CAP patients with M0 disease at the time of diagnosis

Values are shown as the median (range).

 
Follow-Up and Prognosis.
The patients were included in the study from January 1986 until September 1991 and were followed until March 1997. The median follow-up time and range for the survivors was 92 months (71–135 months). Corresponding values for the patients who died of CAP and for the patients who died of other diseases were 43 months (8–121 months) and 52 months (3–119 months), respectively. Overall survival is shown in Fig. 1Citation . This figure also includes the expected survival of an unselected population of the same age.



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  		Fig. 1. Overall survival of 179 CAP patients with M0 disease at the time of diagnosis compared with the expected survival of an unselected population of the same age.

 
The impact of different factors on time to progression and time to death from CAP, as calculated by Cox univariate regression analysis, is given in Table 3Citation . Of the parameters measured, T-PSA showed the strongest impact on both time to progression and time to death from CAP, whereas total and free S-PSA and the ratio of free:total S-PSA were less important in this respect. For analysis of outcome, patients were divided into three approximately equal-sized groups according to the level of T-PSA and studied by a life table analysis: (a) group 1, patients with low T-PSA levels (0.002–0.192 µg PSA/µg DNA); (b) group 2, patients with intermediate T-PSA levels (0.193–1.171 µg PSA/µg DNA); and (c) group 3, patients with high T-PSA levels (1.172–58.0 µg PSA/µg DNA). At the end of the observation period, 93% of the patients in group 1 (patients with low levels of T-PSA), 15% of patients in group 2, and 0% of the patients in group 3 had progressed (Fig. 2A;Citation Table 4Citation ). Corresponding figures for CAP-specific death were 87%, 10%, and 0%, respectively (Fig. 2B;Citation Table 5Citation ). Similar but less pronounced relationships were found between tumor progression and CAP-specific death on the one hand and between clinical stage, cytological grade, and DNA ploidy on the other (Figs. 3Citation 4Citation 5Citation ; Table 4Citation and Table 5Citation ).


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  		Table 3 Cox univariate regression analysis with respect to time to progression and time to death in 179 M0 CAP patients with stage T2–T4 disease

 


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  		Fig. 2. Time to progression (A) and time to disease-specific death (B) related to T-PSA level at the time of diagnosis in 179 CAP patients with M0 disease.

 

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  		Table 4 Survival analysis with respect to time to progression in 179 M0 CAP patients with stage T2–T4 disease

 

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  		Table 5 Survival analysis with respect to time to death in 179 M0 CAP patients with stage T2–T4 disease

 


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  		Fig. 3. Time to progression (A) and time to disease-specific death (B) related to cytological grade at the time of diagnosis in 179 CAP patients with M0 disease.

 


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  		Fig. 4. Time to progression (A) and time to disease-specific death (B) related to T stage at the time of diagnosis in 179 CAP patients with M0 disease.

 


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  		Fig. 5. Time to progression (A) and time to disease-specific death (B) related to DNA ploidy of the tumor at the time of diagnosis in 179 prostatic cancer patients with M0 disease.

 
Evaluation of background factors using Cox stepwise regression analysis showed that T-PSA was the only factor of significant importance for time to progression. T-PSA and, to a lesser degree, T stage, were the only significantly important factors for time to death from CAP (Table 6)Citation .


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  		Table 6 Cox stepwise regression analysis with respect to time to progression and time to death in 179 M0 CAP patients with stage T2–T4 disease

 
In an additional analysis, we excluded 25 patients with tumors in stage T4, which are well known to have an adverse prognosis, despite the fact that these patients were considered metastasis free at the time of diagnosis. The results for the 154 patients with T2-T3 tumors were almost identical to these presented for the total clinical material in Tables 3Citation 4Citation 5Citation 6Citation , except for T stage, which had no prognostic value (data not shown).


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The fine-needle aspiration biopsy technique introduced by Franzén et al. (13) enables minimally invasive collection of tissue samples from prostatic tumors. Aspirates were used primarily for cytological grading. Tribukait (16) subsequently used the aspirates for DNA flow cytometry. Our group developed a method for quantitation of PSA in this type of aspiration material (8) , making it possible to measure PSA at the very site of its formation. Compared to S-PSA, T-PSA values are probably less dependent on factors not related to the production of the protein in a given amount of tissue, such as the volume of the PSA-producing tissue, transport of PSA into the blood, and clearance of the protein from the circulation (19) . It is therefore not surprising that T-PSA is more closely related to the properties of the tumor itself, such as cytological grade, T stage, DNA ploidy, and histopathology and also to its sensitivity to endocrine treatment than S-PSA (8, 9, 10 , 20) .

In previous studies, we could relate a decrease in T-PSA values to increased malignancy grade and tumor stage and a shift from diploid to tetraploid/aneuploid tumors (9) . Similar results have also been obtained by Yang et al. (20) , who demonstrated higher T-PSA values in tissue samples from benign prostatic hyperplasia than in samples from CAP. In a prospective study, we could further show that PSA measurements from fine-needle aspirates appeared to be valuable for the prediction of progressive disease in hormone-treated patients with M0 and M1 disease who were followed for 2 years (10) . In the present study, only patients with M0 disease at time of diagnosis were included, and the follow-up period was 10 years or until death due to CAP.

T-PSA proved to be strikingly superior to all other variables studied in predicting the outcome of endocrine treatment. This was true for time to progression and time to CAP-specific death in patients with CAP who were metastasis free at the time of diagnosis. The Cox stepwise regression analysis showed T-PSA to be the most significant factor for time to progression and time to death. The significance of T-PSA was also true for the clinically most interesting group of patients, those with T2-T3 tumors only.

After subdivision into three categories, none of the patients with high T-PSA values showed progression, irrespective of cytological grade, tumor stage, and ploidy. In contrast, patients with low T-PSA values had an extremely poor prognosis and can be regarded as insensitive to hormonal treatment. The intermediate group responded in a manner similar to that of the high T-PSA group. Additional studies are therefore needed to define the optimal cutoff values for T-PSA.

Compared with T-PSA, both total and free S-PSA were clearly of less prognostic value. The prognostic value of total and free S-PSA has been discussed, for example, by Carter et al. (7) .

In conclusion, the present study has shown T-PSA levels at the time of diagnosis to be a superior marker for the prediction of outcome of endocrine treatment in patients with M0 CAP. However, because no data on the occurrence of lymph node or soft tissue metastases were available at the time of diangosis, additional studies on a more defined clinical material including M0N0 as well as M0N1 patients would be necessary. The analytical procedure has a potential for simplification and partial automatization. However, it is of vital importance that the aspiration procedure is highly standardized and performed by an experienced pathologist.


   ACKNOWLEDGMENTS
 
We thank Bo Nilsson (Department of Cancer Epidemiology and Biostatistics, Karolinska Hospital, Stockholm, Sweden) for providing statistical analyses.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by grants from the Swedish Medical Research Council (Grant 11615), Karolinska Institutets fonder, and Leo Research Foundation. Back

2 To whom requests for reprints should be addressed. Phone: 46-8-585-825-79; Fax: 46-8-585-826-25. Back

3 The abbreviations used are: CAP, prostate cancer; PSA, prostate-specific antigen; T-PSA, tissue PSA; S-PSA, serum PSA. Back

Received 4/30/99; revised 10/ 1/99; accepted 10/ 7/99.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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