Tumor Volume and Prostate Specific Antigen: Implications for Early Detection and Defining a Window of Curability

Vol. 154,1808-1812,November 1495 Printed in U S A

TUMOR VOLUME AND PROSTATE SPECIFIC ANTIGEN: IMPLICATIONS FOR EARLY DETECTION AND DEFINING A WINDOW OF CURABILITY R. JOSEPH BABAIAN,* PATRICIA TRONCOSO, LINDA C. STEELHAMMER, J. LLORETA-TRULL AND EDILBERTO I. RAMIREZ From the Departments

of

Urology and Pathology, University of Texus, M. D. Anderson Cancer Center, Houston, Texas

ABSTRACT

Purpose: We attempted to determine the relationship between tumor volume and extent of localized prostate cancer, as well as the interrelationships of tumor volume with prostate specific antigen (PSA) level, grade and stage. Materials and Methods: Serial whole mount sections from 128 patients who underwent radical prostatedomy were analyzed using a computer assisted volumetric program. Statistical evaluations were performed using logistic and simple regression analyses. Results: The median tumor volume for patients with organ confined disease was significantly lower than for those with extraprostatic extension (1.25versus 2.94 cc, p CO.001).A significant incidence (32%)of small volume cancers (0.51 to 1.5 cc) exhibited extraprostatic extension while that of extraprostatic disease increased to 66% for patients with tumor volumes greater than 1.5 cc (p <0.001). Of men with clinically significant (greater than 0.5 cc, or Gleason score 7 or more) pathological stage B disease 31% had a serum PSA value of 4 ng./ml. or less. Multivariate regression analysis of tumor volume as a function of PSA, grade and stage demonstrated that log PSA had the strongest association with tumor volume. Goodness-of-fit analysis (coefficient of determination) revealed that only 40 to 50%of the PSA levels are explained by tumor volume. Conclusions: These data suggest that the window of curability for prostate cancer decreases significantly once the tumor grows to a volume greater than 1.5 cc, and that grade and tumor volume are more significantly related to stage than PSA. KEYWORDS: antigens, neoplasm; prostatic neoplasms; diagnostic tests, routine There has been an 89% increase in the incidence of clinical prostate cancer in the United States during the last 4 years.' With the increased diagnosis of this malignancy and the realization of the limitations of radiotherapy as a curative treatment option,2 radical prostatectomy has become the treatment preferred by most urologists. Historically, the best candidates for surgical intervention have been patients with organ confined disease but more recently the indications for this treatment have been expanded. If cure or enhanced long-term survival is the primary objective of surgery, then reaffirmation of the limitations of radical prostatectomy and enhancement of clinical staging are paramount to the proper selection of patients for this operation. As reported by Walsh, cancer control should be the primary focus for surgical intervention.3 Positive surgical margins and/or seminal vesicle invasion is reported to occur in 45 to 71% of men undergoing prostatectomy.4-6 Since these men are at high risk for relapse, attempting to identify patients with extraprostatic extension clinically preoperatively is becoming increasingly important. The manner in which the current diagnostic tools, namely prostate specific antigen (PSA)and transrectal ultrasonography, are used must be refined if possible. The ability of transrectal ultrasonography to stage cancer has been disappointing and while PSA is highly associated with tumor stage, it is of limited value on an individual basis.7.8 While some investigators have shown the importance of tumor volume as it relates to tumor stage and as an independent predictor of disease progression, others have reported that once grade, pathological stage and margin status are considered the tumor volume did not provide any predictability of

progression.S.10 We explored the interrelationships of PSA, tumor volume, grade and stage to improve their use in defining selection criteria that enhance detection and treatment outcome. MATERIALS AND METHODS

Between 1987 and 1992,314men underwent radical prostatectomy at our institution. Of the prostatectomy specimens 128 were subjected to computer assisted volumetric analysis to provide an equal distribution of cancers that were organ confined or demonstrated extraprostatic extension. Specimens with positive margins of resection without histological evidence of extraprostatic extension were excluded from this study. The prostate glands were evaluated according to a previously described protocol with some modification.ll Briefly, the glands were weighed, pinned to a paraffin block and fixed in neutralized 10%formalin for 48 hours. After fixation, the entire surface of the prostate was inked and the seminal vesicles were removed at the level of the prostate base. The apical portion of the prostate (distal 0.5 to 1.0cm. depending on the configuration of the apex) was separated from the remainder of the prostate and radially sectioned. The remaining prostate was then sectioned with a commercial meat slicer at 4 mm. intervals in a transverse plane perpendicular to the posterior surface. The cross sections were processed as whole organ sections. The margin at the base of the prostate or bladder neck was evaluated with either en face (51 cases) or perpendicular (77) sections, Each tumor focus was outlined on the histological sections, and the total number of tumor foci and the zonal distribuAccepted for publication April 13, 1995. uests for repnnts: Department of Urology, Box 110.Univer- tions were recorded. Each focus was classified according to si;y%%exas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., the Gleason grading system.12 The assigned histological Houston, Texas 77030. grade for the specimen was that of the dominant lesion ex1808

1809

RELATIONSHIP OF PROSTATE SPECIFIC ANTIGEN TO 8TAQE AND TUMOR VOLuYe

e p t for dominant transition zone tumors of lower histo@cal grade than peripheral zone foci, in which case the P ~ t b o l o g i d y 66 , mhn had 0d d (88 ) dbassigned grade was that of the largeat peripheral ZOM fbcu. eaau and 69 demonrtrabd atmpnmhtic srbarioo. Of tbe Volume determination. The software d to determine latter man 26 W negative rurgicd m ( m C - ) , 25 tumor volume produced 3-dime~ionalimages and deter- had paoitive mrgkd mnrgin8 (m C ' ) d 13 hdaeunind mined the volume of serially sectioned objects baaed on veaiele involvement (&qpclv). planimetry tracings. The cross sectionswere projected with a R&huhipafPSAands@jp. I e 8 O ~ t h e t ~ w u photographic enlarger onto sheets of tracing paper, and the conridemi rpbcimencosltia6d. Tba mwlirn PSALSvd in paperipheries of each cross section and each individual tumor tients with orgun conhod pmrtrb (6.2 agM)vma focus were outlined. The maps of each mom d o n mre significantly diftsreat from that in patient. with exhapme placed on a backlit digitizing tablet and the outlinea of each tatic ertension (9.4 ngJml., p ~0.O001).Figure 1 7 structure were traced. The volume of each separately the median PSAvalueaofmen with oqpamhaddl.uuto stored 8tNCtUR-e was determined by multiplying the sum t h o e w i t h t h e v a r i o u s s u b c a t t e # i e r o f* ~SrQnof the areas of all cross sections by the d o n thicknese eion.'Ikrewasalmasig&hntditBareaoc behRbsntbsmb (4 mrn.). dian PSA Valdmell with and without rpsfimsbrmlnd The potential influences on volume eatimata attributable cancer (6.6 vemu 10.8 nglml.. p
-

-

-

RELATIONSHIP OF PROSTATE SPECIFIC ANTIGEN TO STAGE AND TUMOR VOLUME

1810

TABLE1. Relationship ofPSA to tumor volume in 128 patients No.Pta. With F'SA Value (ng./ml.) VOl. tcc)

2.5 or Less

2.64

6 4 1 0 0 0 0 11

0.014.50 0.61-1.00 1.01-1.60 1.51-2.00 2.013.00 3.01-4.00 More than 4.00

Totals

2 5

6 2 1

0 1 17

4.1-7

7.1-10

1 6 11 3 5 2 6 34

1 3 5 2 5 4 5 25

10.1-15

15.1-20

Total No. More Than 20

0 0 0

0 1 2 4 5 6 5 23

0 0 0 0 2 0

0 1 1

s

8 -

8

10

(%)

10 (8) 19 (15) 25 (19) 11 (9) 19 (15) 13 (10) 31 (24) 128 (100)

tients (82%) with a PSA level of 2.5 ng./ml. or less had organ confined disease: 6 (67%)had a volume of 0.5 cc or less and 3 had a volume of 1.0 cc or less. Of the 17 patients whose PSA level was 2.6 to 4.0 ng./ml. 14 (82%) had organ confined disease (tumor volumes 1.0cc or less in 6, 1.1 to 1.5 cc in 6, 1.51 to 2.0 in 1 and greater than 4 cc in 1).Univariate logistic regression analysis showed a significant relationship of PSA, tumor volume and tumor grade to specimen and organ confined disease, with Gleason score and tumor volume being the best predictors of organ and specimen confined cancer, respectively (table 3). Multivariate analysis showed that only Gleason score and tumor volume had a s i e i c a n t relationship with extent of disease. Using chi-square analysis the combination of both parameters did not enhance the predictability of the model compared to that of either parameter alone to determine whether the cancer was either organ or specimen confined. PSA did not demonstrate a significant at v ~ o m association with either category of tumor extent on multivanc.2. Incidence o f p ~ ~ and less than4 ng~d. riate analysis (table 3). Univariate regression analysis of tumor volumes up to 2 a.N.S.,not signi6cant. tumor volume as a function of PSA,tumor grade and extent of disease showed that all of these factors were significantly associated. However, by multivariate analysis, only log PSA and extent of disease were related to tumor volume, and there was no additive effect by incorporating any other studied parameter (table 4). Univariate regression analysis showed a significant association of PSA with the independent variables of tumor volume, Gleason score and stage, whereas onIy tumor volume and Gleason score maintained a significant relationship to PSA by multivariate analysis. Modeling for goodness-of-fit(coefficientof determination) revealed that 45% of the PSA levels are explained by tumor volume and the addition of the other variables does not significantly enhance the explanation of PSA levels. 0

I0

20

30

40

80

50

PSA (nglrnl)

FIG. 3. Scatterplot of PSA value ainst cancer volume for 128 patients. Correlation between log P% and log cancer volume was 0.64.

volumes greater than 3.0 cc in men with disease that was and was not specimen confined (23% versus 61%, p <0.001). Relationship of PSA, volume, stage and grade. Analysis of PSA and tumor volume by stage revealed that 9 of 11 pa-

DISCUSSION

The Parameter of cancer volume has been proposed as a valuable addition to staging, since numerous studies during the last 5 years have demonstrated a significant association between this variable and Gleason score, capsular penetration, seminal vesicle involvement, lymph node metastases and margin status of resection.13.14 McNeal proposed that the biological aggressiveness of prostate cancer is a direct function of the tumor volume.15 Unfortunately, an accurate

TABLE2. Relationship ofpathological stage to tumor volume in 128 patients No. P~B. [%) VOl. (cc) 0.01-0.50 0.51-1.00 1.01-1.50 1.51-2.00 2.01-3.00 3.01-4.00

More than 4.00 Totals

Total No.

Stage B

Stage

10 (15.4) 15 (23.1) 15 (23.1) 4 (6.2) 8 (12.3) 1 (1.51 12 (18.5) -

0 (0) 2 (8) 9 (36) 2 (8) 4 (16) 3 (12) 5 (20) 25

65

C-

-

Stage C'

0 (0) 2 (8) 1 (4) 1 (4) 5 (20) 6 (24) 10 (40) 25

Stage

(B)

CE"

0 (0) 0 (0) 0 (0) 4 (30.8) 2 (15.4) 3 (23.1) 4 (30.8) 13

10 17.8) 19 (14.8) 25 (19.5) 11 18.6) 19 (14.8) 13 (10.2) 31 124.2) 128 1100)

RELATIONSHIP OF PROSTATE SPECIFIC ANTIGEN TO STAGE AND TUMOR VOLUME

1811

(32%) with tumor volumes of 0.51 to 1.5 cc hbtologically had extraprostatic extension of dimam, including 3 (21%) with a p i t i v e margin of resection. "hue, a signiseant number of small volume cancers exhibit extracap~ularextension, limit ing surgical curability. Stamey et al first reported the relationship of PSA to tumor volume and demonetrated a correlation coefficient of 0.70.14 Our results are comparable, with a COefFicient of 0.64. The significance of thew observations is that only 40 to 6056 of the PSA deteminations are explained by tumor volume. Consequently, approximately 50% of the PSA levels are related to another factor or factors, for example tumor grade, stage. prostatitis, patient age, benign prostatic hyperplasia (glandular), catabolism, access to serum,a leakage phenomenon or cross reactivity with kallikreine. Our data clearly demonstrate the decreasing incidence of a normal PSA level (4 ngJml. or less) as tumor volume increasee: from 80%in 8 of FIG. 4. Median tumor volume distributed b athological stage 10 tumors with a volume of 0.5 cc or less (ineignifieant diewith comparative p values. B, organ m n h d extrapwtatic ease) to 18% in 2 of 11 with a volume of 1.51 to 2.0 cc (p = with negative surgical margin. C+,extraprostaticwith positive sur- 0.007). Once the tumor volume exceeds 3 cc it is uncommon gical margin. Csv, extraprostaticwith seminal vesicle involvement. (2%, 1 of 44)to find a patient with a normal serum PSA level. However, because of the overlap of FSA value^ and tumor TABLE3. Results of logistic regression annlysis of organ and volume between patients with pathological stages B and C epecimen confined disease as a function of PSA level, t u m r volume disease these parameters can only functionas general guideand emde lines when counseling about treatment. PSA has been shownto be significantly associated with the Statistical S i c a n c e (p value) Independent Variable clinical and pathological stages of dieeaee.8.19 However, data univariate Multivariate regarding absolute PSA levels and pathological stage have Organ confined disease: been lacking. The median PSA level for organ confined disease in this study was 6.2 nglml., with 23 of 65 patients PSA 0.002 Not -cant Tumor vol. 0.001 0.033 (35%) having a PSA level of 4 nglml. or lese. Of these 23 Gleason score eo.001
&,

TAB= 4. Remession analysis - of. log- tumor volume as a function of log PSA, g t d e and stage Independent Variable

% Coe5cient of Determination goodness of fit)

Signifcance of Regression Coefficients (p value)

Univariate

Multivariate

~

Gleason score organconfined Specimen confined

45 15 16 14

Lag F'SA and organ confined Log F'SA and specimen confined Lag PSA and Gleason scorn Log F'SA, Gleason score and stage

48 48 46 48

F'SA

<0.001

10.001

<0.001

Not significant

<0.001 <0.001

0.0149

0.0203

1812

RELATIONSHIP OF PROSTATE SPECIFIC ANTIGEN TO STAGE AND TUMOR VOLUME

CONCLUSIONS 7. Lorenhen, T., Nerstrom, H.,Ivereen, P. and Torp-Pedersen, S. T.: Local staging of prostate cancer with transrectal ultraIn addition to defining a potential window of curability, we sound a literature review. Prostate, suppl., 4: 11,1992. presented 2 important facts that have implicationsr e g d g 8. Babaian, R. J., Camps, J. L., Frangos, D. N., W i r e z , E. I., the u8e of an absolute value of PSA as a threshold for the Tenney, D. M., Hassell, J. S. and Fritsche, H. A: Monoclond early detection of prostate cancer: 1) a significant number of prostate specific-antigen in untreated prostate cancer. Relasmall volume cancers (0.51 to 1.50 cd exhibit extraprostatic tionship to clinical stage and grade. Cancer, 67: 2200,1991. extension (32%) and 2) a significant number of men (31%) 9. Epstein, J. I., Carmichael, M., Partin, A. W.and Walsh, P. C.:IS tumor volume an independent predictor of progression followwith clinically significant (greater than 0.5 cc or Gleason ing radical prostatectomy? A multivariate analysis of 185 clinscore 7 or greater)pathological stage B disease have a serum ical stage B adenocarcinomas of the prostate with 5 years of PSA value of 4 ng./ml. or less, with 65%of these men having followup. J. Urol., 149 1478,1993. a level of 2.51 to 4.0 ng./ml. These observations suggest that, 10. Humphrey, P. A. and Vollmer, R. T.: Intraglandular tumor exmuch like the recommendation for mammography in women, tent and prognosis in prostatic carcinoma: application of a grid men should obtain a baseline PSA level at age 45 years. A method to prostatedomy specimens. Hum. Path., 21: 799, change (as yet undefined in PSA velocity) from an individual 1990. baseline level could signal the potential risk of cancer even 11. Ayala, A. G., Ro,J. Y.,Babaian, R. J., Tronmso, P. and Grignon, D.: The prostatic capsule: does it exist? Its importance in the though the PSA value is still less than 4.0 ng./ml., thus staging and treatment of prostatic carcinoma. h e r . J. Surg. enhancing early detection and optimizingthe benefit of early Path., 1 3 21,1987. therapy. This hypothesis must be tested in a prospective 12. Gleason, D. F.: Histologic grading and clinical staging of prosrandomized study. tatic carcinoma. In: Urologic Pathology: The Prostate. Edited Perhaps more significantly, we demonstrated that while by M. Tannenbaum. Philadelphia: Lea & Febiger, pp. 171PSA level has a significant relationship to stage, grade and 197, 1977. tumor volume are more significantlyrelated to stage. PSA is 13. McNeal, J. E.,V i e r s , A. A, Redwine, E. A., Freiha, F. S.and best associated with tumor volume. However, since only 40 to Stamey, T. A: Histologic differentiation, cancer volume, and 50% of the serum PSA levels are due to tumor volume, the pelvic lymph node metastasis in adenocarcinoma of the prostate. Cancer, 1225,1990. other causes of detectable serum PSA levels must be considered, particularly when using PSA for the detection of pros- 14. Stamey, T. A., Kabalin, J. N., McNed, J. E., Johnstone, I. M., Freiha, F., Redwine, E. A. and Yang, N.: Prostate specific tate cancer.

=.

antigen in the diagnosis and treatment of adenocarcinoma of the prostate. 11. Radical prostatectomy treated patients. J. Urol., 141: 1076,1989. 1. Boring, C. C., Squires, T. S.,Tong, T. and Montgomery, S.: 15. McNeal, J. E.: Cancer volume and site of origin of adenocarcinoma of the Drostate: relationshiD to local and distant spread. Cancer statistics. CA, a4: 7, 1994. Hum. Path.,-=. 258,1992. 2. Stamey, T. A, Ferrari, M. K and Schmid, H.-P.: The value of serial prostate specific antigen determinations 5 years after 16. Partin. A. W..E~stein.J. I.. Cho. K. R.. Gittelsohn. A. M. and Walsh, P. C.: Morphometkc measurement of &or volume radiotherapy: steeply increasing values characterize 80% of and per cent of gland involvement as predictors of pathologic patients. J. Urol.. 1% 1856,1993. stage in clinical stage B prostate cancer. J. Urol., 141: 341, 3. Walsh, P. C.: Radical prostatectomy. preservation of sexual function, cancer control. The controversy. Urol. Clin. N. h e r . , 14: 1989. 17. Stamey, T. A., McNeal, J. E., Freiha, F. S. and Redwine, E.: 663,1987. Morphometric and clinical studies on 68 consecutive radical 4. Catalona, W.J. and Bigg, S. W.:Nerve-sparing radical prostaprostabtomies. J. Urol., 139 1235, 1988. tectomy: evaluation of results after 250 patients. J. Urol., 143: 18. Bostwick, D. G.,Graham, S. D., Jr., Napalkov, P., Abrahamsson, 538. 1990. P. A., di Sant’agnese, P. A., Algaba, F., Hoisaeter, P. A., Lee, 5. Wahle, S.,Remicek, M., Fallon, B., Platz, C. and Williams,R.: F., Littrup, P., Mostofi, F. K., Denis, L., Schroeder, F. and Incidence of surgical margin involvement in various forms of Murphy, G. P.: Staging of early prostate cancer: a proposed proetatectomy. Urology, 36:23,1990. tumor volume-based prognostic index. Urology, 41:403,1993. 6. Roeen, M.A,Goldstone, L., Lapin, S., Wheeler, T. and Scardino, P. T.: Frequency and location of extracapsular extension and 19. Stamey, T. A. and Kabalin, J. N.: Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. I. positive surgical margins in radical pmstatectomy- specimens. 3. uroi., 148:3 1 , 1992. Untreated patients. J. Urol., 141: 1070,1989. REFERENCES