Adenocarcinoma of the Prostate Part II: Tissue Prognosticators

Transcription

1 ANATOMIC PATHOLOGY Review Article Adenocarcinoma of the Prostate Part II: Tissue Prognosticators PETER A. HUMPHREY, MD, PHD,* AND PHILIP J. WALTHER, MD, PHDf In this second review article of a two-part series on adenocarcinoma of the prostate, both established and experimental tissue prognosticators for adenocarcinoma of the prostate will be discussed. Consideration should be given to tissue indicators of prognosis for patients with prostatic carcinoma because this malignant neoplasm may exhibit remark- ably variable biologic behavior. As in the first article, which addressed prostatic tissue sampling issues, the discussions will be centered on tissue specimen types. A final section focuses on experimental prognosticators for adenocarcinoma in prostatic tissues. (Key words: Prostate; Cancer; Prognosis) Am J Clin Pathol 1993;100: In general, the morphologic features of histologic grade, pathologic stage, and tumor extent (tumor volume or percent tumor) in prostatic tissues are important prognosticators. However, these prognosticators in prostate cancer do not have the capacity to predict the outcome absolutely for individual patients. 1,2 As with all prognosticators, these tissue prognosticators indicate trends and the likelihood of outcome; they are not absolute predictors of the future. Currently, much effort is being directed toward development of additional and more quantitative prognosticators in prostatic carcinoma. PROGNOSTIC FEATURES IN NEEDLE CORE BIOPSIES OF THE PROSTATE At present, the most significant morphologic prognosticators in needle core biopsies are histologic grade and extension into the periprostatic tissues. Although there are roughly 40 histologic grading schemes for prostatic adenocarcinoma, the most commonly used schemes are those of Gleason 3 and a simple three-tiered classification, identifying well-differentiated, moderately differentiated, and poorly differentiated adenocarcinomas of the prostate. It has been recommended 4 that the Gleason grade or World Health Organization grade 5 be recorded in every surgical pathology report on a 14-gauge core needle biopsy of the prostate that reveals adenocarcinoma. An additional recommendation is that the Gleason histologic grade be reported in every case, even when the grade from the second system is also reported. 6 The Gleason histologic grade is an important prognosticator that is closely tied to tumor volume, capsular penetration, seminal vesicle involvement, lymph node metastases, clinical and pathologic stage, and patient survival. However, only a few studies 7 " 9 have related Gleason grade in needle biopsies alone to prognosis; most studies have combined biopsy and other prostatic tissues in relating histologic grade to prognosis. There are several difficulties with the application of histologic grading systems to needle core biopsies. One difficulty From the *Deparlment of Pathology. Division of Surgical Pathology, and the ^Department of Surgery. Division of Urology. Duke University Medical Center. Durham. North Carolina. Address reprint requests to Dr. Humphrey: Department of Pathology, Division of Surgical Pathology, Barnes Hospital at Washington University Medical Center, One Barnes Hospital Plaza, St. Louis, MO with the Gleason system, as with all histologic grading systems, is the inherent subjectivity. Several comparative studies have demonstrated reasonable reproducibility of the Gleason method, 10 " 12 but others have not Apparently, none of the studies focused solely on needle biopsies. A second difficulty in applying the Gleason grade method to 14-gauge core needle biopsies is the size of the needle biopsy itself, in which an appreciation of a distinctive Gleason pattern may be difficult. Indeed, the common tendency with needle biopsy is to undergrade the carcinoma because of the difficulty in identifying the infiltrative pattern of a higher-grade carcinoma. Third, because the tissue in the needle biopsy usually represents only a small fraction of the entire tumor and prostatic carcinoma may exhibit histologic grade heterogeneity within the same tumor, the grade in the needle biopsy does not always accurately predict the grade of the tumor in the whole gland, 9 "" 17 particularly with limited carcinoma and low-grade carcinomas. 18 The correlation is, however, of sufficient strength to warrant continued application of the Gleason approach to grading when using 14-gauge needle biopsies. The inability of histologic grade to predict the tumor grade absolutely in the entire prostate and its biologic behavior is highlighted by reports of lowgrade carcinoma on needle biopsy associated with high-grade carcinoma in the prostatectomy specimen 18 and lymph node metastases. 919 Finally, because biopsy-gun needle biopsies are smaller than core needle biopsies, it is even more difficult to apply a grading scheme based on tumor growth pattern, such as that of Gleason, to these specimens. It has been recommended that grading on biopsy-gun biopsies be performed based on nuclear anaplasia (and the Gleason method does not incorporate nuclear anaplasia). 4 However, no formal studies have been published on the predictive capacity of the different histologic grading schemes as applied to biopsy-gun needle biopsies. Until such studies have been performed, we recommend application of the Gleason method to biopsy-gun needle biopsies. The identification of prostatic adenocarcinoma in extraprostatic tissues sampled by needle biopsy of the prostate should also be recorded in surgical pathology reports because this provides important information on the pathologic stage. Seminal vesicle tissue and periprostatic adipose tissue may be sampled by some needle biopsies, and the finding of prostatic adenocarcinoma in these tissues is indicative of extraprostatic spread of the carcinoma. Although it has been claimed that the finding of tumor infiltrating around ganglion cells is also diagnostic of 256

2 HUMPHREY AND WALTHER 257 Adenocarcinoma of the Prostate II extracapsular extension because ganglion cells are only found in periprostatic soft tissue, 20 others have identified ganglion cells within the prostatic capsule. 21,22 Therefore, the finding of carcinoma around ganglion cells may not necessarily always indicate extracapsular disease. Although minimal extracapsular spread in the form of capsular penetration may not relate to prognosis, 23 it is not possible, using a needle biopsy result, to determine the extent of capsular penetration. The finding of extraprostatic spread therefore should be reported. Seminal vesicle invasion relates strongly to prognosis. 24 It should be noted that prostatic adenocarcinoma in skeletal muscle and perineural adenocarcinoma do not necessarily imply extraprostatic spread because nerves and skeletal muscle have been identified within the prostate gland. Although perineural invasion is in general not considered to be an important prognosticator, 25 one study did report an association with a worse prognosis, 26 and a second recent study has indicated an association with pathologic stage. 27 We would therefore recommend recording perineural invasion, when identified in needle biopsies, in the microscopic description. It is currently not possible to measure intraglandular carcinoma volume based on needle biopsies, although the extent of carcinoma in the needle biopsy specimen should be recorded in the microscopic description. 4 It has been hypothesized that the extent of carcinoma in a needle core biopsy may relate to the prognosis, 28 and it has been reported that the extent of carcinoma in six ultrasound-guided random systematic biopsy-gun biopsies provides valuable information on cancer volume, 29 but no formal study relating the extent of carcinoma in needle biopsies to any prognostic end point has been reported. The presence of isolated high-grade prostatic intraepithelial neoplasia (PIN) in needle biopsies should also be reported because it is associated with a high incidence of adenocarcinoma on repeat biopsy, 30 and then, in a sense, it represents a prognosticator. Finally, rare variants of prostatic carcinoma may be identified on needle biopsy and should be reported because they carry a worse prognosis. These rare histologic types with a worse prognosis include mucinous carcinoma, 31 ' 32 small-cell undifferentiated carcinoma, 33 prostatic duct adenocarcinoma, signet ring adenocarcinoma, 3637 and sarcomatoid carcinoma. 38,39 STAGE A CARCINOMA AND PROGNOSTIC FEATURES IN CHIPS FROM TRANSURETHRAL RESECTION OF THE PROSTATE (TURP) Before consideration of the prognostic features in TURP chips, it is important to define and discuss clinical stage A carcinoma (which is most often diagnosed in TURP chips) and to provide a brief overview of clinical staging systems for prostate carcinoma to contrast stage A versus stages B-D carcinoma. To compare treatment results of various modalities and to provide an orderly stratification of disease outcome, clinicians have developed clinical staging systems that provide a "freezeframe" assessment of the extent of disease at the time of diagnosis. As a result of the use of such systems, treatment options for the individual patient can be defined based on previously reported outcomes on a stage-by-stage basis. It is obvious that definitions of each stage are highly arbitrary; although there is usually an attempt at coordinating the boundaries of each stage based on biologically relevant factors, the modes of therapy and diagnostic modalities available also have a substantial im- Stage A1 A2 Bl B2 C Dl D2 TABLE 1. WHITMORE-JEWETT CLINICAL STAGING SYSTEM FOR PROSTATE CANCER Extent of Invasion Incidental focal microscopic tumor detected in clinically benign prostate specimen Incidental diffuse microscopic tumor detected in clinically benign prostate specimen Clinically palpable tumor confined to one lobe of the prostate Clinically palpable tumor involving more than one lobe of the prostate Locally invasive beyond prostate but without metastases Metastases to regional pelvic lymph nodes Distant metastases pact on the extent of stratification. As a result, staging systems are redolent with substratifications based on additional parameters considered to connote additional prognostic significance. Because the combination of clinical and pathologic information may have a significant impact on the therapeutic algorithm chosen for the management of prostate cancer, it is imperative that the surgical pathologist has a good working understanding of the commonly used clinical staging systems employed by the urooncologist. The dominant staging system in the American urooncologic community for the last 25 years (and it remains the most likely used system in "casual" professional communication) is that of Whitmore 40 as modified by Jewett 41 (Table 1). Undoubtedly, the main reason for its continued popularity is its simplicity. Here, stage A disease by definition is incidental carcinoma diagnosed in TURP chips or simple prostatectomy specimens, and stage B disease is clinically palpable within the prostate gland. Patients with stage B disease (and stage A) might be seriously considered for radical surgery. However, for those patients with disease palpably extending beyond the prostate gland (stage C), only radiation is usually considered. Finally, evidence of metastasis that would likely render the patient's disease incurable is denoted by the stage D category; hormonal therapy would be considered in this circumstance. Treatment of stage A disease is a major controversy, and this will be discussed. Substratifications are globally defined in Table 1. In an effort to provide greater precision in defining the local primary disease in conjunction with nodal and distant sites of disease, the American Joint Commission (AJC) devised a tumornode-metastasis (TNM) staging system for prostate cancer; 42 unfortunately, it was little used by urologists. In 1987, a compromise system between the AJC and the International Union Against Cancer (UICC) was developed (Table 2). 43 Another system was developed by the Organ Site Coordinating Center (OSCC), 44 which will not be reproduced except to discuss clinically undetected (stage A) disease (see subsequent discussion). The attempt of the latter classification was to combine the benefits of the TNM with the highly recognized and used Whitmore-Jewett system. It is evident that extent of disease at the time of diagnosis can be highly dependent on the degree of aggressiveness in screening for disease and the general nature of the availability of health care to a population of interest. Nevertheless, using the Whitmore-Jewett clinical staging system, Table 3 depicts the stage-specific distribution of disease from selected prominent series over several decades. The most recent series by Murphy Vol. 100-No. 3

3 258 ANATOMIC PATHOLOGY Review Article T T2 T3 T4 N M TABLE 2. AJC/UICC CLINICAL CLASSIFICATION FOR PROSTATE CANCER Primary tumor TX Primary tumor cannot be assessed TO No evidence of primary tumor Tl Tumor is incidental histologic finding Tla ^3 microscopic foci of carcinoma Tib >3 microscopic foci of carcinoma Tumor present clinically or grossly, limited to the gland T2a Tumor =S 1.5 cm in greatest dimension, with normal tissue on at least three sides T2b Tumor > 1.5 cm in greatest dimension or in more than one lobe Tumor invades into the prostatic apex or into or beyond the prostatic capsule, bladder neck, or seminal vesicle, but is not fixed Tumor is fixed or involves adjacent structures other than those listed in T3 Regional lymph nodes (the lymph nodes of the true pelvis, which essentially are the pelvic lymph nodes below the bifurcation of the common iliac arteries; laterality does not affect the "N" classification) NX Regional lymph nodes cannot be assessed NO No regional lymph node metastases Nl Metastases in one lymph node <2 cm in greatest dimension N2 Metastases in one lyph node, being >2 cm but =s5 cm in greatest dimension, or in multiple lymph nodes, none being > 5 cm in greatest dimension N3 Metastases in one lymph node >5 cm in greatest dimension Distant metastases MX Presence of distant metastasis cannot be assessed MO No distant metastasis M1 Distant metastasis and co-workers, 45 a comprehensive study by the American College of Surgeons, represents an incorporation of various staging techniques, such as technetium radionuclide bone scans, in addition to the determination of serum acid phosphatase levels. Although more than one fourth of all patients whose tumors are diagnosed as prostate cancer have disseminated disease at diagnosis, fully 50% still have clinically localized disease (and, hence, are potentially curable). These studies do not reflect two major techniques that recently have been developed for the detection of localized prostate cancer, ie, serologic detection of prostate-specific antigen (PSA) and endorectal ultrasonography. These recent advances are obviously extremely important because the advent of PSA testing has stimulated large-scale screening efforts for prostate cancer detection; endorectal ultrasonography can be used to detect small lesions in Reference Flocks el al. m VACURG 186 Murphy el a/. 45 TABLE 3. CLINICAL STAGE DISTRIBUTION OF PROSTATE CANCER Values arc percentages. Year A <3 <14 26 Clinical Stage B >3 >14 29 C D TABLE 4. AGE-SPECIFIC INCIDENCE OF SURGICALLY DISCOVERED CLINICALLY UNSUSPECTED PROSTATE CANCER* Age (years) * Modified from Sheldon el a/. 187 Range of Incidence (average /o) 0-4.0(1.9) (6.3) (10.4) (18.5) (28.7) (37.1) (60.0) the range of 5 mm, which can undergo biopsy under ultrasound guidance even though disease is not palpable by digital examination. The net result of these changes is that the incidence of low-stage disease will increase in the clinical stage distribution. Staging classifications presently extant do not accommodate patients whose disease is diagnosed in this manner. Clearly, it would seem reasonable to consider them a variant of stage A, and efforts are presently ongoing to incorporate these recent changes in practice. Until recently, the patient with an impalpable focus (or foci) of prostatic cancer had been identified only when a malignant neoplasm was identified in the surgical specimen after either transurethral or open prostatectomy. Although anecdotal case reports of focal carcinoma identified incidentally at the time of prostatectomy for benign disease began to surface early in the twentieth century, Bugbee 46 was among the first to report a major American series of such patients. Despite limited followup, all such patients in that series appeared to do well without evident progression; therefore, it is not surprising that this "curiosity" was given little clinical emphasis for many years. A number of series have reported that incidentally found malignant neoplasms occur in approximately 10% of cases performed for benign prostatism, 47,48 but this statistic is clearly dependent on the thoroughness of the specimen review. The recognition of cancer in specimens from suprapubic prostatectomy for benign disease (a technique that preceded the development of transurethral prostatectomy) has historically been infrequent. Prostate cancer was diagnosed in only 6.5% of patients in one review of 847 cases. 47 Turner and Belt 49 reported that incidental malignancy was rarely found (3.4%) in their large study (1,694 patients) of outcomes in patients who had undergone simple perineal prostatectomy for prostatism. It also is important to note that the development of prostate cancer for all stages is highly age dependent. As a result, the apparent incidence is dependent on the age distribution of the patient cohort. This is especially relevant for stage T1 disease; as Table 4 demonstrates, the incidence of incidental prostate cancer in the seventh decade of life approaches 20%. It is this age range in which the most controversy regarding the aggressiveness of intervention will continue to be seen. An indicator of the difficulty in defining the biologic risk of this subset of patients (stage Tl tumors) may be that the definition of stage using a formalized system has been so controversial itself. Foremost in this discussion is the recognition that the Whitmore-Jewett system does have deficiencies, both biologically and logistically. It has been the general assumption that TNrvl systems in most organ systems can provide a more pre- A.J.C.P. September 1993

4 HUMPHREY AND WALTHER 259 Adenocarcinoma of the Prostate II TABLE 5. COMPARISON OF RECOGNIZED STAGING SYSTEMS FOR CLINICALLY UNSUSPECTED PROSTATE CANCER AJC/UICC system TO No evidence of primary tumor Tl Incidental histologic finding la *s3 microscopic foci lb >3 microscopic foci OSCC classification TA Digitally unrecognizable, but present histologically* TA1 Estimated ^5% of total surgical specimen and low or medium grade TA2 >5% of total specimen and/or high grade TAX Stratification not possible * Tumor volume assessed al low power evaluating the entire specimen to determine proportion of specimen involved by tumor. cise description of the clinical (and, hence, biologic) status for both the comparison of treatment outcomes and the determination of prognosis. As alluded to earlier, there are two TNMtype systems that have been defined in recent years, ie, the AJC/UICC system and the OSCC system. Currently, neither of these staging systems includes the incidentally found ultrasound-defined impalpable small volume lesion. Table 5 provides a comparison of the definitions of "stage A" disease using these two systems. Note that the major difference in stage A disease between the AJC/UICC and the OSCC classification schemes are twofold: in the former, an absolute number of foci (three) serves as a threshold differentiating Tla versus Tib, whereas, in the latter, a quasivolumetric estimation of the extent of disease based on the total pathologic specimen is made. Second, only in the latter classification does the grade of the tumor have an impact on the stratification. Jewett subclassified stage A disease into the subcategories of A1 and A2 based on whether the disease was focal or diffuse. 41 Inherent in the whole discussion of substratifying stage A disease into two subsets is an attempt to identify a population of patients who have aggressive disease which, if left unchecked, would progress to clinically advanced disease. Therefore, in simplistic terms, the real crux of the issue is where to draw the line dividing the two groups so that the second group could be safely managed expectantly. A substantial number of definitions differentiating stage Al versus stage A2 have been used, and these have been recently reviewed. 50 Although most adhere principally to volumetric considerations determined by an arbitrary sampling statistic (eg. less than three foci, less than five foci, or less than 5% of the specimen), some have simply used the percentage (specifically, 5%) of the involved chips 51 in such definitions. Others have counted chips with cancer; some have used the definition of more than three chips as the definition of stage A2 disease. Recently, the Mayo Clinic group reported an update of their stage A clinical outcomes after radical prostatectomy using the definition of stage Al as being 1 cm 3 or less of tumor or low-grade tumor (Mayo grade 2 or less) versus stage A2 being a larger volume or high-grade tumor (Mayo grade 3 or 4). 52 Substantial differences in the relative distribution of patients between stage A1 and stage A2 have been reported with these different definitions. For instance, it has been shown that the definition of three chips as a demarcation between stage A1 and stage A2 will result in approximately two thirds of patients being categorized as stage A2. 53,54 That this difficulty with arbitrary definitions has occurred is not surprising in itself; a continuum of the relative risk of progression would appear to exist based on the extent of disease. Such a continuum is evidenced when the percentage of chips with carcinoma is used as a prognosticator. 50 Consequently, staging definitions are only valid to the extent that the therapeutic goal is defined, namely, the threshold of the risk of progression one is willing to accept to avoid aggressive intervention. This biologic risk is at the heart of definitions used by some who specifically have excluded high-grade carcinomas from the stage A1 category regardless of volume; this will be discussed further subsequently. The biologic risk of stage A prostate cancer has been extraordinarily difficult to define; consequently, its management has been a controversy for more than four decades. During the 1950s and 1960s, it was often referred to as "occult" or "latent" carcinoma; some even referred to it as "carcinoma in situ." 55 Consequently, many advocated a conservative posture of expectant management for such patients during this era. Nesbit and Baum 56 noted only two deaths in 42 patients followed with occult carcinoma. Likewise, Greene and Simon 57 in the 1950s reviewed the Mayo Clinic experience up to that date and observed that such patients had only a slightly less likelihood of survival than the actuarial projection. By contrast, there were advocates of aggressive therapy who also provided arguments justifying intervention, 58 " 60 but evidence supporting such contentions was sketchy at that time. Over the intervening years, the characterization of the biologic risk began to incorporate a more quantitative assessment of the extent of disease in the initial surgical specimen. In 1960, "size" (not defined in the article) was noted to be an important predictor of tumor progression. 47 Of those with "small" lesions, only 9 of 23 (39%) ultimately had progressive disease. By contrast, those with "large" lesions were at greaterrisk;20 of 29 (69%) of these patients had an "unfavorable outcome." Correa and co-workers 61 distinguished focal disease from diffuse cancer; those authors considered only the focal disease as "latent" because these patients had a survival indistinguishable from an actuarial comparison. By contrast, they noted in an aside that 60% of those patients with "diffuse" disease subsequently were demonstrated to have residual or progressive disease. The histologic grade of the incidental malignancy initially was not seriously factored into the biologic risk assessment. However, investigators began to reassess the natural history of occult malignant neoplasms and realized that the grade of the incidentally found tumor could have substantial importance. In a review of 55 suprapubic prostatectomy cases in which unsuspected cancer was discovered, grading of the disease (using the three-tiered grading system) resulted in a substantial difference in ultimate survival. 47 The patients with well-differentiated disease (28 of 55 patients, or 51%) were stratified and compared with the rest of the series. Whereas patients with well-differentiated disease had a 47% 10-year survival rate, those with "less well-differentiated" (their term) disease did far less well (a 14% 10-year survival rate). Heaney and associates 62 reported a retrospective study that helped to link the concepts of extent of disease with grade of disease by putting it in the context of a biologic risk of progression. In this study, they evaluated a cohort of 100 patients with "clinically undiagnosed" prostate cancer before surgery for benign disease. All patients had undergone surgery more than 12 years before the retrospective analysis. Small lesions were predominantly low grade (82%), and focal disease was also predominantly low grade (75%). By contrast, grade III disease was Vol. 100 No. 3

5 260 ANATOMIC PATHOLOGY Review predominantly large and diffuse; grade II disease also tended that way. When they compared the survival of these patients to that of an actuarial estimation, patients with grade I disease overlapped the actuarial curve. By contrast, those with grades II and III disease combined fared far worse. The overall population had 5- and 10-year survival rates of 67% and 41%, respectively not significantly different from that of the age-matched population. However, the 10-year survival rate of patients with grade I disease was 57%; those with higher-grade disease had a 10-year survival rate of only 25%. Unfortunately, multivariate analyses were not commonly performed at that time, and assessment of the relative risk of progression by analyzing grade versus the various parameters of extent was not made. Furthermore, the definitions of "focal" and "diffuse" and "small" and "large" are potentially difficult to reproduce consistently in clinical practice. Nevertheless, this comprehensive study linked much of the previously heterogeneous retrospective single-institutional data that had confounded the discussions of risk of progression of stage A disease up to that day. It has been hoped that the development of more precise reproducible assessments of the extent of disease by analysis of TURP tissue could more precisely define the biologic risk. Formal morphometric analyses (or semiquantitative assessments of "tumor area") have been considered potentially a more objective tool to assess such risk. Using this approach to define "tumor area," Cantrell and colleagues 63 reviewed the Johns Hopkins institutional experience to determine those patients who had subsequently had progressive disease of those who had been originally declared to have stage A1 tumors and who had not undergone radical prostatectomy. They decided that 5% tumor area (intraglandular extent) as the upper limit of stage A1 disease represented a reasonable threshold level to differentiate the two subgroups by biologic risk; all high-grade disease (Gleason sum, 8-10) was also excluded from the stage A1 designation. Using that definition, they noted that only 2% of patients with stage A1 tumors had disease progression within 4 years. By contrast, patients with a tumor area of 6-25% demonstrated a 26% incidence of progression. One of the troubling aspects of the Johns Hopkins morphometric definition of stage A1 is the variance from the conclusions of earlier studies by others that would have appeared to validate the policy of including only low-grade tumors in the stage A1 category (if this category was to be the one containing only "indolent" disease); earlier studies incorporating a fairly large population of patients noted that a substantial change of biologic risk appeared to exist at the threshold drawn between low- and intermediate-grade cancer. Using the modern-day Gleason grading system, this transition would be between Gleason 4 and 5 sums. Epstein and Walsh 64 had argued that intermediate Gleason grade low-volume disease, when considered as stage A1, accurately classified 60% of patients as having indolent disease. One could question whether such a classification is precise enough. It should be emphasized (and, in fairness, they also point out) that if Gleason sum 4 or less were exclusively used with low-volume (5%) disease, only 14 of 82 patients could be said to have stage A1 disease in their original study; none of those patients have had disease progression. It is noteworthy that, in the Duke experience of patients with stage A tumors who had been treated with radical prostatectomy, only patients with Gleason sum 3 or less remained tumor-free, and the one patient with Gleason sum 4 who had a relapse did so only at 12 years. 65 If one is looking for a working definition designed with a therapeutic goal to detect patients who do not need aggressive therapy, low volume (less than 5% tumor area) and a Gleason sum not greater than 4 would appear to be a more precise definition of stage A1. Nevertheless, an updated review from the Johns Hopkins experience has reported that, of 50 patients defined as "low-risk" by their definition of stage Al still alive greater than 8 years from diagnosis, 16% ultimately had disease progression. 66 Six of these eight who had progressive disease had had a Gleason score of 4 or less on the original assessment. Stage A1 disease, even when defined using highly rigorous criteria, is not entirelyrisk-freefor progression if patients live 8 years or longer. Recently, the updated Hopkins experience has been confirmed because patients defined as having stage A1 tumors (with a Gleason score of 4 or less) were found to have a 10% incidence of progression on extended follow-up. 67 Statistical evidence supporting the validity of a more rigorous definition of stage Al, particularly in relation to grade, has been more recently published by Lowe and Listrom. 68 In a comprehensive statistical analysis of 232 patients with stage A prostate cancer, they demonstrated that only 7% of patients with a stage A tumor of Gleason sum of only 2-3 had relapses, whereas 27% of patients with a Gleason sum 4 tumor subsequently showed evidence of recurrence. Moreover, Kaplan- Meier estimates for time to progression showed only a limited likelihood of progression for Gleason sum of 2-3; by contrast, tumors with a Gleason sum of 4 showed a slow but progressive likelihood of progression. Is it sufficient to rely solely on an assessment of the resected tissue to determine biologic risk? Some have advocated a "restaging TURP" to determine "residual disease." 69 An analysis of the outcome of such a strategy in reassigning of stage ("upstaging" stage A1 to stage A2) on the basis of a second endoscopic procedure has been conflicting. However, Babaian and associates 70 have recently reported their experience in carefully mapping the prostates of patients who had undergone radical cystoprostatectomy for bladder carcinoma. Of the 20 patients who had adenocarcinoma of the prostate diagnosed as an incidental finding and had disease in the so-called transurethral resection zone, 8 had only stage A1 disease after evaluation of the whole gland. (The definition of stage A2 disease was more than three foci or Gleason grade sum of 8 or greater in the whole gland.) However, of the 12 patients who had stage A2 disease, none had more than three foci within the tissue likely to be resected; this means that they would have been considered stage A1 tumors if diagnosed in the normal fashion by TURP only. As a result, it appears that two clinical postures are now being used clinically. One is expectant management (surveillance but not dismissal) for all patients initially staged as having stage Al disease; as discussed earlier, there is no doubt that those with stage Al tumors do have a defined incidence of progression and need careful monitoring. Although there is some uncertainty regarding the most appropriate observation algorithm to use to monitor such patients, digital examination, endorectal ultrasonography, and PSA can be used. For instance, Zhang and colleagues 71 used endorectal ultrasonography in this highly restricted population to monitor progression (in conjunction with serologic PSA measurements). The alternative approach is more clinically aggressive; an assessment of the relative risk of progression is made, and those at a defined higher risk are treated immediately and aggressively. Age usually is the variable that engenders this more aggressive posture. Moreover, because of concerns that misstaging can occur A.J.C.P. tember 1993

6 HUMPHREY AND WALTHER 261 Adenocarcinoma of the Prostate II using only TURP chip specimens to evaluate the biologic risk (in the Mayo Clinic experience, 52 pathologic upstaging was frequent), "young" patients are at greater risk for a potentially unavoidable tumor progression within their actuarially defined probability of survival. As a result of staging error rates and the extended potential period of risk in younger patients (< 60 years), Zincke and co-workers 52 recommend, in particular, immediate surgery for all such healthy patients. In a way, this is an implicit confirmation of the risk factor assessment constructed by Lowe and Listrom, 68 who constructed proportional-hazards tables based on grade, tumor extent, and age at the first detection of cancer. Once again, stage A1 definitions need to be well defined as part of such treatment algorithms; the surgical pathologist can help by providing the "raw data" to the surgeon (tumor extent and grade) to be then used in one of the approaches described. It is clear, then, that the most important tissue prognosticators in TURP chips are histologic grade and tumor extent. As noted previously, this prognostication is not absolute, and for both stage Al and stage A2 carcinomas, histologic grade and tumor extent in resectates are unreliable in predicting the residual tumor volume. 72 " 75 Although there is a correlation between histologic grade and percent tumor in TURP chips and the final pathologic stage, this predictability for the individual patient is poor. 76 In this study, the percentage of tumor was superior compared with the histologic grade and tumor volume in predicting the final pathologic stage; 76 in two additional studies, 77,78 the percentage of tumor was superior to the tumor volume in TURP chips in predicting tumor progression. In addition, the percentage of tumor has been found to be superior to histologic grade as a predictor of clinical progression of stage A carcinoma. 63 The percentage of tumor involvement in TURP chips may be easily determined, as described. 63 Basically, this determination, also known as the pathologist's percentage estimate, is made by circling areas of carcinoma and then deciding in a subjective fashion, by naked-eye examination of the circled areas, the percentage of the tissue involved. A second method that has been found to be an important prognosticator for all clinical stages is the determination of percent-positive chips. 50,79,80 We found this method of determining percent-positive chips to be less subjective than histologic grading; 50 a second independent study also reported achieving a high degree of reproducibility. 80 Finally, the percent chip involvement was found to be of similar strength in predicting survival as a sophisticated computer-assisted morphometric measurement. 81 In the surgical pathology report on TURP chips, one should probably provide the percentage of tumor involvement, the number of positive chips, and the total number of chips. Recent studies have suggested that, in addition to the histologic grade and tumor extent, DNA ploidy, 82,83 nuclear roundness factor, 78,84,85 and PSA immunoreactivity 78 may be important prognosticators in stage A carcinoma. Although controversial (see section regarding experimental prognosticators), the importance of DNA ploidy as a prognosticator not dependent on histologic grade or tumor extent has, in general, not been established. 86 " 88 A recent study 78 did not find nuclear DNA content in stage A2 carcinomas, as measured by image cytophotometric study of Feulgen-stained histologic sections and flow cytometric study of propidium iodine-labeled suspensions of nuclei obtained from paraffin-embedded blocks, to be a significant prognosticator. Most of the literature suggests, then, that at this time, DNA ploidy analysis should not be performed on carcinoma in TURP chips as a routine practice. The morphology of prostatic carcinoma nuclei, as assessed by computerized digitization, has been shown to be of prognostic significance when the nuclear roundness factor and ellipticity factor have been calculated (see section regarding experimental prognosticators). The time necessary to perform such digitization and cost of a nuclear morphometry system may limit the widespread use of these nuclear morphologic prognosticators. Finally, although PSA immunostaining of stage A2 carcinomas was a significant prognosticator, there was such an overlap of staining patterns so as to preclude the use of this immunostain as a practical prognosticator in TURP chips with carcinoma. Isolated high-grade PIN (PIN grade 2 or 3 of 3) should be diagnosed in surgical pathology reports on TURP chips because there is an association of isolated PIN 3 in TURP chips and carcinoma within the prostate gland. 89 This association is, however, weaker than the association of isolated PIN 3 in needle biopsy specimens and carcinoma within the prostate gland. Also, the finding of isolated PIN 3 in TURP chips is not related to the extent of carcinoma within the prostate gland. 89 As described for needle biopsies, rare histologic variants of prostatic carcinoma should be diagnosed in TURP chips because many of these carry a worse prognosis. In particular, one should specifically exclude prostatic duct carcinoma when carcinoma is identified in TURP chips because of the predilection of this aggressive tumor type to involve large prostatic ducts, 35 which will be readily sampled by TURP. PROGNOSTIC FEATURES IN OPEN OR SIMPLE PROSTATECTOMY (ENUCLEATION) SPECIMENS The important prognostic features for these incidental stage A carcinomas in simple prostatectomy tissue are the same as those in TURP chips. Indeed, most investigations 63,77,78 combine the study of TURP chips and simple prostatectomies to determine tissue prognosticators. PROGNOSTIC FEATURES IN RADICAL PROSTATECTOMY SPECIMENS Well-established tissue prognosticators in radical prostatectomy specimens include histologic grade, margin positivity, pathologic stage, and intraglandular tumor extent (as assessed by tumor volume or the percentage of gland involvement). Also, as discussed previously, certain rare histologic variants of prostatic carcinoma carry a worse prognosis and should be reported. In general, the well-established tissue prognosticators are interrelated such that good-prognosis tumors tend to be of low histologic grade, low pathologic stage, and low volume, with a low incidence of positive margins, whereas tumors with an increasingly worsening prognosis exhibit increasingly higher histologic grade, pathologic stage, tumor volume, and incidence of positive margins. An increasing histologic grade in radical prostatectomy specimens is related to an increasing tumor volume, 90 increasing clinical and pathologic stage, 91,92 an increased likelihood of tumor progression, 86,93,94 and a decreasing interval to treatment failure. 95 Most of these studies used the Gleason method, although other grading methods have also been used. The percentage of poorly differentiated (Gleason grade 4 and/or 5) carcinoma was a significant prognosticator. 90 It is difficult to assess the independence of histologic grade as a prognosticator because it is so closely related to tumor size. In our experience, only slight additional predictive ability was obtained with the Vol. 100-No. 3

7 262 ANATOMIC PATHOLOGY Review Article concurrent use of tumor extent and histologic grade in multivariate analysis. 86,94 Positive surgical margins are also important tissue prognosticators in radical prostatectomy specimens. Positive margins have been related to tumor size, 96 " 98 pathologic stage, 99 elevated postoperative serum PSA, 100 and survival. 95 It should be noted, however, that a positive surgical margin does not necessarily mean that residual carcinoma is present. 101 The prostatic apex is the most common site for margin involvement by carcinoma, accounting for almost one half of all margin-positive cases in one series. 102 At this site, incision into the prostate may result in positive margins, even for small-volume tumors. 96 With surgical incision into the prostatic apex, one may have a positive margin without capsular penetration by the carcinoma. For the posterior (rectal) and posterolateral peripheral margins, margin positivity is often associated with capsular penetration. It is not clear whether the site of margin positivity influences the prognosis. Also not established is whether the extent of carcinoma in the margin is prognostically significant. Finally, the establishment of margin positivity is dependent on sampling and the observer. Different pathologists may have different views of what constitutes a negative margin, a margin with tumor closely approaching or extending to the margin, and a positive margin. For posterior, posterolateral, and anterior margins, we prefer to identify ink directly on tumor cells to designate a margin as positive. If the distal margin is taken as a thin tissue shave that is microscopically devoid of normal prostatic glands, then identification of carcinoma anywhere in this tissue should be considered a positive margin. Similarly, if the proximal (basilar) margin is taken as a thin shave margin, then carcinoma glands infiltrating the large smooth muscle bundles anywhere in this tissue should be interpreted as a positive margin. The margin status of these different anatomic sites should be recorded in the surgical pathology report. In particular, the status of the posterolateral margins should be specified when a nerve-sparing prostatectomy is performed because this is the anatomic site adjacent to the preserved neurovascular bundles. The determination of final pathologic stage is a critical aspect in the microscopic evaluation of radical prostatectomy specimens. This information is obtained by assessing for penetration of the carcinoma through the prostatic capsule, seminal vesicle involvement by the carcinoma, and regional lymph node involvement by the carcinoma. Extension of carcinoma beyond the capsule (capsular penetration, perforation, or transgression) is a significant tissue prognosticator ,95 Invasion into the capsule is not. 25 Capsular penetration as a prognosticator appears to be dependent on tumor volume. 102 The extent of capsular penetration, tumor volume, and positive lymph nodes and seminal vesicles are all closely interrelated. 102 Although the term "capsular penetration" is used to denote extension of the carcinoma outside the prostate, the prostate does not have a true capsule but, rather, has an outer fibromuscular band; 103 this band is absent at the apex of the gland 102 and is ill-defined anteriorly and near the base (proximal region) of the gland, 99 thereby making the assessment of capsular penetration at these sites difficult. One way to identify anterior capsular penetration is to scan the section for nearby normal glands, assume that the normal glands would have extended in a rounded, smooth outline, and then decide if the carcinomatous glands have extended beyond this outline. 99 In practice, identification of capsular penetration at this site may be difficult and subjective. In the posterior and posterolateral regions of the gland, capsular penetration may be identified by irregu- FIG. 1. Perineural adenocarcinoma extending outside the capsule of the prostate into periprostatic adipose tissue (arrows). Hematoxylin and eosin (x32). larity and nodularity of the peripheral aspect of the gland, which is caused by periprostatic soft tissue invasion by the carcinoma, with an associated desmoplastic response. In these areas, malignant glands often travel along prostatic nerves as a mechanism for penetrating the capsule, 104 and it is common to identify perineural adenocarcinoma in posterolateral periprostatic, soft tissue (Fig. 1). Finally, identification of carcinoma within adipose tissue indicates capsular penetration. Although capsular penetration is important to diagnose in the surgical pathology report, at this time, it is probably not necessary to report the extent of penetration because, overall, the extent of capsular penetration seems to be dependent on tumor volume. 102 Seminal vesicle invasion by adenocarcinoma of the prostate is an indication of a poor prognosis 25 ' 91 ' 105 " 108 and is strongly related to the tumor volume 109 and extent of capsular penetration. 23 The prognostic strength of seminal vesicle invasion has recently been questioned, however, because in multivariate analysis, seminal vesicle invasion was not an independent predictor of lymph node metastasis after histologic grade and tumor volume were present in the model. 110 Lastly, pelvic lymph node involvement by the carcinoma is a highly significant prognosticator. 1 """ 7 It is controversial as to whether the number of involved nodes is a prognosticator. One view is that metastatic disease of any volume imparts a poor prognosis and that, without a sufficiently long follow-up, it is A.J.C.P. September 1993

8 HUMPHREY AND WALTHER 263 Adenocarcinoma of the Prostate II difficult to ascribe prognostic significance definitively to the number of involved nodes. On the other hand, a recent study 1 '' presented a dramatic disease-free 10-year survival difference for patients with metastasis in one lymph node (65%) compared with that in patients with bilateral disease (0%). It has been proposed that the histologic appearance of metastatic prostatic adenocarcinoma in the lymph nodes may be prognostically significant because patients with poorly differentiated metastases did worse than those with moderately differentiated metastases." 8 " 9 The influence of lymph node sampling, including serial sectioning of blocks, on the detection of metastatic prostatic adenocarcinoma in pelvic lymph nodes and on prognostication has not been studied. Tumor extent within the prostate gland is one of the most important tissue prognosticators in radical prostatectomy specimens.' 10 Intraglandular tumor extent is strongly related to histologic grade, capsular penetration, seminal vesicle invasion, lymph node metastasis, tumor progression, 86 and estimated survival probability. 94 In our experience, intraglandular tumor extent, as measured by the percentage of carcinoma, was somewhat better than histologic grade in predicting tumor progression and patient survival 86,94 and was substantially better than DNA ploidy in predicting clinical progression. 86 Also, the percentage carcinoma determination was more objective than the determination of histologic grade, with better interobserver agreement. 94 Intraglandular carcinoma extent may be measured as the carcinoma volume (in cubic centimeters) or as a percentage of the prostate gland involved by the carcinoma. A direct comparison of the percentage of gland involvement versus the tumor volume found that the percentage of gland involved with tumor was a somewhat better predictor of pathologic stage than was the tumor volume alone. 92 Moreover, calculation of the tumor volume requires digitization and computer-assisted morphometric analysis of the tumor area; it is doubtful that such a labor-intensive, time-intensive, and expensive approach will be widely adapted by surgical pathology laboratories around the country. As an alternative, the percentage carcinoma may be determined by one of two methods. First, the pathologist's percentage estimate may be obtained by circling all identifiable foci of carcinoma with a marking pen and then estimating the percentage of total tissue involved by tumor (in the categories of 0-5%, 6-25%, 26-50%, and %). 63 A second method uses a grid from a plastic ruler to quantify more precisely the percentage of involvement. 94 In our experience, these two methods of determining the percentage tumor are nearly equivalent in prognostic ability, require only a marking pen 63 or a ruler, 94 and do not require either expensive technology or training. The visual estimate may be easier to obtain but separates the percentage of carcinoma involvement into the aforementioned four rather broad groups; the grid morphometric technique is more precise. Regardless of the method used, intraglandular tumor extent should be quantified and reported for all radical prostatectomy specimens. In addition to a standard reporting of histologic grade, margin positivity, pathologic staging information, and intraglandular tumor extent, consideration should be given to reporting the presence and extent of PIN and any atypical adenomatous hyperplasia, 4 the location of the tumor, and sampling of the prostatic tissue for DNA ploidy. The extent of PIN in the presence of carcinoma may be a weak prognosticator because recent data suggest an inverse relationship between PIN 3 extent and pathologic stage. 120 Tumor location may be reported as central and/or peripheral, right sided and/or left sided, or if quadrants are reported, asrightapex, left apex,rightbase, and/ or left base involvement. Most central prostatic carcinomas (thought to be of transition zone origin) are low volume and low grade, 110 but it is not established that location is a prognosticator independent of volume and grade. In one series, pure central carcinomas were rare, and there was no difference in survival rates between peripheral versus peripheral combined with central tumors. 25 DNA ploidy in carcinoma from radical prostatectomy specimens is a significant prognosticator but is substantially weaker than grade and intraglandular extent. In our experience, it is not an independent prognosticator. 86 We therefore concur with a recent recommendation that DNA ploidy information be obtained when feasible, but that the value of the obtained information would be limited. 4 Lymphatic and vascular invasion in radical prostatectomy specimens is a moderately strong predictor of disease progression, but grade and pathologic stage are far stronger predictors. 121 The prognostic significance of lymphatic and vascular invasion was not an independent prognosticator but, rather, was dependent on carcinoma histologic grade. 121 EXPERIMENTAL PROGNOSTICATORS IN PROSTATIC TISSUES Potential future tissue prognosticators for adenocarcinoma of the prostate include DNA ploidy, nuclear features, growth fraction, enzyme markers, oligosaccharides, new prostatic antigens defined by monoclonal antibodies, steroid hormone receptor status, differentiation markers, neovascularization, growth factor receptors, karyotypic abnormalities, and alterations in oncogenes and tumor-suppressor genes. The independent value of many of the potential prognosticators has not been determined in multivariate analysis, in which the well-established prognosticators of histologic grade, intraglandular tumor extent, and pathologic stage are allowed to compete directly with the experimental prognosticator. The prognostic value of DNA content or ploidy in prostatic adenocarcinoma is controversial but probably provides only limited prognostic information after the determination of tumor size and grade. Most, but not all, multivariate studies have not demonstrated an independent predictive capacity of DNA ploidy. 82 ' 86 " Some of the difficulties with ploidy include methodologic sources of error, 124 intratumor heterogeneity of ploidy, 125 the fact that a diploid carcinoma may metastasize, and a lack of absolute specificity of aneuploidy for the carcinoma. 126 ' 127 The recent finding of both diploid and aneuploid cell populations in a substantial number of cases of prostatic carcinoma represents a potentially profound confounding factor in the use of DNA ploidy as a predictor. 125 Because of this potential for sampling error and that diploid carcinomas may be clinically aggressive, the predictive value of DNA ploidy for the individual patient is uncertain. 128 Additional nuclear features of prostatic adenocarcinoma cells, including argyrophilic nucleolar organizer regions (Ag- NORs), nucleolar surface area, and nuclear size and shape variations, have been reported to be of prognostic value. The Ag- NOR number and area generally increase from prostatic hyperplasia to PIN to carcinoma, 129 " 132 but interobserver variation may represent a practical difficulty in manual counting. 133 Significant overlap in the various proliferative states may be encountered even with more objective counting using an image analysis system. 134 In most studies, AgNORs were not related Vol. No. 3

9 264 ANATOMIC PATHOLOGY Article to histologic grade, but they were tied to grade in two reports and to clinical stage in one of these investigations. In addition, AgNORs have been reported to be predictive of metastatic disease. 135 Further studies will be necessary to define the relationship of AgNORs to clinical end points such as progression and survival. Nucleolar prominence, as determined by an ultrastructural method, was an objective and significant prognosticator, 136 but prospective performance of electron microscopy on each case of prostatic carcinoma is not practical. Morphometric analysis of nuclear shape (nuclear roundness factor) 78,84,85 and nuclear perimeter 137 appears to be significant in prognostication but may be impractical in routine practice. It has been characterized in a recent review 138 as being of questionable predictive value. Morphometric measurement of nuclear size variation has also been shown to be of prognostic utility, but it also requires computerized digitization of individual nuclei. Overall, although morphometric analysis of nuclear features of prostatic carcinoma are fairly objective prognosticators, such analyses are arduous and seem to provide relatively little additional prognostic information after Gleason grade determination. 140 In addition, it should be noted that simple light microscopic and nonmorphometric nuclear grading, using a three-tiered stratification of slight, moderate, and marked variation in nuclear size and shape, was of prognostic utility. 141 The growth fraction of prostatic adenocarcinoma has been reported to be significant in the assessment of patient prognosis. This tumor proliferation rate or index may be assessed by a number of methods, including mitotic counts, flow cytometry (S-phase fraction [SPF]), nucleotide radiolabeling or immunodetection, and immunohistochemical analysis. Mitoses are uncommon in prostatic adenocarcinoma. In one large series of 267 radical perineal prostatectomies, only 27 cases had identifiable mitoses, 142 but when present, mitoses were associated with significantly more cancer deaths. The mitotic count was also found to be a significant predictor of progression in a multiparameter analysis. 137 Determination of the SPF byflowcytometry of formalin-fixed, paraffin-embedded prostatic carcinomas has been difficult because of high backgrounds and broad DNA histogram peaks, but a recent investigation used a background correction model and found this corrected SPF predicted survival better. 144 The prognostic significance of SPF is controversial; one view 128 holds that SPF is only a minor prognostic factor, although a recent study 145 presents data showing SPF and S + G2/M to be highly significant predictors of patient survival. The nucleotides thymidine or bromodeoxyuridine have been used to estimate the growth fraction, and correlations with histologic grade and ploidy have been reported, but relationships to clinical end points were not studied. Ki-67 immunostaining has also been used as a measure of the growth fraction 147 " 151 and, in general, has demonstrated a low proliferative activity of prostatic adenocarcinoma, with a mean from three studies of 3.8% of malignant nuclei stained compared with 0.9% of benign nuclei. Ki-67 staining has been correlated with histologic grade and the response to therapy' but has not predicted the time to progression in individual patients undergoing hormonal therapy. 151 Immunostaining for proliferating cell nuclear antigen has been found to be of little, if any, prognostic value. 145 Additional potential tissue prognosticators include enzyme markers such as 5-a-reductase, 152 plasminogen activator, 153 prostatic acid phosphatase, 154 oligosaccharides, 155 new prostatic antigens defined by monoclonal antibodies, 156 haptoglo- bin-related protein epitopes, 157 estramustine-binding protein, 158 neuroendocrine differentiation, 159 " 16 ' nerve growth factor receptor, 162 and steroid hormone receptor proteins, particularly nuclear androgen receptors. 163 " 165 These androgen receptors may be detected by immunohistochemical analysis, but a difficulty with this approach is the heterogeneity of the androgen receptor immunoreactivity. 164 ' 166 Finally, genetic markers such as alterations in chromosomes, oncogenes, and tumor-suppressor genes may be useful prognosticators. The study of these markers in prostatic carcinoma has just recently been initiated, and our knowledge of genetic aberrations in adenocarcinoma of the prostate is limited relative to that of other epithelial tumors. Studies on prostate cancer karyotypes have been hampered by frequent overgrowth in culture of the cancer cells by the normal diploid cells. 167 Thus far, clonal karyotypic changes have been associated with an unfavorable outcome in patients with prostatic cancer. 168 Cytogenetic alterations involving specific chromosomes (particularly 2, 7, 8, 10, and 16) have been identified, 167 but these changes as yet have not been linked to prognosis. The loss of heterozygosity has been frequently found in prostatic carcinoma, and one study suggested that loss of 17p may be a marker for advanced carcinomas of the prostate, 169 and thereby a prognosticator. Oncogene abnormalities have not yet been correlated with prognosis. For example, some patients with adenocarcinoma of the prostate had elevated c-myc transcripts, 170 but the prognostic significance of thisfindingis unknown. The most commonly mutated oncogene in human cancer, ras, is rarely altered in human prostatic adenocarcinoma in the United States Alterations in immunoreactivity of the potential oncoproteins neu and the epidermal growth factor receptor have been described; 173 " 176 in one study, 176 although immunoreactive epidermal growth factor receptor was a significant prognosticator, it did not have independent prognostic value. Emerging data suggest that tumor-suppressor genes may be located on chromosomes 8, 10, 11, and 16, 177 "' 79 and mutations in the tumor-suppressor genes p " 182 and RB have been detected; recent evidence suggests that p53 protein accumulation, which is usually indicative of p53 mutation, is predictive of poor survival for a small percentage (8%) of patients with adenocarcinoma of the prostate.' 81 Thus, many new prognostic tissue markers for patients with adenocarcinoma of the prostate are being developed. The challenge for investigations on these potential future prognosticators will be, first, to establish independent prognostic significance in direct multivariate analysis comparisons with the established tissue prognosticators of pathologic stage, histologic grade, and intraglandular tumor extent and, second, to develop inexpensive, nonlabor-intensive, fast, and simple methods for assessing these potential tissue prognosticators. Note added in proof: A recently published TNM staging protocol does categorize as stage Tic clinically unapparent prostate cancer (Tl) that was neither palpable nor visible by imaging but that was identified by needle biopsy because of an elevated serum PSA and categorizes as stage T2 those carcinomas confined to the prostate that are palpable or visible by radiologic means (Schroder FH, Hermanek P, Fair WR, et al. The TNM classification of prostate cancer. Prostate Suppl 1992;4: ). Acknowledgments. The authors thank Susan Embry and Steve Con- Ion for assistance with the photomicrographs and Charlotte Noblin for typing the manuscript. In addition, the authors thank Dr. Robin Vollmer for his critical review of the manuscript. A.J.C.P. 1993

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