Gleason grading system The Gleason grading system resulted from the Veterans Administration Cooperative Urological Research

[463,464] Group study of more than 4000 patients between 1960 and 1975. It is based on the degree of architectural differentiation (Table 9-24; Fig. 9-32). Tumor heterogeneity is accounted for by assigning a primary pattern for the dominant grade and a secondary pattern for the non-dominant grade; the histologic score is derived by adding these two patterns together. Early studies described the addition of the clinical stage (14 scale) to create the Gleason sum, but this did not achieve widespread use and was abandoned decades ago. Nuclear grade was also originally considered for inclusion by Gleason, but added little or no incremental predictive accuracy for patient outcome beyond the architectural patterns, and was discarded to avoid complexity (Bostwick, personal communication).

Table 9-24 -- Gleason grading system for prostatic adenocarcinoma: histologic patterns

Patter Peripheral n borders 1

Stromal invasion

Appearance of glands Simple, round, monotonously replicated

Size of Architectur Cytoplasm glands e of glands Medium Closely , regular packed rounded masses Similar to benign epithelium

Circumscribe Minimal d pushing, expansible

Less Mild with, Simple, round, Medium Loosely circumscribed definite some variability in , less packed ; early separatio shape regular rounded infiltration n of masses glands by stroma Infiltration Marked Angular, with Medium Variable variation in shape to large packed irregular masses Angular, with Small variation in shape Variable packed irregular masses

Similar to benign epithelium

3A

More basophilic than patterns 1 and 2 More basophilic than patterns 1 and 2 More basophilic than patterns 1 and 2

3B

Infiltration

Marked

3C

Smooth, rounded

Marked

Papillary and cribriform

Irregular Round to elongate masses

Patter Peripheral n borders 4A Ragged infiltration

Stromal invasion Marked

Appearance of glands Microacinar papillary, and cribriform Microacinar, papillary and cribriform

Size of Architectur Cytoplasm glands e of glands Irregular Fused, with Dark chains and cords Irregular Fused, with Clear chains and (hypernephroid cords ) Variable

4B

Ragged infiltration

Marked

5A

Smooth, rounded

Marked

Comedocarcinom Irregular Round to a elongate masses Difficulty to identify gland lumina Irregular Fused sheets

5B

Ragged infiltration

Marked

Variable

Fig. 9-32 Gleason grading of prostatic adenocarcinoma.

The success of the Gleason grading system is due to four factors:

Histologic patterns are identified by the degree of acinar differentiation without relying on morphogenetic or histogenetic models. A simplified and standardized drawing is available. The Veterans Administration study provided abundant prospective information that allowed objective computer-generated development of this self-defining grading system. Unlike any other grading system in the body, the Gleason system provided for tumor heterogeneity by identifying primary and secondary patterns.

The Gleason score is a scalar measurement that combines discrete primary and secondary groups into a [465,466] total of nine discrete groups (scores 210). Bibbo et al. noted that optimal grading creates a continuum that incorporates the findings of a variety of diagnostic clues, including acinar formation, luminal area, acinar fusion, type of acinar fusion, acinar packing, acinar size, acinar uniformity, thickness of acinar epithelial layer, nuclear size, nuclear variability, nuclear shape, chromatin pattern, and nucleolar [466] size. Using these architectural and nuclear features, Bibbo et al. developed and tested a bayesian belief network for grading prostatic adenocarcinoma and attained agreement with Gleason grading in 241 of 256 microscopic fields. Common misinterpretations in Gleason grading are presented in Table 9-25.

Table 9-25 -- Four common misinterpretations in prostate cancer grading

Misinterpretation

Comment

1. If a biopsied focus of Unlikely! Most cancers (over 80% in Gleason's original cancer is small, it is Gleason series) are primary grade 3. When the size is too small to call cancer, suspicious is the prudent default. Size of the grade 1 or 2, or well differentiated focus of cancer has no bearing on Gleason grade at prostatectomy 2. If a biopsied focus is suspicious for cancer, it is best called Gleason grade 1 or 2, or well differentiated The prudent diagnosis in the absence of sufficient features for cancer is atypical small acinar proliferation (ASAP). Optimism seems naturally to lead one to consider low Gleason grade; but if there is cancer, it is usually moderately differentiated, since most peripheral zone cancers are moderately differentiated

3. Confusing the large gland Cancer acini occasionally are rounded, and medium to variant of Gleason grade 3 large, like benign acini. Look for microvacuolated cancer with benign acini cytoplasm, nuclear enlargement, and macronucleoli to diagnose cancer 4. All cribriform acinar formations are Gleason grade 3
Recent trends in grading Since the introduction of PSA testing, the incidence of low-grade prostate cancer has [467] declined. Interpretive and chronological biases caused expansion of the moderately differentiated category at the expense of well-differentiated cancer and significant deviation in cancer-specific survival [468,469] curves. One report found that Gleason score re-readings in 20002002 were higher than the original [470] readings from 19901992 (mean score increased from 5.95 to 6.8). Consequently, the Gleason scorestandardized contemporary mortality rate (1.50 deaths per 100 person-years) appeared to be 28% lower than standardized historical rates (2.08 deaths per 100 person-years), even though the overall outcome

Some cribriform acinar formations are grade 4. These sieve-like spaces lose their round, rigid, punched-out contours, and elongate; the acini collapse into solid areas

was unchanged. This decline in the reported incidence of low-grade prostate cancer appeared to be the result of Gleason score reclassification over the past decade, reflecting a statistical artifact known as the [470] [471] Will Rogers phenomenon. Ghani et al. noted that all Gleason 24 reports were upgraded to Gleason 57 cancer. Reproducibility of Gleason grading Inter- and intraobserver variability has been studied with the Gleason grading system and others. The subjective nature of grading precludes absolute precision, no matter how carefully the system is defined, but significant correlation with virtually every outcome measure attests to the predictive strength and utility of grading in the hands of most investigators. Intraobserver agreement was exact in up to 78% of cases and +1 score unit in up to 87%. Melia [479] and eight British uropathology colleagues found a rate of intraobserver agreement of 77%. Gleason [464] himself noted exact reproducibility of score in 50% of needle biopsies and 1 score in 85%. Interobserver agreement was exact in up to 81% of cases and +1 score unit in up to [472,473,475,477,478,480492] 86%. Some investigators have expressed concerns with Gleason grading because of the significant incidence of interobserver variability. One study reported a high level of disagreement among three pathologists evaluating 41 cases of well- to moderately differentiated [483] adenocarcinoma. Another report compared the level of interobserver agreement in a consecutive series of 100 prostatic adenocarcinomas and found complete agreement of Gleason score in only 66% of [482] cases. To perform the analysis, the authors compressed the Gleason scores into three grade groups: [493] 25, 67 and 810. Coard and Freeman demonstrated a 60% overall concordance in consensus Gleason scores, which increased to 80% when considered as < 7 versus 7 or more. The greatest discordance seemed to be in distinguishing Gleason score 6 from 7, and was more frequent among biopsy specimens with low cancer volume, particularly among those with less than 30% involvement. Allsbrook led a group of 10 urologic pathologists who studied 46 needle biopsies and found a k coefficient ranging from 0.56 to 0.70 (substantial agreement) for Gleason score. The eight nonconsensus cases included low-grade cancer, cancer with small cribriform proliferation, and cancer whose histology was on the border between Gleason patterns. When Allsbrook shared the 38 consensus cases with a group of 41 general pathologists, the k coefficient was 0.44 (moderate agreement), with consistent [488] undergrading of Gleason scores 56 (47%), 7 (47%) and, to a lesser extent, 810 (25%). Interobserver reproducibility of percentage grades 4 and 5 was at least as good as that of Gleason [494,495] score. Grading was most difficult when cancer was present in multiple biopsies or contained cribriform or fused patterns. Reproducibility of the modified Gleason score (primary grade + highest grade) (see below) was as high as that of Gleason score, but there was clustering in odd scores and severe disagreement was more [496] commonly observed than with classic Gleason score. The authors concluded that tertiary Gleason pattern needed to be better defined. Concordance of biopsy and prostatectomy grade There is a significant discordance between biopsy and matched prostatectomy grades. Needle core [497 biopsy underestimates tumor grade in 3345% of cases and overestimates in 432% (Table 9-26) 499] Grading errors are common in biopsies with small amounts of tumor and low-grade [500] tumor, probably due to tissue sampling error, tumor heterogeneity, and undergrading of needle [498] biopsies; however, this has been refuted. Men with high-risk cancer (higher PSA concentration or more positive cores) were more likely to have cancer upgraded at prostatectomy, and obtaining more [501505] biopsy cores reduced the likelihood of upgrading. Biopsy grading error did not correlate with [506] amount of adenocarcinoma on the biopsy or with clinical staging error. In one study the accuracy of
[487] [464,472478]

biopsy was highest for the primary Gleason pattern, but the secondary pattern on biopsy appeared to be sufficiently accurate in predicting prostatectomy grade to provide useful predictive information, particularly [507] when combined with primary pattern to create the Gleason score (Figs 9-32-9-34). Based on these results, Gleason grading is recommended for all needle biopsies, even those with small amounts of [462] tumor, similar to the original recommendation of Gleason.

Table 9-26 -- Concordance of needle biopsy and radical prostatectomy Gleason scores: selected reports

Authors

No. of patients

Setting

No. pathologists involved in grading

% Exact Gleason correlation

%1 %>1 Gleason Gleason unit unit

Bostwick[1269] 316 Spires et al.[1270] Kojima et al.[1271]

Academic 1

35

39

26

67

Academic Multiple

58

36

135

Academic 1

48

43

Thickman et al.[1272] 124 Cookson et al.[1273]

Community Multiple

28

24

38

226

Academic Multiple

31

43

26 Not available

Steinberg et al.[485] 499 531 with Gleason score 6

Community Multiple

34

32

Sved et al.[1274] Hiseh et al.[1275]

Academic Multiple

51

52

Community Multiple Academic Multiple

31 43

King et al.[498] 371

Authors

No. of patients

Setting

No. pathologists involved in grading

% Exact Gleason correlation

%1 %>1 Gleason Gleason unit unit

Tomioka et al.[497] Means

223

Community Multiple

37

70

30

Fig. 9-33 Gleason grading. (A) 2 + 2 = 4. (B, C) 3 + 3 = 6. (D) 4 + 4 = 8. (E) 5 + 5 = 10. (F) 5 + 5 = 10
(comedocarcinoma pattern).

Fig. 9-34 Gleason pattern 3 adenocarcinoma, large acinar type, consisting of an irregular aggregate of rigid angulated
acini with variability of size, shape, and spacing.

Kramer et al. compared the Gleason score in 14-gauge needle biopsies with matched lymph node metastases and found exact correlation in 17 of 42 cases (40%), 1 in 32 of 42 cases (76%), and 2 in 40 of 42 cases (95%). The lack of a more anaplastic pattern in the metastatic deposits implied that factors other than loss of differentiation were responsible for the cells ability to metastasize. Among patients with Gleason score 8 carcinoma, 45% had a lower Gleason score in the radical [509] prostatectomy specimen and a correspondingly more favorable long-term outcome. Predictors of downgrading were lower clinical stage (T1c) and Gleason score 8 in the biopsy specimen. In another report, clinical stage, serum PSA, and biopsy Gleason score had a predictive accuracy of 0.80 for [510,511] Gleason sum upgrading between biopsy and prostatectomy. The distribution of cancer grades was not associated with prostate volume. The concordance rate between needle biopsy and radical prostatectomy of the Gleason scores of the greatest tumor percentage in the core, Gleason score of core with maximal tumor length, and the highest Gleason score was 64%, [513] 62%, and 57%, respectively. Ross and colleagues showed that DNA ploidy analysis of biopsies predicted grade shifting, that it was a more sensitive and specific indicator of final grade at radical prostatectomy than the original needle [514] biopsy grade, and that ploidy status independently predicted postoperative cancer recurrence. Proposed modifications to Gleason grading Numerous modifications have been proposed for Gleason grading to improve its discriminatory capabilities, including the addition of tertiary grading, nuclear grading and morphometric grading, grade compression, measuring the amount of high-grade adenocarcinoma, and subdividing Gleason score 7 (3 [515,516] + 4 vs 4 + 3) (Table 9-27).
[512]

[508]

Table 9-27 -- Proposed modifications of Gleason grading

Grading of tertiary pattern Nuclear grading and morphometric grading Grade compression Amount of high-grade adenocarcinoma (Gleason patterns 4 and 5) Subdivision of Gleason 7 (3 + 4 vs. 4 + 3)
Tertiary grade Prostate cancer is heterogeneous for grade. In up to 5% of biopsies three (and very rarely four) separate Gleason grades are encountered. Gleason noted that more than 50% of adenocarcinomas in his series [463,464] [517] contained two or more patterns. Similarly, Aihara et al. found a mean of 2.7 different Gleason grades per case (range, 15) in a series of 101 totally embedded prostatectomies, and more than 50% of adenocarcinomas contained at least three different grades. The number of grades increased with greater cancer volume, and the most common finding was high-grade adenocarcinoma within a larger, well- or moderately differentiated adenocarcinoma (53% of cases). Tertiary Gleason pattern 5 was the strongest [518] predictor of an unfavorable outcome in surgically treated patients with Gleason grade 7 carcinoma. Most urologists want the highest Gleason grade reported by the pathologist, even if this is the tertiary grade (as it almost always is) and accounts for only a small percentage of the cancer volume present in [519] the specimen. Our group deals with the issue of tertiary grade by providing the classic Gleason score as noted above and simply adding a statement such as: In addition, there is a small (5%) component of Gleason grade 5 present. The International Society of Urologic Pathology (ISUP) recently proposed modification of the Gleason score to include the sum of most common grade and worst grade present to account for cases with three [520] separate Gleason scores. For example, if a radical prostatectomy has 60% Gleason grade 3 cancer, 35% grade 4, and 5% grade 5, the ISUP grade would be 3 (most common) + 5 (worst grade) = score 8; the classic Gleason score would be 3 (most common) + 4 (second most common) = score 7. We believe that this modified system requires the following before acceptance: prospective validation; renaming this new approach (e.g., modified Gleason score) to avoid confusion with the classic Gleason scoring system that has remained essentially intact and unaltered for more than 40 years and has been used successfully in more than 3000 published papers; and multidisciplinary discussion and consensus creation. Patients with a tertiary pattern had a 5-year risk of PSA progression of 37% versus 13% in cases in which [521] no tertiary Gleason pattern was present. There was no prognostic difference between patients with a higher-grade tertiary pattern and those with a lower-grade tertiary pattern. This suggests that tumor multifocality, rather than the presence of a higher-grade tertiary Gleason pattern, has prognostic value.

Nuclear grading and morphometric grading Nuclear and nucleolar enlargement are important diagnostic clues for the diagnosis of malignancy. Morphometric methods allow objective evaluation of nuclear size, roundness, shape, chromatin texture, and other features. Numerous investigators have used morphometry to improve the predictive value of [70,460,522525] Gleason grading, but these methods are not used routinely. Nuclear roundness has been the subject of considerable interest for more than 20 years, but is not [460,522,523] routinely employed. Mean nuclear roundness accurately predicted prognosis in patients with untreated stage T1b prostatic adenocarcinoma and other clinical stage adenocarcinomas. However, many of these reports were limited by small sample size (fewer than 30 patients), use of the same patient cohort in multiple publications, failure to describe the morphologic variations and nuclear roundness extremes, and bias in patient selection. Further, significant problems of reproducibility have been encountered, and the results obtained by different digitizing instruments are not comparable. Nuclear roundness identified patients with tumor recurrence following radiation therapy for well-differentiated [526] adenocarcinoma. The good correlation of morphologic nuclear grade in biopsies and prostatectomies is probably due to the large number of cases that fall into the nuclear grade 2 (of 3) category. Tannenbaum et al. compared nucleolar surface area in 40 biopsies and matched prostatectomies with adenocarcinoma, reporting no significant difference in 70% of cases. Nucleolar grading of prostatic adenocarcinoma has also been proposed, but has not been adopted (grade 1: large and prominent [529] nucleoli in virtually every cell; grade 2: intermediate; grade 3: tiny nucleoli that are difficult to find). Grade compression Many authors have simplified the Gleason grading system by compressing (lumping) the scores into [530] groups, usually creating three groups: 234, 567, and 8910. Unfortunately, compression diminishes the statistical strength of grading. Further, the choice of grouping is often problematic; the most important cut point is between Gleason scores 6 and 7, owing to the emergence of poorly differentiated adenocarcinoma (pattern 4) in score 7, yet many studies combine these scores. Gleason argued against grade compression, except for studies with a small number of patients in which grouping [464] is unavoidable; in such cases a cut point between scores 6 and 7 is preferred. The probability of lymph node metastases is significantly greater in patients with score 7 adenocarcinoma than in those with score 6. Amount of high-grade adenocarcinoma The volume of high-grade adenocarcinoma appears to be an important prognostic factor: as tumor [531] volume increases, the frequency and volume of high-grade tumor increases. McNeal et al. suggested that the Gleason grade stratifies adenocarcinomas into three subgroups with different levels of 3 aggressiveness. Gleason pattern 1 and 2 adenocarcinomas are almost always small usually < 1 cm and are indolent, localized, and frequently limited to the transition zone. Grade 3 adenocarcinomas are variable in size and very common. Grade 4 and 5 adenocarcinomas are usually larger and more aggressive than lower-grade tumors, and are likely to extend beyond the prostate or to metastasize. In a study of 209 radical prostatectomies from patients with clinical stage T1 and T2 adenocarcinomas, [532] Gaffney et al. studied the extent of solid undifferentiated carcinoma in 24 cases and found a strong [533] correlation with tumor progression. Bostwick et al. found that Gleason score and the percentage of patterns 4 and 5 adenocarcinoma showed a positive correlation with tumor volume. Vis and [534] colleagues from the European Randomized Study of Screening for Prostate Cancer found that the amount of high-grade cancer (Gleason patterns 4 and 5) was the strongest predictor of biochemical [535537] failure after radical prostatectomy, similar to the results of others. The cumulative data suggest that [538] the volume of high-grade adenocarcinoma is of prognostic significance, refuting Gleason's contention [464] that prostatic carcinoma behaves according to the average of histologic grades.
[527,528]

Gleason 7 subdivision (3 + 4 vs. 4 + 3) Gleason score 7 cancer is common and heterogeneous, and should be considered a specific prognostic [539] category. Most authors claim that it is important to separate predominant pattern 3 from predominant pattern 4. Among patients with Gleason score 7, primary grade 4 indicates a likelihood of higher tumor [540] stage and a higher probability of PSA recurrence after surgery than does primary pattern [518,541,542] 3. However, it does not independently predict a worse outcome after controlling for other known [518,543,544] prognostic parameters associated with disease progression, and appears to be of less value in [545,546] [547] patients treated by brachytherapy. Conversely, Rasiah and colleagues found that patients with primary Gleason grade 4 cancer were more likely to have seminal vesicle involvement and extraprostatic extension and, along with patients with tertiary Gleason grade 5, a significantly shorter time to cancer recurrence. Of the patients with Gleason pattern 3 + 4 tumors on biopsy, 24% were upgraded to primary pattern 4 or [548] more on final pathologic analysis. Of the patients with Gleason pattern 4 + 3 tumors on biopsy, 47% were downgraded to primary pattern 3 or less on final pathologic analysis. Dedifferentiation Histologic dedifferentiation of prostatic adenocarcinoma has been reported by numerous investigators, but these studies included only cases with more than one resection, probably selecting for adenocarcinomas that are more aggressive and hence more likely to require repeat operation. [549] Brawn reported dedifferentiation in 65% of repeat transurethral resections. Cumming et [550] al. described 74 patients with repeated transurethral resections with a mean interval of 2.4 years: Gleason score remained constant in 12, increased in 49, and decreased in seven, and dedifferentiation occurred in untreated adenocarcinomas and in those subjected to expectant management. Whittemore et [551] al. suggested that dedifferentiation to high-grade adenocarcinoma is unusual in low-grade (Gleason 3 patterns 13), small-volume (1 cm ) adenocarcinomas, occurring in only 2.4% of patients in 7 years. Their hypothesis explained the large discrepancy in the incidence of clinical cancer among populations with similar prevalences of occult cancer, and indicates that volume of occult cancer is an important marker of aggressive adenocarcinoma. A recent report followed 67 men with median time to follow-up biopsy of 22 months (range, 760), and found that Gleason score was unchanged in 20 patients (30%), upgraded in [552] 19 (28%), and downgraded in 27 (40%); 21 (31%) had no malignancy on follow-up biopsy. They concluded that there was no consistent histologic upgrading on follow-up biopsy at a median of 22 [553] months in untreated, low to intermediate-grade, clinically localized prostate cancer. Interestingly, in men over 80 years of age with PSA concentration > 30 ng/mL, at least 97% had cancer [554] and more than 90% had high-grade cancer. Therefore, there may be ascertainment bias if one does not correct for patient age. Recent epidemiological evidence has revealed that dedifferentiation is a major mechanism of progression in prostate cancer. Tumors may dedifferentiate during the screen-detectable phase; consequently, [555] screening with PSA and early treatment may prevent dedifferentiation. There was a trend toward histologic dedifferentiation when prostate carcinoma metastasizes to regional [556] lymph nodes. Gleason score in lymph node metastases was higher than in the primary tumor in 45% of cases, lower in 12%, and matched exactly in 43%. The 5-year progression-free survival was significantly lower in patients with histologic dedifferentiation (88% 3) and those without dedifferentiation (94% 2) (P= 0.04; however, dedifferentiation was not associated with progression when adjusted for lymph node cancer volume). Grading after therapy Grading after radiation therapy

Grading of specimens after radiation therapy yielded conflicting results, with some observers noting no difference from pre-therapy grade and others finding a substantial increase in grade. Bostwick et [557] al. found no apparent difference in grade before and after external beam therapy in 40 patients. [558] Conversely, Wheeler et al. found an increase in tumor grade following treatment that they attributed to [559] time-dependent tumor progression. Similarly, Siders and Lee evaluated matched tissue specimens from 58 men before therapy and more than 18 months after therapy, and found a significant increase in Gleason score. There was a 24% increase in poorly differentiated adenocarcinoma (scores 810) and a shift toward aneuploid DNA content in 31% of pretreatment diploid tumors, indicating increasing histologic and biologic tumor aggressiveness; no outcome data were provided to support this assertion. In grade 4 cancer, radiotherapy may cause the disappearance of glandular lumina, resulting in grade 5 morphology. Despite conflicting results, some investigators recommend grading of specimens after therapy, recognizing that the biologic significance of grade may be different than in untreated cancer. We believe that Gleason grading after radiation therapy is potentially misleading, particularly the risk of overestimation, and we do not report it unless requested to do so and always with the appropriate disclaimer (Grading of adenocarcinoma after radiation therapy is not validated and may create spurious and misleading higher Gleason grade, so these results may not be predictive of patient outcome and should be interpreted with caution). Grading systems have been proposed for therapy-induced adenocarcinoma regression, chiefly by [560,561] German investigators, but have not been widely adopted. These systems are considered useful following androgen deprivation therapy and radiation therapy because the histologic changes in cancer cells may be similar. Bcking suggested that reversible cell damage in prostate cancer is characterized by cytoplasmic vacuolization, nuclear shrinkage, and reduction in the number and size of nucleoli, whereas irreversible cell damage is characterized by rupture of the cytoplasm, nuclear pyknosis, and loss of [560] nucleoli. Grading after androgen deprivation therapy Following androgen deprivation therapy (e.g., leuprolide, flutamide) there may be an increase in Gleason grade accompanied by a marked reduction in nuclear and nucleolar size and prominent cytoplasmic [562] [563] clearing. Ellison et al. found a significant increase in Gleason grade, a decrease in nuclear grade, and a decrease in the extent of PIN in a control study of cases treated with androgen deprivation therapy; the uncoupling of the architectural and cytologic pattern was considered vexing owing to identification of small shrunken nuclei within malignant acini. Conversely, there was no significant alteration in Gleason [271] grade following monotherapy with the anti-androgen bicalutamide or the 5-reductade inhibitors [277,564,565] [566] finasteride and dutasteride. Despite a potential increase in grade with some agents, adenocarcinoma following androgen deprivation therapy is probably not more clinically aggressive than when untreated; however, no outcome data are available to confirm this assertion. Therefore, we and most investigators conclude that Gleason grading [562] after androgen deprivation therapy is potentially misleading and is not recommended. Clinical significance of grading Grade is one of the strongest predictors of biologic behavior in prostatic adenocarcinoma, including invasiveness and metastatic potential, but is not reliable when used alone to predict pathologic stage or outcome for individual patients. Grade is included among other prognostic factors in therapeutic decisionmaking, including patient age and health, clinical stage, and serum PSA level. Men with smaller prostates had more high-grade cancer and more advanced disease and were at greater risk of progression after [567] prostatectomy. Correlation of grade with recurrence and survival

Virtually every measure of recurrence and survival is strongly correlated with adenocarcinoma grade, [568573] including overall survival, tumor-free survival following treatment, metastasis-free survival, and [574,575] [576578] cause-specific survival. Humphrey et al. found that the Gleason score was the strongest predictor of time to recurrence after radical prostatectomy. Biopsy Gleason grade is an integral component of nomograms that predict the 10-year probability of recurrence after radical prostatectomy (in [579] combination with PSA, clinical stage, and number of involved cores). Schroeder et al. measured the impact on cancer-specific survival of 12 histopathologic characteristics used in grading prostatic adenocarcinoma. In their analysis of 346 patients treated by perineal prostatectomy, they found that four characteristics provided independent predictive value: acinar arrangement (architecture), nuclear size, nuclear shape, and the presence of mitotic figures. Correlation of grade and tumor volume The strong correlation between the Gleason grade and cancer volume has been shown in [581] [531] biopsies, transurethral resections, and radical prostatectomies. McNeal et al. showed that low3 grade adenocarcinoma (Gleason patterns 1 and 2) was rarely larger than 1 cm , whereas high-grade 3 adenocarcinoma (patterns 4 and 5) was almost always larger than 1 cm . The probability of tumor progression is best indicated by grade and volume; when cancer volume was held constant, grade had residual prognostic value, indicating that it provided additional independent information, although these two prognostic factors are closely linked. Correlation of grade and PSA concentration Adenocarcinoma associated with elevated serum PSA is more likely to be of higher grade, larger volume, and more advanced pathologic stage than adenocarcinoma associated with a normal serum PSA level. [582] Blackwell et al. found a significant positive correlation between serum PSA and primary Gleason grade, the percentage of Gleason patterns 4 and 5, nuclear grade, and DNA content in a large series of totally embedded prostatectomies. Adenocarcinoma with Gleason scores = 7 had a significantly higher median serum PSA and median cancer volume than cancers with lower (<7) Gleason scores. Also, patients with adenocarcinoma consisting of > 30% Gleason patterns 4 and 5 had a significantly higher median serum PSA and cancer volume than those with = 30% Gleason patterns 4 and 5. Further, the median serum PSA level was greater in tumors with Gleason pattern > 3 than in those with Gleason 3 pattern < 3 after controlling for tumor volume in 5 cm increments. Partin et al. found that serum PSA was of limited usefulness for staging localized prostatic adenocarcinoma because of the influence of tumor grade; by controlling for cancer volume but not gland volume (PSA/cancer volume), they found a negative correlation with the Gleason score, suggesting that [582] PSA concentration was determined by multiple confounding factors. However, Blackwell et al. found that combining PSA with gland volume and cancer volume (PSA/cancer density) increased the reliability and predictive value for pathologic stage and tumor grade. Although individual cells in poorly differentiated adenocarcinoma produce less PSA than cells in well- and moderately differentiated adenocarcinoma, they are usually present in such large numbers (greater cancer volume) and replace more of the prostate that serum PSA level is higher. Serial measurements of PSA suggest that prostatic adenocarcinoma has a constant log-linear growth rate, with mean PSA doubling times of 2.4 years for localized adenocarcinoma and 1.8 years for [584] metastatic adenocarcinoma. Higher Gleason grades are associated with faster doubling times. Correlation of grade and pathologic stage Grade is one of the strongest and most useful predictors of pathologic stage, according to numerous [585587] univariate and multivariate studies. This predictive ability applies to virtually every measure of pathologic stage, including extraprostatic extension, seminal vesicle invasion, lymph node metastases,
[583] [580]

and bone metastases. Some investigators claim that a Gleason score of 8 or higher on biopsy is strongly predictive of lymph node metastases and suggest dispensing with staging lymph node dissections in [588] [589] these cases, although this has been refuted. Despite the optimism for grading to predict clinical stage, the predictive value is not high enough to permit its application for individual patients, particularly in those with moderately differentiated adenocarcinoma. Correlation of grade and tumor location Grade may be related to the site of origin of adenocarcinoma within the prostate. Adenocarcinoma arising in the transition zone of the prostate appears to be lower grade and less aggressive clinically than the [442] more common adenocarcinoma arising in the peripheral zone. The majority of transition zone adenocarcinomas arise in foci adjacent to nodular hyperplasia, with one-third actually originating within [49,366] nodules. These adenocarcinomas are better differentiated than those in the peripheral zone, accounting for the majority of Gleason pattern 1 and 2 tumors.

Fig. 9-32 Gleason grading of prostatic adenocarcinoma.