Introduction
Prostate cancer (CaP) is the most common malignancy
in men and the second cause of cancer-related mortality after lung
cancer (1). The diagnosis of CaP
is mainly performed by digital rectal examination (DRE), serum
prostate-spesific antigen (PSA) measurement and transperineal or
transrectal ultrasound-guided biopsies. Prostate needle biopsy is
one of the most common procedures performed in the common
urological clinical practice; it is estimated that, in the U.S.
alone, at least 800,000 prostate biopsies are performed annually
(2).
Prostate biopsy has evolved over the years, starting
from the technique described by Astraldi in 1937 (3) until the sextant prostate biopsy,
described by Hodge et al in 1989 (4). Prostatic needle biopsy is currently
considered the gold standard for the diagnosis of CaP and may be
performed transrectally or transperineally, guided by ultrasound.
The detection rates of these two techniques are comparable
(5,6) and there is no final consensus
regarding the optimal number of samples, although the British
Prostate Testing for Cancer and Treatment Study has recommended 10
core biopsies (7), with antibiotic
therapy, commonly quinolone, under local anesthesia.
The International Society of Urological Pathology
(ISUP) Conference was held in March, 2005 in San Antonio, Texas
(8), during which a panel of
international expert uropathologists updated the Gleason grading,
in order to increase the reproducibility and reliability of the
evaluation of the biopsy specimens. A correct assignment of the
Gleason score (GS) may be crucial in terms of prognostic and
therapeutic management of CaP. Several studies have assessed the
effect of the ISUP Conference on the concordance of Gleason pattern
and the possible change of prognostic group.
Billis et al (9) evaluated 172 patients who underwent
prostate needle biopsy and subsequent radical prostatectomy and
described a significant effect of the ISUP Conference modifications
on the evaluation of the Gleason patterns and the resulting change
in prognostic group. Following re-evaluation of the specimens, an
increase by 1 or even 2 score points was observed in 16.8 and 0.6%
of the cases, respectively.
Furthermore, 26.7% of the ‘reassigned’ patients had
a higher preoperative PSA level, a larger tumor, more frequent
positive surgical margins and higher-stage pathological disease.
After the re-evaluation, a higher number of patients was assigned
to the prognostic group of GS 8–10, exhibiting, at follow-up, a
shorter time to biochemical disease recurrence (log-rank P=0.011)
(9).
In a more recent study that evaluated 590 biopsy
specimens according to the classic and modified GS, the number of
cores with 75–100% pattern 4 cancer was increased by 95% (10). Over the last few years, the bioptic
GS has become increasingly important, since several patients may be
offered therapeutic alternatives to radical prostatectomy, such as
active surveillance, and prostate biopsy results represent a
crucial point in the management of the disease.
Several studies have evaluated the correlation
between bioptic and pathological GS, documenting a correlation
ranging between 30 and 60%, particularly regarding low GS. The aim
of this study was, therefore, to evaluate the association between
bioptic and pathological GS in a series of patients undergoing
prostate needle biopsy and subsequent radical prostatectomy and the
possible prognostic factors of upgrading and upstaging.
Materials and methods
Patients
We prospectively collected and retrospectively
reviewed data from 300 consecutive patients who underwent radical
retropubic prostatectomy or laparoscopic robot-assisted
prostatectomy at our Institution between January, 2010 and May,
2012. Patients who underwent prostate needle biopsy, transrectal or
transperineal, at our Institution or at other centers, with a
minimum of 5 samples, were included in this study.
Data collection
We collected clinical data regarding age, serum PSA
level, free to total ratio, prostate volume calculated by
transrectal ultrasound and clinical stage. Cases with neoadjuvant
therapy were excluded from this analysis.
Surgical treatment
All the patients were subjected to radical
prostatectomy within 6 months following prostate biopsy. The
radical prostatectomy was performed by five operators. Retropubic
prostatectomies were performed according to the technique described
by Walsh and Donker (11) and
robot-assisted laparoscopic prostatectomies were performed as
previously described in the literature (12). Pelvic lymphadenectomy was performed
in accordance with the indications of the Guidelines of the
European Association of Urology (13).
Specimen grading
All the specimens were processed by two experienced
uropathologists according to the TNM of 2009. The biopsies not
performed at our center were not subjected to central review.
Upgrading and downgrading were defined as an increase or decrease,
respectively, from one prognostic grade group to another, similar
to up- or downstaging. The grading prognostic groups were
established according to the GS and grouped as follows: 5–6, 3+4,
4+3, 8 and 9–10.
Statistical analysis
Continuous variables were evaluated using mean and
standard deviation or median and interquartile range, according to
their distribution. The association between upgrading or upstaging
and age, preoperative PSA level, PSA density, free to total ratio,
number of positive samples and weight of the surgical specimen were
evaluated using the Student’s t-test or the Mann Whitney U test,
depending on their distribution. The association between upgrading
or upstaging and rectal findings, type and site of biopsy were
evaluated using the Chi-square test, Student’s t-test and
multivariate logistic regression, as appropriate. Statistical
analyses were performed using SPSS software, version 16.0 (SPSS
Inc., Chicago, IL, USA).
Results
Clinicopathological characteristics
The clinical and pathological characteristics of the
study population are summarized in Table I. The mean age of the patients was
62.97 years and 64.7% of patients were aged <65 years. The mean
PSA level was 7.83 ng/ml, with a free/total mean ratio of 12.66%.
Approximately 67% of the patients had a PSA level in the grey zone
between 4 and 10 ng/ml. The majority of the patients (79.7%)
presented with a negative DRE; 51.3% of the population underwent a
transperineal prostate biopsy. Approximately half of the patients
(48.0%) underwent prostate biopsy at our Institution.
 | Table IClinicopathological characteristics of
the patients. |
Table I
Clinicopathological characteristics of
the patients.
| Characteristics | Values |
|---|
| Age, years |
| Mean | 62.97 |
| Median | 63 |
| Range | 41–77 |
| PSA, ng/ml |
| Mean | 7.83 |
| Median | 6.1 |
| Range | 0.6–57.4 |
| Free/total ratio,
% |
| Mean | 12.66 |
| Median | 11 |
| Range | 2–48 |
| Volume,
cm3 |
| Mean | 42.69 |
| Median | 40 |
| Range | 13–120 |
| PSA density,
ng/ml/cm3 |
| Mean | 0.20 |
| Median | 0.15 |
| Range | 0.02–1.4 |
| Clinical stage, no.
(%) |
| cT1c | 239 (79.7) |
| T2a - b | 36 (12.0) |
| cT2c | 25 (8.3) |
| Biopsy, no. (%) |
| Transperineal | 154 (51.3) |
| Transrectal | 146 (48.7) |
| Biopsy site, no.
(%) |
| Our institution | 144 (48.0) |
| Other
institution | 156 (52.0) |
| Cores, no. |
| Mean | 13.57 |
| Median | 14 |
| Range | 5–28 |
| Positive cores,
no. |
| Mean | 4.15 |
| Median | 3 |
| Range | 1–15 |
| Bioptic Gleason
score, no. (%) |
| NA | 5 (1.7) |
| 4 | 2 (0.7) |
| 5 | 14 (4.7) |
| 3+3 | 192 (64.0) |
| 3+4 | 47 (15.6) |
| 4+3 | 17 (5.7) |
| 8 | 20 (6.6) |
| 9–10 | 3 (1.0) |
| Specimen weight,
g |
| Mean | 56.91 |
| Median | 52 |
| Range | 20–140 |
| Pathological Gleason
score, no. (%) |
| NA | 5 (1.7) |
| 5 | 3 (1.0) |
| 3+3 | 93 (31.0) |
| 3+4 | 133 (44.3) |
| 4+3 | 23 (7.6) |
| 8 | 26 (8.7) |
| 9–10 | 17 (5.7) |
| Surgical margins, no.
(%) |
| Negative | 227 (76.0) |
| Positive | 73 (24.0) |
Upgrading and downgrading
The prostate volume was <50 cm3 in
70.0% of the cases. The most frequently represented bioptic GS was
3+3 (64.0%) followed by 3+4=7 (15.6%), whereas the most frequent
pathologic GS was 3+4 (44.3%), followed by 3+3 (31.0%). The
surgical margins were negative in 227 patients. Table II shows the correspondence between
bioptic and pathological GS. With regard to the bioptic GS 4-5-6
group, approximately half of the specimens (46.7%) was subsequently
upgraded to GS 3+4, and 5.3% to 4+3.
| Table IIUpgrading and downgrading. |
Table II
Upgrading and downgrading.
| 4-5-6 | 3+4=7 | 4+3=7 | 8 | 9–10 | NA | Total |
|---|
|
|
|
|
|
|
|
|
|---|
| Bioptic GS | no. | % | no. | % | no. | % | no. | % | no. | % | no. | % | no. | % |
|---|
| RP GS |
| 0-NA | 3 | 1.4 | 1 | 2.1 | 0 | 0.0 | 0 | | 0 | | 1 | 20.0 | 5 | 1.7 |
| 5–6 | 92 | 44.2 | 2 | 4.3 | 0 | 0.0 | 0 | | 0 | | 2 | 40.0 | 96 | 32.0 |
| 3+4=7 | 97 | 46.7 | 27 | 57.4 | 4 | 23.5 | 3 | 15.0 | 0 | | 2 | 40.0 | 133 | 44.3 |
| 4+3=7 | 11 | 5.3 | 5 | 10.7 | 6 | 35.3 | 1 | 5.0 | 0 | | 0 | 0.0 | 23 | 7.6 |
| 8 | 3 | 1.4 | 9 | 19.1 | 5 | 29.4 | 8 | 40.0 | 1 | 33.3 | 0 | 0.0 | 26 | 8.7 |
| 9–10 | 2 | 1.0 | 3 | 6.4 | 2 | 11.8 | 8 | 40.0 | 2 | 66.7 | 0 | 0.0 | 17 | 5.7 |
| Total | 208 | 100.0 | 47 | 100.0 | 17 | 100.0 | 20 | 100.0 | 3 | 100.0 | 5 | 100.0 | 300 | 100.0 |
With regards to the bioptic GS 3+4 group, 57.4% was
confirmed in the surgical specimen. In the 4+3 group, 23.5% of the
cases were downgraded to 3+4 and 35.3% were confirmed. With regards
to the stage, ~39.7% of the patients received an upstaging on the
pathological specimen.
Correlation analysis
We evaluated the correlations between preoperative
serum PSA level, prostate volume, DRE and biopsy type and none of
the variables considered exhibited a correlation with any upgrading
(P>0.05). We also evaluated the correlations between the
aforementioned variables and upstaging and, at the multivariate
analysis, only a serum PSA level <4 ng/ml was found to be an
independent variable predictive of upstaging (P 0.017) (Table III).
| Table IIIUpstaging multivariable analysis. |
Table III
Upstaging multivariable analysis.
| Variables | SE | P-value | 95% CI |
|---|
| Age, years | 0.259 | 0.280 | 0.455–1.256 |
| ≤65 | | | |
| DRE | 0.302 | 0.655 | 0.633–2.071 |
| PSA, ng/ml |
| <4 | 0.372 | 0.017a | 1.171–5.027 |
| >4 | 0.333 | 0.877 | 0.495–1.824 |
| Volume <50
cc | 0.270 | 0.625 | 0.673–1.936 |
| Biopsy |
| TP | 0.378 | 0.997 | 0.477–2.100 |
| TR | 0.273 | 0.795 | 0.545–1.591 |
| Bio =
trans | - | - | - |
Discussion
The determination of the GS remains crucial in the
evaluation of patients affected by CaP and in the management of
this disease, which may range from an active surveillance protocol
to radical prostatectomy and multimodal therapies. Several previous
studies have analyzed the correlation between the biopsy evaluation
and the results obtained from surgical specimens.
The comparisons between the results of the
histological biopsy compared to the surgical specimen exhibited a
correlation equal to ~50% (14–17).
The results of the prostate biopsy and the surgical specimen may
differ for several reasons, such as incorrect evaluation by the
pathologist, sampling errors and the presence of borderline
grading. Several studies demonstated that a higher number of cores,
compared to the sextant biopsy, may lead to a lower percentage of
upgrading.
Capitanio et al (18) evaluated a series of 301 patients
with low-risk CaP according to the D’Amico criteria (19) (clinical stage T1c - T2a, PSA<10
ng/ml and biopsy GS 6) that underwent extended prostate biopsy
(median number of cores, 18) and subsequent radical prostatectomy.
The GS agreement between biopsies and surgical specimens was 47.5%
(143 patients), while upgrading was recorded in 38.5% cases (116
patients), 31.9% of which (96 patients) presented with a
significant upgrade to GS ≥7. In patients evaluated with 10–12 core
biopsies, the upgrading was 47.9%, compared to 31.6 and 23.5% with
13–18 or >18 cores, respectively, with a statistically
significant P-value, demonstrating that a larger sampling of the
gland may avoid subsequent upgrading and may help in planning an
appropriate treatment approach.
In our series, however, variables predictive of
upgrading were not detected and the type of biopsy or the number of
samples taken were not identified as predictors of upgrading. In
2012, Epstein et al (20)
evaluated the largest series in the literature, with 7,643
patients, analysing the correlation between bioptic and definitive
GS. Of the patients with GS 5–6, 36.3% underwent an upgrading and
~20% of the patients exhibited a tertiary Gleason pattern. In half
of the remaining cases, there was an equal proportion of up- and
downgrading. Half of the cases had matching GS 3+4=7 at biopsy and
RP, with an approximately equal number of cases down- and upgraded
at RP.
A bioptic GS 8 led to an almost equal distribution
between RP GS 4+3=7, 8 and 9–10. A total of 58% of the cases had
matching GS 9–10 at biopsy and RP. In addition, at the multivariate
analysis, the authors reported that increasing age (P<0.0001),
increasing serum prostate-specific antigen level (P<0.0001),
decreasing RP weight (P<0.0001) and increasing maximum
percentage cancer/core (P<0.0001) predicted the upgrading from a
bioptic GS 5–6 to a higher one at RP (20). In our series, the presence of
tertiary pattern was not assessed; therefore, we could not perform
an evaluation regarding the presence and possibility of up- or
downgrading.
In our study, with regards to GS 4-5-6, 44.2% of
cases matched, while there was an upgrading in 54.4% of the cases.
With pattern 3+4, there was a correlation between bioptic and
definitive GS in 57.4% of the cases, downgrading in 6.4% of the
cases and upgrading in 36.2%, a higher percentage when compared to
the data presented by our colleagues. With GS 4+3, concordance was
obtained in 35.3% of cases and a preponderance of upgrading (41.2%)
compared to the downgrading (23.5%), an even higher percentage if
compared to the data presented by Epstein et al (20). GS 8 was matched in 40% and GS 9–10
in 66.7% of the cases, almost overlapping with the data presented
by our colleagues.
Epstein et al (20) also conducted a wide literature
review, selecting only studies that evaluated series of patients
with numerosity >100, documenting the presence of GS upgrading
from 6 to 7 in 3,975 out of 11,472 cases (35%), with a mean
percentage of 36.0% and a median of 35.5%, with results ranging
from 14 to 51% (21–23). In our series, none of the analyzed
variables was identified as an independent predictor of up- or
downgrading, whereas a PSA level <4 ng/ml was found to be
predictive of upstaging. In the literature, as in our study, age
was not found to be a variable correlated with upgrading or
upstaging, whereas age was found to be predictive in the study of
Epstein et al (20), with a
difference between the 2 groups of only 1.6 years.
PSA values, in contrast to our data, are often found
to be predictive of upgrading, albeight with weak associations.
According to our data, a preoperative PSA <4 ng/ml was found to
be an independent predictor of upstaging; this highlights the
questions regarding cancer as an incidental finding, which, even
with low PSA levels, is found to be significant, as already
suggested by Thompson et al (24). Moreover, in the literature, an
increase in prostate volume was found to be less predictive of
upgrading, while in the study of Epstein et al a decrease
was documented in the upgrading ratio in prostate glands weighing
>75 g.
Approximately half of the studies available in the
literature documented an association between the percentage of
cores invaded by cancer and upgrading; however, in this study, we
did not consider this variable. The significance of the ability to
predict a possible upgrading or upstaging of prostate biopsy lies
with the risk of ‘falsely’ estimating a low GS, which may lead to
the selection of a treatment not adequately aggressive, potentially
putting the patient at risk of poor oncologic outcomes. For this
reason, Serkin et al (25)
retrospectively evaluated 2,884 patients who underwent radical
prostatectomy, documenting an upgrading in 36.8% of patients with a
bioptic GS 6. The authors of that study also demonstrated that the
status of the surgical margins, capsule, seminal vesicles and lymph
node involvement were more favorable in patients with a GS
correlation between bioptic and surgical specimens
(P<0.0001).
Moreover, patients with lower prostate volume had a
higher PSA density and an increased risk of upgrading. The
Kaplan-Meier curves suggested that patients with upgrading were at
an increased risk of biochemical disease recurrence compared to
patients with a correlation between the specimens (P<0.0001) and
a higher risk to undergo salvage hormone therapy (P<0.0001).
Our study had several limitations, as follows: the
design of the study was retrospective and over half of the biopsies
were not performed in our Institution; we did not perform a
centralized review of the specimens, with a variable number of
biopsies and with the inability to evaluate, in some cases, the
percentage of cores involved; we do not have an oncological
follow-up of the patients and, therefore, we cannot correlate the
biopsy results with the follow-up of the patients.
The upgrading and upstaging from prostate biopsy to
radical prostatectomy is an important topic of discussion and may
be of significant value at the clinical level, for treatment
planning, as well as for the prediction of cancer outocomes.
Therefore, new tools are required to predict upgrading and
upstaging of our patients, in order to ensure better counseling for
optimal treatment planning.
References
|
1
|
Hanno P, Malkowicz SB and Wein AJ:
Clinical Manual of Urology. 3rd edition. McGraw-Hill; New York, NY:
pp. 5192001
|
|
2
|
Maccagnano C, Scattoni V, Roscigno M, et
al: Anaesthesia in transrectal prostate biopsy: which is the most
effective technique? Urol Int. 87:1–13. 2011. View Article : Google Scholar : PubMed/NCBI
|
|
3
|
Astraldi A: Diagnosis of cancer of the
prostate: biopsy by rectal route. Urol Cutaneous Rev. 41:421–422.
1937.
|
|
4
|
Hodge KK, McNeal JE, Terris MK and Stamey
TA: Random systematic versus directed ultrasound guided transrectal
core biopsies of the prostate. J Urol. 142:71–74; discussion 74–75.
1989.PubMed/NCBI
|
|
5
|
Hara R, Jo Y, Fujii T, et al: Optimal
approach for prostate cancer detection as initial biopsy:
prospective randomized study comparing transperineal versus
transrectal systematic 12-core biopsy. Urology. 71:191–195. 2008.
View Article : Google Scholar
|
|
6
|
Takenaka A, Hara R, Ishimura T, et al: A
prospective randomized comparison of diagnostic efficiency between
transperineal and transrectal 12-core prostate biopsy. Prostate
Cancer Prostatic Dis. 11:134–138. 2008. View Article : Google Scholar : PubMed/NCBI
|
|
7
|
Donovan J, Hamdy F, Neal D, et al; ProtecT
Study Group. Prostate testing for cancer and treatment (ProtecT)
feasibility study. Health Technol Assess. 7:1–88. 2003. View Article : Google Scholar : PubMed/NCBI
|
|
8
|
Epstein JI, Allsbrook WC Jr, et al; ISUP
Grading Committee. The 2005 International Society of Urological
Pathology (ISUP) Consensus Conference on Gleason Grading of
Prostatic Carcinoma. Am J Surg Pathol. 29:1228–1242. 2005.
View Article : Google Scholar : PubMed/NCBI
|
|
9
|
Billis A, Guimaraes MS, Freitas LL, et al:
The impact of the 2005 International Society of Urological
Pathology consensus conference on standard Gleason grading of
prostatic carcinoma in needle biopsies. J Urol. 180:548–553. 2008.
View Article : Google Scholar : PubMed/NCBI
|
|
10
|
Delahunt B, Lamb DS, Srigley JR, et al:
Gleason scoring: a comparison of classical and modified
(International Society of Urological Pathology) criteria using
nadir PSA as a clinical end point. Pathology. 42:339–343. 2008.
View Article : Google Scholar : PubMed/NCBI
|
|
11
|
Walsh PC and Donker PJ: Impotence
following radical prostatectomy: insight into etiology and
prevention. J Urol. 128:492–497. 1982.PubMed/NCBI
|
|
12
|
Ficarra V, Novara G, Fracalanza S, et al:
A prospective, non-randomized trial comparing robot-assisted
laparoscopic and retropubic radical prostatectomy in one European
institution. BJU Int. 104:534–539. 2009. View Article : Google Scholar : PubMed/NCBI
|
|
13
|
Heidenreich A, Bellmunt J, Bolla M, et al:
EAU guidelines on prostate cancer. Part 1: screening, diagnosis,
and treatment of clinically localised disease. Eur Urol. 59:61–71.
2011. View Article : Google Scholar : PubMed/NCBI
|
|
14
|
Mian BM, Lehr DJ, Moore CK, et al: Role of
prostate biopsy schemes in accurate prediction of Gleason scores.
Urology. 67:379–383. 2006. View Article : Google Scholar : PubMed/NCBI
|
|
15
|
Sengupta S, Slezak JM, Blute ML, et al:
Trends in distribution and prognostic significance of Gleason
grades on radical retropubic prostatectomy specimens between 1989
and 2001. Cancer. 106:2630–2635. 2006. View Article : Google Scholar : PubMed/NCBI
|
|
16
|
Melia J, Moseley R, Ball RY, et al: A
UK-based investigation of inter- and intra-observer reproducibility
of Gleason grading of prostatic biopsies. Histopathology.
48:644–654. 2006. View Article : Google Scholar : PubMed/NCBI
|
|
17
|
Kvåle R, Møller B, Wahlqvist R, et al:
Concordance between Gleason scores of needle biopsies and radical
prostatectomy specimens: a population-based study. BJU Int.
103:1647–1654. 2009.PubMed/NCBI
|
|
18
|
Capitanio U, Karakiewicz PI, Valiquette L,
et al: Biopsy core number represents one of foremost predictors of
clinically significant Gleason sum upgrading in patients with
low-risk prostate cancer. Urology. 73:1087–1091. 2009. View Article : Google Scholar : PubMed/NCBI
|
|
19
|
D’Amico AV, Whittington R, Malkowicz SB,
et al: Biochemical outcome after radical prostatectomy, external
beam radiation therapy, or interstitial radiation therapy for
clinically localized prostate cancer. JAMA. 280:969–974. 1998.
|
|
20
|
Epstein JI, Feng Z, Trock BJ and
Pierorazio PM: Upgrading and downgrading of prostate cancer from
biopsy to radical prostatectomy: incidence and predictive factors
using the modified Gleason grading system and factoring in tertiary
grades. Eur Urol. 61:1019–1024. 2012. View Article : Google Scholar : PubMed/NCBI
|
|
21
|
Budaus L, Graefen M, Salomon G, et al: The
novel nomogram of Gleason sum upgrade: possible application for the
eligible criteria of low dose rate brachytherapy. Int J Urol.
17:862–868. 2010. View Article : Google Scholar : PubMed/NCBI
|
|
22
|
Colleselli D, Pelzer AE, Steiner E, et al:
Upgrading of Gleason score 6 prostate cancers on biopsy after
prostatectomy in the low and intermediate tPSA range. Prostate
Cancer Prostatic Dis. 13:182–185. 2010. View Article : Google Scholar : PubMed/NCBI
|
|
23
|
Ruijter E, van Leenders G, Miller G, et
al: Errors in histological grading by prostatic needle biopsy
specimens: frequency and predisposing factors. J Pathol.
192:229–233. 2000. View Article : Google Scholar : PubMed/NCBI
|
|
24
|
Thompson IM, Pauler DK, Goodman PJ, et al:
Prevalence of prostate cancer among men with a prostate-specific
antigen level < or = 4 ng per milliliter. N Engl J Med.
350:2239–2246. 2004. View Article : Google Scholar
|
|
25
|
Serkin FB, Soderdahl DW, Cullen J, et al:
Patient risk stratification using Gleason score concordance and
upgrading among men with prostate biopsy Gleason score 6 or 7. Urol
Oncol. 28:302–307. 2010. View Article : Google Scholar : PubMed/NCBI
|
