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Urological Oncology
2010 BJU INTERNATIONAL
INDEX LESION AND FOCAL THERAPY IN PROSTATE CANCER
BOTT
ET AL.
BJUI
The index lesion and focal therapy: an analysis
of the pathological characteristics of
prostate cancer
BJU INTERNATIONAL
Simon R.J. Bott, Hashim U. Ahmed*, Richard G. Hindley†,
Ahmad Abdul-Rahman*, Alex Freeman‡ and Mark Emberton*
Frimley Park Hospital NHS Foundation Trust, *Division of Surgery and Interventional Sciences, University College,
Frimley, Surrey, London/NIHR University College Hospital Comprehensive Biomedical Research Centre, London,
†
North Hampshire and Basingstoke NHS Foundation Trust, Basingstoke, Surrey, and ‡Department of Histopathology,
University College Hospital NIHR Comprehensive Biomedical Research Centre, London, UK
Accepted for publication 18 February 2010
OBJECTIVE
RESULTS
To determine the pathological characteristics
of radical prostatectomy specimens with
respect to index and secondary lesions.
Overall, 374 foci were examined. The median
number of tumours per patient was 3.5
(range 1–15). The overall median tumour
volume was 1.4 mL (range 0.1–18.2), the
median volume of the largest (index) tumour
was 0.95 mL (range 0.1–18.2) and the
median volume of the largest secondary
tumour was 0.2 mL (range 0.05–1.7). There
were no patients in whom the index lesion
was insignificant and secondary tumours
were significant (by grade or extra-capsular
disease). Seventy-seven fulfilled the clinical
parameters of low-to-intermediate-risk
disease. If focal therapy can be delivered
with the aim of ablating all clinically
significant disease, with untreated areas
harbouring no cancer or clinically
insignificant disease, between 58.5 and
METHODS
A total of 100 consecutive radical
prostatectomy specimens examined at a
single hospital were assessed. Patients
undergoing salvage prostatectomy or those
who had received neoadjuvant hormonal
manipulation were excluded. Preoperative
data and the number, volume and Gleason
grade of each tumour focus were recorded.
Criteria used to define a clinically significant
lesion were tumour volume ≥0.5 mL and/or
Gleason pattern 4 or 5 and/or extra-capsular
disease.
INTRODUCTION
The incidence of prostate cancer has tripled in
the last three decades as a result of greater
public awareness, more men undergoing PSA
testing and higher cancer detection rates
from the intensification of biopsy strategies.
The earlier detection has resulted in a well
documented downward migration of both
stage and grade [1,2]. The effect of this stage
migration has been to reduce the burden of
disease at the time of diagnosis. Men
diagnosed as a result of a slightly higher PSA
level are likely to have disease localized to the
prostate and have an mean of between one
and three cancer foci, of which the largest
©
accounts for 80–90% of the tumour volume.
The total mean cancer volume occupies no
more than 5–10% of the volume of the
prostate [3].
This observation has led a number of
investigators to evaluate the feasibility and
utility of treating all the cancer as opposed to
the whole of the prostate. This novel
approach, which has been given the term
focal therapy, has been proposed and
discussed by several groups and has been
accepted as one of the key research questions
in the field of prostate cancer [4–7]. Several
authors have already looked at radical
prostatectomy specimens to determine what
67.5% might have been suitable for such a
strategy.
CONCLUSIONS
The proportion of men with low-tointermediate-risk prostate cancer who may
potentially be suitable for a focal therapy
approach is unknown. The key question is
whether the volume of individual lesions
points to clinically significant cancer and
whether ablation of these lesions alone
would lead to cancer control. This research
question is currently undergoing evaluation
within a prospective clinical trial.
KEYWORDS
prostate cancer, risk stratification,
multifocal, index lesion, focal therapy
proportion of patients might be amenable to
focal therapy [8]. Nearly all of these studies
have taken a very absolute definition of
focality and, as a result, have taken the view
that any patient with a secondary or
contralateral cancer focus would be ineligible
for focal treatment. Our own analysis,
presented in this paper, adds to this work by
asking a similar question about eligibility, but
departs from previous research by imposing
thresholds of clinically important disease
rather than taking the presence or absence
of any measurable disease as the key
determinants of who should and should not
be eligible for a treatment that aims to
preserve prostate tissue.
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B OT T ET AL.
METHODS
The pathological details of 100 consecutive
patients who underwent open radical
prostatectomy were extracted from a radical
prostatectomy database held in one centre
between 2003 and 2004. Each radical
prostatectomy specimen was embedded and
processed as previously described [3]. Patients
who had received neoadjuvant androgen
suppression therapy or who had undergone
salvage radical prostatectomy were excluded.
The corresponding biopsy and radical
prostatectomy reports and, where necessary,
the whole mounts were extracted and reexamined. The preoperative features,
including the PSA level, the percentage of
biopsy cores and the biopsy Gleason score
were collated. From the radical prostatectomy
specimen, the total number of tumour foci
and the volume, stage and Gleason grade of
each focus were recorded. Significant tumour
foci were defined using either tumour volume
≥0.5 mL, presence of any Gleason pattern 4 or
5 or evidence of extra-capsular disease [9].
To be able to generalize the results of the
present study to other series, we undertook a
separate analysis of patients who conformed
to a low-to-intermediate-risk population
based on preoperative variables (TRUS-guided
biopsies and clinical/radiological staging).
Patients who conformed to the following
criteria on preoperative variables were
attributed a low-to-intermediate risk: PSA
≤20ng/mL, Gleason score ≤7 or ≤66% of the
cores declared positive [10,11].
RESULTS
Table 1 lists the patient characteristics
of the 100 men who underwent radical
prostatectomy. A total of 374 tumour foci
were examined. The median number of
tumour foci per patient was 3.5 (range 1–15).
The overall median tumour volume was
1.4 mL (range 0.1–18.2), the median tumour
volume of the index tumour (largest focus)
was 0.95 mL (range (0.1–18.2) and the median
volume of the largest secondary tumour was
0.2 mL (range 0.05–1.7). The index lesion
comprised a mean of 73% (SD 25) of the total
tumour volume. Overall, clinically significant
prostate cancer was found in 89% of patients.
In addition, there were no cases where the
index lesion was insignificant and the
secondary tumours significant (by grade or
extra-capsular disease). Specimen-confined
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TABLE 1 Baseline demographics and tumour characteristics at radical prostatectomy for 100 men with
prostate cancer
Variable
Mean (SD) age, years
Median (range) PSA, ng/mL
Median (range) % of positive cores
Biopsy Gleason grade
Value
61 (±3.5)
8.0 (0.7–33)
25% (10–100%)
68
20
7
5
3.5 (1–15)
13
14
1.4 (0.1–18.2)
83
60
44
89
21
19
6
16
36
3+3
3+4
4+3
4+4
Median (range) number of tumours
Overall tumours
Secondary tumours
Unilateral
Unifocal
Median (range) volume, mL
Volume ≥0.5ml
Grade >3 + 3
Stage >T3a
Total significant index
Median volume, mL
Volume ≥0.5 mL
Grade >3 + 3
Stage >T3a
Total significant secondary
disease was found in 70% (59/84) of patients
with multifocal disease (46 with pT2 and 13
with pT3a-negative surgical margin disease).
Including cases with unifocal disease, a total
of 56 patients had organ-confined disease
and 71 had specimen-confined disease.
two by stage alone. There were no patients
who had more than one significant secondary
tumour.
Fifteen patients had unilateral cancer with
one or more foci. A single focus of
adenocarcinoma (unifocal) was identified in
16 patients (one patient had unifocal disease
where the tumour crossed the midline). The
pathological stages in this unifocal group
were pT2 (10/16), pT3a (4/16; two specimenconfined, two with positive postero-lateral
surgical margins), pT3b (1/16) and pT4 (1/16)
– 12/16 had specimen-confined disease.
A total of 77 men fulfilled the criteria of lowto-intermediate-risk prostate cancer based on
preoperative variables (Table 2). In low-tointermediate-risk patients, 51 had pT2 disease,
16 had pT3a disease (12 with negative
surgical margins), three had pT3b disease and
seven had pT4 disease. Overall, 63 (82%) had
specimen-confined disease. The median
number of tumours was four (range 1–11),
which was similar to the whole cohort; 14 had
unifocal disease and 13 had unilateral
prostate cancer. Significant prostate cancer
was found in 70 (90%) patients; the number
of patients with significant secondary foci
was 19 (25%) compared with 36 (36%) for the
whole cohort.
In 84 specimens with multifocal prostate
cancer, 36 had significant secondary tumours.
The secondary tumour was significant by
volume (≥0.5 mL) in 21, by grade (any pattern
4 or 5) in 19 and by stage (extra-capsular
extension) in six (Fig. 1). In five specimens,
both the volume of the tumour and the
Gleason grade were clinically significant; in
three both the volume and stage were
significant; and in one the volume, grade and
stage were significant. In 12 patients, the
secondary tumour was significant by volume
alone, in 13 by Gleason grade alone and in
LOW-TO-INTERMEDIATE-RISK GROUP
A total of 11.7% (9/77) had unilateral disease
with absence of any cancer on the
contralateral side; 41/77 had multifocal
disease, with 33/41 having an index lesion
in one lobe with clinically insignificant
secondary tumours in the contralateral lobe.
In the 8/41 with clinically significant
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INDEX LESION AND FOCAL THERAPY IN PROSTATE CANCER
FIG. 1. Significant secondary tumours by volume, grade and pathological stage.
Tumour volume ≥ 0.5 mL
n = 21
Gleason grade > 6
n = 19
secondary tumours, three (out of 13) were
significant by volume alone (all three
contralateral) and 10 were significant by
grade alone (eight contralateral, two
ipsilateral).
DISCUSSION
n=5
n = 12
SUMMARY OF RESULTS
n = 13
Of 100 consecutive men who underwent
radical prostatectomy for prostate cancer, 77
fulfilled the clinical variables of low-tointermediate-risk disease. Within this group, if
only specimen-confined pT2 disease was
considered, 11.7% (9/77) may have been
suitable for hemi-ablation of the affected
lobe with absence of any cancer in the
contralateral lobe. This proportion was 15.6%
(12/77) if specimen-confined pT2/T3a was
considered for focal therapy.
n=1
n=3
n=0
n=2
Stage > pT2
n=6
TABLE 2 Baseline demographics and tumour characteristics at radical prostatectomy for 77 men with
low-to-intermediate-risk prostate cancer
Variable
Mean (SD) age, years
Median (range) PSA, ng/mL
Median (range) % of positive cores
Biopsy Gleason grade
3+3
3+4
4+3
Median (range) number of tumours
Unilateral
Unifocal
Volume ≥0.5 mL
Grade >3 + 3
Stage >T3a
Total significant index
Volume ≥0.5mL
Grade >3 + 3
Stage >T3a
Total significant secondary
Index tumour
Secondary tumours
secondary tumours, two were significant by
volume (one contralateral, one ipsilateral) and
six were clinically significant by Gleason score
(four contralateral, two ipsilateral). None of
the eight was clinically significant by both
grade and volume. No secondary tumours
were extra-capsular in the low-to-
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Value
60 (± 0.7)
8.0 (0.7–17.9)
25% (8–60%)
62
12
3
4.0 (1–11)
13
14
57
41
26
70
9
12
4
19
intermediate-risk group with multifocal
disease.
Taking the group of patients with pT2/T3a
disease that was specimen-confined, 51 had
multifocal disease; 38/51 had insignificant
secondary tumours. Of those with significant
If a hemi-ablation plan was used to ablate the
side in which the index lesion was situated
and there was clinically insignificant disease
on the contralateral lobe (absence of Gleason
pattern 4; lesion volume ≤0.5 mL) with overall
specimen-confined pT2 cancer, then 46.8%
(36/77) would, in addition, be suitable for
focal therapy. If specimen-confined pT2/T3a
was considered, this proportion would be
51.9% (40/77).
Focal therapy can be delivered with the aim of
ablating all clinically significant disease, with
untreated areas harbouring no cancer or
clinically insignificant disease that would then
undergo surveillance. In this retrospective
cohort that have already undergone radical
prostatectomy, we have found that, of the
low-to-intermediate-risk group, between 58.5
and 67.5% may have been suitable for such a
strategy.
METHODOLOGICAL LIMITATIONS
Before considering the implications of the
findings of the present study in relation to the
case selection for patients for focal therapy, a
number of methodological issues require
some attention. First, patients undergoing
radical prostatectomy are not necessarily
representative of all patients who are seeking
treatment as a result of a diagnosis of
prostate cancer. Patients who have radical
prostatectomy have been selected as suitable
for radical surgery. It is not clear whether they
represent a spectrum of patients with more or
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B OT T ET AL.
less advanced disease than those who would
be seeking a focal treatment as a result of
today’s stage and grade migration. What we
can say is that the characteristics of patients
in our cohort are not too distinct from other
published cohorts [9].
The second issue relates to the sampling
frame. Although radical prostatectomy stepsection histopathology is regarded as the
reference standard in studies such as this, it
remains subject to sampling and processing
error. In this series, step-sectioning of the
prostate was performed at 5-mm intervals, in
line with the standard method for assessing
radical prostatectomy specimens [12].
Furthermore, during the preparation of a
whole-mount slide, the tissue block is
‘trimmed’ to achieve a ‘full face’, with
subsequent loss of prostate tissue for
analysis. Both step-sectioning and trimming
can result in an under-estimate of the number
and volume of tumour foci. However, these
inaccuracies are likely to be small and
probably of little clinical consequence.
The third methodological issue relates to
inter-observer agreement on precisely what
constitutes a tumour focus. There appears to
be no agreement as to how the status of
‘focus’ should be conferred. On axial
orientation the cross-sectional area of a
‘focus’ may be influenced by the presence of
normal tissue within it. Contouring is the
usual process whereby the pathologist defines
the limits of the foci in the X- and Y-planes.
This contouring is subjective and probably –
as it has not been tested – varies between
departments and between pathologists. The
derivation of the Z-plane is subject to
sampling error that is dependent upon the
thickness of each section. The issue of
adjacency remains problematic. In the present
study, where one tumour focus overlay a
focus on a more caudal or cephalic wholemount slice, a single focus was recorded, and
where there was no overlay, the tumours
would be counted as separate foci. All these
errors influence the volume and number of
foci that are declared in any one prostate.
IMPLICATIONS
Despite these limitations we feel that the
findings of the present study do indicate that
focal therapy may be feasible in a substantial
proportion. Other series, when considering a
hemi-ablative focal strategy, have concluded
that about one-third of patients may be
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suitable [7,8]. Most studies of this type have
limited their discussion to the presence or
absence of any cancer. We have, instead,
sought to define tumour volumes and
Gleason grading in an attempt to classify
lesions as either clinically important or
otherwise.
This approach is not unreasonable given what
we know about the natural history of prostate
cancer. Most men will develop prostate cancer
in their lifetime [13] and the vast majority will
harbour insignificant lesions. Men with
insignificant disease are not likely to benefit
from curative therapy and, as a result, will
only experience harm if subjected to
treatment. However, the definition of
clinically significant disease has not been
agreed. There are many definitions, most of
which represent a small departure from that
proposed by Epstein. For this definition, it was
found that in those patients with organconfined disease at radical prostatectomy, a
tumour volume <0.5 mL and a Gleason
pattern ≤3 had a very low chance of future
progression [10]. Other researchers have taken
this further and proposed that the index
lesion alone may drive progression [4,14].
Whilst much more work needs to be done to
explore and understand the biology of the
different tumour foci, clinical studies are also
vital. Focal therapy that targets only the index
lesion in addition to any other adjacent foci
that are deemed to be clinically important,
and leaves small ‘clinically insignificant’
lesions that may be sub-clinical in many
cases, may allow a greater number of
individuals to consider this kind of treatment
[15].
The other implication of our findings has now
been well recognised by others [16]. We have
shown that the preoperative prediction of
patients suitable for focal therapy is
problematic when reliance is placed on
standard TRUS-guided biopsies. Sampling
error is greater if tumours are situated in the
anterior or apical zones [17], where grade
variation exists within a single focus and in
multifocal tumours [13]. Attempts have been
made to aid the prediction of multifocal
disease using PSA level, but neither PSA level
nor PSA density is able to predict unifocality
or multifocality [18].
Accurately identifying all significant tumour
foci using template-guided biopsies [19] and/
or multi-functional MRI [20] will be needed if
patients are to be selected with any degree of
precision for prostate tissue-preserving
therapy.
CONCLUSIONS
The increasing incidence of men with low-tointermediate-risk prostate cancer, and the
realization that in most men such disease is
clinically insignificant and unlikely to have an
impact on life expectancy, has meant a shift in
emphasis from radical treatments to less
invasive alternatives with less impact on
quality of life. The multifocality of prostate
cancer and the ability to identify and
selectively treat prostate cancer foci have
hampered focal therapy to date. Increasingly,
imaging and biopsy strategies are evolving to
accurately identify significant tumour foci
within the prostate. Furthermore, tools to
treat discrete areas of the prostate are being
used to successfully ablate regions of the
prostate, preserving normal adjacent
structures critical to the preservation of
urinary, bowel and erectile function. The
present study shows that, while most radical
prostatectomy specimens contain multiple
tumour foci, a third have organ-confined
disease and insignificant secondary tumour
foci. Carefully designed clinical trials are
needed to assess the long-term outcomes
when either all significant lesions are targeted
or an index-lesion-only ablative strategy is
used with surveillance of clinically
insignificant lesions.
ACKNOWLEDGEMENTS
Mark Emberton is funded in part by the NIHR
UCLH/UCL Comprehensive Biomedical
Research Centre. Hashim U. Ahmed holds an
MRC Clinical Fellowship award. We are
grateful to the Pelican Cancer Foundation,
Prostate Research Campaign (Prostate UK), St
Peters Trust and Prostate Cancer Research
Centre charities for their financial support of
work in focal therapy.
CONFLICT OF INTEREST
Hasmid U. Ahmed declares a conflict of
interest due to USHIFU, MISONIX, UKHIFU and
STEBA BIOTECH. Mark Emberton declares a
conflict of interest due to funding from AMD,
MISONIX, USHIFU and STEBA BIOTECH. Source
of funding: MRC, Pelican Cancer Foundation,
Prostate UK, St Peters Trust, Prostate Cancer
Research Foundation, Prostate Cancer
Research Centre (all charities).
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Correspondence: Hashim Uddin Ahmed,
Division of Surgery and Interventional
Science, c/o National Medical Laser Centre,
67 Riding House Street, London, W1P 7NN.
e-mail: [email protected]
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