Download Handling and Staging Radical Prostatectomy Specimens

Handling and Staging Radical Prostatectomy Specimens: Recommendations from
the 2009 ISUP Consensus Conference
Lars Egevad
Dept of oncology-pathology, Karolinska Institutet, Stockholm, Sweden
The clinical importance of the pathology reports of radical prostatectomy (RP) specimens
has increased in recent years. Patients with adverse histopathological findings may now
be offered adjuvant therapies such as radiotherapy, chemotherapy or hormonal
treatment.1 In the future we will most likely see more individualized therapy in these
cases. Thus, it is increasingly important that the pathologist is able to make a correct
assessment of stage and grade of RP specimens. With this in mind the International
Society of Urological Pathology (ISUP) organized a consensus meeting on Handling and
Staging Radical Prostatectomy Specimens, held in Boston, Massachusetts, USA at the
2009 USCAP meeting. All senior ISUP members were invited to the consensus process
and 157 members from 26 countries participated. Prior to the meeting a web-based
survey was completed by the delegates. The conference was conducted by 5 working
groups and attended by 116 delegates. At least 65% agreement was required for
consensus.
1.
Handling of radical prostatectomy specimens
The prostate undergoes rapid autolysis because of the presence of proteolytic enzymes.
Thus, RP specimens should be either immediately fixed in abundant formalin or promptly
transported fresh on ice to the pathology laboratory. Upon arrival to the laboratory, the
prostate should be weighed and measured in three dimensions (vertical, transverse and
sagittal) to enable correlation with e.g. radiological exams. It was agreed that the weight
of the prostate itself must be recorded independent of the seminal vesicles, i.e. after their
removal. The size of the seminal vesicles varies and some surgeons may choose not to
remove the entire seminal vesicles. Therefore, recording of only the total weight of the
specimen can be misleading.
A variety of methods are used for harvesting of fresh tissue for research. 2-5 Most
pathologists take shave or punch biopsies from the cut surfaces of an incision into the
prostate (68%) or very rarely fine needle aspirates or scrapings. The harvesting method
was not standardized by the consensus panel.
Inking the prostate is mandatory. It was decided that a minimum of two colors should be
used to distinguish between right and left side. Before final cutting for embedding the
prostate should be fully fixed. Bread-loafing of the unfixed prostate is not recommended
because of the difficulties to obtain slices of equal thickness and because of the risk that
surgical margins do not get adequately examined. Techniques for enhanced fixation such
as formalin injection and microwaving are useful and may shorten fixation time of RP
specimens. 2, 5-7
1
The surgical margins of the apex and base of the prostate need to be carefully examined.
There was a consensus that the cone method with sagittal slicing should be used both at
the apex and the base. The shave method where a thin shave slice from apex or base is
embedded en face is discouraged. 8
Whether whole mounts or standard-size blocks should be used was not addressed by the
meeting as this is up to the discretion of the individual pathologist. A contentious area is
whether the prostate should be completely or partially embedded. In a previous survey
study among pathologists from 217 laboratories in 15 west European countries as many
as 71.6% of respondents always embedded the entire prostate and only 10.8% always
practiced partial embedding. 9 There seems to be a geographic variation in terms of
embedding routines. The delegates at the consensus meeting were almost equally split
between total and partial embedding. There was an overwhelming consensus that if
partial embedding is used, the specific sampling method should be documented. 10
A proposal was launched to assign a stage pT2a to cases with no cancer found in the RP
specimen but with cancer in preoperative needle biopsy specimens. This proposal was
however rejected and it was agreed that these cases should continue to be considered pT0.
2.
T2 substaging and prostate cancer volume
A prostate cancer that is found to be organ-confined in the RP specimen is assigned stage
pT2. In recent decades there has been a significant stage shift of prostate cancer and pT2
tumors have become more common. In TNM 2002 pT2 was substaged in pT2a (Tumor
involves one half of one lobe or less), pT2b (Tumor involves more than half of one lobe,
but not both lobes), and pT2c (Tumor involves both lobes). 11 This substaging has been
heavily criticized. The pT2 substaging is a direct translation of the cT2 substaging, which
is based on digital rectal exam findings, while the pT2 substaging is based on tumor
involvement of histopathological slides taken throughout the prostate. The definition of
pT2b and pT2c is problematic. An objection against pT2b is that it is very unlikely that a
tumor would be large enough to fill out more than 50% of one half of the prostate and
still be both organ-confined and restricted to one side of the midline. There is a large
variation in the distribution of TNM 2002 pT2 substages among different prostate cancer
series, with pT2b varying from 0% to 19.1% of cases. 12, 13 Furthermore, it is unclear
whether the main tumor has to be bilateral for stage pT2c. Yet, 71% of the pre-meeting
survey responders would assign a pT2c to a case with a separate minute contralateral
tumor focus. In the TNM 2010 staging, the pathological substaging of pT2 prostate
cancers has been retained, although the prognostic value of this has been questioned. 14
There was an agreement that the current pT2 substaging should not be used, but there was
no consensus as to what sort of substaging it should be replaced with. Among proposals
were reduction of the current 3-tier substaging to a 2-tier substaging (by omitting the
current pT2b category) or to use a simple to measure and potentially clinically relevant
tumor volume parameter as a cut-off between pT2a and pT2b. A 10 mm diameter cut-off
was discussed (corresponding to a sphere volume of 0.5 ml) but no decision was taken as
2
to the exact definition of such a cut-off. There was also a proposal that there should be a
minimum size for a second tumor to be considered for the whole case to be classified as
pT2c. However, again the delegates failed to agree on a common definition.
Prostate cancer is strikingly multifocal. At the 2005 ISUP consensus conference on
Gleason grading, it was decided that a separate Gleason score should be assigned to each
of the dominant tumor foci. 15 It was now discussed whether the index tumor should be
defined as a) the largest tumor b) the tumor with the highest Gleason score or c) the
tumor with the highest stage, but no consensus was reached.
It has been debated whether transition zone tumors may have a better outcome than
peripheral zone tumors of corresponding grade and stage. 16, 17 Clinically these tumors
sometimes undergo multiple biopsies because of persistent PSA-elevation until they are
diagnosed. 18 It was agreed that the zonal / anterior localization of the index tumor in a
prostatectomy specimen should therefore be mentioned in the pathology report.
Volume of prostate cancer correlates with other prognostic factors such as grade, stage
and ploidy and also with prognosis after radical prostatectomy. Some authors have
reported that tumor volume is not an independent predictor of prognosis when Gleason
score, extra-prostatic extension, surgical margins and seminal vesicle invasion are
included in the analysis, 19, 20, while others found tumor size to be an independent
predictor of outcome 21. An overwhelming majority of delegates supported that a measure
of the tumor size should be given (such as volume, diameter or percentage).
3.
Extraprostatic extension, lymphovascular invasion and locally advanced
disease
Extraprostatic extension (EPE) is the preferred designation for cancer growing beyond
the confines of the prostate gland and the term capsular penetration is no longer
recommended. The prostatic capsule is a rather poorly defined plane between the
prostatic stroma and the extraprostatic loose connective tissue. The prostate is particularly
poorly circumscribed anteriorly and at the apex and base. The definition of EPE is
therefore contentious, particularly in these areas. Cancer growth into adipose tissue is
helpful when diagnosing EPE although the pathologist must be aware that occasional
intraprostatic fat cells may cause a false positive EPE diagnosis. 22 The assessment of
cancer growing into extraprostatic connective tissue is even more complicated and
subject to interobserver variability. 23 It was decided by the consensus meeting that even
in the absence of fat involvement, EPE can be identified posteriorly and posterolaterally
when there is tumor within fibrous tissue bulging beyond the contour of the gland. An
example of this situation is when cancer is growing in connective tissue on the same level
as adjacent extraprostatic adipose tissue. Similarly, EPE is difficult to determine
anteriorly where the prostatic stroma merges with thick smooth muscle bundles. Yet, a
majority of delegates thought it is possible to identify EPE anteriorly. Anterior EPE can
be diagnosed either when cancer invades adipose tissue or when it grows beyond the
general contour of the gland, as extrapolated from posterior and posterolateral regions.
3
Benign glands are frequently admixed with striated muscle in the apex and anteriorly.
Thus, tumor growing around striated muscle cells is not by itself diagnostic of EPE.
It has been shown that the amount of EPE has prognostic importance and that patients
with focal EPE have a more favorable outcome than those with extensive EPE. 24 Several
definitions of focal EPE have been proposed. Epstein et al defined focal EPE as a few
glands immediately exterior to the prostate in 1 to 2 sections. 24 Wheeler et al considered
tumor outside the prostate to a depth of less than one high-power field in 1 to 2 sections
as focal EPE. 25 Sung et al recently advocated a quantitative assessment of the depth of
EPE by measuring the radial diameter. 26 They found that EPE reaching less than
0.75 mm outside the prostate was the best cut-off and claimed this measure to be superior
to more subjective methods. There are certain limitations with all these methods. It is
subjective what is meant by a few neoplastic glands. The definition using a high-power
field depends of the size of the visual field of the microscope. A disadvantage with
measuring the radial diameter is that it may be difficult to determine the level of the
capsular plane which hampers an exact measurement. This method may also require
measurement with an ocular micrometer which is time-consuming. Thus, the optimal
method for quantitation of EPE remains to be determined. In line with this, the consensus
meeting decided that EPE should be somehow quantitated but there was no consensus as
to what method to use.
Bladder neck invasion was designated as pT4 in previous editions of TNM. 11 However,
it has been shown that patients with microscopic bladder neck invasion (neoplastic cells
within thick smooth muscle bundles at the base of the prostate), have a prognosis similar
to ordinary EPE and it was decided that these cases should be assigned a stage pT3a. 27, 28
This has been changed accordingly in TNM 2010. 14 pT4 should be restricted to cases
with grossly visible bladder neck invasion.
Lymphovascular invasion in RP specimens has been reported to be an independent
predictor of lymph node metastases and biochemical recurrence and should be reported.
29, 30
4.
Seminal vesicles and lymph nodes
Seminal vesicle invasion (SVI) by prostate cancer has been shown to be a predictor of
poor prognosis after RP. However, there have been no uniform recommendations on to
how to handle and report the seminal vesicles. Only 38% of pre-meeting survey
responders practiced total embedding and it was decided at the consensus conference that
it should not be mandatory to totally embed the seminal vesicles in all specimens. In a
classical study by Ohori et al (1993), three different routes of SVI were described. 31 The
most common variant was invasion through the base of the seminal vesicle. Thus, if
partial embedding is used, it should include a block from the base.
The base of the seminal vesicle is inserted into the prostate and surrounded by prostatic
tissue. It has been suggested that cancer invasion into the intraprostatic portion of the
seminal vesicles has better prognosis than extraprostatic SVI. It was decided that invasion
4
of the intraprostatic seminal vesicle should not be considered as SVI, and hence be
reported as pT3a rather than pT3b. 32 There was no consensus whether tumor present only
within endothelial lined spaces in the muscular wall of the seminal vesicles should be
consider pT3b.
A positive vas deferens margin is exceptionally rare and basically only occurs in
advanced cases with positive margins elsewhere. Yet, some pathologists routinely sample
the vas deferens margins, while others find it unnecessary. It was decided that sampling
of the vas deferens margins should not be mandatory.
There was no consensus on how to sample lymph nodes. Some of the conference
delegates sample all tissue from lymph node dissections while a majority would only
sample grossly visible lymph nodes. The number of lymph nodes seen on microscopy
was reported by most respondents of the pre-meeting survey. However, counting pelvic
lymph nodes is more difficult than in other lymph node specimens, because of the
pronounced fat infiltration. The diameter of the largest lymph node metastasis is the most
predictive parameter for these specimens and should therefore be reported. 33
5.
Surgical Margins
The purpose of radical prostatectomy is to remove the entire tumor. It has been shown
that margin status is a predictor of biochemical recurrence. 34-37 The definition of a
positive margin is cancer reaching ink. It has been shown that patients with cancer
coming close to the margin have the same outcome as margin negative patients. 38, 39 It
was therefore decided that tumor extending close to the “capsular” margin yet not to it
should be reported as a negative margin.
There is some evidence that the location of margin positivity may correlate with
prognosis 40 although results are conflicting 41. A positive bladder neck margin may have
worse prognosis although it is unclear if bladder neck location is an independent predictor
of outcome. 40, 42 Furthermore, it has some importance for the surgeon to know where the
surgical margin is positive as this feedback enables them to modify their surgical
technique when necessary. Locations of positive margins should be reported as Posterior,
posterolateral, lateral, anterior at either the apex, mid, base.
Extent of margin positivity correlated with prognosis in most studies. 34, 35, 43, 44 Several
efforts have been made to define focal margin positivity. Epstein defined focal margin
positivity as limited involvement with only 1 or 2 areas showing tumor extending to
margins. 34 Babaian et al and Weldon et al used 3 mm as a cutoff. 35, 44Vis et al diagnosed
a focally positive margin when only a few tumor cells touched ink. 37 Watson et al
allowed only one single gland to touch ink to call it focally positive. 36 No consensus
could be reached as to what definition to use for focal margin positivity. The conference
recommended that until we can reach such a consensus, we should report the extent of a
positive margin as millimeters of linear involvement.
5
It has been suggested that the grade of a cancer at a positive margin may have prognostic
importance but it was decided that this should be left up to the pathologist’s discretion. 45
The significance and reporting of intraprostatic (“capsular”) incision has been debated. A
recent study showed that isolated intraprostatic incision into tumor entails a higher rate of
biochemical recurrence than organ confined or focal extraprostatic extension with
negative margins. 45 Another study found that intraprostatic incision into tumor has a
prognosis comparable to pT3a disease with positive margins. 46 Conflicting results may
be explained by controversial diagnostic criteria for intraprostatic incision, particularly at
the apex. A majority (72%) of the pre-meeting survey respondents would report
intraprostatic incision into cancer when present. However, no consensus could be reached
whether intraprostatic incision should be reported in cases with tumor at ink without
benign glands cut across at the apical perpendicular margin section. There was no
consensus either whether intraprostatic incision should be reported when benign glands
are at the ink in the absence of cancer at ink. It was agreed that tumor in skeletal muscle
without benign glands at the apical perpendicular margin section should be reported as
organ-confined.
It was recommended that the proximal and distal margins should be reported as bladder
neck and apical margins, respectively. The terms proximal and distal urethral margins
should be avoided as the urethra is often retracted and the true surgical margin mainly
consists of prostatic tissue or extraprostatic connective tissue.
6.
Concluding remarks
The ISUP 2009 consensus conference on Handling and Staging Radical Prostatectomy
Specimens was the third in a series of consensus meetings organized by ISUP. The aim
was to provide guidelines for practicing pathologists on how to handle these specimens.
As far as possible we attempted to seek evidence-based consensus although in some areas
with scant data in the literature, majority decisions were taken based on common sense
and wide-spread practice. Several areas were identified where there is a need of further
studies.
References
1
2
3
Gonzalez, JR, Laudano, MA, McCann, TR et al. A review of high-risk prostate
cancer and the role of neo-adjuvant and adjuvant therapies. World J Urol 2008;
26: 475-480.
Egevad, L, Engström, K, Busch, C. A new method for handling radical
prostatectomies enabling fresh tissue harvesting, whole mount sections and
landmarks for alignment of sections. Journal of Urologic Pathology, in press
1998; 9: 17-28.
Furman, J, Murphy, WM, Rice, L et al. Prostatectomy tissue for research:
balancing patient care and discovery. Am J Clin Pathol 1998; 110: 4-9.
6
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Wheeler, TM, Lebovitz, RM. Fresh tissue harvest for research from prostatectomy
specimens. Prostate 1994; 25: 274-279.
Hoedemaeker, RF, Ruijter, ETG, Ruizeveld-de Winter, JA et al. Processing
Radical Prostatectomy Specimens. Journal of Urologic Pathology 1998; 9: 211222.
Jonmarker, S, Valdman, A, Lindberg, A et al. Tissue shrinkage after fixation with
formalin injection of prostatectomy specimens. Virchows Arch 2006; 449: 297301.
Ruijter, ET, Miller, GJ, Aalders, TW et al. Rapid microwave-stimulated fixation
of entire prostatectomy specimens. Biomed-II MPC Study Group. J Pathol 1997;
183: 369-375.
Epstein, JI, Amin, M, Boccon-Gibod, L et al. Prognostic factors and reporting of
prostate carcinoma in radical prostatectomy and pelvic lymphadenectomy
specimens. Scand J Urol Nephrol Suppl 2005: 34-63.
Egevad, L, Algaba, F, Berney, DM et al. Handling and reporting of radical
prostatectomy specimens in Europe: a web-based survey by the European
Network of Uropathology (ENUP). Histopathology 2008; 53: 333-339.
Sehdev, AE, Pan, CC, Epstein, JI. Comparative analysis of sampling methods for
grossing radical prostatectomy specimens performed for nonpalpable (stage T1c)
prostatic adenocarcinoma. Hum Pathol 2001; 32: 494-499.
Sobin, LH, Wittekind, C: TNM classification of malignant tumours, 6th ed. New
York: Wiley-Liss, pp. 184-187, 2002
Eichelberger, LE, Cheng, L. Does pT2b prostate carcinoma exist? Critical
appraisal of the 2002 TNM classification of prostate carcinoma. Cancer 2004;
100: 2573-2576.
Quintal, MM, Magna, LA, Guimaraes, MS et al. Prostate cancer pathologic stage
pT2b (2002 TNM staging system): does it exist? Int Braz J Urol 2006; 32: 43-47.
Edge, SB, Byrd, DR, Compton, CC et al: AJCC cancer staging manual, 7th ed.
Chicago: Springer, 2010
Epstein, JI, Allsbrook, WC, Jr., Amin, MB et al. The 2005 International Society
of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of
Prostatic Carcinoma. Am J Surg Pathol 2005; 29: 1228-1242.
Ohori, M, Dunn, JK, Wheeler, TM et al. Is there really a difference between
peripheral zone and transition zone prostate cancer? J Urol 1995; 153: 1153.
Al-Ahmadie, HA, Tickoo, SK, Olgac, S et al. Anterior-predominant prostatic
tumors: zone of origin and pathologic outcomes at radical prostatectomy. Am J
Surg Pathol 2008; 32: 229-235.
Mai, KT, Moazin, M, Morash, C et al. Transitional zone and anterior peripheral
zone of the prostate. A correlation of small-volume cancer in the biopsy cores and
high psa with positive anterior margins in radical prostatectomy specimens. Urol
Int 2001; 66: 191-196.
Kikuchi, E, Scardino, PT, Wheeler, TM et al. Is tumor volume an independent
prognostic factor in clinically localized prostate cancer? J Urol 2004; 172: 508511.
Epstein, JI, Carmichael, M, Partin, AW et al. Is tumor volume an independent
predictor of progression following radical prostatectomy? A multivariate analysis
7
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
of 185 clinical stage B adenocarcinomas of the prostate with 5 years of followup.
J Urol 1993; 149: 1478-1481.
Eichelberger, LE, Koch, MO, Eble, JN et al. Maximum tumor diameter is an
independent predictor of prostate-specific antigen recurrence in prostate cancer.
Mod Pathol 2005; 18: 886-890.
Sung, MT, Eble, JN, Cheng, L. Invasion of fat justifies assignment of stage pT3a
in prostatic adenocarcinoma. Pathology 2006; 38: 309-311.
Evans, AJ, Henry, PC, Van der Kwast, TH et al. Interobserver variability between
expert urologic pathologists for extraprostatic extension and surgical margin
status in radical prostatectomy specimens. Am J Surg Pathol 2008; 32: 15031512.
Epstein, JI, Carmichael, MJ, Pizov, G et al. Influence of capsular penetration on
progression following radical prostatectomy: a study of 196 cases with long-term
followup. J Urol 1993; 150: 135-141.
Wheeler, TM, Dillioglugil, O, Kattan, MW et al. Clinical and pathological
significance of the level and extent of capsular invasion in clinical stage T1-2
prostate cancer. Hum Pathol 1998; 29: 856-862.
Sung, MT, Lin, H, Koch, MO et al. Radial distance of extraprostatic extension
measured by ocular micrometer is an independent predictor of prostate-specific
antigen recurrence: A new proposal for the substaging of pT3a prostate cancer.
Am J Surg Pathol 2007; 31: 311-318.
Dash, A, Sanda, MG, Yu, M et al. Prostate cancer involving the bladder neck:
recurrence-free survival and implications for AJCC staging modification.
American Joint Committee on Cancer. Urology 2002; 60: 276-280.
Zhou, M, Reuther, AM, Levin, HS et al. Microscopic bladder neck involvement
by prostate carcinoma in radical prostatectomy specimens is not a significant
independent prognostic factor. Mod Pathol 2009; 22: 385-392.
de la Taille, A, Rubin, MA, Buttyan, R et al. Is microvascular invasion on radical
prostatectomy specimens a useful predictor of PSA recurrence for prostate cancer
patients? Eur Urol 2000; 38: 79-84.
Ferrari, MK, McNeal, JE, Malhotra, SM et al. Vascular invasion predicts
recurrence after radical prostatectomy: stratification of risk based on pathologic
variables. Urology 2004; 64: 749-753.
Ohori, M, Scardino, PT, Lapin, SL et al. The mechanisms and prognostic
significance of seminal vesicle involvement by prostate cancer. Am J Surg Pathol
1993; 17: 1252-1261.
Soh, S, Arakawa, A, Suyama, K et al. The prognosis of patients with seminal
vesicle involvement depends upon the level of extraprostatic extension. J Urol
1998; 159: 296A.
Boormans, JL, Wildhagen, MF, Bangma, CH et al. Histopathological
characteristics of lymph node metastases predict cancer-specific survival in nodepositive prostate cancer. BJU Int 2008; 102: 1589-1593.
Epstein, JI, Pizov, G, Walsh, PC. Correlation of pathologic findings with
progression after radical retropubic prostatectomy. Cancer 1993; 71: 3582-3593.
Weldon, VE, Tavel, FR, Neuwirth, H et al. Patterns of positive specimen margins
and detectable prostate specific antigen after radical perineal prostatectomy. J
Urol 1995; 153: 1565-1569.
8
36
37
38
39
40
41
42
43
44
45
46
Watson, RB, Civantos, F, Soloway, MS. Positive surgical margins with radical
prostatectomy: detailed pathological analysis and prognosis. Urology 1996; 48:
80-90.
Vis, AN, Schroder, FH, van der Kwast, TH. The actual value of the surgical
margin status as a predictor of disease progression in men with early prostate
cancer. Eur Urol 2006; 50: 258-265.
Epstein, JI, Sauvageot, J. Do close but negative margins in radical prostatectomy
specimens increase the risk of postoperative progression? [see comments]. J Urol
1997; 157: 241-243.
Emerson, RE, Koch, MO, Daggy, JK et al. Closest distance between tumor and
resection margin in radical prostatectomy specimens: lack of prognostic
significance. Am J Surg Pathol 2005; 29: 225-229.
Obek, C, Sadek, S, Lai, S et al. Positive surgical margins with radical retropubic
prostatectomy: anatomic site-specific pathologic analysis and impact on
prognosis. Urology 1999; 54: 682-688.
Sofer, M, Hamilton-Nelson, KL, Civantos, F et al. Positive surgical margins after
radical retropubic prostatectomy: the influence of site and number on progression.
J Urol 2002; 167: 2453-2456.
Buschemeyer, WC, 3rd, Hamilton, RJ, Aronson, WJ et al. Is a positive bladder
neck margin truly a T4 lesion in the prostate specific antigen era? Results from
the SEARCH Database. J Urol 2008; 179: 124-129; discussion 129.
Emerson, RE, Koch, MO, Jones, TD et al. The influence of extent of surgical
margin positivity on prostate specific antigen recurrence. J Clin Pathol 2005; 58:
1028-1032.
Babaian, RJ, Troncoso, P, Bhadkamkar, VA et al. Analysis of clinicopathologic
factors predicting outcome after radical prostatectomy. Cancer 2001; 91: 14141422.
Chuang, AY, Nielsen, ME, Hernandez, DJ et al. The significance of positive
surgical margin in areas of capsular incision in otherwise organ confined disease
at radical prostatectomy. J Urol 2007; 178: 1306-1310.
Shuford, MD, Cookson, MS, Chang, SS et al. Adverse prognostic significance of
capsular incision with radical retropubic prostatectomy. J Urol 2004; 172: 119123.
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