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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e3182211ce0
Review Articles

International Society of Urological Pathology Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens

Egevad, Lars MD, PhD*; Srigley, John R. MD, FRCPC; Delahunt, Brett MD, FRCPA

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*Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada

Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand

No funding has been received from National Institutes of Health (NIH); Wellcome Trust or Howard Hughes Medical Institute (HHMI).

Disclosure/Conflict of Interest: The authors have no conflicts of interest to declare.

Reprints: Lars Egevad, MD, PhD, Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital Solna, Radiumhemmet P1:02, 171 76 Stockholm, Sweden (e-mail: lars.egevad@ki.se).

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Abstract

The 2009 International Society of Urological Pathology consensus conference on handling and staging of radical prostatectomy specimens issued recommendations for standardization of pathology reporting of radical prostatectomy specimens. The conference addressed specimen handling, T2 substaging, prostate cancer volume, extraprostatic extension, lymphovascular invasion, seminal vesicle invasion, lymph node metastases, and surgical margins. This review summarizes the conclusions and recommendations resulting from the consensus process.

The clinical importance of histopathologic reporting of radical prostatectomy specimens has increased in recent years. Patients with adverse histopathologic findings may now be offered a variety of adjuvant therapies such as radiotherapy, chemotherapy, or hormonal treatment.1 Standardization of routines for the handling and reporting of these specimens is likely to facilitate treatment decisions. With this in mind, the International Society of Urological Pathology (ISUP) organized a consensus meeting in 2009 in Boston, Massachusetts, to address these issues. The purpose of this review is to summarize the proceedings of the consensus conference.2–7

The ISUP has previously hosted consensus meetings on the grading of carcinomas of the urinary bladder and on Gleason grading of prostatic adenocarcinoma.8,9 Participation in these meetings was restricted to acknowledged specialists in the field, although it was recognized that this may potentially cause selection bias, with overrepresentation of academic pathologists. To achieve a more balanced representation all senior members of the ISUP were invited to participate in the current consensus process. Residents who had not completed their training in anatomic pathology were not eligible to participate.

A premeeting survey was circulated, with the purpose of collecting data relating to current practice.2 Responses to the survey were received from 157 members from 26 countries, corresponding to a 62% response rate. Of these, 116 delegates from 23 countries attended the consensus conference that was held in conjunction with the 2009 United States and Canadian Academy of Pathology meeting in Boston. This included 69 patients (62%) from North America, 6 patients (5%) from South America, 22 patients (19%) from Europe, 11 patients (10%) from Asia, and 5 patients (4%) from Australia and New Zealand. Among the delegates, 82 (74%) were from university/academic practice, 11 (10%) were from community hospitals, 11 (10%) were from private health care, and 7 (6%) were from other institutions.

At the conference, 5 working groups presented background information and survey results (Table 1). A 65% agreement was considered to represent consensus and among the 43 questions, which were considered, consensus was reached for 30 questions (70%).

Table 1
Table 1
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HANDLING OF RADICAL PROSTATECTOMY SPECIMENS

The purpose of gross examination and processing of radical prostatectomy specimens is to ensure that the preoperative diagnosis is confirmed and that histopathologic prognostic factors are accurately assessed. In the prostate gland, these procedures are less guided by macroscopic inspection and localization of the cancer than in tumor specimens from other organs. A high level of standardization of laboratory routines is thus possible (Table 2).

Table 2
Table 2
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Radical prostatectomy specimens may arrive in the pathology department either in formalin or in an unfixed state. The seminal vesicles are usually attached to the gland. The weight of the prostate should be measured as this correlates with estimates of prostate size from preoperative radiologic studies and from the findings of digital rectal examination.3 For this reason, the seminal vesicles should to be removed before weighing the gland and the size of the prostate should be measured in 3 dimensions.

Techniques for the harvesting of fresh tissue were not discussed at the consensus meeting but according to the premeeting survey, the most commonly used methods are either harvesting from the cut surface by shave sampling or punch biopsies.

It was agreed that, after the measurement of the size of the gland, the surface of the prostate should be painted with ink or silver nitrate. It was recommended that at least 2 colors should be used to ensure that the left and right side of the prostate can be distinguished histologically. There was agreement that final slicing of the prostate should not take place until after full fixation. This was considered appropriate as it was recognized that slices of unfixed prostatic tissue will become deformed upon fixation, which in turn will impair the examination of surgical margins.

The apex is a common location for the detection of tumor positive surgical margins and this area must undergo careful examination. The shave technique for examination of the apical margin is no longer recommended as this may result in either underdiagnosis or overdiagnosis of positive margins, depending on how it is applied.10 There was total agreement at the consensus meeting that the apex should be cut by a modified cone method. Using this technique, a thick section is amputated from the apex and then cut and embedded sagittally. A similar modified cone method was recommended for examination of the prostatic base. Tumor-positive surgical margins are less frequently seen at the base of the gland when compared with the apex and as a consequence in some institutions it is still considered acceptable to cut the base as a thin shave slice, which is embedded en face.10

It was debated as to whether or not embedding of the entire prostate should be obligatory. The meeting recognized that a major problem, when handling radical prostatectomy specimens, is that the cancer is often not visible on gross examination and further that tumor extent is always underestimated by naked eye examination. It was agreed that the safest method to avoid undersampling of cancer is submission of the entire prostate for processing; however, it was decided that partial embedding should also be permitted, with the understanding that financial constraints relating to health care in some countries may not permit total embedding of the specimen. It is interesting to note that, only 23.6% of the 157 participants involved in the consensus process stated that they would consider partial embedding of a specimen. There was a consensus that if partial embedding was undertaken, then the method used should be documented in the pathology report.

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T2 SUBSTAGING AND PROSTATE CANCER VOLUME

Staging category pT2 includes tumors that are confined within the prostate gland and among controversies relating to tumors that present in this staging category are issues relating to the value of substaging, the reporting of multifocal tumors, and the relevance of tumor size as a prognostic parameter.4

The pathologic substaging of pT2 prostate cancers currently mirrors clinical T2 substaging. A pT2a tumor is defined as a unilateral tumor, occupying less than half of 1 lobe, a pT2b tumor is unilateral, occupying more than half of 1 lobe, whereas a pT2c tumor is bilateral. There are several problems with this classification. Stage pT2b is a very rare finding, as most tumors that are larger than 1 lobe of the prostate gland grow across the midline and are rarely organ-confined. Tumors classified as pT2b are thus large and have less favorable outcome than pT2c tumors. The definition of pT2c is unclear and in particular it is uncertain if the presence of separate but minute foci of tumor in the contralateral lobe is sufficient to classify a tumor as pT2c, or if the main tumor focus must cross the midline before being considered pT2. There is also debate as to why extension across the midline of the gland should be considered an important prognostic feature. In line with this, a majority of the delegates present at the consensus meeting voted to abandon the current pT2 substaging category. Several alternative substaging systems were discussed but none of these gained consensus support. pT2 substaging is included in the seventh edition of the tumor node metestasis (TNM) classification,11 but it was recommended at the meeting that it should not be applied in clinical practice and that a designation of pT2 is sufficient for the staging of organ-confined cancers (Table 3). Given the favorable prognosis of organ-confined disease, it can also be questioned whether substaging is at all justified.

Table 3
Table 3
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It has been suggested that transition zone tumors have a more favorable prognosis than peripheral zone tumors of the same grade and size, with the reason being that these tumors are usually sited at a greater distance from the prostatic capsule/margin. Anterior tumors are also more likely to remain undetected by needle biopsies and multiple biopsy procedures may thus be necessary to provide a definitive diagnosis. For these reasons, it was agreed that reports of radical prostatectomy specimens should contain a comment regarding the zonal origin of any cancer present.

The concept of an index tumor was discussed, however, there was no agreement as to an appropriate definition for this. In particular, no consensus was reached as to which parameter should have priority for defining the index tumor when there is a conflict between highest grade, stage, or volume between separate tumor foci.

There are several methods for estimation of tumor volume, including planimetry, the grid method, assessment of the percentage of the specimen involved by cancer, and measurement of maximum tumor diameter. Volume of prostate cancer correlates with other prognostic factors such as grade, stage, and ploidy and also with prognosis in patients who have undergone radical prostatectomy. Some investigators have reported that tumor volume is not an independent predictor of prognosis when Gleason score, the presence of extraprostatic extension, surgical margin positivity, and seminal vesicle invasion are included in the analysis.12 Other studies, based on series with larger tumors, have found that tumor volume is an independent prognostic factor.13 On account of these conflicting data, it was recommended that measurement and reporting of tumor volume should not be mandatory but that it was reasonable to give an objective measure of tumor size, such as greatest diameter of the largest tumor focus.

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EXTRAPROSTATIC EXTENSION, LYMPHOVASCULAR INVASION, AND LOCALLY ADVANCED DISEASE

The prostatic capsule is a poorly defined structure and not a true capsule, but is rather a transition between condensed prostatic stroma and more loosely arranged extraprostatic connective tissue.5 This structure is particularly poorly defined around the apex, the anterior prostate, and at the base of the gland. For these reasons, extraprostatic extension is considered a more appropriate terminology than capsule penetration. Extraprostatic extension is most frequently encountered in the posterolateral region at the neurovascular bundle. It was agreed that tumor adjacent to or invading into adipose tissue is diagnostic of extraprostatic extension. However, contrary to the situation with core biopsies, it was also agreed that prostatectomy specimens may be diagnosed with extraprostatic extension even when extraprostatic cancer is surrounded by desmoplastic connective tissue. Thus, tumor within a fibrous band, beyond the prostatic parenchyma or beyond condensed smooth muscle, is sufficient to diagnose extraprostatic disease.

In areas where the capsule is particularly poorly defined such as at the anterior, the apex, and at the bladder neck, growth into or at the level of adipose tissue is required for the diagnosis of extraprostatic extension. At the apex and anteriorly, there is a continuous transition between prostatic tissue and the striated muscle tissue of the pelvic floor. Hence, it was agreed that tumor growth around striated muscle does not necessarily indicate extraprostatic extension.

Extraprostatic extension can be stratified as focal or established (or extensive or nonfocal).14,15 Patients with focal extraprostatic extension have a more favorable outcome after radical prostatectomy than those with established/extensive extraprostatic extension and it was agreed that the extent of extraprostatic extension should therefore be specified in the report.5 There is, however, no uniform definition of these categories and measures such as “a few glands outside the prostate”14 or “less than one high power field in no more than two sections”15 have been used to define focal extraprostatic extension. Recently, Sung et al16 proposed that the radial distance of extraprostatic extension should be used, with a cutoff at 0.75 mm having prognostic significance. This method has some disadvantages: it is labor intensive and because the prostatic capsule is so poorly defined, it is very difficult to know from where this distance should be measured. It was recommended at the consensus conference that extraprostatic extension be stratified as focal or established, but no consensus was reached as to the definitions of these categories.

It has been shown that lymphovascular invasion correlates with risk of recurrence after radical prostatectomy, both in univariate and multivariate analysis.17,18 Thus, it was agreed that this should be reported when present.

In previous editions of the TNM classification, bladder neck invasion was classified as pT4 disease, even when invasion was microscopic rather than macroscopic. It has, however, been shown that these patients have an outcome similar to those with ordinary extraprostatic extension and it was agreed that the TNM classification should be revised accordingly. Indeed, in the latest edition, microscopic bladder neck invasion is now considered pT3a disease, whereas macroscopic bladder neck invasion is categorized as pT4.11

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SEMINAL VESICLES AND LYMPH NODES

Cancer invading the seminal vesicle conveys a poor prognosis. Cancer usually invades by direct overgrowth from the basal parts of the prostate and 3 anatomic patterns of seminal vesicle invasion have been described.19 Despite this the prognostic value of these categories has not been confirmed by others.20

Invasion into what some consider the “intraprostatic portion of the seminal vesicle” has been reported to have a better prognosis than tumor invading the extraprostatic portion and for this reason it was agreed that extraprostatic seminal vesicle invasion must be present for stage pT3b; “intraprostatic portion of the seminal vesicle” should not be used in the diagnostic report.6

There was no consensus as to the optimal method for sampling lymph nodes, with options being submission of all the tissue that has been received, submission of macroscopically identifiable nodal tissue or of a sample of each lymph node identified. Quantitation of the number of lymph nodes seen on microscopic examination is undertaken by almost all pathologists, although it has been noted that the diameter of the largest metastasis is a better predictor of prognosis than the number of positive nodes alone.21–23 In prostate cancer, extranodal extension in lymph node metastases is not predictive on multivariate analysis and it was agreed that there is no need to report this.22

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SURGICAL MARGINS

In general, a prostatectomy specimen is surrounded by a thin layer of connective tissue and a wide surgical margin cannot be expected. Cancer must be seen extending to an inked margin for that margin to be considered positive.7 A margin is reported as negative if cancer is separated from the inked surface by as little as a few collagen fibers. Tumor close to, but not extending to a margin, should be reported as a margin negative as this does not influence prognosis. Positive margins are most common seen at the apex of the gland but may occur anywhere. Similar to extraprostatic extension, stratification of margin positivity into focal and more than focal may be useful, but the consensus conference failed to agree on methods for defining this. Among proposed definitions of focal margin positivity were: (1) only a few tumor cells in contact with the inked margin24; (2) margin positivity involving 1 gland in 1 section25; (3) 3 mm or less of positive margin in 1 section26; and (4) limited margin positivity in only 1 to 2 areas.14 Until a clinically relevant cutoff is decided upon, it was recommended that the linear extent of margin positivity be reported. Similar to the case of extraprostatic extension, it was agreed that the location of any tumor positive margin should be reported, as this gives important feedback to the clinician. It was further recommended that proximal and distal margins are more appropriately described as bladder neck and apical margins respectively.

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CONCLUSIONS

Standardization of handling and reporting of surgical specimens is necessary to enable efficient procurement of research data. It is also of clinical value when cancer therapy is individually tailored according to risk stratification. With an increasing diagnostic burden facing clinicians, there is a need to develop rational strategies for handling and reporting of specimens by pathologists to secure accurate diagnostic and prognostic information in a cost efficient manner.

The recommendations issued at this consensus conference have already been incorporated into the College of American Pathologists and the Royal College of Pathologists of Australasia's protocols for the reporting of radical prostatectomy specimens.27,28 It is anticipated that the results will further influence future guidelines and staging systems, including the Union Internationale Contre le Cancer (UICC)/American Joint Committee on Cancer (AJCC) TNM staging of prostate adenocarcinoma.

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REFERENCES

1. 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

2. Egevad L, Srigley JR and Delahunt B. International Society of Urological Pathology (ISUP) consensus conference on handling and staging of radical prostatectomy specimens: rationale and organization. Mod Pathol.. 2011;24:1–5

3. Samaratunga H, Montironi R, True L, et al. International Society of Urological Pathology (ISUP) consensus conference on handling and staging of radical prostatectomy specimens: working group 1 specimen handling. Mod Pathol.. 2011;24:6–15

4. van der Kwast TH, Amin MB, Billis A, et al. International Society of Urological Pathology (ISUP) consensus conference on handling and staging of radical prostatectomy specimens: working group 2 T2 substaging and prostate cancer volume. Mod Pathol.. 2011;24:16–25

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6. Berney DM, Wheeler TM, Grignon DJ, et al. International Society of Urological Pathology (ISUP) consensus conference on handling and staging of radical prostatectomy specimens: working group 4 seminal vesicles and lymph nodes. Mod Pathol.. 2011;24:39–47

7. Tan PH, Cheng L, Srigley JR, et al. International Society of Urological Pathology (ISUP) consensus conference on handling and staging of radical prostatectomy specimens: working group 5 surgical margins. Mod Pathol.. 2011;24:48–57

8. 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

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10. 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;216:34–63

11. Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual. 2010 Chicago Springer

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13. Humphrey PA, Walther PJ, Currin SM, et al. Histologic grade, DNA ploidy, and intraglandular tumor extent as indicators of tumor progression of clinical stage B prostatic carcinoma: a direct comparison. Am J Surg Pathol.. 1991;15:1165–1170

14. Epstein JI, Pizov G, Walsh PC. Correlation of pathologic findings with progression after radical retropubic prostatectomy. Cancer.. 1993;71:3582–3593

15. 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

16. 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

17. Herman CM, Wilcox GE, Kattan MW, et al. Lymphovascular invasion as a predictor of disease progression in prostate cancer. Am J Surg Pathol.. 2000;24:859–863

18. May M, Kaufmann O, Hammermann F, et al. Prognostic impact of lymphovascular invasion in radical prostatectomy specimens. BJU Int.. 2007;99:539–544

19. 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

20. Epstein JI, Partin AW, Potter SR, et al. Adenocarcinoma of the prostate invading the seminal vesicle: prognostic stratification based on pathologic parameters. Urology.. 2000;56:283–288

21. Cheng L, Bergstralh EJ, Cheville JC, et al. Cancer volume of lymph node metastasis predicts progression in prostate cancer. Am J Surg Pathol.. 1998;22:1491–1500

22. Cheng L, Pisansky TM, Ramnani DM, et al. Extranodal extension in lymph node-positive prostate cancer. Mod Pathol.. 2000;13:113–118

23. Boormans JL, Wildhagen MF, Bangma CH, et al. Histopathological characteristics of lymph node metastases predict cancer-specific survival in node-positive prostate cancer. BJU Int.. 2008;102:1589–1593

24. 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

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26. 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

27. Srigley JR, Humphrey PA, Amin MB, et al. Protocol for the examination of specimens from patients with carcinoma of the prostate gland. Arch Pathol Lab Med.. 2009;133:1568–1576

28. Kench J, Clouston D, Delahunt B, et al. Prostate Cancer (Radical Prostatectomy) Structured Reporting Protocol. 20101st ed Sydney Royal College of Pathologists of Australasia IBSN 978-1-74187-462-4.

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Keywords:

prostate; adenocarcinoma; radical prostatectomy; stage; prognosis

© 2011 Lippincott Williams & Wilkins, Inc.

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