Pathology (January 2015) 47(1), pp. 1–3
EDITORIAL
Active surveillance for prostate cancer: the role of the pathologist BRETT DELAHUNT1, ELIZABETH HAMMOND2, LARS EGEVAD3, HEMAMALI SAMARATUNGA4, JOHN R. SRIGLEY5, PETER A. HUMPHREY6, MARK RUBIN7, JONATHAN I. EPSTEIN8, DANIEL W. LIN9, JOHN L. GORE9, JOHN N. NACEY10, LAURENCE KLOTZ11, HOWARD SANDLER12, ANTHONY L. ZIETMAN13, STUART HOLDEN14, RODOLFO MONTIRONI15, ANDREW J. EVANS16, JESSE K. MCKENNEY17, DAN BERNEY18, THOMAS M. WHEELER19, ARUL M. CHINNAIYAN20, LAWRENCE TRUE21, BEATRICE KNUDSEN22 AND MAHUL B. AMIN23 1Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand, 2Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA, 3Department of Oncology and Pathology, Karolinska University Hospital, Solna, Stockholm, Sweden, 4Aquesta Pathology and University of Queensland, Brisbane, Qld, Australia, 5Trillium Health Partners, Mississauga and McMaster University, Hamilton, ON, Canada, 6Department of Pathology, Yale University School of Medicine, New Haven, CT, USA, 7Institute for Precision Medicine and the Department of Pathology and
Laboratory Medicine, Weill Medical College of Cornell, University and New York-Presbyterian Hospital, New York, NY, USA, 8Department of Pathology, Urology and Oncology, Johns Hopkins School of Medicine, Baltimore, MA, USA, 9Department of Urology, University of Washington, Seattle, WA, USA, 10Department of Surgery, Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand, 11Division of Urology, Sunnybrook Health Sciences, Centre, University of Toronto, Toronto, ON, Canada, 12Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA, 13Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 14Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA, 15Section of Pathological Anatomy, Department of Biomedical Sciences and Public Health, Polytechnic University of the Marche Region (Ancona), Ancona, Italy, 16University Health Network, University of Toronto, Toronto, Ontario, Canada, 17Pathology and Laboratory Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH, USA, 18Department of Cellular Pathology, The Royal London Hospital, London, UK, 19Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA, 20Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA, 21Department of Pathology, University of Washington Medical Center, Seattle, CA, USA, 22Department of Biomedical Sciences and Department of Pathology & Laboratory Medicine Cedars-Sinai Medical Center, Los Angeles, CA, USA, and 23Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Prostate cancer is the most common visceral cancer diagnosed in males in Australia and New Zealand.1,2 Most cancers are found in asymptomatic men following prostate specific antigen screening and digital rectal examination, and increasingly tumours are shown to be localised to the prostate at the time of presentation. There is considerable debate as to the role of active treatment in patients whose cancer is unlikely to become clinically significant.3–5 Despite these arguments there is no doubt that some forms of prostate cancer pursue an aggressive clinical course and in the absence of curative treatment will result in morbidity and ultimately patient mortality. The efficacy of prostate cancer screening is hotly debated internationally and unfortunately much of this debate is hampered by the confounding influence of poorly designed clinical trials. Considerable emphasis is placed on treatment-associated morbidity and it would appear that these arguments have some validity for clinically insignificant slow growing tumours. There is increasing evidence that low grade, organ confined tumours will remain quiescent for substantial periods, thus supporting the concept that treatment may be deferred.1,2 Active surveillance (AS), where the patient is followed by regular clinical assessment and repeat prostate biopsies, has been advocated as an appropriate management option for these
Print ISSN 0031-3025/Online ISSN 1465-3931 DOI: 10.1097/PAT.0000000000000186
#
patients. This has the benefit of delaying curative treatment with its potential morbidity, while ensuring that the tumour has not progressed to clinical significance.6 The role of the pathologist is critical to the determination that a patient is appropriate for AS. A variety of protocols have been developed for enrolment of patients onto AS and for the initiation of definitive treatment for those on AS; however, there is no consensus and it has been noted that criteria vary from institution to institution.7 In order to develop a consensus protocol for AS of prostate cancer, the College of American Pathologists assembled expert groups from its membership, as well as from the International Society of Urological Pathology (ISUP) and the Association of Directors of Anatomic and Surgical Pathology. These groups have met regularly over the past 2 years, both face to face and in teleconferences, and have developed a series of consensus recommendations designed to assist pathologists in the assessment of specimens from patients undergoing AS for prostate cancer.8 It was noted that, although permitted in some protocols, prostate specific antigen (PSA) levels or kinetics are not generally used to define progression for patients on AS. It was also agreed that tumour grade is key for determining the
2014 Royal College of Pathologists of Australasia
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
2
DELAHUNT et al.
appropriateness of enrolling a patient in an AS program, and further, for determining if clinical reclassification is appropriate with conversion of AS into definitive curative management. It is recommended that repeat biopsies, undertaken as part of an AS protocol, should be systematic with sampling of the prostatic base, mid-gland and apex in the mid and lateral peripheral zones being considered appropriate. At present saturation biopsy is not mandated, but may be undertaken at the discretion of the urologist after patient consultation. Aspects relating to tumour quantification were considered. It was recommended that the total number of cores and the number of positive cores be recorded. It was also recommended that for the core showing the greatest involvement by tumour, the amount of cancer present should be recorded as a percentage of the total core length estimated by visual inspection or as the linear extent of tumour measured in millimetres. It was agreed that the amount of tumour in the other cores (percentages of total sampled tissue or total linear extent in millimetres) may also be reported. The assessment of tumour volume in a core, if the tumour foci are discontinuous, is problematic and a variety of measurement methodologies have been proposed. In such instances it was agreed that at least one of two measurements should be provided. Firstly, the amount of tumour expressed as a percentage of core length (visual estimation or linear millimetre measurement) in which the separate lengths of individual foci are summed. For the second measurement, the total length of core spanned by the discontinuous tumour foci, including the intervening benign tissue, should be given as a percentage of the total length of each involved core. The quantitation of tumour volume may be hampered by core fragmentation, which is frequently seen when multiple cores are submitted in a single specimen pot.9 It was noted that core fragmentation, as well as short cores, may bias percentage measurement and it was recommended that if any core or core fragment was 14,000 radical prostatectomy specimens, no tumour of Gleason score 6 showed metastatic spread of tumour to lymph nodes.14 In earlier reports, based upon large series of radical prostatectomy specimens, the occurrence of lymph node metastases were also found to be limited in Gleason score 6 tumours, being present in up to 3% of cases only.14,15 At present enrolment into an AS program and the decision to initiate definitive treatment for patients undergoing AS is dependent on clinical and pathological assessment. There are currently no predictive molecular or genetic biomarkers for prostate cancer to assist decision making with respect to AS, although a number of genetic based studies are in progress. Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. Address for correspondence: Professor Brett Delahunt, Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand. E-mail: brett. [email protected]
References 1. Australian Institute of Health and Welfare (AIHW). Prostate Cancer. Cancer series no. 79. Cat. no. CAN76. Canberra: AIHW, 2013; 79. 2. Prostate Cancer Taskforce. Diagnosis and Management of Prostate Cancer in New Zealand Men: Recommendations from the Prostate Cancer Taskforce. Wellington: Ministry of Health, 2012. 3. Etzioni R, Penson DF, Legler JM, et al. Overdiagnosis due to prostatespecific antigen screening: lessons from US prostate cancer incidence trends. J Natl Cancer Inst 2002; 94: 981–90. 4. McGregor M, Hanley JA, Boivin JF, McLean RG. Screening for prostate cancer: estimating the magnitude of overdetection. CMAJ 1998; 159: 1368–72. 5. Cooperberg MR, Broering JM, Kantoff PW, Carroll PR. Contemporary trends in low risk prostate cancer: risk assessment and treatment. J Urol 2007; 178: S14–9. 6. Xia J, Trock BJ, Cooperberg MR, et al. Prostate cancer mortality following active surveillance versus immediate radical prostatectomy. Clin Can Res 2012; 18: 5471–8. 7. Dall’Era MA, Cooperberg MR, Chan JM, et al. Active surveillance for early-stage prostate cancer: review of the current literature. Cancer 2008; 112: 1650–9. 8. Amin MB, Lin DW, Gore JL, et al. The critical role of the pathologist in determining eligibility for active surveillance as a management option of patients with prostate cancer. Consensus statement with recommendations supported by the College of American Pathologists, International Society of Urological Pathology, Association of Directors of Anatomic and Surgical Pathology, the New Zealand Society of Pathologists and the Prostate Cancer Foundation. Arch Pathol Lab Med 2014; 138: 1387–405. 9. Fajardo DA, Epstein JI. Fragmentation of prostatic needle biopsy cores containing adenocarcinoma: the role of specimen submission. BJU Int 2010; 105: 172–5. 10. Helpap B, Egevad L. The significance of modified Gleason grading of prostatic carcinoma in biopsy and radical prostatectomy specimens. Virch Arch 2006; 449: 622–7.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
ACTIVE SURVEILLANCE FOR PROSTATE CANCER
11. Delahunt B, Lamb DS, Srigley JR, et al. Gleason scoring: a comparison of classical and modified International Society of Urological Pathology (ISUP) criteria using nadir PSA as a clinical end point. Pathology 2010; 42: 339–43. 12. Epstein JI, Allsbrook WCJR, 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: 1228–42.
3
13. Epstein JI. An update of the Gleason grading system. J Urol 2010; 183: 433–40. 14. Ross HM, Kryvenko ON, Cowan JE, et al. Do adenocarcinomas of the prostate with Gleason score (GS), 6 have the potential to metastasize to lymph nodes? Am J Surg Pathol 2012; 36: 1346–52. 15. Liu J-J, Lichtensztajn DY, Gomez SL, et al. Nationwide prevalence of lymph node metastases in Gleason score 3 þ 3 ¼ 6 prostate cancer. Pathology 2014:306–10.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
EDITORIAL
Active surveillance for prostate cancer: the role of the pathologist BRETT DELAHUNT1, ELIZABETH HAMMOND2, LARS EGEVAD3, HEMAMALI SAMARATUNGA4, JOHN R. SRIGLEY5, PETER A. HUMPHREY6, MARK RUBIN7, JONATHAN I. EPSTEIN8, DANIEL W. LIN9, JOHN L. GORE9, JOHN N. NACEY10, LAURENCE KLOTZ11, HOWARD SANDLER12, ANTHONY L. ZIETMAN13, STUART HOLDEN14, RODOLFO MONTIRONI15, ANDREW J. EVANS16, JESSE K. MCKENNEY17, DAN BERNEY18, THOMAS M. WHEELER19, ARUL M. CHINNAIYAN20, LAWRENCE TRUE21, BEATRICE KNUDSEN22 AND MAHUL B. AMIN23 1Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand, 2Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA, 3Department of Oncology and Pathology, Karolinska University Hospital, Solna, Stockholm, Sweden, 4Aquesta Pathology and University of Queensland, Brisbane, Qld, Australia, 5Trillium Health Partners, Mississauga and McMaster University, Hamilton, ON, Canada, 6Department of Pathology, Yale University School of Medicine, New Haven, CT, USA, 7Institute for Precision Medicine and the Department of Pathology and
Laboratory Medicine, Weill Medical College of Cornell, University and New York-Presbyterian Hospital, New York, NY, USA, 8Department of Pathology, Urology and Oncology, Johns Hopkins School of Medicine, Baltimore, MA, USA, 9Department of Urology, University of Washington, Seattle, WA, USA, 10Department of Surgery, Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand, 11Division of Urology, Sunnybrook Health Sciences, Centre, University of Toronto, Toronto, ON, Canada, 12Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA, 13Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 14Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA, 15Section of Pathological Anatomy, Department of Biomedical Sciences and Public Health, Polytechnic University of the Marche Region (Ancona), Ancona, Italy, 16University Health Network, University of Toronto, Toronto, Ontario, Canada, 17Pathology and Laboratory Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH, USA, 18Department of Cellular Pathology, The Royal London Hospital, London, UK, 19Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA, 20Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA, 21Department of Pathology, University of Washington Medical Center, Seattle, CA, USA, 22Department of Biomedical Sciences and Department of Pathology & Laboratory Medicine Cedars-Sinai Medical Center, Los Angeles, CA, USA, and 23Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Prostate cancer is the most common visceral cancer diagnosed in males in Australia and New Zealand.1,2 Most cancers are found in asymptomatic men following prostate specific antigen screening and digital rectal examination, and increasingly tumours are shown to be localised to the prostate at the time of presentation. There is considerable debate as to the role of active treatment in patients whose cancer is unlikely to become clinically significant.3–5 Despite these arguments there is no doubt that some forms of prostate cancer pursue an aggressive clinical course and in the absence of curative treatment will result in morbidity and ultimately patient mortality. The efficacy of prostate cancer screening is hotly debated internationally and unfortunately much of this debate is hampered by the confounding influence of poorly designed clinical trials. Considerable emphasis is placed on treatment-associated morbidity and it would appear that these arguments have some validity for clinically insignificant slow growing tumours. There is increasing evidence that low grade, organ confined tumours will remain quiescent for substantial periods, thus supporting the concept that treatment may be deferred.1,2 Active surveillance (AS), where the patient is followed by regular clinical assessment and repeat prostate biopsies, has been advocated as an appropriate management option for these
Print ISSN 0031-3025/Online ISSN 1465-3931 DOI: 10.1097/PAT.0000000000000186
#
patients. This has the benefit of delaying curative treatment with its potential morbidity, while ensuring that the tumour has not progressed to clinical significance.6 The role of the pathologist is critical to the determination that a patient is appropriate for AS. A variety of protocols have been developed for enrolment of patients onto AS and for the initiation of definitive treatment for those on AS; however, there is no consensus and it has been noted that criteria vary from institution to institution.7 In order to develop a consensus protocol for AS of prostate cancer, the College of American Pathologists assembled expert groups from its membership, as well as from the International Society of Urological Pathology (ISUP) and the Association of Directors of Anatomic and Surgical Pathology. These groups have met regularly over the past 2 years, both face to face and in teleconferences, and have developed a series of consensus recommendations designed to assist pathologists in the assessment of specimens from patients undergoing AS for prostate cancer.8 It was noted that, although permitted in some protocols, prostate specific antigen (PSA) levels or kinetics are not generally used to define progression for patients on AS. It was also agreed that tumour grade is key for determining the
2014 Royal College of Pathologists of Australasia
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
2
DELAHUNT et al.
appropriateness of enrolling a patient in an AS program, and further, for determining if clinical reclassification is appropriate with conversion of AS into definitive curative management. It is recommended that repeat biopsies, undertaken as part of an AS protocol, should be systematic with sampling of the prostatic base, mid-gland and apex in the mid and lateral peripheral zones being considered appropriate. At present saturation biopsy is not mandated, but may be undertaken at the discretion of the urologist after patient consultation. Aspects relating to tumour quantification were considered. It was recommended that the total number of cores and the number of positive cores be recorded. It was also recommended that for the core showing the greatest involvement by tumour, the amount of cancer present should be recorded as a percentage of the total core length estimated by visual inspection or as the linear extent of tumour measured in millimetres. It was agreed that the amount of tumour in the other cores (percentages of total sampled tissue or total linear extent in millimetres) may also be reported. The assessment of tumour volume in a core, if the tumour foci are discontinuous, is problematic and a variety of measurement methodologies have been proposed. In such instances it was agreed that at least one of two measurements should be provided. Firstly, the amount of tumour expressed as a percentage of core length (visual estimation or linear millimetre measurement) in which the separate lengths of individual foci are summed. For the second measurement, the total length of core spanned by the discontinuous tumour foci, including the intervening benign tissue, should be given as a percentage of the total length of each involved core. The quantitation of tumour volume may be hampered by core fragmentation, which is frequently seen when multiple cores are submitted in a single specimen pot.9 It was noted that core fragmentation, as well as short cores, may bias percentage measurement and it was recommended that if any core or core fragment was 14,000 radical prostatectomy specimens, no tumour of Gleason score 6 showed metastatic spread of tumour to lymph nodes.14 In earlier reports, based upon large series of radical prostatectomy specimens, the occurrence of lymph node metastases were also found to be limited in Gleason score 6 tumours, being present in up to 3% of cases only.14,15 At present enrolment into an AS program and the decision to initiate definitive treatment for patients undergoing AS is dependent on clinical and pathological assessment. There are currently no predictive molecular or genetic biomarkers for prostate cancer to assist decision making with respect to AS, although a number of genetic based studies are in progress. Conflicts of interest and sources of funding: The authors state that there are no conflicts of interest to disclose. Address for correspondence: Professor Brett Delahunt, Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand. E-mail: brett. [email protected]
References 1. Australian Institute of Health and Welfare (AIHW). Prostate Cancer. Cancer series no. 79. Cat. no. CAN76. Canberra: AIHW, 2013; 79. 2. Prostate Cancer Taskforce. Diagnosis and Management of Prostate Cancer in New Zealand Men: Recommendations from the Prostate Cancer Taskforce. Wellington: Ministry of Health, 2012. 3. Etzioni R, Penson DF, Legler JM, et al. Overdiagnosis due to prostatespecific antigen screening: lessons from US prostate cancer incidence trends. J Natl Cancer Inst 2002; 94: 981–90. 4. McGregor M, Hanley JA, Boivin JF, McLean RG. Screening for prostate cancer: estimating the magnitude of overdetection. CMAJ 1998; 159: 1368–72. 5. Cooperberg MR, Broering JM, Kantoff PW, Carroll PR. Contemporary trends in low risk prostate cancer: risk assessment and treatment. J Urol 2007; 178: S14–9. 6. Xia J, Trock BJ, Cooperberg MR, et al. Prostate cancer mortality following active surveillance versus immediate radical prostatectomy. Clin Can Res 2012; 18: 5471–8. 7. Dall’Era MA, Cooperberg MR, Chan JM, et al. Active surveillance for early-stage prostate cancer: review of the current literature. Cancer 2008; 112: 1650–9. 8. Amin MB, Lin DW, Gore JL, et al. The critical role of the pathologist in determining eligibility for active surveillance as a management option of patients with prostate cancer. Consensus statement with recommendations supported by the College of American Pathologists, International Society of Urological Pathology, Association of Directors of Anatomic and Surgical Pathology, the New Zealand Society of Pathologists and the Prostate Cancer Foundation. Arch Pathol Lab Med 2014; 138: 1387–405. 9. Fajardo DA, Epstein JI. Fragmentation of prostatic needle biopsy cores containing adenocarcinoma: the role of specimen submission. BJU Int 2010; 105: 172–5. 10. Helpap B, Egevad L. The significance of modified Gleason grading of prostatic carcinoma in biopsy and radical prostatectomy specimens. Virch Arch 2006; 449: 622–7.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
ACTIVE SURVEILLANCE FOR PROSTATE CANCER
11. Delahunt B, Lamb DS, Srigley JR, et al. Gleason scoring: a comparison of classical and modified International Society of Urological Pathology (ISUP) criteria using nadir PSA as a clinical end point. Pathology 2010; 42: 339–43. 12. Epstein JI, Allsbrook WCJR, 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: 1228–42.
3
13. Epstein JI. An update of the Gleason grading system. J Urol 2010; 183: 433–40. 14. Ross HM, Kryvenko ON, Cowan JE, et al. Do adenocarcinomas of the prostate with Gleason score (GS), 6 have the potential to metastasize to lymph nodes? Am J Surg Pathol 2012; 36: 1346–52. 15. Liu J-J, Lichtensztajn DY, Gomez SL, et al. Nationwide prevalence of lymph node metastases in Gleason score 3 þ 3 ¼ 6 prostate cancer. Pathology 2014:306–10.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
