NEWS & VIEWS BLADDER CANCER
Normal cystoscopy, malignant cytology in NMIBC: why biopsy? Antonio Lopez-Beltran
Bladder biopsy of normal-looking mucosa, as determined by cystoscopy, might not add clinical value in patients with positive voided-urine cytology after treatment of non-muscle-invasive bladder cancer. Methods to add value to bladder biopsies, such as characterization of molecular alterations, should be considered. Lopez-Beltran, A. Nat. Rev. Urol. 11, 550–551 (2014); published online 26 August 2014; doi:10.1038/nrurol.2014.225
Musser et al.1 have reported on the potential clinical significance of bladder biopsies performed in normal-looking mucosa seen at cystoscopy during follow-up surveillance of patients with treated non-muscle- invasive bladder cancer (NMIBC) and positive voided-urine cytology. Recurrence and progression rates were determined for 101 patients who underwent biopsy and 343 patients who were followed with cystoscopy alone. They found that all these patients, who had malignant cytology despite normal cystoscopy, had a high recurrence rate. In this setting, biopsy of bladder mucosa with a normal appearance was rarely positive and did not alter recurrence patterns.
‘‘
In assessing carcinoma in situ, voided-urine cytology has shown specificity up to 99%…
’’
Some urologists advocate random (map ping) bladder biopsies for complete evalu ation of NMIBC, given that carcinoma in situ can have a normal appearance on cystoscopy, but this approach remains somewhat controversial.2,3 On the basis of limited evidence, some clinically oriented guidelines advise routine biopsy of the bladder along with upper tract evaluation.1–3 Currently, random biopsies are indicated for multiple tumours or positive urine cytology.2,3 Cystoscopy and voided-urine cytology are the foundations of surveillance for patients with a history of NMIBC.2 False-negative results associated with cystoscopy can range from 10% to 40%. With respect to carcinoma in situ, cystoscopy can miss up to 20% of lesions because of their flat nature or resemblance to erythema from benign urological conditions. Overall sensitivities reported for urinary cytology are in the order of 25–65%, with lower values for low-grade urothelial tumours. Studies have demonstrated that 550 | OCTOBER 2014 | VOLUME 11
urine cytology has a high specificity (>90%) with a low false-negative interpretation. In assessing carcinoma in situ, voided-urine cytology has shown specificity up to 99% in some studies, leading to proposals that it should be the method of choice.4–6 Malignant cytology in the setting of a negative cystoscopy is a common clinical scenario and represents a diagnostic and therapeutic challenge. In the study by Musser et al.1 of patients with normallooking mucosa at cystoscopy, 23% underwent biopsy, and 2.5% of the biopsies had a pathological diagnosis of carcinoma in situ. The observed first-recurrence rates were similar in both groups: 5% in patients with biopsy and 4.4% in patients followed by cystoscopy alone. On the basis of these data, the authors concluded that biopsy might not be helpful in the clinical management of patients with NMIBC. Of note in this series is the fact that a selection bias might be present as a result of the exclusion criteria that were used. Patients who had a “questionable lesion that was focally biopsied” after the cytology result was known were not included in this study, and small papillary tumours were fulgurated in the clinic without biopsy and were considered to be recurrences. These exclusion criteria might have led to a selection of cases in this group of patients with normal-looking mucosa, which might in part explain the unexpectedly low rate (2.5%) of carcinoma in situ identified by biopsy in the current series. Important information is missing from the report by Musser et al.1 relating to the diagnosis of other intraepithelial lesions of the bladder mucosa, such as urothelial dysplasia (low-grade intraurothelial neoplasia).4 Urothelial dysplasia is considered a premalignant lesion of the urothelium that indicates urothelial instability and has the potential to increase recurrence (by 30–70%)
inkstock glu/iStock/Th Ali Altug Kiriso
and progression (by 15–19%) of NMIBC.4–7 Urothelial dysplasia is typically associated with molecular alterations including aberrant cytokeratin 20 expression, frequent p53 accumulation and deletions of chromosomes 9 and 17. These molecular alterations are also associated with carcinoma in situ, suggesting that dysplasia is a precursor to carcinoma in situ.4–6 Even normal-looking urothelium can harbour molecular alterations, such as chromosome 9 deletions and fibroblast growth factor receptor 3 mutations, which are believed to increase the potential for recurrence in patients with NMIBC.8 The study by Musser et al.1 highlights a problematic area of bladder pathology. Malignant cytology is associated with a high level of recurrence, despite normal cysto scopy results, and despite negative results of random bladder biopsies. Further studies should determine whether the pattern of mucosal biopsy sampling can be optimized to improve the detection rate in normallooking bladder mucosa, and whether the assessment of molecular alterations in biopsy tissues could provide additional predictive value in the surveillance of patients with a history of NMIBC. Promising biomarkers include cytokeratin 20, p16 or p53 detection at an immunohistochemical level, and CCND3 amplification or chromo somal gains or deletions at 3p or specific loci (such as p16INK4), detected by fluorescence in situ hybridization. Incorporating tissue biomarker characterization in bladder biopsy protocols has already improved bladder cancer detection in different clinical scenarios, and is now the standard for patho logy departments in a number of institutions across the USA and EU. www.nature.com/nrurol
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS
5.
Competing interests The author declares no competing interests.
6.
1.
2.
3.
4.
Musser, J. E. et al. Bladder biopsy of normal‑appearing mucosa is not helpful in patients with unexplained positive cytology after non-muscle invasive bladder cancer. J. Urol. http://dx.doi.org/10.1016/ j.juro.2014.06.068. Jones, J. S. & Larchian, W. A. in CampbellWalsh Urology 10th edn Ch. 81 (eds Wein, A., Kavoussi, L. R., Novick, A. C., Partin, A. W. & Peters, C. A.) 2335–2354 (Elsevier Saunders, 2012). May, F., Treiber, U., Hartung, R. & Schwaibold, H. Significance of random bladder biopsies in superficial bladder cancer. Eur. Urol. 44, 47–50 (2003). Lopez-Beltran, A., Montironi, R., Vidal, A., Scarpelly, M. & Cheng, L. Urothelial dysplasia of the bladder: diagnostic features and clinical
7.
8.
significance. Anal. Quant. Cytopathol. Histopathol. 35, 121–129 (2013). Sanfrancesco, J., Jones, J. S. & Hansel, D. E. Diagnostically challenging cases: what are atypia and dysplasia? Urol. Clin. North Am. 40, 281–293 (2013). Mazzucchelli, R. et al. Chromosomal abnormalities in macroscopically normal urothelium in patients with bladder pT1 and pT2a urothelial carcinoma: a fluorescence in situ hybridization study and correlation with histologic features. Anal. Quant. Cytopathol. Histopathol. 27, 143–151 (2005). Kiemeney, L. A., Witjes, J. A., Heijbroek, R. P., Debruyne, F. M. & Verbeek, A. L. Dysplasia in normal-looking urothelium increases the risk of tumour progression in primary superficial bladder cancer. Eur. J. Cancer 30A, 1621–1625 (1994). Lopez-Beltran, A. et al. Loss of heterozygosity at 9q32–33 (DBC1 locus) in primary noninvasive papillary urothelial neoplasm of low malignant potential and low-grade urothelial carcinoma of the bladder and their associated normal urothelium. J. Pathol. 215, 263–272 (2008).
IN MEMORIAM
Remembering Professor Chris F. Heyns André van der Merwe and Amir Zarrabi
The international and African urology communities lost a great academic leader and mentor when Professor Chris Heyns died suddenly on 2nd August 2014. He chaired a meeting as President of the South African Urology Association (SAUA) just hours before his death, making the shock of losing him even more intense. van der Merwe, A. & Zarrabi, A. Nat. Rev. Urol. 11, 551–552 (2014); published online 9 September 2014 doi:10.1038/nrurol.2014.246
Professor Heyns was born in Stellenbosch where he completed his high school career as one of the top three academic students in his province—a major achievement. At medical school he met Isabel Loubser, and they married a few years later, going on to have three children, Marianka, Christiaan, and Larissa, and, later, three grandchildren. Although he was Afrikaans speaking, he excelled at the English written language, Latin, and mathematics during his years at school. As a medical student he successfully wrote short stories for South African magazines to supplement his pocket money, and his language skills were evident throughout his life—his publications are testimony to his simplistic and beautiful academic writing style. His attention to detail will be remembered by all who worked with him; on occasion, he would jokingly refer to himself as a ‘hair splitter’.
‘‘
He was loved and respected by his students and never let an opportunity slip to share a joke
’’
His remarkable natural leadership skills were evident early in his career, from chairman of the residence he stayed in during his student days, to President of the College of Urologists of South Africa, President of the South African Urological Association (SAUA) and President of the Pan-African Urological Surgeons Association (PAUSA). In 2012 he was elected President of the Société Internationale d’Urologie (SIU), the most prestigious accomplishment that any South African urologist could hope to achieve. At the time of his death he was immediate Past President of the SIU. Chris Heyns was a true and natural academic with a wide range of interests within urology, including prostate cancer 1,2 and
NATURE REVIEWS | UROLOGY
Image courtesy of A. van der Merwe
Department of Pathology, Champalimaud Clinical Center, Champalimaud Foundation, Lisbon 300‑873, Portugal. [email protected]
infectious diseases.3,4 The title of his PhD thesis was ‘The Gubernac ulum During Testicular Descent in the Fetus—Collagen, Glycosaminoglycans and Androgen Recep tor Cont ent’. An impressive number of publications followed, many of which are still quoted in current leading textbooks.5–8 He authored many books and book chapters, including the student Textbook of Urology used by medical students at the University of Stellenbosch, and served on the editori al boards of several respected urological journals, including Nature Reviews Urology. He was loved and respec ted by his students and never let an opportunity slip to share a joke. Everything he did, he did to the very best of his ability and superbly well, even if it was a simple case report. 9 He had the insight to develop a new visual urinary symptom score (VPSS) for illiterate patients and validated this against the International Prostate Symptom Score (IPSS).10 These are only a few of his many achievements. At the end of his life we remember him as always being helpful and trustworthy. When he passed away so unexpectedly, he was just 4 months away from retirement. The world of urology has lost not only a superb academic and writer, but also a really good guy. Department of Urology, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Tygerberg 7550, South Africa (A.v.d.M., A.Z.). Correspondence to: A.v.d.M. [email protected] Competing interests The authors declare no competing interests.
VOLUME 11 | OCTOBER 2014 | 551 © 2014 Macmillan Publishers Limited. All rights reserved
Normal cystoscopy, malignant cytology in NMIBC: why biopsy? Antonio Lopez-Beltran
Bladder biopsy of normal-looking mucosa, as determined by cystoscopy, might not add clinical value in patients with positive voided-urine cytology after treatment of non-muscle-invasive bladder cancer. Methods to add value to bladder biopsies, such as characterization of molecular alterations, should be considered. Lopez-Beltran, A. Nat. Rev. Urol. 11, 550–551 (2014); published online 26 August 2014; doi:10.1038/nrurol.2014.225
Musser et al.1 have reported on the potential clinical significance of bladder biopsies performed in normal-looking mucosa seen at cystoscopy during follow-up surveillance of patients with treated non-muscle- invasive bladder cancer (NMIBC) and positive voided-urine cytology. Recurrence and progression rates were determined for 101 patients who underwent biopsy and 343 patients who were followed with cystoscopy alone. They found that all these patients, who had malignant cytology despite normal cystoscopy, had a high recurrence rate. In this setting, biopsy of bladder mucosa with a normal appearance was rarely positive and did not alter recurrence patterns.
‘‘
In assessing carcinoma in situ, voided-urine cytology has shown specificity up to 99%…
’’
Some urologists advocate random (map ping) bladder biopsies for complete evalu ation of NMIBC, given that carcinoma in situ can have a normal appearance on cystoscopy, but this approach remains somewhat controversial.2,3 On the basis of limited evidence, some clinically oriented guidelines advise routine biopsy of the bladder along with upper tract evaluation.1–3 Currently, random biopsies are indicated for multiple tumours or positive urine cytology.2,3 Cystoscopy and voided-urine cytology are the foundations of surveillance for patients with a history of NMIBC.2 False-negative results associated with cystoscopy can range from 10% to 40%. With respect to carcinoma in situ, cystoscopy can miss up to 20% of lesions because of their flat nature or resemblance to erythema from benign urological conditions. Overall sensitivities reported for urinary cytology are in the order of 25–65%, with lower values for low-grade urothelial tumours. Studies have demonstrated that 550 | OCTOBER 2014 | VOLUME 11
urine cytology has a high specificity (>90%) with a low false-negative interpretation. In assessing carcinoma in situ, voided-urine cytology has shown specificity up to 99% in some studies, leading to proposals that it should be the method of choice.4–6 Malignant cytology in the setting of a negative cystoscopy is a common clinical scenario and represents a diagnostic and therapeutic challenge. In the study by Musser et al.1 of patients with normallooking mucosa at cystoscopy, 23% underwent biopsy, and 2.5% of the biopsies had a pathological diagnosis of carcinoma in situ. The observed first-recurrence rates were similar in both groups: 5% in patients with biopsy and 4.4% in patients followed by cystoscopy alone. On the basis of these data, the authors concluded that biopsy might not be helpful in the clinical management of patients with NMIBC. Of note in this series is the fact that a selection bias might be present as a result of the exclusion criteria that were used. Patients who had a “questionable lesion that was focally biopsied” after the cytology result was known were not included in this study, and small papillary tumours were fulgurated in the clinic without biopsy and were considered to be recurrences. These exclusion criteria might have led to a selection of cases in this group of patients with normal-looking mucosa, which might in part explain the unexpectedly low rate (2.5%) of carcinoma in situ identified by biopsy in the current series. Important information is missing from the report by Musser et al.1 relating to the diagnosis of other intraepithelial lesions of the bladder mucosa, such as urothelial dysplasia (low-grade intraurothelial neoplasia).4 Urothelial dysplasia is considered a premalignant lesion of the urothelium that indicates urothelial instability and has the potential to increase recurrence (by 30–70%)
inkstock glu/iStock/Th Ali Altug Kiriso
and progression (by 15–19%) of NMIBC.4–7 Urothelial dysplasia is typically associated with molecular alterations including aberrant cytokeratin 20 expression, frequent p53 accumulation and deletions of chromosomes 9 and 17. These molecular alterations are also associated with carcinoma in situ, suggesting that dysplasia is a precursor to carcinoma in situ.4–6 Even normal-looking urothelium can harbour molecular alterations, such as chromosome 9 deletions and fibroblast growth factor receptor 3 mutations, which are believed to increase the potential for recurrence in patients with NMIBC.8 The study by Musser et al.1 highlights a problematic area of bladder pathology. Malignant cytology is associated with a high level of recurrence, despite normal cysto scopy results, and despite negative results of random bladder biopsies. Further studies should determine whether the pattern of mucosal biopsy sampling can be optimized to improve the detection rate in normallooking bladder mucosa, and whether the assessment of molecular alterations in biopsy tissues could provide additional predictive value in the surveillance of patients with a history of NMIBC. Promising biomarkers include cytokeratin 20, p16 or p53 detection at an immunohistochemical level, and CCND3 amplification or chromo somal gains or deletions at 3p or specific loci (such as p16INK4), detected by fluorescence in situ hybridization. Incorporating tissue biomarker characterization in bladder biopsy protocols has already improved bladder cancer detection in different clinical scenarios, and is now the standard for patho logy departments in a number of institutions across the USA and EU. www.nature.com/nrurol
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS
5.
Competing interests The author declares no competing interests.
6.
1.
2.
3.
4.
Musser, J. E. et al. Bladder biopsy of normal‑appearing mucosa is not helpful in patients with unexplained positive cytology after non-muscle invasive bladder cancer. J. Urol. http://dx.doi.org/10.1016/ j.juro.2014.06.068. Jones, J. S. & Larchian, W. A. in CampbellWalsh Urology 10th edn Ch. 81 (eds Wein, A., Kavoussi, L. R., Novick, A. C., Partin, A. W. & Peters, C. A.) 2335–2354 (Elsevier Saunders, 2012). May, F., Treiber, U., Hartung, R. & Schwaibold, H. Significance of random bladder biopsies in superficial bladder cancer. Eur. Urol. 44, 47–50 (2003). Lopez-Beltran, A., Montironi, R., Vidal, A., Scarpelly, M. & Cheng, L. Urothelial dysplasia of the bladder: diagnostic features and clinical
7.
8.
significance. Anal. Quant. Cytopathol. Histopathol. 35, 121–129 (2013). Sanfrancesco, J., Jones, J. S. & Hansel, D. E. Diagnostically challenging cases: what are atypia and dysplasia? Urol. Clin. North Am. 40, 281–293 (2013). Mazzucchelli, R. et al. Chromosomal abnormalities in macroscopically normal urothelium in patients with bladder pT1 and pT2a urothelial carcinoma: a fluorescence in situ hybridization study and correlation with histologic features. Anal. Quant. Cytopathol. Histopathol. 27, 143–151 (2005). Kiemeney, L. A., Witjes, J. A., Heijbroek, R. P., Debruyne, F. M. & Verbeek, A. L. Dysplasia in normal-looking urothelium increases the risk of tumour progression in primary superficial bladder cancer. Eur. J. Cancer 30A, 1621–1625 (1994). Lopez-Beltran, A. et al. Loss of heterozygosity at 9q32–33 (DBC1 locus) in primary noninvasive papillary urothelial neoplasm of low malignant potential and low-grade urothelial carcinoma of the bladder and their associated normal urothelium. J. Pathol. 215, 263–272 (2008).
IN MEMORIAM
Remembering Professor Chris F. Heyns André van der Merwe and Amir Zarrabi
The international and African urology communities lost a great academic leader and mentor when Professor Chris Heyns died suddenly on 2nd August 2014. He chaired a meeting as President of the South African Urology Association (SAUA) just hours before his death, making the shock of losing him even more intense. van der Merwe, A. & Zarrabi, A. Nat. Rev. Urol. 11, 551–552 (2014); published online 9 September 2014 doi:10.1038/nrurol.2014.246
Professor Heyns was born in Stellenbosch where he completed his high school career as one of the top three academic students in his province—a major achievement. At medical school he met Isabel Loubser, and they married a few years later, going on to have three children, Marianka, Christiaan, and Larissa, and, later, three grandchildren. Although he was Afrikaans speaking, he excelled at the English written language, Latin, and mathematics during his years at school. As a medical student he successfully wrote short stories for South African magazines to supplement his pocket money, and his language skills were evident throughout his life—his publications are testimony to his simplistic and beautiful academic writing style. His attention to detail will be remembered by all who worked with him; on occasion, he would jokingly refer to himself as a ‘hair splitter’.
‘‘
He was loved and respected by his students and never let an opportunity slip to share a joke
’’
His remarkable natural leadership skills were evident early in his career, from chairman of the residence he stayed in during his student days, to President of the College of Urologists of South Africa, President of the South African Urological Association (SAUA) and President of the Pan-African Urological Surgeons Association (PAUSA). In 2012 he was elected President of the Société Internationale d’Urologie (SIU), the most prestigious accomplishment that any South African urologist could hope to achieve. At the time of his death he was immediate Past President of the SIU. Chris Heyns was a true and natural academic with a wide range of interests within urology, including prostate cancer 1,2 and
NATURE REVIEWS | UROLOGY
Image courtesy of A. van der Merwe
Department of Pathology, Champalimaud Clinical Center, Champalimaud Foundation, Lisbon 300‑873, Portugal. [email protected]
infectious diseases.3,4 The title of his PhD thesis was ‘The Gubernac ulum During Testicular Descent in the Fetus—Collagen, Glycosaminoglycans and Androgen Recep tor Cont ent’. An impressive number of publications followed, many of which are still quoted in current leading textbooks.5–8 He authored many books and book chapters, including the student Textbook of Urology used by medical students at the University of Stellenbosch, and served on the editori al boards of several respected urological journals, including Nature Reviews Urology. He was loved and respec ted by his students and never let an opportunity slip to share a joke. Everything he did, he did to the very best of his ability and superbly well, even if it was a simple case report. 9 He had the insight to develop a new visual urinary symptom score (VPSS) for illiterate patients and validated this against the International Prostate Symptom Score (IPSS).10 These are only a few of his many achievements. At the end of his life we remember him as always being helpful and trustworthy. When he passed away so unexpectedly, he was just 4 months away from retirement. The world of urology has lost not only a superb academic and writer, but also a really good guy. Department of Urology, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Tygerberg 7550, South Africa (A.v.d.M., A.Z.). Correspondence to: A.v.d.M. [email protected] Competing interests The authors declare no competing interests.
VOLUME 11 | OCTOBER 2014 | 551 © 2014 Macmillan Publishers Limited. All rights reserved
