NEWS & VIEWS PAEDIATRICS
often refer to results obtained before introduction of targeted therapies. This large COG series represents a very helpful database to assist future guidelines development, especially if further therapeutic information and extended follow-up data become available. In this regard, the issue concerning the high rate of lymph node involvement is significant. The implication of positive lymph nodes—a common finding among adolescents with translocation RCCs—as a negative prognostic biomarker is debated, and, therefore, so is the role of routine radical lymphadenectomy in children with RCC. In a previous literature review,5 >90% of children remained disease-free after a median 4.4 years when involved nodes were completely resected, in the absence of distant metastases. Thus, long-term follow-up data from the COG report is necessary before any favourable short-term outcome can be confirmed. Obtaining a comprehensive validation of the prognostic value of lymph node involvement might help in defining the role of retroperitoneal node dissection. In addition, as the sensitivity of imaging to rule out lymph node involvement is poor, the lack of sampling in the series reported by Geller (41% of cases failed to have lymph nodes sampled) is troubling, and alerts us to the need for improved education regarding this issue among paediatric surgeons. Radical nephrectomy remains the mainstay of treatment for children and adolescents with RCC. Small renal tumours in adults are increasingly managed with nephron-sparing interventions when technically feasible, but reports of elective partial nephrectomy performed for the treatment
Towards evidence-based management of paediatric RCC Refers to Geller, J. I. et al. Characterization of adolescent and paediatric renal cell carcinoma: a report from the Children’s Oncology Group study AREN03B2. Cancer http://dx.doi.org/10.1002/cncr.29368
Filippo Spreafico
In a recent study published in Cancer, Geller et al.1 described 120 patients with RCC (median age was almost 13 years), prospectively registered on the Children’s Oncology Group (COG) study AREN03B2, forming, for the first time, a large series of well characterized paediatric renal cancers.
‘‘
…imaging sensitivity for the detection of nodal metastases remains poor…
’’
RCC in children and adolescents typically presents at advanced stage, with Xp11.2 translocation type being the most commonly identified—47% of patients in Geller and colleagues’ study. Lymph node involvement was frequent (48%), even among patients with small associated primary tumours, and imaging sensitivity for the detection of nodal metastases remains poor, an observation made in earlier studies and confirmed here. As recent reports speculate whether translocation carcinomas might be associated with chemotherapy for previous unrelated tumours,2 it is a shame that the authors of the COG series did not include data regarding patient history of chemotherapy exposure—if any—to better study this relationship. Although translocation RCCs were initially described as typically childhood tumours, adult translocation RCCs overall vastly outnumber paediatric cases because of the much higher general incidence of RCC in the adult population. Diagnostic
challenges with TFE immunohistochemical staining, lack of consistency in translocation RCC morphology, and infrequent use of specific FISH assays are likely to explain the fluctuating proportion of childhood cases within different reports. It is realistic to assume that paediatric RCCs reported as papillary or clear-cell types in previous series would, if re-examined today, turn out to be unrecognized translocation RCCs. Translocation RCC, which forms a distinct category characterized by trans locations involving Xp11.2 chromosome or, less frequently, 6p21, likely comprises the majority of paediatric RCCs.3 On the basis of clinical, morphological, immuno histochemical, and genetic similarities, the 2013 International Society of Urologic Pathology Vancouver classification of renal neoplasia grouped these tumours together under the heading of “MiT family translocation RCC”.4 Understanding whether translocation RCC represents the same disease across age groups might enable a wider cooperation with adult oncologists. If this is the case, adult trials of new drugs—where increased resources have been allocated to characterize such tumours—might open to adolescents as well, offering improved treatment options for paediatric patients. Guidelines for the management of paediatric RCCs suffer from a lack of data from prospective large observational studies, limiting the level of evidence. Many published reviews on the therapeutic manage ment of children and adolescents with RCC
NATURE REVIEWS | UROLOGY
Image courtesy of F. Spreafico
Renal cell carcinoma (RCC) is rare in childhood, and pathological diagnosis and optimal treatment approach of paediatric RCC remains a challenge. A recent study describes a large cohort of 120 children with RCC, providing important epidemiological and clinical information; however, a number of questions remain regarding the optimal medical and surgical therapy.
VOLUME 12 | AUGUST 2015 © 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS
‘‘
…translocation RCCs were initially described as typically childhood tumours…
’’
of translocation RCCs are uncommon, even in adults.6 Thus, we need additional data before this experience can be transferred to the paediatric population, where the translocation subtype is predominant.7 As lymph nodes are typically not sampled during partial nephrectomies, but are frequently involved even in small translocation tumours—observations confirmed in the present study by Geller et al.1—understaging and undertreatment are serious concerns for children with translocation RCC. Given that current adjuvant therapies are not curative, it might be worth considering whether a more compulsive approach to radical lymphadenectomy is warranted to achieve a surgically complete disease resection in these patients. One difficulty with applying this recommendation to the paediatric population might be that most children with a renal mass are suspected of having Wilms tumour rather than RCC, the standard surgery for which does not require formal retroperitoneal lymphadenectomy. I wonder whether the observations on lymph node spread confirmed in this large cohort by Geller and co-workers might support the systematic use of preoperative percutaneous renal tumour biopsy in all children older than 10–12 years of age, to guide the consequent surgical treatment. These observations (high incidence of nodal involvement, low incidence of sampling—especially when surgery is partial nephrectomy, and low sensitivity of imaging in detecting lymph node spread), together with the fact that the first renal tumour to suspect in a child is a Wilms tumour, mean that the possibility of early diagnosis of a renal mass in an adolescent as RCC, and not Wilms tumour, could be extremely valuable.
AUGUST 2015 | VOLUME 12
Systemic therapies for adult metastatic RCC have been changed by the introduction of drugs targeting tumour-related angiogenesis,7 although results so far have been modest. However, the largest clinical efficacy trials on targeted molecules have been conducted on clear cell RCC (ccRCC), which accounts for >75% of RCCs in adults, but only one of which was diagnosed in the COG centres participating in Geller and colleagues’1 study. Von HippelLindau (VHL) gene inactivation has been identified as a main driver in ccRCC, with somatic mutations or hypermethylation being present in >90% of cases,8 enabling the rationale for therapies targeting tumour angiogenesis. However, although such drugs have become the standard of care for adult metastatic ccRCC, few data exist regarding their effectiveness in paediatric translocation RCC, and their use should only be considered for patients with unresect able metastatic or advanced-stage disease.9 Some studies have suggested that the mTOR pathway could be an attractive potential therapeutic target for transl ocation tumours, owing to elevated expression of phosphorylated S6 in Xp 11 translocation RCC.10 This could be an attractive target, but research is limited by the difficulty of designing a clinical trial with so few cases. In their report, Geller and co-workers provided several important pieces of information with the potential to improve patient care and outcomes for children with RCC, particularly with regard to the need for lymph node sampling and prospective histological up-to-date diagnosis. However, further data are needed to determine the optimal medical approach, as these tumours have only been recently recognized and their natural history is poorly defined. Extended follow-up monitoring is recommended because, regardless of the age of the patient, translocation RCCs have the potential to metastasize many years after initial
diagnosis and treatment. This is my request to the authors—to support us in the near future with treatment and outcome data for the patients included in this COG series. Paediatric Oncology Unit, Haematology and Paediatric Onco-Haematology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, via Giacomo Venezian 1, 20133 Milano, Italy. [email protected] doi:10.1038/nrurol.2015.158 Published online 7 July 2015 Competing interests The author declares no competing interests. 1.
Geller, J. I. et al. Characterization of adolescent and paediatric renal cell carcinoma: a report from the Children’s Oncology Group Study AREN03B2. Cancer http://dx.doi.org/ 10.1002/cncr.29368. 2. Argani, P. et al. Translocation carcinomas of the kidney after chemotherapy in childhood. J. Clin. Oncol. 24, 1529–1534 (2006). 3. Spreafico, F., Collini, P., Terenziani, M., Marchianò, A. & Piva, L. Renal cell carcinoma in children and adolescents. Expert Rev. Anticancer Ther. 10, 1967–1978 (2010). 4. Srigley, J. R. et al. The International Society of Urological Pathology (ISUP) Vancouver Classification of renal neoplasia. Am. J. Surg. Pathol. 37, 1469–1489 (2013). 5. Geller, J. I. et al. Translocation renal cell carcinoma: lack of negative impact due to lymph node spread. Cancer 112, 1607–1616 (2008). 6. Gorin, M. A., Ball, M. W., Pierorazio, P. M., Argani, P. & Allaf, M. E. Partial nephrectomy for the treatment of translocation renal cell carcinoma. Clin. Genitorurin. Cancer 13, e199–e201 (2014). 7. Bhatt, J. R. & Finelli, A. Landmarks in the diagnosis and treatment of renal cell carcinoma. Nat. Rev. Urol. 11, 517–525 (2014). 8. Nickerson, M. et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumours. Clin. Cancer Res. 14, 4726–4734 (2008). 9. Malouf, G. G. et al. Targeted agents in metastatic Xp11 translocation/TFE3 gene fusion renal cell carcinoma (RCC): a report from the juvenile RCC network. Ann. Oncol. 21, 1834–1838 (2010). 10. Argani, P. et al. Xp11 translocation renal cell carcinoma (RCC): extended immunohistochemical profile emphasizing novel RCC markers. Am. J. Surg. Pathol. 34, 1295–1303 (2010).
www.nature.com/nrurol © 2015 Macmillan Publishers Limited. All rights reserved
often refer to results obtained before introduction of targeted therapies. This large COG series represents a very helpful database to assist future guidelines development, especially if further therapeutic information and extended follow-up data become available. In this regard, the issue concerning the high rate of lymph node involvement is significant. The implication of positive lymph nodes—a common finding among adolescents with translocation RCCs—as a negative prognostic biomarker is debated, and, therefore, so is the role of routine radical lymphadenectomy in children with RCC. In a previous literature review,5 >90% of children remained disease-free after a median 4.4 years when involved nodes were completely resected, in the absence of distant metastases. Thus, long-term follow-up data from the COG report is necessary before any favourable short-term outcome can be confirmed. Obtaining a comprehensive validation of the prognostic value of lymph node involvement might help in defining the role of retroperitoneal node dissection. In addition, as the sensitivity of imaging to rule out lymph node involvement is poor, the lack of sampling in the series reported by Geller (41% of cases failed to have lymph nodes sampled) is troubling, and alerts us to the need for improved education regarding this issue among paediatric surgeons. Radical nephrectomy remains the mainstay of treatment for children and adolescents with RCC. Small renal tumours in adults are increasingly managed with nephron-sparing interventions when technically feasible, but reports of elective partial nephrectomy performed for the treatment
Towards evidence-based management of paediatric RCC Refers to Geller, J. I. et al. Characterization of adolescent and paediatric renal cell carcinoma: a report from the Children’s Oncology Group study AREN03B2. Cancer http://dx.doi.org/10.1002/cncr.29368
Filippo Spreafico
In a recent study published in Cancer, Geller et al.1 described 120 patients with RCC (median age was almost 13 years), prospectively registered on the Children’s Oncology Group (COG) study AREN03B2, forming, for the first time, a large series of well characterized paediatric renal cancers.
‘‘
…imaging sensitivity for the detection of nodal metastases remains poor…
’’
RCC in children and adolescents typically presents at advanced stage, with Xp11.2 translocation type being the most commonly identified—47% of patients in Geller and colleagues’ study. Lymph node involvement was frequent (48%), even among patients with small associated primary tumours, and imaging sensitivity for the detection of nodal metastases remains poor, an observation made in earlier studies and confirmed here. As recent reports speculate whether translocation carcinomas might be associated with chemotherapy for previous unrelated tumours,2 it is a shame that the authors of the COG series did not include data regarding patient history of chemotherapy exposure—if any—to better study this relationship. Although translocation RCCs were initially described as typically childhood tumours, adult translocation RCCs overall vastly outnumber paediatric cases because of the much higher general incidence of RCC in the adult population. Diagnostic
challenges with TFE immunohistochemical staining, lack of consistency in translocation RCC morphology, and infrequent use of specific FISH assays are likely to explain the fluctuating proportion of childhood cases within different reports. It is realistic to assume that paediatric RCCs reported as papillary or clear-cell types in previous series would, if re-examined today, turn out to be unrecognized translocation RCCs. Translocation RCC, which forms a distinct category characterized by trans locations involving Xp11.2 chromosome or, less frequently, 6p21, likely comprises the majority of paediatric RCCs.3 On the basis of clinical, morphological, immuno histochemical, and genetic similarities, the 2013 International Society of Urologic Pathology Vancouver classification of renal neoplasia grouped these tumours together under the heading of “MiT family translocation RCC”.4 Understanding whether translocation RCC represents the same disease across age groups might enable a wider cooperation with adult oncologists. If this is the case, adult trials of new drugs—where increased resources have been allocated to characterize such tumours—might open to adolescents as well, offering improved treatment options for paediatric patients. Guidelines for the management of paediatric RCCs suffer from a lack of data from prospective large observational studies, limiting the level of evidence. Many published reviews on the therapeutic manage ment of children and adolescents with RCC
NATURE REVIEWS | UROLOGY
Image courtesy of F. Spreafico
Renal cell carcinoma (RCC) is rare in childhood, and pathological diagnosis and optimal treatment approach of paediatric RCC remains a challenge. A recent study describes a large cohort of 120 children with RCC, providing important epidemiological and clinical information; however, a number of questions remain regarding the optimal medical and surgical therapy.
VOLUME 12 | AUGUST 2015 © 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS
‘‘
…translocation RCCs were initially described as typically childhood tumours…
’’
of translocation RCCs are uncommon, even in adults.6 Thus, we need additional data before this experience can be transferred to the paediatric population, where the translocation subtype is predominant.7 As lymph nodes are typically not sampled during partial nephrectomies, but are frequently involved even in small translocation tumours—observations confirmed in the present study by Geller et al.1—understaging and undertreatment are serious concerns for children with translocation RCC. Given that current adjuvant therapies are not curative, it might be worth considering whether a more compulsive approach to radical lymphadenectomy is warranted to achieve a surgically complete disease resection in these patients. One difficulty with applying this recommendation to the paediatric population might be that most children with a renal mass are suspected of having Wilms tumour rather than RCC, the standard surgery for which does not require formal retroperitoneal lymphadenectomy. I wonder whether the observations on lymph node spread confirmed in this large cohort by Geller and co-workers might support the systematic use of preoperative percutaneous renal tumour biopsy in all children older than 10–12 years of age, to guide the consequent surgical treatment. These observations (high incidence of nodal involvement, low incidence of sampling—especially when surgery is partial nephrectomy, and low sensitivity of imaging in detecting lymph node spread), together with the fact that the first renal tumour to suspect in a child is a Wilms tumour, mean that the possibility of early diagnosis of a renal mass in an adolescent as RCC, and not Wilms tumour, could be extremely valuable.
AUGUST 2015 | VOLUME 12
Systemic therapies for adult metastatic RCC have been changed by the introduction of drugs targeting tumour-related angiogenesis,7 although results so far have been modest. However, the largest clinical efficacy trials on targeted molecules have been conducted on clear cell RCC (ccRCC), which accounts for >75% of RCCs in adults, but only one of which was diagnosed in the COG centres participating in Geller and colleagues’1 study. Von HippelLindau (VHL) gene inactivation has been identified as a main driver in ccRCC, with somatic mutations or hypermethylation being present in >90% of cases,8 enabling the rationale for therapies targeting tumour angiogenesis. However, although such drugs have become the standard of care for adult metastatic ccRCC, few data exist regarding their effectiveness in paediatric translocation RCC, and their use should only be considered for patients with unresect able metastatic or advanced-stage disease.9 Some studies have suggested that the mTOR pathway could be an attractive potential therapeutic target for transl ocation tumours, owing to elevated expression of phosphorylated S6 in Xp 11 translocation RCC.10 This could be an attractive target, but research is limited by the difficulty of designing a clinical trial with so few cases. In their report, Geller and co-workers provided several important pieces of information with the potential to improve patient care and outcomes for children with RCC, particularly with regard to the need for lymph node sampling and prospective histological up-to-date diagnosis. However, further data are needed to determine the optimal medical approach, as these tumours have only been recently recognized and their natural history is poorly defined. Extended follow-up monitoring is recommended because, regardless of the age of the patient, translocation RCCs have the potential to metastasize many years after initial
diagnosis and treatment. This is my request to the authors—to support us in the near future with treatment and outcome data for the patients included in this COG series. Paediatric Oncology Unit, Haematology and Paediatric Onco-Haematology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, via Giacomo Venezian 1, 20133 Milano, Italy. [email protected] doi:10.1038/nrurol.2015.158 Published online 7 July 2015 Competing interests The author declares no competing interests. 1.
Geller, J. I. et al. Characterization of adolescent and paediatric renal cell carcinoma: a report from the Children’s Oncology Group Study AREN03B2. Cancer http://dx.doi.org/ 10.1002/cncr.29368. 2. Argani, P. et al. Translocation carcinomas of the kidney after chemotherapy in childhood. J. Clin. Oncol. 24, 1529–1534 (2006). 3. Spreafico, F., Collini, P., Terenziani, M., Marchianò, A. & Piva, L. Renal cell carcinoma in children and adolescents. Expert Rev. Anticancer Ther. 10, 1967–1978 (2010). 4. Srigley, J. R. et al. The International Society of Urological Pathology (ISUP) Vancouver Classification of renal neoplasia. Am. J. Surg. Pathol. 37, 1469–1489 (2013). 5. Geller, J. I. et al. Translocation renal cell carcinoma: lack of negative impact due to lymph node spread. Cancer 112, 1607–1616 (2008). 6. Gorin, M. A., Ball, M. W., Pierorazio, P. M., Argani, P. & Allaf, M. E. Partial nephrectomy for the treatment of translocation renal cell carcinoma. Clin. Genitorurin. Cancer 13, e199–e201 (2014). 7. Bhatt, J. R. & Finelli, A. Landmarks in the diagnosis and treatment of renal cell carcinoma. Nat. Rev. Urol. 11, 517–525 (2014). 8. Nickerson, M. et al. Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumours. Clin. Cancer Res. 14, 4726–4734 (2008). 9. Malouf, G. G. et al. Targeted agents in metastatic Xp11 translocation/TFE3 gene fusion renal cell carcinoma (RCC): a report from the juvenile RCC network. Ann. Oncol. 21, 1834–1838 (2010). 10. Argani, P. et al. Xp11 translocation renal cell carcinoma (RCC): extended immunohistochemical profile emphasizing novel RCC markers. Am. J. Surg. Pathol. 34, 1295–1303 (2010).
www.nature.com/nrurol © 2015 Macmillan Publishers Limited. All rights reserved
