EURURO-5645; No. of Pages 13 EUROPEAN UROLOGY XXX (2014) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Collaborative Review – Kidney Cancer Editorial by XXX on pp. x–y of this issue
Understanding Pathologic Variants of Renal Cell Carcinoma: Distilling Therapeutic Opportunities from Biologic Complexity Brian Shuch a,*, Ali Amin b, Andrew J. Armstrong c, John N. Eble d, Vincenzo Ficarra e, Antonio Lopez-Beltran f, Guido Martignoni g, Brian I. Rini h, Alexander Kutikov i a
Department of Urology, Yale School of Medicine, New Haven, CT, USA;
Brown University, Providence, RI, USA; Durham, NC, USA;
d
c
b
Department of Pathology and Laboratory Medicine, Alpert School of Medicine,
Divisions of Urology and Medical Oncology, Departments of Medicine and Surgery, Duke School of Medicine,
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA;
e
Department of
Oncologic, Surgical and Gastrointestinal Sciences, Urologic Unit, University of Padova, Padova, Italy; f Unit of Anatomical Pathology, Department of Surgery and Pathology, University of Cordoba, Faculty of Medicine, Cordoba, Spain; g Department of Pathology and Diagnostic, University of Verona and Pederzoli Hospital, Peschiera del Garda, Verona, Italy;
h
Department of Solid Tumor Oncology and Urology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH,
USA; i Division of Urologic Oncology, Department of Surgery, Fox Chase Cancer Center, Philadelphia, PA, USA
Article info
Abstract
Article history: Accepted April 29, 2014
Context: Once believed to represent a uniform malignant phenotype, renal cell carcinoma (RCC) is now viewed as a diverse group of cancers that arise from the nephron. Objective: To review the pathologic characteristics, clinical behavior, molecular biology, and systemic therapy options of recognized RCC histologic subtypes. Evidence acquisition: A systematic review of English-language articles was performed using the Medline and Web of Science databases. Manuscripts were selected with consensus of the coauthors and evaluated using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria. Evidence synthesis: The major findings of the evaluated manuscripts are discussed with an emphasis on the description of the pathologic features, clinical behavior, prognosis, and therapeutic strategies. Conclusions: Classification schemes for kidney cancer have undergone dramatic changes over the past two decades. Improvements in these classification schemes are important, as pathologic variants differ not only in disease biology, but also in clinical behavior, prognosis, and response to systemic therapy. In the era of genomic medicine, further refinements in characterization of RCC subtypes will be critical to the progress of this burgeoning clinical space. Patient summary: Kidney cancer can be subdivided into related but different cancers that arise from the kidney’s tubules. In this article we review current classifications for kidney cancer, discuss their characteristics, and provide an overview of each subtype’s clinical behavior and treatment. We stress that each subtype harbors unique biology and thus responds differently to available treatment strategies. # 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords: Kidney cancer Pathology Subtype Systemic therapy Molecular biology
* Corresponding author. Department of Urology, Yale School of Medicine, 310 Cedar Avenue, Room 238A, New Haven, CT 06510, USA. Tel. +1 203 737 8076; Fax: +1 203 785 6475. E-mail address: [email protected] (B. Shuch).
http://dx.doi.org/10.1016/j.eururo.2014.04.029 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Shuch B, et al. Understanding Pathologic Variants of Renal Cell Carcinoma: Distilling Therapeutic Opportunities from Biologic Complexity. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.04.029
EURURO-5645; No. of Pages 13 2
EUROPEAN UROLOGY XXX (2014) XXX–XXX
1.
Introduction
Renal cell carcinoma (RCC) has emerged as one of the most rapidly evolving areas of solid tumor oncology. The past two decades have seen a dramatic change in the clinical landscape that shapes both RCC understanding and treatment. Development of minimally invasive techniques for surgery in the retroperitoneum, emergence of focal therapy, reemergence of percutaneous renal biopsy, introduction of active surveillance strategies, renewed interest in immunotherapy, and the clinical development of targeted therapies for patients with advanced disease have all revolutionized kidney cancer care. Nevertheless, arguably, one of the most significant paradigm shifts in the clinical constructs that shape kidney cancer care is the change in the pathologic classification of RCC (Fig. 1). Efforts aimed at morphologically grouping specific cancers into distinct pathologic subtypes have not only allowed a common descriptive language, but are helping to crystallize the understanding of RCC’s molecular origins and its clinical behavior. Indeed, these improved insights into the similarities and differences among RCC variants should offer clinical and therapeutic opportunities to improve patient care. 2.
Evidence acquisition
A systematic review of the literature was performed to evaluate the role histologic RCC subtypes have on patient prognosis and response to systemic therapy. The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria [1]. Searches were carried out on the Medline, Embase, and Web of Science databases using the terms renal cell carcinoma in combination with pathology or classification and prognosis or systemic therapy. We limited our search to English-language articles published between January 1985 and February 2014. Cited references from selected articles and prior reviews helped identify significant manuscripts not previously included with this search, including important articles outside the time period of the initial search. After exclusion of duplicates and papers outside the scope of this review, we identified a list of 412 relevant manuscripts. The full text of each article was reviewed for level of evidence, sample size, study design, and relevance to the review. Based on these criteria, 112 manuscripts were selected with consensus of the authors and critically assessed. The review is based on
evidence synthesis from the interactive peer-review process of the panel. 3.
Evidence synthesis
3.1.
History of renal cell carcinoma classification
In the late 1900s, significant disagreement existed in the pathology community over the origins of kidney tumors. Initially, Grawitz, largely due to the similarity in histologic architecture between normal adrenal tissue and clear cell RCC (ccRCC), proposed that these tumors originated from cells of the adrenal gland, a hypothesis that was later supported by Lubarsch [2]. Despite disagreement from other leading pathologists of the early 20th century, the terms hypernephroma or Grawitz tumor were used for many decades and still are occasionally seen in modern pathology reports [3]. Although ccRCC was recognized as the predominant histologic subtype, descriptions of tumors with papillary histologic configuration were also detailed in the early reports [2,4]. Papillary RCC was better characterized in the 1980s, when Kovacs et al. noted that these tumors contained >75% of papillary features and did not have characteristic 3p chromosomal loss on karyotype analysis [5]. Later, it was recognized there were two different classes of papillary tumors [6]. Chromophobe RCC, the third most common RCC subtype, was described in in the mid-1980s by Theones et al. [7]. Additional, rare, histologic subtypes were reported in the 1990s and included collecting duct, medullary RCC, translocation RCC, and mucinous tubular and spindle-cell RCC [8]. Consequently, in 2004, the World Health Organization updated the kidney tumor classification scheme [9]. In 2013, the International Society of Urological Pathology (ISUP) Vancouver Consensus Statement added five more epithelial tumor subtypes: tubulocystic RCC, acquired cystic disease-associated RCC, clear cell tubulopapillary RCC, the micropthalmia (MiT) family translocation RCCs, and hereditary leiomyomatosis–RCC syndrome-associated tumors (Table 1) [10]. Furthermore, this Consensus Statement mentioned three new entities that were given a provisional status: thyroid-like follicular RCC, succinate dehydrogenase B deficiency-associated RCC; and anaplastic lymphoma kinase translocation RCC (Table 1) [10]. 3.2.
General clinical implications stemming from histologic
classification of kidney cancer
Fig. 1 – Evolution of kidney cancer classification schemes.
The importance of robust classification schemes for tumors arising from the kidney cannot be overstated. For instance, up to 20% of enhancing small renal masses are benign and may not need treatment [11]. Tumors such as papillary adenomas, pure oncocytomas, and angiomyolipomas (except a rare epitheloid variant) do not possess metastatic potential. Only if large can these tumors cause local symptoms such as pain or hemorrhage, as is the case for angiomyolipomas >4 cm. Because lipid-poor angiomyolipomas and oncocytomas cannot be easily distinguished
Please cite this article in press as: Shuch B, et al. Understanding Pathologic Variants of Renal Cell Carcinoma: Distilling Therapeutic Opportunities from Biologic Complexity. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.04.029
EURURO-5645; No. of Pages 13 EUROPEAN UROLOGY XXX (2014) XXX–XXX
Table 1 – Renal cell tumors listed in the International Society of Urological Pathology Vancouver Modification ISUP Vancouver Modification of WHO (2004) Histologic Classification of Kidney Tumors [8] Renal cell tumors Papillary adenoma Oncocytoma Clear cell RCC Multilocular cystic clear cell of low malignant potential Papillary RCC (types 1 and 2) Chromophobe RCC Hybrid oncocytic chromophobe tumor Carcinoma of the collecting ducts of Bellini Renal medullary carcinoma MiT family translocation RCC [Xp11, t(6:11)] Carcinoma associated with neuroblastoma Mucinous tubular and spindle cell carcinoma Clear cell tubulopapillary RCC Hereditary leiomyomatosis RCC RCC, unclassified ISUP = International Society of Urological Pathology; MiT = micropthalmia transcription factor; RCC = renal cell carcinoma; WHO = World Health Organization.
from RCC radiographically, patients with these lesions often undergo resection [12]. Even on percutaneous renal biopsy, pathologists often have difficulty differentiating between the eosinophilic variant of chromophobe RCC and renal oncocytoma [13]. However, this distinction is critical, as those with a resected oncocytoma do not warrant further follow-up. Among the three most common RCC subtypes, ccRCC is more likely to present with advanced T stage, metastatic disease, and higher grade [14,15]. While papillary RCC is less ubiquitous than ccRCC, multifocality is frequent. As such, the incidence of papillary and ccRCC are similar in patients who present with synchronous multifocal RCC [16]. Importantly, not all multifocal tumors share the same histology. In patients with contralateral tumors, histologic concordance is 88% and 69% for synchronous and metachronous lesions, respectively [17]. For patients who undergo nephron-sparing surgery for synchronous, ipsilateral tumors, the malignant and histologic concordances are 77% and 59%, respectively [18]. Chromophobe RCC, while considered more indolent than the other major subtypes, usually presents at a larger tumor size [14,15]. Despite this, these tumors are generally confined to the kidney (stages I and II). The rare subtypes, such as medullary, collecting duct, translocation RCC, and unclassified renal tumors, are often extremely aggressive and frequently present with advanced stage and nodal or distant metastatic disease [7]. Meanwhile, tumors such as multicystic clear cell, mucinous tubular and spindle-cell RCC, and mixed-epithelial stromal tumors generally have a more indolent course [7]. Oncologic outcomes following treatment of localized disease may also vary among histologic subtypes; however, stage and grade at presentation appear to play a more critical role. Clear cell RCC has a much worse cancer-specific and overall survival (OS) than papillary and chromophobe
3
tumors [19,14]. Nevertheless, when controlling for multiple prognostic variables, Patard and colleagues have reported that that histology may not be an independent predictor of outcome, based on a large multi-institutional dataset [20]. Notably, this report did not include a central pathology review, perhaps influencing the results of this study. Non–clear cell histology accounts for approximately 10% of cases of metastatic RCC [21]. In the metastatic setting, the influence of histology on prognosis is less defined, due to the rarity of metastatic non–clear cell tumors, the heterogeneity of this group, and lack of pathology review in large series. In the immunotherapy era, Motzer and colleagues demonstrated that median survival in these patients is
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Collaborative Review – Kidney Cancer Editorial by XXX on pp. x–y of this issue
Understanding Pathologic Variants of Renal Cell Carcinoma: Distilling Therapeutic Opportunities from Biologic Complexity Brian Shuch a,*, Ali Amin b, Andrew J. Armstrong c, John N. Eble d, Vincenzo Ficarra e, Antonio Lopez-Beltran f, Guido Martignoni g, Brian I. Rini h, Alexander Kutikov i a
Department of Urology, Yale School of Medicine, New Haven, CT, USA;
Brown University, Providence, RI, USA; Durham, NC, USA;
d
c
b
Department of Pathology and Laboratory Medicine, Alpert School of Medicine,
Divisions of Urology and Medical Oncology, Departments of Medicine and Surgery, Duke School of Medicine,
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA;
e
Department of
Oncologic, Surgical and Gastrointestinal Sciences, Urologic Unit, University of Padova, Padova, Italy; f Unit of Anatomical Pathology, Department of Surgery and Pathology, University of Cordoba, Faculty of Medicine, Cordoba, Spain; g Department of Pathology and Diagnostic, University of Verona and Pederzoli Hospital, Peschiera del Garda, Verona, Italy;
h
Department of Solid Tumor Oncology and Urology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH,
USA; i Division of Urologic Oncology, Department of Surgery, Fox Chase Cancer Center, Philadelphia, PA, USA
Article info
Abstract
Article history: Accepted April 29, 2014
Context: Once believed to represent a uniform malignant phenotype, renal cell carcinoma (RCC) is now viewed as a diverse group of cancers that arise from the nephron. Objective: To review the pathologic characteristics, clinical behavior, molecular biology, and systemic therapy options of recognized RCC histologic subtypes. Evidence acquisition: A systematic review of English-language articles was performed using the Medline and Web of Science databases. Manuscripts were selected with consensus of the coauthors and evaluated using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria. Evidence synthesis: The major findings of the evaluated manuscripts are discussed with an emphasis on the description of the pathologic features, clinical behavior, prognosis, and therapeutic strategies. Conclusions: Classification schemes for kidney cancer have undergone dramatic changes over the past two decades. Improvements in these classification schemes are important, as pathologic variants differ not only in disease biology, but also in clinical behavior, prognosis, and response to systemic therapy. In the era of genomic medicine, further refinements in characterization of RCC subtypes will be critical to the progress of this burgeoning clinical space. Patient summary: Kidney cancer can be subdivided into related but different cancers that arise from the kidney’s tubules. In this article we review current classifications for kidney cancer, discuss their characteristics, and provide an overview of each subtype’s clinical behavior and treatment. We stress that each subtype harbors unique biology and thus responds differently to available treatment strategies. # 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords: Kidney cancer Pathology Subtype Systemic therapy Molecular biology
* Corresponding author. Department of Urology, Yale School of Medicine, 310 Cedar Avenue, Room 238A, New Haven, CT 06510, USA. Tel. +1 203 737 8076; Fax: +1 203 785 6475. E-mail address: [email protected] (B. Shuch).
http://dx.doi.org/10.1016/j.eururo.2014.04.029 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Shuch B, et al. Understanding Pathologic Variants of Renal Cell Carcinoma: Distilling Therapeutic Opportunities from Biologic Complexity. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.04.029
EURURO-5645; No. of Pages 13 2
EUROPEAN UROLOGY XXX (2014) XXX–XXX
1.
Introduction
Renal cell carcinoma (RCC) has emerged as one of the most rapidly evolving areas of solid tumor oncology. The past two decades have seen a dramatic change in the clinical landscape that shapes both RCC understanding and treatment. Development of minimally invasive techniques for surgery in the retroperitoneum, emergence of focal therapy, reemergence of percutaneous renal biopsy, introduction of active surveillance strategies, renewed interest in immunotherapy, and the clinical development of targeted therapies for patients with advanced disease have all revolutionized kidney cancer care. Nevertheless, arguably, one of the most significant paradigm shifts in the clinical constructs that shape kidney cancer care is the change in the pathologic classification of RCC (Fig. 1). Efforts aimed at morphologically grouping specific cancers into distinct pathologic subtypes have not only allowed a common descriptive language, but are helping to crystallize the understanding of RCC’s molecular origins and its clinical behavior. Indeed, these improved insights into the similarities and differences among RCC variants should offer clinical and therapeutic opportunities to improve patient care. 2.
Evidence acquisition
A systematic review of the literature was performed to evaluate the role histologic RCC subtypes have on patient prognosis and response to systemic therapy. The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria [1]. Searches were carried out on the Medline, Embase, and Web of Science databases using the terms renal cell carcinoma in combination with pathology or classification and prognosis or systemic therapy. We limited our search to English-language articles published between January 1985 and February 2014. Cited references from selected articles and prior reviews helped identify significant manuscripts not previously included with this search, including important articles outside the time period of the initial search. After exclusion of duplicates and papers outside the scope of this review, we identified a list of 412 relevant manuscripts. The full text of each article was reviewed for level of evidence, sample size, study design, and relevance to the review. Based on these criteria, 112 manuscripts were selected with consensus of the authors and critically assessed. The review is based on
evidence synthesis from the interactive peer-review process of the panel. 3.
Evidence synthesis
3.1.
History of renal cell carcinoma classification
In the late 1900s, significant disagreement existed in the pathology community over the origins of kidney tumors. Initially, Grawitz, largely due to the similarity in histologic architecture between normal adrenal tissue and clear cell RCC (ccRCC), proposed that these tumors originated from cells of the adrenal gland, a hypothesis that was later supported by Lubarsch [2]. Despite disagreement from other leading pathologists of the early 20th century, the terms hypernephroma or Grawitz tumor were used for many decades and still are occasionally seen in modern pathology reports [3]. Although ccRCC was recognized as the predominant histologic subtype, descriptions of tumors with papillary histologic configuration were also detailed in the early reports [2,4]. Papillary RCC was better characterized in the 1980s, when Kovacs et al. noted that these tumors contained >75% of papillary features and did not have characteristic 3p chromosomal loss on karyotype analysis [5]. Later, it was recognized there were two different classes of papillary tumors [6]. Chromophobe RCC, the third most common RCC subtype, was described in in the mid-1980s by Theones et al. [7]. Additional, rare, histologic subtypes were reported in the 1990s and included collecting duct, medullary RCC, translocation RCC, and mucinous tubular and spindle-cell RCC [8]. Consequently, in 2004, the World Health Organization updated the kidney tumor classification scheme [9]. In 2013, the International Society of Urological Pathology (ISUP) Vancouver Consensus Statement added five more epithelial tumor subtypes: tubulocystic RCC, acquired cystic disease-associated RCC, clear cell tubulopapillary RCC, the micropthalmia (MiT) family translocation RCCs, and hereditary leiomyomatosis–RCC syndrome-associated tumors (Table 1) [10]. Furthermore, this Consensus Statement mentioned three new entities that were given a provisional status: thyroid-like follicular RCC, succinate dehydrogenase B deficiency-associated RCC; and anaplastic lymphoma kinase translocation RCC (Table 1) [10]. 3.2.
General clinical implications stemming from histologic
classification of kidney cancer
Fig. 1 – Evolution of kidney cancer classification schemes.
The importance of robust classification schemes for tumors arising from the kidney cannot be overstated. For instance, up to 20% of enhancing small renal masses are benign and may not need treatment [11]. Tumors such as papillary adenomas, pure oncocytomas, and angiomyolipomas (except a rare epitheloid variant) do not possess metastatic potential. Only if large can these tumors cause local symptoms such as pain or hemorrhage, as is the case for angiomyolipomas >4 cm. Because lipid-poor angiomyolipomas and oncocytomas cannot be easily distinguished
Please cite this article in press as: Shuch B, et al. Understanding Pathologic Variants of Renal Cell Carcinoma: Distilling Therapeutic Opportunities from Biologic Complexity. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.04.029
EURURO-5645; No. of Pages 13 EUROPEAN UROLOGY XXX (2014) XXX–XXX
Table 1 – Renal cell tumors listed in the International Society of Urological Pathology Vancouver Modification ISUP Vancouver Modification of WHO (2004) Histologic Classification of Kidney Tumors [8] Renal cell tumors Papillary adenoma Oncocytoma Clear cell RCC Multilocular cystic clear cell of low malignant potential Papillary RCC (types 1 and 2) Chromophobe RCC Hybrid oncocytic chromophobe tumor Carcinoma of the collecting ducts of Bellini Renal medullary carcinoma MiT family translocation RCC [Xp11, t(6:11)] Carcinoma associated with neuroblastoma Mucinous tubular and spindle cell carcinoma Clear cell tubulopapillary RCC Hereditary leiomyomatosis RCC RCC, unclassified ISUP = International Society of Urological Pathology; MiT = micropthalmia transcription factor; RCC = renal cell carcinoma; WHO = World Health Organization.
from RCC radiographically, patients with these lesions often undergo resection [12]. Even on percutaneous renal biopsy, pathologists often have difficulty differentiating between the eosinophilic variant of chromophobe RCC and renal oncocytoma [13]. However, this distinction is critical, as those with a resected oncocytoma do not warrant further follow-up. Among the three most common RCC subtypes, ccRCC is more likely to present with advanced T stage, metastatic disease, and higher grade [14,15]. While papillary RCC is less ubiquitous than ccRCC, multifocality is frequent. As such, the incidence of papillary and ccRCC are similar in patients who present with synchronous multifocal RCC [16]. Importantly, not all multifocal tumors share the same histology. In patients with contralateral tumors, histologic concordance is 88% and 69% for synchronous and metachronous lesions, respectively [17]. For patients who undergo nephron-sparing surgery for synchronous, ipsilateral tumors, the malignant and histologic concordances are 77% and 59%, respectively [18]. Chromophobe RCC, while considered more indolent than the other major subtypes, usually presents at a larger tumor size [14,15]. Despite this, these tumors are generally confined to the kidney (stages I and II). The rare subtypes, such as medullary, collecting duct, translocation RCC, and unclassified renal tumors, are often extremely aggressive and frequently present with advanced stage and nodal or distant metastatic disease [7]. Meanwhile, tumors such as multicystic clear cell, mucinous tubular and spindle-cell RCC, and mixed-epithelial stromal tumors generally have a more indolent course [7]. Oncologic outcomes following treatment of localized disease may also vary among histologic subtypes; however, stage and grade at presentation appear to play a more critical role. Clear cell RCC has a much worse cancer-specific and overall survival (OS) than papillary and chromophobe
3
tumors [19,14]. Nevertheless, when controlling for multiple prognostic variables, Patard and colleagues have reported that that histology may not be an independent predictor of outcome, based on a large multi-institutional dataset [20]. Notably, this report did not include a central pathology review, perhaps influencing the results of this study. Non–clear cell histology accounts for approximately 10% of cases of metastatic RCC [21]. In the metastatic setting, the influence of histology on prognosis is less defined, due to the rarity of metastatic non–clear cell tumors, the heterogeneity of this group, and lack of pathology review in large series. In the immunotherapy era, Motzer and colleagues demonstrated that median survival in these patients is
