EURURO Vol. 73 No. 1

79 148

Platinum Priority – Editorial
Referring to the article published on pp. 71–78 of this issue
Papillary Renal Cell Carcinoma: A Family Portrait
Ronan Flippot Eva Compe´rat Nizar M. Tannir Gabriel G. Malouf
a Department of Medical Oncology, Pitie´-Salpeˆtrie`re Hospital, AP-HP, University Pierre and Marie Curie, Paris, France; bDepartment of Pathology, Tenon
Hospital, AP-HP, University Pierre and Marie Curie, Paris, France; cDepartment of Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston,
TX, USA
Papillary renal cell carcinomas (pRCCs) are a diverse family
of tumors with mysteries awaiting to be unraveled. PRCCs
account for up to 15% of renal cell carcinomas and share a
common origin with the more frequent clear-cell subtype,
arising from the proximal nephron . PRCCs can be divided
into two established histological subtypes, type 1 pRCCs,
which bear recurrent oncogenic MET alterations, and type
2 pRCCs, which represent a wide range of diseases including
hereditary cancer syndromes such as germline mutations of
FH . From a histological point of view, pathologists are
aware that type 2 pRCCs are a heterogeneous group that will
probably have to be divided into different entities in the
future. This is probably not possible with only morphologi-
cal tools, with integration of molecular findings also
required. An important and intriguing element of pRCCs
is a distinct evolution between indolent localized tumors
and aggressive metastatic disease, with no biological basis
for this difference identified to date Treatments
targeting the VEGF pathway and mTOR inhibitors have
produced modest benefit in unselected patients with
metastatic disease . Thus, molecular profiling of pRCCs
represent a unique opportunity to better understand the
oncogenic mechanisms responsible for such diverse pre-
sentations, and will help in the design of rational therapies
based on relevant targets in human tissue.
The cancer genome atlas (TCGA) effort is the first global
attempt at a broader assessment of pRCC ontogeny
. Along with confirmation of MET alterations in >80%
of type 1 pRCCs, it revealed that type 2 RCCs encompassed
multiple diseases, with three independent subgroups that
differ according to their prognosis, molecular alterations,
and methylation profiles. Notably, TCGA uncovered
multiple molecular alterations associated with type
2 pRCCs, including dysregulation of cell cycle genes and
the NRF2-ARE pathway, as well as mutations in chromatin-
remodeling genes and the Hippo signaling pathway; a
CpG islands methylator phenotype (CIMP) was also
observed in cases with FH mutation, often associated
with young age and poor outcome in the context of
hereditary leiomyomatosis and renal cell carcinoma
syndrome (HLRCC) . These data improved our under-
standing of pRCCs, but encompassed mostly localized
tumors (97%), which may not be representative of
metastatic disease.
In this issue of European Urology, Pal et al take a bold
step towards molecular characterization of advanced pRCC
via targeted sequencing of 315 genes in tumors from
169 patients, of whom 60% had stage IV disease. Most of
their findings are in line with TCGA highlights, but shed
light on pivotal issues that characterize metastatic disease.
MET is yet again a central oncogenic alteration in type
1 pRCCs, with mutations in 20% and amplifications in 13% of
cases. These MET alterations in one-third of the patients
compare to >80% with MET alterations in the TCGA data set.
Indeed, Pal et al chose to consider copy number alterations
(CNAs) with only high-level MET amplifications (>6). While
this choice might ultimately be a more relevant marker in
predicting the efficacy of MET inhibitors, it will have to be
validated in prospective trials. What we also learned is that
the ontogeny of type 2 pRCC might share similarities with
type 1 pRCC. Indeed, both subtypes exhibit alterations in
cell cycle genes CDKN2A/B, TERT, RAS/RAF signaling, the DNA
damage pathway, and the mTOR pathway with comparable
frequency. Above all, we still have to understand whether
type 2 pRCCs encompass similar entities or multiple
diseases. The answers might come from dedicated studies
ava ilable at
journal homepage:
DOI of original article: .
* Corresponding author. Department of Medical Oncology, Pitie´-Salpeˆtrie`re Hospital, 47-83 Boulevard de l’Hoˆpital, 75013 Paris, France.
E-mail address: (G.G. Malouf).
0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.