EURURO Vol. 72 No. 6

Introduction

Renal cell carcinoma (RCC) is a relatively rare cancer,

although it is estimated that there are

338 000 new cases

annually, with a 22% increase projected by 2020

[1] .

RCC is

characterized by distinct histological subtypes defined by

the 2016 World Health Organization classification

[2]

. Among the malignant tumors, clear-cell RCC (ccRCC)

accounts for approximately 75% of kidney cancer. Subtypes

making up the remaining 20–25% RCCs are papillary types

(pRCC) 1 and 2, chromophobe (chRCC), collecting duct,

translocation, medullary, and other very rare RCCs; collec-

tively, these variants of kidney cancer are often termed

‘‘non-ccRCCs’’. Like ccRCCs, these entities may be hereditary

or sporadic

[3] ;

however, unlike ccRCCs, limited data are

available for evidence-based treatment management, large-

ly due to a lack of trials specific to this population. As ‘‘non-

ccRCC’’ is a nondesignation, we employ the inclusive

nomenclature ‘‘rare kidney cancers’’ (RKCs).

The European Association of Urology (EAU) RCC Guideline

Panel recently performed a systematic review of manage-

ment strategies for ‘‘non-ccRCCs’’

[4] .

The outcome of this

process revealed an almost complete lack of evidence. In

response to this systematic review, the authors of this paper

met in San Francisco, USA, to reach a consensus on ‘‘how to

improve outcomes for ‘rare kidney cancer’ patients as a global

effort.’’ Specialists (urologists, medical oncologists, and

nephrologists) focused on the care of patients with RKCs,

as well as patient advocates and two RKC survivors,

unanimously agreed on the urgent need for improved

medical management of RKCs. This paper is a call to action

to appreciate the burden of RKCs and move forward with a

roadmap to improve the outcome for these patients with

well-coordinated clinical trials and translational research

efforts.

Evidence acquisition

In addition to the search results derived from the systematic

review, we queried the relevant literature in Pubmed,

Medline, abstracts fromproceedings of European Society for

Medical Oncology, and American Society of Clinical

Oncology(-GU) until February 18, 2017, in addition to

consulting key opinion leaders and stakeholders. A conven-

tional narrative review strategy was adopted to summarize

the data, available online (Appendices A and B).

Evidence synthesis

The evidence for systemic treatment of metastatic non-

ccRCC shows a trend toward favoring vascular endothelial

growth factor (VEGF) pathway–targeted therapy over

inhibitors of the mammalian target of rapamycin (mTOR),

although statistical significance was not reached

[4]

. The

lack of strong evidence calls for experimental data and

recommendations fromexperts in the field of RKCs as well as

key stakeholders to help generate informed management

strategies

[5] .

3.1.

Definition of RKCs

RKCs comprise a broad spectrum of over a dozen histopath-

ological entities

[2]

. Papillary RCCs (pRCC types 1 and 2) and

chRCCs are more common than the other RKCs. Distinguish-

ing genomic characteristics help characterize RKCs (Supple-

mentary Tables 1 and 2). An estimated 5–8% of RCCs have a

strong hereditary component, and 13 distinct hereditary RCC

syndromes are known, each associated with specific germ-

line mutations, RCC histology, and nonrenal manifestations

[6]

: von Hippel–Lindau syndrome (VHL; MIM193300),

hereditary pRCC (MIM605074), Birt–Hogg–Dube´ (BHD;

MIM135150) syndrome, hereditary leiomyomatosis and

renal cell cancer (HLRCC; MIM150800), tuberous sclerosis

(TS; MIM191100), germline succinate dehydrogenase (SDH)

mutations, hyperparathyroidism–jaw tumor syndrome

(MIM145001), phosphatase and tensin homolog (PTEN)

hamartoma syndrome (MIM601728), constitutional chro-

mosome 3 translocation (MIM144700),

BAP1

hereditary

cancer predisposition syndrome (MIM614327), and

MITF

associated susceptibility to melanoma and RCC syndrome

(MIM614456). The current best practice is to consider

genetic counseling for individuals suspected of having a

hereditary predisposition including early age of onset (age

46 yr), since timely diagnosis could prevent or identify

comorbidities at an early stage

[7] .

Somatic fusion transloca-

tions of

TFE3

and

TFEB

may affect 15% of patients with RCC

45 yr and 20–45% of children and young adults with RCC

(MIM300854). Even though some hereditary RCC syndromes,

such as VHL, predispose to ccRCC and not to one of the RKC

subtypes, all hereditary RCC syndromes should be considered

as RKCs since they typically require specialized care.

3.2.

Current treatment options

Cytoreductive nephrectomy should be considered carefully

in RKC patients, with the exception of pRCC type 1, where it

is considered beneficial

[8]

. In the metastatic setting,

limited available data suggest that RKCs are less responsive

to single-agent VEGF pathway–targeted therapy or mTOR

inhibitors than ccRCCs

( Table 1

). In a retrospective study

including 252 patients with RKCs and 1963 patients with

ccRCCs treated with targeted therapies, the median overall

Patient summary:

Patients confronted with rare kidney cancers are often treated the same

way as clear-cell renal cell carcinoma patients, despite little evidence from randomized

trials. Molecular characterization of tumors to stratify patients may improve outcomes.

Availability of potential agents and trials remain a problem. Collaboration among medical

centers is important to pool scarce data.

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