D i a g n o s i s o f R e n a l Ce l l

C a rc i n o m a
A Clinician’s Perspective
Laurence Albiges, MD, PhDa, André P. Fay, MDa, Rana R. McKay, MDa,b,
Marina D. Kaymakcalan, PharmDa, Toni K. Choueiri, MDa,b,*

KEYWORDS
 Renal cell carcinoma  Clear cell  Biopsy  Prognosis  Biomarker

ABSTRACT Molecular Genetics, Surgical Pathology Clinics,

R
2015, Volume 8, Issue 4 and Mehra et al, Emerging
enal cell carcinoma (RCC) is a heteroge- Entities in Renal Neoplasia, Surgical Pathology
neous disease. A rigorous diagnostic Clinics, 2015, Volume 8, Issue 4) plays a crucial
assessment by a pathologist with close role in both localized and metastatic settings where
communication with the clinician provides more the findings therein define the appropriate manage-
accurate prognostication and informed treatment ment of patients with kidney cancer.
decisions. In the localized setting, an accurate In the localized setting, the pathologist’s analysis
prognostic assessment directs patients to poten- of the tumor biopsy triggers distinct strategies in
tial adjuvant clinical trials. For patients with the management of small unilateral or bilateral renal
advanced disease, the pathologic assessment masses. After partial or radical nephrectomy, the pa-
may have a direct impact on the systemic therapy thology assessment of the tumor defines the risk of
algorithm. Additionally, it provides the basis for recurrence and aids in determining the monitoring
continuous efforts in biomarker development. In and follow-up plans. In the metastatic setting, the
rare histologic subtypes, the interaction between pathologic findings can direct the systemic treat-
clinicians and pathologists provides an opportu- ment approach. Non–clear cell RCC (non-ccRCC)
nity to offer patients specific clinical trials. Molec- deserves special attention given the limited thera-
ular characterization platforms may identify peutic agents for this heterogeneous category of
targets for therapeutic intervention. disease entities. Over the past decade, new RCC
subtypes have been identified for which the clinical
outcome may not be fully established.3 In addition,
OVERVIEW some specific pathologic features, such as the pres-
ence of sarcomatoid differentiation, add major prog-
Renal cell carcinoma (RCC) is a relatively common nostic information that clinicians are likely to use
cancer. In 2014, the incidence of RCC in the United both to refine the overall prognosis estimation and
States was estimated to be 63,920 cases (kidney to select treatment options.
and renal pelvic cancers), potentially resulting in This article aims to summarize the clinician’s
13,860 deaths.1 Pathologic assessment2 (see also perspective on the pathologic diagnosis of RCC,
Hirsch et al, Adult Renal Cell Carcinoma: A Review with a focus on clinicians’ expectations of the
of Established Entities Form Morphology to pathologist to optimize the use of pathologic
surgpath.theclinics.com

Disclosures: All authors have declared no conflict of interest for this work.
a
Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue (DANA 1230), Boston, MA
02215, USA; b Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
* Corresponding author. Dana-Farber Cancer Institute, 450 Brookline Avenue (DANA 1230), Boston, MA
02215.
E-mail address: [email protected]

Surgical Pathology 8 (2015) 657–662

http://dx.doi.org/10.1016/j.path.2015.08.001
1875-9181/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
658 Albiges et al

features, including not only histologic assessment genetic alterations associated with metanephric
but also immunohistochemistry and cytogenetic adenoma (MA), a rare indolent kidney tumor that
and molecular strategies, in the management of may be difficult to differentiate from a small malig-
kidney cancer. nant kidney cancer. Because this is a benign tumor,
surveillance may be appropriate in most situations,
sparing the loss of nephrons. This study identified
RENAL MASS BIOPSY: EXPECTATIONS FROM the v-raf murine sarcoma viral oncogene homolog
THE CLINICIANS B1 (BRAF) V600E mutation in 26 of 29 MA cases
(approximately 90%). Given that BRAF V600E mu-
SMALL RENAL MASSES AND LOCALIZED tations are present in approximately 90% of all MA
RENAL CELL CARCINOMA cases11 and BRAF immunohistochemistry is sensi-
tive and specific,12 this could serve as a potential
The increasing incidence of small renal masses valuable diagnostic tool in the differential diagnosis
(SRMs), defined as less than 4 cm,4 has led of SRMs undergoing a kidney biopsy.
to the development of more conservative manage-
ment strategies to include ablative techniques or METASTATIC RENAL CELL CARCINOMA
active surveillance in select cases. To choose the
best strategy, clinicians rely on the biopsy diag- The use of renal mass biopsy in patients presenting
nosis provided by pathologists to distinguish with radiological findings suggestive of metastatic
from 3 chief groups of lesions: benign tumor, indo- disease is usually more limited. It is commonly
lent cancer, and aggressive cancer. restricted to patients not eligible for primary ne-
Percutaneous biopsy for diagnostic assessment phrectomy due to comorbidities or to other poor
of SRMs has the potential to avoid unnecessary prognostic criteria,13 which usually drive physi-
surgeries and support treatment decisions, espe- cians to offer patients upfront systemic ther-
cially in patients at increased surgical risk.5 It has apy.14,15 In this specific setting, the role of biopsy
been demonstrated that SRM biopsies have both is not only to confirm the RCC diagnosis but also
acceptable sensitivity, ranging from 86% to to specify the histologic subtype of the tumor,
100%, and specificity for the diagnosis of malig- especially if it is of the clear cell subtype where ther-
nancy.6 The overall positive predictive value for apeutic options may be available. Conversely,
the diagnosis of malignancy in a report encom- despite the lack of specific systemic therapies for
passing 2474 renal tumor biopsies was 97.5%, non-ccRCC, identification of such specific histo-
with an overall sensitivity of 92.1% and a speci- logic tumor subtypes is critical for communicating
ficity of 89.7%.7 Although these results may be information about prognosis and potential thera-
illustrative of high-volume centers, such accuracy peutic options for patients with metastatic disease,
is now expected of routine renal mass biopsies, including the potential for clinical trials.
with the understanding that the rate of nondiag-
nostic biopsy, commonly due to insufficient mate-
rial, is approximately 22%, according to a large NEPHRECTOMY SPECIMEN: EXPECTATIONS
report of 1000 biopsies from a single institution.8 FROM THE CLINICIANS
In addition to differentiating malignant tumors
(see also Hirsch et al, Adult Renal Cell Carcinoma: Unlike other tumor types where histology can drive
A Review of Established Entities Form Morphology distinct therapeutic approaches, RCC is still
to Molecular Genetics, Surgical Pathology Clinics, managed with the same algorithm irrespective of
2015, Volume 8, Issue 4 and Mehra et al, Emerging histologic subtype. In patients with localized or
Entities in Renal Neoplasia, Surgical Pathology locally advanced disease who underwent partial
Clinics, 2015, Volume 8, Issue 4) from benign le- or radical nephrectomy with a curative intent, the
sions (see also Arias-Stella and Williamson, Up- pathologist’s report encompasses the distinct
dates in Benign Lesions of the Genitourinary parameters that define the risk of recurrence.16
Tract, Surgical Pathology Clinics, 2015, Volume Among these, tumor stage and grade are impor-
8, Issue 4) histologic subtype and Fuhrman grade tant features for the prediction of RCC recurrence
can be assessed on a core biopsy with success after nephrectomy. The primary tumor stage, as
rates of 86% to 100%6 and 64% to 93%, determined by the latest version of the TNM
respectively.9,10 staging system, is a powerful predictor of
Molecular analysis performed on renal biopsy cancer-specific survival (CSS).17,18 According to
specimens may also serve as a diagnostic tool the 2009 TNM staging system, the 5-year CSS
and be part of the decision-making process. ranges from 94.9% in pT1a to 27.1% in pT4
Recently, a study attempted to characterize the cancers. In addition, one of the most commonly
 Diagnosis of Renal Cell Carcinoma 659

used postoperative integrated staging system to enroll patients in clinical trials given that many
(ISS) models, referred to as Leibovich ISS, inte- of them are restricted to specific histologies. For
grates several pathologic parameters in addition example, patients with sarcomatoid features or
to the T and N stages: tumor size, Fuhrman grade, with collecting duct or medullary-type RCC can
and presence or absence of necrosis.19 Leibovich benefit from cytotoxic platinum-based chemo-
ISS is restricted to patients with ccRCC and its therapy,29 which is not used for the conventional
predictive accuracy was externally validated with type of RCC (ie, ccRCC). Similar to localized dis-
a discriminant ability of 78%. Similarly, the predic- ease, pathologic markers have not been included
tion of RCC CSS and overall survival in the postop- in the prognostic models for patients treated with
erative setting relies strongly on the pathologic targeted therapy in the metastatic setting.13,30–32
assessment of several features. Both the Karakie-
wicz nomogram20 and the University of California,
Los Angeles, ISS,21 use the TNM stage in combi- EVOLVING FIELD OF PROGNOSIS AND
nation with Fuhrman grade and clinical parameters PREDICTIVE BIOMARKERS IN RENAL CELL
(Eastern Cooperative Oncology Group perfor- CARCINOMA
mance status or symptoms classification). There-
fore, accurate pathologic determination is vital in Multiple predictive biomarkers have been investi-
assessing recurrence risk, RCC-specific mortality, gated in ccRCC,33 but most have fallen short of clin-
and overall survival. ical expectations and none have entered into current
Although several molecular markers for disease clinical practice. New studies, however, continue to
progression have been proposed, currently no bio- show promise. For example, the identification of
markers have been established to assess the risk chromatin remodeling gene mutations as the sec-
of recurrence in clinical practice. Recently, Schutz ond most frequent molecular event in ccRCC has
and colleagues22 investigated the association of sin- led to the identification of distinct molecular sub-
gle nucleotide polymorphisms in genes implicated in groups of RCC with distinct phenotypes.34,35 It is
RCC pathogenesis with the likelihood of RCC recur- anticipated that once commonly available for diag-
rence after intended curative treatment. In this nostic use, the immunohistochemical staining of
study, a germline single nucleotide polymorphism BAP1 and PBRM1, which correlates with the muta-
in the c-MET gene (rs11762213) was associated tional profile in these genes, may provide important
with an increased risk of recurrence in patients prognostic information in ccRCC,36 although thera-
with localized disease. An external validation set peutic implications remain unknown.
confirmed this association and this germline alter- In the era of immunotherapy, despite robust
ation may be incorporated in future prognostic tools clinical evidence of activity in a small number of
or used to plan further adjuvant clinical trials.23 patients, the well-designed SELECT trial failed to
More elaborate approaches to assess recur- identify patients more likely to benefit from high-
rence risk, such as gene expression signatures, dose interleukin-2 treatment.37 The identification
have been reported, with 3 models already avail- of the role of checkpoint blockade in RCC, how-
able,24–26 including a 16-gene signature, recently ever, has generated a strong resurgence of inter-
externally validated in stage I–III ccRCC.27 These est in identifying biomarkers of response to the
tools, however, are not currently available in clin- programmed cell death 1 (PD-1)/programmed
ical practice, and, given the lack of approved adju- death–ligand 1 (PD-L1) inhibitions.38 This exciting
vant therapy, the relevance of these signatures is discovery emphasizes that the role of the patholo-
limited to the ability of providing additional prog- gist is key in identifying new potential biomarker
nostic information without direct influence on ther- candidates and standardizing methodologies to
apeutic or monitoring guidelines. assess these biomarkers. Furthermore, the char-
In patients with metastatic disease, the impact of acterization of changes induced by previous ther-
nephrectomy pathology reports is similar to that of apies may help guide future treatments and clinical
biopsy reports, with the main information sought by research. As an example, the biomarker phase I
clinicians the confirmation of the histologic subtype study of nivolumab in metastatic RCC identified,
and the presence or absence of sarcomatoid/rhab- on sequential biopsies performed prior to PD-1 in-
doid differentiation. First and foremost, the confir- hibition and at cycle 2, increased T-cell infiltrates
mation of RCC is required for administration of by medians of 70% (CD31; range 53%–220%)
systemic therapy or for eligibility of clinical trial and 88% (CD81; 61%–257%) respectively.39
participation. Additionally, the histologic subtype, Accordingly, the expression of PD-L1 as a
although not integrated in the available prognostic biomarker is being investigated as a pathologic
models, may be associated with a distinct prog- assessment to serve as a predictive biomarker of
nosis28 and is a key piece of information needed PD-1 or PD-L1 inhibitors in metastatic RCC. This
660 Albiges et al

involves defining the nature of the staining (tumor refractory population based on promising results
cells vs infiltrating lymphocytes) as well as the from a phase II study.47 A phase III clinical trial
threshold of positivity (any positivity vs 5% for comparing cabozantinib versus everolimus is
example).38–41 Callea and colleagues42 have also currently under way (NCT01865747).
reported on the differential PD-L1 expression
between primaries and matching metastases, SUMMARY
highlighting that PD-L1 expression is mostly
observed in areas of highest tumor grade. Pathol- In summary, given the constant evolution re-
ogists remain the stakeholders of such efforts, and garding the classification of RCC,2,48,49 with the
continued translational collaboration is required to identification of new entities driven by specific
make significant progress in such studies. molecular alterations (see also Hirsch et al, Adult
Unlike other tumor types, few definitive Renal Cell Carcinoma: A Review of Established
target alterations have been identified in non- Entities Form Morphology to Molecular Genetics,
ccRCC despite ongoing studies, including the Surgical Pathology Clinics, 2015, Volume 8, Issue
recent molecular characterization of chromophobe 4 and Mehra et al, Emerging Entities in Renal
tumors.43 Given the rarity of some of these less Neoplasia, Surgical Pathology Clinics, 2015, Vol-
common histologic subtypes, increased collabora- ume 8, Issue 4), the pathologist’s role can include
tion among pathologists may prove beneficial, (1) highlighting the differences between newly
especially in the context of ongoing, large aca- characterized entities in terms of macroscopic
demic or consortia-led programs, such as The and microscopic features; (2) understanding the
Cancer Genome Atlas Network. Additionally, accu- underlying biology associated with these entities;
rate diagnosis of non–clear cell histology also en- (3) recommending the appropriate diagnostic tools
sures access to dedicated clinical trials, which (immunohistochemical staining, fluorescence in
may offer patients promising drugs in develop- situ hybridization, sequencing, or other tech-
ment. As an illustration, MET inhibition in papillary niques); and (4) reporting appropriate specific
RCC has yielded intriguing results in a phase II prognostic information, if and when available. Ulti-
trial44 and an active program investigating this mately, the close collaboration between clinicians,
approach in correlation with the status of MET mu- both urologists and oncologists, with pathologists
tation or other specific alterations is ongoing facilitates optimal management of a patient with
(NCT02127710 and NCT01524926). kidney cancer. The accurate assessment of tumor
Lastly, pathologists may also play a key role in histology and extent is key to offering patients the
investigating target modulation after systemic ther- most appropriate plan of care. Moreover, a pathol-
apy.45 Such findings may ultimately have an impact ogist’s expertise is needed to move the field of
on treatment sequencing offered to patients or have biomarker investigation forward, especially in the
an impact on the design of clinical trials with combi- context of new target identification and new drug
nation strategies. Increased expression of the re- development. Finally, non–clear cell histology is a
ceptor MET after vascular endothelial growth rapidly evolving field. Motivated by the lack of
factor (VEGF)/VEGF receptor (VEGFR) inhibition46 effective systemic therapies available to date, the
is one of the key features that has led to an ongoing tremendous effort of molecular characterization
investigation of a dual MET and VEGFR inhibitor (ca- may ultimately translate into meaningful clinical
bozantinib) in a VEGFR tyrosine kinase inhibitor information.

Pathologic Key Features Box

Pathologic Key Features Expected by Clinicians

Localized Setting Metastatic Setting
On Biopsy On Nephrectomy Specimen On Biopsy On Nephrectomy Specimen
Histology subtype Tumor size Histology subtype Histology subtype
Tumor stage (TN) Grade if possible Sarcomatoid features
Furhman grade Potential biomarkers (research
Histology subtype collaboration)
Necrosis
Vascular invasion
 Diagnosis of Renal Cell Carcinoma 661

12. Pinto A, Signoretti S, Hirsch MS, et al. Immunohisto-

Differential Diagnosis chemical staining for BRAF V600E supports the
diagnosis of metanephric adenoma. Histopathology
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Metastasis from another —
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grated staging systems for renal cell carcinoma. Eur
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17. Ficarra V, Novara G, Iafrate M, et al. Proposal for re-
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