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Hematol Oncol Clin North Am. Author manuscript; available in PMC 2024 December 01.
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Published in final edited form as:

Hematol Oncol Clin North Am. 2023 October ; 37(5): 977–992. doi:10.1016/j.hoc.2023.04.019.

Renal cell carcinoma of variant histology: Biology and therapies

Pavlos Msaouel, MD, PhDa,b,c,*, Giannicola Genovese, MD, PhDa,c,d,e, Nizar M. Tannir, MD;
FACPa
aDepartment of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer
Center, Houston, Texas, 77030, USA
bDepartment of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer
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Center, Houston, Texas, 77030, USA

cDavid
H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas,
MD Anderson Cancer Center, Houston, Texas, 77030, USA
dDepartment of Genomic Medicine, The University of Texas M.D. Anderson Cancer Center,
Houston, Texas, 77030, USA
eTRACTION platform, Division of Therapeutic Discoveries, The University of Texas M.D.
Anderson Cancer Center, Houston, Texas, 77030, USA

Keywords
chromophobe renal cell carcinoma; collecting duct carcinoma; non-clear cell renal cell carcinoma;
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MiTF translocation renal cell carcinoma; papillary renal cell carcinoma; renal medullary
carcinoma

Introduction
Renal cell carcinomas (RCCs) are divided into distinct subtypes characterized by specific
molecular alterations.1 Clear cell renal cell carcinoma (ccRCC) is the most common subtype
consisting of ~75% of RCC cases, while the remaining 25% is classified under the umbrella
term variant histology renal cell carcinomas (vhRCCs) also known as non-clear cell RCCs.1
The prognosis and efficacy of therapies can widely vary between vhRCC subtypes thus
posing a challenge to clinicians managing these tumors. Herein, we provide guidance on
how to choose appropriate treatment options for vhRCCs based on our evolving clinical
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and biological knowledge. We will restrict our focus to RCCs and not address non-RCC
histologies that can arise from the kidney, such as Wilms tumors (nephroblastomas),
malignant rhabdoid tumors (MRTs), urothelial carcinomas of the renal pelvis, and kidney
sarcomas. We will also prioritize the more common vhRCC subtypes that practicing
oncologists are likely to encounter at least once in their careers including papillary RCC
(PRCC), chromophobe RCC (CHRCC), microphthalmia transcription factor (MiTF) family
RCC (TRCC), renal medullary carcinoma (RMC), fumarate hydratase-deficient RCC (FH-

*
Corresponding Author: Pavlos Msaouel, MD, PhD, Department of Genitourinary Medical Oncology, Division of Cancer Medicine,
The University of Texas MD Anderson Cancer Center, 1155 Pressler St., Unit 1374, Houston, Texas 77030, Fax: (713) 745-0422,
[email protected].
 Msaouel et al. Page 2

RCC), collecting duct carcinoma (CDC), unclassified RCC (URCC), and vhRCCs with
sarcomatoid and rhabdoid dedifferentiation.1
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Systemic Therapies for vhRCC

There are four broad categories of systemic therapies typically used for RCCs:
cytokine-based immunotherapies, cytotoxic chemotherapies, targeted therapies, and immune
checkpoint therapies (ICTs). Cytokine-based immunotherapies such as high-dose IL-2 or
interferon-alpha do not typically yield responses in vhRCCs and are therefore currently not
recommended for any vhRCC subtype.2 Each vhRCC histology has a different sensitivity to
each of the remaining three therapeutic modalities (Table 1).1,3–5 The randomized controlled
trials (RCTs) comparing the anti–vascular endothelial growth factor (VEGF) multireceptor
tyrosine kinase inhibitor (TKI) sunitinib with mechanistic target of rapamycin (mTOR)
inhibitors such as everolimus or temsirolimus in vhRCCs6–9 were previously reviewed and
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summarized with the results weakly favoring sunitinib over mTOR inhibition although the
benefit was modest using either modality across vhRCC subtypes.1

For this chapter, we have updated the previously reported 2021 meta-analysis1 of objective
response rates (ORR) of ICTs in PRCC and CHRCC, the two most common vhRCC
subtypes, based on a review of the literature in PubMed, Medline, and abstracts from the
Proceedings of the European Society for Medical Oncology (ESMO) and the American
Society of Clinical Oncology (ASCO) between September 2012 and January 2023 (Figure
1).10–24 The results suggest that although PRCC demonstrates lower response rates (ORR
25.7% with 95% confidence interval [CI] of 17.7% to 34.4%) to ICT-based regimens than
what has been observed in ccRCC,1,25 it is nevertheless far more likely to respond to such
therapies than CHRCC (ORR 6.3% with 95% CI of 1.9% to 12.4%).
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Management of Papillary Renal Cell Carcinoma

PRCC is a heterogeneous malignancy that was previously subclassified into the papillary
type 1 and papillary type 2 morphologic subtypes. Type 1 PRCC is clinically more indolent
and biologically more associated with activating MET mutations and copy number gains of
the MET gene on chromosome 7, suggesting that c-MET inhibitors such as cabozantinib
may be particularly effective for this subtype. The entity formerly defined as type 2 PRCC
is clinically more aggressive and more biologically heterogeneous.1 As mentioned in the
chapter by Matar et al in this book, there is a major shift following the recent WHO
2022 classification from characterizing PRCC as type 1 or 2, to a therapeutically-focused
classification based on the potential dependence on the MET pathway.
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As reviewed in detail elsewhere,1 a number of TKIs targeting c-MET have been

investigated in PRCC, including foretinib,26 crizotinib,27,28 tivantinib,29 savolitinib,28,30,31
and cabozantinib.28 The practice-changing randomized, multicenter, four-arm, phase 2
PAPMET trial was designed to compare cabozantinib versus crizotinib, sunitinib, or the
selective c-MET inhibitor savolitinib in patients with PRCC who had received up to
one prior systemic therapy that did not include VEGF-directed or MET-directed drugs.28
However, the savolitinib and crizotinib arms were found to underperform during an interim

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analysis and PAPMET was thus modified into a two-arm, randomized, phase 2 trial focused
on comparing cabozantinib versus sunitinib.28 Following accrual completion, there was an
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efficacy signal favoring the primary endpoint of progression-free survival (PFS) with a
covariate-adjusted hazard ratio (HR) of 0.6 and 95% CI 0.37 to 0.97.32 The estimates for the
secondary endpoint of overall survival (OS) were inconclusive with HR = 0.84, 95% CI 0.47
to 1.51.28

Cabozantinib is now a standard for PRCC given the biological rationale and robust efficacy
signal, including the fact that it has demonstrated responses in cases that are resistant to
savolitinib.33 Although not as effective as in ccRCC, ICT-based combination therapies such
as nivolumab + ipilimumab are approved therapies for RCC and can yield responses in
patients with PRCC (Figure 1). Cabozantinib-based combination ICT regimens such as
nivolumab + cabozantinib that have shown efficacy in PRCC (Figure 1) should be prioritized
in patients with particularly aggressive PRCC that needs to quickly respond to at least one of
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the drugs in the regimen as it is unlikely that there will be time to administer these therapies
sequentially. PAPMET2 will help answer the question whether such a combination would be
a robust recommendation for all or most patients with PRCC. Emerging data also suggest
that lenvatinib + pembrolizumab is another ICT + TKI regimen that can yield high response
rates in PRCC (Figure 1).24

Other TKI-based regimens include the combination of lenvatinib + everolimus which

yielded objective responses in 3/20 (15%) of patients with treatment-naïve PRCC.34 While
data in the salvage setting for PRCC are scarce,35 lenvatinib + everolimus has shown
efficacy in ccRCC refractory to prior anti-VEGF TKIs, including cabozantinib.35 While the
combination of bevacizumab with the anti-epidermal growth factor receptor (anti-EGFR)
TKI erlotinib appears to be particularly effective against FH-RCC, it can also produce
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objective responses in 35% of patients with PRCC (95% CI 22.1% to 50.6%).36 Molecular
testing may also help further subclassify PRCC tumors, particularly those not showing
a morphologically classic pattern, and guide tailored management. For example, heavily
pretreated patients with PRCC harboring ALK-EML4 fusions have shown responses to the
ALK inhibitor alectinib.37

Management of Chromophobe Renal Cell Carcinoma

CHRCC is typically more indolent than either ccRCC or PRCC. However, between 5–10%
of patients with CHRCC will develop metastatic disease that is particularly refractory
to the ICT and TKI regimens developed for ccRCC.1,38–40 The presence of sarcomatoid
dedifferentiation, noted in ~20% of patients with metastatic CHRCC,40 is associated with
a particularly aggressive and treatment-refractory clinical course.1,41 (Figure 1).38,41 Novel
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pathways of interest include the targeting of ferroptosis as a metabolic vulnerability of

ChRCC.42

TKIs such as sunitinib and cabozantinib are generally less effective against chRCC but
can occasionally produce responses.5,33,43 Uniquely compared with other RCCs such as
ccRCC and PRCC, the mutation landscape of metastatic CHRCC includes a large proportion
of TP53 mutations (58% of cases), PTEN mutations (24%) and imbalanced chromosome

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duplications.39 In addition other mTOR pathway mutations can be found less commonly
in CHRCC in TSC1, TSC2, and mTOR.39 This provides a mechanistic rationale for using
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mTOR inhibitors such as everolimus in CHRCC.6,9 To that end, lenvatinib + everolimus

has yielded a signal of increased efficacy against CHRCC with 4 of 9 patients responding
to therapy34. Notably, lenvatinib + everolimus did not produce responses in a retrospective
report of five patients with sarcomatoid CHRCC.38 Furthermore, emerging data suggest
that the combination of lenvatinib with pembrolizumab yields far less responses in CHRCC
compared with other histologies such as PRCC (Figure 1).24

The overall poor response of CHRCC to the currently available systemic therapies motivates
the use of definitive local therapies such as metastasectomy in oligometastatic CHRCC. Of
note, CHRCC is almost twice as likely to spread to the liver than ccRCC.44

Management of MiTF Renal Cell Carcinomas

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The MiTF family of transcription factors is comprised of TFE3, TFEB, TFEC, and
MiTF.45 Aberrant activation of these transcriptions can happen either via translocations
leading to oncogenic fusions or via copy number amplifications.46 TRCCs can occur most
commonly due to TFE3 translocations, TFEB amplifications (second most common), and
TFEB translocations (third most common).47 The list of fusion partner genes for TFE3 and
TFEB continues to be expanded, and each fusion partner confers distinct histomorphological
and biological features.46 TFE3 translocation TRCC is the most common pediatric RCC
comprising more than 40% of RCCs in children and young adults. TFE3 translocation
TRCCs in adults may be more clinically aggressive and likely to harbor more genetic
alterations such as 17q gain compared with the pediatric population.1 In approximately 20%
of TFE3 translocation TRCC cases, a history of prior chemotherapy during childhood for
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malignancies, autoimmune disorders, or conditioning for bone marrow transplant.1 TRCCs

can be challenging to diagnose because they can mimic other RCC subytpes such as clear
cell RCC and PRCC on histologic examination.46 TRCC should be suspected in children
and young adults, particularly women, with RCCs that contain mixed clear cell and papillary
morphologies, especially if they have a history of chemotherapy during childhood.

Responses to dual ICT therapies are typically low with one retrospective study reporting
ORR to dual ICT in 1/18 TRCC patients (5.5%), whereas ICT + TKI yielded objective
responses in 4/11 patients (36%).48 Conversely, another retrospective study of 23 patients
with TRCC who received either ICT monotherapy or dual ICTs as salvage therapy noted
partial responses in 3 patients (13%) and stable disease in 3 patients (13%) for a disease
control rate of 26%.49
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Oncogenic TFE3 fusions can upregulate the MET pathway and one recent multi-center
retrospective study of 52 patients with TRCC reported ORR 17.3% with cabozantinib,
including 2 complete responses,50 A retrospective study of salvage therapy with mTOR
inhibitor monotherapy showed a durable objective response in one heavily pretreated patient
with TRCC and stable disease in the remaining 6 patients for a median PFS of 3 months.51
Therefore, mTOR inhibition alone or in combination with TKIs such as lenvatinib may have
a role in TRCC therapy.

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Management of Fumarate Hydratase-Deficient Renal Cell Carcinoma

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FH-RCC is an aggressive RCC that most commonly arises in individuals with germline
inactivating mutations in the fumarate hydratase (FH) gene as part of the hereditary
leiomyomatosis and renal cell carcinoma (HLRCC) syndrome.52,53 Up to 35% of
individuals with HLRCC syndrome will develop FH-RCC.54 Less than 20% of FH-RCC
cases will occur due to sporadic FH mutations in individuals without HLRCC.52,55 FH-RCC
will typically be negative for FH by immunohistochemistry (IHC). Because FH inactivation
results in aberrant succination of cellular proteins due the high fumarate levels, this stable
chemical modification can be detected by IHC for S-(2-succino)-cysteine (2SC).54 All
FH-RCC cases will show strong cytoplasmic and nuclear 2SC expression, with negative IHC
staining in the background non-tumor cells making this another highly sensitive assay for
FH-RCC.54,56
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Because FH is a critical metabolic enzyme in the Krebs cycle, its inactivation in FH-RCCs
results in a Warburg-like metabolism characterized by aerobic glycolysis and a subsequent
dependence on glucose.57 The combination of bevacizumab with erlotinib was developed to
inhibit glucose uptake by the tumor cells,57 and has been shown to yield an ORR of 72.1%
(95% CI 57.2% to 83.4%) and a median PFS of 21.1 months (95% CI 15.6 to 26.6) in
patients with FH-RCC.36 FH-RCC also often harbors copy number gains of chromosome 7q,
where MET is located,58,59 and retrospective data suggest that cabozantinib can yield higher
efficacy than ICT regimens or mTOR inhibitors in FH-RCC.60 Furthermore, cabozantinib
in combination with nivolumab yielded objective responses in 5/5 patients with FH-RCC
treated in a single-center phase 2 study.21 Emerging retrospective data also suggest that
lenvatinib in combination with either everolimus or pembrolizumab can yield responses in
patients with FH-RCC.55 Anecdotal experience suggests that at least some patients with
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FH-RCC may demonstrate deep responses to ICT monotherapy or combination ICT +

anti-VEGF TKI.61,62 Given that bevacizumab + erlotinib has shown excellent efficacy in
anti-VEGF TKI-refractory FH-RCC,36 it may be reasonable to start with first-line ICT
combinations and use bevacizumab + erlotinib as a salvage regimen.

Management of Renal Medullary Carcinoma

RMC is a highly aggressive malignancy that mainly occurs in young individuals with sickle
hemoglobinopathies such as sickle cell trait, Sβ, SC, or sickle cell disease.3,63 All sickle
hemoglobinopathies appear to confer a similar risk for RMC. However, because sickle cell
trait is far more prevalent than the other sickle hemoglobinopathies, most patients with
RMC will harbor the sickle cell trait.63 RMC is more common in men than women (~2:1
ratio) and arises from the right kidney in ~75% of cases due to the increased risk of
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renal medullary infarcts in the right kidney in the setting of sickle hemoglobinopathies.63,64
High-intensity exercise may increase RMC risk by aggravating renal medullary hypoxia
induced by red blood cell sickling.64 Less than 10% of RMC cases occur in patients
without sickle hemoglobinopathies, and these tumors are designated as RCC unclassified
with medullary phenotype (RCCU-MP) to distinguish from typical RMC associated with
sickle hemoglobinopathies.3 All RMC tumors demonstrate loss of INI1 (encoded by the
SMARCB1 gene) by IHC.3,65

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Platinum-based cytotoxic chemotherapy such as carboplatin + paclitaxel is the preferred

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first-line therapy for RMC as it has occasionally led to complete responses in patients
with metastatic RMC.3 Due to the high propensity of RMC to metastasize even when the
primary tumor size is small, upfront cytotoxic chemotherapy is strongly recommended even
in radiologically localized RMC. The only exception may be the rare cases where the
primary tumor is ≤ 4 cm in greatest dimension and the disease is clearly confined to the
kidney.3 Patients whose tumors respond to upfront chemotherapy can subsequently undergo
nephrectomy with curative intent.

The response rates of RMC to platinum-based cytotoxic chemotherapy are approximately

29% and can often be brief.66 Retrospective data reported that gemcitabine in combination
with doxorubicin yielded partial responses in 3/16 (19%) patients with platinum-refractory
RMC making this a viable second-line option.4 A recently completed clinical trial
(NCT03587662) will report on the efficacy of adding the proteasome inhibitor ixazomib
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to gemcitabine + doroxubicin. The EGFR pathway is significantly upregulated in RMC,65

and retrospective experience noted that EGFR targeting with erlotinib in combination with
bevacizumab can produce objective responses in heavily pretreated patients with RMC
who had progressed on prior platinum-based chemotherapy followed by gemcitabine +
doxorubicin.67 This approach is therefore a reasonable third-line option for patients with
RMC. Regarding ICT, the efficacy of nivolumab + ipilimumab in RMC was prospectively
investigated in a clinical trial that stopped early for futility (NCT03274258). Due to the
notably high upregulation of LAG3 in RMC, an ongoing phase 2 clinical trial is testing
high doses of the LAG3 inhibitor relatlimab in combination with nivolumab in patients with
RMC (NCT05347212).

Management of Collecting Duct Carcinoma.

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Other malignancies such as RMC, FH-RCC, NF2-mutant RCC (see below section on
Management of URCC) and ALK-translocation RCC should be excluded prior to making
a diagnosis of CDC.52 Platinum-based cytotoxic chemotherapy such as gemcitabine plus
cisplatin or carboplatin plus paclitaxel can be effective in CDC.1,68 In contrast to RMC,
CDCs can be sensitive to VEGF inhibition with cabozantinib demonstrating ORR of 35%
(including one complete response) in a phase 2 single-center trial in 23 patients with
CDC (BONSAI).69 The addition of bevacizumab to platinum-based chemotherapy may also
improve outcomes but increase toxicity.70 ICTs have also anecdotally produced responses
in patients with CDC.13,15 HER2 amplification has also be noted in up to 45% of CDC
tumors and the triple combination of capecitabine + lapatinib + trastuzumab produced a
partial response in a case report of a patient with CDC.71,72 Loss of chromosome 9p,
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where CDKN2A and CDKN2B are located, confers poor prognosis in CDC73 and a partial
response lasting more than 6 months with the CDK4/6 inhibitor palbociclib was reported in
a patient with metastatic CDC harboring homozygous CDKN2A/B deletion.74

Management of Unclassified Renal Cell Carcinoma

Aggressive URCC variants frequently harbor mutations in NF2 (18%), SETD2 (18%),
BAP1 (13%), KMT2C (10%), and mTOR (8%).75 URCCs with NF2 mutations may

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nowadays be considered a distinct subtype of NF2-mutated RCCs that can occasionally

show dramatic responses to ICT76 and may be susceptible to therapeutic targeting of the
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Hippo pathway. NF2-mutated RCCs may also respond to inhibition of the mTOR77–79 and
EGFR80 pathways. Prior to making a diagnosis of URCC, clinicians should look for clues
in the patient’s clinical and family history that can point to a specific vhRCC subtype. For
example, a personal history of prior chemotherapy in childhood may point to a diagnosis of
TRCC. IHC for ALK can occasionally establish the diagnosis of ALK-translocation RCC.81

Sarcomatoid or/and Rhabdoid Dediffentiation

Sarcomatoid or rhabdoid dedifferentiation is associated with worse prognosis than RCCs
without such morphological features and can occur across vhRCC subtypes.41,82 The
presence of sarcomatoid dedifferentiation attenuates responses to mTOR inhibitors and
anti-VEGF TKIs.82,83 The addition of cytotoxic chemotherapy agents such as gemcitabine
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to TKIs such as sunitinib or axitinib increases toxicity and is typically not favored.84 RCCs
with sarcomatoid and rhabdoid dedifferentiation often harbor higher PD-L1 expression and
increased density of tumor-infiltrating lymphocytes.85,86 Accordingly, ICT combinations
such as nivolumab + ipilimumab can produce durable complete responses in up to 18% of
patients with sarcomatoid ccRCC,87 making such regimens the contemporary therapeutic
mainstay for this histology. However, the role of ICT is less well defined in vhRCCs
with sarcomatoid or rhabdoid dedifferentiation. There is anecdotal evidence of durable
and deep responses to ICT in PRCCs with sarcomatoid and rhabdoid dedifferentiation.88
Conversely, sarcomatoid CHRCC typically responds poorly to currently available ICT
regimens, consistent with the overall experience with this vhRCC subtype (Figure 1).38

Adjuvant Therapy Considerations

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The KEYNOTE-564 phase 3 RCT randomized patients with ccRCC to either adjuvant
pembrolizumab or placebo and found a strong signal of benefit with adjuvant
pembrolizumab for the primary endpoint of disease-free survival leading to the FDA
approval of this regimen across RCCs.89 However, data are urgently needed on the
efficacy of adjuvant pembrolizumab in particular vhRCC histologies. In the absence of such
data, clinicians can use structured frameworks, reviewed extensively elsewhere and may
occasionally extrapolate from Keynote-427, a first-line study of single agent pembrolizumab
in vhRCC and inform patient-centered decisions.14,90

Conclusions
Each vhRCC subtype has distinct clinical and biological characteristics that influence
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management as summarized in Table 2. Accurate diagnosis is therefore critical because

certain histologies such as RMC are refractory to the therapies established for ccRCC and
are instead sensitive to cytotoxic chemotherapy. Trials dedicated to each vhRCC subtype
should emphasize RCTs for the more heterogeneous and common entities such as PRCC
requiring robust inferences, and biology-driven interventional studies, including umbrella
and basket trials,91 for the more rare and homogeneous vhRCCs driven by well-defined
biological drivers.

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ACKNOWLEDGEMENTS
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The authors would like to thank Dr. Jeffrey Graham for providing the exact numbers of PRCC and CHRCC
responders in the Graham et al. study used in our meta-analysis.22 Pavlos Msaouel is supported by the MD
Anderson Khalifa Scholar Award, the Andrew Sabin Family Foundation Fellowship, a Translational Research
Partnership Award (KC200096P1) by the United States Department of Defense, an Advanced Discovery Award
by the Kidney Cancer Association, a Translational Research Award by the V Foundation, the MD Anderson
Physician-Scientist Award, donations from the Renal Medullary Carcinoma Research Foundation in honor of Ryse
Williams, as well as philanthropic donations by the Chris “CJ” Johnson Foundation, and by the family of Mike
and Mary Allen. Giannicola Genovese is supported by the NIH R01CA258226, the NIH R21 CA259799-01A1 and
Translational Research Partnership Award (KC200096P1) by the United States Department of Defense.

DISCLOSURES
PM reports honoraria for scientific advisory boards membership for Mirati Therapeutics, Bristol Myers Squibb,
and Exelixis; consulting fees from Axiom Healthcare; non-branded educational programs supported by Exelixis
and Pfizer; leadership or fiduciary roles as a Medical Steering Committee member for the Kidney Cancer
Association and a Kidney Cancer Scientific Advisory Board member for KCCure; and research funding from
Takeda, Bristol Myers Squibb, Mirati Therapeutics, and Gateway for Cancer Research. GG has no disclosures.
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NT has received honoraria for service on Scientific Advisory Boards for Eisai Medical Research; Bristol-Myers-
Squibb; Intellisphere; Oncorena; Merck Sharp & Dohme; Neoleukin; Exelixis; and AstraZeneca; for strategic
council meetings with Eisai Inc.; steering committee meetings with Pfizer, Inc.; as well as research funding for
clinical trials from Bristol-Myers-Squibb; Nektar Therapeutics; Arrowhead Pharmaceuticals; Novartis, Calithera
Biosciences, and Exelixis.

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Key Points:
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• Accurate pathologic subclassification is needed to guide management of

variant histology renal cell carcinomas.

• Unclassified renal cell carcinoma and collecting duct carcinoma are diagnoses
of exclusion.

• Each vhRCC subtype responds differently to cytotoxic chemotherapy,

immune checkpoint inhibitors, and targeted therapies such as tyrosine kinase
inhibitors.

• Due to its poor response to systemic therapies, local therapies such as

surgical metastasectomy may be preferred in certain vhRCC subtypes, in
oligometastatic disease.
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• Platinum-based cytotoxic chemotherapy is the preferred first-line option for

certain rare subtypes such as renal medullary carcinoma and collecting duct
cancers.
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 Msaouel et al. Page 15

Synopsis
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The term variant histology renal cell carcinomas (vhRCC), also known as non-clear cell
renal cell carcinomas, refers to a diverse group of malignancies with distinct biologic
and therapeutic considerations. The management of vhRCC subtypes is often based on
extrapolating results from the more common clear cell renal cell carcinoma studies or
basket trials that are not specific to each histology. Herein, we discuss how tailored
recommendations can be made for each vhRCC histology informed by ongoing research
to improve our biologic understanding and clinical experience. The unique management
of each vhRCC subtype necessitates accurate pathologic diagnosis and dedicated research
efforts.
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 Msaouel et al. Page 16

CLINICS CARE POINTS

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• Identifying the specific vhRCC subtype for each patient is critical for proper
management.

• Although most vhRCC histologies are refractory to cytotoxic chemotherapy,

it is the preferred treatment strategy for certain rare subtypes such as renal
medullary carcinoma.

• Certain vhRCC subtypes such as renal medullary carcinoma are refractory to

the targeted therapies and immune checkpoint blockade strategies developed
for clear cell renal cell carcinoma.
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 Msaouel et al. Page 17
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Figure 1.
Forest plots summarizing the reported objective responses to immune checkpoint–based
therapies of papillary and chromophobe renal cell carcinomas.
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Table 1.

Sensitivity of vhRCC subtypes to systemic therapy modalities.

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Histology Potentially sensitive to cytotoxic Potentially sensitive to targeted therapies Potentially sensitive to currently
chemotherapy developed for clear cell renal cell available immune checkpoint
carcinomas therapies
PRCC No Yes Yes
CHRCC No Yes* Yes*
FH-RCC No Yes Yes*
TRCC No Yes# Yes#
RMC Yes No No
CDC Yes Yes# Yes#
URCC No Yes# Yes#

*
Low probability of response based on currently available evidence
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#
Probability of response may depend on specific biological driver

Abbreviations: ccRCC, clear cell renal cell carcinoma; CDC, collecting duct carcinoma; CHRCC, chromophobe renal cell carcinoma; FH-RCC,
fumarate hydratase-deficient renal cell carcinoma; PRCC, papillary renal cell carcinoma; RCC, renal cell carcinoma; RMC, renal medullary
carcinoma; vhRCC, variant histology renal cell carcinoma;
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Table 2.

Specific considerations for each vhRCC subtype.

Incidence
Histologic Median
among all Common Molecular Alterations Clinical Considerations Systemic Therapy Options
subtype age
Msaouel et al.

RCCs
Papillary renal cell 10–20% 62 c-MET pathway: • Clinically and molecular heterogeneous • Cabozantinib +/−ICT
carcinoma
(PRCC) • MET amplifications • “PRCC of classic pattern” (formerly • ICT alone
type 1 PRCC) is more frequently
• Chromosome 7 gain associated with c-MET pathway • Lenvantinib + everolimus after
alterations cabozantinib
• HGF amplifications
• Bevacizumab + erlotinib (less
• MET kinase domain response than FH-RCC)
mutations
9p loss
NF2 loss (may be included in NF2-RCC
subtype)
ALK translocations (ALK translocation
RCC subtype)

Chromophobe 5% 58 PTEN and TP53 mutations • 5%−10% of patients with CHRCC will • Suntinib or Cabozantinib have
renal cell Imbalanced chromosome duplications develop metastatic disease limited efficacy
carcinoma mTOR pathway alterations
(CHRCC) Low TMB • Metastatic CHRCC with sarcomatoid • Lenvatinib + everolimus yields
features is highly aggressive high ORR though efficacy in
presence of sarcomatoid features
unknown
• Currently available ICTs are not
effective.
• Local definitive therapies such
as surgical metastasectomy are
preferred whenever feasible in
oligometastatic CHRCC

Microphthalmia Up to 1% 31–49 Defined by MiTF alterations. Most • Most common RCC in children and • TKIs such as cabozantinib
transcription commonly in TFE3 and less commonly in young adults. Adults may have worse
factor (MiTF) TFEB. prognosis. • mTOR inhibitors alone or in
family renal cell 9p21.3 homozygous deletions found in combination with lenvatinib
• More common in women.

Hematol Oncol Clin North Am. Author manuscript; available in PMC 2024 December 01.
carcinoma ~20% of cases
• ICTs have shown heterogeneous
(TRCC) TFEB translocation confers a better
• Prior chemotherapy during childhood is albeit generally modest efficacy.
prognosis compared to TFE3 translocation
a risk factor.
• TFEB amplification is
• Should always be considered in RCC
common and more
cases with histomorphological features
aggressive
of both clear cell and papillary
• TFE3 fusions upregulate histologies.
the MET pathway
• The FISH assay used to detect TFE3
alterations is different from the one
used to detect TFEB alterations. These
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Incidence
Histologic Median
among all Common Molecular Alterations Clinical Considerations Systemic Therapy Options
subtype age
RCCs
• TFE3 fusions may assays cannot provide information on
upregulate the PI3K/AKT/ the specific fusion partners in TFE3 or
mTOR pathway TFEB translocation cases
Msaouel et al.

Typically low TMB

Fumarate < 1% 39–45 FH inactivation in all cases • Between 20–35% of patients with • Cabozantinib alone or in
hydratase- 7q gain germline FH mutations (HLRCC combination with ICT appears
deficient renal cell 9p loss syndrome) will develop FH-RCC.
carcinoma (FH- NF2 loss Between 11–16% of FH-RCC cases • Lenvatinib in combination either
RCC) Low TMB will occur due to sporadic FH ICT or everolimus
mutations
• Bevacizumab + erlotinib can be
• Loss of FH by IHC is highly specific used either in first-line or in the
but not as sensitive as positive 2SC salvage setting
staining by IHC in diagnosing FH-RCC

Renal medullary < 1% 27 All RMC cases are characterized by loss • Highly aggressive • Refractory to anti-VEGF TKIs
carcinoma (RMC) of INI1 encoded by the SMARCB1 gene
8q gain • Right kidney is more commonly • Refractory to standard ICT
Low TMB but high focal copy number involved Regimens
alterations
• More often in men than women • Carboplatin + paclitaxel is the
preferred first-line therapy
• Mainly afflicts young individuals
with sickle cell trait or other sickle • Gemcitabine + doxorubicin
hemoglobinopathies effective second line
• Often associated with history of high- • EGFR pathway targeting with
intensity exercise erlotinib can yield responses in
heavily pretreated patients

Collecting duct Very rare 65 HER2 amplification can be found in up to • Diagnosis of exclusion. Necessary to • Platinum-based cytotoxic
carcinoma (CDC) 45% of cases rule out specific subtypes such as RMC chemotherapy or anti-VEGF
Loss of CDKN2A gene located in and FH-RCC TKIs such as cabozantinib are
chromosome 9p is found in up to 62% of reasonable options
cases • Occurs in older individuals than RMC
• Addition of bevacizumab to
• Expresses INI1 and FH by IHC cytotoxic chemotherapy may
and is not associated with sickle improve responses but increase
hemoglobinopathies toxicity

Hematol Oncol Clin North Am. Author manuscript; available in PMC 2024 December 01.
• ICTs can anecdotally produce
responses in some CDC cases
• Capecitabine + lapatinib +
trastuzumab can be considered in
CDCs with HER2 overexpression
• CDK4/6 inhibitors such as
palbociclib can be considered in
CDCs with 9p loss
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Incidence
Histologic Median
among all Common Molecular Alterations Clinical Considerations Systemic Therapy Options
subtype age
RCCs
Unclassified renal < 5% 50–55 Molecularly heterogeneous • Diagnosis of exclusion. Necessary to • ICTs and targeted therapies are
cell carcinoma NF2, SETD2, BAP1, KMT2C, and/or rule out specific vhRCC subtypes such the therapeutic mainstays
(URCC) mTOR mutations are found in aggressive as TRCC
URCC variants • NF2-mutated RCCs are emerging
Msaouel et al.

• IHC for ALK may establish the as a distinct subtype that may
diagnosis of ALK-translocation RCC respond to ICTs and targeting of
the mTOR and EGFR pathways
• ALK-translocation RCC may
respond to ALK inhibitors

Abbreviations: 2SC, S-(2-succino)-cysteine; ALK, anaplastic lymphoma kinase; CDC, collecting duct carcinoma; ccRCC, clear cell renal cell carcinoma; EGFR, epithelial growth factor receptor;
FISH, fluorescence in situ hybridization; FH, fumarate hydratase; HLRCC, hereditary leiomyomatosis and renal cell carcinoma; ICT, immune checkpoint therapy; IHC, immunohistochemistry; MiTF,
micropthalmia transcription factor family; vhRCC, variant histology renal cell carcinoma; PD-L1, programmed death-ligand 1; Pt, patient; CHRCC, chromophobe renal cell carcinoma; PRCC, papillary
renal cell carcinoma; RCC, renal cell carcinoma; RMC, renal medullary carcinoma; TKIs, tyrosine kinase inhibitors; Tumor mutation burden, TMB; VEGF, vascular endothelial growth factor.

Hematol Oncol Clin North Am. Author manuscript; available in PMC 2024 December 01.
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