Submitted - Februray 14, 2023 | Revised March 9, 2023 | Revised Manuscript Accepted - March 15, 2023 | ePublished - March 30, 2023
https://doi.org/10.52733/KCJ21n1-a1
ABSTRACT
Chromophobe renal cell carcinoma (chRCC) is a rare histologic variant that is morphologically and molecularly distinct
compared to the more common clear cell renal cell carcinoma
(ccRCC). Due to the relatively lower incidence and lack of phase III trials, treatment for metastatic chRCC is often extrapolated from ccRCC.
In this case report, we discuss a 58-year-old male with metastatic
chRCC who was treated with nivolumab and ipilimumab and achieved
a complete response. Though there are no definite predictive biomarkers, tumors that respond to checkpoint inhibitors (CPI) have a high
immunogenic gene signature, high PD-L1 expression, MSI instability,
or a high tumor mutational burden. Despite a comprehensive genetic
profile predicting poor response to CPI, the current patient showed
sustained radiologic response over three years. This case challenges
the current paradigm of predicted response to CPIs in the setting of
chRCC and shows that further biomarker driven research is needed to
evaluate the efficacy of these agents in chRCC.
INTRODUCTION
Renal cell carcinoma (RCC) is the
eighth most common malignancy
in the United States.1
RCC can be
divided into the more common clear
cell renal cell carcinoma (ccRCC) and
non-clear cell renal cell carcinoma
(nccRCC). Chromophobe renal cell
carcinoma (chRCC) is the third most
common histologic variant of RCC,
accounting for 5% of cases.2 Although
computerized tomography (CT) is
the preferred imaging modality in
diagnosis and staging, histologic and
molecular analysis are required to
differentiate the histologic variants
of RCC. chRCC can be differentiated
by its characteristic aneuploidy with
the entire loss of chromosomes
1,2,6,10,13, and 17. The high
expression of mitochondrial gene
mutations and accumulation of
abnormal mitochondria suggest that
the organelle is important in the
pathogenesis of chRCC.3 ChRCC can
also occur in autosomal dominant
genetic syndromes such as BirtHogg-Dube’ and tuberous sclerosis
complex.3
There is limited evidence
regarding the first-line treatment
of metastatic chRCC.2 VEGFRTKIs (cabozantinib and sunitinib)
and mTOR inhibitors (everolimus)
have traditionally been utilized in
the treatment of nccRCCs due to
their proven efficacy in ccRCC.4
Nivolumab, a PD-L1 inhibitor, has
also shown promise in treating
ccRCC resistant to VEGFR-TKIs,
but there are limited evidence in the
current literature addressing their
efficacy in the treatment of chRCC.2,5
We present the case of a patient
with cabozantinib-resistant chRCC
successfully treated with nivolumab
and ipilimumab.
CASE PRESENTATION
The patient is a 58-year-old
Caucasian male who initially
presented with left flank and lower
abdominal wall pain associated with
a 30-pound weight loss over one
year. Magnetic resonance imaging
(MRI) of abdomen showed a large
left renal mass with invasion of the
left renal vein. PET/CT confirmed
FDG avid left kidney mass. (Figure
1) Biopsy of the mass confirmed
chRCC. Subsequently, he underwent
left nephrectomy with lymph node
dissection and adrenalectomy.
Pathology confirmed chRCC
with extensive tumor necrosis,
lymphovascular invasion, renal
sinus and perinephric fat invasion.
(Figure 2A & 2B) The surgical
margins were negative as well as
the lymph nodes and adrenal gland
were negative for metastatic disease.
Reassessment after surgery with CT
and bone scan revealed a solitary lytic
lesion in the first lumbar vertebrae,
and the patient received 30Gy/3fxs
stereotactic body radiation to the
area.
Subsequent restaging with
CT showed disease progression with
biopsy-proven liver metastases two
months after surgery, and he started
first-line systemic therapy with
cabozantinib 40 mg daily. Due to
the development of severe hand-foot
syndrome, the dose of cabozantinib
was reduced to 20 mg daily. Despite
six months of therapy, the patient
continued to have significant disease
progression, including new sites of
metastases in the lungs. (Figure 3A
& 3B). At this point in the disease
course, therapy was switched to
dual checkpoint inhibitor therapy
with nivolumab and ipilimumab.
Following the fourth cycle of this
regimen, reassessment with CT
showed partial response with
improved liver metastases and
resolution of the lung metastases.
However, immunotherapy was
discontinued after 5 months due to
development of an immune-related
adverse event (IRAE) in the form
of polyneuropathy causing Bell’s
palsy, dysphagia, and bilateral lower
extremity weakness. Brain and spine
imaging was negative for metastatic
disease or stroke. Cerebrospinal
fluid analysis showed an increase
in protein levels but was otherwise
unremarkable for infection. He was
treated with a prolonged tapering
dose of high dose prednisone with
gradual improvement of symptoms.
Despite stopping therapy after
5 months due to IRAEs, he has
ongoing complete response in the
liver, lung without any evidence of
active cancer for over 3 years now
(Figure 4). Also, he has recovered
from the IRAEs.
DISCUSSION
Although localized chRCC can be
managed with surgery alone with
excellent outcomes, metastatic
disease requires the addition of
systemic therapy with palliative
intent and is generally associated
with poor outcomes. The ASPEN
phase II randomized control trial
of 108 nccRCC patients showed
everolimus, when comparable to
sunitinib, showed improved overall
response rate (33% versus 10%
respectively).4 Within VEGFRTKIs, cabozantinib has been shown
to have improved progression-free
survival when compared to sunitinib
in randomized controlled trials.6
After finding resistance to
cabozantinib, we initiated second
line therapy with nivolumab plus
ipilimumab. In a retrospective
analysis of 39 patients with nccRCC
treated with nivolumab with or
without ipilimumab, only seven
patients showed objective response
6 months after therapy initiation.7
This is in comparison to the phase
3 CheckMate 214 trial that showed
objective response rate of 42%
in patients with ccRCC treated
with nivolumab plus ipilimumab
treatment in first line setting. In
another review by Bersanelli et al, the
objective response rates with CPIs
as monotherapy or in combination
with other TKIs in chRCC ranged
anywhere between 0% to 28.5%.8
The studies evaluating nivolumab
plus cabozantinib, atezolizumab plus
cabozantinib and pembrolizumab
plus lenvatinib showed objective
response rates of 0%, 11% and
13.3% respectively.8 Overall the
decreased responses in chRCC
when compared to ccRCC can be
explained by the unique molecular
pathogenesis with lower PD-L1
expression, microsatellite stability,
and low tumor mutational burden
(TMB) in chRCC.2 Targeted genomic
sequencing with FoundationOne
testing which combines DNA and
RNA sequencing to identify common
genomic alterations and complex
nucleic acid fusion events was
performed on the patient’s tumor
specimen. The tumor was also
found to be MSI-stable with a TMB
of 4 mutations per megabase. PDL1 immunohistochemical analysis
revealed a tumor proportion score of
1%.
Despite the lack of any predictive
markers of response to checkpoint
inhibitors on the genomic profile,
our patient responded well to
combination immunotherapy,
albeit with serious immune-related
adverse events (IRAEs). A couple
of retrospective studies in patients
with metastatic RCC treated with
CPI revealed a correlation between
the incidence of IRAEs and
improved oncologic outcomes.9,10
The exact mechanism underlying
this association is unclear. One
hypothesis is bystander effect of
activated cytotoxic T-cells in an
organ with low-level inflammation
that is potentiated after an IRAE
with CPI therapy. In particular,
local inflammation caused by
IRAEs may activate the immune
system and lead to an increased
antigen presentation, release of
pro-inflammatory cytokines, and
recruitment of immune cells to the
tumor microenvironment. This could
lead to an increased efficacy of the
CPI therapy, as the immune system
recognizes and responds to the
tumor antigens. In a post-mortem
study of patients with fulminant
myocarditis secondary to CPI, T-cell
receptor gene sequencing revealed
similar high frequency TCRs in T
cells om myocardium and tumor
tissue.11 Another study revealed
similar T-cell clones and antigens
in the tissue obtained from the site
of IRAEs and tumor.12 Though the
onset of IRAE is a potential clinical
marker of response to CPI, it is critical
to identify those individuals at risk
before therapy and understand the
underlying mechanism that can aid
in enhancing oncologic outcomes
while minimizing serious IRAEs.
SUMMARY
In summary, while CPIs
have shown some promise in the
treatment of metastatic chRCC,
more biomarker driven research
is needed to fully understand
their effectiveness in this specific
subtype of RCC. Despite having low
PD-L1 expression, MSI-stability,
and a low TMB, our patient had a
durable response with nivolumab
and ipilimumab. Additional studies
of nivolumab and ipilimumab
are needed in a larger cohort of
metastatic chRCC, along with
further elucidation of mechanisms
of IRAEs.
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* Corresponding Author: Rohan Garje, MD
Chief of Genitourinary Medical Oncology, Miami Cancer Institute, Baptist Health South Florida
8900 N. Kendall Drive | Miami, FL 33176 Email Id: rohan.garje@baptisthealth.net
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