Renal Cell Carcinoma Associated with Germline Mutations in the Krebs Cycle
Eric Lu 1, Brian Shuch,2, Alexandra Drakaki1,2
1 Division of Hematology/Oncology, University of California, Los Angeles, Los Angeles, CA, USA;
2 Institute of Urologic Oncology, University of California Los Angeles, Los Angeles, CA, USA;
ABSTRACT
Germline mutations in the fumarate hydratase (FH) and succinate dehydrogenase
(SDH) genes lead to hereditary leiomyomatosis and RCC (HLRCC)
and hereditary paraganglioma and pheochromocytoma, respectively. The
renal cell carcinomas that arise in these conditions are characterized by dysregulated
Krebs cycles, accumulation of oncometabolites, downstream changes in
gene expression, and epigenetic modifications that carry unique therapeutic implications.
In this review, we evaluate the current literature on these tumors, including
the epidemiology, clinical course, screening guidelines, and management of
localized and metastatic disease.
INTRODUCTION
Renal cell carcinoma (RCC) is one of
the most common cancers in the United
States, with approximately 72,000 new
cases and 13,000 deaths projected for
20211. While most RCC occurs sporadically,
there is an increasing recognition
of the hereditary component for a subset
of patients. It is believed that approximately
5-8% of RCC has a strong hereditary
component; however, heritability
is complex, and kidney cancer genetic
predisposition may extend far beyond
monogenetic diseases2,3. Current estimates,
while likely biased, do reinforce
that these estimates are not too far off;
for instance, large studies such as The
Cancer Genome Atlas Program (TCGA)
have reported that clear cell, papillary,
and chromophobe RCC are associated
with germline pathogenic mutations in
6%, 9%, and 6% of individuals respectively.
4 Single-institution series have
reported higher numbers of pathogenic
germline mutations (up to 16%) with
further enrichment in non-clear cell
variants. However, over two-thirds of
these mutations did not occur in classic
RCC genes, suggesting that they are potentially
unrelated or, alternatively, that
we have yet to characterize the full spectrum
of kidney cancer predisposition5.
Several autosomal dominant
RCC syndromes and associated germline
mutations have been well-described,
including von Hippel-Lindau
(VHL gene), hereditary papillary renal
cell carcinoma (MET gene), Birt-Hogg-
Dube´ (FLCN gene), hereditary leiomyomatosis
and RCC (FH gene), succinate
dehydrogenase (SDH) deficient
kidney cancer (SDHA, SDHB, SDHC,
SDHD genes), tuberous sclerosis complex
(TSC1 and TSC2 genes), Cowden
syndrome (PTEN gene), and microphthalmia-
associated transcription factor
kidney cancer (MITF gene)6.
Herein, we will focus on hereditary
leiomyomatosis and RCC (HLRCC)
and SDH-deficient kidney cancer (also
known as hereditary paraganglioma and
pheochromocytoma), as these two conditions
are characterized by Krebs cycle
dysfunction, accumulation of oncometabolites,
and subsequent predisposition
of affected individuals to various
malignancies6. This link between mitochondrial
physiology and tumorigenesis
was first observed in the 1920s by Otto
Warburg7 Accordingly, the genes encoding
the Krebs cycle enzymes fumarate
hydratase (FH) and the succinate
dehydrogenase complex (SDHA, SDHB,
SDHC, SDHD as well as SDHAF2 which
encodes a protein essential for complex
assembly) act as tumor suppressors,
with germline mutations in these genes
leading to accumulation of fumarate
and succinate, respectively8 These deficits
in mitochondrial respiration have
been linked to tumorigenesis via several
proposed mechanisms. Accumulation
of fumarate and succinate as oncometabolites
has been shown to inhibit
the degradation of HIF1, leading to a
state of pseudohypoxia and subsequent
downstream gene expression leading to
tumorigenesis. Concurrently, excessive
fumarate and succinate accumulation
leads to DNA and histone methylation,
resulting in altered gene expression via
epigenetic silencing9-11. More recent
work has demonstrated that oncometabolite-
induced disruption of chromatin
signaling leads to an intrinsic homologous
recombination DNA repair
defect and perhaps further mutational
burden. Such findings suggest that FHand
SDH-deficient RCC may represent
unique forms of kidney cancer that require
different therapeutic approaches.
Figure 1. Krebs Cycle Deficiency and Oncometabolite Accumulation (A) Fumarate hydratase deficiency leads to the
accumulation of the oncometabolite fumarate and (B) succinate dehydrogenase deficiency leads to accumulation of
the oncometabolite succinate.
HLRCC
The FH gene encodes for the Krebs cycle
enzyme fumarate hydratase, which
catalyzes the conversion of fumarate to
malate (Figure 1A). The loss of function
in the FH gene leads to the autosomal
dominant cancer syndrome known
as HLRCC, which is characterized by
cutaneous leiomyomas, early-onset and
highly symptomatic uterine leiomyomas,
adrenal macronodular hyperplasia,
and a very aggressive form of kidney
cancer now recognized as its own
subtype – FH-deficient kidney cancer.
This subtype can resemble papillary
type 2, collecting duct, and tubulocystic
RCC (Figure 2)13,14. The incidence
and prevalence of HLRCC are currently
unknown, but now several hundred
families have been described in the literature.
15. The prevailing consensus was
that HLRCC is quite rare, and among
those with pathogenic FH mutations,
the lifetime cumulative risk of RCC was
15-30%16,17. However with the widespread
availability of panel testing that
included the FH gene, many more patients
are now being identified, leading
to the belief that this condition is under-
recognized. With large exome databases
available, it is now evident that
FH alterations are very common with
carrier estimates between 1/1000 and
1/2500 individuals, suggesting a much
lower RCC penetrance closer to 2-6%18.
Figure 2. HLRCC-associated Renal Cell Carcinoma. (A) Contrast-enhanced CT scan (coronal view) showing large renal
mass, large tumor thrombus, and retroperitoneal lymphadenopathy. (B) Demonstrated lesion is FDG-PET avid with associated
mediastinal FDG-PET avid metastases. (C) Microscopic evaluation (40X) of a renal tumor with papillary-like morphology. FH was
Renal tumors in HLRCC tend
to develop at an earlier age, with one
series reporting a median age of onset
of 37 years with a range of 10-773. Tumors
tend to be unilateral and solitary
with a particularly aggressive biological
behavior compared to other types of hereditary
kidney cancer. Imaging characteristics
frequently demonstrate an
infiltrative nature (>85%) with the invasion
of the renal sinus fat (>80%) (Figure
2)19. Even smaller tumors have a
propensity for early and rapid nodal and
distant metastasis, as evidenced by one
series in which four of seven patients
with 2.0-6.7 cm T1 tumors had spread
to regional lymph nodes or had distant
metastases at the time of nephrectomy.
20 Another study found that among
HLRCC patients with RCC, 47% (16/34)
were metastatic at diagnosis, and another
35% (12/34) became metastatic within
3 years of diagnosis21.
Due to this accelerated growth
rate and potential for metastatic spread
even with small primary tumors, annual
abdominal imaging (MRI favored over
CT) is recommended for surveillance
starting at age 8-10 for those at risk16,22.
For localized tumors, surveillance is not
recommended, even for smaller tumors
less than 1 cm. Rather, partial nephrectomy
with wide surgical margins with consideration
of retroperitoneal lymphadenectomy
is recommended. Radical
nephrectomy could also be considered
if partial nephrectomy is not felt to be
able to achieve a wide margin.16 Although
enucleation for small RCC tumors
has increased in popularity over
recent years, for FH-deficient RCC, the
surgeon must keep a safe distance away
from the tumor as local recurrences are
common.
For metastatic HLRCC patients,
therapeutic options are unfortunately
limited with no accepted standard.
Given that oncometabolite (fumarate)
accumulation leads to a disruption of
the Krebs cycle and a shift towards dependence
on aerobic glycolysis for energy
needs, these tumors may become
uniquely dependent on aerobic glycolysis,
which is sustained by high glucose
influx. Furthermore, tumorigenesis is
driven by the pseudohypoxia pathway,
rendering these tumors particularly
sensitive to drugs directed against molecular
targets downstream of HIF1-alpha.
Consequentially, vascular endothelial
growth factor receptor (VEGF)
pathway inhibitors represent the most
rational therapeutic choice over immunotherapy.
Several ongoing clinical trials
are testing rational drug targets in patients
with HLRCC-associated renal tumors.
The combination of bevacizumab
plus erlotinib has shown promising activity
in an ongoing phase II clinical trial
of patients with papillary RCC, both HLRCC
and sporadic (NCT01130519). Results
from an abstract published in May
of 2020 detail that for the 83 treated
patients, the objective response rate was
64% (27/42) in the HLRCC cohort and
37% (15/41) in a sporadic papillary RCC
cohort. Median PFS was 21.1 months
in the HLRCC cohort and 8.7 months
in the sporadic cohort23. Most adverse
events were grade 1-2, and the most
notable grade ≥3 adverse events were
hypertension (34%) and proteinuria
(13%), as expected from bevacizumab.
In addition, one patient died from
gastrointestinal hemorrhage possibly
attributable to bevacizumab therapy.
The investigators postulated that the increased
activity among HLRCC patients
may be related to FH inactivation resulting
in upregulation of HIF, with the
resulting metabolic alterations leading
the tumors to be uniquely susceptible to
this combination.
The responsiveness to this regimen
was also observed in a small retrospective
series from South Korea where
the objective response rate was 50%
(5/10)24. A more recent randomized
phase 2 trial, SWOG 1500, established
cabozantinib (a dual MET and VEGF
inhibitor) as a promising option for
patients with papillary RCC. However,
given that HLRCC-associated renal tumors
(previously classified as papillary
type 2) represent a distinct morphologic
and molecular subset that is metabolically
deficient, rather than MET-driven
as with papillary tumors, it remains unclear
whether the results from this trial
are generalizable to HLRCC patients.
Nonetheless, for the small subset of patients
in this trial with HLRCC, it will be
important to follow the long-term outcomes
on cabozantinib14,25.
Other strategies involving immunotherapy
have been described in
case reports. In one instance, the use
of axitinib plus the PD-1 blocker sintilimab
in a patient with metastatic
HLRCC-associated RCC resulted in
disease stabilization and improvement
of symptoms26. In another case, combination
immunotherapy with nivolumab
plus ipilimumab for metastatic disease
led to a complete response with an ongoing
durable remission at 68 weeks27.
However, given that larger studies are
lacking, it remains unclear at this time
what role immunotherapy plays in the
treatment of this disease22.
SDH-DEFICIENT RCC
SDH is an enzyme complex that is composed
of four subunits (SDHA, SDHB,
SDHC, SDHD) and assembled with
SDHAF1 and SDHAF2 mitochondrial
proteins. This enzyme plays a critical
role in mitochondrial respiration; specifically,
it catalyzes the oxidation of
succinate to fumarate within the Krebs
cycle and is also critical to complex 2
of the electron transport chain (Figure
1B). Those with germline loss of
function mutations in one of these SDH
genes are at risk for paragangliomas,
pheochromocytomas, gastrointestinal
stromal tumors (GIST), and RCC.28
RCC has been reported in individuals
with SDHB, SDHC, and SDHD
mutations, and more recently, in patients
with SDHA mutations29. Histology
can be variable and may depend on
the subunit affected. SDHB-deficient tumors
are characterized by a unique oncocytic
and vacuolated appearance. By
contrast, SDHC-deficient tumors tend
to present with clear cell histology28,30.
Various other histologies, including
papillary, sarcomatoid, and unclassified
RCCs have been reported in patients
with germline mutations of SDH subunit
genes (Figure 3).
Figure 3. SDHA-deficient Pheochromocytoma and Renal Cell Carcinoma. (A) A 33-year-old gentleman who presented with a
large invasive left pheochromocytoma invading the inferior vena cava in patient with germline pathogenic SDHA mutation. (B) Six
years later at age 39, the patient developed a 4.5 cm left renal mass. The patient’s IVC graft from the pheochromocytoma is shown
with a red arrow. (C) The patient had a robotic partial nephrectomy for a pT1b papillary type I RCC with some atypical nuclear
characteristics.
As opposed to sporadic RCC, SDH-deficient RCC tends to occur at an
earlier age with a reported median age
of onset 30 years and range from 15 to
61 in one series3. Given that these tumors
share common underlying metabolic
features with FH-deficient RCC,
some may behave in a similarly aggressive
manner and present with metastatic
disease; however, others may have a
more low-grade appearance and present
with non-invasive tumors (Figure 3).
Although penetrance for paragangliomas
and pheochromocytomas are much
higher in those with a germline SDH
mutation (18-95% by age 60), RCC can
also present as the sole finding in such
individuals28,31. The true penetrance
for RCC in SDH-deficiency is unknown
and may vary by the affected subunit,
but some reports estimate that risk
could be up to 14% by age 7032. Given
the variable histologies and uncertain
penetrance of RCC in SDH-deficiency,
screening recommendations vary. The
National Comprehensive Cancer Network
recommends abdominal imaging
(MRI or CT) with and without contrast
every 4-6 years starting at age 1222.
However this approach should be individualized
based on family risk.
SDH-deficient RCC tends to
have a lower risk for metastatic disease
but a high incidence of bilateral
tumors (with 26% bilateral tumors in
one series of 27 patients with prolonged
up). Nonetheless, surveillance,
even for smaller tumors, is not recommended32. For individuals with non-invasive
tumors, nephron-sparing surgery
can be considered. However, for individuals
with higher risk tumors (large,
invasive, high-grade, infiltrative), the
risk for development of metastatic disease
is high, and radical nephrectomy
with lymph node dissection should be
considered33. Patients will require longterm
follow-up due to potential for late
recurrences, metachronous disease, and
other syndromic manifestations of germline
SDH deficiency (ie, paraganglioma,
pheochromocytomas, GIST).
For metastatic SDH-deficient
RCC, there is no widely accepted frontline
therapy, as evidence is limited to
single case series. Much like HLRCC,
given the unique metabolic disturbance
caused by oncometabolite (succinate)
accumulation, VEGF inhibitors are
commonly used. One case of widely
metastatic RCC of unclassifiable histology
with high-grade features was initially
treated with sunitinib with a 15-month
duration of response, followed by temsirolimus
with only a 2-month duration of
response, before ultimately being found
to be positive for a SDHB mutation. The
patient was subsequently treated with
pazopanib (a multi-kinase angiogenesis
inhibitor) with symptomatic response
and stabilization of metastatic disease.
However, the patient experienced progression
of his cancer 6 months later
and ultimately succumbed to the disease.
34 In another report, an individual
with SDHC-deficient clear cell RCC who
eventually developed widespread metastases
not amenable to locally directed
therapies was treated with sunitinib
and remained on therapy for 34 months
with a near-complete response35. In a
third case, an individual with a SDHA
germline mutation developed a highgrade
papillary type 2 RCC with sarcomatoid
dedifferentiation that was initially
refractory to anti-PD-1 treatment,
but later experienced disease stabilization
while on a series of VEGF tyrosine
kinase inhibitors (sunitinib, pazopanib,
and sorafenib)36.
CONCLUSIONS
Although accounting for a minority of
RCC cases, Krebs cycle deficient RCC
represents a molecularly distinct subset
that is often extremely clinically aggressive.
Given the complexities of diagnosis
and management of such diseases,
a multi-disciplinary approach is critical.
For now, early surgical excision is
the standard for localized disease, and
VEGF-based therapy remains the mainstay
for metastatic disease. However,
moving forward, the unique metabolic
features of Krebs cycle deficient tumors
may be amenable to more refined therapeutic
targeting, and many such efforts
are already underway to improve clinical
outcomes.
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Correspondence:Alexandra Drakaki, MD, PhD. Division of Hematology/Oncology
and Institute of Urologic Oncology UCLA Health. adrakaki@mednet.ucla.edu
Disclosures: None
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