Rare Kidney Tumors Comprehensive Multidisciplinary

Management and Emerging Therapies

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Preface

In recent years, researchers have made significant progress in the treatment of meta-
static clear-cell renal cell carcinoma (ccRCC). Patients with ccRCC now benefit
from a range of therapeutic options. However, advances in the treatment of rare,
non-clear cell RCC variants have lagged behind those of their more common coun-
terparts. Additionally, it is important to recognize that while these malignancies
occur less frequently than ccRCC in the general population, they are the predomi-
nant variants in specific, often vulnerable, populations. For example, translocation
RCC is the most common kidney cancer among children and young adults, and
renal medullary carcinoma (RMC) specifically afflicts individuals with sickle
hemoglobinopathies such as sickle cell trait. These patients will benefit from ongo-
ing research efforts to elucidate the biology of these rare kidney tumors and develop
therapeutic strategies aimed at improving the outcomes of these patients.
Comprehensive biological profiling initiatives such as The Cancer Genome Atlas
(TCGA) have led to an unprecedented understanding of the molecular underpin-
nings of papillary and chromophobe RCC, the two most common non-clear cell
variants. Similar efforts are underway for many of the less common non-clear cell
RCCs. Currently available targeted therapies against ccRCC were informed by bio-
logical insights gained from the study of hereditary von Hippel-Lindau disease, and
in a similar manner, the study of hereditary syndromes associated with non-clear
cell RCCs is enhancing our understanding of rare kidney tumors. These efforts can
guide the development of targeted therapies and immunotherapy approaches tai-
lored to each non-clear cell variant.
As more non-clear cell tumors are being recognized and incorporated into clas-
sification systems, our published clinical experience with these entities is growing.
This includes case reports, retrospective analyses, and even a steady trickle of pro-
spective clinical trials. Nevertheless, most published therapeutic clinical trials dedi-
cated to non-clear cell RCC do not distinguish among different histological subtypes.
However, as we learn more about the features shared among non-clear cell variants,
and those unique to each one, current and upcoming clinical trials are becoming
more specific. For example, there are now trials focused on targeting the MET path-
way in papillary RCC and proteotoxic stress in RMC.

vii
viii Preface

In this rapidly changing landscape, it can be daunting for busy clinicians to keep
abreast of new developments in the management of malignancies that are not part of
their everyday repertoires. This book is intended to provide practicing clinicians and
trainees with a concise overview of the biology, clinical presentation, diagnostic
approaches, and treatment of rare kidney tumors. We hope that the information pro-
vided herein will benefit patients suffering from these diseases.

Strasbourg, France Gabriel G. Malouf

Houston, TX Nizar M. Tannir
Contents

1 Hereditary Renal Cell Carcinomas��������������������������������������������������������    1

Eric Jonasch and Patrick G. Pilie
2 Wilms Tumor-Nephroblastoma��������������������������������������������������������������   11
Marie V. Nelson, Arnauld Verschuur, and Jeffrey S. Dome
3 Renal Cell Carcinoma in Children ��������������������������������������������������������   31
Ryan D. Bitar and Najat C. Daw
4 Chromophobe Renal Cell Carcinoma����������������������������������������������������   43
Aaron R. Lim and W. Kimryn Rathmell
5 Papillary Renal Cell Carcinoma������������������������������������������������������������   53
Ramaprasad Srinivasan and Kai Hammerich
6 Renal Medullary Carcinoma������������������������������������������������������������������   65
Pavlos Msaouel, Priya Rao, and Nizar M. Tannir
7 Collecting Duct Carcinoma ��������������������������������������������������������������������   77
Hendrik Van Poppel, Evelyne Lerut, Raymond Oyen,
Maria Debiec-Rychter, Herlinde Dumez, Maarten Albersen,
and Steven Joniau
8 TFE/Translocation Morphology Renal Cell Carcinoma����������������������   93
James I. Geller, Nicholas G. Cost, and Mariana M. Cajaiba
9 Renal Cell Carcinoma with Sarcomatoid Features������������������������������ 105
Borchiellini Delphine, Ambrosetti Damien, and Barthélémy Philippe

ix
Hereditary Renal Cell Carcinomas
1
Eric Jonasch and Patrick G. Pilie

Cancer initiation and progression is the result of an accumulation of mutations.

Mutations occurring in cancer tissue are termed somatic, whereas mutations in
germline DNA may be passed onto subsequent generations and are often termed
hereditary. Deleterious germline mutations in key tumor suppressor genes can lead
to hereditary cancer syndromes whereby family members carrying the mutation
have an increased susceptibility to developing certain tumor phenotypes. Common
features of hereditary cancer syndromes include early age of onset, multiple affected
generations, rare tumor types, and/or multiple primary malignancies.
Renal cell carcinoma (RCC) is a diverse entity with variable histologic subtypes,
and hereditary RCC, due to an inherited germline mutation, accounts for approxi-
mately 5 to 8% of all RCC cases, with variable penetrance depending on the gene
mutated [1]. The majority of mutations in genes implicated in hereditary RCC are
also seen in the significant majority of sporadic RCCs, such as von Hippel-Lindau
(VHL) in clear cell RCC (ccRCC) and MET proto-oncogene in type 1 papillary
RCC [2, 3]. Although distinct histologic subtypes of RCC exist, a shared feature
across hereditary and sporadic RCC cases is dysregulation of the hypoxia-inducible
factor (HIF) axis and aberrant tumor metabolism. In general, the median age of
onset of hereditary RCC is 27 years younger than that observed for RCC in a gen-
eral population, 37 years old versus 64 years old [1, 4]. If there is a concern for a
hereditary RCC, the affected patient should be referred to a genetic counselor and
tested for specific mutations based on the patient’s personal medical and cancer his-
tory, family history, and RCC histology [4]. RCC that occurs in individuals 46 years
old or younger may prompt referral to a genetic counselor and consideration for
germline mutation testing regardless of family history or syndrome criteria [1].

E. Jonasch (*) · P. G. Pilie

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson
Cancer Center, Houston, TX, USA
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 1

G. G. Malouf, N. M. Tannir (eds.), Rare Kidney Tumors,
https://doi.org/10.1007/978-3-319-96989-3_1
2 E. Jonasch and P. G. Pilie

In this chapter, we will detail the various hereditary RCC syndromes and discuss
genetic testing, cancer screening, and treatment in these unique populations.

1.1 von Hippel-Lindau Disease

Germline mutations in the von Hippel-Lindau (VHL) gene, a tumor suppressor

found on chromosome 3p25, are inherited in an autosomal dominant fashion giving
way to the potential development of a spectrum of tumor types including clear cell
renal cell carcinoma (ccRCC), hemangioblastomas (HBs), pheochromocytomas,
retinal hemangioblastomas, and pancreatic neuroendocrine tumors (pNETs) [5, 6].
Germline VHL mutations may be inherited from a parent or in rare cases due to de
novo mutations occurring early on in embryogenesis. VHL disease occurs in
approximately 1 in 35,000 births, and the morbidity and mortality associated with
VHL disease center around the progression of ccRCC as well as the neurologic
complications of hemangioblastomas [7]. The most common mutations seen in both
sporadic and hereditary ccRCC are mutations in VHL. In general, individuals with
ccRCC and a known family history of VHL or a VHL clinical phenotype, including
bilateral or multifocal tumor presentation or a family history of renal tumors, should
warrant VHL gene mutation testing [4]. Previous studies have shown that the spe-
cific type of genotypic alteration in the VHL gene may give way to the variance of
phenotypic outcomes across families and individuals with VHL disease [8, 9].
Recommended surveillance for persons with known VHL germline mutations
includes annual abdominal imaging and a central nervous system MRI every other
year, annual audiometry and ophthalmologic exam, and annual laboratory work to
include plasma metanephrines and chromogranin.
VHL disease-related lesions are in general highly vascular owing to the loss of
the underlying anti-angiogenic function of the VHL gene product [7, 10]. The main
function of the VHL gene product, pVHL, is to act as an oxygen sensor as part of the
ubiquitin ligase E3 complex in normoxic conditions. pVHL exists as two domains,
α and β, and forms a ternary complex with the transcription elongation factors C and
B, which aid in stabilizing pVHL. This pVHL complex recognizes hydroxylated
HIF-1α and HIF-2α and leads to the HIFs’ proteosomal degradation. Without pVHL
activity, as is the case in hypoxic conditions and VHL syndrome, HIF-1α and
HIF-2α are allowed to transactivate their downstream pro-angiogenic elements,
such as VEGF, PDGF, FGF, and GLUT1 and 3 in an unchecked manner. In the set-
ting of pVHL loss, inhibition of HIF-2α is sufficient to suppress tumor formation
[11]. pVHL also has non-HIF-related functions including key roles in extracellular
matrix assembly, cilia maintenance, apoptosis regulation, genomic stability, and
DNA damage repair [10, 12–14].
Given the variety of tumor types within a single individual with VHL disease,
treatment necessitates a personalized, multidisciplinary approach; and given that
the most frequent alterations in sporadic ccRCC involve the loss of the 3p chromo-
somal arm including the VHL gene, treatment discoveries for this rare, heritable
disease have implications for a much wider patient population [2]. The primary
1 Hereditary Renal Cell Carcinomas 3

treatment of VHL-associated lesions is surgical. HBs are the most frequently seen
lesion in VHL disease, occurring in over 70% of patients. The next most frequent
lesions include renal cysts and ccRCC tumors which occur in up to 60% of patients
with VHL disease and often present as bilateral or multifocal disease [7]. Patients
with known VHL mutations should undergo regular surveillance imaging including
annual abdominal imaging for the presence of ccRCC. If discovered on surveillance
imaging, RCC lesions are then monitored until the largest solid kidney tumor mea-
sures 3 cm or greater, which should prompt surgical intervention to prevent metas-
tasis [15]. Once surgery is indicated, the goal is to preserve kidney function via a
nephron-sparing approach and minimize surgical interventions and their associated
morbidity as much as possible. Prior studies have shown that only 3% or fewer of
patients with hereditary renal cell cancers undergoing repeat or salvage renal sur-
gery progress to needing hemodialysis [16]. In general, the surgeon’s desire to pre-
serve kidney function in VHL-associated ccRCC is not different than in sporadic
cases; but nephron-sparing is particularly important in hereditary kidney cancer
populations given its typical earlier age of onset and bilateral or multifocal presenta-
tions necessitating multiple surgeries.
Patients with VHL disease with ccRCC will inevitably have progressively grow-
ing lesions or multiple synchronous tumors making surgical approaches difficult or
contraindicated. Systemic treatment options for VHL-related ccRCC do not differ
from those treatment options for sporadic cases at this time. Given that pVHL inac-
tivation leads to inappropriate angiogenesis, tyrosine kinase inhibitors (TKIs) such
as sunitinib, pazopanib, and cabozantinib directed against VEGF and other pro-
angiogenic pathways are approved for metastatic ccRCC in sporadic and hereditary
cases. A pilot study of sunitinib in 15 patients with germline VHL mutations with
measurable VHL disease-associated lesions showed the drug had acceptable toxic-
ity and 33% (6/18) of RCC lesions showed a partial response [17]. RCC in the
endothelium displayed higher levels of pVEGFR-2 expression when compared to
HBs, and interestingly, 0/21 HB lesions showed response to treatment with suni-
tinib. However, immunohistochemical expression levels of phosphorylated FGFR
substrate 2 were higher in HBs, highlighting the heterogeneous nature of VHL-
related lesions. A pilot trial of dovitinib, an inhibitor of VEGF and FGF signaling,
was undertaken in patients with VHL syndrome and measurable HB lesion; how-
ever, the study drug yielded only stable disease as best response and was associated
with significant toxicities [18]. A prior case study has shown that VHL-associated
HBs can respond to pazopanib with reduction in size and symptoms, leading to a
phase II trial of pazopanib in VHL syndrome patients with measureable lesions,
which has shown early promising results with significant and sustained disease con-
trol in a number of VHL patients enrolled on the study [19]. Currently, if there is
evidence of metastatic ccRCC in VHL patients, treatment approaches are the same
as those in sporadic disease, which are evolving and may include multiple TKIs
and/or immune checkpoint inhibition. A recent study that sequenced multiple
ccRCCs from patients with VHL germline mutations has shown that even multiple
tumors within a single individual display somatic heterogeneity and clonal indepen-
dence [20]. There is no medical therapy that has been identified that works in all
4 E. Jonasch and P. G. Pilie

patients with VHL disease or even on all lesions within the same patient. Lastly,
there are currently no preventative agents targeted or otherwise in use for prevention
of VHL-related lesions.

1.2 Tuberous Sclerosis Complex Syndrome

Germline mutations in TSC1/2 genes, located on chromosomes 9q34 and 16p13,

respectively, can lead to a syndrome known as tuberous sclerosis complex (TSC)
syndrome, which is inherited in an autosomal dominant fashion or may occur spo-
radically. The prevalence of TSC syndrome worldwide is approximately one million
affected individuals. Clinically TSC syndrome is characterized by hamartomas and
angiomyolipomas, which may spontaneously hemorrhage, as well as pulmonary
lymphangioleiomyomatosis, subependymal giant cell astrocytomas, and RCC [7].
RCC in TSC syndrome is typically ccRCC in TSC1 mutation carriers, but chromo-
phobe histology is also seen in TSC2 carriers, and TSC2 is also mutated in sporadic
chromophobe RCC [21]. In addition, as is seen in VHL disease, patients with TSC
syndrome may develop kidney cysts associated with ciliary dysfunction. Typically,
patients with TSC syndrome will develop multiple renal cysts and angiomyolipo-
mas, which can invade adjacent renal parenchyma and lead to chronic kidney dis-
ease and ultimately death in this population [22].
Germline testing for TSC1/2 mutations should be prompted based on clinical
history, physical exam, and family history. Kidney cancer is not typically seen as a
singular presentation of TSC syndrome. Active surveillance in patients with TSC
syndrome should include brain and abdominal imaging every 1–3 years, chest
imaging every 2–3 years, and an annual dermatologic exam. In addition, patients
should undergo dental evaluation regularly, and an echocardiogram should be per-
formed every 1–3 years.
TSC1 (hamartin) and TSC2 (tuberin) form a heterodimer that works as a tumor
suppressor to regulate mTOR complex 1 signaling cascade. TSC1/2 mutations lead
to mTORC1 dysregulation and overexpression, which aids cancer cells in prolifera-
tion, cytoskeletal rearrangements, nutrient excess, and protein synthesis [23].
Clinical trials using mTOR inhibitors in TSC syndrome patients showed efficacy,
with a 42% response rate seen with everolimus, leading to its FDA approval for
angiomyolipoma associated with TSC syndrome [23]. The majority of patients in
this study had bilateral angiomyolipomas and 40% had invasive procedures; thus,
everolimus should be considered in patients who are not surgical candidates and/or
those with multifocal disease.

1.3  hosphatase and Tensin Homolog

P
Hamartoma Syndrome

Phosphatase and tensin homolog (PTEN) is a well-known tumor suppressor gene

located on chromosome 10q23 and is responsible for AKT suppression and is inte-
gral in DNA damage repair. PTEN somatic mutations are seen in approximately 5%
1 Hereditary Renal Cell Carcinomas 5

of sporadic RCCs with posttranslational loss of PTEN protein expression seen fre-
quently in RCC [2]. Deleterious germline mutations in PTEN give way to the PTEN
hamartoma syndrome, a hereditary cancer disorder which is characterized by muco-
cutaneous lesions and cutaneous hamartomas as well as breast cancer, endometrial
cancer, melanoma, and follicular thyroid cancer. Individuals with PTEN germline
mutations have an approximately 34% lifetime risk of RCC, and RCC onset is typi-
cally at a younger than average age (~40 years old) [24]. Multiple case reports have
shown the mTOR inhibitor sirolimus may be effective in individuals with PTEN
hamartoma syndrome, and a clinical trial (NCT00971789) was completed but not
yet reported [25, 26].

1.4 Succinate Dehydrogenase-Associated

Renal Cell Carcinoma

Rare germline mutations in the tricarboxylic acid cycle (Krebs) gene, succinate
dehydrogenase (SDH), can give way to a multiple primary tumor phenotype that
may include ccRCC. SDH is a family of genes including SDHA, SDHB, SDHC, and
SDHD. Germline mutations in SDHB were first described in families with RCC
and/or hereditary paragangliomas or gastrointestinal stromal tumors, though RCC
may be the only clinical manifestation in individuals with germline SDHB, SDHC,
and SDHD genes. In small, family-based retrospective studies, the mean and median
age of SDHB-associated RCC was 33 and 30 years, respectively [27]. SDHB/C/D
germline mutation testing may be considered in patients with early-onset RCC or
for those with a family history of RCC and/or paragangliomas and pheochromocy-
tomas. There are no guidelines for surveillance, but yearly abdominal imaging for
RCC should be considered.
SDH is a key enzyme in the Krebs cycle, and mutations in SDH subunits cause
accumulation of succinate as well as inhibition of proly hydroxylation of HIF-1α
and HIF-2α. Cells with mutated Krebs cycle enzymes exhibit increased glucose
uptake, aerobic glycolysis, and fatty acid synthesis, which are also known as the
Warburg effect. Thus, targeting these metabolic shifts may be particularly suited for
SDH mutant-related RCC.

1.5  ereditary Papillary Renal Cell Carcinoma

H
and Hereditary Leiomyomatosis and RCC

Papillary renal cell carcinoma is the second most common histologic subtype,
accounting for 15–20% of RCC. Two major subtypes of papillary RCC exist, includ-
ing type 1 and type 2, and these subtypes have distinct genetic alterations and asso-
ciated hereditary syndromes.
Hereditary papillary RCC (HPRC) or type 1 papillary RCC is an autosomal dom-
inant cancer syndrome due to mutations in the proto-oncogene MET on chromo-
some 7q31, with somatic MET mutations found in 13–15% of sporadic papillary
RCC [3, 28]. Persons with HPRC syndrome typically display multiple tumors in
6 E. Jonasch and P. G. Pilie

bilateral kidneys, and extrarenal manifestations are not reported. However, meta-
static potential of these tumors is low. Active surveillance with annual CT/MRI
abdominal imaging is recommended, and nephron-sparing surgery is considered
when a tumor reaches 3 cm or greater to mitigate risk of metastatic disease while
preserving renal function.
The MET gene product is a cell surface receptor protein for hepatocyte growth
factor (HGF) which promotes tumor cell migration, invasion, proliferation, and
angiogenesis. A phase II study of the MET/VEGFR2 inhibitor, foretinib, was per-
formed in 74 patients with papillary RCC, including 11 patients with pathogenic
germline MET mutations. In this trial, objective response rate (ORR) was 13.5%
with ten responders achieving a partial response (PR) only. Analysis based on germ-
line MET mutational status revealed that 50% of germline carriers achieved a PR,
while only 9% of those patients without a germline mutation achieved a PR [29].
Type 2 papillary RCC is a heterogeneous disease with multiple subtypes.
Germline mutations in the fumarate hydratase (FH) gene on chromosome 1q42 give
way to aggressive type 2 tumors seen in the context of hereditary leiomyomatosis
and RCC (HLRCC) syndrome. The clinical phenotype of HLRCC syndrome typi-
cally includes cutaneous and/or uterine leiomyomas and type 2 papillary RCC. The
median age of onset for papillary RCC in this population is 37 years, and surveil-
lance should include dermatologic evaluation every 1–2 years, annual abdominal
MRI, and annual gynecologic exam and ultrasound. Given the aggressive nature of
the type 2 papillary RCC in HLRCC syndrome, immediate surgery for an identified
renal tumor is warranted rather than the typical 3 cm size threshold used in other
hereditary renal syndromes. Fumarate hydratase is a Krebs cycle enzyme that con-
verts fumarate to malate. FH biallelic inactivation in HLRCC syndrome results in
complete loss or reduction of the FH enzymatic activity which then leads to intra-
cellular fumarate accumulation and a metabolic shift to aerobic glycolysis, termed
the Warburg effect [30, 31]. Combination therapy targeting VEGFR and EGFR
using bevacizumab in conjunction with erlotinib has been shown to have activity
against familial type 2 papillary RCC in HLRCC syndrome, and a prospective phase
II trial is underway (NCT01130519) [32]. In addition, a clinical trial using vande-
tanib, a multikinase inhibitor including targets VEGFR and EGFR, in combination
with metformin is underway (NCT02495103) for patients with advanced HLRCC
and sporadic papillary RCC.

1.6 Birt-Hogg-Dubé

Birt-Hogg-Dubé (BHD) is an autosomal dominant syndrome characterized by

fibrofolliculomas, pulmonary cysts, and/or renal lesions, typically oncocytomas or
chromophobe RCC. The risk of developing RCC in patients with BHD is estimated
to be 16% by age 70, and BHD patients have a 50-fold increased risk of developing
a pneumothorax across age groups. BHD is the result of germline loss-of-function
mutations in folliculin (FLCN) gene found on chromosome 17p11, with hotspot
mutation areas in exons 11–13 [33, 34]. The FLCN gene product is downstream of
1 Hereditary Renal Cell Carcinomas 7

mTORC1 signaling and localizes to cilia. Loss of FLCN function leads to mTORC1
activation and dysregulated ciliogenesis. Single allele loss leading to haploinsuffi-
ciency is enough to lead to skin manifestations of BHD, while biallelic loss is
required for the development of RCC lesions [34].
Surveillance of patients with known FLCN germline mutations should include
yearly abdominal imaging. In addition, given the risk of pulmonary cysts and pneu-
mothorax, patients with BHD should have consultation with a pulmonologist stress-
ing risk reduction strategies and smoking cessation if applicable [35].
Similar to most other hereditary RCC syndromes, active surveillance of renal
lesions should be performed until a lesion reaches a size of 3 cm, at which time
nephron-sparing resection is recommended. Preclinical data has suggested mTOR
inhibition is effective at prolonging survival in FLCN-deficient mice; however, a
clinical trial of topical rapamycin for BHD-associated fibrofolliculomas did not
reduce size or burden of cutaneous lesions. Due to the rarity of this syndrome and
its associated tumors, tailored treatment strategies are lacking, and thus, multi-insti-
tutional, global partnered trials are crucial.

1.7  RCA1-Associated Protein-1 Predisposition

B
to Familial ccRCC

Approximately 5–15% of sporadic ccRCCs show loss-of-function mutations in the

BRCA1-associated protein-1 (BAP1), a gene which resides on chromosome 3p21.1
[36]. BAP1 protein functions as a nuclear deubiquitinase that interacts with poly-
comb group proteins at open chromatin and promotes double-strand break repair.
Germline mutations in BAP1 have been seen in association with familial ccRCC in
addition to other cancers including uveal melanoma, malignant mesothelioma, and
cutaneous melanoma; however, the prevalence of BAP1 syndrome and the associ-
ated risk of RCC are not well understood due to its rarity [37]. Like other familial
cancer syndromes, cancers associated with BAP1 germline mutations seem to have
early age of onset and more aggressive phenotypes [38]. Early-onset RCC screening
may be pursued based on the age of initial presentation of ccRCC.

Conclusions
Hereditary cancers account for approximately 10% of all cancers including
RCC. Populations with hereditary cancer syndromes present unique challenges
to oncology healthcare teams including risk assessment, counseling, surveil-
lance, and therapeutic management. A thorough family and personal medical
history in combination with a patient’s RCC histology and phenotypic presenta-
tion will help guide genetic testing and interpretation. If a pathogenic germline
mutation is discovered, then tailored surveillance and intervention strategies
should be followed. A proband’s family members should then be counseled on
their own risk of carrying the pathogenic variant and can decide on genetic test-
ing with the help of a certified genetic counselor. Unaffected carriers should
undergo specified surveillance as early detection is currently the only clinically
8 E. Jonasch and P. G. Pilie

available prevention strategy for hereditary RCC syndromes. As noted, there is

considerable overlap between gene mutations in hereditary and sporadic RCC,
and research into these rare hereditary cancer syndromes has greatly informed
the understanding of RCC tumorigenesis as a whole [2, 3, 21]. Despite the var-
ied, complex pathways involved in hereditary RCC syndromes, they share a
common dysregulation of the HIF-VEGF axis coupled with aberrant tumor
metabolism which offers targetable pathways for precision medicine approaches
in RCC syndromes. There is ongoing research into alternative treatment strate-
gies to improve the targeting of VEGF or mTOR pathways as well as identify
new druggable targets for the treatment of the varied RCC histologies. As with
all hereditary cancer syndromes, targeted prevention strategies coupled with
improved biomarkers for early detection and treatment monitoring are needed to
make a significant impact on quality of life and long-term survival in RCC
patients with pathogenic germline mutations and their family members who are
unaffected carriers. With paired germline and somatic next-generation sequenc-
ing becoming ubiquitous across major cancer centers, it is likely that novel muta-
tions may be discovered that are associated with hereditary RCC syndromes
[39]. It is important particularly in these rare cancer syndromes that the medical
community work together to qualify and quantify the genotype-phenotype cor-
relations associated with these pathogenic germline mutations so that we can
improve upon risk stratification, prevention, surveillance, and treatment for our
patients and their families.

References
1. Shuch B, Vourganti S, Ricketts CJ, et al. Defining early-onset kidney cancer: implications for
germline and somatic mutation testing and clinical management. J Clin Oncol. 2014;32:431–7.
2. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear
cell renal cell carcinoma. Nature. 2013;499:43–9.
3. Cancer Genome Atlas Research Network, Linehan WM, Spellman PT, et al. Comprehensive
Molecular Characterization of Papillary Renal-Cell Carcinoma. N Engl J Med.
2016;374:135–45.
4. Linehan WM. Evaluation and screening for hereditary renal cell cancers. Can Urol Assoc J.
2013;7:324–5.
5. Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppres-
sor gene. Science. 1993;260:1317–20.
6. Butman JA, Linehan WM, Lonser RR. Neurologic manifestations of von Hippel-Lindau dis-
ease. JAMA. 2008;300:1334–42.
7. Ho TH, Jonasch E. Genetic kidney cancer syndromes. J Natl Compr Cancer Netw.
2014;12:1347–55.
8. McNeill A, Rattenberry E, Barber R, et al. Genotype-phenotype correlations in VHL exon
deletions. Am J Med Genet A. 2009;149A:2147–51.
9. Lonser RR, Butman JA, Huntoon K, et al. Prospective natural history study of central nervous
system hemangioblastomas in von Hippel-Lindau disease. J Neurosurg. 2014;120:1055–62.
10. Gossage L, Eisen T, Maher ER. VHL, the story of a tumour suppressor gene. Nat Rev Cancer.
2015;15:55–64.
1 Hereditary Renal Cell Carcinomas 9

11. Kondo K, Kim WY, Lechpammer M, et al. Inhibition of HIF2alpha is sufficient to suppress
pVHL-defective tumor growth. PLoS Biol. 2003;1:E83.
12. Thoma CR, Frew IJ, Hoerner CR, et al. pVHL and GSK3beta are components of a primary
cilium-maintenance signalling network. Nat Cell Biol. 2007;9:588–95.
13. Ding X-F, Zhou J, Hu Q-Y, et al. The tumor suppressor pVHL down-regulates never-in-mitosis
A-related kinase 8 via hypoxia-inducible factors to maintain cilia in human renal cancer cells.
J Biol Chem. 2015;290:1389–94.
14. Metcalf JL, Bradshaw PS, Komosa M, et al. K63-ubiquitylation of VHL by SOCS1 mediates
DNA double-strand break repair. Oncogene. 2014;33:1055–65.
15. Duffey BG, Choyke PL, Glenn G, et al. The relationship between renal tumor size and metas-
tases in patients with von Hippel-Lindau disease. J Urol. 2004;172:63–5.
16. Metwalli AR, Linehan WM. Nephron-sparing surgery for multifocal and hereditary renal
tumors. Curr Opin Urol. 2014;24:466–73.
17. Jonasch E, McCutcheon IE, Waguespack SG, et al. Pilot trial of sunitinib therapy in patients
with von Hippel-Lindau disease. Ann Oncol. 2011;22:2661–6.
18. Pilie PG, Matin SF, Woodson AH, et al. Pilot study of dovitinib in patients with VHL disease.
J Clin Oncol. 2016;34:587.
19. Jonasch E, Gombos DS, Waguespack SG, et al. Phase II study of pazopanib in patients with
von Hippel-Lindau disease. J Clin Oncol. 2017;35:4516.
20. Fei SS, Mitchell AD, Heskett MB, et al. Patient-specific factors influence somatic variation
patterns in von Hippel-Lindau disease renal tumours. Nat Commun. 2016;7:11588.
21. The .somatic genomic landscape of chromophobe renal cell carcinoma. – PubMed – NCBI.
2018. https://www.ncbi.nlm.nih.gov/pubmed/25155756?dopt=Abstract. Cited 2018 Mar 22.
22. Shepherd CW, Gomez MR, Lie JT, et al. Causes of death in patients with tuberous sclerosis.
Mayo Clin Proc. 1991;66:792–6.
23. Bissler JJ, Kingswood JC, Radzikowska E, et al. Everolimus for angiomyolipoma associated
with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multi-
centre, randomised, double-blind, placebo-controlled trial. Lancet. 2013;381:817–24.
24. Tan M-H, Mester JL, Ngeow J, et al. Lifetime cancer risks in individuals with germline PTEN
mutations. Clin Cancer Res. 2012;18:400–7.
25. Marsh DJ, Trahair TN, Martin JL, et al. Rapamycin treatment for a child with germline PTEN
mutation. Nat Clin Pract Oncol. 2008;5:357–61.
26. Schmid GL, Kässner F, Uhlig HH, et al. Sirolimus treatment of severe PTEN hamartoma
tumor syndrome: case report and in vitro studies. Pediatr Res. 2014;75:527–34.
27. Ricketts CJ, Shuch B, Vocke CD, et al. Succinate Dehydrogenase Kidney Cancer (SDH-RCC):
An Aggressive Example of the Warburg Effect in Cancer. J Urol. 2012;188:2063–71. http://
www.ncbi.nlm.nih.gov/pmc/articles/PMC3856891/. Cited 2016 Nov 12
28. Schmidt L, Duh FM, Chen F, et al. Germline and somatic mutations in the tyrosine
kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet.
1997;16:68–73.
29. Choueiri TK, Vaishampayan U, Rosenberg JE, et al. Phase II and biomarker study of the dual
MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J Clin Oncol.
2013;31:181–6.
30. Vocke CD, Ricketts CJ, Merino MJ, et al. Comprehensive genomic and phenotypic character-
ization of germline FH deletion in hereditary leiomyomatosis and renal cell carcinoma. Genes
Chromosomes Cancer. 2017;56:484–92.
31. Menko FH, Maher ER, Schmidt LS, et al. Hereditary leiomyomatosis and renal cell cancer
(HLRCC): renal cancer risk, surveillance and treatment. Familial Cancer. 2014;13:637–44.
32. Modi PK, Singer EA. Improving our understanding of papillary renal cell carcinoma with
integrative genomic analysis. Ann Transl Med. 2016;4:143. http://www.ncbi.nlm.nih.gov/
pmc/articles/PMC4842405/. Cited 2016 Nov 11
33. Luijten MNH, Basten SG, Claessens T, et al. Birt-Hogg-Dube syndrome is a novel ciliopathy.
Hum Mol Genet. 2013;22:4383–97.
10 E. Jonasch and P. G. Pilie

34. Bratslavsky G, Woodford MR, Daneshvar M, et al. Sixth BHD Symposium and First
International Upstate Kidney Cancer Symposium: latest scientific and clinical discoveries.
Oncotarget. 2016;7:15292–8.
35. Johannesma PC, van de Beek I, van der Wel JWT, et al. Risk of spontaneous pneumothorax due
to air travel and diving in patients with Birt-Hogg-Dubé syndrome. Springerplus. 2016;5:1506.
36. Yu H, Pak H, Hammond-Martel I, et al. Tumor suppressor and deubiquitinase BAP1 promotes
DNA double-strand break repair. Proc Natl Acad Sci U S A. 2014;111:285–90.
37. Popova T, Hebert L, Jacquemin V, et al. Germline BAP1 mutations predispose to renal cell
carcinomas. Am J Hum Genet. 2013;92:974–80.
38. Rai K, Pilarski R, Cebulla CM, et al. Comprehensive review of BAP1 tumor predisposition
syndrome with report of two new cases. Clin Genet. 2016;89:285–94.
39. Mandelker D, Zhang L, Kemel Y, et al. Mutation Detection in Patients With Advanced Cancer
by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-
Based Germline Testing. JAMA. 2017;318:825–35.
Wilms Tumor-Nephroblastoma
2
Marie V. Nelson, Arnauld Verschuur, and Jeffrey S. Dome

2.1 Introduction

Nephroblastoma, or Wilms tumor (WT), is the second most common extracranial

solid tumor and the most common malignant renal tumor in children, accounting for
5% of all malignancies and 80% of all diagnosed renal cancers in children and teen-
agers. The overall survival has increased to over 90% due to international collabora-
tion in cooperative group studies and employment of a multimodal treatment
approach including surgery, radiation, and chemotherapy [1, 2]. The earliest of
these studies, led by the National Wilms Tumor Study Group (NWTSG), which was
superseded by the Children’s Oncology Group (COG) in 2002, and the International
Society of Paediatric Oncology (SIOP), stratified patients based on tumor stage
alone. However, over time, the discovery of additional clinical, histological, and
biological prognostic factors has led to more precise treatments that augment ther-
apy for patients at high risk of relapse while reducing therapy for patients at low risk
of relapse.
The progress in outcome made over the last four decades has made WT one of
the successes of Paediatric oncology and of modern medicine. Despite the success,
more advancement is required, as certain patient subgroups continue to have high
risk for tumor recurrence and death. As the molecular mechanisms and biology
underlying WT are studied and better understood, there is hope that there will not
only be more survivors in the future but survivors living healthier lives.

M. V. Nelson · J. S. Dome (*)

Center for Cancer and Blood Disorders, Children’s National Health System,
Washington, DC, USA
e-mail: [email protected]
A. Verschuur
Centre de Cancérologie Pédiatrique, Hôpital d’Enfants de la Timone,
Marseille, France

© Springer Nature Switzerland AG 2019 11

G. Malouf, N. M. Tannir (eds.), Rare Kidney Tumors,
https://doi.org/10.1007/978-3-319-96989-3_2
12 M. V. Nelson et al.

WT is a malignancy with a rich historical background that not only unites the
disciplines of development and genetics but also surgery, radiation therapy, and
oncology in its treatment. The following pages review the epidemiology and patho-
genesis, presentation, important prognostic factors, treatment, outcome, and future
directions of research and therapy of WT.

2.2 Pathogenesis and Epidemiology

WT is a malignant embryonal tumor of young children, with most cases diagnosed

in children under the age of 5 years. In the United States and Canada, the estimated
incidence is 9.0 per million, affecting 1 in 10,000 children [3, 4]. Similar rates have
been reported in Europe, Australia, and New Zealand, with lower rates in Asia and
Central and South America, while in areas of Africa, such as Harare, Zimbabwe, the
incidence is as high as 16.5 per million [3]. The diagnosis of WT is extraordinarily
rare in adults, with incidence of only 0.2 cases per million [5].
WT was first described in 1899, when Max Wilms established the classical
description of a “mixed tumor,” comprised of epithelial, blastemal, and stromal cells
[6, 7]. He hypothesized that WT cells arose from a common, undifferentiated renal
cell, which has since been supported, holding that WT evolution is rooted in normal
kidney development. During development, the fetal kidney arises from the ureteric
bud which forms the collecting ducts and the metanephric mesenchyme or blastema
which forms the stroma and the other tubular structures, including the glomeruli,
proximal and distal tubules, and loop of Henle [8]. While the blastemal component
usually disappears by 36-week gestation, 1% of infants will retain these collections
of embryonic cells, referred to as “nephrogenic rests.” Nephrogenic rests are poten-
tially precursor lesions of WT and can be found in 40% of patients, and over 90%
of patients with bilateral disease, suggesting a germline mutation may predispose to
the persistence of such rests. Most cases of WT are unilateral, with 5–10% of cases
affecting both kidneys. Bilateral WT is more common in patients with underlying
genetic syndromes.
More than 15 different syndromes are associated with WT, including WAGR
(Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation),
Denys-Drash (Wilms tumor, diffuse mesangial sclerosis leading to early-onset renal
failure, and intersex disorders that can range from ambiguous to normal-appearing
female genitalia in both XY and XX individuals), and Beckwith-Wiedemann
(embryonal tumors, macrosomia, macroglossia, hemihypertrophy, visceromegaly,
omphalocele, neonatal hypoglycemia, and ear creases/pits) [9]. Less than 5% of WT
cases are associated with an underlying syndrome, and therefore, the etiology of
most cases is unknown. However, a strong genetic contribution is suggested given
that geographical variation is closely linked to ancestry and that 2% of WT cases are
familial [10].
Beckwith–Wiedemann Syndrome (BWS), the most common overgrowth syn-
drome, and isolated hemihypertrophy are associated with genetic or epigenetic