Review
Hereditary renal cancer
Julián Sanz-Ortega, Carlos Olivier*, Pedro Pérez Segura**,
Isabel Galante Romo*, Luis San José Mansó*, Mamen Saez
Servicio de Anatomía Patológica, *Urología y **Oncología. Hospital Clínico San Carlos.
Madrid, Spain
Unidad Clínica del Cáncer Renal Hereditario (UCCRH)
(Integrado en
ACTAS UROLÓGICAS ESPAÑOLAS 2009;33(2):127-133
|
Abstract |
|
Renal cancer is the tenth leading cause of death from cancer. There are
an increasing number of genes known to be associated with an increased risk
for specific types of renal cancer. |
|
People with von Hippel‑Lindau (VHL) syndrome have approximately a
40% risk of developing multiple bilateral clear cell renal cancer. They can
also develop retinal and brain hemangioblastoma, renal or pancreatic cysts,
pheochromocytoma, and endolymphatic sac tumors. Four VHL phenotypes with
different risks of renal cancer and pheochromocytoma have been reported
depending on germline mutation. |
|
Hereditary papillary renal cell carcinoma
syndrome has papillary type 1 renal cell carcinomas associated with proto‑oncogene
c‑MET germline mutations. |
|
The Birt‑Hogg‑Dubé syndrome has FLCN
gene mutations associated with fibrofolliculomas, lung cysts with a high risk
for spontaneous pneumothorax, and a 15% to 30% risk of renal cancers (most
classified as chromophobe carcinoma, oncocytoma or oncocytic hybrid tumor,
but clear cell and papillary renal cancers have also been reported). Histopathological findings such as oncocytosis and
oncocytic hybrids are very unusual outside the syndrome. |
|
Hereditary
leiomyomatosis and renal cell cancer syndrome show mutations in the fumarate hydratase gene and cutaneous
leiomyomata in 76% of affected patients, uterine leiomyomata in 100% of
females, and unilateral, solitary, and aggressive papillary renal cancer in
10% to 16% of patients. Prominent eosinophilic
nucleoli with a perinucleolar halo are specific histopathological changes. |
|
Tuberous
sclerosis complex is one of the most prevalent (1/5.800) hereditary syndromes
where renal disease is the second leading cause of death, associated to
angiomyolipomas (70%), renal cysts, oncocytomas, or clear cell renal
carcinoma. |
|
Keywords: renal cancer;
Von‑Hippel‑Lindau; germline mutations; HLRCC; leiomyomas |
Renal
cancer is the seventh and ninth most common cancer in males and females
respectively, and the tenth leading cause of death from cancer overall. It is
estimated that 54,390 new cases of renal cancer (33,130 males and 21,260 females)
will be diagnosed in
Renal
cancer is not a single disease, but encompasses different conditions with
different biological behavior, morphology, and molecular basis. There are an
increasing number of genes which are associated to an increased risk of renal
cancer. Some of these hereditary syndromes have been reported very recently and
renal prevalence is not known with certainty, but at least 5% of renal
carcinomas are thought to have a hereditary basis. Identification of a genetic
syndrome in a family may help develop a cancer screening plan and, in some
cases, establish a better treatment.
This
review analyzes the characteristics of the most common hereditary syndromes,
usually associated to a specific histological subtype, tumor frequency, the
available genetic tests, and the recommended screening/early detection programs
and treatments.
Familial
syndromes associated to different types of renal cancer include:
•
Von Hippel‑Lindau (VHL): Bilateral and multifocal clear cell renal
carcinoma. Patients with VHL syndrome are also at risk for CNS
hemangioblastoma, retinal angioma, pheochromocytoma, and endolymphatic sac
tumors.
•
Hereditary papillary renal cancer (HPRC): Bilateral, multifocal papillary type 1
carcinoma.
•
Hereditary leiomyomatosis and renal cell cancer (HLRCC): Solitary renal tumors
such as papillary type 2 carcinoma. Patients with HLRCC may experience multiple
cutaneous and/or uterine leiomyomas of an early and aggressive onset.
• Birt‑Hogg‑Dubé: Renal tumors are
usually multifocal and bilateral. They include oncocytoma, chromophobe
carcinoma, oncocytic hybrid tumor, and clear cell renal carcinoma in a
minority. The syndrome is associated to skin fibrofolliculomas.
•
Tuberous sclerosis: This is associated to angiomyolipoma.
In
these syndromes, the mutation inherited should be present in the germline and
thus in all cells. Testing of peripheral blood is recommended because of its
greater specificity, simplicity, and rapidity. Paraffin‑embedded or
frozen archived material from tumors and normal tissue may also be tested.
This
reviews details the adequate clinical and/or histopathological criteria for
deciding in each syndrome whether a patient is amenable to genetic testing.
Thus, a hereditary syndrome may be suspected by pathologists, urologists,
dermatologists, or other specialists, sometimes in concert. Patients must be
examined and informed of the consequences and scope of the study by the genetic
counseling team. If patients cannot be seen in person and want to send a sample
for genetic testing, the first “indispensable” requirement is to obtain their
informed consent (biomedical research act 14/2007, July 3, 2007). The next step
is DNA extraction from blood (or frozen or paraffin‑embedded tissue, when
applicable) and molecular analysis, as described below.
HEREDITARY SYNDROMES
Von hippel‑lindau (VHL) syndrome
Characteristics: People with
VHL have a greater risk of several types of tumors(2-10). Most these tumors are
benign in nature. However, patients with VHL have a 40% risk for developing
renal cancer, which is main cause of death. The specific type of renal cancer
related to VHL is clear cell renal carcinoma. Other parts of the body where
tumors may develop include the eye (angioma5,6), brain7 and spinal cord
(hemangioblastoma), adrenal glands (pheochromocytoma), and ears (endolymphatic
sac tumor8).
Patients with VHL may also develop cysts in their kidney or pancreas. VHL
symptoms usually develop at 20 and 30 years, but may occur in childhood.
Approximately 20% of patients with VHL have no family history of the disease.
Diagnosis: Clinical diagnosis of
von Hippel‑Lindau syndrome is made in2:
•
A person who does not report or know a family history but has two or more characteristic lesions,
e.g. two or more hemangioblastomas of the retina or cerebellum or a single
hemangioblastoma associated to a visceral manifestation such as renal or
pancreatic cysts, renal cell carcinoma before the age of 60, pheochromocytoma
and, less commonly, endolymphatic sac tumor, papillary cystadenoma of
epididymis or broad ligament, or neuroendocrine tumors of the pancreas9.
•
A person with a family history of VHL syndrome with only one of the previous
manifestations.
Pathological suspicion: In addition
to the above characteristics, the pathologist may suspect the syndrome in the
event of synchronic or metachronic occurrence of the following:
•
Spectrum of bilateral lesions: Clear cell renal carcinoma (CCRC) and renal
cysts.
•
Cystic precursor lesions and early forms of CCRC.
Gene: VHL is the only gene
associated to VHL (chromosome 3p25‑p26). Inheritance is autosomal
dominant. VHL acts as a tumor‑suppressing gene and is an essential
component of a protein complex that is bound to and degrades protein HIF‑1
(hypoxia‑inducible factor). When VHL function is lost, HIF‑1 remains
abnormally active, acting as a stimulus of carcinogenetic molecular pathways
that activate cell proliferation.
Molecular genetic testing10-12: Diagnosis of VHL
syndrome is suspected in subjects with the characteristic lesions. Molecular
genetic testing of the VHL gene detects mutations in almost 100% of subjects
affected.
•
Confirmatory diagnostic tests
•
Prediction tests
•
Prenatal diagnosis
•
Preimplantation genetic diagnosis
•
Sequence analysis. Analysis of sequences of the three exons to detect point
mutations (~ 72% of VHL mutations).
•
Various methods (e.g. semiquantitative PCR) may be used for detecting partial
or complete loss of the chromosome region of the gene, accounting for
approximately 28% of all VHL mutations12.
•
For people with signs of VHL who do not strictly meet diagnostic criteria and
do not have a detectable VHL germline mutation, de novo somatic mutations should be considered13. In some cases,
molecular genetic testing in the offspring of these subjects demonstrates the
VHL mutation.
Genotype‑phenotype correlations14-16:
Four
classical VHL phenotypes have been reported based on the risk of
pheochromocytoma or renal cell carcinoma.
VHL
type 1 is characterized by a low risk of pheochromocytoma and missense
mutations disturbing protein folding.
VHL
type 2 is characterized by a high risk of pheochromocytoma and other missense
mutations. VHL type 2 is in turn subdivided into:
•
Type 2A: low risk of renal cell carcinoma,
•
Type 2B: high risk of renal carcinoma, and
•
Type 2C: with risk of pheochromocytoma.
Management17. Conservative renal surgery for
successive multiple lesions (partial nephrectomy when possible) of clear cell
renal carcinoma; kidney transplant after bilateral nephrectomy; excise
pheochromocytomas. Prevention of secondary deficits such as hearing loss,
vision loss, and neurological symptoms. Monitoring: annual ophthalmological
examination, starting before five years of age; annual blood pressure
monitoring and measurement of catecholamines in urine from the age of five
years in families with a high incidence of pheochromocytoma; annual abdominal
ultrasound starting at 16 years of age, followed by evaluation of suspicious
lesion with CT or MRI.
Tests in relatives at risk: Clarify the
genetic status of family members to avoid the need for high monitoring costs in
those who have not inherited the mutation.
Penetrance: Almost all subjects
having a mutation in the VHL gene will experience symptoms related to the
disease before 65 years of age.
Prevalence: VHL incidence is
approximately one out of every 36,000 births18.
Hereditary papillary renal cell carcinoma
(HPRCC)
HPRCC
is suspected when two or more close relatives have been diagnosed of type 1 papillary
renal carcinoma. Patients with HPRCC may develop multiple renal tumors in one
or both kidneys. Patients from families in which the HPRCC mutation is
identified should undergo annual screening by ultrasound, MRI and/or computed
tomography from approximately 30 years of age.
The
HPRCC‑associated gene is called c‑met (located in chromosome 7q31).
It is a proto‑oncogene, and therefore produces proteins promoting normal
cell growth. Type 1 papillary carcinoma is also characterized, both in its familial
and sporadic forms, by trisomy in chromosomes 7, 16, or 17, and in males by
loss of chromosome Y19.
The
inheritance pattern is consistent with autosomal dominant transmission with low
penetrance.
Birt‑hogg‑dubé (BHD) syndrome
Summary: The BHD syndrome is a
rare condition described in 199720 associated to fibrofolliculomas (benign tumors of
hair follicles, usually white or flesh‑colored), lung cysts, and an
increased risk of renal cancer. Patients with BHD have a 15%‑30% risk of
developing renal cancer. Most renal cancers associated to BHD are classified as
chromophobe carcinomas and oncocytomas, but clear cell renal and papillary
carcinomas may also occur. Because of the greater risk of renal cancer, annual
screening with ultrasound, MRI, and CT should be considered from 25 years of
age.
Clinical characteristics20-25. These include skin
manifestations (fibrofolliculomas, trichodiscomas, and acrocordons), lung cysts
and history of pneumothorax, and various types of renal tumors. Disease
severity may vary substantially. Skin lesions usually occur during the third or
fourth decades of life and increase in size and number with age. Most lung
cysts are bilateral, multifocal, and asymptomatic, but involve a high risk of
spontaneous pneumothorax. Approximately 15% of patients with BHD syndrome
develop renal tumors, which are bilateral and multifocal and usually grow
slowly; mean age at tumor diagnosis is 48 years. Most common tumors include
oncocytoma, chromophobe carcinoma, or a hybrid of both types of tumor.
Clinical diagnosis:
•
Multiple small cutaneous manifestations as papules distributed over the face,
neck, and upper trunk. The characteristic triad consists of fibrofolliculomas
(multiple hamartomas of hair follicles), trichodiscomas, and acrocordons, but
only fibrofolliculomas are specific for the BHD syndrome. Dermatological
diagnosis of the Birt‑Hogg‑Dubé syndrome is made in subjects who
have five or more papulas with at least one histologically documented
fibrofolliculoma25.
Note: A scrape biopsy is
usually not sufficient.
•
Lung cysts and spontaneous pneumothorax. Most patients (89%) with BHD syndrome
have multiple bilateral lung cysts, identified by CT of the chest. The total
number of cysts per individual lung ranges from 0 and 166 (mean 16). Twenty‑four
percent (48/198) of patients with BHD syndrome had a history of one or more
episodes of pneumothorax25.
•
Renal tumors. Renal tumors are usually multifocal and bilateral. They include
in combination: oncocytoma, chromophobe carcinoma, oncocytic hybrid tumor, and
clear cell renal carcinoma in a minority.
*Note: The original
description and diagnosis of the Birt‑Hogg‑Dubé syndrome is based
on skin pathology. However, recent research has shown that some subjects with
Birt‑Hogg‑Dubé syndrome could have a pulmonary syndrome and/or
renal tumors without skin lesions.
•
Pathological suspicion: When a combination of chromophobe carcinomas and
oncocytomas exists, particularly in the presence of early
"oncocytosis" lesions or oncocytic hybrids that are uncommon outside
the hereditary syndrome.
Diagnosis/testing26-27. FLCN (BHD)
is the only gene associated to the Birt‑Hogg‑Dubé syndrome. FLCN
gene mutations are detected in 84% of affected individuals.
Genetic counseling. Inheritance is autosomal dominant.
Molecular genetic testing:
•
Sequence analysis. An insertion or deletion in exon 11 (mutational hotspot) was
found in 53% (27 of 51) of families with Birt‑Hogg‑Dubé syndrome28.
Analysis
of sequencing of all exons (exon 4-14) increases mutation detection to 84%.
Genotype‑phenotype correlations: Patients who have a deletion in exon 11 may
have a lower risk of renal cancer than those with other mutations28.
Penetrance: Based on the three
major clinical manifestations, penetrance of the Birt‑Hogg‑Dubé
syndrome is considered very high.
Prevalence: More than 60 families affected have been
reported29.
Hereditary leiomyomatosis and renal cell
carcinoma (HLRCC)
Summary30-35: HLRCC is a
syndrome described in 2001 whose renal incidence is unknown30. Seventy‑six
percent of patients with HLRCC will develop cutaneous nodules called
leiomyomas. Nodules mainly occur in the arms, legs, chest, and back. Women with
HLRCC develop uterine leiomyoma (100%) or, less commonly, leiomyosarcoma.
Patients with HLRCC also have a 20% risk of developing type 2 papillary renal
carcinoma. Women in these families should also undergo gynecological tests
because uterine leiomyomas are usually asymptomatic and lead to early
hysterectomy (mean age, 30 years). The gene associated to HLRCC is called FH
(fumarate hydratase).
Clinical diagnosis35: No consensus exists on the diagnostic
criteria for HLRCC. The clinical condition may be suspected, amongst others, by
dermatologists, urologists, and pathologists based on the following:
•
Multiple cutaneous leiomyomas with at least one histologically documented
leiomyoma.
•
A single leiomyoma in the presence of a positive family history of HLRCC.
•
One of more type 2 papillary renal carcinomas with or without a family history
of HLRCC.
•
Typical histopathological features in type 2 papillary renal carcinomas and/or
uterine leiomyomas: presence of eosinophilic macronuclei surrounded by a clear
halo.
Note: Because of the high
prevalence of uterine leiomyoma in the general population, a solitary uterine
leiomyoma is not sufficient for HLRCC diagnosis.
Genetic testing strategy31-32: Inheritance of HLRCC is autosomal
dominant. Genetic tests are intended to detect a germline mutation in the FH
gene, usually by direct sequencing of all exons.
Measurement
of fumarate hydratase activity may be of help for diagnosing HLRCC in cases
with atypical presentation and undetectable FH mutations.
Genotype‑phenotype correlations: No genotype‑phenotype
correlations have been reported. Mutations associated to HLRCC are distributed
along the FH gene.
Penetrance: Based on three major clinical
manifestations, HLRCC penetrance is considered to be very high.
Prevalence: The syndrome has recently been described
and its prevalence is unknown. More the 100 families with HLRCC have been
reported.
Tuberous sclerosis
Characteristics36,37: Tuberous sclerosis (TE) involves
changes in skin (hypopigmented maculas, facial angiofibroma, facial fibrous
plaque, ungueal fibroma) and brain (cortical plaques, subependymal nodules,
seizures, mental retardation or delayed development), kidney (angiomyolipoma,
cysts), and heart (rhabdomyoma, arrhythmia). CNS tumors are the main causes of
morbidity and mortality, while kidney disease is the second leading cause of
premature death.
Kidney. Kidney disease is
the second leading cause of premature death (27.5%) in patients with tuberous
sclerosis38.
It is estimated that 80% of children with tuberous sclerosis have an
identifiable renal lesion at a mean age of 10.5 years. Five different renal
lesions occur in TE: benign angiomyolipoma (70% of affected individuals),
epithelial cysts (20%-30%), oncocytoma (benign adenomatous hamartoma) (1%),
malignant angiomyolipoma (<1%), and renal cell carcinoma (<3%).
Diagnosis/testing. TE diagnosis is based on clinical
findings. Two causative genes have been identified, TSC1 and TSC238-39.
Clinical diagnosis: Diagnostic criteria for
tuberous sclerosis (TE) have been reviewed40.
Genetic counseling38-39.
TE inheritance is autosomal dominant. Two thirds of affected patients have TE
as the result of a de novo genetic
mutation. Twenty‑seven percent of mutations occur in TSC1, and 73% in
TSC2.
Molecular genetic testing:
•
Sequence analysis. TSC1 mutations are mainly small insertion and deletions and
nonsense mutations. By contrast, TSC2 mutations may also include a significant
number of major rearrangements and deletions that may not be detected by
sequence analysis.
Molecular
genetic testing of TSC1 and TSC2 is complex because of the big size of both
genes, the high number of diseases causing mutations, and the high rate of
somatic mosaicism (10%-25%).
•
Genomics‑microarray analysis/FISH: (SignatureChipTM) includes
evaluation of 125 clinically relevant loci using 589 BAC clones for detecting
whether or not the DNA region tested is present.
No
identifiable mutation is found in 20%-30% of patients with tuberous sclerosis,
that may therefore not be considered as a genetic subtype.
Genotype‑phenotype
correlations: TSC1
mutations usually appear to cause a less severe phenotype than TSC2 mutations.
•
Al‑Saleem et al (1998)37 reported a greater risk of renal neoplasm in
patients with TSC2 mutations.
Penetrance:
TSC penetrance appears to be 100%.
Prevalence: TSC
incidence may be as high as one in every 580036.
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Correspondence author: Dr. Julián Sanz-Ortega
Servicio de Oncología Médica
Hospital Clínico San Carlos
Prof. Martín Lagos, s/n - 28040 Madrid
Tel.: 913 303 822
Author email:
jsanzo.hcsc@salud.madrid.org
Paper information: Review – Renal
cancer
Manuscript received: october 2008
Manuscript accepted: november 2008