<title>1. INTRODUCTION</title> <p>The incidence of renal cell
carcinoma is increasing. This disease affects approximately 150 000 people
annually worldwide, causing nearly 78000 deaths [##UREF##0##1##]. Of these cases,
approximately 4% are thought to be associated with autosomal dominant hereditary
cancer syndromes [##REF##14634372##2##].</p> <p>Hereditary renal cancer
differs from sporadic renal cancer in several important respects. A hallmark of
hereditary renal cancer is that it is often multiple and bilateral.</p> <p>These distinct forms of
inherited epithelial kidney cancer include von Hippel-Lindau disease (VHC),
hereditary papillary renal carcinoma (HPRC), Birt-Hogg-Dubé syndrome (BHD),
hereditary leiomyomatosis renal cell carcinoma (HLRCC) and renal carcinoma
associated with hereditary paraganglioma [##REF##14634372##2##]. The genes for each of
these disorders have been identified by positional cloning including the VHL gene, the MET
proto-oncogene, the BHD gene, the FH gene, and the SDHB gene [##REF##14634372##2##].
Recently, familial renal carcinoma (FRC) has been described. Families with
multiple members with
renal carcinoma who do not have one of the known inherited forms of renal
carcinoma are considered to have FRC. FRC is currently a diagnosis of
exclusion [##REF##17222609##3##].</p> <p>A small percentage of renal
cell carcinomas (RCCs), which are subclassified by histology into clear cell
(75% of cases), papillary (10–15%), and chromophobe (5%) RCCs, and renal
oncocytoma (3%–5%), are due to inherited cancer syndromes [##REF##9390023##4##]. Each
inherited cancer syndrome, such as VHL, HPRC and hereditary leiomyomatosis and
renal cell carcinoma (HLRCC), is characterized by the development of specific
histologic types of renal cancer [##REF##14634372##2##]. For example, affected members of
families with VHL syndrome frequently develop clear cell RCCs, whereas patients
with HPRC are predisposed to develop type-1 papillary renal carcinomas [##REF##9140397##5##]. Patients with HLRCC, by contrast, develop aggressive
papillary type-2 renal carcinomas [##REF##11248088##6##] (see ##TAB##0##Table 1##).</p> <p>The widespread use of body
imaging in recent years has led to a significant increase in the incidence of
renal cell carcinoma (RCC). A distinction between benign and malignant small
renal masses cannot be made based on radiographic data alone and percutaneous
renal mass biopsy is still controversial [##REF##17997455##7##]. Clinicians therefore,
when confronted with small renal masses, must carefully weight the risks and
benefits of surgical removal [##UREF##1##8##].</p> <p>Herein, we will review the
features of hereditary renal cancers, the basic principles of genetic relevant
to these syndromes, and the various histopathologic features of renal cancer.
In addition, we will describe the known familial syndromes associated with
small renal masses.</p>
<title>8. CONCLUSIONS</title> <p>Small renal masses in the case
of renal cancer syndromes must be studied from a particular point of view
because hereditary renal cancers can lead to multiple and/or bilateral kidney
tumors. The primary goal of managing patients with familial renal syndromes is
prevention of metastatic disease. Nephron sparing surgery has the potential to
preserve renal function while maintaining oncology efficacy for selected
patients. In some syndromes, it is appropiate to develop a watchful waiting attitude,
3 cm size tumor seems to be the threshold for renal surgery. Due to the
aggressive form of renal carcinoma in the case HLRCC, initial surgical approach
is recommended.</p>
<p>Recommended by J. Rubio</p> <p>During the past two decades, several new hereditary renal cancers have been discovered but are not yet widely known. Hereditary renal cancer syndromes can lead to multiple bilateral kidney tumors that occur at a younger age than that at which the nonhereditary renal cancers occur. The aim of our work is to review the features of hereditary renal cancers, the basic principles of genetic relevant to these syndromes, and the various histopathologic features of renal cancer. In addition, we will describe the known familial syndromes associated with small renal masses.</p>
<title>2. VON HIPPEL-LINDAU DISEASE</title> <p>Von Hippel-Lindau (VHL)
disease is an autosomal dominant syndrome that affects multiple organ systems.
Extrarenal manifestations of VHL include central nervous system
hemangioblastomas, endolymphatic sac tumors, retinal angiomas, pheocromocytomas,
and pancreatic cysts and tumors [##UREF##2##9##].</p> <p>Renal cancer occurs in 25–45%
of patients with VHL; if cystic lesions are included in this estimate, the
incidence increases to over 60% [##REF##11176466##10##]. As renal tumors in VHL tend to be
multifocal and bilateral and unaffected renal tissue is at risk for developing
additional tumors [##REF##7500446##11##], management of these patients is a challenge. The
primary goal of managing patients with VHL is prevention of metastatic disease [##UREF##2##9##].
However, the capacity for CT to detect solid renal masses at an earlier stage
increases the importance of secondary goals, such as preservation of renal
function and maximization of quality of life, by minimizing the number of
surgical procedures that patients must undergo [##REF##11176466##10##].</p> <p>In VHL, patients inherit a
germline mutation of the VHL gene on chromosome 3p25 [##REF##8493574##12##]. The VHL gene
encodes pVHL, which is part of a complex (including elongin B/C and CUL2) that
targets the <italic>α</italic>-subunit of hypoxia-inducible factors 1 and 2 (HIF1<italic>α</italic> and HIF2<italic>α</italic>) for ubiquitin-mediated proteasomal degradation. If
the second copy of the VHL gene in a patient is inactivated, HIF1<italic>α</italic> and HIF2<italic>α</italic> accumulate. This leads to an increased transcription
of genes that encode downstream substrates of HIF1<italic>α</italic> and HIF2<italic>α</italic>, such as vascular endothelial growth factor, platelet-derived growth
factor and transforming growth factor-<italic>α</italic> (TGF-<italic>α</italic>). These molecules are thought to be important in VHL
tumorigenesis [##REF##15448019##13##].</p> <p>In the pre-CT era, strategies
for managing VHL renal tumors were often limited to watchful waiting or
bilateral nephrectomy with renal replacement therapy (dyalisis or renal
transplantation). The high historical rate of metastasis (13–42%) [##REF##10210376##14##],
despite the generally low grade of VHL renal tumors, makes watchful waiting an
unappealing strategy. Some researchers have advocated bilateral nephrectomy as
a means of removing all renal tissue at risk for tumor development [##REF##1593671##15##].</p> <p>Performing bilateral
nephrectomy necessitates renal replacement therapy. Goldfarb et al. compared 32
patients with VHL who underwent bilateral nephrectomy and subsequent renal
transplantation with a matched cohort of renal transplant recipients without
VHL [##REF##9422410##16##].</p> <p>No significant differences in
graft survival or renal function were observed between the two groups. Five
deaths ocurred in both groups; three in the VHL group were due to metastatic
disease. Five-year survival was 65%. The authors concluded that renal
transplantation was an effective form of renal replacement therapy for VHL
patients with limited risk of cancer recurrence [##REF##9422410##16##].</p> <p>Nephron-sparing surgery (NSS)
has the potential to preserve renal function while maintaining oncology
efficacy for appropiately selected patients. Favorable results were achieved in
several cohorts of VHL patients undergoing NSS [##UREF##2##9##].</p> <p>Factors associated with
successful NSS outcomes were small tumor size and low tumor grade; larger
tumors (&gt;5 cm) had higher local recurrence and metastatic rates [##REF##8437247##17##].</p> <p>Even though many VHL patients
are young and otherwise healthy, the morbidity of hemodialysis and
immunosuppression is significant; five-year survival rates for a cohort of
patients demographically similar to VHL patients were 71% on hemodialysis and
86% following renal transplantation [##UREF##2##9##].</p> <p>Although salvage partial
nephrectomy carries a high rate of perioperative morbidity. However, more than
three-quarters of operated kidneys can be preserved with only modest decreases
in renal function. These patients are able to avoid or postpone the associated
morbidity of dialysis, including some patients with solitary kidney.
Oncological outcomes are encouraging at intermediate followup with no evidence
of detectable metastatic disease [##REF##17997447##18##].</p> <p>Undergoing frequent surgeries
for small renal masses is not an appealing prospect for VHL patients; an
observational strategy in combination with NSS is more attractive.</p> <p>A cohort of patients with VHL
and renal masses were observed until the largest tumor in a renal unit was 3 cm
in diameter, at which time surgery was
recommended. The pattern of recurrence, bilaterality, and number of tumors were
not taken into consideration [##REF##10210376##14##]. The rate of metastases increases with
increasing tumor size (##TAB##1##Table 2##).</p> <p>The 3 cm threshold is not an absolute threshold demarcating development
of metastatic disease; rather it is a point at which the risk of metastasis with the potential morbidities
of multiple procedures are
balanced [##UREF##2##9##].</p> <p>Because of the high rate of
recurrence of renal tumors in VHL and the difficulties associated with repeated
renal surgery, ablative technologies such as cryoablation and radiofrequency
ablation (RFA) have been valid alternatives. Ablative procedures have been
performed both laparoscopically and percutaneously [##UREF##2##9##].</p> <p>The potential role of the
heat-shock protein 90 inhibitor 17-allylamino-17-desmethoxy-geldanamycin in VHC
is currently being evaluated in patients with small (2-3 cm) presurgical renal
lesion. Inhibition of heat shock protein 90, a molecular chaperone of HIF,
facilitates proteasomal degradation of HIF [##UREF##2##9##]. These approaches, which
target the abnormal molecular pathways involved in VHL tumorigenesis, represent
a potential future approach to treatment of patients with both sporadic and
VHL-associated clear-cell kidney cancer.</p> <p>NSS-bases approaches to
management of VHL-associated renal tumors, using a 3 cm tumor size threshold
for recommendation of surgery, can provide good cancer control while preserving
renal function and minimizing interventions. This type of strategy mandates
diligent screening and followup. More experience with minimally invasive
techniques is needed before their role in treatment of VHL renal tumors can be
defined. Medical therapy with new molecular-targeted agents is a promising
potential development in the management of VHL renal tumors [##UREF##2##9##].</p> <title>3. HEREDITARY PAPILLARY RENAL CARCINOMA</title> <p>Papillary renal carcinoma
(PRC) comprises 10% to 15% of kidney epithelial tumors and it is histologically
subdivided into types 1 and 2 [##REF##9195569##20##]. Hereditary papillary renal
carcinoma (HPRC) is an uncommon form of inherited kidney cancer characterized
by the predisposition to develop bilateral, multifocal renal tumors with type-1
papillary architecture [##REF##7853572##21##]. Tumors show frequent trisomy of chromosome
7 and they appear to arise from independent clonal events. HPRC is associated
with a mutation of the A <italic>MET</italic> proto-oncogene at 7q31.3. The gene was originally described in 1984 but was not
linked with papillary renal cancer until 1997 [##REF##9140397##5##]. This gene codes for
a transmembrane receptor tyrosine kinase. Mutations lead to activation of the
MET protein, which is also the receptor for hepatocyte growth factor. The
tumors produced in hereditary papillary renal cancer are well differentiated
type-1 papillary renal cancers [##REF##12511666##22##].</p> <p>Hereditary papillary renal
tumors are generally hypovascular and enhance only 10–30 HU after intravenous
administration of contrast material. This mirrors the experience with sporadic
papillary renal cancers, which are also typically hypovascular. Papillary renal
cancers can be mistaken for cysts, and one must be careful to obtain accurate
attenuation measurements before and after contrast enhancement. Ultrasonography
can be particularly misleading with this disorder, because small tumors are
often isoechoic [##REF##12511666##22##].</p> <p>Patients in HPRC have
previously been reported to have renal cancer on average in the sixth decade of
life [##REF##7853572##21##], later than other inherited renal cancer syndromes such as
VHL disease, which often develops in patients in the third and fourth decades
of life. Schmidt and colleagues reported on 3 families with HPRC in which, individuals in HPRC
are at risk for bilateral, multifocal kidney cancer earlier in life (second
decade) [##REF##15371818##23##]. In addition, this report emphasizes that HPRC can be a
lethal disease since a number of affected individuals in these families died of
metastatic kidney cancer. Type-1 papillary renal carcinoma in patients with
HPRC is a malignant tumor that can be lethal if it is not detected and treated early [##REF##15371818##23##].</p> <title>4. BIRT-HOGG-DUBÉ SYNDROME</title> <p>Birt-Hogg-Dubé syndrome (BHD)
is an autosomal dominant cancer syndrome characterized by the development of
small dome-shaped papules on the face, neck, and upper trunk
(fibrofolliculomas). In addition to these benign hair follicle tumors, BHD
confers and increases the risk of renal neoplasia and spontaneous pneumothorax. The gene has been mapped to chromosome
17p11.2 and recently identified, expressing a novel protein called folliculin [##REF##12471204##24##].</p> <p>Recently, individuals with BHD
syndrome were found to have a seven-fold higher risk over the general
population of developing kidney neoplasms [##UREF##3##25##].</p> <p>Unlike renal tumors in
patients with other inherited kidney cancer syndromes, renal tumors from BHD
patients exhibit a spectrum of histologic types, including chromophobe (34%),
oncocytoma (5%), clear cell (9%), papillary (2%), and an oncocytic hybrid (50%)
with features of chromophobe RCC and renal oncocytoma [##REF##12459621##26##]. Germline mutations have been identified in a
novel gene, BHD in affected family members [##REF##12204536##27##]. BHD encodes a
protein, folliculin, which is named for the hallmark dermatologic lesions found
in BHD patients. All germline mutations identified to date are frameshift or
nonsense mutations that are predicted to truncate folliculin, including
insertions or deletions of a tract of eight cytosines (C8) in exon 11 [##REF##12204536##27##].</p> <p>Pavlovich et al. [##REF##12459621##26##] reported 130 solid renal tumors resected from 30 patients with BHD in 19
different families. Preoperative CT demonstrated a mean of 5.3 tumors per patient
(range 1–28 tumors), the largest tumors averaging 5.7 cm in diameter (±3.4 cm, range 1.2–15 cm). Multiple and bilateral tumors were noted at an
early age (mean 50.7 years). The resected tumors consisted predominantly of
chromophobe renal cell carcinomas (34%) or of hybrid oncocytic neoplasms that
had areas reminiscent of chromophobe renal cell carcinoma and oncocytoma (50%).
Twelve clear cell (conventional) renal carcinomas (9%) were diagnosed. The
tumors were on average larger (4.7 ± 4.2 cm) than the chromophobe (3.0 ± 2.5 cm) and hybrid
tumors (2.2 ± 2.4 cm). Microscopic
oncocytosis was found in the renal parenchyma of most patients, including the
parenchyma of five patients with evidence of clear cell renal cell carcinoma.
These findings suggest that microscopic oncocytic lesions may be precursors of
hybrid oncocytic tumors, chromophobe renal cell carcinomas, and perhaps clear
cell renal cell carcinomas in patients with BHD syndrome.</p> <p>The malignant nature of BHD
associated renal tumors has not been previously established. BHD associated kidney cancer has the
potential to be a lethal disease based on family histories of death from
metastatic RCC in several patients with BHD. Pavlovich and colleagues [##REF##15821464##28##] suggest that BHD-associated chromophobe and hybrid oncocytic RCC may be of
lesser malignant potential than BHD associated clear cell RCC but these lesions
cannot be considered completely benign based on their cytomorphology and the
known occasionally malignant behavior of chromophobe tumors. In families in
which multiple members are found to have chromophobe or hybrid oncocytic renal
carcinomas, BHD should be considered. Efforts
are currently underway to determine why some BHD families have kidney cancer
and others do not [##REF##15821464##28##].</p> <p>Urological surgeons who treat
patients with BHD should keep in mind the potential for perioperative
pneumothorax in these patients. A high percent of patients with BHD is affected
with pulmonary cysts (almost 90%) and more than 20% have a history of
spontaneous pneumothorax.</p> <p>To address the mutation status
of the BHD gene in tumors from Birt-Hogg-Dubé patients, Vocke and colleagues [##REF##15956655##29##] analized a panel of 77 renal tumors by direct DNA sequence analysis. Tumor
samples, as well as matched normal samples, were obtained from 12 affected
members of BHD families after renal surgery. BHD patients were often found to
have bilateral, multifocal tumors and underwent staged bilateral partial
nephrectomies, providing tumor samples for the study. The entire coding region
of BHD (exons 4–14) was sequenced in each tumor sample, following polymerase
chain reaction (PCR) amplification. Their data showed that the tumors from a
given BHD patient have different second hits. These observations strongly
suggest that multiple renal tumors from some BHD patients are independent,
clonal events, each arising from a separate and unique second mutation in the
BHD gene. However, some tumors with mixed histologies shared a common somatic
mutation in the distinct histologic regions within each tumor. This finding
suggests that in some cases, a somatic second hit precedes histologic
diversification within a single tumor. The molecular mechanism that drives
these events is unknown. These results document the high frequency and wide
spectrum of second mutations, which strongly support a tumor suppressor role of
BHD. Inactivation of both copies of BHD ocurred in several histologic types of
renal tumors, suggesting that BHD may act at an early stage of renal
oncogenesis. Further understanding of the mechanism of BHD-induced tumorigenesis
awaits functional studies of the follicullin protein [##REF##15956655##29##].</p> <p>In addition, BHD is an
autosomal dominant hereditary cancer syndrome, in which affected individuals
are at risk for cutaneous fibrofolliculomas, pulmonary cysts, spontaneous
pneumothorax, and kidney tumors. Almost 30% of affected patients with BHD
examined had solid renal tumors. Because of the spectrum of renal tumor
histologies found in patients with BHD, their variable natural history, and the
risk of recurrent renal tumors in such patients, it is important for urologists
to be aware of this syndrome. The current management approach for BHD
associated renal tumors is to perform nephron sparing surgery when possible [##REF##15821464##28##].</p> <title>5. HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER</title> <p>A hereditary form of kidney cancer
referred to as hereditary leiomyomatosis and renal cell cancer (HLRCC) has been
identified, in which affected family members have cutaneous leiomyomas, uterine
fibroids, and/or kidney cancers [##REF##11248088##6##]. The renal malignancies that
develop in HLRCC families are often metastatic at presentation and are a
significant cause of mortality in these families. Analysis of families with
this disorder has identified the responsible gene locus as FH [##REF##11865300##30##].
This gene encodes fumarate hydratase (FH), an enzyme that is part of the
mitochondrial Krebs or tricarboxylic acid (TCA) cycle, located at 1q42.2-42.3.
The gene is inherited in an autosomal dominant manner. The mechanism by which
alterations in FH lead to HLRCC remains to be determined, but it apparently
involves increased cellular dependence on glycolysis.</p> <p>The reason why <italic>FH</italic> alterations are associated with tumor
formation in HLRCC families is not entirely clear at this time. It seems
intuitively that a cell that lacks functional FH (and hence has a defective TCA
cycle) would be at a metabolic disadvantage, particularly with regard to the
efficiency of nutrient catabolism. HLRCC is not, however, the only hereditary
cancer syndrome associated with a defective enzyme of the Krebs cycle. Germline
mutations in the succinate dehydrogenase complex have been identified that
predispose to the development of hereditary paragangliomas. Succinate
dehydrogenase catalyzes the conversion of succinate to fumarate—the step in the
TCA cycle that immediately precedes the reaction catalyzed by FH. Mutations in
subunits B, C, and D of the succinate dehydrogenase complex have all been
linked to hereditary paraganglioma.</p> <p>The extrarenal manifestations
of HLRCC were described previously [##REF##11248088##6##]. The most frequent
manifestation is uterine leiomyomas in affected females (75% to 98%). More than
90% of the women underwent myomectomy or hysterectomy and approximately half
had undergone hysterectomy by age of 30 years. Cutaneous leiomyomas are firm,
skin-colored to light brown or red papules. They may be segmental and
multifocal, and are mainly found on the trunk and extremities. They may be
painful. Mean age at onset of cutaneous manifestations is 25 years (range 10 to
47) [##REF##12772087##31##]. The incidence is 36% to 85%.</p> <p>There are several unique aspects to HLRCC-associated renal tumors that
differentiate them from other inherited forms of kidney cancer. Whereas tumors
in VHL, HPRC, and BHD twins are often
multifocal and involve the 2 kidneys [##REF##14634372##2##], renal tumors in patients with
HLRCC may be solitary.</p> <p>Toro et al. [##REF##12772087##31##] reported 19 patients with hereditary leiomyomatosis and renal cell cancer
associated renal tumors. Individual considered affected by HLRCC had greater
than 10 skin lesions clinically compatible with leiomyoma and a minimum of 1
lesion histologically confirmed as leiomyoma or tested positive for a germline FH mutation. Patients underwent precontrast and
postcontrast CT of the chest, abdomen, and pelvis after informed consent was
provided. Renal lesions were considered indeterminate if they were too small
(less than 1 cm in diameter) to be accurately classified as solid or cystic.
Only lesions 1 cm or greater and enhancing more than 20 HU that were
predominantly solid were considered renal tumors.</p> <p>For HLRCC they did not adhere
to the strategy of expectant management for tumors less than 3 cm, as we
previously described for other hereditary kidney cancer syndromes, such as VHL,
HPRC, or BHD [##REF##14634372##2##, ##REF##15201738##19##, ##REF##15821464##28##].</p> <p>HLRCC-associated renal tumors
appear to represent a significantly more aggressive type of renal cancer than
that in patients with VHL, HPRC, or BHD. Even small HLRCC renal tumors are
associated with nodal and metastatic disease. In the reported study [##REF##17509289##32##],
they often treat patients with VHL, HPRC,
and BHD and small (less than 3 cm) tumors expectantly, recommending surgery in
many when the largest lesion reached 3 cm. To their knowledge no patients with
VHL, HPRC, or BHD who presented with tumors less than 3 cm have had metastatic
disease using this clinical management approach [##REF##10210376##14##, ##REF##15201738##19##]. Because of the
aggressive nature of the renal cancer in HLRCC in the current study [##REF##17509289##32##] and the potential for small tumors to metastasize, the data suggest that small
lesions prospectively identified in patients at risk for HLRCC should not be
managed by an expectant, nonsurgical strategy. Experience with nephron sparing
surgery in the setting of HLRCC is limited to date and no formal
recommendations regarding the most efficacious surgical approach (radical versus
partial nephrectomy) for clinically localized renal tumors can be made at this
time, nephron-sparing
surgery could be potentially as curative as radical nephrectomy as has been
demonstrated in nonhereditary forms of RCC.</p> <p>A family history of renal
tumors, especially causing death at a young age, early hysterectomy in women
due to symptomatic fibroids, cutaneous leiomyomas, and importantly small tumors
with a lymph node or metastatic disease burden out of proportion to tumor size
should alert clinicians to the possibility of HLRCC. Renal tumors found in this
syndrome, which are frequently described as papillary type II or collecting
duct histology, appear to be significantly more aggressive than other forms of
hereditary renal cancer. Because of limited experience with screening and
treating these patients, optimal management strategies remain to be defined.
However, the early experience with HLRCC-associated renal carcinoma suggests
that extreme caution is warranted. Observational strategies that are suitable
for select patients with small renal masses associated with other hereditary
renal cancer syndromes are not appropriate for patients with HLRCC. HLRCC-associated
kidney cancer is markedly different from kidney cancer associated with other
hereditary cancer syndromes, such as VHL, HPRC, and BHD. These patients should
be evaluated and treated cautiously [##REF##17509289##32##].</p> <title>6. RENAL CARCINOMA ASSOCIATED WITH HEREDITARY PARAGANGLIOMA</title> <p>Germline mutations
of the genes encoding succinate dehydrogenase subunits B (SDHB) and D (SDHD)
predispose to paraganglioma syndromes type-4 (PGL-4) and type-1 (PGL-1),
respectively. In both syndromes, pheochromocytomas as well as head and neck
paragangliomas occur; however, details for individual risks and other clinical
characteristics are unknown.</p> <p>The paraganglioma
syndromes have been relatively newly delineated as unique entities. Although
paraganglioma has been clinically recognized for more than 40 years, only in
the last 4 years they have been classified based on molecular genetics: SDHD
mutations predispose to PGL-1, mutations in an unidentified gene on chromosome
11 to PGL-2, SDHC mutations to PGL-3, and SDHB mutations to PGL-4. In Neumann et al. report [##REF##15328326##33##],
consistent with the apparently aggressive nature of SDHB dysfunction, 5
mutation carriers in their study were also found to have extra paraganglial
malignancies (e.g., renal cell carcinoma and thyroid papillary carcinoma).
Kidney carcinomas are considered oncocytic tumors (replete with mitochondria)
and thus, the involvement of a mitochondrial complex II gene in kidney
carcinogenesis may be explained. The apparently more aggressive nature of the
tumors in SDHB mutation carriers may be postulated to be a consequence of the
prevention of assembly of the catalytic complex that normally comprises SDHA
and SDHB, thus leaving only complexes of the structural SDHC and SDHD moieties.</p> <p>Mutations in other genes can
be causes of hereditary renal carcinoma. These genes include hepatocyte nuclear
factor 1 <italic>α</italic> and 1 <italic>β</italic>, the tuberous sclerosis genes and and SDHB [##REF##15328326##33##].</p> <title>7. FAMILIAL RENAL CARCINOMA</title> <p>There are several interrelated
questions when approaching the family with multiple members with renal
carcinoma. The first issue is determining whether the family is affected with
one of the known inherited forms of renal carcinoma. The diagnosis of one of
the known inherited forms of renal carcinoma is based on clinical evaluation
and DNA testing. Families with 2 or more members with renal carcinoma who do
not have one of the known inherited forms of renal carcinoma are considered to
have FRC. Recently, Zbar et al. [##REF##17222609##3##], reported a study in which familial
renal carcinoma (FRC) was described and provisionally clasified (##TAB##2##Table 3##). They
evaluated 141 at risk asymptomatic relatives of affected individuals from 50
families with 2 or more members with renal carcinoma. Histology slides of renal
tumors from affected family members were reviewed and were not found to be VHL,
BHD, HLRCC, or HPRC. At risk, members from renal carcinoma families were
screened for occult renal neoplasms by renal ultrasound and computerized
tomography. DNA from selected families was
tested for germline mutations of known renal carcinoma genes when clinically
indicated and constitutional cytogenetic analysis was performed to search for
germline chromosome alterations. This collection of renal carcinoma families
represents a well-studied population from which families with the 4 well-known
causes of inherited renal carcinoma were removed from the study.</p> <p>Findings suggested that, when
confronted with a family with FRC, careful analysis should be performed of the
family to search for known causes of inherited renal carcinoma (##TAB##3##Table 4##). The
manifestations of hereditary leiomyoma renal carcinoma may be particularly
difficult to identify. The most likely cause of aggressive, early onset FRC was
hereditary leiomyoma renal cell carcinoma. In general, bilateral multiple renal
carcinomas in more than 1 family member are highly suggestive of an autosomal
dominant form of renal carcinoma. If
there is a suggestion of hereditary renal cancer, appropriate biopsies and
scans should be performed and DNA mutation studies should be performed to
confirm the diagnosis.</p>
<table-wrap id="tab1" position="float"><label>Table 1</label><caption><p>Characteristics of autosomal dominant (AD)
forms of kidney cancer (adapted from Zbar et al. [##REF##17222609##3##]).</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Disease</th><th align="left" rowspan="1" colspan="1">Gene</th><th align="left" rowspan="1" colspan="1">Renal Tumor histology</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">VHL </td><td align="left" rowspan="1" colspan="1">VHL</td><td align="left" rowspan="1" colspan="1">Clear cell Ca</td></tr><tr><td align="left" rowspan="1" colspan="1">HPRC</td><td align="left" rowspan="1" colspan="1">MET</td><td align="left" rowspan="1" colspan="1">Papillary type 1</td></tr><tr><td align="left" rowspan="1" colspan="1">HLRCC</td><td align="left" rowspan="1" colspan="1">FH</td><td align="left" rowspan="1" colspan="1">Renal cell Ca, HLRC type</td></tr><tr><td align="left" rowspan="1" colspan="1">BHD</td><td align="left" rowspan="1" colspan="1">BHD</td><td align="left" rowspan="1" colspan="1">Chromophobe/hybrid
oncocytic neoplasm/clear cell Ca</td></tr></tbody></table></table-wrap> <table-wrap id="tab2" position="float"><label>Table 2</label><caption><p>Comparision of tumor size and metastaes
(adapted from Duffey et al. [##REF##15201738##19##]).</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Tumor Size (cm)</th><th align="center" rowspan="1" colspan="1">Number of metastases</th><th align="center" rowspan="1" colspan="1">Number of patients</th><th align="center" rowspan="1" colspan="1"> Percentage of patients with metastases</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">≤3.0</td><td align="center" rowspan="1" colspan="1">0</td><td align="center" rowspan="1" colspan="1">108</td><td align="center" rowspan="1" colspan="1">0</td></tr><tr><td align="left" rowspan="1" colspan="1">3.1–4.1</td><td align="center" rowspan="1" colspan="1">1</td><td align="center" rowspan="1" colspan="1">27</td><td align="center" rowspan="1" colspan="1">4</td></tr><tr><td align="left" rowspan="1" colspan="1">4.1–5.5</td><td align="center" rowspan="1" colspan="1">4</td><td align="center" rowspan="1" colspan="1">19</td><td align="center" rowspan="1" colspan="1">21</td></tr><tr><td align="left" rowspan="1" colspan="1">5.6–10.0</td><td align="center" rowspan="1" colspan="1">10</td><td align="center" rowspan="1" colspan="1">20</td><td align="center" rowspan="1" colspan="1">50</td></tr><tr><td align="left" rowspan="1" colspan="1">≥10.1</td><td align="center" rowspan="1" colspan="1">5</td><td align="center" rowspan="1" colspan="1">7</td><td align="center" rowspan="1" colspan="1">71</td></tr></tbody></table></table-wrap> <table-wrap id="tab3" position="float"><label>Table 3</label><caption><p>Clinical and pathological subtypes of familial renal carcinoma
(adapted from Zbar et al. [##REF##17222609##3##]).</p></caption><table frame="hsides" rules="groups"><tbody><tr><td align="left" rowspan="1" colspan="1">(1) Single clear cell renal carcinomas</td></tr><tr><td align="left" rowspan="1" colspan="1">(2) Bilateral multiple clear cell renal carcinomas, without VHL</td></tr><tr><td align="left" rowspan="1" colspan="1">(3) Single clear cell renal carcinomas
and renal oncocytomas*</td></tr><tr><td align="left" rowspan="1" colspan="1">(4) Single clear cell renal carcinomas
and papillary renal carcinomas**</td></tr><tr><td align="left" rowspan="1" colspan="1">(5) Single and multiple renal
oncocytomas without the other clinical features of BHD syndrome</td></tr><tr><td align="left" rowspan="1" colspan="1">(6) Single or multiple bilaterally renal
carcinomas but not HPRC or HLRCC</td></tr><tr><td align="left" rowspan="1" colspan="1">(7) Other</td></tr><tr><td align="left" rowspan="1" colspan="1">*Families with some members affected with single
clear cell renal carcinomas and other members affected with single renal
oncocytomas</td></tr><tr><td align="left" rowspan="1" colspan="1">
**Families with one member affected with single clear
cell renal carcinoma and another member affected with single clear cell renal
carcinoma and another member affected with papillary renal carcinoma</td></tr></tbody></table></table-wrap> <table-wrap id="tab4" position="float"><label>Table 4</label><caption><p>FRC versus
autosomal dominant (AD) forms of kidney cancer. (adapted
from Zbar et al. [##REF##17222609##3##]).</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Disease</th><th align="left" rowspan="1" colspan="1">Inheritance mode</th><th align="left" rowspan="1" colspan="1">Age at onset</th><th align="left" rowspan="1" colspan="1">Tumor multiciplicity</th><th align="left" rowspan="1" colspan="1">Histology</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">FRC</td><td align="left" rowspan="1" colspan="1">Complex</td><td align="left" rowspan="1" colspan="1">Late</td><td align="left" rowspan="1" colspan="1">Single </td><td align="left" rowspan="1" colspan="1">varied</td></tr><tr><td align="left" rowspan="1" colspan="1">VHL</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">Adolescence</td><td align="left" rowspan="1" colspan="1">Bilat, multiple</td><td align="left" rowspan="1" colspan="1">Clear cell</td></tr><tr><td align="left" rowspan="1" colspan="1">HPRC</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">40–49 years</td><td align="left" rowspan="1" colspan="1">Bilat, multiple</td><td align="left" rowspan="1" colspan="1">Papillary type 1</td></tr><tr><td align="left" rowspan="1" colspan="1">BHD</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">30–39 years</td><td align="left" rowspan="1" colspan="1">Bilat, multiple</td><td align="left" rowspan="1" colspan="1">Chromophobe/hybrid oncocytic</td></tr><tr><td align="left" rowspan="1" colspan="1">HLRCC</td><td align="left" rowspan="1" colspan="1">AD</td><td align="left" rowspan="1" colspan="1">10–20 years</td><td align="left" rowspan="1" colspan="1">Single or multiple</td><td align="left" rowspan="1" colspan="1">Renal cell Ca, HLRCC type</td></tr></tbody></table></table-wrap>
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Adv Urol. 2008 Aug 4; 2008:413505