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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_32_библиотеки_им_акад_М_И_Перельмана
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Genitourinary Malignancies
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JONATHAN WALKER and NICHOLAS G COST
Topics covered
21
Pediatric renal tumors
Wilms tumor
Renal cell carcinoma
Congenital mesoblastic nephroma
PEDIATRIC RENAL TUMORS
Introduction
Renal tumors account for approximately 5–10%
of all pediatric cancers, with the most common
malignant renal tumor in children being Wilms
tumor (WT). Other renal tumors, such as congenital mesoblastic nephroma (CMN) and renal
cell carcinoma (RCC) are more likely to be diagnosed in patients younger than 6 months and
older than 12 years, respectively. Regardless of the
nal pathologic diagnosis, any newly diagnosed
renal tumor in a child should be approached in
a standardized fashion based on the assumption
that it is a malignant.
Genitourinary rhabdomyosarcoma
Prepubertal primary testicular tumors
the tumor burden at the time of diagnosis. e
most common presenting symptom is a palpable
abdominal mass. Other symptoms may include
hematuria (10%), hypertension, lower extremity
edema, or the features associated with a related
condition or syndrome which predisposes the
child to develop renal malignancy. ere is a broad
dierential diagnosis for a childhood renal mass
but key points in the history and physical examination ndings can help to narrow the diagnostic
possibilities. Specically, age at presentation, the
presence of a known predisposing syndrome or
medical condition and the characteristics of the
tumor on imaging may all help the clinician to
identify the most likely etiology of the renal mass.
Initial Evaluation
Presentation and Differential
Diagnosis
e clinical presentation of a renal tumor in childhood can vary depending on the child’s age and
Diagnostic evaluation of a palpable abdominal
mass in children should always begin with an
abdominal ultrasound (Figure 21.1A). is will
help to establish t he anatomical locat ion of t he mass
and provide a guide to further imaging. In the case
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of a newly diagnosed solid renal mass, the ultrasound scan should ideally be followed by a singlesetting computed tomography (CT) of the chest,
abdomen, and pelvis with intravenous contrast.
In addition to the renal mass itself, the key ndings which may be demonstrated on CT include:
possible presence of a tumor in the contralateral
kidney (Figure 21.1B), local or regional lymphade-
nopathy, tumor thrombus in the renal vein and
inferior vena cava (Figure 21.1C), and metastatic
disease, particularly in the lung elds. In children
presenting with gross hematuria, intraoperative
retrograde pyelography of the renal collecting
system can help to identify tumor involvement of
the renal pelvis or ureter, which may be present in
up to 2% of cases. Laboratory evaluation should
include a complete blood count (CBC), urinalysis and metabolic screen. Coagulation screening
should also be performed in view of the 4–8% risk
of acquired Von Willebrand disease associated
with WT. Although not typically of renal origin,
if a paraganglioma or neuroblastoma is part of the
dierential diagnosis, urinary vanillylmandelic
acid, homovanillic acid, and plasma free metanephrine levels can be checked to rule out these
common retroperitoneal tumors (Table 21.1).
Wilms Tumor
Etiology and epidemiology
Wilms tumor, also known as nephroblastoma,
is the most common primary renal malignancy in children with an incidence of 7–10
per million children. There are approximately
600 new cases a year in the United States (US)
alone. Since WT accounts for more than 90%
of renal malignancies in childhood this is the
presumed diagnosis in most children presenting with a renal mass. The peak age of diagnosis is 3–5 years. Approximately, 5–7% of WTs
are bilateral at the time of presentation and
10% are associated with a predisposing syndrome (Ta ble 21.2). These syndromes are typically categorized by their association with the
WT1 or WT2 genes on the short arm of chromosome 11. Because of the known association
with certain syndromes, it is recommended
that children with these syndromes should
be monitored with an abdominal ultrasound
scan at 3–4 monthly intervals until 8–10 years
of age. Although routine surveillance has not
been shown to confer increased survival from
WT it may help to minimize treatment morbidity by facilitating earlier intervention.
Histopathology and molecular
biology
Classically, WT is described as having a triphasic appearance on microscopy with stromal,
blastemal, and epithelial components present
(Figure 21.2). e blastemal portion gives rise
to the nomenclature of “small round blue cell”
tumor. ese cells are highly aggressive but typically more chemo-sensitive. e most common
stromal components seen in WTs include smooth
and skeletal muscle, bone, fat, or cartilage.
Immature renal tubules, glomeruli, or papillary
structures are classied as epithelial elements.
Of note, there is not always equal distribution of
these components, and not all of these components are always present in every WT.
e designation of favorable vs unfavorable
histology was an important milestone in the treatment of WT, as it provided one of the rst sources
of risk stratication. Unfavorable histology, such
as anaplasia, is associated with a poorer prognosis
and resistance to chemotherapy. WTs with unfavorable histology only represent approximately
10% of all WTs but are responsible for the majority of deaths.
Recent advances in molecular biology have
enabled further risk stratication for patients
with favorable histology (FH) Wilms tumors.
Studies undertaken by the children’s oncology
group (COG) have demonstrated that abnormalities identied on chromosomes 1 and 16 are
predictive of worse overall survival. Loss of heterozygosity (LOH) of chromosomes 1p and 16q
is also associated with a poorer outcome and a
requirement for additional and more prolonged
chemotherapy.
Staging
e children’s oncology group (COG), Société
Internationale d’Oncologie Pédiatrique (SIOP),
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Figure 21.1 (A) Renal ultrasound of the right kidney performed during the initial evaluation of a
suspected intra-abdominal mass conrming the presence of a heterogeneous renal mass. (B) Axial
computed tomography (CT) with IV contrast images of a patient with a large, left-sided renal mass
and a second, smaller lesion in the right kidney. (C) Coronal CT images from the same patient
reveal an associated tumor thrombus extending from the left renal vein into the intra-hepatic
inferior vena cava.
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Table 21.1 Investigational tools for a new renal mass
Test Purpose
Ultrasound Primary investigation; helps direct additional imaging work-up
CT chest, abdomen, pelvis
with contrast
Complete metabolic panel Renal and liver function assessment
Complete blood count Assess for anemia or infectious etiology
Urinalysis or urine studies Identies hematuria, proteinuria, or VMA if indicated
Coagulation panel Assess for the presence of bleeding disorder
Brain imaging and bone scan Reserved for patients with concerning central nervous system
VMA, vanillylmandelic acid.
Table 21.2 Wilms tumor predisposition syndromes and associated features
Syndrome Genetics WT risk (%) Features
Denys-Drash WT1 50–90 XY DSD, hypospadias, UDT, renal failure
WAGR 11p13, WT1 30–50 WT, aniridia, GU anomalies, mental retardation
Perlman WT2 20–60 Prenatal overgrowth, high infant mortality
Frasier WT1 5–20 XY DSD, renal failure
Beckwith-Weideman 11p15, WT2 5–10 Hemihypertrophy, Macroglossia
Simpson-Golabi-
Behmel
DSD, difference in sexual development; GU, genitourinary; UDT, undescended testicle.
Ideal imaging for solid renal mass; aids in surgical planning and
staging
symptoms or evidence of bone metastasis on standard imaging;
Not typically included in initial evaluation
X-linked,
GPC3
5–10 Skeletal and cardiac abnormalities, accessory
nipples
Figure 21.2 Triphasic nephroblastoma. Photomicrograph of a core-biopsy from a 3-year-old child
with a unilateral renal mass showing the characteristic triphasic histological features of Wilms tumor.
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and the UK National Wilms Tumor Study Group
(NWTSG) are independently engaged in multicenter studies of various aspects of treatment of
WTs. e staging protocol adopted by the COG is
as follows; (Figure 21.3):
●
Stage I (40–45%): Tumor conned to the
kidney, completely resected, with no evidence
of local or distant spread
●
Stage II (20%): Tumor spread beyond the
kidney, completely resected, with no evidence
of local or distant spread
●
Stage III (20–25%): Preoperative chemother-
apy or biopsy, tumor incompletely resected,
or positive nodal involvement
●
Stage IV (10%): Distant tumor spread
(metastasis)
●
Stage V (5%): Bilateral disease
Management and treatment
●
Surgery
●
Chemotherapy
●
Radiation
In North America, the denitive treatment of
WT typically involves a combination of surgery
and chemotherapy, with the possible addition
of radiation therapy. e children’s oncology
group recommends that most renal tumors are
managed by primary radical nephrectomy and
lymph node sampling. Staging is performed aer
nephrectomy, with recommendations on further
treatment being based on the surgical ndings
and tumor histology prior to any chemotherapy.
Exceptions to this protocol include bilateral
tumors (stage V), tumors which appear to be
too locally advanced for initial surgical resection (locally invasive into solid organs) or tumors
which are accompanied by thrombus in the inferior vena cava ( IVC) extending above the hepatic
veins. Another exception relates to children suffering from syndromes which predispose them
to developing Wilms tumor. In these dierent
scenarios chemotherapy is given prior to surgical
resection in order to minimize morbidity during nephrectomy or permit a nephron-sparing
approach where appropriate.
e backbone of chemotherapy is dual-agent
vincristine and actinomycin (VA). Patients who
Figure 21.3 Children’s oncology group staging of Wilms tumor. Stage I: tumor conned to the
kidney and completely excised macro- and micro-scopically. Stage II: tumor extending beyond the
kidney but completely excised macro- and micro-scopically. Stage III: tumor (a) biopsied preoperatively or those patients receiving preoperative chemotherapy; (b) incompletely resected;
(c) intraoperative tumor spillage; (d) positive lymph nodes. Stage IV: metastatic disease (usually
pulmonary). (e) Stage V: bilateral Wilms tumors.
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meet stage III or IV criteria receive additional
doxorubicin chemotherapy as well as radiation. ose with unfavorable histology may also
receive cyclophosphamide, etoposide, and carboplatin in addition to VA.
A dierent approach is adopted in the UK
and in majority of European countries, which
follow the SIOP protocols. is approach consists of upfront chemotherapy prior to a delayed
nephrectomy. Historically, specialist practice
in the UK favored initial biopsy to determine
next steps in management- either chemotherapy
or upfront surgery depending on the histology.
However, recently published data indicates that
for patients aged 6 months to 10 years, such
biopsy adds little information to change management. us, the UK group now follows the
general SIOP practice of upfront chemotherapy
for routine cases.
e rationale for upfront chemotherapy is to
down-stage tumors prior to surgery, facilitate
easier surgical resection and decrease the risk of
intraoperative tumor spillage. e indications for
radiation therapy or additional chemotherapy
are determined by a number of factors including
tumor response to primary chemotherapy, further
imaging/staging and the histological ndings.
e surgical approach to the resection of
Wilms tumors is fairly standardized (Figure
21.4a–e). A wide transverse abdominal incision
(a) gives ready access to the retroperitoneum,
particularly the aected kidney and great vessels
(aorta and vena cava). Once the overlying colon
and its mesocolon have been reected medially
(b), the ureter and gonadal vessels are identied,
divided, and followed proximally to the renal
hilum. Vascular control of the renal artery and
vein is obtained (c). Before ligating the renal
vein, careful palpation of the vessel should be
performed to conrm the absence of tumor
thrombus, regardless of whether the ndings on
preoperative imaging were negative. Aer the
renal artery and vein have been divided (d), the
kidney is removed from the retroperitoneum.
Care is needed to avoid capsular rupture (e), as
this can aect staging and increase the need for
local radiotherapy. e adrenal gland can be le
in situ if appropriate. Sampling of a minimum of
7–10 retroperitoneal lymph nodes is essential to
permit accurate staging and to guide subsequent
management (Figure 21.5).
Minimally invasive nephrectomy for WT has
been reported but further studies are needed to
select the patients for whom this might be safe
and appropriate.
Overall survival for patients with WT has
improved dramatically over the last half-century,
rising from 70% in the 1970s to over 90% today
(Table 21.3). is is due in large part the introduction of multi modal therapy and the ndings
of collaborative studies undertaken by the COG,
SIOP, and NWTSG. Despite dierences in the
approach to treatment, the overall survival rates
of children treated on the varying protocols are
remarkably similar. Both the COG and SIOP
are running studies to identify which children
with advanced disease can be eectively treated
without recourse to extended chemotherapy and
radiation therapy.
Renal Cell Carcinoma
Epidemiology and etiology
Renal cell carcinoma (RCC) accounts for only
5% of renal tumors in children but is the commonest renal tumor in the second decade of life,
accounting for >50% of renal malignancies in
this age group. It is more common in patients of
Afro-Caribbean descent. Since renal cell carcinomas are indistinguishable from Wilms tumors
on imaging by CT or MRI they should both be
considered in the dierential diagnosis of any
renal mass in a child, particularly in the older
age group. Nodal involvement and/or metastatic
spread are more common at the time of presentation in children than in adults with RCC. A
number of conditions are known to predispose
to RCC including; Von Hippel Lindau syndrome,
sickle cell trait or disease (for renal medullary
carcinoma), hereditary leiomyomatosis, and
tuberous sclerosis.
Histology and molecular biology
In children and adults under the age of 30 years,
RCC is associated with histological appearances
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Figure 21.4 Surgical steps of open radical nephrectomy for pediatric renal tumors. See text for
expanded description.
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Figure 21.5 (a) Nephrectomy specimen stage
II Wilms tumor. Localized penetration of renal
capsule with some tumor extension. Full macroscopic and histological clearance achieved.
(b) A nephrectomy specimen from a patient
with a Wilms tumor. The renal capsule is intact
and there was obvious tumor extension into the
renal vein and inferior vena cava.
linked to a translocation of the TFE3 gene on
the X chromosome in >50% of cases. is variant carries a worse prognosis. Papillary RCC are
more common in children than adults and there
Table 21.3 Four-year overall survival (OS) rates
for Wilms tumor based on stage and histology
Favorable
histology 4 yr OS
Stage
I 95–100 75–90
II 95–100 80–85
III 95–100 50–90
IV 85–90 30–75
V 95–100 65–100
(%)
Unfavorable
histology 4 yr OS
(%)
is a higher incidence of renal medullary carcinoma in patients with sickle cell trait and disease.
Staging
Staging for RCC in children follows the same
American Joint Committee on Cancer (AJCC)
tumor, node, metastasis (TNM) staging that is
used for adult patients with RCC.
Management and treatment
●
Surgery
●
Targeted therapy/clinical trial
e initial evaluation and surgical approach to
RCC is exactly the same as for WT. Unlike WT
and other pediatric renal malignancies, RCC is
primarily a surgical disease and adjuvant therapy
is reserved for advanced tumors with unresectable disease. Metastatic lesions, most oen in the
lungs, should be surgically removed if possible, as
complete surgical resection leads to signicantly
improved overall survival in adolescents and
young adults with RCC. Stage I and II disease have
80–90% 5-year overall survival, decreasing to only
14% for patients with stage IV RCC. Trials of chemotherapy and immunotherapy are in progress to
try and improve survival for these patients.
Congenital Mesoblastic Nephroma
(CMN)
Epidemiology and etiology
CMN is the most common form of renal tumor
in the rst 6 months of life but it nevertheless
accounts for less than 5% of all pediatric renal
tumors. It commonly presents as a palpable
abdominal mass in the neonatal period but is
detected on prenatal ultrasound in up to 15%
cases. e diagnostic evaluation is the same as for
WT and RCC, with an initial abdominal ultrasound followed by cross-sectional imaging.
Staging and histology
CMNs are staged by the same criteria as WT, with
the vast majority being stage I or II at the time
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of initial diagnosis. ere are three CMN histologic subtypes: classic, cellular, and mixed. Classic
and cellular subtypes represent the majority of
CMNs, and cellular histology is prone to a more
aggressive natural history.
Management and treatment
Despite being commonly regarded as a benign
tumor, CMN has the potential to recur locally
or give rise to distant metastases aer initial
therapy. Because most CMNs are localized to the
kidney, surgical excision is the primary treatment
modality. Even in cases of stage III disease, surgery alone may be curative. Stage III tumors and
those with a “cellular” histologic subtype carry a
higher risk of recurrence. ere is no standardized approach to the management of recurrent or
more advanced CMN cases, which oen require a
combination of surgery, chemotherapy, and radiation therapy.
Overall survival for children with CMN is
excellent (96%). Treatment – related complications of surgery or chemotherapy are common
causes of death in the small minority who do not
survive. e higher mortality rate in children presenting with CMN within the rst month of life
highlights the need for specialized, multi-disciplinary treatment planning for these extremely
young patients.
RHABDOMYOSARCOMA
Introduction
Rhabdomyosarcoma (RMS) is the most common so-tissue sarcoma in children and arises
from undierentiated skeletal muscle precursors.
ese tumors are relatively rare in children, with
an incidence of approximately 4 in 1 million, of
which only 15–25% arise within the genitourinary
systems. In the United States, this approximates to
90 new cases of genitourinary RMS a year. ere
is a bimodal age distribution of presentation with
the rst peak in the early years of life and a second in adolescence. e location of the tumor,
Table 21.4 Favorable vs unfavorable sites of
rhabdomyosarcoma
Favorable Unfavorable
Biliary tract Bladder/prostate
Orbit Urachal
Head and neck (excluding
parameningeal)
Paratesticular/penis Extremity
Vaginal/uterine Parameningeal
Retroperitoneal
classied as favorable vs unfavorable (Table 21.4),
is an important factor determining plays the treatment and prognosis of genitourinary (GU) RMS.
Favorable GU sites include paratesticular, vaginal/
vulvar, uterine, and penile. Unfavorable GU sites
include bladder/prostate (BP), retroperitoneal and
urachal. e most common GU sites are BP and
paratesticular. Risk factors for the development of
RMS include advanced maternal age, birth weight
>4.0 kg, and several syndromic conditions including Li Fraumeni syndrome, DICER-1 and Costello
syndromes and neurobromatosis and multiple
endocrine neoplasia Type 2A.
Histology and Molecular Biology
e embryonal type of histology (EMRS) is the
commonest, accounting for 60% of all rhabdomyosarcomas in children and up to 90% of
genitourinary rhabdomyosarcomas. is histological pattern is associated with higher overall
survival (80% 5 years event-free survival) and
includes subtypes such as the botryoid variant
commonly seen in vaginal RMS. Tumors with
the alveolar type of histology (ARMS) are more
common in older children, behave more aggressively and have a poorer prognosis (60% 5-years
EFS). Tumor genetics, namely the “fusion value”
are probably of greater predictive value than the
histologic classication. Fusion value refers to the
presence or absence of a translocation between the
FOX01 genes and PA X3 or PAX7 on chromosomes
2 and 13, respectively. Up to 80% of tumors displaying alveolar histology are PAX/FOX01 fusion
positive. Alveolar tumors which are “fusion negative” behave almost identically to tumors with the
less aggressive embryonal histology.
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