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Current Issues in the Diagnosis and Management of Wilms' Tumor

Current Issues in the Diagnosis and Management of Wilms' Tumor

ABSTRACT: Significant advances have been made in the treatment of children with Wilms' tumor. Whereas 50 years ago overall survival was less than 10%, current survival estimates approach 90%. This progress has been made possible by the cooperation of pediatric oncologists, surgeons, pathologists, radiation oncologists, and support personnel in their joint quest to find a cure for this intriguing childhood neoplasm. The next goals are to determine better treatment for patients with unfavorable histology tumors or recurrent disease and to identify patients who may not require adjuvant therapy. Also, the role of renal parenchymal-sparing resections needs to be defined further. [ONCOLOGY 10(10):1553-1571, 1996]

Introduction

Major advances have occurred over the last 50 years in the treatment
of children with Wilms' tumor. These advances, made possible by
the joint efforts of pediatric oncologists, surgeons, pathologists,
radiation oncologists, and support personnel, have led to a dramatic
improvement in survival, which currently approaches 90%.

Despite this progress, however, several controversies relating
to the diagnosis and management of this intriguing childhood neoplasm
remain unresolved. This article explores these controversial issues.
As background to the dis-cussion, a brief overview of the epidemiology,
etiology, histology, diagnosis, and treatment of this tumor will
be presented.

Overview

Wilms' tumor is the most common intra-abdominal tumor of childhood,
affecting approximately 1 child per 10,000 worldwide.[1] The disease
has no sex predilection, and the median age at presentation is
approximately 3.5 years. Patients with bilateral tumors have been
reported to present at a younger age.[2,3]

Specific congenital anomalies have been associated with Wilms'
tumor; these include hemihypertrophy, aniridia, and genitourinary
abnormalities. The WAGR syndrome (Wilms' tumor, aniridia, genitourinary
malformation, and mental retardation) and the Denys-Drash syndrome
(intersexual disorders, nephropathy, and Wilms' tumor) have been
linked to a deletion and point mutation, respectively, within
chromosome 11p13 (WT1 gene). The Beckwith-Wiedemann syndrome (macroglossia,
organomegaly, hemihypertrophy, and omphalocoele) has been linked
to the 11p15 locus (WT2 gene) and is thought to result from overexpression
of a gene that is normally expressed by one of the paternal alleles.
The incidences of Wilms' tumor in the WAGR, Denys Drash, and Beckwith-Wiedemann
syndromes have been reported to be more than 30%, more than 90%,
and less than 5%, respectively.[4]

Knudson and Strong have proposed a two-hit hypothesis model to
explain the earlier age of onset and bilateral presentation in
children with a familial history of Wilms' tumor.[5] In this hypothesis,
a tumor develops from two mutational events--the first may be
prezygotic or postzygotic and the second is always postzygotic.
If the first mutation is prezygotic, the tumor would be heritable
and may present as multiple tumors, following a Poisson distribution.
Wilms' tumor development, however, still depends on a second postzygotic
mutation. In contrast, if the first mutation is postzygotic, the
tumor is nonhereditary and single.

Wilms' tumor is thought to arise from nephrogenic rests, persistent
embryonal remnants in the kidney. The presence of multiple nephrogenic
rests (nephroblastomatosis), especially when intralobar, places
the child at increased risk for Wilms' tumor formation in the
contralateral kidney.[6]

The classic histologic pattern for Wilms' tumor is triphasic,
consisting of epithelial, blastemal, and stromal elements. Most
neoplasms have a good prognosis and are classified as favorable
histology. Unfavorable histologies include focal or diffuse anaplasia
and clear cell sarcoma of the kidney. The results of the third
National Wilms' Tumor Study (NWTS 3) indicate a survival rate
approaching 90% for patients with a favorable histology tumor
and 55% to 75% for most patients with anaplasia or clear cell
sarcoma. The staging system devised by the NWTS is summarized
in Table 1.[7]

The most common presentation is an asymptomatic abdominal mass.
Hematuria, hypertension, malaise, and abdominal pain have also
been documented. Several paraneoplastic syndromes have been reported;
these include erythrocytosis, hypercalcemia, Cushing's syndrome,
and acquired von Willebrand's disease.[8]

Ultrasound has replaced the IV pyelogram (IVP) in the work-up
of a patient with an abdominal mass. Unlike the IVP, ultrasound
does not expose the patient to radiation. Furthermore, ultrasound
can aid in determining whether the mass originates from the kidney,
the status of the contralateral kidney, and the presence of a
tumor thrombus in the renal vein or inferior vena cava.

Abdominal CT can provide detailed information regarding enlarged
lymph nodes, tumor thrombi, the contralateral kidney, and the
relationship of the tumor to adjacent organs. Liver involvement
or invasion identified on the CT scan usually turns out to be
nonexistent at surgical exploration.[9]. A chest x-ray, preferably
in four projections (posteroanterior, lateral, and two oblique
views), is mandatory for determining whether a child has stage
IV disease.

Treatment of a child with Wilms' tumor involves a radical or modified
radical nephrectomy. A stage is assigned to the patient based
on pathologic findings and imaging studies. The results of three
National Wilms' Tumor Studies (NWTS 1-3) have provided guidance
for further management.[7,10,11] In patients with stage I or II,
favorable histology tumors and those with stage I, anaplastic
histology, postoperative radiation is unnecessary if dactinomycin
(Cosmegan) and vincristine are given in combination. The NWTS
2 showed that the duration of dactinomycin and vincristine can
be restricted to 10 weeks.

For patients with stage III or IV, favorable histology lesions,
the addition of doxorubicin has been shown to improve outcome.
For stage III, favorable histology disease, the administration
of fractionated radiation therapy at a dose of 1,000 cGy to the
flank or abdomen is as effective as 2,000 cGy. Patients with tumors
classified as stage IV, favorable histology who have at least
stage III local disease receive the same radiation dose to the
flank or abdomen as do those with stage III, favorable histology
lesions.

The most common site of hemato-genous metastases is the lungs.
For patients with lung metastases, whole-lung radiation therapy
is employed and is given in a fractionated fashion to a dose of
1,200 cGy. For stage II-IV anaplastic tumors and all clear cell
sarcomas, the renal bed or abdomen is at risk for local recurrence,
and radiation therapy is given to reduce this risk.

Overall survival at 4 years ranges from 97% for patients with
stage I, favorable histology disease to 54% for those with stage
II-IV, anaplastic disease (Table 2). Despite the phenomenal improvement
in the prognosis of patients with Wilms' tumor, various aspects
of the diagnosis and management of this neoplasm remain controversial.
These unresolved issues include the extent of surgery, the role
of chemotherapy as an adjuvant and as treatment for recurrence,
the optimal dose and timing of radiation therapy, and the approach
to managing bilateral tumors.

Surgical Management

Using a transverse supraumbilical incision, the abdomen is explored
with attention to possible metastasis in the peritoneal cavity.
The opposite kidney is visually inspected, and all surfaces are
palpated for any lesions. Any suspicious nodules are biopsied.
The involved kidney is then handled carefully to avoid tumor rupture
and upstaging of the patient, which would require more extensive
therapy. The kidney and hilar structures are removed en bloc along
with a generous segment of the ureter. The renal vein and inferior
vena cava are palpated to detect tumor thrombi prior to vessel
ligation. The liver and para-aortic nodes are inspected, and gross
nodules or enlarged nodes are biopsed. A random biopsy of the
para-aortic nodes is performed if the lymph nodes appear normal.

In some patients, the tumor is found to be extensive, compromising
vital structures. These tumors are biopsied and treated with chemotherapy
and/or radiation therapy, which reduces the tumor burden and allows
for subsequent resection. In NWTS 3, the use of preoperative treatment
facilitated surgical resection in 93% of initially unresectable
patients.[12]

Should the Contralateral Kidney Be Explored?

Whether the contralateral kidney should be explored surgically
is the subject of controversy. This procedure involves opening
Gerota's fascia so that the surgeon can inspect and palpate the
contralateral kidney. The finding of a contralateral tumor significantly
changes patient management, as will be discussed below. Some have
argued that exploration of the contralateral kidney adds to possible
surgical morbidity and unnecessarily prolongs anesthesia duration,
and have suggested that advances in diagnostic imaging obviate
the need for this exploration. Table 3 summarizes current data
on the pro-portion of patients with bilateral Wilms' tumor detected
by preoperative imaging.

In NWTS 2 and 3, approximately one third of patients with bilateral
tumors were not detected preoperatively by IVP or CT.[2] Based
on these findings, the NWTS surgical committee recommended careful
exploration of the contralateral kidney in patients suspected
to have Wilms' tumor in order to rule out bilateral involvement.[13]

Recent studies by Koo et al and Goleta Dy et al have challenged
this approach.[14,15] Concern has been raised over the potential
morbidity caused by handling and mobilizing the opposite kidney,
the longer incision, and complete mobilization of the contralateral
colon. In both series, all bilateral tumors were diagnosed pre-
operatively. In the report by Koo et al, patients had one or more
of the following examinations: IVP, ultrasound, CT, and MRI. In
Goleta Dy's report, all bilateral tumors were detected by ultrasound
and/or CT.

Of the more commonly employed preoperative examinations, CT has
identified more bilateral tumors than IVP or ultrasound. In the
NWTS 4 report by Ritchey et al, 96% of involved kidneys were detected
by CT.[16] Likewise, at St. Jude 97% of patients with bilateral
Wilms' tumor were identified preoperatively by CT scanning.[17]

Does the morbidity from exploration of the contralateral kidney
warrant elimination of this added procedure? In an NWTS 3 report
of 1,910 children, 19.8% had some form of surgical complication,
but none of these complications was attributable to contralateral
kidney exploration.[18] Likewise, in the study by Koo et al, 52
patients underwent contralateral kidney exploration without added
morbidity.

Furthermore, the argument that exploration of the contralateral
kidney necessitates a longer incision also is questionable. Patients
who undergo surgery for Wilms' tumor almost always require a long
incision to avoid rupture or spillage from a large tumor.

Finally, it should be noted that those who argue against performing
contralateral kidney exploration have made their recommendations
based on a combined total of 12 children with bilateral tumors.
This contrasts with the more favorable experiences with this procedure
in the 322 children from the NWTS and St. Jude. At present, therefore,
formal inspection and palpation of the contralateral kidney are
still necessary.

Can Partial Nephrectomy Be Used for Unilateral Tumors?

Concern has been raised regarding the potential for significant
long-term renal dysfunction in patients with Wilms' tumor who
have undergone unilateral nephrectomy.[19,20] Focal segmental
glomerulosclerosis has been reported in patients with a unilateral
kidney after nephrectomy for nephroblastoma.[21,22] The mechanisms
of renal failure or dysfunction may include radiation nephritis,
chemotherapy-related nephrotoxicity, and hyperfiltration of remaining
nephrons secondary to removal of a significant amount of renal
tissue.[23] Theoretically, biopsy of the tumor, followed by chemotherapy
and subsequent partial nephrectomy after tumor shrinkage, should
preserve renal tissue and result in less morbidity for the patient.

Several authors have addressed the role of renal-sparing procedures
in children with Wilms' tumors. At the Hospital for Sick Children
in Toronto, 37 patients with a histologic diagnosis of Wilms'
tumor after percutaneous biopsy were treated with a 4- to 6-week
course of combination chemotherapy. Nine patients (four with a
unilateral tumor and five with bilateral disease) underwent partial
nephrectomy; of these, two patients had an intra-abdominal recurrence
18 months and 24 months, respectively, after partial nephrectomy.[24]
After preoperative chemotherapy, only 4 (13.3%) of 30 patients
with unilateral tumors were amenable to partial nephrectomy.

The abdominal CT scans of 43 children with nonmetastatic unilateral
Wilms' tumor at St. Jude Children's Research Hospital were reviewed
retrospectively. Criteria for partial nephrectomy included tumor
involving only one pole and less than one-third of the kidney,
a functioning kidney, no invasion of the collecting system or
renal vein, and clear margins between the tumor, kidney, and surrounding
structures. Preoperative CT scans met these criteria in only 2
(4.7%) of 43 cases.[25]

In a report by the Austrian/Hungarian Wilms' Tumor Study, 3 of
21 patients with a stage I Wilms' tumor underwent partial nephrectomy
after preoperative chemotherapy, allowing renal preservation.
Selection criteria for renal preservation included tumor involving
only one pole, without collecting system or renal vein involvement;
less than 25% residual tumor at week 4 after preoperative chemotherapy;
normal excretion of tumor-involved kidney; more than 50% remaining
renal parenchyma to be preserved after partial nephrectomy; and
absence of Wilms' tumor nodules. These three patients remain disease-free
26 to 60 months after partial nephrectomy.[26]

Other authors also have advocated partial nephrectomy for unilateral
Wilms' tumor.[27]

In a report by Ritchey et al from NWTS 1-4, 55 children developed
renal failure after undergoing treatment for Wilms' tumor. Patients
who had a nephrectomy for a unilateral Wilms' tumor and had a
normal contralateral kidney had a .25% incidence of renal failure.
The authors concluded that parenchymal-sparing procedures, such
as partial nephrectomy, may not benefit this subset of patients
because of their low risk of renal failure. They also concluded
that children with bilateral Wilms' tumor or tumor in a solitary
kidney should be considered for renal parenchymal-sparing operations
because of their significant risk of renal dysfunction.[28]

In summary, partial nephrectomy, either before or after chemotherapy,
remains experimental for unilateral Wilms' tumor. Additional trials
are needed to determine the role of partial nephrectomy in a disease
for which cure rates approach 90% and the risk of renal failure
is lesas than 1%. Because of the small numbers of patients who
may be amenable to partial nephrectomy, it may be impossible to
conduct such trials.

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