Pediatric Tumor WILMS TUMOR
also known as nephroblastoma
most common primary malignant renal tumor of childhood
second most common malignant abdominal tumor in
childhood
most common sites of metastases are the lungs, regional
lymph nodes, and liver
Histologically, the classic WT is made up of varying
proportions of blastemal, stromal, and epithelial cells
Epidemiology -6% of pediatric malignancies
->95% of kidney tumors in children.
-(US) 8 cases per 1 million children <15 yr of age per year
-75% of the cases are <5 yr with a peak incidence at 2-3 yr
-bilateral WTs is 7%
-Sporadic, 2% with family history
-Associated with hemihypertrophy, aniridia, genitourinary
anomalies, and a variety of rare syndromes, including
Beckwith-Wiedemann syndrome and Denys-Drash
syndrome
Pathogenesis derived from incompletely differentiated renal
mesenchyme (nephrogenic rests)
GERM CELL TUMOR
- rare, with an incidence of 12 cases per 1 million persons
younger than 20 yr of age.
-Most malignant tumors of the gonads in children are GCTs.
Sacrococcygeal tumors occur predominantly in infant girls.
Testicular GCTs occur predominantly before age 4 yr and
after puberty.
Klinefelter syndrome is associated with an increased risk of
mediastinal GCTs
Down syndrome, undescended testes, infertility, testicular
atrophy, testicular microlithiasis, testicular dysgenesis
syndrome, and inguinal hernias are associated with an
increased risk of testicular cancer.
Risk of testicular cancer in patients with cryptorchidism is
reduced but not
eliminated if orchiopexy is performed before 13 yr of age.
GCTs and non-GCTs arise from primordial germ cells and
coelomic
epithelium, respectively
Mutations in WT1, a gene located at 11p13 and encoding a
zinc finger transcription factor, are observed in 15-20% of Testicular and sacrococcygeal GCTs arising during early
tumors. childhood characteristically have deletions at chromosome
(WT1 gene critical for normal renal and gonadal arms 1p and 6q and gains at 1q, and lack the
development) isochromosome 12p that is highly characteristic of
- Germline truncating mutations - genitourinary anomalies malignant GCTs of adults.
or the
WAGR (Wilms, aniridia, genitourinary anomalies, Testicular GCT also may demonstrate loss of imprinting.
mental retardation)
syndrome. Ovarian GCTs from older girls characteristically have
- Missense germline mutations are usually observed in
deletions at 1p and gains at 1q and 21.
children
with Denys-Drash syndrome in which early-onset
Extensive sectioning is essential to confirm the correct
renal failure is
observed. diagnosis. The many histologically distinct subtypes of
Mutations in CTNNB1, encoding -catenin, which acts as a GCTs include teratoma (mature and immature),
major endodermal sinus tumor, and embryonal carcinoma.
regulatory point in the wnt signaling pathway and also acts
at the Non-GCTs of the ovary include epithelial (serous and
cytoplasmic membrane (15% of WTs). WTX, a gene located mucinous) and sex cordstromal tumors; non-GCTs of the
on the X chromosome that encodes a protein that also plays testicle include sex cord/stromal (e.g., Leydig cell, Sertoli
a role in wnt pathway regulation, is mutated (20% of cell) tumors.
tumors).
- CTNNB1 and WTX mutations are somatic. DICER1 mutations have been observed in nonepithelial
Loss of heterozygosity (usually copy number neutral) or loss ovarian cancers, especially in Sertoli-Leydig tumors.
of imprinting at imprinted loci at 11p15 (WT2 gene)
- Beckwith-Wiedemann syndrome
DICER1 gene, located at 14q31
- pleuropulmonary blastoma

A family history of WT is noted in approximately 2% of WT

patients,
and predisposition is inherited as an autosomal dominant
trait with
incomplete penetrance.
Genetic linkage analyses of large WT families have localized
predisposition genes to 19q and 17q
Somatic alterations at 1q, 7p, 16q, chromosome 12, and
other
 genomic regions are observed in some WTs
Clinical -most common initial clinical presentation: incidental
Manifestation asymptomatic abdominal mass
-Hypertension (25%) - attributed to increased renin
activity.
-Abdominal pain, gross painless hematuria, and fever.
-Occasionally, rapid abdominal enlargement and anemia
occur as a result of bleeding into the renal parenchyma or
pelvis.
-WT thrombus extends into the inferior vena
cava in 4-10% of patients, rarely into the right atrium.
-might have microcytic anemia from iron deficiency or
anemia of
chronic disease, polycythemia, elevated platelet count, and
acquired
deficiency of von Willebrand factor or factor VII deficiency.
Diagnostic and An abdominal mass in a child should be considered
Staging malignant until
diagnostic imaging, laboratory findings, and pathology can
define its
true nature.
Diagnostics to define the intrarenal origin of the mass and
differentiate it from adrenal masses (e.g., neuroblastoma)
and other masses in the abdomen.
-Plain abdominal radiography
-Abdominal ultrasonography - solid vs cystic, and with
Doppler - evaluate the collecting system and demonstrate
tumor thrombi
-CT of the abdomen and chest - useful to define the extent of
the disease, integrity of the contralateral kidney, and
metastasis.
WT might show focal areas of necrosis or hemorrhage and
hydronephrosis caused by obstruction of the renal pelvis by
Depends on location
Ovarian tumors often are quite large by the time they are
diagnosed
Extragonadal GCTs occur in the midline, including the
suprasellar region, pineal region, neck, mediastinum, and
retroperitoneal and sacrococcygeal areas
Symptoms relate to mass effect, but the intracranial GCTs
often present with anterior and posterior pituitary deficits.
Serum -fetoprotein (AFP) level is elevated with
endodermal
sinus tumors and may be minimally elevated with
teratomas. Infants
normally have higher levels of AFP, which fall to normal
adult levels
by about age 8 mo; consequently, high AFP levels must be
interpreted
with caution in this age group.
Elevation of the subunit of human chorionic
gonadotropin, which is secreted by syncytiotrophoblasts,
is seen with choriocarcinoma and germinomas.
Lactate dehydrogenase, although nonspecific, may be a
useful marker.
Physical examination and imaging studies, including plain
radiographs of the chest and ultrasonography of the
abdomen. CT or MRI can further delineate the primary
tumor.
Diagnosis of intracranial lesions can be established with
imaging and AFP or -human chorionic gonadotropin
determinations of serum and cerebrospinal fluid.
 the tumor.
The diagnosis is usually made by imaging studies and
confirmed by histology at the time of nephrectomy.
Management 2 major schools of thought in the management of WT:
1. Childrens Oncology Group, formerly National Wilms Tumor
Study
Group - upfront surgery prior to initiating treatment
Advantage: accurate diagnosis and staging, and can
facilitate risk-adapted therapy
2. International Society of Pediatric Oncology - preoperative
chemotherapy
Adevantage: surgery is easier and reduces the risk of
intraoperative tumor rupture and hemorrhage.
Surgery
-Radical nephrectomy and lymph node sampling
-Partial nephrectomy for bilateral disease or with unilateral
Gonadoblastomas often occur in patients with gonadal
dysgenesis
and all or parts of a Y chromosome. Gonadal dysgenesis is
characterized
by failure to fully masculinize the external genitalia.
- ultrasonography or CT is performed
- prophylactic resection of dysgenetic gonads at the time
of diagnosis is recommended
Teratomas occur in many locations, presenting as masses
- sacrococcygeal region is the most common site
- most commonly in infants (girls), diagnosed in utero or
at birth.
Germinomas occur intracranially, in the mediastinum, and
in the
gonads. In the ovary, they are called dysgerminomas; in
the testis, seminomas.
- tumor-markernegative masses despite being
malignant.
Nongerm cell gonadal tumors are very uncommon in
pediatrics
and occur predominantly in the ovary.
Complete surgical excision of the tumor usually is
indicated, except for
patients with intracranial tumors, where the primary
therapy consists
of radiation therapy and chemotherapy.
When complete excision cannot be accomplished,
preoperative chemotherapy is indicated, with second-look
surgery.
Primary surgical resection is indicated for tumors deemed
resectable. For older patients with testicular tumors,
ipsilateral retroperitoneal lymph node sampling may be
required.
 WT and a predisposing syndrome such as Denys-Drash and
WAGR, so as to minimize the risk of future renal failure. Cisplatin-based chemotherapy regimens usually are
curative in GCTs
Chemotherapy that cannot be completely resected, even if metastases are
Stages I & II - vincristine and actinomycin D every 1-3 wk for present
a total of 18 wk (regimen EE4A).
Stages III & IV - vincristine, doxorubicin, and actinomycin D) Except for GCTs of the central nervous system, radiation
every 1-3 wk for a total of 24 wk (regimen DD4A) and therapy is limited to those tumors that are not amenable to
radiation therapy. complete
excision and are refractory to chemotherapy.
Radiation
Regional lymph node metastases, residual disease after
surgery, or tumor rupture, and lung metastases receive
radiation therapy to the area.

Anaplastic histology (focal and diffuse) - intensive

chemotherapy regimens that include vincristine,
cyclophosphamide, doxorubicin, etoposide, carboplatin, and
ifosfamide, in addition to radiation therapy

Recurrent disease: approximately 15% of WT patients with

favorable histology and 50% of those with anaplastic
histology suffer relapse; most relapses occur early (within 2
yr of diagnosis).
Prognosis Despite some adverse risk factors that decrease prognosis Overall cure rate is >80%
(metastases, unfavorable histology, recurrent disease, and
loss of heterozygosity of both 1p and 16q), most children Age is the most predictive factor of survival for
with WT have a very favorable prognosis. extragonadal GCTs.

Absence of anaplasia - favorable histologic finding Children older than 12 yr of age have a 4-fold higher risk of
death, and a 6-fold higher risk if the tumor is thoracic.
Survivial 90%
Histology has little effect on prognosis.
Late sequelae:
- musculoskeletal Nonresected extragonadal GCTs have a slightly worse
effects prognosis.
- cardiac toxicity
- pulmonary
disease
- reproductive
problems
- renal dysfunction
- second malignant
neoplasms.