This document discusses neuroblastoma and nephroblastoma (Wilms tumor). Neuroblastoma is the most common extracranial solid tumor in children, arising from the sympathetic nervous system. It presents heterogeneously from spontaneous regression to aggressive forms. The causes are largely unknown. Nephroblastoma (Wilms tumor) is the most common malignant renal tumor of childhood. Both tumors are diagnosed through imaging and urine/blood tests. Prognosis and treatment varies depending on tumor histology and staging. Aggressive forms of neuroblastoma and anaplastic Wilms tumor remain difficult to treat.

1. Neuroblastoma and nephroblastoma
Mahajna mohammed
Sackler’s faculty of medicine
Tel-Aviv Uni

2. definition
embryonal cancers of the peripheral sympathetic nervous
system
heterogeneous clinical presentation and course, ranging
from tumors that undergo spontaneous regression to very
aggressive tumors
The causes of most cases remain unknown, and although
significant advances have been made in the treatment of
children with these Tumors
the outcomes for aggressive forms of neuroblastoma
remain poor.

3.  the most common extracranial solid tumor in children and
the most commonly diagnosed malignancy in infants.
 8-10% of childhood malignancies and 33% of cancers in
infants.
 accounts for >15% of the mortality from cancer in children.
 The median age of children at diagnosis of neuroblastoma
is 22 months
 90% diagnosed by 5 yr of age.
 The incidence is slightly higher in boys and in whites.
EPIDEMIOLOGY

4.  variable degrees of neural differentiation, ranging from tumors with
1. primarily undifferentiated small round cells (neuroblastoma)
2. tumors consisting of mature and maturing Schwannian stroma with
ganglion cells (ganglio-neuroblastoma or ganglio-neuroma).
 The tumors may resemble other small round blue cell tumors, such as
rhabdomyosarcoma, Ewing sarcoma, and non Hodgkin lymphoma.
 The prognosis varies with the histologic features of the tumor, and
prognostic factors
1. Schwannian stroma,
2. the degree of tumor cell differentiation,
3. mitosis-karyorrhexis index.
PATHOLOGY

5. • The etiology of neuroblastoma in most cases remains unknown
• Familial neuroblastoma accounts for 1-2% of all cases, is associated with a
younger age ,mutations in PHOX2B and ALK genes.
• The BARD1 gene has also been identified as a major genetic contributor to
neuroblastoma risk.
• associated with other neural crest disorders, [Hirschsprung disease, central
hypoventilation syndrome, and neurofibromatosis type I] and potentially
congenital cardiovascular malformations (Table 498-1).
• associated with parents occupation,chemical although no single environmental
exposure has been shown to directly cause neuroblastoma.
PATHOGENESIS

6.  Genetics include
1. amplification of the MYCN (N-myc) : strongly associated with advanced tumor
stage and poor outcomes
2. ploidy :Hyperdiploidy confers better prognosis if the child is younger than 1 yr
of age at diagnosis
3. Other: including loss of heterozygosity of 1p, 11q, and 14q, and gain of 17q,
associated with worse outcomes.
 In addition, tumor vascularity and the expression levels of nerve growth factor
receptors : (TrkA, TrkB),
chromogranin Aneuropeptide YLDHferritin
ganglioside GD2CD44telomerase

9. CLINICAL MANIFESTATIONS
Symptoms
Site
Staging
Tumor
type
Tumor
origin
Disease
extent
Patient

10. Metastatic disease can cause a variety of signs and symptoms:
1. Fever
2. Irritability
3. failure to thrive
4. bone pain
5. Cytopenias
6. bluish subcutaneous nodules
7. orbital proptosis
8. periorbital ecchymoses
Localized disease can manifest as an asymptomatic mass or can cause symptoms
because of the mass itself:
1. spinal cord compression,
2. bowel obstruction, and superior vena cava syndrome.
superior cervical ganglion can result in Horner syndrome.
Paraspinal neuroblastoma tumors can invade the neural foramina, causing spinal
cord and nerve root compression.
paraneoplastic syndrome of autoimmune origin, termed opsoclonus–
myoclonus–ataxia syndrome, in which patients experience rapid,
uncontrollable jerking eye and body movements, poor coordination,

11. Some tumors produce catecholamines that can cause
1. increased sweating and hypertension
some release vasoactive intestinal peptide
1. causing a profound secretory diarrhea.
Children with extensive tumors can also experience tumor lysis
syndrome
and disseminated intravascular coagulation.
Infants younger than 1 yr of age also can present in unique fashion,
termed stage 4S :
• widespread subcutaneous tumor nodules
• massive liver involvement
• limited bone marrow disease
• small primary tumor without bone involvement or other metastases.

12. Staging
 Neuroblastoma may develop at any site of sympathetic nervous system tissue.
 50% of neuroblastoma tumors arise in the adrenal glands
 Metastatic spread :
1. mainly in 1 yr of age at diagnosis,
2. occurs via local invasion
3. distant hematogenous
4. lymphatic routes.
5. The most common sites of metastasis are the regional or distant lymph nodes,
long
a) bones and skull, bone marrow
b) liver, and skin
c) Lung and brain metastases are rare, occurring in >3% of cases.

14. DIAGNOSIS
RADIOLOGY : MRI / CT  mass or multiple masses may be hemorrhagic or
calcified
Urin samples :
Tumor markers, catecholamine metabolites homovanillic acid and vanillylmandelic
acid, are elevated in the urine in 95% of
Evaluations for metastatic disease should include CT or MRI of the
chest and abdomen, bone scans to detect cortical bone involvement,
and at least 2 independent bone marrow aspirations

15. • A :CT scan of an abdominal neuroblastoma with central necrosis at diagnosis.
• B :Coronal fused CT and metaiodobenzylguanidine(MIBG) image of same child with
extensive retroperitoneal mass and central necrosis, probably an adrenal primary
with extensive lymph node involvement.
• C :MIBG avid neuroblastoma with increased uptake of radiolabeled tracer can be
detected in multiple sites of disease, including bone and soft tissue.

19. These agents are almost invariably given in combination
Commonly used combinations include the following:
•Vincristine, cyclophosphamide, and doxorubicin
•Carboplatin and etoposide
•Cisplatin and etoposide
•Cyclophosphamide and topotecan
Consolidation regimens used in neuroblastoma include the following:
•Carboplatin and etoposide with melphalan or cyclophosphamide
•Thiotepa and cyclophosphamide
•Melphalan and total body irradiation

20. Induction chemotherapy for children with high-risk neuroblastoma includes
combinations
1. Cyclophosphamide
2. topotecan,
3. Doxorubicin
4. Vincristine
5. Cisplatin
6. etoposide.
 After completion autologous stem cell rescue and focal radiation therapy to tumor
sites.
 significantly better survival with chemotherapy plus autologous stem cell rescue
than with chemotherapy alone.
 The further addition of 13-cis-retinoic acid resulted in further improvements in
survival rates.

21. Now hush little baby, don't you cry
Everything's gonna be alright
Stiffen that upper lip up little lady, I
told ya Daddy's here to hold, ya
through the night

23. • Wilms tumor (WT), also known as nephroblastoma, is the most common
primary malignant renal tumor of childhood;
• other renal tumors are very rare.
• It is the second most common malignant abdominal tumor in childhood.
• The most common sites of metastases
1. lungs,
2. regional lymph nodes
3. and liver.
Histologically:varying proportions
1. Blastemal
2. Stromal
3. epithelial cells

24. EPIDEMIOLOGY
 6% of malignancies and more than 95% of kidney tumors.
 75% occur in children younger than 5 yr with a peak incidence at 2-3 yr of age.
 It can arise in 1 or both kidneys; bilateral WTs is 7%.
 Most cases are sporadic, but approximately 2% of patients have a family history.
 In 8-10% of patients, WT is observed in the context of hemihypertrophy, aniridia,
genitourinary anomalies, and a variety of rare syndromes:
 Beckwith-Wiedemann syndrome and Denys-Drash syndrome (Table 499-2).
An earlier age of diagnosis and an increased incidence of bilateral
disease are generally observed in syndromic and familial cases.

26. ETIOLOGY: GENETICS AND
MOLECULAR BIOLOGY
Wilms tumor is thought to be caused by alterations of genes
responsible for normal genitourinary development. Examples
of common congenital anomalies associated with Wilms tumor
are
1. Cryptorchidism
2. a double collecting system
3. horseshoe kidney
4. and hypospadias. |
Environmental exposures, although considered, seem relatively
unlikely to play a role

27.  a gene located at 11p13 and encoding a zinc finger transcription factor
 15-20% of tumors. These are homozygous and result in loss of WT1 Function.
 The majority of WT1 mutations are somatic, result in loss of WT1 function, and
are present homozygously.
 germline WT1 mutations are also observed, primarily in patients with WT-
associated syndromes, or sometimes in patients with bilateral disease.
 In these instances, the wild-type allele present in the germline is mutated or
lost in the tumor, resulting in loss of WT1 function. Interestingly, nephrogenic
rests assessed from patients heterozygous

29. CLINICAL PRESENTATION

30.  80% asymptomatic abdominal mass:
 abdominal mass occurs in 80% of children at presentation.
 Abdominal pain or hematuria occurs in 25%.
 Urinary tract infection
 varicocele are less common findings than these.
 Hypertension, gross hematuria, and fever are observed in 5-30
 A few patients with hemorrhage into their tumor may present with
hypotension, anemia, and fever.
 Rare patients with advanced disease may present with respiratory
symptoms related to lung metastases.

32. Imaging studies
1. plain abdominal radiography,
2. abdominal ultrasonography,
3. CT of the
4. Abdominal ultrasonography helps differentiate solid from cystic
Masses
5. Ultrasonography with Doppler imaging of renal veins and the
inferior
vena cava is a useful first study that not only can look for WT but also
can evaluate the collecting system and demonstrate tumor thrombi in
the renal veins and inferior vena cava.

36. •Favorable - Contains well developed components mentioned above
•Anaplastic - Contains diffuse anaplasia (poorly developed cells)