1. NEUROBLASTOMA AND KIDNEY TUMORS IN PEDIATRIC
STAV DEBI

2. ADRENAL GLAND
Paired organ, retroperitoneal, in the epigastric
region, yellowish.
Measurements:
 Length- ∼50mm
 Breadth ∼30mm
 Thickness ∼10mm
 Weight ∼5g
In birth, the gland ∼1/3 of the kidney size
In adults, the gland ∼ 1/30 of the kidney size
30% of the mass of the adrenal gland
Contians chromaffin cells which secrets adrenalin (80%) and
noradrenalin (20%) in response to stimulation by sympathetic nervous
system from thoracic segmenets pass through celiac ganglion.
It also secrets small amount of Dopamine.
Epinephrine- is more potent stimulator of the heart and metabolic
activities
Norepinephrine – is more influential on peripheral vasoconstriction
and blood pressure

3. TOPOGRAPHIC ANATOMY OF ADRENAL GLAND
Right adrenal gland
Anterior
 IVC
 Right lobe of liver
Posterior
 Right crus of
diaphragm
Left adrenal gland
Anterior
 Stomach
 Pancreas
 Spleen
Posterior
 Left crus of
diaphragm

4. ADRENAL GLAND ANATOMY
 Located on the upper medial pole of the kidney
 The right gland is pyramidal in shape, sit on the top of the upper pole of the kidney.
 The left gland is semi lunar in shape, hangs more on the medial side, superior to the
hilum.The upper anterior portion is covered w/ peritoneum.

5. BLOOD SUPPLY
Most of blood supply of the adrenal
glands enters through medulla cortex,
except for some vessels which supply
the medulla directly.
Each gland is supplied by 3 vessels:
1. Suprerior suprarenal a, branch of
inferior phrenic a.
2. Middle suprarenal a, branch of
abdominal a.
3. Inferior suprarenal a, branch of
renal a.

7. VENOUS DRAINAGE OF ADRENAL GLAND
Each gland is drained by only single vein
which emerges from the hilus of the gland:
 Right suprarenal vein  IVC
 Left suprarenal vein  left renal vein

8. INNERVATION
 Adrenal medulla is innervated by type B (medium diameter, myelinated) preganglionic nerve fibers.
 These nerve fibers leave the intermediolateral cell column of the lateral horn of the spinal cord from theT5 –T8
segments of the spinal cord and bypass the paravertebral sympathetic ganglion chain.
 The fibers converge after bypassing the sympathetic trunk, forming the greater splanchnic nerve.
 No post ganglionic neuron.

9. INTRODUCTION
 Neuroblastoma (NB) is a malignancy of the sympathetic nervous system consists of neruoectodermal cells,
hence, it can originate throughout the sympathetic nervous system.This tumor has the capacity to undergo
regression
 Neuroblastoma is exclusively a pediatric neoplasm
 Neuroblastoma is the most common extracranial tumor of children and the third most common diagnosed
malignancy in infants after leukemias and brain tumors
 The most common primary site is adrenal medulla
 Approximately 40-50% of neruoblastoma tumors arise in adrenal medulla
They are known to have broad spectrum of clinical behavior which can range from spontaneous regression, to
maturation to benign ganglioneuroma, or aggressive behaviour with metastatic dissemination leading to death

10. EPIDEMIOLOGY
 8-10% of all childhood malignancies
 Neuroblastoma accounts for >15% of the mortality from cancer in children
 Median age of children at diagnosis is 22 months, and 90% are diagnosed before the age 5 years
 The incidence is slightly higher in boys and in Caucasian populations (ratio of 1.7 ♂, 1.9 ♀ white infants and 1.0
for black infants)
 The most common cancer among infants younger than 12 months (incidence rate is almost twice that of
leukemia- 58 vs 37 per one million infants)

11. Copyrights apply

12. RISK FACTORS
The early onset of NB suggests that gestational environmental events may play a role in NB development.
Maternal factors
 *Opiate consumption: In at least one
case control study they have found
that maternal consumption of
opiates, particularly codeine while
pregnant or breastfeeding increases
the risk developing NB.
 **Folate deficiency: maternal folate
consumption as been a/w decreased
risk of NB.
Fetal factors
 ***Size of gestational age: being born
either small or large for gestational age
and, among children younger than 18
months, having congenital
malformations, were significantly
associated with NB.
 Congenital abnormalities: Some
studies have shown an excess of
congenital abnormalities in children
who have been diagnosed with NB.
Trisomy 21, cardiovascular
malformations, pyloric stenosis,
urogenital malformations. NB risk
increasing with increasing number of
anomalies per child.

13. RISK FACTORS
Genetic factors
In one study examining genetic determinants of pediatric cancer they found:
 Germline mutations in succinate dehydrogenase complex, subunit B (SDHB), adenomatous polyposis coli
anaplastic lymphoma kinase (ALK), and breast cancer susceptibility gene 2 (BRCA2) in 1 out of 100 patients
neuroblastoma
 Higher incidence in girls w/ Turner syndrome
 Hirschsprung’s disease
 Central hypoventilation
 Neurofibromatosis 1 (NF1)
 Familial NB – 1-2% of cases there is a family history of NB. These cases appear to be inherited by AD pattern
incomplete penetrance. Usually have earlier onset than sporadic.
 Germline variants at the TP53 locus (Li-Fraumeni syndrome)

14. SYNDROMES A/W NB

15. NORMAL EMBRIOLOGY
 During the 1st week of development, neurocrest cells start migrating along the future spine, as they migrate
they differentiate into neurons of the sympathetic nervous system.
 They form components of many tissues: brachial arches, cardiac and thoracic vessels, sympathetic nervous
system which includes the adrenal medulla.
 In the lumbar region  adrenal medulla.
 The developing adrenal medullary cells migrate and begin merging with the developing adrenal cortex during
the 7th week on gestation.

17. PATHOGENESIS
The pathology of NB varies considerabely between patients, age, location of tumor, and host/tumor immune
interactions likely playing a major roles in the tumor biological behaviour.
Various molecular and cytogenic factors have been implicated in:
1. Pathogenesis of NB
2. Proven useful in predicting clinical behavior

18. PATHOGENESIS
Neuroblasts undergo epithelialand
mesenchymal transition in the EMT
(epithelial mesenchymal transition zone) via
histone modification, DNA methylation,
transcription factors expression etc.
Neuroblastoma arises during the course of
embryonal neural crest specification and
differentiation.
Multiple different changes can induce tumor
formation, the timing and character of
causative oncogenic events may well define
the phenotype of the resulting cancer.

21. THE INTERNATIONAL NEUROBLASTOMA PATHOLOGY CLASSIFICATION
(INPC)
The INPC classifies tumors of neuroblastic origin based on the balance between neural crest cells (primitive
neuroblasts, maturing neuroblasts, and ganglion cells) and Schwann type cells (Schwannian-blasts and mature
Schwann cells) into one of three types:
1. Neuroblastoma
2. Ganglioneuroblastoma
3. Ganglioneuroma

23. LOCATIONS
Primary tumor
1. Adrenal gland (40-50%)
2. Abdominal ganglia (25%)
3. Thoracic ganglia (15%)
4. Cervical ganglia (5%)
5. Pelvic ganglia (5%)
Metastasis locations
More common in children >1 yo at diagnosis, occurs via local invasion, distant
hematogenous or distant lymphogenous routes.
1. Lymph nodes
2. Bone marrow
3. Long bones and skull
4. Liver
5. Skin
6. Dura
7. Orbits
8. <3% of the cases– lung and brain

25. SIGNS AND SYMPTOMS
The signs and symptoms of NB reflect the location of the primary tumor and the extent of local invasion and
metastatic disease, metabolic disturbances.
Abdominal tumors- approximately 2/3 of NB tumors originate in the abdomen, among these 2/3 originate in the
adrenal medulla.
 Abdominal pain, fullness
 Abdominal mass (retroperitoneal or hepatic).The mass is typically nontender, fixed, and firm
 Constipation
 Large tumors can compress IVC and lymphatic drainage  scrotal and lower extremity edema
Catecholamines secretion – 70-90% of the NB secrete catecholamines  high levels of catecholamines metabolies
Homovanillic acid (HVA), and vanillylmandelic acid (VMA), dopamine, norepinephrine.The excess production of
catecholamines can cause increased sweating, and HTN. Hypertension occurs more commonly in the setting of
renal artery compression.
The MS stage - <18 mo old

27. DISTANT METASTASIS
NB has a particular predilication to spread to metaphyseal, skull, and orbital bone sites. It can cause classical presentation:
 Peri-orbital ecchymosis (Raccoon eyes)
 Proptosis (protruison of eyeball)
 Visual impairment
 Bone pain
Other systemic symptoms
 Fever
 Irritability
 Failure to thrive
 Cytopenias
 MS stage (<18 mo) – skin nodules and/or diffuse liver involvement, and hepatomegaly, often a/w respiratory compromise,
limited bone marrow disease, and a small primary tumor w/out bone involvement or other metastasis. Can spontaneously
regress.

30. DIAGNOSTIC EVALUATION OF NB
1. Complete history + physical examination
2. Laboratory evaluations: CBC, serum chemitry, LFT’s, kidney function test
3. Urine evaluation of catecholamines metabolitesVMA, HVA (diagnosis and monitoring)
4. Pathologic evaluation is required for defenitive diagnosis – biopsy
5. Genetic status evaluation for MYCN and DNA ploidy
6. CT or MRI of the chest and abdomen, bone scans to deteact distant metastasis

31. PATHOLOGICAL EVALUATION OF NB
Two separate sites are assessed resulting in 4 samples:
2 Biopsy of primary tumor – posterior iliac crests
2 Bone marrow aspiration with the presence of small round
blue cells tumors +VMA and HVA elevation
Bone marrow biopsy – small round cells

32. DIAGNOSTIC CRITERIA
A definitive diagnosis of neuroblastoma requires one of the following:
 An unequivocal histologic diagnosis from tumor tissue by light microscopy, with or without
immunohistochemistry, electron microscopy, or increased urine (or serum) catecholamines or their metabolites
 Evidence of metastases to bone marrow on an aspirate or trephine biopsy with concomitant elevation of urinary
or serum catecholamines or their metabolites

33. DIFFERENTIAL DIAGNOSIS OF ADRENAL MASSESS

34. THE INTERNATIONAL NEUROBLASTOMA RISK GROUP STAGING SYSTEM
(INRGSS)
 The International Neuroblastoma Risk Group Staging System (INRGSS) uses results from imaging tests (such
as CT or MRI and MIBG scan) to help decide a stage and risk group.The INRGSS can be determined before
treatment has started.
 The stage can then be used to help predict how resectable the tumor is – that is, how much of it can be removed
with surgery.
 The INRGSS uses image-defined risk factors (IDRFs).

35. THE INTERNATIONAL NEUROBLASTOMA RISK GROUP STAGING SYSTEM
(INRGSS)

36. NB – IMAGE DEFINED RISK FACTORS - IDRF
CROSS/EXTENDING
 From one compartment to another (chest to neck, abdomen
to chest, abdomen to pelvis)
 Through sciatic notch/foramen
ENCASINGVESSELS
 Carotid artery
 Vertebral artery
 Internal jugular vein
 Subclavian artery/vein
 Aorta
 SVC IVC
 Celiac artery
 Superior mesenteric artery
 Iliac artery or vein
COMPRESSING
 Trachea
 Primary bronchi
ENCASING NERVES
 Brachial plexus
INVADING/INFILTRATING
 Skull base
 Spinal canal
 Costrovertebral junction
 Porta hepatis, hepatoduodenal ligament, liver
 Pericardium

37. INTERNATIONAL NEUROBLASTOMA STAGING SYSTEM
 Stage 1: The tumor can be removed completely during surgery. Lymph nodes attached to the tumor removed
during surgery may or may not contain cancer, but other lymph nodes near the tumor do not.
 Stage 2A: The tumor is located only in the area it started and cannot be completely removed during surgery.
Nearby lymph nodes do not contain cancer.
 Stage 2B: The tumor is located only in the area where it started and may or may not be completely removed
during surgery, but nearby lymph nodes do contain cancer.
 Stage 3: The tumor cannot be removed with surgery. It has spread to regional lymph nodes (lymph nodes
near the tumor) or other areas near the tumor, but not to other parts of the body.
 Stage 4: The original tumor has spread to distant lymph nodes (lymph nodes in other parts of the body),
bones, bone marrow, liver, skin, and/or other organs, except for those listed in stage 4S, below.
 Stage 4S: the patient is <1yo, the cancer is on one side of the body. The original tumor is located only where
it started (as in stage 1, 2A, or 2B), and it has spread only to the skin, liver, and/or bone marrow, in infants
than one. The spread to the bone marrow is minimal, usually less than 10% of cells examined show cancer.

38. EVALUATION OF METASTATIC BONE DISEASE
Evaluation of metastatic bone disease is required for patietns
diagnosed w/ NB.
I123 – MIBG scan- metaiodobenzylguanidine
I-123 MIBG scintigraphy is an imaging test used to detect certain
types of neuroendocrine tumors.
This scan is able to detect these tumors because the compound
MIBG is very similar to norepinephrine/noradrenaline,
a neurotransmitter chemical that is taken up by neuroendocrine cells.

39. PROGNOSTIC MARKERS
 Age- younger patietns <12-18months are more likely to be cured than older patients.
 Tumor histology- undifferentiated cells tend to have less favorable prognosis compared with higher level of
differentiation.
 DNA ploidy- Neuroblastoma cells with about the same amount of DNA as normal cells (a DNA index of 1)
are classified as diploid. Cells with increased amounts of DNA (a DNA index higher than 1) are
diploid. NB cells w/ more DNA are a/w better prognosis, especially if they <2 yo. Not useful in older
children.
 MYCN gene amplification- Neuroblastomas with too many copies (amplification) of the MYCN oncogene
tend to grow quickly and can be harder to treat.
 Chromosomal changes- Tumor cells that are missing certain parts of chromosomes 1 or 11 (known as 1p
deletions or 11q deletions) may predict a less favorable prognosis. Having an extra part of chromosome 17
chromosome 17 (17q gain) is also linked with a worse prognosis.
 Neurotrophin (nerve growth factor) receptors: These are substances on the surface of normal nerve cells
and on some neuroblastoma cells. They normally allow the cells to recognize neurotrophins – hormone-like
chemicals that help the nerve cells mature. Neuroblastomas that have more of certain neurotrophin

40. SERUM/BLOOD SUBSTANCES LEVEL
 Ferritin- high ferritin level  worse prognosis
 Neuro specific enloase (NSE) and LDH- high levels are linked with worse prognosis

42. TREATMENT APPROACH
Different tx modalities- surgery, chemotherapy, and radiation therapy.
Surgery
It can be used both in dx and tx
It is the primary tx for low risk tumors.Children w/ localized disease, w/out MYCN amplification  gross surgical excision
is the main requirement for cure.
Resectability is determined by-
 Tumor location
 Mobility
 Relationship to major nerves and blood vessels,
 Presence of metastasis
 Patient age.

43. TREATMENT APPROACH
Chemotherapy
Adjuvant or neoadjuvant approach
 Low risk disease: mutli agent low or moderate intensity chemotherapy is reserved for those: tumors cannot
resected, threataning sx of spinal cord compression or respiratory or bowel compromise.
 Intermediate risk disease: moderately intensive multiagents chemotherapy is applied before attempted
resection.
 High risk disease: intensive chemotherapy w/ a combination of agents is used to shrink primary and
tumors.

44. TREATMENT APPROACH
Radiotherapy
 Low risk disease: reserved for unresectable tumors, progressive tumors unresponsive to chemotherapy, life
thretaning complications, neurologic compromise, tumor related organ dysfunction unresponsive to
chemotherapy.
 Intermediate risk disease: recommanded it only in the setting of disease progression despite surgery and
chemotherapy.
 High risk disease: intensive chemotherapy w/ a combination of agents is used to shrink primary and
tumors.

45. Low risk NB:

49. WILM’S TUMOR– NEPHROBLASTOMA
Nephroblastoma is most common renal malignancy in children (95%), with approximately 500 new cases
diagnosed in the United States each year.
Dr. MaxWilm’s,German surgeon (1867- 1918) first described this kind of tumor

50. EPIDEMIOLOGY
 The second most common malignant abdominal tumor in childhood
after neuroblastoma
 6% of pediatric tumors
 Peak incidence for Wilm’s tumor is between 2-5y
 95% of tumors occur before the age of 10y, 70% occur before 5y
 Approximately 5%-10% of tumors involve both kidneys.
Simultaneously (synchronous) or either one after the other
(metachronous).
 Left kidney > right kidney
 Bilateral Wilm’s tumors have a median age of onset ∼ 10m earlier than
tumor restricted to one kidney
 5-7% multiple foci in one kidney, most cases are solitary lesions
 ♀ are slightly more affected. ♂0.92 :♀ 1 (unilateral disease), ♂0.6 :♀ 1
1
 The majority ∼75% of cases occur in otherwise healthy children, ∼25%
a/w other developmental abnormalities
 Most cases are sporadic, 2% w/ family history
Early age at diagnosis and
increased incidence of bilateral
are generally observed in
syndromic and familial cases

51. RISK FACTORS
 Increased risk ofWilm’s tumor a/w congenital malformation a/w distinct chromosomal loci
1. Wagr Syndrome
2. Denys Drash syndrome
3. Beckwith Wiedemann syndrome
4. Fraiser syndrome
5. Fanconi anemia
6. Trisomy 18
7. Perlman syndrome

52. KIDNEY EMBRIOLOGY
The urogenital system arises
from intermediate
mesoderm which forms a urogenital

53. ETIOLOGY
Wilm’s tumor appears to be caused by abnormal renal development, resulting in proliferation of the metanephric
blastema without normal tubular and glomerular differentiation.
a/w mutations in in genes related to kidney development.
Leads to incomplete mesenchymal-to-epithelial transformation.
Majority ofWilm’s tumor arise from somatic mutations restricted to tumor tissue.
Nephrogenic rest- 100% in bilateral disease

56. CLINICAL MANIFESTATION EARLY FINDINGS
 The most common clinical presentation an incidential asymptomatic palpable mass in the abdomen
Firm, non-tender, smooth mass.
 Functional defects are unlikely to be found at early stage
 HTN (25%)
 Abdominal pain (40%)
 Painless hematuria (18%)
 Constitutional symptoms- fever, anorexia, weight loss

57. CLINICAL FEATURES
 Tumor rupture w/ hemorrhage into peritoneal mimics acute abdomen
 Anemia  tumor bleeding into renal parenchymal and pelvis
 Microcytic anemia d/t iron deficiency or anemia of chronic disease
 Polycytemia
 Elevated platelet count
 Acquired deficiency of vWF or factorVII (8%)
 Extension into renal vein or IVC varicocele, hepatomegaly d/t hepatic vein obstruction, ascites, congestive
heart failure (<10%)
 Thrombus extends into IVC, rarely can enter right atrium  pulmonary embolism

58. METASTASIS SITES
1.Lungs – most common site
2.Regional lymph nodes
3.Liver

59. DIAGNOSTIC INVESTIGATION
The definitive diagnosis of Wilms tumor is made by histologic confirmation at the time of either surgical
excision or biopsy.
Abdominal imaging
 Abdominal US initial test- detects: hydronephrosis, multicystic kidney disease
 Doppler US to detect tumor infiltration of the renal vein or IVC and to assess patency of blood flow
 Contrast CT / MRI – to assess the extent of the tumor, CT or MRI also may detect small lesions of tumor or
nephrogenic rests in the opposite kidney, which were not detected by ultrasonography.
Chest imaging – CT
To rule our lung metastasis.

60. DIAGNOSTIC INVESTIGATION
The definitive diagnosis of Wilms tumor is made by histologic confirmation at the time of either surgical
excision or biopsy.
Laboratory testing
 Serum creatinine - detect any reduction in glomerular filtration rate prior to surgical intervention.
 Urinalysis – to detect proteinuria
 Liver function tests- to rule out liver metastasis
 Coagulation studies

61. STAGING
Based on anatomic extent of the tumor w/out consideration of genetic, histology, or biological markers
The higher the stage the worse the prognosis and the treatment regime is more aggressive

62. NATIONAL WILMS TUMOR STUDY (NWTS)
The NWTS system is based upon surgical evaluation prior to the administration of chemotherapy. It is used
throughout the United States and Canada.

63. INTERNATIONAL SOCIETY OF PEDIATRIC ONCOLOGY STAGING
SIOP staging is used extensively in Europe and is based upon surgical evaluation after administration of
chemotherapy to reduce the size of the tumor.

64. PROGNOSIS
5-year-survival rate has improved d/t improve modality of tx  90%
Prognostic factors – at the time of dx increase the risk of death or recurrence:
1. Tumor histology- favorable able histology (no anaplasia), foci anaplasia, diffuse anaplasia (anaplasia is the most
important predictor of adverse outcome in children with Wilms tumor)
2. Tumor stage
3. Molecular and genetic markers
4. Age >2y

65. TREATMENT APPROACHES
NWTS/COG approach
Primary surgical resection in unilateral disease followed by adjuvant chemotherapy.
Radiation therapy is used in patient w/ stage III-IV
Stage I-II: Primary surgical resection is followed by 19 weeks of vincristine and dactonomycin. No radiation therapy
therapy is required.
Stage III-IV: Primary surgical resection is followed by 25 weeks of three-drug chemotherapy with vincristine,
dactinomycin and doxorubicin. Radiation therapy

66. TREATMENT APPROACHES
SIOP approach
Patients are treated with preoperative chemotherapy for four weeks (six weeks if there is evidence of metastatic
disease) followed by surgical resection and postoperative chemotherapy that is based upon the staging and
histology assessment performed after initial chemotherapy
Non-metastatic disease chemotherapy agents consists of vincristine and dactinomycin.
Metastatic disease triple drug regime consists of vincristine, dactinomycin and doxorubicin for 6 weeks

67. BILATERAL INVOLVEMENT
The treatment approach for children with stageVWilms tumor is similar in NWTS/COG and SIOP protocols.
Intensive combinatin chemotherapy at the time of dx to reduce tumor size and facilitate early nephron sparing
surgery and better preservation of parenchymal
Triple therapy regime:
1. Vincristine
2. Actinomycin
3. Doxorubicin
Postoperative chemotherapy and radiotherapy based upon histopathology findings of the resected tumor and
the presence tumor in lymph nodes or the peritoneal cavity