CHILDHOOD SOLID TUMORS CHILDHOOD SOLID TUMORS
WILMS’ TUMORWILMS’ TUMOROsler in 1879, Wilms in 1899Osler in 1879, Wilms in 1899
Wilms’ tumor, or nephroblastoma, accounts for Wilms’ tumor, or nephroblastoma, accounts for about 6% of all pediatric malignant disease.about 6% of all pediatric malignant disease.
This embryonal tumor develops from remnants This embryonal tumor develops from remnants of immature kidney.of immature kidney.
Survival has improved from 30% in 1930s to Survival has improved from 30% in 1930s to over 85% currentlyover 85% currently
Median age of 3.5 years.Median age of 3.5 years.
More than 80% of patients identified before 5 More than 80% of patients identified before 5 years of age.years of age.
Male-to-female ratio 0.92 : 1Male-to-female ratio 0.92 : 1
Relatively more common in blacks than in Relatively more common in blacks than in whites and is less common in East Asians.whites and is less common in East Asians.
Bilateral disease occurs in 5-7% of patients with Bilateral disease occurs in 5-7% of patients with WT.WT.
Associated disordersAssociated disorders Children with various congenital abnormalities have an Children with various congenital abnormalities have an
increased predisposition to wilms tumorincreased predisposition to wilms tumor
Sporadic aniridiaSporadic aniridia
WAGR syndrome ( wilms, aniridia, genitourinary WAGR syndrome ( wilms, aniridia, genitourinary malformations, mental retardation)malformations, mental retardation)
Denys - Drash syndrome ( wilms, intersex, nephropathy)Denys - Drash syndrome ( wilms, intersex, nephropathy)
Perlman syndrome (overgrowth syndrome with mental Perlman syndrome (overgrowth syndrome with mental
retardationretardation))
Beckwith-Wiedemann syndromeBeckwith-Wiedemann syndrome - - exomphalosexomphalos visceromegalyvisceromegaly macroglossia macroglossia umbilical defects umbilical defects hemihypertrophy hemihypertrophy hypoglycemiahypoglycemia
increased susceptibility to a number ofincreased susceptibility to a number ofpediatric cancers including wilms, pediatric cancers including wilms, adrenocortical carcinoma adrenocortical carcinoma & hepatoblastoma & hepatoblastoma
Exomphalos
Hemihypertrophy
Macro-glossia
Hypogly-cemia
Molecular biologyMolecular biology
WT1 gene - deletion at 11p13 – tumor WT1 gene - deletion at 11p13 – tumor suppressor gene seen in WAGR & Denys-suppressor gene seen in WAGR & Denys-DrashDrash
WT2 gene - 11p15 locus. Over WT2 gene - 11p15 locus. Over expression of this gene results in expression of this gene results in overgrowth seen in BWS.overgrowth seen in BWS.
Pathology Pathology Classic wilms tumor has three components seen Classic wilms tumor has three components seen in normal kidney differentiation: Blastema, tubules in normal kidney differentiation: Blastema, tubules & stroma.& stroma.
When all three components are seen it is called When all three components are seen it is called triphasic. Tumor can be mono or diphasic.triphasic. Tumor can be mono or diphasic.
Tumor may exhibit aberrant differentiation – Tumor may exhibit aberrant differentiation – adipose, skeletal muscle, cartilage & boneadipose, skeletal muscle, cartilage & bone
Tendency to grow into veins – tumor thrombusTendency to grow into veins – tumor thrombus
Tumor with differentiated components have best Tumor with differentiated components have best prognosis and the histology is termed favorable.prognosis and the histology is termed favorable.
Anaplastic tumors are characterized by cells with Anaplastic tumors are characterized by cells with nuclear enlargement from two –three times the nuclear enlargement from two –three times the diameter of adjacent cells, hyperchromatic nuclei & diameter of adjacent cells, hyperchromatic nuclei & abnormal mitotic figures.abnormal mitotic figures.
Overall incidence of anaplasia varies from 3 – 7%Overall incidence of anaplasia varies from 3 – 7%
The single most important indicator of poor The single most important indicator of poor prognosis is presence of anaplasia – called prognosis is presence of anaplasia – called unfavorable histology.unfavorable histology.
Nephrogenic restsNephrogenic rests
These are potentially premalignant lesions These are potentially premalignant lesions found within the kidneys of 30 – 40% of found within the kidneys of 30 – 40% of patients with wilms tumor. patients with wilms tumor.
These are small foci of persistent primitive These are small foci of persistent primitive blastemic cells that are normally found in blastemic cells that are normally found in neonatal kidney.neonatal kidney.
Clinical FeaturesClinical Features Usually presents as asymptomatic abdominal massUsually presents as asymptomatic abdominal mass
Urinary disturbances, microscopic haematuria, Urinary disturbances, microscopic haematuria, malaise, weight loss, anemia, left sided varicocoelemalaise, weight loss, anemia, left sided varicocoele
Thrombus in IVC can present with venous edema of Thrombus in IVC can present with venous edema of lower limb. Thrombus can extend into the heart & lower limb. Thrombus can extend into the heart & produce cardiac malfunction.produce cardiac malfunction.
Urologic anomalies such as cryptorchidism, Urologic anomalies such as cryptorchidism, Hypospadias may be seen.Hypospadias may be seen.
Occasionally hypertension due to renal vein Occasionally hypertension due to renal vein occlusion by tumor thrombusocclusion by tumor thrombus
InvestigationsInvestigations
IVP: Spider leg appearanceIVP: Spider leg appearance
USG – Organ of origin, consistency, Tumor thrombus USG – Organ of origin, consistency, Tumor thrombus in renal vein/IVC/atrium, anomalies of kidney.in renal vein/IVC/atrium, anomalies of kidney.
CT – Assess operability, Structure & function of CT – Assess operability, Structure & function of opposite kidney, Liver/node involvementopposite kidney, Liver/node involvement
MRIMRI
Xray Chest/CT.Xray Chest/CT.
NWTS – National Wilms Tumor NWTS – National Wilms Tumor Study groupStudy group . .
As there were only an estimated 450 – 500 As there were only an estimated 450 – 500 cases of wilms tumor occurring annually in the cases of wilms tumor occurring annually in the united states it was realized that collaboration united states it was realized that collaboration was mandatory in order to obtain statistically was mandatory in order to obtain statistically significant numbers of patients, hence NWTS significant numbers of patients, hence NWTS was born in 1969 to set up treatment was born in 1969 to set up treatment protocols trials & give guidelines. protocols trials & give guidelines.
Currently NWTS – 5 is in progress.Currently NWTS – 5 is in progress.
StagingStaging II –– Tumor limited to kidney & completely resectedTumor limited to kidney & completely resected with intact renal capsulewith intact renal capsuleIIII - Tumor extended beyond kidney & completely - Tumor extended beyond kidney & completely resected.resected. There may be penetration of the capsule, There may be penetration of the capsule, tumor violated by previous biopsy, spillage confined tumor violated by previous biopsy, spillage confined to the flankto the flankIIIIII – Residual non-hematogenous tumor– Residual non-hematogenous tumor like renal like renal hIlar nodes, tumor implants on peritoneal surface, hIlar nodes, tumor implants on peritoneal surface, local infiltration into vital structures, gross tumor local infiltration into vital structures, gross tumor spillage not confined to the flank.spillage not confined to the flank.IVIV – Hematogenous metastatic disease– Hematogenous metastatic disease to the to the lungs, liver, bone & brainlungs, liver, bone & brainVV – Bilateral renal involvement at diagnosis– Bilateral renal involvement at diagnosis
SurgerySurgery
According to the NWTSG protocol, the first step in According to the NWTSG protocol, the first step in the treatment of WT is surgical staging followed by the treatment of WT is surgical staging followed by radical nephrectomy, if possible.radical nephrectomy, if possible.
Thorough exploration of the abdominal cavity Thorough exploration of the abdominal cavity through a transverse abdominal incision .through a transverse abdominal incision .
Formal exploration of the contralateral kidney Formal exploration of the contralateral kidney should be performed before nephrectomyshould be performed before nephrectomy
If bilateral disease is diagnosed, nephrectomy is If bilateral disease is diagnosed, nephrectomy is not performed but biopsy specimens are obtained.not performed but biopsy specimens are obtained.
If the disease is unilateral, radical nephrectomy If the disease is unilateral, radical nephrectomy and regional lymph node dissection or sampling and regional lymph node dissection or sampling are performedare performed
The renal vein and IVC are palpated to excludeThe renal vein and IVC are palpated to exclude
intravascular tumor extension before vessel intravascular tumor extension before vessel ligation.ligation.
If the tumor is unresectable, biopsies are If the tumor is unresectable, biopsies are performed and the nephrectomy is deferred performed and the nephrectomy is deferred until after chemotherapy.until after chemotherapy.
TreatmentTreatment FH:FH:
Stages I & II: Surgery + chemo ( Actinomycin + Vincristine)Stages I & II: Surgery + chemo ( Actinomycin + Vincristine)Stage III: Surgery + Radiotherapy + chemo ( Actinomycin + Stage III: Surgery + Radiotherapy + chemo ( Actinomycin + Vincristine + Doxorubicin)Vincristine + Doxorubicin)Stage IV: Surgery + Radiotherapy + chemo ( Actinomycin + Stage IV: Surgery + Radiotherapy + chemo ( Actinomycin + Vincristine +Doxorubicin)Vincristine +Doxorubicin)
Local Excision of secondariesLocal Excision of secondaries
Anaplastic:Anaplastic:Stage I: Surgery + ChemotherapyStage I: Surgery + ChemotherapyStages II – IV: Surgery + Radiotherapy + chemo Stages II – IV: Surgery + Radiotherapy + chemo
( Actinomycin + Vincristine + Doxorubicin +/- ( Actinomycin + Vincristine + Doxorubicin +/- Cyclophosphamide)Cyclophosphamide)
Stage V (FH/Ana): Stage V (FH/Ana):
Obtain biopsies Obtain biopsies
Each side staged individually.Each side staged individually.
Chemo/radio as per higher stageChemo/radio as per higher stage
Repeat CT. Once tumor reduces in size renal Repeat CT. Once tumor reduces in size renal preserving surgery on both sides & close preserving surgery on both sides & close follow up for recurrencefollow up for recurrence
In case of thrombus in the IVC/Atrium give In case of thrombus in the IVC/Atrium give chemotherapy at least 3 courses & repeat chemotherapy at least 3 courses & repeat imaging. Then Surgery.imaging. Then Surgery.
PrognosisPrognosis
Approximately 80-90% of diagnosed Approximately 80-90% of diagnosed children survive with current multimodality children survive with current multimodality therapy.therapy.
Patients with FH tumors have at least an Patients with FH tumors have at least an 80% overall survival rate at 4 years after 80% overall survival rate at 4 years after initial diagnosis, even in patients with stage initial diagnosis, even in patients with stage IV disease.IV disease.
Synchronous bilateral cases have a 70-80% Synchronous bilateral cases have a 70-80% survival ratesurvival rate
NeuroblastomaNeuroblastoma
Tumor of neural crest originTumor of neural crest origin
May arise in the adrenal medulla or May arise in the adrenal medulla or sympathetic ganglia from neck to pelvissympathetic ganglia from neck to pelvis
Spontaneous tumor regression & tumor Spontaneous tumor regression & tumor maturation from malignant to benign maturation from malignant to benign histologic form have been noted rarely, histologic form have been noted rarely, especially under 3 months of age.especially under 3 months of age.
Incidence 1 in 8000 – 10000Incidence 1 in 8000 – 10000
90% occur in first 8 yrs of life90% occur in first 8 yrs of life
> 50% are under the age of 2yrs at the time of > 50% are under the age of 2yrs at the time of diagnosisdiagnosis
M:F IS 1.2:1M:F IS 1.2:1
Most common intraabdominal malignancy of Most common intraabdominal malignancy of newbornnewborn
Associations: BWS, Hirschsprung’s disease, Associations: BWS, Hirschsprung’s disease, fetal alcohol syndrome, fetal hydantoin fetal alcohol syndrome, fetal hydantoin syndromesyndrome
Neuroblast is derived from primordial neural Neuroblast is derived from primordial neural crest cells that migrate from the mantle crest cells that migrate from the mantle layer of developing spinal cordlayer of developing spinal cord
Locations:Locations: 75% in retroperitoneum – adrenal 75% in retroperitoneum – adrenal
medulla(50%), paraspinal ganglia(25%)medulla(50%), paraspinal ganglia(25%)
20% in posterior mediastinum20% in posterior mediastinum
5% in neck / pelvis5% in neck / pelvis
Pathology Pathology
Gross examination: Highly vascular purple-grey Gross examination: Highly vascular purple-grey solid mass with necrotic and hemorrhaghic areas.solid mass with necrotic and hemorrhaghic areas.
Microscopy: Appears like small round cell tumor. In Microscopy: Appears like small round cell tumor. In undifferentiated form there are closely packed undifferentiated form there are closely packed small spheroidal cells with hyper chromatic nuclei.small spheroidal cells with hyper chromatic nuclei.
Rosette formation is a classical finding in Rosette formation is a classical finding in neuroblastoma. The center is formed by a tangle of neuroblastoma. The center is formed by a tangle of fine nerve fibres surrounded by a palisade of fine nerve fibres surrounded by a palisade of neuroblasts/ganglion cells – called neuroblasts/ganglion cells – called Homer - Wright Homer - Wright pseudo rosettes.pseudo rosettes.Stroma rich tumors carry better prognosis.Stroma rich tumors carry better prognosis.
Clinical presentationClinical presentation
Related to site of tumor, presence of Related to site of tumor, presence of metastases & production of certain metabolic metastases & production of certain metabolic byproductsbyproductsNodular, painful abdominal mass, weight Nodular, painful abdominal mass, weight loss, failure to thrive, distension, fever, loss, failure to thrive, distension, fever, anemiaanemia25% have hypertension due to production of 25% have hypertension due to production of catecholamines. Flushing, sweating & catecholamines. Flushing, sweating & irritability may be seenirritability may be seenRespiratory distress / Dysphagia due to Respiratory distress / Dysphagia due to compression in the mediastinumcompression in the mediastinum
Neoplasms in neck/mediastinum may present with Neoplasms in neck/mediastinum may present with Horner’s syndromeHorner’s syndrome – ptosis, miosis, enophthalmos, – ptosis, miosis, enophthalmos, heterochromia of iris & anhydria on affected side.heterochromia of iris & anhydria on affected side.
Tumor extension through intervertebral foramina may Tumor extension through intervertebral foramina may produce paraplegiaproduce paraplegia
Acute cerebellar ataxia – opsomyoclonus with nystagmus Acute cerebellar ataxia – opsomyoclonus with nystagmus – – Dancing eye syndromeDancing eye syndrome – occasionally seen in mediatinal – occasionally seen in mediatinal tumors, represents antigen-antibody reactiontumors, represents antigen-antibody reaction
WDHA syndrome due to VIP productionWDHA syndrome due to VIP production
Spontaneous rupture – hemoperitoneumSpontaneous rupture – hemoperitoneum
Metasases to liver, bone marrow, bone cortex & Metasases to liver, bone marrow, bone cortex & nodesnodes
Metasasis to orbit produces proptosis or b/l orbital Metasasis to orbit produces proptosis or b/l orbital ecchymosis – ecchymosis – Panda eye signPanda eye sign
Diagnosis:Diagnosis:
Plain X ray – Stippled tumor calcificationPlain X ray – Stippled tumor calcificationUSGUSGCT – adrenal massCT – adrenal massMRI for spinal extensionMRI for spinal extensionIsotopic bone scintigraphy using technitium99Isotopic bone scintigraphy using technitium99Meta iodo benzyl guanidine scanMeta iodo benzyl guanidine scanBone marrow aspirationBone marrow aspirationTumor markers (APUD): Tumor markers (APUD):
24 hr urine HVA & VMA 24 hr urine HVA & VMA Serum adrenaline, nor adrenaline, dopamineSerum adrenaline, nor adrenaline, dopamine Serum LDH, Ferritin, NSESerum LDH, Ferritin, NSE
EVANS STAGING SYSTEMEVANS STAGING SYSTEM
II: confined to organ of origin: confined to organ of origin
IIII: beyond organ of origin, not crossing : beyond organ of origin, not crossing midline, ipsilateral nodes may be involvedmidline, ipsilateral nodes may be involved
IIIIII: Extends beyond midline, b/l nodes : Extends beyond midline, b/l nodes involvementinvolvement
IVIV: Distant metastasis: Distant metastasis IV-SIV-S: Infants younger than 1yr,stg I or II, : Infants younger than 1yr,stg I or II,
remote disease confined to liver, remote disease confined to liver, subcutaneous tissue & bone marrow.subcutaneous tissue & bone marrow.
Factor Good Prognosis Poor Prognosis
Age < 1yr > 1yr
Stage I.II,IV-S III, IV
Pathology Stroma rich Stroma poor
Site Mediastinum, Pelvis, Neck
Adrenal, Coeliac axis
> 10 copies of N-myc gene No Yes
Elevated Serum Ferritin No Yes
NSE No Yes
LDH No Yes
Diarrhea Yes No
Dancing eye Yes No
High HVA/VMA No Yes
Prognostic indicators
Treatment Treatment
Stage I: Complete surgical excisionStage I: Complete surgical excision
Stage II: Complete surgical excisionStage II: Complete surgical excision +/- Radiotherapy+/- Radiotherapy Poor prognostic indicators – Surgery + Chemo Poor prognostic indicators – Surgery + Chemo
(Cisplatin, Doxorubicin, Cyclophosphamide, (Cisplatin, Doxorubicin, Cyclophosphamide, Etoposide)Etoposide)
Stages III & IV: Chemotherapy is mainstay followed Stages III & IV: Chemotherapy is mainstay followed by excision if mass responds to chemo & becomes by excision if mass responds to chemo & becomes operableoperable
Aggressive management includes near Aggressive management includes near fatal chemo (myeloablative) with fatal chemo (myeloablative) with irradiation with BMTirradiation with BMT
New modalities include use of biological New modalities include use of biological response modifiers like 13-cis retinoic response modifiers like 13-cis retinoic acid that causes tumor differentiation, acid that causes tumor differentiation, II131131 labeled antiGD2 antibody therapy. labeled antiGD2 antibody therapy. (monoclonal antibodies).(monoclonal antibodies).