Dr Marty Campbell Paediatric Oncologist Royal Children's Hospital, Melbourne FRACP lecture series Oct 2014
Background Neuroblastoma (NB) is the most common solid tumour outside the CNS in children 6-10% of all childhood cancers. Peak incidence in infancy and rare after age 6. NB was first described by Virchow in 1864 in a child with an abdominal mass In 1901, Pepper described 6 cases of newborns with an adrenal tumour, and 6 cases of infants with massive hepatic metastases that regressed spontaneously.
Background 1% have a +ve FHx of NB Often associated with germline mutation of ALK gene Increased risk in Hirschprung's disease and Ondine's curse
Pathology A neuroblastic tumour of 'small round blue cells' Derived from progenitor cells of the sympathetic nervous system 4 basic morphological categories Neuroblastoma (Schwannian stroma-poor) -- undifferentiated, poorly differentiated and differentiating Ganglioneuroblastoma (GNB), intermixed (Schwannian stroma-rich) GNB, nodular Ganglioneuroma (GN) maturing and mature
Biology MYCN amplification (2p24) 25% of tumours Highly associated with advance stage and poor outcome Numerous non-random cytogenetic abnormalities 1p36 deletion, 11q loss and 17q gain all associated with a poor prognosis ALK mutations (~8-10%) Numerical abnormalities (hyperdiploidy) associated with favourable prognosis Segmental abnormalities associated with less favourable prognosis
Clinical presentation NB can arise anywhere along the sympathetic nervous chain Clinical presentation reflects site of disease, the presence of metastases as well as the presence of any paraneoplastic syndrome Most (70%) primary tumours arise in the abdomen, with over half of these arising from the adrenal gland Neck (4%) lesions mimic adenopathy and may lead to Horner's syndrome Thoracic (15%) lesions may present with resp distress, Horner's or be found incidentally Pelvic/sacral (5%) tumours may present with a mass, dysuria or constipation
Clinical presentation Metastases/disseminated disease Non-specific symptoms such as fever, pallor, anorexia, bone pain and irritability (classic exam history) Proptosis and peri-orbital ecchymoses suggest orbital mets (classic exam picture) Spinal cord compression The anatomical connection between the SNS and the spinal cord accounts for the propensity of NB to infiltrate the intervertebral foraminae. Motor deficits are most common followed by radicular back pain, bladder and bowel dysfunction and rarely sensory deficits. Only ~5% have clinical evidence of epidural compression
Clinical presentation Paraneoplastic syndromes Opsoclonus-myoclonus ataxia syndrome (OMAS) occurs in 2-3% of NB patients and is characterised by multi-directional rapid eye movements, myoclonus and brainstem ataxia. Symptoms may predate the detection of any tumour and in many cases require immunosuppressive therapy despite removal of the tumour. VIP secretion can lead to intractable watery diarrhoea. Hypertension Increased catecholamine production Renal artery compression
Staging (INSS surgical) Stage 1 (17%): Localized tumour confined to the area of origin. Stage 2A: Unilateral tumour with incomplete gross resection; identifiable ipsilateral and contralateral lymph node negative for tumor. Stage 2B: Unilateral tumour with complete or incomplete gross resection; with ipsilateral lymph node positive for tumour; identifiable contralateral lymph node negative for tumour. Stage 3 (16%): Tumour infiltrating across midline with or without regional lymph node involvement; or unilateral tumor with contralateral lymph node involvement; or midline tumour with bilateral lymph node involvement. Stage 4 (44%): Dissemination of tumour to distant lymph nodes, bone marrow, bone, liver, or other organs except as defined by Stage 4S. Stage 4S (7%): Age <1 year old with localized primary tumour as defined in Stage 1 or 2, with dissemination limited to liver, skin, or bone marrow (less than 10 percent of nucleated bone marrow cells are tumours).
Staging (INRGSS) Stage L1: Localized disease without image-defined risk factors. Stage L2: Localized disease with image-defined risk factors. Stage M: Metastatic disease. Stage MS: Metastatic disease "special" where MS is equivalent to stage 4S.
Staging and diagnosis Primary site imaging -- CT/MRI Bilat BMATs Tumour biopsy for histology/ploidy/cytogenetics/fish/microarray MIBG scan Bone scan (if non-mibg avid) +/- PET Urine catecholamines (HVA/VMA) -- spot not 24hr collection (90% sensitivity in children >1yr)
Treatment Depends on age, stage, histology and genetic/molecular features Subdivided into 3 broad categories Low (44%) Intermediate (20%) High (36%)
Treatment Low risk Definition Stage 1 all Stage 2a/2b (>50% resected) NMYC-NA Any histology (unless UH/diploid/11q loss) No segmental alterations Stage 4S NMYC-NA, DI>1, FH OBSERVATION ONLY OUTCOMES: 89% 5YR EFS AND 97% OS
Treatment High risk Definition Stage 4 NMYC-Amp at any age > 18/12 old 12/12 to 18/12 If UH or segmental chromosmal abnormalities Stage 3 NMYC-Amp at any age UH and >18/12 Stage 2A/2B/4S NMYC-Amp
Treatment High risk Intensive induction chemotherapy Cisplatin/etoposide/cyclophosphamide/vincristine doxorubicin Surgery High-dose chemotherapy and stem cell rescue Carboplatin/etoposide/melphalan Busulfan/melphalan Radiation Immunotherapy incl: cis-retinoic acid
Treatment High risk Immunotherapy COGANBL0032 a landmark study Randomised comparison of CRA versus Ch14.18 mab with GM-CSF and IL2 plus CRA 2yr EFS 66% vs 46% in favour of immunotherapy 2yr OS 86% vs 75% (p<0.05) All patients now receive immunotherapy but have to be enrolled on study as drug not yet commercially available
Treatment Intermediate risk Definition All the rest! Many factors determine the amount of chemo required Age, stage, histology and biology/genetics Vary from 2 to 8 cycles of chemo Outpatient based therapy. Aim now only for a PR (>50% reduction in size) Outcomes 3yr OS 96%
Relapsed neuroblastoma Low risk Further surgery +/- chemo Intermediate risk Further surgery + chemo High risk Palliation MIBG therapy Standard chemotherapy (multiple options) Phase II and phase I studies
Summary Excellent outcomes are achieved for low and intermediate-risk neuroblastoma Reduction in therapy now an aim for these groups, with better stratification on genetic/molecular factors Immunotherapy has been the biggest breakthrough for high-risk neuroblastoma in a long time but improvement is still needed, especially as some patients never respond to induction chemo Relapsed high-risk neuroblastoma essentially remains incurable
...and other renal tumours
Wilms tumour First classified as a kidney tumour in 1814 Surgeon Max Wilms described the tumour in a 90 page monograph in 1899
Epidemiology 6-7% of all childhood cancers 7/1,000,000 children <15yrs old Most frequent malignant renal tumour in kids F>M Peak at 2-3yrs Bilateral tumours peak at a younger age
Risk factors (classic exam q) WAGR syndrome Wilms, Aniridia, Genital deformity and Retardation Denys-Drash syndrome Pseudohermaphroditism, glomerulopathy and Wilms Beckwith-Wiedemann syndrome Hemihypertrophy, omphalocoele, macrosomy, macroglossia, hypoglycaemia Perlman syndrome Macrocephaly, deep rooted eyes and ears, macrosomia and organomegalia NF1 Isolated hemihypertrophy (WT most common, then HB) Urogenital malformations Cryptorchidism, hypospadias, pseudohermaphroditism and gonadal dysgenesis Family history
Presentation Incidental finding Asymptomatic palpable or visible abdo mass Pain and haematuria are NOT common Hypertension secondary to increased renin activity Coagulopathy caused by an acquired Von willebrand syndrome
Diagnosis/work up Imaging U/S good at looking for renal vein or IVC thrombus CT/MRI abdomen ( claw sign) CT chest Chemo vs nephrectomy (up front) Chemo then nephrectomy (Europe SIOP), Therapy dependent on histological response to chemo Upfront nephrectomy (Nth America COG) then chemo Therapy dependent on initial stage and histology Either (Australia)
Histopathology Classic (triphasic) Blastemal Epithelial Mesenchymal Anaplasia (7.5% of renal tumours) Focal Diffuse
Staging Stage 1 Complete resection Tumour limited to kidney Renal sinus NOT involved Stage 2 Complete resection but tumour extends through renal capsule or into renal sinus Stage 3 Incomplete resection LN involvement Tumour rupture Previous (surgical) biopsy Stage 4 Haematogenous metastases (lung, liver, brain, bone) or distant LNs Stage 5 Bilateral
Treatment Surgery Total nephrectomy remains standard of care in unilateral Wilms tumour but small studies now showing that nephronsparing surgery possible in some cases Chemotherapy Most cases require it VCR/Act-d for most Doxorubicin/Cyclophosphamide/Etoposide/carbo for HR Radiotherapy Stage 3 +/- Lung metastases
Outcomes (FH) Very Low risk Stage 1, <2yrs, <550g 85% EFS with surgery only, >95% OS Low risk Stage 1/2, FH, favourable biology 90%+ EFS, 98% OS Standard risk Stage 3 85% 4yr RFS and 94% 4yr OS Higher Stage 4 75% 4yr RFS
Bilateral Wilms tumour Pre-operative chemo always indicated Aim to preserve as much healthy kidney as possible Nephron-sparing surgery possible on both sides in >50% of cases Post-op chemo is determined by histology and the local stage in which the highest risk group of the 2 sides Prognosis usually favourable (70% OS at 10yrs)
Clear cell sarcoma of the kidney 3% of malignant tumours of the kidney Peak incidence 1-4yrs M>F Prognosis good if non-metastatic and use more intensive chemo (3-4 drugs)
Rhabdoid tumour of the kidney 2% of malignant tumours of the kidney 80% <2yrs Poor prognosis High metastatic rate 15% have synchronous brain lesions Fever, haematuria and hyperglycaemia can occur
Renal cell carcinoma 2-5% of of paediatric renal tumours 20% have metastatic disease at diagnosis Lung, bone, liver or brain Older age (~10yrs) May have specific cytogenetic abnormality ASPL-TFE3 gene fusion Abdo pain, fever and haematuria Survival 90-100% for stage 1 10% for stage 4
Summary The majority of renal malignancies in children are Wilms tumours The majority of Wilms tumours are of favourable histology The majority of FH Wilms tumours are cured