Paediatrics Flashcards
Describe the epidemiology and pathology for a craniopharyngioma.
- Craniophryngioma
- Arises from Rathke’s pouch, which abuts the hypothalamus and 3rd ventricle superiorly.
- No formal staging –benign, slow growing but locally aggressive and destructive
Epidemiology:
* Bimodal distribution -
* 5% of all pediatric tumors. ~200-570 cases per year. 5-14 and 50-60
* M=F
* Comprises a little more than half of tumours in the sella-chiasmatic region in peds.
- Pathology
- 2 subtypes
- Adamantinomatous histology (90%) -more frequent LR
○ Macro: lobular solid and cystic pattern,
* Fluid that drains from it is called “crankcase oil”. Proteinaceous fluid with cholesterol crystals.
○ Micro: well circumscribed cords/lobules of squamous eipithelium and peripheral paliscading columnar cells. Anucleate squmaous cells (ghost) wet keratin
○ Microscopic invasion into brain
○ associated with WNTmt and CTNNB1 ( B catenin)
○ IHC:
* Pos CK7,8,19, B catenin
* Neg: BRAF - Papillary (less common < 10% peds, 1/3 of adults).
○ Discrete encapsulated mass
○ Micro: solid WD nonkeratinising squmous. Papilla around fibrovascular core.
○ BRAF mutations
○ IHC:
* CK 7, EMA, BRAF
* Neg CK 7 CK20
- Adamantinomatous histology (90%) -more frequent LR
Describe the history, examination and work up for a craniopharyngioma. What is the differential diagnosis of a suprasella tumour?
- Presenting symptoms:
- Children: growth retardation
- Adults: abnormal vision, hormonal deficiencies
- Hypothalamus symptoms: homeostasis, hormones, metabolism, temperature, food/water intake, emotions, circadian cycle
- Work up:
- History: visual field defect, endocrinopathy, generalized headache, N+V
- Exam: cranial exam incl visual field, opthal review, endocrinopathy
- Don’t need biopsy: dx based on imaging
- MRI: cystic with calcifications, solid and encapsulated.
- Adamantinomatous- T1 iso, T2 hyperintense
○ Audiometry.
○ Ophtho exam.
○ Blood and CSF tumor markers to rule out other suprasellar tumors.
- Adamantinomatous- T1 iso, T2 hyperintense
Describe the surgical management of craniopharyngioma and associated toxicities.
Management:
Observation
* Surgery
* GTR- alone 70-85% with LF 20%-> Observation
* Adj RT can cause hypopit, diabetes insipidus, vision loss, and hypothalamic dysfunction, personality change. Hence, observe
* STR - alone 30% DFS-> 70-80% DFS STR+RT
* Recommend PORT 54Gy/30F
* In children <5-7yo, RT can be deferred, salvage RT has similar LC as Adj RT.
- Lateral pterional approach (temporal) is typically employed.
- Transsphenoidal surgery appears to be best to minimize endocrinopathies, but is only for intrasellar tumors.
- Children’s Memorial: Around 25% of patients with planned GTR will actually have GTR.
- St. Jude (1984-1997) [Merchant IJROBP ‘02]: GTR vs. Limited surgery/RT.
Planned STR appears to have less IQ detriment.
○ 30 pts. Mean age 8.6y.
○ Mean IQ lost of 9.8→ 1.25 points. - Treatment strategies in Childhood Craniopharyngioma [Puget Frontiers in Endo ‘12]:
○ It may be best to stratify for planned GTR based on the extent of hypothalamic involvement.
○ For STR, may observe if < 5yo.
Toxicity
* Surgical mortality < 4%, with morbidity ranging from 8 and 14%.
* Endoscopic endonasal approach resections appear to be the safest for suprasellar stalk and intrasellar stalk origin. However, the majority of tumors are central-type or hypothalamic stalk in origin and resection of these tumors are associated with hypothalamic injury
* Greater loss of IQ with radical surgery vs. limited surgery + RT.
* Vision loss (2% of surgery).
* Hypopituitarism: delayed puberty in 14-50% depending on age, decreased IQ,
* Hypothalamic obesity, defective short term memory.
○ Limit to 45 Gy.
* DI - Treatment with desmopressin.
Describe the management of craniopharyngiomas with radiotherapy.
- Radiotherapy
* Indications:
* Adjuvant: STR
* Definitive: unresectable, not surgical candidate
* Salvage
* Technique: EBRT, IMRT, Protons
* Volume:
* GTV = surgical cavity, any residual enhancing lesions based and cystic components based on post op MRI T1 gad and T2 flair and CT.
* CTV = GTV +5mm (use larger CTV eg 10mm if weekly MRI cannot be done)
* PTV = CTV + 3mm
○
○ Dose: 54Gy/30# @ 1.8Gy/#
▪ Limited by surrounding structures
* Control rate worse if <54Gy
▪ SRS 12-14Gy
○ Image Verification: daily CBCT matched to bone
* Cyst and tumor swelling during and after RT prompts multiple MRIs while on treatment, q1-2w.
* During treatment: repeat MRI weekly as there can be cyst and tumour swelling during RT. Any acute symptoms during RT may be likely due to cystic enlargement and may require urgent drainage +/- replan .
* 20-30% will have growth of the cystic component within 6 months after RT.- Recurrent cyst –cyst injection of radioactiveisotope or bleomycin
- Recurrence:
- Surgery
- SRS
- BRAF inhibitor
Describe radiotherapy treatment planning for craniopharyngioma.
Treatment Planning
ESTRO-ACROP Guidelines for target volume delineation of skull base tumors [Combs RTO ‘20]
* Max safe resection (vision preserving) or decompression of cyst prior to RT.
○ GTR alone 70-85% DFS (20% failure)→ cost of DI, vision loss, hypothalamic dysfunction. Observation.
○ STR: 30% DFS. PORT to 54 Gy. STR + RT 85-90% DFS
§ RT can be deferred for children < 5-7y after surgery, salvage RT with similar LC as adjuvant RT.
* MRI 3D T1 images are best for solid portions, while fast spin-echo T2 ± fat suppression are most useful for cystic components of the tumor.
* Recurrent setting: Intralesional chemo (bleo) or colloids P32: 200-250 Gy to cyst wall [Cavalheiro JNS ‘10]
○ Intralesional treatments are an option if the cyst is > 50% total bulk and ≤ 3 cysts (solitary is ideal), or recurrent cysts after surgical resection. Limited data, but ~30% CR and MPFS 1.8y with intralesional bleomycin [Hukin Cancer ‘07].
* Target volume:
○ GTV: Tumor + cyst wall. Prefer to cover the 3rd ventricle if the cyst occupied this area previously.
○ CTV: GTV + 0.3-0.5-1.0 cm (historically, 1.0-2.0 cm); PTV + 0.3-0.5 cm.
§ For weekly MRIs, use 0.5 cm margin. Otherwise, 1.0 cm.
* Dose 54 Gy conventional, range of 50-55 Gy acceptable.
○ Inferior LC with size > 6 cm [Hetelekidis IJROBP ‘93] and < 55 Gy [Varlotto IJROBP ‘02].
* SRS may be reasonable for small residual or recurrent craniopharyngiomas. Single fraction up to 18 Gy and 20-25/3-5 have been employed at a reasonable distance to chiasm.
* Cyst and tumor swelling during and after RT prompts multiple MRIs while on treatment (at least mid treatment), q1-2w.
○ Around 20-30% will have growth of the cystic component within 6 months after RT. If your surgeon wants to cut after RT, encourage cystic drainage or minimal surgery.
○ Acute symptoms during RT likely due to cystic enlargement, may require urgent drainage. Up to 1 in 8 may enlarge during RT.
Describe the prognosis and follow up for craniopharyngioma.
Follow up
* 10y OS 70-92%, 20y OS 76%.
* 10y LC for GTR or STR 40%, Surgery + RT 85%, regardless if adjuvant or salvage.
* 3y OS 85%, LC very high 90%.
* Regrowth typically occurs within 2 years, but may take up to 9 years.
Make sure younger patients are followed closely and initiated on GH replacement within a year of radiation therapy, if warranted. RoR
Overall outcome: 80-90% 10 year control
Treatments:
Surgery GTR = 30% reccurrence
<2cm 90% GTR
3-4cm 20% GTR
Transspenoidal through nose
Transcranial (much worse pituitary function)
Surgery subtotal resection
Observation 70% recurrence
Adjuvant RT 20% recurrence
Definitive RT -survival similar to adjuvant RT or GTR
Describe the epidemiology and risk factors for wilm’s tumours.
I: Incidence
* 40 cases annually in Australia
* Accounts for 5% of childhood malignancies
* most common renal tumour of infants and children
* most common abdominal cancer in childhood
A: Median age is 4 years old (2-5) >70%
* Slightly earlier if bilateral (germline mutation)
* incidence >10 years rare
G: Slight female predominance (1.25:1)
G: No significant geographical variation.
R: African children have higher incidence, followed by caucasion, asian lowest incidence
Aetiology
1) Majority have no clear cause (90%) 2) Genetic syndromes (10%) a. WT1 germline deletion i. 33% lifetime risk of Wilm's ii. WAGR syndrome --> Wilm's, Aniridia, Genitourinary malformation, Retardation b. Denys-Drash syndrome (WT1 missense mutation) i. 90% lifetime risk of Wilm's ii. Gonadal dysgenesis + early-onset nephropathy c. Beckwith-Wiedemann syndrome (WT2 imprinting abnormalities) i. Often demonstrate IGF-2 overexpression ii. Organomegaly, macroglossia, hemihypertrophy iii. Also get adrenocortocoma, hepatoblastoma
Describe the pathogenesis and natural history for wilm’s tumours.
Pathogenesis
- childhood embryonal tumour thought to arise through abortive or disrupted development
- linked to nephrogenesis- Normally:
- intermediate mesoderm differentiates into metanephric mesenchyme which condenses around the braching ureteric bud structures
- undergoes MET to form renal vesicles which expand to give rise to the majority of cell types in the functional kidney
Develop from persistent metanephric tissue or nephrogenic rests
- Clusters of persistent embryonal cells
- Thought to be a precursor to Wilm’s
Genetic alterations occur during embryological development of the genitourinary tract
- WT1 is most implicated (chr 11)
- WT2 is also implicated
10% occur bilaterally
- Worse prognosis
- Higher risk of germline mutation
Natural Hx
- Local extension- renal capsule, renal sinus + vessels
○ Increased risk of relapse if:
§ Inflammatory pseudocapsule
§ Extensive infiltration of renal capsule
§ Involvement of renal sinus
§ Tumour in intrarenal vessels
- LN spread- renal hilar or ParaAortic LN
- DM: liver + lung most commonly, other sites rare (question diagnosis)
○ Lung: 15% at diagnosis
- Other renal tumours:
○ CCSK: brain + bone mets (bone mets a hallmark)
○ RTK: brain mets
Describe the pathology for wilm’s tumours.
Histopathology
Macroscopic
- Large, solitary, well circumscribed masses
○ Demarcated from normal renal parenchyma
○ Often with a pseudocapsule
- Cut section demonstrates soft, homogenous tan-grey tumour
○ Occasional haemorrhage, cystic change or necrosis is seen
Microscopic
- Classic triphasic appearances (don’t need all 3)
○ Blastema = sheets of small undifferentiated cells
○ Epithelial = abortive glomeruli and tubular structures
○ Stromal = varying differentiation, oval to spindle cells with bland nucleoli, may have heterologous components
- Anaplasia is associated with poorer prognosis (5-10% of cases)
○ Associated with p53 mutation
○ Requires all three of
§ Atypical mitoses
§ Marked nuclear enlargement
§ Hyperchromasia
§
Immunohistochemistry
- POS = WT1, PAX8, vimentin
○ Epithelial will have CKs, EMA
○ Stromal will have vimentin, desmin + mygenin
- NEG = AMACR, CK7, melanocytic markers (MelanA, HMB45)
Cytogenetics
- p53 mutation (70%)
- IGF2 mutation (70%
- 1q gain (30%)
- WT1 (20%)
Loss of heterozygosity 1p and 16q = poorer prognosis
i) Favourable Histology (FH) 90% – no anaplasia, often with epithelial component with no sarcomatoid changes.
ii) Unfavourable Histology (UH) 10% – anaplasia present, can be triphasic, focal or diffuse (only diffuse anaplasia has clinical significance = resistance to chemotherapy and often p53 mutations)
Compare and contrast wilm’s tumours from neuroblastoma.
Describe variants of Wilm’s tumours and DDx
- Variants/Other Types/DDX
○ RCC
§ Rare in children/adolescents, 4/1mil
§ Age 15-19 years, 2/3rd kidney lesions are RCC
§ Often presents with more advanced disease
§ Risk factors: prev RT/CT, Von hipplel lindau, tuberous sclerosis, familial RCC
§ Prognostic factors: stage, LN
□ 5year OS: St I-II 100%, III 71%, IV 8%
§ Management: radical nephrectomy + LN dissection
§ Micro: papillary subtype most common then mixed, clear cell
□ Translocation transcription factor E3 gene
○ Clear cell sarcoma of kidney (CCSK)
§ 3% of childhood renal malignancies, 2:1 M: F
§ 29% nodal met at presentation
§ most commonly site if recurrence= bone, lung, followed by abdo and brain
§ Separate entity to Wilms tumour
§ Poorer than FH Wilms, Predisposition for bony metastases
§ Prognostic factors: young age, stage 4
§ Micro: Cytoplasmic vacuolization, nests or cords separated by fibrovascular stroma
§ Mx: clinical trial, surgery, CT + RT
○ Rhabdoid tumour of the kidney (RTK)
§ 2% childhood malignancies, 80% < 2yo
§ 1.5 M:F
§ charaterised by INI-1
§ assoc with primary intracranial mass or brain met- > need brains staging
§ Risk factors: rhabdoid predisposition syndrome (germline mutation SMARCB1)
§ Very aggressive, Predisposition for brain metastases
§ Presents with fever, haematuria, mean age 11 months, advanced disease
§ Mx: no standard mx, multi modality therapy is best with surgery + chemo (vnc,cyc,doxo,carb, etops) + RT
Describe the prognostic factors for Wilm’s tumour
Describe the history, examination and work up for Wilm’s tumour
Consultation
- History
○ HPI (USUALLY WELL CHILD)
§ Asymptomatic abdominal mass
§ Abdominal pain
§ Anorexia
§ Vomiting
§ HTN, haematuria
§ Varicocele
○ PMHx
§ Genetic syndromes
□ WAGR syndrome
□ Denys-Drash
§ Previous malignancy
§ Previous radiotherapy
○ Family History
§ Previous malignancies
- Examination ○ General wellness of child ○ Blood pressure (25% are hypertensive) ○ Examine for syndromic abnormalities ○ 1% of wilms have Aniridia. 40% will have Wilms ○ Abdominal palpation § Care must be taken not to examine rigorously (risk of capsule rupture) § Hemihypertrophy -left or right side bigger than other eg. Arm or leg. § May have cryptorchidism, hypospadias, horseshoe kidney
Work-Up
- Abdominal ultrasound
○ Initial investigation to establish presence of abdominal mass
○ Should be able to identify nephrogenic site
- CT CAP ○ Assess size and location of disease ○ Assess patency of renal vessels ○ Assess para aortic LN (important for staging) - MR Abdomen is a reasonable alternative if available - Bloods ○ FBC ○ EUC + CMP (renal function from impaired kidney) ○ LFT (liver metastases) ○ Coagulation studies § Acquired von Willebrand disease is possible - Urinalysis ○ Urinary protein (Denys-Drash) ○ Blood - Histopathology ○ Surgical resection (no biopsy) ○ Biopsy = tumour spill (upstages pt to Stage III= radiotherapy) For clear cell sarcoma of kidney : skeletal survey, MRI brain, bone marrow biopsy
Describe the COG/ SIOP staging for Wilm’s tumour
Describe the general management paradigm for Wilm’s tumour.
- General treatment principles:
- Multidisciplinary approach:
○ Surgery: local control + diagnosis - all need
○ Chemo: prevent LR and distant relapse - all need but intensity varies based on stage, histo, LOH
▪ Favourable
▪ Unfavourable = anaplasia, clear cell, rhabdoid = chemo resistance
○ RT: reduce LR and treat DM - certain cases only - Intensity of treatments is influenced by stage, FH or UH, bilateral or unilateral disease
- All need to be treated on a protocol and via an MDT
- The COG and SIOP have fundamentally different approaches.
Both approaches comparable outcomes with 5yr OS >90%
○ COG = upfront surgical resection (nephrectomy), with adjuvant therapies to follow
§ Gives accurate stage and pathological diagnosis upfront
□ 60% are stage 1 -2 = no RT
□ Tailor adjuvant treatment
□ Avoid treatment of benign tumours
○ SIOP = neoadjuvant chemotherapy, followed by surgical resection and adjuvant therapies to follow
§ Preop RT or chemo reduces rupture risk from 30% to 5% (rupture needs RT)
§ Good for unresectable disease, tumour thrombus, bilateral tumours (or tumoru in solitary kidney)
§ Disadvantages:
○ Diagnosis not confirmed by bx - pts treated on clinical and radiological grounds
○ 1.4% benign disease or incorrect histology treatment
○ Histology reflected chemotherapy-induced changes
○ Lose prognostic info.
- Multidisciplinary approach:
Describe the management of stage I/II/III Wilm’s tumour
Describe the management for stage IV and V Wilm’s tumour.
Describe radiotherapy management for wilm’s tumour.
Radiotherapy
Must be initiated within 10-14 days post-operatively
- Biggest detriment seen with unfavourable histology 40% vs 7%
- Mixed picture in retrospective study for <> 10 days. For non-metastatic disease <14 days better.
Causes for RT treatment delay
- final pathology and stage needed within a few days to determine if child needs RT
- need time to do simulation
- younger children may need anaesthesia
- simulating all children with renal masses seem to be inappropriate
Describe surgical management of Wilm’s tumour and the possible complications.
- Surgery
- Role- critical for LC & to Ax + stage intra-abdo dx (for subsequent CT + RT plan)
- Nephrectomy, inspection of contralat kidney
- LN sampling for St 1/2; resection of grossly involved LN for St3/4
- Absence of LN sampling is poor prognostic feature
- Indications for renal sparing surgery:
- Solitary kidney
- Horseshoe kidney
- Predisposition for bilateral tumours
- Denys-Drash or Frasier syndrome to delay time to dialysis
Complications:
* Can occur in 20% primary nephrectomy
* Risk factors for complications:
* Intravascular extension into IVC
* Nephrectomy performed through flank
* Advanced local disease
* Resection of other organs
* Tumour >10cm
* Intestinal obstruction
* Intra-op hemorrhage
* Visceral organ damage
* Vascular complication
* Wound infection
* Hernia
Describe the flank radiotherapy technique for Wilm’s tumour
Flank RT
Presim:
* Anaesthetic consult
* renal function
* review preop imaging + surgical report
* Start RT within 10 days postop
Sim:
* Supine, vacbag, may require anaesthetic, CT scan
Volumes:
* Pre-op GTV= pre-op/CT tumour bed + kidney
* Includes the outline of the kidney and the associated tumour
* CTV= pre-op GTV+1cm in all directions
* PTV= CTV+ 1cm
* Boost GTV= residual dx, CTV=GTV+1cm, PTV= CTV+0.5-1cm
Fields:
* AP/PA fields (field based is standard)with field borders at edge of PTV
* Superior, inferior and lateral borders of RT field are placed at edge of PTV
* Medial border extends across midline to include entire VB (with a margin of 1cm) at level concerned but not to overlap contralat kidney
* Need to cover entire vertebral body to avoid abnormal development/growth
* RT field should not extend to the dome of the diaphragm unless tumour extends to that height
* If positive LN have been surgically removed then the entire length of the PA chain from (crus to L5) should be included in RT field
Dose prescription: 10.8Gy/6#/1.8 to MPD, AP/PA fields, 6MV photons. Boost: addit 10.8 Gy
-IF Unfavourable Histology (Diffuse anaplasia, clear cell, rhabdoid) then treat to 19.8Gy
OAR:
* Spinal cord
* Heart (Doxorubicin chemo also)
* Lung
* Contralateral kidney
* liver
* Gonads/Uterus
"these are the OAR and I would refer to COG protocol for dose constraints”
Describe the whole abdomen radiotherapy technique for Wilm’s Tumour
Whole Abdominal RT
Presim:
* Anaesthetic consult
* renal function
* Review preop imaging + surgical report
* MDT discussion
* Exam: assess wound healing
* Explain SE - consent
* Genetic counselling if appropriate
* Family support
* Start RT within 10 days postop
Sim:
* Supine arms above head
* Vacbag
* May require anaesthetics
* Tattoos at level of isocenter midline + L+R lateral
* CT mid thorax to mid pelvis
* Fusion: pre-op imaging
Volumes:
* No GTV
* CTV= entire peritoneal cavity from dome diaphragm to pelvic diaphragm
* Extends laterally to the right and left abdo wall
* AP/PA fields with field borders:
* Sup= 1cm above dome of diaphragm
* Inf= bottom obturator foramen
* Lat= 1cm beyond lateral abdo wall
* Shield femoral heads, acetabulum + testes (boys)
Abdominal boost:
* Boost: GTV: gross peritoneal deposists
* CTV- GTV+5mm
* PTV - CTV+10mm
Dose prescription- 10.5Gy/7# (1.5Gy/F)
* Boost 10.5Gy/7# to the gross peritoneal deposits - total 21Gy/14#
* Block out contralateral kidney after 9Fr (13.5Gy) if treating to 21Gy
Technique:
* WART- MPD, AP/PA fields, 6MV photons, Midline as per ICRU 50
* Abdominal Boost- conformal technique
QA:
* Weekly tx review, history, exam
Target verification:
* Daily KV imaging, bone match, review soft tissue
OAR:
* As per COG protocol
* Contralateral kidney: dmean <14 Gy, ALARA
* Lung <12Gy
* Heart < 15Gy
* Liver 20Gy to 50% of total liver volume
* Ovary/testis ALARA (<5Gy)
Describe the whole lung radiotherapy technique for Wilm’s tumour
Whole Lung RT
Indications:
○ Only pts whose lung mets are NOT in CR after 3-drug chemo on 6 week CT scan
○ Initial tumour size, number of lesions or CT/xray detectability are NOT considerations
Presim:
○ Anaesthetic consult
○ renal function
○ Review preop imaging + surgical report
○ MDT discussion
○ Exam: assess wound healing
○ Explain SE - consent
○ Genetic counselling if appropriate
○ Family support
○ Start RT within 10 days postop
Sim:
○ Supine arms above head, vacbag
○ may require anaesthetic
○ CT +/- contrast if nodes
○ Breath hold technique
○ Fusion with pre-op imaging
Volumes:
○ CTV= both lungs, mediastinum, pleural recesses
○ PTV= CTV+ 0.5 to 1cm (usually 1cm)
○ AP/PA fields with field borders 1cm beyond CTV:
○ Shield shoulder joints
Dose prescription- 12Gy in 8F (1.5Gy/F) to MPD, AP/PA fields, 6MV photons.
○ If <12m then 10.5Gy in 7F
Fields:
○ Both lungs given RT regardless of number and location of mets
○ Superior, inferior and lateral borders are placed 1cm become CTV
○ Superior: above apices of both lungs
○ Inferior: inf extent of ant and post costo-diaphragmatic recesses of pleural cavity should be included ~level of L1
○ Lateral: 1cm beyond thoracic wall
QA:
○ Weekly tx reviews
Target verification:
○ Daily KV images, bone match, review soft tissue
OAR:
○ As above COG protocol
○ Shoulder joints protected by MLC shielding
○ <2/3 of contralat kidney >14.4Gy
<1/2 liver 19.8Gy
Dose constraints
** Localised mets persisting two weeks after delivery of whole lung RT should be excised or given extra 7.5Gy/5# (volume of lung in this boost should be <30% to reduce acute/long term pneumonitis) **
Describe the prognosis and follow up for Wilm’s tumour
5yr OS with treatment >90%. (all comers)
Diffuse anaplastic poor
Pulmonary metastasis: 5% at 10 years
Unilateral WILM: <1% renal failure
Bilateral: 10-15% renal failure
Heart failure: up to 5% (doxorubicin also contributes)
Describe the epidemiology and risk factors for Neuroblastoma.
Incidence
- 40 children diagnosed annually in Australia
- 10% of all childhood malignancies
- most common extra cranial solid tumour
- most common malignancy in <1y
Median age is 18 months
- Exclusively a disease of children (>98% of cases prior to 10yo)
Slight male predominance (1.5:1)
Slight racial difference (white > black)
Most common anatomical sites
- Adrenal (35%)
- Paraspinal ganglia (30%)
- Posterior mediastinum (20%)
- Cervical ganglia (5%)
5year survival 70%
Stage 4 25%
Aetiology
No clear risk factors established
Postulated risks:
- Maternal opiate consumption
- Folate deficiency
- Congenital abnormality
- Size for gestational age
- Gestational diabetes
1% of cases may be familial, these pt tend to be younger at dx
- ALK gene is implicated
○ 75% of familial cases - aberrant activation of gremlin ALK signalling pathway
- PHOX2b mutated (Hirshprung, central hypoventilation, neural crest disorders)
- Li-fraumeni,
- Beckwith- Wiedemann,
- NF1
Describe the pathogenesis and subtypes for neuroblastoma.
Pathogenesis of neuroblastoma:
* Arises from early neural crest precursor cells (fetal adrenergic neuroblasts of neural crest tissues) that undergo transformation from genetic or epigenetic changes leading to blocked or aberrant development
* neural crest is a transient embryologic tissue much migrates out of the neural cord during development→EMT → migrates and forms components of
○ branchial artches
○ cardiac and thoracic vessels
○ SNS
○ adrenal glands
* May arise from any site in the sympathetic nervous system
Molecular Abnormalities:
* Segmental chromosome abberations:
○ deletions (as detected by LOH and segmental chromosome aberrations found in approx 50%
○ localized to chromosomes 1p, 11q, and 14q
* nMYC amplification (increased copy no.) and over expression of oncogene MYCN
○ N-MYC amplification is a key factor in the genesis of NB
○ high levels of MYCN protein→ DNA binding transcription factor known to cause malignant transformation
* Older: TERT promoter rearrangment, ALK copy number and gene amplification,
Subtypes
Spectrum of diseases with differing maturation of embryonal neural crest cells
- Neuroblastoma (malignant) -most undifferentiated
- Ganglioneuroblastoma
- Ganglioneuroma (benign)
arise from primitive sympathetic ganglion cells
Have the capacity to synthesis and secrete catecholamines
Describe the prognostic features for neuroblastoma.
Key Prognostic Factors
- Stage
- Age<1.5
- Favourable histology (Shimada classification)
- N-MYC amplification (One of the defining features for high risk disease)
- alk, TR amplification
- DNA ploidy
- Ferritin, LDH, NSE
Describe the history and classic signs of neuroblastoma.
Consultation
- HPI (UNWELL CHILD) ○ Abdominal symptoms § Pain § Palpable mass § Bloating and distention § Bowel changes ○ Paraneoplastic § Opsoclonus-myoclonus syndrome (jerking random eye movements) § Vasoactive intestinal peptide syndrome (diarrhoea with hypokalaemia) § Flushing from catecolamines ○ Other § Proptosis +/- peri-orbital bruising (metastases obstructing veins) racoon eyes § Bone pain - Examination ○ General wellness of child ○ Abdominal palpation
Classic signs of neuroblastoma:
- Blueberry muffin sign: Nontender blue skin nodules.
- Raccoon eyes: orbital mets with proptosis and bruising.
- Pepper syndrome: Massive involvement of liver with possible respiratory compromise.
- Hutchinson syndrome: Bone pain, refusal to walk, skull masses.
- Kerner-Morrison: Diarrhea, hypoK, due to VIP secretion.
- Opsoclonus-myoclonus-truncal ataxia: a paraneoplastic syndrome of myoclonic jerking and random eye movements that is associated with early stage and may persist after cure.
Describe the workup for neuroblastoma
Work-Up
- Bloods ○ FBC ○ EUC and CMP ○ LFT ○ Serum catecholamines - Urine catecholamines - Initial US imaging - Biopsy ○ Surgical resection should be considered in the setting of localised disease, particularly in the absence of image-defined risk factors (IDRFs) ○ When biopsy rather than upfront resection is indicated, open biopsy may be prefered to get adequate tissue ○ Core biopsy (20 or more samples required) ○ FNA not recommended - Bone marrow biopsy- widespread infiltration with neuroblastoma cells - Imaging ○ Staging CT or MRI (Chest and Abdomen at minimum) § Calcification is classic § Vascular encasement with contralateral extension ○ I-123 MIBG scan § MIBG is an analogue of norepinephrine § If this study is negative (at the primary site also), needs FDG-PET § Also used for progress scans ○ Poor prognosis imaging factors:
Describe the management of very low, low and intermediate risk neuroblastoma
Describe the management of high risk and stage IVS Neuroblastoma.
Describe prognosis and complications from management of neuroblastoma.
Describe the staging for retinoblastoma.
Staging
International classification for Rb specifies 5 groups: (COG)
* Group A- small tumours (<3mm) confined to retina + away from optic n + fovea (critical structures) → Virtually all eyes preserved with good acuity.
* Group B - confined to retina, but larger (>3mm) or close to fovea/optic n→ 95% of eyes preserved, but visual acuity varies depending on location.
* Group C - focal spread (<3mm from Retina) into vitreous or subretinal space→ 80% eyes preserved.
* Group D - diffuse spread (>3mm from Retina) into vitreous or subretinal space→ 60% eyes preserved.
* Group E - Eye destroyed by tumour→ only 2% salvaged.
Describe the pathology for paediatric rhabdomyosarcoma ( Alveolar, Embryonal and sclerosing/spindle).
2 more uncommon subtypes
Pleomorphic (aggressive)
Spindle cell/sclerosing (good prognosis)
Botyroid (grapes) 2-3yo
Risk of nodal spread
- Extremity cases are more likely to have nodal metastases
Alveolar types are more likely to have nodal metastases
Describe favourable and unfavourable paediatric rhabdomyosarcoma.
Primary Site
Stratification of patients based on fusion status as favourable or unfavourable
Favourable = PAX3 or 7/FOXO1 negative ( *Favourable = all embryonal, spindle cells (not MYOD1 mutated), botryoid RMS)
Unfavourable = PAX3 or 7/FOXO1 positive (Unfavourable = all alveolar tumours (including the solid-alveolar variant)
Stratification of size and age
Favourable <5cm and <10 years
unfavourable >5cm and >10 years
Describe the staging for paediatric rhabdomyosarcoma.
Describe the management paradigm for low and standard risk rhabdomyosarcoma.
Describe radiotherapy management of paediatric rhabdomyosarcoma
2) Radiotherapy
- Very Radiosensitive tumours
- Radiotherapy is considered essential to improve LC for most patients with RMS
○ Exception: Clinical group 1, embryonal histology (FOX01 negative) (localised disease with R0 resection)- not RT for this people
- RT for all involved nodes ○ including if resected - RT for metastases for many ○ usually recommended to treat all sites if possible ○ IF FAR-RMS favourable- treat all sites; IF unfavourable- randomised to RT or none to mets - Radiotherapy is given concurrently with chemotherapy ( on week 13) ○ Typically administered after 4 cycles of chemotherapy - Dose and timing of RT dictated by the clinical group Dose: ○ Complete resection (alveolar histo only) → 36Gy/20F 1.8Gy/F ○ Micro residual (N0) → 36Gy/20F ○ Micro residual (N1) → 41.4Gy/23F ○ Macroscopic dx → 50.4Gy/28F (if <5cm) 59.4Gy/33F (>5cm) ○ Orbit 45Gy/25F (some use 50.4Gy as lower LC in IRSV) ○ Metastatic lung/pleural effusion – whole lung 15Gy/10F (12Gy/8F in kids) Timing of RT: Concurrent with chemo ○ Historically upfront for parameningeal or pts with symptomatic cord comp, loss of vision or other function-threatening condition - can consider to delay for appropriate chemo ○ Low risk and Intermediate Risk: Week 13 ○ High risk: Week 20
Describe the radiotherapy technique for paediatric rhabdomyosarcoma.
REMEMBER: RT Timing !!! (this depends on the COG Risk Group)
* If Low/ Intermediate risk- RT at week 13
* If High risk- RT at week 20
○ Everyone resected embryonal with BONG are low risk
○ All alveolar are intermediate risk, unless metastatic
○ All metastatic are high risk, unless embryonal and <10yo
Based on FAR-RMS guidelines
Dose+Technique:
* Prescribed to PTV as per ICRU83, VMAT, 6MV photon, 9F per fortnight
* Concurrent with 3 weekly VAC (vincristine, actinomycin, cyclophosphamide)
* 2 doses level in sequential phases
* Phase 1: 41.4Gy/23F
* Phase 2: boost to 9Gy/5F to total 50.4Gy (if <5cm prechemo) or 18Gy/10F to total 59.4 (if >5cm prechemo)
Volume:
Phase 1 (36 or 41.4Gy):
* GTVpPre: prechemo gross primary
* GTVpPost: residual gross primary after chemo
* GTVnPre: prechemo gross node
* CTV36/41.4: GTVpPre+1cm , ensure to include the nodal basin within 3cm of GTVnPre, GTVpPost+5mm
○ include surgical bed+scar (IF Adj RT) and Bx tract
○ If mets disease at dx, include this in the CTV: met+5mm
* PTV36/41.4: CTV+5mm (adjust according to immobilisation)
Phase 2 [Use if treating > 41.4Gy, except for orbit*, Can boost to 50.4 (<5cm) or 59.4 (>5cm)]
* CTVboost: GTVpPost + 5mm
* PTVboost: CTVboost+5mm (adjust according to immobilisation)
If intracranial involvement then start RT with week 1 or 2 of chemo (<4 weeks)
*If treating the orbit 45Gy/25F, then use only 1 phase
Discuss radiotherapy for specific sites of paediatric rhabdomyosarcoma.
Describe prognosis and follow up for paediatric rhabdomyosarcoma.
Discuss late effects of radiotherapy for paediatric patients, in regards to:
-Ocular
-Hearing
-Pneumonitis
-GU
-Spine
-H&N
- Occular - retinopathy 5% at 42Gy, 50% at62Gy
- Hearing - related to dose and age <5% at <35Gy; 30% at 50Gy
○ 25-40% <5 years, 10% over; severe loss 18Gy higher >3 years
○ HL develops 3 years post RT
○ 300Mg/m2 platinum = 7Gy - Post SCT idiopathic pneumonitis. Post TBI 16%, 50% mortality
○ Steep dose gradient in teens
○ RR 24/Gy - GU <5% renal toxicity with <10/5Gy; 12-14Gy TBI 6-8 moderate, 2-3% renal Failure (* also chemo effects)
- Spine (limited events) 56Gy to Cx cord seems safe (conventional fx)
○ Latency- later with higher dose (doesn’t make much sense)
○ Cord tolerance 39.6 with chemo vs 49.7 without - H&N limited data - reocmmend adult limits (26Gy)
○ teeth <20Gy
○ Dose the back teeth rather than the front (smile)
- Hearing - related to dose and age <5% at <35Gy; 30% at 50Gy
Discuss late effects of radiotherapy for paediatric patients, in regards to:
-Endocrine
-Cardiovascular
-Pulmonary
-Liver
-Brain Re-irradiation
-Secondary malignancies
-Psychosocial
- Endocrine = article central endocrine complications among childhood cancer survivors
○ GH D50 24.9-27Gy, 5% with 15Gy and 6.5 % per Gy at 24 Gy
§ TSH D50 39Gy; 20% at 22Gy
§ ACTH D50 61Gy and 20% at 34Gy
○ Primary thryoid = higher in girlds and >15Gy
○ Male reproductive - 44-88Gy oligospermia <1Gy with 75-100% recoivery at 12 months, over 1Gy 90% at 12 months
○ Female reproductive - look at article- Cardiovascular for every 10Gy increase in mean cardiac radiatgion dose, HR of 2.01 for CAD
○ 1.87 for HF, and valvular disease, 1.88 for any cardiac disease
§ For each 100mg/m2 increase in cumulative anthraacycline dose, the HR for HR was 1.93; Approx 10.5Gy
§ Dose <10Gy with no antracyclines, minimal risk - Pulmonary
○ RP risk after partial thoracic RTR with mean lung dose MLD <14Gy and total V20Gy <30 is low
○ Pt often aasymptomatic; abnormal PFTs common and severity correlates with lung dose - Liver
○ Hepatic sinusoidail obstructive syndrome - Reirradiation
○ Recurrent brain tumours, re-irradiation with total EQD2/2 of about 112Gy is associated with less thhan 5-6% incident of brain/brainstem necrosis with conventional prescruption doses after meddian 2.3 years - Secondary malignancies
○ Pooled EOR/Gy for meningiomas 0.45
○ Malignant CS tumours 0.16
○ Sarcoma 0.12
○ Lung 0.14
○ Seems more related to high dose region
○ RR rises with dose , except for thyroid (after which dose becomes ablative)
○ Chemo aslo increases risks for some - Pschosocial
○ Less likely to complete education
○ Attain emploiyment
○ Marry - Impaired neurocognition/iQ
- Cardiovascular for every 10Gy increase in mean cardiac radiatgion dose, HR of 2.01 for CAD
