Bones,Moans &Groans

8/4/2019 Bones,Moans &Groans

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Dr. Najat Mahdi

Dr. Jinan Darwish

31.3.2010

Groans, moans & bones


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A. H. (060109114)

4 year old Bahraini malek/c/o G6PD reduced activity; sct

Admission one: 8 dec, 2009

Admission two: 26th dec, 2009

admissions


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Intermittent fever two monthsWeight loss and anorexia two

months

Bone pain in right shoulder&arm

one month then both legs onemonth

Pallor one month

Right thigh & hip pain three days


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Negative hx for :

Joint swelling

Morning stiffness

Rash

Red eyes

Trauma


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Fever

Bone pain

weightloss


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Clinical exam

Pale

Temp 38.5 hR 160bpm

Cvs tachycardic

GIT abdomen distended, no splenomegaly

Heent, resp,cns, all unremarkable

MS : Limitation of walking, tenderness over

back & legs

Eyes no raccoon eyes, fundoscopyunremarkable, normal vision

No LN,no splenomegaly


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PMHx

DOB 27.01.06

FT LSCS (previous LSCS for triplets)

Uneventful pregnancy

Birthweight 3kg

Vaccinated up to age

Normal developmental milestones

NKDA

Blood transfusion

Meds: Elemental iron, Naproxen, Alludrox

Managed as Juvenille Rheumatoid Arthritis


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Family & social Hx

Non-consaginous parents

Mother G6PD reduced activity and SCT

Father policeman

Mother housewife

Triplet elder sisters


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what would you order?


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Hb 6.1 g/dl plt 313 x 109/l wcc

13.2 x 109/l LDH 1446u/l. HPLC

Hb S/A G6PD reduced activity


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VMA

spot VMA

Vma/cr 33.3

umol/mmol of cr

(2.3-4.30)


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Immunohistochemistry&

Immunophenotyping

Strongly positive Neuron specific

enolase

Negative CD 99

Negative Desmin increase in b-cells expressing cd19

41% &cd20 36%

Negative cd10,hla dr & cd 34


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Contrast enhanced CT

abdomen 31.12.09

Multiple enlarged LN in pre, paraaortic &

aortcaval area encasing IVC, right renal vein &

artery.One shows central necrosis.

Biopsy was advised to differentiate it fromneuroblastoma.


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Bone scan 07.01.10

Wide spread bone infiltration involving axial &

peripheral skeleton


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Bone marrow differential

60% blastoid cells Morphologic features

suggestive of marrow

infiltration by

neoplastic cells of asmall round blue cell

tumour


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Investigations

Bilateral bone marrow trephine biopsies: extensive infiltration

of marrow

neoplastic cells with hyperchromatic nuclei,scant cytoplasm

Fibrillary backgroundOcassional ill-defined rosettes

Infiltration of marrow by metastatic neuroblastoma


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FISH karyotype

46, XY [19]

17 (t(15;17) (q22;21))

Normal diploid signal pattern

No fusion signals were observed


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Tumour markers

Neurone specific endolase 36.8 ng/ml (

less than 12.5; borderline 12.5-20)


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Diagnosis Stage 4 Neuroblastoma withprimary site at retroperitoneal

sympathetic chain with mets tobone & bone marrow


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Rx

High risk neuroblastoma protocol

Memorial Sloan-Kettering Cancer Center

regimen

Five cycles combined chemRx Stem cell collection post 3rd/4th cycle (clear

BM)

Residual primary tumour resection + high

dose chemoRx Autologous stem cell transplant (

Singapore- Parkway center)


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Most common extracranial solid tumor in children

The minimum criterion for a diagnosis:

Unequivocal pathologic diagnosis

tumor tissue light microscopy

(+/- immunohistology, electron microscopy, or increased serum

catecholamines or urinary catecholamine metabolites).

C

ombination of bone marrow aspirate or trephine biopsycontaining unequivocal tumor cells (e.g., syncytia or

immunocytologically-positive clumps of cells) & increased levels of

serum catecholamines or urinary catecholamine metabolites


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Neuroblastoma

8-10% of childhood cancers

90-95% of cases diagnosed before age 10

More common in boys and Caucasians

? Genetic

Polymorphism chromosome 6p22 clinically aggressive

Germline deletion at the 1p36 or 11q14-23 locus

primary cause of familial-germline mutation in the ALKgene

environmental factors


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Epidemiology

Most common cancer in children < 1

y.o.

2/3 are in children < 5 y.o.

70% of all patients have mets at dx One of the small blue round cell

tumors

[leukemia, lymphoma, Ewing/PNET,

RMS, Wilms, desmoplastic]


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Neuroblastoma

Evaluation

H x & P/E

Biopsy Urine catecholamine studies

Metastatic work up

CXR

Bone marrow biopsy Bone scan

CT or MRI


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Clinical findings

Most common: masseffect sxs, bone pain,proptosis/periorbitalecchymoses from

retrobulbar mets Can invade neural

foramina, paralysis

Less commonly: fever,

anemia, HTN Rarely: VIP secretion

diarrhea, cerebellarataxia,

opsoclonus/myoclonus


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Work-up is therefore:

mIBG (meta-iodo-benzyl guanidine)

scan or bone scan

CT/MR to look for nodes and evaluate

liver

CXR

Catecholamines

Tumor biology, at least for myc-n andploidy

BMA and Bx

Path on any relevant nodes (if not already

stage 4)


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Neuroblastoma

Small blue round cell tumor

Immunohistochemical stains:

neurofilament proteins,synaptophysin, NSE

Electron microscopy:

neurosecretory granules,

microtubules and filaments

Chromosome 1 deletions orN-

myconcogene amplification

From, Principles and Practice of Pediatric Oncology, Lippincott Williams & Wilkins,p 903.


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Neuroblastoma

Treatment

Surgery

Chemotherapy Intermediate- or High-risk

Low-risk with recurrence

Cyclophosphamide, ifosfamide, doxorubicin,

teniposide, etoposide, cisplatin or carboplatin Radiation Therapy

Limited use


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Prognostic factors

Tumor grade

DNA ploidy -hyperdiploid cells are

associated with earlier stages of disease,

better response to therapy, and thus agenerally better outcome than diploid cells.

Cytogenetics-46 chromosomes more

aggressive ; "1p deletions" or "11q

deletions" have a worse prognosis


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Prognostic factors Stage (males present

later, but o/w male isnot worse)

Age (


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Shimada

Favorable Unfavorable

Age > 5y

Age


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Prognostic factors, cont.

Biology, esp. myc-n but also:

Good: hyperdiploidy, TRK-A (high-affinity nerve growthfactor receptor, proto-oncogene), LNGFR, HA-ras p 21

Bad: 1p-, 17/17q-, B-myb oncogene, increasedtelomerase RNA (hTR), high ferritin, neuron-specificenolase, high LDH, low tumor CD44

NOT catecholamine levels


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Treatment and Prognosis

1: > 90%, still good even with local recurrence.Surgery only UNLESS: age > 2y, myc-namplified, unfavorable histology, ? +LN

2: 75-90%. Bx/surg, chemo (4-6 mos ofCTX/DOX), then definitive surg.

3, 1y: 50-70%. Surg + chemo, +/- XRT. Mayneed SCT if myc-n amplified.


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Rx and Px, cont.

4, 1y: 10-40%, avg. 15%*; SCT better than

chemo alone 4S: 57-100%, better if no sxs

Recurrent Dz: bad if disseminated; usuallydisseminated. CNS involvement common,UNLIKE at primary Dx.


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Prognosis

5-year survival by age: children younger than age 1 -

83%

children between 1 and 4 years

old - 55%

children 5 years and older - 40%

10-year (long-term) survival by

risk group:

Low-risk children - 95%

Intermediate-risk children - 80%

High-risk children - 30%


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Summary

Common as paediatric solid tumors

go Excellent Px in infants without myc-n

amplification

Current Px on the new high-risk

protocol is generally being quotedaround 30-40%

Incredibly variable clinical course,largely based on tumor biology, has

made this an attractive tumor tostudy look for a vaccine protocolto come down the pike in the nextfew years.


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Take home message

Fever with bony pain mandates early

haematologist consultation.

Multidisciplinary evaluation and appropriate

care is essential. tumour samples for biologic

Studies for risk-assignment and

administration of appropriate therapy


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Discussion

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