20.06.22 Paediatric tumours

Question 1

What are malignant small round cell tumours

Answer 1

• Characterised by small round, relatively undifferentiated cells that arise from primitive embryonal cells.
• Cytologically: uniform population of round-oval cells that stain blue on H&E sections. High nuclear to cytoplasmic ratio
• e.g. Ewing sarcoma, rhabdomyosarcoma, retinoblastoma, medulloblastoma, Non-Hodgkin’s lymphoma

Question 2

Why is a multimodal approach important for diagnosis

Answer 2

• Due to the primitive undifferentiated character, differential diagnosis is limited
• Useful techniques= IHC, flow cytometry, PCR-based techniques (MLPA, rt-PCR), FISH, electron microscopy.

Question 3

Review of Ewing sarcoma

Answer 3

• 2nd most common sarcoma in bone and soft tissue in children. Occurs in 2nd decade of life
• Predominates in second decade of life.
• Pelvis and femur are most commonly affected sites.
• Recurrent t(11;22)(q24;q12) (85% cases) EWS-FLI1
• Amino terminal transcriptional activation domain of EWS with ETS DNA binding domain.
• Fusion genes act as aberrant transcription factors, deregulating oncogenic target genes.
• Chromosome banding, interphase FISH, RT-PCR, S. blotting.

Question 4

Review of rhadomyosarcoma

Answer 4

• Most common soft tissue sarcoma in children.
• Arise from skeletal muscle progenitors.
• Embryonal (60% cases). Isodisomic 11p of paternal origin. Allelic loss of maternal 11p15.5 and overexpression of IGF2 locus. Seen in Beckwith Wiedmann syndrome.
• alveolar (20-40%). Poor prognosis. Recurrent t(2;13)(q35;q14) in 60% cases. PAX3 DNA binding domain with FOXO1A transactivation domain. Potent transcriptional activator
• Translocation detected by FISH, G-banding, RT-PCR

Question 5

Review of Wilms Tumor

Answer 5

• Malignant neoplasm of kidney, most common renal tumour in children.
• 1:10,000
• WT1 (11p13) is altered in 20% cases. A transcription factor, critical to kidney and gonad development.
• WAGR (Wilms tumour, aniridia, genital anomalies and retardation) is caused by contiguous deletion at 11p13 (involving WT1 and PAX6).
• UPD of 11p15.5. causes BWS, 7% have Wilms Tumor.
• Sequencing of WT1, methylation of 11p15.5, array for WAGR.

Question 6

Review of retinoblastoma

Answer 6

• Malignant tumour occurring in the embryonic neural retina.
• 1 in 15-20,000 live births.
• RB1 (13q14)
• 40% cases are hereditary. 1 inherited+ 1 somatic mutation/LOH (60%)/hypermethylation of CpG island 5’ to RB1.
• Basis for Knudson’s two hit hypothesis of carcinogenesis. Disease develops due to inactivation of both alleles of RB1 (tumour suppressor)
• RB1 binds to transcription factor E2F, repressing transcription of genes needed for S phase.
• Non-hereditary RB: 2 somatic mutations. Risk of second malignancy is not increased.
• Mutation analysis of blood, but to identify 2nd hit, need tumour sample (not always possible). MLPA, genotyping of polymorphic loci within/flanking RB1 to identify LOH, MS-MLPA, cytogenetic analysis for rearrangements involving 13q14

Question 7

Review of neuroblastoma

Answer 7

• 3rd most common solid malignant tumour of infancy (7-10% of paed malignancy)
• Arises from neuroblasts (neural crest-derived cells) that form sympatheitc nervous system in embryo.
• 1% are familial. Due to activating mutations in ALK (2p23) or PHOX2B. AD.
• Gain of chr 17 is most common finding, although only unbalanced gains result in poor prognosis. Or MYCN amplification.
• Near triploid occurs in 55% (good prognosis)
• DI/tetrapolid in 45% (poor prognosis)
• Interphase FISH, MLPA, karyotype.

Question 8

Review of synovial sarcoma

Answer 8

• Mesenchymal spindle cell tumour with variable epithelial differentiation
• 5-10% of soft tissue sarcoma
• Characterised by t(x;18)(p11;q11) SYT- SSX1 (75%) or SYT- SSX2 (25%)
• FISH, RT-PCR for rapid diagnosis.

Question 9

Medulloblastoma

Answer 9

• Malignant invasive embryonal tumour of cerebellum
• Isochromosome 17q in 50% cases.
• Amplification of MYC (10-20% cases) associated with poor prognosis.