Small Blue Cells

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• Small Blue Cells
• Not always lymphoma

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Case

• 21 year old with no PMH who noted increasing
  abdominal girth and pain
• Within 1 week of diagnosis, patient had increased
  abdominal distention, palpable masses now on exam

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Radiology
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Pathology nests of PD small round blue cells
with an increased mitotic activity surrounded by
a prominent desmoplastic stroma
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Differential

• Small cell carcinomas
• Lymphomas (Burkitts)
• melanoma
• PNET
• Ewing sarcoma
• Rhabdomyosarcoma
• Mesenchymal chondrosarcoma
• Small cell osteosarcoma
• Neuroblastoma

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Pathology

• IHC trilineage coexpression
• epithelial (cytokeratin, EMA)
• mesenchymatous (desmin, vimentin)
• neural (NSE)
• Negative for CD3,20, 45, 30
• Our patient
• Strongly cytokeratin, vimentin, desmin positive

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Desmoplastic small round cell tumors

• Type of primitive sarcoma
• First described in 1989
• more than 150 cases reported
• Usually adolescents and Male
• Mean age 22 4.71 males females
• Occurs in the abdominal cavity and peritoneal
  surfaces multifocal local recurrences
• Very aggressive with poor prognosis (lt2yr)

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MSKCC and Mayo Data

• MCKCC
• Largest series of patients (n109)
• 90 males 19 females
• ages 6-49 years old median 22 years
• 103 had abdominal cavity lesion
• 4 thoracic, 1 intracranial, and 1 hand
• Mayo
• 32 patients 29 males, 3 females 25 yrs old
• 88 had abd origin, 1 ethmoid, 1 scalp/BM

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MSKCC and Mayo Clinic Data
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Cytogenetics

• First described in 1992
• 45 pts had a reciprocal translocation
  t(1122)(p13q12)
• 2 variant translocations have since been
  described (found in 5 of cases)

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Characterization of Translocation(Ladanyi and
Gerald Cancer Reasearch 1994)

• EWS is at 22q12
• involved in 3 sarcoma-associated translocations
• They took 5 DSRCTs and candidate genes and used
  Southern blot
• Both EWS and WT1 were rearranged
• They co-migrated together indicating fusion
• Northern blot showed aberrant EWS and WT1
  transcripts of the same size suggesting chimeric
  protein
• This was confirmed by RT-PCR using exon7 EWS and
  exon 8,9 WT1

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Southern Blots of EWS and WT1
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Characterization of Translocation(Candidate Gene
Approach)(Ladanyi and Gerald Cancer Reasearch
1994)

• WT1 is at 11p13 involved in primitive tumor
• Encodes a protein product with 4 zinc fingers
  (DNA binding) and acts as TSG
• Has 2 isoforms due to alternative splicing
• The chimeric RNA encoded a protein in which the
  RNA binding domain of EWS is replaced by the 3
  carboxy terminal zinc fingers of the WT1 DNA
  binding domain

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Fusion of EWS with WT1
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EWS-WT1

• The hallmark of DSRCTs (pathognomonic)
• 2 isoforms due to alternative splicing
• 5'EWS- 3'WT1(-KTS) has ability to transform cells
  in vitro
• Many target genes that are deregulated and play a
  role in the tumorigenesis of DSCRT

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PDGFa as a target of EWS-WT1(Lee et al Nature
Genetics 1997)

• Osteosarcoma cell lines inducible for ETS-WT1
  upregulated PDGFa expression 10fold
• PDGFa is not normally regulated by WT-1
• PDGFa is expressed within tumor cells of DSRCTs
  but NOT Wilms tumor or Ewing sarcomas (with
  EWS-FLI)
• The oncogenic fusion results in induction of
  PDGFa which a a potent fibroblast growth factor
  that contribute to the fibrosis assoc with this
  tumor
• The reciprocal fusion product is not detectable
  indicating this one alone underlies the
  pathogenesis of DSRCTS

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IGF-1R promoter and EWS-WT1(Karneili et al J
Biol Chem 1996)

• Wild type WT-1 binds and represses IGF-1R
  promoter
• Co-transfected osterosarcoma cell lines with
  IGF1R promoter
• Fusion protein activates it 340 over controls
  (if KTS-) illustrating a gain-of-function
  mutation

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IGF-1R activity
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Clinical Data

• 35 overall progression-free survival at 5 yrs
  median survival of about 17 months, although
  tumors are responsive to aggressive therapy in
  some cases

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MSKCC P6 protocol

• 12 patients (10 untreated 2 previously trt)
• 7 courses of chemotherapy
• Course 1,2,3, and 6
• CTX 2.1g/m2/d over 6 hours day 1,2
• Adria 25mg/m2/d civi over 3 days
• VCR .67/m2/d civi for 3 days
• Course 4,5, and 7
• Ifos 9g/m2 (1.8/m2/d for 5 days)
• VP16 500/m2 (100/m2 over 5 days)
• Courses started when ANC gt500 and plt 100K

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MSKCC P6 protocol

• Post treatment options
• Thiotepa 900/m2 carbo 1500/m2 with SCT (n4)
• Radiotherapy (n5)
• Surgery of residual mass (n11)

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MSKCC P6 protocolResults

• 12 patients 11 males 1 female
• Age range 7-22 years (median 14 years)
• Of untreated patients
• 7 CRs after chemo and surgery
• 5 pts in CR 9,12,13,33,and 38 months from start
• 1 died in CR at 12 months from infection
• 1 relapsed after 4 months off treatment
• 2 PRs (1 pt had SCT and PD and 1pt had slow
  disease progression on single agents)
• Of previously treated patients
• Both in PR after chemo
• 1 had SCT but PD 4 months later
• 1 pt had PFS at 34 months

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MSKCC P6 protocolResults

• Posttreatment
• 5 got XRT
• 2 had PR
• 4 got SCT
• 2 had CR at 13 and 34 months
• 2 had measurable disease that did not respond
• Toxicity
• Intensive transfusions and Abx needed
• Grade 3-4 mucositis occurred regularly
• Grade 3-4 hepatotoxicity in 1 pt

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Whole Abdominopelvic Radiation

• MSKCC (where else!)
• 21 patients retrospectively studied
• 7 cycles of P6 protocol between 1992-2001
• Followed by surgical debulking and 30Gy
• Median follow up 28 months

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Whole Abdominopelvic Radiation

• Results
• 3 yr OS 48 median 32 months
• 3 yr RFS 19 median 19 months
• Toxicity
• Grade 2 GI toxicity approximately 75
• Grade 4 thrombocytopenia 76
• Grade 4 anemia 33
• SBO 33 after surgery and radiation

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Our case

• Treated with Adria/Ifos for 2 cycles but
  developed Ifos toxicity (encephalopathy) on day 2
• Switched to Adria/CTX with partial response on CT
• VAC for 5 cycles -- decrease in majority of
  liver lesions but increase in one (8-9cm)
• Abdominal lesion now 4.5cm
• MDACC consult this week

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• The End