Malignant Rhabdoid Tumor of the Liver

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Malignant Rhabdoid Tumor of the Liver

• Sharon McDonald, M.D.Pediatric
  Hematology/Oncology Fellow
• March 7, 2008

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Case presentation

• 7 month old male
• Previously healthy
• Presented to PMD
• F/U after 3 day gastroenteritis illness
• Exam hepatomegaly
• Ultrasound showed 2 liver masses
• Referred to SLCH

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Case presentation

• PMHx
• 36wk newborn, C/S (breech), hyperbilirubinemia
• Family
• No liver disease
• Paternal grandmother skin/breast/lung/cervical
  CA
• Paternal aunt Crohns disease
• Maternal grandmother peptic ulcer disease
• Meds None
• All NKDA

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Case presentation

• T 36.1, HR 145, RR 48, BP 105/69
• Wt 7.75 kg (25th), Ht 68.5 cm (50th), HC 42.8 cm
• Exam normal except hepatomegaly (3 cm down)
• Labs
• CMP normal except ALT 53 (ULN 50)
• Coags normal
• CBC WBC 29.6, Hgb 10.2, Hct 31.9, Plts 693,
  diff of 17 N, 68 L, 5 M, 10 E.
• U/A normal
• LDH 544 (130-400), Uric acid 2.5 (normal)
• AFP 57.2 (0-8.1 ng/mL)

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Case presentation

• Abdominal CT performed 2 liver masses seen
• Larger mass 9.5 cm x 6.6 cm x 10 cm in size, in
  the right hepatic lobe and medial segment of the
  left hepatic lobe.
• Smaller mass posteriorly 2.4 cm x 1.7 cm x 1.6 cm

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Case presentation

• Open biopsy done
• Diffuse infiltration of primitive neoplastic
  cells with variable, clear cytoplasm and large
  nuclei with prominent nucleoli. Focal areas of
  necrosis.
• Immunohistochemical stains
• Diffuse and intense cytoplasmic positivity for
  vimentin
• Diffuse cytoplasm positivity for CAM 5.2
• These highlight filamentous influsions
• CD99 diffuse membrane positivity
• AFP/desmin negative
• BAF47 loss of nuclear staining in neoplastic
  tissue, preserved in other liver structures
• Overall consistent with Malignant Rhabdoid Tumor

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Malignant Rhabdoid Tumor

• Originally described as a renal tumor
• Beckwith/Palmer (1978) in Cancer
• Variant of Wilms tumor
• Seen in CNS
• Atypical teratoid rhabdoid
• Atypical locations
• Liver, pelvis, skin, neck, lungs, etc.
• Soft tissues

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MRT of the liver

• First case described by Gonzalez-Crussi in 1982
• 25 cases in literature
• Rare and highly aggressive
• Primarily seen in infants
• Median age at diagnosis 11 months
• Median survival after diagnosis 15 weeks

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(No Transcript)
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Pathology

• Vesicular nuclei, prominent nucleoli,
  eosinophilic cytoplasmic inclusions
• Staining positive for cytokeratin, epithelial
  membrane antigen, vimentin. Negative for INI1
  protein.

a) Vimentin. b) CK8. c) CK18. d) CK7
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Genetics

• Chromosome 22q11.2
• Versteege in 1998
• Mapped most frequent deletion in 13 MRT cell
  lines biallelic, truncating mutations
• SNF5/INI1 gene 9 exons, 50 kb
• Encodes subunit of SWI/SNF chromatin-remodeling
  complexes
• Creates stable form of chromatin
• Tumor suppressor gene
• Now named SMARCB1 gene (SWI/SNF related,
  Matrix-associated, Actin-dependent Regulator of
  Chromatin)

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SNF5 gene

• Mouse model (Roberts in 2000)
• Widely expressed during embryogenesis with high
  expression in 1st branchial arch and CNS
• Homozygous knock out lethal by embryonic day 7
• Heterozygous not lethal but as early as 5
  weeks MRT tumors, mostly from areas of the 1st
  branchial arch

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SNF5/INI1 Gene
Versteege in 1998 6 homozygous
deletions Frameshift/nonsense in 6 other cell
lines Truncating mutations of one allele assoc
with loss of other allele. Did not see
corresponding deletions in constitutional DNA.
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Genetics
Al Knudson, MD

• Sevenet (1999)
• ?Germline mutation (Knudson 2-hit model)
• Looked at tumor and constitutional DNA
• Found that could see same mutation in both with
  normal alleles in the parents
• Ped-4 shows same mutation in two different tumors
  as well as constitutionally

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Current treatment

• In my patient
• Tumor extensive and unresectable
• Liver transplant will be carried out after 4
  courses of chemotherapy given
• Was placed on AREN0321 (high risk renal tumor
  study) allows for MRTs of the kidney and
  extra-renal sites excluding CNS

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Current treatment

• Window therapy with weekly VCR and 2 week course
  of irinotecan up front for unresectable MRTs and
  stage IV diffuse anaplastic Wilm's
• However, window had closed because patients
  placed on it had progressed despite the treatment
• So he went directly to UH-1 regimen

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AREN0312UH-1 Regimen
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Future treatments

• Flavopiridol
• Synthetic flavonoid derived from rohitukine
  (medicinal plant in India)
• Being developed by Aventis
• Originally looked at in CLL
• First cyclin dependent kinase (cdk) inhibitor
• Competitive inhibitor of multiple cdks
• Binds to ATP binding site
• Arrests the cell cycle at G1 or G2
• Reintroduction of INI1 induces G0/G1 arrest,
  activates cdk inhibitors p16 and p21

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Flavopiridol

• Recently in Clin Cancer Res (1/15/08)
• Tested in vitro with rhabdoid tumor cell lines
  and in vivo with xenografted tumor models

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IC50 200 nmol/L Increased exposure to drug
improves percentage killing
Cells arrested at G2 at lower concentrations and
G1 at higher concentrations.
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In vivo Studies

• MRT cells inoculated into SCID mice and tumors
  established
• Treatment 2.5 or 5 mg/kg 5 days/week for 3 weeks
  ? minimal effect on tumor growth
• Increased to 7.5 mg/kg 5 days/week for 2 weeks ?
  significant inhibition (based on tumor weight and
  volume)

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Flavopiridol

• Phase 1 trials
• Adult MTD 40 mg/m2/day x3 doses
• Dose limiting toxicity secretory diarrhea
• Higher MTD achieved with prophylaxis
• In children
• Toxicity profile, kinetics, MTD similar to adults
• MTD 62.5 mg/m2/day (without prophylaxis) and 80
  mg/m2/day (with prophylaxis) (given for 3 days)