ANAPLASTIC THYROID CANCER

1
ANAPLASTIC THYROID CANCER

• Sam J. Cunningham, MD, PhD
• Francis B. Quinn, Jr., MD
• UTMB Dept of Otolaryngology
• May 11, 2005

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Anaplastic Thyroid Cancer (APC)

• One of the most aggressive malignancies
• Survival measured in months
• Rare (2 per million per year)
• 1.6 of all thyroid cancers
• Often associated with well differentiated thyroid
  cancers (evidence of dedifferentiation, lt1)
• History
• Path
• Incidence declining
• IHC staining in 80s
• Iodination of food
• More aggressive treatment on WDTC

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Clinical Presentation

• 60s-70s
• 55-77 female
• Most patients present with rapidly enlarging neck
  mass (mean size at presentation 8cm)
• Some incidentally discovered
• Local compressive symptoms
• Cervical lymphadenopathy in gt40
• 30 with TVC paralysis
• 90 with direct invasion
• 50 present with distant metastasis
• 75 develop distant mets during course of disease
• Lung 80, Bone 6-15, Brain 5-13, Intestine

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Diagnosis

• FNA accurate in 90
• Unencapsulated
• Tan-white
• Direct extension into soft tissues
• No radioactive iodine uptake
• CT to eval extent

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Pathology

• Microscopically 3 histologic patterns (no
  prognostic difference)
• Spindle
• Giant-cell
• Squamoid
• Previous nomenclature
• Small cell (lymphoma)
• Insular cell (morphology)

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Molecular Pathology

• NM23 deletion
• Metastasis suppressor gene
• P53 mutants found in 14 of all thyroid
  cancers-more commonly in APC
• Loss of genome stability

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Prognostic Factors

• Distant mets (Vankatesh) 8mos vs 3mos
• Acute symptoms, tumor gt5cm, distant mets,
  leukocytosis (Sugitani) Multivariate analysis
  reveals each an independent risk factor
• Longer duration of symptoms, tumor lt10cm,
  incidental findings within WDTC (Ojeda) better
  prognosis overall

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Treatment

• Surgery
• Radiation
• Chemotherapy
• Multimodality

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Surgery Controversial

• Mayo Clinic 50 year experience (134pts)
• Neither the extent of operation nor the
  completeness of resection had a significant
  impact on survival

• Kobayashi 37 patients
• Removal of macroscopic disease increased survival
  from 2mos to 6mos

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Radiotherapy

• Local control
• ATC relatively radioresistent
• Treatment morbidity
• Palliative local control achieved 68-80
• Levendag 51 patients receiving gt30Gy had median
  survival of 3.3months. lt30Gy had median survival
  of 0.6months.
• Junor no survival benefit with radiation
  therapy, despite 80 initial response and 39
  initial complete response.

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Chemotherapy Monotherapy

• Treatment of distant mets
• Unsuccessful at altering the fatal outcome of ATC
• Doxorubicin (most frequent) lt20 response rate
  and no evidence of complete response.
• Ain 53 response rate in a Phase II trial using
  paclitaxel.
• All eventually died of their disease
• Median survival 24 weeks
• Responders to paclitaxel32 weeks,
  nonresponders7weeks.
• Stimulated further study

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Chemotherapy Combination

• Doxirubicin, bleomycin, cyclophosphamide
  combination very little effect in multiple
  studies
• Yeung combination of paclitaxel and manumycin
  (farnesyprotein transferase inhibitor) enhanced
  cytotoxic effect and increased apoptotic cell
  death in vitro and in vivo.
• Inhibits angiogenesis
• Apoptosis regulatory pathway.

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Multimodality Therapy

• Tennvall 33patients treated with
  hyperfractionated radiotherapy, doxorubicin
  followed by surgical debulking.
• Local control achieved 50
• Only 24 death due to local failure
• Median survival only 4.5 mos
• Only 4 survived gt2years

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Multimodality Therapy

• Sugino 40 patients retrospectively evaluated
• Improved 1 year survival with surgical debulking
  radiation vs radiation only (60 vs 20)
• Debulking thyroidectomy for WDTC with foci of
  ATC

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Multimodality Therapy

• MD Anderson121 patients
• 12 patients with complete macroscopic resection
  of tumor survived longer than 24mos.
• 10/12 post op chemo and radiation

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Multimodality Therapy

• Haigh 26 patients surgical resection
  (retrospective)
• 8 resection for cure, no residual or minimal
  residual disease
• Median survival 43 months
• 18 palliative resection
• Median survival 3 months
• Both groups received post op radiation,
  chemotherapy or both.
• Selection bias

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Future Investigations

• More detailed understanding of dedifferentiation
  at the molecular level
• Better understanding of genes involved in
  regulatory pathways
• Chromosome mapping studies
• Chromosome 7 and 16
• Clinical trials involving gene therapy

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Current Molecular Investigations

• Adenovirus-mediated p53 gene therapy shown to
  increase chemosensitivity to adriamycin and
  doxorubicin
• Bone morphogenic protein (BMP-7) shown to inhibit
  proliferation of ATC cells by G1 arrest
• Bovine seminal ribonuclease induced highest rate
  of apoptosis in ATC cells
• Injection into nude mice with established ATC
  tumors resulted in complete regression of tumor

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Current Molecular Investigations cont.

• Histone deacetylase inhibitors promote apoptosis
  and differential cell cycle arrest in ATC cells
• Human sodium iodide symporter (hNIS) when
  transfected into ATC cells, in vitro and in vivo,
  established uptake of iodide.

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Summary

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