Poorly Differentiated Thyroid Cancer (THPD)

Overview

Poorly differentiated thyroid carcinoma (PDTC) is an intermediate-grade follicular-cell-derived thyroid malignancy that sits between well-differentiated (papillary, follicular) and anaplastic thyroid cancers in the OncoTree hierarchy (parent: THYROID). It is defined histologically by two competing diagnostic criteria: the Turin proposal (solid/nested/insular growth + absent papillary nuclear features + mitoses ≥3/10 HPF or necrosis) and the MSKCC criteria (≥5 mitoses/10 HPF and/or necrosis with follicular differentiation, irrespective of growth pattern). These criteria select biologically distinct sub-populations — Turin enriches for RAS-driven tumors with distant-metastasis tropism, while MSKCC enriches for BRAF-driven tumors with locoregional-nodal tropism.

Cohorts in the corpus

  • thyroid_mskcc_2016: 84 PDTC tumors (plus 33 ATC) profiled by MSK-IMPACT 341-gene panel; 80 FFPE + 37 frozen; paired normal available for 78 PDTC PMID:26878173

Recurrent alterations

  • BRAF V600E in 33% of PDTC; BRAF-mutant PDTCs are smaller, more often nodal-metastatic, and classified predominantly by MSKCC criteria PMID:26878173
  • NRAS/HRAS/KRAS collectively in 28% of PDTC; mutually exclusive with BRAF and gene fusions; RAS-mutant PDTCs meet Turin criteria and tend toward distant metastasis PMID:26878173
  • TERT promoter mutations (C228T or C250T) in 40% of PDTC, stepwise enriched from 9% in PTC; clonal in PDTC vs subclonal in PTC; co-occurs with BRAF/RAS (OR 3.4, P=0.004); TERT-mutant PDTCs develop more distant metastases (56% vs 20%, P=0.01) PMID:26878173
  • EIF1AX mutated in 11% of PDTC via N-terminal hotspot or thyroid-specific p.A113splice site; near-perfect co-occurrence with RAS (OR 58.3, P<0.001); associated with shorter survival (logrank P=0.048) PMID:26878173
  • TP53 mutated in only 8% of PDTC (vs 73% in ATC; P<1×10⁻⁴) — a key feature distinguishing PDTC from anaplastic thyroid cancer PMID:26878173
  • PI3K/AKT/mTOR pathway (PIK3CA, PTEN, MTOR, etc.) disrupted in 11% of PDTC PMID:26878173
  • SWI/SNF complex alterations in 6% of PDTC; histone-methyltransferase mutations in 7% PMID:26878173
  • Gene fusions in 14% of PDTC (RET/PTC, PAX8-PPARG, ALK rearrangements); absent in ATC; mutually exclusive with BRAF/RAS PMID:26878173
  • Median mutation burden 2 mutations (across 341 genes) vs 6 in ATC and 1 in PTC; higher burden correlates with older age, larger tumor, distant metastasis, and worse survival PMID:26878173

Subtypes

  • Turin-PDTC: predominantly RAS-mutant, distant-metastasis tropism, larger tumors PMID:26878173
  • MSKCC-PDTC: predominantly BRAF-mutant, locoregional-nodal tropism, smaller tumors, female-enriched (P=0.005) PMID:26878173
  • TERT+BRAF/RAS double-mutant: extreme-risk sub-group with high rate of distant metastasis and shorter survival PMID:26878173

Therapeutic landscape

  • BRAF-V600E prevalence (33%) supports consideration of BRAF-inhibitor strategies PMID:26878173
  • PI3K/AKT/mTOR pathway alterations (11%) suggest potential for pathway inhibitors PMID:26878173
  • No drugs were administered or tracked in the MSKCC sequencing study; all therapeutic implications are inferred PMID:26878173

Sources

  • PMID:26878173 — Landa et al., MSKCC MSK-IMPACT sequencing of 84 PDTC and 33 ATC

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