Encapsulated Thyroid Tumors of Follicular Cell Origin with High Grade Features (EFHG): A Clinico-Pathologic and Molecular Study of 25 Cases
M Rivera, J Ricarte-Filho, S Patel, RM Tuttle, A Shaha, JP Shah, JA Fagin, R Ghossein. Memorial Sloan-Kettering Cancer Center, New York
Background: EFHG are unusual neoplasms. Non-invasive EFHG create a major therapeutic and diagnostic dilemma stemming from lack of studies with long term follow up (FU) and controversy regarding their true nature.
Design: EFHG were defined as encapsulated tumor of follicular cell origin with >=5 mitosis/10 high power fields and/or tumor necrosis. Tumors with extra-thyroid extension were excluded. Available paraffin tissues from these cases were subjected to a thyroid cancer-specific platform for mass spectrometry high-throughput genotyping. The latter consisted of 111 known mutations in 16 different genes: BRAF, RET, NRAS, HRAS, KRAS, PIK3CA, MAP2K1, AKT1, MET, IKBKB, PIK3R5, PRKCZ, RHEB, RPS6AK3, RPS6KB1, FRAP1..
Results: Necrosis was present in 56.0% (n=14) and extensive in 32.0% (n=8) of the 25 cases found over a 23 year period. Eight (32%) of 25 tumors were completely non-invasive. Eighty eight percent (n=22) of the patients were free of disease with a median FU of 8.5 years. All 8 non-invasive tumors did not recur despite the presence of focal/extensive necrosis in 3 cases (37.5%) and a median FU of 11.9 years. EFHG with no vascular invasion (VI) did not recur or metastasize while 3 (21%) of 14 patients with VI had distant metastases (DM). In the subgroup without DM at presentation (n=24), 2 (33%) of 6 patients with extensive VI relapsed while none of the 18 patients with absent or even focal VI recurred (p=0.054). Overall mutations were found in 9 (41%) of 22 cases tested. There was a significantly higher frequency of N-RAS codon 61 mutation (8 of 22, 36%) than B-RAF V600E mutations (1 of 22, 4.5%) (p=0.02). Three (37.5%) of 8 non-invasive tumors harbored mutations. The N-RAS positivity rate in our non-invasive cases (25%) is similar to the N-RAS codon 61 mutations frequency reported in atypical adenoma and minimally invasive follicular carcinoma (23.3 % and 22.2% respectively) but different from the one published for typical adenomas (0%). (Vasko et al. JCEM 88:2745, 2003)
Conclusions: 1) Non-invasive EFHG have an indolent behavior even in the presence of extensive tumor necrosis and the molecular data suggest they have started their malignant progression 2) In cases without DM at presentation, EFHG with absent or focal VI have an excellent prognosis 3) Mutations of NRAS are the most frequent oncogenic event in EFHG, which as opposed to BRAF mutations in non-encapsulated high grade tumors, are associated with a favorable prognosis.
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 86, Tuesday Afternoon