Papillary thyroid carcinomas with cervical lymph node metastases can be stratified into clinically relevant prognostic categories using oncogenic BRAF, the number of nodal metastases, and extra-nodal extension

Abstract

Background: Papillary thyroid carcinoma (PTC) patients presenting with cervical lymph nodes (LN) metastases (M) have a variable outcome. The objective of this study is to assess the value of meticulous histopathologic examination and genotyping in stratifying these patients into clinically relevant prognostic subgroups.

Methods: This was a retrospective clinical and histopathological review of PTC patients with lymph node metastases at presentation identified between 1980 and 2002 in a single institution. Primary tumors from patients who later recurred were matched to a group of patients who did not recur and subjected to mass spectrometry genotyping encompassing the most significant oncogenes in thyroid carcinomas.

Results: There were 246 patients who satisfied the inclusion criteria. The median follow-up was 10.8 years. The presence of >3 metastatic nodes was an independent predictor of decreased recurrence free survival (p=0.03). In patients <45 years, none of 45 with 1-2 metastatic LN recurred, including 26 patients followed for a median of 13 years without radioactive iodine (RAI) therapy. BRAF mutations were found in 28 (78%) of 36 genotyped tumors. Combined positivity for BRAF and extra-nodal extension was much stronger in predicting disease specific survival (DSS) (p=0.004) than the single analysis of BRAF (p=0.12) or extra-nodal extension (p=0.02).

Conclusions: (i) The number of metastatic LN is an independent predictor of recurrence in all age groups and identifies a subset of young patients with excellent prognosis who may not benefit from RAI therapy. (ii) Combined positivity for BRAF and extra-nodal extension has additive prognostic value in predicting DSS. (iii) Classification systems that assign the same magnitude of risk for recurrence or death to all patients with N1 disease should be revisited.

FIG. 1.

(A) Low-power view of a metastatic lymph node displaying an irregular contour (thick black line) due to extra-nodal extension in a 77-year-old man with multiple nodal metastases (>3) who recurred ∼3 years after diagnosis. (B) High-power view of the same lymph node. The extra-nodal tumor nest (arrow) has elicited a desmoplastic response (d) in the peri-nodal adipose tissue (f).

FIG. 2.

(A) Overall recurrence free survival (RFS) stratified by number of positive nodes in the whole patient cohort. Patients with >3 metastatic nodes have a significantly lower RFS than those with <3 metastatic nodes. (B) Overall RFS stratified by number of positive nodes in patients <45 years old. Patients with >3 metastatic nodes have a significantly lower RFS than those with <3 metastatic nodes. (C) Neck RFS stratified by number of positive nodes in patients >45 years old. Patients with >5 metastatic nodes have a significantly lower RFS than those with ≤5 metastatic nodes. (D) Disease specific survival (DSS) stratified by combined BRAF^V600E mutational and extra-nodal extension (ENE) status in 36 genotyped patients (15 with recurrence and 25 without) matched for various clinico-histopathologic parameters. Patients with extra-nodal extension who are BRAF^V600E positive have a lower DSS than the remaining individuals. +ve, positive nodes.