Response to Letter to the Editor From Boucai et al: "BRAF V600E Status Sharply Differentiates Lymph Node Metastasis-associated Mortality Risk in Papillary Thyroid Cancer".

Although the clinical significance of cervical lymph node metastasis (LNM) in papillary thyroid cancer (PTC) is sometimes debatable, large clinical studies, such as our recent one (1), usually show its significant association with PTC-related mortality (1). In fact, major thyroid cancer staging models, such as the American Joint Committee on Cancer (AJCC) staging system for mortality risk, virtually all have LNM as an integral stage defining component (2). In such risk-staging practice for thyroid cancer, LNM is often used in an “all or none” manner: its presence defines 1 stage and lack defines another (lower) stage; the prognostic significance of LNM in 1 patient is treated as the same to that of similar LNM in another. Such a practice uses the conventional wisdom that focuses purely on the present clinical presentations, ignoring the possible inherent potential of diseases to progress differently. With today’s modern wisdom incorporating the principle of genetic-based precision medicine, the fundamental concept is becoming widely accepted that genetic backgrounds govern the different inherent progression potential of initially similarly presented diseases of thyroid cancer. This concept is now particularly easy to understand for PTC given the several well-established disease aggressiveness-driving mutations, such as BRAF V600E and TERT promoter mutations (3, 4). Our recent multicenter study demonstrating a sharp differentiation in LNM-associated mortality risk by the BRAF status in PTC represents a new testament to this concept (1). In this study, LNM-associated mortality risk is sharply higher in BRAF V600E cases than wild-type BRAF cases in virtually all patient groups. In the absence of BRAF V600E, LNM shows virtually no increased mortality risk. The difference in mortality risk is most striking between patients with both LNM and BRAF V600E and patients with neither, demonstrating a strong synergistic effect of the two. Thus, all LNM is not equal in mortality risk in PTC; the genetic background, such as the BRAF status, largely determines the mortality risk associated with LNM in PTC. Such an effect of BRAF mutation on the aggressiveness of PTC has well-documented molecular mechanisms to support (5, 6).

The effect of BRAF V600E on LNM-associated mortality risk is still present after adjustment for common clinicopathological variables, including patient age, sex, tumor size, multifocality, extrathyroidal extension, and I-131 treatment, illustrating the strength of the adverse effect of BRAF V600E (1). Thus, when managing LNM in PTC, it is helpful to know the BRAF status to better understand the clinical significance of LNM. Boucai and Tuttle suggested that the multivariable adjustment should also include AJCC stages (7). We believe that this would be statistically inaccurate because AJCC staging incorporates and is actually based on the clinicopathological factors; simultaneous adjustment for them and AJCC stages would duplicate the adjustment for the key components in the staging model. Boucai and Tuttle also suggested adjusting distant metastasis in assessing the effect of BRAF mutation on mortality in PTC. This is worth discussing. Distant metastasis is one of the strongest clinicopathological factors (probably the strongest factor) directly linked to mortality in thyroid cancer; perhaps distant metastasis, in a sense, could be considered “equal” to patient death. As such, to some extent, adjustment for distant metastasis in assessing the mortality risk in PTC is like adjustment for mortality itself, which would artificially (and misleadingly) cancel the adverse effect of BRAF mutation.

To fully appreciate this notion, it is wise and necessary to understand the clinical significance of BRAF V600E from its biological perspective, not to completely rely on imperfect conventional statistical adjustment models focusing only on mathematical number calculations and ignoring that it is the genetically governed molecular biological fundamentals that underlie the clinical manifestations and drive the disease aggressiveness of PTC. Obviously, the presence of aggressive tumor behaviors (such as advanced stages or distant metastasis) is needed for patient death to occur in PTC; without such biologically driven aggressive tumor behaviors, no mortality would happen. Therefore, when statistically adjusting for such clinicopathological risk factors, or “removing” them, in assessing the effect of BRAF mutation on PTC-related mortality, the effect could become superficially insignificant (8). It has been previously pointed out that multivariable analyses adjusting for aggressive tumor behaviors could artificially nullify the effect of BRAF V600E on mortality, underestimating its prognostic value for potential disease progression of PTC.

From a practical perspective, a simple way to think about the clinical value of BRAF V600E in LNM might be as follows: because LNM in patients with wild-type BRAF is associated with virtually no increased mortality risk, relatively conservative styles in the management of LNM in such patients is justified in appropriate clinical settings. In contrast, LNM in patients with BRAF V600E belongs to a different category and needs to be relatively more aggressively managed whether the increased mortality risk is directly from LNM or from other tumor behaviors associated with it. Previous studies have demonstrated a nearly complete concordance in the BRAF V600E status between the metastatic tumor in cervical lymph nodes and the primary PTC tumor in the thyroid gland. Previous studies, including our recent one (1), have also shown that BRAF V600E is not only associated with increased patient mortality but also increased disease recurrence of PTC, the latter usually representing emergence of progressive metastatic diseases in cervical lymph nodes. This suggests that BRAF mutation has a direct adverse biological effect on LNM, making metastatic lymph node diseases progress and increasing the chance of neck disease aggressiveness and possible distant metastasis from metastatic lymph node diseases.

In conclusion, LNM-associated mortality risk in PTC is genetically governed. LNM conceivably deserves special attention in management in patients with BRAF V600E and may be relatively conservatively managed in patients with wild-type BRAF. Incorporation of also other clinically relevant genetic alterations, such as the TERT promoter mutation, into this genetic-based precision management strategy, will likely further the improvement in accurately managing PTC and its associated LNM (3, 4).