Is lymph node involvement associated with mortality risk in younger patients with papillary thyroid cancer?

KEYWORDS:

• Papillary thyroid cancer
• young age
• lymph node metastasis
• AJCC staging
• survival

The burgeoning incidence of thyroid cancer observed over the last several decades represents the largest rate of incidence rise amongst all malignancies diagnosed. The annual incidence has now reached a level of an estimated 62,450 new cases in the United States in 2015 and is expected to become the third most common cancer among young women within the next three years [1]. The dominant histologic variant representing over 85% of all well-differentiated thyroid cancer cases is papillary thyroid cancer (PTC) [2,3].

It has been known that patients with PTC frequently present with metastases to regional lymph nodes. Indeed, up to 50% of patients can be found to have pathologic evidence of cervical lymph node metastases at presentation, and this is inclusive of even those with a small primary tumors [4,5]. The current American Thyroid Association (ATA) guidelines recommend that all patients with PTC undergo detailed cervical neck ultrasound evaluation to preoperatively identify lymph node involvement, providing for a more appropriate risk stratification and treatment planning [2,6].

A distinct age dichotomization at 45 years has been considered to have unique prognostic qualities in the natural history of PTC. In the absence of distant metastatic disease, younger patients less than 45 years are considered to have an unaffected survival outcome when compared to those patients diagnosed at 45 years or older. This perception has existed for decades and has been integrated within several different proposed staging systems for PTC [7–9]. For example, in the current American Joint Committee on Cancer staging system, patients <45 years with PTC have two possible stages of disease dependent on the absence (Stage I) or presence (Stage II) of distant metastases. Patients older than 45 years are more traditionally stratified into four oncologic stages of disease based on a typical Tumor, Node, Metastases classification [7]. Ultimately, those M0 patients less than 45 years of age at diagnosis of PTC are all grouped into the same oncologic disease stage even if they harbor extensive cervical lymph node metastases.

For those older than 45 years at diagnosis, the data have consistently demonstrated altered survival in the context of cervical lymph node disease [10–12]. Hughes et al. analyzed data from 200 differentiated thyroid cancer patients who were treated at a single institution over a 50-year period. Lymph node metastasis was associated with compromised 20-year disease-specific survival for patients ≥45 but not for those <45 years [10]. However, as the 20-year disease-specific mortality for PTC exceeds 90% for all patients without distant metastasis, such single institution studies will remain statistically underpowered in showing a difference in long-term outcome. In a much larger analysis of 15,497 patients with PTC from the Surveillance, Epidemiology, and End Results (SEER) Database, Zaydfudim et al. demonstrated that lymph node metastasis was associated with decreased overall survival in patients ≥45 years, while it did not impact survival in patients <45 years [11]. However, it is important to point out that the results reported by Zaydfudim et al. did not adjust for potential confounders that are known to have a direct impact on survival, such as presence of distant metastases, extent of thyroid surgery, and surgical margins. Succeeding examinations within the SEER database in 49,240 patients with differentiated thyroid cancer actually demonstrated compromised survival in young patients less than 45 years with N1 disease [13].

In a recent analysis that focused on younger patients, Adam et al. analyzed the data of nearly 70,000 PTC patients less than 45 years of age without distant metastases from the National Cancer Data Base and SEER registries. They found that after adjustment for patients’ demographics, tumor characteristics, extent of surgery, and surgical margins, overall survival was compromised for patients with lymph node metastasis compared to those without lymph node metastasis. Congruent with the reported effect of lymph node metastasis on survival of patients ≥45 years, lymph node metastasis was associated with a 32% increase in risk of death. This significant association was externally validated in a similar SEER database cohort. Compromised survival was further associated with the number of metastatic disease reaching asymptote at six metastatic lymph nodes. A greater number of positive lymph nodes over six did not confer additional risk of death [14]. These data challenge the in-grained position deeming prognostic insignificance of N1 disease in patients less than 45 years. The adverse consequence of loco-regional metastasis exists comparably in all patients with PTC regardless of age. These results support a more thorough and experienced preoperative ultrasound lymph node examination for young patients with suspicious nodular disease. Indeed, the 2015 ATA guidelines recommend detailed preoperative neck ultrasound to screen for cervical lymph node involvement in all patients undergoing surgery for malignant or suspicious-for-malignancy cytologic and molecular FNA biopsy findings [2,6].

Due to the indolent nature of PTC and excellent overall survival, the prognostic significance of cervical metastatic disease has historically been more scrutinized by examining the end point of disease recurrence. Unfortunately, large data examining the true long-term recurrence rates of regional metastatic disease for PTC patients less than 45 years are lacking.

While the recent data by Adam et al. clearly demonstrate the significant association between cervical lymph node disease and survival in young patients with PTC, translation of these data into altered treatment strategies may need to be carefully considered. The association between metastatic lymph node disease and survival may have implications for evolving risk stratification and tailoring of treatment, but there are still significant limitations in our understanding. These data thus far do not differentiate between macroscopic and microscopic lymph node metastases. It is unclear if compromised survival is a generalizable phenomenon for young patients with micrometastatic disease. Given the high prevalence of micrometastases reaching rates of up to 90% of cases in some reports, studies answering this relevant question are sorely needed. While it is likely that there are many patients with micrometastatic disease included in the study by Adam et al.’s study, it is plausible to solely attribute the increase in mortality to the aggressive biology represented as macrometastatic disease.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.