Site-Specific Metastasis and Survival in Papillary Thyroid Cancer: The Importance of Brain and Multi-Organ Disease

Abstract

Introduction-heterogeneity in clinical outcomes and survival was observed in patients with papillary thyroid cancer (PTC) and distant metastases. Here, we investigated the effect of distant metastases sites on survival in PTC patients. Methods-patients with a diagnosis of PTC and known metastases were identified using the Surveillance, Epidemiology, and End Results database (1975-2016). Univariate and multivariate Cox regression analyses were performed to analyze the effect of distant metastases sites on thyroid cancer-specific survival (TCSS) and overall survival (OS). Results-from 89,694 PTC patients, 1819 (2%) developed distant metastasis at the initial diagnosis, of whom 26.3% presented with the multiple-organ disease. The most common metastatic sites were lung (53.4%), followed by bone (28.1%), liver (8.3%), and brain (4.7%). In metastatic patients, thyroid cancer-specific death accounted for 73.2%. Kaplan-Meier curves showed decreased OS in patients with metastases to the brain (median OS = 5 months) and liver (median OS = 6 months) compared to lung (median OS = 10 months) and bone (median OS = 23 months). Moreover, multiple organ metastasis had a higher mortality rate (67.4%) compared to single organ metastasis (51.2%, p < 0.001). Using multivariate analysis, risk factors that significantly influence TCSS and OS were male gender (HR = 1.86, 95% CI = 1.17-2.94, p < 0.001, and HR = 1.90, 95% CI = 1.40-2.57, p = 0.009), higher tumor grade (HR = 7.31, 95% CI = 2.13-25.0, p < 0.001 and HR = 4.76, 95% CI = 3.93-5.76, p < 0.001), multiple organ involvement (HR = 6.52, 95% CI = 1.50-28.39, p = 0.026 and HR = 5.08, 95% CI = 1.21-21.30, p = 0.013), and brain metastasis (HR = 1.82, 95% CI = 1.15-2.89, p < 0.001 and HR = 4.21, 95% CI = 2.20-8.07, p = 0.010). Conclusion-the pattern of distant metastatic organ involvement was associated with variability in OS in PTC. Multi-organ metastasis and brain involvement are associated with lower survival rates in PTC. Knowledge of the patterns of distant metastasis is crucial to personalize the treatment and follow-up strategies.

Keywords: metastasis; multiple organ metastasis; survival; thyroid cancer.

Figure 1

The site and the number of metastatic organs. Data are presented as the number of patients (percentage). (A) Frequency of patients according to the site of distant metastasis. (B) Frequency of patients according to the number of organs involved. (C) Frequency of patients according to the combination of metastases sites per patient.

Figure 2

Differential impact of single- and multi-organ distant metastases on survival. SODM: single organ distant metastasis, MODM: multiple organ distant metastasis. (A) Histogram comparing the survival in SODM and MODM groups. Mann–Whitney U test was applied. (B–D) Kaplan–Meier survival curves comparing between SODM and MODM groups for overall survival and thyroid cancer-specific survival. Log Rank test was used. Overall survival was defined as the time between diagnosis and death from any cause, and thyroid cancer specific survival was defined as the time between diagnosis and death from DTC.

Figure 3

Impact of the site of metastasis at presentation on overall survival. (A) Five-year overall survival. (B) Kaplan–Meier survival curve comparing between patients presenting with metastasis at different sites. Log Rank test was used.

Figure 4

Risk of mortality in patients with metastasis compared to non-metastatic patients. (A) Overall analysis for identifying risk factors of overall survival. (B) Overall analysis for identifying risk factors for thyroid cancer-specific survival. (C) Subgroup analysis for identifying risk factors of overall survival. (D) Subgroup analysis for identifying risk factors for thyroid cancer specific survival. Multivariate cox regression models were employed on the whole study population either with or without metastasis. In overall analysis, risk in the presence of metastasis was first performed adjusted with other variables. Next, iterations were performed after replacing the metastasis variable with each other variable listed in the sub-analysis section. Metastasis in each site is compared to all cohorts without metastasis. HR: hazard ratio, 95% CI: confidence interval, SODM: single-organ distal metastasis, MODM: multi-organ distant metastasis, vs: versus, mets: metastasis.