Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy (1). The incidence of PTC is on the rise over the past two decades (2, 3). In Saudi Arabia, PTC is the second commonest cancer affecting women, after breast cancer (4). PTC is an indolent disease with favorable prognosis in majority of patients. However, a subset of PTC patients (approximately one-third of all cases) will relapse (5–7), which could impact the quality of life for these patients. Thus, identification of clinical markers that could help to predict patients at high risk for recurrence is of great clinical importance for effective therapeutic interventions.

PTC is known to affect women more than men (1, 8). In fact, in Saudi Arabia, the age standardized incidence rate of thyroid cancer in women and men was 8.4 and 2.5 per 100,000 persons, respectively (4). The prognostic significance of sex in PTC remains controversial. While many studies have demonstrated the correlation between male sex and advanced stage, higher death rate, poor prognosis, and higher risk of recurrence in PTC (9–12), others have failed to identify prognostic difference between male and female PTCs when adjusting for age, stage, tumor size, and other influencing factors (13–15). Furthermore, current guidelines for risk stratification issued by the American Thyroid Association (ATA) does not include patient’s sex factor that could affect the risk of recurrence (16).

Despite the high incidence of PTC in Saudi Arabia and relatively high recurrence rate (17–19), the impact of sex on recurrence risk in PTC from Middle Eastern ethnicity remains unknown. Thus, we carried out this study on a large cohort of Middle Eastern adult PTC to investigate the impact of sex on clinico-pathological characteristics and patients’ prognosis. We also assess if male sex is an independent risk factor for recurrence of PTC from Middle Eastern ethnicity.

While sex disparity in the incidence of PTC and its clinical impact have been well documented, detailed analysis of prognostic impact of sex on PTC from Middle Eastern ethnicity has not been fully illustrated. Our study of more than 1,400 adult PTCs documented their clinico-pathological characteristics and demonstrated significantly more aggressive disease in men than women. The presence of extrathyroidal extension and lymphovascular invasion was seen significantly more commonly in men than women. There was a higher rate of distant metastasis and regional LN metastasis in men than women. Moreover, a higher rate of advanced disease (stage II, III, and IV according to the latest AJCC staging system) and a higher rate of patients with intermediate- or high-risk disease were also observed in male PTC patients. Interestingly, our subgroup analysis showed that aggressive PTC was more common in men even at young age. This further supports the notion that men inherently have more aggressive PTC behavior, which may not be attributable solely to delay in diagnosis. Several previous studies have shown the association between male sex and advanced disease (9, 10, 13, 22, 23).

Median age of the study population was 39.2 years. This finding is similar to studies from other Middle Eastern ethnicities (24–27), but lower than that seen in Western population (28). This most likely represents the inherent aggressive nature of PTC in the Middle Eastern ethnicity. Another consideration that needs to be taken into account is the age of the general population. In Saudi Arabia, the population pyramid is skewed toward younger age groups, showing a cone-shaped pattern. Indeed, nearly 60% of the Saudi population are under the age of 30 years. It has been shown previously that age of the population could partly explain the variability of age of onset for cancer, whereby younger populations tended to have a higher incidence of early-onset cancer (29, 30).

The rate of recurrence was 18.2% (260/1,430) in the overall cohort, which is relatively higher than what has been reported previously (31–33). The long follow-up duration and the low rate of PCLND may have contributed to the relatively high rate of recurrence in our study. The long median follow-up of 9.5 years might increase the likelihood to detect more recurrence in PTC patients than other studies with shorter median follow-up. In addition, PCLND has not been routinely performed in our center but rather it was performed based on tumor size and LN status, according to ATA guidelines (16). However, we have found that 343 PTC patients met the criteria for PCLND and yet did not undergo the procedure. In fact, 21.9% (75/343) of these patients developed recurrence during the follow-up period, which further contributed to the relatively high recurrence rate in our study. Furthermore, our study showed a higher recurrence risk in men than women. The recurrence risk was 1.7-fold higher in men presenting with AJCC stage I and II, compared to women. However, recurrence risk does not show significant difference between men and women for AJCC stage III and IV.

Our study findings showed that men had significantly poor RFS even in multivariate analysis where tumor stage and other influencing factors were considered. Moreover, significant prognostic differences between men and women was noted even when PTC was localized to the thyroid gland, which may suggest a truly aggressive PTC behavior in Middle Eastern men, even with small tumor size. Some previous studies have shown that sex was associated with poor prognosis (12, 23, 34, 35), whereas others found no prognostic difference between men and women (13–15). The lack of consensus among previous studies could be attributed to cohort size, classification used, and the inability to differentiate persistent disease from recurrent disease.

Another important finding is the significant association between male PTC and RAI refractoriness (RAIR). We attempted to explore the molecular features that might contribute to RAIR in male PTC patients, especially BRAF and TERT mutations. A large body of evidence have documented the correlation between BRAF and/or TERT mutation and poor RAI response (36–38). BRAF mutation data were available for 1,369 patients while TERT mutations were available in 1,288 patients of the study cohort. Interestingly, no correlation between BRAF mutations and male PTC patients was noted. However, a significantly higher rate of TERT mutations was observed in male PTC patients compared to female patients. A large meta-analyses, involving 32 studies, also found a significant association between TERT promoter mutations and male sex (39).

Our study has certain limitations. First, it has a historical, retrospective nature, it lacks complete information on some tumor features including TERT and BRAF mutations, and 3% of the patients were lost to follow-up. Second, the study cohort was limited to Middle Eastern ethnicity and it is from a single center that could slightly impact the generalizability of our results to other populations. Thirdly, our study population included a high rate of high-risk patients, which could be attributed to genetics or differences in presentation owing to the unique ethnicity. Whether this could also be partly attributed to delay in seeking healthcare remains to be explored.

In summary, our study demonstrated that men present with more advanced stage of disease, at older age and with higher rate of aggressive molecular and histopathological features. Men have a higher rate of recurrence and a shorter recurrence-free survival. Moreover, male gender was an independent prognostic factor for RFS in Middle Eastern PTC patients. Overall, the results of this study strongly suggest that sex should be considered as an important predictor of prognosis and therefore men with PTC may benefit from more aggressive initial treatment and intense follow-up.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the Research Ethics Committee, King Faisal Specialist Hospital and Research Centre. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Study concept and design: KA-K, SP, and AS. Executed the study: SP, AS, PA, NS, SA-S, and FA-D. Statistical analysis: SP. Drafting the article: KA-K, AS, and SP. Critical revision of the article for important intellectual content, writing of the article, and approval of the final version: KA-K, SP, AS, PA, NS, SA-S, and FA-D. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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