The incidence of differentiated thyroid cancer (DTC) has markedly increased during recent decades (1, 2), largely driven by the widespread use of imaging studies and fine-needle aspiration biopsies (FNAB) (3, 4),overdiagnosis, and changes in the professional guideline recommendations (5, 6). Age-standardized incidence rates were reported to be higher among women and those older than 50 years, and higher mortality has been reported among patients aged 80–84 years old (1, 3, 7).

In Saudi Arabia, thyroid cancer (TC) remains one of the most common types of cancer, especially among women aged 15–29 years old and above with an observed increase of 0.9% from 2001 to 2020 (8, 9). The incidence of TC in Saudi Arabia has increased by 3.7% since 2001 (8). Double-peak recurrence rates were observed among Saudi patients with TC at 1–2 years and 13 and 14 years from the time of diagnosis, with lower recurrence rates among patients who had received radioactive iodine therapy (RAI) (10).

The outcomes after therapy of TC vary from excellent response to structural incomplete response. Excellent response to therapy is defined as stimulated thyroglobulin (Tg) <1 ng/mL, suppressed Tg <0.1 ng/mL, and no evidence of the disease by imaging (11). Biochemical incomplete response is defined as high Tg or rising thyroglobulin antibodies following treatment without structural evidence of disease (12). TC patients with biochemical incomplete response still have a good long-term survival rate, whereas a structural incomplete response to initial therapy was associated with significantly worse clinical outcome (13, 14). Structural incomplete response to therapy, defined as having anatomical evidence of disease regardless of the Tg level and the status of anti-Tg antibodies, has worse clinical outcomes (15–17). Older age, male gender, multifocality, mediastinal or lateral lymph node (LN) involvement, and class III extent of the disease by De Groot have been identified as strong predictors of incomplete response to therapy (15, 18, 19).

Risk stratification after the initial therapy and the long-term outcome of patients with TC has been advocated for by most clinicians to prognosticate and predict the risk for persistent or recurrent disease. Data in this regard remain limited in patients with TC in the Middle East. Here, we report our experience at King Saud Medical City in Saudi Arabia and identify predictors of worse response to treatment in patients with TC.

TC is the most common endocrine malignancy with an increasing prevalence worldwide (1–4). A 2020 report from Saudi Arabia showed a TC prevalence rate of 12.9% with OR = 6.77 (2.34–19.53) (21). This current study showed a steep rise from 7.4% to 45.8% over the last 20 years, 90.4% of which were of the papillary type. This is consistent with earlier reports from both local and international studies (3, 10, 22). Many believe that the papillary type has favorable survival rates. However, patients are confronted with misperceptions and mixed emotions, particularly in their fight toward embattling the disease (23). The financial impact on thyroid cancer survivors reports greater psychological financial hardship than non-thyroid cancer survivors (24). There is also the issue of overdiagnosis and overtreatment of low-risk thyroid cancer, where physicians perform inappropriate biopsies and radioactive iodine treatment (25).

Women in the 40–50 age group seemed more vulnerable, which is consistent with previous studies from Saudi Arabia where TC has a significant preponderance to the female gender (8, 9). However, the recurrence rate and the proportion of a more advanced disease are higher among men (26). In this study, 24.3% and 28.2% of men with TC had intermediate- and high-risk histology compared with 17.9% and 19.7% of women. A higher proportion of men had extranodal involvement and distant metastasis despite both genders having no significant difference in the treatment received. This is consistent with the report of Zahedi et al. in 2020 and other previous studies that men tend to present with more advanced diseases (26–28).

We also found that the size of cancer >3 cm is an independent risk factor for the persistence of the disease, concordant with reports from previous studies (29–31). A larger tumor size may have an impact on the relative risk of not being cured (29). Lymphovascular invasion has been associated with disease recurrence and compromised survival in patients with thyroid cancer. Tumor size has been found to be positively associated with the risk of lymphovascular invasion, particularly in the papillary type of TC (29–31). The same goes with extrathyroidal extension since patients are considered to be in the advanced stage of the tumor (32).

One interesting finding in this study is the significant association of obesity with structural incomplete response to therapy, thus a higher risk of worse outcomes validating reports from previous studies (4, 33–37). Obesity has been proposed as a risk factor for several diseases including increased risk for TC. In many studies, women who were diagnosed with TC had a higher prevalence of obesity with higher waist circumference and higher adipose ratio (4, 33). The OR reported from other countries was 1.63 per 5 kg/m (2) increase in BMI (4, 33–36). One article reported that in one of every six TCs diagnosed among adults 60 years or older, nearly two-thirds of the patients were overweight to obese (37). According to Schmid et al., a 0.1-point rise in the waist-to-hip ratio and a five-point increase in BMI each may increase the risk of thyroid cancer by 30% and 14%, respectively (38). According to reports, there are a number of factors that raise the risk of thyroid cancer in those who are obese. The risk for the development of thyroid cancer may increase if aromatase levels are raised and activated because of an imbalance in estrogen and androgen hormones (39, 40). Another potential mechanism is an upsurge in oxidative stress brought on by immune system non-specific activation and inflammatory substances like cytokines and adipokines that lead to an excess of reactive oxygen species (ROS) (39–43). Recent studies have consistently found evidence that obesity raises the risk for thyroid cancer (39–43). However, a precise molecular mechanism underlying the association between obesity and TC needs to be identified. Clinicians should closely monitor patients, regardless of their initial risk categorization, in light of the recent compelling evidence associating obesity with thyroid cancer and its higher risk of a worse disease outcome. Additional clinical evaluations should be carried out to frequently check the thyroid function of obese patients.

The diagnostic performance of the different imaging procedures revealed that the US of the neck was positive in 63.8% of the patients who ultimately had a structural incomplete response to treatment. This implies that US offers a high sensitivity and positive predictive value for TC screening (44, 45). In addition, preoperative ultrasound may change the intended surgical strategy (46, 47). According to a meta-analysis, CT exhibited an overall sensitivity of 62% and a specificity of 87% for detecting cervical lymph node metastases in TC patients (48, 49).

This study showed a structural incomplete response to treatment in 29.2% to 61.5% of patients with moderate- to high-risk histology according to the ATA risk stratification and 9.2% among those with low risk, consistent with previous studies (18, 50). Both for intermediate-risk and high-risk groups, the ATA risk class demonstrated to be a strong and credible predictor of structural persistent disease (51). We followed our patients for a longer period of time (20 years) compared with the study of Grani et al. (51) This indicates that even for long-term prediction of TC treatment results, the ATA risk stratification’s dependability is consistent. Additionally, data demonstrate that ATA risk stratification adequately classifies patients based on a variety of crucial clinical outcomes (50–55).

Many authors have proposed various characteristics that are associated with disease-free survival (DFS), including primary tumor size, multifocality, vascular invasion, extrathyroid extension, lymphovascular invasion, and lymph node ratio (50–59). In line with earlier research, extranodal involvement, lymphovascular invasion, and initial tumor size—particularly those >3 cm in size—were the most important predictors of a structural incomplete response to therapy. Patients with high-risk histology who underwent surgery and then RAI have the best prognoses and have high chances of disease-free survival (56, 60, 61). Consistent with the findings from earlier studies, we found that patients with TC treated with surgery and RAI had significantly longer recurrence-free survival times compared with patients with the papillary type treated with surgery alone and also longer recurrence-free survival times compared with patients with the follicular type treated with surgery alone or with RAI (60–63).

The extensive 20-year follow-up period is a major strength of our study. Moreover, we have studied a larger number of patients (n = 674) than those reported by other studies (20). However, our study has several limitations, including the retrospective nature of the study that limited us to identify several potential predictors as well as the assessment of disease-specific mortality. Furthermore, the study spanned 20 years of follow-up, in which treatment time and surgical strategies have significantly changed and probably also the number of patients with obesity. Also, the gender disparity between excellent response and structural incomplete response may have raised concern about possible selection biases since most of our patients were women. Other potential risk factors for the course of the disease, such as family history, the environment, and lifestyle choices, were not documented.

The size of cancer, lymphovascular invasion, and obesity are strong predictors of a structural incomplete response to therapy among patients with TC. Patients with obesity should be carefully followed up regardless of the risk stratification in light of the recent compelling evidence associating obesity with thyroid cancer and its higher risk of a worse disease outcome. ATA risk stratification is well correlated with patient long-term outcomes and the type of response and can help to determine the initial type of surgery and radioactive iodine as well as the follow-up plan.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by the King Saud University Medical City College of Medicine IRB Board, Riyadh, Saudi Arabia. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

AJ: Conceptualization, Formal Analysis, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing. IA: Data curation, Investigation, Methodology, Resources, Writing – review & editing. EA: Data curation, Formal Analysis, Methodology, Writing – review & editing. MA: Data curation, Investigation, Methodology, Resources, Writing – review & editing. AA: Formal Analysis, Investigation, Methodology, Software, Writing – review & editing. MA-S: Conceptualization, Data curation, Investigation, Methodology, Resources, Validation, Visualization, Writing – review & editing.