Predisposition to and Prognosis of Thyroid Cancer May Not Be Affected by Graves’ Disease, But Some Questions Still Remain

• Clin Thyroidol 2022;34:59–62
• Background:
  • Graves’ disease (GD) is an autoimmune thyroid disorder that is the leading cause of hyperthyroidism
  • Understanding whether GD predisposes patients to thyroid cancer has been of interest for a long time
  • Previous research on the link between GD and the risk of concurrent thyroid cancer was based mostly on surgically treated GD patients, and the results were inconsistent
  • Furthermore, there are still controversies about the impact of GD on the clinical features and outcomes of thyroid cancer
  • Therefore, in the current study, Yoon and colleagues aimed to investigate the overall prevalence of thyroid cancer in patients with GD, as well as the clinicopathologic characteristics, prognosis, and predictive factors of its development
• Methods:
  • This retrospective multicenter study collected data on all patients with GD treated at three tertiary referral hospitals in South Korea between January 2010 and December 2019
  • During their follow-up for GD, all participants in the study underwent at least one high-resolution neck ultrasound
  • All included patients were followed-up for at least one year
  • Demographic information, status of GD, antithyroid medications for the treatment of GD, as well as clinicopathologic characteristics, surgical and postoperative management, and prevalence and clinical outcomes of concomitant thyroid cancer in patients with GD were described
  • In the subgroup analysis, patients were divided into nodular GD and non-nodular GD groups based on the presence of thyroid nodules other than the primary thyroid cancer lesion(s)
  • Clinicopathologic features and thyroid cancer prognosis were compared between the two subgroups
  • Using binary logistic-regression analysis, risk factors for thyroid cancer recurrence / persistence were further investigated
• Results:
  • The current study was composed of 15,159 patients with GD, including 262 (1.7%) with coexisting thyroid cancer
  • The majority of the patients (251 [95.8%]) had undergone cytologic assessment of thyroid tissue prior to surgery, while the remaining patients (11 [4.2%]) were diagnosed with occult thyroid cancer after thyroid surgery was performed for other indications, such as compression symptoms caused by a large goiter and / or uncontrolled hyperthyroidism
  • In 245 (93.5%) and 17 (6.5%) of the patients, total thyroidectomy and lobectomy, respectively, were performed
  • Micro–thyroid carcinomas were found in 182 GD patients (69.5%), which was comparable to the proportion of those in without GD (19,397 of 30,231 [64.2%])
  • The mean (±SD) age of patients with GD and coexisting thyroid cancer was 55.1±13.9 years
  • Active GD, defined as newly diagnosed GD or the use of anti-thyroid drugs, was found in 229 patients (87.4%)
  • Papillary thyroid cancer (PTC) accounted for nearly all (260 [99.2%]) of the histologic thyroid cancer subtypes
  • Extrathyroidal extension and lymph node metastases were identified in 65 (24.8%) and 89 (34.0%) of the patients, respectively
  • None of the patients had distant metastases
  • In 113 (43.1%) of the patients, radioiodine ablation was administered after surgery
  • There was no evidence of thyroid cancer in 242 (92.4%) of patients at a median follow-up of 59.1 months, while 20 (7.6%) had recurrent / persistent thyroid cancer
  • In the subgroup analysis, thyroid cancer patients with nodular GD were older (61.9±12.8 vs. 52.1±13.3 years, P = 0.001) and more were female (86.3% vs. 75.3%, P = 0.046) than those with non-nodular GD
  • There was no difference in thyroid cancer aggressiveness, according to preoperative cytologic and ultrasonographic assessments, between the groups
  • However, there was a substantial difference in the non-classic PTC subtypes between the two groups: patients in the nodular GD group had only follicular variant PTC, whereas the non-nodular GD group had seven patients with non–follicular variant, non-classic PTC subtypes
  • Although thyroid cancer recurrence was detected only in patients with non-nodular GD, the difference was not considered to be significant
  • Furthermore, multivariate analysis revealed that only lymph node metastasis (odd ratio, 4.359; 95% confidential interval, 1.267–14.944; P = 0.020) was independently associated with recurrent / persistent thyroid cancer
  • Conclusions:
  • This multicenter retrospective study of GD patients, including those without surgical intervention for GD, showed that the proportion of coexisting thyroid cancer was substantially lower than previously reported
  • The small proportion of thyroid cancer patients with concomitant GD had a generally favorable prognosis for their thyroid cancer, but those with lymph node metastases may need to be monitored more closely
• The possible association between thyroid cancer and autoimmune thyroid diseases, mainly GD and Hashimoto’s thyroiditis (HT):
  • Has been of considerable interest for a long time
• Although an underlying autoimmune pathology exists in both conditions, HT features chronic inflammatory infiltration in the thyroid gland, whereas GD involves the critical presence of thyroid stimulating antibody (TSAb)
• As growing evidence suggests that there is an increased risk of thyroid cancer in patients with HT, interest has also focused on the role of GD in the development and prognosis of thyroid cancer
• However, data from available studies have provided conflicting information
• A large-scale cohort study conducted in Taiwan has suggested a higher risk of thyroid cancer in GD patients:
  • In 5025 newly diagnosed GD patients, 52 thyroid cancer events were identified (1.0%), as compared with 20 events recorded in 20,100 non-GD subjects (0.1%)
  • However, there was little information on how these thyroid cancers were diagnosed
  • Given that patients with GD are more likely to undergo thyroid examination, including ultrasonography, than those without GD, we should not easily attribute a possible increased prevalence of thyroid cancers to GD per se, but rather to the attentive surveillance of the thyroid provided to GD patients
• The current study was based on all ultrasound-screened GD patients, including nonsurgically treated patients, in contrast to many previous studies in which only surgery-treated patients were included
• Hence, this study avoided selection bias generated from indications toward surgical management
• The rate of coexisting thyroid cancer in GD patients was higher than that in the above-mentioned Taiwan cohort (1.7% vs. 1.0%, P<0.001).;
  • Again, this suggests that routinely performing ultrasound screening leads to more cancer cases being found
• Although the authors could not directly compare the prevalence of thyroid cancer between GD patients and non-GD patients in their study, another population-based study performed at Health Promotion Center of Asan Medical Center, South Korea, provides some insight:
  • In 15,000 subjects who were ultrasound-screened and underwent fine-needle aspiration of suspicious thyroid nodules, 267 patients (1.8%) were identified with a coexisting thyroid cancer
  • Here, we notice that once ultrasound screening is uniformly applied on the population level, the prevalence of thyroid cancer in the general population and in GD patients is comparable
• Taken together, these studies suggest that GD may not increase the risk for thyroid cancer
• To avoid overdiagnosis of thyroid cancer, universal screening for thyroid cancer among GD patients should not be encouraged
• The current study also reported favorable thyroid cancer outcomes in patients with coexisting GD and thyroid cancer, although a comparison could not be made directly with non-GD patients
• There remain some questions to be answered;
  • First, in vitro studies have linked TSAb to mitogenic, antiapoptotic and angiogenic effects probably mediated through its binding to the TSH receptor and stimulation of various signaling pathways:
    • Would changing TSAb status over time (e.g., persistently high titers vs. rapidly declining titers) impact the clinical features and prognosis of thyroid cancer in GD patients differently?
  • Second, nearly 70% of the thyroid cancer patients found in this cohort had papillary microcarcinomas (<1 cm), which is the most indolent type of thyroid cancer:
    • Is it possible that the effects of GD on thyroid cancer outcomes might be more pronounced in more clinically relevant cases (i.e., larger or more aggressive thyroid cancers)?
    • This hypothesis is supported by a multicenter study in Italy, which indicated that GD was associated with a worse outcome of coexisting thyroid cancer only if the cancer was larger than 1 cm
  • Third, for patients with GD who have surgical indications, current American Thyroid Association guidelines recommend near-total or total thyroidectomy:
    • However, for GD patients whose thyroid function and TSAb titers are well controlled by antithyroid drugs, yet elect to have their coexisting low-risk PTC resected, what would be the optimal procedure to avoid overtreatment of these two diagnoses?
  • These important questions await further investigation

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