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Page 2 of 8 Izkhakov et al. J Cancer Metastasis Treat 2021;7:24 https://dx.doi.org/10.20517/2394-4722.2021.24

INTRODUCTION
Recent trends show a significant increase of the incidence of thyroid cancer (TC) . The most common
[1,2]
type of TC is differentiated thyroid cancer (DTC), which includes follicular and papillary types and
constitutes about 90% of all TC. DTC usually occurs in individuals younger than 50 years of age. Females
are more affected than males, with a ratio of 3:1. DTC patients can expect a reassuring prognosis, with a 5-
[3,4]
year survival rate reaching 90%-95% . Taken together, these trends highlight the importance of studying
long-term morbidity for the increasing population of DTC survivors.

The traditional treatment regimens for DTC have included thyroidectomy, radioactive iodine therapy (I-
131), and thyroid stimulating hormone (TSH) suppression therapy (subclinical exogenous hyperthyroid
[5]
state) with levothyroxine (LT4) according to the extent of the disease . Lately, there has been a gradual shift
towards a more conservative, personalized approach for some low-risk subjects, ranging from watchful
surveillance for isolated very small lesions (e.g., < 10 mm) to lobectomy only, withholding of radioiodine
treatment and/or lesser suppression of TSH (e.g., 0.5-2 µIU/mL) for low-risk subjects undergoing
lobectomy only and/or no imaging or biochemical evidence for residual disease during follow-up .
[6]

Pharmacological suppression of TSH proved useful in reducing recurrence and mortality in clinically
detected differentiated thyroid cancer . However, recent cumulative evidence supports a strong correlation
[7]
between endogenous hyperthyroidism and higher mortality rates associated with cardiovascular heart
disease and cerebrovascular disease in patients who have multinodular goiter and those treated with
radioactive iodine, in comparison to the general population [8-11] . Furthermore, even endogenous subclinical
hyperthyroidism is apparently associated with an increased risk of coronary heart disease and mortality .
[12]
Lastly, a low serum TSH concentration, presumably indicative of hyperthyroxinemia, was linked with a 3-
fold higher risk for atrial fibrillation (AF) during the following decade in subjects ≥ 60 years of age .
[13]

This review aims to provide updated data on all-cause cardiovascular mortality and cardiovascular
morbidity and present pathophysiological mechanisms that are considered as probably contributing to these
conditions among TC survivors.

CARDIOVASCULAR AND ALL-CAUSE MORTALITY
TSH suppression therapy is the mainstay treatment for decreasing the risk of recurrence among patients
who are at high-risk of DTC. Klein Hesselink et al. evaluated the risk of cardiovascular and all-cause
[14]
mortality among 524 Dutch DTC survivors compared to 1572 matched controls. A median 8.5-year follow-
up period revealed 100 deaths among DTC survivors and 85 deaths among the controls. The authors
reported a 3.3-fold increased risk of cardiovascular mortality (4.2% vs. 1.5%, respectively) and a 4.4-fold
increased risk of all-cause mortality (19.1% vs. 5.4%, respectively) among DTC survivors. Mortality from
DTC constituted 7.4%. In that study, each 10-fold decrease in geometric mean TSH level was independently
linked to a 3.1-fold elevated cardiovascular mortality. A nomogram composed of data from the Surveillance,
Epidemiology and End Results program predicted the risk of death among 29,225 TC survivors . The 5-
[15]
year probability of mortality was 1.9% due to thyroid cancer, 0.8% due to another cancer, and 1.7% due to
non-cancer causes after a median follow-up of 7 years. The most common causes of mortality, which did
not result from cancer among TC survivors, were heart disease (39%) and cerebrovascular disease (10.4%).
Data from an Israeli population-based study of 5677 TC survivors and 23,962 matched controls reveal a
higher risk of all-cause mortality among the TC survivors (10.2% vs. 5.2%, respectively, HR = 1.89, 95%CI:
1.71-2.1; (abbreviated in all following items to the HR value followed by the 95% CI range of values in
square parenthesis) , which was associated with an elevated prevalence of cardiovascular disease (33.6%
[16]
vs. 22.3%, P = 0.05), hypertension (14.6% vs. 10.3%, P = 0.002) and dyslipidemia (11.4% vs. 7.2%, P < 0.001) at