Gender Differences in Thyroid Cancer

Reina Yao; Connie G Chiu; Scott S Strugnell; Sabrina Gill; Sam M Wiseman

Disclosures

Expert Rev Endocrinol Metab. 2011;6(2):215-243. 

In This Article

Abstract and Introduction

Abstract

It has long been known that the incidence of thyroid cancer in women is significantly higher than that in men. The objective of this article is to review gender differences in thyroid cancer, as well as epidemiological, clinical and experimental research on the role of sex hormones, their receptors and other molecular factors in this well-established thyroid cancer gender discrepancy. Although more common in women, thyroid cancer typically presents at a more advanced stage and with a worse disease prognosis in men. Clinical evidence on the impact of estrogen and other sex hormones on thyroid cancer has remained inconclusive, although numerous experimental studies have suggested that these hormones and their receptors may play a role in tumorigenesis and tumor progression. Studies of thyroid cancer cell lines suggest that an imbalance between the two estrogen receptor (ER) isoforms, α and β, may be responsible for the cell proliferation seen with estrogen treatment. Expression studies on thyroid tumors indicate that they express ER and possibly progesterone receptors and androgen receptors, but there is conflicting evidence as to whether or not there is a difference in receptor status between thyroid cancers, benign thyroid lesions and normal thyroid tissue. There have been few studies evaluating the ERα/ERβ profiles in thyroid tumors and normal thyroid tissue. Our understanding of the underlying basis for sex differences in thyroid cancer has improved over the last few decades, but the relationship between gender and thyroid cancer risk has remained elusive. Areas for future research include ERα/ERβ profiling of normal and neoplastic thyroid tissue, association between ER status and tumor dedifferentiation, and evaluation of the signaling pathways by which estrogen and other sex steroids exert their effects on thyroid cancer cells. Sex steroid receptors, and then downstream signaling pathways, represent promising future therapeutic targets for thyroid cancer treatment, and further study is required.

Introduction

Thyroid cancer is the most commonly diagnosed non-gynecologic human endocrine malignancy. It accounts for approximately 2% of all cancers in Canada[1] and the USA,[201] and just over 1% of all cancers worldwide.[2] However, the incidence of thyroid cancer is significantly higher in women compared with men. The 2002 GLOBOCAN database reports 103,589 female thyroid cancer cases worldwide compared with only 37,424 male thyroid cancer cases, representing a female to male (F:M) ratio of greater than 2:1. This overall increased incidence of thyroid cancer in females is observed across different geographic populations, with a F:M ratio ranging from 1.44 in Northern Territory, Australia to 7.40 in Granada, Spain,[3] as well as across ethnicities, ranging within the USA from 2.88 in Caucasians to 3.57 in Hispanics.[201] However, this incidence pattern is not observed across all thyroid cancer types. When categorized by histology, the incidence of differentiated thyroid cancer (DTC; papillary thyroid carcimona [PTC] or follicular thyroid carcinoma [FTC]) is three-times higher in women than in men, while that of anaplastic thyroid carcinoma (ATC) is twice as common in women than men. There is no significant difference in the incidence of medullary carcinomas (MTC) between men and women.[4]

While the only currently established causative risk factor for thyroid cancer is exposure to ionizing radiation,[4] the discrepancy between male and female disease incidence has led to the suggestion that female gender is a possible epidemiologic risk factor. A prospective cohort study by Iribarren et al. of 204,964 individuals living in San Francisco (CA, USA) reported a relative risk of 1.56 for the development of thyroid cancer for female gender by multivariate Cox proportional hazard models.[5] No other studies have analyzed female gender as a risk factor for thyroid cancer in the general population. Regardless, the marked variation in thyroid cancer incidence between females and males has long led to speculation about possible underlying biological theories in the development and progression of thyroid cancer.

Although women are more likely to be diagnosed with thyroid cancer, multiple surgical series suggest that men have a worse prognosis once diagnosis is established. The Age, Metastases, Extent and Size (AMES) criteria, which classifies DTC patients as low or high risk based on patient age, presence of metastases, extent of tumor invasion and tumor size, takes gender into account in patient risk-stratification. The age cutpoint at which patients without distant metastases are considered high-risk individuals, and therefore prognostically less favorable, is 10 years lower for men (age 41) as compared with women (age 51). A high-risk designation defined by the AMES criteria indicates a mortality rate of 46%, compared with 1.8% for low-risk individuals.[6] Furthermore, patients in the high-risk group are more likely to undergo more aggressive treatment such as lymph node dissection and radioactive iodine therapy. Other systems that use gender as a variable in staging, whereby female sex is prognostically favorable, include the European Organisation for the Research and Treatment of Cancer and sex, age and grade classifications.[7]

The increased F:M ratio in thyroid cancer incidence does not remain static with age. Female predominance peaks at puberty. This has been observed in a study reported by Farahati et al. of children and adolescents where the peak F:M ratio was found to be as high as 14,[8] although other studies, such as reports by dos Santos Silva et al. and Henderson et al. suggest a lower ratio of 3[9] or 5.3,[10] respectively, which then declines with age.[8–11] This pattern occurs as the thyroid cancer incidence begins to increase at an earlier age in females than in males,[9] leading to a rise in the F:M ratio. The ratio starts to decline as the male incidence rate begins to increase and, concurrently, the rate of increase in female incidence rate slows down.[201,9] The steady decrease in F:M ratio with age continues, and the peak male rate does not occur until between 65 and 69 years of age, compared with the earlier peak female rate between 45 and 49 years of age,[201] just before the mean age of menopause at 50 years.

In reference to historical trends, thyroid cancer incidence has steadily increased overall. Over the period 1973–2002, there was a 2.4-fold increase in age-adjusted rate of incidence of thyroid cancer.[201] However, the F:M ratio has remained fairly constant during this time period,[12,13] and the rate of increase in incidence in females has been similar, if not slightly higher, than in males.[201,13,14]

The objective of this review is to evaluate the gender differences in thyroid cancer, as well as epidemiological, clinical and experimental research on the role of sex hormones, their receptors and other molecular factors in this well-established thyroid cancer gender discrepancy.

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