Many patients naturally want to know "Why did I get thyroid cancer?". Most patients have no known risk factors or family history and were often previously in good health. Scientists and physicians do not have good answers to this question yet, but many research programs are looking into this issue.
A substantial number of thyroid cancers appear to exhibit genetic abnormalities in one or more chromosomes, but the reason for these types of chromosomal abnormalities Allelotyping of follicular thyroid carcinoma: frequent allelic losses in chromosome arms 7q, 11p, and 22q. J Clin Endocrinol Metab. 2001 Sep;86(9):4268-72 remain incompletely understood. Increasingly, it is now recognized that well differentiated thyroid cancer, such as papillary and follicular thyroid cancer, commonly occurs in families, with males having a slightly greater risk of developing cancer in the setting of a positive family history. In contrast, females are 3x more likely to develop thyroid cancer in the general population. Genetic analysis of European populations, confirmed in other populations of European descent, have revealed that genetic variants in two specific genes, designated Forkhead Factor E1 (FoxE1) and a second gene in the region of the transcription factor Nkx2.1, substantially increase the risk of well differentiated thyroid cancer. Both of these genes have previously been shown to be involved in the development and/or function of the thyroid. Specific variants in the DNA in the region of these genes significantly increases the risk of developing thyroid cancer as described in Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations Nature Genetics Published online: 6 February 2009 | doi:10.1038/ng.339
Regardless of the advances in understanding how genetic differences impact the risk for thyroid cancer, dozens of studies have demonstrated that the vast majority of patients with well differentiated thyroid cancer (papillary thyroid cancer) have an excellent prognosis, as outlined in Papillary thyroid carcinoma: Monoinstitutional 40-year experience on 2500 patients. Eur J Cancer. 2006 Oct 26; [Epub ahead of print]
A very common mutation detected in papillary thyroid cancer is activation of the Ret or Trk signaling pathways, leading to enhanced cell growth. Similarly, mutations have also been detected in BRAF, a cell signaling molecule whose activities are coupled to stimulation of cell growth. BRAF mutations appear to be detected in papillary but not follicular thyroid cancer, as shown in High Prevalence of BRAF Mutations in Thyroid Cancer: Genetic Evidence for Constitutive Activation of the RET/PTC-RAS-BRAF Signaling Pathway in Papillary Thyroid Carcinoma. Cancer Res. 2003 Apr 1;63(7):1454-1457 and Detection of BRAF Mutation on Fine Needle Aspiration Biopsy Specimens: A New Diagnostic Tool for Papillary Thyroid Cancer. J Clin Endocrinol Metab. 2004 Jun;89(6):2867-72.
Furthermore, the presence of BRAF mutations appear to be associated with an increased risk of extrathyroidal tumor extension, and a higher risk of recurrence as described in BRAF Mutation Predicts a Poorer Clinical Prognosis for Papillary Thyroid Cancer. J Clin Endocrinol Metab. 2005 Sep 20; [Epub ahead of print]
In contrast, specific genetic mutations have also been identified in follicular thyroid tumors. 3p25 rearrangements of the peroxisome proliferator-activated receptor gamma (PPARgamma) gene have been detected in follicular epithelial tumors of the human thyroid gland. Eleven of 42 (26%) low-stage follicular carcinomas, 0 of 40 follicular adenomas, 1 of 30 Hurthle cell carcinomas, 1 of 90 papillary carcinomas, and 0 of 10 nodular goiters had 3p25 rearrangements by interphase fluorescence in situ hybridization. Hence, this abnormality likely contributes to the development of follicular thyroid cancer. See Genetic and biological subgroups of low-stage follicular thyroid cancer. Am J Pathol. 2003 Apr;162(4):1053-60.
Molecular genetic studies suggest that exposure to ionizing radiation is associated with specific genetic changes that activate oncogenes, or cancer-causing genes, in thyroid tissue. For example, see Distinct pattern of ret oncogene rearrangements in morphological variants of radiation- induced and sporadic thyroid papillary carcinomas in children. Cancer Res. 1997 May 1;57(9):1690-4 and Oncogene 1997 Sep;15(11):1263-73 High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation. More recent studies have demonstrated that intrachromosomal rearrangements involving the BRAF oncogene also play an important role in the development of radiation-induced thyroid cancer in many patients as described in Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest. 2005 Jan;115(1):94-101. Although the majority of patients with thyroid nodules and a history of radiation exposure will end up having benign nodules, the presence of multiple nodules increases the risk of thyroid cancer in these patients, and often requires biopsies of one or more smaller nodules to make the diagnosis. See Size, number and distribution of thyroid nodules and their risk of malignancy in radiation-exposed patients who underwent surgery J Clin Endocrinol Metab. 2008 Apr 1; [Epub ahead of print]
The majority of patients with non-medullary thyroid cancer, including patients with well differentiated thyroid cancers (WDTC) such as papillary or follicular thyroid cancers, do not have a familial component to their disease, and usually do not pass on a markedly increased risk of cancer to their children. Nevertheless, a small percentage of even WDTC patients do appear to develop the disease as a result of an as yet unknown genetic predisposition. Intriguingly, a rare subset of patients with a RETV804M mutation appear to develop both medullary thyroid cancer and papillary thyroid cancer One hundred and seven family members with the rearranged during transfection V804M proto-oncogene mutation presenting with simultaneous medullary and papillary thyroid carcinomas, rare primary hyperparathyroidism, and no pheochromocytomas: is this a new syndrome--MEN 2C? Surgery. 2009 Dec;146(6):998-1005.
Many patients have more than one papillary carcinoma within the removed thyroid, often referred to as multifocal disease. Genetic analysis of the tumors in some studies indicates that the different tumors appear to arise from independent events, and are not genetically related or derived from the same original tumor as described in Independent clonal origins of distinct tumor foci in multifocal papillary thyroid carcinoma. N Engl J Med. 2005 Jun 9;352(23):2406-12. However, these results have not been universally confirmed, as similar studies have concluded that multifocal tumors often arise from a single common primary lesion Molecular evidence for the same clonal origin of multifocal papillary thyroid carcinomas. Clin Cancer Res. 2006 Apr 15;12(8):2414-8
Several studies Ann Intern Med 1999:131:738-44 suggest that survivors of bone marrow transplants may also have a slightly increased risk of thyroid cancer. For example, children receiving allogeneic BMT clearly exhibit an increased number of thyroid cancers several years after treatment, and should be followed closely with regular thyroid assessments. See Secondary thyroid carcinoma after allogeneic bone marrow transplantation during childhood. Bone Marrow Transplant. 2001 Dec;28(12):1125-8.
Analysis of patients treated with high dose radiotherapy at Memorial Sloan-Kettering Cancer Center revealed 13 patients with well differentiated thyroid cancer. The median interval from the time of radiation therapy until the recognition of thyroid disease was 13.0 years (range, 6.2-30.1 years). See Thyroid neoplasms after therapeutic radiation for malignancies during childhood or adolescence. Cancer. 2003 May 15;97(10):2397-403.
Similarly, transplant patients receiving prolonged immunosuppression appear to be a greater risk for development of thyroid cancer Cancer incidence in a kidney-transplanted population Transpl Int 2000;13 Suppl 1:S394-8. and Thyroid cancer in the renal transplant population: epidemiological study. ANZ J Surg. 2005 Mar;75(3):106-9 Furthermore, patients with radioactive iodine exposure during childhood also exhibit an increased risk of thyroid cancer years later during adulthood as outlined in Risk of thyroid cancer after exposure to 131I in childhood. J Natl Cancer Inst. 2005 May 18;97(10):724-32. Patients exposed to radiation have an increased risk of developing benign thyroid nodules as well as thyroid cancer. Nevertheless, the majority of patients with thyroid cancer have no history of radiation exposure.
Genetic Syndromes and Thyroid Cancer
Patients with Medullary Thyroid Cancer (MTC) will frequently have a genetic mutation that is responsible for development of the cancer. A substantial proportion of patients with MTC will have a mutation in the ret oncogene, and such patients should have genetic screening of their families to identify other potential gene carriers. For an overview of MTC diagnosis and treatment, see Cancer 2000 Mar;88(5): 1139-1148 Medullary thyroid carcinoma: Clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. For a general overview of the diagnosis and treatment of genetic forms of thyroid cancer, see Familial thyroid cancer Curr Opin Oncol 2001 Jan;13(1):44-51.
Some patients with MTC may also have other endocrine tumors, such as adrenal tumors (pheochromocytomas) or Parathyroid Adenomas (or parathyroid hyperplasia) that comprise a genetic syndrome known as the Multiple Endocrine Neoplasia II syndrome (MEN 2). Patients with MEN 1, a different genetic disease, may also have parathyroid disease but generally do not get thyroid cancer as an associated feature of the MEN 1 syndrome.
Patients with familial adenomatous polyposis (FAP) also appear to have an increased incidence of papillary thyroid cancer. J Clin Endocrinol Metab 2000 Jan;85(1):286-92 Germline mutations of the APC gene in patients with familial adenomatous polyposis-associated thyroid carcinoma: results from a European cooperative study. In one studies, multiple thyroid tumors developed, each harboring a different mutation in the FAP gene. See Molecular evidence for multicentric development of thyroid carcinomas in patients with familial adenomatous polyposis. Am J Pathol. 2000 Dec;157(6):1825-7.
In patients with FAP tha underwent a screening ultrasound, thyroid cancer
was ultimately detected in 12% of the patients as outlined in Prevalence
of Thyroid Cancer in Familial Adenomatous Polyposis Syndrome and the Role
of Screening Ultrasound Examinations.
Clin Gastroenterol Hepatol. 2007 Jan 25; [Epub ahead of print]
Patients with Cowden's syndrome have an increased risk of several malignancies, and exhibit an increased risk of benign and malignant thyroid disease. Cowden's syndrome patients have a mutation in the gene designated PTEN, that encodes a protein tyrosine phosphatase.
Thyroid cancer may cluster in isolated families in about 2% of all cases. The genetic basis for these syndromes remains unknown, but is under active investigation. For example, see Clin Endocrinol (Oxf) 1999 May;50(5):589-94 Familial non-medullary thyroid carcinoma: pathology review in 27 affected cases from 13 French families. Indeed, other reports have suggested that the incidence of familial papillary carcinoma may be higher than 2%, as high as 9% in some centers. See Familial papillary carcinoma of the thyroid: a report of nine first-degree relatives of four families Eur J Surg Oncol 2000 Dec;26(8):789-791.
A new syndrome, transmitted in an autosomal dominant manner with incomplete penetrance has been described that links papillary thyroid cancer, nodular thyroid disease, and papillary renal neoplasia (kidney tumors) in certain families. The putative gene has been localized to chromosome 1q21, but the gene has not yet been definitively identified. There may also be a slightly increased risk of premenopausal breast cancer in patients with this mutation. For an overview, see Papillary thyroid carcinoma associated with papillary renal neoplasia: genetic linkage analysis of a distinct heritable tumor syndrome. J Clin Endocrinol Metab. 2000 May;85(5):1758-64.
Independent analysis of families of women who had either breast or ovarian cancer also indicate a slightly increased risk of thyroid cancer in the children. See Familial breast and ovarian cancer: a Swedish population-based register study. Am J Epidemiol. 2000 Dec 15;152(12):1154-63.
The incidence of thyroid cancer, especially well differentiated thyroid cancer, has increased over the past few decades, as documented in several cancer registries in both North America and Europe. See Incidence of thyroid cancer in adults recorded by French cancer registries (1978-1997). Eur J Cancer. 2002 Sep;38(13):1762. The Canadian Cancer Society Epidemiology Statistics are also provided in an easy to use Web-based format. Examine the changing trends in thyroid cancer incidence by region, age, sex, or compare variables. See Cancer of the Thyroid, Both Sexes Combined, All Ages, 1998.
Am I at risk for the development of other cancers if I have been diagnosed with thyroid cancer?
Although there are some rare genetic syndromes which may predispose towards the development of thyroid cancers and other malignancies, the vast majority of patients diagnosed with papillary thyroid cancer are not at markedly increased risk for the development of second cancers Risk of Second Primary Malignancies in Women with Papillary Thyroid Cancer. Am J Epidemiol. 2006 Jan 18; However, other studies imply a slightly increased risk of a second cancer once a diagnosis of thyroid cancer has been established, perhaps due in part to the close medical follow-up of young patients with thyroid cancer Second primary cancers in thyroid cancer patients: a multi-national record linkage study. J Clin Endocrinol Metab. 2006 Feb 14; [Epub ahead of print]
Is thyroid cancer becoming more common?
Although it is difficult to provide a precise explanation for the increasing incidence of thyroid cancer in many countries, several studies do show that a thyroid cancer diagnosis is more common now compared to 20-30 years ago. Many experts feel that this is due to increased detection of small well differentiated papillary thyroid cancers, perhaps due to increased utilization of ultrasounds, rather than a real jump in the number of large cancers, as outlined in Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006 May 10; 295 (18): 2164-7. Furthermore, there is objective evidence that the average size of thyroid cancers is becoming smaller, suggesting that these lesions are now detected earlier, and likely accounting for the excellent prognosis associated with this disease. See Trend in thyroid carcinoma size, age at diagnosis, and histology in a retrospective study of 500 cases diagnosed over 20 years. Thyroid. 2006 Nov;16(11):1151-5.
Indeed while the number of patients with thyroid cancer is increasing, most of the increase appears to be due to detection of smaller tumors, likely due to enhanced diagnostic efficiency and widespread use of ultrasound technology. See Increased incidence of differentiated thyroid carcinoma and detection of subclinical disease CMAJ. 2007 Nov 20;177(11):1357-61
For a discussion of the rising incidence of thyroid cancer, encompassing environmental and other risk factors, as well as more sensitive diagnostic techniques, see
Geographic influences in the global rise of thyroid cancer Nat Rev Endocrinol. 2019 Oct 15. doi: 10.1038/s41574-019-0263-x