Pathophysiology and Etiology of Papillary Thyroid Cancer

Chromosomal rearrangements were the first oncogenic events identified in PTC, encompassing the rearranged during transfection (RET) proto-oncogene, which arises from a paracentric inversion of chromosome 10. In nearly 20% of PTC the RET fusion proteins (the RET / PTC family) seem to have an oncogenic role, with the RET / PTC 1, RET / PTC 2, and RET / PTC 3 representing the vast majority of cases. In addition, the NTRK 1 and the MET proto-oncogene may be overexpressed and / or amplified.

Evidence also suggests that some molecules that physiologically regulate the growth of the thyrocytes, such as interleukin-1 and interleukin-8, or other cytokines (eg, insulin-like growth factor 1, transforming growth factor beta, epidermal growth factor) could play a role in the pathogenesis of this cancer.

Mutation in the BRAF gene resulting in the BRAF V600E protein is prominent in PTC. Mathur et al, in a single-institution study reported higher rates of BRAF V600E mutations in PTC from 1991 to 2005, proposing that this may be contributing to the rise in rates of thyroid cancer. The BRAF V600E mutation is related with aggressive clinicopathological characteristics of PTC, including lymph node metastasis, extrathyroidal invasion, and loss of radioiodine avidity, which may lead to failure of radioiodine treatment and disease recurrence. 

The thyroid gland is very sensitive to the effects of ionizing radiation, both accidental and medical exposure to ionizing radiation has been linked to increased risk for thyroid cancer. Around 7% of individuals exposed to the atomic bombs in Japan developed thyroid cancers. The inhabitants, especially children, who lived in Ukraine during the Chernobyl nuclear accident have higher risk of developing PTC [28-30]. It has been documented that PTC in patients who have been exposed to radiation from the Chernobyl accident could be easily distinguished from sporadic PTC in patients with no history of radiation exposure, on the basis of gene expression profiles involving seven genes (ie, SFRP1, MMP1, ESM1, KRTAP2-1, COL13A1, BAALC, PAGE1). 

From 1920 to 1960, therapeutic irradiation was used to treat tumors and benign conditions, including acne; excessive facial hair; tuberculosis in the neck; fungus diseases of the scalp; sore throats; chronic coughs; and enlargement of the thymus, tonsils, and adenoids. Approximately 5% to 10% of individuals who were treated with head and neck irradiation for such disorders developed thyroid cancer after a latency period of 30 to 50 years.

The greater exposure to diagnostic radiation, particularly computed tomography, is a potential culprit for the increased incidence of PTC. Individuals who receive radiotherapy for certain types of head and neck cancer, especially during childhood, may have an increased risk of developing thyroid cancer. Factors that heighten the risk for developing PTC after exposure to radiation include female gender, radiation for childhood cancer, and a family history of thyroid cancer.

There is some small evidence that polybrominated diphenyl ethers (PBDEs), that are flame retardants, that may be found in electrical appliances, plastics, televisions, computers, building supplies, foams, carpets, and upholstery, could possibly contribute to the development of thyroid cancer. PBDEs and their metabolites have a structural similarity to thyroxine and can accumulate in tissues. These compounds have been shown to be endocrine disrupters, with thyroid and estrogen effects being the most common. PBDEs have been shown to have increased oncogenic potential in other tissues which has made them a desirable candidate for additional research in thyroid cancer pathogenesis.

Obesity has repeatedly been cited as a possible etiologic factor in the pathogenesis of thyroid cancer and has been postulated to be a possible origin of the increase incidence of this disease worldwide. Undeniably, being overweight and obesity have been associated with an increased risk of developing numerous malignancies, including thyroid, breast, colorectal, kidney, and endometrial cancers. In the United States from 1995 to 2015, one out of every six PTC and two thirds of PTC greater than 4 cm in size have been linked to being overweight or obesity, based on an analysis of data from three large national US databases. Kitahara et al projected that the total relative risk for PTC was 1.26 for persons who are overweight (body mass index [BMI] 25 to 29 kg/m2) and 1.30 for those who are obese (BMI ≥ 30  kg/m2), compared with persons with normal-weight BMI (18.5 to 24.9 kg/m2). The risk in PTCs greater than 4 cm in size was nearly 3-fold higher (hazard ratio [HR] = 2.93, 95% CI 1.25-6.87) with overweight individuals, and more than 5-fold higher (HR = 5.42, 95% CI 2.24-13.1) in obese individuals compared with normal-weight individuals. A study by Leitzmann et al, found that obese adults had a nearly 40% higher risk for developing thyroid cancer when compared with normal-weight individuals. More research is needed to define the exact role of obesity in the development of thyroid cancer, particularly as the incidence of obesity continues to climb throughout the world. 

Most thyroid cancers are sporadic in nature; nonetheless, roughly 5% of non-medullary thyroid cancers are hereditary. These hereditary cases have been divided into two groups: those tumors associated with a familial cancer syndromes, such as Cowden’s disease, familial adenomatous polyposis (FAP), and its variant Gardner’s syndrome, Carney’s complex type 1, and Werner’s syndrome, and those with thyroid neoplasms as the primary feature such as familial non-medullary thyroid cancer (FNMTC). Particularly FAP is associated with an elevated risk of developing a rare variant of PTC called cribriform morula variant of PTC (CMV-PTC). In a study by Uchino et al, of 129 patients with FAP who underwent screening with cervical ultrasound identified 11 cases of PTC, eight of which were CMV-PTC. All the patients with CMV-PTC were women 35 years of age or younger. 

FNMTC is defined by the presence of three or more first-degree relatives with well-differentiated thyroid cancer. When only two family members are affected only 38% will have FNMTC. When three or more family members are affected there is a 96% likelihood of having FNMTC [47]. The pattern of inheritance is autosomal dominant with incomplete penetrance. Individuals with FNMTC will have a more aggressive biology compared to their sporadic counterparts. 

Numerous articles have shown a connection between iodine deficiency and thyroid cancer [49]. Various other ailments have been linked as predisposing factors to PTC, including oral contraceptive use, benign thyroid nodules, late menarche, and late age at first birth. Smoking appears to be associated with a decreased risk of thyroid cancer.

#Arrangoiz #CancerSurgeon #ThyroidSurgeon #HeadandNeckSurgeon #SurgicalOncologist #ThyroidCancer #PapillaryThyroidCancer #CASO #CenterforAdvancedSurgicalOncology #Miami #Hialeah

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