The thyroid gland of children is especially vulnerable to the carcinogenic action of ionizing radiation. To provide insights into various modifying influences on risk, seven major studies with organ doses to individual subjects were evaluated. Five cohort studies (atomic bomb survivors, children treated for tinea capitis, two studies of children irradiated for enlarged tonsils, and infants irradiated for an enlarged thymus gland) and two case-control studies (patients with cervical cancer and childhood cancer) were studied. The combined studies include almost 120,000 people (approximately 58,000 exposed to a wide range of doses and 61,000 nonexposed subjects), nearly 700 thyroid cancers and 3,000,000 person years of follow-up. For persons exposed to radiation before age 15 years, linearity best described the dose response, even down to 0.10 Gy. At the highest doses (> 10 Gy), associated with cancer therapy, there appeared to be a decrease or leveling of risk. For childhood exposures, the pooled excess relative risk per Gy (ERR/Gy) was 7.7 (95% CI = 2.1, 28.7) and the excess absolute risk per 10(4) PY Gy (EAR/10(4) PY Gy) was 4.4 (95% CI = 1.9, 10.1). The attributable risk percent (AR%) at 1 Gy was 88%. However, these summary estimates were affected strongly by age at exposure even within this limited age range. The ERR was greater (P = 0.07) for females than males, but the findings from the individual studies were not consistent. The EAR was higher among women, reflecting their higher rate of naturally occurring thyroid cancer. The distribution of ERR over time followed neither a simple multiplicative nor an additive pattern in relation to background occurrence. Only two cases were seen within 5 years of exposure. The ERR began to decline about 30 years after exposure but was still elevated at 40 years. Risk also decreased significantly with increasing age at exposure, with little risk apparent after age 20 years. Based on limited data, there was a suggestion that spreading dose over time (from a few days to > 1 year) may lower risk, possibly due to the opportunity for cellular repair mechanisms to operate. The thyroid gland in children has one of the highest risk coefficients of any organ and is the only tissue with convincing evidence for risk about 1.10 Gy.

Thyroid Cancer after Exposure to External Radiation: A Pooled Analysis of Seven Studies

Thyroid nodules are common, with up to 8% of the adult population having palpable nodules. With the use of ultrasound, up to 10 times more nodules are likely to be detected. Increasing numbers of nodules are being detected serendipitously because of the rising use of imaging to investigate unrelated conditions. The primary aim in investigating a thyroid nodule is to exclude the possibility of malignancy, which occurs in about 5% of nodules. This begins with a thorough history, including previous exposure to radiation and any family history of thyroid cancer or other endocrine diseases. Clinical examination of the neck should focus on the thyroid nodule and the gland itself, but also the presence of any cervical lymphadenopathy. Biochemical assessment of the thyroid needs to be followed by thyroid ultrasound, which may demonstrate features that are associated with a higher chance of the nodule being malignant. Fine-needle aspiration biopsy is crucial in the investigation of a thyroid nodule. It provides highly accurate cytologic information about the nodule from which a definitive management plan can be formulated. The challenge remains in the management of nodules that fall under the "indeterminate" category. These may be subject to more surgical intervention than is required because histological examination is the only way in which a malignancy can be excluded. Surgery followed by radioactive iodine ablation is the mainstay of treatment for differentiated thyroid cancers, and the majority of patients can expect high cure rates.

Management of the Solitary Thyroid Nodule

Thyroid nodules continue to be a source of concern to patients, and their management remains a controversy among physicians. Several diagnostic techniques have been proposed to distinguish benign nodules (the majority) from malignant lesions (the minority). The trend in the management of thyroid nodular disease has been to use these diagnostic techniques with increasing frequency. The past decade has seen widespread application of fine-needle aspiration biopsy, new radionuclide scanning agents, and sensitive ultrasonography for diagnosing thyroid nodular disease. The diagnostic techniques used to distinguish benign from malignant nodules, however, vary in reliability. Furthermore, technological improvements have introduced new problems — . . .

Nodular thyroid disease. Evaluation and management.

Molecular
genetic aberrations and the related phenotypes were investigated in 191
papillary thyroid carcinomas (PTCs) from patients exposed at
young age to radioiodine released from the Chernobyl reactor. A high
prevalence of RET gene rearrangements (62.3%) with a
significant predominance of ELE1/RET (PTC3) over
 H4/RET (PTC1) rearrangements was found in PTCs of the
first post-Chernobyl decade. NTRK1 rearrangements were
rare (3.3%). In 3.3%, we observed novel types of RET 
rearrangements: GOLGA5/RET (PTC5),
 HTIF/RET (PTC6), RFG7/RET (PTC7), and an
as yet undefined RFGX/RET . RET 
rearrangements, preferentially ELE1/RET , are related to
rapid tumor development. At longer intervals after exposure to ionizing
radiation, the prevalence of RET rearrangements declines
with a shift from ELE1/RET to H4/RET ,
most significantly in female patients. The prevalence of specific types
of rearrangements is independent of age at irradiation. A significantly
higher prevalence of ELE1/RET was observed in the most
heavily contaminated Oblasts, Gomel and Brest, suggesting a
preferential formation of this type of rearrangement after high thyroid
doses. RET rearrangement is related to aggressive
growth: Rearrangement-positive PTCs were in a more advanced pT category
and more frequently in the pN 1 category at presentation
than rearrangement-negative PTCs. ELE1/RET is related to
the solid variant of PTC, H4/RET more frequently to
typical papillary structures. The genotype/phenotype evaluation of
post-Chernobyl PTCs reveals a characteristic spectrum of gene
rearrangements that lead to typical phenotypes with important
biological and clinical implications.

https://clincancerres.aacrjournals.org/content/clincanres/6/3/1093.full.pdf

Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications.

Records of 792 patients with differentiated thyroid carcinoma seen at the Lahey Clinic Foundation over a 40-year period were analyzed; 631 patients had a minimum followup period of 15 years. Differentiated types currently constitute nearly 90% of thyroid carcinomas. The clinical presentation has improved substantially through the years, and the results of treatment generally have improved. The per cent of patients with primarily incurable and locally unresectable disease or distant metastases has decreased from 7% before 1950 to 1% currently, and this group resulted in almost one third of the total fatalities and one half of fatalities within the first 5 years after treatment. Clear relationships were demonstrated between older age, men, extraglandular extension, blood vessel invasion, major capsular involvement, multifocal disease, and higher mortality rates. Lymph node metastases were found to exert a protective effect in all categories of disease analyzed, and this effect was directly related to the number of lymph node metastases present such that no deaths occurred in those patients who had more than 10 node metastases. Surgical treatment recommended is subtotal thyroidectomy for patients at high risk of death from disease as defined by combinations of age, sex, and extraglandular extension. Patients at low risk or with small carcinomas can be treated satisfactorily by lobectomy. Lymph node resections should be of a limited type or a modified neck dissection and should be performed only therapeutically. No improvement, as judged by mortality or recurrence rates, could be demonstrated by the use of radio therapy after surgery, and its use should be discouraged. Thyroid hormone administered for suppression of endogenous thyroid-stimulating hormone production improved mortality rates significantly in patients with papillary and mixed forms of carcinoma in all age groups but did not affect survival in patients with follicular carcinoma of the thyroid.20

Changing clinical, pathologic, therapeutic, and survival patterns in differentiated thyroid carcinoma.

The level of thyroglobulin in plasma was measured in 904 subjects with a history of head and neck irradiation during childhood to evaluate its potential value in screening for and differentiating thyroid neoplasms. Mean plasma thyroglobulin level was significantly elevated in subjects with nodular thyroid disease versus those without evidence of nodules (49.8 versus 27.0 ng/ml). However, the overlap with normal subjects does not allow thyroglobulin assays to serve as the only screening procedure. The mean levels in subjects with benign and malignant thyroid nodules were indistinguishable (48.8 versus 53.9 ng/ml). Thirteen percent of otherwise normal-appearing subjects had elevated values that may represent clinically inapparent thyroid disease. It is concluded that in screening large numbers of persons at risk for thyroid neoplasia, thyroglobulin assays are useful in combination with other modes of evaluation. The assay is without value in distinguishing benign from malignant disease.

Plasma Thyroglobulin in Detecting Thyroid Carcinoma after Childhood Head and Neck Irradiation

To evaluate the reliability of thyroid scintigraphy in the diagnosis of nodular growths, scintigrams of patients who later underwent thyroidectomy were reviewed and correlated with pathologic findings. The scintigrams were all obtained with a 5-mm single-hole collimator-equipped gamma-scintillation camera after intravenous injection of 5 millicuries of sodium pertechnetate Tc 99m. In the group of 92 patients, six of whom had two histologically different lesions, 149 nodules were identified pathologically. There were 26 nodules 2 to 5 mm in diameter, of which 22 were benign and four were malignant. None of the 22 benign nodules were delineated scintigraphically. Superior image quality and resolution, low radiation dose, technical simplicity, and speed make Tc pinhole-camera scintigraphy the best procedure available for routine thyroid imaging. (JAMA235:1235-1238, 1976)

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=JAMA&articleId=344494&pdfFileName=jama_235_12_021.pdf

Thyroid Scintigram: Sensitivity With Sodium Pertechnetate Tc 99m and Gamma Camera With Pinhole Collimator

Histories, physical examinations and 99mTc-pertechnetate imaging were used to evaluate 1,452 persons who had had x-ray therapy to the neck region for benign conditions 18 to 35 years previously. Thyroid abnormalities were found in 301 patients (21%) and thyroid malignancy was found in 29% of 193 patients with abnormal studies who were explored surgically. Thyroid imaging detected 96% of these abnormalities, 40% of which would not have been unequivocally established by physical examination alone. Nuclear imaging could not distinguish benign from malignant lesions.

99mTc-pertechnetate thyroid scintigraphy in patients predisposed to thyroid neoplasms by prior radiotherapy to the head and neck.

From January 1 to September 30, 1974, we examined 1056 of 5266 subjects (20.1 per cent) who had received therapeutic irradiation primarily for infections and inflammatory disease of the upper respiratory tract at our institution during the 1940's and 1950's. The tonsillar and nasopharyngeal region was the treatment site in 85 per cent of those examined. Palpable nodular thyroid disease was found in 16.5 per cent, and nonpalpable lesions were detected by 99mTc pertechnetate thyroid imaging in an additional 10.7 per cent, for a prevalence of nodular disease of 27.2 per cent. Operation on 71 per cent with nodular disease revealed thyroid cancer in 33 per cent (60 of 182). Preliminary analysis for potential risk factors suggests a correlation between radiation exposure and the presence of thyroid nodules (P<0.001). These findings indicate that nodular thyroid disease, both benign and malignant, continues as a major health problem for at least 35 years in exposed subjects. (N Engl J Med 294:1019–1025,...

https://www.nejm.org/doi/pdf/10.1056/NEJM197605062941901?listPDF=true

Thyroid cancer occurring as a late consequence of head-and-neck irradiation. Evaluation of 1056 patients.

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Plasma Thyroglobulin in Detecting Thyroid Carcinoma after Childhood Head and Neck Irradiation

Thyroid Scintigram: Sensitivity With Sodium Pertechnetate Tc 99m and Gamma Camera With Pinhole Collimator

99mTc-pertechnetate thyroid scintigraphy in patients predisposed to thyroid neoplasms by prior radiotherapy to the head and neck.

Thyroid cancer occurring as a late consequence of head-and-neck irradiation. Evaluation of 1056 patients.