Primary Thyroid Carcinoma in Childhood Cancer Survivors
With modern therapies and supportive care, the number of the childhood cancer survivors (CCS) has increased considerably. However, these patients suffer from the late-onset complications such as endocrine impairments, neuropsychological problems and second malignancies. These late-onset complications often do not become clinically apparent until decades after therapy. Since the likelihood of follow-up decreases with time, it is important for physicians as well as patients and family members to be aware of the late-onset complications over their lifetime.
Patients who received upper-body radiotherapy for childhood cancer have an increased risk of developing primary thyroid cancer later in life. Brignardello et al set forth the recommendations for monitoring the late-onset complications of thyroid carcinoma by thyroid ultrasound screening into young adulthood, and beyond, in CCS. They observed a very high occurrence of thyroid carcinoma as a second malignant neoplasm in a total of 129 CCS who were previously treated with radiotherapy involving the head, neck, or upper thorax. The patients had had brain tumors, Hodgkin’s disease, acute lymphoblastic leukemia and received preventive brain irradiation or total body irradiation for bone marrow transplantation. Thyroid ultrasound surveillance usually began 5 years after radiotherapy and was repeated every third year, if negative. Median follow-up time since the primary childhood cancer diagnosis was 15.8 years (range 6.1 to 34.8 years). Solid thyroid nodules were found in 35 patients included patients with palpable nodules (n=6) as well as those with solid nodules larger than 0.5 cm detected by thyroid ultrasound. Fourteen patients had nodules over 1 cm, 8 of which were not palpable. Fine-needle aspiration was performed in 19 patients, of which 14 had nodules over 1 cm. Cytological examination of specimens resulted in papillary carcinoma diagnosed in 5 patients and follicular carcinoma in 6 patients. In the remaining 8 patients, 7 had a diagnosis of nodular hyperplasia and one had lymphocytic thyroiditis. The cytological diagnosis of papillary thyroid carcinoma was confirmed by histological examination in all 5 subjects who underwent surgery. Notably, only 2 of these patients had palpable nodules; the other 3 were smaller than 1 cm and were only detected by ultrasound. However, histological examination showed nodal metastases in 2 of them. In all 6 patients with follicular neoplasms who underwent surgery, the histological examination showed a benign lesion (goiter, n=3; follicular adenoma, n=3). Thyroid function was normal in 87 subjects, whereas 42 had primary hypothyroidism (n=37) or central hypothyroidism (n=5).
This is a very interesting article; it provides important information for physicians who care for CCS. Because survival rates of childhood cancer patients have improved markedly in recent years, the risk of developing a thyroid neoplasm clearly increases over many years after radiation therapy involving the head, neck, or upper thorax during childhood. Brignardello et al reported the prevalence of thyroid cancer, thyroid nodules and other thyroid alterations increased in the long-term follow-up of CCS.
There are 2 other papers on the subject worthy of discussion. In a 2003 retrospective study of all survivors of childhood and adolescent malignancies treated at Memorial Sloan-Kettering Cancer Center, Acharya et al1 reported 33 patients who developed a clinically apparent thyroid neoplasm after therapeutic radiation. The median age at the time of diagnosis of the primary malignancy was 12.0 years (range, 3.7 to 18.3 years). The most common primary malignancy seen was Hodgkin’s disease (n=18 patients), followed by non-Hodgkin’s lymphoma (n=10 patients). The median interval from the time of radiation therapy until the recognition of thyroid disease was 13.0 years (range, 6.2 to 30.1 years). Thirteen of 33 thyroid lesions (39%) were malignant (11 papillary carcinomas and 2 follicular carcinomas). All thyroid abnormalities were detected on routine physical examination. Seventeen patients presented with a single nodule, 7 with multiple nodules, 5 with a multinodular goiter, 2 with lobar enlargement, 1 with a diffuse goiter, and 1 with an enlarged cervical lymph node and a normal thyroid gland. Thyroid ultrasound results were abnormal in 18 of 19 patients. Ultrasound revealed the presence of multiple nodules in 33% of patients, whereas only 15% of those patients had multiple nodules that were appreciated on physical examination.
In 2005, Sigurdson et al reported 72 cases with pathologically confirmed thyroid cancer from 14054 survivors (5 years or longer) of cancer during childhood from the Childhood Cancer Survivor Study cohort.2 Childhood cancers were diagnosed between 1970 and 1986 with cohort follow-up to 2000. Of the 72 cases with secondary thyroid neoplasms, 56 (78%) were papillary, 11 (15%) follicular, and 5 (7%) of other or unspecified histology; 29 cases had a first diagnosis of Hodgkin’s lymphoma and 14 had leukemia. They showed that the risk of subsequent primary thyroid cancer after a first tumor in childhood rose with increasing radiation dose (greatest risk 20–29 Gy), but decreased at doses of more than 30 Gy. Patients younger than 10 years at first cancer diagnosis had a higher risk of thyroid cancer than patients aged 10 years or older.
It is evident from these studies that thyroid nodules, even those greater than 1.5 cm, cannot always be palpated. In the study of Brignardello et al only 2 of the 5 patients with papillary thyroid carcinoma had palpable nodules. In the other 3 cases, the nodules were less than 1 cm, and were only detected by ultrasound. Therefore, the authors recommended monitoring the thyroid cancer by thyroid ultrasound screening in CCS previously treated by radiotherapy involving the head, neck, or upper thorax. Early detection of secondary thyroid cancers could improve the outcome of the patients. However, because thyroid ultrasound also detects many small lesions, the majority of which are benign, a very careful evaluation is needed to ascertain the results of thyroid ultrasound screening.
Brignardello et al emphasized the need for long-term follow-up for all CCS, which clearly must be extended well beyond childhood. Follow-up must address transitional strategies to avoid dropout and improve the overall outcome of childhood cancer treatment and survivors. Also it is necessary for physicians, as well as patients and family members, to know that late-onset complications of a cancer survivor can occur even after many years following cancer treatment.3
Yoshikazu Nishi, MD
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