Thyroid Cancer, Childhood

Introduction

Survival rates for almost all types of childhood cancer have improved dramatically over the last 30 years. Estimates suggest that 1 of every 450 adolescents and young adults is a long-term survivor of childhood cancer. This is based on estimates that cancer occurs in 1 per 600 children and in 1 per 300 adolescents. With current therapy, 75% are cured. The increased number of survivors has focused attention on the many long-term or late sequelae of treatment. Late effects can be defined as any adverse effect that does not resolve after completion of therapy or any new problem that becomes evident after completion of therapy. Most of these effects are not detectable at the end of therapy but become evident with maturation (puberty), growth, and the normal aging process.

These effects are discussed by organ system, keeping in mind that many survivors have at least one organ system affected. Psychosocial issues and development of second malignancies are also addressed. Late relapses of the primary cancer, although uncommon, do occur and are the major contributor to late mortality. Late effects following bone marrow transplantation are discussed in Bone Marrow Transplantation, Long-Term Effects.

For excellent patient education resources, visit eMedicine's Endocrine System Center. Also, see eMedicine's patient education article Thyroid Problems.

• Heart damage can occur secondary to radiation therapy (RT) that includes all or part of the heart within the radiation field (eg, mantle irradiation for Hodgkin disease, spinal irradiation for some brain tumors). Patients who present with cardiac toxicity due to RT alone generally present with pericardial effusions or constrictive pericarditis. Radiation can also lead to premature coronary artery disease. Heart damage can also be caused by chemotherapy, especially the anthracycline drugs, such as doxorubicin and daunomycin, and occasionally cyclophosphamide when administered at high doses.
• Patients with anthracycline-induced cardiomyopathy usually present with symptoms of congestive heart failure (CHF), which may develop spontaneously or be initiated by stressors such as extreme exertion, as in weight lifting or difficult labor. Pericarditis may also be present, further compromising cardiac function. Additionally, ventricular arrhythmias may occur.
• Subclinical or mild toxic effects can be found in a significant number of treated children depending on the methods used to assess damage. One study of children who received anthracyclines for acute lymphoblastic leukemia (ALL) showed that 57% had abnormalities of afterload or contractility on echocardiography (ECHO). Abnormalities are more frequent and more severe in patients who receive both RT and chemotherapy. However, the incidence of early and late CHF from anthracycline chemotherapy is still only 1-2%. Problems in predicting which patients are going to develop clinically significant heart disease are still recognized.

Risk factors for cardiac toxicity

• Age at diagnosis: Infants and toddlers with ALL or neuroblastoma who receive anthracyclines have more frequent abnormalities on ECHO than older children who receive the same treatment. This suggests the heart is not capable of increasing its workload sufficiently to keep up with a growing child.
• Sex: In several studies, girls had about a 2-fold higher risk of cardiac toxicity than boys.
• Cumulative dose of anthracyclines: In adults, the incidence of CHF was 3% at a cumulative dose of 400 mg/m2 of doxorubicin, 7% at a cumulative dose of 550 mg/m2, and 18% at cumulative doses over 700 mg/m2. In a review of 6493 children on Pediatric Oncology Group studies, the risk of developing CHF was 5 times higher with cumulative doses over 550 mg/m2 than with lower doses. This phenomenon has been best studied with the anthracycline doxorubicin. Other anthracyclines have different threshold doses for cardiac toxicity.
• Method of anthracycline delivery: Fewer toxic effects were observed with intravenous infusion over 24 hours than with intravenous bolus or infusion over 15-30 minutes.
• Anthracycline schedule: Fewer toxic effects were observed with weekly infusions than with infusions every 3 weeks.
• Mediastinal or spinal irradiation: Radiation-induced fibrosis occurs most often in the pericardium, causing acute and late pericarditis. Myocardial infarction and death can occur from fibrosis of the myocardium or the coronary vessels. Studies in children receiving mantle irradiation for Hodgkin disease show a greater susceptibility to premature coronary artery disease in adolescents exposed to mediastinal radiation doses greater than 4000 cGy. In one study of 16 children treated with spinal irradiation for malignancies, 75% had a maximal cardiac index below the fifth percentile and the group as a whole had significantly higher estimated posterior wall stress. Thirty one percent had pathologic Q waves in the inferior leads.
• Length of time since diagnosis: Studies in both adults and children have shown increasing incidence of abnormal findings on ECHO in patients monitored for more than 10 years than in those monitored for less than 10 years.

Pathophysiology of anthracycline cardiotoxicity

• Free radical damage
• Focal fibrosis
• Dropout of muscle fibers
• Increased wall stress and afterload
• Dilated cardiomyopathy

Cardiac toxicity from radiation therapy

• Pericarditis can be acute, occurring during RT or years later, or chronic, with pericardial effusion or constrictive pericarditis. Children who receive mantle irradiation for Hodgkin disease have a 0-2.5% long-term incidence of pericarditis. As many as 43% of patients in one study were found to have pericardial thickening by ECHO; the rate was even higher in patients monitored for at least 6 years.
• Late coronary artery disease with development of myocardial infarction is observed in patients who receive mantle irradiation for Hodgkin disease.
• Mitral insufficiency and myocardial fibrosis are other cardiotoxic effects.

Cardiac monitoring tests

• Serial ECG: Low QRS voltage and ST-T wave abnormalities occur late and are not useful for detecting early cardiac damage. Prolongation of the QTc interval may be predictive of late cardiac decompensation. Significant dysrhythmias can be asymptomatic and may be missed by routine ECG, so 24-hour Holter monitor ECG has been recommended as part of routine long-term follow-up.
• Serial ECHO (two-dimensional and M-mode): Noninvasive and easy to perform in children, ECHO provides measurements of left ventricular shortening fraction, diastolic filling times, and end-systolic wall stress (a measure of afterload). Studies conducted with stress or exercise tend to show more abnormalities than those conducted at rest.
• Radionuclide angiocardiography (RNA) or multiple gated acquisition (MUGA) scan: Well studied in adults, these tests measure left ventricular ejection fraction and are used to evaluate regional wall motion. Again, exercise studies show more abnormalities than resting ones.
• Endomyocardial biopsy: This procedure is invasive, requiring cardiac catheterization, but it allows quantitation of cardiac toxicity that is predictive of later decompensation. It can also be used to differentiate between malignant infiltration, infection, and anthracycline toxicity.
• Serum markers: Plasma natriuretic peptides (NP) have been studied in children treated with anthracyclines as measures of subclinical ventricular dysfunction. B-type NP may be more sensitive than atrial NP for detection of left ventricular damage. Serum cardiac troponin T levels are also being studied as markers of mild myocardial damage.

General pulmonary toxicity

• Toxicity can be acute and lethal or, more commonly, insidious in onset over a period of months to years, resulting in pneumonitis and pulmonary fibrosis. Symptoms include a dry hacking cough, dyspnea on exertion, and exercise intolerance.
• Physical examination may reveal crackles in the lung bases and, rarely, a pleural friction rub. The chest radiograph may show infiltrates, although more often the findings are normal. Pulmonary function tests (PFTs) usually reveal evidence of restrictive lung disease with a decreased forced vital capacity or total lung capacity as well as decreased diffusing capacity (DLCO).
• Corticosteroids have been used with some success in radiation-induced pneumonitis. However, results in pneumonitis secondary to bleomycin have widely varied. Radiation pneumonitis is associated with significant morbidity and mortality.

Pathophysiology of lung injury

The pulmonary pathologic processes for most chemotherapeutic agents and RT are thought to be similar. Because most alveolus formation and enlargement occurs in infancy and childhood, the effects of chemotherapy and radiation may be more severe in children than in adults.

• Initial response is oxidative injury to the pulmonary capillary endothelium and pneumocytes.
• An influx of granulocytes releases chemotactic actors, elastase, collagenase, and myeloperoxidase.
• Lymphocytes and plasma cells then infiltrate, secreting growth factors that stimulate fibroblasts to deposit collagen.
• Pulmonary fibrosis ensues.

Pulmonary toxicity from chemotherapeutic agents

• Drugs such as bleomycin, busulfan, the nitrosoureas, and methotrexate can cause long-term toxic effects on the lungs. Effects are additive or synergistic with RT.
• Bleomycin is used most commonly in children with germ cell tumors and lymphomas. Pulmonary toxicity is related mainly to dose and increases exponentially with cumulative doses over 200 units (12-17% incidence in adults). Although DLCO is a rather insensitive predictor, most oncologists advocate monitoring it and stopping bleomycin if DLCO drops below 50% of predicted.
• Nitrosoureas, especially carmustine (BCNU), have been shown to cause pneumonitis in children with brain tumors. One study reported a mortality rate of 35% in children treated with BCNU and RT to the spine. One group has found a significantly increased risk of BCNU pneumonitis when high-dose BCNU is administered within 120 days of mantle irradiation.
• Methotrexate administered weekly by mouth for ALL in adults and in patients with rheumatoid arthritis has been shown to cause restrictive lung disease. The incidence is probably less than 1%.

Pulmonary toxicity from radiation therapy

• The most common causes of pulmonary toxic effects include mantle or mediastinal irradiation for Hodgkin disease, lung irradiation in children with lung metastases from sarcomas or Wilms tumor, and spinal irradiation in children with brain tumors.
• In mantle irradiation for Hodgkin disease, toxicity is dose related; 40-55% of children studied had abnormal findings on PFTs or abnormal DLCO, although most received chemotherapy as well as RT. Few were symptomatic. One study from St. Jude Children's Hospital prospectively evaluated 37 children with Hodgkin disease who received chemotherapy that included bleomycin and low-dose (ie, 1800-2000 cGy) involved-field RT. Decreases in vital capacity and DLCO were noted over the first 6 months, but these were followed by improvement. Only one patient was symptomatic, but DLCO per unit of alveolar volume still was decreased significantly in most patients at the 2-year follow-up visit.
• Studies in children who received 1200-cGy to 2000-cGy lung irradiation for metastases from Wilms tumor have also shown significant drops in total lung capacity and vital capacity, with worsening of function, 18-48 months after therapy. On the other hand, 1600 cGy of whole lung irradiation to children (mostly adolescents) with osteosarcoma did not produce any long-term abnormalities in PFT findings.
• In patients who were treated as young children, the appearance of restrictive lung disease may relate to the inadequate growth of the chest wall and lung cavity following radiation therapy, a problem not observed in the older pediatric patient.

Endocrine Effects

As many as 40% of all long-term survivors of childhood cancer have evidence of endocrine toxicity. Radiation to the hypothalamic-pituitary axis, thyroid gland, or gonads can affect growth and reproductive capabilities. Alkylating agents can affect ovarian and testicular function as well.

The hypothalamus tends to be more sensitive to effects of radiation than the pituitary gland. Growth hormone is the first hormone to be affected, followed by gonadotropins and then adrenocorticotrophic hormone secretion. This is related to total dose and fraction size of radiation received. Age at the time of treatment is also a factor; younger patients are more sensitive than older children to the growth hormone–lowering effects of radiation.

Effects on growth

Short stature can result from growth hormone deficiency (GHD), hypothyroidism, and poor skeletal growth after radiation therapy (RT). GHD is the most common toxic endocrine effect of RT caused by cranial radiation. (Hypothyroidism is more common but results from RT directly to the gland.) Infants and toddlers are more likely to develop GHD than older children who, in turn, are more sensitive to the effects of radiation than adults. The incidence of GHD is 100% in children who receive more than 4500 cGy for optic chiasm gliomas and as much as 75% in children who receive 2900-4500 cGy for medulloblastoma. As many as 50% of children who receive 2400 cGy prophylactic cranial irradiation (CRT) for ALL develop GHD during the year or two after treatment, while those who receive 1800 cGy are less prone to GHD (0-14% incidence). Although most children recover adequate hormone levels, they do not experience catch-up growth. Treatment with growth hormone also does not result in catch-up growth, especially in children who also received spinal irradiation because of a direct growth-inhibiting effect on bone and soft tissue.

Precocious puberty has been reported in some children after CRT. Younger age at the time of radiation increases the risk, and both sexes may be affected. Studies in girls with acute lymphoblastic leukemia (ALL) report onset of puberty about 1 year earlier than in the general population.

Spinal irradiation (and thoracic/abdominal radiation including the spine) impairs growth by limiting growth of vertebral bodies. Estimates suggest that a 10-year-old child who undergoes spinal radiation loses 5.5 cm of final adult height with proportionately more growth retardation in younger children.

Thyroid dysfunction

Damage to the thyroid gland is common after neck or mantle irradiation, as used in children with Hodgkin disease, or spinal irradiation, as in children with brain tumors. Hypothyroidism is the most common thyroid abnormality after cancer therapy. Compensated hypothyroidism (ie, elevated thyroid-stimulating hormone [TSH], normal thyroxine levels) occurs in 14-75% of children irradiated for Hodgkin disease with doses of 4000 cGy or more and about 9% of children who receive prophylactic CRT with doses greater than or equal to 2400 cGy for ALL. Overt hypothyroidism occurs in 16-21% of Hodgkin disease patients and 2% of ALL patients after radiation with 2400 cGy. In one large study from Stanford of children irradiated for Hodgkin disease, the incidence of compensated or overt hypothyroidism after 26 years of follow-up was 47%. Compensated or overt hypothyroidism is observed in 47-68% of children who receive spinal irradiation for medulloblastoma.

In the Stanford study of children irradiated for Hodgkin disease and monitored for 26 years, the incidence of benign thyroid nodules was 3.3%; Graves disease, 3.1%; thyroid cancer, 1.7%; and Hashimoto thyroiditis, 0.7%. The contribution of chemotherapy to the development of hypothyroidism has been controversial. Although most studies did not show an increased risk, others question whether hypothyroidism occurs earlier in patients treated with both radiation and chemotherapy than in those treated with radiation alone.

Despite prophylaxis with oral iodide, children who receive therapeutic doses of iodine I 131 metaiodobenzylguanidine for relapsed neuroblastoma have developed primary hypothyroidism.

Thyroid replacement is recommended even in those with compensated hypothyroidism because chronic stimulation of the thyroid gland by elevated TSH has been suggested, but not proven, to increase the risk of secondary thyroid cancer in humans.

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