Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Pediatric Thyroid Malignancies Introduction - Cancer in the Pediatric Population Cancer ranks second only to trauma as a cause for childhood deaths. Mortality data for 1984 reports that cancer accounted for over 1700 deaths in that year. The most common pediatric malignancies are leukemia, CNS tumors, lymphoma and neuroblastoma. Primary neoplasms of the head and neck account for only 5% of all neoplasms; however, 25% of pediatric malignancies eventually involve the head and neck. Of pediatric head and neck malignancies, half of these are lymphomas; thyroid cancers account for 10%. The most common presentation of head and neck malignancy is an asymptomatic mass. It is recommended that biopsy be considered for all lymphadenopathy (LAD) that enlarges or persists for 6 weeks after a 14 day course of antibiotics. The diagnosis of malignancy in a child is frequently delayed because the presenting symptoms of LAD, otalgia, otorrhea, rhinorrhea, nasal congestion, and headache are also frequently seen with common benign processes; unfortunately, the history and exam alone can not reliably distinguish benign from malignant disease. Voice change, hoarseness, stridor, dysphagia and hemoptysis suggest upper aerodigestive tract compromise and occur late in the disease process. Epidemiology, Diagnosis and Evaluation Thyroid cancer is a relatively uncommon malignancy that occurs dominantly in children more than 10 years of age; there is an increased incidence at puberty, but it can occur at any age, even in the neonatal period. Unlike adult cases, a strong female preponderance of 3:1 is not seen; females are only slightly greater than males in a ratio of 1.5 - 2:1. Ten percent of cases of thyroid cancer occur in patients less than 20 years of age. The first case of thyroid cancer in a child was reported in 1902. In 1970 Winship and Rosvoll wrote a classic treatise outlining the epidemiology and natural history of these cancers. The majority of children have well-differentiated cancers. Figures vary by the series but usually more than 70% cases are papillary or mixed papillary-follicular carcinomas, followed by follicular (18%), medullary (MCT) (4-10%), and anaplastic (2-5%.) In adults, Hurtle cell tumors, lymphoma and metastatic tumors also occur in the thyroid, but these are exceedingly rare in children. Previous radiation therapy is the most well known risk factor for pediatric thyroid cancer. It was the most important factor in thyroid cancer from 1945 to 1975 because of the use of XRT for a variety of benign disease including thymic enlargement, adenoid and tonsillar hypertrophy, cervical adenitis, mastoiditis, and acne to name a few. Risk of cancer exists for up to 30 years after exposure. It remains a risk factor today, however because of children receiving XRT for childhood malignancies; the National Cancer Institute recommends a careful head and neck exam every 2 years for a child's lifetime to evaluate for second malignancies. During the Chernobyl disaster (1986), 50 million curies of radioactive material were dispersed and already an increased incidence of papillary cancer is reported. The evaluation of a child with a thyroid mass begins with the history and exam, including laryngoscopy (to evaluate the function of the vocal cords). Patient's are usually euthyroid but thyroid function tests probably should be checked. Anti-thyroid antibody, if elevated, suggests inflammatory disease, but does not rule out malignancy. Calcitonin levels are elevated in medullary cancer but this is not a routine part of the evaluation for a thyroid mass. Screening in at-risk families is indicated for early diagnosis. Thyroglobulin levels are not helpful in the diagnosis of cancer, but may be valuable in follow-up. Ultrasound may also be helpful for assessing the size, position, multiplicity, and cystic vs. solid components of a thyroid mass; it can also be used to assist in FNA. Of note, the presence of a small simple, cyst suggests benign disease (96%), but it should be noted that cancers may undergo cystic degeneration and 25% of larger or complex cysts may harbor malignancy. It should be noted that there may be a higher incidence of malignancy in children with multinodular disease than their adult counterparts (25%, in one study). CT scan or MRI of the head and neck may be indicated in some cases to assess the extent of disease. All children with a documented head and neck malignancy should have CXR. Radionucleotide scanning can assist in the evaluation of thyroid masses. Technetium pertechnetate is a good screening test; it is inexpensive, convenient and rapid. 123I is the physiologically optimal test; however, this test takes longer and is expensive. It is used to reevaluate positive Tc scans. The functional characteristics of nodules depend on the tissue's ability to uptake and process tracer particle. A "hot" nodule indicates an area of increased functional activity. Cancer is rare in functional nodules (0.7%), but even the presence of a hot nodule on scanning does not preclude the need to obtain a tissue diagnosis, especially in children. A "cold" nodule indicates the absence of functional activity in a nodule. Warm and cool nodules have intermediate functional levels and should be treated as cold nodules in children. Malignancy occurs in 14% - 40% of solid thyroid nodules in children, not just predominately cold ones; this is as opposed to 5% - 25% of cold nodules in adults. Tissue diagnosis is ultimately required in children with a thyroid mass. FNA has the best predictive value of minimally invasive techniques in distinguishing benign from malignant disease. It is suggested that due to the high rate of malignancy in thyroid nodules, that, in children, all solitary, solid or cold nodules or those other nodules in which the FNA cytology is inconclusive be surgically excised. Biopsy consists of lobectomy with isthmusectomy and intraoperative frozen section; surgery obviously should stop there if the frozen section is inconclusive (10% of cases). The histopathologic hallmark of papillary cancer is the ground glass appearance of its nuclei ("Orphan Annie" cells). Follicular cancer appears as a variable pattern of solid and follicular growth, and is differentiated from follicular adenoma by its invasiveness into the capsule and/or blood vessels. Medullary cancer originates from cells of neural crest origin (parafollicular or C-cells). Clusters of the round or polyhedral cells typically associated with neural crest tumors are seen on histology. There is a granular eosinophilic cytoplasm, often with an amyloid stroma that is peculiar to MCT. Immunohistologic staining for calcitonin is also diagnostic. Microscopically, anaplastic cancer resembles rhabdomyosarcoma; it is an unencapsulated tumor with many mitoses and has areas of invasion and necrosis. Well-differentiated thyroid cancers usually present with a solid, asymptomatic anterior neck mass; 60% - 86% of children have regional metastasis to cervical lymph nodes at the time of diagnosis and this may be the presenting symptom. Pulmonary metastases occur in 5% -15% of pediatric patients. Bone metastases appear in 5% of cases. Patients with MCT also present with a solid anterior neck mass (usually asymptomatic); 50% present with LAD; metastasis usually occurs in the lung, liver, or bone. MCT may be associated with MEN II. MCT tends to be multicentric, especially in the familial form. Ten to twenty-seven percent of patients have a familial form of MCT that may be associated with MEN IIA or IIB; the worst and earliest cancer occurs in MEN IIB. Pheochromocytoma typically appears later and is rarely malignant, thus the thyroid cancer is the life-threatening facet of this complex. The phenotype of type IIB syndrome consists of mucosal neuromas, ganglioneuromas of intestines, characteristic facial appearance, and marfanoid habitus. Elevated basal or elevated calcium or pentagastrin-stimulated calcitonin levels can be early indicators of MCT or C-cell hyperplasia, the premalignant precursor to MCT. When this tumor is suspected or suggested by family history, familial screening is recommended. When patients are diagnosed with clinical disease there is a 40-50% rate of LN metastasis, but when the diagnosis is made by elevated basal calcitonin only 14% have LN metastasis and this drops to 0% when the diagnosis is made by elevated stimulated calcitonin. Screening should begin at 1 year of age in MEN IIA or at birth in MEN IIB. New on the horizon is the discovery of the gene for MEN IIA on chromosome 10 and a new method for determining which children in a MEN IIA family are at risk for MCT. Anaplastic cancer is exceedingly rare in children and behaves as in adult cases. Anaplastic cancer may present with a bulky tumor, rapid growth, and higher rate of compressive symptoms (hoarseness, respiratory distress, dysphagia); this tumor is associated with advanced disease and widespread metastasis. Surgery In adults, lobectomy may be considered in some very select cases of limited, less than 1.5 cm, localized papillary cancer, in patients with no history of XRT and free of LN metastasis. However this is not the optimal treatment plan and is not recommended in children. Near-total or total thyroidectomy when possible, depending on the extent of tumor, is recommended for well- differentiated cancer. Despite the risks associated with surgery (hypothyroidism, permanent hypoparathyroidism and recurrent nerve injury) aggressive surgical management for children is supported by the increased incidence of multicentric disease and the improvement in postoperative follow-up achieved by the near total removal of disease. In adults with well-differentiated cancers prophylactic neck dissection does not improve survival risk compared to waiting until the nodal metastasis become clinically evident. In children, however, neck dissection should be entertained in N0 cases because of the high risk (26%) of occult LAD and thus the high rate of recurrent or persistent disease. Modified neck dissections should be added when there is documented bilateral disease or intraoperatively palpable LAD. The regions at highest risk are the pretracheal and paratracheal. Next highest risk regions are the upper, middle, and lower jugular LN and the lower spinal accessory. Neck dissection should include these regions. Bilateral central compartment neck dissections should be performed in all cases of MCT. More extensive surgery, such as laryngectomy and tracheal resection for laryngeal and tracheal extension, is controversial. Consideration of auto transplantation of parathyroid tissue is suggested when preservation of the parathyroid glands or blood supply is in question. After surgery for well-differentiated thyroid cancer, total body scanning is performed to evaluate for residual disease. Total body scan will not accurately identify distant metastasis when significant thyroid tissue remains in the neck. After the residual thyroid is ablated (see below), the child can be evaluated for recurrent/metastasis disease by periodic total-body thyroid scanning. Intervals of one-year have been suggested for re-evaluation of thyroid metastasis, but in aggressive disease this may be shortened to 3 to 6 month intervals. Thyroxin supplementation is recommended after surgery for thyroid cancer to maintain a euthyroid state and to maximize TSH suppression because TSH is believed to have a growth promoting effect on well-differentiated cancer. Recurrences, Metastasis and Prognosis Radioablation with 131I improves survival in well differentiated cancer (doubtful benefit in medullary cancer); it requires that the remaining tumor cells take up iodine and local irradiation of tissue with limited side effects. Radioablation by 131I acts by locally irradiating tissues in the region of concentration and the ability to do this depends on uptake of the material. Toxicities include pulmonary fibrosis when extensive pulmonary metastases are present, temporary bone marrow suppression, reversible spermatogenetic damage, possibly an increased incidence of leukemia after treatment and possibly a risk of converting a well-differentiated tumor into an anaplastic one. A newly developed technique of using antibody directed 131I may be useful in the future for cases that do not uptake iodine. Periodic evaluation for loco-regional recurrence and metastatic disease by total-body thyroid scanning (TBI) after surgery and radioablation is routinely performed in patients with well-differentiated thyroid cancer. Thyroglobulin levels by Tg-RIA testing is highly sensitive and specific as a tumor marker after known thyroid disease and tissue have been ablated. Patients must first be tested for anti-thyroid Ab because its presence will result in false negative results. A positive study dictates a need to search for metastasis. Annual CXR is recommended. Bone metastasis is usually identified by TBI, and is helpful in evaluating cases that do not uptake iodine. Detection of metastasis may be aided by the analysis of Tg in FNA samples from non-thyroidal masses. Treatment consists of surgical resection in amenable cases and ablation with high doses of 131I or XRT. Some authors have suggested concurrent use of both radioablation and XRT as 19% - 25% of well-differentiated cancer metastasis do not concentrate 131I and will not respond to radioablation. External beam XRT is recommended in cases of metastatic or recurrent well-differentiated cancers that do not concentrate iodine and those which have failed radioablation; it is also important in palliation of distant metastasis, especially bone metastasis. It may also be useful when: tumor is growing fast, is inoperable, in a functionally significant location and when the delayed response to 131I is unacceptably long. In medullary cancer, surgery is still the mainstay. However, XRT may improve survival especially when excision has been incomplete. XRT is part of the multimodality treatment regimen for anaplastic cancer. Children with well-differentiated cancer have a substantially better prognosis than adults despite the presentation with more advanced disease and the high incidence of regional and distant metastasis at time of diagnosis: one-hundred percent survival at 5 years for all well-differentiated cancers and, at 20 years, this reaches 86% (papillary) and 85% (follicular). This improved prognosis does not hold for children with medullary or anaplastic tumors. Survival is 44% at 20 years (medullary) and 19% at 20 years (anaplastic). In 75% of all cases of thyroid malignancy, the immediate cause of death is infection, obstruction or asphyxia caused by the tumor in the neck, mediastinum or lungs. Case Presentation An 8-year-old girl presented to the pediatric service with a two month history of an asymptomatic neck mass. She had no hoarseness, dysphagia, respiratory symptoms or fever. On exam there was a hard and fixed anterior neck mass and palpable, bilateral firm LAD. She was euthyroid and the anti-thyroid Ab was moderately elevated. Tc99m thyroid scanning revealed patchy distribution of tracer activity throughout both lobes, suggestive of thyroiditis. Re-evaluation with 123I scanning confirmed a heterogeneous distribution of functional activity in both lobes, also suggestive of thyroiditis. The otolaryngology service was consulted and a fine needle aspiration of the mass was obtained. The cytology was diagnostic for bilateral papillary thyroid carcinoma. A CXR showed tracheal deviation, but no evidence of pulmonary metastasis. An ultrasound demonstrated a markedly enlarged gland bilaterally with hypoechoic areas consistent with neoplasm. A CT scan of the chest and abdomen was also obtained and did not reveal any pulmonary or hepatic metastasis. She underwent total thyroidectomy, bilateral neck dissections, bilateral paratracheal node dissections and mediastinal node dissection; tumor found to be grossly involving both recurrent laryngeal nerves. The right inferior parathyroid was the only one readily identified and it was reimplanted in the SCM. Her post operative course was complicated by asymptomatic hypocalcemia requiring IV and PO calcium supplementation. She was discharged on the ninth day on Vitamin D, Calcium, a low iodine diet and no thyroid supplementation. After induction of hypothyroidism, 131I total body scanning was performed and showed residual neck. 102 mCi radioactive 131I was administered for thyroid ablation. Thyroid supplementation with thyroxine was implemented and there are plans to follow-up with repeat total body scan in 6 - 12 months. Bibliography Ashcraft MW, van Herle AJ. Management of thyroid nodules. I. History and physical examination, blood tests, x-ray tests, and ultrasonography. Head Neck Surg 1981;3:216-230. Ashcraft MW, van Herle AJ. Management of thyroid nodules. II. Scanning techniques, thyroid suppressive therapy, and fine needle aspiration. Head Neck Surg 1981;3:297-322. 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J Clin Endocrinol Metab 1992;94:1401-1404. Peake RL. Clinical evaluation of thyroid tumors. In: Thawley SE, Panje WR. Comprehensive Management of Head and Neck Tumors, volume 2. Philadelphia: Saunders; 1987:1580-1598. Pillay R, Graham-Pole J, Miraldi F, Yulish B, Newman A, Liebman J. Diagnostic x-irradiation as a possible etiologic agent in thyroid neoplasms of childhood. J Pediatr 1982;101:566-4568. Ross DS. Long-term management of differentiated thyroid cancer. Endocrinol Metab Clin North Am 1990;19:719-739. Rougier P, Parmentier C, Laplanche A, Lefevre M, Travagli J-P, Caillou B, et al. Medullary thyroid carcinoma: prognostic factors and treatment. Int J Radiation Oncol Biol Phys 1983;9:161-169. Simpson WJ, Panzarella T, Carruthers JS, Gospodarowicz MK, Sutcliffe SB. Papillary and follicular thyroid cancer: Impact of treatment in 1578 patients. Int J Radiation Oncol Biol Phys 1988;14:1063-1075. Tubiana M, Lacour J, Monnier JP, Bergiron C, Gerard-Marchant, R. Roujeau J, et al. External radiotherapy and radioiodine in the treatment of 359 thyroid cancers. Br J Radiol 1975;48:894-907. Winship T, Rosvoll R. Childhood thyroid carcinoma. Cancer 1961;14:734-738.
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