Advanced presentation of paediatric papillary thyroid cancer: A plea for heightened awareness

Authors


  • Conflict of interest: All authors have no conflicts of interest to disclose.

Up to 90% of children will experience cervical lymphadenopathy during childhood, and approximately 2% will have a solitary thyroid nodule.[1] Although most cases represent benign conditions, malignancy must be excluded. Papillary thyroid carcinoma (PTC), which arises from follicular epithelial cells, is the most common thyroid cancer and accounts for 1.4% of new childhood malignancies and 90% of paediatric thyroid cancers.[2, 3] Its peak incidence is between ages 15 and 19 years, with a variable female-to-male ratio that ranges from 1.2:1 in children younger than 10 years old and 3.6:1 in older patients.[4] Although PTC has an excellent prognosis and low cancer-specific mortality, paediatric patients tend to present with advanced disease involving lymphatic and pulmonary sites, likely from delays in diagnosis.[5] This increases operative morbidity that can result in lifelong disability.

Case 1

A 15-year-old female singer, with a family history of PTC, presented with a right-sided neck mass for 2 years, no associated dysphonia, dysphagia or hemoptysis. Primary care evaluation included laboratory studies demonstrating normal thyroid function. Two years later, she presented with enlargement of the mass. Non-contrast computed tomography (CT) scan demonstrated a large thyroid mass and pulmonary nodules.

She was referred to our institution for further evaluation and management. The patient was euthyroid and had a fixed right thyroid mass with palpable right-sided lymphadenopathy (Fig. 1). Ultrasound and intravenous (IV)-contrast CT scan demonstrated several large lobular masses replacing the right thyroid lobe, multiple right lateral neck lymph nodes and pulmonary nodules. Fine-needle aspiration biopsy (FNAB) was diagnostic for PTC. Laryngoscopic evaluation revealed normal vocal cord mobility.

Figure 1.

Preoperative ultrasound mapping of the neck. Case 1.

The patient underwent total thyroidectomy. Her right recurrent laryngeal nerve (RLN) was infiltrated with tumour and was resected en bloc. An ansa cervicalis nerve graft was performed. She also had bilateral central compartment node dissection and a right modified radical neck dissection (MRND). Histopathology revealed PTC with central and lateral compartment nodal metastases with extrathyroidal and extranodal extension. Postoperatively, whole body I123 scan demonstrated uptake in the neck and chest. She subsequently received 150 mCi of radioactive iodine131 (RAI) and thyroid-stimulating hormone (TSH) suppression with levothyroxine. She is now 18 years old with detectable suppressed thyroglobulin levels (22) and persistent but smaller lung metastases. She can no longer sing.

Case 2

A 16-year-old girl presented to our clinic 1 year after she developed left cervical lymphadenopathy. Her primary care provider (PCP) performed thyroid function tests, which showed minimally elevated TSH and normal T4 levels. Several months later, the repeat labs were unchanged except for positive thyroid peroxidase and thyroglobulin antibodies.

Her local endocrinologist identified a 3 cm left thyroid nodule. Additionally, neck ultrasound and non-contrast CT scan demonstrated another suspicious area within the thyroid and extensive cervical lymphadenopathy. FNAB was consistent with poorly differentiated thyroid carcinoma. To better delineate the extent and type of disease, during her preoperative evaluation at our institution, we performed ultrasound mapping, FNAB, chest X-ray, IV-contrast CT of the neck and vocal cord examination (Fig. 2). This additionally demonstrated supraclavicular nodal involvement.

Figure 2.

Preoperative ultrasound mapping of the neck. Case 2.

She underwent a total thyroidectomy with en bloc resection of a portion of left RLN (which was encased in tumour), left ansa cervicalis nerve graft, central compartment node dissection and left MRND (Fig. 3). Her postoperative course was complicated by temporary right vocal cord paralysis requiring short-term tracheostomy with decannulation prior to discharge. Pathology showed metastatic grade 2 PTC with extracapsular extension and metastasis to multiple centro-cervical and left lateral nodes. Additional treatment included 50 mCi of RAI. She is now 19 years old. Repeat neck imaging demonstrates no detectable disease. Her speaking voice is satisfactory.

Figure 3.

(a), (b) and (c) CT neck/chest: neck disease extending into the mediastinum, (d) ansa cervicalis nerve graft to RLN, (e) resected jugular chain nodes and thyroid. CT, computed tomography; RLN, recurrent laryngeal nerve.

Discussion

The presence of a paediatric thyroid nodule warrants a thorough investigation as children have a relatively higher risk of malignancy compared with adults (25% vs. 5%) (Fig. 4).[6] Any history of previous thyroid disease, ionising radiation or a positive family history for thyroid cancer is concerning. High-risk familial syndromes include familial adenomatous polyposis, Gardner syndrome, Cowden syndrome and Carney complex.[7]

Figure 4.

Recommended diagnostic work-up and management of a paediatric patient with a new thyroid mass. CT, computed tomography; FNAB, fine-needle aspiration biopsy; RAI, radioactive iodine; TSH, thyroid-stimulating hormone; US, ultrasound.

Up to 70% of children with thyroid cancer will have a thyroid mass at initial presentation.[8] Hoarseness, dysphagia and hemoptysis may indicate locoregional invasion. Of particular concern are thyroid nodules in children under 10 years old and in males.[9] Carcinoma is more likely if the thyroid nodule is large, hard, fixed, irregular or accompanied by cervical lymphadenopathy.[10] At least 36% of children with thyroid malignancy will have palpable cervical adenopathy at presentation.[5] Distant metastasis, frequently to the lung, is seen in 6 to 20% of paediatric PTC patients.[5, 11]

Diagnostic evaluation

The diagnostic process is as outlined by the American Thyroid Association (ATA) Management Guidelines.[12] First, obtain TSH levels. Most patients will be euthyroid, but a suppressed TSH warrants a thyroid uptake scan to identify any hyperfunctioning nodules, which are rarely malignant. Potential diagnoses include solitary nodules associated with Grave's or Plummer's disease.[10]

Neck ultrasound is critical for further characterising and localizing any suspicious nodules and lymphadenopathy. Furthermore, this non-invasive exam provides a map of involved lymphatics, enabling a more precise surgical approach.[13] Ultrasonographic features of malignancy include hypoechogenicity, increased vascularity, irregular margins and microcalcifications.[12]

An ultrasound-guided FNAB of the suspicious lesion should be the next step. If the initial FNAB is non-diagnostic, repeat FNAB should be performed prior to a definitive surgical approach. Only 1–5% of benign FNABs are false negatives,[14] but these patients still need follow-up. Open excisional biopsies are not recommended unless FNAB is suspicious for lymphoma, as poorly planned incisions can hinder surgical planning for future operations.

Supraclavicular adenopathy or lymphadenopathy that lingers for more than 6 weeks and fails to respond to antibiotics should prompt an ultrasound evaluation with possible FNAB.[15] This should be performed in the setting of a suspicious lymph node even in the absence of thyroid nodules. Such an approach may lead to a diagnosis of other head and neck neoplasms, lymphoproliferative disorders and occult thyroid cancers.

Chest radiograph should be performed to rule out pulmonary metastases. If there is a high suspicion of distant metastasis, non-contrast CT of the chest may be performed. If worrisome features are present, IV-contrast CT scan of the neck and mediastinum is warranted to better delineate locoregional spread to the trachea, oesophagus and major vascular structures.[13] Direct laryngoscopy should always be performed to evaluate vocal cord status, especially if dysphonia is present.[13]

Management

The first step in managing paediatric PTC is surgical resection. The general consensus is to perform total or near-total thyroidectomy (removing all thyroid tissue except a small remnant adjacent to a superior parathyroid gland on the contralateral side). This surgical approach is associated with excellent disease-free survival and reduced rates of recurrence,[11, 16] as PTC is frequently multifocal and bilateral.[17-19] Total thyroidectomy further facilitates postoperative imaging, RAI treatment and surveillance with thyroglobulin levels.

All palpable and ultrasound detected lymph nodes should be systematically removed by performing central and sometimes MRND for biopsy-proven positive lateral neck nodes. In order to minimise postoperative complications, we strongly advocate the operation be performed by an experienced, high-volume surgeon,[20, 21] with expected rates of permanent hypocalcaemia and RLN injury less than 2% and 3%, respectively.[21-23]

Postoperative RAI imaging and ablation is the next step in treating high-risk patients (large primary tumour, extra-thyroidal extension, known distant metastases and high-risk histology). Initially, whole body scan is performed using either low dose I123 or I131 isotopes at approximately 6 weeks postoperatively to identify remaining local or distant metastatic disease.[13] TSH should be >30 μU/mL either by thyroxine withdrawal or recombinant human thyrotropin injections, allowing for optimal radioiodine uptakes. If disease is present, the child should undergo RAI I131 ablation. This also eradicates remaining thyroid tissue, rendering thyroglobulin levels more representative of disease burden at follow-up. Although there is a higher incidence of pulmonary metastasis in children, disease-specific morbidity and mortality remain low.[24] Patients with lung metastasis can become disease-free following RAI treatment. Nevertheless, serious consideration should be given to administration of repeated doses of RAI,[25, 26] as therapy carries inherent risk including the development of leukaemia, secondary tumours, pulmonary fibrosis and azoospermia.[24, 26] Side effects include sialoadenitis, gastrointestinal upset, pain at the site of residual disease, loss of taste and smell, and transient bone marrow suppression.[13] RAI therapy should be considered on an individual basis and aimed at the lowest possible dose.

Following RAI treatment, patients should be placed on a suppressive dose of thyroid hormone replacement to minimise stimulation of cancer cells of follicular origin.[13] The ATA recommends suppressing TSH to <0.1 μU/mL for high-risk patients and between 0.1 μU/mL and 0.5 μU/mL for low-risk patients.[12] Follow-up includes obtaining thyroglobulin and thyroglobulin antibody levels, TSH levels and ultrasound at 6 months and 1 year post-therapy. Thyroglobulin antibody levels should always be checked concurrently as their presence renders the interpretation of thyroglobulin levels measurement unhelpful.[27] If the patient remains disease-free, testing can continue on a yearly basis. If, however, evidence of disease is present, whole body scan, ultrasound with FNAB and possibly positron emission tomography scan may be utilised to further evaluate for extent of disease.

Conclusions

Papillary thyroid cancer is uncommon in the paediatric population. When it does occur, it has the propensity to present as advanced disease involving lymphatics and distant metastasis, most often to the lungs. It is therefore imperative that the diagnosis of thyroid cancer be entertained when children and adolescents present with a new thyroid nodule or have chronic cervical lymphadenopathy without a satisfactory explanation. Paediatric PCPs are frequently the initial physicians who evaluate these young patients and play an important role in initiating a prompt and appropriate work-up. Fortunately, even advanced paediatric PTC carries with it an excellent prognosis. With a diligent multidisciplinary team approach involving primary care physicians, paediatric endocrinologists and high-volume thyroid surgeon, patients can be effectively managed and treated.

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