Solitary Thyroid Nodule Workup

Several laboratory studies are helpful in assessing the nature of a thyroid nodule and in monitoring response to surgical treatment.

Initially, thyroid function tests can determine whether a nodule is functioning or autonomous. However, a large percentage of malignant nodules cause no change in thyroid function tests. An elevated thyroid-stimulating hormone (TSH) level may indicate agenesis of a thyroid lobe or thyroiditis. A very low TSH level indicates an autonomous or hyperfunctioning nodule. Levels of free thyroxine (T4), triiodothyronine (T3), and TSH are used to direct medical therapy.

Some centers also find antithyroid antibodies helpful in diagnosing chronic lymphocytic thyroiditis (ie, Hashimoto thyroiditis); however, a positive antibody test result does not exclude the possibility of malignancy (it actually may indicate a higher risk).

A CBC count may be obtained if abscess is suspected.

Calcium levels should be monitored immediately postoperatively to assess parathyroid function and the need for supplementation. In addition, certain laboratory findings should be monitored for therapeutic purposes and for the recurrence of disease after surgical excision.

TSH levels should be completely suppressed, but clinical euthyroidism should be maintained if the patient is on replacement therapy following total thyroidectomy for malignancy. This approach prevents TSH stimulation of any remaining tumor cells. As the child grows, periodic thyroid hormone levels help determine thyroid hormone replacement adequacy and any changing needs due to development.

Some laboratory tests can also be used to monitor for recurrence of disease. Thyroglobulin levels may be useful but only after total thyroidectomy is performed. Thyroglobulin levels exceeding 1 ng/mL in patients on thyroxine therapy or 10 ng/mL in patients off thyroxine therapy indicate recurrence. Calcitonin should be monitored after thyroidectomy for medullary thyroid carcinoma. Measurable calcitonin after surgery may indicate return of disease.

Once a thyroid nodule is palpated and thyroid function is obtained, several imaging studies are necessary to determine the nature of the lesion. Controversy surrounds the efficacy of imaging studies and fine-needle aspiration biopsy (FNAB) because precision and accuracy vary among centers. In general, the studies described below are useful but do not replace clinical judgment. When in doubt, perform excisional biopsy, especially in pediatric patients because of the higher rates of malignancy and aggressiveness of disease in this population.

Ultrasonography

Ultrasound examination of the nodule is helpful for determining the nature of the nodule, whether cystic, solid, or mixed. ^[2] In addition, knowing the exact location of the nodule and the size can be helpful when planning FNAB. Ultrasonography can also be used to exclude the presence of other nodules, which indicates a multinodular disease process.

The radiologist should also assess the overall anatomy of the gland, searching for anatomic defects or developmental anomalies that can determine diagnosis or affect surgical excision. Discovery of a developmental error that explains physical findings, such as a thyroglossal duct cyst or agenesis of one lobe, may prevent the child having to undergo invasive biopsy or surgery.

A study by Richman et al found that characteristics on ultrasound examination which were associated with malignant nodules included larger size, solid parenchyma, taller-than-wide shape, speckled calcifications, lack of a smooth margin, and the presence of abnormal lymph nodes. In addition, the rate of malignancy in patients with a solitary nodule (29.4%) was higher than that in patients with multiple nodules (14.2%). ^[13]

Scintigraphy

Once a nodule has been confirmed as having a solid component, radioiodine scintigraphy is used to determine the activity of the nodule as cold, warm, or hot.

Scintigraphy can also be used to detect ectopic thyroid tissue or identify the thyroid tissue that will be lost with thyroglossal duct cyst removal, requiring lifelong thyroid hormone replacement.

The activity of the nodule determines the next step in therapy. Hot nodules often require antithyroid medications before surgery, whereas cold nodules have a much higher incidence of malignancy. Scintigraphy is also used postoperatively to exclude the presence of metastases, especially after total thyroidectomy.

Chest radiography, CT scanning, and MRI

Other useful imaging tests include chest radiography, CT scanning, and MRI. If malignancy is suspected, chest radiography should be performed, given the high incidence of early metastases to the lungs. However, chest radiography has only 60% sensitivity in this setting and, therefore, should be confirmed with postoperative CT scanning and scintigraphy.

If the tumor is large, and invasion of the airway or mediastinum is suspected, an MRI or CT scanning of the neck and chest may be used to analyze the extent of disease.

Fine-needle aspiration biopsy is used for definitive diagnosis. FNAB has attracted much attention in the adult population in the evaluation of thyroid nodules. However, because of the uncertain results with FNAB in many centers, no clear-cut protocol regarding its use in pediatric patients has been established. FNAB can decrease rates of surgery by 25-50% in adults and has demonstrated promise in children; however, consistency in results is lacking.

FNAB remains unpopular in children because of their smaller neck sizes, the need for heavier amounts of anesthesia and sedation, and the amount of specimen needed. Furthermore, because the higher rates of malignancy in children, definitive pathologic diagnosis is much more in demand.

Results with FNAB are much more consistent at centers with staff that are skilled in aspiration in children and with experienced cytopathologists. However, even in these centers, distinguishing benign follicular adenomas and Hürthle cell hyperplasia from their malignant counterparts is difficult because of the amount of specimen obtained using FNAB. Results are more accurate with papillary and undifferentiated carcinomas.

Despite of the difficulties associated with FNAB, in a series involving 41 children, Al-Shaikh et al reported 100% sensitivity, 86% specificity, and a 59% decrease in surgery rates. ^[14] However, Lugo-Vicente et al found no decrease in rates of surgery, 80% sensitivity, and 60% specificity; they used results to treat individuals with a frankly malignant gland more aggressively. ^[15]

Current recommendations suggest the removal of nodules in children younger than 13 years. The risk of cancer in adolescents more closely approximates that of adults; therefore, FNAB is more useful. FNAB is not necessary or recommended in the case of toxic nodules. Thyrotoxicosis should be controlled with antithyroid medications, and nodules should be removed, regardless of pathology.

Clinical suspicion of cancer because of a history of ionizing radiation, a family history of thyroid cancer, or clinical signs and symptoms of malignancy also should preclude the use of FNAB in favor of excisional biopsy.

FNAB can be very useful in centers with the appropriate experience level. In the individual with a suspected benign cyst, surgery can be avoided if aspiration causes resolution without recurrence and cytopathology of the cyst wall demonstrates no malignant cells. Cytopathology of cyst fluid is not useful in the assessment of malignancy. FNAB may also prevent surgery in adolescents with hypofunctioning and isofunctioning nodules in the absence of clinical suspicion of malignancy.

Each child should have close clinical follow-up to confirm the absence of malignancy. Remember that the incidence of malignancy in pediatric thyroid nodules is high, and the risk of surgical complications can be significant.

As documentation and experience with FNAB in children continues, its use will continue to expand. If any doubt surrounds the pathologic diagnosis, surgical excision is recommended.

Once a biopsy is performed, whether by fine-needle aspiration or excision, close examination of the tissue obtained is necessary to determine diagnosis and definitive treatment. Findings may be benign or malignant.

The most common histology is follicular adenoma. These tumors maintain the follicular architecture of the gland and are usually encapsulated without evidence of infiltration. Follicular adenomas are not associated with the development of malignancy.

In contrast, many papillary adenomas, which exhibit papillary structures within follicular and cystic spaces, have microscopic evidence of invasion and malignancy on further examination, raising doubts about the benign nature of this tumor.

Hashimoto thyroiditis is often associated with nodule development; therefore, it may be observed on biopsy. Histologic findings include lymphocytic infiltration and replacement of gland architecture with lymphocytes, plasma cells, and macrophages.

Hürthle cells, characteristic of Hashimoto thyroiditis, are also observed, having characteristic bright eosinophilic cytoplasm.

More rarely, Graves disease may present with a nodule. This condition reveals a hypercellular picture (cells increased in height and number with the formation of pseudopapillary beds), which may be confused with cancer.

Another benign condition that may be found on biopsy of a midline neck mass, especially in children, is a residual thyroglossal duct cyst. This structure retains the thyroid acinar epithelium and may be surrounded by lymphocytic infiltrate. It may also become infected and progress to abscess formation.

Major thyroid gland malignancies

Remember that the incidence of malignancy in pediatric thyroid nodules is high. The 4 major malignancies that may be found in the thyroid gland are papillary carcinoma, follicular carcinoma, anaplastic carcinoma, and medullary thyroid cancer. Papillary and follicular carcinomas occur more frequently and carry a better prognosis than anaplastic carcinoma and medullary thyroid cancer.

The most common thyroid gland malignancies, papillary carcinomas, are infiltrative, often with multiple centers of development. They rarely invade blood vessels, preferring early spread to regional lymph nodes. They tend to grow slowly and may display follicular elements. However, these tumors have certain unique identifiers. Psammoma bodies are pathognomonic for papillary cancer and may be surrounded by calcified rings. In addition, the nuclei, often called "Orphan Annie eyes," are hypochromatic, sometimes with nuclear grooves and eosinophilic nuclear inclusions, representing the invasion of cytoplasm. Ischemic necrosis and cystic changes may be present.

In contrast, follicular carcinomas demonstrate no nuclear features and lack psammoma bodies. These tumors prefer capsular and vessel invasion; therefore, they metastasize earlier to bone, lung, and liver, sometimes with no lymph node involvement. These tumors can be difficult to distinguish from their adenomatous counterparts because microscopic capsular invasion may be the only evidence of malignancy and may be missed by FNAB.

Less common are the anaplastic and medullary cancers, each comprising approximately 5% of all thyroid cancers and carrying a much worse prognosis. Anaplastic thyroid carcinomas present in 3 patterns. Spindle cell tumors have a sarcomatoid appearance. Small cell cancers closely resemble other small cell cancers and may be difficult to distinguish from bronchogenic cancer metastases and lymphoma. Giant cell carcinoma is the most anaplastic variety, characterized by huge bizarre cells, often with multiple nuclei and visible mitoses.

Medullary thyroid cancer of the parafollicular cells rarely presents as a single nodule, often affecting both lobes of the thyroid, especially in association with multiple endocrine neoplasia (MEN) 2A and MEN 2B. However, when found on biopsy, medullary thyroid cancer is characterized by large deposits of amyloid substance, surrounded by sheets of pleomorphic epithelial cells.

Finally, the thyroid may be affected by metastases from occult malignancies, most commonly lymphoma and leukemia but including many other cancers. In these incidents, histology obviously depends on the primary tumor. However, metastatic disease in the thyroid gland in children is not common.

When evaluating thyroid cancer, include several aspects useful for staging. Accurately record the size and location of the nodule and the presence of other nodules. Careful mapping of abnormal lymph nodes is vital to an effective dissection. Investigate evidence of fixation to surrounding tissues. In addition, obtain a preoperative chest radiograph to investigate the presence of pulmonary metastases.

A tumor, node, metastases (TNM) staging system has been developed for the adult population, but little data exist about its usefulness in children. The lack of distant metastases in patients younger than 45 years designates the cancer stage I, whereas the presence of metastases signifies stage II. Any anaplastic cancer is considered stage IV.

Medullary thyroid cancer is classified differently, as follows:

• Stage I consists of a T1 tumor, less than 10 mm, with no nodes or metastases.

• Stage II includes larger tumors, also without nodes or metastases.

• Stage III classification involves lymph nodes.

• Stage IV indicates the presence of distant metastases.

Although the TNM staging system may be proven to be useful in the future, current recommendations in children with thyroid cancer include various factors.

Palpation should be followed by ultrasound, scintigraphy, and FNAB. Scintigraphy can identify areas of increased radioactive iodine uptake (ie, hot areas), even in cystic lesions, and FNAB can be employed even in largely hot nodules if a malignancy is possible. However, in general, scintigraphy with 123I is most useful for solid nodules, and FNAB is most useful for nodules that are considered cold.

All toxic nodules should be surgically removed.

Lobectomy may be used for smaller nodules; however, any indication of malignancy with spread beyond one lobe should lead to total thyroidectomy with lymph node dissection. The adult size threshold for total thyroidectomy versus lobectomy is 1 cm. However, in children, the answer is not so clear. Evidence of local spread should encourage total thyroidectomy, whereas a small well-circumscribed lesion may be removed using lobectomy.