pediatric endocrinology clinic of this hospital because of an enlarging neck mass.

CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL
Richard C. Cabot, Founder, Nancy Lee Harris, M.D., Editor, Jo-Anne O. Shepard, M.D., Associate Editor, Eric S. Rosenberg, M.D., Associate Editor, Alice M. Cort, M.D., Associate Editor, Sally H. Ebeling, Assistant Editor, Christine C. Peters, Assistant Editor
Case 38-2010 — A 13-Year-Old Girl with an Enlarging Neck Mass
Madhusmita Misra, M.D., M.P.H., Sareh Parangi, M.D., Douglas S. Ross, M.D., Randheer Shailam, M.D., and Peter M. Sadow, M.D., Ph.D.
N Engl J Med 2010; 363:2445-2454December 16, 2010
ArticleReferences
PRESENTATION OF CASE
Dr. Michelle L. Katz (Pediatrics): A 13-year-old girl was seen in the


pediatric endocrinology clinic of this hospital because of an enlarging neck mass.



Eight days earlier, the patient noted swelling of her neck and pain on swallowing. Two days later, her primary care provider noted that the patient had an enlarged thyroid gland. The level of serum thyrotropin was 5.59 μIU per milliliter (reference range, 0.28 to 3.89), free thyroxine 0.88 ng per deciliter (reference range, 0.58 to 1.64), and total triiodothyronine 159 ng per deciliter (reference range, 87 to 178). The anti–thyroid peroxidase antibody level was 244 IU per milliliter (reference range, <35), and the antithyroglobulin antibody level was greater than 3000 IU per milliliter (reference range, <40); complete blood count and electrolyte levels were normal. The patient was referred to the pediatric endocrinology unit at this hospital, where she was seen 5 days later.
The patient reported tightness in her neck and occasional nausea but no difficulty breathing or swallowing. She did not have a sensation of feeling hot or cold; changes in weight, appetite, degree of thirst, energy level, hair, or skin; palpitations; diarrhea; constipation; abdominal pain; vomiting; urinary frequency; skin lesions; or musculoskeletal symptoms.
The patient was born after a full-term gestation, without complications. Menarche occurred at 9 years of age, and her menstrual cycles had recently become regular, lasting about 5 days. Her most recent menses had begun 16 days earlier. She reported migraines approximately once a month and other headaches once or twice weekly that did not awaken her from sleep or occur in the early morning. She took over-the-counter analgesics as needed for headaches and had no known allergies. She lived with her parents and two younger siblings and did well in school. Her mother, maternal grandmother, maternal aunt, and cousin had hypothyroidism, and a thyroid nodule that had recently developed in her mother was being evaluated.
On examination, the patient appeared well. The height was 162 cm (77th percentile for age), the weight 59.4 kg (88th percentile), and the body-mass index (the weight in kilograms divided by the square of the height in meters) 22.6 (86th percentile). The blood pressure was 126/66 mm Hg, and the pulse 79 beats per minute. There was no exophthalmos, and extraocular movements were normal. The thyroid was firm and possibly had an ill-defined mass on the left. The right lobe measured 4.5 cm and the left lobe 6.5 cm in greatest dimension; the left lobe was rotated laterally more than the right. There were no enlarged cervical lymph nodes. The patient was fully pubertal and the remainder of the physical and neurologic examination was normal. The administration of levothyroxine (50 μg daily) was begun, and ultrasonography of the thyroid gland was scheduled.
Fifteen days after the patient's initial evaluation, her mother called to report that the thyroid gland was increasing in size. The next day, ultrasonography of the thyroid revealed a diffusely enlarged thyroid, with the left lobe (5.9 cm by 3.6 cm by 2.7 cm) larger than the right (5.1 cm by 2.1 cm by 1.9 cm). The parenchyma was heterogeneous. A predominantly cystic lesion in the right isthmus had a hyperechoic component and showed minimal Doppler flow. Multiple punctate, hyperechoic foci were present diffusely in the thyroid gland. Numerous lymph nodes lay on either side of the thyroid gland, lateral to both common carotid arteries and posterior to the left clavicular head. Lateral to the left common carotid artery, there was an enlarged lymph node (1.2 cm by 1.9 cm by 0.5 cm), with echotexture resembling that of the thyroid.
Nine days later, on a repeat physical examination, the thyroid had increased in greatest dimension to 6 cm on the right and 7 cm on the left and was firm to palpation. Small cervical lymph nodes were palpable. The patient had pain during swallowing but reported no weight change, hoarseness, or difficulty breathing.
A diagnostic procedure was performed.




TO BE CONTINUED

DIFFERENTIAL DIAGNOSIS
Dr. Madhusmita Misra: I am aware of the diagnosis in this case. This teenage girl presented with rapid thyroid enlargement (goiter), mild hypothyroidism, and serologic evidence of autoimmune thyroiditis.


Causes of Goiter

Differential Diagnosis of Goiter in an Adolescent with Mild Hypothyroidism or Euthyroidism.
. When thyroglossal-duct cysts become infected, the patient typically presents with cystic swelling in the midline of the neck. Patients with mild forms of dyshormonogenesis may sometimes present in late childhood with hypothyroidism and goiter; however, rapid enlargement of the thyroid, as seen in this case, is not a feature of either condition. Also, neither condition is associated with serologic evidence of autoimmune thyroiditis. This patient had a firm (not cystic) thyroid mass that was enlarging rapidly, and tests for antibodies were strongly positive, making these diagnoses unlikely. This patient had no history of ingestion of goitrogenic foods and no history of an unusual or fad diet that would suggest iodine deficiency. Colloid goiters commonly occur in adolescent girls but are not associated with rapid thyroid enlargement or autoantibodies.

Thyroiditis
Among inflammatory conditions, an absence of tenderness, fever, or fatigue made acute suppurative or subacute granulomatous thyroiditis unlikely in this patient. Chronic autoimmune thyroiditis is a common cause of goiter in teenagers, and clinical or serologic evidence of the condition is seen in 1 to 2% of all children and adolescents. The condition is most common in white girls and is associated with elevations in anti–thyroid peroxidase and antithyroglobulin antibodies. It may be associated with euthyroidism or compensated or overt hypothyroidism. In chronic autoimmune thyroiditis, the goiter is firm and diffuse, although it may sometimes be irregular or even nodular. This patient had a firm goiter, positive antibody tests, and a slightly elevated thyrotropin level, features that are indicative of this condition. However, the dysphagia and rapid enlargement of the thyroid were of concern since neither of these features is typical of chronic autoimmune thyroiditis. The possibility of nodules was also of concern.

Thyroid Nodules
Chronic autoimmune thyroiditis may have a nodular appearance as a result of thyrotropin-induced hyperplasia of follicular tissue or focal lymphocytic infiltrates, but true nodules may also occur. Ultrasonographic evaluation is useful in differentiating apparent nodules from true nodules; in addition, a reduction in the size of the nodules after replacement therapy with levothyroxine is reassuring.2 However, this patient's thyroid increased in size after the administration of levothyroxine was begun. Rapid enlargement of the thyroid can occur when there is hemorrhage within a cystic nodule, hemorrhagic degeneration of a nodule, or associated cancer. Approximately 5% of thyroid nodules in adults are malignant, whereas approximately 20% of thyroid nodules in pediatric patients are cancers (reported range, 2 to 40%).3,4 This patient had additional risk factors for cancer, including chronic autoimmune thyroiditis,2 an elevated thyrotropin level (associated with a 10-fold increase in cancer risk),5 rapid growth, an abnormal cervical lymph node, and symptoms of upper aerodigestive tract compression. Male sex and a history of radiation also confer an increased risk of cancer in children. On the basis of the history of a rapidly enlarging gland and dysphagia and the continued growth of the thyroid while the patient was being treated with levothyroxine, we were very concerned about the presence of cancer.

Thyroid Cancers
Papillary thyroid cancers are the most common type of thyroid cancer in children, followed by follicular and medullary thyroid cancers. Anaplastic cancers, primary thyroid lymphomas, and metastatic cancer are typically seen in older adults and rarely in children. Among papillary cancers, the well-differentiated and follicular variants are most common and are associated with an excellent prognosis (20-year survival, >90%), but they typically present as slow enlargement of a nodule, rather than rapid, diffuse enlargement of the thyroid. However, the diffuse sclerosing variant is associated with larger and more aggressive tumors and higher rates of local and distant metastases than is the common type of papillary cancer. A rapidly enlarging mass is also more common in anaplastic carcinoma and large B-cell lymphoma than in typical papillary carcinoma. Positive tests for antithyroid antibodies have been reported in up to 75% of patients with the diffuse sclerosing variant of papillary thyroid cancer6 and in 50 to 90% of patients with primary thyroid lymphomas.7,8 In view of this patient's age, the presence of antithyroid antibodies, and the history of rapid enlargement, the most likely diagnosis was the diffuse sclerosing variant of papillary carcinoma, with primary thyroid lymphoma and anaplastic carcinoma being less likely because of her age.
I asked for an ultrasonographic examination of the thyroid gland, with a plan for a subsequent fine-needle aspiration biopsy. May we review the images?
Dr. Randheer Shailam: Ultrasound examination of the thyroid showed diffuse enlargement of both lobes, with abnormal heterogeneous echotexture and numerous hyperechoic foci, features that were consistent with microcalcifications

Ultrasonogram of the Thyroid Gland.
). An abnormal-appearing lymph node with echotexture similar to the thyroid was present lateral to the left lobe of the thyroid. A small complex cystic nodule was present in the isthmus and had features that were indeterminate for cancer.
Most cases of thyroid cancer are manifested as a suspicious nodule, which was not present in this case. Diffuse thyroid enlargement is suggestive of a benign process, but the presence of microcalcifications in a diffusely heterogeneous thyroid gland and the presence of a regional lymph node with an appearance similar to that of the thyroid (suggesting involvement by the same process) raise concerns about thyroid cancer. Papillary thyroid cancer may present with microcalcifications and without an associated mass.9 For this reason, a biopsy was recommended.

to be continued........

DR. MADHUSMITA MISRA'S DIAGNOSIS

Diffuse sclerosing variant of papillary thyroid carcinoma, associated with chronic autoimmune thyroiditis.
PATHOLOGICAL DISCUSSION

Dr. Peter M. Sadow: Examination of specimens from fine-needle aspiration biopsy of the thyroid and an adjacent lymph node revealed papillary thyroid carcinoma within the right isthmus of the thyroid and a metastatic focus of papillary thyroid cancer in a left cervical lymph node (Figure 2AFIGURE 2
Specimens from Thyroid Biopsy and Resection.
).
DISCUSSION OF MANAGEMENT

Dr. Sareh Parangi: After the diagnosis of papillary thyroid carcinoma was made, the patient was referred to me. The initial goal of the endocrine surgeon is to remove the entire primary tumor and affected lymph nodes with minimal complications, reducing the risk for recurrence. After surgery, the patient's disease can be staged on the basis of both the surgical findings and the pathologic specimen. Surgical removal of the tumor and any normal surrounding thyroid tissue also allows for radioactive iodine therapy if needed, as well as permitting long-term surveillance.
Preoperative Evaluation
My management of this patient's condition began with physical examination and ultrasonography. Surgeon-performed ultrasonography is used to carefully assess the extent of the tumor and any involved lymph-node basins and has been shown to alter surgical treatment in up to 40% of patients.10 In this case, ultrasound examination confirmed the presence of bilateral thyroid enlargement, with microcalcifications throughout the gland; there were multiple enlarged central nodes bilaterally, low in the neck, as well as lymph nodes bilaterally along both internal jugular veins, that raised suspicion.
Magnetic resonance imaging (MRI) is not commonly used in patients with papillary thyroid cancer, although some advocate its use in children because of somewhat better imaging of retropharyngeal lymph nodes than with ultrasonography. Computed tomography (CT) with the administration of contrast material is generally not used for preoperative imaging because the iodine load can delay postoperative administration of radioactive iodine, should this be necessary. Neither MRI nor CT was performed in this patient. Fiberoptic laryngoscopy was not used to assess vocal-cord function, since such an assessment has been shown to be of little value when there are no symptoms of dysphonia and no obvious voice changes on physical examination.11 The distant metastatic disease burden is generally not assessed preoperatively in patients with papillary carcinoma.
Operative Management
Considerable controversy exists surrounding the surgical treatment of papillary thyroid cancers that are small or have a low risk of recurrence. The American Thyroid Association consensus guidelines12 recommend a total thyroidectomy for patients with papillary cancers that are larger than 1 to 1.5 cm. Although only one study has shown a survival benefit for total thyroidectomy as compared with lobectomy for papillary cancers larger than 1 cm,13 the trend in the United States is for patients with papillary thyroid cancers to undergo total thyroidectomy.14 In this patient, total thyroidectomy was clearly indicated because of her presentation with diffuse disease in the thyroid and bulky nodal disease.
Papillary thyroid carcinomas have a propensity to spread through the lymphatic system, in contrast to follicular thyroid carcinomas, which spread hematogenously. Papillary thyroid cancer typically spreads first to the central nodes (closest to the thyroid, also known as level VI), then to the ipsilateral lateral nodes surrounding the internal jugular vein (levels II, III, and IV), and subsequently to the nodes in the contralateral lateral compartments. When extensive lymph-node dissections are performed, whether prophylactically or because of a suspicion of papillary thyroid cancer, up to 40% of lymph nodes are found to harbor disease. Nonetheless, lymph-node involvement by itself does not affect survival, especially in patients younger than 45 years of age.15 The American Thyroid Association consensus statement recommends that the central lymph nodes be considered for removal.16,17 The lymph nodes in the central and lateral neck compartments needed to be addressed in this patient, since ultrasound examination showed that both compartments had tumor involvement.
Risks Associated with Total Thyroidectomy and Lymph-Node Dissection
Total thyroidectomy is usually safe when performed by a skilled and experienced surgeon. The major complications are unilateral or bilateral injury to the recurrent laryngeal nerves and hypoparathyroidism. Permanent injury to one recurrent laryngeal nerve occurs in 1 to 2% of patients who undergo thyroid surgery with an experienced surgeon but can occur in up to 7% of patients whose surgeons are inexperienced.18 Bilateral nerve injury is very rare. Temporary palsies due to stretching or bruising of the nerve can occur in up to 5% of patients but often resolve within 6 months. Permanent hypoparathyroidism, which occurs when none of the four parathyroid glands retain function after thyroid surgery, is seen in 2% of patients; temporary hypoparathyroidism occurs in up to 20% of patients.
Lymph-node dissection increases the risk of injury to adjacent anatomical structures. Dissection of the central nodes may slightly increase the risk of permanent hypoparathyroidism and nerve injury. Dissection of the lateral nodes in the neck confers the additional risks of injury to the thoracic duct, with chylous leakage, and of Horner's syndrome, from injury to the sympathetic chain behind the carotid artery. Injury to the brachial plexus or major cranial nerves traversing the area can also occur, especially in patients with bulky nodal disease.19
Operative Procedure for This Patient
In this patient with extensive disease in the neck, a device was placed on the endotracheal tube for intraoperative monitoring of the recurrent laryngeal nerve. In one large study, nerve monitoring was not shown to be associated with a reduction in injury rates,20 whereas other studies suggest that its use in surgery for recurrent disease may be beneficial in decreasing the incidence of permanent injury to the recurrent laryngeal nerve.21 This technique has gained some popularity, and I find it helpful and use it regularly. An experienced surgeon and adequate exposure of the nerve remain crucial for minimizing injury to the recurrent laryngeal nerve.
I used a transverse incision, because it allows access to all the compartments that needed to be dissected and because the long-term cosmetic result is good. While the patient was anesthetized and on the operating table, ultrasonography was used to mark the extent of the involved lymph nodes, so that I could be sure that a transverse incision would be appropriate for the removal of all potentially involved nodes. The strap muscles were divided, and a total thyroidectomy was performed. Both recurrent laryngeal nerves were identified and preserved. Evaluation of intraoperative frozen sections of parathyroid tissue confirmed that we had located both upper parathyroid glands, which I autotransplanted into the sternocleidomastoid muscles, since I thought they would not be viable in situ. Normal non-neoplastic parathyroid tissue is one of the few organs in the body that can be autotransplanted with success. Successfully autotransplanted parathyroid glands can function at least 80% of the time.22
Bilateral central neck nodal dissection (level VI) and bilateral modified radical neck dissection were performed. The left thoracic duct was clipped, and no drain was placed. Many surgeons place drains after lymph-node dissection, but not using a drain does not change the complication rate or worsen the cosmetic appearance of the wound.23 In addition, drain removal can be somewhat traumatic in the pediatric population. The operation took approximately 11 hours.