Assessing the cause of symptoms in a patient with thyroid cancer

A 75-year-old woman had undergone a total thyroidectomy, with histologic evidence of poorly differentiated follicular thyroid cancer. She subsequently received an ablative dose of iodine-131. After a disease-free interval of about 2 years, she presented with evidence of recurrence in the thyroid bed. She had enlarged cervical lymph nodes and complained of dyspnea on exertion.

The patient underwent a central and lateral neck dissection, with histology confirming recurrent carcinoma. She received 2 additional ablative doses of 150 mCi iodine-131. Her chest radiograph revealed multiple pulmonary nodules of varying sizes in a predominantly basilar distribution, suggesting pulmonary metastases (Figure 1).

Whole-body fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) was performed after treatment; the results were negative. However, a serum thyroglobulin level of 100 ng/mL was reported by the laboratory.

Five days after the last radioiodine treatment, the patient was seen in the outpatient clinic, complaining of worseningshortness of breath. She denied allergy, fever, chills, rigors, hemoptysis, and chest pain. The patient, a nonsmoker, reported a weight loss of about 25 lb over the previous 6 months.

Physical examination revealed an afebrile woman with a pulse rate of 96 beats per minute, blood pressure of 110/70 mm Hg, and respiration rate of 18 breaths per minute. A thyroidectomy scar was evident on examination of the neck. No clubbing or cyanosis was noted. The first and second heart sounds were normal. Breath sounds were decreased at both lung bases. The abdominal and neurologic examination findings were unremarkable.

White blood cell count was 1160/µL, with 74% neutrophils, 20% lymphocytes, and 6% monocytes. Hemoglobin level was 12.7 g/dL, and hematocrit level was 31%. The blood gases on room air were pH, 7.44; PCO₂, 34 mm Hg; and PO₂, 72 mm Hg.

A whole-body iodine-131 scan was performed (Figure 2).

What is the likely diagnosis?

Answer on next page.

Assessing the cause of symptoms in a patient with thyroid cancer. The patient had impaired pulmonary function because of metastases from follicular thyroid carcinoma. Her increasing dyspnea after radioiodine therapy suggests complicating radiation pneumonitis.

The iodine-131 scan shows moderately intense increased activity in the right thyroid bed and a second small focus in the inferior left thyroid bed. The scan showed bilateral, diffusely increased pulmonary activity, with a small, more intense focus of increased uptake peripherally in the right pulmonary base. There also was increased liver activity.

The patient, after a disease-free interval of about 2 years, presented with palpable nodules in the thyroid bed and an elevated serum thyroglobulin level. These findings are consistent with local recurrent and/or metastatic disease. The lack of FDG uptake on the PET scan and a moderate elevation in thyroglobulin level suggest that the tumor, despite spread to the cervical nodes and lungs, is not highly aggressive. In aggressive widespread disease, thyroglobulin levels higher than 10,000 ng/mL have been reported.

In view of the persistently elevated thyroglobulin levels and suggestion of metastatic disease on the chest radiograph, 150 mCi iodine-131 was administered and a whole-body iodine-131 scan was performed. The evidence of diffuse pulmonary activity is consistent with innumerable micrometastases as well as macrometastases. The diffusely increased liver activity can be explained by enhanced thyroglobulin and bound iodine removal from the circulation by the liver, with resultant free hepatic iodine.

Discussion

Carcinoma of the thyroid gland is the most common malignancy of the endocrine system, with about 14,000 new cases annually in the United States. It affects more women than men, usually occurring in those aged 25 to 65 years. Average life expectancy after diagnosis is 25 years. There are about 250,000 thyroid cancer survivors in the United States. The most recent data indicate 1400 deaths a year from thyroid cancer.

In as many as 50% of cases, the diagnosis is made when the patient is examined for another condition--such as CT evaluation of neck injury and sonographic evaluation of the carotid arteries. More than 10% of adults in the United States are found to have thyroid nodules on sonography.

Well-differentiated tumors confined to the gland and regional nodes (papillary or follicular) are treatable and are usually curable. The current treatment protocol for thyroid cancer includes total thyroidectomy followed by radioiodine ablation of remnant tissue. Poorly differentiated papillary and follicular cancers are less common and are seen more frequently in the elderly.

Well-differentiated tumors not cured by initial treatment may undergo dedifferentiation over time and progress to a more aggressive form. They may then metastasize and have a poor prognosis. Columnar cell variant of papillary tumors, Hürthle cell carcinomas, insular carcinomas, and anaplastic tumors all have a less favorable prognosis. Patients with anaplastic cancer rarely survive more than 6 months.

Papillary tumors account for 84% of all thyroid tumors; follicular and Hürthle cell carcinomas, 10%; medullary carcinoma, 5%; and anaplastic carcinoma, 1%. Distant metastases, usually in the lungs and bones, occur in10% to 15% of patients with differentiated thyroid carcinomas.^1,2 The overall survival rate 10 years after the discovery of distantmetastases is about 40%.³ Positive results on a PET scan indicate more aggressive tumor activity and have a negative prognostic value.

Diffuse pulmonary metastases are typically treated with 200 mCi iodine-131, although those concentrating more than 50% of the diagnostic dose of iodinemay be treated with a reduced dose to avoid lung injury. There is an increased risk of radiation pneumonitis and fibrosis if more than 80 mCi is deposited in the lungs.

Radiographically, the pulmonary metastases from papillary thyroid cancers tend to have a micronodular pattern (resembling miliary tuberculosis) or a reticulonodular pattern (simulating interstitial fibrosis). In contrast, metastases from follicular carcinoma tend to develop into larger parenchymal nodules and are more frequently associated with skeletal metastases. Pulmonary metastases from thyroid cancer rarely calcify.⁴

Thyroglobulin is a glycoprotein produced in the body only by thyroid cells (benign or neoplastic). It should not be detectablein persons who have undergone successful total thyroid ablation. Significantly increased thyroglobulin levels indicate recurrent local or metastatic disease.

Thyroglobulin levels are suppressed by thyroxine administration. During follow-up, if no thyroglobulin is detected in a suppressed patient, the level should be reassessed after withdrawal of thyroxine or after the administration of recombinant thyrotropin (TSH). Thyroglobulin assays are invalidated by the presence of thyroglobulin autoantibodies; all samples must therefore be screened.

FDG PET scanning has become an increasinglyimportant functional imaging modality in clinical oncology. Iodine-131 scintigraphy and FDG PET imaging are complementary methods for the evaluation of recurrent or metastatic thyroid cancer.⁵ The iodine uptake of a tumor is inversely related to its glucose metabolism. Tumor uptake is also related to the degree of tumor differentiation. In general, highly differentiated thyroid carcinomas are iodine-131-positive and FDG PET-negative, while less differentiated cancers show the reverse pattern.

Older patients in high-risk categories who have minimally iodophilic metastases are sometimes treated with doses as high as 300 to 400 mCi. The maximum safe single dose is limited by the dose delivered to bone marrow. Formal dosimetry may be performed, as described by Benua and Leeper,⁶ to ensure that the marrow is not exposed to a dose of more than 200 rads. If there is renal insufficiency, radioiodine retention may be prolonged and a considerably lower dose of radioiodine may be required. Additional doses may be safely administered at intervals of 1 year. There is no total dose limitation.

Administration of supraphysiologic oral doses of levothyroxine has been widely used after surgery and radioiodine treatment. This regimen is based on the assumption that suppression of endogenous TSH production deprives neoplastic cells of an important growth-promoting influence. The goal of thyroxine therapy is significant suppression of pituitary TSH secretion, with laboratory values well below normal if tolerated by the patient.

External beam radiation may also be beneficial in the treatment of poorly differentiated tumors that are not concentrating radioiodine. It is not useful for the treatment of pulmonary metastases in most patients.

The role of surgery is limited. Surgical intervention should be considered only for patients who have no evidence of extrathoracic disease, have no medical contraindication to pulmonary resection, have nodules that are resectable (no absolute limit on the number of nodules), and have satisfactory residual pulmonary function and for those patients whose primary tumor is well controlled.⁷

Follow-up of patients after therapy includes periodic physical examination, repeated radioiodine imaging, ultrasonography, and measurement of TSH and thyroglobulin levels in the blood.

Case and figures courtesy of Reene Brown, MD, Abhineet Sayal, MD, Donald Margouleff, MD, Yana Studentsova, MD, and Arunabh Talwar, MD, of Long Island Jewish Medical Center, New Hyde Park, New York, and North Shore University Hospital, Manhasset, New York.

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