Correspondence *Department of Medicine, Endocrinology Service, Memorial Sloan–Kettering Cancer Center, Room 834, Zuckerman Research Building, 1275 York Avenue, New York, NY 10021, USA

Email tuttlem@mskcc.org

The case

A 55-year-old man was referred to an endocrinologist by his primary care physician for evaluation of a large multinodular goiter that had been present for more than 25 years. The thyroid had several nodules measuring less than 1 cm with the right lobe containing a dominant 7–8 cm nodule that was benign and had undergone fine-needle aspiration (FNA) on several occasions over the years. He refused surgical resection of the nodule, preferring continued observation since he was asymptomatic. He denied any changes in his voice, difficulty in breathing or problems swallowing, but did note that the dominant nodule had enlarged over the past year. His mother and brother had a family history of benign nodular thyroid disease. He denied a history of radiation exposure. About 2 months after presentation he underwent a total thyroidectomy, which revealed a 7 cm poorly differentiated tumor that was confined within the right lobe among a background of bilateral benign nodular hyperplasia. Six months later, he developed a palpable 2 cm lymph node in the right neck and underwent right-modified radical neck dissection with 2 out of 52 resected lymph nodes shown to be positive for poorly differentiated thyroid cancer (PDTC). He refused radioactive iodine (RAI) therapy after both surgeries. His routine chest radiographs were normal for the following 2 years. His serum thyroglobulin (Tg) on thyroid-stimulating hormone (TSH) suppression was <1 units/ml with negative anti-Tg antibodies for two additional years. Two years later, a chest radiograph and chest CT scan showed the presence of multiple 1 mm-sized bilateral pulmonary nodules. He decided against RAI therapy because he was asymptomatic. Serial chest radiographs were stable for the next 2 years but serum Tg rose from <0.3 g/l to 3 g/l within a year, and increased to 5.3 g/l the following year. The patient was lost to follow-up for the next 4 years. During a routine CT scan of the chest, abdomen, and pelvis for unrelated reasons, multiple lower-lobe bilateral pulmonary nodules (2.6 cm) were detected and prompted re-evaluation. His serum Tg on TSH suppression had risen to 210 units/ml at that time. Owing to the dramatic change in the size of the pulmonary lesions, concerns for a second malignancy led to CT-guided FNA of the largest pulmonary lesion. This biopsy confirmed metastatic PDTC, similar to the original thyroid lesion resected 12 years earlier. Further [¹⁸F]-2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT scan staging revealed numerous metabolically inactive pulmonary nodules up to 2.8 cm in size. Recombinant human TSH (rhTSH)-stimulated RAI scanning with ¹²⁴I dosimetry confirmed RAI-avid metastatic disease in the neck and chest (Figure 1). The patient received 248 mCi of ¹³¹I and a post-therapy scan confirmed the expected RAI-avid disease in the neck and chest (Figures 2 and 3). The true effectiveness of RAI therapy in this particular patient is unknown because he was only recently treated; however, repeat chest CT scans 6 months after RAI therapy showed a decrease in size of many of the pulmonary nodules while others remain stable. The patient is followed-up with cross-sectional imaging of the neck and chest, and serum Tg on TSH suppression every 6 months.

Figure 1 ¹²⁴I PET-CT scan of the patient.

(A) Bilateral pulmonary nodules seen on the fused PET/CT image (arrows). (B) The maximum intensity projection image shows iodine-avid disease in neck and bilateral lung fields.

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Figure 2 ¹³¹I post-therapy scan.

Whole body RAI scan performed several days after RAI therapy demonstrates successful targeting of ¹³¹I to the metastatic disease in neck and chest.

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Figure 3 ¹³¹I post-therapy transaxial single-photon-emission CT.

In this image, the post-therapy RAI scan is fused to the CT image to delineate which pulmonary metastases are RAI-avid. While some of the pulmonary nodules exhibit intense RAI-avidity (red arrows), several others do not seem to be concentrating significant quantities of RAI, reflecting the diverse nature of metastatic disease (white arrows).

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Discussion of diagnosis

Several studies have demonstrated that thyroid nodules can be detected by physical examination in as many as 5% of all women and 1% of all men over the age of 50 years in the US.^{1, 2} The prevalence of abnormalities within the thyroid as detected by ultrasonography is as much as 10-fold higher than physical examinations would suggest, and approaches 50% in adults aged 60 years or older.³ Only 5–10% of thyroid nodules are found to be malignant; the remaining 90–95% are benign nodules that usually remain asymptomatic, have essentially no malignant potential, and require no specific therapy beyond observation.^{1, 2} Several well-established risk factors increase the probability of malignancy in a thyroid nodule; prior radiation exposure, male gender, extremes of age (less than 10 or more than 60 years old), rapid increase in size, palpable cervical lymphadenopathy, and previous history of thyroid cancer or evidence of local invasion (i.e., vocal cord paralysis, dysphagia or fixation to surrounding structures in the neck).^{1, 2} Despite the use of molecular markers to improve the diagnostic accuracy of FNA cytology, none has, so far, been proved sufficiently accurate to be used routinely in clinical practice. In this patient, the large size of the dominant nodule, which continued to increase in size, was highly suggestive of malignancy despite previous benign FNA findings and the lack of local invasive symptoms.

Differential diagnosis

FNA leads to a correct cytological diagnosis in more than 95% of cases⁴; however, false-negative results do occur, as demonstrated in this patient, and the false-negative rate can be as high as 5%. False-negative results are often attributed to sampling error in very large nodules, but can also be seen in well-differentiated thyroid cancers that are very similar on cytology to normal thyroid follicular cells. Integration of the FNA with the clinical presentation is critical in the identification of rare malignant cases that are characterized as benign by FNA. As such, surgery should still be considered in patients with high-risk features for thyroid cancer even if the FNA is benign. Even when the thyroid nodules are found to be malignant, more than 85% are papillary thyroid cancer, which has an expected 30-year disease-specific survival rate of greater than 90%.⁵

Treatment and management

Treatment for thyroid cancer requires surgical removal of the thyroid, often with a compartmental neck dissection of involved lymph nodes and RAI to destroy any residual benign or malignant thyroid cells. Compartmental resection of visibly abnormal lymph nodes should be recommended; however, the role of routine lymph-node dissection in patients without clinically apparent lymph-node metastases remains controversial. Chemotherapy and external-beam irradiation are not used except in very aggressive cases.⁶ The management strategy after initial therapy includes an emphasis on the suppression of TSH with levothyroxine and early detection of recurrent disease with neck ultrasonography and Tg.

The behavior of those cancers that comprise the PDTC group is intermediate between the excellent prognosis of well-differentiated papillary thyroid cancer, and the very aggressive behavior of anaplastic thyroid cancer.⁷ PDTCs seem to arise from either papillary or follicular thyroid cancer. The term 'poorly differentiated' is applied using a variety of definitions in various studies, which makes a meaningful review of the literature difficult.^{8, 9} In addition to the prognostic utility of careful histologic examination, many studies have documented poor outcomes in older patients with differentiated thyroid cancers greater than 4 cm, especially when associated with gross extrathyroidal extension.^{5, 6}

Despite differing definitions, most studies demonstrate that PDTCs are rather aggressive tumors with low Tg production, which respond poorly to RAI, and are often positive on FDG-PET scanning. These characteristics reflect the undifferentiated nature of the tumor; however, at least 25% of patients with PDTC retain the ability to concentrate RAI, as in this case.¹⁰ These RAI-avid PDTCs do not have high metabolic activity and are usually negative on FDG-PET scanning. RAI scanning and therapy may, therefore, be useful for disease detection in PDTCs, particularly when the metastatic disease in not detected by FDG. Furthermore, as in this case, some PDTCs also make serum Tg,¹¹ therefore, measurement of this protein should be a part of the follow-up of well-differentiated and poorly differentiated tumors. Many PDTCs produce low amounts of Tg, therefore serum Tg may not be a reliable indicator of persistent PDTC. The follow-up of patients with this form of thyroid cancer often requires additional cross-sectional imaging of the neck and chest, and FDG-PET scanning to detect recurrent/persistent disease. Recurrences are treated with either repeat surgery, additional RAI, or both, depending on the location, size, and RAI-avidity of the lesion.⁶ Patients with PDTC often have distant metastatic disease that may require surgical resection or external-beam irradiation, depending on the location and size of the lesion.^{12, 13}

FDG-PET scanning has developed into a critical tool for the detection of non-RAI-avid thyroid cancer. PET-positive metastatic lesions are associated with a more-rapid disease progression, higher mortality, and resistance to RAI therapy.^{14, 15} As in this case, metastatic lesions that are PET-negative often concentrate RAI adequately to allow RAI scanning and therapy. The advent of ¹²⁴I PET now facilitates a more-accurate assessment of individual lesion dosimetry that can be detected on standard PET equipment.¹⁶ This technique is a marked improvement over the whole-body dosimetry studies previously conducted, which simply calculated the maximum safe dose, rather than the individual lesional dose. While our routine practice is to use whole-body and blood dosimetry to deliver high-dose RAI in patients with metastatic disease, other centers continue to use empiric RAI dosing without dosimetry with apparently similar results. As seen in this case, metastatic lesions often vary dramatically in their ability to concentrate RAI, even within an individual patient. On the basis of the ¹²⁴I PET dosimetry, tumoricidal doses are likely to be achieved in some of the pulmonary lesions. Notably, it is possible for an improvement to be observed in some metastatic lesions, while others continue to grow, as demonstrated at the 6-month follow-up in this patient. Currently, ¹²⁴I PET studies are not routinely available at most centers, and are not used in the care of patients with thyroid cancer; however, with the commercial availability of ¹²⁴I, research into this exciting field is expected to increase. While rhTSH is currently only FDA-approved for diagnostic RAI scanning and stimulation of Tg measurements, this case illustrates that rhTSH can be used to achieve tumoricidal radiation doses in metastatic lesions in selected patients. Further studies are needed before rhTSH is routinely recommended as preparation for RAI therapy. Unfortunately, most patients with PDTC do not respond to RAI therapy. Since traditional chemotherapy has generally been associated with disappointing results in thyroid cancer, patients with non-RAI avid, progressive thyroid cancer that cannot be managed with surgery or external-beam therapy should be referred for clinical trials.⁶

Conclusions

The clinical course of PDTCs is usually aggressive with higher recurrence rate, higher rate of distant metastases, and a higher rate of local extrathyroidal invasion than well-differentiated thyroid tumors. PDTCs tend to be FDG-PET-positive, and not RAI-avid; however, as this case demonstrates, some PDTCs do concentrate significant amounts of RAI, produce reasonable amounts of Tg, and are FDG-PET-negative. One would suspect that the clinical outcome in these tumors will be superior to the more commonly seen pattern of FDG-PET-positive and RAI-negative thyroid cancer. Until we can confidently identify those PDTCs that will not respond to RAI, we routinely offer RAI therapy in the management of these patients; however, many of these patients will have persistent or recurrent disease that is non-RAI-responsive. While additional surgery and external-beam irradiation can be used to manage individual lesions, novel systemic therapies are urgently needed for patients with progressive PDTC.

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Subject areas under which this article appears: Radiotherapy