Follicular Thyroid Carcinoma Metastasis to the Esophagus detected by FDG PET/CT

Unusual Patients

Follicular Thyroid Carcinoma Metastasis to the EsophagusDetected by 18FDG PET=CT

Belinda Lee,1 Gary Cook,2 Lynn John,3 Kevin Harrington,1 and Chris Nutting1

We report an unusual case of an esophageal metastasis demonstrated on integrated 18F-fluorodeoxyglucose(18FDG) positron emission tomography=computed tomography (PET=CT) scanning. A 55-year-old male withtreated well-differentiated follicular thyroid carcinoma (FTC) had persistently raised thyroglobulin levels despiteboth negative whole-body CT scan and 131I scans. An initial 18FDG PET=CT scan showed moderate focal uptakein the esophagus, which was initially thought to be physiological. A subsequent comparative 18FDG PET=CTscan showed more intense uptake. A diagnostic endoscopy revealed a pedunculated esophageal polyp, whichhistological examination confirmed to be metastatic FTC. Such a case has not previously been reported.

Introduction

Thyroid carcinoma comprises approximately 1% of allmalignancies (1). Its incidence in Europe is 3 in 100,000

people per year. Follicular thyroid carcinoma (FTC) ismore common in patients with iodine-deficient diets andrepresents 10–20% of all thyroid malignancies. It occursmost commonly in the fifth and sixth decades (1). Earlydiagnosis is crucial to maximize the possibility of cure. Sur-gery is the treatment of choice with total thyroidectomy,followed by radioiodine (131I) ablation of the thyroid rem-nant. Thyroid hormone replacement with triiodothyroninemaybe be commenced initially after thyroidectomy; however,long-term thyroid-stimulating hormone (TSH) suppressivetherapy with thyroxine (T4) should be used to suppress TSH< 0.1mU=L.

Total thyroidectomy is necessary for successful radioiodineablation, which is effective in ablation of small thyroid rem-nants and pulmonary metastases, but less effective in thetreatment of bone metastases (1–3). Ten-year survival is be-tween 70% and 95% with recurrence occurring in approxi-mately 20% of treated cases (2,3). Distant metastases andhematogenous spread occur in around 20% of patients, usu-ally to bones, lungs, and brain (1–3).

Following treatment of FTC, progression or recurrence ismonitored through a combination of clinical examination,

ultrasound imaging of the neck, serial serum thyroglobulinmeasurements, and whole-body 131I radioiodine scanning.However, in 18% of cases, recurrent FTC does not concentrate131I because of downregulation of membrane sodium-iodidesymporter (NIS) (4). In 131I scan–negative patients, 18F-fluor-odeoxyglucose (18FDG) positron emission tomography (PET)scanning can localize metastatic sites with high accuracy (5,6).Sensitivities of up to 95%, with only a small number of falsepositives, have been described in 131I scan–negative patientswith elevated thyroglobulin levels (5–8). The sensitivity canbe enhanced by withdrawing T4 4 weeks before attending thediagnostic radioiodine scan or giving recombinant humanTSH (rhTSH) (9). The introduction of positron emissiontomography=computed tomography (PET=CT) has furtherimproved diagnostic accuracy by improving anatomical lo-calization, reducing false positives due to physiological vari-ants and reducing equivocal interpretations (9). We report thecase of an extremely rare metastasis to the esophagus diag-nosed on PET=CT.

Case Report

A 55-year-old male patient presented with an enlargingthyroid mass on the background of a multinodular goiter.Preoperative assessment suggested an FTC, and he under-went a total thyroidectomy and level VI nodal dissection for a

1Thyroid Unit, Clinical Oncology Department, Royal Marsden Hospital, London, United Kingdom.2Department of Nuclear Medicine and PET, Royal Marsden Hospital, Sutton, United Kingdom.3Cromwell Hospital, London, United Kingdom.

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pT1pN0well-differentiated FTC. Following adjuvant ablativeradioiodine treatment (3.7GBq 131I), his thyroglobulin levelwas measured to be 140 ng=mL (Fig. 1). A year later the thy-roglobulin level 2 weeks after T4 withdrawal prior to radio-iodine scanning was 559 ng=mL (TSH: 7mU=L) (Fig. 1).Physical examination of the neck did not reveal any abnor-mality. 131I radioiodine whole-body scan showed evidenceof uptake in functioning thyroid tissue in the neck with adiscrete metastatic focus in the right parietal region of theskull. An ultrasound of the neck was not undertaken as therewas no clinical indication. The patient received furtherradioiodine therapy with rhTSH prior to 131I radioiodine ad-ministration.

Six months later, thyroglobulin level following a furtherdose of 131I radioiodine (5.5GBq) was 1444 ng=mL, with aTSH of 39mU=L (Fig. 1). Clinical examination disclosed nonew signs. A repeat 131I radioiodine body scan was taken,which showed no focal uptake in the skull nor elsewhere,suggesting noniodine avid FTC. Concomitant thyroglobulinwas 1400 ng=mL, with a TSH of 38mU=L (Fig. 1). An obser-vation policy was pursued.

A year later, the patient presented with left-sided cervicallymphadenopathy. Fine-needle aspiration revealed meta-static FTC in a left level II node. A modified neck dissectionwas performed, which confirmed well-differentiated meta-static FTC in one single enlarged lymph node. At 6-month

follow-up, the thyroglobulin level had fallen from 14,386 to1860 ng=mL (off T4 prior to radioiodine scanning). Bothwhole-body CT scan and diagnostic 131I scan were negative.An integrated 18FDG PET=CT scan and repeat diagnostic 131Iscan was arranged. The integrated 18FDG PET=CT scan (Fig.2A) described no abnormal uptake in the thyroid bed orsurrounding tissue but commented on a focus of moderateuptake in the upper esophagus, which was thought to beunlikely to be related to thyroid cancer. Serum thyroglobulinlevel was elevated at 1812 ng=mL (TSH: 23mU=L, off T4) (Fig.1). A year later, the thyroglobulin level remained elevated at1042 ng=mL (TSH: 0.06mU=L, on T4), and repeat integrated18FDG PET=CT (Fig. 2B) revealed no new abnormalities butmore prominent uptake in the upper esophagus when com-pared to the previous study. This correlated with a rise in thestandardized uptake value (SUV) from 3.3 to 4.0. An eso-phagoscopy revealed a 2 cm pedunculated polyp in the mid-esophagus (Fig. 3). Histological examination of the biopsyspecimen showed metastatic FTC, positive for thyroglobulinon immunohistochemical staining. Following resection of thepolyp, the thyroglobulin level fell from 1042 to 358 ng=mL.Subsequent 18FDG PET=CT scans were negative, but thepersistently raised thyroglobulin level may represent per-sisting occult disease. The patient remains under close sur-veillance with repeat 18FDG PET=CT scans carried out every6–12 months.

FIG. 1. Graph of serial thyroglobulin and TSH levels over the course of treatment and follow-up.

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FIG. 2. Recombinant human TSH–stimulated 18FDG PET=CT scan showing abnormal signal in midthoracic esophagus. seeabove: (A) Initial PET=CT scan showing faint FDG accumulation in mid esophagus; (B) Subsequent PET=CT scan showingmore intense FDG accumulation in the same site in the mid esophagus.

Discussion

We report a very rare esophageal metastatic lesion fromFTC that was detected by 18FDG PET=CT. Although this wasinitially felt unlikely to be related to thyroid cancer in view ofthe unusual distribution, a subsequent scan showed an in-crease in activity and prompted a diagnostic endoscopy.

Well-differentiated FTC has a good prognosis with a 10-year survival between 70% and 95% and recurrence occurringin 20% of treated cases. The recurrence rate increases withtime, and 40-year recurrence rates are approximately 35%(2,3). The risk of recurrence or metastasis in FTC can beidentified at the time of diagnosis by prognostic factors, suchas extremes of age, male sex, tumors with poorly differenti-ated histological features, advanced tumor stage, and extra-thyroidal invasion (10).

The most common sites of FTC metastasis are to the lungs,bones, and brain, in around 20% of cases (1–3). Extrathyroidalinvasion and extracapsular lymph node metastasis in localadvanced FTC are associated with a higher risk of aero-digestive invasion than in patients with intrathyroidal FTCand no lymph node metastasis (11). In this case, the loweresophagus was initially thought to be an unlikely site of me-tastasis as there was no clinical evidence of extrathyroid in-vasion at presentation or 2 years later with the localized levelII nodal recurrence. Further, the metastasis was entirely mu-cosal; therefore, direct extension through the esophageal wallis excluded as a mechanism of spread.

Extranodal FTC extension and lymph node metastaseslarger than 2 cm at presentation are associated with an in-creased risk of recurrence, distant metastases, and lowersurvival rate. In locally advanced FTC, direct invasion mostcommonly involves structures in the central neck such as therecurrent laryngeal nerve, laryngotracheal tree, esophagus,and strap muscles (11). Metastases to the esophagus withoutevidence of local invasion are rare and have not previouslybeen cited in the literature. In fact, esophageal invasion by FTCis usually associated with tracheal invasion and would nor-mally presentwith features of dysphagia or odynophagia (11).

In iodine avid FTC,whole-body 131I radioiodine scanning isuseful for detecting sites of metastasis. However, in cases likethe one reported, with elevated serum thyroglobulin andnegative 131I radioiodine scans, integrated 18FDG PET=CToffers a synergistic method of improving detection of recur-rence. Scanning under TSH stimulation may further improvesensitivity (9). The use of integrated 18FDG PET=CT in thefollow-up of thyroid carcinoma is not a part of the routineprotocol, but maybe indicated in cases with markedly ele-vated thyroglobulin levels and equivocal 131I scans.

18FDG is a radiolabelled glucose analog that accumulates inmetabolically active cells. As a result, 18FDG tends to accu-mulate in tumor cells in a greater quantity than it does innormal tissue. However, increased glucose utilization is notspecific to malignant tissue, and a number of benign falsepositives and normal variants have been described, includinginflammatory changes due to esophagitis, recent surgical in-tervention, Teflon granulomas, uptake into activemuscle, andphysiological brown fat activity, some of which are morelikely to be correctly interpreted with combined PET=CT (5–7). In addition to these benefits, the use of combined PET=CTmay also improve false negative reporting because smallmetastases, particularly in the lung, whichmay be overlookedin a single PET investigation, can be visualized. CombinedPET=CT has been found to be particularly useful and com-plementary to 131I whole-body scan and serum thyroglobulinmeasurements for detecting metastases to cervical lymphnodes. In this case, the unusual uptake in the esophagus wasinitially thought to represent physiological uptake. However,with the rise in SUV and persistently raised thyroglobulinlevel the following year, the concern that an additional lesionwas in fact present was raised and lead to further endoscopicinvestigation.

Conclusion

This case highlights the need for an awareness of the pos-sibility of genuine metastatic deposits in unexpected sites.These unusual presentations should be followed up to dif-ferentiate between metastasis and other unrelated causes offocal 18FDG activity. Follow-up should be life-long becauseFTC has a prolonged natural history. As exemplified in thiscase, unusual recurrences may occur and can be successfullymanaged.

Learning Points

� FTC represents 10–20% of all thyroid malignancies.� Surgical resection with total thyroidectomy is the pri-mary treatment. Postoperative radioiodine ablation withthyroid hormone for TSH suppression is also imperativeafter surgical resection to decrease the risk of recurrenceand improve survival.

� Follow-up should be based on clinical examination, se-rial serum thyroglobulin levels, ultrasonography of theneck, and whole-body 131I scanning. 18FDG PET scan-ning has a role in 131I-negative patients with elevatedthyroglobulin level and is most sensitive under TSH-stimulated conditions.

� Ten-year survival is between 70% and 95% with recur-rence occurring in 20% of treated cases.

FIG. 3. Persistent FDG uptake in midesophagus at the siteof metastasis of follicular thyroid cancer.

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� Metastasis is usually to bone, lung, and brain. However,deposits may occur in unexpected sites, including theesophagus, which should be fully investigated.

� FTC has a prolonged natural history. Late recurrencesthat occur can be successfully managed as in this case.

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Address reprint requests to:Dr. Chris Nutting, B.Sc., MRCP, FRCR, M.D.

Thyroid UnitClinical Oncology Department

Royal Marsden HospitalFulham Road

London SW3 6JJUnited Kingdom

E-mail: chris.nutting@rmh.nhs.uk

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