Sacral Metastasis in Follicular Thyroid Carcinoma: Cytology Pitfalls and Serum Thyroglobulin Utility

Abstract

Sacral bone metastasis from primary follicular thyroid carcinoma (FTC) is rare. Most reported cases include factors indicative of thyroid origin, such as a history of treated thyroid cancer or newly identified thyroid nodules with malignant cytology. We herein report a 57-year-old woman with a metastatic sacral lesion of thyroid origin, initially misdiagnosed due to a false-negative fine-needle aspiration (FNA) cytology result of a thyroid nodule. The diagnosis was suspected based on an abnormally elevated serum thyroglobulin (sTg) level and confirmed through repeat core biopsy with thyroid-specific immunohistochemistry. This case highlights the limitations of FNA cytology in large thyroid nodules and underscores the potential role of sTg in diagnosing metastatic FTC in certain clinical scenarios. Thyroid carcinoma should be considered in the differential diagnosis of sacral metastases when the primary tumor is unknown.

Introduction

Bone represents the second most common site of distant metastases in thyroid carcinoma. Among histological subtypes, follicular thyroid carcinoma (FTC) exhibits a higher propensity for bone metastasis than papillary thyroid carcinoma, primarily due to its hematogenous spread. ¹ The vertebrae are the most common site, while sacral region metastases are exceedingly rare.

Thyroid carcinoma is seldom considered in the initial differential diagnosis of isolated sacral bone metastases. We herein report a case of FTC metastasizing to the sacrum, where a false-negative fine-needle aspiration (FNA) cytology result delayed the diagnosis. This case highlights the importance of considering thyroid carcinoma in osseous metastases of unknown origin and the role of serum thyroglobulin (sTg) in guiding diagnosis.

Case Report

A 57-year-old woman presented with progressive sacral pain for 1 month. She denied any history of neurological deficits, trauma, or tuberculosis. A benign goiter had been diagnosed 20 years prior but was not monitored. Clinical examination revealed sacral tenderness without palpable lesions or lymphadenopathy. Thyroid examination identified a 6 cm right lobe thyroid nodule with regular margins.

Magnetic resonance imaging showed multifocal lytic bone lesions at the lumbar spine, iliac bones, and femoral heads. The largest mass (81 mm × 82 mm) in the sacrum exhibited hyperintense signals on T2W and STIR, with evidence of muscle invasion, suggestive of metastasis (Figure 1).

Figure 1.

Sagittal magnetic resonance imaging shows a heterogeneous signal mass of sacral regions with a slightly hyperintense signal on T1W (A) and hyperintense signal on T2W (B); multifocal osteolytic lesions of lumbar vertebrae (C: yellow arrows).

Hematologic and biochemical tests were normal. Thyroid ultrasound revealed a 9 cm TIRADS 4 nodule (Figure 2). FNA cytology was classified as Bethesda II. To determine the primary tumor, a core biopsy of the sacrococcyx was performed. Histopathology showed small round cells with an immunohistochemical (IHC) profile: CK (−), Vimentin (+), S100 (−), CD34 (−), Desmin (−), CD3 (−), CD20 (−), Ki67 (+) 5%, HMB45 (−), and CD138 (−), suggesting metastatic carcinoma but an unknown primary origin.

Figure 2.

Sonography showed a 90 mm, solid, hypoechoic, wider-than-tall, smooth margin nodule without calcification in the right lobe thyroid nodule, classified as TIRADS-4.

Thoraco-abdominopelvic CT and Positron Emission Tomography (PET)/CT failed to identify a clear primary tumor. However, PET revealed abnormal metabolic activity in the sacral coccyx and left femoral neck, along with increased uptake in the thyroid gland. Several pulmonary nodules were identified without FDG uptake.

Laboratory tests showed an unexpectedly elevated sTg (>500 ng/mL), raising suspicion of a thyroid malignancy. The tumor board recommended a re-biopsy of the sacral lesion. IHC analysis (CK7 [+]/CK20 [−]/TTF-1 [+]/Thyroglobulin [+]) confirmed bone metastasis from thyroid carcinoma (Figure 3).

Figure 3.

Histopathology of the second sacral bone biopsy. (A) Hematoxilin & Eosin staining (×40) shows malignant epithelial cells in clusters. (B) IHC staining for Tg demonstrates strong positivity in thyroid follicular cells. IHC, immunohistochemical; Tg, thyroglobulin.

Consequently, the patient underwent a total thyroidectomy. Histopathology confirmed FTC with vascular invasion. The tumor board subsequently recommended molecular testing to identify potential targetable genetic alterations that could guide future targeted therapies in the event of radioactive iodine (RAI)-refractory progression. However, due to financial constraints, molecular profiling was not performed. As the sacral metastasis-related pain remained well controlled with analgesics, palliative radiotherapy and systemic chemotherapy were not indicated at that time. A therapeutic dose of 200 mCi of RAI was administered, with no additional interventions. Despite receiving supportive care, the patient’s clinical condition progressively declined, leading to mortality 6 months later.

Discussion

Spinal bone metastases frequently occur in advanced-stage cancers, with primary origins including breast (21%), lung (19%), prostate (19%), kidney (5%), gastrointestinal tract (4.5%), and thyroid gland (2.5%). ² Among differentiated thyroid carcinoma (DTC), FTC is most commonly associated with bone metastases, with rates ranging from 7% to 28%. Up to 84.7% of cases present with bone metastases at initial diagnosis. ³ Vertebrae are the most affected sites, followed by the pelvis, skull, and long bones.

Sacral metastases from FTC are exceedingly rare, with only a few reported cases.^4-7 In these cases, most patients have indicators that help promptly identify the thyroid origin, including a prior thyroid surgery or newly confirmed malignant thyroid nodules through FNA. By contrast, our case represents a unique scenario in which the likely benign thyroid cytology result (Bethesda II) initially misled diagnosis. The high sTg level incidentally raised suspicion of a thyroid origin. The diagnosis was confirmed only after re-biopsy with thyroid-specific IHC staining. Postoperative pathology further validated FTC metastasis.

The false-negative FNA cytology result was a critical factor in delayed diagnosis. While FNA is generally considered a reliable diagnostic tool, it has inherent limitations, particularly when applied to large nodules. The diagnostic value of FNA in larger nodules remains inconsistent. Some studies have demonstrated that FNA can be accurate even for nodules ≥3 cm, with a false-negative rate of approximately 2%, ⁸ whereas other studies suggest that nodules ≥4 cm may necessitate diagnostic lobectomy or multi-site aspiration to reduce false negatives.^9,10 Consequently, there is no universally consistent guideline in this setting, requiring larger, prospective studies with a uniform methodology to inform standardized recommendations. In addition, it is essential to highlight the limitations of cytologic assessment in well-differentiated follicular lesions, as these lesions often exhibit bland cellular morphology, which complicates accurate interpretation. False-negative FNA results can delay diagnosis and worsen outcomes, emphasizing the need for careful evaluation of large thyroid nodules.

Another crucial finding in this case was the extremely high sTg level. Although sTg is primarily used for postoperative surveillance, emerging evidence supports its role as a preoperative biomarker for thyroid cancer. Kars et al reported a significantly higher malignancy risk in patients with preoperative sTg >188.5 ng/mL. ¹¹ In addition, a threshold of 63.4 ng/mL has been identified as a predictor of initial distant metastasis in DTC. ¹² The markedly elevated sTg level (>500 ng/mL) in this case served as a crucial diagnostic indicator, prompting reconsideration of the thyroid as the primary malignancy.

This case also underscores the necessity of thyroid cancer consideration in metastatic bone lesions, particularly FTC. Initial diagnostic workup failed to identify the thyroid as the primary origin. The diagnosis was only confirmed after a second biopsy with IHC analysis. Given FTC’s tendency to metastasize to bones, it should be included in differential diagnoses once more common malignancies, such as lung, breast, or prostate cancer, are ruled out.

The 10-year survival rate of DTC declines from about 90% to 35%-40% in cases with distant metastases. ⁵ While thyroidectomy and metastasectomy improve outcomes, ¹³ the extensive sacral involvement in this case precluded surgical intervention. RAI therapy is the standard treatment for RAI-avid lesions but has limited efficacy in lytic bone metastases, with remission rates of 10% to 17% compared to >50% in lung metastases. ¹⁴ In this case, whole-body scintigraphy showed well-avid multifocal bone metastases, supporting RAI therapy. Disease progression impaired the patient’s performance status, ultimately leading to mortality.

Conclusion

This case highlights an unusual presentation of sacral metastasis from FTC, initially misdiagnosed due to false-negative cytology of a large thyroid nodule. In cases of spinal metastases of unknown primary, thyroid carcinoma should be considered after ruling out more common malignancies. FNA cytology of large thyroid nodules should be interpreted cautiously due to potential false-negative results. sTg level may serve as a crucial adjunct in the diagnosis of primary thyroid cancer.