Primary synovial sarcoma of the thyroid mimicking medullary thyroid cancer

Abstract

The differential diagnosis of a rapidly enlarging thyroid mass includes poorly differentiated thyroid carcinoma, anaplastic carcinoma, medullary thyroid carcinoma (MTC), lymphoma, and metastatic disease. Although fine-needle aspiration (FNA) provides important diagnostic clues, it may not be definitive. We report a 43-year-old woman with a long-standing goiter that enlarged rapidly over 6 months. FNA suggested MTC; however, serum calcitonin and carcinoembryonic antigen levels were within normal limits, creating clinicobiochemical discordance. Given this discrepancy, further evaluation was undertaken. Core needle biopsy of the thyroid mass demonstrated a spindle cell neoplasm, and immunohistochemistry supported a diagnosis of primary synovial sarcoma. Gallium-68–labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid–octreotate positron emission tomography–computed tomography revealed distant metastases involving the lungs, bones, and bone marrow. In view of advanced disease with vascular encasement and metastatic spread, neoadjuvant chemotherapy was initiated. This case highlights the importance of histopathologic confirmation in atypical presentations of thyroid malignancy and underscores the limitations of cytology in rare spindle cell tumors.

Introduction

Synovial sarcoma (SS) is a high-grade soft tissue malignancy of mesenchymal origin that accounts for ∼5% to 10% of all soft tissue sarcomas [1]. It most commonly arises in the periarticular regions of the lower extremities, whereas involvement of the head, neck, or trunk is uncommon and represents a minority of cases. The tumor is characterized by the chromosomal translocation t(X;18)(p11.2;q11.2), resulting in the formation of SS18::SSX (also known as SYT::SSX) fusion transcript, which serves as a molecular hallmark of the disease [2].

Primary involvement of the thyroid gland by SS is exceptionally rare, with only a few cases reported in the literature. Because clinical and radiologic features are nonspecific, these tumors may mimic more common aggressive thyroid malignancies, including anaplastic thyroid carcinoma (ATC) or medullary thyroid carcinoma (MTC), leading to diagnostic uncertainty and potential therapeutic misdirection. We report a case of primary thyroid SS with distant metastases that was initially thought to be MTC on fine-needle aspiration cytology (FNAC) but was eventually diagnosed by core needle biopsy and immunohistochemistry (IHC).

Case presentation

A 43-year-old woman was admitted for evaluation of progressive anterior neck swelling. She had a long-standing goiter, with rapid enlargement over the preceding 6 months. Hoarseness developed 1 month before presentation, along with dyspnea in the supine position. She denied dysphagia, diarrhea, flushing, or pruritus. Her medical history was significant for type 2 diabetes mellitus diagnosed 5 years earlier and hypertension diagnosed 3 years earlier. There was no personal or family history of thyroid or other malignancy. On examination, a grade III asymmetric goiter (right > left) was noted (Fig. 1). The mass was firm to hard in consistency, nontender, and moved with deglutition. The lower pole was not palpable. Pemberton sign was negative. Multiple enlarged cervical lymph nodes were palpable on the right side at level II, level III, and level IV.

Figure 1.

Grade 3 goiter prior to treatment (chemotherapy).

Diagnostic assessment

Biochemical evaluation revealed euthyroid status with negative antithyroid peroxidase antibodies. High-resolution ultrasonography demonstrated a lesion classified as American College of Radiology Thyroid Imaging Reporting and Data System category 5, measuring 44 × 55 × 63 mm in the right thyroid lobe. The lesion was poorly defined, heterogeneous, hypoechoic, and contained internal ring calcifications. Multiple enlarged lymph nodes were identified at levels II, III, and IV on the right side, as well as in the supraclavicular region. FNAC was suggestive of MTC. However, serum calcitonin and carcinoembryonic antigen (CEA) levels were within normal limits (calcitonin 4.84 pg/mL [SI: 4.84 ng/L] [reference range, <10 pg/mL; SI: <10 ng/L]; CEA 0.712 ng/mL [SI: 0.712 µg/L] [reference range, <5 ng/mL; SI: <5 µg/L]), arguing against a diagnosis of MTC and raising concern for diagnostic discordance. Flexible laryngoscopy confirmed right recurrent laryngeal nerve palsy.

Contrast-enhanced computed tomography (CECT) of the neck and thorax demonstrated a 50 × 50 × 62 mm heterogeneously enhancing lesion arising from the right lobe and isthmus, with coarse ring-like calcifications. The mass displaced the trachea and esophagus to the left but showed no retrosternal extension. Multiple enlarged lymph nodes were identified at levels II, III, and IV on the right side, as well as in the central compartment (Fig. 2). Given the discrepancy between cytology and tumor markers, a core needle biopsy was performed. Histopathology demonstrated a spindle cell neoplasm. Differential considerations included MTC, spindle epithelial tumor with thymus-like differentiation (SETTLE), and SS.

Figure 2.

CECT axial (A and B) and coronal (C) images showing a heterogeneously enhancing mass (asterisk) with coarse calcification involving the isthmus and right lobe of the thyroid gland. The mass is displacing the adjacent right carotid artery and internal jugular vein with evidence of a few metastatic neck nodes (white arrows).

IHC revealed strong diffuse positivity for cluster of differentiation 99 (CD99), B-cell lymphoma 2 protein (BCL2), and transducin-like enhancer of split 1 (TLE1), with focal positivity for epithelial membrane antigen (EMA). Tumor cells were negative for pancytokeratin, cytokeratin 7 (CK7), calcitonin, thyroid transcription factor-1 (TTF-1), and chromogranin A. These findings supported a diagnosis of SS (Figs. 3 and 4). Fluorescence in situ hybridization performed on the biopsy sample confirmed SS18(SYT) gene rearrangement establishing the molecular diagnosis of SS in our case.

Figure 3.

(A) FNA smears show high cellularity with spindle cells having elongated to round nuclei and a coarsely granular chromatin, PAP stain, 400×; (B) Tru-cut biopsy of the thyroid mass consisted of multiple cores of a tumor, H&E stain, 100×; (C) the tumor is composed of long interlacing fascicles of spindle cells. The nuclei are elongated, have coarse chromatin, and show numerous mitoses (H&E stain, 400×); (D) the tumor cells are negative for TTF-1. The entrapped thyroid follicular cells show nuclear positivity on IHC (200×).

Figure 4.

(A) The tumor cells are negative for calcitonin (IHC, 200×); (B) the tumor cells show strong and diffuse membranous positivity for CD99 (IHC, 200×); (C) the tumor cells show strong and diffuse membranous positivity for BCL2 (IHC, 200×).

Gallium-68–labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid–octreotate (⁶⁸Ga-DOTATATE) positron emission tomography–computed tomography (PET–CT) demonstrated a heterogeneously somatostatin receptor–expressing necrotic mass involving the right lobe and isthmus of the thyroid. Minimally somatostatin receptor–avid necrotic cervical lymph nodes were observed in levels I, IV, and V, as well as in the supraclavicular region. Minimal to nonsomatostatin receptor–avid lesions were noted in bilateral lung nodules, skeletal sites, and bone marrow, consistent with metastatic disease (Fig. 5). The selection of ⁶⁸Ga-DOTATATE PET–CT over ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET–CT was driven by the initial cytological suggestion of MTC—a neuroendocrine tumor characteristically expressing somatostatin receptors. In retrospect, ¹⁸F-FDG PET–CT would have been more appropriate for staging a confirmed soft tissue sarcoma, and both modalities may be considered complementary in diagnostically uncertain cases.

Figure 5.

⁶⁸ Ga-DOTATATE PET–CT axial (A) and coronal (B) images showing a heterogeneously SSTR-expressing lesion in the right lobe and isthmus of the thyroid.

Treatment

In view of locoregional lymph node involvement, vascular displacement, and distant metastases, primary surgical resection was deferred. Neoadjuvant chemotherapy with ifosfamide and doxorubicin was initiated. Surgical debulking was planned contingent upon treatment response.

Outcome and follow-up

The patient received 1 cycle of neoadjuvant chemotherapy with ifosfamide and doxorubicin, following which she was lost to follow-up. She resided in a remote interior region with limited accessibility, and attempts to contact her via telecommunication were unsuccessful. Clinical and radiologic reassessment had been planned to evaluate tumor response and determine surgical feasibility; however, this could not be accomplished given the loss to follow-up. No treatment-related adverse events were documented during the single cycle of chemotherapy administered.

Discussion

Based on a comprehensive review of the available published literature, this appears to be among the few documented cases of primary SS of the thyroid gland reported globally, with only 16 cases having been previously described to the best of our knowledge [3]. Our patient had a long-standing goiter without symptoms of thyroid dysfunction and presented with rapid enlargement over 6 months accompanied by compressive symptoms. FNA suggested MTC; however, both serum calcitonin and CEA levels were within normal limits. Given the rarity of double-negative MTC and the differences in surgical management among thyroid malignancies, further tissue confirmation was pursued. Core needle biopsy followed by immunohistochemical analysis established the diagnosis of SS. In view of vascular involvement and distant metastases, neoadjuvant chemotherapy was initiated, with surgical intervention to be reconsidered based on treatment response.

Thyroid SS, a tumor of mesenchymal origin, is an aggressive malignancy associated with poor outcomes [1]. Despite its name, SS does not arise from synovial tissue. Current evidence suggests it originates from multipotent mesenchymal stem cells residing within the thyroid capsule and stromal connective tissue, capable of aberrant epithelial and spindle cell differentiation—thereby explaining its occurrence at sites entirely devoid of synovium [2, 4]. The pathognomonic t(X;18)(p11.2;q11.2) translocation generates the SS18::SSX fusion oncogene, which dysregulates BRG1/BRM-associated factor (BAF) chromatin remodeling machinery and drives oncogenesis at such ectopic locations [5]. It frequently presents with locoregional and distant metastases, which are associated with a worse prognosis compared with localized disease [2]. Previous case reports have documented early relapse, often within 5 years, even after total thyroidectomy or wide local excision [2]. The mean age at diagnosis is ∼40 years (range 15-72 years), with a male predominance [6]. There are no pathognomonic clinical features; most patients present with a rapidly enlarging neck mass that may mimic ATC. Compressive symptoms such as dysphagia, dyspnea, dysphonia, and excessive salivation are common. Imaging findings on ultrasonography and computed tomography are nonspecific. Importantly, FNA cytology may be misleading, as prior reports have described cytologic interpretations suggestive of MTC, follicular neoplasm, or papillary thyroid carcinoma.

Definitive diagnosis requires histopathologic evaluation supported by IHC and, when necessary, molecular analysis. Histologically, SS is categorized as biphasic or monophasic based on the presence of epithelial and mesenchymal components [4]. The biphasic subtype contains both spindle and epithelial elements and is generally easier to recognize. In contrast, the monophasic spindle cell variant, as in our case, poses significant diagnostic challenges. On IHC, more than 90% of SS cases demonstrate focal cytoplasmic CK and EMA positivity. Expression of CK7 and CK19 has been reported to be relatively specific [7]. Tumors frequently express CD99, vimentin, and BCL2, which supported the diagnosis in our patient.

A systematic review identified 5 common types of thyroid sarcoma: angiosarcoma, malignant hemangioendothelioma, malignant fibrous histiocytoma, leiomyosarcoma, and fibrosarcoma [8]. Among these, angiosarcoma is the most frequently reported subtype. Most primary thyroid sarcomas present as large, painless goiter, with local invasion or distant metastasis occurring in approximately one-third of cases. SS appears to be among the rarest subtypes and is often associated with aggressive clinical behavior.

The histologic differential diagnosis of thyroid SS includes MTC, undifferentiated or ATC, and SETTLE. Elevated calcitonin levels are characteristic of MTC. Histologically, MTC typically demonstrates plasmacytoid, spindle, or mixed cellular morphology and expresses calcitonin and neuroendocrine markers [9]. In SETTLE, the mitotic rate is usually low, and necrosis is uncommon; tumor cells are positive for keratin and vimentin [10]. ATC typically affects older patients and presents as a rapidly enlarging mass. Histology reveals pleomorphic spindle cells, giant cells, abundant cytoplasm, frequent mitoses, and tumor necrosis. Tumors commonly express PAX8 and frequently harbor p53 mutations [11]. In contrast, our patient's tumor lacked thyroid lineage markers and demonstrated strong CD99, BCL2, and TLE1 expression, favoring SS. It is worth noting that calcitonin measurement in fine-needle aspiration washout fluid (FNA-calcitonin) is a validated ancillary technique for MTC diagnosis, with sensitivity approaching 98% and near-perfect specificity at thresholds exceeding 100 pg/mL (SI: 100 ng/L) [12]. In our patient, the normal serum calcitonin of 4.84 pg/mL (SI: 4.84 ng/L) already argued strongly against MTC, rendering FNA-calcitonin washout redundant; core needle biopsy was instead pursued to obtain definitive histopathologic characterization.

Molecular confirmation of SS is achieved by identifying the SYT::SSX fusion transcript resulting from this translocation [13]. This alteration can be detected by reverse transcriptase polymerase chain reaction or fluorescence in situ hybridization. Although molecular testing is not universally required, it is valuable in cases that are diagnostically challenging.

There is no established consensus regarding optimal management of thyroid SS because of its rarity. When feasible, wide surgical excision with negative margins (R0 resection) is preferred [14]. However, primary surgical resection may not be appropriate in cases with invasion of major vascular structures or distant metastases. Given the relative chemosensitivity of SS, neoadjuvant chemotherapy with ifosfamide and doxorubicin is a reasonable approach in advanced disease [15]. Adjuvant or neoadjuvant radiotherapy may also be considered, particularly in locally advanced tumors [16]. Intensity-modulated radiation therapy has been associated with improved local control and survival outcomes.

Beyond conventional chemotherapy, targeted and immunological therapies deserve consideration in advanced or refractory disease. Pazopanib, a multitargeted tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors 1–3 (VEGFR 1–3), platelet-derived growth factor receptor (PDGFR), and c-KIT, is approved for nonadipocytic metastatic soft tissue sarcoma after failure of anthracycline-based chemotherapy, demonstrating a median overall survival of ∼10.3 months and median progression-free survival of 5.3 months in metastatic SS [17]. Conventional immune checkpoint inhibitors have shown limited activity in SS owing to its immunologically cold tumor microenvironment and low tumor mutational burden. However, afamitresgene autoleucel—an engineered T-cell receptor therapy targeting melanoma-associated antigen A4 (MAGE-A4)—demonstrated significant activity in the phase II SPEARHEAD-1 trial, representing a major emerging therapeutic option. In our case, pazopanib may be considered upon progression, and MAGE-A4 expression testing on the biopsy specimen could determine eligibility for T-cell receptor therapy [18].

Data regarding mortality rates remain limited. Nevertheless, SS is generally associated with a poor prognosis. Tumor size, presence of locoregional or distant metastases, and completeness of surgical resection are major determinants of survival.

Learning points

• Primary SS of the thyroid is an exceptionally rare and aggressive malignancy that may clinically mimic more common thyroid cancers.

• FNAC alone may be misleading; clinicobiochemical discordance, such as normal calcitonin in suspected MTC, should prompt further tissue evaluation.

• IHC is essential for diagnosis, particularly in the monophasic spindle cell variant, which can resemble ATC or other spindle cell tumors.

• Functional imaging aids in staging and may help exclude neuroendocrine malignancy, but is not diagnostic of SS.

• Advanced disease with vascular involvement or distant metastasis may require multimodal therapy, including neoadjuvant chemotherapy.

Contributors

All authors made individual contributions to the authorship. S.S.B. and S.R. were involved in the diagnosis and management of the patient and manuscript submission. K.K.B. was involved with follow-up of the patient and coordinated multidisciplinary care. B.S. was involved in imaging and the preparation of the CT images. A.K.A. was involved in and the preparation of histology images. U.N.S. reviewed the slides and was involved in the genetic analysis of the biopsy sample. All authors reviewed and approved the final draft.

Funding

No public or commercial funding.

Disclosures

The authors report no conflict of interest.

Informed patient consent for publication

Signed informed consent obtained directly from the patient.

Data availability

Data sharing is not applicable to this article.