Intrathyroidal thymic carcinoma (ITTC), also termed carcinoma showing thymus-like differentiation (CASTLE), is a rare thyroid malignancy with low-grade malignant potential, resembling thymic carcinoma histopathologically (1). Thymic tissue arises from the third and fourth branchial pouches during embryogenesis and descends into the mediastinum. ITTC, likely originating from ectopic thymic tissue within or adjacent to the thyroid or from embryonic thymic remnants, was first described by Miyauchi in 1985 as “intrathyroidal epithelial thymoma” (2, 3). Chan and Rosai renamed it CASTLE and outlined its clinicopathological characteristics (4). In 2004, the World Health Organization (WHO) recognized ITTC as a distinct thyroid tumor entity in its Classification of Thyroid Tumors (5), and in the 2017 WHO Classification of Endocrine Tumors, it was formally designated as “intrathyroidal thymic carcinoma” (6). Most reported cases occur in Asia, particularly in China and Japan (6).

Although ITTC and thymic carcinoma share similar histopathological and immunohistochemical profiles, differences exist in EGFR and p53 expression. ITTC exhibits chromosomal imbalances resembling those of thymic carcinoma (7). In addition, TERT promoter C228T mutations were reported in 22% of ITTC cases, but not in thymic carcinoma (8). Clinically, ITTC tends to affect younger patients and generally carries a more favorable prognosis than thymic carcinoma, although aggressive cases have also been documented (8, 9).

Given the rarity of ITTC, most reported cases to date consist of case reports and literature reviews (10–12), with no established guidelines for diagnosis or treatment. To enhance understanding of this disease, this study analyzed clinical and imaging data from 14 patients, summarizing their clinical characteristics, radiographic features, diagnostic process, and treatment outcomes.

ITTC tumors are categorized as thyroid carcinomas, although they resemble thymic carcinomas and are thought to originate from the intrathyroidal ectopic thymus or embryonic cervical descent of the thymus. Owing to their rarity, most masses are diagnosed as thyroid cancer or thyroid malignancy on the basis of radiographic findings. In our study, 85.7% (12/14) of cases were initially classified as thyroid cancer or thyroid malignancy radiographically. Thus, surgery was adopted as the initial treatment in 8 patients (57.1%, 8/14) owing to frequent misdiagnosis, and the definitive diagnosis relied on surgical pathology, particularly immunohistochemistry. Accurate pretreatment diagnosis is crucial, but whether surgery should be the initial choice, particularly for advanced cases, and whether clinical and imaging findings improve diagnostic accuracy remain key issues.

ITCC tumors occur in middle-aged individuals with a mean age of 50 years (12). In our study, the median age at diagnosis was 53 years, with a male-to-female ratio of 1.8:1 (9:5). Although males appeared more frequently affected in our cohort, this likely reflects the limited sample size rather than a true sex bias. Conversely, Gao observed a slight female predominance in a larger series of 89 patients (13). Thyroid hormone levels were nonspecific in our cases. Hoarseness was a prominent symptom among patients, as approximately two-third of them (64.3%) experienced it.

In our study, more than half of the tumors (64.3%) were located in the tracheoesophageal groove, with or without extension to the lower thyroid pole, often accompanied by hoarseness due to recurrent laryngeal nerve paralysis. A few tumors extended into the supraclavicular fossa, suprasternal fossa, or even the vascular space of the anterior superior mediastinum. These locations are consistent with the embryonic origin of thymic remnants.We hypothesize that the location of the tracheoesophageal groove and the resulting concomitant symptoms may be key points for distinguishing this tumor from other thyroid tumors.

Radiographically, most of the masses were irregular and ill-defined and had low soft tissue density with uniform attenuation on plain CT. Central calcification was present in 2 patients; calcification within masses has been reported in a few studies (14). On contrast-enhanced CT, tumors demonstrated mild heterogeneous or homogeneous enhancement, while marked heterogeneous enhancement was rare but has been reported (15). Importantly, neither calcification nor marked enhancement should exclude ITTC from consideration.

ITTC tumors usually present with a slow course and are prone to invading surrounding organs. The relatively small masses appeared to be round or oval in shape and confined to the tracheoesophageal groove or lower pole of the thyroid. Larger masses with irregular shapes often present locally advanced disease, grow along the lower thyroid gland or the tracheoesophageal groove, invading surrounding structures such as the supraclavicular fossa, ipsilateral strap muscles, trachea and esophagus, and suprasternal fossa, and even infiltrate the upper mediastinum vascular space. The growth characteristics in our cases were similar to those reported previously (15). Tracheal invasion leading to stenosis was seen in 28.6% of our patients, slightly lower than the 38% reported in the literature (1).

A distinctive imaging feature in our series was a well-defined margin between involved and uninvolved thyroid tissue, forming an arc-shaped boundary in over half of the cases. Best visualized on multiplanar reconstruction, this feature distinguishes ITTC from primary thyroid malignancies and has not been previously reported. It may reflect the ectopic thymic origin of ITTC rather than a thyroidal origin, though validation in larger cohorts is warranted. MRI provided no diagnostic advantage but was more sensitive in detecting extrathyroidal invasion. FDG PET/CT revealed avid focal uptake, consistent with prior reports (16).

In our study, nodal metastasis was pathologically confirmed in only one patient, and the overall incidence of nodal enlargement was low. The pattern of Level VI and VII involvement resembled that of other thyroid malignancies. Previous reports indicated that 84.3% of metastases occur in the central compartment and 15.6% in the lateral compartment, and nodal involvement is considered a prognostic risk factor (13). Ito (17) further demonstrated that larger tumor size (>4 cm) was significantly associated with nodal metastasis. During follow-up, three patients developed lung metastases, consistent with the lung being the most common metastatic site in earlier studies (18).

A definitive diagnosis of ITTC before surgery remains challenging. In our cohort, 5 patients underwent fine-needle aspiration cytology (FNAC) prior to treatment, but none yielded a definitive diagnosis. In contrast, 3 of 8 patients (37.5%) who underwent core needle biopsy (CNB) were correctly diagnosed with ITTC on the basis of pathology and immunohistochemistry. Preoperative FNAB failed to establish a diagnosis of ITTC in any patient, as the thin needles yield only cellular material rather than tissue cores. Although FNAB identified 98.5% of cases as malignant, its sensitivity for correctly diagnosing ITTC was only 8.3% (13). By contrast, CNB markedly reduces diagnostic uncertainty, offers superior accuracy, and is not associated with significant complications (19).

Regarding immunohistochemistry, most ITTC cases were positive for CD5, a marker for carcinoma of thymic origin, as well as for p63, CD117, CK5/6 and negative for thyroid transcription factor 1 (TTF-1), to distinguish it from other thyroid tumors, also described in the literature (20). Two patients with negative CD5 expression were positive for CK5/6 and p63 but negative for TTF-1, presented with typical carcinoma showing thymus-like differentiation of the thyroid gland morphologically. Expression of synaptophysin (Syn) was evaluated in a subset of patients. According to Yamazaki et al, the expression of neuroendocrine markers such as Syn and CgA in ITTC also supports the idea that this thyroid cancer originates in the thymus, as neuroendocrine markers have been reported to have a focal or dispersed positive distribution in thymus cancer (21).

The most common differential diagnosis for ITTC might involve primary thyroid malignancies. ITTC tumors confined to the lower pole of the thyroid should be distinguished from papillary thyroid carcinoma, which more often shows fine granular calcifications. Additional imaging signs include irregular rings, marginal defects, and blurred enhancement (22). Papillary carcinoma also has a high incidence of nodal metastasis, and characteristic nodes with abundant vascularity, calcification, or cystic change are useful in the differential diagnosis (23). In clinical practice, papillary carcinoma is often readily diagnosed intraoperatively, whereas in our cohort none of the ITTC patients who underwent surgery achieved a definitive diagnosis on frozen section.

Locally advanced ITTC should also be differentiated from undifferentiated thyroid carcinoma and primary squamous cell carcinoma of the thyroid. Undifferentiated carcinoma typically exhibits the hallmarks of highly aggressive disease, with nodal metastases being common. Primary squamous cell carcinoma usually affects older men, progresses rapidly, and appears as thyroid enlargement with low-density shadows, calcification, and necrosis on CT (24). Beyond thyroid primaries, ITTC must further be distinguished from isolated recurrent laryngeal nerve node metastasis of esophageal or subpharyngeal squamous cell carcinoma, which can similarly present with hoarseness. In clinical practice, when patients present with hoarseness, gastroscopy and laryngoscopy are necessary. On the basis of these considerations, when ITTC is suspected based on imaging and clinical manifestations, CNB combined with cytology and immunohistochemistry should be recommended before surgery.

The prognosis for ITTC is generally favorable, with reported 5- and 10-year survival rates of 90% and 82%, respectively (1). Gurizzan demonstrated that advanced local stage is the strongest prognostic factor for mortality (18). In our study, 64.2% (9/14) of patients were staged as T4 due to invasion of adjacent structures, necessitating extensive resection. One patient was diagnosed with poorly differentiated thyroid carcinoma by FNAB and underwent total thyroidectomy, lymph node dissection, tracheal reconstruction, and postoperative radiotherapy, but died after 25 months. Another patient, initially misdiagnosed and treated inappropriately with ¹³¹I, later developed local recurrence and underwent re-resection with tracheal reconstruction followed by radiotherapy, remaining alive with pulmonary metastasis at 146 months. These findings suggest that, beyond local stage, misdiagnosis and inappropriate initial treatment may also compromise long-term outcomes.

ITTC is considered as a radiosensitive tumor due to its histological relationship to thymic carcinoma (25). Most scholars found that the surgical resection of the tumor followed by radiotherapy or combined with chemotherapy provided a better prognosis (13, 26), and Gao also reported that radiotherapy significantly improved survival (13). ITTC is also chemosensitive, with responsiveness reported to cisplatin, doxorubicin, vincristine, cyclophosphamide, carboplatin, and paclitaxel (27). In our series, most patients who received adjuvant radiotherapy or chemoradiotherapy achieved long-term survival without recurrence, whereas one patient who declined adjuvant treatment relapsed within 19 months. Reports of radical radiotherapy alone for advanced ITTC are rare (28). In our study, 4 patients with mediastinal vessel involvement underwent radical chemoradiotherapy, with doses of 60–64 Gy in 3 patients and 70 Gy in 1, consistent with the National Comprehensive Cancer Network (NCCN) guidelines for thymic carcinoma (29). One patient showed poor response and was switched early to anlotinib after multidisciplinary discussion. All 4 patients survived without progression, with follow-up times of 96, 86, 41, and 33 months.

Although multimodality treatment has improved outcomes, preserving physiological function in aggressive tumors may be feasible through neoadjuvant approaches that reduce tumor burden prior to surgery. Chow reported a patient who was not suitable for immediate resection and was successfully managed with neoadjuvant carboplatin and etoposide followed by 66 Gy radiotherapy and surgery, achieving recurrence-free survival 1.8 years after treatment (25). In addition, emerging systemic therapies may further expand treatment options. Anlotinib, a multitarget tyrosine kinase inhibitor, has demonstrated activity in advanced thymic carcinoma (30, 31) and was recently used in life-threatening recurrent ITTC (32). Likewise, pembrolizumab has been approved as a second-line treatment for thymic carcinoma (33), and partial remission has been reported in a metastatic ITTC case (34). Despite these encouraging reports, targeted therapy and immunotherapy have not yet been validated as initial treatment options for locally advanced ITTC, and prospective studies are needed to guide clinical practice. Two cases of ITTC without immunoreactivity to CD5 are alive without recurrence or metastasist with follow-up times of 63, 33 months respectively, one of them received radiotherapy after the operation and another one underwent radical chemoradiotherapy. Can CD5 negativity in patients affect their prognosis? Our research was limited by the small number of patients, perhaps more attention will be paid to the molecular changes of this disease in the future research.

In this retrospective study of 14 patients with ITTC, the tumors often exhibited invasive features but the prognosis was generally favorable, with a median overall survival of 86 months. Preoperative diagnosis remains challenging, but imaging signs such as an arc interface and hoarseness due to tumor location may aid recognition. CNB with immunohistochemistry is recommended when ITTC is suspected. For locally advanced inoperable ITTC cases, radical chemoradiotherapy is effective, while the role of targeted and immunotherapy requires further exploration.