Hyalinizing trabecular tumors (HTTs) of the thyroid, which were first described by Carney et al (1) in 1987, represent a rare subtype of thyroid neoplasm that continues to present both clinical and pathological diagnostic challenges. These tumors are defined by their characteristic hyalinized stroma and trabecular growth pattern (2). Clinically, HTTs that usually present as asymptomatic, well circumscribed and solitary masses exhibit a benign course, with no evidence of capsular or vascular invasion (3). Even in rare cases where malignant features, such as focal invasion, are observed, the prognosis remains favorable, with no reports of recurrence or metastasis following surgical resection (1,4). Therefore, HTTs have traditionally been classified and managed as benign entities. Despite their benign nature, HTTs are frequently misdiagnosed as papillary thyroid carcinomas (PTCs) due to overlapping nuclear features, such as nuclear grooves, and intranuclear pseudoinclusions observed under light microscopy (5,6). These shared features can lead to confusion in the preoperative setting, particularly because PTC is a much more common malignant tumor of the thyroid with distinct clinical and histological implications (5,6). Furthermore, the amyloid-like appearance of the hyalinized stroma in HTTs may mimic the amyloid deposits characteristic of medullary thyroid carcinoma (MTC), leading to diagnostic confusion (5). Preoperative differentiation of HTTs from these malignancies is particularly challenging using fine needle aspiration biopsy (FNAB), often resulting in unnecessary overtreatment such as total thyroidectomy or lymph node dissection that is inappropriate for benign tumors. The potential harm of overtreatment of these cases emphasizes the need for a more nuanced understanding of HTTs and highlights the importance of refining diagnostic tools to differentiate them from other thyroid tumors. The present study aimed to address these diagnostic challenges by analyzing the clinical characteristics of HTTs over an 11-year period at a tertiary referral center. The findings of the present study may aid in the establishment of more accurate differential diagnostic criteria and guide the development of appropriate management strategies for similar cases.

HTTs are described in the literature as rare neoplasms originating from follicular cells, occurring in middle-aged women between 40 and 70 years and typically exhibiting benign behavior (15-18). The etiology of HTTs remains unclear; however, associations with chronic lymphocytic thyroiditis, Hashimoto's thyroiditis, multinodular goiter, a history of neck radiation exposure and PTC have been documented (17-19). Notably, instances of HTTs coexisting with micropapillary thyroid carcinoma have also been reported (20). In the present study, 4 out of 11 cases (36.4%) were accompanied by PTC in either the contralateral or ipsilateral lobe, and 2 patients presented with concurrent Hashimoto's thyroiditis. These findings are consistent with the aforementioned previous reports highlighting conditions associated with HTTs.

HTTs were first described by Carney et al (1) in 1987, who characterized their clinical and pathological features as either solitary lesions or components of multinodular presentations. These tumors are generally small, measuring ≤2 cm, with gross pathology revealing well-defined margins and capsular formation (1,2). Microscopically, HTTs are distinguished by the trabecular arrangement of polygonal, oval or spindle-shaped tumor cells set within a hyalinizing stroma (21-23). Certain trabeculae may appear curved, forming ribbon- or festoon-like patterns (24).

Although cases of HTTs with capsular invasion, vascular invasion, lymph node metastases and even lung metastases have been reported (25,26), Carney et al (2) noted that of 19 patients with HTTs, 18 exhibited benign clinical courses without malignancies, even in tumors with features suggestive of malignancy, and no recurrences or metastases were observed during long-term follow-up. Similarly, in the present study, none of the 11 patients demonstrated evidence of recurrence or metastasis during the follow-up period.

On preoperative FNAB, HTTs may present nuclear grooves, intranuclear inclusions and occasionally psammoma bodies, which can result in a misdiagnosis of PTC (19,21,22). Additionally, the hyalinizing stroma can mimic amyloid deposits, leading to potential diagnostic confusion with MTC (27). In certain cases, the tumor cells form glandular patterns, posing challenges in distinguishing HTTs from paragangliomas (23). Misdiagnoses due to cytological similarities with PTC or MTC have been documented, underscoring the necessity for meticulous histopathological evaluation and further research to refine diagnostic approaches for HTTs (20,22,24,27). The clues for an accurate diagnosis of HTTs include the absence of papillary structures or fibrovascular stalks and the presence of elongated nuclei in association with hyaline stroma (11,12). Although certain studies have explored the use of preoperative US, FNAB and frozen-section histopathology to identify HTTs, no definitive clinical diagnostic criteria for preoperative differentiation have been established (28,29). In the present study, only 1 patient was suspected to represent HTT based on preoperative FNAB, while diagnostic challenges were evident in 6 patients suspected as having PTC or unspecific carcinoma.

The final diagnosis of HTTs can only be confirmed through pathological examination. In cases where distinguishing tumor types based on histological features is challenging, IHC analysis plays a pivotal role. Unlike PTCs, which typically demonstrate minimal reactivity to the MIB-1 antibody, HTTs exhibit strong positive reactivity to MIB-1, localized along the tumor cell membranes. In the present study, 9 cases displayed MIB-1 positivity. Additionally, while PTCs exhibit strong positive IHC staining for galectin-3, HMCK and cytokeratin 19, HTTs generally show negative or weakly positive staining for these markers (30-32). IHC staining also distinguishes HTTs from MTCs, as HTTs are positive for thyroglobulin and negative for neuroendocrine markers, such as calcitonin, synaptophysin and chromogranin, whereas MTCs exhibit the opposite staining pattern (27).

Molecular analyses have further identified RET/PTC rearrangements in both PTCs and HTTs; however, BRAF and N-Ras mutations commonly observed in PTCs are absent in HTTs (13,33,34). Notably, Nikiforova et al (35) reported a high prevalence of GLIS rearrangements, particularly PAX8-GLIS3, in HTTs but not in PTCs. Among indeterminate FNAB results, PAX8-GLIS3 was detected in 0.1% of cases, and all 5 surgically confirmed cases were diagnosed as HTT, underscoring the utility of molecular testing using preoperative FNAB material (35). The incidence of HTT in the present study (~0.12%) aligns with the aforementioned reported rate, further highlighting the rarity of this entity. The lack of genetic testing is the main limitation of the present study. The current study was conducted over an 11-year-long period, which includes a notable time before the introduction of molecular testing for HTT. However, further research on the clinical impact of molecular testing, including GLIS rearrangements, on the diagnosis and treatment of HTT will be an important topic for future studies.

Despite these diagnostic advances, the utility of US and FNAB in reliably diagnosing HTTs preoperatively remains limited (28,29). Nevertheless, when preoperative US findings suggest the occurrence of benign tumors, but FNAB results raise suspicion for malignancy, particularly PTC, the differential diagnosis should include HTT. Particularly for FNAB results suspicious for PTC, the absence of BRAF mutations may heighten the suspicion for HTT. However, as demonstrated by the low incidence of HTT in the present study (only 11 cases among 9,169 thyroidectomy patients), its rarity poses an important diagnostic challenge for clinicians and pathologists (11). Limited exposure of clinicians to HTTs and their cytological features may further contribute to the difficulty in achieving a preoperative diagnosis. It is imperative for clinicians and pathologists to recognize the key clinical, cytological and molecular characteristics of HTT, including the use of additional tests, such as GLIS rearrangements, to improve diagnostic accuracy (36).

However, in cases of thyroid nodules, >30% of patients fall into the non-diagnostic, indeterminate and follicular neoplasm categories under the Bethesda System (8,9), where treatment decisions are unclear. However, cytological IHC and molecular testing are not performed for all cytologically difficult cases. IHC and molecular testing on preoperative cytological material could be helpful in the differential diagnosis, but this is only possible when clinicians or pathologists suspect HTT through conventional clinical aspects, including basic FNAB and US findings. As is often the case with rare entities, the main obstacle to diagnostic accuracy seems to be simply considering the diagnosis of HTT. Therefore, the present study is likely to help clinicians in suspecting HTT and considering further diagnostic tests.

Early clinical suspicion for HTT is crucial, as it may prevent unnecessary surgical procedures, such as total thyroidectomy. Compared with total thyroidectomy, thyroid lobectomy offers several advantages, including preservation of thyroid function, reduced dependence on lifelong thyroid hormone replacement therapy and avoidance of complications, such as recurrent laryngeal nerve injury and hypocalcemia (37). The type of thyroid surgery significantly impacts patient quality of life; therefore, when HTT is suspected preoperatively, a diagnostic lobectomy is preferable to total thyroidectomy to optimize patient outcomes through reduced surgical intervention (38).

In conclusion, while the diagnostic utility of US and FNAB for HTTs remains limited, their findings, in conjunction with molecular and IHC analyses, can aid in the identification of HTT preoperatively. In cases where preoperative US findings appear benign but discrepancies with FNAB results raise suspicion for PTC, HTT should be considered in the differential diagnosis. When HTT is clinically suspected, diagnostic lobectomy is recommended over total thyroidectomy to minimize surgical burden and preserve quality of life.