Hyalinizing clear-cell carcinoma (HCCC) is a rare malignant epithelial tumor of the salivary gland that accounts for <1% of tumor arising from the minor salivary glands (1). Despite its rarity, HCCC shows a predilection for the minor salivary glands of the oral cavity, particularly the tongue and floor of the mouth. Clinically, HCCC is generally considered a low-grade malignancy characterized by an indolent course, low incidence of regional or distant metastasis, and favorable prognosis following complete surgical excision. To date, the effectiveness of radiotherapy and chemotherapy has not been clearly established, and wide surgical resection with adequate margins remains the mainstay of treatment (2). Owing to the limited number of reported cases, the clinicopathological and molecular features of HCCC have yet to be fully defined. Therefore, we report a case of CCC of the tongue with stromal hyalinization, histopathological findings, immunohistochemical profile, and molecular characteristics, to aid in the accurate diagnosis and improve awareness of this rare cancer. Informed consent was obtained from the patient included in the study, and permission was granted for the publication of clinical photographs.

Patient consent. A 54-year-old man was admitted to our hospital in March 2019 with chief complaint of a mass on the right lateral border of the tongue. The patient’s medical history included type 2 diabetes mellitus, hyperlipidemia, and bronchial asthma. He was a smoker with a Brinkman index of 640 but had no history of alcohol consumption. Clinical examination revealed an exophytic, pedunculated mass measuring approximately 18×15×8 mm at the base of the right side of the tongue, with partial surface ulceration. The lesion was elastic and firm, with no spontaneous pain or tenderness on contact (Figure 1). Incisional biopsy suggested moderately differentiated squamous cell carcinoma. Contrast-enhanced computed tomography demonstrated a well-defined lesion with high contrast enhancement at the base of the right side of the tongue. Scattered cervical lymph nodes were observed bilaterally, with no radiological evidence of metastasis (Figure 2A). Positron-emission tomography−computed tomography showed increased ¹⁸F-fluorodeoxyglucose uptake at the primary site (Figure 2B). Magnetic resonance imaging revealed a low signal intensity on T2-weighted imaging (Figure 3A), with high signal intensity on T1-weighted and short tau inversion recovery imaging (Figure 3B and C), and heterogeneous contrast enhancement at the tumor site. No distant metastases were detected.

Based on these findings, a clinical diagnosis of tongue cancer was established (T1N0M0: stage I). Right partial glossectomy was performed under general anesthesia, after which the surgical defect was covered using a polyglycolic acid sheet with fibrin glue (Figure 4).

Histopathological examination of the resected specimen revealed tumor cells arranged in alveolar and nested patterns. The tumor consisted predominantly of polygonal cells with eccentrically located nuclei, including areas composed of clear cells intermixed with pale eosinophilic cells. Marked stromal hyalinization was observed surrounding some of the tumor nests.

Immunohistochemical staining revealed positivity for cytokeratin AE1/AE3, cytokeratin 7 (CK7) and p63, and negativity for CK20, α-smooth muscle actin, S-100 protein, vimentin, and cluster of differentiation 10 (CD10). The CK7-positive CK20-negative profile supported tumor of salivary gland origin, whereas p63 positivity with the absence of other myoepithelial markers aided in differential diagnosis. Periodic acid–Schiff (PAS) staining demonstrated intracytoplasmic glycogen accumulation (PAS-positive and diastase-sensitive). The absence of CD10 expression excluded metastatic renal cell carcinoma (Figure 5). Furthermore, molecular analysis detected the presence of a Ewing sarcoma breakpoint region 1 (EWSR1)–activating transcription factor 1 (ATF1) fusion gene. Based on histopathological, immunohistochemical, and molecular findings, the tumor was diagnosed as HCCC of minor salivary gland origin arising from the tongue. The postoperative course was uneventful, and no evidence of local recurrence or metastasis had been observed during more than 5 years of follow-up (Figure 6).

HCCC, previously referred to as CCC, is a rare malignancy of the salivary glands that is currently recognized as a distinct entity in the fifth edition of the World Health Organization Classification of Head and Neck Tumors (3). In 1996, Ellis and Auclair first described this tumor type as clear-cell adenocarcinoma in the Armed Forces Institute of Pathology classification (4). Earlier reports had described similar lesions under various terms, including HCCC and glycogen-rich CCC (5-8), reflecting historical uncertainty in nomenclature and classification.

HCCC is an extremely rare tumor, accounting for fewer than 1% of all salivary gland tumors and is said to be more common in the minor salivary glands (1, 9). A comprehensive literature review identified 254 cases reported between 1983 and 2020, with the palate being the most common site, followed by the tongue (10). Overall, HCCC represents approximately 0.2-1% of all salivary gland tumors, shows a slight female predominance, and predominantly affects the minor salivary glands (>80% of cases) (5). Consistent with this observation, the tumor in the present case originated from a minor salivary gland at the base of the tongue. Histopathologically, HCCC is characterized by nests comprising sheets of clear cells with polygonal nuclei embedded in a hyalinized stromal background. The tumor cells typically contain abundant intracytoplasmic glycogen (5), as demonstrated by PAS positivity that was abolished by diastase digestion, and lack mucin production on mucicarmine or Alcian blue staining. Immunohistochemically, the tumor cells expressed epithelial markers, such as cytokeratin (AE1/AE3) and epithelial membrane antigen but not myoepithelial markers, including S-100 protein, α-smooth muscle actin, vimentin, calponin, and p63 (9). The characteristic clear-cell morphology, diastase-sensitive PAS positivity, and expression of epithelial marker supported this diagnosis in the present case. Although p63 positivity was observed focally, the absence of other myoepithelial markers was consistent with the previously reported immunoprofile for HCCC.

Recent advances have highlighted the diagnostic importance of molecular alterations in salivary gland tumors. In 2012, fusion genes resulting from chromosomal rearrangements were identified in recurrent CCCs. Jin et al. reported EWSR1 gene rearrangement in both primary and recurrent CCCs of the tongue, including high-grade recurrent lesions (11). Subsequently, Antonescu et al. demonstrated that the EWSR1–ATF1 fusion gene, involving the rearrangement between EWSR1 exon 11 and ATF1 exon 3, observed this as a consistent molecular feature of HCCC in 18 out of 22 cases (12). Since then, multiple variants of EWSR1-related fusion gene have been reported in CCCs arising from the salivary glands. Hirose et al. identified a fusion variant in CCC arising from the salivary glands, EWSR1 exon 15 – ATF1 exon 5 and suggested it to be associated with an indolent clinical course (13). In contrast, certain EWSR1–ATF1 fusion variants (EWSR1 exon 8–ATF1 exon 4) commonly observed in clear-cell sarcomas have been associated with aggressive behavior, including local recurrence and metastasis (14). These findings suggest that molecular characterization may contribute not only to accurate diagnosis but also to prognostic assessment. In the present case, detection of the EWSR1–ATF1 fusion gene strongly supported the diagnosis of HCCC.

Furthermore, whole-body fluorodeoxyglucose positron emission tomography imaging revealed no evidence of malignancy in other organs, including the kidneys, which helped exclude metastatic clear-cell renal cell carcinoma.

HCCC is generally considered a low-grade tumor, with lymph node and distant metastasis reported infrequently (10, 15). However, cases of local recurrence after surgical resection (17), lymph node metastasis (16), and distant metastasis to the lungs and other organs (17, 18) have been described. Therefore, complete surgical resection with adequate safety margins remains the treatment of choice (10). Although Grenevicki et al. reported tumor shrinkage following combined chemotherapy with of 5-fluorouracil and cisplatin (1), evidence supporting the efficacy of chemotherapy or radiotherapy remains limited. In the current case, surgical resection was selected with an adequate safety margin and was performed alone, with no evidence of recurrence or metastasis at follow-up after more than 5 years. Nevertheless, given reports of aggressive behavior and poor outcomes in some cases (16, 17), long-term surveillance remains essential.

HCCC of the tongue is a rare malignancy originating from the minor salivary gland and may present diagnostic challenges due to its overlapping histological features with other clear-cell neoplasms. This case highlights the importance of integrating histopathological evaluation, immunohistochemical profiling, and molecular analysis, particularly the detection of the EWSR1–ATF1 fusion gene, for accurate diagnosis. Complete surgical resection with adequate margins promoted a favorable outcome, with no evidence of recurrence or metastasis after long-term follow-up. Awareness of this entity and its characteristic molecular features is essential for appropriate diagnosis, management, and prognostic assessment.

All Authors declare that they have no conflicts of interest.

KS, HT, DH, YK, ST and AT were involved in the treatment of the patient and made substantial contributions to the conception and design, acquisition of data, and analysis and interpretation of data. YO and JO made substantial contributions to the histopathological diagnosis.

No artificial intelligence (AI) tools, including large language models or machine-learning software, were used in the preparation, analysis, or presentation of this manuscript