Extremely rare primary tracheal hyalinizing clear cell carcinoma: two case reports
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Key findings
• We report two extremely rare cases of primary tracheal hyalinizing clear cell carcinoma (HCCC). Both patients underwent segmental tracheal resection with reconstruction and achieved complete microscopic tumor removal (R0 resection). One case showed an EWSR1::ATF1 fusion, while the other demonstrated an EWSR1 rearrangement by fluorescence in situ hybridization.
What is known and what is new?
• Primary tracheal HCCC is an uncommon low-grade malignant tumor that may be difficult to distinguish from other clear cell tumors based on morphology alone. Histopathological examination, immunohistochemistry, and molecular testing are important for establishing the diagnosis.
• This report adds two surgically treated cases and highlights the diagnostic value of detecting EWSR1 alterations, including the identification of an EWSR1::ATF1 fusion in primary tracheal HCCC. The cases also support the feasibility of complete tracheal resection and reconstruction for appropriately selected patients.
What is the implication, and what should change now?
• HCCC should be considered in the differential diagnosis of patients with an endotracheal or tracheal clear cell lesion. A combination of morphology, immunohistochemistry, and molecular testing should be used to confirm the diagnosis. When technically feasible, complete surgical resection with negative margins should be considered the preferred treatment for localized disease, followed by long-term surveillance because the clinical behavior and optimal management of this rare tumor remain incompletely defined.
Introduction
Primary tracheal malignancies are uncommon, and squamous cell carcinoma and adenoid cystic carcinoma are the predominant histological types. Salivary gland type tumors account for a small subset of primary tracheal malignancies. Tracheal salivary-gland-type tumors originate from scattered submucosal seromucinous minor salivary-gland epithelium embedded within the tracheal wall. Primary tracheal hyalinizing clear cell carcinoma (HCCC) is an exceptionally rare neoplasm with distinct histopathological characteristics (1). This low-grade carcinoma commonly occurs in salivary gland in middle-aged women, with tracheal involvement being particularly uncommon (2). Histologically, it comprises monomorphic glycogen-rich clear cells arranged in nests, cords, or trabeculae within a hyalinized stroma. Morphologically analogous tumors may arise in the tracheobronchial tree, where they are considered to originate from submucosal seromucinous glands and are classified as salivary gland-type tumors. Molecularly, HCCC is characterized by rearrangement of Ewing sarcoma breakpoint region 1 (EWSR1), most commonly resulting in an EWSR1::ATF1 fusion, in which ATF1 denotes activating transcription factor 1. Less frequently, other EWSR1-associated fusions such as EWSR1::CREM (cAMP responsive element modulator), have been reported. These fusions are thought to encode aberrant transcriptional regulators that contribute to tumorigenesis. Identification of an EWSR1 rearrangement or fusion supports the diagnosis, although it must be interpreted with morphology, immunophenotype, anatomical site, and exclusion of metastatic disease (3).
Clinically, it typically manifests as progressively enlarging endoluminal masses, often presenting with symptoms of cough, hemoptysis, and potentially upper airway obstruction. Segmental tracheal resection with primary reconstruction remains the definitive surgical intervention for this condition (3). To our knowledge, current English literature documented only four cases (1,4-6), occurring in female patients aged 34–66 years, with three cases managed by surgical resection and one treated with combined endoscopic laser ablation and cryotherapy. We present this article describing two cases of primary tracheal HCCC, including their clinical presentations, diagnostic challenges, and treatment approach. We present this article in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0844/rc).
Case presentation
Case 1
A 56-year-old female, nonsmoker, presented with a 6-month history of progressive cough and dyspnea. Her past medical history included type 2 diabetes mellitus controlled with oral hypoglycemic agents. Contrast-enhanced thoracic computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated an endoluminal mass originating from the posterior wall of the mid-trachea, with suspected esophageal infiltration (Figure 1). Positron emission tomography (PET)-CT revealed mild fluorodeoxyglucose (FDG) avidity without evidence of distant metastasis, consistent with a primary tracheal neoplasm. Diagnostic bronchoscopy identified a 1.6 cm × 1.0 cm × 1.0 cm obstructive lesion causing 50% luminal stenosis (Figure 2, see Figure 2A), with initial histopathological assessment suggesting poorly differentiated squamous cell carcinoma.
Case 2
A 38-year-old female, nonsmoker, presented with progressive respiratory symptoms including recurrent cough, productive sputum, and exertional dyspnea over the past 10 months. This ultimately limited her daily activities and required medical intervention. Bronchoscopy revealed a 1.3 cm exophytic lesion on the anterior tracheal wall at about 6 cm distal to the vocal cord, causing 80% luminal obstruction with contact bleeding (Figure 3A-3C). Emergency therapeutic bronchoscopy with transbronchial electrocautery resection was performed to reestablish airway patency. Histopathological examination confirmed tracheal HCCC. Postoperative PET/CT demonstrated persistent FDG-avid focus at the primary site, suggestive of residual disease (Figure 3D-3E). The patient was subsequently referred to our center for definitive surgical treatment.
Surgical technique and prognosis
Both patients received total intravenous anesthesia with non-intubated spontaneous ventilation, maintaining an unobstructed surgical field, facilitating bronchoscopic tumor localization, margin assessment, and anastomotic suturing (7,8). A partial upper sternotomy was performed as the surgical approach, which provided adequate exposure of the intrathoracic trachea and adjacent vessels. Flexible bronchoscopy was used to identify the proximal and distal resection margins intraoperatively. Following tumor excision and confirmation of negative margins by frozen-section analysis, tracheal reconstruction was performed using interrupted end-to-end anastomotic sutures. Anastomotic tension was minimized by neck flexion and careful tracheal mobilization with preservation of the lateral blood supply. Anastomotic integrity was subsequently verified using a standardized air leak test at 30 cmH2O positive pressure. The thymus pedicle flaps were used as a buttress over the anastomosis to separate the anastomosis from adjacent mediastinal structures and enhance blood supply. A chest drain was placed in the anterior mediastinal space for postoperative drainage. The median sternotomy wounds were closed using interrupted stainless steel wire sutures, and subsequent layered closure of the subcutaneous tissue and skin using absorbable monofilament sutures. And both patients underwent successful surgical resection with tracheal segment excisions measuring 1.5 cm and 2.0 cm, respectively, achieving microscopically negative margins (R0 resection) confirmed by paraffin pathological examination. The postoperative recovery was uneventful and both patients discharged on postoperative day 12 and day 13, respectively, following standard postoperative protocols.
The case 1 demonstrated no evidence of local recurrence or long-term complications during 18 months of postoperative surveillance, including CT imaging and bronchoscopic evaluations. The case 2 had received surgical intervention 1 month ago. During the initial postoperative follow-up period, surveillance CT and bronchoscopy demonstrated no evidence of disease recurrence or surgical complications. Neither patient received any adjuvant therapy.
All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of The First Affiliated Hospital of Guangzhou Medical University. The requirement for patient consent for publication of this case report and accompanying images was waived by the same committee.
Pathological results
Case 1
The histopathological and molecular diagnostic findings were as follows (Figure 2B-2D):
- Histological: the neoplastic cells demonstrated solid or nested growth patterns, exhibiting round to ovoid morphology with indistinct cell borders. Cytoplasmic features ranged from clear to eosinophilic, with occasional small nucleoli and rare mitotic figures. The stroma contained hyalinized vascular channels accompanied by focal lymphoplasmacytic infiltrates;
- Immunohistochemical profile: P63 (+), P40 (+), S-100 (focal +), CD117 (−), Ki-67 (1%+);
- Special staining: Alcian blue (−);
- Next-generation sequencing (NGS) analysis: EWSR1::ATF1 gene fusion: EWSR1 (exon 11)-ATF1 (exon 3), EWSR1 (exon 12)-ATF1 (exon 2).
Case 2
The histopathological and molecular diagnostic findings were as follows (Figure 4):
- Histological: the neoplastic cells demonstrated nested or trabecular growth patterns, exhibiting admixed clear and eosinophilic cytoplasmic features within a hyalinized fibrous stromal matrix;
- Immunohistochemical profile: CK7 (+), P40 (partial +), CK (+), CK5/6 (+), P63 (+), TTF-1 (−), NapsinA (−), Ki-67 (5%+), S-100 (−), Calponin (−), PAX-8 (−);
- Special staining: periodic acid Schiff (PAS) (+);
- Fluorescence in situ hybridization (FISH): EWSR1 (EWSR1 gene break positive).
The histopathological and molecular features are diagnostic of primary tracheal HCCC, fulfilling World Health Organization (WHO) classification criteria. Both cases demonstrated full-thickness tracheal wall invasion with microscopically negative resection margins (R0), confirmed through comprehensive histopathological evaluation.
Discussion
HCCC is a rare salivary gland-derived tumor predominantly occurring in the head and neck region. The clinicopathological characteristics, treatments, and outcomes of previously reported cases are summarized in Table 1. Although HCCC most frequently arises in the salivary glands of the head and neck, morphologically and molecularly analogous tumors can occur in the tracheobronchial tree. These tumors are considered to originate from the seromucinous glands of the submucosal layer of the airway and are therefore classified among salivary gland-type tumors of the trachea and lung. Tracheal involvement constitutes an exceptionally uncommon presentation. The observation that the tumors showed “mild FDG avidity” on PET/CT is a valuable clinical finding that reflects the low-grade nature of the malignancy. However, this finding is nonspecific and should not be used alone to predict biological behavior. Bronchoscopic biopsy specimens often yield diagnostic ambiguity due to histological overlap with squamous cell carcinoma and other salivary gland-type neoplasms. This diagnostic challenge was illustrated by case 1, which was initially diagnosed as poorly differentiated squamous cell carcinoma. HCCC typically comprises uniform monomorphic clear or eosinophilic cells arranged in nests, cords, or trabeculae within a hyalinized stroma. Squamous cell carcinoma with clear cell change may share cytokeratin and p40/p63 expression but generally shows greater cytological atypia, mitotic activity, keratinization, or intercellular bridges. Mucoepidermoid carcinoma contains mucous, intermediate, and epidermoid cells and frequently harbors a MAML2 gene rearrangement. Epithelial-myoepithelial carcinoma displays a biphasic tubular architecture, whereas myoepithelial carcinoma generally expresses multiple myoepithelial markers. Metastatic clear cell renal cell carcinoma should be excluded by clinical imaging and, when indicated, PAX8 and carbonic anhydrase IX (CAIX).
Table 1
| Patient | Symptoms | Tumor location | Size of tumor (cm) | IHC/special stains | Molecular testing | Treatment | Surgical margins | Adjuvant therapy | Follow-up/outcome |
|---|---|---|---|---|---|---|---|---|---|
| 46-year-old male, nonsmoker (5) | N/A | Trachea | N/A | Positive: p63; negative: S100 and SMA | EWSR1-ATF1 rearrangement | Resection | N/A | Chemoradiation with cisplatin/etoposide, carboplatin/taxol/pembrolizumab followed one year later with radiation | Deceased 6 years after first diagnosis |
| 66-year-old female, former smoker (4) | Worsening shortness of breath | The left posterolateral wall of the trachea approximately 2 cm above the carina | 1.3 cm × 1.1 cm × 1.1 cm | Positive: p63, AE1/AE2, CK7, CK5; negative: TTF-1, Napsin-A, synaptophysin, chromogranin, and S-100 | A recurring translocation of the EWSR1 gene | Bronchoscopic intervention: cryobiopsy for histopathology; Nd: YAG laser therapy plus cryotherapy debulking on tumor stalk to induce delayed tumor necrosis | N/A | N/A | N/A |
| 55-year-old female, Smoker (6) | Hemoptysis | 2.5 cm intraluminal polypoid distal tracheal mass | N/A | Positive: CK7, p40, CK5/6, p63; negative: S-100 and SOX-10 | Positive for EWSR break-apart | Distal tracheal resection with mediastinal LN resection | N/A | Adjuvant radiation therapy | No evidence of recurrent disease, 12 months after initial diagnosis |
| 34-year-old female, nonsmoker (1) | 1-month persistent cough + intermittent dyspnea | The posterior wall of the trachea at the level of the thoracic inlet | 2.3 cm × 2.0 cm | Positive: p40 and p63; negative: CD56, TTF‐1, Napsin A, and Synaptophysin | Positive EWSR1 gene rearrangement | Radical tracheal resection via median sternotomy with end-to-end tracheal anastomosis; no lymph node dissection | 1 cm negative proximal/distal surgical margins | N/A | 36 months (3 years) postoperative follow-up; no local recurrence or distant metastasis, patient alive and disease-free |
AE1/AE2, cytokeratin cocktail; ATF1, activating transcription factor 1; CK7, cytokeratin 7; EWSR1, Ewing sarcoma breakpoint region 1; IHC, immunohistochemistry; N/A, not availabl; p63, tumor protein p63; S100, S100 calcium-binding protein; SMA, smooth muscle actin.
No single immunohistochemical marker is specific for HCCC. The essential immunohistochemical panel includes pan-cytokeratin and p40 or p63 to establish epithelial and basal/squamous differentiation, together with S100 and SOX10 to assess myoepithelial differentiation. HCCC usually expresses pan-cytokeratin, p63/p40, and CK5/6, whereas S100 and other myoepithelial markers are variable. A low Ki-67 index supports low proliferative activity but is not diagnostic. Additional markers should be selected according to the differential diagnosis.
Molecularly, HCCC is characterized by recurrent EWSR1 rearrangements, most commonly resulting in an EWSR1::ATF1 fusion, although alternative partners such as CREM have been reported. This fusion fuses the transcriptional activation domain of EWSR1 with the DNA-binding domain of ATF1, generating an aberrant transcription factor that is thought to disrupt CREB-responsive transcriptional programs and promote tumorigenesis (5).
In diagnostically challenging cases, break-apart FISH allows rapid screening suitable for small biopsies, whereas RNA-NGS identifies exact fusion transcripts. EWSR1 rearrangements have been reported in approximately 87–91% of head and neck HCCC, but EWSR1 rearrangement is not specific to HCCC and may occur in other neoplasms. Given EWSR1 aberrations exist in many other neoplasms, molecular results should be interpreted alongside morphology, immunophenotype, lesion site and metastatic exclusion. For ambiguous tracheal clear-cell lesions, EWSR1 testing serves as a key method to exclude high-grade mimics and guide conservative surgery without adjuvant chemotherapy. EWSR1 testing should be considered in morphologically and immunophenotypically suggestive cases, particularly when the differential diagnosis includes squamous cell carcinoma, mucoepidermoid carcinoma, epithelial-myoepithelial carcinoma, myoepithelial carcinoma, or metastatic clear-cell carcinoma (9). Among four previously reported primary tracheal HCCC cases, molecular analyses uniformly confirmed EWSR1 rearrangements, with one case exhibiting EWSR1::ATF1 fusion (Table 1). In our series, this fusion was identified in one of two cases.
Postoperative surveillance includes CT and bronchoscopy every 6 months to assess tumor recurrence and airway healing, with annual computational fluid-dynamic analysis of airway flow. Case 1 remained recurrence-free at 18 months, whereas the 1-month follow-up of case 2 was insufficient for long-term evaluation, warranting continued surveillance. Continued monitoring remains necessary.
To improve the practical value of this report, we developed a diagnostic and management algorithm for suspected primary tracheal HCCC (Figure 5). The algorithm integrates imaging, bronchoscopy, histopathology, immunohistochemistry, and selective molecular confirmation by EWSR1 break-apart FISH or RNA-based NGS, followed by assessment of resectability, definitive treatment, and long-term surveillance. It may assist clinicians in avoiding diagnostic misclassification and selecting an appropriate management strategy.
Current therapeutic approaches for tracheal HCCC remain non-standardized. Historical management strategies have included: endoscopic laser ablation with cryotherapy (outcomes unreported), surgical resection plus adjuvant chemotherapy (disease-free at 12 months), resection with chemoradiation (mortality at 6 months), and resection alone (disease-free at 36 months). For localized and technically resectable tumors, segmental tracheal resection with airway reconstruction and microscopically negative margins remains the preferred potentially curative approach, particularly when full-thickness tracheal wall invasion limits the likelihood of durable control with endoscopic treatment. Bronchoscopic interventions, including electrocautery, laser ablation, cryotherapy, or mechanical debulking, may provide temporary relief of severe airway obstruction and can be used as bridging procedures while definitive treatment is being planned. In our second case, bronchoscopic electrocautery was performed to debulk the obstructing tumor before surgical resection. Bronchoscopic treatment may also have a palliative role in medically inoperable patients or in those with unresectable or recurrent disease; however, its long-term local control remains uncertain and it should generally not be considered a definitive alternative to complete resection in resectable HCCC. Definitive surgery may be unsuitable when the tumor involves an extensive length of trachea, invades adjacent structures that cannot be safely separated, prevents construction of a tension-free anastomosis, or when the patient has prohibitive medical comorbidities. Our institutional experience establishes segmental tracheal resection with airway reconstruction as the curative therapeutic approach, particularly given histopathologic evidence of full-thickness tracheal wall invasion that limits effective endoscopic ablation.
Adjuvant radiotherapy is not routinely indicated after R0 resection but may be considered for positive margins, nodal metastasis, or extensive soft-tissue invasion. The benefit of postoperative radiotherapy in these settings remains uncertain because available evidence is based mainly on isolated cases and small series. Selective nodal sampling improves staging, whereas the value of routine systematic lymphadenectomy remains uncertain. No evidence supports adjuvant chemotherapy or targeted therapy for HCCC; therapies directed at EWSR1::ATF1-related pathways remain investigational.
HCCC demonstrates indolent biological behavior characterized by low-grade histological features, infrequent lymph node involvement, and low distant metastatic potential (5). Following complete surgical excision, local recurrences remain uncommon. Hence, given this tumor characteristic, adjuvant chemotherapy or radiotherapy may be omitted following complete microscopic resection. However, further research is needed to look into survival analysis and benefits of adjuvant therapy in this tumor.
Conclusions
Primary tracheal HCCC should be considered in the differential diagnosis of tracheal clear cell tumors, particularly when bronchoscopic biopsy findings are inconclusive. In diagnostically challenging cases, EWSR1 FISH or NGS provides important molecular confirmation when integrated with morphology and immunohistochemistry. Segmental tracheal resection with R0 resection is the definitive curative intervention for this malignancy. Given the extremely limited published experience and uncertain long-term behavior of this rare malignancy, prolonged clinical, radiological, and bronchoscopic surveillance is warranted.
Acknowledgments
None.
Footnote
Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0844/rc
Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0844/prf
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0844/coif). S.L. serves as an unpaid editorial board member of Translational Lung Cancer Research from February 2026 to January 2027. The other authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of The First Affiliated Hospital of Guangzhou Medical University. The requirement for patient consent for publication of this case report and accompanying images was waived by the same committee.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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