Hemangioblastoma-like Clear Cell Stromal Tumor of the Lung: A Comprehensive Review With Insights From a Case.

CASE REPORT
A 53-year-old Chinese man with a history of cerebral infraction presented to the First People’s Hospital of Changde City on August 7, 2024. A week prior, a routine chest computed tomography (CT) had incidentally revealed a pulmonary nodule. Physical examination showed slightly diminished strength in the distal right upper limb due to his prior stroke, but no other abnormalities observed, including cough, expectoration, chest tightness, shortness of breath, nausea, and vomiting. Laboratory examination was not remarkable. The CT scan identified a solid nodule in the anteromedial basal segment of the left lower lobe, measuring about 15.3× 12.8 mm (Fig. 1), The lesion had clear boundaries but malignancy could not be ruled out. Twelve days after the CT scan, the patient underwent video-assisted thoracic surgery (VATS) for resection of the anteromedial basal segment of the left lower lobe. The patient had an uneventful postoperative recovery and was discharged 2 weeks later, with no further treatment required. At follow-up, there was no evidence of recurrence or distant metastasis.

GROSS AND HISTOLOGIC FINDINGS
A 10 × 6 × 2 cm segment of lung tissue was resected. Gross examination revealed a gray-white, firm, and solid mass of about 20 × 12 × 10 mm located 3 mm from the resection margin. Histologically, the tumor exhibited a solid, nested, and trabecular growth pattern without a clear fibrous capsule. At low magnification, the tumor is composed of oval to spindled-shaped cells, with evidence of stromal vascular proliferation and lymphocytic infiltration, closely adjacent to the bronchus and poorly demarcated from the surrounding tissue. At higher magnification, the tumor cells appeared epithelioid, with abundant, clear or eosinophilic cytoplasm. The nuclei displayed mild pleomorphism, with fine chromatin and marginal condensation, inconspicuous nucleoli, and rare mitotic figures.

IMMUNOHISTOCHEMICAL (IHC) AND FLUORESCENCE IN SITU HYBRIDIZATION (FISH) FINDINGS
Immunohistochemically, the tumor cells showed TFE3 (+), Vimentin (+), PAS (+), TLE-1 (+), CDK4 (+), ALK (weak +), Brg1 (+), Ki67 (~15%+), CK-Pan (−), LCA (−), Langerin (−), TTF-1 (−), CK7 (−), S-100 (−), Inhibin-α (−), CD34 (−), HMB45 (−), Desmin (−), SMA (−), CD10 (−), PAX8 (−), and INSM1 (-) (Fig. 2). FISH testing revealed no YAP1-TFE3 gene fusion (Fig. 3). Histologic analysis combined with immunohistochemical staining revealed hemangioblastoma-like clear cell stromal tumor.

SYSTEMATICALLY REVIEW OF HLCCST
On the basis of our comprehensive analysis of a case of HLCCST of the lung, we further conducted a systematic review of the PubMed database, focusing on 2 keywords: (1) “Hemangioblastoma-like clear cell stromal tumor of the lung” or (2) “Clear cell stromal tumor of the lung”. In addition to our case report, we also identified a total of 7 publications,5,7–12 comprising 19 cases of hemangioblastoma-like clear cell stromal tumor of the lung (excluding conference papers/abstracts, non-English studies, and studies without primary patient data) (Table 1). The patients’ age ranged from 29 to 77 years (mean age: 51.4 y), with a male-to-female ratio of ~1 : 3. Tumor sizes ranged from 8 to 95 mm (mean size: 40.3 mm; 1 case lacked size data). Characteristic symptoms included cough, chest pain, fever, dyspnea, and hemoptysis. Surgical resection was the primary treatment modality, with some cases involving biopsy or chemotherapy. Histopathologically, the tumor was well-circumscribed with abundant stromal vasculature and composed of epithelioid cells arranged in solid sheets or nests. The cells had clear or eosinophilic cytoplasm, with nuclei that were round, oval, or plump spindle-shaped, displaying hyperchromasia, or vacuolated chromatin with inconspicuous nucleoli. The prognosis for these patients is generally favorable, only 1 out of 19 patients died during follow-up (5.26%); Molecular genetic analysis revealed that the majority of cases were associated with YAP1::TFE3 gene fusion. Of the 12 cases tested for molecular alterations, 10 (83.33%) exhibited YAP1::TFE3 gene fusion. Although our case did not demonstrate this fusion, it remains a common finding in the majority of reported HLCCST cases. Therefore, we speculate that HLCCST belongs to a family of tumors associated with TFE3 expression and YAP1::TFE3 fusions.

FURTHER INSIGHTS INTO HLCCST
HLCCST was first described in 1943.6 Early cases were characterized by multiple, frequently bilateral tumors in patients with extrapulmonary disease, leading to their initial interpretation as metastatic lesions. The existence of Hemangioblastoma-like clear cell stromal tumors as primary lung neoplasm has been recognized only for the last few years.1 HLCCST in the lung is characterized by a hypervascular stroma and dilated blood vessels. It predominantly consists of epithelial-like cells arranged in solid sheets or nests, with uniform morphology. These cells have abundant, clear, or eosinophilic cytoplasm. The nuclei are relatively consistent in size, varying from oval to spindle-shaped, with deeply stained or vacuolated chromatin and inconspicuous nucleoli. Tumor necrosis is typically absent, and mitotic figures are rare. Immunohistochemically, HLCCST in the lung often shows positivity for vimentin and TFE3 but lacks expression of markers such as CK, EMA, TTF-1, P40, CGA, SYN, CD56, CD34, CD31, STAT6, desmin, calponin, SMA, GATA3, SOX-10, Bcl-2, S-100, and HMB-45.9 Recently, HLCCST in lung has been reported to express TFE3 and harbor YAP1::TFE3 fusions,8 suggesting it belongs to a family of tumors associated with TFE3 expression and YAP1::TFE3 fusions. HLCCST in the lung needs to be distinguished from similar entities, such as hemangioblastoma outside the central nervous system, vascular epithelioid cell tumor (PEComa) (clear cell “sugar” tumor), and metastatic clear cell carcinoma. Hemangioblastoma is a mesenchymal neoplasm, composed of an admixture of clear “lipid-rich” epithelioid cells embedded in a highly vascularized stroma rich in capillaries,13 which is considered a marker lesion of von Hippel-Lindau disease (VHL) with VHL alteration.14 Hemangioblastomas are typically positive for vimentin, NSE, inhibin, and S-100. PEComa, a member of the perivascular epithelioid cell tumor family, shares similar morphological features with HLCCST in the lung. However, unlike HLCCST in the lung, PEComa expresses markers such as HMB45, Melan A, SMA, and calponin. The morphology and immunohistochemical profile of metastatic clear cell carcinoma are generally similar to the primary tumor.
HLCCST in the lung is generally considered benign, and surgical resection is the primary treatment. Overall prognosis is favorable. However, few cases have exhibited distant metastasis or been deemed unresectable.12 In 2022, Dehner et al reported a case of unresectable HLCCST that was treated with chemotherapy, and one patient died of the disease 7 months after diagnosis.12 In such cases, chemotherapy may be beneficial, although HLCCST is extremely rare and not included in the 2021 WHO classification of pulmonary mediastinal tumors. Consequently, there is no established clinical guidance for the disease when surgery is not feasible. Thus, it is crucial for future clinical practice to ensure thorough patient follow-up and explore alternative therapeutic strategies tailored to individual disease progression.
In conclusion, HLCCST in lung is an extremely rare disease, and generally considered benign. However, current knowledge regarding its demographics, presentation, and clinical behaviors is limited. This review highlights the importance of recognizing and accurately diagnosing this rare tumor to ensure appropriate treatment and improve patient outcomes.