Pulmonary epithelioid hemangioendothelioma with pleural dissemination: a case report of prolonged diagnostic delay and the role of surgical biopsy

Pulmonary epithelioid hemangioendothelioma with pleural dissemination: a case report of prolonged diagnostic delay and the role of surgical biopsy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Pulmonary epithelioid hemangioendothelioma with pleural dissemination: a case report of prolonged diagnostic delay and the role of surgical biopsy Rui Yan, weiwei Feng, Lu Lu, Yi Gong, Guifang Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9473715/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background Pulmonary epithelioid hemangioendothelioma (PEH) is a rare vascular tumor with low incidence and nonspecific clinical and radiological features, frequently leading to misdiagnosis and delayed diagnosis. Case presentation: We report a 32-year-old man with bilateral pulmonary nodules that were followed for 6 years before the development of a new left lower lobe mass, pleuritic chest pain, dyspnea, and massive pleural effusion in 2025. Initial imaging revealed diffuse miliary nodules that remained relatively indolent for several years. Two transbronchial lung biopsies (TBLB) and repeated pleural fluid cytology failed to establish a diagnosis. Definitive diagnosis was achieved only after video-assisted thoracoscopic surgery (VATS), with immunohistochemical support for endothelial differentiation and molecular confirmation of the WWTR1–CAMTA1 fusion gene. The patient underwent surgery, systemic therapy, and intrapleural treatment, followed by maintenance sirolimus. Disease remained clinically and radiologically stable during 6 months of follow-up. Conclusions PEH presents substantial diagnostic challenges because of its indolent course and nonspecific clinical and radiological features. For patients with unexplained multiple pulmonary nodules and pleural involvement, especially when minimally invasive investigations remain repeatedly nondiagnostic, early surgical biopsy combined with endothelial immunophenotyping and molecular testing is essential for timely diagnosis and optimal management. pulmonary epithelioid hemangioendothelioma pleural dissemination diagnostic delay surgical biopsy case report Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor originating from endothelial cells, with an incidence of less than one per millio 1 . Its biological behavior is intermediate between benign hemangioma and highly aggressive angiosarcoma. EHE can arise in multiple organs, most commonly the liver, lungs, bone, and soft tissue 2 . Pulmonary epithelioid hemangioendothelioma (PEH) accounts for approximately 12–18% of all EHE cases and predominantly affects young to middle-aged individuals, with a female predominance 3 . Clinically, PEH is highly heterogeneous, and up to 50% of patients are asymptomatic at diagnosis 4 . When present, symptoms are usually nonspecific and may include cough, sputum production, dyspnea, and chest pain; pleural involvement may lead to pleural effusion 5 . Radiologically, PEH typically manifests as multiple bilateral pulmonary nodules distributed along bronchovascular bundles, or, less commonly, as diffuse pleural thickening with effusion 6 , 7 . However, these findings are not specific and frequently overlap with miliary tuberculosis, metastatic malignancies, and malignant mesothelioma, resulting in frequent misdiagnosis and delayed diagnosis 8 . Here, we report a case of PEH with pleural dissemination that required a prolonged diagnostic course of 6 years, including repeated nondiagnostic bronchoscopic biopsies and pleural cytology, before definitive diagnosis was achieved. This case highlights the diagnostic challenges of PEH and underscores the importance of timely surgical biopsy and molecular confirmation in patients with persistent diagnostic uncertainty. Case presentation A 32-year-old man with no significant past medical history presented with a long-standing history of pulmonary nodules. He was a never-smoker and denied any history of occupational exposure to dust, asbestos, or other toxic substances. There was no personal or family history of malignancy or hereditary disease. Initial presentation and early follow-up (2019–2023) In June 2019, incidental chest computed tomography (CT) performed during a routine health examination revealed diffuse bilateral miliary pulmonary nodules, with the largest measuring approximately 3 mm in diameter (Fig. 1 A). Tuberculosis was excluded at a local hospital, and the patient was subsequently placed under annual radiological surveillance because he remained asymptomatic. In April 2023, follow-up CT demonstrated interval progression, with multiple bilateral nodules and the largest lesion measuring approximately 12 × 6 mm in the lateral basal segment of the left lower lobe (Fig. 1 B). Pulmonary function testing showed mild obstructive ventilatory dysfunction with reduced small airway indices (MMEF, MEF50, and MEF25), while bronchodilator testing was negative. Laboratory findings were unremarkable. Given the radiological progression, diagnostic bronchoscopy with transbronchial lung biopsy (TBLB) was performed on April 7, 2023. Biopsy specimens obtained from the lingular segment of the left upper lobe and the posterior basal segment of the left lower lobe revealed no evidence of malignancy. Histopathological examination showed mild lymphocytic infiltration and eosinophilic material within alveolar spaces, with negative Congo red and periodic acid–Schiff (PAS) staining. Metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid detected Aspergillus fumigatus at low sequence counts (sequence count: 5), which was considered of uncertain clinical significance. External pathological consultation at a tertiary referral center confirmed these findings, and no definitive diagnosis was established. Disease progression and repeated nondiagnostic evaluations (2023–2025) In December 2023, repeat CT imaging demonstrated persistent diffuse bilateral micronodules, some with calcification, together with interval enlargement of solid nodules in the right upper lobe and left lower lobe. The patient was evaluated at another tertiary hospital; however, in the absence of significant symptoms, he declined further invasive investigations, including repeat bronchoscopy and positron emission tomography–CT (PET-CT), and continued observation. A follow-up chest CT obtained in March 2024, shown in the lung and mediastinal windows, demonstrated relative stability compared with the immediately preceding examination, although the bilateral nodules persisted (Fig. 1 C,D). The patient remained largely asymptomatic during continued follow-up, and the overall course from 2019 to 2024 was characterized by slow progression. The clinical course changed substantially in May 2025, when he developed cough and left-sided chest pain that worsened with deep inspiration, followed by chest tightness and dyspnea. On June 20, 2025, CT imaging revealed a newly developed mass lesion in the left lower lobe, indicating overt disease progression (Fig. 1 E,F). A second bronchoscopy demonstrated deformation and narrowing of the left lower lobe bronchus with mucosal abnormalities. Bronchoalveolar lavage and biopsy were repeated. Microbiological investigations, including testing for tuberculosis, fungi, and bacteria, were negative. Histopathological examination showed scattered atypical cells with hyperchromatic and irregular nuclei within inflammatory fibrinous exudates; however, these findings remained inconclusive for malignancy. Pleural effusion evaluation and diagnostic challenges In early July 2025, the patient’s condition deteriorated, with the onset of high fever (up to 39.5°C) and progressive dyspnea. Chest CT revealed massive left pleural effusion with partial left lung collapse (Fig. 1 G, H). On July 17, 2025, he was admitted to our hospital for further evaluation. Contrast-enhanced CT confirmed massive left pleural effusion with partial lung collapse. Thoracentesis yielded exudative pleural fluid with abundant red blood cells and predominantly lymphocytic infiltration. Initial pleural fluid cytology showed no malignant cells. On admission, physical examination revealed decreased breath sounds over the left lower lung field. Laboratory investigations demonstrated elevated C-reactive protein (23.02 mg/L), CA125 (487.00 U/mL), and D-dimer (2.34 mg/L), while white blood cell count, hemoglobin level, and liver and renal function tests were within normal ranges. Whole-body bone scintigraphy showed no evidence of skeletal metastasis. Pulmonary function testing revealed severe mixed ventilatory dysfunction with moderately reduced diffusing capacity. Repeated pleural fluid cytological examinations remained nondiagnostic: the second sample showed only occasional mesothelial cells, while the third demonstrated rare atypical cells suspicious for malignancy. However, the material was insufficient to determine tumor origin. Despite repeated minimally invasive investigations, including two bronchoscopic biopsies and multiple pleural fluid analyses, a definitive diagnosis could not be established, highlighting the diagnostic challenge. [Insert Fig. 1 here] Definitive diagnosis Given the persistent diagnostic uncertainty, video-assisted thoracoscopic surgery (VATS) was performed in July 2025 following multidisciplinary discussion and informed consent. Intraoperatively, extensive pleural adhesions were observed, together with approximately 500 mL of serosanguinous effusion. The parietal pleura was diffusely studded with numerous miliary and rice-like gray-white nodules, and two firm nodular lesions were identified on the mediastinal pericardium. Surgical procedures included pleural biopsy, wedge resection of the left lower lobe, and excision of mediastinal lesions. Histopathological examination confirmed the diagnosis of pulmonary epithelioid hemangioendothelioma (PEH). Microscopically, epithelioid tumor cells with abundant eosinophilic cytoplasm and intracytoplasmic vacuoles were arranged in nests and cords within a myxohyaline stroma, with focal necrosis (Fig. 3 ). Immunohistochemistry demonstrated positivity for CD31, ERG, FLI-1, and vimentin, and negativity for CK-pan, TTF-1, WT1, calretinin, and CK7. The Ki-67 proliferation index was approximately 8%. Fluorescence in situ hybridization (FISH) confirmed CAMTA1 gene rearrangement, indicating the presence of the WWTR1–CAMTA1 fusion gene. The final diagnosis was pulmonary epithelioid hemangioendothelioma with diffuse pleural dissemination (T4NxM1a, stage IV). [Insert Fig. 2 here] Treatment and follow-up Postoperatively, the patient received intrapleural interleukin-2 therapy, followed by six cycles of systemic therapy consisting of paclitaxel polymer, cisplatin, and bevacizumab, aiming to control pleural disease and systemic tumor burden. Follow-up chest CT demonstrated radiological stable disease (Fig. 2 ). After completion of chemotherapy, maintenance therapy with oral sirolimus was initiated in view of its reported activity in vascular tumors. At the latest follow-up of 6 months, the patient remained clinically and radiologically stable, with no evidence of disease progression. [Insert Fig. 3 here] Discussion and conclusions 1. Epidemiology and clinical characteristics of PEH Epithelioid hemangioendothelioma (EHE) was first described by Dail and Liebow in 1975 as an “intravascular bronchioloalveolar tumor” based on its growth pattern along alveolar septa and within vascular lumina 9 . Subsequent ultrastructural and immunohistochemical studies confirmed its endothelial origin, leading to its current classification 10 . Pulmonary epithelioid hemangioendothelioma (PEH) is a rare subtype, accounting for approximately 12–18% of all EHE cases, and typically affects young to middle-aged individuals, with a female predominance 3 , 11 , 12 . However, the present case involved a young male patient, highlighting the variability in demographic distribution. Clinically, PEH is characterized by a highly heterogeneous and often indolent course. Up to 50% of patients are asymptomatic at diagnosis, with lesions frequently detected incidentally 13 . When symptoms occur, they are nonspecific and may include cough, dyspnea, or chest pain, particularly in cases with pleural involvement 5 . In our case, the patient remained asymptomatic for several years before developing chest pain and pleural effusion, reflecting the typical indolent-to-progressive disease trajectory. Due to its nonspecific presentation, PEH is frequently misdiagnosed as metastatic lung cancer 14 , tuberculosis, or malignant mesothelioma. 2. Diagnostic challenges and causes of delayed diagnosis 2.1 Imaging features and differential diagnosis Radiologically, PEH typically presents as multiple bilateral pulmonary nodules (< 1–2 cm) distributed along bronchovascular bundles, reflecting its vascular origin 15 . Nodules may be well- or ill-defined and occasionally exhibit calcification. Less common patterns include solitary masses, diffuse pleural thickening, or ground-glass opacities. The biological behavior of PEH is highly variable, ranging from indolent disease to aggressive progression with metastasis 5 , 16 . In the present case, imaging evolution was highly characteristic, with long-term stable diffuse micronodules followed by abrupt progression to a mass lesion with pleural dissemination. This dynamic pattern may serve as an important diagnostic clue. Given the nonspecific imaging findings, PEH should be differentiated from metastatic tumors, primary lung cancer, and sarcoidosis. Key distinguishing features include the presence of a known primary tumor in metastasis, spiculated margins and pleural retraction in primary lung cancer, and mediastinal lymphadenopathy in sarcoidosis. 2.2 Limitations of bronchoscopic and cytological diagnosis A major challenge in diagnosing PEH lies in the limited diagnostic yield of minimally invasive procedures. Although histopathology remains the gold standard 8 , the method of tissue acquisition critically determines diagnostic success. Transbronchial lung biopsy (TBLB) is often insufficient, particularly for small or peripherally located lesions. Previous studies have reported diagnostic accuracies as low as 44% for nodules smaller than 1 cm 17 , and PEH lesions are frequently difficult to sample adequately 18 , 19 . In our case, two TBLB procedures and multiple pleural fluid cytological examinations failed to establish a diagnosis, illustrating the inherent limitations of these approaches. Pleural fluid cytology may yield false-negative results due to low tumor cell burden, as demonstrated by the delayed detection of atypical cells in this patient. 2.3 Role of surgical biopsy Surgical biopsy remains the most reliable diagnostic modality. Liu et al. reported higher diagnostic yields for thoracoscopic wedge resection compared with transbronchial or CT-guided biopsy 15 . Although CT-guided biopsy is less invasive 17 , 20 , video-assisted thoracoscopic surgery (VATS) offers direct visualization and enables adequate multi-site sampling. In this case, definitive diagnosis was achieved only after VATS biopsy, emphasizing its critical role in patients with persistent diagnostic uncertainty. Therefore, in patients with indeterminate pulmonary nodules and pleural effusion—particularly those with a prolonged disease course and repeatedly nondiagnostic minimally invasive tests—early consideration of surgical biopsy is strongly recommended. 3. Pathological and molecular characteristics The histopathological features of PEH are distinctive. Tumors typically consist of epithelioid cells with abundant eosinophilic cytoplasm and intracytoplasmic vacuoles, arranged in nests or cords within a myxohyaline stroma 21 , 22 . Mitotic activity is usually low, with a Ki-67 index below 10%, supporting its classification as a low- to intermediate-grade malignancy. Immunohistochemistry plays a crucial role in diagnosis. Tumor cells consistently express endothelial markers such as CD31, ERG, CD34, and factor VIII, while epithelial and mesothelial markers are typically negative, facilitating differential diagnosis from carcinoma and mesothelioma 21 , 23 . Molecular diagnostics have further improved diagnostic accuracy. The characteristic WWTR1–CAMTA1 fusion gene, present in approximately 90% of cases 24 , 25 , results in dysregulation of the Hippo signaling pathway and contributes to tumorigenesis 26 , 27 . In the present case, the combination of characteristic histopathology, endothelial immunophenotype, and molecular confirmation by FISH established a definitive diagnosis, highlighting the importance of an integrated diagnostic approach. [Insert Fig. 4 here] 4. Treatment strategies and emerging therapies Due to its rarity, no standardized treatment guidelines exist for PEH 28 , and management should be individualized. Surgical resection remains the preferred option for localized disease, with favorable long-term outcomes 12 , 29 , although its role in advanced disease is less clear 30 . For unresectable or metastatic disease, systemic therapy is the mainstay. Conventional chemotherapy has shown limited efficacy, with median progression-free survival generally less than 6 months 31 , 32 . Given the vascular nature of PEH, anti-angiogenic therapies, including bevacizumab, sorafenib, and pazopanib, have demonstrated promising results 33 , 34 . Combination regimens may achieve prolonged disease stabilization 35 . mTOR inhibitors, particularly sirolimus, have emerged as a promising therapeutic option, with reported median progression-free survival of approximately 12 months 36 , 37 . In this case, a multimodal strategy combining cytoreductive surgery, anti-angiogenic therapy, and maintenance sirolimus resulted in sustained disease stability, supporting the potential role of targeted therapy in advanced PEH. Recent advances have focused on targeting the Hippo–YAP/TAZ–TEAD signaling pathway, with TEAD inhibitors representing a promising therapeutic direction 27 , 38 . Additionally, immune-based therapies are under investigation, although current evidence remains limited 39 . 5. Prognosis The prognosis of EHE is highly variable, with a 5-year survival rate of approximately 60% and a median survival of 4.6 year 40 . Pulmonary involvement, particularly with bilateral disease or pleural dissemination, is associated with worse outcomes 41 . Adverse prognostic factors include high mitotic activity, nuclear atypia, necrosis, large tumor size, multi-organ involvement, and older age. Despite advanced-stage disease, the relatively low Ki-67 index and stable clinical course in this patient suggest a more indolent biological behavior, highlighting the heterogeneity of PEH. Conclusion PEH is a rare vascular tumor with significant diagnostic challenges due to its nonspecific clinical and radiological features. This case illustrates a prolonged diagnostic course of six years, during which repeated minimally invasive investigations failed to establish a diagnosis. Definitive diagnosis was achieved only through VATS biopsy combined with molecular confirmation of the WWTR1–CAMTA1 fusion gene. For patients with indeterminate pulmonary nodules and pleural involvement, particularly those with persistent diagnostic uncertainty, early multidisciplinary evaluation and timely surgical biopsy are essential. Integration of histopathology, immunohistochemistry, and molecular diagnostics is critical for accurate diagnosis and optimal management. Advances in targeted therapies may further improve outcomes, although longer follow-up is required to evaluate long-term efficacy. Abbreviations CT computed tomography EHE epithelioid hemangioendothelioma FISH fluorescence in situ hybridization FLI-1 Friend leukemia integration 1 transcription factor mNGS metagenomic next-generation sequencing PAS periodic acid–Schiff PEH pulmonary epithelioid hemangioendothelioma PET positron emission tomography TBLB transbronchial lung biopsy VATS video-assisted thoracoscopic surgery WWTR1 WW domain-containing transcription regulator 1 CAMTA1 calmodulin-binding transcription activator 1 ERG ETS-related gene CK cytokeratin Declarations Ethics approval and consent to participate Ethics approval was waived for this case report in accordance with institutional policy. Written informed consent to participate was obtained from the patient. Consent for publication Written informed consent was obtained from the patient for publication of this case report and the accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on reasonable request. Availability of data and materials All data generated or analyzed during this study are included in this published article. Additional anonymized clinical information is available from the corresponding author on reasonable request, subject to the protection of patient privacy. Competing interests The authors declare that they have no competing interests. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Authors' contributions RY collected the clinical data, reviewed the literature, prepared the figures, and drafted the manuscript. LL participated in data collection, figure preparation, and manuscript revision. YG contributed to study conceptualization, supervision, and critical revision of the manuscript, and served as a co-corresponding author. GW contributed to study conceptualization, supervision, and critical revision of the manuscript, and served as a co-corresponding author. All authors read and approved the final manuscript. Acknowledgements Not applicable. References Stacchiotti S, Frezza AM, Blay JY, et al. Ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society community of experts on the incidence threshold and the list of entities. Cancer. 2021;127(16):2934–42. Paulson KG, Ravi V, Rubin BP, et al. Incidence, demographics, and survival of malignant hemangioendothelioma in the United States. Cancer Med. 2023;12(14):15101–6. Thway K, Mentzel T, Perrett CM, Calonje E. Multicentric visceral epithelioid hemangioendothelioma, with extremity dermal deposits, unusual late recurrence on the nasal bridge, and TFE3 gene rearrangement. Hum Pathol. 2018;72:153–9. Schattenberg T, Kam R, Klopp M, et al. Pulmonary epithelioid hemangioendothelioma: Report of three cases. Surg Today. 2008;38(9):844–9. SHAO J, ZHANG J. Clinicopathological characteristics of pulmonary epithelioid hemangioendothelioma: A report of four cases and review of the literature. Oncol Lett. 2014;8(6):2517–22. Xiong W, Wang Y, Ma X, Ding X. Multiple bilateral pulmonary epithelioid hemangioendothelioma mimicking metastatic lung cancer: case report and literature review. J Int Med Res. 2020;48(4):300060520913148. Chen X, Wang Y, Che G, Shen C. An extremely rare case of pulmonary epithelioid hemangioendothelioma. Thorac cancer. 2023;14(24):2519–22. Tang B, Zhao S, Wang J, Xiang M, Dai J, Liu Q. Pulmonary epithelioid haemangioendothelioma: A comprehensive review of clinical and molecular advances. Clinics. 2025;80:100789. Dail DH, Liebow AA, Gmelich JT, et al. Intravascular, bronchiolar, and alveolar tumor of the lung (IVBAT). An analysis of twenty cases of a peculiar sclerosing endothelial tumor. Cancer. 1983;51(3):452–64. Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer. 1982;50(5):970–81. Kim M, Chang J, Choi H, et al. Pulmonary epithelioid hemangioendothelioma misdiagnosed as a benign nodule. World J Surg Oncol. 2015;13(1):107. Ye B, Li W, Feng J, Shi JX, Chen Y, Han BH. Treatment of pulmonary epithelioid hemangioendothelioma with combination chemotherapy: Report of three cases and review of the literature. Oncol Lett. 2013;5(5):1491–6. Shiba S, Imaoka H, Shioji K et al. Clinical characteristics of Japanese patients with epithelioid hemangioendothelioma: a multicenter retrospective study. BMC Cancer 2018;18(1). Noh GT, Lee KJ, Sohn HJ, et al. Pulmonary epithelioid hemangioendothelioma misconceived as pulmonary metastasis of other malignancies. Yeungnam Univ J Med. 2016;33(1):72. Liu H, Wang J, Lang J, Zhang X. Pulmonary Epithelioid Hemangioendothelioma: Imaging and Clinical Features. J Comput Assist Tomogr. 2021;45(5):788–94. Mesquita RD, Sousa M, Trinidad C, Pinto E, Badiola IA. New Insights about Pulmonary Epithelioid Hemangioendothelioma: Review of the Literature and Two Case Reports. Case Rep Radiol. 2017;2017:1–14. Sasaki A, Egashira H, Sugimoto H, et al. CT-guided Biopsy for the Diagnosis of Pulmonary Epithelioid Hemangioendothelioma Mimicking Metastatic Lung Cancer. Intern Med (Tokyo Japan). 2018;57(24):3631–5. Mao X, Liang Z, Chibhabha F, et al. Clinico-radiological features and next generation sequencing of pulmonary epithelioid hemangioendothelioma: A case report and review of literature. Thorac cancer. 2017;8(6):687–92. Fan Y, Wang F, Li S, Ye C, Ying Y, Mao H. Pleural Epithelioid Hemangioendothelioma: A Case Report and Literature Review. J Natl Med Assoc. 2016;108(2):124–9. Aung TT, Chu A, Kondapi D, Markabawi D, Mirchia K, Kaul P. A Case of Pulmonary Epithelioid Hemangioendothelioma with Literature Review. Case Rep Oncological Med. 2020;2020:8048056. Zhang S, Liang Y, Yang Y, Guo L, Li W, Shi S. Clinicopathological features, risk model and prognosis of 115 cases of epithelioid hemangioendothelioma: A single-center study. Front Oncol. 2025;15:1577968. Murali R, Zarka MA, Ocal IT, Tazelaar HD. Cytologic features of epithelioid hemangioendothelioma. Am J Clin Pathol. 2011;136(5):739–46. Li W, Li JK, Zheng X, Chen LL, Yang YH. [Clinicopathological features of primary pulmonary epithelioid hemangioendothelioma: a study of 7 cases]. Zhonghua zhong liu za zhi [Chinese journal of oncology]. 2025;47(3):269–74. Tanas MR, Sboner A, Oliveira AM, et al. Identification of a Disease-Defining Gene Fusion in Epithelioid Hemangioendothelioma. Sci Transl Med. 2011;3(98):ra9882–9882. Doyle LA, Fletcher CDM, Hornick JL. Nuclear Expression of CAMTA1 Distinguishes Epithelioid Hemangioendothelioma From Histologic Mimics. Am J Surg Pathol. 2016;40(1):94–102. Ma S, Kanai R, Pobbati AV, et al. The TAZ-CAMTA1 Fusion Protein Promotes Tumorigenesis via Connective Tissue Growth Factor and Ras–MAPK Signaling in Epithelioid Hemangioendothelioma. Clin Cancer Res. 2022;28(14):3116–26. Seavey CN, Pobbati AV, Rubin BP. Unraveling the Biology of Epithelioid Hemangioendothelioma, a TAZ-CAMTA1 Fusion Driven Sarcoma. Cancers 2022;14(12). Chen X, Wang Y, Che G, Shen C. An extremely rare case of pulmonary epithelioid hemangioendothelioma. Thorac cancer. 2023;14(24):2519–22. Stacchiotti S, Miah AB, Frezza AM, et al. Epithelioid hemangioendothelioma, an ultra-rare cancer: a consensus paper from the community of experts. ESMO open. 2021;6(3):100170. Tsuchihashi K, Baba E. Epithelioid hemangioendothelioma-its history, clinical features, molecular biology and current therapy. Jpn J Clin Oncol. 2024;54(7):739–47. Frezza AM, Ravi V, Lo Vullo S, et al. Systemic therapies in advanced epithelioid haemangioendothelioma: A retrospective international case series from the World Sarcoma Network and a review of literature. Cancer Med. 2021;10(8):2645–59. Yousaf N, Maruzzo M, Judson I, Al-Muderis O, Fisher C, Benson C. Systemic treatment options for epithelioid haemangioendothelioma: the Royal Marsden Hospital experience. Anticancer Res. 2015;35(1):473–80. Agulnik M, Yarber JL, Okuno SH, et al. An open-label, multicenter, phase II study of bevacizumab for the treatment of angiosarcoma and epithelioid hemangioendotheliomas. Ann Oncol. 2013;24(1):257–63. Semenisty V, Naroditsky I, Keidar Z, Bar-Sela G. Pazopanib for metastatic pulmonary epithelioid hemangioendothelioma—a suitable treatment option: case report and review of anti-angiogenic treatment options. BMC Cancer 2015;15(1). Telli TA, Okten IN, Tuylu TB, et al. VEGF-VEGFR pathway seems to be the best target in hepatic epithelioid hemangioendothelioma: A case series with review of the literature. Curr Probl Cancer. 2020;44(5):100568. Stacchiotti S, Provenzano S, Dagrada G, et al. Sirolimus in Advanced Epithelioid Hemangioendothelioma: A Retrospective Case-Series Analysis from the Italian Rare Cancer Network Database. Ann Surg Oncol. 2016;23(9):2735–44. Stacchiotti S, Tap W, Leonard H, Zaffaroni N, Baldi GG. New Molecular Insights, and the Role of Systemic Therapies and Collaboration for Treatment of Epithelioid Hemangioendothelioma (EHE). Curr Treat Options Oncol. 2023;24(6):667–79. Harvey KF, Tang TT. Targeting the Hippo pathway in cancer. Nat Rev Drug Discovery. 2025;24(11):852–69. Wang Y, Xu H, Sa Q, et al. Efficacy and safety of vascular-targeting agents in advanced soft tissue sarcoma: a systematic review and network meta-analysis. Therapeutic Adv Med Oncol. 2025;17:17588359251378934. Xiong W, Wang Y, Ma X, Ding X. Multiple bilateral pulmonary epithelioid hemangioendothelioma mimicking metastatic lung cancer: case report and literature review. J Int Med Res 2020;48(4). Stacchiotti S, Simeone N, Vullo SL, et al. Activity of sirolimus in patients with progressive epithelioid hemangioendothelioma: A case-series analysis within the Italian Rare Cancer Network. Cancer. 2020;127(4):569–76. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9473715","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":637647405,"identity":"422302ac-6e50-4123-af1e-6bab0834065f","order_by":0,"name":"Rui Yan","email":"","orcid":"","institution":"Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Yan","suffix":""},{"id":637647406,"identity":"4da833e5-cff0-40a4-894c-830933664da0","order_by":1,"name":"weiwei Feng","email":"","orcid":"","institution":"Fudan University","correspondingAuthor":false,"prefix":"","firstName":"weiwei","middleName":"","lastName":"Feng","suffix":""},{"id":637647407,"identity":"ebaaa12a-019b-4e1b-acd2-ac2baa4f6872","order_by":2,"name":"Lu Lu","email":"","orcid":"","institution":"Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Lu","middleName":"","lastName":"Lu","suffix":""},{"id":637647408,"identity":"7900d345-1b11-4f67-beff-06a82e965eb6","order_by":3,"name":"Yi Gong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA90lEQVRIiWNgGAWjYNACAwkefvnHBx+DOczMDURpkZFsSEs2BrKAWhiJ0cLAYGNwIMdMGqyFgYAWeffew695Cix4DA4cS6suqPgTzd8O1PKjYhtOLYZnzqVZ8wD9Inmw+djtGWcMcmccZmxg7DlzG7eWGTlmxiAtfIfZ0m7zthnkNgC1MDO2EaGF4RiPWTFIy3xCWuQlcowfg7QInOExYwZp2UBIiwHPGTPGOSC/zGBLluY5Y5y7EajlID6/yLf3GH9486fOnl+C+eBnngq53HnnDx988KMCjy0HGNikeNBFD+BUD7KlgYH54w98KkbBKBgFo2AUAAAhiVR4AShwlAAAAABJRU5ErkJggg==","orcid":"","institution":"Fudan University","correspondingAuthor":true,"prefix":"","firstName":"Yi","middleName":"","lastName":"Gong","suffix":""},{"id":637647409,"identity":"04384a90-b59e-47cb-814a-09e1042d3aba","order_by":4,"name":"Guifang Wang","email":"","orcid":"","institution":"Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Guifang","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2026-04-20 14:39:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9473715/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9473715/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109170730,"identity":"7ff8eb8d-e259-44d3-b760-35335dd7c978","added_by":"auto","created_at":"2026-05-13 08:50:59","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":420530,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eClinical course and radiological evolution from June 2019 to July 2025.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA,\u003c/strong\u003eInitial chest CT in June 2019 showing diffuse bilateral miliary pulmonary nodules, with the largest measuring approximately 3 mm. \u003cstrong\u003eB,\u003c/strong\u003eFollow-up chest CT in April 2023 demonstrating interval enlargement of bilateral pulmonary nodules; the largest lesion in the left lower lobe measured approximately 12 × 6 mm. Transbronchial lung biopsy was nondiagnostic, and metagenomic next-generation sequencing of bronchoalveolar lavage fluid was negative. \u003cstrong\u003eC and D,\u003c/strong\u003e Follow-up chest CT in March 2024, shown in the lung and mediastinal windows, demonstrating overall relative stability compared with the previous examination. The patient remained largely asymptomatic, and the disease course from 2019 to 2024 was slowly progressive. \u003cstrong\u003eE(a) and E(b),\u003c/strong\u003e Chest CT in June 2025 (lung window) showing slight interval enlargement of the left lower lobe and right middle lobe lesions (arrows).\u003cstrong\u003eF,\u003c/strong\u003e The corresponding mediastinal-window image more clearly demonstrates a newly developed mass lesion in the left lower lobe, indicating overt disease progression. At this stage, the patient developed new-onset left-sided chest pain and dyspnea, and repeat bronchoscopy remained nondiagnostic. \u003cstrong\u003eG and H,\u003c/strong\u003e Chest CT in July 2025 showing massive left pleural effusion with partial collapse of the left lung.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9473715/v1/cb874090344fcb6ff0598411.jpg"},{"id":109170731,"identity":"a124f721-7dfc-444f-843b-2ba2f08f983a","added_by":"auto","created_at":"2026-05-13 08:50:59","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":415362,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHistopathological and immunohistochemical findings.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA,\u003c/strong\u003eHematoxylin and eosin staining showing nests of atypical epithelioid tumor cells with enlarged nuclei, conspicuous nucleoli, coarse chromatin, and frequent mitotic figures (arrows) (×40).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB,\u003c/strong\u003eImmunohistochemical staining for cytokeratin (CK) showing focal positivity in tumor cells (×20).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC,\u003c/strong\u003eImmunohistochemical staining for CD34 demonstrating positivity in vascular endothelial cells and tumor cells (arrows) (×40).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eD,\u003c/strong\u003eKi-67 labeling index of approximately 8% (×20).\u003c/p\u003e\n\u003cp\u003eThese findings support endothelial differentiation.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9473715/v1/b6a270a646f1aebc3ec6d3de.jpg"},{"id":109170732,"identity":"786c4ba3-11b4-4f1c-9c4c-c88953e7cbc0","added_by":"auto","created_at":"2026-05-13 08:50:59","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":259770,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRadiological findings before and after treatment.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA and B,\u003c/strong\u003e Chest CT on August 11, 2025, at the same axial level (Im122), shown in the lung and mediastinal windows, demonstrating a solid nodule in the right middle lobe (arrow) with incomplete expansion of the left lung and pleural effusion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC and D,\u003c/strong\u003e Chest CT on January 23, 2026, shown in the lung and mediastinal windows, demonstrating reduction of the right middle lobe nodule (arrow) and persistent but decreased left pleural effusion after six cycles of chemotherapy, consistent with radiological stability.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9473715/v1/4cfab126d0518d4be47308cf.jpg"},{"id":109170733,"identity":"788c5e38-1d8b-4a38-86c0-ecd534e69586","added_by":"auto","created_at":"2026-05-13 08:50:59","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":21537,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDiagnostic workflow of the present case.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSchematic summary of the prolonged diagnostic course. The patient underwent long-term follow-up for bilateral pulmonary nodules and two hospital-based diagnostic evaluations. Repeated minimally invasive tests, including two bronchoscopic biopsies and multiple pleural fluid cytology examinations, failed to establish a diagnosis. Definitive diagnosis was achieved only after video-assisted thoracoscopic surgery, followed by histopathological, immunohistochemical, and molecular confirmation of PEH.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9473715/v1/0896ca843746c8530b5ae26a.jpg"},{"id":109170734,"identity":"73b14db4-c2a6-4cee-89b4-8190868a696d","added_by":"auto","created_at":"2026-05-13 08:51:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1337055,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9473715/v1/54a9d921-41af-4a32-a785-e094b541c441.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pulmonary epithelioid hemangioendothelioma with pleural dissemination: a case report of prolonged diagnostic delay and the role of surgical biopsy","fulltext":[{"header":"Background","content":"\u003cp\u003eEpithelioid hemangioendothelioma (EHE) is a rare vascular tumor originating from endothelial cells, with an incidence of less than one per millio\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Its biological behavior is intermediate between benign hemangioma and highly aggressive angiosarcoma. EHE can arise in multiple organs, most commonly the liver, lungs, bone, and soft tissue\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Pulmonary epithelioid hemangioendothelioma (PEH) accounts for approximately 12\u0026ndash;18% of all EHE cases and predominantly affects young to middle-aged individuals, with a female predominance\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eClinically, PEH is highly heterogeneous, and up to 50% of patients are asymptomatic at diagnosis\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. When present, symptoms are usually nonspecific and may include cough, sputum production, dyspnea, and chest pain; pleural involvement may lead to pleural effusion\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Radiologically, PEH typically manifests as multiple bilateral pulmonary nodules distributed along bronchovascular bundles, or, less commonly, as diffuse pleural thickening with effusion\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. However, these findings are not specific and frequently overlap with miliary tuberculosis, metastatic malignancies, and malignant mesothelioma, resulting in frequent misdiagnosis and delayed diagnosis\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHere, we report a case of PEH with pleural dissemination that required a prolonged diagnostic course of 6 years, including repeated nondiagnostic bronchoscopic biopsies and pleural cytology, before definitive diagnosis was achieved. This case highlights the diagnostic challenges of PEH and underscores the importance of timely surgical biopsy and molecular confirmation in patients with persistent diagnostic uncertainty.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 32-year-old man with no significant past medical history presented with a long-standing history of pulmonary nodules. He was a never-smoker and denied any history of occupational exposure to dust, asbestos, or other toxic substances. There was no personal or family history of malignancy or hereditary disease.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eInitial presentation and early follow-up (2019–2023)\u003c/h2\u003e \u003cp\u003eIn June 2019, incidental chest computed tomography (CT) performed during a routine health examination revealed diffuse bilateral miliary pulmonary nodules, with the largest measuring approximately 3 mm in diameter (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eA). Tuberculosis was excluded at a local hospital, and the patient was subsequently placed under annual radiological surveillance because he remained asymptomatic.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn April 2023, follow-up CT demonstrated interval progression, with multiple bilateral nodules and the largest lesion measuring approximately 12 × 6 mm in the lateral basal segment of the left lower lobe (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eB). Pulmonary function testing showed mild obstructive ventilatory dysfunction with reduced small airway indices (MMEF, MEF50, and MEF25), while bronchodilator testing was negative. Laboratory findings were unremarkable.\u003c/p\u003e \u003cp\u003eGiven the radiological progression, diagnostic bronchoscopy with transbronchial lung biopsy (TBLB) was performed on April 7, 2023. Biopsy specimens obtained from the lingular segment of the left upper lobe and the posterior basal segment of the left lower lobe revealed no evidence of malignancy. Histopathological examination showed mild lymphocytic infiltration and eosinophilic material within alveolar spaces, with negative Congo red and periodic acid–Schiff (PAS) staining. Metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid detected Aspergillus fumigatus at low sequence counts (sequence count: 5), which was considered of uncertain clinical significance. External pathological consultation at a tertiary referral center confirmed these findings, and no definitive diagnosis was established.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDisease progression and repeated nondiagnostic evaluations (2023–2025)\u003c/h3\u003e\n\u003cp\u003eIn December 2023, repeat CT imaging demonstrated persistent diffuse bilateral micronodules, some with calcification, together with interval enlargement of solid nodules in the right upper lobe and left lower lobe. The patient was evaluated at another tertiary hospital; however, in the absence of significant symptoms, he declined further invasive investigations, including repeat bronchoscopy and positron emission tomography–CT (PET-CT), and continued observation.\u003c/p\u003e \u003cp\u003eA follow-up chest CT obtained in March 2024, shown in the lung and mediastinal windows, demonstrated relative stability compared with the immediately preceding examination, although the bilateral nodules persisted (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eC,D). The patient remained largely asymptomatic during continued follow-up, and the overall course from 2019 to 2024 was characterized by slow progression.\u003c/p\u003e \u003cp\u003eThe clinical course changed substantially in May 2025, when he developed cough and left-sided chest pain that worsened with deep inspiration, followed by chest tightness and dyspnea. On June 20, 2025, CT imaging revealed a newly developed mass lesion in the left lower lobe, indicating overt disease progression (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eE,F). A second bronchoscopy demonstrated deformation and narrowing of the left lower lobe bronchus with mucosal abnormalities. Bronchoalveolar lavage and biopsy were repeated. Microbiological investigations, including testing for tuberculosis, fungi, and bacteria, were negative. Histopathological examination showed scattered atypical cells with hyperchromatic and irregular nuclei within inflammatory fibrinous exudates; however, these findings remained inconclusive for malignancy.\u003c/p\u003e\n\u003ch3\u003ePleural effusion evaluation and diagnostic challenges\u003c/h3\u003e\n\u003cp\u003eIn early July 2025, the patient’s condition deteriorated, with the onset of high fever (up to 39.5°C) and progressive dyspnea. Chest CT revealed massive left pleural effusion with partial left lung collapse (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eG, H). On July 17, 2025, he was admitted to our hospital for further evaluation. Contrast-enhanced CT confirmed massive left pleural effusion with partial lung collapse. Thoracentesis yielded exudative pleural fluid with abundant red blood cells and predominantly lymphocytic infiltration. Initial pleural fluid cytology showed no malignant cells.\u003c/p\u003e \u003cp\u003eOn admission, physical examination revealed decreased breath sounds over the left lower lung field. Laboratory investigations demonstrated elevated C-reactive protein (23.02 mg/L), CA125 (487.00 U/mL), and D-dimer (2.34 mg/L), while white blood cell count, hemoglobin level, and liver and renal function tests were within normal ranges. Whole-body bone scintigraphy showed no evidence of skeletal metastasis. Pulmonary function testing revealed severe mixed ventilatory dysfunction with moderately reduced diffusing capacity.\u003c/p\u003e \u003cp\u003eRepeated pleural fluid cytological examinations remained nondiagnostic: the second sample showed only occasional mesothelial cells, while the third demonstrated rare atypical cells suspicious for malignancy. However, the material was insufficient to determine tumor origin. Despite repeated minimally invasive investigations, including two bronchoscopic biopsies and multiple pleural fluid analyses, a definitive diagnosis could not be established, highlighting the diagnostic challenge. [Insert Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e here]\u003c/p\u003e\n\u003ch3\u003eDefinitive diagnosis\u003c/h3\u003e\n\u003cp\u003eGiven the persistent diagnostic uncertainty, video-assisted thoracoscopic surgery (VATS) was performed in July 2025 following multidisciplinary discussion and informed consent. Intraoperatively, extensive pleural adhesions were observed, together with approximately 500 mL of serosanguinous effusion. The parietal pleura was diffusely studded with numerous miliary and rice-like gray-white nodules, and two firm nodular lesions were identified on the mediastinal pericardium. Surgical procedures included pleural biopsy, wedge resection of the left lower lobe, and excision of mediastinal lesions.\u003c/p\u003e \u003cp\u003eHistopathological examination confirmed the diagnosis of pulmonary epithelioid hemangioendothelioma (PEH). Microscopically, epithelioid tumor cells with abundant eosinophilic cytoplasm and intracytoplasmic vacuoles were arranged in nests and cords within a myxohyaline stroma, with focal necrosis (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Immunohistochemistry demonstrated positivity for CD31, ERG, FLI-1, and vimentin, and negativity for CK-pan, TTF-1, WT1, calretinin, and CK7. The Ki-67 proliferation index was approximately 8%. Fluorescence in situ hybridization (FISH) confirmed CAMTA1 gene rearrangement, indicating the presence of the WWTR1–CAMTA1 fusion gene. The final diagnosis was pulmonary epithelioid hemangioendothelioma with diffuse pleural dissemination (T4NxM1a, stage IV).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e[Insert Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e here]\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eTreatment and follow-up\u003c/h3\u003e\n\u003cp\u003ePostoperatively, the patient received intrapleural interleukin-2 therapy, followed by six cycles of systemic therapy consisting of paclitaxel polymer, cisplatin, and bevacizumab, aiming to control pleural disease and systemic tumor burden. Follow-up chest CT demonstrated radiological stable disease (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). After completion of chemotherapy, maintenance therapy with oral sirolimus was initiated in view of its reported activity in vascular tumors. At the latest follow-up of 6 months, the patient remained clinically and radiologically stable, with no evidence of disease progression. [Insert Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e here]\u003c/p\u003e "},{"header":"Discussion and conclusions","content":"\u003cp\u003e \u003cb\u003e1. Epidemiology and clinical characteristics of PEH\u003c/b\u003e \u003c/p\u003e\u003cp\u003eEpithelioid hemangioendothelioma (EHE) was first described by Dail and Liebow in 1975 as an “intravascular bronchioloalveolar tumor” based on its growth pattern along alveolar septa and within vascular lumina\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Subsequent ultrastructural and immunohistochemical studies confirmed its endothelial origin, leading to its current classification\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Pulmonary epithelioid hemangioendothelioma (PEH) is a rare subtype, accounting for approximately 12–18% of all EHE cases, and typically affects young to middle-aged individuals, with a female predominance\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. However, the present case involved a young male patient, highlighting the variability in demographic distribution. Clinically, PEH is characterized by a highly heterogeneous and often indolent course. Up to 50% of patients are asymptomatic at diagnosis, with lesions frequently detected incidentally\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. When symptoms occur, they are nonspecific and may include cough, dyspnea, or chest pain, particularly in cases with pleural involvement\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. In our case, the patient remained asymptomatic for several years before developing chest pain and pleural effusion, reflecting the typical indolent-to-progressive disease trajectory. Due to its nonspecific presentation, PEH is frequently misdiagnosed as metastatic lung cancer\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, tuberculosis, or malignant mesothelioma.\u003c/p\u003e \u003cb\u003e2. Diagnostic challenges and causes of delayed diagnosis\u003c/b\u003e \u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e\u003cp\u003e \u003cb\u003e2.1 Imaging features and differential diagnosis\u003c/b\u003e \u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e\u003cp\u003eRadiologically, PEH typically presents as multiple bilateral pulmonary nodules (\u0026lt; 1–2 cm) distributed along bronchovascular bundles, reflecting its vascular origin\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Nodules may be well- or ill-defined and occasionally exhibit calcification. Less common patterns include solitary masses, diffuse pleural thickening, or ground-glass opacities. The biological behavior of PEH is highly variable, ranging from indolent disease to aggressive progression with metastasis\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. In the present case, imaging evolution was highly characteristic, with long-term stable diffuse micronodules followed by abrupt progression to a mass lesion with pleural dissemination. This dynamic pattern may serve as an important diagnostic clue. Given the nonspecific imaging findings, PEH should be differentiated from metastatic tumors, primary lung cancer, and sarcoidosis. Key distinguishing features include the presence of a known primary tumor in metastasis, spiculated margins and pleural retraction in primary lung cancer, and mediastinal lymphadenopathy in sarcoidosis.\u003c/p\u003e\u003cp\u003e \u003cb\u003e2.2 Limitations of bronchoscopic and cytological diagnosis\u003c/b\u003e \u003c/p\u003e\u003cp\u003eA major challenge in diagnosing PEH lies in the limited diagnostic yield of minimally invasive procedures. Although histopathology remains the gold standard\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e, the method of tissue acquisition critically determines diagnostic success. Transbronchial lung biopsy (TBLB) is often insufficient, particularly for small or peripherally located lesions. Previous studies have reported diagnostic accuracies as low as 44% for nodules smaller than 1 cm\u003csup\u003e17\u003c/sup\u003e, and PEH lesions are frequently difficult to sample adequately\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. In our case, two TBLB procedures and multiple pleural fluid cytological examinations failed to establish a diagnosis, illustrating the inherent limitations of these approaches. Pleural fluid cytology may yield false-negative results due to low tumor cell burden, as demonstrated by the delayed detection of atypical cells in this patient.\u003c/p\u003e\u003cp\u003e \u003cb\u003e2.3 Role of surgical biopsy\u003c/b\u003e \u003c/p\u003e\u003cp\u003eSurgical biopsy remains the most reliable diagnostic modality. Liu et al. reported higher diagnostic yields for thoracoscopic wedge resection compared with transbronchial or CT-guided biopsy\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Although CT-guided biopsy is less invasive\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, video-assisted thoracoscopic surgery (VATS) offers direct visualization and enables adequate multi-site sampling. In this case, definitive diagnosis was achieved only after VATS biopsy, emphasizing its critical role in patients with persistent diagnostic uncertainty. Therefore, in patients with indeterminate pulmonary nodules and pleural effusion—particularly those with a prolonged disease course and repeatedly nondiagnostic minimally invasive tests—early consideration of surgical biopsy is strongly recommended.\u003c/p\u003e\u003cp\u003e \u003cb\u003e3. Pathological and molecular characteristics\u003c/b\u003e \u003c/p\u003e\u003cp\u003eThe histopathological features of PEH are distinctive. Tumors typically consist of epithelioid cells with abundant eosinophilic cytoplasm and intracytoplasmic vacuoles, arranged in nests or cords within a myxohyaline stroma\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Mitotic activity is usually low, with a Ki-67 index below 10%, supporting its classification as a low- to intermediate-grade malignancy. Immunohistochemistry plays a crucial role in diagnosis. Tumor cells consistently express endothelial markers such as CD31, ERG, CD34, and factor VIII, while epithelial and mesothelial markers are typically negative, facilitating differential diagnosis from carcinoma and mesothelioma\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Molecular diagnostics have further improved diagnostic accuracy. The characteristic WWTR1–CAMTA1 fusion gene, present in approximately 90% of cases\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e, results in dysregulation of the Hippo signaling pathway and contributes to tumorigenesis\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. In the present case, the combination of characteristic histopathology, endothelial immunophenotype, and molecular confirmation by FISH established a definitive diagnosis, highlighting the importance of an integrated diagnostic approach.\u003c/p\u003e\u003cp\u003e[Insert Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e here]\u003c/p\u003e\u003cp\u003e \u003cb\u003e4. Treatment strategies and emerging therapies\u003c/b\u003e \u003c/p\u003e\u003cp\u003eDue to its rarity, no standardized treatment guidelines exist for PEH\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e, and management should be individualized. Surgical resection remains the preferred option for localized disease, with favorable long-term outcomes\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e, although its role in advanced disease is less clear\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. For unresectable or metastatic disease, systemic therapy is the mainstay. Conventional chemotherapy has shown limited efficacy, with median progression-free survival generally less than 6 months\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Given the vascular nature of PEH, anti-angiogenic therapies, including bevacizumab, sorafenib, and pazopanib, have demonstrated promising results\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Combination regimens may achieve prolonged disease stabilization\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. mTOR inhibitors, particularly sirolimus, have emerged as a promising therapeutic option, with reported median progression-free survival of approximately 12 months\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. In this case, a multimodal strategy combining cytoreductive surgery, anti-angiogenic therapy, and maintenance sirolimus resulted in sustained disease stability, supporting the potential role of targeted therapy in advanced PEH. Recent advances have focused on targeting the Hippo–YAP/TAZ–TEAD signaling pathway, with TEAD inhibitors representing a promising therapeutic direction\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. Additionally, immune-based therapies are under investigation, although current evidence remains limited\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e \u003cb\u003e5. Prognosis\u003c/b\u003e \u003c/p\u003e\u003cp\u003eThe prognosis of EHE is highly variable, with a 5-year survival rate of approximately 60% and a median survival of 4.6 year\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. Pulmonary involvement, particularly with bilateral disease or pleural dissemination, is associated with worse outcomes\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. Adverse prognostic factors include high mitotic activity, nuclear atypia, necrosis, large tumor size, multi-organ involvement, and older age. Despite advanced-stage disease, the relatively low Ki-67 index and stable clinical course in this patient suggest a more indolent biological behavior, highlighting the heterogeneity of PEH.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePEH is a rare vascular tumor with significant diagnostic challenges due to its nonspecific clinical and radiological features. This case illustrates a prolonged diagnostic course of six years, during which repeated minimally invasive investigations failed to establish a diagnosis. Definitive diagnosis was achieved only through VATS biopsy combined with molecular confirmation of the WWTR1\u0026ndash;CAMTA1 fusion gene. For patients with indeterminate pulmonary nodules and pleural involvement, particularly those with persistent diagnostic uncertainty, early multidisciplinary evaluation and timely surgical biopsy are essential. Integration of histopathology, immunohistochemistry, and molecular diagnostics is critical for accurate diagnosis and optimal management. Advances in targeted therapies may further improve outcomes, although longer follow-up is required to evaluate long-term efficacy.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecomputed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEHE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eepithelioid hemangioendothelioma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFISH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efluorescence in situ hybridization\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFLI-1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFriend leukemia integration 1 transcription factor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003emNGS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emetagenomic next-generation sequencing\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePAS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eperiodic acid\u0026ndash;Schiff\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePEH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epulmonary epithelioid hemangioendothelioma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePET\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epositron emission tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTBLB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etransbronchial lung biopsy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eVATS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003evideo-assisted thoracoscopic surgery\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWWTR1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWW domain-containing transcription regulator 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCAMTA1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecalmodulin-binding transcription activator 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eERG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eETS-related gene\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCK\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecytokeratin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval was waived for this case report in accordance with institutional policy. Written informed consent to participate was obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this case report and the accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article. Additional anonymized clinical information is available from the corresponding author on reasonable request, subject to the protection of patient privacy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRY collected the clinical data, reviewed the literature, prepared the figures, and drafted the manuscript. LL participated in data collection, figure preparation, and manuscript revision. YG contributed to study conceptualization, supervision, and critical revision of the manuscript, and served as a co-corresponding author. GW contributed to study conceptualization, supervision, and critical revision of the manuscript, and served as a co-corresponding author. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eStacchiotti S, Frezza AM, Blay JY, et al. Ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society community of experts on the incidence threshold and the list of entities. Cancer. 2021;127(16):2934\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePaulson KG, Ravi V, Rubin BP, et al. Incidence, demographics, and survival of malignant hemangioendothelioma in the United States. Cancer Med. 2023;12(14):15101\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThway K, Mentzel T, Perrett CM, Calonje E. Multicentric visceral epithelioid hemangioendothelioma, with extremity dermal deposits, unusual late recurrence on the nasal bridge, and TFE3 gene rearrangement. Hum Pathol. 2018;72:153\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchattenberg T, Kam R, Klopp M, et al. Pulmonary epithelioid hemangioendothelioma: Report of three cases. Surg Today. 2008;38(9):844\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSHAO J, ZHANG J. Clinicopathological characteristics of pulmonary epithelioid hemangioendothelioma: A report of four cases and review of the literature. Oncol Lett. 2014;8(6):2517\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXiong W, Wang Y, Ma X, Ding X. Multiple bilateral pulmonary epithelioid hemangioendothelioma mimicking metastatic lung cancer: case report and literature review. J Int Med Res. 2020;48(4):300060520913148.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen X, Wang Y, Che G, Shen C. An extremely rare case of pulmonary epithelioid hemangioendothelioma. Thorac cancer. 2023;14(24):2519\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTang B, Zhao S, Wang J, Xiang M, Dai J, Liu Q. Pulmonary epithelioid haemangioendothelioma: A comprehensive review of clinical and molecular advances. Clinics. 2025;80:100789.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDail DH, Liebow AA, Gmelich JT, et al. Intravascular, bronchiolar, and alveolar tumor of the lung (IVBAT). An analysis of twenty cases of a peculiar sclerosing endothelial tumor. Cancer. 1983;51(3):452\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer. 1982;50(5):970\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim M, Chang J, Choi H, et al. Pulmonary epithelioid hemangioendothelioma misdiagnosed as a benign nodule. World J Surg Oncol. 2015;13(1):107.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYe B, Li W, Feng J, Shi JX, Chen Y, Han BH. Treatment of pulmonary epithelioid hemangioendothelioma with combination chemotherapy: Report of three cases and review of the literature. Oncol Lett. 2013;5(5):1491\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShiba S, Imaoka H, Shioji K et al. Clinical characteristics of Japanese patients with epithelioid hemangioendothelioma: a multicenter retrospective study. BMC Cancer 2018;18(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNoh GT, Lee KJ, Sohn HJ, et al. Pulmonary epithelioid hemangioendothelioma misconceived as pulmonary metastasis of other malignancies. Yeungnam Univ J Med. 2016;33(1):72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu H, Wang J, Lang J, Zhang X. Pulmonary Epithelioid Hemangioendothelioma: Imaging and Clinical Features. J Comput Assist Tomogr. 2021;45(5):788\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMesquita RD, Sousa M, Trinidad C, Pinto E, Badiola IA. New Insights about Pulmonary Epithelioid Hemangioendothelioma: Review of the Literature and Two Case Reports. Case Rep Radiol. 2017;2017:1\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSasaki A, Egashira H, Sugimoto H, et al. CT-guided Biopsy for the Diagnosis of Pulmonary Epithelioid Hemangioendothelioma Mimicking Metastatic Lung Cancer. Intern Med (Tokyo Japan). 2018;57(24):3631\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMao X, Liang Z, Chibhabha F, et al. Clinico-radiological features and next generation sequencing of pulmonary epithelioid hemangioendothelioma: A case report and review of literature. Thorac cancer. 2017;8(6):687\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFan Y, Wang F, Li S, Ye C, Ying Y, Mao H. Pleural Epithelioid Hemangioendothelioma: A Case Report and Literature Review. J Natl Med Assoc. 2016;108(2):124\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAung TT, Chu A, Kondapi D, Markabawi D, Mirchia K, Kaul P. A Case of Pulmonary Epithelioid Hemangioendothelioma with Literature Review. Case Rep Oncological Med. 2020;2020:8048056.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang S, Liang Y, Yang Y, Guo L, Li W, Shi S. Clinicopathological features, risk model and prognosis of 115 cases of epithelioid hemangioendothelioma: A single-center study. Front Oncol. 2025;15:1577968.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMurali R, Zarka MA, Ocal IT, Tazelaar HD. Cytologic features of epithelioid hemangioendothelioma. Am J Clin Pathol. 2011;136(5):739\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi W, Li JK, Zheng X, Chen LL, Yang YH. [Clinicopathological features of primary pulmonary epithelioid hemangioendothelioma: a study of 7 cases]. Zhonghua zhong liu za zhi [Chinese journal of oncology]. 2025;47(3):269\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTanas MR, Sboner A, Oliveira AM, et al. Identification of a Disease-Defining Gene Fusion in Epithelioid Hemangioendothelioma. Sci Transl Med. 2011;3(98):ra9882\u0026ndash;9882.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDoyle LA, Fletcher CDM, Hornick JL. Nuclear Expression of CAMTA1 Distinguishes Epithelioid Hemangioendothelioma From Histologic Mimics. Am J Surg Pathol. 2016;40(1):94\u0026ndash;102.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMa S, Kanai R, Pobbati AV, et al. The TAZ-CAMTA1 Fusion Protein Promotes Tumorigenesis via Connective Tissue Growth Factor and Ras\u0026ndash;MAPK Signaling in Epithelioid Hemangioendothelioma. Clin Cancer Res. 2022;28(14):3116\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeavey CN, Pobbati AV, Rubin BP. Unraveling the Biology of Epithelioid Hemangioendothelioma, a TAZ-CAMTA1 Fusion Driven Sarcoma. Cancers 2022;14(12).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen X, Wang Y, Che G, Shen C. An extremely rare case of pulmonary epithelioid hemangioendothelioma. Thorac cancer. 2023;14(24):2519\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStacchiotti S, Miah AB, Frezza AM, et al. Epithelioid hemangioendothelioma, an ultra-rare cancer: a consensus paper from the community of experts. ESMO open. 2021;6(3):100170.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTsuchihashi K, Baba E. Epithelioid hemangioendothelioma-its history, clinical features, molecular biology and current therapy. Jpn J Clin Oncol. 2024;54(7):739\u0026ndash;47.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrezza AM, Ravi V, Lo Vullo S, et al. Systemic therapies in advanced epithelioid haemangioendothelioma: A retrospective international case series from the World Sarcoma Network and a review of literature. Cancer Med. 2021;10(8):2645\u0026ndash;59.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYousaf N, Maruzzo M, Judson I, Al-Muderis O, Fisher C, Benson C. Systemic treatment options for epithelioid haemangioendothelioma: the Royal Marsden Hospital experience. Anticancer Res. 2015;35(1):473\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAgulnik M, Yarber JL, Okuno SH, et al. An open-label, multicenter, phase II study of bevacizumab for the treatment of angiosarcoma and epithelioid hemangioendotheliomas. Ann Oncol. 2013;24(1):257\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSemenisty V, Naroditsky I, Keidar Z, Bar-Sela G. Pazopanib for metastatic pulmonary epithelioid hemangioendothelioma\u0026mdash;a suitable treatment option: case report and review of anti-angiogenic treatment options. BMC Cancer 2015;15(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTelli TA, Okten IN, Tuylu TB, et al. VEGF-VEGFR pathway seems to be the best target in hepatic epithelioid hemangioendothelioma: A case series with review of the literature. Curr Probl Cancer. 2020;44(5):100568.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStacchiotti S, Provenzano S, Dagrada G, et al. Sirolimus in Advanced Epithelioid Hemangioendothelioma: A Retrospective Case-Series Analysis from the Italian Rare Cancer Network Database. Ann Surg Oncol. 2016;23(9):2735\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStacchiotti S, Tap W, Leonard H, Zaffaroni N, Baldi GG. New Molecular Insights, and the Role of Systemic Therapies and Collaboration for Treatment of Epithelioid Hemangioendothelioma (EHE). Curr Treat Options Oncol. 2023;24(6):667\u0026ndash;79.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarvey KF, Tang TT. Targeting the Hippo pathway in cancer. Nat Rev Drug Discovery. 2025;24(11):852\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Y, Xu H, Sa Q, et al. Efficacy and safety of vascular-targeting agents in advanced soft tissue sarcoma: a systematic review and network meta-analysis. Therapeutic Adv Med Oncol. 2025;17:17588359251378934.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXiong W, Wang Y, Ma X, Ding X. Multiple bilateral pulmonary epithelioid hemangioendothelioma mimicking metastatic lung cancer: case report and literature review. J Int Med Res 2020;48(4).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStacchiotti S, Simeone N, Vullo SL, et al. Activity of sirolimus in patients with progressive epithelioid hemangioendothelioma: A case-series analysis within the Italian Rare Cancer Network. Cancer. 2020;127(4):569\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"pulmonary epithelioid hemangioendothelioma, pleural dissemination, diagnostic delay, surgical biopsy, case report","lastPublishedDoi":"10.21203/rs.3.rs-9473715/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9473715/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePulmonary epithelioid hemangioendothelioma (PEH) is a rare vascular tumor with low incidence and nonspecific clinical and radiological features, frequently leading to misdiagnosis and delayed diagnosis.\u003c/p\u003e\u003ch2\u003eCase presentation:\u003c/h2\u003e \u003cp\u003eWe report a 32-year-old man with bilateral pulmonary nodules that were followed for 6 years before the development of a new left lower lobe mass, pleuritic chest pain, dyspnea, and massive pleural effusion in 2025. Initial imaging revealed diffuse miliary nodules that remained relatively indolent for several years. Two transbronchial lung biopsies (TBLB) and repeated pleural fluid cytology failed to establish a diagnosis. Definitive diagnosis was achieved only after video-assisted thoracoscopic surgery (VATS), with immunohistochemical support for endothelial differentiation and molecular confirmation of the WWTR1\u0026ndash;CAMTA1 fusion gene. The patient underwent surgery, systemic therapy, and intrapleural treatment, followed by maintenance sirolimus. Disease remained clinically and radiologically stable during 6 months of follow-up.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003ePEH presents substantial diagnostic challenges because of its indolent course and nonspecific clinical and radiological features. For patients with unexplained multiple pulmonary nodules and pleural involvement, especially when minimally invasive investigations remain repeatedly nondiagnostic, early surgical biopsy combined with endothelial immunophenotyping and molecular testing is essential for timely diagnosis and optimal management.\u003c/p\u003e","manuscriptTitle":"Pulmonary epithelioid hemangioendothelioma with pleural dissemination: a case report of prolonged diagnostic delay and the role of surgical biopsy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-13 08:50:43","doi":"10.21203/rs.3.rs-9473715/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"197342244247241074540232466097098129909","date":"2026-05-05T16:16:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"293330488253429420299262966079065158780","date":"2026-05-05T14:01:55+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-05T06:50:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"316599389516057210382209915299707619581","date":"2026-05-05T04:35:41+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-05-05T01:24:22+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-05-04T10:04:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-30T14:00:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-30T14:00:53+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2026-04-20T14:25:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a94a6a8d-3b93-4a07-90d2-1b894c1cc5ea","owner":[],"postedDate":"May 13th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"197342244247241074540232466097098129909","date":"2026-05-05T16:16:09+00:00","index":30,"fulltext":""},{"type":"reviewerAgreed","content":"293330488253429420299262966079065158780","date":"2026-05-05T14:01:55+00:00","index":28,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-05T06:50:17+00:00","index":27,"fulltext":""},{"type":"reviewerAgreed","content":"316599389516057210382209915299707619581","date":"2026-05-05T04:35:41+00:00","index":26,"fulltext":""},{"type":"reviewersInvited","content":"11","date":"2026-05-05T01:24:22+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-05-04T10:04:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-30T14:00:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-30T14:00:53+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-13T08:50:43+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-13 08:50:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9473715","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9473715","identity":"rs-9473715","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}