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

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.

Background

Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor originating from endothelial cells, with an incidence of less than one per million [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. The diagnostic and treatment timeline is summarized in Table 1.

Table 1.

Diagnostic and treatment timeline of the present case

Time	Institution	Clinical status	Imaging/procedures	Results/management
June 2019	A local hospital in Yunnan Province	Asymptomatic; pulmonary nodules were detected during routine health examination.	Chest CT showed diffuse bilateral miliary pulmonary nodules, with the largest measuring approximately 3 mm.	Tuberculosis was excluded, and radiological surveillance was recommended.
April 2023	A local hospital in Yunnan Province	Still largely asymptomatic.	Chest CT showed enlargement of bilateral pulmonary nodules; the largest lesion was located in the left lower lobe and measured approximately 12 × 6 mm. Bronchoscopy with TBLB and BAL mNGS was performed.	No definitive diagnosis was established.
December 2023	A local hospital in Yunnan Province	No significant respiratory symptoms.	Further bronchoscopy and PET/CT were recommended.	The patient declined further invasive diagnostic procedures and PET/CT; continued follow-up was advised.
March 2024	Follow-up at a local hospital in Yunnan Province	Asymptomatic during follow-up.	Follow-up chest CT showed overall stability compared with previous imaging.	Continued surveillance.
June 2025	A local hospital in Shenzhen, Guangdong Province	New-onset cough, left-sided chest pain, and dyspnea.	Chest CT showed interval enlargement of pulmonary lesions and a newly developed mass lesion in the left lower lobe. Repeat bronchoscopy and biopsy were performed.	Bronchoscopy showed narrowing of the left lower lobe bronchus, but biopsy remained nondiagnostic.
July 2025	Emergency Department, our institution	Fever, progressive dyspnea, and massive left pleural effusion.	Chest CT showed massive left pleural effusion with partial lung collapse. Thoracentesis and repeated pleural fluid cytology were performed.	Pleural fluid analyses failed to establish a definitive diagnosis.
July 2025	Department of Respiratory Diseases and Critical Care Medicine, our institution	The patient was admitted for persistent symptoms, massive pleural effusion, and unresolved diagnosis. Further evaluation, repeat thoracentesis, and pleural fluid cytology were performed.	Repeat thoracentesis and pleural fluid cytological examinations were performed.	Initial pleural fluid examinations showed mesothelial cells without definite malignant cells; subsequent samples showed occasional enlarged atypical cells suspicious for malignancy but were insufficient to determine tumor origin.
July 2025	Department of Thoracic Surgery, our institution	Repeated pleural fluid cytology showed rare atypical cells suspicious for malignancy but was insufficient to determine tumor origin.	Video-assisted thoracoscopic surgery was performed, including pleural biopsy, left lower lobe wedge resection, and mediastinal lesion excision.	Histopathology, immunohistochemistry, and FISH confirmed pulmonary epithelioid hemangioendothelioma with diffuse pleural dissemination.
August 2025	Our institution	Postoperative recovery and initial antitumor treatment.	Postoperative management and initial treatment were performed.	The patient received intrapleural interleukin-2 therapy and the first cycle of systemic therapy consisting of paclitaxel polymer, cisplatin, and bevacizumab.
After discharge in August 2025 to January 2026	A local hospital in Yunnan Province	Continued postoperative systemic treatment and follow-up after returning to Yunnan Province.	The remaining cycles of systemic therapy and follow-up chest CT examinations were performed locally.	The patient completed six cycles of systemic therapy consisting of paclitaxel polymer, cisplatin, and bevacizumab, followed by maintenance sirolimus. Follow-up chest CT showed radiologically stable disease, and the patient remained clinically stable at the latest follow-up.

Abbreviations: BAL Bronchoalveolar lavage, CT Computed tomography, FISH Fluorescence in situ hybridization, mNGS metagenomic next-generation sequencing, PET/CT Positron emission tomography/computed tomography, TBLB transbronchial lung biopsy, VATS Video-assisted thoracoscopic surgery

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. 1A). Tuberculosis was excluded at a local hospital. Given the very small lesion size, diffuse bilateral distribution, absence of symptoms, and lack of radiological features strongly suggestive of malignancy, invasive biopsy was not pursued at that stage, and annual radiological surveillance was selected.

Fig. 1.

Clinical course and radiological evolution from June 2019 to July 2025. A Initial chest CT in June 2019 showing diffuse bilateral miliary pulmonary nodules, with the largest measuring approximately 3 mm. B Follow-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. C and D 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. E(a) and E(b), Chest CT in June 2025 (lung window) showing slight interval enlargement of the left lower lobe and right middle lobe lesions (arrows). F 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. G and H Chest CT in July 2025 showing massive left pleural effusion with partial collapse of the left lung

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. 1B). 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. At that time, the CT findings were interpreted as a diffuse bilateral micronodular process rather than a single dominant mass-forming lesion; although the largest nodule was located in the lateral basal segment of the left lower lobe and measured approximately 12 × 6 mm, it remained relatively small and was technically difficult to access by routine bronchoscopic biopsy. Therefore, TBLB was performed from radiologically involved and more accessible segments, including the lingular segment of the left upper lobe and the posterior basal segment of the left lower lobe. The biopsy specimens 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 and PET/CT.

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. 1C, 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. 1E, 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. 1G, 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. PET/CT was again discussed for systemic staging and assessment of disease extent, but the patient declined the examination because of financial concerns. Pulmonary function testing revealed severe mixed ventilatory dysfunction with moderately reduced diffusing capacity. The test was performed as part of the preoperative evaluation before VATS to assess respiratory reserve and surgical fitness, and the results were interpreted with caution because massive pleural effusion and partial lung collapse may have contributed to the observed ventilatory impairment.

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.

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. 2). 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).

Fig. 2.

Histopathological and immunohistochemical findings. A Hematoxylin and eosin staining showing nests of atypical epithelioid tumor cells with enlarged nuclei, conspicuous nucleoli, coarse chromatin, and frequent mitotic figures (arrows) (×40). B Immunohistochemical staining for cytokeratin (CK) showing focal positivity in tumor cells (×20). C Immunohistochemical staining for CD34 demonstrating positivity in vascular endothelial cells and tumor cells (arrows) (×40). D Ki-67 labeling index of approximately 8% (×20). These findings support endothelial differentiation

Treatment and follow-up

Postoperatively, the patient received intrapleural interleukin-2 therapy at our institution, followed by the first cycle of systemic therapy consisting of paclitaxel polymer, cisplatin, and bevacizumab. After discharge in August 2025, the patient returned to his local hospital, where he completed the remaining cycles of systemic therapy and radiological follow-up. A total of six cycles of systemic therapy were administered, followed by maintenance therapy with oral sirolimus in view of its reported activity in vascular tumors. Follow-up chest CT demonstrated radiologically stable disease. At the latest follow-up of 6 months, the patient remained clinically and radiologically stable, with no evidence of disease progression (Fig. 3).

Fig. 3.

Radiological findings before and after treatment. A and B 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. C and D 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

Discussion and conclusions

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. To summarize the characteristics of previously published cases, we reviewed selected pulmonary EHE reports with pleural involvement, pleural effusion, pleural dissemination, or relevant diagnostic features (Table 2). These cases showed heterogeneous presentations, ranging from incidentally detected pulmonary nodules to symptomatic disease with cough, dyspnea, pleuritic chest pain, hemoptysis, recurrent pleural effusion, lung collapse, or diffuse pleural involvement. Imaging findings also varied from multiple small bilateral nodules to dominant pulmonary masses with pleural extension or dissemination. Treatment strategies and outcomes were highly variable, reflecting the rarity of the disease and the absence of a standardized therapeutic approach.

Table 2.

Main features of selected pulmonary epithelioid hemangioendothelioma cases with pleural involvement, pleural effusion, pleural dissemination, or relevant diagnostic features

Study	Patient	Main presentation	Imaging and pleural findings	Diagnostic approach	Treatment and outcome
Horiguchi et al., 2025 [15]	46/F	Cough and chest pain with rapid worsening within 1 month	Multifocal EHE involving the liver and both lungs; later pulmonary progression with a large left pleural effusion and pleural dissemination	Pleural fluid cytology was negative; semi-rigid thoracoscopic pleural cryobiopsy confirmed EHE; WWTR1-CAMTA1 fusion was detected	Previously treated with ablation, pazopanib, and docetaxel; died 2 months after admission
Gonzalez and Seth, 2024 [16]	43/M	Progressive dyspnea and thoracic pain for 4 months	A 5.9 cm left upper lobe mass extending to the pleura; multiple PET-avid pulmonary and pleural nodules and mediastinal lymphadenopathy	Thoracoscopy showed pleural plaques and papules; pleural and nodal lesions were positive for vascular markers and CAMTA1; NGS showed WWTR1-CAMTA1 fusion	No surgery had been scheduled at the time of publication; radiotherapy was being considered
Xuan et al., 2024 [17]	50/F	Lung shadow detected during routine examination, followed by cough and sputum	Enlarging left upper lobe mass; PET/CT showed uptake in the pulmonary lesion, adjacent mediastinal pleura, and hilar/mediastinal lymph nodes	Thoracoscopic lung wedge resection and pleural biopsies; CD31, CD34, ERG, and Fli-1 were positive	Received chemotherapy, targeted therapy, and immunotherapy; disease progressed with bone, soft tissue, and lymph node involvement; the patient later died
Mohamed et al., 2023 [18]	51/F	Persistent dry cough for 5 months	Right pleural effusion and pleural nodularity; restrictive pattern on pulmonary function testing	VATS washout with multiple pleural biopsies and right lower lobe wedge biopsy; CAMTA1-WWTR1 fusion was detected	Surgical washout and biopsy; postoperative chest radiograph showed no residual pleural effusion; further follow-up NR
Gong et al., 2022 [19]	50/M	Intermittent bloody sputum for more than 1 year and dyspnea for 1 week	Right main bronchial obstruction, right upper lobe atelectasis, and bilateral pulmonary nodules	Bronchoscopic biopsy of the endobronchial mass confirmed EHE; NGS revealed a POLE mutation	Treated with DEB-BACE followed by pembrolizumab plus sirolimus; stable disease after more than 1 year
Aung et al., 2020 [20]	58/F	Chest tightness and shortness of breath	Bilateral scattered ground-glass opacities; later enlargement of an 8 mm left lower lobe nodule; PET showed no increased uptake	Bronchoscopy and prior VATS wedge biopsy were nondiagnostic; transthoracic needle biopsy of the enlarging nodule confirmed PEH	No treatment was initiated; surveillance only; no progression after more than 1 year
Mesquita et al., 2017 [21]	35/M; 67/F	Case 1 was asymptomatic. Case 2 presented with productive cough, hemoptysis, and progressive left dorsal pain	Case 1 showed bilateral small pulmonary nodules without pleural effusion. Case 2 showed a left lower lobe mass in contact with the pleura, partial atelectasis, bilateral nodules, pleural effusion, pleural implants, and rapid pleural progression	Case 1 was diagnosed by surgical lung biopsy. Case 2 required repeated biopsy, thoracotomy wedge resection, and pleural implant biopsies	Case 1 survived 48 months without symptoms. Case 2 progressed rapidly despite chemotherapy and died of respiratory failure
Sasaki et al., 2018 [22]	69/M	Incidentally detected pulmonary nodules	Multiple bilateral 2–10 mm pulmonary nodules; no pleural thickening or effusion; PET/CT showed almost normal uptake	CT-guided biopsy of the largest subpleural nodule confirmed PEH	Observation only; no progression during 24 months of follow-up
Bahrami et al., 2008 [23]	37/M	Progressive severe upper back pain for more than 1 year	Left hilar mass extending towards the apex, encasing a bronchus and part of the pulmonary artery; dissemination to the pleura, pericardium, and diaphragm; later large pleural and pericardial effusions	Bronchoscopic and transthoracic biopsies were nondiagnostic; exploratory thoracotomy confirmed EHE	Radiotherapy followed by cisplatin and etoposide; no tumour reduction; died 11 months after diagnosis
Amin et al., 2006 [24]	70/F	Incidentally detected abnormal left upper lung shadow	A 5 × 4.2 cm left upper lobe mass with lymph node swelling; invasion of the pulmonary pleural surface and pleural metastases	TBLB was nondiagnostic; left upper lobectomy with mediastinal lymph node resection confirmed PEH	Surgery only; suspected recurrence 31 months later; followed without treatment
Belmont et al., 2008 [25]	41/M	Fever, cough, breathlessness, and weight loss	Bilateral calcified nodules, pulmonary infiltrates/consolidation, and bilateral pleural effusions	Bloody pleural fluid showed no malignant cells; bronchoscopy was normal; thoracoscopy with pleural and pulmonary biopsies confirmed EHE	Bevacizumab-based therapy achieved partial response and clinical improvement; stable 13 months after diagnosis
Ye et al., 2013 [12]	40/M; 54/F; 44/F	Dry cough, dyspnea, haemoptysis, chest pain, pleuritic pain, or irritable cough	All three cases had bilateral pulmonary nodules or masses; one case had a small right pleural effusion	Bronchoscopic evaluation was unrevealing or insufficient; all cases were diagnosed by thoracoscopic lung biopsy	Combination chemotherapy including platinum, paclitaxel, bevacizumab, or endostar improved symptoms or temporarily stabilized disease; progression occurred; survival ranged from 6 to 25 months
Mizota et al., 2011 [26]	59/F	Pulmonary tumour initially; later dry cough and severe respiratory distress after lobectomy	Diffuse bilateral ground-glass opacities, pleural effusions, and enlarged liver lesions during progression	Right upper lobectomy confirmed PEH with CD31-positive tumour cells, intravascular extension, lymph node metastases, and satellite lesions	Carboplatin, paclitaxel, and bevacizumab improved symptoms and imaging after two cycles; later cerebral infarctions and pneumonia occurred; died 3 months after chemotherapy initiation
Kim et al., 2010 [27]	44/F	Bilateral pulmonary nodules followed for 15 years; later enlargement and lumbago due to sacral metastasis	Bilateral pulmonary nodules with liver and bone metastases at diagnosis; pleural involvement NR	bronchoscopy and CT-guided needle biopsy were nondiagnostic; VATS confirmed EHE	Radiotherapy to the sacrum; carboplatin/paclitaxel plus zoledronic acid, followed by carboplatin/paclitaxel/bevacizumab; disease progressed despite bevacizumab
Chou et al., 2011 [28]	54/M	Dry cough for 1 month	Multiple small nodules up to 1.0 cm scattered in both lungs; PET showed no increased FDG uptake; no pleural effusion or pleural involvement reported in the pulmonary case	VATS wedge resection confirmed pulmonary EHE; CD31 and CD34 were positive	Surgery only; no chemotherapy or radiotherapy; no recurrence or progression at 16 months

This table summarizes selected representative pulmonary EHE cases with pleural involvement, pleural effusion, pleural dissemination, or relevant diagnostic features, rather than all reported pulmonary EHE cases

Abbreviations: CT Computed tomography, DEB-BACE Drug-eluting bead bronchial arterial chemoembolization, EHE epithelioid hemangioendothelioma, FDG Fluorodeoxyglucose, NGS Next-generation sequencing, NR Not reported, PEH pulmonary epithelioid hemangioendothelioma, PET/CT Positron emission tomography/computed tomography, TBLB transbronchial lung biopsy, VATS Video-assisted thoracoscopic surgery

Diagnostic challenges and causes of delayed diagnosis

Factors contributing to delayed diagnosis

Several factors contributed to the prolonged diagnostic delay in the present case.

First, PEH is an exceptionally rare neoplasm, with an estimated incidence of less than one case per million individuals. Because most clinicians encounter few, if any, cases during their careers, the disease is rarely included in the initial differential diagnosis of diffuse pulmonary nodules, resulting in low clinical suspicion. Second, the disease exhibited an indolent clinical course over several years. The patient remained asymptomatic for nearly six years, while serial imaging demonstrated only slow enlargement of the pulmonary nodules. Such prolonged stability generally favors benign or low-grade conditions and may reduce the urgency for invasive diagnostic procedures. Third, the radiological findings were nonspecific and closely resembled more common diseases. The initial presentation of diffuse bilateral micronodules with partial calcification raised consideration of benign granulomatous disease, healed infection, pneumoconiosis, or other indolent pulmonary disorders rather than a rare vascular malignancy. Even after the appearance of a dominant pulmonary mass, the imaging findings remained insufficiently specific to establish a definitive diagnosis. Finally, the diagnostic yield of minimally invasive procedures was limited. Two separate transbronchial lung biopsies failed to obtain representative tumor tissue, likely reflecting the peripheral and multifocal distribution of PEH lesions. Similarly, repeated pleural fluid cytological examinations were initially negative and only demonstrated suspicious atypical cells on the third assessment. These findings are consistent with previous reports indicating that both transbronchial biopsy and pleural fluid cytology may have limited sensitivity in PEH.

Together, these factors explain why the diagnosis was delayed despite repeated evaluations. In patients with unexplained pulmonary nodules that continue to progress or become associated with pleural effusion, pleural thickening, or pleural nodularity, repeated nondiagnostic minimally invasive tests should prompt timely reassessment of the biopsy target and consideration of surgical tissue sampling.

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 [5, 21]. 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.

Multimodal imaging may help guide further diagnostic workup in selected patients with indeterminate pulmonary nodules, masses, or pleural disease. A retrospective study of 35 patients with EHE reported variable but most commonly moderate FDG uptake on PET/CT, and suggested that PET/CT may be useful for whole-body disease assessment, staging, and treatment-response evaluation; however, it should be interpreted together with CT or MRI because some pulmonary or hepatic lesions may be missed by PET/CT [29] . MRI may provide complementary morphological information when local extension or extrapulmonary soft-tissue involvement is suspected. Beyond its established gastrointestinal applications, EUS provides high-resolution, real-time visualization of structures adjacent to the esophagus, and longitudinal-array EUS allows image-guided tissue sampling. Its broader use has also been reported in selected cardiovascular and thoracic diagnostic settings, including the sampling of anatomically accessible mediastinal or hilar lymph nodes. Nevertheless, EBUS-guided sampling and EUS-FNA are not standard diagnostic approaches for PEH itself and should be considered selectively according to lesion location and accessibility [30, 31]. In this patient, PET/CT was recommended during the earlier diagnostic workup but was declined; after massive pleural effusion and diffuse pleural nodularity developed, VATS was considered more appropriate for direct pleural inspection and multi-site tissue sampling.

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 [22], and PEH lesions are frequently difficult to sample adequately [32, 33]. Early pleural fluid samples showed mesothelial cells without definite malignant cells, whereas later cytological and cell-block specimens revealed occasional enlarged atypical cells suspicious for malignancy. However, the cellular material was insufficient to determine the tumor origin or establish a specific pathological diagnosis. These findings indicate that pleural fluid cytology may suggest malignancy but cannot reliably replace tissue biopsy in PEH, particularly when tumor cells are sparse or obscured by hemorrhagic and inflammatory backgrounds.

Role of surgical biopsy

For a pulmonary mass or progressively enlarging nodule of unknown etiology, diagnostic workup should generally be escalated in a stepwise manner, including multimodal imaging, minimally invasive biopsy, image-guided biopsy, and, when necessary, surgical biopsy or resection. Surgical biopsy remains the most reliable diagnostic modality when minimally invasive investigations are repeatedly nondiagnostic. Liu et al. reported higher diagnostic yields for thoracoscopic wedge resection compared with transbronchial or CT-guided biopsy [34]. Although CT-guided percutaneous lung biopsy is less invasive and may be useful for accessible peripheral pulmonary nodules [20, 22], it was not performed in the present case because the patient rapidly developed massive pleural effusion, partial lung collapse, high fever, and progressive dyspnea after the emergence of the left lower lobe mass. Under these circumstances, percutaneous biopsy was considered to have potentially reduced diagnostic yield and increased procedural risk. Pleuroscopy with pleural biopsy was discussed; however, imaging suggested not only pleural disease but also pulmonary and mediastinal involvement. After multidisciplinary reassessment and discussion with the patient, VATS was ultimately selected because it allowed direct pleural inspection, drainage of pleural effusion, and multi-site tissue sampling from the pleura, lung parenchyma, and mediastinal lesions. Histopathological examination of the pleural, pulmonary, and mediastinal specimens obtained during VATS ultimately established the diagnosis.

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 [35, 36]. 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 [35, 37]. Molecular diagnostics have further improved diagnostic accuracy. The characteristic WWTR1–CAMTA1 fusion gene, present in approximately 90% of cases [38, 39], results in dysregulation of the Hippo signaling pathway and contributes to tumorigenesis [40, 41]. 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 (Fig. 4).

Fig. 4.

Diagnostic workflow of the present case. Schematic 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

Treatment strategies and emerging therapies

Due to its rarity, no standardized treatment guidelines exist for PEH, and management should be individualized [42]. Surgical resection remains the preferred option for localized disease, with favorable long-term outcomes [12, 43], although its role in advanced disease is less clear [44]. 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 [45, 46]. Given the vascular nature of PEH, anti-angiogenic therapies, including bevacizumab, sorafenib, and pazopanib, have demonstrated promising results [47, 48]. Combination regimens may achieve prolonged disease stabilization [49]. mTOR inhibitors, particularly sirolimus, have emerged as a promising therapeutic option, with reported median progression-free survival of approximately 12 months [50, 51]. 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 [41, 52]. Additionally, immune-based therapies are under investigation, although current evidence remains limited [53]. Future work should move beyond isolated case descriptions toward a clearer diagnostic and therapeutic framework for PEH. For diagnosis, the key unmet need is to identify when apparently indolent pulmonary nodules should be escalated from surveillance to tissue confirmation. In particular, the development of a new mass-like lesion, pleural effusion, pleural thickening, or pleural nodularity should prompt early multidisciplinary reassessment and acquisition of adequate tissue for histopathological, immunohistochemical, and molecular confirmation. For treatment, future studies should distinguish indolent asymptomatic disease from symptomatic, progressive, or pleural-disseminated disease, as these groups are unlikely to benefit from the same strategy. Multicenter registries with standardized imaging, molecular testing, treatment, and long-term follow-up data are needed to define prognostic subgroups and treatment sequencing. In parallel, emerging therapies should be evaluated in biologically defined cohorts, particularly anti-angiogenic agents, mTOR inhibitors, and approaches targeting the WWTR1–CAMTA1/YAP1–TFE3 fusion biology and the Hippo–YAP/TAZ–TEAD pathway.

Prognosis

The prognosis of EHE is highly variable, with a 5-year survival rate of approximately 60% and a median survival of 4.6 years [6]. Pulmonary involvement, particularly with bilateral disease or pleural dissemination, is associated with worse outcomes [54]. 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

Authors’ contributions

RY collected the clinical data, reviewed the literature, prepared the figures, and drafted the manuscript. WF participated in clinical data collection, literature review, figure preparation. 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.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

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.

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.

Competing interests

The authors declare no competing interests.