Epithelioid hemangioendothelioma is a rare vascular tumor arising from endothelial cells, which can occur in the liver, lungs, bones and soft tissues. When it involves the lungs, it is known as pulmonary epithelioid hemangioendothelioma (PEH), which is characterized by a low to moderate malignant potential (1,2). Historically, PEH was initially described in the medical literature as an ‘intravascular bronchoalveolar tumor’. Over time, its nomenclature and understanding have greatly evolved; however, its rarity has limited comprehensive research and the development of standardized treatment protocols (3). The etiology of PEH remains largely unclear, although it is deemed to be associated with a combination of genetic predispositions and environmental exposures. The condition predominantly affects young women and is often identified incidentally upon imaging analyses, typically presenting as multiple bilateral pulmonary nodules (1). The clinical behavior of PEH exhibits considerable variability among patients, ranging from indolent disease progression in some cases, to rapid advancement and metastasis in others (4,5).

The clinical presentation of PEH is non-specific, with some patients remaining asymptomatic until the disease reaches the advanced stages. By contrast, others may develop symptoms, such as dyspnea or chest pain as a result of tumor growth or associated complications (4). Given its rarity, PEH is often misdiagnosed as other pulmonary conditions. Its incidence is markedly low, estimated at <1 case per million individuals annually, with ~250 cases reported in the medical literature (1). The present case report describes a case of symptomatic PEH in a young male worker found upon computed tomography (CT) angiography. The case was written in accordance with the CaReL guidelines (6). In addition, all references were checked to avoid citing non-peer-reviewed data (7).

Pulmonary epithelioid hemangioendothelioma is a rare, low-grade vascular tumor characterized by a low to intermediate potential for malignancy. It typically presents as multiple small nodules in both lungs (8). Due to its rarity, data on this disease remain limited. A study reported a male-to-female ratio of 1:1 among 16 patients with PEH (9). Conversely, another study indicated that the disease predominantly affects women, with an incidence rate of 2- to 4-fold higher in females compared to males (2). The age range for the diagnosis of PEH exhibits vast variability. A previous study reported an age range of 25 to 54 years (4), while another study identified an average onset age of ~47.75 years (9). Similarly, Xuan et al (2) reported an average age of onset of ~40 years. Herein, in reviewing 12 cases of PEH (2,5,10-16), the age of patients was found to range from 35 to 70 years, with a mean age of 53.9 years, including 7 males and 5 females. The disease was equally distributed, with unilateral and bilateral involvement observed in 6 cases each (50%) (Table I). The case presented herein was that of a male smoker in his thirties who presented with bilateral PEH.

The etiology of PEH remains uncertain. Although an association with estrogen receptors has been observed in some cases, its occurrence in both sexes challenges the hormonal hypothesis (4). No definitive risk factors or causes have been identified for this condition, and it often presents with nonspecific symptoms (10,12,13). Clinical manifestations vary significantly, with common symptoms including cough, shortness of breath and chest pain. In a previous study, 17 of 18 patients exhibited respiratory symptoms, such as cough and shortness of breath (17). Similarly, another study reported that 7 of 16 patients experienced symptoms such as cough, sputum, shortness of breath, hemoptysis and chest pain (9). Some cases may remain asymptomatic and are detected incidentally during imaging for unrelated indications (10,12,13). Pleural thickening and pleural effusion have been observed, particularly in cases involving pleural metastases (9). A previous case report described a patient presenting with a loculated pleural effusion, which was initially misdiagnosed as necrotizing pneumonia (18). Less commonly, hemoptysis and abdominal pain have been reported (5,15,17). In a previous study, abdominal pain was noted in a single case where respiratory symptoms were absent (17). In the present study, among the 12 reviewed cases, the most common presenting symptoms were coughing (33.3%), dyspnea (25%), chest pain or tightness (16.7%) and hemoptysis (16.7%). However, 33.3% of cases were incidentally diagnosed. The only symptom in the current case was chest pain, and he had a smoking history for 10 years.

Pulmonary epithelioid hemangioendothelioma generally has a favorable prognosis, with a median survival of 4.6 years and a 5-year survival rate of ~60%. However, PEH tends to have a worse prognosis compared to soft tissue or bone primaries, particularly when bilateral pulmonary involvement, pleural invasion, or concomitant liver disease is present. This contributes to a relatively higher mortality risk in PEH cases. By contrast, epithelioid hemangioendothelioma originating in soft tissue or skin often behaves more indolently and is associated with better outcomes after surgical resection (19).

Key factors influencing outcomes include anemia, pleural invasion, and lymph node and distant metastases (2). A multinodular pattern on CT scans is linked to improved survival, while pleural involvement with malignant effusion is associated with poorer outcomes (11). The literature review by Amin et al (20), reviewing >90 cases, identified the male sex, symptomatic presentation, and pleural effusion as independent predictors of reduced survival. The tumor can metastasize, involving pleural and mediastinal lymph nodes, as well as distant organs such as the liver, skin, bones, spleen, and central nervous system (2). In a study of 18 patients with PEH, extrapulmonary involvement was identified in 7 cases, notably affecting the liver and bones (21). A total of 4 cases (33.3%) reviewed in the present study were metastatic (2,5,15,16). The metastatic regions included bones, soft tissues, lymph nodes, spleen, chest wall, liver, pleura, mediastinum and brain. In the present case report, despite the positron emission tomography (PET) scan not yet being performed, an initial follow-up ultrasound revealed a suspicious right axillary lymph node. However, fine-needle aspiration was negative for malignancy.

On CT imaging, PEH typically manifests as numerous small nodules distributed across both lungs, generally measuring <2 cm in diameter. These nodules are frequently located near blood vessels, reflecting their vascular endothelial origin (21). In some cases, punctate calcifications may be present within the nodules, and associated pleural thickening can also be observed (8). PET/CT scans often reveal increased fluorodeoxyglucose uptake in PEH lesions, signifying heightened metabolic activity and potential metastasis. A positive association exists between lesion size and maximum standardized uptake values (21). Isolated lesions in PEH are uncommon; when present, they may exceed 5 cm in their largest dimension (2). The diagnosis of PEH depends on a histopathological examination supported by immunohistochemistry, as the disease lacks specific clinical or imaging features. Microscopically, tumor cells form irregular nests, strips, or sheets with eosinophilic, polygonal cytoplasm that may contain vacuoles. Primitive vascular lumens with erythrocytes are occasionally seen. Tumor cells often extend along alveolar septal blood vessels, with reactive hyperplasia in adjacent alveolar epithelium. Rarely, they invade alveolar or bronchial walls in an infiltrative pattern. Immunohistochemistry reveals the positivity of the tumor cells for vascular endothelial markers, such as CD31, CD34, Fli-1 and ERG, with CD31 being highly specific (2). Histological atypia (high nuclear grade, necrosis, high mitoses), larger tumor size and multi-organ involvement are pathological features associated with higher metastasis risk and poorer prognosis in epithelioid hemangioendothelioma, whereas routine immunostaining profiles and fusion status primarily aid diagnosis rather than prognosis (22).

Among the cases reviewed herein, immunohistochemistry data were available for 9 cases, all of which were positive for CD31. In the present case, immunohistochemical staining supported the PEH diagnosis with ERG positivity and TTF1 and AE1/AE3 negativity.

Due to its rarity, PEH lacks a standard treatment approach (2). In patients with localized PEH or disease confined to one lung or discrete lesions, complete surgical resection remains the mainstay of potentially curative therapy. It is associated with favorable local control and improved long-term outcomes when feasible, whereas the benefit of surgery in multifocal or systemic disease is less clear (2,23). For patients with multifocal pulmonary nodules, bilateral disease, pleural involvement, or distant metastases not amenable to surgery, the role of standard cytotoxic chemotherapy is limited, and no consensus regimen exists. Combination chemotherapy has yielded mixed results and generally limited efficacy in PEH (3). Given its vascular origin, therapies targeting angiogenesis are rational options in advanced disease. Agents that inhibit the vascular endothelial growth factor (VEGF) signaling pathway, such as tyrosine kinase inhibitors, like pazopanib, have demonstrated prolonged disease stabilization and symptomatic improvement, while other VEGF/VEGFR pathway inhibitors, including sorafenib, sunitinib, and bevacizumab, have shown variable responses (24,25). In selected patients with indolent or asymptomatic disease, a watchful waiting/active surveillance approach may also be considered, as some PEH cases exhibit slow progression (23).

Among the 12 cases reviewed herein, 6 patients succumbed to disease progression and related complications. Following 3 months of follow-up of the present case, the CT scan demonstrated stable disease with no evidence of progression. A notable limitation of the present report is the lack of long-term follow-up data to assess outcomes and consequences. Other limitations include unretrievable histopathology figure of initial CT-guided core needle biopsy and the lack of molecular testing for WWTR1-CAMTA1 fusion or immunohistochemistry for CAMTA1, CD31 and CD34 to support the diagnosis further.

In conclusion, PEH may present with non-specific symptoms and may often be diagnosed incidentally during checkups.