Pulmonary epithelioid hemangioendothelioma: a case report and review of literature

Introduction

Background

Epithelioid hemangioendothelioma (EHE) stands as a confounding conundrum in the domain of vascular neoplasms. Residing on the histopathological spectrum between benign hemangiomas and aggressive angiosarcomas, its nature is emblematic of the vast and intricate variations inherent within vascular tumors (1). Although the incidence of pulmonary epithelioid hemangioendothelioma (PEHE) is extremely low, with an estimated occurrence of approximately one in a million, its significance lies not only in its rarity but also in its complex diagnostic and therapeutic dilemmas (2,3).

The clinical presentation of PEHE can be insidious, often mimicking other common pulmonary conditions. Symptoms such as pleuritic chest pain, cough, shortness of breath, and weight loss may overlap with those of more prevalent diseases, complicating early diagnosis. Furthermore, its radiologic findings are heterogeneous, ranging from solitary masses to multifocal nodules, with some cases showing pleural thickening or infiltration.

Rationale and knowledge gap

The therapeutic approach to PEHE remains controversial, as no standard treatment protocol exists due to its rare and unpredictable nature. Management may range from observation for asymptomatic cases to aggressive multimodal interventions for advanced disease. Surgical resection is often considered the primary treatment for localized or resectable tumors, while systemic therapies, including chemotherapy and targeted agents, have been explored with varying degrees of success.

Objective

This case report highlights a rare presentation of PEHE in a 69-year-old female with significant pleural involvement. In addition, we provide a comprehensive review of the literature, summarizing demographic, clinical, radiologic, and histopathologic characteristics of PEHE, as well as current treatment strategies and outcomes.

By integrating this case with current knowledge, we seek to enhance understanding of PEHE’s spectrum and inform clinical practice. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-64/rc).

Case presentation

A 69-year-old Caucasian female presented to the neurosurgery clinic with complaints of chest pain, along with right-sided neck and shoulder pain. Her symptoms began about 2 years prior to presentation, after physical exertion and worsened following an incident in which she was kicked in the chest by a large boxer puppy. Additionally, the patient reported an 18–24-month history of a persistent cough, for which she had received multiple courses of antibiotics with intermittent improvement. Over the past 18 months, she also experienced a significant weight loss of 15–20 pounds. Her past medical history included type 2 diabetes, hypertension, gastroesophageal reflux disease (GERD), and hyperlipidemia. The patient is a non-smoker with occasional alcohol consumption.

On physical examination, mild weakness in the right upper extremity and reduced range of motion in the right shoulder due to chest wall discomfort were noted. The rest of the examination was unremarkable.

Radiological evaluation began with a chest X-ray, which revealed a significant right pleural effusion with associated infiltrates and atelectasis (Figure 1A). A cervical spine X-ray performed on the same day showed evidence of cervical spondylosis with uncovertebral joint facet joint osteoarthritis, most pronounced at C4–C5, which likely contributed to her neck and shoulder pain.

Figure 1 Radiologic findings. (A) Chest X-ray revealed a significant right pleural effusion (black circle). (B) CT revealed a right superior mediastinal mass obstructing the right brachiocephalic vein (red arrow). (C) Cross-sectional PET/CT showing increased uptake in the enlarged right superior mediastinal and hilar lymph nodes (red arrow). (D) Full PET/CT showed marked metabolic activity in mediastinum (red arrow). CT, computed tomography; PET, positron emission tomography.

The patient underwent a thoracentesis which yielded 650 mL of transudate fluid. Cytopathology results from the thoracentesis were non-contributory, with no evidence of malignancy. A contrast-enhanced computed tomography (CT) scan of the chest, abdomen, and pelvis (Figure 1B) demonstrated a right superior mediastinal mass, obstructing the right brachiocephalic vein and significantly narrowing the superior vena cava. Additionally, the right middle and lower lobes were collapsed, and mild mediastinal and right diaphragmatic lymphadenopathy were noted. These findings raised concern for a malignant process.

Subsequent evaluation with a positron emission tomography (PET)/CT scan (Figure 1C,1D) revealed marked metabolic activity in the enlarged right superior mediastinal and hilar lymph nodes, further suggesting malignancy.

A right thoracoscopy, total parietal pleurectomy, and wedge resection of the right middle and lower lobes with biopsy were performed. This was deemed necessary given the extensive pleural involvement, the patient’s worsening symptoms, and the need to achieve both diagnostic clarification and therapeutic debulking. Pleurectomy was selected over limited biopsy due to concerns that inadequate tissue sampling might delay diagnosis and treatment planning. Histological examination of the resected tissue revealed nodules characterized by a central hyalinized stroma interspersed with plump eosinophilic epithelioid cells, exhibiting bland nuclei and cytoplasmic vacuoles (Figure 2A,2B). There was no evidence of necrosis or increased mitotic activity. Immunohistochemical (IHC) analysis demonstrated strong and diffuse positivity for CD31 (Figure 2C), while staining for CD34 (Figure 2D), calretinin, WT1, CK7, CK20, TTF-1, CK5/6, synaptophysin, and CDX2 was negative. These findings were consistent with the diagnosis of PEHE.

Figure 2 Histopathologic findings. (A) H&E staining ×4 showing centralized hyalinized stroma (black circle). (B) H&E ×20 revealed a central hyalinized stroma intermixed with plump eosinophilic epithelioid cells exhibiting bland nuclei and cytoplasmic vacuoles (red arrows). (C) Diffusely positive CD31 immunostaining (red arrows). (D) Negative CD34 immunostaining (red arrows). H&E, hematoxylin and eosin.

To manage the vascular compression and alleviate her pain, the patient underwent stent placement in the superior vena cava and brachiocephalic veins. Conservative measures were initially considered; however, given the significant symptom burden, and imaging evidence of near-complete vascular obstruction, prompt intervention was deemed necessary. A multidisciplinary team, including hematology and interventional radiology, evaluated the need for anticoagulation, and the patient was started on apixaban post-stenting with close monitoring. No bleeding complications occurred during follow-up. She was then referred to a comprehensive cancer treatment center and started on Trametinib, a MEK inhibitor, in accordance with the SARC033 trial protocols. A follow-up CT scan conducted 4 months later showed no evidence of disease progression.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

A comprehensive Medline search focused on case report on PEHE yielded 58 patient reports from 1995 to 2023. Excluding cases of lung metastasis from extrapulmonary primaries, Table 1 summarizes the demographic, clinical, radiologic, and histologic characteristics.

Patients aged from 14 to 76, with a median age of 50 years. Females represented the majority, comprising 55% of cases. Most patients were asymptomatic at diagnosis, with incidental detection of pulmonary nodules via chest X-ray or CT scan. Symptomatic presentations typically indicate advanced disease or concurrent systemic conditions. Smoking history was infrequently reported; however, among recorded cases, most were non-smokers. Chest CT findings varied from multiple tiny nodules to solitary masses, with approximately 80% of nodules exhibiting increased uptake on PET scans. Immunohistochemistry, notably positive for CD31, played a pivotal role in diagnosis confirmation. Treatment modalities varied widely among cases, with variable responses and survival outcomes. Table S1 provides a comprehensive list of all the studies reviewed with study characteristics.

EHE is a rare vascular neoplasm belonging to the uncommon sarcoma subtypes with an incidence of approximately one per one million (2,3). While it can manifest in both children and adults, diagnosis usually occurs between the ages of 20 and 60 years, with a median age of 36 years old at diagnosis (3). Even though it’s more common in women, no known risk factors exist for EHE (3).

EHE’s behavior varies dramatically. Its spectrum extends from benign, indolent tumors reminiscent of hemangiomas to aggressive forms akin to angiosarcomas (1). The latter warrants an emphasis on the importance of early diagnosis and intervention. A significant proportion are diagnosed incidentally by radiographic imaging. For symptomatic EHE, pain emerges as the foremost symptom. The tumor’s location largely dictates additional symptoms, with bones, liver, and lung as common organs involved (4).

PEHE often presents with pleuritic chest pain, cough, shortness of breath, hemoptysis, and weight loss (3), consistent with the summary of the common symptoms in Table 1.

PEHE often manifests as three distinct imaging patterns on chest CT: (I) multiple pulmonary nodules with a perivascular distribution; (II) multiple pulmonary reticulonodular opacities; or (III) diffuse infiltrative pleural thickening (5). The major characteristic radiographic feature of PEHE is the presence of perivascular nodules which are usually found near medium-sized vessels and bronchi (5,6), which was as in our case.

Histopathological examination remains the cornerstone of EHE diagnosis. EHE is characterized by an abnormal population of epithelioid endothelial cells within a myxohyaline stroma (7). This tumor is molecularly defined by specific gene fusions: WWTR1::CAMTA1, which is present in approximately 90% of cases, and YAP1::TFE3, found in about 10% of cases (8,9). These gene fusions are considered pathognomonic for EHE, distinguishing it from other vascular tumors such as angiosarcoma and epithelioid hemangioma. IHC or molecular testing for these gene fusions is highly recommended for diagnosis. However, currently, these translocations are not targets for any known effective drug treatment, nor do they offer prognostic or predictive value for patient management.

The management of EHE, particularly in its advanced stages, remains a challenging endeavor. Surgical resection is the primary treatment for localized and resectable advanced/metastatic PEHE (10,11). The risk of local recurrence following complete surgical resection is in the range of 10% to 15% (1). The main types of general surgical resection include extended resection and wedge resection (12). Radiation therapy (RT) is often used either preoperatively or postoperatively, depending on various factors such as tumor size and surgical margins. Previous studies showed that combining surgery and RT improved 10-year local control rates compared to surgery alone (13,14). For unresectable disease, observation is suggested if the disease burden is limited, and the patient is asymptomatic (13). In cases with significant disease burden or rapid progression, antiangiogenic therapy (e.g., sunitinib or pazopanib) is preferred over anthracycline-based chemotherapy (15,16). Several cases have been reported regarding these antiangiogenetic agents, and some have observed marked responses to the treatment (16,17). Other targeted agents such as trametinib (18), bevacizumab (19), and sorafenib (20) have demonstrated modest clinical efficacy in phase II trials.

In our case, the diagnosis of PEHE was an unexpected finding with the presentation of pleuritic pain and imaging which led to a definitive diagnosis with transthoracic biopsy. Since this patient has symptoms and was found to have advanced EHE, she went through total parietal pleurectomy, and wedge resection of the right middle and lower lobes. As no standard systemic agents have a good effect on progressive EHE, patients should be always considered for clinical study when available. Our patient was followed by trametinib treatment and monitoring regularly. Overall, the treatment approach for EHE requires careful consideration of disease stage and patient-specific factors, with a preference for surgery and radiation in localized cases, and targeted therapies for advanced stages.

Conclusions

This case accentuates the clinical ambiguity of EHE and the importance of a multidisciplinary approach to diagnosis and management. In the context of advanced disease, as exemplified by our patient, surgical intervention followed by targeted therapy may offer a viable management pathway. Continued research into the molecular underpinnings of EHE could pave the way for novel therapeutic targets.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-64/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-64/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-64/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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