Cryoablation for airway stenosis caused by malignant pulmonary epithelioid hemangioendothelioma: a case report

Introduction

Background on epithelioid hemangioendothelioma (EHE)

EHE is a rare, low-grade malignant vascular tumor with an incidence rate of approximately 1 per 1 million people (1). This tumor can occur in various organs, with the liver, lungs, and bones being most commonly affected (2). The prognosis of patients with primary liver and lung disease is poor, and the mortality rate of pulmonary epithelioid hemangioendothelioma (P-EHE) is the highest (65%) (3,4).

Clinical challenges and prognosis

The biological behavior of EHE is unpredictable, contributing to challenges in clinical management and prognosis. P-EHE, in particular, has the worst prognosis among its variants, with no established treatment guidelines available (5). Furthermore, airway stenosis as a complication of P-EHE is exceedingly rare, adding another layer of complexity to its management.

Case significance

This report presents a case of airway stenosis secondary to P-EHE, which was managed with comprehensive airway interventional therapy based on cryoablation. The intervention led to improved tracheal stenosis and enhanced lung consolidation, achieving satisfactory local control and significantly ameliorating symptoms of airway obstruction. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-106/rc).

Case presentation

In January 2018, a 46-year-old female patient was admitted to The First Affiliated Hospital of Soochow University presenting with unexplained pain in the lower abdomen and proximal right lower limb. She had no significant medical history including hypertension, diabetes, or exposure to toxins or chemicals, nor any notable family medical history. An initial ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT) scan revealed a 33-mm lobulated mass in the right upper lobe of the lung, characterized by spiculated margins and dense shadows [maximum standardized uptake value (SUVmax): 4.8], right hilar lymph node enlargement (SUVmax: 3.9), and multiple nodules across both lungs (Figure 1A). Bone destruction in the right 7th rib, right iliac bone, and increased local radiation uptake in the right-thigh muscle group (SUVmax: 4.7). Imaging diagnosis was considered to be lung malignancy with metastasis. The patient had obvious bone pain, no fever, no obvious symptoms of cough and sputum, no abnormal inflammatory indicators and tumor indicators, and the pathology of tracheoscopy still failed to confirm the diagnosis of malignant tumor. Despite T-cell spot test (T-SPOT) (−), the patient could not exclude pulmonary tuberculosis and bone tuberculosis. After anti-infection therapy combined with isoniazid and rifampicin anti-tuberculosis treatment, the right upper lung mass and obstructive pneumonia were better than before (Figure 1B).

Figure 1 Imaging findings before diagnosis. (A) Before anti-infective treatment, lesions in right upper lung and hilum and multiple nodules in both lungs were observed. (B) After anti-infective treatment, the mass and obstructive inflammation in the right upper lung were slightly improved. (C) ¹⁸F-FDG-PET/CT showed a mass in the right upper lobe of the lung with increased FDG uptake. (D) ¹⁸F-FDG-PET/CT showed a soft tissue mass in the right elbow with increased FDG uptake. R, right; L, left; ¹⁸F-FDG-PET/CT, ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography.

In April 2019, the patient complained of right elbow pain, PET/CT showed a mass in the right upper lobe of the lung, and a soft tissue mass in the right elbow with FDG uptake increased (Figure 1C,1D). The patient underwent right elbow tissue biopsy and lung biopsy. Pathological examination of the right lung lesion indicated diffuse growth of cartilaginous tissue and fibrinous necrosis. Tumor cells tested positive for vimentin, CD10 (scattered positive), S100 (scattered positive), Ki-67 (3% positive), and CD34 (positive), while negative for desmin, smooth muscle actin (SMA), CD68, cytokeratin (CK), P63, calponin, AE1/AE3, CD31 (mixed), and erythroblast transformation specificity (ETS)-related gene (ERG) (Figure 2A,2B). These findings led to a diagnosis of malignant EHE in both the right lung and elbow, confirmed by the Department of Pathology at Shanghai Pulmonary Hospital.

Figure 2 Hematoxylin-eosin staining and immunohistochemical staining were used for pathological observation. (A) Hematoxylin-eosin staining showed diffuse growth of cartilage-like tissue and fibrinoid necrosis (magnification, ×400). (B) Immunohistochemical staining: vimentin (+), CK (−), Ki-67 (+ 3%), CD31 (−/+) and CD34 (+) (magnification, ×400). CK, cytokeratin.

Subsequently, the patient underwent treatment with liposomal doxorubicin combined with anlotinib at another facility, followed by local resection of the right elbow mass and radiotherapy at The First Affiliated Hospital of Soochow University, which alleviated her elbow pain. However, in May 2021, she developed cough, expectoration, and dyspnea without obvious triggers. Chest CT showed multiple compression and narrowing of the main trunk and branches of the right lower pulmonary artery, and the distal end was not clearly displayed (Figure 3A,3B). On May 12, 2021, lidocaine was anesthetized by a bronchoscope (Olympus, model: 1TQ290, Japan), which revealed a yellow-white fibrotic necrosis in the right endobronchus, with no bronchoscope passage (Figure3C). Cryoablation was performed three times (German ERBE, model 20416-032, Germany), each time for 2 minutes (Figure 3D), and the bronchial stenosis was significantly improved (Figure 3E,3F). Multiple cryotherapy for airway stenosis under lidocaine surface anesthesia was performed on 9 June 2021 and 29 June 2021. After the operation, the patient reported that chest tightness was significantly relieved, but occasionally hemoptysis was observed. On June 29, 2021, occlusion of the right main bronchus was observed under bronchoscopy, and the opening of the right main bronchus was more open than before after repeated cryotherapy. On July 8, 2021, PET/CT indicated that the right lower atelectasis was significantly better than before, but the stiff vascular texture of both lungs increased significantly (Figure 3G,3H), and the left axillary lymph and T12 vertebral body metastasized, and the patient’s condition was still progressing. On September 29, 2021, fiberbronchoscopy was performed again. The lumen at the opening of the right main bronchus was narrow, and the opening of the right lower lobe was enlarged. Although the patient’s clinical symptoms were relieved by bronchoscopic cryoablation, the patient finally discontinued treatment and died at home 2 months after discharge due to the repeated aggravation of the patient’s symptoms and the lack of effective treatment options.

Figure 3 Hematoxylin-eosin staining and immunohistochemical staining were used for pathological observation. (A,B) Chest CT before cryoablation showed that the main trunk and branches of the right lower pulmonary artery were multiple compressed and narrowed, and the distal end was not clearly displayed. (C) Before tracheoscopic treatment, yellow and white fibrin-like necrosis was observed in the right main bronchus, which could not be passed through by tracheoscopy. (D) Cryotherapy was performed 3 times for 2 minutes each. (E,F) After transbronchial cryoablation, the opening of the right main bronchus was enlarged. (G,H) After bronchial cryoablation, ¹⁸F-FDG-PET/CT showed that the right lower lung atelectasis improved significantly, but the stiffness of the blood vessels in both lungs increased significantly. ¹⁸F-FDG-PET/CT, ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography.

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 (as revised in 2013). Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

Discussion

Key findings

P-EHE is a rare tumor, with a broad age distribution. Its incidence is significantly higher in women than in men, approximately 1:4, although clinical symptoms are more prevalent and prognosis is worse in male patients (2,6). In China, the initial diagnostic accuracy for P-EHE is only about 25%, underscoring significant challenges in early detection and management (7). Our case report highlights a relatively rare instance of P-EHE in a middle-aged woman, who experienced symptomatic improvement following bronchoscopic cryoablation.

Strengths and limitations

Bronchoscopy has become a vital tool in both the diagnosis and treatment of lung diseases (8,9). Palliative bronchoscopic cryoablation can significantly reduce tumor burden, alleviate symptoms, and enhance patient quality of life (10). Compared to traditional surgery, cryoablation offers reduced trauma, fewer adverse reactions, and quicker recovery (11). The integration of ablation therapy with other treatments like immunotherapy and chemotherapy may further improve outcomes and reduce complications (8). Cryoablation is especially widely used in minimally invasive interventional treatment of lung tumors, but there are also risks of hemorrhage, pneumothorax, infection, cold shock and so on.

Comparison with similar researches

P-EHE often presents asymptomatically at diagnosis, with many patients discovered to have multiple lung nodules or only mild nonspecific symptoms such as chest pain, dyspnea, cough, hemoptysis, and weight loss (2,12). These tumors are predominantly characterized by the presence of either unilateral or bilateral multiple pulmonary nodules; solitary lesions are rare, while multiple nodules are more commonly observed and associated with longer survival (13). The nodules typically range in size from 1–2 cm, and unlike metastatic carcinoma—which they are frequently misdiagnosed as—their growth is generally slow, as shown by serial CT examinations (6). The definitive diagnosis of P-EHE relies heavily on pathological findings, with endothelial markers such as CD31, CD34, factor VIII, vimentin, and CK often expressed. Notably, CD34 shows a positivity rate of 100%, and factor VIII is positive in 97.5% of cases (14). Despite these markers, no specific tumor markers for P-EHE exist, complicating the diagnosis. The tumor is generally considered low to moderate in malignancy with an unpredictable clinical course, which may include spontaneous regression or rapid progression leading to death. The prognosis varies widely, with a local recurrence rate of approximately 10% and a metastasis rate of 20%. Life expectancy can range from 1 to 15 years, with a 5-year survival rate of around 60% (15). The unpredictable nature of P-EHE’s clinical course includes reports of spontaneous regression as well as rapid progression leading to death (12). Male, symptomatic patients, cough, hemoptysis, chest pain, multiple unilateral nodules, pleural effusion, metastasis, and lymph node metastasis are significant risk factors for PEH. Pleural effusion is significantly associated with poor survival, and most patients die of respiratory failure (6,15). Because of its rarity, EHE has no treatment standard and practically few treatment options, the general treatment principle is that surgical resection is preferred for patients with single or resectable nodules. Wide pneumonectomy does not improve long-term survival compared with wedge pneumonectomy (15). For patients who do not have surgical conditions, chemoradiotherapy can be tried, but the treatment effect is not exact and may increase unnecessary side effects. At present, it is not recommended to treat asymptomatic patients. Continuous imaging monitoring may be a reasonable choice for asymptomatic patients, and long-term follow-up is necessary.

Explanations of findings

As a minimally invasive technique, tumor ablation, particularly cryoablation, offers a safe and effective palliative treatment option for patients with advanced diseases. It is characterized by fewer complications and less damage to normal tissues compared to other procedures, underscoring its suitability for lung tumor treatments. The use of bronchoscopic cryoablation in treating lung tumors is notably rare but shows potential for significant patient benefit without impacting lung function.

Implications and actions needed

Bronchoscopic cryoablation represents a promising new treatment modality for P-EHE, providing effective local control and substantial symptom relief in cases where traditional surgery is not feasible. This approach not only offers a new avenue for treating inoperable patients but also significantly enhances their quality of life. Continued research and development in this area are essential to refine techniques and expand their applicability.

Conclusions

P-EHE is a rare clinical entity that often presents without initial pulmonary symptoms, leading to frequent misdiagnosis or delayed diagnosis. In this case, the absence of early symptoms resulted in a significant delay in accurate identification and management of the disease. After thorough discussion with the patient regarding treatment options, palliative airway interventional therapy was selected. Initially, the patient experienced apprehension about the treatment; however, the positive outcomes from the initial intervention led to an optimistic outlook and improved compliance with the treatment plan.

Our experience underscores that bronchoscopic cryoablation, as part of a comprehensive airway interventional therapy strategy, can significantly enhance pulmonary function and alleviate symptoms and pain in patients with P-EHE. This method has proven to be an effective alternative for managing conditions like tracheal stenosis, which are rarely associated with P-EHE yet can severely impact patient quality of life. Thus, bronchoscopic cryoablation not only addresses the immediate complications associated with airway obstruction but also offers a new therapeutic option for managing this complex and challenging disease.

Acknowledgments

Funding: This research has been funded by Suzhou Science and Technology Development Plan (No. SKY2023162) and Suzhou University Horizontal Project (Nos. P112208521 and P112201223).

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-106/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-106/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-106/coif). The authors report that this research has been supported by Suzhou Science and Technology Development Plan (No. SKY2023162) and Suzhou University Horizontal Project (Nos. P112208521 and P112201223). The authors have no other 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 (as revised in 2013). Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

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/.

References

1. Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer 1982;50:970-81. [Crossref] [PubMed]
2. Lau K, Massad M, Pollak C, et al. Clinical patterns and outcome in epithelioid hemangioendothelioma with or without pulmonary involvement: insights from an internet registry in the study of a rare cancer. Chest 2011;140:1312-8. [Crossref] [PubMed]
3. Somers N, Creytens D, Van Belle S, et al. Diagnosis of epithelioid hemangioendothelioma eight days postpartum: Is there a link with pregnancy? A case report and review of the literature. Acta Clin Belg 2022;77:157-62. [Crossref] [PubMed]
4. Weiss S. Epithelioid haemangioendothelioma. Pathology & Genetics Tumours of Soft Tissue & Bone 2002. Available online: https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/Pathology-And-Genetics-Of-Tumours-Of-S oft-Tissue-And-Bone-2002
5. Gómez-Arellano LI, Ferrari-Carballo T, Domínguez-Malagón HR. Multicentric epithelioid hemangioendothelioma of bone. Report of a case with radiologic-pathologic correlation. Ann Diagn Pathol 2012;16:43-7. [Crossref] [PubMed]
6. Amin RM, Hiroshima K, Kokubo T, et al. Risk factors and independent predictors of survival in patients with pulmonary epithelioid haemangioendothelioma. Review of the literature and a case report. Respirology 2006;11:818-25. [Crossref] [PubMed]
7. Makhlouf HR, Ishak KG, Goodman ZD. Epithelioid hemangioendothelioma of the liver: a clinicopathologic study of 137 cases. Cancer 1999;85:562-82. [Crossref] [PubMed]
8. Xu F, Song J, Xu B, et al. Clinical study of systemic chemotherapy combined with bronchoscopic interventional cryotherapy in the treatment of lung cancer. BMC Cancer 2020;20:1089. [Crossref] [PubMed]
9. Aboudara M, Rickman O, Maldonado F. Therapeutic Bronchoscopic Techniques Available to the Pulmonologist: Emerging Therapies in the Treatment of Peripheral Lung Lesions and Endobronchial Tumors. Clin Chest Med 2020;41:145-60. [Crossref] [PubMed]
10. Ye X, Fan W, Wang H, et al. Expert consensus workshop report: Guidelines for thermal ablation of primary and metastatic lung tumors (2018 edition). J Cancer Res Ther 2018;14:730-44. [Crossref] [PubMed]
11. Duan H, Zheng SY, Luo C, et al. Cryoablation for advanced non-small cell lung cancer: a protocol for a systematic review. BMJ Open 2020;10:e033460. [Crossref] [PubMed]
12. Kitaichi M, Nagai S, Nishimura K, et al. Pulmonary epithelioid haemangioendothelioma in 21 patients, including three with partial spontaneous regression. Eur Respir J 1998;12:89-96. [Crossref] [PubMed]
13. Mesquita RD, Sousa M, Trinidad C, et al. New Insights about Pulmonary Epithelioid Hemangioendothelioma: Review of the Literature and Two Case Reports. Case Rep Radiol 2017;2017:5972940. [Crossref] [PubMed]
14. Mentzel T, Beham A, Calonje E, et al. Epithelioid hemangioendothelioma of skin and soft tissues: clinicopathologic and immunohistochemical study of 30 cases. Am J Surg Pathol 1997;21:363-74. [Crossref] [PubMed]
15. Bagan P, Hassan M, Le Pimpec Barthes F, et al. Prognostic factors and surgical indications of pulmonary epithelioid hemangioendothelioma: a review of the literature. Ann Thorac Surg 2006;82:2010-3. [Crossref] [PubMed]