Endobronchial Epstein-Barr Virus-Associated Smooth Muscle Tumor in Advanced HIV Infection: A Rare Case

Introduction

Epstein-Barr virus-associated smooth muscle tumor (EBV-SMT) is a rare neoplasm first described in the 1970s and is now recognized as a distinct oncological entity occurring predominantly in immunocompromised individuals [1]. Although Epstein-Barr virus (EBV) infection is highly prevalent, present in 50% to 89% of children and more than 90% of adults, it typically remains clinically silent unless immune surveillance is impaired [2,3]. EBV is also implicated in the pathogenesis of several malignancies, including nasopharyngeal carcinoma and lymphomas [4].

EBV-SMT can be categorized into 3 groups: post-transplant–associated (PT-SMT), HIV-associated (HIV-SMT), and congenital immunodeficiency-associated tumors (CI-SMT) [5]. Unlike conventional leiomyosarcoma, the biological behavior of EBV-SMT is not closely correlated with histological grade but is influenced by tumor burden and the degree of immunosuppression [1,6]. These tumors frequently occur at multiple anatomical sites and generally have a low rate of distant metastasis [1]. Despite its rarity, EBV-SMT has been reported in approximately 1% to 5% of immunocompromised patients, although its true incidence remains uncertain [1].

Clinically, EBV-SMT can mimic other neoplastic or infectious conditions, leading to diagnostic challenges [1]. Endobronchial involvement is particularly uncommon and is easily mistaken for primary lung malignancies or other spindle cell tumors. In patients with advanced HIV infection, the disease often occurs in the setting of profound immunosuppression and can coexist with multiple opportunistic infections, further complicating clinical evaluation and management.

Currently, there is no established curative treatment for EBV-SMT [7]. Management strategies are largely individualized and include antiretroviral therapy in HIV-positive patients, along with surgical or bronchoscopic intervention in cases of symptomatic or obstructive lesions [1,8]. The role of chemotherapy and radiotherapy remains unclear due to limited evidence [1].

Herein, we report a rare case of EBV-SMT presenting as an endobronchial mass in a patient with advanced HIV infection, highlighting the diagnostic complexity, the impact of severe immunosuppression with concurrent infections, and the therapeutic challenges associated with this condition.

Case Report

A 48-year-old woman presented at Maharaj Nakorn Chiang Mai Hospital with progressive dyspnea on exertion for 2 years. Ten days prior to admission, she developed fever and dry cough, followed by worsening dyspnea for 3 days. Upon arrival at the hospital, she rapidly developed acute respiratory failure requiring endotracheal intubation within a few hours. Arterial blood gas analysis demonstrated severe hypoxemia with a PaO2/FiO2 ratio of less than 100. She was subsequently deeply sedated and received neuromuscular blockade for ventilatory support. An anti-HIV test was performed prior to intubation and returned reactive, with a CD4 count of 1% (2 cells/μL), indicating advanced immunosuppression. The patient had no prior history of HIV diagnosis and was newly diagnosed during this admission.

Initial chest radiography showed complete opacification of the left lung and ground-glass infiltration of the right lung. Computed tomography (CT) of the chest revealed a 1.6×2.3×1.8 cm endobronchial mass in the left main bronchus causing total atelectasis of the left lung, along with diffuse ground-glass opacities in the right lung, an enlarged right lower paratracheal lymph node, and multiple bilateral adrenal and hepatic lesions. Bronchoscopy demonstrated a whitish mass completely obstructing the mid-left main bronchus (Figure 1).

Given the patient’s clinical presentation and imaging findings, the initial differential diagnoses included primary lung carcinoma, lymphoma, and other spindle cell neoplasms, as well as infectious etiologies. Multiplex PCR from nasal swab and bronchoalveolar lavage (BAL) identified respiratory syncytial virus (RSV) and Pneumocystis jirovecii, while BAL also demonstrated a high cytomegalovirus (CMV) viral load (32,036 copies/mL; 4.51 log). Other infectious workups, including viral hepatitis, fungal infections, and mycobacterial studies, were negative. The patient was managed with broad-spectrum antimicrobial therapy, including piperacillin/tazobactam, trimethoprim/sulfamethoxazole, ganciclovir, ribavirin, and dexamethasone, resulting in partial clinical improvement.

After stabilization, a multidisciplinary team involving pulmonology, infectious disease, and pathology was consulted. One week after admission, flexible bronchoscopy with cryorecanalization was performed by an interventional pulmonologist to relieve airway obstruction. The tumor was completely removed endoscopically. The patient’s oxygenation improved significantly, and she was successfully extubated the following day.

Histopathological examination (Figure 2) revealed a submucosal epithelioid-to-spindle cell lesion with low mitotic activity (3 mitoses per 10 high-power fields) and no necrosis or significant pleomorphism. Immunohistochemical studies showed positivity for vimentin and negativity for cytokeratin (CK), S100, and CD45, helping exclude carcinoma, melanoma, and lymphoma. Further staining demonstrated positivity for smooth muscle markers (actin, desmin, caldesmon, and HHF35). Epstein-Barr virus-encoded RNA in situ hybridization (EBER-ISH) was positive, confirming the diagnosis of EBV-associated smooth muscle tumor (Figure 3).

During the 3-week hospitalization, the patient developed multiple infectious complications, including Enterococcus faecalis septicemia and candidemia, which were successfully treated with appropriate antimicrobial therapy. She was subsequently discharged in a clinically improved condition, and antiretroviral therapy was initiated after stabilization of infections.

However, during follow-up several weeks after discharge, the patient experienced clinical deterioration, likely related to her underlying disease burden and persistent immunosuppression. Due to her poor performance status, she was not considered a candidate for systemic oncologic therapy. The patient was transitioned to palliative care for symptom control. At the time of the last follow-up, the patient was alive and receiving palliative care.

Discussion

Epstein-Barr virus-associated smooth muscle tumor (EBV-SMT) is a distinct clinicopathologic entity that arises almost exclusively in immunocompromised individuals, including patients with human immunodeficiency virus (HIV) infection, post-transplant immunosuppression, and congenital immunodeficiency syndromes [1,5]. Unlike conventional leiomyosarcoma, the biological behavior of EBV-SMT does not correlate well with histologic grade but is instead influenced primarily by immune status and overall tumor burden [1,9].

In the present case, the patient’s profoundly impaired immune function, reflected by a CD4 count of only 2 cells/μL, highlights the critical role of immune surveillance in the pathogenesis of EBV-SMT. Previous studies have demonstrated an association between low CD4 counts and the development of EBV-SMT in HIV-infected patients, supporting the concept that EBV-driven smooth muscle proliferation occurs in the setting of severe immunodeficiency [8,9]. The presence of lesions in multiple organs, including the bronchus, adrenal glands, and liver, is consistent with prior observations that EBV-SMTs often arise synchronously at multiple sites rather than representing true metastatic disease [1,6].

Endobronchial involvement by EBV-SMT is particularly rare and has been reported only in a limited number of cases [10,11]. Similar to previously reported cases, our patient presented with airway obstruction and radiologic findings that could mimic primary lung carcinoma or lymphoma. However, compared with earlier reports, our case is notable for the coexistence of multiple opportunistic infections and extremely advanced immunosuppression, which significantly complicated both diagnosis and management. This highlights the importance of maintaining a high index of suspicion for EBV-SMT in immunocompromised patients presenting with endobronchial masses.

From a diagnostic perspective, EBV-SMT poses significant challenges due to its nonspecific clinical and radiologic features. Histologically, these tumors are characterized by spindle-shaped cells with smooth muscle differentiation and relatively bland cytology. However, morphology alone is insufficient for definitive diagnosis. Immunohistochemical positivity for smooth muscle markers such as actin, desmin, caldesmon, and HHF35, together with detection of Epstein-Barr virus within tumor cells using EBER-ISH, is essential for distinguishing EBV-SMT from other spindle cell tumors, including leiomyosarcoma and inflammatory myofibroblastic tumor [9,12]. In addition to EBER-ISH, which remains the gold standard for confirming EBV involvement, several emerging biomarkers have been explored. These include identification of EBV DNA in the tissue via PCR [10].

One of the major diagnostic challenges in this case was the overlap between neoplastic and infectious processes in a profoundly immunocompromised host. In contrast to previously reported cases of endobronchial EBV-SMT, which often present as isolated airway lesions, our patient exhibited concurrent multiple opportunistic infections, including Pneumocystis jirovecii, CMV, and RSV, which obscured the clinical picture and delayed definitive diagnosis. Furthermore, radiologic findings mimicked more common entities such as primary lung carcinoma or lymphoma, emphasizing the importance of tissue diagnosis and EBV-specific testing. Compared to prior reports, the combination of extreme immunosuppression (CD4 count of 2 cells/μL) and multifocal disease in this case represents a more aggressive clinical scenario.

The clinical behavior and management of EBV-SMT vary according to the underlying cause of immunosuppression [1,5,9]. In PT-SMT, reduction of immunosuppressive therapy can result in tumor stabilization or regression [5]. In contrast, in HIV-associated EBV-SMT, immune reconstitution through antiretroviral therapy (ART) is the cornerstone of management [1,8]. However, in patients with profound immunodeficiency, as in our case, immune recovery may be delayed or inadequate, thereby limiting therapeutic options [8,9]. Furthermore, patients with PT-SMT are generally more suitable candidates for surgical resection or systemic therapy, whereas HIV-associated cases are often complicated by opportunistic infections and poor performance status, which further restrict treatment feasibility [1,5]. In the present case, bronchoscopic resection was selected as the initial intervention due to life-threatening airway obstruction, providing immediate symptomatic relief and enabling definitive histopathological diagnosis. This approach is consistent with previous reports that emphasize the role of local tumor control in symptomatic lesions [1,11,13]. Although ART was initiated to promote immune reconstitution, the patient’s severe immunosuppression and multiple concurrent infections precluded further oncologic treatment, including chemotherapy [7,8].

Prognosis in EBV-SMT is variable and is largely determined by the degree of immunosuppression and tumor burden rather than histologic features alone [1,9]. Patients with better immune reconstitution may achieve disease stabilization, whereas those with profound immunodeficiency, as in our case, often experience rapid clinical deterioration. The coexistence of opportunistic infections further worsens outcomes and complicates management decisions.

A range of therapeutic approaches has been utilized in patients with EBV-SMT, including surgical procedure, chemotherapy, allogeneic hematopoietic stem cell transplantation, and antiviral therapies [14]. Emerging therapeutic strategies for EBV-SMT are increasingly focused on immune-based approaches [14,15]. EBV-specific adoptive T-cell therapy has shown promising results in other EBV-driven malignancies, particularly in post-transplant settings, and may offer potential benefit in selected cases of EBV-SMT [15]. In addition, engineered T-cell therapies aimed at enhancing host immune response are under investigation [15]. However, their application in HIV-associated EBV-SMT remains limited due to concerns regarding immune-related toxicity and the complexity of managing coexisting infections [1,14]. Further studies are needed to determine the safety and efficacy of these approaches in severely immunocompromised patients [14,15]. Overall, this case highlights the rare presentation of EBV-SMT as an endobronchial lesion in a patient with advanced HIV infection, underscoring the diagnostic complexity, the profound impact of severe immunosuppression, and the limitations of current treatment strategies. Compared with previously reported endobronchial EBV-SMT cases, our case is distinguished by the degree of immunosuppression, multifocal organ involvement, and the coexistence of multiple opportunistic infections, all of which contributed to a more complicated clinical course and restricted therapeutic options. These challenges emphasize the importance of early recognition and a multidisciplinary approach to optimize patient outcomes in this condition.

Conclusions

This case reinforces the importance of considering EBV-SMTs in differential diagnoses of endobronchial lesions in immunocompromised patients. The diagnosis relies on a combination of histopathology and viral detection, and management necessitates a multidisciplinary approach tailored to tumor location, patient immune status, and overall health. Early recognition and integrated care strategies are vital to improving outcomes in this challenging patient population.

Further research is needed to better define optimal management strategies for EBV-SMT, particularly in patients with advanced immunosuppression. Future studies should focus on the role of immune reconstitution, the development of standardized treatment guidelines, and the evaluation of novel therapeutic approaches, including immune-based therapies such as EBV-specific adoptive T-cell therapy. Additionally, accumulating and analyzing more case data, especially from patients with rare presentations such as endobronchial involvement, may improve understanding of disease behavior and guide clinical decision-making.