Introduction: Fibrosing mediastinitis is a benign but fatal disorder characterized by the proliferation of fibrous tissue in the mediastinum, causing encasement of mediastinal organs and extrinsic compression of adjacent bronchovascular structures. FM-associated pulmonary hypertension (FM-PH) is a serious complication of FM, resulting from the external compression of lung vessels. Pathologic assessment is important for etiologic diagnosis and effective treatment of this disease. Case Presentation: A 59-year-old male patient presented at our hospital and was diagnosed with FM-PH. He declined surgical biopsy that is the reference standard for pathologic assessment, in consideration of the potential risks. Therefore, an endobronchial ultrasound examination was performed, which identified the subcarinal lesion. Under ultrasound guidance, four needle aspirations were carried out, followed by one cryobiopsy. Histopathological examination of transbronchial needle aspiration specimens was inconclusive, while samples from cryobiopsy suggested a diagnosis of idiopathic FM. Further immunophenotyping demonstrated the infiltration of lymphocytes, macrophages, and FOXP3-positive cells in FM-PH. Conclusion: Mediastinal cryobiopsy might be a novel and safe option for FM-PH patients who are unwilling or unsuitable for surgical procedure.

Established Facts

  • Fibrosing mediastinitis-associated pulmonary hypertension (FM-PH), an uncommon and severe disorder, is associated with a poor prognosis owing to a lack of accurate diagnosis and effective therapy.

  • While surgical biopsy is the procedure of choice for pathologic diagnosis of FM-PH, its utilization is restricted due to the related complications.

Novel Insights

  • New information: Endoscopic transbronchial mediastinal cryobiopsy might be a safe and efficient diagnostic approach for FM-PH patients unwilling or unsuitable for surgical procedure.

Pulmonary hypertension is an advancing and life-threatening pulmonary vascular abnormality that, if not appropriately managed, could lead to severe hemodynamic complications and heightened mortality [1]. Fibrosing mediastinitis (FM) is an uncommon and non-malignant condition characterized by fibroproliferation in the mediastinal region, which could lead to pulmonary hypertension through the compression of nearby pulmonary vessels [2]. The prognosis of FM-associated pulmonary hypertension (FM-PH) is discouraging due to the dearth of accurate diagnosis and effective therapy [3].

Surgical biopsy is regarded as the standard for pathologic diagnosis of FM-PH; however, its clinical use is largely restricted because of the high risk of procedural complications [4]. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is currently the most widely adopted method for mediastinal sampling, but the relatively small tissues obtained by needle aspiration might limit its diagnostic ability for benign disorders and rare tumors [5‒7]. Notably, EBUS-guided transbronchial mediastinal cryobiopsy, a newly introduced mediastinal sampling technique, has shown superior diagnostic accuracy in comparison to traditional needle biopsy [8, 9]. Here we present the first case where FM-PH was successfully diagnosed solely through transbronchial mediastinal cryobiopsy.

A 59-year-old male with a 10-pack-year smoking history presented to our clinic for cough and shortness of breath. He had no additional complaints and was not taking any medications. Laboratory tests showed CA125 37.9 U/mL, C-reactive protein 163 mg/L, erythrocyte sedimentation rate 56 mm/h, and D-dimer 0.67 mg/L, with no other abnormal findings. CT pulmonary angiogram demonstrated the dilatation of the pulmonary trunk, the narrowing of pulmonary artery branches in the bilateral hilar region, mediastinal and hilar lymphadenopathy, pericardial effusion, and left pleural effusion (Fig. 1a). The echocardiogram revealed enlarged right ventricle, compressed left heart, and markedly increased systolic right ventricle pressure, suggesting severe pulmonary hypertension (Fig. 1b). The right heart catheterization showed elevated mean pulmonary artery pressures, reaching 62 mm Hg, with a pulmonary capillary wedge pressure of 14 mm Hg. These observations lead to an initial diagnosis of pulmonary hypertension resulting from compressive arterial stenosis.

Fig. 1.

a CT pulmonary angiogram shows the hilar and mediastinal lymphadenopathy and the narrowing of the pulmonary artery, suggesting mediastinal lesion-induced vascular compression (red arrow). b Echocardiograph shows the enlarged right ventricle, compressed left heart, and elevated right ventricle systolic pressure, suggesting pulmonary hypertension. c Endobronchial doppler image shows the blood flow of the mediastinal mass. d EBUS-TBNA (red arrow) biopsy of the mediastinal mass. e EBUS-guided transbronchial incision was made with the high-frequency needle knife to create a working channel for the cryoprobe (red arrow). f Transbronchial mediastinal cryobiopsy was done by inserting the cryoprobe (red arrow) into the lesion under EBUS monitor. g Samples (red arrow) were obtained by transbronchial mediastinal cryobiopsy.

Fig. 1.

a CT pulmonary angiogram shows the hilar and mediastinal lymphadenopathy and the narrowing of the pulmonary artery, suggesting mediastinal lesion-induced vascular compression (red arrow). b Echocardiograph shows the enlarged right ventricle, compressed left heart, and elevated right ventricle systolic pressure, suggesting pulmonary hypertension. c Endobronchial doppler image shows the blood flow of the mediastinal mass. d EBUS-TBNA (red arrow) biopsy of the mediastinal mass. e EBUS-guided transbronchial incision was made with the high-frequency needle knife to create a working channel for the cryoprobe (red arrow). f Transbronchial mediastinal cryobiopsy was done by inserting the cryoprobe (red arrow) into the lesion under EBUS monitor. g Samples (red arrow) were obtained by transbronchial mediastinal cryobiopsy.

Close modal

To identify the disease etiology, a regular bronchoscopy was scheduled, showing minor distortion of the main bronchi with no further notable findings. The patient declined surgical procedures due to concerns about potential complications. Hence, an EBUS examination was conducted with conscious sedation through intravenous administration of midazolam, effectively identifying the subcarinal lesion (Station 7) (Fig. 1c). Using a 21-gauge needle (Olympus NA-201SX-4021), four needle aspirations were carried out, and mediastinal specimens were further collected for glass slide-based cytology and cell block analyses. Following that, an incision was made on the airway wall next to the lesion using a high-frequency needle knife (Olympus KD-31C-1) that was monitored with the EBUS scope (Fig. 1d). Thereafter, the 1.1-mm flexible cryoprobe (Erbe 20402-401) was inserted into the lesion under ultrasound guidance via the cut on the airway (Fig. 1e). One-time cryobiopsy was performed, wherein the cryoprobe was cooled to −60°C for 7 s with liquid carbon dioxide. The probe, with the harvested tissue affixed to its tip, was extracted from the site together with the EBUS scope (Fig. 1f). The specimen was obtained by thawing it in saline solution and then fixed in formalin. No preoperative antibiotics were used, and the procedure was well-tolerated. Minor to moderate bleeding occurred during TBNA that subsided without the requirement for additional therapeutic interventions, and there was no significant bleeding during cryobiopsy. The patient did not report any severe discomforts or complications immediately after the procedure and throughout the 1-month follow-up period.

Histopathological examination of TBNA samples showed small clusters of lymphocytes presented in the red blood cell mass, with no atypical cells observed (Fig. 2a). The specimens harvested by cryobiopsy revealed a substantial number of lymphocytes along with hyperplastic fibrous tissues, scattered carbon deposition, and the absence of granuloma, suggesting a diagnosis of idiopathic FM (Fig. 2b). Immunohistochemistry staining demonstrated SMA(+), Desmin(−), IgG4(−), BCL2(perifollicular T cells +), Ki-67(<5% +), CD3(+), CD4(+), CD8(scattered few +), CD20(+), CD21(follicular dendritic cells +), CD68(+), CD163(+), and FOXP3(+) (Fig. 2c). Immunophenotyping identified the infiltration of macrophages, T lymphocytes, and FOXP3-positive cells in FM-PH, in addition to the known CD20-positive B lymphocytes [10]. This patient was referred to the Department of Cardiology for interventional therapy.

Fig. 2.

a H&E staining of the sample from EBUS-TBNA. b H&E staining of the sample from mediastinal cryobiopsy. c Immunohistochemistry staining of the sample from mediastinal cryobiopsy (CD20: B cell marker, CD163: macrophage marker, FOXP3, regulatory t cell marker). Scale bars = 30 μm. EBUS-TBNA, endobronchial ultrasound-guided transbronchial needle aspiration.

Fig. 2.

a H&E staining of the sample from EBUS-TBNA. b H&E staining of the sample from mediastinal cryobiopsy. c Immunohistochemistry staining of the sample from mediastinal cryobiopsy (CD20: B cell marker, CD163: macrophage marker, FOXP3, regulatory t cell marker). Scale bars = 30 μm. EBUS-TBNA, endobronchial ultrasound-guided transbronchial needle aspiration.

Close modal

FM arises due to a dense invasive fibrotic infiltration of the mediastinum, resulting in the encasement of mediastinal organs and compression of bronchovascular structures. Pulmonary hypertension, along with resultant right heart failure, is the dominant cause of FM-related mortality. One of the primary contributors to the unfavorable prognosis of FM-PH is the challenge in achieving a timely and accurate histologic diagnosis. Given the multifactorial pathogenesis of FM-PH, including irradiation, infection, and systemic fibroinflammatory disorders, the elucidation of the disease etiology possesses important guiding significance to personalized therapy [11].

Clinical diagnosis of FM-PH normally requires CT scan and right heart catheterization, while a biopsy is essential to establish a pathological diagnosis and rule out secondary causes. Currently, the recommended approach is a surgical procedure, which is preferred to needle aspiration biopsy due to the necessity of extensive sampling that is essential for confidential exclusion of fibrosis-producing neoplasms, such as lymphoma [12]. The inferiority of needle-based techniques in FM-PH might lie in the limited amount of retrieved tissues that are frequently suitable for cytopathological examination only, leading to lower diagnostic effectiveness for non-lung cancer mediastinal disorders [13]. Accordingly, the largest meta-analysis on the diagnostic efficacy of EBUS-TBNA for lymphoma reveals a pooled sensitivity of 66.2% [14]. On the other hand, it should be noted that thoracic surgery and general anesthesia might carry substantial risks for FM-PH patients with compromised health status or impaired cardiorespiratory function [15].

Transbronchial mediastinal cryobiopsy, capable of offering the largest quantity of intact mediastinal tissues among the minimally invasive biopsy approaches, allows for deeper histopathologic insight and facilitates further molecular and immunological assessments [16]. Consequently, this approach exhibits superior overall diagnostic efficiency in contrast to needle aspiration, particularly for patients with rare tumors and benign diseases [8]. Although only a single cryobiopsy is done, our previous report has proven its ability to yield larger mediastinal tissues, even compared to three consecutive forceps biopsies [8]. In accordance, a conclusive pathologic diagnosis is established solely by mediastinal cryobiopsy but not EBUS-TBNA in our case. Given that idiopathic mediastinal fibrosis is recognized as an immune-mediated disorder, we further explore its immunological properties [17]. Immunohistochemistry examination reveals the accumulation of macrophages, T lymphocytes, and FOXP3-positive cells in FM-PH, apart from B lymphocytes that have been priorly identified, suggesting the involvement of multiple immunocytes in the pathogenesis of this disease [10].

Conscious sedation is chosen based on our experience with its good tolerability and safety in nearly 500 mediastinal cryobiopsy cases, which avoids potential complications associated with general anesthesia [8, 9]. Concerns have arisen regarding bleeding risks due to high intravascular pressure and rich collateral system in FM-PH. However, this patient had no noticeable hemorrhage during cryobiopsy, which is possibly the result of the coagulative effect of electrocautery during airway incision and the avoidance of regions with abundant blood vessels by Doppler ultrasound. Our finding is supported by recent research implicating a favorable safety profile of the EBUS procedure in nodes with rich blood supply due to superior vena cava syndrome, which similarly causes elevated vessel pressure [18]. Nevertheless, despite the absence of severe complications and possible advantages over surgical procedures, additional data from a larger set are needed to further validate the safety and indication of this technique in FM-PH. In conclusion, transbronchial mediastinal cryobiopsy might be a novel diagnostic choice for FM-PH.

We thank the allied health professions, including nurses and radiographers, for their valuable work.

This case was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The data collection was approved by the Ethics Committees of the Third Military Medical University (2019-062-01), and written informed consent was obtained from the patient for publication of this case report and any accompanying images.

The authors have no conflicts of interest to declare.

This work was supported by Grants from the National Natural Science Foundation of China (82122003, 82370061).

Ya-Ting You, Hao Zuo, Jing-Meng Li, Xian-Bo Zhu, and Jing Zhang contributed equally to this work. Ya-Ting You, Hao Zuo, Jing-Meng Li, Xian-Bo Zhu, Jing Zhang, and Ye Fan were involved in the study design. Zan-Sheng Huang and Ye Fan performed the procedure described. Ya-Ting You, Jing-Meng Li, and Xian-Bo Zhu collected data. Ya-Ting You, Hao Zuo, Wan-Lei Fu, and Ye Fan analyzed the data. Felix J Herth provided helpful guidance and suggestions. Ye Fan wrote the first draft of the manuscript. Ya-Ting You, Hao Zuo, Jing-Meng Li, Xian-Bo Zhu, Jing Zhang, Wan-Lei Fu, Zan-Sheng Huang, Felix J Herth, and Ye Fan edited and approved the final version.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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