Mediastinal granuloma and fibrosing mediastinitis

INTRODUCTION — Mediastinal granuloma and fibrosing mediastinitis are rare causes of mediastinal masses [1]. Mediastinal granuloma is characterized by a granulomatous mass-like lesion in the hilum or mediastinum. Fibrosing mediastinitis (also known as sclerosing mediastinitis or mediastinal fibrosis) is characterized by an excessive fibrotic reaction in the mediastinum. Both entities are uncommon complications of prior histoplasmosis infection. Involvement of mediastinal structures results in symptoms based upon the organs involved. Differentiating these two benign disorders from each other is important since the sequelae, potential interventions, and prognosis of both diseases are very different.

The etiology, clinical presentation, diagnosis, treatment, and outcome of mediastinal granuloma and fibrosing mediastinitis are reviewed here. The presentation and treatment of pulmonary histoplasmosis and the approach to mediastinal masses are discussed separately. (See "Pathogenesis and clinical features of pulmonary histoplasmosis" and "Diagnosis and treatment of pulmonary histoplasmosis" and "Approach to the adult patient with a mediastinal mass".)

ETIOLOGY — It is widely thought that fibrosing mediastinitis and mediastinal granuloma are two divergent host responses that occur in mediastinal lymph nodes from a previous infection (or insult). Most cases are thought to be due to previous infection with Histoplasma capsulatum, which is by far the most common cause in the United States. Infection with Mycobacterium tuberculosis is a less common cause. Cases due to other infections or noninfectious etiologies and idiopathic cases are rare in the United States. However, etiologies may be regionally dependent. For example, in a series of 27 patients from France with pulmonary hypertension due to fibrosing mediastinitis, almost one-half were due to sarcoidosis, one-third due to tuberculosis, and the remainder were due to mediastinal irradiation or were idiopathic [2]. There were no cases of histoplasmosis.

Histoplasmosis — Among the etiologies, the dimorphic fungus, Histoplasma capsulatum, is by far the most common etiology for both disorders in the United States [1]. This is supported by the higher concentration of reported cases in endemic areas (eg, southeastern, mid-Atlantic, and central United States along the Ohio and Mississippi River valleys) and the lower number of reported cases in other regions of the world where infection with Histoplasma is rare (eg, northeastern United States, Europe, and Asia) [2,3].

Other infection — Mediastinal granuloma due to tuberculosis is well described and may be more commonly seen in patients who live or have previously lived in endemic areas (eg, West Africa, India) [4-6].

Tuberculosis is also often included as a potential precipitant of fibrosing mediastinitis, but it rarely stimulates an invasive fibrotic reaction similar to that seen following histoplasmosis [7,8].

Case reports have also described the development of fibrosing mediastinitis secondary to infection with Aspergillus [9-12], Wuchereria bancrofti [13], Blastomyces [14], Actinomyces, and Treponema (syphilis) [11]. While these micro-organisms could also be associated with mediastinal granuloma, they may be more likely to cause active inflammation of mediastinal lymph nodes (ie mediastinal adenitis) rather than mediastinal granuloma.

Noteworthy is that coccidioidomycosis is rarely, if ever, associated with mediastinal granuloma or fibrosis.

Autoimmune — Several autoimmune disorders have been reported to be associated with fibrosing mediastinitis. Other than sarcoidosis, none of these autoimmune diseases has been described in association with mediastinal granuloma.

●Some cases of fibrosing mediastinitis occur within the spectrum of immunoglobulin G4 (IgG4)-related diseases, such as retroperitoneal fibrosis, orbital pseudotumor, Behçet disease, and Riedel's (fibrous) thyroiditis [15-17].

●Sarcoidosis has also been reported as a cause of fibrosing mediastinitis, particularly in Europe [17].

●Rare cases of mediastinal fibrosis have been described occurring in association with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and large-vessel arteritis [18].

Miscellaneous — Case reports have described the development of fibrosing mediastinitis due to mediastinal radiation [19-21], methysergide, and silicosis [22,23]. One case of mediastinal fibrosis has also been described in association with synovitis-acne-pustulosis-hyperostosis-osteomyelitis (SAPHO) syndrome [17].

Idiopathic — In most patients with mediastinal granuloma or fibrosing mediastinitis, a microorganism cannot be found. While in the past this has been termed idiopathic, signs of old Histoplasma infection (eg, calcification in the lymph nodes, liver, and spleen) are often present. Thus, most experts believe that "idiopathic" disease is likely a sequela of infection with Histoplasma capsulatum (or another infection) and that the inability to identify a microorganism is due to the fact that both conditions are an abnormal response to infection rather than due to direct invasion of the mediastinum by microorganisms.

Some experts, including us, believe that there is a different form of fibrosing mediastinitis that may be truly idiopathic in nature [18]. These cases are rare but lack the calcifications that are typical of old Histoplasma infection. In addition, the radiological appearance of fibrosis may be different in these patients ("thinner" and "tracks" along vessels or airways). Alternatively, the idiopathic version may represent disease due to undiagnosed autoimmune disorders such as IgG4 disease. (See 'Autoimmune' above.)

PATHOGENESIS — Mediastinal granuloma and fibrosing mediastinitis are considered rare and long-term sequela of infection with Histoplasma capsulatum (figure 1). It is thought that mediastinal granuloma and fibrosing mediastinitis begin as a relatively benign-occurring respiratory infection that disseminates to the mediastinal lymph nodes before specific cell-mediated immunity develops to contain the organism. In rare cases and for unclear reasons, two divergent responses can occur: mediastinal granuloma or fibrosing mediastinitis. These processes may develop over months to years. While it was originally believed that the pathophysiologic process represented a continuum from intense active granulomatous inflammation on one end to dense collagen formation at the other end, we now believe that each response is separate and has no overlap.

●Mediastinal granuloma – Mediastinal granuloma is the more common response [4,24]. The involved mediastinal lymph nodes can enlarge and coalesce into an inflamed necrotic mass referred to as a mediastinal granuloma. Although the natural history is unclear, mediastinal granuloma is more likely to be self-limiting or spontaneously resolve (possibly by regression or fistulization) than fibrosing mediastinitis, explaining why the majority of cases are found incidentally on chest imaging. However, in some cases, the enlarged mass compresses and less commonly, fistulizes with nearby mediastinal structures. Histopathology is discussed below. (See 'Diagnosis' below.)

●Fibrosing mediastinitis – This reaction is extremely rare and is one of uncontrolled, invasive fibrosis that crosses fat planes. It is believed that fibrosing mediastinitis results from the leakage of fungal antigens (not the organism itself) from lymph nodes into the mediastinal space, leading to a hypersensitivity reaction followed by an exuberant fibrotic response [25]. Fibrosis is typically unilateral, although it can be bilateral. It is commonly progressive, resulting in compression and sometimes invasion of adjacent normal structures. Histopathology is discussed below. (See 'Diagnosis' below.)

In both conditions, calcification frequently occurs and when seen radiologically, clinically supports old Histoplasma infection. (See 'Clinical presentation' below and 'Diagnostic evaluation' below.)

Neither condition is believed to reflect extranodal infection because the organism is not typically identified in biopsy specimens [4,25]. However, in patients with suspected mediastinal granuloma, the chance of identifying an organism may be higher if infection is recently acquired or overwhelming (eg, in an immunosuppressed patient) or significant caseations are present [25-27]. In our experience, an organism is found in up to 20 percent of cases with mediastinal granuloma who undergo surgical resection for their disease. In such cases, mediastinal granuloma needs to be distinguished from an infectious adenitis, which is discussed below. (See 'Forming a differential diagnosis' below.)

It is unknown why some patients develop mediastinal granuloma while others develop fibrosing mediastinitis. However, certain genotypes may increase the odds of developing fibrosing mediastinitis, including HLA-A2 and HLA DQB1*04:02 [28,29]. A genome-wide association study performed on 58 fibrosing mediastinitis patients compared with 7115 nondiseased controls identified several additional candidate genes that need further evaluation [30]. (See "Human leukocyte antigens (HLA): A roadmap".)

While in the past it was believed that mediastinal granuloma was a precursor lesion for fibrosing mediastinitis, there are no clinical or preclinical data to support this hypothesis. In our clinical experience that includes review of over 200 cases of fibrosing mediastinitis, we have seen no evidence of mediastinal granuloma preceding fibrosing mediastinitis.

It is assumed that the mechanism responsible for mediastinal granuloma and fibrosing mediastinitis due to tuberculosis is similar to that due to histoplasmosis [8]. The mechanism that underlies fibrosing mediastinitis associated with autoimmune disorders or other precipitants is unknown.

EPIDEMIOLOGY — Mediastinal granuloma and fibrosing mediastinitis are rare conditions. Precise epidemiologic data are not available and are generally limited to case series. Cases in the United States are concentrated in endemic regions for Histoplasma (ie, along the Ohio and Mississippi River valley in the midwest United States) and are lower in other regions where Histoplasma infection is unusual (eg, northeast United States, Europe, and Asia).

While it has been estimated that over 500,000 people per year in the United States are infected with Histoplasma and over 80 percent of inhabitants of endemic regions have a positive Histoplasma skin test [31], less than 1 percent of patients with histoplasmosis develop mediastinal granuloma or fibrosing mediastinitis (figure 1) [32].

Mediastinal granuloma may account for up to 10 percent of mediastinal masses in surgical series [4].

The largest series of fibrosing mediastinitis was from an institution in an endemic region, and it described only 94 patients over a nine-year period [33]. The average age at diagnosis was 33 years, 81 percent were White patients, and there was a slight male preponderance. Similar demographics have been reported by other series [4,34].

MEDIASTINAL GRANULOMA — Mediastinal granuloma is a granulomatous mass that occurs in the hilum or mediastinum. Mediastinal granuloma is thought to be an uncommon immune response to infection with prior histoplasmosis or, less commonly, tuberculosis. Other causes of mediastinal granuloma are rare (eg, sarcoidosis) (see 'Etiology' above). Lesions are classically heterogeneous on imaging and have various patterns of calcification. In most cases, patients with mediastinal granuloma are asymptomatic. However, symptoms occur when the mass results in compression of or fistulization with nearby structures (table 1).

Clinical presentation

●Signs and symptoms – In most patients, mediastinal granuloma is asymptomatic. Patients are typically young (4^th decade) and present with an incidental localized soft-tissue mediastinal mass with calcification on chest computed tomography (CT) performed for another reason (image 1). The history of Histoplasma infection is usually remote (or unknown) [27]. Patients are often asymptomatic for years after the development of the mediastinal lesion. However, in some patients these lesions can become enlarged and tense, leading to symptoms from extrinsic compression of compliant adjacent paratracheal, hilar, or mediastinal structures. In some cases, fistulous tracks may develop into adjacent structures (eg, esophagus, airway, or pericardium), leading to decompression of the lesion, a process that may be symptomatic or asymptomatic.

•Compression of adjacent structures (eg, vessels, esophagus, airway) can result in symptoms [24,35,36]. For example, obstruction of the superior vena cava (SVC) (image 2) may lead to the signs and symptoms of SVC syndrome (eg, headache, facial swelling), while obstruction of the esophagus may cause chest pain, odynophagia, or dysphagia. In younger children, there is potential for extrinsic compression to obstruct the trachea due to increased tracheal ring compliance, but this is less common in adults [37,38]. Bronchial or lung compression may result in cough and symptoms of obstructive pneumonia. Unlike fibrosing mediastinitis, pulmonary hypertension is not a manifestation of mediastinal granuloma. (See "Malignancy-related superior vena cava syndrome", section on 'Clinical features' and "Approach to the evaluation of dysphagia in adults".)

•Fistulizing disease is the more concerning potential sequela of mediastinal granuloma. This may be an asymptomatic occurrence (eg, minor fistulization into the esophagus), but symptoms may develop and likely depend upon the site of drainage [24]:

-Lungs and bronchi (image 3) – Drainage into the lung may cause malaise, night sweats, cough, dyspnea, sputum production, and hemoptysis. Bronchial erosion by calcific lymph nodes can lead to broncholithiasis. (See "Tracheo- and broncho-esophageal fistulas in adults".)

-Esophagus – Drainage into the esophagus may lead to chest pain, dysphagia, odynophagia, or gastrointestinal bleeding.

-Heart and pericardium – Fistulization into the pericardium resulting in pyopneumopericardium and cardiac tamponade is a particularly life-threatening complication [39,40]. Fistulization into the aorta has not been described. (See "Pericardial effusion: Approach to diagnosis", section on 'Diagnostic approach'.)

-Skin – Anecdotal cases of drainage through the skin exist (eg, via a mediastinoscopy site).

•Some patients may present with symptoms of acute bacterial superinfection of the granuloma. For example, in cases of esophageal fistula formation, lesions have been known to develop retrograde bacterial infection from oral or enteric organisms, which can be particularly dangerous [1,24,35].

●Chest radiography – Findings of mediastinal granuloma on the chest radiograph are typically limited to a mass-like lesion within the mediastinum or hilum. However, features of complications may also be evident (eg, atelectasis from bronchial obstruction). Calcifications may or may not be appreciated on plain radiograph. Chest CT findings are described below. (See 'Chest computed tomography with contrast' below.)

●Laboratory studies – General laboratory studies such as complete blood count and routine chemistries are nonspecific and not helpful unless an acute or complicating event has occurred (eg, pneumonia or bacterial superinfection).

Diagnostic evaluation — Mediastinal granuloma should be suspected in a young asymptomatic patient who has an abnormal mass on chest radiograph; the threshold for suspicion should be higher in patients who live or have previously lived in regions that are endemic for Histoplasma (eg, along the Ohio and Mississippi River valley in central United States). Mediastinal granuloma should also be suspected in patients with a mediastinal mass who have unexplained progressive pulmonary or esophageal symptoms. The diagnostic evaluation of a patient with suspected mediastinal granuloma centers on obtaining further imaging, typically chest CT with contrast, since in many cases a clinical diagnosis can be made without having to acquire tissue for histopathology. Serologic studies are of limited benefit because they frequently fail to establish the diagnosis of Histoplasma but do confirm previous exposure.

Chest computed tomography with contrast — Chest CT with contrast is indicated in patients with suspected mediastinal granuloma. Chest CT classically shows a well-defined mass-like lesion (or conglomerate lesions) of heterogeneous density with rim-enhancing and/or scattered or diffuse calcifications. CT also typically reveals evidence of prior Histoplasma infection, such as calcified lymph nodes and hepatic or splenic calcifications. There may be extrinsic compression of mediastinal structures at an isolated anatomical point, but there should be no evidence of circumferential compression of structures, the latter being more typical of fibrosing mediastinitis. The presence of air within a mediastinal granuloma may be an indication that it has recently drained (image 3), but assessment of this requires prior knowledge that a mediastinal granuloma was present.

Contrast is preferred to distinguish vascular from other structures within the mediastinum. The routine protocol used for administration of contrast is typically one that can visualize the SVC and the pulmonary artery (ie, early contrast administration). Unlike fibrosing mediastinitis, late administration of contrast to opacify the pulmonary veins is not typically necessary.

Forming a differential diagnosis — Differentiating mediastinal granuloma from fibrosing mediastinitis can be accomplished on review of chest CT performed with contrast. Mediastinal granuloma typically has the appearance of a well-encapsulated heterogeneous mass-like lesion without circumferential obstruction and with evidence of old Histoplasma infection (eg, calcifications in lymph nodes, liver, or spleen). In contrast, fibrosing mediastinitis appears as a dense homogeneous fibrous infiltrate within the mediastinum that may encompass mediastinal structures, leading to obstruction. (See 'Chest computed tomography with contrast' above and 'Chest computed tomography with contrast' below.)

For atypical presentations (eg, no lesional calcifications on CT) or those that include risk factors for malignancy, mediastinal granuloma needs to be differentiated from other causes of a mediastinal mass. In such cases, biopsy is often indicated, the details of which are provided separately. (See "Approach to the adult patient with a mediastinal mass", section on 'Tissue diagnosis' and "Pathology of mediastinal tumors" and "Primary mediastinal large B cell lymphoma".)

For those with a mediastinal mass who present with obstructive syndromes, the differential is also discussed separately:

●Vascular (see "Malignancy-related superior vena cava syndrome" and "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Evaluation and approach to clinical diagnosis' and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Initial differential diagnosis')

●Airways (see "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults", section on 'Differential diagnosis' and "Overview of the initial evaluation, diagnosis, and staging of patients with suspected lung cancer", section on 'Differential diagnosis')

●Esophageal (see "Approach to the evaluation of dysphagia in adults", section on 'Approach to diagnostic testing')

Mediastinal granuloma should also be distinguished from Histoplasma-related adenitis. While both diseases may cause a mediastinal mass, patients with Histoplasma-related adenitis lack calcifications and may have evidence of infection elsewhere. In addition, evidence of microorganism invasion is more likely to be seen with adenitis (serology and histology), and risk factors for invasive disease may be present (eg, immunosuppression). On gross pathology, mediastinal granulomas contain a large amount of necrotic proteinaceous debris while Histoplasma adenitis contains a dense cellular infiltrate. (See "Pathogenesis and clinical manifestations of disseminated histoplasmosis" and "Diagnosis and treatment of pulmonary histoplasmosis".)

Asymptomatic patients with classic features — In many patients, the classic CT appearance in an asymptomatic young individual is typically sufficient to make the diagnosis without any further testing. These patients can be followed until the lesion grows or becomes symptomatic. The rationale for this approach is that most patients who are asymptomatic do not need treatment with excisional surgery; in addition, biopsy of the mass may be associated with risk, including superinfection due to spillage of the contents into the mediastinum [41]. In some patients, when a lesion is close to a vital structure such as a major vessel or the heart, referral to a specialized center is prudent to determine whether excisional biopsy is warranted. (See 'Diagnosis' below.)

Patients with atypical features, symptoms, or fistulization — Patients with atypical lesions, symptoms, or complications such as significant obstruction or fistulous formation need additional investigation, typically tissue biopsy.

Indications for tissue biopsy — Tissue biopsy is aimed at ruling out other more common and more serious causes of a mediastinal mass or fistula (eg, lung cancer, esophageal cancer, lymphoma, thymoma). (See "Approach to the adult patient with a mediastinal mass" and "Tracheo- and broncho-esophageal fistulas in adults".)

The choice of procedure depends upon the location of the mediastinal mass and the presentation:

●Atypical presentation – In patients with atypical lesions, mediastinal granuloma needs to be distinguished from other causes of a mediastinal mass (eg, lung cancer, lymphoma). Atypical presentations include a CT appearance that has no calcifications or calcification in lymph nodes only but absent in the lesion, or a lesion that is new and rapidly growing or occurring in a patient with risk factors for cancer or lymphoma (eg, older age, smoking, asbestos exposure, previous radiation). In most patients with atypical presentations, the initial procedure of choice is endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), provided the mass is EBUS accessible. During bronchoscopy, bronchoalveolar lavage (BAL) samples should be taken for cytology and microbiological culture. In our experience, enough material can be obtained with EBUS-TBNA for the diagnosis of mediastinal granuloma and also for ruling out cancer. However, other procedures including endoscopic ultrasound-guided fine needle aspiration (EUS-FNA for esophageal lesions) or CT-guided FNA (lesions not accessible by EBUS or EUS) are appropriate. When TBNA or FNA is nonspecific or does not sufficiently rule out cancer, patients should undergo surgical excisional biopsy.

●Typical presentations (ie, with symptoms or complications) – In symptomatic patients who have classic imaging that demonstrates complications (eg, fistulization) or patients who have symptoms suggestive of fistulization (eg, cough with sputum production), we prefer excisional biopsy since this is both a diagnostic and therapeutic procedure. This can be done via mediastinoscopy or video-assisted thoracoscopic surgery (VATS) and is dependent on the location of the lymph nodes and the surgeon's preference. The advantage of excisional biopsy is that it avoids puncturing the granuloma with spillage of contents into the mediastinum that may be associated with TBNA/FNA procedures; however, the procedural risk is higher. (See "Approach to the adult patient with a mediastinal mass", section on 'Tissue diagnosis' and "Endobronchial ultrasound: Indications, contraindications, and complications" and "Endobronchial ultrasound: Technical aspects" and "Endoscopic ultrasound-guided sampling of the mediastinum: Technique, indications, contraindications, and complications".)

Other tests — In all patients with suspected mediastinal granuloma, Histoplasma antigen testing (eg, blood, BAL, urine) and serologic testing are frequently performed, but results are often unrevealing or just confirm previous exposure only. (See "Diagnosis and treatment of pulmonary histoplasmosis" and "Diagnosis and treatment of disseminated histoplasmosis in patients without HIV".)

Similarly, investigative testing for other etiologic disorders such as tuberculosis or sarcoidosis is indicated based upon the suspicion for such disorders, but is not routinely performed. (See "Diagnosis of pulmonary tuberculosis in adults" and "Clinical manifestations and diagnosis of sarcoidosis".)

Diagnosis — Mediastinal granuloma is frequently diagnosed in the appropriate clinical context (eg, incidental finding in a young nonsmoking patient from a region endemic for histoplasmosis) when a mediastinal mass has the classic features on chest CT (ie, mass-like lesion or conglomerate lesions of heterogeneous density with rim-enhancing and/or scattered or diffuse calcifications). In such cases, when the patient is asymptomatic and no other disorder is reasonably suspected, biopsy is not needed. In contrast, when patients are symptomatic, have complications, or have atypical presentations, the diagnosis is made histopathologically on tissue aspiration or excisional biopsy specimens.

Gross pathology (on excisional biopsy) may identify a large mass with a "gelatinous" center (from caseation and necrosis) surrounded by a fibrous capsule that is thin or thick. Histopathologically, intense inflammation is seen with caseating or noncaseating granulomas; microbiologic staining (eg, Histoplasma, fungus, Actinomyces, and Mycobacterium) is typically negative. Unlike fibrosing mediastinitis, there is little or no surrounding collagen deposition. In rare cases of "old" mediastinal granuloma, the active inflammation may have resolved and left behind only a fibrous capsule.

Pathologically, mediastinal granuloma may be distinguished from Histoplasma-related adenitis by the presence of caseation or necrosis and absence of a microorganism, rather than active inflammation associated with identification of the microorganism that is typical of adenitis.

Treatment — Due to the rarity of mediastinal granuloma, there are no clinical trials describing outcomes from individual therapies. Treatment recommendations are based upon data derived from retrospective case series and clinical experience. Referral to centers familiar with the presentation and management of mediastinal granuloma should be considered.

●Asymptomatic patients with classic appearance – In general, patients with asymptomatic disease AND a classic CT appearance are monitored with serial chest CT imaging; however imaging intervals have not been established. We typically image patients every six months for one to two years, then yearly thereafter. This approach is based upon the rationale that most patients do not progress and some may spontaneously regress or resolve. Patients who demonstrate growth or develop symptoms should be referred for surgical excision. In our experience, spontaneous resolution of mediastinal granuloma can occur, which may possibly be related to silent fistula formation and drainage.

Exceptions to this rule of observation in patients with asymptomatic disease are asymptomatic patients who have had clinical evidence of prior fistula formation (eg, episodic cough with thick sputum) and those with lesions in close proximity to life-threatening organs (eg, heart). In such cases, excisional biopsy is appropriate.

●Atypical and symptomatic patients – For patients with atypical presentations and patients who have developed symptomatic extrinsic compression or fistulizing disease, we prefer surgical excision with removal of the free wall and evacuation of the internal contents and, if present, repair of the fistula [1,24]. Portions of the capsule may be adherent to critical mediastinal structures and do not need to be resected in their entirety. Patients who are not surgical candidates have limited options, although some patients may be treated endoscopically (eg, with stents), the details of which are provided separately. (See "Tracheo- and broncho-esophageal fistulas in adults" and "Airway stents" and "Endoscopic stenting for palliation of malignant esophageal obstruction" and "Endoscopic interventions for nonmalignant esophageal strictures in adults".)

Antifungals targeted at Histoplasma (typically itraconazole) are not routinely administered unless patients have evidence of active infection or active infection is highly suspected (ie, Histoplasma adenitis). (See "Diagnosis and treatment of pulmonary histoplasmosis", section on 'Treatment'.)

In patients who have developed superinfection with bacteria from esophageal fistulization or following diagnostic biopsy, broad spectrum antibiotics including gram-negative and anaerobic coverage should be administered, typically for 10 to 14 days.

Prognosis — The natural history of mediastinal granuloma is unknown. However, the fact that most cases are discovered incidentally and don't progress suggests that this disorder has a relatively benign, self-limiting course, especially when compared with patients who have fibrosing mediastinitis.

However, patients with compression and fistulization may have a worse prognosis unless the lesion can be surgically removed. Surgical removal of the granuloma is typically successful and few patients recur.

Prognosis may be worse in those who develop fistulization with the pericardium resulting in cardiac tamponade and sudden death and in those with esophageal fistulization who develop bacterial superinfection from enteric flora.

For those who are not surgical candidates, spontaneous fistulous drainage into the esophagus may also result in resolution of the original lesion, but in some patients the granuloma may reaccumulate, leading to a cycle of recurrent drainage.

FIBROSING MEDIASTINITIS — Fibrosing mediastinitis (also known as sclerosing mediastinitis or mediastinal fibrosis) is a rare disorder that is characterized by aggressive fibrosis of the mediastinum. Similar to mediastinal granuloma, fibrosing mediastinitis is considered to be a rare and abnormal immune response to infection, typically histoplasmosis or less commonly tuberculosis. Other infectious or noninfectious etiologies of fibrosing mediastinitis are rare (see 'Etiology' above). Unlike mediastinal granuloma, most patients are symptomatic due to compression of nearby mediastinal structures. In addition, diagnostic investigation and treatment options are limited and fraught with challenges.

Clinical presentation — Compression of mediastinal structures is more common in patients with mediastinal fibrosis than in patients with mediastinal granuloma. Thus, patients with fibrosing mediastinitis are more likely to present with symptoms. Asymptomatic disease is unusual.

●Signs and symptoms – The signs and symptoms of fibrosing mediastinitis depend upon which structures of the mediastinum are involved and the degree to which those structures are compromised. Symptoms are slowly progressive over two to five years [25]. The history of infection with Histoplasma is usually remote or unknown.

However, patients may present with acute or chronic symptoms from acute complications such as pulmonary infarction, superior vena cava (SVC) syndrome, or obstructive pneumonia. Common symptoms at presentation are exertional dyspnea, cough, chest pain, hemoptysis, and findings consistent with SVC syndrome (facial swelling, headache). Unlike patients with mediastinal granuloma, symptoms from fistulization do not occur.

Signs and symptoms include those from obstruction at the following commonly involved anatomical sites:

•Great vessels – Symptoms due to obstruction of the pulmonary circulation and SVC are the most common.

-Pulmonary vascular obstruction is the most common presenting feature of fibrosing mediastinitis [31,42,43]. This includes the development of pulmonary artery (image 4) and/or pulmonary vein obstruction (image 5). Pulmonary arterial or venous obstruction can lead to the development of pulmonary hypertension and acute pulmonary infarction on the ipsilateral side (image 6). Symptoms include dyspnea, cough, chest pain, and/or hemoptysis; hemoptysis may be due to functional anastomoses between the intercostal or bronchial arteries (from pulmonary artery obstruction) or due to pulmonary venous hypertension (from pulmonary vein obstruction, ie, pseudo-mitral stenosis). (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical manifestations' and "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Evaluation and approach to clinical diagnosis' and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Clinical presentation'.)

-Obstruction of the SVC in fibrosing mediastinitis can lead to chronic or acute chronic SVC syndrome. Not all patients with SVC compromise become symptomatic (eg, facial swelling and headache). This is because SVC obstruction due to fibrosing mediastinitis typically develops slowly over a period of years, allowing the formation of an extensive collateral circulation that may be adequate to prevent both stasis and elevated pressure in the tributaries of the SVC [4,33]. However, thrombosis can occur in the setting of a stricture, leading to a more acute presentation. (See "Malignancy-related superior vena cava syndrome", section on 'Clinical features'.)

-While we have seen some patients where fibrosing mediastinitis tracks along vessels, constriction of the aorta or heart has not been seen.

•Airways – Compression of lobar airways can lead to postobstructive pneumonia or atelectasis [15,34]. Common symptoms include dyspnea, cough, sputum production, and/or hemoptysis (from necrotizing pneumonia or broncholith). Rarely are airway symptoms due to broncholiths or direct invasion by fibroblasts. Tracheal stenosis is uncommon in adults and more common in children.

•Esophagus – Esophageal compression can lead to chest pain, dysphagia, and/or odynophagia [15,34]. (See "Approach to the evaluation of dysphagia in adults".)

•Other – One case report of fibrosing mediastinitis involving the thoracic spine has been reported [44]. Involvement of the phrenic nerve to cause diaphragmatic paralysis can also occur. (See "Etiology, clinical presentation, and diagnosis of chylothorax".)

●Chest radiograph — The manifestations of fibrosing mediastinitis on chest radiography are nonspecific, the most common findings consisting of mediastinal widening and/or hilar or mediastinal lymphadenopathy. Other manifestations include lobar or segmental consolidation or atelectasis, a unilateral small pulmonary artery, septal lines, pleural effusion, or cardiomegaly. An effusion may be due to pulmonary venous hypertension, acute pulmonary embolus, or chylothorax [45]. The extent of disease is often underestimated, with the chest radiograph appearing relatively normal even in patients with extensive disease (ie, disease causing major central airway obstruction and vascular occlusion) [4,15]. Calcifications are not always appreciated [46].

●Laboratory studies – General laboratory studies such as complete blood count and routine chemistries are nonspecific and not helpful unless an acute event has occurred (eg, postobstructive pneumonia).

Diagnostic evaluation — Fibrosing mediastinitis should be suspected in a patient with slowly progressive pulmonary symptoms or SVC obstruction of unclear etiology who has an abnormal appearing mediastinum on chest radiograph; the threshold for suspicion should be higher in patients who live or have previously lived in regions that are endemic for histoplasma (ie, along the Ohio and Mississippi valley in the central United States). Additional imaging studies, usually chest computed tomography (CT) with contrast, are necessary to confirm the diagnosis of an infiltrative process in the mediastinum to help exclude malignancy and to assess the integrity of mediastinal structures (image 7). While biopsy may be required to rule out malignant mediastinal pathologies, it may not be necessary if the patient has a typical clinical and radiologic presentation consistent with fibrosing mediastinitis. Biopsy is difficult because of the dense fibrosis and calcification and may be hazardous as a result of bleeding from engorged collateral vessels. Serologic studies are of limited benefit because they frequently fail to establish the diagnosis of Histoplasma.

Additional imaging — Patients with suspected fibrosing mediastinitis should undergo additional imaging, specifically chest CT with contrast, and in some cases, chest magnetic resonance imaging (MRI). Case reports have demonstrated positive uptake on fluorodeoxyglucose positron emission tomographic (FDG-PET) scanning in some patients, although PET scanning is not routinely performed in suspected cases and is nonspecific [47,48].

Chest computed tomography with contrast — Contrast-enhanced chest CT is the imaging modality of choice for evaluating patients with suspected fibrosing mediastinitis because it accurately depicts the location and severity of disease, presence and extent of vascular and/or airway narrowing or obstruction, and the presence or absence of calcification [49]. Multiplanar and three dimensional (3D) reformations are particularly helpful in the optimal evaluation of the extent and severity of vascular and airway involvement [49]. The characteristic CT findings consist of a dense infiltrative heterogeneous mediastinal process that obliterates fat planes, with or without a discrete mass (image 4 and image 5) [4,34,50]. Calcifications are classically seen within the mediastinal process. In one series, 86 percent of patients had calcification on their CT scan, approximately 50 percent of which was not visible on the chest radiograph alone [46]. CT may also reveal evidence of prior Histoplasma infection, such as calcified lymph nodes distant from the lesion and hepatic or splenic calcifications [49]. Extrinsic compression of mediastinal structures is often circumferential. Fistulization is usually absent. Increased lung attenuation, thickened interlobular septa, and peribronchial cuffing are usually seen with pulmonary venous obstruction while abrupt cutoff of a major pulmonary artery may be seen with pulmonary artery involvement. In the idiopathic version of fibrosing mediastinitis, the fibrosis may be "thinner" and behave as if it is tracking along vessel or airway planes. (See 'Idiopathic' above.)

Administration of intravenous contrast is essential in assessing the degree of vascular occlusion, if present, and demonstrating collateral blood flow around obstructed vessels [50,51]. When fibrosing mediastinitis is suspected, contrast timing should be modified to include both pulmonary arterial and pulmonary venous opacification (ie, later contrast that allows the pulmonary artery and veins and aorta to be filled). Noteworthy is that this contrast protocol is different from routine CT angiography of the pulmonary artery (ie, early contrast that maximizes pulmonary artery opacification). Thus, specifying why contrast is needed with the radiologist is important.

About 80 percent of patients with fibrosing mediastinitis have unilateral disease affecting only one hilum or one nodal station [4,34]. Of the unilaterally affected patients, the majority will have right-sided disease. Bilateral disease may be associated with a worse prognosis. (See 'Prognosis' below.)

Magnetic resonance imaging — MRI is comparable with CT for assessing the presence and extent of fibrosing mediastinitis and, therefore, may be helpful in select cases to further evaluate the degree of vascular involvement [49,50]. The infiltrative soft tissue in fibrosing mediastinitis usually demonstrates intermediate signal intensity on T1-weighted images, variable signal intensity on T2-weighted images, and variable heterogeneous enhancement following intravenous administration of gadolinium-based contrast material [49].

Forming a differential and deciding to acquire tissue biopsy — For many patients, fibrosing mediastinitis needs to be differentiated from other causes of a mediastinal mass. This includes benign causes such as mediastinal granuloma or malignancies such as bronchogenic cancer and lymphoma. Sclerosing lymphoma is a particularly aggressive form of B cell lymphoma that may mimic fibrosing mediastinitis. However, most patients with malignancies of the mediastinum have a relatively faster clinical course of progression and lack calcification on imaging in the mass or lymph nodes, which is more typical of fibrosing mediastinitis. In contrast, mediastinal fibrosis tends to be more slowly progressive, have calcifications, and give the appearance of "creeping" as the fibrosis tracks along vascular planes. Ultimately, biopsy is needed to distinguish cancers of the mediastinum from fibrosing mediastinitis. This differential is discussed separately. (See 'Forming a differential diagnosis' above and "Approach to the adult patient with a mediastinal mass", section on 'Tissue diagnosis'.)

In general, patients with the classic chest CT features of fibrosing mediastinitis do not need tissue biopsy for diagnosis; in our experience, up to 80 percent have classic presentations and do not need biopsy. The rationale for this approach is that there is no curative therapy for this disease, and biopsy may be fraught with difficulty and complicated by hemorrhage due to obstruction of the pulmonary veins and/or development of collateral vascularization. However, patients with atypical presentations (eg, lack lesional calcification on chest CT) or patients in whom other serious pathologies are suspected (eg, esophageal or lung cancer, lymphoma, IgG4 disease) typically undergo biopsy. The choice of procedure depends upon the location of the mediastinal mass. In general, the procedure with the lowest risk of complications that can avoid biopsy of vital mediastinal structures and minimize hemorrhage is chosen first. We prefer to discuss such cases with several specialties, and the high risk nature of tissue biopsy should be explained in full detail with the patient. In most cases, the initial procedure of choice is endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). However, other procedures including endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) or CT-guided FNA are appropriate. When the diagnosis remains in doubt, surgical biopsy (mediastinoscopy, video-assisted thoracoscopic surgery [VATS], or thoracotomy) is appropriate. (See "Approach to the adult patient with a mediastinal mass", section on 'Tissue diagnosis' and "Endobronchial ultrasound: Indications, contraindications, and complications" and "Endobronchial ultrasound: Technical aspects" and "Endoscopic ultrasound-guided sampling of the mediastinum: Technique, indications, contraindications, and complications".)

Diagnosis — Fibrosing mediastinitis may be diagnosed in the appropriate clinical context (eg, young nonsmoking patient from a region endemic for histoplasmosis) when a mediastinal mass has the classic features on chest CT (ie, infiltrative mediastinal process that obliterates fat planes, contains calcifications, with or without a discrete mass) (image 4 and image 5). In such cases, when no other disorder is reasonably suspected, biopsy is not needed. In contrast, patients with atypical presentations need a tissue biopsy to distinguish mediastinal fibrosis from other disorders (typically malignancy).

Histopathology typically shows large amounts of mature, concentrically deposited acellular collagen resembling keloid scar tissue [25]. The fibrotic tissue infiltrates and obliterates adipose tissue. Little inflammation is appreciated, but a lymphocytic or mononuclear cell infiltrate may be appreciated.

When idiopathic fibrosing mediastinitis is suspected, we typically look for extrathoracic sites of possible IgG4 disease using contrast-enhanced CT scan of the abdomen and pelvis and serology for IgG subsets. (See "Clinical manifestations and diagnosis of IgG4-related disease".)

Treatment — There is no curative therapy for fibrosing mediastinitis. Therapy is largely targeted at alleviating symptoms and avoiding life-threatening vital organ involvement. Referral to a specialized center is appropriate. Resources for clinicians and patients can be found at the National Organization for Rare Disorders.

Symptomatic therapy — Percutaneously placed vascular stents and bronchoscopically placed airway stents have been used to treat vascular obstruction and airway obstruction, respectively [52,53].

●Vascular stents may be effective in improving symptoms in patients with central vascular obstruction due to fibrosing mediastinitis [54-56]. In a series of 77 vascular stents placed in 40 patients to relieve lesions in the pulmonary artery, pulmonary vein, or SVC, there were significant increases in vessel caliber and reductions in pressure gradients [54]. Symptomatic improvement was reported in 87 percent of patients for whom follow-up was available. Procedure-related complications occurred in 24 percent, and symptomatic recurrent stenosis requiring further intervention occurred in 28 percent. (See "Basic principles of vascular stents used in hemodialysis arteriovenous access intervention" and "Endovenous intervention for thoracic central venous obstruction".)

●Airway dilation and placement of an airway stent may be useful in selected cases of fibrosing mediastinitis complicated by severe extrinsic obstruction of central airways (down to the second order of bronchi (figure 2)) [57]. In a report of seven patients from the Mayo Clinic undergoing airway dilation and silicone stent placement, airway remodeling allowing stent removal occurred in five patients [57]. Of note, patients were selected who did not have concomitant vascular obstruction. Concomitant vascular obstruction in these patients may be associated with an increased risk of bleeding during bronchoscopy [4]. (See "Airway stents".)

●Esophageal stenting may also be considered for those with esophageal obstruction [58].

When intravascular, bronchoscopic, or endoscopic therapies fail, surgery may be an option, although morbidity and mortality are high and success variable. Surgery has been performed to palliate symptoms by relieving airway, vascular, and esophageal obstruction [33,59]. However, its success has been variable. Extensive fibrosis, calcification, and collateral vessels increase the risk and limit the benefits of surgery and are responsible for substantial morbidity and mortality [4,33,59]. This was illustrated in a series of 18 patients with fibrosing mediastinitis secondary to histoplasmosis, which reported three deaths (19 percent) during the early postoperative period [59].

●Resection of the stenotic airway and/or the distal lung parenchyma has been performed in cases of fibrosing mediastinitis complicated by recurrent postobstructive infection or poor gas exchange secondary to shunt physiology. Sleeve lobectomy, carinal resection, or pneumonectomy may be required [59]. In this population, airway surgery is technically difficult and associated with significant mortality [59]. Patients should be referred to centers with surgeons who are experienced in managing fibrosing mediastinitis.

●SVC bypass surgery with a spiral saphenous vein graft has been used for symptomatic relief in some patients with SVC obstruction. The saphenous vein is harvested and then opened longitudinally through its entire length. It is then wrapped around a stent in a spiral manner and sutured to create a bioprosthesis of the desired length and diameter. The stent is then removed and the graft is placed in the mediastinum anterior to the aorta. The largest series of patients treated in this fashion included four individuals with SVC syndrome due to fibrosing mediastinitis; all were symptom-free two years after the operation [60,61].

Targeted therapy — Agents targeted at the fibrosing mediastinitis itself are limited to antifungal agents, glucocorticoids, and investigational agents. However, we do not routinely treat patients with antifungals or glucocorticoids.

●Antifungals – While older case reports in the 1980s suggested possible benefit, newer studies suggest that antifungal agents are ineffective, which is consistent with our experience [4,33,34,62].

●Glucocorticoids – Glucocorticoids do not appear to be beneficial in typical cases of fibrosing mediastinitis, although controlled trials have not been performed [4,59]. However, in fibrosing mediastinitis due to sarcoidosis, improvement may sometimes be seen [2]. Another possible exception is autoimmune fibrosing mediastinitis, which may respond more favorably to glucocorticoid therapy [15]. (See "Treatment of pulmonary sarcoidosis: Initial approach".)

Options are limited in those with progressive or refractory disease, although rituximab may have limited efficacy. We try this agent in patients with life-threatening disease (eg, tracheal occlusion, bilateral disease), although data to support its use are limited. Based upon the finding of CD20-positive B lymphocytes in tissue samples from patients with fibrosing mediastinitis, a preliminary report of off-label treatment with rituximab found a therapeutic response and reduction of both lesion size and metabolic activity on PET in three patients with progressive and refractory disease [48].

Follow-up — Asymptomatic patients should be followed clinically and radiologically at 6 months, 12 months, and 24 months to look for signs and symptoms of disease progression. Monitoring thereafter depends on the lesion location. If there is no obvious evidence of vascular occlusions or other impending problems, we often space out to every two to five years or if symptoms develop. Patients who undergo therapy should also be followed for complications of the therapy and for recurrence of obstructive symptoms. Follow-up is generally life-long.

Prognosis — Fibrosing mediastinitis is an insidious, progressive disease with a variable natural history. It is unlikely that available therapies improve survival since they are mostly palliative and disease can recur despite such therapies. The rate of progression varies but older data suggest 1 mm/year [4,25].

In a large cohort of 134 patients, there were 11 deaths in the group over 20 years, with 8 of the 11 deaths occurring in patients with bilateral disease [63]. A second series of 71 patients noted a worse prognosis, with 21 patients (30 percent) dying during follow-up [4]. The mean interval between the development of symptoms and death was less than six years in these patients, and death resulted most frequently from cor pulmonale or relentless respiratory compromise due to recurrent infection, bronchial obstruction, or hemoptysis. Disease involving subcarinal structures conferred a worse prognosis because bilateral lung involvement was more common in these patients. However, many of these series were reported in the era when intravascular and airway stents were not available.

SUMMARY AND RECOMMENDATIONS

●Mediastinal granuloma and fibrosing mediastinitis are rare disorders of the mediastinum. It is widely thought that these disorders represent two divergent host responses in mediastinal lymph nodes that result from a prior infection (or insult). In the United States, infection with previous Histoplasma capsulatum is the most common cause. Cases due to infection with Mycobacterium tuberculosis are less common and other infectious etiologies are rare (eg, Aspergillus, Wuchereria, Blastomyces, Actinomyces, and Treponema). Noninfectious etiologies of fibrosing mediastinitis include sarcoidosis, silicosis, immunoglobulin G4 (IgG4) disease, radiation, autoimmune vasculitides, and select drugs; some cases are idiopathic. (See 'Introduction' above and 'Etiology' above.)

●Mediastinal granuloma and fibrosing mediastinitis are more likely to be encountered in patients who live or have lived in regions that are endemic for histoplasma (ie, along the Ohio and Mississippi valley in the central United States), but geographic variation in the incidence is likely. (See 'Epidemiology' above.)

●In most patients, mediastinal granuloma is asymptomatic. Patients are typically young and present with an incidental localized soft-tissue mediastinal mass with lesional calcification on chest imaging. A small proportion present with symptoms due to obstruction of or fistulization with nearby mediastinal structures. This is most commonly the superior vena cava (SVC; eg, facial swelling and headache), lower airway (eg, fever, cough, hemoptysis from postobstructive pneumonia), or esophagus (chest pain, dysphagia, odynophagia). (See 'Clinical presentation' above.)

•In patients with suspected mediastinal granuloma, chest computed tomography (CT) with contrast is indicated. The classic CT appearance shows a well-defined mass-like lesion (or conglomerate lesions) of heterogenous density with rim-enhancing and/or scattered or diffuse calcifications. Features consistent with prior Histoplasma infection, such as lymph nodal, hepatic, and/or splenic calcifications, are also typically present. Involvement of mediastinal structures is not circumferential. (See 'Chest computed tomography with contrast' above.)

•In patients who are asymptomatic who have the classic CT appearance of mediastinal granuloma and in whom no other reasonable diagnosis is suspected, no further testing is needed and a clinical diagnosis is made. The rationale for this approach is that treatment is not typically indicated and biopsy carries an unnecessary risk of rupture and spillage of contents into the mediastinum. (See 'Asymptomatic patients with classic features' above and 'Diagnosis' above.)

•Patients with atypical lesions (eg, lack calcifications), symptoms, or complications such as significant obstruction or fistulous formation, need tissue biopsy. Tissue biopsy distinguishes mediastinal granuloma from more serious causes of a mediastinal mass or fistula (eg, lung cancer, esophageal cancer, lymphoma, thymoma). (See 'Patients with atypical features, symptoms, or fistulization' above and 'Indications for tissue biopsy' above and 'Diagnosis' above.)

-In most atypical cases, the initial procedure of choice is endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), provided the lesion is EBUS-accessible.

-In symptomatic patients who have classic imaging that demonstrates complications (eg, fistulization) or patients who have symptoms suggestive of fistulization (eg, cough with sputum production), we prefer excisional biopsy since this is both a diagnostic and therapeutic procedure.

-Histopathologically, intense inflammation is seen with caseating granulomas; microbiologic staining (eg, for Histoplasma, fungus, Actinomyces, and Mycobacterium) is typically negative. There is little or no surrounding collagen deposition.

•In all patients with suspected mediastinal granuloma, Histoplasma antigen testing (eg, from blood, bronchoalveolar lavage [BAL], and urine) and serologic testing are frequently performed but results are frequently unrevealing or just confirm previous exposure only. (See 'Other tests' above.)

•For patients who develop or present with symptomatic extrinsic compression or fistulizing disease, we suggest surgical excision rather than observation (Grade 2C). For asymptomatic patients with mediastinal granuloma who have a classic CT appearance, we suggest observation using periodic clinical and radiological surveillance rather than surgical excision (Grade 2C). However, excisional surgery is also appropriate in some asymptomatic patients including those who have had prior evidence of fistula formation (eg, episodic coughing with thick sputum) and those with lesions in close proximity to life-threating organs (eg, pericardium). We suggest not administering antifungals targeted at Histoplasma (Grade 2C), unless patients have evidence of active infection or active infection is highly suspected. (See 'Treatment' above and "Diagnosis and treatment of pulmonary histoplasmosis", section on 'Treatment'.)

•In general, the prognosis of patients with mediastinal granuloma is good. However, prognosis may be worse in those with fistulization into a critical structure (eg, pericardium) or with bacterial superinfection from esophageal fistulization, especially when surgical candidacy is poor. (See 'Prognosis' above.)

●Patients with fibrosing mediastinitis present with slowly progressive symptoms due to compression of mediastinal structures (eg, over two to five years). Symptoms due to compression of the pulmonary circulation and SVC are the most common, followed by obstruction of the airways and esophagus. Asymptomatic disease is uncommon. (See 'Clinical presentation' above.)

•Patients with suspected fibrosing mediastinitis should undergo chest CT with contrast. Chest CT classically shows a dense infiltrative heterogeneous mediastinal process that obliterates fat planes and contains calcifications. Evidence of old Histoplasma is typically present (eg, calcification in lymph nodes, liver, and spleen). Extrinsic compression of mediastinal structures is often circumferential and fistulization is absent. In some cases, chest magnetic resonance imaging (MRI) may be performed to further define the extent of disease, particularly the degree of vascular involvement. (See 'Additional imaging' above.)

•In general, patients with the classic chest CT features of fibrosing mediastinitis in whom no other condition is reasonably suspected, do not need tissue biopsy for diagnosis. However, patients who are symptomatic from complications, patients with atypical presentations (eg, lack lesional calcification on chest CT), or patients in whom other serious pathologies are suspected (eg, esophageal or lung cancer, lymphoma, IgG4 disease) typically undergo biopsy. Biopsy may be hazardous because of a significant risk of bleeding from engorged collateral vessels. Histopathology typically shows large amounts of mature, concentrically deposited acellular collagen that infiltrates and obliterates adipose tissue. Little inflammation is appreciated, but a lymphocytic or mononuclear cell infiltrate may be appreciated (picture 1). Microbiologic staining is typically negative. (See 'Diagnostic evaluation' above.)

•There is no curative therapy for fibrosing mediastinitis. Therapy is largely targeted at alleviating symptoms and avoiding life-threatening vital organ involvement. For patients with airway, vascular, or esophageal involvement from fibrosing mediastinitis, we suggest endoscopic stent placement rather than surgery (Grade 2C). This includes bronchoscopic placement of an airway stent(s), percutaneous placement of an endovascular stent, or endoscopic placement of an esophageal stent. For patients in whom intravascular, bronchoscopic, or endoscopic therapies fail, surgery may be an option, although morbidity and mortality are high and success is variable. We suggest not administering antifungal therapy (Grade 2C) since it is generally considered ineffective. Glucocorticoids may be reserved for patients with fibrosing mediastinitis from autoimmune disorders or sarcoidosis. Other agents remain investigational (eg, rituximab). (See 'Treatment' above.)

•Fibrosing mediastinitis is an insidious, progressive disease with a variable natural history. It is unlikely that available therapies improve survival since they are mostly palliative and disease can recur despite such therapies. Most patients require life-long follow-up with chest CT imaging.