What Is Fibrosing Mediastinitis?

Fibrosing mediastinitis (FM), alternatively referred to as mediastinal fibrosis or sclerosing mediastinitis, is a rare, benign(not life-threatening if treated), and progressive(increases slowly over time) condition which is characterized by an abnormal increase in overgrowth of fibrous tissue within the mediastinal region.^1,4 The mediastinum is the area in your body which is located within your chest, between the lungs.⁵ This holds your heart, as well as other important structures such as blood vessels and the trachea.⁵

There are several classifications of FM.⁴ The granulomatous type is caused by infections such as tuberculosis and histoplasmosis, whereas the non-granulomatous form is attributed to idiopathic (arising spontaneously with unknown cause) responses linked to autoimmune syndromes, medication, and radiation exposure.⁴ The preferred diagnostic method is imaging techniques via contrast-enhanced CT, enabling both diagnosis and the assessment of the extent and severity of the condition. Common symptoms of FM include but are not limited to breathlessness, occasional cough, and diffused chest pain spanning three months.¹

Both forms are rare.^1,4 Generally, symptoms do not manifest until the condition has advanced significantly, leading to substantial obstruction in blood circulation within the affected blood vessel or airflow within the obstructed central airway.^1,4 The accumulation of scar tissue tends to develop at a gradual pace (approximately 1 mm per year), although sporadic instances of accelerated growth have been documented.^1,4 The onset of symptoms might be sudden despite the condition's gradual progression over several years. Notably, the expansion of scar tissue in the mediastinal region does not in itself induce any symptoms.^1,4

Causes 

Associated with histoplasmosis infection

In most cases, fibrosing mediastinitis (FM) arises from an abnormal immune response triggered by exposure to Histoplasma capsulatum that results in a granulomatous inflammation which could subsequently cause fibrosis.⁶ This fungus is commonly found in soil within regions prone to its presence, notably the Mississippi and Ohio River valleys in the United States.2,6 The fungus resides in the soil, becoming airborne when the soil is disturbed and is subsequently inhaled.6 Histoplasma is also linked to bird and bat droppings.6 While birds may carry the fungus on their feathers without infection, bats can have their gastrointestinal tracts colonized by the fungus.²  In humans, the inhaled fungus causes a mild upper respiratory tract infection with flu-like symptoms.^1,4,6 

Other potential causes and triggers

Idiopathic FM is very different from that caused by histoplasmosis. Reports have been documented in cases of autoimmune diseases, such as Behcet's disease, ANCA-associated vasculitides including granulomatosis with polyangiitis, IgG4-related disease, rheumatic fever, past radiation therapy, severe viral coxsackie B infections, or trauma.² 

Other possible causes

t can coincide with other unexplained fibroinflammatory disorders outside the chest area, which may be a risk factor for developing Fibrosing Mediastinitis.^1,6 These encompass conditions like retroperitoneal fibrosis, sclerosing cholangitis, Riedel thyroiditis, orbital pseudotumor, and others. Many of these have now been recognized as further expressions of systemic IgG4-related disease.² 

Clinical presentation

The majority of patients will present with symptoms such as progressive breathlessness, cough and shortness of breath, usually due to compressions of the structures within the mediastinum (blood vessels and trachea). 

Other symptoms include (NORD):

• Face Puffiness 
• Redness of the eye conjunctiva
• Headaches 
• The feeling of lightheadedness.¹
• Fatigue
• Coughing up blood (haemoptysis)
• Difficulty swallowing 
• Swelling of the arms, face and legs
• Loss of stamina 
• Chest pain
• Recurrent chest infections 
• Fever, sweats, chills

The list provided above is a common list of symptoms from which some symptoms or may not be present depending on the underlying cause of fibrosing mediastinitis. Moreover, this list may not be exhaustive. In the majority of cases, symptoms of fibrosing mediastinitis might be present for years prior to diagnosis.^1,4,6 

Diagnosis

Imaging techniques: Chest X-ray, CT scan, MRI

Diagnosing either type of FM is most effectively achieved through a chest CT scan, a diagnostic tool that is useful to image the unusual tissue within the mediastinum. A clear pattern of mediastinal irregularity on a chest CT scan in an individual who has resided in a region where histoplasmosis is prevalent can conclusively diagnose Post Histoplasma FM in numerous instances, particularly when interpreted by a pulmonologist or radiologist with expertise in this condition.^1,6

Incorporating intravenous contrast into a chest CT scan is often essential to highlight any possible vascular obstruction that might be present.⁷ Non-enhanced chest CT scans are also valuable in definitively identifying calcifications within the mediastinal tissue, which are indicative of post-histoplasma  FM.^1,7 A perfusion nuclear medicine scan might also be conducted to quantify the extent of reduced blood flow to lung regions due to vascular narrowing.⁷ In specific cases, magnetic resonance angiography (MRA) of the heart or cardiac MRI (cMRI) can provide additional insight, especially for a more comprehensive assessment of the pulmonary veins where they enter the left atrium – an area frequently affected by FM.^1,7

The chest CT scan may also exhibit one or multiple nodules within lung tissue, which might possess internal calcifications as well.^1,7 These lung nodules frequently signify the initial focus of Histoplasma infection inhaled into the lungs.^1,7 Calcifications within the spleen (an immune organ aiding in responding to Histoplasma infection) or, less frequently, the liver are also commonly observed. In cases of complete obstruction of blood flow to or from a lung region, signs of lung infarction may be evident, including thickening of septal membranes within the lung or scattered opacities.^1,7

In scenarios where a conclusive diagnosis cannot be solely derived from the CT scan, often occurring when internal calcifications characteristic of mediastinal abnormalities are absent, Histoplasma serologies can be particularly informative.^1,4,6,7 This test detects Histoplasma antibodies and is positive in the majority of Post Histoplasma FM cases, although not universally.^1,7 Ideally, an assay that identifies Histoplasma antibodies via both complement fixation and immunodiffusion should be employed.^1,7 Histoplasma antigen testing, which detects proteins released by living Histoplasma organisms, consistently yields negative results in FM cases.^1,7 The absence of calcifications within a lesion that otherwise fulfils radiographic FM criteria often prompts serological assessment for conditions known to be linked with idiopathic FM, including IgG4-related disease and granulomatosis with polyangiitis.¹

Laboratory tests: serology, fungal cultures

In scenarios where a conclusive diagnosis cannot be solely derived from the CT scan, often occurring when internal calcifications characteristic of mediastinal abnormalities are absent, Histoplasma serologies can be particularly informative.^1,7 This test detects Histoplasma antibodies and is positive in the majority of Post Histoplasma FM cases, although not always.^1,7 Ideally, an assay that identifies Histoplasma antibodies via both complement fixation and immunodiffusion should be employed. Histoplasma antigen testing, which detects proteins released by living Histoplasma organisms, consistently yields negative results in FM cases.^1,7 The absence of calcifications within a lesion that otherwise fulfils radiographic FM criteria often prompts serological assessment for conditions known to be linked with idiopathic FM, including IgG4-related disease and granulomatosis with polyangiitis.^1,7

Occasionally, a biopsy (removing a piece of tissue to examine under the microscope in the lab) of the anomalous mediastinal tissue is necessary to rule out malignancy, such as lymphoma, especially when the CT scan indicates that the abnormal tissue lacks characteristic internal calcifications associated with post-Histoplasma syndrome.^1,7 This can be performed through bronchoscopy using ultrasound guidance to obtain transbronchial needle aspiration samples via CT-guided transthoracic needle biopsy or surgical biopsy through thoracotomy or mediastinoscopy.^1,7 It's important to note that bronchoscopic biopsy should be approached cautiously if the lesion appears to be a mediastinal granuloma based on radiographic features, as non-sterile airways during transbronchial sampling may introduce bacteria and lead to infection necessitating surgical intervention.^1,7 Given this, and considering that lymphoma is a primary alternative diagnosis in many such cases and typically requires a sizable surgical biopsy specimen for definitive characterization, a surgical biopsy is often preferred to differentiate between mediastinal granuloma and lymphoma.¹

Differential diagnosis

Diagnosis might experience delays over the years due to nonspecific symptoms or unrecognized characteristic findings on scans.^1,7 Initial misdiagnoses may include asthma, pneumonia, chronic obstructive lung disease, pulmonary embolism with lung infarction, and, in cases involving impairment of the pulmonary veins, mitral stenosis with congestive heart failure.^1,7 The current widespread utilization of chest CT scans has significantly advanced the detection and diagnosis of FM.¹

Treatment

A standardized medical approach for FM has yet to be established. Medications such as corticosteroids have been utilized for their anti-inflammatory properties.^1,7 However, there is a lack of available efficacy data, and instances of reported improvement have been primarily observed in cases with diffuse mediastinal involvement.^1,7 Attempts have also been made with antifungal agents due to the connection between FM and endemic mycoses.^1,7 It's important to note that active infection is generally not evident at the time of diagnosis.^1,7 The 2007 practice guidelines issued by the Infectious Disease Society of America discourage the use of antifungal therapy for FM associated with histoplasmosis.^1,7 

Surgical intervention presents technical challenges, mainly due to the considerable risk of haemorrhage resulting from dilated collateral vessels. Surgical strategies encompass debulking and endovascular procedures like stenting or balloon angioplasty. In situations involving airway compression or obstruction, removal of the affected airway and related lung tissue might be necessary.² 

Prognosis

The prognosis of FM is dependent upon the size and location of the fibrotic mass. Notably, more severe clinical outcomes and elevated mortality rates are often associated with bilateral involvement.^1-7 In a comprehensive study conducted by Peikert et al., involving 80 patients, the overall survival rate was comparable to age-matched control groups. Interestingly, within their cohort, the sole two deaths related to FM transpired in cases where patients exhibited bilateral mediastinal involvement.² 

Summary and key points

• Fibrosing mediastinitis (FM) is a  rare yet progressive condition characterized by the abnormal overgrowth of fibrous tissue within the mediastinum, leading to a gradual constriction of airway and blood vessel structures commonly located in the mediastinum.^1,7
• FM is categorized into two distinct radiological subtypes: focal and diffuse. The focal subtype appears as a localized mass with soft-tissue density and stippled or dense calcification, whereas the diffuse subtype manifests as a widespread, infiltrating, and uniform soft-tissue presence throughout the mediastinal area.^1,7
• When encountering symptoms suggestive of respiratory or blood vessel compression, such as increasing breathlessness, chest pain, facial swelling, reddened conjunctiva, headaches, and dizziness, in a young patient, it's important to include FM in the list of potential differential diagnoses.^1,7
• CT scans and MRI scans play a pivotal role in diagnosing, assessing, and monitoring this condition.³