Granulomatous fibrosing mediastinitis is characterized by the idiosyncratic proliferation of fibrous tissue in response to antigenic stimulation and occurs in regions where the soil-based fungus Histoplasma capsulatum is endemic (such as the Ohio and Mississippi River valleys), and many patients are seropositive for histoplasma antigens [14]. However, other infections, such as tuberculosis [12], aspergillosis [15, 16], blastomycosis [17], mucormycosis [14], and cryptococcosis [2], can also cause granulomatous fibrosing mediastinitis as can sarcoidosis [18].

When granulomatous fibrosing mediastinitis results from respiratory histoplasmosis, the initial infection typically is subclinical [14]. As the fungus disseminates throughout the reticuloendothelial system, a cell-mediated immune response ensues, leading to granuloma formation in involved organs; these granulomas are prone to caseous necrosis and dystrophic calcification [1, 11]. Consequently, the hallmark of histoplasmosis is the formation of calcified granulomas in the lung, mediastinal lymph nodes, liver, and spleen.

Typically, mediastinal granulomas are well encapsulated and do not affect adjacent mediastinal fat or viscera. However, in a minority of patients, the mediastinal granulomas enlarge and rupture, releasing histoplasma antigens into the mediastinum and stimulating a fibroinflammatory reaction that can be localized or diffuse [18]. It remains unclear why only certain patients develop fibrosing mediastinitis, but humoral variables have been implicated. One case-control study of 19 granulomatous fibrosing mediastinitis patients found that presence of the HLA-A2 antigen was associated with a 3.32-fold relative risk for fibrosing mediastinitis [13]. Regardless of the underlying cause, the specific manifestations of fibrosing mediastinitis depend on the structures involved and their function, mechanical compliance, and ability to resist constriction.

Granulomatous fibrosing mediastinitis appears as a focal mass with variable contrast enhancement and dense or stippled calcification [19, 20] (Figs. 1B, 1C, 2B, 3A, and 3B). Other signs of histoplasmosis may be present, such as calcified granulomas in the lungs, liver, and spleen (Figs. 3C and 4D) and broncholithiasis [21–23], which results when calcified granulomas encroach on or erode into bronchi.

The chest radiograph is abnormal in most cases of fibrosing mediastinitis, but features are usually not specific. The most common findings are mediastinal widening and lymphadenopathy in subcarinal, right paratracheal, and right hilar regions [19, 50, 51]. Calcification of mediastinal or hilar nodes is present in up to 86% of patients [14].

On contrast-enhanced CT, the fibrotic tissue has variable enhancement. CT also shows the extent and severity of visceral encroachment. Multiplanar reformatted views help in showing stenoses of airways and vessels (and collateral pathways) and in planning therapeutic interventions (Figs. 4A, 4B, 4C, and 4D).

MRI is equivalent to CT in identifying mediastinal and hilar lymphadenopathy [20, 24], and MR angiography may add information about vascular compromise beyond that provided by CT. Granulomatous fibrosing mediastinitis typically has intermediate signal intensity on T1-weighted MRI and variable intensity on T2-weighted MRI; contrast enhancement is variable [20, 24] (Figs. 2A, 2B, and 2C). Foci of relative hypointensity may be seen on both T1- and T2-weighted images, caused by calcification or by hypocellular collagenous scar [24, 52].

Imaging should be tailored to address the specific clinical question. Because the radiographic findings of granulomatous fibrosing mediastinitis are nonspecific and because MRI does not reliably show calcification, CT is the modality of choice in suspected granulomatous fibrosing mediastinitis. Although catheter angiography remains the reference standard for characterizing vascular compromise by granulomatous fibrosing mediastinitis, it has been mostly supplanted by CT and MR angiography, and its main current use is for placing vascular stents.

Radionuclide pulmonary scintigraphy may show partial or complete compromise of ventilation or perfusion. Both qualitative and quantitative techniques may help in evaluating pulmonary arterial or airway compromise [26, 53–55]. However, ¹⁸F-FDG PET is not routinely used for the evaluation of granulomatous fibrosing mediastinitis; case reports have shown variable FDG-avidity [56–59].

In the appropriate clinical setting, characteristic imaging findings may suffice for diagnosis. Specifically, when a young patient from an area endemic for histoplasmosis presents with a calcified mediastinal mass, granulomatous fibrosing mediastinitis is the most likely diagnosis. Concomitant calcified granulomas in the lungs, liver, or spleen strongly suggest antecedent histoplasmosis [1]; however, other causes of nodal calcification must be considered, such as tuberculosis, treated lymphoma, and metastatic osteosarcoma or mucinous adenocarcinoma [60].

When the mediastinal mass does not contain calcifications and no secondary signs of histoplasmosis are present, the diagnosis of granulomatous fibrosing mediastinitis is less certain. A practical differential diagnosis for granulomatous fibrosing mediastinitis includes primary lung cancer, mediastinal or hilar metastasis (particularly sclerosing adenocarcinomas, such as the breast), sclerosing non-Hodgkin lymphoma, and nodular sclerosing Hodgkin disease [61, 62]. A definitive diagnosis requires histologic analysis and culture [19, 51]. Any infiltrating and fibrous lesion must be sampled extensively to exclude occult malignancy underlying the fibrosis [2]. Biopsy of such a mass usually requires mediastinoscopy, thoracoscopy, or open thoracotomy.

The prognosis for patients with granulomatous fibrosing mediastinitis is uncertain. Although most cases progress slowly, some remain stable for several years and spontaneous regression has been reported [14]. Patients with bilateral or subcarinal disease may be have worse outcomes [11]. Causes of death include recurrent postobstructive pneumonia [63], hemoptysis, and cor pulmonale [30, 32].

According to guidelines issued by the Infectious Diseases Society of America, medical treatment of histoplasma-associated granulomatous fibrosing mediastinitis is usually unnecessary, although there is some support for a 12-week course of itraconazole in patients with symptomatic mediastinal granulomata [64]. Isolated reports have described successful management of fibrosing mediastinitis with corticosteroids [36] and tamoxifen [65], but organized trials are lacking.

Symptomatic airway constriction can be treated with bronchoscopic balloon dilation and stenting [14, 66]. Hemoptysis and pulmonary hemorrhage can be treated with transcatheter embolization and endobronchial laser coagulation [55]. Stenosis of the SVC or pulmonary artery can be treated with percutaneous balloon angioplasty and stenting [67–73], but retreatment is often needed and many patients go on to surgical repair [11, 14, 74].