Fungal fibrosing mediastinitis in pregnancy - Case report with review of literature.

Fibrosing mediastinitis (FM) is characterized by extensive and invasive fibro-inflammatory proliferation, triggered by a delayed hypersensitivity reaction to variety of infective or noninfective stimuli. The infective agents often have a geographic distribution such as Histoplasma capsulatum in North America and Mycobacterium tuberculosis in Asian regions. In few reports, the mediastinitis is caused by fungi, particularly Aspergillus species. We report the first case of possible aspergillous FM in a young pregnant woman.

Introduction

Mediastinitis is inflammation of the connective tissue that surrounds the structures contained within the mediastinum. In sharp contrast to the acute exudative inflammatory response seen in acute mediastinitis, chronic mediastinitis is characterized by extensive and invasive fibro-inflammatory proliferation. Hence, it is often designated as fibrosing mediastinitis (FM) or sclerosing mediastinitis or simply as mediastinal fibrosis.[1] The exuberant proliferation of fibrous tissue is triggered by a delayed hypersensitivity reaction to variety of infective or noninfective stimuli, resulting in compression of mediastinal structures; this leads to significant morbidity and at times even mortality.[2] The infective agents often have a geographic distribution, for example, in North America; FM is commonly associated with Histoplasma capsulatum,[2] whereas in Asian regions, it may be related to tuberculosis.[3] In few reports, FM has resulted from infection with Aspergillus species.[4] We report the first case of possible aspergillous FM in a young pregnant woman with a review in the last 10 years.

Case Report

A 26-year-old woman with 32-week amenorrhea had been admitted in a private health-care facility with complaints of headache for the past 20 days. This was followed by three episodes of generalized seizures and unconsciousness. A clinical diagnosis of eclampsia (blood pressure of 150/100 mmHg) had been made, for which emergency lower segment cesarean section was performed. She was treated with anticonvulsants, magnesium sulfate, and antibiotics. The condition stabilized over the next 2 days, but on postpartum day 3, she again had generalized tonic–clonic convulsions. Magnetic resonance imaging (MRI) of the brain revealed presence of tuberculomas in the right frontal and parietal regions. She was then transferred to our tertiary-care institute. On examination, her general condition had been fair; she was conscious and oriented. The pulse was 90/min and blood pressure was 150/100 mmHg. Apart from moderate neutrophilia (21,700/cmm), her other hematological and biochemical investigations had been normal. Serological workup for HIV and hepatitis B/C was negative. A repeat MRI of brain revealed a large (5.3 × 3.9 × 3.6 cm) heterogeneous mass (isointense on T1 and hypointense on T2) in right frontoparietal region with significant mass effect, which was interpreted as tuberculoma. She received antituberculous drugs, intracranial tension-lowering agents, and anticonvulsants. Despite the therapy, the patient developed severe headache, convulsions, left-sided hemiparesis, motor aphasia and increasing drowsiness, and finally succumbed. A complete autopsy was requested.

Remarkable findings were seen in the mediastinum and the brain. The anterior mediastinum showed a large 9 × 8 × 6 cm slightly H-shaped [Figure 1a], extremely firm to stony hard, partially capsulated mass with a pale yellow to focally congested cut surface. It had encased the superior vena cava and its tributaries, arch of aorta and its branches [Figure 1b], the pulmonary arteries, the trachea, main bronchi, and proximal 4 cm of the descending thoracic aorta [Figure 1c]. It was also adherent to the esophagus and right lung hilum. The mediastinal mass was essentially composed of densely collagenized fibrous tissue with foci of vascularisation, lymphoplasmacytic infiltrate, occasional aggregates of neutrophils and eosinophils, and scattered granulomatous reaction [Figure 1d and e]. In many areas, there was abundant perivascular inflammation with focal vasculitis and luminal fibrin thrombi [Figure 2a and b]. The central portion of the mass showed a large area of coagulative necrosis [Figure 2c]. The giant cells were of both foreign body and Langhan's types. The cytoplasm in some of them contained refractile, slender, and lightly basophilic septate hyphal structures [Figure 2d]. The fibro-inflammatory reaction had infiltrated into surrounding adipose tissue. Other structures were not involved.

Figure 1

(a) Large slightly H_shaped anterior mediastinal mass, partially capsulated with tags of adipose tissue; the mass had a yellowish brown cut surface and had encased (b) the right RIV and left innominate (LIV), veins, and arch of aorta, and (c) the proximal descending thoracic aorta (DTA) and tracheo_bronchial tree (LB = left bronchus, RB = right bronchus, T = trachea); (d) granulomatous inflammation amidst extensive sclerosis (H and E × 250); and (e) Langhan's giant cells (arrows) accompanied by lymphocytes and few plasma cells (H and E × 400)

Figure 2

Small vessels showing (a) nonocclusive fresh fibrin thrombus (arrow) and (b) fibrinous and inflammatory obliteration (H and E × 400), (c) coagulative necrosis (H and E × 250), and (d) lightly basophilic intracytoplasmic septate hyphal form (arrow) seen in the giant cell (H and E × 400)

The brain was extremely edematous and very friable. On serial coronal slices, a large well-circumscribed, nodular, firm mass was seen in the right frontoparietal region [Figure 3a]. The histology showed dense perivascular mononuclear inflammation, granulomatous inflammation, and vasculitis with fibrin thrombi; many acute-angle branching septate fungal filaments were seen amidst and within the giant cells [Figure 3a–d]. Gomori methanamine silver stain confirmed the presence of fungal filaments [Figure 3, inset]. Their morphology was suggestive of Aspergillus species. The kidneys showed acute tubular necrosis. Multiple sections taken from the lungs did not show any involvement; rest of the organs were unremarkable.

Figure 3

(a) Well_preserved coronal slice showing a circumscribed friable subcortical area (arrow) in the right frontoparietal region, (b) there was prominent perivascular lymphohistiocytic infiltrate (arrows, H and E × 250), (c) the giant cells (arrow), and (d) obliterated vessels and the white matter showed presence of septate hyphal forms (arrows, H and E × 400). Inset shows septate hyphae demonstrated by the Gomori methenamine silver (×400)

Discussion

In this report, we have presented a pregnant woman with neurological manifestations, who had a clinically undetected, circumscribed inflammatory mediastinal mass. It was composed of granulomatous reaction with intense fibro-collagenization replete with septate hyphae, which suggested the morphology of Aspergillus species. In general, both infective and noninfective cases of FM share similar histopathologic features, mainly in the form of edematous fibromyxoid tissue to dense lamellar or whorled collagenic fibrosis with prominent lymphoplasmacytic infiltration and obliterative vascultitis.[1] Most of the infective causes of FM are due to fungal (especially Histoplasma) and mycobacterial infections. The agents induce myofibroblastic proliferation and collagen overproduction as an idiosyncratic reaction mediated via cytokines released by activated lymphocytes and macrophages.[2] Added feature is the presence of granulomatous reaction, and such a “granulomatous infection-associated“ FM is said to be localized, calcified, and often right-sided.[5] Our case had a large, localized, H-shaped (possibly the thymic configuration) mass caused possibly by Aspergillus species. Since its first description in 1971,[6] there have been only five cases[4789] published in the last 10 years [Table 1], indicating that this is an uncommon manifestation. It is important to distinguish this mass-forming aspergillous infection from the mediastinal invasion and abscess formation seen in immunocompromised or immunosuppressed individuals.

Table 1

Fibrosing mediastinitis due to Aspergillus species

S. no. and Ref.	Age and sex	Clinical presentation	Organism	Treatment/Outcome
1. Wightman et al.[4]	78 years, female	Immunocompetent	Aspergillus flavus	Voriconazole therapy
		Community-acquired pneumonia 5 years ago with persistence of right lower lobe infiltrate		Alive
		Asymptomatic with progression and formation of right hilar mass with encasement of the right lower lobe bronchus, inferior pulmonary vein, and encroachment on the left atrium
2. Brooks et al.[7]	27 years, female	Immunocompetent	Aspergillus flavus	Initial Voriconazole therapy
		Asymptomatic		Development of mobile bi-atrial masses and occlusion of the right upper and lower pulmonary veins (operated)
		Routine trauma CT series – incidental right pulmonary nodules, hilar lymphadenopathy, and a large inferior mediastinal mass
				Septic left coronary, splenic, the posterior tibial artery, and hepatic arteries
				Voriconazole and caspofungin therapy
				Development of left subdural hematoma, cerebellar vermis abscess, left parietal hemorrhage and mycotic aneurysm of the middle cerebral artery
				Alive
3. Chatterjee et al.[8]	29 years, male	Immunocompetent	Aspergillus flavus	Antibiotic therapy
		Fever, shortness of breath, cough, hemoptysis		Expired; autopsy – Aspergillus pancarditis with dissemination to kidneys and spleen
		CT – homogeneous plaque-like mass encasing the heart, tracheobronchial tree, pulmonary arteries, and all thoracic segments of the aorta; minimal pericardial effusion along the lateral wall of right atrium; normal lung fields
		Echocardiography – mass over thickened posterior mitral leaflet
4. Chatterjee et al.[8]	40 years, male	Immunocompetent	Fungal speciation not performed	Antibiotic therapy
		Chest pain, cough with expectoration, shortness of breath, streaky hemoptysis, and hematuria		Expired; autopsy – Aspergillus pancarditis with dissemination to kidneys and pancreas
		Echocardiography – minimal pericardial effusion; mobile mass attached to the posterior mitral leaflet and left atrial wall
5. Stern et al.[9]	42 years, female	Immunocompetent	Aspergillus flavus	Voriconazole therapy
		Low-grade fever, cough		Alive
		CT – mediastinal mass surrounding the left pulmonary artery and the descending aorta, with compression of the left main bronchus; solitary round lesion in the right frontal lobe
6. Present case	26 years, female	Pregnant	Fungal speciation not performed	Antituberculous therapy
		Headache, generalized seizures, unconsciousness		Expired; autopsy – fungal granuloma in right frontoparietal region
		MRI – mass lesion over right frontoparietal region

In general, the clinical presentations of FM are related to compression and obstruction of vital mediastinal structures, irrespective of the etiopathogenesis. Important among them are major airways, superior vena cava, pulmonary arteries, and pulmonary veins, though some patients can remain asymptomatic.[10] As can be seen from the tabulation of the recently reported cases, all patients had been immunocompetent and only two patients[47] were asymptomatic at the initial presentation, despite concomitant lung involvement (favored site of Aspergillus colonization/infection). Our patient was also asymptomatic as regards to the mediastinal mass and did not have any lung lesion. She was pregnant, and pregnancy is usually considered as an immunomodulated state with increased vulnerability to infections, which includes fungal etiology as well.[11] Well-formed granulomas were noted not only in the FM but also in the cerebral mass lesion, which had been documented in one other case.[9] It is of interest to note that such mass lesions induced by Aspergillus in the central nervous system are also very uncommon.[12] Our case is also unique as reports of FM in pregnancy are vanishingly rare with few reports.[1314]

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Conflicts of interest

There are no conflicts of interest.