280 Thorax 1995;50:280-283 Sclerosing mediastinitis: a report on 18 cases Thorax: first published as 10.1136/thx.50.3.280 on 1 March 1995. Downloaded from

T M Mole, J Glover, M N Sheppard

Abstract obstruction.2 The condition was thought to be Background - Sclerosing mediastinitis is secondary to or syphilis until 1925 a rare condition which causes dense fib- when Knox reported an association with fungal rosis of the . Few large stud- .3 It is very rare and there are few ies have been reported to date. The clinical details concerning large groups of sclerosing and pathological features of cases have mediastinitis. At the Royal Brompton Hospital been studied in a specialist referral centre we have collected, in the last 20 years, 18 cases in the UK. of sclerosing mediastinitis. The object of this Methods - The pathological files of the study was to detail the epidemiological, patho- Royal Brompton Hospital were examined logical, and clinical features of these cases. and 18 cases of sclerosing mediastinitis were identified between 1970 and 1993. The clinical notes were obtained and the patho- Methods and results logical specimens analysed. The histopathology files from 1970 to 1993 Results - There were 12 men and six were studied and 18 cases diagnosed as women of age range 9-64 years. Twelve sclerosing mediastinitis were found. The case patients presented with shortness of notes and all the histopathological sections of breath, six had haemoptysis, three had each case were studied. In each patient the age, hoarseness, four had pleuritic chest pain, sex, nationality, family history, drug exposure, three general weakness, two had dys- previous disease, chemotherapy, radiotherapy, phagia, and one was asymptomatic. Nine travel, radiology, investigations for , patients had a previous history of pul- diagnosis, surgical procedure, and follow up monary tuberculosis. Two had auto- were analysed. immune disease - one rheumatoid arthritis and the other systemic lupus erythematosus. There were three cases PATIENT DETAILS http://thorax.bmj.com/ of previous malignancy - two un- Twelve of the 18 patients were men; their age differentiated carcinoma of the lung and range was 9-64 years. Eleven (62-5%) were the other Hodgkin's disease. Serological smokers. None had a family history of tests revealed only one positive reaction to sclerosing mediastinitis but 12 (66%) had a Histoplasma. The erythrocyte sedi- previous history of other disease. Two had well mentation rate and serum immuno- established autoimmune disease (one rheum- globulins were raised in nine patients. atoid arthritis and the other systemic lupus Diagnosis was usually by thora- erythematous), three had a previous malig- on September 26, 2021 by guest. Protected copyright. cotomy with biopsy. All cases had fib- nancy (two non-small cell carcinoma of the rosis and chronic with no lung with mediastinal lymph node involvement active . No infective organisms and one Hodgkin's disease), all diagnosed and or positive cultures were obtained in any treated at least three years before presentation case. Ten of the 18 cases are alive up to 15 of their mediastinal symptoms. These three years after diagnosis, with only two deaths patients had been given cytotoxic chemo- and six lost to follow up. therapy and radiotherapy to the chest. Nine Conclusions - Sclerosing mediastinitis is patients had a history of previous pulmonary Department of Surgery a slowly progressive condition associated tuberculosis, one ofwhom also had rheumatoid T M Mole with previous tuberculosis, mediastinal arthritis, another non-small cell carcinoma of malignancy, and autoimmune disease. the lung, while one other had lived in the USA Department of Radiology The outlook is excellent for those cases for five years in an area in which Histoplasma J Glover without underlying malignancy. was endemic and seroconverted for Histoplasma (Thorax 1995;50:280-283) whilst there after an -like illness with Department of Pathology respiratory symptoms. None had taken specific M N Sheppard Keywords: sclerosing mediastinitis, tuberculosis, histo- drugs associated with fibrogenesis, in particular plasmosis, autoimmune disease. methysergide. Royal Brompton in National Heart and The clinical features are summarised the Lung Hospital, table. The highest documented erythrocyte London SW3 6NP, UK Sclerosing mediastinitis is a rare condition in sedimentation rate was 55 mm/hour. Details Reprint requests to: which there is and sclerosis of the me- concerning BCG immunisation were not found Dr N Sheppard. diastinum with resulting obstruction to intra- in the case notes. Serological tests for hepatitis, Received 13 August 1993 thoracic organs. It was first reported by fungi, mycoplasma, cytomegalovirus, influenza Retumed to authors 10 January 1994 Oulmont in 1855 who classified it as idiopathic virus, adenovirus, and psittacosis were negative Revised version received fibrous mediastinitis.1 In 1930 Osler described in all patients tested, except for the one case 13 May 1994 Accepted for publication additional patients with mediastinal fibrosis of in whom the Histoplasma titre was positive. 23 November 1994 unclassified aetiology and superior vena caval Radiological details are also given in the table. Sclerosing mediastinitis: a report on 18 cases 281 Clinical and radiologicalfeatures of 18 patients with sclerosing mediastinitis n Thorax: first published as 10.1136/thx.50.3.280 on 1 March 1995. Downloaded from Symptoms Shortness of breath 12 Haemoptysis 6 Dysphagia 2 Hoarseness 3 Pleuritic chest pain 4 Malaise 3 Asymptomatic 1 Investigations ESR (16-55 mm/hour) 9 IgG (16-20g/1) 9 Mantoux (17) +7 Histoplasma (6) +1 Radiology Mediastinal widening 9 Hilar widening 5 Calcification 7 Vena caval obstruction 6 ESR =erythrocyte sedimentation rate.

.W,._ B.k;X..-...**. -. .. Calcification ofthe mediastinal mass was noted Figure 2 Section of tissue from mediastinum showing hyaline fibrosis in the centre with the periphery containing in seven of the patients (fig 1). No evidence of lymphoidfollicles infiltrating fat. Original magnification active tuberculosis was seen. One case showed x 200 reduced to 61% in origination. diffuse infiltration ofthe right middle lobe while another showed a large mass at the right hilum. Six patients had superior vena cavagrams, all of whom had clinical evidence of vena caval obstruction. The initial impression in all and another for a suspected thymic mass. Two had a one for a right patients was of mediastinal malignancy. patients thoracotomy, middle lobectomy and the other a right lower lobectomy for associated with a right hilar mass. Two cases were diagnosed SURGICAL PROCEDURES Bronchoscopy was performed in all patients at necropsy. In each surgical case sufficient material was removed for diagnostic purposes

and in two cases there was evidence of external http://thorax.bmj.com/ compression because the wall of the but complete resection of the fibrous mass was In all cases who underwent surgery appeared to be distorted and narrowed but no impossible. was of thoracic endobronchial lesions were seen. Both pro- there extensive involvement vided sufficient biopsy material to make a diag- organs by the fibrosing process, with the lungs nosis in keeping with sclerosing mediastinitis. being involved in 11 cases, the phrenic nerve seven, vena cava in and Four patients proceeded to mediastinoscopy in the superior eight, because of a mass at the hilum with probable the pulmonary artery in two. Six patients had a superior vena caval bypass with woven silicone

paratracheal and subcarinal lymph node in- on September 26, 2021 by guest. Protected copyright. volvement. Eight patients had a median stern- prostheses (three cases), autogenous saphenous otomy, six for superior caval bypass grafting, vein graft (two cases), and glutaraldehyde fixed routine bovine pericardial graft (one case) from the one for coronary artery bypass grafting, junction of the right and left brachiocephalic veins to the superior vena cava, bypassing the fibrous mediastinal mass. No stents were used in any of the grafts.

PATHOLOGICAL FINDINGS One bronchial biopsy sample showed pro- liferation of dense fibrous tissue within the wall of the bronchus associated with plasma cells and lymphocytes, while a second sample showed chronic inflammmation only. These were considered sufficient evidence to make a probable diagnosis of sclerosing mediastinitis. During the other procedures several blocks of tissue taken from the mediastinum showed areas of dense hyaline sclerosis with interlacing bundles of fibrous tissue extending into loose connective tissue and fat (fig 2). The fibrous tissue often contained acellular hyaline fibrosis as its centre with an inflammatory edge in- cluding lymphocytes with lymphoid follicle Figure 1 Computed tomographic scan through the mediastinum at the level of the aortic formation. This fibrous proliferation extended arch. A confluent abnormal soft tissue mass can be seen surrounding and deforming the main bronchi. A focus of calcification is seen in the subcarinal region, presumably within into the lumen of the mediastinal blood vessels a lymph node mass. Previous history of tuberculosis. (fig 3). Admixed with the fibrous tissue were 282 Mole, Glover, Sheppard monest cause in the USA4), aspergillosis, mu- cormycosis, cryptococcosis, blastomycosis, and ...... mycobacteria. Non-infectious causes5 include autoimmune disease, , rheumatic Thorax: first published as 10.1136/thx.50.3.280 on 1 March 1995. Downloaded from fever, neoplasms such as Hodgkin's disease, traumatic haemorrhage and drugs, particularly methysergide.6 In rare instances it is familial and multifocal with patients presenting with retroperitoneal and mediastinal fibrosis, scler- osing cholangitis, Riedel's thyroiditis, and pseudotumour of the orbit.7 This is the first analysis of a relatively large group at one referral centre and demonstrates the association with pulmonary tuberculosis, 50% of the cases having a history of tuber- culosis, most of whom were British. Only one case was associated with - in contrast to the situation in the USA where histoplasmosis is the most frequently im- plicated aetiological factor8 - and even this case had a history of previous pulmonary tuber- culosis. Mediastinal lymphadenopathy can be Figure 3 Inflammatory fibrous tissue containing plasma cels and lymphocytes a prominent feature in some cases of adult infiltrating the wall and lunmen (arrows) of a mediastinal vein. Original magnification tuberculosis in the UK, especially in im- x 250, reduced to 71% in origination. migrants, and has been reported as progressing to sclerosing mediastinitis in some.9 There was many plasma cells and lymphocytes. No nec- no evidence of any other infective agent playing rosis, granulomas, or giant cells were noted a part in the aetiology ofsclerosing mediastinitis in any of the sections examined. In the two in our study. No active granulomas or infectious pulmonary resection specimens the fibrosing agent could be found in the resected tissues, process extended into the pleura and the in- which is the usual finding when fibrosis is terstitium ofthe lung. Appearances were ident- extensive.4 ical to fibrosing alveolitis. Special stains for Surgery was necessary in most of the cases acid fast bacilli and fungi were negative in for a specific diagnosis as suspicion of malig- all tissues examined and cultures were also nancy was high. It is essential to sample ex- http://thorax.bmj.com/ negative. tensively in order not to miss an underlying neoplasm as there can be considerable fibrosis associated with some tumours, especially FOLLOW UP lymphomas. In all patients it was not possible Twelve patients were followed up for 5-20 to resect the fibrous tissue, and bypass of the years while six were lost to follow up. These superior vena cava was undertaken in six cases six had been referred from abroad and contact with good results which have been reported was lost. Ten patients were alive and free from previously.'0 However, others have found sur- on September 26, 2021 by guest. Protected copyright. symptoms, including three who had superior gery for bypass difficult with poor results." vena caval bypass grafting. Death occurred in The pathogenesis of extensive progressive only two cases due to Hodgkin's disease and fibrosis within the mediastinum remains un- non-small cell bronchial carcinoma. The clear. Kunkel et al'2 suggested that mediastinal patient with Hodgkin's disease died ofbroncho- fibrosis resulted from traumatic rupture of within two years of diagnosis; granulomatous lymph nodes. Goodwin et all" no residual tumour was found at necropsy but proposed the currently most acceptable hy- there was widespread fibrosis of the media- pothesis that sclerosing mediastinitis results stinum with involvement of both lungs. The from a delayed hypersensitivity reaction to other patient also died of fungal, mycobacterial, or other unknown an- with an enlarged mediastinum but no necropsy tigens. The history of tuberculosis in half of was performed so the possibility of residual our patients, the infiltration of the fibrous mass tumour could not be eliminated. There are no by plasma cells and lymphocytes, and the raised details available concerning the use of anti- serum immunoglobulin levels support an im- tuberculous and antifungal agents or steroids munological reaction. The use of antifungal in any of the cases. and antituberculous agents has been advocated in cases with evidence of active granulomas'4 but these, as well as steroids, are generally Discussion not useful in established cases with extensive Sclerosing mediastinitis is a rare condition and fibrosis.'5 Most reports emphasise the benign only 180 cases had been reported up to 1969.4 nature of the condition and advocate minimal Since then reports in Europe have been of intervention unless symptoms become life single cases or small groups as experience of threatening."5 this condition is limited. Among the accepted causes of sclerosing mediastinitis infection is The authors wish to thank Mr SC Lennox, Mr P Goldstraw, the most common, especially fungal infections and Mr D Kaplan for access to their patients and Miss Pinuccia including histoplasmosis (which is the com- Mole for typing the manuscript. Sclerosing mediastinitis: a report on 18 cases 283

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New York: Raven Press, 1984:16-28. granuloma. J Thorac Surg 1954;27:565-74. 6 Graham JR, Suby HI, LeCompte PR, Sadowsky NL. Fib- 13 Goodwin RA, MickellJA, Des Prez RM. Mediastinal fibrosis rotic disorders associated with methysergide therapy for complicating healed primary histoplasmosis and tuber- headache. N Engl Med 1966;274:359-68. culosis. Medicine 1972;51:227-46. 7 Comings DE, Skubi KB, Van Eyes J, Motulski AG. Familial 14 Urschel HC Jr, Razzuk MA, Netto GJ, Disiere J, Chung multifocal fibrosclerosis. Findings suggesting that retro- SY. Sclerosing mediastinitis: improved management with peritoneal fibrosis, mediastinal fibrosis, sclerosing histoplasmosis titer and ketoconazole. Ann Thorac Surg cholangitis, Riedel's thyroiditis and pseudotumour of the 1990;50:215-21. orbit may be different manifestations of a single disease. 15 Dines DE, Payne WS, Bematz PE, Pairolero PC. Me- Ann Intern Med 1967;66:884-92. diastinal granuloma and fibrosing mediastinitis. Chest 8 Anonymous. Case records of the Massachusetts General 1979;75:320-4. http://thorax.bmj.com/ on September 26, 2021 by guest. Protected copyright.