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A 44-Year-Old Man With Chronic Cough, Weakness, and a Mediastinum MassMan With Cough, Weakness, and Mediastinum Mass FREE TO VIEW

Dimitrios Theofilos, MD; Christina Triantafillidou, MD, PhD; Athanasios Zetos, MD; Danai Bisirtzoglou, MD, PhD; Froso Konstantinou, MD; Charalampos Marketos, MD; Georgios Politis, MD, PhD
Author and Funding Information

From the Pulmonary Department (Drs Theofilos, Triantafillidou, Zetos, Bisirtzoglou, Marketos, and Politis), Agios Savvas Anticancer-Oncology Hospital of Athens; and 6th Pulmonary Department (Dr Triantafillidou) and Internal Medicine Department (Dr Konstantinou), Sotiria General Hospital of Chest Diseases, Athens, Greece.

CORRESPONDENCE TO: Christina Triantafillidou, MD, PhD, 6th Pulmonary Dept, Sotiria General Hospital of Chest Diseases, 2 Limnou St, Palaiopanagia-Peania, 19002 Athens, Greece; e-mail: xristina.triantafyllidou@gmail.com


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(3):e86-e90. doi:10.1378/chest.14-2982
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A 44-year-old white man presented with a 3-month history of dry cough and weakness. He had already been treated with antibiotics without any relief. He did not report dyspnea, fever, or expectoration. The patient’s medical history was significant for mild arterial hypertension and autoimmune thyroiditis with normal thyroid hormone levels. He was a nonsmoker and had been in excellent health until symptom onset.

Figures in this Article

Physical examination revealed a BP of 130/80 mm Hg, pulse of 80 beats/min, respiratory rate of 15 breaths/min, temperature of 36.7°C, and oxygen saturation of 98% on room air. Lung examination revealed normal breath sounds, and the rest of examination was normal.

The patient had a normal WBC count, hematocrit and platelet levels, coagulation study results, and urinanalysis. Complete metabolic panel values, ECG, spirometry, and diffusing capacity of lung for carbon monoxide were also normal. Chest radiograph was normal. Chest CT scan (Fig 1) revealed a soft-tissue mass adjacent to the aortic arch with enlargement of the aortopulmonary window lymph nodes. The lung parenchyma appeared normal. Subsequent CT imaging of the abdomen was unremarkable. Fiber-optic bronchoscopy did not reveal pathologic endobronchial findings, and bacterial and fungal cultures and acid-fast staining of bronchial washing and aspirates were negative. A surgical biopsy of the mediastinal mass was performed, and pathologic examination revealed extensive fibrotic tissue infiltrating adipose tissue and regional vessels associated with dense polyclonal lymphoplasmacellular infiltration with more IgG4-positive (IgG4+) plasma cells (Fig 2). Grocott methenamine silver staining was negative. Serum IgG4 level was increased (174 mg/dL [normal values < 135 mg/dL]).

Figure Jump LinkFigure 1 –  Chest CT scan showing a soft-tissue mass adjacent to the aortic arch with enlargement of aortopulmonary window lymph nodes.Grahic Jump Location
Figure Jump LinkFigure 2 –  A, Mediastinal mass section obtained by thoracic surgery showing a storiform pattern of fibrosis and intense tissue infiltration by nonspecific-type inflammatory cells. Also showing are lymphoplasmatic infiltrate and obliterative phlebitis (hematoxylin-eosin, original magnification × 200). B, Immunohistochemical stains showing diffuse and intense distribution of IgG4-positive plasma cells with local confluence of > 50 IgG4-positive plasma cells per high-power field (original magnification × 200).Grahic Jump Location
What is the diagnosis?
Diagnosis: IgG4-related fibrosing mediastinitis

IgG4-related disease (IgG4-RD) encompasses a spectrum of fibroinflammatory conditions once regarded as entirely separate diseases associated with elevated circulating levels of IgG4, which can potentially affect almost every organ system. Since the first reports of increased IgG4 in autoimmune pancreatitis in 2001, knowledge has been rapidly growing about the pathogenesis, clinical features, histopathology, and treatment strategies of these novel lymphoproliferative disorders, leading to a growing number of new entities now recognized as IgG4-RD. Pancreas, liver, thyroid, salivary, and lacrimal glands are the most frequently affected organs. The clinical picture depends on the organ affected; thus, it is highly heterogeneous.

An international symposium on IgG4-RD convened in 2011 established comprehensive diagnostic criteria for IgG4-RD. The diagnosis of IgG4-RD is supported by the combined presence of the characteristic histopathologic appearance, more IgG4-staining plasma cells in the biopsy specimen of a patient with either localized or diffuse edema or mass or dysfunction in single or multiple organs, and a hematologic examination showing elevated serum IgG4 concentrations. Histopathologic features comprise a dense lymphoplasmatic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. IgG4 immunostaining is an essential test for diagnosis; at least 10 IgG4+ cells per high-power field or a ratio of IgG4+ cells to total IgG+ plasma cells exceeding 0.4 to 0.5 is required for a definite diagnosis. The positive predictive value of an elevated serum IgG4 level is poor, being in the range of 34% in one recent study. Conversely, the negative predictive value has been demonstrated to be > 95%. Normal concentrations of serum IgG4 are mainly noticed among patients with IgG4-RD with single-organ involvement, whereas the mean IgG4 level among patients with multiorgan disease is higher compared with those with single-organ disease. Probable and possible cases are also recognized according to criteria (Table 1).

Table Graphic Jump Location
TABLE 1 ]  Comprehensive Clinical Diagnostic Criteria for IgG4-RD

Criteria as proposed in 2011 by Umehara et al: definite, 1 + 2 + 3; probable, 1 + 3; possible, 1 + 2. IgG4-RD = IgG4-related disease.

The first reports of IgG4-related lung disease included patients with autoimmune pancreatitis and diffuse interstitial lung disease or pulmonary nodules. Since, a wide and heterogeneous spectrum of intrathoracic abnormalities has been reported, with mediastinal and hilar lymphadenopathy being the most common manifestations. However, patterns of pulmonary involvement in IgG4-RD of the lung can take the form of solitary or multiple lung masses and nodules, ground glass opacities, diffuse infiltrates or consolidation, interstitial lung disease, airway stenosis and obstruction, bronchiectasis, and pleural disease (pleural effusion, thickening and nodular pleural lesions). In a cross-sectional study of 114 patients with IgG4-RD, 14% were given a diagnosis of lung or pleural involvement, whereas in another retrospective study, approximately one-half of patients with IgG4-related autoimmune pancreatitis had evidence of pulmonary disease on imaging studies.

Fibrosing mediastinitis is an unusual manifestation of IgG4-RD because only a few cases of IgG4-related fibrosing mediastinitis have been reported in the literature. Interestingly, in a retrospective study of 15 cases of histologically confirmed fibrosing mediastinitis, three patients were given a diagnosis of definite IgG4-RD, a fact that may reflect the possible underestimation of this combined entity. The rarity of fibrosing mediastinitis in association with IgG4-RD stands in contrast to retroperitoneal fibrosis, which is much more common within the spectrum of IgG4-RD.

Mediastinal fibrosis or fibrosing mediastinitis is a benign but potentially progressive and life-threatening disorder characterized by an excessive storage of dense fibrous tissue within the mediastinum. Many cases of fibrosing mediastinitis are idiopathic, but most cases in the United States are believed to be a sequence of abnormal immunologic response to Histoplasma capsulatum infection. The disease progresses slowly over years and does not respond to antifungal, corticosteroid, or other antiinflammatory agents. However, in Greece, no data exist regarding the isolation of H capsulatum from soil and animals, and the few H capsulatum infections reported are considered imported. Fibrosing mediastinitis may be asymptomatic until the disease has progressed to cause damage to any organ or tissue of the mediastinum, leading to signs and symptoms of obstruction or compression of the affected organ, such as superior vena cava syndrome, dyspnea, pericarditis, thoracic pain, and dysphagia.

Corticosteroids are considered the mainstay of treatment of IgG4-RD, and for many of its manifestations, response to therapy is favorable. The usual regimen consists of prednisolone or prednisone at a dose of between 30 mg/d and 1 mg/kg/d, but the optimal dose and duration of corticosteroid therapy remains to be defined. A number of other immunosuppressant drugs, such as azathioprine, mycophenolate mofetil, cyclophosphamide, and methotrexate, have also been used as corticosteroid-sparing agents. Additionally, successful treatment of IgG4-RD has been reported with bortezomib and rituximab. For treatment of IgG4-related fibrosing mediastinitis in particular, evidence for efficacy is anecdotal and based mainly on case reports. In three previous case reports of IgG4-related fibrosing mediastinitis, patients improved after steroid therapy, a noticeable event because mediastinal fibrosis is considered resistant to pharmacologic treatment. Specifically, two patients presented with symptoms from extrathoracic disease, whereas one patient complained of exertional dyspnea. In all patients, the size of mediastinal mass decreased after initiation of corticosteroids, and the patient with dyspnea showed remission of symptoms. A few other cases have been described in terms of retrospective analysis without information regarding treatment outcome.

Clinical Course

The patient met criteria for definite diagnosis of IgG4-RD. Specifically, the patient had documented organ involvement, an elevated serum IgG4 level > 135 mg/dL, and compatible histopathologic features. He was treated with prednisolone 0.6 mg/kg/d. One month after treatment was initiated, the patient was asymptomatic, and his new chest CT scan was significantly improved (Fig 3).

Figure Jump LinkFigure 3 –  Chest CT scan 1 mo after treatment showing a significant reduction in the size of the mediastinum mass.Grahic Jump Location

  • 1. IgG4-related fibrosing mediastinitis is a rare but likely underdiagnosed entity and, thus, requires a high clinical and pathologic suspicion to be diagnosed with certainty.

  • 2. The diagnosis of IgG4-RD is supported by the combined presence of the characteristic histopathologic appearance and more IgG4-staining plasma cells in the biopsy specimen of a patient with either localized or diffuse edema or a mass or dysfunction in single or multiple organs and hematologic examination showing elevated serum IgG4 concentrations.

  • 3. IgG4-related fibrosing mediastinitis may respond to steroid therapy in contrast to other forms of fibrosing mediastinitis, which do not typically respond to steroids or other antiinflammatory agents.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344(10):732-738. [CrossRef] [PubMed]
 
Kapotsis GE, Daniil Z, Malagari K, et al. A young male with chest pain, cough and fever. Eur Respir J. 2004;24(3):506-509. [CrossRef] [PubMed]
 
Taniguchi T, Kobayashi H, Fukui S, Ogura K, Saiga T, Okamoto M. A case of multifocal fibrosclerosis involving posterior mediastinal fibrosis, retroperitoneal fibrosis, and a left seminal vesicle with elevated serum IgG4. Hum Pathol. 2006;37(9):1237-1239. [CrossRef] [PubMed]
 
Inoue M, Nose N, Nishikawa H, Takahashi M, Zen Y, Kawaguchi M. Successful treatment of sclerosing mediastinitis with a high serum IgG4level. Gen Thorac Cardiovasc Surg. 2007;55(10):431-433. [CrossRef] [PubMed]
 
Peikert T, Shrestha B, Aubry MC, et al. Histopathologic overlap between fibrosing mediastinitis and IgG4-related disease. Int J Rheumatol. 2012;2012:207056. [CrossRef] [PubMed]
 
Ryu JH, Sekiguchi H, Yi ES. Pulmonary manifestations of immunoglobulin G4-related sclerosing disease. Eur Respir J. 2012;39(1):180-186. [CrossRef] [PubMed]
 
Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22(1):21-30. [CrossRef] [PubMed]
 
Fujimori N, Ito T, Igarashi H, et al. Retroperitoneal fibrosis associated with immunoglobulin G4-related disease. World J Gastroenterol. 2013;19(1):35-41. [CrossRef] [PubMed]
 
Ngwa TN, Law R, Murray D, Chari ST. Serum immunoglobulin G4level is a poor predictor of immunoglobulin G4-related disease. Pancreas. 2014;43(5):704-707. [CrossRef] [PubMed]
 
Carruthers MN, Khosroshahi A, Augustin T, Deshpande V, Stone JH. The diagnostic utility of serum IgG4 concentrations in IgG4-related disease. Ann Rheum Dis. 2015;74(1):14-18. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Chest CT scan showing a soft-tissue mass adjacent to the aortic arch with enlargement of aortopulmonary window lymph nodes.Grahic Jump Location
Figure Jump LinkFigure 2 –  A, Mediastinal mass section obtained by thoracic surgery showing a storiform pattern of fibrosis and intense tissue infiltration by nonspecific-type inflammatory cells. Also showing are lymphoplasmatic infiltrate and obliterative phlebitis (hematoxylin-eosin, original magnification × 200). B, Immunohistochemical stains showing diffuse and intense distribution of IgG4-positive plasma cells with local confluence of > 50 IgG4-positive plasma cells per high-power field (original magnification × 200).Grahic Jump Location
Figure Jump LinkFigure 3 –  Chest CT scan 1 mo after treatment showing a significant reduction in the size of the mediastinum mass.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Comprehensive Clinical Diagnostic Criteria for IgG4-RD

Criteria as proposed in 2011 by Umehara et al: definite, 1 + 2 + 3; probable, 1 + 3; possible, 1 + 2. IgG4-RD = IgG4-related disease.

Suggested Readings

Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344(10):732-738. [CrossRef] [PubMed]
 
Kapotsis GE, Daniil Z, Malagari K, et al. A young male with chest pain, cough and fever. Eur Respir J. 2004;24(3):506-509. [CrossRef] [PubMed]
 
Taniguchi T, Kobayashi H, Fukui S, Ogura K, Saiga T, Okamoto M. A case of multifocal fibrosclerosis involving posterior mediastinal fibrosis, retroperitoneal fibrosis, and a left seminal vesicle with elevated serum IgG4. Hum Pathol. 2006;37(9):1237-1239. [CrossRef] [PubMed]
 
Inoue M, Nose N, Nishikawa H, Takahashi M, Zen Y, Kawaguchi M. Successful treatment of sclerosing mediastinitis with a high serum IgG4level. Gen Thorac Cardiovasc Surg. 2007;55(10):431-433. [CrossRef] [PubMed]
 
Peikert T, Shrestha B, Aubry MC, et al. Histopathologic overlap between fibrosing mediastinitis and IgG4-related disease. Int J Rheumatol. 2012;2012:207056. [CrossRef] [PubMed]
 
Ryu JH, Sekiguchi H, Yi ES. Pulmonary manifestations of immunoglobulin G4-related sclerosing disease. Eur Respir J. 2012;39(1):180-186. [CrossRef] [PubMed]
 
Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22(1):21-30. [CrossRef] [PubMed]
 
Fujimori N, Ito T, Igarashi H, et al. Retroperitoneal fibrosis associated with immunoglobulin G4-related disease. World J Gastroenterol. 2013;19(1):35-41. [CrossRef] [PubMed]
 
Ngwa TN, Law R, Murray D, Chari ST. Serum immunoglobulin G4level is a poor predictor of immunoglobulin G4-related disease. Pancreas. 2014;43(5):704-707. [CrossRef] [PubMed]
 
Carruthers MN, Khosroshahi A, Augustin T, Deshpande V, Stone JH. The diagnostic utility of serum IgG4 concentrations in IgG4-related disease. Ann Rheum Dis. 2015;74(1):14-18. [CrossRef] [PubMed]
 
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