Pulmonary IgG4 disease

Definition

Pulmonary IgG4 disease is a form of systemic hyper IgG4 disease. It is frequently associated with disease in other organs.

Epidemiology

This is a disease of adults. There is a male predominance.

Clinical features

Patients may have an allergic disposition with bronchial asthma, allergic or chronic rhinitis or allergies. They may present with cough or bloody sputum. Pulmonary disease has been reported in association with autoimmune pancreatitis, sclerosing sialadenitis or retroperitoneal fibrosis. There may be associated lymphadenopathy or sclerosing sialadenitis. Serum IgG and IgG4 levels are raised. The histological subtypes listed below show no significant histological differences.

Radiology

Four patterns have been described:

There may be a solitary nodule resembling a primary carcinoma.
Bronchovascular type shows thickening of bronchovascular bundles and interlobular septa.
Alveolar interstitial type shows diffuse reticular shadowing resembling interstitial pneumonia.
Multiple round ground glass opacities resembling bronchoalveolar carcinoma

Pleural involvement may produce visceral or parietal nodules.

Macroscopic appearances

The lesions are solid gray nodules, located either peripherally or centrally in the lungs. Alveolar interstitial type produces firm lung parenchyma. Multiple round ground glass opacities are associated with ill-defined nodules up to 1.5 cm in diameter. Pleural disease is seen as pleural thickening extending into the lung parenchyma.

Histopathology

The IgG4/IgG plasma cell ratio is typically more than 30%, compared to less than 10% in other inflammatory conditions.

The histological appearances in the lung may resemble organising pneumonia (OP), non-specific interstitial pneumonia (NSIP), plasma cell granuloma or lymphomatoid granulomatosis. Typical features include:

fibrosis and inflammation involving the visceral pleura and interlobular septa.
an inflammatory infiltrate comprising plasma cell, lymphocytes and histiocytes, sometimes with eosinophils
peribronchial inflammation
there may be marked formation of lymphoid follicles
histiocytes may aggregate within dilated lymphatics; they may be positive for S100 and show emperipolesis
a vasculitis involving both arteries and veins predominantly of the intima, without necrosis, producing an arteritis or obliterative phlebitis.
vessels show intimal thickening, occlusion and recanalisation
fibrinous pleuritis

Granulomata are rare and, when present, are small and vague.

Immunohistochemistry

Numerous plasma cells stain for IgG4, representing form 40% to 90% of IgG positive plasma cells. The are not clonal by in situ hybridisation.

	IgG4 plasma cell score
	0	1	2	3
Pulmonary disease associated with auto-immune pancreatitis			1/61	5/61
Pulmonary disease resembling that seen in association with auto-immune pancreatitis but unknown auto-immune pancreatitis status			5/121	7/121
Pulmonary disease associated with Rosai Dorfman disease	2/81		1/81	5/81
Erdheim-Chester disease	3/31
Pulmonary Sjogren syndrome	19/191
Inflammatory myofibroblastic tumour	6/101		4/101
Extranodal marginal zone lymphoma	3/31
Alveolar haemorrhage	3/31
Desquamative interstitial pneumonia	2/21
Lymphoid hyperplasia	4/51	1/51
Lymphocytic interstitial pneumonia	1/31	2/31
Non-necrotizing granulomas	2/31	1/31
Bronchiolitis / follicular bronchiolitis	10/111	1/111
Hypersensitivity pneumonitis	7/81	1/81
Usual interstitial pneumonia	3/81	3/81	2/81
Nonspecific interstitial pneumonia	22/291	4/291	3/291
Pleuritis, fibrinous, and fibrous	4/51		1/51
Rheumatoid arthritis nodules			1/11
Inflammatory myofibroblastic tumour	4/101	2/101	1/101	3/101
Organising pneumonia	10/131	2/131		1/131
Diffuse alveolar damage	4/51			1/51
Necrotizing granulomatous inflammation				1/11
Metastatic calcification	1/11
Cytomegalovirus pneumonitis	1/11

Differential diagnosis

Lymphomatoid granulomatosis: atypical cells are present, positive for Epstein-Barr virus;
Sarcoidosis shows a lymphangitic distribution but there are well-formed non-caseating epithelioid granulomata: there is not a marked lymphoplasmacytic component. IgG4 disease does not produce a raised serum ACE (angiotensin converting enzyme).
Erdheim-Chester disease; there are characteristic lesions in long bones; vascular inflammation is lacking; there is no increase in IgG4-positive plasma cells
Rosai-Dorfman disease shows a lymphangitic distribution with emperipolesis and an increase in IgG4-positive plasma cells. There may be an overlap with hyper IgG4 disease.
Multicentric Castleman's disease: the proportion of IgG4-positive plasma cells has not been documented and raised serum IgG4 has been reported. There may be overlap cases.
NSIP: The presence of eosinophils, obliterative vascular changes and lymphoid follicles is an indication to stain for IgG4.
Inflammatory pseudotumours with numerous plasma cells positive for IgG4 are probably a manifestation of IgG4 disease. Other cases are not IgG4-related and are of fibrohistiocytic subtype
Inflammatory myofibroblastic tumour is a true neoplasm; there are fascicles of spindle cells; a case with many IgG4-psoitive plasma cells has been reported.

Management

Many patients undergo resection on suspicion of a carcinoma. Treatment is with corticosteroids.

Prognosis

Unlike salivary gland and pancreatic disease, progression to lymphoma or carcinoma has not been established in the lungs.

References

1 Shrestha B, Sekiguchi H, Colby TV, Graziano P, Aubry MC, Smyrk TC, et al. Distinctive pulmonary histopathology with increased IgG4-positive plasma cells in patients with autoimmune pancreatitis: report of 6 and 12 cases with similar histopathology. Am J Surg Pathol. 2009 Oct;33(10):1450-62.

2 Zen Y, Inoue D, Kitao A, Onodera M, Abo H, Miyayama S, et al. IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases. Am J Surg Pathol. 2009 Dec;33(12):1886-93.