IgG4-RELATED LUNG

DISEASE

Erik Baltaxe
Institute of Pulmonary Diseases
Chaim Sheba Medical Center
 Case Presentations
Case Age / Sex Initial Presentation Associated
Conditions

1 44 / F Cough, shortness of Dry eyes (d/t

breath dacryoadenitis)

2 21 / M Productive cough, Asthma

pleuritic chest pain

3 58 / M Pleural thickening – Retroperitoneal

incidental CT finding fibrosis, mesenteric
panniculitis, aortitis
Case Radiology Pathology Serum
Clinical Cases Summary IgG4
(mg/dl)
1 Multifocal bilateral * Core needle biopsy (lung). 573
alveolar infiltrates. * Thickened interstitium with
Peribronchovascular lymphoplasmocytic infiltrate.
* Obliterative phlebitis.
infiltrates
* 30 - 40 IgG4 + cells / HPF.
* No granulomas

2 Right upper lobe solid * RU Lobectomy 416

* Lymphoplasmocytic infiltration.
mass (3 cm) with * No vasculitis.
spiculated margins * 20 – 25% IgG4 + cells.
* Ratio of IgG4/IgG + cells: 20 -
25%
3 Right pleural thickening * Core needle biopsy. 177
* Densely fibrotic paucicellular
including the anterior pleura.
mediastinum, with * Lung parenchyma with dense
calcified lesions. lymphoplasmocytic infiltrate.
* IgG4 negative.
* No asbestos bodies or silica
particles.
Case FEV1 (%) FVC (%) FRC (%) TLC (%) DLCO (%)

1 94 96 119 102 68

2 77 85 102 81 79

3 85 82 84 79 75
Stone JH et al. N Engl J Med 2012;366:539-551.
 Physiology and Pathogenesis
 Elevations in serum and tissue IgG4 also found in
 multicentric Castleman’s disease
 allergic disorders
 Churg-Strauss syndrome
 lung cancer
 sarcoidosis
 Clinical Presentation

(hepatobiliary)

Zen Y., et al. IgG4-Related Disease. A Cross-sectional Study of 114

Cases. Am J Surg Pathol. 2010:1812-19.
 Clinical Presentation
Single and multiorgan involvement.
Subacute development of a mass in the
affected organ.
Multiple organs in 60 - 90 %.
Lymphadenopathy is common
Symptoms of asthma or allergy in 40%.
Absence of fever or other constitutional
symptoms.
Incidental finding (radiology or histology).
Previously Recognized Conditions Now Acknowledged to Fall
within the Spectrum of IgG4-Related Disease

Stone JH et al. N Engl J Med 2012;366:539-551.

 Clinical Presentation
 Cough, effort dyspnea and chest pain in 50%.
 3 reported cases with constitutional symptoms and
elevated inflammatory markers.
 50% asymptomatic with incidental findings on chest
radiology.

 Zen Y, et al. IgG4-related lung and pleural disease: a clinicopathologic

study of 21 cases. Am J Surg Pathol. 2009
 Inoue D, et al. Immunoglobulin G4-related lung disease: CT findings with
pathologic correlations. Radiology. 2009
 Sun X, et al. Refractory IgG4-related Lung Disease with Constitutional
Symptoms and Severe Inflammation. AJRCCM. 2014
 Radiological Features
Inoue D el al. (2009) described 4 patterns:
Solid nodular
Round-shaped “ground-glass” opacity
Alveolar interstitial (honeycombing,
bronchiectasis and diffuse GGO).
Bronchovascular
Ryu JH el al. (2012) described mediastinal
lymphadenopathy.
Yamashita K, et al. (2008) and Sekiguchi H, et
al. (2012) described pleural involvement.
 Radiological Features
 Solid Nodular (Case #2)
 Radiological Features
 Round-shaped “ground-glass” Opacity

Inoue D, et al. Immunoglobulin G4-related lung disease: CT

findings with pathologic correlations. Radiology. 2009
 Radiological Features
 Alveolar Interstitial (honeycombing, bronchiectasis and
diffuse GGO)

Inoue D, et al. Immunoglobulin G4-related lung disease: CT

findings with pathologic correlations. Radiology. 2009
 Radiological Features
 Bronchovascular (Case #1)

Inoue D, et al. Radiology.

2009
 Radiological Features
 Mediastinal Lymphadenopathy (Case #1)

Ryu JH, et al.. Eur Resp J. 2012

 Radiological Features
 Pleural Thickening (Case #3)
 Radiological Features

Inoue D, et al. Immunoglobulin G4-related lung disease: CT

findings with pathologic correlations. Radiology. 2009
 Pathology
Key histopathological findings:
Dense lymphoplasmocytic infiltrate
Storiform-type fibrosis
Obliterative phlebitis
Mild-to-moderate eosinophilic infiltration
Fibrosis may predominate in the late phases.
Differential diagnosis with lymphomas.
The presence of granulomas generally
excludes the diagnosis of IgG4-related
disease.
Prominent neutrophilic infiltrate is inconsistent
with the diagnosis.
 Pathology
Lung pathology is characterized by:
Nonspecific Interstitial Pneumonia
(NSIP) pattern.
Irregular fibrosis in the nodular and
pleural lesions.
Obliterative phlebitis.
Eosinophilic infiltration.

Zen Y, et al. IgG4-related lung and pleural disease: a clinicopathologic study of 21

cases. Am J Surg Pathol. 2009
 Diagnosis
 Consensus statement on the pathology of IgG4-related
disease. Modern Pathology. 2012

 Histologically Highly Suggestive of IgG4-Related

Disease
 At last two of the following:
 Dense lymphoplasmacytic infiltrate
 Fibrosis, usually storiform in character
 Obliterative phlebitis.
 IgG4+ plasma cell counts differ between organs and
type of sample:
 Core needle biopsy: > 20 cells / hpf
 Lung surgical specimen: > 50 cells / hpf
 Diagnosis
 Probable Histological Features of IgG4-Related
Disease
 Cases with only a single histopathological feature
 Meningeal and cutaneous disease
 Needle biopsies
These cases require additional evidence to confirm the
diagnosis of IgG4-related disease, such as:
 Serum IgG4 > 135 mg/dl.
 Other organ involvement, as demonstrated by
radiological or pathological examination.
 Insufficient Histopathological Evidence of IgG4-
Related Disease
 Sampling artifact, the effects of previous therapy, and
progression to a fibrotic stage.
 Diagnosis
IgG4 levels are increased in BAL fluid.
These levels were observed to correlate with
the serum IgG4 level.
Bronchoalveolar lavage data relating to
IgG4-related pulmonary disease are sparse
and its role in the evaluation of patients
remains to be clarified.

Tsushima K, et al. Pulmonary involvement of autoimmune pancreatitis. Eur J Clin Invest.

2009.
 Treatment

Oral Steroids
Favorable response usually observed
within 2 wks.

In a series of 4 cases Khosroshahi A et al.

(2010) showed a rapid decline of serum
IgG4 levels after Rituximab treatment.
 Prognosis
 Long-term follow up data has not been published.
 Extrathoracic lesions in follow-up: months to years.
 Persistent radiological abnormalities.
 3/21 patients is Zen el al. series (2009)
 Association with lymphoma, pancreatic cancer and
lung cancer.
 2/21 of lung cancer in Zen el al. series (2009)
 Increased risk of malignancy?
 Progression to fibrosis in untreated cases.
 Poor response to steroids when fibrosis is
established.
 Conclusions
IgG4-related disease is a poorly understood
inflammatory condition.
Systemic disease.
Thoracic disease can involve the lung
parenchyma, airways, mediastinum and
pleura.
Diagnosis is based on histology and serum
IgG4 levels.
Good response to steroid therapy.
Uncertain relationship with malignancy.