Immunoglobulin G4-related disease presenting as a pulmonary nodule with an irregular margin.

We report a case of immunoglobulin G4 (IgG4)-related lung disease presenting as a solitary pulmonary nodule with an irregular margin on computed tomography. The nodule showed a high standardized uptake value on positron emission tomography. A malignant pulmonary tumour could not be excluded. Middle lobectomy was performed. Histological analysis revealed marked lymphoplasmacytic infiltration and storiform fibrosis. Immunostaining indicated the presence of IgG4-positive plasma cells. A definitive diagnosis of IgG4-related disease was confirmed.

Introduction

Recently, considerable attention has been focused on immunoglobulin G4‐related disease (IgG4‐RD); this is a systemic progressive inflammatory condition. Immunoglobulin G4‐related disease is clinically characterized by swelling or masses in various organs. It is diagnosed using histopathological features involving marked infiltration of IgG4‐positive plasma cells and storiform fibrosis. Few cases of solitary pulmonary nodules associated with IgG4‐RD have been reported. We report a case of solitary pulmonary nodule associated with IgG4‐RD that had an irregular margin mimicking lung cancer.

Case Report

A 71‐year‐old woman presented with a mass in the right lower lung field on a chest radiograph. The patient was a non‐smoker and her physical examinations were normal. She had undergone high anterior resection of the rectum 5 years previously, for rectal cancer. Pathological examination of the resected specimen revealed a well‐differentiated adenocarcinoma of the rectum (p‐T2N0M0; p‐Stage II). Computed tomography (CT) of the chest revealed a 3.1‐cm pulmonary nodule with an irregular margin in the right middle lobe (Fig. 1). No enlarged lymph nodes were found. No significant findings were detected on abdominal CT scans. The pulmonary lesion indicated a high standardized uptake value of 8.5 on positron emission tomography (PET). The level of neuron‐specific enolase was elevated to 19.4 ng/mL (normal level < 14.4). These findings suggested malignancy. The serum levels of carcinoembryonic antigen and squamous cell carcinoma (SCC) antigen were within normal ranges. However, the presence of a malignant pulmonary tumour could not be excluded. The patient underwent video‐assisted thoracoscopic surgery (VATS) involving middle lobectomy with lymph node dissection. The mass was detected hard on palpation, and the cut surface of the resected specimen appeared uniformly yellow‐grey; it was a solid nodular lesion with an irregular margin. Microscopic examination revealed extensive infiltration of plasma cells and storiform fibrosis in the solid lesion. Thickening of the interlobular septa and a bronchovascular bundle with lymphoplasmacytic infiltration and fibrosis were identified around the solid lesion. Obliterative arteritis and phlebitis were also noted (Fig. 2A). Immunohistochemical staining indicated diffuse infiltration of IgG4‐positive plasma cells, with an IgG4‐positive/IgG‐positive plasma cell ratio of 0.65 and an average number of 92 IgG4‐positive plasma cells per high‐power field (HPF) (Fig. 2B, C). Atypical cells suggestive of malignancy, epithelioid granuloma, and necrosis could not be identified. No specific changes were found in the lymph nodes. The overall histological findings were consistent with IgG4‐RD. The serum level of IgG4, which was subsequently checked for, was elevated (141 mg/dL). Other diseases such as sarcoidosis, Wegener granulomatosis, and lymphoma were excluded. A definitive diagnosis of IgG4‐RD was confirmed. Pathological features of lymphoplasmacytic infiltration and fibrosis along the lymphatic routes around the solid lesion corresponded to the radiological finding of an irregular margin. The patient was followed‐up without medication. No evidence of recurrence or another organ involvement was found at 18 months after surgery.

Figure 1

Computed tomography scan. Solitary pulmonary nodule with an irregular margin.

Figure 2

Histolopathological and immunohistochemical examination of tissue sections. (A) Photomicrograph showing extensive lymphoplasmacytic infiltration with storiform fibrosis (haematoxylin and eosin staining, ×100). (B) Photomicrograph showing infiltration of immunoglobulin (IgG)‐positive plasma cells (IgG stain, ×400). (C) Photomicrograph showing infiltration of immunoglobulin G4 (IgG4)‐positive plasma cells (IgG4 stain, ×400).

Discussion

Immunoglobulin G4‐related disease is a recently recognized chronic inflammatory disease involving various organs. The diagnostic criteria for IgG4‐RD consist of three parts: (1) clinical examination showing characteristic diffuse/localized swelling or masses in single or multiple organs; (2) an elevated serum IgG4 concentration (≥135 mg/dL); and (3) histological examination showing: marked lymphocyte and plasmacyte infiltration and fibrosis; and infiltration of IgG4‐positive plasma cells (ratio of IgG4‐positive/IgG‐positive cells > 40% and an IgG4‐positive plasma cell count > 10 per HPF) 1. It has been reported that obliterative arteritis and phlebitis in lung lesions are organ‐specific features, but are not diagnostic factors 2, 3, 4. Immunoglobulin G4‐related disease involves various organs, and mostly affects the pancreas, kidneys, salivary and lacrimal glands, bile ducts, lungs, and other organs 1. The IgG4‐RD has two major clinical phenotypes, Mikulicz's disease and autoimmune pancreatitis 2. Matsui et al. 2 reported that pulmonary and mediastinal involvement was found in 13 (54%) of 25 patients with Mikulicz's disease. Fujinaga et al. 3 reported that various forms of pulmonary involvement were found in 25 (54%) of 46 patients with autoimmune pancreatitis. Immunoglobulin G4‐related lung disease should be taken into consideration when patients have IgG4‐RD in extrapulmonary lesions. Isolated lung involving IgG4‐RD, especially solitary pulmonary nodules, is rare. Features of IgG4‐RD on chest CT images can take various forms, such as a nodule, ground‐glass opacity, thickening of the interlobular septa, and thickening of the bronchovascular bundle 5. Various combinations of radiological features are often found in the same patient 2, 3, 5. Immunoglobulin G4‐related lung disease should be taken into consideration when patients have pleomorphic radiological features on chest CT. A pulmonary nodule with an irregular margin on CT usually indicates malignancy. In the present case, a malignant lung tumour was strongly suspected because the pulmonary nodule was a single lesion with an irregular margin on CT, and had a high standardized uptake value on PET. The diagnosis of IgG4‐RD requires histopathological examination. Although the results of transbronchial lung biopsy may suggest inflammatory conditions, the architecture and immunostaining characteristics are unlikely to have been identified. A VATS biopsy of the lung may be needed to obtain adequate specimens for establishing the diagnosis of IgG4‐RD and excluding other pathologies especially malignancy. In the present case, histological features of massive lymphoplasmacytic infiltration with fibrosis along the lymphatic routes around the solid lesion corresponded to the radiological findings of a nodule with an irregular margin. The pulmonary nodule associated with IgG4‐RD can have a margin that is not well‐demarcated and rather irregular, which makes it difficult to distinguish these lesions from lung cancer.

Disclosure Statements

No conflict of interest declared.

Appropriate written informed consent was obtained for publication of this case report accompanying images.