IgG4-related lung disease with recurrent pulmonary lesions during steroid therapy and difficulty in differentiating from malignancy: a case report

Since autoimmune pancreatitis with high serum immunoglobulin (Ig) G4 concentrations was reported in 2001, the new disease concept of IgG4-related disease (IgG4-RD) has been widely recognized [1]. IgG4-RD is characterized by the development of inflammatory lesions in various organs of the body; however, there are only a few reports on the clinical course of pulmonary lesions. In this report, we describe a case of IgG4-related lung disease (RLD) with recurrent pulmonary lesions during steroid therapy that was difficult to differentiate from malignancy, and the surgical approach was useful in determining the appropriate diagnosis and treatment plan. This case report is in line with the SCARE Criteria.

A 61-year-old man undergoing treatment for bronchial asthma was referred to our hospital because of an abnormal mass shadow on chest radiography. At the time of his first visit, he had a fever of approximately 37 °C, accompanied by persistent fatigue and mild dyspnea on exertion. He had a history of bronchial asthma, hypertension, and dyslipidemia, and was under medical treatment. He had no history of allergies and had smoked 20 cigarettes a day for 7 years between the ages of 18 and 25 years. He had worked as a pilot, but after retiring, he worked as a tree trimmer. Blood tests showed a mild increase in C-reactive protein levels to 3.5 mg/dL, but no other abnormalities in blood count or biochemical findings were observed. No elevation of tumor markers related to lung cancer was observed, but interleukin (IL)-2R was elevated to 536 U/mL (normal value 124–466 U/mL). Electrocardiography and echocardiography revealed no abnormalities. Chest computed tomography (CT) showed a middle lobe hilar mass with irregular margins and swelling of the right hilar and mediastinal lymph nodes (Fig. 1). ¹⁸F-fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT revealed a mass lesion with a maximum diameter of 5.5 cm and maximum standardized uptake value (SUVmax) of 11.0, and high SUV areas in the hilar and mediastinal lymph nodes (Fig. 2). Therefore, we included middle lobe lung cancer with mediastinal lymph node metastasis (T3N2M0 Stage IIIB) and malignant lymphoma in the differential diagnosis. Transbronchial lung biopsy of the mass showed no malignant findings. Based on the above, we decided to perform a thoracoscopic lung biopsy; if intraoperative histology revealed malignant findings, a radical middle lobectomy plus lymph node dissection was planned.

IgG4-RD is a relatively new disease concept that was historically proposed based on observations of autoimmune pancreatitis and Mikulicz’s disease with high IgG4 levels in the serum [1, 2]. This disease is characterized by the formation of inflammatory lesions with fibrosis and infiltration of IgG4-positive plasma cells and lymphocytes in various organs (e.g., pancreas, biliary tract, lacrimal gland, salivary gland, kidney, and retroperitoneum). Although the frequency of lung or pleural lesions in IgG4-RD has been reported to be 14%, there are still only a few reports of IgG4-RLD [3]. The clinical symptoms may be nonspecific, such as cough, respiratory distress, fever, and chest pain, but may also be asymptomatic. The ACR/EULAR IgG4-RD classification criteria were developed and proposed in 2019 as diagnostic criteria [4]. According to the IgG4-RD classification criteria proposed by Wallace et al., the diagnostic criteria are as follows: pathological tissue score, immunohistochemistry (IHC) score, serum IgG4, and findings in each organ. In this patient, the pathological tissue score was 13 points, the IHC score was 7 points, the serum IgG4 was 0 points, and the organs were 4 points, for a total of 24 points according to the test results when VATS lung biopsy was performed. At the time of VATS partial lung resection, the test results were 4 points for the pathological tissue score, 14 points for the IHC score, 0 points for serum IgG4, and 4 points for organs, for a total of 22 points. Since this case met the diagnostic criteria of > 20 points, the patient was diagnosed with IgG4-RD. Epidemiologically, it is more common among middle-aged and older men and varies from systemic to single-organ diseases. According to previous reports, imaging findings such as consolidation, ground-glass opacity, nodular shadows, and septal thickening are often seen in the peripheral lung fields, and abnormalities are often seen just below the pleura on chest CT. Fibrosis has been observed but is less common. The presence of fibrosis may be accompanied by honeycombing and traction bronchiectasis [5].

In our case, FDG-PET/CT scans showed a mass lesion measuring 5.5 cm in size in the middle lobe with an SUVmax of 11.0, and high SUV areas in the hilar and mediastinal lymph nodes. IL-2R levels were elevated, and it was difficult to differentiate malignant tumors from benign lung disease based on preoperative examination. Thoracoscopic lung biopsy was performed, which led to the diagnosis of IgG4-RLD with minimal invasion. Intraoperative findings were characterized by firm adhesions with loss of normal laminae, which is atypical for cancer invasion, suggesting a severe inflammatory reaction around the tumor. In general, glucocorticoids are effective in the treatment of IgG4-RLD, and it is recommended to start them with an equivalent PSL dose ranging from 20 to 60 mg/day depending on the severity of the presentation [5‐7].

We started treatment with intravenous PSL at 60 mg/day, and after 1 month, the lesion had shrunk, and symptoms, such as fever and cough, had improved. However, when the dose was reduced to 30 mg/day orally in the third month of PSL therapy, multiple nodular shadows appeared in both lungs on chest CT.

Previous reports have shown that malignancies tend to be associated with IgG4-RD. Wallace et al. reported that 20 of 125 patients diagnosed with IgG4-RD had a history of malignancy, with a standardized prevalence ratio as high as 2.5 [8]. Yamamoto et al. reported that 10.4% of patients with IgG4-RD had malignant complications, and the standardized incidence ratio was as high as 383 [9].

Based on the imaging findings of our case, the possibility of multiple lung metastases due to malignant disease was also suspected. To determine the treatment plan, thoracoscopic partial lung resection was performed on the newly appearing multiple nodules in the left lung. Extensive adhesions were also found in the left thoracic cavity, but they were more detachable than the adhesions in the right thoracic cavity. Early surgical intervention after the appearance of the lesions and the fact that the patient was taking PSL medication may have contributed to the mild adhesions. We found that IgG4-RLD refractory to PSL monotherapy showed shade changes from a solitary large mass (pseudotumor) to multiple nodules on chest CT. In addition, since the mass in the middle lobe was shrinking and the new shadow was not a malignant metastasis, the possibility of a malignant tumor was almost completely ruled out.

It has been reported that the combination of immunosuppressants and steroids is effective in treating IgG4-RLD refractory to PSL monotherapy [10], and we are considering the combination of azathioprine and PSL as a future treatment.

We encountered a patient with IgG4-RLD refractory to PSL monotherapy with a change in shade from a solitary large mass (pseudotumor) to multiple nodules on chest CT. It was difficult to distinguish malignancy from IgG4-RLD, and the active surgical approach was useful in making the diagnosis and determining the treatment strategy.