IgG4-related Lung Disease With Recurrent Pulmonary Lesions During Steroid Therapy and Diculty in Differentiating From Malignancy: Case Report and Literature Review

Background: Immunoglobulin G4-related disease (IgG4-RD) is characterized by the formation of inammatory lesions with brosis and inltration of IgG4-positive plasma cells and lymphocytes in various organs of the body. Since the rst report of IgG4-related autoimmune pancreatitis, IgG4-RD affecting various organs has been reported; however, there are still only a few reports of IgG4-related lung disease (IgG4-RLD). In this report, we describe a case of IgG4-RLD with recurrent pulmonary lesions during steroid therapy that were dicult to differentiate from malignancy. Case presentation: A 61-year-old man was referred to our hospital after an abnormal chest shadow on X-ray was noted during his visit to his previous doctor for asthma treatment. Chest computed tomography (CT) revealed a middle lobe hilar mass with irregular margins and swelling of the right hilar and mediastinal lymph nodes. 18 F-uorodeoxyglucose-positron emission tomography revealed a mass lesion with a maximum diameter of 5.5 cm, maximum standardized uptake value (SUVmax) of 11.0, and areas with high SUV in the hilar and mediastinal lymph nodes. We suspected lung cancer or malignant lymphoma and performed a thoracoscopic lung biopsy to conrm the diagnosis. A total of ve tumor sites and an enlarged lymph node (LN#10) were biopsied; histopathological examination revealed no malignant ndings, and IgG4-RLD was diagnosed. One month after treatment with prednisolone (PSL), the tumor had shrunk, but a CT scan during the third month of PSL treatment revealed multiple nodular shadows in both lungs. Considering the possibility of malignant complications and multiple lung metastases, we performed thoracoscopic partial lung resection of the new left lung nodules to determine the treatment strategy. Histopathological examination revealed no malignant ndings in any of the lesions, and the patient was diagnosed with IgG4-RLD refractory to PSL monotherapy. We are considering the combination of

ray was noted during his visit to his previous doctor for asthma treatment. Chest computed tomography (CT) revealed a middle lobe hilar mass with irregular margins and swelling of the right hilar and mediastinal lymph nodes. 18 F-uorodeoxyglucose-positron emission tomography revealed a mass lesion with a maximum diameter of 5.5 cm, maximum standardized uptake value (SUVmax) of 11.0, and areas with high SUV in the hilar and mediastinal lymph nodes. We suspected lung cancer or malignant lymphoma and performed a thoracoscopic lung biopsy to con rm the diagnosis. A total of ve tumor sites and an enlarged lymph node (LN#10) were biopsied; histopathological examination revealed no malignant ndings, and IgG4-RLD was diagnosed. One month after treatment with prednisolone (PSL), the tumor had shrunk, but a CT scan during the third month of PSL treatment revealed multiple nodular shadows in both lungs. Considering the possibility of malignant complications and multiple lung metastases, we performed thoracoscopic partial lung resection of the new left lung nodules to determine the treatment strategy. Histopathological examination revealed no malignant ndings in any of the lesions, and the patient was diagnosed with IgG4-RLD refractory to PSL monotherapy. We are considering the combination of azathioprine and PSL as future treatment.
Conclusions: IgG4-RLD refractory to PSL monotherapy showed changes from a solitary large mass (pseudotumor) to multiple nodules on chest CT. It was di cult to distinguish malignancy from IgG4-RLD based on imaging tests and blood samples alone, and performing thoracoscopic lung biopsies and partial lung resection were useful in determining the diagnosis and treatment plan.

Background
Since autoimmune pancreatitis with high serum IgG4 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 in ammatory lesions in various organs of the body; however, there are only a few reports on pulmonary lesions and their clinical course. In this report, we describe a case of IgG4-RLD with recurrent pulmonary lesions during steroid therapy that was di cult to differentiate from malignancy.

Case Presentation
A 61-year-old man undergoing treatment for bronchial asthma was referred to our hospital because of an abnormal mass shadow on chest radiography. Blood tests showed a mild increase in C-reactive protein to 3.5 mg/dL, but no other abnormalities in blood count or biochemical ndings 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 to 466). Chest computed tomography (CT) revealed a middle lobe hilar mass with irregular margins and swelling of the right hilar and mediastinal lymph nodes ( Figure 1). 18 Fuorodeoxyglucose-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 ( Figure 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 revealed no malignant ndings. Based on the above, we decided to perform a thoracoscopic lung biopsy; if intraoperative histology revealed malignant ndings, a radical middle lobectomy plus lymph node dissection was planned.
Surgical ndings: A 1.5-cm camera port was made on the mid-axillary line of the 7th intercostal space, and the thoracic cavity was observed; however, it was di cult to evaluate the pleural effusion because of extensive pleural adhesions. After thoracoscopic dissection of the pleural adhesions, a total of ve tumor sites and an enlarged lymph node (LN#10) were biopsied; however, intraoperative rapid pathological examination revealed no malignant ndings. Identi cation of the interlobar pulmonary artery was impossible due to severe interlobar adhesions, and a right total pneumonectomy was necessary to completely resect the primary lesion. Since it would be over-invasive to perform a total right pneumonectomy in a patient with an undetermined diagnosis, we decided to terminate the surgery and determine the treatment plan based on the results of the histopathological examination.
Histopathological ndings: Hematoxylin-eosin (HE) staining showed an in ammatory cell in ltrate consisting of plasma cells, lymphocytes, and neutrophils. Storiform brosis was observed using the silver impregnation method. Immunohistochemical staining showed that there were approximately 40 IgG4positive cells per High Power Field (HPF), and the IgG4/IgG ratio was approximately 20% (Figure 3).
Based on the above ndings, the patient was diagnosed with IgG4-RD occurring only in the lungs, and treatment with prednisolone (PSL) 60 mg/day was initiated. After one month of treatment with PSL, the mass had shrunk, and improvement in fever and cough symptoms was observed. However, a CT scan during the third month of PSL treatment (30 mg/day) showed multiple nodular shadows in both lungs ( Figure 4). No physical symptoms were observed. Considering the possibility of malignant complications and multiple lung metastases, we performed thoracoscopic partial lung resection of the newly appearing left lung nodules to determine the treatment strategy.
Surgical ndings: We performed 3-port video-assisted thoracic surgery (VATS). Extensive pleural adhesions were observed in the thoracic cavity. After detachment of the adhesions, the surgery was completed with partial lung resection of the lower lobe.
Histopathological ndings: HE staining revealed a dense in ammatory cell in ltrate consisting of plasma cells, lymphocytes, and neutrophils. Immunohistochemical staining showed that there were approximately 40 IgG4-positive cells per HPF, and the IgG4/IgG ratio was approximately 70% ( Figure 5).
There was no evidence of malignancy.

Discussion
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 in ammatory lesions with brosis and in ltration of IgG4-positive plasma cells and lymphocytes in various organs (e.g., pancreas, biliary tract, lacrimal gland, salivary gland, kidney, 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-related lung disease (RLD) [3]. The clinical symptoms may be nonspeci c, such as cough, respiratory distress, fever, and chest pain, but it may also be asymptomatic. The ACR/EULAR IgG4-RD classi cation criteria were developed and proposed in 2019 as diagnostic criteria [4]. According to the IgG4-RD classi cation criteria proposed by Wallace et al., the diagnostic criteria are as follows: pathological tissue score, immunohistochemistry (IHC) score, serum IgG4, and ndings 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 over 20 points, the patient was diagnosed with IgG4-RD. Epidemiologically, it is more common in middle-aged and older men and varies from systemic to single-organ diseases. According to previous reports, imaging ndings such as consolidation, ground-glass opacity, nodular shadows, and septal thickening are often seen in the peripheral lung elds, and abnormalities are often seen just below the pleura on chest CT. Fibrosis has been observed but is less common. The presence of brosis 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 also elevated, and it was di cult to differentiate malignant tumors from benign lung disease based on the preoperative examination. Thoracoscopic lung biopsy is useful in determining the diagnosis of IgG4-RLD.
In general, glucocorticoids are effective in the treatment of IgG4-RLD, and it is recommended to start glucocorticoids with an equivalent PSL dose ranging from 20 mg to 60 mg/day depending on the severity of the presentation [5,6,7].
We started treatment with PSL at 60 mg/day, and after one month, the lesion had shrunk, and symptoms, such as fever and cough, had improved. However, when the dose was reduced to 30 mg/day 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-related disease 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 ndings 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. As a result, 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.

Conclusion
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 di cult to distinguish malignancy from IgG4-RLD, and actively undertaking thoracoscopic lung biopsies and partial lung resection were useful in determining the diagnosis and treatment plan. Abbreviations IgG4, immunoglobulin G4; IgG4-RD, IgG4-related disease; IgG4-RLD, IgG4-related lung disease; CT, computed tomography; FDG-PET, 18 F-uorodeoxyglucose-positron emission tomography; SUVmax, maximum standardized uptake value; PSL, prednisolone; IL, interleukin; HE, hematoxylin-eosin; HPF, high power eld; VATS, video-assisted thoracic surgery; IHC, immunohistochemistry Declarations Ethics approval and consent to participate Not applicable.

Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this Figure 1 Chest CT a, b) Chest CT revealed a middle lobe hilar mass with irregular margins and swelling of the right hilar and mediastinal lymph nodes.  Microscopic examination a) HE staining showed an in ammatory cell in ltrate consisting of plasma cells, lymphocytes, and neutrophils. b) Storiform brosis was observed using the silver impregnation method. c) Immunohistochemical staining showed that there were approximately 40 IgG4-positive cells per HPF, and the IgG4/IgG ratio was approximately 20%.

Figure 4
Chest CT view at the third month of PSL treatment (30 mg/day) a, b) Chest CT showing a shrinking middle lobe hilar mass and multiple nodular shadows in both lungs.