Introduction

IgG4-RD is a rare multi-organ disease, is clinically recognized by three distinct pathologic features, namely lymphoplasmacytic infiltrate enriched in IgG4 positive plasma cells, fibrosis in storiform pattern, and obliterative phlebitis [1]. Autoimmune pancreatitis (AIP) in IgG4-RD can mimic pancreatic carcinoma, 3%–9% of patients suspected with pancreatic malignancy and undergo surgery have autoimmune pancreatitis [2]. AIP is generally defined into type 1 AIP and type 2 AIP by the criteria of clinical presentation, pathological findings, and IgG4 antibody [3]. Type 1 AIP is defined histologically as lymphoplasmacytic sclerosing pancreatitis, is a pancreatic manifestation of the IgG4-RD syndrome. Type 2 AIP is not related to IgG4-RD and has very few IgG4 positive plasma cells. There are three typical findings of AIP: diffuse, focal, and multifocal. The most common type is diffuse pattern which presents as diffusely enlarged sausage-like pancreas and loss of the lobular contour, is less likely misdiagnosed as malignancy [4]. Focal type is less common than diffuse type but manifests as a focal mass often involved in the pancreatic head, an appearance highly mimics pancreatic malignancy [5]. The most common clinical presentation of AIP in IgG4-RD is painless obstructive jaundice that can also be confused with pancreatic cancer. Pulmonary involvement has been reported in 14% of patients with IgG4-RD syndrome [6]. IgG4 related lung disease manifests as nodular lesions, non-specific infiltrates, “ground-glass” appearance with pleural thickening, and effusion [7]. The pulmonary involvements of IgG4-RD are defined as parenchyma, airway, vasculature, mediastinum and pleural involvement based on the anatomic structure. In the study of Lung involvement in IgG4-RD published by Xie’s group, 3 of 50 patients present with mass lesion (diameter of lesion is larger than 3.0 cm in the CT image), 50 of 89 patients present with lung nodules, other presentation are ground-glass opacity (21/50), thickening of pleura (9/50), thickening of interlobular septa (4/50), thickening of bronchial wall (3/50), pleural effusion (4/50), interstitial changes (5/50), and mediastinal or hilar lymphadenopathy (32/50) [8].

Among the patients of IgG4-RD presenting with type 1 AIP, there are as many as 13% patients who also have IgG4-related pulmonary disease [9]. Here, we report a novel case of IgG-RD involving a focal pattern of AIP highly suspected as malignancy resulting in invasive Whipple procedure and later found enlarging mass lesion of the lung, which turned out to be one of the manifestations of IgG4-RD. In the study published by Takaaki Ogoshi, fourteen of the 35 AIP patients (40%) were diagnosed with lung involvement in AIP [10]. But the report of IgG4-RD involving both pancreas and lung in a mass formation simultaneously is rare. To our knowledge, there is one case report from Germany [11] where an 82 year old male patient presented with cancer of the head of pancreas with pulmonary nodules but not mass, later the mass of pancreas and lung nodules has surprisingly disappeared after treatment with steroids. Therefore, we like to present a case of Ig-G4 RD presented as both pancreas and lung mass.

Case presentation

A 70-year-old Asian male presented to a local family practitioner with obstructive jaundice. CT abdomen shows focal and well demarcated lesion at the head of pancreas (Figure 1a) and dilated common bile duct consistent with biliary obstruction (Figure 1b) which was subsequently investigated with ERCP (endoscopic retrograde cholangiopancreatography). He was found to have pancreatic head mass with obstructing CBD (common bile duct) stricture, and a bile duct stent was placed during ERCP to relieve the obstruction. Afterward, he was referred for surgery and the Whipple procedure was undertaken. Incidentally, he was also found to have two 1 cm pulmonary nodules which were stable compared to studies 6 months earlier on imaging studies. Whipple resection revealed a 5.0 × 4.2 × 2.7 cm poorly differentiated tan-white indurated tumor located within the head of pancreas (Figure 1c). The surgical pathology report of excision was negative for malignancy but indicated extensive chronic pancreatitis with mass forming fibrosis (sclerosis) (Figure 2a). Twenty-two lymph nodes were biopsied intra-operatively; all were negative for malignancy. Immunopathology revealed CD-138 positivity in plasma cells, with almost 100% of plasma cells positive for IgG4 stain (Figure 2b). These findings confirmed the diagnosis of IgG4-RD. Subsequently, the patient was diagnosed with Type 1 autoimmune pancreatitis.

With the pancreatic malignancy ruled out, the patient was discharged with a diagnosis of IgG4-RD. After discharge, the patient was followed by his primary care doctor for several months until he was referred to us, with the complaints of coughing, unintentional weight loss over the last six months, and the subsequent findings of a large lung mass on imaging. At the time of visit, the patient acknowledged that he had smoked one pack of cigarettes per day for the last 35 years. The patient denied hemoptysis, fever, chills and night sweats. Laboratory investigation showed a hemoglobin level of 10.8, a platelet count of 215, a white blood cells (WBC) count of 9.35. Other values including total IgG were elevated at 2260. The initial chest X-ray showed mass in the patient’s left lower lobe. A computed tomography (CT) scan of the chest revealed a 4.6 × 2.3 cm pleural-based lobulated mass in the left lower lobe with spiculated margins up to 8 mm (Figure 3). The transbronchial biopsy of the left lower lobe lung mass was performed. Histopathological analysis demonstrated dense fibroelastosis and interstitial lymphoplasmacytic infiltration. However, there was no evidence of granulomas or carcinoma. Flow cytometry was negative for immunophenotypic of non-Hodgkin’s lymphoma. However, immunohistochemistry staining revealed CD-138 and kappa/lambda Ig light chains with highlighted polytypic plasma cells; these lacked nuclear expression of cyclin D1 (Figure 4). Nevertheless, a large subset of plasma cells was positive for IgG, a subset of which appeared positive for IgG4. IgG4 level in plasma was elevated to 480 mg/dl (Normal, 135 mg/dl,). In total, the overall Immunohistochemistry and morphology were consistent with IgG4-RD. Patient was then diagnosed with IgG4-RD involving both pancreas and lung, presented as pancreas mass and lung mass. Initially, the patient began a course of oral prednisone, due to intolerance, rituximab was then initiated. At a follow-up visit, the patient was free of cough while under surveillance, meanwhile a decrease in lung mass was found after two months of rituximab treatment.

The case has been reported according to Scare Guideline 2020 [12].

Discussion

IgG4-RD affects multiple organs and leads to variable presentations. Patients suffering IgG4-RD are frequently misdiagnosed as having malignancies since IgG4-RD highly mimic tumors by presenting with mass lesions within organs. Focal mass forming types of AIP in IgG4-RD presenting with obstructive jaundice with a pancreatic mass are very difficult to diagnose due to mimicking pancreatic cancer [5]. IgG4-RD involving the pancreas accounts for approximately 27% of Whipple resections conducted due to suspicion of pancreatic carcinoma [13]. In the multicenter nationwide study, 67 patients with AIP in Korea, 52% of the patients present with obstructive jaundice. Fifty four patients (81%) present with typical diffuse swelling of pancreas and sclerosing pattern of pancreatic duct on pancreatogram. Thirteen patients showed focal type AIP with the mass lesion in the head, body and tail [14]. As in our case the AIP represents the focal pattern which highly mimics pancreatic cancer, the patient was initially presented with painless jaundice and weight loss resulting in a massive Whipple procedure. Among the 67 patients of AIP, 12 patients were misdiagnosed with pancreatic carcinoma and finally went through surgery [14]. Therefore, It is extremely essential to differentiate IgG4-RD which manifests with AIP from pancreatic cancer since both can highly mimic each in clinical presentation and image study. Increased awareness of the existence and use of necessary techniques such as measurement of serum IgG4 levels in making the preoperative diagnosis could have prevented invasive Whipple procedure.

The patient in our case presented with persistent cough and with enlarging lung mass several months later and was suspicious for lung carcinoma. The suspicion of lung malignancy was further strengthened by finding pleural-based opacity in the lower lung lobe in CT imaging [15]. Later biopsy of the lung mass which showed IgG4 positive plasma cells proliferation by immunostaining and elevated plasma IgG4 established the diagnosis as IgG4-RD. IgG4-RD can manifest as a solitary parenchymal mass and is often misdiagnosed as a primary lung cancer [16]. Pulmonary involvement in IgG4-RD may have various manifestations in image studies such as solid parenchymal nodules or even mass lesions; round shaped ground-glass opacification can highly mimic bronchioloalveolar carcinoma but diffuse ground glass opacification may resemble interstitial pneumonia; thickening of bronchovascular bundles is often misdiagnosed as sarcoidosis [17, 18]. Among those different manifestations, parenchymal nodules and mass like lesions often have spiculated margins and especially located in one lobe, highly resembling the characteristic of malignancy. IgG4-RD is often uncovered from the unexpected biopsy result as patients were first highly suspected of having lung cancer and biopsy was obtained to confirm malignancy. IgG4-RD is generally not included in the differential diagnosis given the rarity of the disease and nonspecific presentation particularly when patients present with lung nodules or mass like lung lesions and has no previous history of concomitant rheumatological disease [19]. More importantly, the lung lesion of IgG4-RD often has hypermetabolic uptake in positron emission tomography (PET) scan which makes the differential diagnosis even more difficult [20] Mass like lesions in IgG4-RD which mimic primary lung carcinoma simultaneously having high uptake of 18-fluorodeoxyglucose can be found on PET scans.

In the single-center retrospective study on a prospectively collected cohort of 98 patients diagnosed with AIP type 1, 15 (15.3%) patients had pulmonary involvement, most of the lung involvement in the patients with AIP type 1 presents with nodular lesions in lungs (54.4%), non-specific infiltrates (36.4%), “ground-glass” appearance (18.2%), pleural thickening (18.2), pleural effusion(18.2%), and mediastinal lymph nodes enlargement (9.1%) [7]. In IgG4-RD, extrapulmonary lesions often precede pulmonary lesions. Our case report appeared to occur simultaneously. Although among IgG4-RD presented as AIP type 1, there are about 15% patients also have lung involvement, there is no data reporting the coexisting mass presentation in both lung and pancreas. The case published by Schimiz etc reported a IgG4-RD presenting with mass in the head of pancreas and multiple lung nodules but not mass formation. Therefore our report is the first case about the IgG4-RD mimicking carcinoma in both pancreas and lung simultaneously.

Glucocorticoids have been the mainstay of treatment for IgG4-RD given their efficacy as well as affordability. An excellent response to steroids within 2–4 weeks is typical of the disease and may help to determine the ultimate diagnosis. In the study of phase II prospective clinical trials of glucocorticoid, the response rate reaches above 93% to glucocorticoids and the complete remission rate is about 66%. Unfortunately, patients in that study had to be maintained on high doses of prednisone and 15% of patients flared during follow up [21]. Two critical issues related to glucocorticoid therapy require further consideration. First, patients with IgG4-RD often have comorbidities that render them weak glucocorticoid candidates. Further, because IgG4-related disease usually affects more aged individuals, many of these patients already have hypertension, osteoporosis, obesity, glucose intolerance, and other pertinent contraindications related to long-term glucocorticoid courses. Although only a small number of patients fail to respond to steroid treatment, a large number of these patients relapse during or after the steroid taper.

The studies of conventional DMARDs (azathioprine, methotrexate, mycophenolate mofetil) have not showed good efficacy for maintaining disease remission better than glucocorticoid monotherapy, but can be efficacious when added to glucocorticoids for maintaining remission [22]. Several cases have suggested rituximab is effective for the treatment of IgG4-RD. The disclosure of oligoclonal-expanded plasmablasts in patients with IgG4-RD and their association with disease activity explains how IgG4-RD might respond by targeting cells of the B cell family [23]. Rituximab, an anti-CD-20 monoclonal antibody, induces B cell depletion resulting in a positive response. A most significant benefit of rituximab in IgG4-RD is that it can still be effective when used as monotherapy. In general, the treatment effects of rituximab are characteristic with rapid symptomatic improvement along with a rapid decline in serum IgG4 concentrations [24]. This observation was noted with our case patient as well.

Learning points

First, IgG4-RD has a broad spectrum of manifestations in various organs among which the mass-like lesion highly resembles malignancy and makes the differential diagnosis very challenging. Second, We report the case of a mass like lesion present in both pancreas and lung simultaneously which was not reported previously. Third, It is essential to consider IgG4-RD as a differential diagnosis before proceeding with an invasive surgery procedure when considering malignancy. Finally, Rituximab is an effective and beneficial treatment option for IgG4-RD.

In conclusion

We report a unique case of IgG4-RD presented with the mass formation in the lung and pancreas, highly mimicking malignancy. Clinicians should be aware of the histologic profile of IgG4-RD and consider it as a differential in patients for whom investigations rule out malignancy. A thorough preoperative process aimed at ruling out differential diagnoses can avoid false diagnoses and extensive surgery.