IgG4-Related Pulmonary Disease Masquerading as Lung Cancer: A Case Report and Literature Review

IgG4-Related Pulmonary Disease Masquerading as Lung Cancer: A Case Report and Literature Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report IgG4-Related Pulmonary Disease Masquerading as Lung Cancer: A Case Report and Literature Review Yang Qin, Yuanzhou He This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8132680/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 13 You are reading this latest preprint version Abstract Background: Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory condition that can involve the lungs (IgG4-RPD). Its clinical and radiological presentation often mimics malignancies, leading to diagnostic challenges. Case Presentation: A 57-year-old man presented with a six-month history of intermittent cough, whitish sputum, chest tightness, and exertional dyspnea. Initial chest CT revealed a right hilar soft tissue mass concerning for malignancy with mediastinal lymphadenopathy and obstructive pneumonia. Histopathological examination of initial lung biopsy and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of lymph nodes were non-diagnostic for malignancy, showing only chronic inflammation. His symptoms progressed over the following month. Laboratory investigation revealed elevated serum IgG4 (1460 mg/dL), IgE, and C-reactive protein. Pulmonary function tests showed moderate obstructive ventilatory dysfunction with a positive bronchodilator response. PET-CT demonstrated intense FDG uptake in the right hilar mass and multiple lymph nodes, highly suspicious for advanced lung cancer. A subsequent percutaneous lung biopsy revealed organizing pneumonia with focal fibroinflammation and a prominent perivascular plasma cell infiltrate. Immunohistochemistry confirmed an IgG4+ plasma cell count of >10/HPF and an IgG4+/IgG+ ratio of >40%, establishing the diagnosis of IgG4-RPD. The patient was also diagnosed with comorbid bronchial asthma. He showed marked clinical and radiological improvement after initiation of prednisone (0.5 mg/kg/day). Discussion: This case underscores that IgG4-RPD can closely simulate lung cancer both radiologically (e.g., hilar mass, lymphadenopathy, high FDG avidity on PET-CT) and clinically. A high index of suspicion is crucial in middle-aged men presenting with such findings, especially when tissue sampling is repeatedly negative for malignancy. Key diagnostic clues include elevated serum IgG4 and IgE, but definitive diagnosis relies on characteristic histopathology. Corticosteroids are the first-line treatment and typically yield excellent responses. Pathologist-clinician communication and specific IgG4 immunostaining are essential to avoid misdiagnosis and unnecessary interventions. Conclusion: IgG4-RPD is an important differential diagnosis for a lung mass with lymphadenopathy. Integration of clinical, serological, and meticulous histopathological findings is critical for accurate diagnosis and appropriate management. IgG4-Related Pulmonary Disease Lung Cancer Case Report Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated, chronic, fibro-inflammatory condition characterized by tumefactive lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and often elevated serum IgG4 concentrations ( 1 , 2 ). Since its initial recognition in the pancreas as autoimmune pancreatitis, the spectrum of IgG4-RD has expanded to encompass virtually every organ system, with the lungs being a frequently involved site, termed IgG4-related pulmonary disease (IgG4-RPD) ( 3 ). The clinical presentation of IgG4-RPD is highly heterogeneous and non-specific, ranging from asymptomatic incidental findings to symptoms such as cough, dyspnea, and chest pain ( 4 ). This diversity, coupled with its ability to mimic a wide array of pathologies, poses a significant diagnostic challenge for clinicians. Radiologically, IgG4-RPD can manifest with various patterns on computed tomography (CT), including solitary or multiple pulmonary nodules, mediastinal lymphadenopathy, bronchial wall thickening, and interstitial lung disease ( 5 ). These features often raise strong suspicion for more common entities, particularly lung cancer, sarcoidosis, or tuberculosis, leading to misdiagnosis and potentially unnecessary invasive procedures ( 6 ). Furthermore, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) CT, while valuable for assessing disease extent and activity, frequently demonstrates high FDG avidity in inflammatory IgG4-RD lesions, further confounding them with malignant processes ( 7 ). The definitive diagnosis of IgG4-RPD relies on a combination of histopathological examination, serological findings, and radiological features. The cornerstone pathological criteria include an IgG4 + plasma cell count of > 10 per high-power field (HPF) and an IgG4+/IgG + plasma cell ratio of > 40% within the affected tissue ( 8 ). However, these characteristic findings may be overlooked if there is a strong clinical pre-test probability for malignancy, leading pathologists to focus on excluding cancer rather than identifying specific inflammatory patterns. Serum IgG4 elevation, while a useful supportive marker, lacks absolute specificity and sensitivity, as it can be normal in a subset of patients with IgG4-RD or elevated in other conditions ( 9 ). We herein present a compelling case of a 57-year-old male who was initially extensively investigated for suspected lung cancer with multiple metastases based on CT and PET-CT findings, a path that was ultimately redirected to a diagnosis of IgG4-RPD after meticulous clinicopathological correlation. This case underscores the critical importance of considering IgG4-RPD in the differential diagnosis of mass-forming lung lesions and highlights the potential pitfalls in its diagnostic journey. Through this report and a concise review of the literature, we aim to enhance clinical awareness of this great mimicker, emphasizing the essential role of histopathology with specific IgG4 immunostaining in achieving an accurate diagnosis and avoiding unnecessary, invasive interventions. Case presentation A 57-year-old man was admitted to our hospital in September 2025 due to "intermittent cough for six months." Over the preceding six months, he had experienced recurrent cough with scant white sputum, accompanied by chest tightness and wheezing that worsened upon exertion. He reported no chills, fever, hemoptysis, or other discomforts. In July 2025, an outpatient chest CT at our institution revealed a soft tissue mass at the right hilum, suggestive of a neoplastic lesion with mediastinal lymph node metastasis and associated obstructive pneumonia (Fig. 1 ). He was subsequently admitted to the Thoracic Surgery department. A video-assisted thoracoscopic lung biopsy was performed. Pathological examination showed compressed mucosal tissue with chronic active inflammation. Immunohistochemistry (IHC) did not indicate a definitive neoplastic process. The IHC results were as follows: PCK (-), CK8/18 (-), TTF-1 (-), P63 (-), P40 (-), CD56 (-), Syn (-), CgA (-), INSM1 (-), P53 (scattered+, suggestive of wild-type pattern), Ki-67 (scattered+). Subsequently, an endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed, sampling stations 4R, 7R, and 10R lymph nodes (Fig. 2 ). Cytology revealed hemorrhage and fragmented lymphoid tissue with aggregates of histiocytes, but no specific diagnostic features. IHC on these samples was also negative: PCK (-), CK8/18 (-). The patient was discharged without specific treatment. One month prior to the current admission, the patient's dyspnea worsened, leading to his admission to the Department of Pulmonary and Critical Care Medicine. Physical examination on admission revealed: Temperature 36.3°C, Pulse 103 beats/min, Respiratory rate 20 breaths/min, Blood pressure 140/102 mmHg, SpO2 96% on room air. He was conscious, alert, ambulatory, in no acute distress, and cooperative. No jaundice was noted in the skin or sclera. No enlarged lymph nodes were palpable in the neck or bilateral supraclavicular fossae. There was no significant cyanosis of the lips, and the tongue was midline. Breath sounds were coarse bilaterally, with no significant dry or wet rales audible. Heart rate was 103 beats/min and regular, with no significant pathological murmurs auscultated over any valve area. The abdomen was soft, non-tender, with no rebound tenderness. The liver and spleen were not palpable below the costal margins. There was no costovertebral angle tenderness, and no edema in the lower extremities. Routine blood tests, tests for respiratory pathogens, liver and kidney function, coagulation profile, D-dimer, blood glucose, procalcitonin, rheumatologic markers, ANCA, lung cancer biomarkers (CEA, CA199, NSE), and angiotensin-converting enzyme levels were all within normal limits. Notable abnormal findings included: High-sensitivity C-reactive protein 39.0 mg/L (elevated), Erythrocyte sedimentation rate 59 mm/H (elevated), Total immunoglobulin E 172.00 IU/mL (elevated). Immunoglobulin and complement levels: Complement C4 0.10 g/L (decreased), Immunoglobulin IgG4 1460 mg/dL (elevated). Pulmonary function tests with bronchodilator response showed: 1. Moderate obstructive ventilatory dysfunction. 2. Positive bronchodilator test (post 400µg cumulative salbutamol via MDI: FEV1 increased by 13.1%, absolute increase 260ml). PET-CT scan revealed multiple enlarged lymph nodes with increased FDG uptake in the right supraclavicular area, bilateral axillae, mediastinal stations 3A, 4R, 7, and the right hilum. Specific findings included a right supraclavicular node (approx. 9mm, SUVmax 3.1), a left axillary node (23x14mm, SUVmax 5.8), and a station 4R node (23x18mm). The right hilum was enlarged (56x28mm) with significantly increased uptake (SUVmax 13.4). Scattered micronodules and small nodules were seen in both lungs, the largest in the right middle lobe (approx. 7mm, SUVmax 1.6). These findings were considered suspicious for malignancy with multiple lymph node metastases (Fig. 3 ). A subsequent percutaneous lung biopsy was performed. Histopathological examination revealed fragmented lung tissue showing organizing pneumonia with local fibrosis. In focal perivascular areas, there was a plasma cell infiltrate. IHC staining showed that a portion (> 40%) of these infiltrating plasma cells were positive for IgG4, with an IgG4 + plasma cell count > 10 per high-power field (HPF). MUM1 was positive. The pathological diagnosis was consistent with IgG4-related disease (IgG4-RD) (Fig. 4 ). Based on the comprehensive history, exclusion of other potential diseases, and the pathological confirmation, the final diagnosis was: 1) IgG4-Related Pulmonary Disease; 2) Bronchial Asthma. Treatment was initiated with oral prednisone 30 mg/day (0.5 mg/kg/day). The patient's cough and dyspnea improved markedly within one week. A follow-up chest CT showed significant resolution of the pulmonary lesions. Prednisone was continued at 30 mg/day for 4 weeks, followed by a gradual taper of 5 mg every 4 weeks. The patient remained asymptomatic, with no cough or shortness of breath. A repeat chest CT one week after treatment initiation demonstrated continued significant radiological improvement (Fig. 5 ). Pulmonary function tests also showed marked improvement. Discussion Immunoglobulin G4-related disease (IgG4-RD) is a chronic, systemic inflammatory condition characterized by tissue infiltration of IgG4-positive plasma cells, capable of affecting multiple organs, with the lungs being a commonly involved site. Due to its non-specific clinical presentation, IgG4-related pulmonary disease (IgG4-RPD) is often mistaken for tuberculosis, lung cancer, or connective tissue diseases, leading to under-diagnosis or misdiagnosis ( 10 ). The clinical manifestations of IgG4-RPD are non-specific, and some patients may even be asymptomatic. Literature review indicates a predilection for middle-aged and elderly males, with approximately 30% of patients having a history of allergic conditions (e.g., allergic rhinitis, asthma, dermatitis), possibly related to genetic predisposition or underlying immune dysregulation ( 11 ). When the lung parenchyma is involved or pleural effusion occurs, symptoms like cough and dyspnea may manifest ( 12 ). Our patient had significant cough and dyspnea, attributable partly to underlying asthma and exacerbated by progressive disease and potential pleural involvement leading to further decline in pulmonary function. Serum IgG4 level is a valuable tool for screening and monitoring IgG4-RPD. Studies suggest a positive predictive value for elevated serum IgG4 of approximately 85.7% ( 13 ). However, elevated serum IgG4 can also occur in malignancies, tuberculosis, and some rheumatologic diseases, necessitating careful clinical correlation. Furthermore, a normal serum IgG4 level does not exclude the diagnosis of IgG4-RPD. Therefore, serum IgG4 should serve as an adjunctive tool rather than a standalone diagnostic criterion ( 14 ). IgG4-RPD is often associated with hypergammaglobulinemia; our patient initially had elevated globulins which later normalized, a finding that was not initially emphasized. Studies also report that about 79.2% of IgG4-RPD patients have elevated IgE, reflecting the disease's association with B-cell hyperactivation and a Th2-dominant immune response. The elevated serum IgG4 and IgE levels in our patient align with this pathophysiological state ( 15 ). Chest CT is the most common modality for evaluating pulmonary and mediastinal involvement in IgG4-RPD. However, the radiological presentation is highly variable. Approximately 89.60% of IgG4-RPD patients show abnormalities on chest CT ( 5 ). The most prominent finding is mediastinal lymphadenopathy (70.10%), which often appears "encasing" around the great vessels, making it difficult to distinguish from malignancy ( 16 ). Other features include peribronchial and perivascular wall thickening, and airway involvement. A minority of patients present with interstitial lung disease or multiple pulmonary nodules, sometimes with a "bronchocentric" distribution. The literature suggests that the co-existence of mediastinal lymphadenopathy, airway wall thickening, and pulmonary nodules should raise strong suspicion for IgG4-RPD, helping to avoid misdiagnosis as lung cancer, sarcoidosis, or tuberculosis ( 17 ). In our case, the initial chest CT also revealed abnormalities, primarily the right hilar mass, mediastinal lymphadenopathy, and obstructive pneumonia. Careful re-evaluation of the CT scan showed that the enlarging mass enveloped the pulmonary artery and right lower lobe bronchus without clear evidence of invasion or destruction of these structures – a potential imaging clue differentiating it from aggressive malignancies. PET-CT is often used for initial differential diagnosis in complex cases and for assessing disease activity and extent. In our patient, the primary intent of the PET-CT was staging under the presumption of lung malignancy. However, the PET-CT findings did not guide towards the correct diagnosis and instead reinforced the suspicion of malignancy. Literature indicates that due to the rich inflammatory cell infiltrate, IgG4-RPD lesions can exhibit high FDG avidity and elevated SUVmax values ( 18 ). Therefore, PET-CT alone cannot reliably distinguish between benign and malignant processes and may not provide the correct diagnostic direction for IgG4-RPD. The gold standard for diagnosing IgG4-RPD remains histopathological examination. The diagnostic pathological criteria include an infiltrate of IgG4 + plasma cells with a count of ≥ 10 cells per HPF and an IgG4+/IgG + plasma cell ratio of > 40%. Other characteristic, though not always present, histological features include: ( 1 ) dense lymphoplasmacytic infiltrate; ( 2 ) storiform fibrosis; ( 3 ) obliterative phlebitis. The absence of these classic features can lead to diagnostic challenges ( 19 ). In our case, the initial clinical suspicion of malignancy, coupled with the less-than-classical appearance on the early small biopsy specimen and the pathologist's focus on excluding cancer, contributed to the delayed diagnosis. Subsequent re-evaluation and communication with the pathologist prompted specific IgG4 staining, which confirmed the diagnosis. Glucocorticoids are the first-line treatment for IgG4-RPD, typically initiated at 0.5–0.6 mg/kg/day prednisone equivalent, followed by a gradual and slow taper after 2–4 weeks ( 20 ). Glucocorticoid resistance is rare, but relapse during dose reduction is common. For patients who are steroid-dependent or relapse, immunosuppressants are often added. Rituximab has shown efficacy in reducing glucocorticoid dependence in IgG4-RD. Other disease-modifying antirheumatic drugs (e.g., azathioprine, mycophenolate mofetil, cyclosporine, methotrexate) may also be used for steroid-sparing purposes, although robust clinical evidence is limited ( 21 ). Other potential treatments include anti-CD19 antibody (inebilizumab), fludarabine or bendamustine combined with rituximab, and anti-IgE (omalizumab) or anti-IL5 (mepolizumab) therapies ( 22 ). Our patient responded well to oral glucocorticoids, with symptomatic and radiological improvement. Subsequent follow-up will monitor for potential steroid dependence. Conclusion In conclusion, when a middle-aged male patient presents with chest CT findings of mediastinal lymphadenopathy, airway wall thickening, and pulmonary nodules, particularly in the absence of definitive vascular or airway invasion, IgG4-RPD should be considered in the differential diagnosis alongside more common entities like tuberculosis and lung cancer. Serum IgG4 and IgE levels should be checked. Upon biopsy, proactive communication with the pathologist to perform IgG4 staining is crucial for an early and accurate diagnosis, preventing inappropriate clinical management and unnecessary complications for the patient. Declarations Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Funding The author(s) declare that financial support was received for the research and/or publication of this article. The present study was supported by the National Science and Technology Major Project of China (No. 2025ZD0549000) and the National Key Research and Development Program of China (No. 2024YFB4710005). Author Contribution Yuanzhou He participated in the management of the patient and wrote the manuscript.Qin Yang designed the study, treated the patient and revised the manuscript. All authors contributed to the article and approved the submitted version. Ethics statement Written informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article References Katz, Guy, Stone JH. Clinical Perspectives on IgG4-Related Disease and Its Classification. Annu Rev Med. 2022;73:545–62. 10.1146/annurev-med-050219-034449 . Perugino CA, Stone JH. IgG4-related disease: an update on pathophysiology and implications for clinical care. Nat reviews Rheumatol vol. 2020;16:702–14. 10.1038/s41584-020-0500-7 . Morales AT, Cignarella AG, Jabeen IS, Barkin JS, Mirsaeidi M. An update on IgG4-related lung disease. Eur J Intern Med. 2019;66:18–24. 10.1016/j.ejim.2019.06.010 . Matsui S. IgG4-related respiratory disease. Mod Rheumatol vol. 2019;29(2):251–6. 10.1080/14397595.2018.1548089 . Liu, Ye, Nie Y. CT Chest findings in IgG4-related disease. Annals Med vol. 2025;57(1):2489745. 10.1080/07853890.2025.2489745 . Gallo JR, Froullet C, Varizat A, Calvo RA, Pisoni C, Cosatti M, Bertoli A, Paira S. Clinical and Imaging Pulmonary Manifestations in IgG4-Related Disease. J Clin rheumatology: practical Rep rheumatic Musculoskelet Dis vol. 2025;31(2):47–52. 10.1097/RHU.0000000000002160 . Campbell SN, Rubio E, Loschner AL. Clinical review of pulmonary manifestations of IgG4-related disease. Annals Am Thorac Soc 11,9 (2014): 1466–75. 10.1513/AnnalsATS.201403-128FR Wallace ZS, Naden RP, Chari S, Choi H, Della-Torre E, Dicaire JF, Hart PA, Inoue D, Kawano M, Khosroshahi A, Kubota K, Lanzillotta M, Okazaki K, Perugino CA, Sharma A, Saeki T, Sekiguchi H, Schleinitz N, Stone JR, Takahashi N, Umehara H, Webster G, Zen Y, Stone JH, Arthritis. & rheumatology (Hoboken, N.J.) 72,1 (2020): 7–19. 10.1002/art.41120 Lanzillotta M, Mancuso G, Della-Torre E. Advances in the diagnosis and management of IgG4 related disease. BMJ (Clinical research ed.) vol. 369 m1067. 16 Jun. 2020, 10.1136/bmj.m1067 Perugino CA, Stone JH. IgG4-related disease: an update on pathophysiology and implications for clinical care. Nat reviews Rheumatol vol. 2020;16:702–14. 10.1038/s41584-020-0500-7 . Zhong W, Zhang W, Dai L, Chen M. The clinical, radiological, postoperative pathological, and genetic features of nodular lung adenocarcinoma: a real-world single-center data. J Thorac disease vol. 2024;16(5):3228–50. 10.21037/jtd-24-510 . Zhang X, Qiao W, Shen J, Jiang Q, Pan C, Wang Y, Bidzińska J, Dai F, Zhang L. Clinical, pathological, and computed tomography morphological features of lung cancer with spread through air spaces. Translational lung cancer Res vol 13,10 (2024): 2802–12. 10.21037/tlcr-24-715 Muller R, Ebbo M, Habert P, Daniel L, Briantais A, Chanez P, Gaubert JY, Schleinitz N. Thoracic manifestations of IgG4-related disease. Respirol (Carlton Vic) vol. 2023;28(2):120–31. 10.1111/resp.14422 . Wallace ZS, Zhang Y, Perugino CA, Naden R, Choi HK, Stone JH. Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts. Annals rheumatic Dis vol. 2019;78(3):406–12. 10.1136/annrheumdis-2018-214603 . Sánchez-Oro R, Alonso-Muñoz EM, Martí Romero L. Review of IgG4-related disease. Revisión de la enfermedad relacionada con la IgG4. Gastroenterol y hepatologia vol. 2019;42:638–47. 10.1016/j.gastrohep.2019.08.009 . Raj R. IgG4-related lung disease. Am J respiratory Crit care Med vol. 2013;188:527–9. 10.1164/rccm.201306-1121ED . Lee LIT, Gillibrand R, Mukerjee D, Kaneria SS. Isolated pulmonary IgG4-related disease mimicking lung malignancy. BJR case reports vol. 3,3 20160134. 12 Apr. 2017, 10.1259/bjrcr.20160134 Mahajan MS, Maitra S, Singh N, Pereira M. IgG4-Related disease simulating paraneoplastic syndrome: Role of 18FDG PET/CT imaging. Indian J Radiol imaging vol. 2017;27(2):249–53. 10.4103/ijri.IJRI_135_16 . Vasaitis L. IgG4-related disease: A relatively new concept for clinicians. Eur J Intern Med. 2016;27:1–9. 10.1016/j.ejim.2015.09.022 . Dragos C, Joseph C, Elwell H, Dey M, Kouranloo K. Pulmonary manifestations, treatments and outcomes of IgG4-related disease-a systematic literature review. Rheumatol Int vol. 2024;44(10):1875–86. 10.1007/s00296-024-05611-7 . Iaccarino L, Talarico R, Scirè CA, Amoura Z, Burmester G, Doria A, Faiz K, Frank C, Hachulla E, Hie M, Launay D, Montecucco C, Monti S, Mouthon L, Tincani A, Toniati P, Van Hagen PM, Van Vollenhoven RF, Bombardieri S, Mueller-Ladner U, Schneider M, Smith V, Cutolo M, Mosca M, Alexander T. IgG4-related diseases: state of the art on clinical practice guidelines. RMD open vol. 4,Suppl 1 e000787. 19 Jan. 2019, 10.1136/rmdopen-2018-000787 Khosroshahi A, Wallace ZS, Crowe JL, Akamizu T, Azumi A, Carruthers MN, Chari ST, Della-Torre E, Frulloni L, Goto H, Hart PA, Kamisawa T, Kawa S, Kawano M, Kim MH, Kodama Y, Kubota K, Lerch MM, Löhr M, Masaki Y, Matsui S, Mimori T, Nakamura S, Nakazawa T, Ohara H, Okazaki K, Ryu JH, Saeki T, Schleinitz N, Shimatsu A, Shimosegawa T, Takahashi H, Takahira M, Tanaka A, Topazian M, Umehara H, Webster GJ, Witzig TE, Yamamoto M, Zhang W, Chiba T, Stone JH. International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease. Arthritis & rheumatology (Hoboken, N.J.) 67,7 (2015): 1688–99. 10.1002/art.39132 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 22 Dec, 2025 Reviews received at journal 15 Dec, 2025 Reviews received at journal 14 Dec, 2025 Reviews received at journal 13 Dec, 2025 Reviewers agreed at journal 13 Dec, 2025 Reviewers agreed at journal 12 Dec, 2025 Reviewers agreed at journal 11 Dec, 2025 Reviewers agreed at journal 11 Dec, 2025 Reviewers invited by journal 10 Dec, 2025 Editor invited by journal 24 Nov, 2025 Editor assigned by journal 21 Nov, 2025 Submission checks completed at journal 21 Nov, 2025 First submitted to journal 17 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8132680","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":560466456,"identity":"d3396dfd-1651-41fb-b02f-7796f8340d2a","order_by":0,"name":"Yang Qin","email":"","orcid":"","institution":"Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Qin","suffix":""},{"id":560466457,"identity":"fefef058-bdc8-47af-8715-e1d65d2a05e7","order_by":1,"name":"Yuanzhou He","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYLACxgYGBgMG5gMGHwxs7EjRwpZQOKMgLZkULTwGn3k+HAKx8QODG8nPHv7cYZO4nb0tcbONwQFmBvbDRzfg15JmbiB5Ji1xZ8/hw8Y5Bnf4GHjS0m7g15JgJmHYdjhxw420NKCWZ8wMEjxmBLSkf5NIBGm5/8b8t4XBYcYGwlpyzCQOgm3hMTBmIEaL5Jk3ZZKNbWnGG86kJRj2GKQlsxHyC9/x9G2SP9tsZDccP3zA4McfGzt+9sPH8GpROIAuwoZPOQjINxBSMQpGwSgYBaMAAIyFU4ODs3l9AAAAAElFTkSuQmCC","orcid":"","institution":"Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology","correspondingAuthor":true,"prefix":"","firstName":"Yuanzhou","middleName":"","lastName":"He","suffix":""}],"badges":[],"createdAt":"2025-11-17 08:23:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8132680/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8132680/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":98437886,"identity":"1cdb92b7-8103-44d1-bcbc-2adb851dac32","added_by":"auto","created_at":"2025-12-17 16:58:12","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":12358914,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript.docx","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/ccdbe1dcc1ba113b0c34f8bf.docx"},{"id":98438548,"identity":"0ca870d0-2b68-4fb2-adef-b801fdc7ce17","added_by":"auto","created_at":"2025-12-17 16:59:30","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5209,"visible":true,"origin":"","legend":"","description":"","filename":"aafbfdf267134db18629c7cb4c7a8ced.json","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/047047c87770e5a9f7427790.json"},{"id":98334506,"identity":"0e1e6726-85ec-495a-981c-4eec4e41ea83","added_by":"auto","created_at":"2025-12-16 16:03:09","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":70029,"visible":true,"origin":"","legend":"","description":"","filename":"aafbfdf267134db18629c7cb4c7a8ced1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/c12d376595e5650a57a2d58d.xml"},{"id":98437043,"identity":"4564cc22-5e89-4a37-ae4b-9ab11ae3103a","added_by":"auto","created_at":"2025-12-17 16:56:51","extension":"jpeg","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2093692,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/73aeabbf01e80da0561b9a3b.jpeg"},{"id":98438836,"identity":"1658156a-213c-462f-8246-33fda801bbc0","added_by":"auto","created_at":"2025-12-17 17:00:09","extension":"jpeg","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1063008,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/c050e7262df0180484e1a2a6.jpeg"},{"id":98437480,"identity":"936dc90b-8db8-473f-a904-cc331df137a4","added_by":"auto","created_at":"2025-12-17 16:57:23","extension":"jpeg","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2656516,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/3321ba2ec2783c78322c8fb4.jpeg"},{"id":98438509,"identity":"04512002-99f9-402b-9795-7ae1affcd694","added_by":"auto","created_at":"2025-12-17 16:59:21","extension":"jpeg","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4355664,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/9e3a7b6be5c1c926878b8279.jpeg"},{"id":98438059,"identity":"c55ebc5b-ab83-444e-ab44-565bbcd0bf64","added_by":"auto","created_at":"2025-12-17 16:58:35","extension":"jpeg","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2157316,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/24ecefc1f9e45aa4cf743192.jpeg"},{"id":98437891,"identity":"85124448-6412-4efd-9dee-acccb83e8dd0","added_by":"auto","created_at":"2025-12-17 16:58:12","extension":"png","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":169793,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/68625000c4e7494a4857c517.png"},{"id":98437349,"identity":"bad6354d-c3a2-4cf5-91a6-814890a3200a","added_by":"auto","created_at":"2025-12-17 16:57:14","extension":"png","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":121216,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/70bd186147d422e6eaf9db0d.png"},{"id":98438978,"identity":"008ce9b8-826a-4499-a5c7-b58ed8b92fc6","added_by":"auto","created_at":"2025-12-17 17:00:37","extension":"png","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":75901,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/419a1082e0e06956c3840ebb.png"},{"id":98438486,"identity":"a8e827b9-71c1-4948-97cb-56e32378b0fa","added_by":"auto","created_at":"2025-12-17 16:59:18","extension":"png","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":325205,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/8ff0d02d3a549d396643e500.png"},{"id":98437903,"identity":"4fc804ed-34f3-4c4e-915c-09eec10829b4","added_by":"auto","created_at":"2025-12-17 16:58:13","extension":"png","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":170363,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/07914ceb917be249685f40f3.png"},{"id":98438579,"identity":"2afa6933-c371-4ff2-913a-dccb15242b99","added_by":"auto","created_at":"2025-12-17 16:59:33","extension":"xml","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":69260,"visible":true,"origin":"","legend":"","description":"","filename":"aafbfdf267134db18629c7cb4c7a8ced1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/09f5b141da204cb51465c083.xml"},{"id":98437799,"identity":"290fb1e8-ccac-4c83-842e-4d1ab4832d69","added_by":"auto","created_at":"2025-12-17 16:57:50","extension":"html","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":75994,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/fac97646d673bcc56554bdeb.html"},{"id":98437344,"identity":"0c068073-b1a2-4699-bcff-9448c1e39cfb","added_by":"auto","created_at":"2025-12-17 16:57:14","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2312542,"visible":true,"origin":"","legend":"\u003cp\u003eAt the time of the initial diagnosis, chest CT imaging revealed a mass shadow in the right hilum, accompanied by mediastinal lymphadenopathy and right-sided obstructive pneumonia. (A) and (B) Lung and mediastinal window at the carinal level; (C) and (D) Lung and mediastinal window at the right middle lobe plane level; (E) and (F) Lung and mediastinal window at the right lower lobe plane.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/0d3d44e6a8200a91f0a2cf7a.png"},{"id":98438041,"identity":"b51274af-7f18-4839-a3fe-90653b5360f5","added_by":"auto","created_at":"2025-12-17 16:58:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":4825385,"visible":true,"origin":"","legend":"\u003cp\u003eEndobronchial Ultrasound (EBUS) images show that the airway mucosa is smooth, and the mediastinal lymph nodes are significantly enlarged. (A) Right upper lobe bronchus; (B) The 4R group of lymph nodes; (C) Right middle lobe bronchus; (D) The 7R group of lymph nodes; (E) Bronchus lobaris inferior dexter; (F) The 7R group of lymph nodes.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/db01330ece8dc9503fb58137.png"},{"id":98437317,"identity":"11317560-eb85-4f77-bb72-f596bffc6473","added_by":"auto","created_at":"2025-12-17 16:57:12","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2533378,"visible":true,"origin":"","legend":"\u003cp\u003ePET-CT shows tumor changes in the right pulmonary hilum and mediastinal lymph node metastasis.(A)The top image of body; (B) and (C) The PET-CT image of the right middle lobe and the right lower lobe.\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/492038d8607b2e662cc40ab8.png"},{"id":98438028,"identity":"17ddb6db-6be5-4ddc-843d-e178430d5cf9","added_by":"auto","created_at":"2025-12-17 16:58:28","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":7561054,"visible":true,"origin":"","legend":"\u003cp\u003eThe results of lung puncture biopsy tissue and immunohistochemical staining. (A) Hematoxylin and eosin stained show lymphocytes and plasma cells are seen infiltrating the lung tissue, and in some areas, there are active fibrotic lesions (100x) and (B) 400x magnification.(C) and (D) immunopathological staining on IgG4 at 100x and 400x magnification. (E) and (F) immunopathological staining on IgG at 100x and 400x magnification.\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/b04245132783455cc59ec0f9.png"},{"id":98437880,"identity":"60ffcaf3-1b7a-430f-8c13-843f23737deb","added_by":"auto","created_at":"2025-12-17 16:58:12","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":2483578,"visible":true,"origin":"","legend":"\u003cp\u003eOne week of glucocorticoid therapy resulted in significant reduction of pulmonary lesions and mediastinal lymphadenopathy as demonstrated by chest CT imaging. (A) and (B) Lung and mediastinal window at the carinal level; (C) and (D) Lung and mediastinal window at the right middle lobe plane level; (E) and (F) Lung and mediastinal window at the right lower lobe plane.\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/41399832869409efe1dc6ae4.png"},{"id":98445714,"identity":"9a74c0ea-17c1-4222-824d-cd3d9d98c78a","added_by":"auto","created_at":"2025-12-17 17:21:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":19548850,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8132680/v1/e0b3f41e-4c67-4787-beef-1d1f7930c763.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"IgG4-Related Pulmonary Disease Masquerading as Lung Cancer: A Case Report and Literature Review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eImmunoglobulin G4-related disease (IgG4-RD) is an immune-mediated, chronic, fibro-inflammatory condition characterized by tumefactive lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and often elevated serum IgG4 concentrations (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Since its initial recognition in the pancreas as autoimmune pancreatitis, the spectrum of IgG4-RD has expanded to encompass virtually every organ system, with the lungs being a frequently involved site, termed IgG4-related pulmonary disease (IgG4-RPD) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe clinical presentation of IgG4-RPD is highly heterogeneous and non-specific, ranging from asymptomatic incidental findings to symptoms such as cough, dyspnea, and chest pain (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). This diversity, coupled with its ability to mimic a wide array of pathologies, poses a significant diagnostic challenge for clinicians. Radiologically, IgG4-RPD can manifest with various patterns on computed tomography (CT), including solitary or multiple pulmonary nodules, mediastinal lymphadenopathy, bronchial wall thickening, and interstitial lung disease (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). These features often raise strong suspicion for more common entities, particularly lung cancer, sarcoidosis, or tuberculosis, leading to misdiagnosis and potentially unnecessary invasive procedures (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Furthermore, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) CT, while valuable for assessing disease extent and activity, frequently demonstrates high FDG avidity in inflammatory IgG4-RD lesions, further confounding them with malignant processes (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe definitive diagnosis of IgG4-RPD relies on a combination of histopathological examination, serological findings, and radiological features. The cornerstone pathological criteria include an IgG4\u0026thinsp;+\u0026thinsp;plasma cell count of \u0026gt;\u0026thinsp;10 per high-power field (HPF) and an IgG4+/IgG\u0026thinsp;+\u0026thinsp;plasma cell ratio of \u0026gt;\u0026thinsp;40% within the affected tissue (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). However, these characteristic findings may be overlooked if there is a strong clinical pre-test probability for malignancy, leading pathologists to focus on excluding cancer rather than identifying specific inflammatory patterns. Serum IgG4 elevation, while a useful supportive marker, lacks absolute specificity and sensitivity, as it can be normal in a subset of patients with IgG4-RD or elevated in other conditions (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe herein present a compelling case of a 57-year-old male who was initially extensively investigated for suspected lung cancer with multiple metastases based on CT and PET-CT findings, a path that was ultimately redirected to a diagnosis of IgG4-RPD after meticulous clinicopathological correlation. This case underscores the critical importance of considering IgG4-RPD in the differential diagnosis of mass-forming lung lesions and highlights the potential pitfalls in its diagnostic journey. Through this report and a concise review of the literature, we aim to enhance clinical awareness of this great mimicker, emphasizing the essential role of histopathology with specific IgG4 immunostaining in achieving an accurate diagnosis and avoiding unnecessary, invasive interventions.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 57-year-old man was admitted to our hospital in September 2025 due to \"intermittent cough for six months.\" Over the preceding six months, he had experienced recurrent cough with scant white sputum, accompanied by chest tightness and wheezing that worsened upon exertion. He reported no chills, fever, hemoptysis, or other discomforts. In July 2025, an outpatient chest CT at our institution revealed a soft tissue mass at the right hilum, suggestive of a neoplastic lesion with mediastinal lymph node metastasis and associated obstructive pneumonia (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). He was subsequently admitted to the Thoracic Surgery department. A video-assisted thoracoscopic lung biopsy was performed. Pathological examination showed compressed mucosal tissue with chronic active inflammation. Immunohistochemistry (IHC) did not indicate a definitive neoplastic process. The IHC results were as follows: PCK (-), CK8/18 (-), TTF-1 (-), P63 (-), P40 (-), CD56 (-), Syn (-), CgA (-), INSM1 (-), P53 (scattered+, suggestive of wild-type pattern), Ki-67 (scattered+). Subsequently, an endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed, sampling stations 4R, 7R, and 10R lymph nodes (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Cytology revealed hemorrhage and fragmented lymphoid tissue with aggregates of histiocytes, but no specific diagnostic features. IHC on these samples was also negative: PCK (-), CK8/18 (-). The patient was discharged without specific treatment. One month prior to the current admission, the patient's dyspnea worsened, leading to his admission to the Department of Pulmonary and Critical Care Medicine.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePhysical examination on admission revealed: Temperature 36.3\u0026deg;C, Pulse 103 beats/min, Respiratory rate 20 breaths/min, Blood pressure 140/102 mmHg, SpO2 96% on room air. He was conscious, alert, ambulatory, in no acute distress, and cooperative. No jaundice was noted in the skin or sclera. No enlarged lymph nodes were palpable in the neck or bilateral supraclavicular fossae. There was no significant cyanosis of the lips, and the tongue was midline. Breath sounds were coarse bilaterally, with no significant dry or wet rales audible. Heart rate was 103 beats/min and regular, with no significant pathological murmurs auscultated over any valve area. The abdomen was soft, non-tender, with no rebound tenderness. The liver and spleen were not palpable below the costal margins. There was no costovertebral angle tenderness, and no edema in the lower extremities.\u003c/p\u003e \u003cp\u003eRoutine blood tests, tests for respiratory pathogens, liver and kidney function, coagulation profile, D-dimer, blood glucose, procalcitonin, rheumatologic markers, ANCA, lung cancer biomarkers (CEA, CA199, NSE), and angiotensin-converting enzyme levels were all within normal limits.\u003c/p\u003e \u003cp\u003eNotable abnormal findings included: High-sensitivity C-reactive protein 39.0 mg/L (elevated), Erythrocyte sedimentation rate 59 mm/H (elevated), Total immunoglobulin E 172.00 IU/mL (elevated). Immunoglobulin and complement levels: Complement C4 0.10 g/L (decreased), Immunoglobulin IgG4 1460 mg/dL (elevated).\u003c/p\u003e \u003cp\u003ePulmonary function tests with bronchodilator response showed: 1. Moderate obstructive ventilatory dysfunction. 2. Positive bronchodilator test (post 400\u0026micro;g cumulative salbutamol via MDI: FEV1 increased by 13.1%, absolute increase 260ml). PET-CT scan revealed multiple enlarged lymph nodes with increased FDG uptake in the right supraclavicular area, bilateral axillae, mediastinal stations 3A, 4R, 7, and the right hilum. Specific findings included a right supraclavicular node (approx. 9mm, SUVmax 3.1), a left axillary node (23x14mm, SUVmax 5.8), and a station 4R node (23x18mm). The right hilum was enlarged (56x28mm) with significantly increased uptake (SUVmax 13.4). Scattered micronodules and small nodules were seen in both lungs, the largest in the right middle lobe (approx. 7mm, SUVmax 1.6). These findings were considered suspicious for malignancy with multiple lymph node metastases (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA subsequent percutaneous lung biopsy was performed. Histopathological examination revealed fragmented lung tissue showing organizing pneumonia with local fibrosis. In focal perivascular areas, there was a plasma cell infiltrate. IHC staining showed that a portion (\u0026gt;\u0026thinsp;40%) of these infiltrating plasma cells were positive for IgG4, with an IgG4\u0026thinsp;+\u0026thinsp;plasma cell count\u0026thinsp;\u0026gt;\u0026thinsp;10 per high-power field (HPF). MUM1 was positive. The pathological diagnosis was consistent with IgG4-related disease (IgG4-RD) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Based on the comprehensive history, exclusion of other potential diseases, and the pathological confirmation, the final diagnosis was: 1) IgG4-Related Pulmonary Disease; 2) Bronchial Asthma.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTreatment was initiated with oral prednisone 30 mg/day (0.5 mg/kg/day). The patient's cough and dyspnea improved markedly within one week. A follow-up chest CT showed significant resolution of the pulmonary lesions. Prednisone was continued at 30 mg/day for 4 weeks, followed by a gradual taper of 5 mg every 4 weeks. The patient remained asymptomatic, with no cough or shortness of breath. A repeat chest CT one week after treatment initiation demonstrated continued significant radiological improvement (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Pulmonary function tests also showed marked improvement.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eImmunoglobulin G4-related disease (IgG4-RD) is a chronic, systemic inflammatory condition characterized by tissue infiltration of IgG4-positive plasma cells, capable of affecting multiple organs, with the lungs being a commonly involved site. Due to its non-specific clinical presentation, IgG4-related pulmonary disease (IgG4-RPD) is often mistaken for tuberculosis, lung cancer, or connective tissue diseases, leading to under-diagnosis or misdiagnosis (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe clinical manifestations of IgG4-RPD are non-specific, and some patients may even be asymptomatic. Literature review indicates a predilection for middle-aged and elderly males, with approximately 30% of patients having a history of allergic conditions (e.g., allergic rhinitis, asthma, dermatitis), possibly related to genetic predisposition or underlying immune dysregulation (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). When the lung parenchyma is involved or pleural effusion occurs, symptoms like cough and dyspnea may manifest (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Our patient had significant cough and dyspnea, attributable partly to underlying asthma and exacerbated by progressive disease and potential pleural involvement leading to further decline in pulmonary function.\u003c/p\u003e \u003cp\u003eSerum IgG4 level is a valuable tool for screening and monitoring IgG4-RPD. Studies suggest a positive predictive value for elevated serum IgG4 of approximately 85.7% (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). However, elevated serum IgG4 can also occur in malignancies, tuberculosis, and some rheumatologic diseases, necessitating careful clinical correlation. Furthermore, a normal serum IgG4 level does not exclude the diagnosis of IgG4-RPD. Therefore, serum IgG4 should serve as an adjunctive tool rather than a standalone diagnostic criterion (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). IgG4-RPD is often associated with hypergammaglobulinemia; our patient initially had elevated globulins which later normalized, a finding that was not initially emphasized. Studies also report that about 79.2% of IgG4-RPD patients have elevated IgE, reflecting the disease's association with B-cell hyperactivation and a Th2-dominant immune response. The elevated serum IgG4 and IgE levels in our patient align with this pathophysiological state (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eChest CT is the most common modality for evaluating pulmonary and mediastinal involvement in IgG4-RPD. However, the radiological presentation is highly variable. Approximately 89.60% of IgG4-RPD patients show abnormalities on chest CT (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). The most prominent finding is mediastinal lymphadenopathy (70.10%), which often appears \"encasing\" around the great vessels, making it difficult to distinguish from malignancy (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Other features include peribronchial and perivascular wall thickening, and airway involvement. A minority of patients present with interstitial lung disease or multiple pulmonary nodules, sometimes with a \"bronchocentric\" distribution. The literature suggests that the co-existence of mediastinal lymphadenopathy, airway wall thickening, and pulmonary nodules should raise strong suspicion for IgG4-RPD, helping to avoid misdiagnosis as lung cancer, sarcoidosis, or tuberculosis (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). In our case, the initial chest CT also revealed abnormalities, primarily the right hilar mass, mediastinal lymphadenopathy, and obstructive pneumonia. Careful re-evaluation of the CT scan showed that the enlarging mass enveloped the pulmonary artery and right lower lobe bronchus without clear evidence of invasion or destruction of these structures \u0026ndash; a potential imaging clue differentiating it from aggressive malignancies.\u003c/p\u003e \u003cp\u003ePET-CT is often used for initial differential diagnosis in complex cases and for assessing disease activity and extent. In our patient, the primary intent of the PET-CT was staging under the presumption of lung malignancy. However, the PET-CT findings did not guide towards the correct diagnosis and instead reinforced the suspicion of malignancy. Literature indicates that due to the rich inflammatory cell infiltrate, IgG4-RPD lesions can exhibit high FDG avidity and elevated SUVmax values (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Therefore, PET-CT alone cannot reliably distinguish between benign and malignant processes and may not provide the correct diagnostic direction for IgG4-RPD.\u003c/p\u003e \u003cp\u003eThe gold standard for diagnosing IgG4-RPD remains histopathological examination. The diagnostic pathological criteria include an infiltrate of IgG4\u0026thinsp;+\u0026thinsp;plasma cells with a count of \u0026ge;\u0026thinsp;10 cells per HPF and an IgG4+/IgG\u0026thinsp;+\u0026thinsp;plasma cell ratio of \u0026gt;\u0026thinsp;40%. Other characteristic, though not always present, histological features include: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) dense lymphoplasmacytic infiltrate; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) storiform fibrosis; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) obliterative phlebitis. The absence of these classic features can lead to diagnostic challenges (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). In our case, the initial clinical suspicion of malignancy, coupled with the less-than-classical appearance on the early small biopsy specimen and the pathologist's focus on excluding cancer, contributed to the delayed diagnosis. Subsequent re-evaluation and communication with the pathologist prompted specific IgG4 staining, which confirmed the diagnosis.\u003c/p\u003e \u003cp\u003eGlucocorticoids are the first-line treatment for IgG4-RPD, typically initiated at 0.5\u0026ndash;0.6 mg/kg/day prednisone equivalent, followed by a gradual and slow taper after 2\u0026ndash;4 weeks (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Glucocorticoid resistance is rare, but relapse during dose reduction is common. For patients who are steroid-dependent or relapse, immunosuppressants are often added. Rituximab has shown efficacy in reducing glucocorticoid dependence in IgG4-RD. Other disease-modifying antirheumatic drugs (e.g., azathioprine, mycophenolate mofetil, cyclosporine, methotrexate) may also be used for steroid-sparing purposes, although robust clinical evidence is limited (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Other potential treatments include anti-CD19 antibody (inebilizumab), fludarabine or bendamustine combined with rituximab, and anti-IgE (omalizumab) or anti-IL5 (mepolizumab) therapies (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Our patient responded well to oral glucocorticoids, with symptomatic and radiological improvement. Subsequent follow-up will monitor for potential steroid dependence.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, when a middle-aged male patient presents with chest CT findings of mediastinal lymphadenopathy, airway wall thickening, and pulmonary nodules, particularly in the absence of definitive vascular or airway invasion, IgG4-RPD should be considered in the differential diagnosis alongside more common entities like tuberculosis and lung cancer. Serum IgG4 and IgE levels should be checked. Upon biopsy, proactive communication with the pathologist to perform IgG4 staining is crucial for an early and accurate diagnosis, preventing inappropriate clinical management and unnecessary complications for the patient.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication:\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThe author(s) declare that financial support was received for the research and/or publication of this article. The present study was supported by the National Science and Technology Major Project of China (No. 2025ZD0549000) and the National Key Research and Development Program of China (No. 2024YFB4710005).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eYuanzhou He participated in the management of the patient and wrote the manuscript.Qin Yang designed the study, treated the patient and revised the manuscript. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003ch3\u003eEthics statement\u003c/h3\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKatz, Guy, Stone JH. Clinical Perspectives on IgG4-Related Disease and Its Classification. Annu Rev Med. 2022;73:545\u0026ndash;62. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1146/annurev-med-050219-034449\u003c/span\u003e\u003cspan address=\"10.1146/annurev-med-050219-034449\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerugino CA, Stone JH. IgG4-related disease: an update on pathophysiology and implications for clinical care. Nat reviews Rheumatol vol. 2020;16:702\u0026ndash;14. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41584-020-0500-7\u003c/span\u003e\u003cspan address=\"10.1038/s41584-020-0500-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorales AT, Cignarella AG, Jabeen IS, Barkin JS, Mirsaeidi M. An update on IgG4-related lung disease. Eur J Intern Med. 2019;66:18\u0026ndash;24. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ejim.2019.06.010\u003c/span\u003e\u003cspan address=\"10.1016/j.ejim.2019.06.010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsui S. IgG4-related respiratory disease. Mod Rheumatol vol. 2019;29(2):251\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/14397595.2018.1548089\u003c/span\u003e\u003cspan address=\"10.1080/14397595.2018.1548089\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu, Ye, Nie Y. CT Chest findings in IgG4-related disease. Annals Med vol. 2025;57(1):2489745. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/07853890.2025.2489745\u003c/span\u003e\u003cspan address=\"10.1080/07853890.2025.2489745\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGallo JR, Froullet C, Varizat A, Calvo RA, Pisoni C, Cosatti M, Bertoli A, Paira S. Clinical and Imaging Pulmonary Manifestations in IgG4-Related Disease. J Clin rheumatology: practical Rep rheumatic Musculoskelet Dis vol. 2025;31(2):47\u0026ndash;52. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/RHU.0000000000002160\u003c/span\u003e\u003cspan address=\"10.1097/RHU.0000000000002160\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCampbell SN, Rubio E, Loschner AL. Clinical review of pulmonary manifestations of IgG4-related disease. Annals Am Thorac Soc 11,9 (2014): 1466\u0026ndash;75. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1513/AnnalsATS.201403-128FR\u003c/span\u003e\u003cspan address=\"10.1513/AnnalsATS.201403-128FR\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWallace ZS, Naden RP, Chari S, Choi H, Della-Torre E, Dicaire JF, Hart PA, Inoue D, Kawano M, Khosroshahi A, Kubota K, Lanzillotta M, Okazaki K, Perugino CA, Sharma A, Saeki T, Sekiguchi H, Schleinitz N, Stone JR, Takahashi N, Umehara H, Webster G, Zen Y, Stone JH, Arthritis. \u0026amp; rheumatology (Hoboken, N.J.) 72,1 (2020): 7\u0026ndash;19. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/art.41120\u003c/span\u003e\u003cspan address=\"10.1002/art.41120\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLanzillotta M, Mancuso G, Della-Torre E. Advances in the diagnosis and management of IgG4 related disease. BMJ (Clinical research ed.) vol. 369 m1067. 16 Jun. 2020, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/bmj.m1067\u003c/span\u003e\u003cspan address=\"10.1136/bmj.m1067\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerugino CA, Stone JH. IgG4-related disease: an update on pathophysiology and implications for clinical care. Nat reviews Rheumatol vol. 2020;16:702\u0026ndash;14. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41584-020-0500-7\u003c/span\u003e\u003cspan address=\"10.1038/s41584-020-0500-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhong W, Zhang W, Dai L, Chen M. The clinical, radiological, postoperative pathological, and genetic features of nodular lung adenocarcinoma: a real-world single-center data. J Thorac disease vol. 2024;16(5):3228\u0026ndash;50. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.21037/jtd-24-510\u003c/span\u003e\u003cspan address=\"10.21037/jtd-24-510\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang X, Qiao W, Shen J, Jiang Q, Pan C, Wang Y, Bidzińska J, Dai F, Zhang L. Clinical, pathological, and computed tomography morphological features of lung cancer with spread through air spaces. Translational lung cancer Res vol 13,10 (2024): 2802\u0026ndash;12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.21037/tlcr-24-715\u003c/span\u003e\u003cspan address=\"10.21037/tlcr-24-715\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMuller R, Ebbo M, Habert P, Daniel L, Briantais A, Chanez P, Gaubert JY, Schleinitz N. Thoracic manifestations of IgG4-related disease. Respirol (Carlton Vic) vol. 2023;28(2):120\u0026ndash;31. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/resp.14422\u003c/span\u003e\u003cspan address=\"10.1111/resp.14422\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWallace ZS, Zhang Y, Perugino CA, Naden R, Choi HK, Stone JH. Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts. Annals rheumatic Dis vol. 2019;78(3):406\u0026ndash;12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/annrheumdis-2018-214603\u003c/span\u003e\u003cspan address=\"10.1136/annrheumdis-2018-214603\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eS\u0026aacute;nchez-Oro R, Alonso-Mu\u0026ntilde;oz EM, Mart\u0026iacute; Romero L. Review of IgG4-related disease. Revisi\u0026oacute;n de la enfermedad relacionada con la IgG4. Gastroenterol y hepatologia vol. 2019;42:638\u0026ndash;47. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.gastrohep.2019.08.009\u003c/span\u003e\u003cspan address=\"10.1016/j.gastrohep.2019.08.009\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaj R. IgG4-related lung disease. Am J respiratory Crit care Med vol. 2013;188:527\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1164/rccm.201306-1121ED\u003c/span\u003e\u003cspan address=\"10.1164/rccm.201306-1121ED\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee LIT, Gillibrand R, Mukerjee D, Kaneria SS. Isolated pulmonary IgG4-related disease mimicking lung malignancy. BJR case reports vol. 3,3 20160134. 12 Apr. 2017, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1259/bjrcr.20160134\u003c/span\u003e\u003cspan address=\"10.1259/bjrcr.20160134\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahajan MS, Maitra S, Singh N, Pereira M. IgG4-Related disease simulating paraneoplastic syndrome: Role of 18FDG PET/CT imaging. Indian J Radiol imaging vol. 2017;27(2):249\u0026ndash;53. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4103/ijri.IJRI_135_16\u003c/span\u003e\u003cspan address=\"10.4103/ijri.IJRI_135_16\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVasaitis L. IgG4-related disease: A relatively new concept for clinicians. Eur J Intern Med. 2016;27:1\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ejim.2015.09.022\u003c/span\u003e\u003cspan address=\"10.1016/j.ejim.2015.09.022\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDragos C, Joseph C, Elwell H, Dey M, Kouranloo K. Pulmonary manifestations, treatments and outcomes of IgG4-related disease-a systematic literature review. Rheumatol Int vol. 2024;44(10):1875\u0026ndash;86. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00296-024-05611-7\u003c/span\u003e\u003cspan address=\"10.1007/s00296-024-05611-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIaccarino L, Talarico R, Scir\u0026egrave; CA, Amoura Z, Burmester G, Doria A, Faiz K, Frank C, Hachulla E, Hie M, Launay D, Montecucco C, Monti S, Mouthon L, Tincani A, Toniati P, Van Hagen PM, Van Vollenhoven RF, Bombardieri S, Mueller-Ladner U, Schneider M, Smith V, Cutolo M, Mosca M, Alexander T. IgG4-related diseases: state of the art on clinical practice guidelines. RMD open vol. 4,Suppl 1 e000787. 19 Jan. 2019, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/rmdopen-2018-000787\u003c/span\u003e\u003cspan address=\"10.1136/rmdopen-2018-000787\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhosroshahi A, Wallace ZS, Crowe JL, Akamizu T, Azumi A, Carruthers MN, Chari ST, Della-Torre E, Frulloni L, Goto H, Hart PA, Kamisawa T, Kawa S, Kawano M, Kim MH, Kodama Y, Kubota K, Lerch MM, L\u0026ouml;hr M, Masaki Y, Matsui S, Mimori T, Nakamura S, Nakazawa T, Ohara H, Okazaki K, Ryu JH, Saeki T, Schleinitz N, Shimatsu A, Shimosegawa T, Takahashi H, Takahira M, Tanaka A, Topazian M, Umehara H, Webster GJ, Witzig TE, Yamamoto M, Zhang W, Chiba T, Stone JH. International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease. Arthritis \u0026amp; rheumatology (Hoboken, N.J.) 67,7 (2015): 1688\u0026ndash;99. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/art.39132\u003c/span\u003e\u003cspan address=\"10.1002/art.39132\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"IgG4-Related Pulmonary Disease, Lung Cancer, Case Report","lastPublishedDoi":"10.21203/rs.3.rs-8132680/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8132680/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eImmunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory condition that can involve the lungs (IgG4-RPD). Its clinical and radiological presentation often mimics malignancies, leading to diagnostic challenges.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Presentation:\u003c/strong\u003e A 57-year-old man presented with a six-month history of intermittent cough, whitish sputum, chest tightness, and exertional dyspnea. Initial chest CT revealed a right hilar soft tissue mass concerning for malignancy with mediastinal lymphadenopathy and obstructive pneumonia. Histopathological examination of initial lung biopsy and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of lymph nodes were non-diagnostic for malignancy, showing only chronic inflammation. His symptoms progressed over the following month. Laboratory investigation revealed elevated serum IgG4 (1460 mg/dL), IgE, and C-reactive protein. Pulmonary function tests showed moderate obstructive ventilatory dysfunction with a positive bronchodilator response. PET-CT demonstrated intense FDG uptake in the right hilar mass and multiple lymph nodes, highly suspicious for advanced lung cancer. A subsequent percutaneous lung biopsy revealed organizing pneumonia with focal fibroinflammation and a prominent perivascular plasma cell infiltrate. Immunohistochemistry confirmed an IgG4+ plasma cell count of \u0026gt;10/HPF and an IgG4+/IgG+ ratio of \u0026gt;40%, establishing the diagnosis of IgG4-RPD. The patient was also diagnosed with comorbid bronchial asthma. He showed marked clinical and radiological improvement after initiation of prednisone (0.5 mg/kg/day).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion:\u003c/strong\u003e This case underscores that IgG4-RPD can closely simulate lung cancer both radiologically (e.g., hilar mass, lymphadenopathy, high FDG avidity on PET-CT) and clinically. A high index of suspicion is crucial in middle-aged men presenting with such findings, especially when tissue sampling is repeatedly negative for malignancy. Key diagnostic clues include elevated serum IgG4 and IgE, but definitive diagnosis relies on characteristic histopathology. Corticosteroids are the first-line treatment and typically yield excellent responses. Pathologist-clinician communication and specific IgG4 immunostaining are essential to avoid misdiagnosis and unnecessary interventions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eIgG4-RPD is an important differential diagnosis for a lung mass with lymphadenopathy. Integration of clinical, serological, and meticulous histopathological findings is critical for accurate diagnosis and appropriate management.\u003c/p\u003e","manuscriptTitle":"IgG4-Related Pulmonary Disease Masquerading as Lung Cancer: A Case Report and Literature Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-16 16:03:04","doi":"10.21203/rs.3.rs-8132680/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-22T09:57:10+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-15T10:36:28+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-15T02:21:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-13T09:05:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"262769317679043836231195318938945845223","date":"2025-12-13T08:27:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"7237812762639695409713828698837988827","date":"2025-12-12T23:31:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"315747770111235387565001401205848591312","date":"2025-12-11T11:18:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"238921193062872938524984867870815554053","date":"2025-12-11T09:36:13+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-10T19:02:06+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-11-24T10:47:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-22T01:44:05+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-22T01:42:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2025-11-17T08:19:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e5666b65-301a-4b4a-84dd-4987c826f567","owner":[],"postedDate":"December 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-01-21T13:08:29+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-16 16:03:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8132680","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8132680","identity":"rs-8132680","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}