Introduction

Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized chronic fibro-inflammatory condition with a histopathological hallmark of dense lymphoplasmacytic cell infiltration, storiform fibrosis and obliterative phlebitis [1]. Almost any organ or tissue can be affected, and these organs include the pancreas, hepatobiliary system, salivary and lacrimal glands, kidney and retroperitoneum [2]. In 2004, Duvic et al. first reported IgG4-related lung disease (IgG4-RLD) [3]. Unfortunately, the literature on IgG4-RLD is limited to single case reports and small case series. Moreover, most of these cases were not pathologically confirmed by lung tissue. Other causes, such as pulmonary infection and congestion, may also lead to pulmonary lesions similar to IgG4-RD, which may be mistaken for IgG4-RLD. Thus, the diagnosis of IgG4-RLD is very challenging, especially with isolated lung involvement or other anatomical site involvement that does not help establish the diagnosis, such as pituitary, meninge and nasal sinus involvement. In this case, IgG4-RLD is often confirmed incidentally from the histopathological findings of lung biopsy or from surgery due to a suspected pulmonary malignancy. Therefore, the clinical analysis of IgG4-RLD based on pathological diagnosis may lead to a more accurate understanding of the disease and improve the diagnosis of this entity. We retrospectively analyzed the clinicopathological characteristics of patients with IgG4-RLD, which was verified pathologically to reduce the risk of misdiagnosis.

Methods

Patients

This retrospective study was conducted at Sun Yat-Sen Memorial Hospital affiliated with Sun Yat-Sen University. We reviewed the pathological reports of 4838 patients who underwent biopsy and/or lung resection between April 2017 and April 2021, and we used the electronic pathological record system to obtain these data. The levels of IgG4 and IgG were assessed by immunohistochemical staining of lung tissue specimens from 65 patients with suspected IgG4-RLD. According to the 2012 international pathological consensus of IgG4-RD [4], which is described briefly below, a total of 10 patients were ultimately pathologically diagnosed with IgG4-RLD, of which 6 patients had pathological results that were highly suggestive of an IgG4-RLD diagnosis and 4 patients had a probable histopathological diagnosis of IgG4-RLD. The flow diagram of the screening and diagnostic process is presented in Fig. 1. Of the 10 patients, 4 patients (cases 1–4) underwent pulmonary lobectomy via video-assisted thoracoscopic surgery (VATS) based on suspicion of lung cancer, 1 patient (case 5) underwent open lung biopsy (OLB), 1 patient (case 6) underwent percutaneous lung biopsy (PLB) and 4 patients (cases 7–10) underwent transbronchial lung biopsy (TLB). Patients with malignant tumors, lymphoproliferative disorders, Castleman’s disease and sarcoidosis were excluded. Once the patients were diagnosed, relevant clinical data were extracted from the electronic medical records. The clinical, serological, radiological and histopathological features, treatments administered and therapeutic response of the patients were retrospectively summarized and analyzed. The present study was performed according to the tenets outlined in the Declaration of Helsinki and was approved by the Ethics Committee of Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University (number, SYSEC-KY-KS-2021-225). The study was exempt from obtaining informed consent because of its retrospective nature.

Fig. 1
figure 1

Flow diagram of the screening and diagnostic process for IgG4-related lung disease

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Diagnostic criteria of IgG4-RLD based on histopathology

The histopathological diagnostic criteria were based on the 2012 international pathological consensus of IgG4-RD [4], which are based primarily on histopathological features such as abundant lymphoplasmacytic cell infiltration, fibrosis (usually storiform fibrosis) and obliterative phlebitis. The number of IgG4 + plasma cells and the IgG4 + /IgG + plasma cell ratio in the tissues are of secondary importance. Three categories were proposed for the pathological diagnosis of IgG4-RLD: histopathologically highly suggestive, histopathologically probable and histopathologically insufficient. The criteria for each category are listed below. Patients in histopathologically highly suggestive and histopathologically probable categories were included in the current study.

  1. 1.

    Histopathologically highly suggestive criteria:

    1. (1)

       ≥ 2 items from the list of histopathological features.

    2. (2)

      The number of IgG4 + plasma cells was > 50 cells/high-power field (HPF).

    3. (3)

      An IgG4 + /IgG + plasma cell ratio > 40%.

  1. 2.

    Histopathologically probable criteria:

    1. (1)

      At least 1 item from the list of histopathological features.

    2. (2)

      The number of IgG4 + plasma cells was > 50 cells/HPF from the lung surgical specimens, > 20 cells/HPF from the biopsy, or an IgG4 + /IgG + plasma cell ratio > 40%.

    3. (3)

      Additional evidence: A serum IgG4 concentration > 2.01 g/l according to the detected range of our hospital or other organ involvement proven by imaging or histopathological examinations.

  1. 3.

    Histopathologically insufficient criterion: Any case that does not conform to the above two categories.

Histopathological studies

Hematoxylin and eosin (H&E) staining and immunohistochemical staining for IgG4 and IgG were conducted at the Department of Pathology in our hospital. Two pathologists (** characteristics of IgG4-RLD and lung cancer on CT suggest that these two diseases may share some pathological mechanisms. For lung cancer, the appearance can be explained by the contraction of internal fibrosis, different growth rates of cancerous cells and the extension of malignant cells along the interstitium [14]. Inoue et al. demonstrated that pathological findings such as fibrosis and diffuse lymphoplasmacytic cell infiltration along the interlobular septa corresponded to the radiological findings of IgG4-RLD [5], which was also observed in our study. We speculate that the imaging manifestations of IgG4-RLD that resemble lung cancer might result from shared characteristics, such as fibrosis and dense lymphoplasmacytic cell infiltration, which mimics the pattern of cancerous invasion. Thus, it is a great challenge to differentiate IgG4-RLD with a pulmonary mass and/or large nodules from lung cancer.

To meet this challenge, we should focus on the following points, especially when patients present with only lung involvement or other organ involvement that does not help establish a definitive diagnosis: (1) In addition to pulmonary masses and/or large nodules, attention should be given to the radiological manifestations of the other subtypes, as mentioned above, which may offer some support for a diagnosis of IgG4-RLD. (2) In this case, serological testing for IgG4 should be performed. Serum IgG4 has high diagnostic value for IgG4-RD, and its concentration has a positive correlation with the number of organs involved [15]. Wang and colleagues reported that 84% of patients with IgG4-RLD had an elevated serum IgG4 concentration [16]. (3) In patients who were initially suspected of having lung cancer, the levels of traditional serum biomarkers are usually measured in routine examinations for the early diagnosis of pulmonary malignancy. Some studies have demonstrated the importance of serum biomarkers in the diagnosis of pulmonary malignancy [17,18,19,20]. They revealed that the concentrations of serum biomarkers such as NSE, CYFRA 21-1, CEA, and CA125 are significantly higher in lung cancer than in pulmonary benign diseases, and various biomarker panels were found to increase the sensitivity and improve the accuracy of the diagnosis of lung cancer. Our study showed that all patients with IgG4-RLD had normal concentrations of serum biomarkers or only a slight increase, while serum IgG4 was elevated in all patients in whom it was measured. However, serum IgG4 is not routinely examined in many hospitals until now. It is not economically feasible to measure serum IgG4 in all patients with pulmonary abnormalities. Therefore, for patients who are initially suspected of having lung carcinoma, if the imaging findings show several different manifestations of lung lesions, such as masses or nodules, bronchovascular bundle thickening, interlobular septa thickening, pleural thickening, bronchiectasis, round-shaped GGOs, diffuse GGOs and consolidation, and the concentrations of NSE, CYFRA 21-1, CEA, and CA125 are within normal limits or are slightly elevated, the serological level of IgG4 should be detected. An increase in serum IgG4 can offer diagnostic support for IgG4-RLD, and experimental steroid therapy can be administered to further confirm the diagnosis. If serum IgG4 is not elevated and lung carcinoma is strongly suspected, lung biopsy can be used to establish the diagnosis. Interestingly, our study showed that ESR and hs-CRP were also elevated in most of the patients, which might reflect acute inflammation in IgG4-RLD.

Glucocorticoids are commonly used as the first-line treatment of IgG4-RD, and most patients respond well to this intervention. However, there is currently no universal consensus on the duration and tapering regimens of glucocorticoids. Glucocorticoids can be combined with immunosuppressive drugs as a first-line treatment when there are factors for recurrence, such as multiple organ involvement, elevated serum IgG4 and immunoglobulin E levels and increased eosinophil counts in the peripheral blood [21]. Consistent with previous reports [7, 9], our study demonstrated the effectiveness of glucocorticoids with or without immunosuppressive drugs for the treatment of IgG4-RLD. Retreatment with glucocorticoids in combination with immunosuppressive drugs still allowed for significant improvement in the patients who experienced relapse. Up to the last follow-up, 1 patient who received symptomatic therapy only remained in a stable condition, as was reported in Sun’s study [7]. This indicates that some patients might have self-limiting IgG4-RLD. However, little is known about the natural history of IgG4-RLD because the follow-up durations in these studies were not long enough. In any case, long-term regular follow-up is essential for this disease.

The strength of our study is that to our knowledge, we are the first to report the incidence of histopathologically confirmed IgG4-RLD. Furthermore, we analyzed the clinicopathological characteristics of the patients with definite IgG4-RLD based on the histopathological diagnosis, and a brief diagnostic approach to distinguish IgG4-RLD from pulmonary cancer was suggested. However, the present study has some limitations. First, the generalizability of these findings may be questionable because our study is a retrospective single-center study with only a small number of cases and inherent selection bias. Large-scale prospective studies are needed for further confirmation. Second, our follow-up time was not sufficiently long, so the entire course of IgG4-RLD could not be well investigated.

Conclusions

IgG4-RLD is a rare disorder that often mimics lung cancer. For clinicians, it is a great challenge to distinguish IgG4-RLD from lung cancer, especially when a single lung is affected or if the involvement of other organs does not provide diagnostic support. This study analyzed the clinical characteristics of 10 patients with pathologically confirmed IgG4-RLD in our hospital. Our results suggest that multiple imaging findings, elevated serum IgG4 level and no significant increase in serum tumor biomarkers could provide diagnostic support for IgG4-RLD, and subsequent experimental steroid therapy could be given to further confirm the diagnosis. If not, lung biopsy can be performed to make a definitive diagnosis.