IgG4-RLD is a rare condition which is still not well understood and the incidence of IgG4-RLD is lacking. Our study showed the incidence of IgG4-RLD pathologically confirmed was 0.2% in our hospital. In the present study, we summarized and analyzed the clinicopathological characteristics of the 10 patients with IgG4-RLD pathologically confirmed based on a single-institution experience.
In our study, there were several important findings: (i) Elevated serum IgG4 was observed in the patients detected and serum tumor markers had no significant elevation in the patients with IgG4-RLD; (ii) Clinical manifestations and radiological findings were nonspecific. Some patients were initially asymptomatic and pulmonary lesions were accidentally identified by chest imaging examination. Moreover, on account of that the imaging often mimics pulmonary malignancy, patients with IgG4-RLD might be misdiagnosed as lung cancer and undergo unnecessary lung resection. Thus, when lung is independently affected or combined with special anatomical site involved which is difficult to help make a definite diagnosis, the diagnosis of IgG4-RLD is challenging, and a brief strategy for combining radiological findings with serum IgG4 and tumor markers was suggested to differentiate IgG4-RLD from lung cancer; (iii) Most patients responded well to prednisone with or without additional immunosuppressive drugs.
The clinical symptoms of IgG4-RLD are nonspecific mainly depending on the location of pulmonary lesions. Our study showed that the initial respiratory symptoms had cough, chest or back pain, hemoptysis and low-grade fever. And pulmonary abnormalities were occasionally found by chest radiological examination in the asymptomatic patients. This phenomenon has been reported to various extent in the previous studies [5–11].
In 2009, Inoue and colleagues proposed four major subtypes on the basis of the predominant radiologic abnormality: solid nodular, round-shaped GGO, alveolar interstitial and bronchovascular type . In addition, additional alveolar consolidation type was observed as the fifth type of imaging classification [6–8]. In present study, pulmonary mass and nodules were commonly seen and it was noteworthy that most were associated with the manifestations of other types, such as thickening of bronchovascular bundle, thickening of interlobular septa, bronchiectasia, round-shaped GGO, diffuse GGO and consolidation. It was not easy to classify them as one of the above five types. Therefore, we divided these patients into mix type when two or more types occurred together. What’s more, we found all pulmonary mass and large nodules with solid pattern had spiculated margins and inhomogeneous enhancement with or without pleural indentation and lobulated appearance, which were usually indicative of malignancy [12, 13]. These overlapping CT characteristics of IgG4-RLD and lung cancer suggested that they might share some pathological bases. For lung cancer, the appearance can be explained by contraction of internal fibrosis, different growth rates of cancerous cells and extension of malignant cells along the lung interstitium . Inoue et al demonstrated that the pathological findings, such as fibrosis and diffuse lymphoplasmacytic infiltration along the interlobular septa corresponded to these radiologic findings in IgG4-RLD , which was also discovered in our study. We speculated that the imaging manifestations of IgG4-RLD resembling lung cancer might be due to shared fibrosis and dense lymphoplasmacytic infiltration simulating the pattern of cancerous invasion. Thus, it is a great challenge to identify IgG4-RLD with pulmonary mass and/or large nodules from lung cancer.
To solve this problem, we should focus on the following points: (i) Beside pulmonary mass and/or large nodules, attention should be paid to the radiological manifestations of other subtypes as mentioned above, which may provide some support for the diagnosis of IgG4-RLD; (ii) In such cases, serum IgG4 should be measured. Serum IgG4 has highly diagnostic value for IgG4-RD and was positively correlated with the number of organs involvedl . Wang and colleague reported 84% patients with IgG4-RLD had an elevated serum IgG4 concentration ; (iii) For patients with initially suspected lung cancer, traditional serum biomarkers are usually measured as a routine examination for the early diagnosis of lung cancer. Several studies have demonstrated the importance of serum tumor markers in diagnosis of lung cancer [17–20]. They investigated that the levels of serum tumor markers, such as NSE, CYFRA 21-1, CEA, CA125 are significantly higher in lung cancer than benign lung diseases and the various biomarker panels can increase the sensitivity and diagnostic accuracy in lung cancer. Our study showed all patients with IgG4-RLD had a normal concentration or only a slight increase of serum biomarkers, while serum IgG4 was elevated in all patients detected. 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 with initially suspected lung cancer, if the imaging finding has multiple different manifestations of lung lesions, such as mass or nodules, bronchovascular bundle thickening, interlobular septa thickening, pleural thickening, bronchiectasia, round-shaped GGO, diffuse GGO and consolidation, and the levels of NSE, CYFRA 21-1, CEA, CA125 are within normal limits or slightly elevated, serum IgG4 should be measured. Elevated IgG4 can offer diagnostic support for IgG4-RLD and then experimental steroid therapy can be used to further confirm the diagnosis. When serum IgG4 is not elevated and lung cancer is strongly suspected, a lung biopsy can be used to establish the diagnosis. Interesting, our study showed elevated ESR and hs-CRP in most patients, which might reflect acute inflammation in IgG4-RLD.
Glucocorticoids are commonly used as the first-line treatment of IgG4-RD and most patients response well to this intervention. However, there is currently no universal consensus on the duration and tapering regimens of glucocorticoids. Glucocorticoids can combine with immunosuppressive drugs as first-line treatment when predictors of relapse are present, such as multiple organ injury, elevated serum IgG4 and immunoglobulin E (IgE) and peripheral eosinophilia . Consistent with previous reports [7, 9] our study demonstrated the effectiveness of glucocorticoids with or without immunosuppressive drugs in IgG4-RLD. Retreatment with glucocorticoids in combination with immunosuppressive drugs still showed significant improvement in the patient with relapses. Up to the last follow-up, 1 patients with symptomatic therapy only remained in a stable condition, which has been reported in Sun’s study . This phenomenon suggested that some patients might have self-limiting IgG4-RLD. However, little is known about the natural history of IgG4-RLD because the follow-up of studies was not long enough. In any case, long-term regular follow-up is essential for IgG4-RLD.
The strength of our study is that to our knowledge, we first reported the incidence of IgG4-RLD pathologically confirmed. Furthermore, we analyzed the clinicopathological characteristics of the patients with definite IgG4-RLD based on histopathological diagnosis and a brief approach to differentiate IgG4-RLD from lung cancer was proposed. However, the present study has some limitations. First, the generalizability of our findings may be questioned because the nature of this study is a single-center retrospective study with just a small amount of cases and the presence of selection bias. Large-scale prospective studies are needed for further confirmation. Second, our follow-up time is short and the whole course of IgG4-RLD can not be well investigated.