Lung nodules and IgG4 related disease: a single-center based experience

Clinical presentation of nodules in the lungs of patients can be a challenge for diagnosis, especially when the nodules are small and asymptomatic. The nodules may be difficult to biopsy for histopathology because of size and location, for example, very small nodules deeply imbedded in the lung. The first diagnosis will likely be some form of neoplasm. When that diagnosis is determined to be incorrect, many physicians, especially respiratory physicians and thoracic surgeons, may be unsure of the next step toward diagnosis and treatment. Affected patients, of course, will be anxious for a confirmed diagnosis since they will likely assume the small nodules are an early stage of lung cancer. A recently recognized disease, immunoglobulin G4-related disease (IgG4-RD), must be considered for such presentation of asymptomatic small nodules, particularly in the lungs, liver, or lymph nodes [1].

IgG4-RD is a chronic, fibrotic inflammation characterized by the involvement of multiple organs. The most common manifestations of the disease include swelling of salivary and lacrimal glands, lymphadenopathy, and type 1 autoimmune pancreatitis (AIP). Other organs, such as lung, bronchi, kidney, retroperitoneum, thyroid, heart, mesenterium, meninges, and skin, can also be involved. Frequently, but not always, serum IgG4 levels will be elevated [2]. IgG4 is the rarest of the IgG subclasses, generally has relatively low antigen affinity, and is unable to bind complement component 1q (C1q) and activate the complement cascade [3]. IgG4 can exchange Fab arms by swapping a heavy chain and attached light chain with a heavy-light chain pair from another IgG4 molecule, which provides the basis for the anti-inflammatory activity attributed to IgG4 antibodies [4] A key pathological feature of IgG4-RD nodules is a dense lymphoplasmacytic infiltrate organized into a storiform pattern, which frequently forms a tumefactive mass that may destroy an involved organ [1]. When the tumefactive mass occurs in the lungs, it may present as a nodule or ground-glass opacity on radiology [5]. IgG4-related lung disease (IgG4-RLD) is the lung involvement of IgG4-RD, which was first described in 2004 in a patient with interstitial pneumonia, autoimmune pancreatitis and IgG4-positive plasma cells in the interstitium [6]. The IgG4-RLD presentation can be heterogeneous, and its radiologic manifestations are often extensive, even when clinically asymptomatic [7].

Although lung nodules have been described in 31 to 46% of IgG4-RLD in a few case reports and reviews to date [5, 8, 9], no study has employed a systematic analysis of IgG4-RD patients with lung nodules. Here we present retrospective data of the clinical and radiological features of IgG4-RD patients from a single medical center’s experience. Our goal is to provide clinical information and insight for the diagnosis of IgG4-RD in patients who present with asymptomatic, non-neoplastic small lung nodules.

From January 2012 to December 2018, a total of 89 patients were diagnosed with definitive IgG4-RD in West China Hospital, Sichuan University, 50 (56%) of whom had CT-confirmed lung nodules were included in this retrospective study.

Lung nodules are small rounded lesions with at least two-thirds of its margins surrounded by lung parenchyma and not associated with atelectasis or lymphadenopathy. In this study, we focused on the lung nodules of IgG4-RD patients and 50 (56%) IgG4-RD patients presented with lung nodules in CT images. As far as we know, there hasn’t been any study concerned about the incidence of lung nodules in IgG4-RD patients. Previous studies have reported that lung nodules were incidentally identified in approximately 15–30% of the social-demographically population [12, 13]. Our result revealed that the incidence of lung nodules in IgG4-RD patients was much higher.

Comparing the clinical characteristics of patients with lung nodules with that of patients without lung nodules, no significant difference was found in terms of age, gender ratio, duration of symptoms before diagnosis, number of extrapulmonary involved organs and serological characteristics, indicating that these factors have no association with the progress of nodule formation. For clinical symptoms, only 7 patients were observed with cough. Most patients, especially patients with small nodules only, were relatively asymptomatic despite substantial burdens of disease within the lung. Clinical symptoms of lung disease depend on the location and size of lesions and are often nonspecific for the diagnosis of some lung disease including IgG4-RLD.

In our study, six patients were diagnosed as definite IgG4-RLD. All of the 6 patients had lung nodules. Consistent with results of previous studies conducted by Inoue et al [5] and Sun et al [14], this result revealed that nodular lesion can be a common manifestation of IgG4-RLD. Together with lung nodules, some other chest CT findings, including mass, solid nodules, round-shaped glass opacity, thickening of bronchovascular bundles and interlobular septa, alveolar interstitial changes like honeycombing and bronchiectasis, lobar or segmental consolidation, and lymph node enlargement et al, were often seen in IgG4-RLD patients. And these CT changes always present as various mixed patterns [5, 9, 14‐18]. In this study, except lung nodules, we also detected mass, ground-glass opacity, thickening of pleura, pleura effusion, mediastinal and hilar lymphadenopathy, and thickening of interlobular septa in IgG4-RLD patients. It is worth noting that IgG4-RLD related nodule lesion reported previously are always single, solid, and large type, together with or without multiple small nodules [5, 9, 14‐18]. And these nodules are always solid and with spiculated or irregular margins. In our study, only 2 IgG4-RLD patients had large nodules, while 4 of the 6 IgG4-RLD patients presented as multiple small nodules. And only one of the 6 patients had nodules with irregular margins. As pulmonary biopsy results are hard to get, this inconsistency may be caused by a small sample size of studies related to IgG4-RLD. Thus more studies are needed to clarify the CT imaging features of IgG4-RLD.

As lung nodules could also be caused by infection, malignancy, or some other pulmonary disorder, we cannot be certain that in the absence of definitive nodular biopsies, all of the lung nodules in our study were related to IgG4-RLD. For an IgG4-RD patient with lung nodules, the probability of lung nodules related to IgG4-RLD is very high especially in the absence of other lung diseases. In a study reported by Tsushima et al, 5 of 6 IgG4-RD patients with lung nodules were confirmed to be IgG4-RLD by biopsy [15]. In our study, most patients had no pulmonary infection or a history of cancer and other chronic pulmonary diseases. For these patients, the probability of lung nodules related to IgG4-RLD is very high. Besides, CT findings of our study also revealed that most of the lung nodules in IgG4-RD patients were small and solid, always with regular margins. Multiple and bilateral distributions was also a major characteristic of these lung nodules. Lung nodules in one patient also showed calcification. These radiologic features and distribution of lung nodules were usually regarded as benign [13, 19].

It is noteworthy that three patients with large lung nodules showed signs of lobulation, spiculation, and pleural indentation, all of which may predict an increased risk of malignancy [13, 19]. As radiological findings of IgG4-RLD varied, these signs can often be observed in lung nodules and masses related to IgG4-RLD [5, 14]. Besides, we also found that the proportion of lung nodules in smokers was significantly higher than that in non-smokers, indicating that smoking may be a risk factor of these lung nodules. The proportion of elderly in IgG4-RD patients was not small. Therefore, for IgG4-RD patients with lung nodules, it’s necessary but hard to differentiate IgG4-RLD from lung cancer. As mentioned above, the simultaneous presence of other kinds of lung lesions may provide support for the diagnosis of IgG4-RLD and help with the differential diagnosis. In our study, most (37/50) patients also had the simultaneous presence of other CT findings, including thickening of pleura, thickening of interlobular septa, thickening of bronchial wall, pleural effusion, presence of an undefined mass, interstitial changes, consolidation, ground-glass opacity and mediastinal or hilar lymphadenopathy, which may help to increase the possibility of IgG4-RLD.

Most IgG4-RLD patients have a significant response to glucocorticoid therapy, which can help to further distinguish IgG4-RD nodules and malignancy [20]. In our study, 16 patients went through a re-examination of CT scan after glucocorticoid therapy with or without immunosuppressive agents. Ten patients, including 2 patients that had large lung nodules with signs of lobulation, spiculation, pleural indentation, and cavity, showed positive responses. A decrease in the size and/or the number of nodules was observed, which helped to further support the diagnosis of IgG4-RLD.

Sometimes during a routine medical examination, patients may present with lung nodules detected without other pulmonary symptoms. Since nodules may resemble bronchoalveolar carcinoma and raise suspicion of malignancy [4], case reports indicate that patients with this type of lung lesions may have undergone wedge resection or lobectomy for suspected malignancy only to discover upon tissue examination that the relevant nodules were a consequence of IgG4-RD [21, 22]. In our study, a patient with bilateral small lung nodules was first misdiagnosed as tuberculosis and another patient with a single large nodule underwent a middle lobectomy and histological findings were consistent with IgG4-RD. Thus, an understanding of nodules related to IgG4-RD is noteworthy. Since IgG4-RD may be a multi-organ disease, the involvement of other organs and serological change can help with diagnosis in patients with undiagnosed lung nodules. In our study, only 6 patients had the pathological proof of IgG4-RLD, while the other patients were diagnosed with IgG4-RD primarily because of clinical manifestations in other organs, particularly salivary glands, lymph nodes, lacrimal gland and pancreas, which is consistent with other studies [16]. In Sun’s study of biopsy-proven IgG4-RLD patients, extrapulmonary involvement was proven in only 1 patient with uveitis mastoiditis. Since patients with only lung involvement are more prone to receive a lung biopsy, the uncommon extrapulmonary involvement may be caused by selection bias [14]. Once the diagnosis of IgG-RD is confirmed, the radiological characteristic and treatment response can help with the diagnosis of IgG4-RLD, thus a regular follow-up is important for these patients.

Our study had some limitations. First, most of the lung nodules involved in our study were not histopathologically proven. Therefore, we were unable to clarify the exact proportion of lung nodules related to IgG4-RLD. Second, due to the retrospective features of our study, the scan protocols of CT varied, and the number of patients with a re-examination of CT was small, which may further limit the value of our study.

The incidence of lung nodules in IgG4-RD patients can be high. For an IgG4-RD patient with lung nodules, the possibility that the lung nodules related to IgG4-RLD is high. It is hard to differentiate IgG4 related lung nodules from other lung diseases, in particular, lung cancer. Radiological characteristics and positive responses to glucocorticoids and immunosuppressive agents can help with the differential diagnosis. For these patients, regular follow-up is also important.