A 66-year-old man who had a past medical history of idiopathic pulmonary fibrosis (IPF) and mass-forming IgG4-related autoimmune cholangitis was admitted to the hospital for a newly-identified consolidative lung mass discovered during follow-up. Chest computed tomography revealed a subpleural nodule in the left lower lobe of the lung in a background of reticular and honeycomb fibrosis (Fig. 1A). ¹⁸F-fluorodeoxyglucose uptake was detected in the subpleural nodule (Fig. 1B). The results of the pulmonary function tests were within normal range: forced vital capacity (FVC) 3.23 L (82% of the predicted value), forced expiratory volume in 1 second (FEV₁) 2.35 L (80% of the predicted value), and FEV₁/FVC 73%. Laboratory test showed an increased serum IgG4 level (232.4 mg/dL). The patient underwent lobectomy under the impression of lung cancer. Grossly, the tumor was ill-defined, gray-tan colored and measured 3.5 × 3.2 × 2.0 cm. The background lung was fibrotic and emphysematous (Fig. 1C). Microscopically, the background lung showed diffuse irregular interstitial fibrosis with dense lymphoplasmacytic infiltration and occasional obliterative phlebitis (Fig. 1D–F). Tumor cells showed both squamous and glandular differentiation. The squamous cell carcinoma component was composed of moderately to poorly differentiated tumor cells that contained keratin pearls (Fig. 1G). The glandular component was mainly acinar pattern with focal micropapillary pattern (Fig. 1H). Diffuse spread through air space of tumor cells was frequently found at the periphery of the mass (Fig. 1I). Multifocal lymphangitic spreading of tumor cells and metastatic lymph nodes were found (Fig. 1I). Dense fibrosis and lymphoplasmacytic infiltration were adjacent to the tumor cells (Fig. 1J). The final pathologic stage was pT2aN2M0 by the American Joint Committee on Cancer seventh staging system. Immunohistochemistry (IHC) staining revealed the squamous cell carcinoma component was focally positive for p63 (1:200, Biocare, Concord, CA, USA), and the glandular component was negative for TTF-1 (1:50, Dako, Glostrup, Denmark). Additional tests for anaplastic lymphoma kinase (ALK) IHC staining (1:40, NCL-ALK, clone 5A4, Novocastra, Newcastle upon Tyne, UK) and epidermal growth factor receptor gene mutation analysis using a PNA clamping kit (Panagene, Inc., Daejeon, Korea) were negative, and up to 10% of the tumor cells showed membrane positivity for programmed death-ligand 1 (RTU, 22C3, Dako). IgG4 (1:2,000, The Binding Site, Birmingham, UK) IHC stain showed diffuse positivity in infiltrating plasma cells (> 50 cells/high-power field), and the IgG4/IgG ratio was over 40% (Fig. 1K). Thus, the patient’s IPF was thought to be a manifestation of IgG4-RLD, and we concluded that primary adenosquamous carcinoma had developed in the background of IgG4-RLD. This study was approved by the Institutional Review Board of the Samsung Medical Center with a waiver of informed consent (IRB No. 2018-11-053) and performed in accordance with the principles of the Declaration of Helsinki.

IgG4-RD was first reported as autoimmune pancreatitis in 2001 [7]. IgG4-RD is known to predominantly involve the pancreas, hepatobiliary tract, salivary glands, and lacrimal glands, and lung or pleural involvement can occur in up to 35% of patients [8]. The histologic patterns of IgG4-RLD are divided into three types: solid nodular type, bronchovascular type, and interstitial lung disease type [4].

It is still debatable whether IgG4-RD is associated with malignancy. Yamamoto et al. [9] observed 106 IgG4-RD patients (primarily with Mikulicz’s disease), and the high standardized incidence rate (SIR) of 3.83 supported the association between IgG4-RD and increased incidence of total malignancies. In a different study, Hirano et al. [10] observed 113 patients with IgG4-RD (primarily with autoimmune pancreatitis), and the SIR was not significant (1.04). These different outcomes likely result from whether the studies considered cases that simultaneously found malignancies and IgG4-RD.

However, none of these studies included patients with IgG4-RD that involved the pulmonary system. The association of IgG4-RLD with lung cancer has not been studied, and only three lung cancer cases in IgG4-RLD patients have been reported with their histopathologic findings [4-6].

The patient in the present case had primary adenosquamous carcinoma, which has not been reported alongside IgG4-RD in the previous literature. The adenosquamous carcinoma was characterized by poorly differentiated squamous and glandular tumor cells with lymph node metastases, and the IgG4-RLD background presented as interstitial lung disease. Inoue et al. [5] and Tashiro et al. [6] reported a well differentiated lepidic pattern of adenocarcinoma accompanied by IgG4-RLD as a solid nodule or ground glass opacity pattern. There were no lymph node metastases in these two cases. Zen et al. [4] reported a moderately differentiated, mixed pattern (including acinar pattern) adenocarcinoma in a background of IgG4-RLD presenting as interstitial pneumonia. Lymph node metastases were found, and the pathologic stage was pT1N2M0. In the present case, similar to Zen’s report, moderately to poorly differentiated carcinoma occurred in a background of IgG4-RLD with an interstitial lung disease pattern. Numerous lymphovascular invasions and lymph node metastases were found, and the final pathologic stage was pT2aN2M0. Table 1 summarizes the clinicopathologic and radiological characteristics of the reported cases of concurrent IgG4-RLD and lung cancer.

There have been no studies on whether IgG4-RLD increases the risk of malignancy. Although there have been a small number of cases, it is likely that lung cancer more frequently occurs in the solid nodular or interstitial lung disease type of IgG4-RLD rather than the bronchovascular type. Thus far, malignancy has not been reported in the bronchovascular type of IgG4-RLD. There is also a possibility that the differentiation or aggressiveness of the tumor may depend on the background type of IgG4-RLD, and the prognosis could be worse in patients with the interstitial lung disease background. Further studies with more cases are needed to elucidate the relationship between tumor aggressiveness and patterns of IgG4-RLD.