Lung adenocarcinoma misdiagnosed as IgG4-related lung disease: A case report and literature review

Abstract

IgG4-related disease (IgG4-RD) is a recently recognized disorder characterized by elevated serum IgG4 levels and infiltration of IgG4 positive blood cells in the affected organs. However, other conditions like malignancy as well as connective tissue diseases, may show similar findings. A 56-year-old male patient visited Second Xiangya Hospital, Central South University for recurrent fever and chest pain for more than 1 month. Preliminary tests diagnosed as IgG4-related lung disease (IgG4-RLD). However, the improvement of symptoms was absent after the treatment with methylprednisolone. The patient underwent the second biopsy and the result eventually demonstrated lung adenocarcinoma. The role of IgG4 in the pathogenesis or prognosis for lung adenocarcinoma remains unclear. Therefore, a thorough evaluation of symptoms, test of specific serum markers and eventually pathological confirmation are required to avoid misdiagnosis.

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IgG4-related disease (IgG4-RD) is chronic immune-mediated systemic disorder usually with typical manifestations, such as an elevated serum level of IgG4 and intensive infiltration of IgG4 positive plasma cells^[1]. In clinical practice, the physicians often encounter great difficulty to differentiate IgG4-RD from other diseases because these characteristics are non-specific and could be observed in infection, malignancy as well as other autoimmune diseases, like vasculitis. The radiological patterns of IgG4-related lung disease (IgG4-RLD) may present as nodular shadow, the enlargement of hilar or mediastinal lymph nodes, the thickness of bronchovascular bundles, and pleural thickening which are also common situations in lung cancer. A concomitant lung cancer with IgG4-RLD was reported lately and the association between both remains unclear^[2]. Herein, we report an interesting case of coexistence of cancer cells and IgG4-positive plasma cells infiltration in a solitary mass.

1. Case presentation

A 56-year-old man who was admitted to the Second Xiangya Hospital, Central South University because of recurrent fever and right chest pain for over one month. The patient experienced a fever with maximum temperature of 42 °C and persistent chest pain months ago. He visited local hospital and the chest computed tomography (CT) scan revealed a solitary mass shadow in the upper of his right lung. Anti-infection and anti-tuberculosis were given but demonstrated ineffectiveness. The patient had a history of smoking and hepatitis B. No positive signs were found on physical examination. His laboratory findings on admission revealed slightly elevated leukocyte count (11.14×10⁹/L, reference range 3.5×10⁹/L-9.5×10⁹/L), moderate anemia (84 g/L, reference range 130-175 g/L), markedly increased erythrocyte sedimentation rate (99 mm/h, reference range 0-15 mm/h) and C-reactive protein (118 mg/L, reference range 0-8 mg/L). Further laboratory studies indicated elevated levels of serum IgG4 (2.21 g/L, reference range 0.03-2.01 g/L), slightly increased carcinoembryonic antigen (6.550 μg/L, reference range 0-5 μg/L), cytokeratin fragment (CYFRA) 21-1 (3.82 ng/mL, reference range 0-1.80 ng/mL), neuron-specific enolase (12.62 μg/L, reference range 0-10.50 μg/L). Tests for procalcitonin, interferon-gamma release assays, anti-nuclear antibody, anti extractable nuclear antigen antibody, rheumatoid factor, myeloperoxidase-antineutrophil cytoplasmic antibodies (ANCA), and proteinase-3-ANCA were all negative. A solitary mass shadow and nodular thickening of interlobular septa were seen in the right upper lobe of the lung on chest CT scan (Figure 1A, 1B). The patient received the first percutaneous lung biopsy under impression of lung cancer and the pathological examination of lung specimen showed infiltration of lymphocytes and plasma cells. Immunohistochemistry revealed CK(+), CD3(+), CD20(+), CD21(follicular+), CD38(+), CD138(+), CD68(+), Ki-67(10%+), IgG(+), and IgG4(+) cells in which the ratio of IgG4(+) to IgG(+) plasma cells was 40% and there were more than 20 IgG4(+) plasma cells per high-power field (HPF) (Figure 2A-2D). A preliminary diagnosis of IgG4-RLD was made according to the first pathologic findings and the absence of distant lesion on abdominal CT scan. The patient was injected by intravenous with 40 mg methylprednisolone per day for 1 week. However, the patient’s symptoms did not improve on steroids. Another percutaneous lung biopsy was strongly suggested to gain more information. Eventually, the second biopsy (Figure 2E, 2F) revealed poorly differentiated adenocarcinoma with CK(+), CK7(+), CAM5.2(+), Ki67(65%+), P53(65%+), PDL-1(+) in immunohistochemistry and further genetic testing indicated mutant epidermal growth factor receptor (EGFR) L858R. The patient was made the diagnosis of pulmonary adenocarcinoma, T3N2M0 IIIB stage finally and icotinib (125 mg, 3 times a day) was given accordingly. On ten month’s follow-up visit, patient’s symptoms and pulmonary lesion were remarkably relieved (Figure 3A, 3B) and the level of serum IgG4 decreased to normal as well.

Figure 1. Chest CT scan on admission shows solitary mass shadow and nodular thickening of interlobular septa in the right upper lobe of the lung.

A: Pulmonary window; B: Mediastinal window.

Figure 2. Results of histopathology and immunohistochemistry (×400).

A: Immunohistochemistry of first lung biopsy shows positive CD38 cells-plasma cells. B: Immunohistochemistry of first lung biopsy shows positive CD138 cells-plasma cells. C: Immunohistochemistry of first lung biopsy with IgG-specific antibody shows positive infiltration of IgG plasma cells. D: Immunohistochemistry of first lung biopsy with IgG4-specific antibody shows enriched IgG4(+) plasma cell infiltration. E: HE staining of second lung biopsy shows lung adenocarcinoma. F: Immunohistochemistry of second lung biopsy shows positive CK7 cells-plasma cells.

Figure 3. Chest CT scan on follow-up visit shows lesion obviously reduced in the right upper lobe of the lung on 10 months of icotinib treatment.

A: Pulmonary window; B: Mediastinal window.

We summarized the clinical infomation, serum IgG4 level, imaging findings, and histopathologic findings of 7 articles related to IgG4-RD and lung cancer (Table 1).

Table 1.

Seven articles related to IgG4-RD and lung cancer

Author	Sex	Age /years	Serum IgG4/(mg·dL-1)	CT scan	IgG4 to IgG ratio in specimen	Pathologic findings of tumor
Ikari, et al[3]	Male	67	2 280	Nodule in the left lower lung	Unknown	Squamous cell carcinoma
Inoue, et al[4]	Male	78	983	Ground-glass opacity with central collapse in S1	Unknown	Adenocarcinoma
Hiroki, et al[5]	Male	72	346	Nodular shadow in the middle lobe of right lung	More than 40%	Lepidic pattern of adenocarcinoma
Abbass, et al[6]	Male	64	289	Multiple lung masses	More than 30/HPF	Small cell carcinoma
Gregory, et al[7]	Male	61	unknown	Nodular shadow in both upper lobes	Unknown	Adenocarcinoma
Lin, et al[8]	Male	65	129	Mass in left upper lobe	More than 40/HPF	Squamous cell carcinoma

2. Discussion

We report an interesting case of lung adenocarcinoma that initially met the proposed IgG4-RD criteria which cause dilemma in clinical practice. IgG4-RD is an auto immune disorder of unknown etiology. Following the release of the comprehensive diagnostic criteria for IgG4-RD in 2011^[9], the 2019 ACR/EULAR diagnostic criteria for IgG4-RLD were reported lately^[10]. Diagnosis is often challenging when the classic features of IgG4-RD are neither specific nor definite. In newly published criteria, the specific exclusion criteria intended to address the elimination of a wide range of IgG4-RD mimickers, including malignant conditions. Differential diagnosis of IgG4-RD and cancers is difficult because IgG4-RD often presents as tumefactive lesions and peritumoral desmoplastic tissue which may occur at nearly any anatomic site. Moreover, none of serologic, radiologic, and histopathologic features provides definitive evidence to differentiation and small biopsy samples are usually not only hard to be obtained but also may not demonstrate the full spectrum of pathologic results. Meanwhile, few have reported a concomitant lung cancer with IgG4-RLD^[2-8]. One explanation is that IgG4-RD can be a source of carcinoma due to the role of inflammation and immune response to the pathogenesis of cancer^[11]. In our case, preliminary diagnosis of IgG4-RLD was made based on elevated serum IgG4 concentration and first pathologic findings. However, the second biopsy demonstrating lung adenocarcinoma nullified the initial diagnosis which complied with exclusion condition according to 2019 IgG-RD classification criteria. The idea that the patients with IgG4 positive cell enriched tumor simultaneously had IgG4-RD seems unlikely for 2 reasons. Firstly, either other intrathoracic changes (fibrosis, infiltration, and ground glass opacity) or involvement of extra thoracic lesions (salivary gland, pancreas, kidney, or lymph nodes) was found, which is very rare in IgG4-RD^[12], Secondly, patient’s condition was remarkably improved on TKI rather than glucocorticoids during the follow-up visit. These suggest us that the cancer is the factor attracting IgG4 positive cells and inducing high level of IgG4 in our case.

Although elevated serum IgG4 is one of characteristic in IgG4-RD, other diseases may present with this similar finding. Serum IgG4 concentration (>1.35 g/L) constitutes one of the comprehensive diagnostic criteria^[9]. However, it is neither sensitive nor specific at lower concentrations when it is often mildly increased in other inflammatory and malignant diseases^[13-15]. Therefore, higher level of IgG4 concentration (>2.8 g/L) is suggested to be used to distinguish IgG4-RD from other diseases^[16]. On the other side, a prospective longitudinal study reported that less than one-quarter of those with an elevated IgG4 meeting the diagnostic criteria and nearly 20% of cases with biopsy-proven IgG4-RD had a normal serum concentration^[16-17]. Therefore, there is pressing need to investigate novel biomarkers for diagnosis. Several novel indicators, including IgG2, serum soluble IL-2 receptor (sIL-2R), and cc-chemokine ligand 18 (CCL18) can be used to accurately diagnose and predict treatment response. A descriptive retrospective study indicated that serum and tissue IgG2 levels could distinguish those with IgG4-RD from healthy controls^[18]. Increased sIL-2R, with respect to IgG4, is accurate in monitoring disease activity and predicting the response of glucocorticoid therapy^[19]. A recent study reported that the serum CCL18 level was related to the number of IgG4-RD affected organs, and disease activity score^[20]. Additionally, both serological and histopathologic immune cells (macrophages, mast cells, and the I-IFN/IL33 pathway) involved in antigen-induced response, innate immune cells as well as subsequent acquired immune cells, may also serve as new biomarkers for IgG4-RD.

The relation between IgG4 and malignancy prognosis is largely unexplored. In melanoma, serum IgG4 concentration correlated inversely with survival possibly due to restrict effector cell functions against tumors^[21]. In our case, the serum level of IgG4 fell to normal with treatment, these effects also occur in other conditions using corticosteroid and allergen immunotherapy^[22-23].

Infiltrating IgG4 positive plasma cells in non-IgG4 related conditions were also recently reported, such as pancreatic cancer, extrahepatic cholangiocarcinomas, granulomatosis with polyangiitis (GPA) as well as adenocarcinoma^{[4, 24]}. Previous reports summarized IgG4 positive plasma cells-enriched lung adenocarcinoma presented as multiple forms, such as solid nodule, ground glass opacity or interstitial pneumonia ^{[4-5, 25]}. Among them, nodular shadow was major manifestation both in IgG4-RLD and adenocarcinoma which causes confuse and difficulty to discern^[26]. Similar to Inoue’s case^[4], pulmonary adenocarcinoma occurred in the background of numerous IgG4 positive plasma cells with solid nodule pattern in our patient. Even under first impression of carcinoma, the negative pathologic finding for tumor cells confused us and led to delay for appropriate treatment. Why IgG4 positive cells are so abundant in carcinoma remains unclear. It is accepted that cancers evade host immune systems via several mechanisms while B cells as well as T cells are mainly involved in tumor immune evasion. IgG4 was one of 4 subclasses of immunoglobulin G produced by human B cells and accounts for 3%-6% of total. Tumor microenvironment might induce or attract IgG4 positive cells through cytokines^[21]. Analysis of 294 patients with non-small cell lung cancer found that considerable IgG4 positive plasma cell infiltration might improve the prognosis in stage I squamous cell carcinoma. However, there is no statistical significance in adenocarcinoma^[27]. On the contrary, the number of IgG4-positive cells increased and was closely associated with disease progression as well as poor in gastric cancer^[28]. The present case showed satisfactory improvement of symptoms and lesion after started on TKI most likely due to the accepted high initial response to first line therapy of adenocarcinoma in those harboring mutant EGFR. Whether IgG4 positive plasma cell infiltration contributes to better treatment response and prognosis in pulmonary adenocarcinoma requires further investigation in larger population.

Patients with IgG4-RD have also been reported to be at high risk of malignancy, especially within one year after onset. Yamamoto et al^[29] indicated that the incidence for malignancies in IgG4-RD was approximately 3.5 times higher than that for the general population. Higher risk for malignancy appears both before and after the diagnosis of IgG4-RD^[30]. An analysis after long term follow-up demonstrated that an active IgG4-RD state is presumed to be a strong risk factor for malignancy development^[31]. Additionally, malignancy may also be associated with subsequent IgG4-RD development suggesting an overlapped pathogenesis may exist^[32].

In the present case and previous literature, the pulmonary nodule associated with IgG4-RD can have a margin that is not well-demarcated and rather irregular, which makes it difficult to distinguish these lesions from lung cancer. The results of transbronchial lung biopsy may be unlikely enough to exclude other pathology especially malignancy. Second biopsy or avideo-assisted thoracic surgery (VATS) biopsy of the lung may be needed to obtain adequate specimens. Positive response to the glucocorticoids and immunosuppressive agents can help with the differential diagnosis. Closely follow-up and evaluation are also important.

In summary, our case indicated that IgG4-positive plasma cells infiltration and elevated serum IgG4 are not only typical features of IgG4-RD but also could be seen in malignant diseases. A thorough evaluation of symptoms, titration of specific serum markers and eventually pathological confirmation are required to avoid misdiagnosis. The role of IgG4 in the pathogenesis or prognosis of lung cancer remains unclear. Further studies with more cases are required to elucidate the potential mechanism.

Funding Statement

This work was supported by the National Key Clinical Specialty Construction Project (2012-650), the National Natural Science Foundation (81800043), and the Natural Science Foundation of Hunan (2020JJ5818), China.

Conflict of Interest

The authors declare that they have no conflicts of interest to disclose.

Note

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