Clinical characteristics of a concurrent condition of IgG4-RD and Castleman’s disease

Immunoglobulin G4-related disease (IgG4-RD) is a relatively recently described disease category which affects multiple organs, including the lacrimal gland, salivary gland, parotid gland, lung, pancreas, and retroperitoneum [1, 2]. Diagnosis of IgG4-RD requires a combination of clinical manifestations, serological evidence, and histological performances. Histology is the mainstay of diagnosis, which is characterized by dense immunoglobulin G4 (IgG4)-positive lymphocytes and plasmacyte infiltration, obliterating phlebitis and storiform fibrosis.

Castleman’s disease (CD) is an atypical lymphoproliferative disorder, which can be classified into three types: plasma cell, hyaline vascular, and their mixture. Plasma cell and mixed types frequently have systemic manifestations, which termed multicentric Castleman’s disease (MCD). Patients with MCD often have abnormal laboratory findings, such as hypergammaglobulinemia, elevated C-reactive protein (CRP), interleukin (IL)-6, and vascular endothelial growth factor (VEGF) levels [3‐5].

It is widely accepted that a diagnosis of IgG4-RD can be made under a premise of ruling out a series of diseases including CD. Actually, sometimes it is really hard to separate the two diseases. In some cases with CD, the histopathological findings, such as IgG4-positive plasma cell infiltrations, are also evident [6‐8]. Otherwise, IgG4-RD may pathologically exhibit CD-like features. Hence, when the pathological performance meets the diagnosis of both IgG4-RD and CD (IgG4-CD) simultaneously, how can we differentiate the two disease entities? Is it IgG4-related CD or “secondary” IgG4-RD of MCD? Do the clinical course and treatment response differ from those of IgG4-RD or MCD? To our knowledge, no comparative study between IgG4-CD and IgG4-RD, or IgG4-CD and MCD has yet been published. In this study, therefore, we attempted to determine the clinical differences between these three groups of patients using clinical data.

To the best of our knowledge, this study is the first relatively big case series to compare the comprehensive clinical characteristics of IgG4-CD and IgG4-RD or MCD, due to the rarity of the three diseases’ condition. We defined patients who synchronously exhibited pathological features of IgG4-RD and CD as IgG4-CD. In China’s largest prospective IgG4-RD and Mimicry study cohort, 15 patients who fulfilled the criteria were found. All of them were human immunodeficiency virus (HIV) negative.

The entanglement of IgG4-RD and CD has a long history. Both the two diseases can involve multiple organs and may have similar clinical and pathological manifestations, such as elevated serum IgG4 and IgG4-positive plasmacyte infiltration in the affected tissue, causing the differential diagnosis of the two diseases in a real dilemma. Lots of efforts had been made at this point to separate the two diseases. It had been reported that orbits, lacrimal glands, salivary glands, pancreas involvement, and complicating allergic disorders were more common in the IgG4-RD patients, whereas the levels of serum IL-6, ESR, CRP, and IgA were significantly higher in the CD patients [12, 13]. Moreover, CD patients had more anemia, hypoalbuminemia, hypocholesterolemia, and thrombocytosis [13, 14]. In the present study, MCD patients presented with higher incidence of fever and LN involvement, and higher levels of ESR, CRP, IgA, IgM, IgG1, IL-6, and IgG1/IgG ratio than IgG4-RD patients, while IgG4-RD patients exhibited elevated incidence of allergic disease history and salivary gland involvement, and higher levels of HGB, Eos, IgG4, and IgG4/IgG ratio than MCD patients. Same as MCD, all IgG4-CD patients had lymph node enlargement (100%); however, IgG4-CD patients presented more frequent involvement of lacrimal gland, submandibular gland, and paranasal sinus, higher HGB, Eos count, serum IgG4 level, and IgG4/IgG ratio, and significantly lower CRP, IL-6 levels, and IgG1/IgG, IgG2/IgG ratio than MCD patients. In addition, there was no difference in allergic disease history between IgG4-CD and IgG4-RD patients. However, IgG4-CD patients had significantly elevated ESR, CRP, IgG, IgG1, IgG3, IgG4, and IgE levels, as compared to IgG4-RD patients. Thirteen patients with IgG4-CD had elevated serum IgG4 levels. Three patients (Nos. 7/11/14) with normal HGB were found elevated serum IL-6, and two of them had slightly decreased serum albumin (Nos. 7/14). Clinically, IgG4-CD patients look more like CD at first glance. But they also had significantly higher incidence of salivary gland involvement, elevated levels of IgG4 and IgE, which are typical characteristics of IgG4-RD. Four out of seven IgG4-CD patients’ tested IL-6 levels were normal. However, it is been universally acknowledged that elevated IL-6 is a characteristic of CD. Therefore, it is hard to phenomenologically classify these IgG4-CD patients as CD or IgG4-RD.

Pathologically, a number of studies had expounded the differences between IgG4-RD and CD. One study in Korean pathologically analyzed 87 CD patients and found that the mean IgG4+/IgG+ plasma cell ratio was 25.1% [15]. Sato et al. [16] reported that the mean IgG4+/IgG+ plasma cell ratio was 57.6% in IgG4-RD patients. They proposed that pathological differentiation of IgG4-RD and CD from lymph node specimens are as follows [16, 17]: (1) the germinal centers of patients with CD were small and regressive, while those of IgG4-RD were normal-hyperplastic; (2) CD showed mature plasma cell sheet-like proliferation in the interfollicular area where IgG4-RD showed proliferation of mature plasma cells with plasmacytoid cells and immunoblasts; (3) IgG4-RD revealed eosinophil infiltration but CD did not. In IgG4-RD patients, the lung lesion was located within the perilymphatic stromal area, and IgG4+/IgG+ cell ratios, eosinophil counts, the extent of active fibrosis, and the number of intravascular lesions were greater. In CD patients, the lung lesion concentrated mainly in the alveolar area besides the perilymphatic stromal area with greater lymphoid follicles [14]. We reviewed the pathological reports of our IgG4-CD patients and found abundant lymphocytes and plasmacyte infiltration in all patients; two patients (Nos. 6/10) showed eosinophil infiltration; four patients (Nos. 2/10/13/15) recorded fibrosis; and two patients (Nos. 10/15) documented obliterating phlebitis.

Our study raises another interesting point regarding the prognosis of IgG4-CD. IgG4-RD usually responds well to glucocorticoids. MCD is somehow a life-threatening disease, and its prognosis is completely different from that of IgG4-RD [16]. The prognosis of IgG4-CD remains unclear, but some studies brought hints that these patients may respond well to glucocorticoids and immunosuppressants. In 2009, Sato et al. [16] examined clinical and pathologic findings of nine patients with systemic IgG4-related lymphadenopathy, three of whom showed CD-like features and one with significantly elevated IL-6. All these three patients were untreated after surgery and remained stable during the follow-up (8–25 months). In 2010, Kojima et al. [18] reported three CD cases of retroperitoneum involvement, with immunohistochemical study demonstrating IgG4(+) plasma cells accounting for more than 50%, two of them with elevated serum IgG4 concentration and normal serum IL-6 levels. One patient responds well to steroids. Two patients were untreated after resection. All three patients were stable during the follow-up period (6–22 months). In 2011, Takenaka et al. [19] described a patient with systemic IgG4-RD whose histopathology mimicked CD was successfully treated with corticosteroids. In 2012, Takeuchi et al. [20] reported a 55-year-old Japanese woman with a 4-year history of sarcoidosis developed erythematous and brown plaques on her back, and she was diagnosed as MCD from a skin biopsy. Laboratory studies revealed anemia, hypoalbuminemia, polyclonal gammaglobulinemia, elevated CRP, and elevated serum IL-6 level. However, serum IgG4 level was remarkably elevated, and the mean IgG4-/IgG-positive cell ratio in her tissue specimens was > 40%, fulfilling the diagnostic criteria of IgG4-RD. Following systemic steroid therapy, the plaques resolved and there was no recurrence observed in 4 months of follow-up. In 2013, Ogoshi et al. [12] reported six CD patients achieved IgG4-RD criteria, four responding well to glucocorticoid monotherapy, one patient with mild disease not receiving any treatment, and one having no response to corticosteroids or repetitive worsening of the symptoms during the tapering of corticosteroids, after being added cyclosporine, following 33 months alive. Very recently, Mochizuki et al. [21] reported a 59-year-old male who was histopathologically diagnosed as CD from his skin lesion with elevated CRP and IL-6 levels, oral prednisolone (PSL) initiated at 0.5 mg/kg relieving his symptoms, but the laboratory data did not improve. After 4 years, he developed lacrimal and salivary gland swelling; histopathological findings in a dacryoadenectomy specimen showed that IgG4+/IgG+ plasma cell ratio was 70%; finally he was diagnosed as IgG4-RD; and rituximab combined PSL treatment were used. Two years after rituximab treatment, the patient’s disease was stable with PSL (0.2 mg/kg). Izumi et al. [22] reported a 50-year-old woman with characteristic features of MCD, including polyclonal hypergammaglobulinemia, multiple enlarged lymph nodes, and pulmonary interstitial infiltration, with elevated serum IgG4 level and a 37.3% IgG4+/IgG+ plasma cell ratio in her biopsy specimen, while without organ involvement of IgG4-RD, corticosteroid treatment resolved the serological and imaging abnormalities. The 14 IgG4-CD patients in present study showed relatively favorable response to glucocorticoid and immunosuppressant therapy, one untreated IgG4-CD patient was stable, during a 33 (4–56)-month follow-up, and this was the same as those reported in the literature.

Our study has some limitations. Although we included patients diagnosed with pathological IgG4-CD in the largest IgG4-RD and Mimicry cohort in China, our results may be affected by institutional bias due to the nature of the single-center study. Secondly, the pathological reports in our hospital were not detailed enough and the biopsy specimens were unaccessible; thus, we failed to do a pathological comparison.

In conclusion, patients with IgG4-CD showed features of both IgG4-RD and MCD. Significantly elevated inflammatory markers in IgG4-CD group patients are similar to those of MCD patients, but those patients also exhibited favorable outcomes as if they were IgG4-RD. It is hard to tell whether it is an overlap, or a subtype of IgG4-RD or CD; therefore, a large cohort study is needed.