A case of marginal zone B cell lymphoma mimicking IgG4-related dacryoadenitis and sialoadenitis

Background IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS), so-called Mikulicz’s disease, is characterized by elevated serum IgG4 and infiltration of IgG4-positive plasma cells in glandular tissues. Recently, several studies reported both malignant lymphoma developed on the background of IgG4-associated conditions and IgG4-producing malignant lymphoma (non-IgG4-related disease). Case presentation We report on the case of a 70-year-old man who was strongly suspected IgG4-DS because of high serum IgG4 concentration (215 mg/dl) and bilateral swelling of parotid and submandibular glands. Biopsies of cervical lymph node and a portion of submandibular gland were performed. These histopathological findings subsequently confirmed a diagnosis of marginal zone B cell lymphoma. Conclusion Differential diagnosis of IgG4-DS is necessary from other disorders, including Sjögren’s syndrome, sarcoidosis, Castleman’s disease, Wegener’s granulomatosis, lymphoma, and cancer. We suggest that biopsy of swollen lesions is important for a definitive diagnosis of IgG4-DS and discuss the mechanism of development in this case.


Background
IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS), also known as Mikulicz's disease (MD), is a unique condition characterized by enlargement of the lacrimal and salivary glands caused by infiltration of lymphocytes. IgG4-DS has been considered a subtype of Sjögren's syndrome (SS) because of certain histopathological similarities, particularly lymphocytic infiltration [1]. However, IgG4-DS patients show elevated serum levels of IgG4 and infiltrating IgG4positive plasma cells in the glandular tissues [2,3]. Similar findings have also been identified in other diseases such as autoimmune pancreatitis [4], interstitial pneumonia [5], retroperitoneal fibrosis [6], and sclerosing cholangitis [7], and these diseases are now referred to as 'IgG4-related disease (IgG4-RD)' [8]. IgG4-DS is now diagnosed by both 'Comprehensive diagnostic criteria for IgG4-related disease (2011)' and 'Diagnostic criteria for IgG4-related Mikulicz's disease D' approved by the Japanese Society for Sjögren's syndrome [9]. However, it is important to differentiate IgG4-RD from malignant tumors (such as cancer, lymphoma) and similar diseases (such as SS, primary sclerosing cholangitis, Castleman's disease, secondary retroperitoneal fibrosis, Wegener's granulomatosis, sarcoidosis, Churg-Strauss syndrome) by histopathological examination of local lesion. We reported the first case of IgG4-producing marginal zone B cell lymphoma (MZL) in salivary glands mimicking IgG4-DS.

Case presentation
A 70-year-old man was referred to our institution with bilateral continuous painless swelling of the parotid glands (PGs) and submandibular glands (SMGs) in March 2013.
He had previously attended another hospital with chief complaints of dry mouth and bilateral swelling of SMGs, which were diagnosed as chronic sialoadenitis by computed tomography (CT) in January 2013. However, he did not receive any treatment at that time and ignored the swelling. He had no medical history of allergic diseases such as bronchial asthma, atopic dermatitis, or allergic rhinitis.
Physical findings showed no fever (body temperature, 36.6°C), a blood pressure of 124/68 mmHg, a pulse rate of 64 beats per min, and arterial oxygen saturation of 98% in room air. He had a dry mouth and stomatitis with reduced unstimulated salivary flow rate (0.9 ml/15 min). Bilateral PGs, SMGs, and sublingual glands were elastic, hard, and swollen, but not painful. Several cervical lymph nodes were enlarged. F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) demonstrated abnormal multiple accumulations in the SMGs (SUVmax, 4.63) and in several systemic lymph nodes (SUVmax, 3.23-4.12) ( Figure 1A). CT and magnetic resonance imaging showed remarkable swelling of bilateral PGs, SMGs, and generalized lymph nodes, including in the neck (Figure 1b). On ultrasonograms, SMGs showed bilateral nodal hypoechoic areas with high vascularization, whereas PGs showed normal or slight change ( Figure 1C).
IgG4-DS was initially suspected because of the enlarged glandular tissues and high serum IgG4 concentration. Open biopsies of the cervical lymph node and a portion of the left SMG were therefore performed for definitive diagnosis. Histologically, all sections showed severe lymphoplasmacytic infiltration with hyperplastic lymphoid follicles, so-called follicular colonization. Furthermore, the plasmacytoid cells showed nuclear pleomorphism. Immunohistochemical staining showed mild infiltration of IgG4-positive plasma cells (IgG4-positive/IgG-positive plasma cell ratio, 10%) and monotypic predominance of kappa-light chain. The infiltrating lymphocytes were positive for B cell markers (CD20 and CD79a) and bcl-2, but negative for T-cell markers (CD3, CD5, CD8, and CD45RO), CD10 and cyclinD1 ( Figure 2).
These histopathological findings and clinical features confirmed a diagnosis of MZL. The patient was treated with 600 mg rituximab for six times as currently recommended regimen [9][10][11]. Swelling of the SMGs diminished slightly, and there was no metastatic spread. PGs and LNs showed no remarkably change on all images,  whereas SMGs had ill-defined borders of nodal hypoechoic areas (Figure 3). Laboratory findings after treatment still revealed high concentrations of serum IgG4 (195 mg/dl) and sIL-2R (752.0 U/ml) ( Table 1).

Conclusions
IgG4-DS is now recognized as a new emerging disorder, characterized by high serum IgG4, marked infiltration of IgG4-positive plasma cells and severe fibrosis with hyperplastic ectopic germinal centers in lacrimal and salivary glands. We recently proposed 'Comprehensive diagnostic criteria for IgG4-RD' [12]. IgG4-RD can be diagnosed using these comprehensive diagnostic criteria combined with organ-specific criteria. If a diagnosis of IgG4-DS is probable or possible based on these criteria, it can be confirmed according to the 'Diagnostic criteria for IgG4-related Mikulicz's disease' approved by the Japanese Society for Sjögren's syndrome in 2008, which include the following items: (i) persistent (longer than 3 months) symmetrical swelling of more than two lacrimal and major salivary glands, (ii) raised serum levels of IgG4 (>135 mg/dl), and (iii) infiltration of IgG4-positive plasma cells in the tissue (IgG4-positive plasma cells/IgG-positive plasma cells >0.4) by immunostaining. For a positive IgG4-DS diagnosis, any two of these three criteria must be fulfilled, including item (i). The present case met criteria (i) and (ii), and IgG4-DS was therefore strongly suspected. However, biopsy of the local lesion is recommended for differential diagnosis from other disorders, including sarcoidosis, Castleman's disease, Wegener's granulomatosis, lymphoma, and cancer. We therefore performed the cervical lymph node and SMG biopsies, resulting in a definitive diagnosis of MZL. These results suggest that biopsy of the swollen lesion is essential for a definitive diagnosis of IgG4-DS. Moreover, we have commonly