Clinicopathologic Reports, Case Reports, and Small Case Series
November 2007

IgG4-Related Chronic Sclerosing Dacryoadenitis

Author Affiliations



Copyright 2007 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2007

Arch Ophthalmol. 2007;125(11):1575-1578. doi:10.1001/archopht.125.11.1575

Recent evidence suggests that Mikulicz disease is distinct from Sjögren syndrome and is an IgG4-related systemic disease.1 Herein we report 4 cases of Mikulicz disease in which the serum IgG4 concentrations were elevated and infiltration of IgG4-stained plasma cells with sclerosing fibrosis was pathologically observed in the lacrimal gland.

Report of Cases

Three women (aged 46, 47, and 64 years) and 1 man (aged 66 years) were referred with swelling of the lacrimal gland region (Table). Every patient had experienced a chronic episode (3 months to 5 years) of progressive eyelid swelling. The 64-year-old woman (patient 3) had a history of surgical resection of a subcutaneous mass in the upper eyelid, which was pathologically diagnosed as lymphoid hyperplasia at a different hospital 2 years prior to the initial visit. Magnetic resonance imaging depicted well-circumscribed masses including bilateral lacrimal glands in the lacrimal fossa (Figure 1). In every patient, swelling of the salivary glands (submandibular or parotid) was also observed (Table). No patients showed symptoms or ophthalmic findings of keratoconjunctivitis sicca. Laboratory data ruled out systemic diseases causative of so-called Mikulicz syndrome, such as sarcoidosis, leukemia, and lymphoma. Concentrations of the serum IgG (reference range, 870-1700 mg/dL; to convert milligrams per deciliter to grams per liter, multiply by 0.01) and IgG4 (reference range, < 135 mg/dL) were obtained prior to treatment (Table). In all of the patients, the serum IgG4 concentration and the ratio of IgG4 to IgG were elevated. All of the patients underwent partial resection of the mass including the lacrimal gland.

Figure 1.
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Magnetic resonance imaging before resection of the lacrimal gland. Bilateral masses including lacrimal glands are shown. A, Coronal T1-weighted image in case 1. B, Axial T1-weighted image in case 2. C, Coronal T1-weighted image with gadolinium enhancement in case 3. D, Axial T1-weighted image with gadolinium enhancement in case 4.

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Clinical Aspects of Patients With IgG4-Related Dacryoadenitis

Lacrimal glands resected from 4 cases pathologically showed severe lymphoplasmacytic infiltration with lymphoid follicles and irregular fibrosis (Figure 2). Inflammatory cells consisted of mature lymphocytes and plasma cells without any atypia. Glandular tissue was atrophied and associated with interacinar and intra-acinar sclerosing inflammation. Hyalinized dense fibrosis was also observed in cases 1 and 2 (Figure 2A and C). Immunostaining revealed that the lymphocytes were polyclonal and composed of B cells (positive for CD20 and CD79α) and T cells (positive for CD3) in all of the cases. Monoclonality was also not evident in the infiltrating plasma cells, which were composed of κ-positive cells and λ-positive cells (not shown). Immunostaining of IgG4 showed that numerous IgG4-positive plasma cells infiltrated the lacrimal glands in all of the cases (Figure 2). IgG4-positive plasma cells were commonly observed in inflammatory areas among lymphoid follicles (Figure 2D and H).

Figure 2.
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Histopathological analysis of the lacrimal gland lesions in case 1 (A and B), case 2 (C and D), case 3 (E and F), and case 4 (G and H). Hematoxylin-eosin staining with low magnification (original magnification ×10) showed lymphoplasmacytic infiltration with lymphoid follicle formations and stromal fibrosis (A, C, E, and G). Dense sclerosis was observed in cases 1 and 2 (A and C, respectively). Lacrimal glands were atrophic in all of the cases. Infiltration of many plasmacytes was detected with higher magnification (insets of A, C, E, and G, original magnification ×100). Immunostaining for IgG4 of the lacrimal gland with low (B and F, original magnification ×10) or high (D and H, original magnification ×100) magnification. Numerous IgG4-positive plasma cells were observed in the sclerosing inflammation, especially in the areas among lymphoid follicle (B and D) and intraglandular (F and H) areas.

Based on these findings, we diagnosed these cases as chronic sclerosing dacryoadenitis, consistent with Mikulicz disease related to IgG4. No patients manifested evidence for IgG4-related sclerosing disease in other organs except salivary glands. Oral prednisolone (starting at 30 or 40 mg) was administered to all but patient 2, who required the control of diabetes mellitus and had no further symptoms with the residual lacrimal glands. In the 3 patients receiving steroids, the symptoms of eyelid swelling and salivary gland enlargement improved. In addition, IgG4 levels improved after steroid treatment in 2 patients tested: 86 mg/dL in case 3 and 36 mg/dL in case 4.


Mikulicz disease is a disorder characterized by symmetrical enlargement of the lacrimal and salivary glands. Beginning with the report by Morgan and Castleman2 in 1953, Mikulicz disease had been considered to be a subtype of primary Sjögren syndrome owing to their resemblance pathologically. However, later studies suggested that these 2 diseases were distinctly different pathologically and clinically, ie, in Mikulicz disease, lacrimal gland acinar cells maintained their function and were not programmed for cell death.3 More recently, Mikulicz disease has been suggested to be a disorder involving IgG4, the rarest subclass of IgG in healthy subjects. The serum level of IgG4 is elevated in patients with Mikulicz disease and prominent infiltration of IgG4-stained plasmacytes is observed pathologically, which are features not seen in Sjögren syndrome.1 Moreover, it has been proposed that Mikulicz disease belongs to the clinical entity IgG4-plasmacytic endocrinopathy, which includes IgG4-related sclerosing diseases such as autoimmune pancreatitis, sclerosing cholangitis, retroperitoneal fibrosis, and chronic sclerosing sialadenitis.4,5 These diseases are characterized by histopathological features that include dense lymphoplasmacytic infiltration intermixed with fibrosis, obliterative phlebitis, and prominent infiltration of IgG4-positive plasma cells. In IgG4-related chronic sclerosing sialadenitis, marked lymphoplasmacytic infiltration is associated with the destruction and atrophy of the salivary gland.5 These histopathological features are identical to those of the 4 cases of Mikulicz disease reported here. Another differential diagnosis would be extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue, which could, however, be excluded in all of the cases on the basis of histological and immunohistochemical findings of those lesions consisting of mature polyclonal lymphocytes and plasma cells. To our knowledge, no relationship between IgG4-related chronic inflammation and lymphoma of the mucosa-associated lymphoid tissue has been reported.

There was variability in the amount of fibrosis and destruction of acinar subunits (Figure 2). Fibrosis is one of the characteristic pathological findings of IgG4-related disease irrespective of the organ of origin. However, hyalinized dense fibrosis as observed in cases 1 and 2 is not typical for IgG4-related diseases to our knowledge. We speculated that this difference might depend on anatomical characteristics of the lacrimal gland (eg, tightly surrounded by muscles and bone) or the duration of this disease. In addition, it is interesting that acinar subunits were considerably atrophied, although no patients showed lacrimal dysfunction such as keratoconjunctivitis sicca. Similarly, pancreas with autoimmune pancreatitis usually shows normal exocrine pancreatic function irrespective of acinar atrophy.4 This discrepancy has not been well documented until now, and further pathophysiological examinations are mandatory for this issue.

In all of the cases, we performed unilateral resection of the lacrimal gland to make a diagnosis. However, surgery was also intended as part of the treatment in case 2 because steroid therapy was undesirable for the patient's diabetes mellitus. The left eyelid swelling, his chief symptom, improved after surgery. Thus, excisions of enlarged lacrimal glands (occasionally bilateral) may be an alternative treatment for Mikulicz disease when steroid treatment is undesirable.

In conclusion, the 4 cases of Mikulicz disease reported here had chronic sclerosing inflammation of the lacrimal gland with IgG4-stained plasma cell infiltration. These findings support the theory that Mikulicz disease is within the clinical spectrum of IgG4-related sclerosing diseases.

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Article Information

Correspondence: Dr Takahira, Department of Ophthalmology, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 9208641, Japan (

Financial Disclosure: None reported.

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