Abstract
Purpose
Recent studies have revealed that Mikulicz disease (MD) differs from Sjögren syndrome and is an immunoglobulin G 4 (IgG 4 )–related systemic disease. Küttner tumor (KT) is also reported to be an IgG 4 -related disease. In this study, we examined the clinicopathologic and serologic findings in MD (39 patients) and KT (6 patients) and attempted to discern the similarities between MD and KT.
Materials and methods
We diagnosed 39 patients with MD and 6 patients with KT. We analyzed the clinicopathologic and serologic findings (IgG subclasses) in 39 patients with MD and 6 patients with KT. Submandibular and labial salivary gland specimens obtained from patients with MD and KT were stained with anti-IgG 4 antibodies.
Results
The mean IgG 4 concentration (±SD) was 931.1 ± 796.2 mg/dL in patients with MD and 756.2 ± 449.2 mg/dL in patients with KT. Abundant infiltration of IgG 4 -positive plasmacytes into the salivary glands was observed in both patients with MD and patients with KT.
Conclusion
The serologic and histopathologic findings in MD and KT are very similar, and these 2 conditions may be IgG 4 -related systemic diseases.
1
Introduction
In 1888, Johann von Mikulicz-Radecki reported a case of bilateral, painless, and symmetrical swelling of the lachrymal, parotid, and submandibular glands. In 1927, Schaffer and Jacobsen compared this case with known diseases that show obvious similarities to this case, such as sarcoidosis and lymphoma, and reported that the symptoms in this case constituted Mikulicz syndrome and designated Mikulicz syndrome of idiopathic origin as Mikulicz disease (MD). In 1933, Sjögren summarized the findings of 19 cases of keratoconjunctivitis sicca; in 2 of these cases, swelling of the major salivary glands was observed. The concept of Sjögren syndrome (SS) was established after this report. In 1953, Morgan and Castleman examined specimens obtained from 18 patients diagnosed with MD. They found that the histologic findings in both MD and SS were similar and reported that most patients diagnosed with MD could be considered to be suffering from SS . Since then, MD has been recognized as a subtype of SS, and no cases of MD have been reported. However, many studies on the relationship between MD and SS have been conducted in Japan. In SS, the minor salivary glands are infiltrated by mononuclear cells; this infiltration resolves with corticosteroid administration, but salivary function does not recover . The histopathologic basis of this phenomenon is the occurrence of extensive apoptosis in the minor salivary glands of patients with SS. Tsubota et al recently reported that the extent of apoptosis in the salivary glands is significantly lower in the case of MD than in the case of SS. It has also been confirmed that in patients with MD, the serum immunoglobulin G 4 (IgG 4 ) concentration is elevated, and IgG 4 -expressing plasmacytes infiltrate the lacrimal and salivary glands . Thus, MD apparently differs from SS and is now thought to be a systemic IgG 4 -related plasmacytic disease.
On the other hand, Küttner tumor (KT), which was first described as chronic sclerosing sialadenitis by Küttner in 1896, is a rare and chronic inflammatory disorder of the salivary glands and most commonly affects the submandibular gland . Patients with KT present with firm swelling of the salivary glands, and clinical differentiation of KT from neoplasm is difficult , hence the name Küttner tumor . Although KT is not infrequently associated with sialoliths, sialolithiasis may be a secondary process in KT . Monoclonal and oligoclonal cytotoxic T-cell populations found in the affected salivary gland of patients with KT suggest an immune reaction to intraductal agent(s) . It has also been suggested that secretory dysfunction of the salivary glands leads to inspissation of saliva in the ducts and chronic inflammation of the salivary glands in patients with KT . Küttner tumor is occasionally associated with similar sclerosing lesions in extrasalivary glandular tissues such as those of the bile duct (sclerosing cholangitis) and the retroperitoneum (retroperitoneal fibrosis) . The concomitant occurrence of such lesions is referred to as multifocal fibrosclerosis, and KT could be regarded as one manifestation of multifocal fibrosclerosis. In addition, there have been several reports of an association between KT and sclerosing pancreatitis . Recent studies have shown that sclerosing pancreatitis, which is also called autoimmune pancreatitis (AIP) or lymphoplasmacytic sclerosing pancreatitis, is a unique IgG 4 -related disease . Kitagawa et al reported that both KT and MD are IgG 4 -related diseases. However, the relationship between MD and KT has not been comprehensively studied.
In this report, we clinically examined patients with MD and KT and histopathologically analyzed tissues specimens obtained from these patients to compare these 2 diseases.
2
Methods
2.1
Patients and materials
We examined 39 patients with MD (15 men, 24 women) and 6 patients with KT (2 men, 4 women). All patients had previously consulted physicians at the Sapporo Medical University and its related facilities between April 1997 and October 2008. Mikulicz disease was diagnosed according to the following criteria: (1) persistent (>3 months) symmetrical swelling of more than 2 lachrymal and major salivary glands; (2) prominent mononuclear infiltration of lachrymal and salivary glands; and (3) exclusion of other diseases that present with glandular swelling, such as sarcoidosis and lymphoproliferative disease. KT was diagnosed according to the following criteria: (1) persistent (>3 months) unilateral or bilateral hard swelling of only the submandibular glands; (2) histologic findings similar to those reported in previous studies ; (3) absence of preceding lesion(s), such as sialolith or mechanical obstruction of the salivary duct. Serum samples were obtained before and after therapy and stored at −80°C. Formalin-fixed, paraffin-embedded blocks of salivary gland tissues from the patients with MD and KT were analyzed. Blocks of salivary glands from the study patients were also examined. Histologic features were comprehensively assessed by several pathologists.
Written consent for use of the findings from these cases was obtained from the patients in accordance with the Declaration of Helsinki.
2.2
Laboratory data
We retrospectively analyzed the following laboratory data, which were obtained from patients with MD and KT during their first visit to the hospital: eosinophil count in peripheral blood and levels of serum γ globulin, antinuclear antibody, anti–SS-A antibody, anti–SS-B antibody, and antineutrophilic cytoplasmic antibody. Immunoglobulin G levels were measured in all serum samples by using a Behring nephelometer (Dade Behring, Deerfield, USA), and IgG subclasses were measured using BS-NIA IgG 1–4 (The Binding Site, San Diego, USA) and by enzyme-linked immunosorbent assay (Yoshitomi Pharmaceutical Industries, Japan).
2.3
Immunohistochemistry
For all immunostainings, the monoclonal antibodies were reacted with steam for 24 hours at 4°C after endogenous peroxidase activity in tissue sections had been blocked. Ant-IgG 4 antibody (mouse antihuman IgG 4 ; The Binding Site) at a dilution 1:500 was used as the primary antibody. The secondary antibody (biotinylated antimouse IgG [H+L]; Vector Laboratories, Burlingame, CA) was used at a dilution of 1:500. Nuclear staining was performed using hematoxylin after indirect peroxidase staining of labial salivary gland specimens collected from the patients with MD and KT. Submandibular gland specimens were also examined. To identify IgG 4 -producing cells, gland specimens from the patients were stained with anti-CD138 antibodies (CD138; Biogenesis, Poole, UK) that were diluted to 1:250. The histopathologic diagnosis was defined including lymphocyte- and IgG 4 -positive plasmacyte infiltration (IgG 4 -positive plasmacytes/IgG-positive plasmacytes >50%) with typical fibrosis or sclerosis in the tissue.
2
Methods
2.1
Patients and materials
We examined 39 patients with MD (15 men, 24 women) and 6 patients with KT (2 men, 4 women). All patients had previously consulted physicians at the Sapporo Medical University and its related facilities between April 1997 and October 2008. Mikulicz disease was diagnosed according to the following criteria: (1) persistent (>3 months) symmetrical swelling of more than 2 lachrymal and major salivary glands; (2) prominent mononuclear infiltration of lachrymal and salivary glands; and (3) exclusion of other diseases that present with glandular swelling, such as sarcoidosis and lymphoproliferative disease. KT was diagnosed according to the following criteria: (1) persistent (>3 months) unilateral or bilateral hard swelling of only the submandibular glands; (2) histologic findings similar to those reported in previous studies ; (3) absence of preceding lesion(s), such as sialolith or mechanical obstruction of the salivary duct. Serum samples were obtained before and after therapy and stored at −80°C. Formalin-fixed, paraffin-embedded blocks of salivary gland tissues from the patients with MD and KT were analyzed. Blocks of salivary glands from the study patients were also examined. Histologic features were comprehensively assessed by several pathologists.
Written consent for use of the findings from these cases was obtained from the patients in accordance with the Declaration of Helsinki.
2.2
Laboratory data
We retrospectively analyzed the following laboratory data, which were obtained from patients with MD and KT during their first visit to the hospital: eosinophil count in peripheral blood and levels of serum γ globulin, antinuclear antibody, anti–SS-A antibody, anti–SS-B antibody, and antineutrophilic cytoplasmic antibody. Immunoglobulin G levels were measured in all serum samples by using a Behring nephelometer (Dade Behring, Deerfield, USA), and IgG subclasses were measured using BS-NIA IgG 1–4 (The Binding Site, San Diego, USA) and by enzyme-linked immunosorbent assay (Yoshitomi Pharmaceutical Industries, Japan).
2.3
Immunohistochemistry
For all immunostainings, the monoclonal antibodies were reacted with steam for 24 hours at 4°C after endogenous peroxidase activity in tissue sections had been blocked. Ant-IgG 4 antibody (mouse antihuman IgG 4 ; The Binding Site) at a dilution 1:500 was used as the primary antibody. The secondary antibody (biotinylated antimouse IgG [H+L]; Vector Laboratories, Burlingame, CA) was used at a dilution of 1:500. Nuclear staining was performed using hematoxylin after indirect peroxidase staining of labial salivary gland specimens collected from the patients with MD and KT. Submandibular gland specimens were also examined. To identify IgG 4 -producing cells, gland specimens from the patients were stained with anti-CD138 antibodies (CD138; Biogenesis, Poole, UK) that were diluted to 1:250. The histopathologic diagnosis was defined including lymphocyte- and IgG 4 -positive plasmacyte infiltration (IgG 4 -positive plasmacytes/IgG-positive plasmacytes >50%) with typical fibrosis or sclerosis in the tissue.
3
Results
3.1
Clinical features
Background characteristics of the patients with MD and KT are shown in Table 1 . The mean age of the patients with MD was 55.2 ± 14.7 years (range, 23−87 years) and that of the patients with KT was 61.8 ± 9.4 years (range, 50−74 years). Salivary function in patients with MD and patients with KT was only slightly decreased (Saxon test: MD, 2.62 ± 2.14 g/2 min; KT, 2.24 ± 2.18 g/2 min). Sialography yielded normal results, and the apple tree sign, which is typical of SS, was not observed. Serologic analysis revealed that the mean total IgG level was 1174.4 ± 588.3 mg/dL in patients with MD and 1167.0 ± 291.0 mg/dL in patients with KT. Anti–SS-A and anti–SS-B antibodies were absent in all patients with MD and patients with KT, except 1.
| MD (n = 39) | KT (n = 6) | |
|---|---|---|
| Gland swelling | Symmetrical swelling of more than 2 major salivary gland | Unilateral or bilateral hard swelling of only the submandibular gland |
| Mean age of disease onset | 55.2 ± 14.7 | 61.8 ± 9.4 |
| Gender ratio (M/F) | 1:1.7 | 1:2 |
| Hyperganmmaglobulinemia (mean serum IgG mg ± SD) | 29 (74.4%) (2848.7 ± 1788.7) | 3 (50.0%) (2344.0 ± 934.4) |
| Anti–SS-A antibody | 1 | 0 |
| Anti–SS-B antibody | 0 | 0 |
| Antinuclear antibody | 5 | 1 |
| Saxon test (g/2 min ± SD) | 2.62 ± 2.10 | 2.24 ± 2.18 |
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