Abstract
IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) is characterized by serum IgG4 elevation and the infiltration of IgG4-positive plasma cells in glandular tissues. For definitive diagnosis of IgG4-DS, biopsies of local lesions are recommended to exclude Sjögren’s syndrome (SS), malignant tumours, and similar disorders. In this study, we examined the diagnostic utility of submandibular gland (SMG) and labial salivary gland (LSG) biopsies in IgG4-DS. Fourteen patients presenting with swelling of the SMG (eight females and six males) underwent both SMG and LSG biopsies. The sensitivity, specificity, and accuracy of SMG biopsies were all 100.0%. In contrast, those of LSG biopsies were 69.2%, 100.0%, and 71.4%, respectively. Thirty-three out of 61 LSG biopsies (54.1%) from all 14 patients were positive for the diagnostic criteria of IgG4-DS (IgG4-positive/IgG-positive plasma cells >0.4). None of the patients experienced complications such as facial nerve palsy, sialocele, or hyposalivation. The IgG4/IgG ratio showed no significant correlation between the LSG and SMG. The final diagnosis was IgG4-DS in 13 patients and marginal zone B-cell lymphoma (MZL) in one. These results suggest that incisional biopsy of the SMG is useful and appropriate for the definitive diagnosis of IgG4-DS, while diagnosis by LSG biopsy alone requires more caution.
In the past, Mikulicz’s disease has been considered a subtype of Sjögren’s syndrome (SS) based on histopathological similarities between the two diseases. However, Mikulicz’s disease has a number of differences compared with typical SS, which include the following: (1) differing gender distribution (Mikulicz’s disease occurs in both men and women, while SS occurs mainly in women); (2) persistent enlargement of lacrimal and salivary glands; (3) normal salivary secretion or mild secretory dysfunction; (4) good responsiveness to corticosteroid treatment; (5) hypergammaglobulinemia and low frequency of anti-Sjögren’s syndrome SS-A and SS-B antibodies on serological analyses; and (6) multiple germinal centre (GC) formations in glandular tissue.
Previously, we reported that SS was characterized by periductal lymphocytic infiltration with atrophy or severe destruction of the acini, while Mikulicz’s disease showed non-periductal lymphocytic infiltration with hyperplastic GCs and mild destruction of the acini. Additionally, Yamamoto et al. reported that patients with Mikulicz’s disease showed elevation of serum IgG4 and infiltration of IgG4-positive plasma cells in lacrimal and salivary glands. Similar findings have been observed in autoimmune pancreatitis (AIP), sclerosing cholangitis, tubulo-interstitial nephritis, Riedel’s thyroiditis, and Küttner’s tumour. These diseases are now referred to as IgG4-related disease (IgG4-RD). We have previously described the concept of IgG4-RD and provided up-to-date information regarding this emerging disease entity. Mikulicz’s disease falls into this category and can be alternatively termed IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS).
We have recently proposed comprehensive diagnostic criteria for IgG4-RD and diagnostic criteria for IgG4-related Mikulicz’s disease. Accordingly, IgG4-RD is now diagnosed using comprehensive diagnostic criteria combined with organ-specific criteria. Both groups of these diagnostic criteria particularly recommend the biopsy of local lesions because of the high associated sensitivity and specificity. In cases of IgG4-DS presenting with swelling of the submandibular gland (SMG), a submandibulectomy has generally been performed for definitive diagnosis of IgG4-DS. However, this invasive procedure often leads to postoperative complications, including bleeding, facial nerve palsy, amblygeustia, and hyposalivation. In this study, we evaluated incisional biopsies of the SMG and labial salivary gland (LSG) as less invasive procedures than submandibulectomy for the diagnosis of IgG4-DS.
Materials and methods
Patients
This study included 14 patients who met the IgG4 criteria before biopsy (six men and eight women; mean age 64.9 ± 9.4 years); these patients presented with bilateral swelling of the SMGs and elevated serum IgG4 (>135 mg/dl). They were referred to the department of oral and maxillofacial surgery of the university hospital, a tertiary care centre, between 2009 and 2014 with complaints of SMG swelling. IgG4-DS was diagnosed according to the following criteria : (1) persistent (longer than 3 months) symmetrical swelling of more than two lacrimal and major salivary glands; (2) elevated serum levels of IgG4 (>135 mg/dl); and (3) 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, at least two of these criteria must be met, to include item 1. Additionally, other disorders, including sarcoidosis, Castleman’s disease, Wegener’s granulomatosis, lymphoma, and cancer, must be excluded. All patients failed to meet the American College of Rheumatology Classification Criteria for Sjögren’s syndrome or the criteria proposed by the American–European Consensus Group for Sjögren’s syndrome.
LSG and SMG biopsies
We performed both LSG and SMG biopsies at the same time. LSG biopsies were performed as described by Greenspan et al. We judged IgG4-DS to be present even if just one of the LSG specimens from an individual showed infiltration of IgG4-positive plasma cells (IgG4-positive plasma cells/IgG-positive plasma cells >0.4). Incisional biopsies of swollen SMGs were performed under local anaesthesia. The method is shown in Fig. 1 .
Salivary flow rate
The stimulated whole saliva (SWS) flow rate was measured by Saxon test. This test was performed by having subjects chew Surgeon Type IV gauze sponges (Hakuzo Medical Corporation, Osaka, Japan) once per second for 2 min and then measuring the weight of the gauze. If the change in the gauze weight was less than 2 g, the subject’s salivary flow rate was regarded to be ‘significantly decreased’.
Statistical analysis
The statistical significance of differences between two groups was determined using the unpaired Student’s t -test, Fisher’s exact test, and Spearman’s rank correlation. A P -value of <0.05 was considered significant. All statistical analyses were performed using JMP software version 8 (SAS Institute, Japan).
The study design was approved by the institutional ethics committee and all participants provided written informed consent.
Results
Clinical findings
Table 1 shows the clinical characteristics of the 14 cases presenting with high serum IgG4 (>135 mg/dl) and bilateral swelling of the SMGs over the course of 3 months. The final diagnosis based on SMG and LSG biopsies was IgG4-DS in 13 patients and marginal zone B-cell lymphoma (MZL) in one. Seven out of 13 patients with IgG4-DS (53.8%) had a history of other IgG4-RD including AIP (six cases), sclerosing cholangitis (four cases), and chronic thyroiditis (one case). All of the patients with IgG4-DS and MZL were negative for anti-Sjögren’s syndrome SS-A and SS-B antibodies, and serum IgA and IgM levels were within normal limits.
| No. | Age | Sex | Disease duration | Complication | Swollen glands | Complaint | Gum test (g/10 min) | Schirmer’s test (R/L) (mm/5 min) | Serological test | Ratio of IgG4+ cells | Final diagnosis | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| LG | PG | SMG | SLG | LSG | Dry mouth | Dry eyes | RF (IU/ml) | ANA | IgG (mg/dl) | IgG4 (mg/dl) | IgA (mg/dl) | IgM (mg/dl) | Anti SS-A | Anti SS-B | SMG (%) | LSG (%) | ||||||||
| 1 | 65 | M | 5 m | Hydronephrosis | − | − | + | − | + | − | − | 12.0 | ND | 20> | – | 3142 a | 1700 a | 128 | 59 | – | – | 86.7 a | 96.9 a | IgG4-DS |
| 2 | 57 | F | 6 m | AIP, SC | + | − | + | − | − | − | − | 9.8 | 3/3 | 20> | – | 1842 a | 748 a | 187 | 63 | – | – | 86.4 a | 55.2 a | IgG4-DS |
| 3 | 61 | F | 3 m | AIP, SC | − | − | + | − | + | + | + | 6.3 | 3/1 | ND | – | 2891 a | 1080 a | 187 | 63 | – | – | 57.2 a | 79.6 a | IgG4-DS |
| 4 | 64 | F | 1 y | AIP | − | + | + | − | − | + | + | ND | ND | 61 a | 2+ a | 2585 a | 456 a | 305 | 53 | – | – | 65.7 a | 87.1 a | IgG4-DS |
| 5 | 79 | F | 10 y | AIP, SC | − | + | + | − | − | + | + | ND | ND | 20> | – | 2430 a | 896 a | 182 | 53 | – | – | 60.8 a | 54.9 a | IgG4-DS |
| 6 | 60 | F | 1 y | AIP, SC | − | − | + | − | − | + | + | 11.6 | ND | 20> | – | 2087 a | 490 a | 276 | 74 | – | – | 55.4 a | 84.7 a | IgG4-DS |
| 7 | 69 | M | 5 m | AIP | − | + | + | + | − | − | − | 12.0 | ND | 20> | – | 2090 a | 484 a | 225 | 40 | – | – | 52.4 a | 12.7 | IgG4-DS |
| 8 | 76 | F | 4 m | DM | − | + | + | − | − | + | + | 5.3 | 4/9 | ND | – | 2381 a | 823 a | 187 | 52 | – | – | 60.1 a | 22.3 | IgG4-DS |
| 9 | 79 | F | 3 m | – | − | + | + | − | − | − | − | ND | ND | 20> | – | 2608 a | 896 a | 132 | 68 | – | – | 66.5 a | 17.5 | IgG4-DS |
| 10 | 46 | F | 6 m | Chronic thyroiditis | + | − | + | + | + | + | − | 8.1 | ND | 20> | – | 2200 a | 769 a | 244 | 78 | – | – | 55.2 a | 54.3 a | IgG4-DS |
| 11 | 66 | M | 5 y | – | + | − | + | − | − | − | − | 17.2 | 3/3 | 20> | – | 2121 a | 344 a | 167 | 45 | – | – | 56.3 a | 2.2 | IgG4-DS |
| 12 | 61 | M | 3 y | Pulmonary nodules | + | + | + | + | − | − | − | 6.8 | 3/1 | 20> | – | 7603 a | 2290 a | 121 | 62 | – | – | 51.2 a | 89.1 a | IgG4-DS |
| 13 | 55 | M | 5 m | – | + | − | + | + | − | + | − | 7.4 | ND | 20> | – | 2332 a | 617 a | 241 | 74 | – | – | 86.4 a | 54.3 a | IgG4-DS |
| 14 | 70 | M | 4 m | – | − | + | + | − | − | + | − | 15.1 | ND | 20> | – | 1177 | 215 a | 179 | 91 | – | – | 4.5 | 10.0 | MZL |
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