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The diagnostic utility of biopsies from the submandibular and labial salivary glands in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease
Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
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.
Interleukin-21 contributes to germinal centre formation and immunoglobulin G4 production in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease.
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),
IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis?.
Research Program for Intractable Disease by Ministry of Health, Labor and Welfare (MHLW) Japan G4 team. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details.
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
Sjögren's International Collaborative Clinical Alliance (SICCA) Research Groups New classification criteria for Sjögren's syndrome: a data-driven expert-clinician consensus approach within the SICCA Cohort.
European Study Group on Classification Criteria for Sjögren's Syndrome Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American–European Consensus Group.
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.
Fig. 1Submandibular gland (SMG) incisional biopsy procedure: (1) an incision of approximately 3 cm in length was made just underneath the SMG; (2) the platysma muscle was incised to disclose the SMG capsule; (3) a spindle-shaped incision of approximately 1 cm in length was made postero-inferior to the SMG, and the biopsy specimen (arrowhead) was extracted; (4) the SMG capsule was closed with absorbent sutures; and (5) the skin was closed with nylon sutures.
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’.
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.
Table 1Clinical characteristics of the 14 cases presenting with bilateral swelling of submandibular glands and high serum IgG4.
Histological findings in the SMG and LSG specimens
Representative histological findings in the SMG and LSG specimens from IgG4-DS and MZL patients are shown in Fig. 2, Fig. 3, respectively. In IgG4-DS patients, all of the SMG specimens showed strong lymphocytic infiltration with hyperplastic GCs, mild destruction of the acini, and selective infiltration by IgG4-positive plasma cells (IgG4-positive plasma cells/IgG-positive plasma cells >0.4) (Fig. 2). In contrast, although some LSG specimens showed similar histological findings (33 out of 56 LSGs from the 13 patients with IgG4-DS), other specimens (23 out of 56 LSGs) showed mild lymphocytic infiltration (IgG4-positive plasma cells/IgG-positive plasma cells ≤0.4) without GCs (Fig. 2). We observed variations between LSG specimens even from the same patient.
Fig. 2Histological findings in submandibular gland (SMG) and labial salivary gland (LSG) specimens from patients with IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS). (A) Both SMG and LSG specimens showed selective infiltration of IgG4-positive plasma cells with hyperplastic germinal centres (GCs); only one LSG showed no lymphoid infiltration (arrowhead). (B) SMG specimens showed selective infiltration of IgG4-positive plasma cells with GCs, whereas only a few lymphocytic infiltrations were seen in all of the LSG specimens. Scale bars, 100 μm.
Fig. 3Histological findings in submandibular gland (SMG) and labial salivary gland (LSG) specimens from a patient with marginal zone B-cell lymphoma (MZL). Both SMG and LSG specimens showed strong lymphocytic infiltration with hyperplastic germinal centres and slight infiltration of IgG4-positive plasma cells. Scale bars, 100 μm.
In contrast, in the patient with MZL, both SMG and LSG specimens (five LSGs) showed severe lymphocytic infiltration with hyperplastic GCs. Immunohistochemical staining showed strong B-cell infiltration, mild infiltration of IgG4-positive plasma cells (IgG4-positive plasma cells/IgG-positive plasma cells, 10%), and monotypic predominance of lambda-light chains (only in the SMG specimen). These histopathological findings and clinical features confirmed the diagnosis as MZL (Fig. 3).
Diagnostic utility and complications of 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 (Table 2). There were no complications of SMG or LSG biopsies including nerve paralysis or paresis, anaesthetic sequelae, haematoma, sialocele, wound infection, hypertrophic scars, or hyposalivation (Saxon test: pre-biopsy 4.12 ± 2.46 g/2 min; post-biopsy 4.37 ± 2.65 g/2 min).
Table 2Diagnostic usability of submandibular gland (SMG) and labial salivary gland (LSG) biopsies.
The ratio was calculated as IgG4-positive cells (%)=IgG4-positive cells/IgG-positive cells×100. The counts were obtained in 1-mm2 sections from five different areas.
IgG4-DS, IgG4-related dacryoadenitis and sialoadenitis.
a The ratio was calculated as IgG4-positive cells (%) = IgG4-positive cells/IgG-positive cells × 100. The counts were obtained in 1-mm2 sections from five different areas.
Relationship of the frequency of IgG4-positive cells between SMG and LSG biopsies from individual IgG4-DS patients
We examined the relationship of the frequency of IgG4-positive cells (IgG4-positive plasma cells/IgG-positive plasma cells) between SMG and LSG biopsies from individual IgG4-DS patients. There was no significant correlation of the frequency of IgG4-positive cells between SMG and LSG biopsies (Fig. 4).
Fig. 4Comparison of the ratio of IgG4-positive cells between SMG and LSG biopsies from individual IgG4-DS patients. The ratio was calculated as IgG4-positive cells (%) = IgG4-positive cells/IgG-positive cells × 100. The counts were obtained in 1-mm2 sections from five different areas. The significance of differences between the groups was determined by Spearman's rank correlation. N.S., not significant.
reported a case of mucosa-associated lymphoid tissue (MALT) lymphoma emerging from a background of IgG4-related chronic inflammation. Therefore, definitive diagnosis of IgG4-DS via biopsy of a local lesion is recommended to select appropriate treatment. The submandibulectomy (excisional biopsy) has been a relatively standard surgical procedure for the treatment of tumours or obstructive conditions of the SMG, but it is associated with a high rate of complications such as facial nerve palsy (up to 36%), lingual nerve palsy (2–5%), and hypoglossal nerve palsy (2–5%).
In this study, we performed incisional biopsies as an alternative diagnostic modality. Patients with bilateral swelling of the SMGs underwent SMG (local lesion) incisional biopsies under local anaesthesia without any complications. Our results suggest that incisional biopsy of the SMG is extremely useful for the diagnosis of IgG4-DS in addition to being a less invasive procedure than excisional biopsy under general anaesthesia. On the other hand, LSG biopsy may be less suitable as a single procedure because of its low sensitivity (Table 2) and poor correlation with the histology of the SMG (Fig. 4). However, as part of this study we performed LSG biopsies in AIP patients (a type of IgG4-RD) without IgG4-DS, and almost half of those patients showed selective infiltration with IgG4-positive plasma cells (IgG4-positive plasma cells/IgG-positive plasma cells >0.4) in the LSG specimens. These results indicate that a single LSG biopsy might be useful for the diagnosis of IgG4-RD in patients who are difficult to biopsy (manuscript in preparation).
Other less invasive procedures include parotid gland incisional biopsy and fine needle biopsy. Pijpe et al.
reported that parotid gland incisional biopsy has diagnostic potential in comparison with LSG biopsy for the diagnosis of SS. In contrast, IgG4-DS patients often show patchy infiltration by IgG4-positive cells, especially in parotid glands. Moreover, parotid glands are usually swollen accompanied by SMG or lacrimal gland swelling, which is an indication that the frequency of parotid gland swelling is significantly lower than that of SMG swelling. We previously performed parotid biopsies in several IgG4-DS patients and obtained negative results for IgG4-DS based on the very small number of IgG4-positive cells found. Furthermore, we also tried to perform SMG fine needle biopsy in several IgG4-DS patients, but we were unable to obtain adequate samples because the SMGs were too hard. These results suggest that clinicians must carefully consider whether samples from parotid gland incisional biopsy or fine needle biopsy are appropriate when considering IgG4-DS. It is a matter of great regret that this study did not include a control group presenting with bilateral swelling of the SMGs in the presence of normal serum IgG4; unfortunately, there were no such patients in our department during the study period.
In conclusion, we have addressed the utility of SMG incisional biopsies for the diagnosis of IgG4-DS. With this procedure, IgG4-DS can be diagnosed quickly and less invasively. Therefore, the biopsy of local lesions should be considered essential for a positive IgG4-DS diagnosis as well as included in the comprehensive diagnostic criteria for IgG4-RD.
Funding
This work was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (26293430) and “Takeda Science Foundation”.
Competing interests
None declared.
Ethical approval
The study design was approved by the Ethics Committee of Kyushu University, Japan (IRB serial number 25-287).
Interleukin-21 contributes to germinal centre formation and immunoglobulin G4 production in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease.
IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis?.
Research Program for Intractable Disease by Ministry of Health, Labor and Welfare (MHLW) Japan G4 team. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details.
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