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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

  • M. Moriyama
    Correspondence
    Address: Masafumi Moriyama, Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. <!-- no-mfc -->Tel:<!-- /no-mfc --> +81 92 642 6447; Fax: +81 92 642 6386.
    Affiliations
    Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
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  • S. Furukawa
    Affiliations
    Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
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  • S. Kawano
    Affiliations
    Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
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  • Y. Goto
    Affiliations
    Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
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  • T. Kiyoshima
    Affiliations
    Laboratory of Oral Pathology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
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  • A. Tanaka
    Affiliations
    Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
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  • T. Maehara
    Affiliations
    Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
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  • J.-N. Hayashida
    Affiliations
    Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
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  • M. Ohta
    Affiliations
    Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
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  • S. Nakamura
    Affiliations
    Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
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Open AccessPublished:July 22, 2014DOI:https://doi.org/10.1016/j.ijom.2014.06.014

      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.

      Keywords

      In the past, Mikulicz's disease has been considered a subtype of Sjögren's syndrome (SS) based on histopathological similarities between the two diseases.
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      A clinicopathologic study of Mikulicz's disease.
      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.
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      • Harrison J.D.
      Mikulicz's disease and Mikulicz's syndrome: analysis of the original case report of 1892 in the light of current knowledge identifies a MALT lymphoma.
      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.
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      Th2 and regulatory immune reactions contribute to IgG4 production and the initiation of Mikulicz disease.
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      Interleukin-21 contributes to germinal centre formation and immunoglobulin G4 production in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease.
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      A new conceptualization for Mikulicz's disease as an IgG4-related plasmacytic disease.
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      Clinical and pathological characteristics of Mikulicz's disease (IgG4-related plasmacytic exocrinopathy).
      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),
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      High serum IgG4 concentrations in patients with sclerosing pancreatitis.
      sclerosing cholangitis,
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      • et al.
      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?.
      tubulo-interstitial nephritis,
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      IgG4-associated idiopathic tubulointerstitial nephritis complicating autoimmune pancreatitis.
      Riedel's thyroiditis,
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      • Kawa S.
      • et al.
      Inflammatory lesions of the lung, submandibular gland, bile duct and prostate in a patient with IgG4-associated multifocal systemic fibrosclerosis.
      and Küttner's tumour.
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      • Sasaki M.
      • Sato Y.
      • Minato H.
      • et al.
      Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Kuttner's tumor).
      These diseases are now referred to as IgG4-related disease (IgG4-RD).
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      Clinical and pathological differences between Mikulicz's disease and Sjögren's syndrome.
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      Proposal for a new clinical entity. IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders.
      We have previously described the concept of IgG4-RD and provided up-to-date information regarding this emerging disease entity.
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      Mikulicz's disease falls into this category and can be alternatively termed IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS).
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      Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations.
      We have recently proposed comprehensive diagnostic criteria for IgG4-RD and diagnostic criteria for IgG4-related Mikulicz's disease.
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      Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011.
      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
      • Umehara H.
      • Okazaki K.
      • Masaki Y.
      • Kawano M.
      • Yamamoto M.
      • Saeki T.
      • et al.
      Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011.
      : (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
      • Shiboski S.C.
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      • Kelly J.A.
      • Radfar L.
      • et al.
      Sjögren's International Collaborative Clinical Alliance (SICCA) Research Groups
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      or the criteria proposed by the American–European Consensus Group for Sjögren's syndrome.
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      • Alexander E.L.
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      • et al.
      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.

      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.
      • Greenspan J.S.
      • Daniels T.E.
      • Talal N.
      • Sylvester R.A.
      The histopathology of Sjögren's syndrome in labial salivary gland biopsies.
      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.
      Figure thumbnail gr1
      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.

      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’.
      • Kohler P.F.
      • Winter M.E.
      A quantitative test for xerostomia—the Saxon test, an oral equivalent of the Schirmer test.

      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.
      Table 1Clinical characteristics of the 14 cases presenting with bilateral swelling of submandibular glands and high serum IgG4.
      No.AgeSexDisease durationComplicationSwollen glandsComplaintGum test (g/10 min)Schirmer's test (R/L) (mm/5 min)Serological testRatio of IgG4+ cellsFinal diagnosis
      LGPGSMGSLGLSGDry mouthDry eyesRF (IU/ml)ANAIgG (mg/dl)IgG4 (mg/dl)IgA (mg/dl)IgM (mg/dl)Anti SS-AAnti SS-BSMG (%)LSG (%)
      165M5 mHydronephrosis++12.0ND20>3142
      Higher than normal values.
      1700
      Higher than normal values.
      1285986.7
      Higher than normal values.
      96.9
      Higher than normal values.
      IgG4-DS
      257F6 mAIP, SC++9.83/320>1842
      Higher than normal values.
      748
      Higher than normal values.
      1876386.4
      Higher than normal values.
      55.2
      Higher than normal values.
      IgG4-DS
      361F3 mAIP, SC++++6.33/1ND2891
      Higher than normal values.
      1080
      Higher than normal values.
      1876357.2
      Higher than normal values.
      79.6
      Higher than normal values.
      IgG4-DS
      464F1 yAIP++++NDND61
      Higher than normal values.
      2+
      Higher than normal values.
      2585
      Higher than normal values.
      456
      Higher than normal values.
      3055365.7
      Higher than normal values.
      87.1
      Higher than normal values.
      IgG4-DS
      579F10 yAIP, SC++++NDND20>2430
      Higher than normal values.
      896
      Higher than normal values.
      1825360.8
      Higher than normal values.
      54.9
      Higher than normal values.
      IgG4-DS
      660F1 yAIP, SC+++11.6ND20>2087
      Higher than normal values.
      490
      Higher than normal values.
      2767455.4
      Higher than normal values.
      84.7
      Higher than normal values.
      IgG4-DS
      769M5 mAIP+++12.0ND20>2090
      Higher than normal values.
      484
      Higher than normal values.
      2254052.4
      Higher than normal values.
      12.7IgG4-DS
      876F4 mDM++++5.34/9ND2381
      Higher than normal values.
      823
      Higher than normal values.
      1875260.1
      Higher than normal values.
      22.3IgG4-DS
      979F3 m++NDND20>2608
      Higher than normal values.
      896
      Higher than normal values.
      1326866.5
      Higher than normal values.
      17.5IgG4-DS
      1046F6 mChronic thyroiditis+++++8.1ND20>2200
      Higher than normal values.
      769
      Higher than normal values.
      2447855.2
      Higher than normal values.
      54.3
      Higher than normal values.
      IgG4-DS
      1166M5 y++17.23/320>2121
      Higher than normal values.
      344
      Higher than normal values.
      1674556.3
      Higher than normal values.
      2.2IgG4-DS
      1261M3 yPulmonary nodules++++6.83/120>7603
      Higher than normal values.
      2290
      Higher than normal values.
      1216251.2
      Higher than normal values.
      89.1
      Higher than normal values.
      IgG4-DS
      1355M5 m++++7.4ND20>2332
      Higher than normal values.
      617
      Higher than normal values.
      2417486.4
      Higher than normal values.
      54.3
      Higher than normal values.
      IgG4-DS
      1470M4 m+++15.1ND20>1177215
      Higher than normal values.
      179914.510.0MZL
      LG, lacrimal gland; PG, parotid gland; SMG, submandibular gland; SLG, sublingual gland; PLG, palatal gland; LSG, labial salivary gland; M, male; F, female; m, months; y, years; R, right; L, left; RF, rheumatoid factor; ANA, antinuclear antibody; Anti SS-A, anti-Sjögren's syndrome SS-A antibodies; Anti SS-B, anti-Sjögren's syndrome SS-B antibodies; ND, not done; IgG4-DS, IgG4-related dacryoadenitis and sialoadenitis; AIP, autoimmune pancreatitis; SC, sclerosing cholangitis; DM, diabetes mellitus; MZL, marginal zone B-cell lymphoma.
      a Higher than normal values.

      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.
      Figure thumbnail gr2
      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.
      Figure thumbnail gr3
      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.
      Definitive diagnosisRatio of IgG4-positive cells
      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.
      Total
      >40%≤40%
      SMG biopsy
       IgG4-DS13013
       Non-IgG4-DS011
       Total13114
       Sensitivity = 100%, specificity = 100%, accuracy = 100%
      LSG biopsy
       IgG4-DS9413
       Non-IgG4-DS011
       Total9514
       Sensitivity = 69.2%, specificity = 100%, accuracy = 71.4%
      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).
      Figure thumbnail gr4
      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.

      Discussion

      Recently, several reports have described that a subset of patients with malignant tumours such as pancreatic and salivary carcinomas
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      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%).
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      Surgical management of nonneoplastic diseases of the submandibular gland. A follow-up study.
      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.
      • Pijpe J.
      • Kalk W.W.
      • van der Wal J.E.
      • Vissink A.
      • Kluin P.M.
      • Roodenburg J.L.
      • et al.
      Parotid gland biopsy compared with labial biopsy in the diagnosis of patients with primary Sjögren's syndrome.
      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).

      Patient consent

      Informed consent was obtained from all patients.

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