So-called Mikulicz's Disease Research Articles

Preferential M2 macrophages contribute to fibrosis in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease

IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) is characterized by bilateral swelling of glandular tissues with extensive fibrosis, and is immunologically considered a Th2-predominant disease. Recent studies reported that alternatively activated (M2) macrophages enhanced Th2 immune responses and fibrosis by production of pro-fibrotic factors (IL-10, IL-13 and CCL18). Therefore, we examined the association between M2 macrophages and fibrosis in submandibular glands from 7 patients with IgG4-DS, 10 patients with chronic sialoadenitis, 10 patients with Sjögren's syndrome, and 10 healthy subjects. The number of M2 macrophages in SMGs from patients with IgG4-DS was also significantly higher than in the other groups. Double immunofluorescence staining showed that IL-10 and CCL18 expression co-localized with M2 macrophage-marker (CD163). Furthermore, the SMG fibrosis score was positively correlated with the frequency of M2 macrophages in only IgG4-DS. These results indicate that IL-10 and CCL18 secreted by preferential M2 macrophages possibly play a key role in the development of severe fibrosis in IgG4-DS.

The diagnostic utility of biopsies from the submandibular and labial salivary glands in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease

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.

Clinical relevance of Küttner tumour and IgG4‐related dacryoadenitis and sialoadenitis

ObjectivesKüttner tumour (KT), so-called chronic sclerosing sialoadenitis, is characterised by concomitant swelling of the submandibular glands secondary to strong lymphocytic infiltration and fibrosis independent of sialolith formation. However, recent studies have indicated that some patients with KT develop high serum levels of IgG4 and infiltration of IgG4-positive plasma cells, namely IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS), so-called Mikulicz's disease. The aim of this study was to clarify the clinical and pathological associations between KT and IgG4-DS.Materials and MethodsFifty-four patients pathologically diagnosed with KT or chronic sialoadenitis were divided into two groups according to the presence or absence of sialolith (KT-S (+) or KT-S (−), respectively).ResultsThere were no significant differences in the clinical findings, including the mean age, sex and disease duration, between the two groups. All patients in the KT-S (+) group showed unilateral swelling without infiltration of IgG4-positive plasma cells or a history of other IgG4-related diseases (IgG4-RD), while those in the KT-S (−) group showed bilateral swelling (37.5%), strong infiltration of IgG4-positive plasma cells (87.5%) and a history of other IgG4-RD (12.5%).ConclusionsThese results suggest an association between the pathogeneses of KT-S (−) and IgG4-DS, but not KT-S (+).

The role of cytotoxic T cells in IgG4-related dacryoadenitis and sialadenitis, the so-called Mikulicz's disease

Objectives. Immunoglobulin (Ig) G4-related dacryoadenitis and sialadenitis, the so-called Mikulicz's disease (MD), is a chronic inflammatory disease. However, little is known about its pathogenesis and pathological condition. In the present study, we used immunohistological techniques to compare the roles of cytotoxic T lymphocytes (CTLs) in MD and primary Sjogren's syndrome (SS). We examined the state of CTLs [cytotoxic granule-positive rate and programmed death-1 (PD-1) expression rate] in the salivary glands.Methods. The study samples comprised 12 submaxillary glands from untreated MD patients and 12 labial glands from SS patients. We performed immunofluorescence and multicolor immunofluorescence to stain CD8, perforin (PRF), granzyme B (GZMB), and PD-1. We measured the total number of CTLs as well as the PRF+CTLs, GZMB+CTLs, and PD-1+CTLs.Results. We found that the degree of infiltration of CTLs was equal in MD and SS, but the rate of CTLs with cytotoxic granules, especially PRF, in MD was less than in SS. In addition, the frequency of PD-1+CTLs in MD was higher than that in SS.Conclusions. Cytotoxic granule-positive CTLs were in the minority in MD salivary glands, and this regulation might relate to PD-1 signals like the state of exhaustion and anergy.

Long-term outcomes and necessity of early intervention for IgG4-related disease

IgG4-related disease is thought to show good prognosis because of positive responsiveness to corticosteroids. Increased long-term observations of IgG4-related disease have provided clinical data regarding the functional prognosis of organs. We analyzed the necessity for early intervention based on those findings and our own experience. It is important for the recovery and maintenance of salivary gland function to start corticosteroid treatment within 2 years after onset, and to maintain clinical remission in cases of IgG4-related dacryoadenitis and sialoadenitis (so-called Mikulicz's disease). Early intervention might be useful in cases of IgG4-related kidney disease because recovery of renal function is insufficient when estimated glomerular filtration before treatment is <60 ml/min. Corticosteroid treatment significantly suppresses relapse in patients with autoimmune pancreatitis showing a relatively high rate of spontaneous remission. Long-term observational studies have demonstrated the transformation of autoimmune pancreatitis into chronic pancreatitis presenting with pancreatic atrophy and stone formation. The treatment protocol and timing of initiation should thus be considered. Although organ dysfunction in IgG4-related disease proceeds more slowly than in conventional chronic inflammatory disorders, sustained IgG4-related lesions still cause accumulation of organ damage with expansion of fibrosis. Intervention as soon as possible would favorably impact IgG4-related disease, considering the side effects of treatments such as corticosteroids.

Interleukin-21 contributes to germinal centre formation and immunoglobulin G4 production in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease

ObjectivesInterleukin (IL)-21 is mainly produced by CD4 T helper (Th) cells including Th2, Th17 and follicular helper T (Tfh) cells. Recent studies have reported that IL-21 is involved in the...

いわゆるMikulicz病発症とともに高ガンマグロブリン血症，リンパ節腫脹を呈したmulticentric Castleman disease類縁症例

シェーグレン症候群(SS)の中には，リンパ節腫脹の状態から悪性リンパ腫に進展する症例がある。いわゆるMikulicz病はSSの一亜型とみなす考え方が一般的であり，今回Mikulicz病にmulticentric Castleman disease (MCD)様病態を呈した症例を経験した。症例は，73歳，男性。両側涙腺，両側顎下腺，両頚部，両鼠径部のリンパ節腫脹し，血清IgG 6530 mg/dl (polyclonal)と高値を示し入院。左顎下腺生検では高度な線維化を伴う慢性唾液腺炎像を示し，左頚部リンパ節生検では悪性所見なく，成熟リンパ球と形質細胞の浸潤を認めた。プレドニゾロン20 mg/日内服開始にて3週後には体表リンパ節は縮小し，血液データも正常化し著効した。本例では顎下腺やリンパ節への形質細胞や成熟リンパ球の浸潤を認めたが，血清IL-6の増加はなく，従来考えられているMCDとは違った成因によるものが存在することが示唆され，境界領域の病変を考える上で重要と考えられ報告した。

Benign Lymphoepithelial Cysts of the Parotid Gland: A Histologic, Cytologic, and Ultrastructural Study

Five cases of benign lymphoepithelial cysts (BLCs) of the parotid gland are reported, and the histologic, aspiration cytologic, and ultrastructural findings are described in detail. These uncommon parotid lesions contain epithelium-lined cystic spaces encased by abundant lymphoid tissue with germinal centers. The epithelium was "mucoepidermoid" in three of our cases and squamous in two. Familiarity with the morphologic features of BLCs should make it possible to distinguish them from similar-appearing cystic lesions, especially low-grade cystic mucoepidermoid carcinoma and cystic types of benign lymphoepithelial lesion (so-called Mikulicz's disease). These distinctions, however, are difficult on aspiration cytology specimens.

いわゆるミクリッツ病の３症例

Three cases with so-called Mikulicz's disease were studied clinically.Case 1 A 35-year-old woman was suffering from bilateral lacrimal and submandibular gland swelling. Biopsy of the submandibular gland and lacrimal gland showed severe atrophy of the glandular tissue and extensive lympoid infiltration accompanied by germinal center. It is five years since she first came to our clinic and has remained generally well without any treatment. The swelling of the gland is naturally decreasing.Case 2 A 62-year-old man was suffering from bilateral lacrimal and submandibular gland diffuse swelling. Histological examination revealed extensive infiltration with lymphocytes and plasma cells. Five months after his first visit, he showed significant changes in clinical and laboratory findings, that is to say, general lymphnode swelling, total protein 9.8 g/dl, hyper gamma globulinemia 50.1%, elevated ESR 119 mm/hr, etc. Steroid treatment resulted in gradual disappearance of the swelling.Case 3 A 69-year-old woman was referred to our clinic for evaluation regarding the enlargement of bilateral parotid gland, submandibular gland, right orbital region and submental lymphnode. This is a case of 45 years' duration and for a long time was treated as sarcoma. Steroid treatment resulted in gradual disappearance of the swelling.

The sialographic differentiation of Mikulicz's disease and Mikulicz's syndrome.

IN THE SEVEN decades since Mikulicz described the disease entity which bears his name, there has been much confusion between Mikulicz's disease and Mikulicz's syndrome. The literature records attempts to differentiate the two by means of biopsy, but histopathology, particularly in Mikulicz's disease, is uncertain. Most of these reports (3, 15, 17, 20) were written before the advent of sialography, and more recently this diagnostic approach has been employed only sporadically, and then with conflicting observations (2, 30, 46, 47). It was for this reason that sialographic studies were undertaken in a group of patients with salivary gland swellings in which histologic proof of Mikulicz's disease or Mikulicz's syndrome had been obtained. The resulting roentgenograms have shown a pattern of variations indicating that sialography can be used for the differential diagnosis of the two conditions. Historically, the disease was first identifled in 1888 by Johann von MikuliczRadecki (23), who described it as a distinct clinical and pathological entity having as its chief characteristic symmetrical tumefactions of the lacrimal and salivary glands which develop gradually, are hard in consistency, painless, and unassociated with other organic involvement. Microscopic examinations of the excised portions of the gland disclosed atrophy of the acinar parenchyma and diffuse replacement by lymphoid tissues. In the following years numerous reports attempted to classify the variations found in what appeared to be cases of Mikulicz's disease. Von Brunn (3) in 1906, and Howard (15) in 1909, distinguished between the disease and pseudoleukemia and true lymphatic leukemia, but this simple classification failed to take into account the varied causes of lacrimal and salivary gland swellings. A more elaborate classification on etiological grounds was made by Thursfield (53) in 1914, and finally Schaffer and Jacobsen (45), in 1927, distinguished between Mikulicz's disease and Mikulicz's syndrome. This remains the accepted classification today and contrasts Mikulicz's disease with its uncertain histopathology against Mikulicz's syndrome, of more clearly defined pathologic nature, including such entities as leukemia, the lymphomas, sarcoidosis, tuberculosis, and syphilis. The sialographic studies comprising this series were initiated at the University of Michigan and continued at the Nat ional Institutes of Health, Bethesda, Md. Fortythree patients have been examined. More than one hundred sialograms have been completed in which reflex stimulation of the salivary glands has been employed. There were 29 cases of Mikulicz's disease (see Table I) and 14of Mikulicz's syndrome, the latter group including 3 cases of leu kemia, 5 of lymphoma, 5 of sarcoidosis, and 1 of tuberculosis. Mikulicz's Disease There is no consistent clinical pattern of symptoms in so-called Mikulicz's disease.