Primary Sjögren's syndrome misdiagnosed as Mikulicz's disease: a case report.

BACKGROUND: Sjögren's Syndrome (SS) is an inflammatory autoimmune disease, and Mikulicz's disease (MD) is a lymphoproliferative disorder. Both MD and SS are more common in middle-aged female, and the dry eyes could be presented in both of them with different degree. The MD patients are characterized by symmetrical swelling of the lacrimal glands which also can occur in the early stage of SS. And the imaging findings between early stage of SS and MD are lack of specificity. Therefore, SS and MD have similarities in the clinical manifestations, imaging and pathological findings and are confused in diagnosis. CASE PRESENTATION: A 51-year-old female patient presented with bilateral swelling of the upper eyelids for 2 years. She also reported having dry mouth and dry eyes which could be tolerated. The Schirmer's test result is positive and the laboratory tests indicate serum total IgG increased. In the bilateral lacrimal gland area could palpate soft masses. The orbital magnetic resonance imaging (MRI) examination showed bilateral lacrimal gland prolapse. While the histopathological result was considered as MD. The immunohistochemical (IHC) staining results were positive for IgG and negative for IgG4. To clarify the diagnosis, SS-related laboratory tests were performed: anti-SSA antibody (+++), anti-SSB antibody (+++), anti-Ro-52 antibody (+++). With a comprehensive consideration, the final diagnosis was SS. CONCLUSION: When the clinical manifestations are atypical, it is necessary to pay attention to the differential diagnosis of SS and MD.

Differentiation between IgG4-related Mikulicz disease and Sjögren's syndrome: A review case report and literature review.

RATIONALE: IgG4-related diseases cause lesions in various organs throughout the body. In otorhinolaryngology, IgG4-related Mikulicz's disease is suspected and diagnosed based on the presence of lesions of the head and neck, salivary and lacrimal gland enlargement, and bilateral sinus opacity concentrated on the maxillary sinuses. However, in some cases, it is necessary to consider about differentiation between IgG4-related Mikulicz's disease and Sjögren syndrome. PATIENT CONCERNS AND DIAGNOSIS: A 75-years-old male patient visited our hospital with bilateral otitis media with effusion, which was resistant to conservative treatment. Other symptoms at presentation included enlarged bilateral submandibular and sublingual glands marked oral dryness, severe decrease in saliva secretion (1 mL/10 minutes), and dry eyes. We conducted a Schirmer's and fluorescent dye tests, both of which were positive. High serum IgG4 levels were observed, and although the Sjögren syndrome (SS)-A/SS-B antibodies were negative, marked hypolacrimation and tear secretion were observed. Therefore, a detailed examination considering both IgG4-related Mikulicz's disease and SS was conducted. Salivary gland scintigraphy performed prior to the salivary gland biopsy revealed a marked decrease in uptake, which satisfied the diagnostic criteria for SS; however, it was difficult to diagnose IgG4-related disease based on the diagnostic definition. INTERVENSIONS: Although a definitive diagnosis of SS was made, the persistent otitis media with effusion that was resistant to conservative treatment and bilateral mixed hearing loss were confirmed. As mixed hearing loss is considered an otological symptom of IgG4-related disease, oral steroid treatment was administered. OUTCOME: Thereafter, marked recovery of hearing and reduced swelling and induration of the bilateral parotid and submandibular glands were observed. Clinically, IgG4-related Mikulicz's disease was strongly suspected, but a definite diagnosis of SS was made. LESSONS: In the absence of an IgG4-related Mikulicz's disease diagnosis, careful differentiation between IgG4-related Mikulicz's disease and 2 diseases and their diagnostic criteria was essential.

Pathology of salivary gland dysfunction and restoration of function.

In this review, the author shows that simultaneous multiple disorders caused by reactivation of Epstein-Barr virus can lead to salivary gland disorders as part of Sjogren's syndrome (SS). Therefore, clinicians must differentiate SS from other diseases when diagnosing and treating salivary gland disorders. In particular, the author explains how microbial infection in SS overcomes immunological tolerance, leading to pathological changes, and how cytokine overexpression and endocrine disrupters contribute to glandular tissue injury. Also, the author suggests that involvement of reactive oxygen species is a common pathogenesis of salivary gland disorders and SS, so regulation of oxidative stress is an effective treatment for both. The results of clinical studies on restoring salivary gland function and regenerating salivary glands with tissue stem cells may provide clues on elucidating the cause of SS.

A case report of Mikulicz's disease.

Mikulicz's disease is a unique condition involving the enlargement of the lacrimal and salivary glands, similar to that observed in Sjogren's syndrome; however, Mikulicz's disease is clinically characterized by infrequent autoimmune reactions and responsiveness to glucocorticoid treatment. The ultrasound features of the lacrimal and salivary glands in patients with IgG4-Mikulicz's disease were characterized by multiple hypoechoic areas of varying sizes within the enlarged glands. IgG4 serum level was also elevated, in contrast to the detection of normal levels in Sjogren's syndrome. In this article, we intended to illustrate a case of Mikulicz's disease with clinical and imaging features.

IgG4-related Disease - A Patient with Multiple Organ Involvement.

IgG4-related diseases represent a heterogeneous group of conditions characterised by elevated serum IgG4 levels and fibrotic or sclerosing changes in the affected organs or systems accompanied by IgG4-positive plasma cells. A disease associated with IgG4 may affect virtually any organ - salivary glands, periorbital tissue, kidneys, lungs, meninges, aorta, prostate, pericardium or skin. Histopathological findings are uniform, characterised by a major lymphoplasmocytic infiltrate and the presence of IgG4-producing plasma cells, irrespective of the affected site. It can be difficult to establish a correct diagnosis due to the lack of clinical symptoms. Treatment with immunosuppressive drugs provides good results and requires interdisciplinary cooperation.

Enfermedad relacionada con IgG4: revisión concisa de la literatura / IgG4-related disease: a concise review of the current literature

La enfermedad relacionada con IgG4 (ER-IgG4) es una entidad recientemente nominada para definir diversas enfermedades caracterizadas por infiltración linfoplasmocítica, fibrosis, presencia de un número aumentado de células IgG4+ y, en gran parte de los casos, niveles aumentados de IgG4 sérica, afectando frecuentemente el páncreas, las glándulas salivales y los ganglios linfáticos pero pudiendo comprometer casi cualquier estructura de la anatomía humana. Aunque su etiología se desconoce, se han realizado avances en el conocimiento de sus bases fisiopatológicas e inmunológicas, al igual que del rol de las células inflamatorias en el desarrollo de daño del órgano blanco. No existe hasta la fecha un consenso internacional sobre su diagnóstico, lo que no ha impedido avances terapéuticos muy importantes en su control y búsqueda de remisión. Se hace una revisión acerca de la historia, hipótesis sobre la etiología de la enfermedad, sus manifestaciones clínicas, abordaje diagnóstico y terapéutico (AU)

IgG4-related disease is the term used to refer to a condition characterized by a lymphoplasmacytic infiltrate, fibrosis and an increased number of IgG4+ cells present in tissue, in most cases, with an elevated serum IgG4 level. This disease frequently affects the pancreas, salivary glands and lymph nodes, but can involve almost any tissue. Its etiology and the exact role of the different inflammatory cells in the damage to the target organ is still unclear. As yet, there is no international consensus about diagnostic criteria for the disease, but there are important advances in its treatment and in the quest to achieve remission. We include a review of the history, possible pathogenesis, clinical manifestations, diagnostic approach and available therapeutic approaches (AU)

[Non-Hodgkin's lymphoma mimicking Mikulicz disease: a case report].

IgG4-related disease is a systemic disorder involving a spectrum of multiple indications, and various histopathological features are shared among different IgG4-related disease subtypes, which challenge diagnosis, although certain syndromes have organ-specific involvement. Among them, Mikulicz's disease affecting the salivary and lacrimal glands, distinguished by often elevated levels of serum IgG4, infiltration of IgG4+ plasma cells into target tissues, and diffuse swelling, mass formation, or fibrosis of affected organs. However, there are several diseases, which could manifest as salivary gland swelling, mimicking Mikulicz's disease, such as Sjogren's syndrome, mumps virus infection, obstruction of parotid duct, non-Hodgkin's lymphoma (NHL), and so on. So differential diagnosis is important and essential as to the salivary gland swelling. In this paper, we analyzed a case of a 59-year-old male with symmetric salivary gland swelling. Mikulicz's disease was misdiagnosed at the beginning without biopsy. Prednisone treatment ever seemed to be effective and antibiotics had no effect. Besides salivary involvement, the patient also manifested as testicle swelling and severe pancytopenia with the development of the disease, which rarely appeared in Mikulicz's disease. Physical examination showed skin, sclera yellow dye, swollen submandibular, sublingual and lacrimal gland and splenomegaly. As a result, biopsy of right submandibular gland was made, and mucosa-associated lymphoid tissue lymphoma was confirmed by morphology and immunohistochemistry. Bone marrow biopsy also confirmed that lymphoma cells were found in the bone marrow. Finally, the diagnosis of mucosa-associated lymphoid tissue lymphoma (Phase IVE, Group A) was made on the patient, who was transferred to the hematology department for the treatment. NHL, especially, primary extranodal lymphoma usually involves the salivary gland, and painless swelling of the salivary gland is a common manifestation, similar with Mikulicz's disease. So although salivary gland swelling is often associated with autoimmune diseases such as Sjogren's syndrome and IgG4-related disease, the awareness and suspicion of a possibility of NHL are essential for rheumatologists. Biopsy is a necessary examination to decrease or avoid misdiagnosis.

Diagnostic performance of serum IgG4 level for IgG4-related disease: a meta-analysis.

An elevated serum IgG4 level is one of the most useful factors in the diagnosis of IgG4-related disease (IgG4-RD). In this study, we performed a meta-analysis of the published articles assessing the diagnostic accuracy of serum IgG4 concentrations for IgG4-RD. The databases of MEDLINE/PubMed, EMBASE and Web of Science were systematically searched for relevant studies. Sensitivities and specificities of serum IgG4 in each study were calculated, and the hierarchical summary receiver operating characteristic (HSROC) model with a random effects model were employed to obtain the individual and pooled estimates of sensitivities and specificities. In total, twenty-three studies comprising 6048 patients with IgG4-RD were included in the meta-analysis. The pooled sensitivity was 85% with a 95% confidence interval (CI) of 78-90%; the pooled specificity was 93% with a 95% CI of 90-95%. The HSROC curve for quantitative serum IgG4 lies closer to the upper left corner of the plot, and the area under the curve (AUC) was 0.95 (95% CI 0.93, 0.97), which suggested a high diagnostic accuracy of serum IgG4 for the entity of IgG4-RD. Our study suggests that serum IgG4 has high sensitivity and specificity in the diagnosis of IgG4-RD.

Case report of Mikulicz's disease: A modern concept of an old entity.

Introduction: Modern knowlegde defines Mikulicz´s disease as a part of immunoglobulin G4-related disease. The main feature is the presence of lymphoplasmacytic infiltrates, immunoglobulin G4 plasma cells positivity, distinctive storiform fibrosis and moderate eosinophilia. Case Report: A 59-years old male presented with a mild keratoconjuctivitis sicca and enlarged lacrimal and salivary glands during the last two years. Althought clinical presentation of the patient was typical, earlier testing did not pinpoint Mikulicz ´s disease. By typical clinical presentation, elevated serum immunoglobulin G4 level and histopathological finding of lacrimal glands tissue we diagnosed Mikulicz´s disease successfully treated with corticosteroid therapy. Conclusion: We reported the first case of IgG4-related Mikulicz´s disease in Serbia. Our report highlights IgG4-related Mikulicz` s disease as an important differential diagnosis with Sjögren`s syndrome and lymphoproliferative disease in rheumatological practice.

Effectiveness of imaging modalities for screening IgG4-related dacryoadenitis and sialadenitis (Mikulicz's disease) and for differentiating it from Sjögren's syndrome (SS), with an emphasis on sonography.

INTRODUCTION: The aim of this study was to clarify the effectiveness of various imaging modalities and characteristic imaging features in the screening of IgG4-related dacryoadenitis and sialadenitis (IgG4-DS), and to show the differences in the imaging features between IgG4-DS and Sjögren's syndrome (SS). METHODS: Thirty-nine patients with IgG4-DS, 51 with SS and 36 with normal salivary glands were enrolled. Images of the parotid and submandibular glands obtained using sonography, 2-[(18)F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT), computed tomography (CT) and magnetic resonance imaging (MRI) were retrospectively analyzed. Six oral and maxillofacial radiologists randomly reviewed the arranged image sets under blinded conditions. Each observer scored the confidence rating regarding the presence of the characteristic imaging findings using a 5-grade rating system. After scoring various findings, diagnosis was made as normal, IgG4-DS or SS, considering all findings for each case. RESULTS: On sonography, multiple hypoechoic areas and hyperechoic lines and/or spots in the parotid glands and obscuration of submandibular gland configuration were detected mainly in patients with SS (median scores 4, 4 and 3, respectively). Reticular and nodal patterns were observed primarily in patients with IgG4-DS (median score 5). FDG-PET/CT revealed a tendency for abnormal (18)F-FDG accumulation and swelling of both the parotid and submandibular glands in patients with IgG4-DS, particularly in the submandibular glands. On MRI, SS had a high score regarding the findings of a salt-and-pepper appearance and/or multiple cystic areas in the parotid glands (median score 4.5). Sonography showed the highest values among the four imaging modalities for sensitivity, specificity and accuracy. There were significant differences between sonography and CT (p = 0.0001) and between sonography and FDG-PET/CT (p = 0.0058) concerning accuracy. CONCLUSIONS: Changes in the submandibular glands affected by IgG4-DS could be easily detected using sonography (characteristic bilateral nodal/reticular change) and FDG-PET/CT (abnormal (18)F-FDG accumulation). Even inexperienced observers could detect these findings. In addition, sonography could also differentiate SS. Consequently, we recommend sonography as a modality for the screening of IgG4-DS, because it is easy to use, involves no radiation exposure and is an effective imaging modality.

A case of mantle cell lymphoma presenting as IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease.

BACKGROUND: Mantle cell lymphoma (MCL) is a relatively uncommon type of non-Hodgkin lymphoma. It develops in the outer edge of a lymph node called the mantle zone. In contrast, IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) is characterized by elevated serum IgG4 and persistent bilateral enlargement of lacrimal glands (LGs) and salivary glands (SGs), with infiltration of IgG4-positive plasma cells. Recent studies indicated the importance of differentiation between IgG4-DS and malignant lymphoma. CASE PRESENTATION: An 82-year-old man was suspected of IgG4-DS because of a high serum IgG level (2174 mg/dL) and bilateral swelling of LGs and SGs. Lip biopsy and fine needle biopsy of submandibular gland were performed, and subsequently, MCL was diagnosed through the histopathological findings. CONCLUSIONS: MCL most commonly occurs in the Waldeyer ring, but rarely in the stomach, spleen, skin, LG, and SG. We report an unusual case of MCL involving LGs and SGs mimicking IgG4-DS, which suggests that IgG4 testing may be useful in the differentiation of IgG4-DS in the presence of bilateral swelling of LGs or SGs.

[Comparative study of clinical features between unilateral and bilateral orbital IgG4-related disease]. / Estudio comparativo de los hallazgos clínicos en la enfermedad orbitaria asociada a IgG4 con afectación unilateral vs. bilateral.

OBJECTIVE: Descriptive and comparative study of patients with orbital IgG4-related disease. MATERIAL AND METHODS: A review and analysis of the cases diagnosed with inflammatory orbital lesion related to IgG4 by the Ophthalmic Pathology Service in the Dr. Luis Sánchez Bulnes Hospital. RESULTS: A total of 9 cases were found, in which 66% were women, and with a mean age of 48 years and time to diagnosis of 2 years. Unilateral involvement was observed in 56% of cases. All the females experienced pain, and there was an optimal response to corticosteroid treatment in 100% of patients who required medical treatment (one case showed spontaneous resolution). In bilateral cases (44%), only 25% were female, and none had pain as a presenting symptom. Furthermore, 25% of these patients required a combination with immunosuppressants to control inflammation. CONCLUSIONS: Clinical presentation of patients with unilateral orbital IgG4-related disease differs from those with bilateral involvement.

A case of marginal zone B cell lymphoma mimicking IgG4-related dacryoadenitis and sialoadenitis.

BACKGROUND: IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS), so-called Mikulicz's disease, is characterized by elevated serum IgG4 and infiltration of IgG4-positive plasma cells in glandular tissues. Recently, several studies reported both malignant lymphoma developed on the background of IgG4-associated conditions and IgG4-producing malignant lymphoma (non-IgG4-related disease). CASE PRESENTATION: We report on the case of a 70-year-old man who was strongly suspected IgG4-DS because of high serum IgG4 concentration (215 mg/dl) and bilateral swelling of parotid and submandibular glands. Biopsies of cervical lymph node and a portion of submandibular gland were performed. These histopathological findings subsequently confirmed a diagnosis of marginal zone B cell lymphoma. CONCLUSION: Differential diagnosis of IgG4-DS is necessary from other disorders, including Sjögren's syndrome, sarcoidosis, Castleman's disease, Wegener's granulomatosis, lymphoma, and cancer. We suggest that biopsy of swollen lesions is important for a definitive diagnosis of IgG4-DS and discuss the mechanism of development in this case.