Introduction_________________________

In 1892, Dr. Johann von Mikulicz, also known as Jan Mikulicz-Radecki, published a paper describing a patient with symmetrical swelling of the lacrimal, parotid, and submandibular glands, along with massive infiltration of these glands by mononuclear cells [1]. Following reports describing similar patients, this condition was named "Mikulicz's disease" (MD). In contrast, patients with similar symptoms, but with diseases such as leukemia, malignant lymphoma, and sarcoidosis were reported to have Mikulicz's syndrome [2]. In 1930, Dr. Henrik Sjögren, an ophthalmologist, published a paper describing a woman with rheumatoid arthritis accompanied by keratoconjunctivitis sicca and severe swelling of the parotid glands, a condition that has been recognized as Sjögren's syndrome (SS) [3]. In 1953, Morgan and Castleman examined 18 patients with MD and concluded that this condition is another manifestation of SS [4]. Since then, MD has attracted very little interest in western countries. In Japan, however, there have been many patients suffering from MD, such that the differences between MD and S S have been clarified [5, 6]. For example, their gender distribution is quite different and MD occurs in both men and women. Following the description of a patient with chronic pancreatitis caused by an autoimmune mechanism [7], lymphoplasmacytic sclerosing pancreatitis (LPSP) was found to be a characteristic histopathological finding in patients with autoimmune pancreatitis (AIP) [8]. These findings led to the concept of AIP, which has characteristics similar to those of other autoimmune diseases, such as hypergammaglobulinemia, the presence of various auto antibodies, lymphocytic infiltration into pancreatic tissue, and good responsiveness to steroids [9]. Following a report showing elevated serum IgG4 concentrations in patients with AIP [10], the pancreatic research team of the Ministry of Health, Labor and Welfare of Japan (MHLW Japan) disclosed that AIP was related to IgG4 levels [11].

IgG4-positive plasma cell infiltration has also been observed in patients with other conditions, including retroperitoneal and mediastinal fibrosis [12, 13], inflammatory pseud o tumor of the lungs and liver [14], Küttner tumor [15], and interstitial nephritis [16], thus indicating that these diseases and conditions collectively constitute a new disease concept known as IgG4-related disease(IgG4-RD).

These findings have led to the establishment of two study groups by the MHLW Japan to analyze the condition of IgG4-RD and to establish the diagnostic criteria for IgG4-related multi-organ lymphoproliferative syndrome(IgG4-MOLPS).

The two teams reached a consensus which stated that IgG4-RD can occur in various organs, including the central nervous system, salivary glands, thyroid gland, lungs, pancreas, biliary duct, liver, gastrointestinal tract, kidneys, prostate gland, retroperitoneum, and lymph nodes, but that clinical symptoms depend on the location of the lesion (Table 1). IgG4-RD mainly affects middle-aged to elderly men. Its clinical symptoms are relatively mild, and the condition usually comes to clinical attention as a result of organ swelling or damage. Many patients with IgG4-RD are treated effectively with steroid therapy. Although the infiltration of IgG4-positive cells and increased serum concentrations of IgG4 are characteristics of IgG4-RD, the severity of fibrosis is dependent on the individual organs involved. For example, storiform fibrosis and obliterative phlebitis are characteristics of pancreatic, biliary tract, and retroperitoneal lesions, but are very seldom found in the salivary glands or lymph nodes.

Table 1. Clinical Manifestations of IgG4-relateddisease 

     Chronic sialadenitis (Küttnertumor)

Orbit

     Lacrimal glands

     Mikulicz disease

     Chronicdacryoadenitis

     Idiopathic orbital inflammation(pseudotumor)

     Lymphoidhyperplasia

     Perineural spread (trigeminal nervebranches)

Sinonasalcavities

     Thyroid gland

     Hashimotothyroiditis

     Riedelthyroiditis

Pituitarygland

     Hypophysitis (pituitary stalk/gland)

Larynx (submucosallesion)

Casereport___________________________

The case presentation involves a 33-year-old man with a soft tissue mass (3×4 cm) on the right side of his frontal area which had enlarged over the space of a year (Table 1). He had not experienced any allergic disorder, weight loss, night sweating, or anorexia and did not smoke or use illicit drugs. On examination his vital signs were normal. He had no complaints of fever, rash or urticaria. A soft, round mass was present on the right side of his frontal area without any pain, tenderness, redness, or discharge over the year. Other examinations wereimmaterial.

Regarding lab studies, white blood cell count was 8,300 with normal differentiation; hemoglobin level was 16.4g/ dl, the platelet count was 204,000 percubic millimeter; the blood urea nitrogen level was 15 mg/dl, and the creatinine level was 0.6 mg/dl. A liver function test was performed a nd it showed an alani n aminotransferase l evel of 75 mg/dl, aspartate aminotransferase level of 30 mg/ dl, and alkaline phophatase of 179 mg/dl. The C-reactive protein level and the erythrocyte sedimentation rate were both normal. Anti-nuclear profile matching was carried out and was also found to be normal. PCR for tuberculosis and the serology test results for viral hepatitis, EBV, CMV and HIV were allnegative.

A brain and posterionasal CT scan was done and showed no abnormality. The patient was then admitted to the otorhinolaryngology ward to undergo a diagnostic biopsy where the fine needle aspiration result was reported as negative for malignant cells. He was then referred to a rheumatologist, by whom a multi-organ evaluation was carried out, which resulted in no major findings. In further laboratory work, the rheumatologist found high IgG4 levels (119.6; normal range: 5.9-86) and in histopathological studies, chronic inflammation and fibrosis infiltrated by lymphomononuclear cells and many eosinophils with a dilated vascular network were reported (Fig.1).

Discussion____________________________

Immunoglobulin G4 (IgG4)-related disease is a systemic disease that is characterized by the abundant infiltration of IgG4-positive plasma cells and lymphocytes with associated fibrosis, leading to organ dysfunction. It has recently been established as a distinct clinico- pathological entity 17, 18]. IgG4-RD occurs predominantly in elderly men and is frequently associated with elevated serum IgG4 levels [19, 20]. One of the characteristics of IgG4-RD is its excellent response to corticosteroid therapy.

The head and neck are commonly involved with the IgG4-RD. Manifestations may occur anywhere in the head and neck, however, the disease most commonly involves the salivary glands, lacrimal glands, orbits, thyroid gland, lymph nodes, sinonasal cavities, and the pituitary stalk (Table 1) [21, 22], and less frequently, other areas such as thelarynx.

The following pathologic entities have recently been included as part of the IgG4-RD spectrum: idiopathic orbital inflammation(inflammatory pseudotumor), orbital lymphoid hyperplasia, Mikulicz disease, Küttner tumor, Hashimoto thyroiditis, Riedel thyroiditis, and pituitaryhypophysitis [8, 11, 14, 16, 17, 19, 20].

When IgG4-RD is suspected in a patient where the manifestations are in the head and neck, a search for further manifestations in other areas is very important as multiorgan involvement is frequently observed in suchcases.

At present, the diagnostic criteria for IgG4-MD (Table 2), and those for IgG4-AIP type 1, have been established. Moreover, a consensus has been reached on two main diagnostic criteria for IgG4-RD, these are: serum IgG4 concentration > 135 mg/dl; and > 40% of IgG-positive plasma cells being IgG4-positive. The MHLW Japan team has proposed the guidelines for the diagnosis ofIgG4-RD [21].

IgG4-RD usually presents itself subacutely and most patients are not constitutionally ill. Fever and increases in C- reactive protein levels are unusual. The disorder is often identified incidentally through radiologic findings or unexpectedly in pathological specimens.

In certain patients the disease is confined to a single organ for many years. Others may have known, or subclinical involvement, of other organs, in addition to the main organ involved. Patients with autoimmune pancreatitis may have pancreatic disease as the major focus of their illness, whereas additional examinations have revealed that 30% also have tubulointerstitial nephritis, indicated by a distinctive radiologic appearance and the presence of mild proteinuria and nonglomerular hematuria [22, 23].

Type 1 autoimmune pancreatitis or AIP (IgG4-relatedpancreatitis)

IgG4-related sclerosingcholangitis

Mikulicz'sdisease(IgG4-relateddacryoadenitisandsialadenitis)

Sclerosingsialadenitis(Küttner'stumor,IgG4-relatedsubmandibularglanddisease)

Inflammatoryorbitalpseudotumor(IgG4-relatedorbitalinflammation ororbitalinflammatorypseudotumor)

Chronicsclerosingdacryoadenitis(lacrimalglandenlargement,IgG4-relateddacryoadenitis)

A subset of patients with "idiopathic" retroperitoneal fibrosis (Ormond's disease) and related disorders (IgG4-related retroperitoneal fibrosis, IgG4-relatedmesenteritis)

Chronic sclerosing aortitis and periaortitis (IgG4-related aortitis or periaortitis)

Riedel's thyroiditis (IgG4-related thyroiddisease)

IgG4-relatedinterstitialpneumonitisandpulmonaryinflammatorypseudotumors(IgG4-relatedlungdisease)

IgG4-related kidney disease (including tubulointerstitial nephritis and membranous glomerulonephritis secondary to IgG4-RD)

IgG4-relatedhypophysitis