MRI showed IgG4-related dacryoadenitis
To understand the concept of IgG4-DS, it may be important to know its histological background. First, in 1888, Dr. Johann von Mikulicz published a paper about a patient with symmetrical swelling of the lacrimal, parotid, and submandibular glands, characterized pathologically by mononuclear cell infiltration, the so-called MD . Then, in 1933, Dr. Henrik Sjögren published a case series of patients with rheumatoid arthritis associated with keratoconjunctivitis sicca and severe swelling of the parotid glands, the so-called SS . Subsequently, in 1953, Morgan and Castleman classified IgG4-DS as a subtype of SS . Since then, little attention has been paid to IgG4-DS for over 50 years. In 2004, Yamamoto unearthed the definitive differences between IgG4-DS and SS based on clinical data . They revealed that IgG4-DS responded well to CST therapy and that was a reversible condition, unlike SS. In 2012, Umehara proposed the novel clinical entity IgG4-RD, encompassing autoimmune pancreatitis (AIP) and IgG4-DS. Thereafter, IgG4-DS has been regarded as one manifestation of IgG4-RD . It has been suggested that lacrimal gland involvement in IgG4-RD should be referred to as IgG4-related dacryoadenitis, and submandibular gland involvement in IgG4-RD should be referred to as IgG4-related Küttner tumor (IgG4-KT)  (Fig. 16.2).
MRI depicted IgG4-related Küttner tumor
AIP, a major component of IgG4-RD, mainly manifesting as obstructive jaundice and/or deterioration of diabetes mellitus, was first reported by Sarles in 1961  and proposed as a clinical entity by Yoshida et al. in 1995 . Hamano revealed serum IgG4 elevation as a useful finding in the diagnosis for AIP . Although the etiology and mechanism of AIP are still unknown, overproduction of Th2 and regulatory cytokines may play an important role [11, 12]. The characteristic findings of AIP such as elevation of the serum IgG4, infiltration of the affected organs such as the pancreas, bile duct, and gallbladder by IgG4-bearing plasma cells, and its reversibility with CST therapy are similar to those of IgG4-DS. However, AIP is associated with IgG4-DS only in a minority of patients. We describe some patients with AIP associated with IgG4-DS, preceded by dacryoadenitis and sialadenitis .
In this section, we summarize the features of IgG4-DS and IgG4-KT from the perspective of AIP because of the paucity of data on the clinical relationship between IgG4-DS/KT and AIP.
Discrimination Between IgG4-Related Mikulicz’s Disease and Sjögren’s Syndrome
Table 16.1 shows the consensus criteria for the diagnosis of IgG4-related Mikulicz’s disease (IgG4-DS) approved by the Japanese society for Sjögren’s syndrome (SS) in 2008 . IgG4-DS is regarded as a component of IgG4-RD characterized by lacrimal gland and/or salivary gland involvement. IgG4-DS must be distinguished from disorders such as sarcoidosis, Castleman’s disease, Wegener’s granulomatosis, lymphoma, and cancer  (Table 16.2).
Diagnostic criteria of IgG4-related Mikulicz’s disease
1. Symmetrical swelling of at least 2 pairs of lacrimal, parotid, or submandibular glands for at least 3 months
2. Elevated serum IgG4 (>135 mg/dl)
3. Histopathological features including lymphocyte and IgG4 + plasma cell infiltration (IgG4 + plasma cells/IgG + plasma cells >50 %) with typical tissue fibrosis or sclerosis
Differential diagnosis between IgG4-related Mikulicz’s disease (IgG4-DS) and Sjögren’s syndrome (SS)
IgG4-related Mikulicz’s disease
Male = Female?
Female ≫ Male
Lower frequency of apoptosis
Apoptosis of acinar/ductal
Serum IgG4 (>135 mg/dl)
Positive 70 %
There are several marked symptomatic differences between IgG4-DS and SS, such as IgG4-DS being characterized by bilateral salivary gland/lacrimal gland swelling without tenderness, while SS tends to show unilateral involvement. Sicca is modest in IgG4-DS. In regard to the sex distribution, SS tends to occur predominantly in females, whereas no gender difference in incidence has been reported in patients with IgG4-DS .
Histopathologically, IgG4-DS had been believed to be a subgroup of SS based on histopathologic similarities between the two entities, such as degeneration and disappearance of the glandular acini due to severe mononuclear cell infiltration, proliferation of the ductal epithelial cells and duct stenosis, formation of myoepithelial islands, and cystic dilatation of the peripheral ducts . However, it has been confirmed that these histopathological features can only be detected in SS, and not in IgG4-DS . The most remarkable difference between IgG4-DS and SS is the marked infiltration of the affected organs by IgG4-bearing plasma cells, with the percentage of IgG4-positive cells relative to the total IgG cell population being characteristically more than 40 % in IgG4-DS [2, 15]. On the other hand, infiltration of the salivary glands by IgG4-bearing plasma cells is almost not noted in SS. In the diagnosis of IgG4-DS, the IgG4+/IgG + plasma cell ratio, whose cutoff value is organ-dependent, is reported as a more powerful tool than the total IgG4+ plasma cell count, which is useful for establishing the diagnosis of IgG4-RD . In addition, apoptosis of the acinar and/or duct cells is reported to be frequent and extensive in SS, but not in IgG4-DS . It might be said that the inflammatory reaction is more potent and irreversible in SS than in IgG4-DS.
In regard to the clinical features, symmetric and persistent swelling of more than two of the lacrimal and major salivary glands is seen in IgG4-DS. Most importantly, parotid gland is the major organ affected in SS, while lacrimal and submandibular glands tend to be mainly involved in IgG4-DS. The swelling is short-lived, usually resolving in about a week in IgG4-DS .
In regard to the gland function, salivary secretion is severely impaired in SS, while salivary gland function is either normal or only slightly disturbed in IgG4-DS, and the function can usually be improved by CST therapy . Serologically, strongly positive results for anti-SSA/Ro and anti-SSB/La antibodies are obtained in patients with SS, but not in those with IgG4-DS . Not only serum IgG4 but also serum total IgG, IgG2, and IgE concentrations are significantly elevated in IgG4 + MOLPS (multiorgan lymphoproliferative syndrome), now accepted as being equivalent to IgG4-RD which includes IgG4-DS, as compared to SS .
Regarding therapy, IgG4-DS is mainly treated with CST and resolution of the gland manifestations is immediately obtained; however, CST therapy is not as effective in most patients of SS as in those with IgG4-DS. However, the relapse rate of IgG4-DS is high as also well-recognized in cases of IgG4-RD.
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Differences Between IgG4-Mikulicz’s Disease and IgG4-Küttner Tumor Based on Our Case Series
IgG4-related sialadenitis is observed in IgG4-DS and IgG4-related Küttner tumor (IgG4-KT; gland swelling is noted only in the submandibular glands; IgG4-related submandibular disease) . Because sialadenitis is a common manifestation in both IgG4-MD and IgG4-KT, as in IgG4-RD, it is said to be difficult to set a strict boundary between IgG4-MD and IgG4-KT . Histological evidence is needed to differentiate between these two clinical entities. Küttner tumor was first described in 1896 as a rarely occurring chronic inflammatory disorder of the salivary glands, most commonly the submandibular glands, manifesting as a palpable hard tumor; this condition is also referred to as unilateral sclerosing sialadenitis . As the differential diagnosis between IgG4-KT and neoplasm is difficult, the entity came to be referred to as KT. Prior to proposition of the concept of IgG4-RD, a significant proportion of cases may have been diagnosed as KT . As KT has also been recognized to result from stones in the Wharton duct , it has been classified into classical KT and IgG4-KT. Geyer JT clarified the histopathologic differences between classical KT and IgG4-KT . Tiemann et al. revealed a monoclonal cytotoxic T-cell population in the affected salivary glands , which suggested that in such cases, KT is IgG4-RD. Takano revealed serologic and histopathologic differences between IgG4-DS and IgG4-KT, such as the mean IgG4 concentration was significantly higher in IgG4-DS than in IgG4-KT . It may be said that the disease activity in IgG4-KT is less than that in IgG4-DS. We diagnosed IgG4-KT based on findings such as persistent bilateral swelling of only the submandibular glands detectable by computed tomography and/or FDG-PET, abundant IgG4-bearing plasma cell infiltration with fibrosis in the submandibular glands on histopathologic examination, and elevated serum IgG4 concentrations (>135 mg/dl) on serological testing (Figs. 16.3 and 16.4).
Submandibular gland biopsy specimen showed dense lymphoplasmacytic infiltration with fibrosis
IgG4-bearing plasma cell infiltrations were noted in biopsy specimen of the submandibular gland
In order to clarify the differences, we retrospectively studied 13 patients with IgG4-KT and 10 patients with IgG4-DS, the patient characteristics illustrated in Table 16.3. All of the patients had been admitted to the Department of Gastroenterology of our hospital; therefore, we could not include IgG4-KT cases without associated AIP, which was a limitation of our study. There were no differences between the two conditions in the mean age at onset, gender ratio, serum IgG level, serum IgG4 level, presence/absence of jaundice, presence/absence of diffuse pancreatic swelling, other organ involvement, relapse, and cancer development. However, IgG4-DS tended to precede the AIP, and in many cases, IgG4-KT was accidentally detected on PET-CT performed during the course of AIP. Diffuse pancreatic swelling tended to be recognized more frequently in patients with IgG4-DS than in patients with IgG4-KT. However, other organ involvement was detected more frequently in IgG4-KT than in IgG4-DS. It could also be said that the inflammation is more aggressive in IgG4-MD than in IgG4-KT. Regarding treatment, IgG4-KT is also treated with CST.
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