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BMJ Case Rep. 2010; 2010: bcr10.2009.2412.
Published online 2010 March 26. doi:  10.1136/bcr.10.2009.2412
PMCID: PMC3028012
Findings that shed new light on the possible pathogenesis of a disease or an adverse effect

A new category for chronic sclerosing sialadenitis as an IgG4 related syndrome

Abstract

This report presents three cases of IgG4 related sclerosing disease complicated with chronic sclerosing sialadenitis. The clinical, radiographic and pathologic findings later suggested that the patients had chronic sclerosing sialadenitis. The submandibular gland tumour regressed in two patients. These patients were suspected to have Mikulicz’s disease or Sjögren’s syndrome, but the diagnostic criteria were not satisfied. The workup for chronic sclerosing sialadenitis revealed a significantly elevated value of serum IgG4. The patient was then diagnosed with IgG4 related sclerosing disease complicated with chronic sclerosing sialadenitis. After administering prednisolone to these patients, the serum IgG4 values decreased after 4 weeks. The current cases may represent a new category for Mikulicz’s disease or Sjögren’s syndrome as an IgG4 related sclerosing disease.

Background

Case of IgG4 related sclerosing disease complicated with sclerosing cholangitis (SC), idiopathic retroperitoneal fibrosis (IRF), and orbital pseudotumour (OPT) was previously reported in this journal.1 This disease, complicated with chronic sclerosing sialadenitis,2,3 autoimmune pancreatitis (AIP),49 SC,1012 abdominal aortic aneurysm,13,14 OPT,15 interstitial lung disease,16 IRF and exhibiting high serum IgG4 values has recently attracted attention, but the findings have been insufficient.17 This report presents three cases of immunoglobulin (Ig) G4 related sclerosing disease complicated with chronic sclerosing sialadenitis.

Case presentation

Case 1

The patient was a 71-year-old woman. During follow-up observations for hypercholesterolaemia, the patient became aware of a dry mouth starting in March 2008. Blood tests revealed hepatic dysfunction, with an aspartate aminotransferase (AST) value of 71 IU/l (normal <32 IU/l) and an alanine aminotransferase (ALT) value of 60 IU/l (normal <34 IU/l). Various virus markers were negative while antinuclear antibodies were positive. Sjögren’s syndrome (SS) was suspected and both anti-SS-A antibodies and anti-SS-B antibodies were negative. Salivary gland scintigraphy was performed using technetium-99m pertechnetate (TPT) and revealed that the left parotid gland failed to adequately secrete TPT. The submandibular gland time/activity graph demonstrated normal uptake of TPT with normal secretion of the radioisotope at the 18 min mark (fig 1). A liver needle biopsy sample showed non-specific findings.

Figure 1
Salivary gland scintigraphy using technetium-99m pertechnetate (TPT) shows that the left parotid gland failed to adequately secrete TPT. The submandibular gland time/activity graph demonstrates normal uptake of TPT with normal secretion of the radioisotope ...

The clinical and radiographic findings suggested that it was chronic sclerosing sialadenitis complicated with non-specific liver injury. The serum IgG4 value was found to be significantly elevated. The IgG subclass was measured based on the high IgG concentration of 2280 mg/dl, resulting in a G1 value of 945 mg/dl (normal: 320–748), an IgG2 value of 1300 mg/dl (208–754), an IgG3 value of 31.0 mg/dl (6.6–88.3), and an IgG4 value of 135 mg/dl (4.8–105). Therefore, the patient was diagnosed with IgG4 related sclerosing disease complicated with chronic sclerosing sialadenitis. Prednisolone administration was initiated. The serum IgG and IgG4 values decreased dramatically. Laboratory data on 18 September 2008 showed an IgG4 concentration of 54 mg/dl. However, pilocarpine hydrochloride was not effective in this case, and her dry mouth continued.

Case 2

The patient was a 67-year-old man. This individual presented for hydrocele testis and lower thigh oedema in April 2007. After an additional workup, abdominal computed tomography (CT) revealed a hydrocele of the testis (fig 2a), and hydronephrosis (fig 2b). In addition, a soft tissue density mass was recognised in the tissue surrounding one of the lower lumbar vertebrae (fig 2c). The patient was diagnosed with idiopathic retroperitoneal fibrosis (IRF), and the symptoms disappeared after prednisolone administration. After 8 weeks, the patient had stopped the oral administration of prednisolone by a self-judgment. Subsequently, a bilateral submandibular swelling was discovered in March 2008 (right: 4×4 cm; left: 2×2 cm) (fig 3a, b) and the right submandibular gland was excised (fig 3c). Histopathology revealed chronic sclerosing sialadenitis (fig 4a). The patient presented again in April with further swelling of the left submandibular gland (fig 5a). A left submandibular tumour excision was also scheduled, and the patient was examined at our clinic in May. The clinical, radiographic and pathological findings suggested IgG4 related syndrome complicated with chronic sclerosing sialadenitis and IRF. The IgG subclass showed a high IgG value of 1734 mg/dl, resulting in a G1 value of 1550 mg/dl, an IgG2 value of 229 mg/dl, an IgG3 value of 10.5 mg/dl, and an IgG4 value of 461 mg/dl, leading to a diagnosis of IgG4 related sclerosing disease complicated with IRF and chronic sclerosing sialadenitis. The left submandibular tumour excision was subsequently cancelled. After prednisolone administration, the serum IgG4 value decreased while the submandibular tumour regressed and diminished after 4 weeks (fig 5b). The excised specimen showed abundant IgG4 positive plasma cell infiltration (fig 4b; immunohistochemical staining for IgG4).

Figure 2
Abdominal computed tomography (CT) revealed a hydrocele of a testis (a), and left hydronephrosis (b). In addition, a soft tissue density mass was recognised in the tissue surrounding one of the lower lumbar vertebrae (c) (arrows).
Figure 3
A bilateral submandibular swelling was discovered in March 2008 (right: 4×4 cm; left: 2×2 cm) (a). Neck CT revealed swelling of bilateral submandibular glands (b). The right submandibular gland was excised (c).
Figure 4
Histopathology revealed chronic sclerosing sialadenitis (a; haematoxylin and eosin (H&E) staining). The excised specimen showed abundant IgG4 positive plasma cell infiltration (b; immunohistochemical staining for IgG4).
Figure 5
The patient presented again in April with further swelling of the left submandibular gland (a) (arrows). After prednisolone administration, the submandibular tumour regressed and diminished after 4 weeks (b) (arrows).

Case 3

The patient was a 76-year-old man. Swelling of the left submandibular gland (3×3 cm) was discovered and the left submandibular gland was excised in February 2009. The histopathological examination of the excised specimen showed chronic sclerosing sialadenitis (fig 6). The patient presented again in May with further swelling of the right submandibular gland (fig 7a, b).

Figure 6
Histopathological examination of the excised specimen showed a considerable degree of acinar cell loss, residual intralobular ducts, lymphocytic infiltrate and pronounced fibrosis. (a; H&E staining), and moderate mononuclear inflammatory infiltrates ...
Figure 7
The patient presented again in May with further swelling of the right submandibular gland (a, b). The submandibular gland tumour regressed and diminished after 4 weeks just as in case 2 (c).

Salivary gland scintigraphy revealed that the bilateral parotid glands and right submandibular gland failed to adequately secrete TPT (fig 8).

Figure 8
Salivary gland scintigraphy revealed that the bilateral parotid glands and right submandibular gland failed to adequately secrete technetium-99m pertechnetate (TPT).

A diagnosis of IgG4 related sclerosing disease complicated with chronic sclerosing sialadenitis was made based on the high IgG value of 2800 mg/dl; the IgG subclass was measured with an IgG4 value of 761 mg/dl. After steroid administration instead of a right submandibular gland tumour excision, the serum IgG4 value decreased while the submandibular gland tumour regressed and diminished after 4 weeks just as in case 2 (fig 7c).

Investigations

These patients were suspected to have Mikulicz’s disease or Sjögren’s syndrome, but the diagnostic criteria were not satisfied. The workup for chronic sclerosing sialadenitis revealed a significantly elevated value of serum IgG4. The patient was then diagnosed with IgG4 related sclerosing disease complicated with chronic sclerosing sialadenitis. After prednisolone administration in these cases, the serum IgG4 values decreased after 4 weeks. The current cases may represent a new category for Mikulicz’s disease or Sjögren’s syndrome as an IgG4 related sclerosing disease.

Differential diagnosis

  • Mikulicz’s disease
  • Sjögren’s syndrome
  • Kuttner tumour
  • Chronic sclerosing sialadenitis.

Treatment

Prednisolone administration instead of a submandibular gland tumour excision.

Outcome and follow-up

A diagnosis of IgG4 related sclerosing disease complicated with chronic sclerosing sialadenitis was made based on the high IgG4 value. After prednisolone administration instead of a submandibular gland tumour excision, the serum IgG4 value decreased while the submandibular gland tumour regressed and diminished after 4 weeks. A strict follow-up of blood IgG4 is recommended in such cases.

Discussion

Mikulicz’s disease (MD) is thought to be a manifestation of Sjögren’s syndrome (SS). The patients presented here were originally thought to have MD, SS, or Kuttner tumour. However, the diagnostic criteria were not satisfied. In addition, two of these patients showed a unilateral submandibular gland tumour mass, which was excised. It is difficult to obtain a needle biopsy from a submandibular tumour mass, in contrast to tumour masses in other organs. In addition, a malignant disease cannot be ruled out because the mass is unilateral, often leaving no choice other than excision. IgG4 related sclerosing disease occurs relatively often among cases of submandibular gland excision and suspected cases of SS (wherein the diagnostic criteria are not satisfied).1820

If a high serum IgG4 value is observed, it is possible to reduce the tumour mass without performing a resection through the administration of steroids. The serum IgG4 value should be measured in patients with lesions such as fibrosis in an organ, and the patient should be managed in close cooperation with each department as well as cooperation between clinics and hospitals.

The swollen salivary glands disappeared and the serum IgG and IgG4 values decreased dramatically following steroid treatment. These cases of IgG4 related sclerosing disease or hyper-IgG4 disease21 appear to belong to the category of either multifocal fibrosclerosis, systemic idiopathic fibrosis, or fibrotic overlap syndrome.2224

No consensus has been reached regarding the definition of IgG4 related sclerosing disease. Recently, Masaki et al proposed a new clinical entity, IgG4 positive multiorgan lymphoproliferative syndrome (MOLPS), based on the clinical features and good response to steroids. Their preliminary diagnostic criteria include increased serum values of IgG4 (>135 mg/dl) and infiltration of IgG4 (+) plasma cells in the tissue (IgG4+/IgG+ plasma cells >50%) with fibrosis or sclerosis.25

The current cases may represent a new category of Japanese patients with IgG4 related sclerosing disease complicated by fibrotic changes in the organs. This may be a variation of IgG4 related sclerosing disease known as hyper-IgG4 disease, or IgG4 positive MOLPS. Larger studies are needed to elucidate the exact mechanism and clinical characteristics of this disorder.

Learning points

In a case of chronic sclerosing sialadenitis with a high IgG value:

  • it would be prudent to measure blood IgG4 value
  • if the value is elevated, careful observation needs to exercised for the development of idiopathic retroperitoneal fibrosis, and/or fibrotic changes in the organs
  • a strict follow-up is recommended in such cases.

Footnotes

Competing interests: None.

Patient consent: Patient/guardian consent was obtained for publication.

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