Abstract
The present case study reports contrast-enhanced magnetic resonance findings in three patients with histopathologically proven IgG4-related chronic sclerosing sialadenitis of the submandibular gland. All three patients presented with painless swelling of the submandibular region. The contrast-enhanced T1-weighted images showed reticular enhancement of the swollen submandibular gland. Radiological–pathological correlation revealed that the characteristic reticular enhancement corresponded to fibrosis and to inflammatory cell infiltration in the interlobular septa and in the periductal region of the submandibular gland.
Keywords: IgG4-related chronic sclerosing sialadenitis, submandibular gland, magnetic resonance imaging, reticular enhancement
Introduction
Chronic sclerosing sialadenitis is a relatively rare disorder causing salivary gland enlargement. This condition is characterized by chronic inflammation of the salivary glands and is recognized as a manifestation of immunoglobulin G4 (IgG4)-related disease. The characteristic histological findings include fibrosis and lymphoplasmacytic infiltration in the interlobular connective tissue stroma and in the periductal region of the submandibular gland. Based on the histological findings, several reports have suggested that reticular hyperechoic structure on ultrasonographic images1–3 and reticular hypodense structure on contrast-enhanced computed tomography (CT) images 4 of the submandibular gland are characteristic of IgG4-related chronic sclerosing sialadenitis. However, to the best of our knowledge, no study has reported the reticular structure of the submandibular gland on magnetic resonance (MR) images. Therefore, we report three cases of pathologically diagnosed IgG4-related chronic sclerosing sialadenitis, in which the reticular enhancement of the submandibular gland was observed on contrast-enhanced MR images.
Case report
Case 1
A 71-year-old man presented with a left submandibular swelling for 10 days. Physical examination revealed swelling and induration of the left submandibular gland that were unrelated to diet. Serum IgG4 level was 994 mg/dl. Within the slightly enlarged left submandibular gland, reticular hyperintense structure on coronal fat-suppressed T2-weighted images (Figure 1(a)) and reticular enhancement on coronal fat-suppressed contrast-enhanced T1-weighted images (Figure 1(b)) were observed. Transverse dynamic contrast-enhanced T1-weighted images taken 60 s after bolus administration of the contrast agent showed reticular hypointense structure (Figure 1(c)). Core needle biopsy of the left submandibular gland was performed. Histopathological examination demonstrated marked acinar atrophy with periductal severe fibrosis and plasma cell infiltration. Hyperchromasia of immunostaining for IgG4 did not allow us to count the number of IgG4-positive plasma cells. Although the lacrimal glands, other salivary glands, and pancreas were normal, whole-body CT examination revealed a right-sided thoracic paravertebral soft-tissue mass, which is characteristic of IgG4-related disease. 5
Figure 1.
A 71-year-old man with IgG4-related chronic sclerosing sialadenitis. (a) Coronal fat-suppressed T2-weighted image shows slight enlargement of the left submandibular gland (arrow) with reticular hyperintense structure (arrowheads); (b) coronal fat-suppressed contrast-enhanced T1-weighted image shows reticular enhancement (arrowheads); (c) transverse dynamic contrast-enhanced T1-weighted image taken 60 s after bolus administration of the contrast agent shows reticular hypointense structure (arrowheads).
Case 2
A 76-year-old woman presented with an enlarged left submandibular gland for a month. Physical examination revealed an elastic, firm, and painless mass in the left submandibular region. Serum IgG4 level was 62 mg/dl. Coronal fat-suppressed T2-weighted images revealed diffuse hyperintensity of the lower pole of the left submandibular gland with reticular hyperintense structure (Figure 2(a)). Furthermore, coronal fat-suppressed contrast-enhanced T1-weighted images demonstrated slightly diffuse enhancement with reticular enhancement (Figure 2(b)). Surgical excision of the left submandibular gland revealed severe fibrosis with infiltration of IgG4-positive plasma cells, predominantly in the interlobular septa and periductal region (Figure 2(c) and (d)). Loss of acini and obliterative phlebitis were also observed. Immunostaining for IgG4 showed that the ratio of IgG4-positive plasma cells/IgG-positive plasma cells was higher than 50%. As a result of whole-body CT screening, the involvement of other organ systems associated with IgG4-related disease was not confirmed.
Figure 2.
A 76-year-old woman with IgG4-related chronic sclerosing sialadenitis. (a) Coronal fat-suppressed T2-weighted image shows diffuse hyperintensity of the lower pole of the left submandibular gland (arrow) with reticular hyperintense structure (arrowheads); (b) coronal fat-suppressed contrast-enhanced T1-weighted image shows slightly diffuse enhancement with reticular enhancement (arrowheads); (c) gross specimen reveals white-colored reticular structure, which indicates fibrosis, along the interlobular stroma; (d) histological specimen shows fibrosis and inflammatory cell infiltration in the interlobular septa and periductal region (arrows).
Case 3
A 58-year-old woman presented with a slowly increasing painless enlargement of the right submandibular gland. Serum IgG4 level was 909 mg/dl. Transverse T2-weighted images showed a marked enlargement and slightly increased signal intensity of the right submandibular gland with a focal hypointense area (Figure 3(a)). In addition, transverse fat-suppressed contrast-enhanced T1-weighted images revealed moderately diffuse enhancement with reticular enhancement (Figure 3(b)). Partial resection of the right submandibular gland verified the manifestation of severe acinar atrophy, inflammatory cell infiltration, mainly composed of IgG4-positive plasma cells in the periductal region, and severe fibrosis within and between the lobules. Immunostaining for IgG4 showed that the ratio of IgG4-positive plasma cells/IgG-positive plasma cells was higher than 50%. The swelling of the lacrimal glands and other salivary glands were not confirmed, but autoimmune pancreatitis was diagnosed by abdominal CT and MR examinations.
Figure 3.
A 58-year-old woman with IgG4-related chronic sclerosing sialadenitis. (a) Transverse T2-weighted image shows a marked enlargement and slightly increased signal intensity of the right submandibular gland (arrow) with a focal hypointense area (arrowhead); (b) transverse fat-suppressed contrast-enhanced T1-weighted image shows moderately diffuse enhancement with reticular enhancement (arrowheads).
Discussion
The head and neck region is the second most commonly affected site in patients with IgG4-related disease, followed only by the pancreatobiliary system. IgG4-related chronic sclerosing sialadenitis most commonly affects the submandibular gland compared with any other salivary gland. Classical histological findings of IgG4-related chronic sclerosing sialadenitis include preserved lobular architecture, thickening of interlobular septa caused by sclerotic tissue, dense lymphoplasmacytic infiltration, preservation of ducts with periductal fibrosis, and variable loss of acini, which are associated with the presence of abundant IgG4-positive plasma cells. 6 Four progressive stages have been described: lymphocytic infiltration around the salivary ducts (stage 1); diffuse lymphocytic infiltration and severe periductal fibrosis (stage 2); prominent lymphocytic infiltration, parenchymal atrophy, and periductal sclerosis (stage 3); marked parenchymal loss and sclerosis (stage 4). 7
Until now, many researchers have reported radiological imaging findings of IgG4-related chronic sclerosing sialadenitis. Ultrasonographic imaging features include an enlargement of the submandibular gland with variously described intraglandular textures, such as multiple hypoechoic areas, reticular/nodal pattern, irregular netlike appearance, heterogeneous echotexture, and diffuse hypoechogenicity. 1 Among them, a reticular pattern and an irregular netlike appearance would reflect the characteristic histological findings of fibrosis and inflammatory cell infiltration in the interlobular septa and periductal region.
Alternatively, CT and MR imaging findings of IgG4-related chronic sclerosing sialadenitis are nonspecific because their respective spatial resolution is inferior compared to ultrasonographic imaging. Typical CT imaging findings include diffuse swelling of the submandibular gland with homogeneous attenuation.8,9 In contrast, MR imaging features include infiltrative growth pattern, or sometimes tumor-like mass, characterized by low to intermediate signal intensity on T2-weighted images, and intermediate signal intensity on T1-weighted images, with diffuse and homogeneous contrast enhancement. 8 Restricted diffusion with relatively low apparent diffusion coefficient values was observed on diffusion-weighted images. 10
Reticular enhancement on contrast-enhanced T1-weighted images and periductal interstitial fibrosis with inflammatory cell infiltration on histological examination were observed in our three cases. In this article, reticular enhancement means that the linear enhancing structures morphologically resembled septa and not vessels. Therefore, reticular enhancement must reflect fibrosis and inflammatory cell infiltration in the interlobular septa and periductal region of the submandibular gland. In addition, dynamic contrast-enhanced T1-weighted images taken 60 s following bolus administration of the contrast agent revealed a reticular hypointense structure in Case 3. This MR imaging finding corresponds to the previously reported reticular hypodense structure on contrast-enhanced CT images. 4 Due to the fact that a delayed enhancement pattern is generally observed in fibrotic tissue, fibrotic areas of the submandibular gland appear as relative hypodensity/hypointensity and relative hyperintensity in the early and in the delayed phase, respectively.
Sjögren's syndrome is a long-term autoimmune disease that affects the lacrimal and salivary glands, and often seriously affects other organ systems. On CT images, heterogeneity, abnormal diffuse fat tissue deposition, and diffuse punctate calcification are specific for Sjögren’s syndrome. 11 The characteristic histological features of Sjögren's syndrome include disruption of salivary gland epithelial cells. The acinar and ductal epithelial cells are implicated in autoimmune destruction as they attract immune cells by producing pro-inflammatory cytokines and chemokines. 12 In patients with Sjögren's syndrome, the dilatation of the ducts within salivary glands (sialectasis) usually occurs subsequent to the destruction of ductal epithelial cells. Typical ultrasonographic abnormalities in Sjögren's syndrome are hypoechogenic areas, hyperechogenic reflections, and poorly defined salivary gland borders. 13 Hypoechogenic areas are assumed to be caused by leakage of saliva which results from ductal destruction. Alternatively, Sjögren's syndrome does not show a reticular appearance at sonography and other imaging modalities; therefore, reticular enhancement on contrast-enhanced T1-weighted images would be useful for the differentiation between IgG4-related chronic sclerosing sialadenitis and Sjögren's syndrome.
In conclusion, reticular enhancement on contrast-enhanced T1-weighted images corresponded to fibrosis and inflammatory cell infiltration in the interlobular septa and periductal region of the submandibular gland. Therefore, it is useful for the diagnosis of IgG4-related chronic sclerosing sialadenitis of the submandibular gland. If IgG4-related chronic sclerosing sialadenitis of the submandibular gland is suspected before MR imaging, a delayed phase following the administration of the contrast material should be added in the MR imaging protocol to facilitate an accurate diagnosis.
Footnotes
Conflict of interest: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iDs
Hiroki Kato https://orcid.org/0000-0001-5926-1895
Masaya Kawaguchi https://orcid.org/0000-0002-2807-0524
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