- Email: [email protected]
Unilateral submandibular swelling
ORIGINAL CONTRIBUTIONS
DIAGNOSTIC CHALLENGE
Unilateral submandibular swelling Xin Lv, BDS; Yunhui Huang, DDS; Guangyan Yu, PhD; Yan Gao, PhD
694 JADA 146(9) http://jada.ada.org
THE CHALLENGE
A
60-year-old woman sought treatment at the Department of Oral Medicine at Peking University Hospital of Stomatology, Beijing, China. Her main symptom was a painless swelling of the left submandibular area that she had had for 2 months (Figure 1). Other symptoms included dry mouth and difficulty swallowing dry food. She did not complain of any other symptoms, such as fever, fatigue, reduced appetite, or weight loss. One year before visiting our department at a local hospital, the patient had undergone a partial thyroidectomy. Pathology results revealed a nodular adenomatoid hyperplasia and fibrosis of the thyroid. Shortly afterward, she began to complain of dry eyes and was diagnosed with xerophthalmia at a general hospital. She was not taking any medications and had no history of hypertension, diabetes mellitus, or other systemic disorders. Physical examination at admission revealed a diffuse, firm swelling of the left submandibular gland and an enlargement in the bilateral sublingual areas, which had a rubbery texture. There was no cervical lymphadenopathy. Her oral mucosa appeared moist, and her unstimulated whole salivary flow rate was measured as 2.0 milliliters for 10 minutes. Blood test results showed that her complete blood count was normal. Test results of serum proteins showed that the total immunoglobulin G (IgG) level in her serum was 21.73 grams per liter (normal range, 8.00-18.00 g/L), with elevated levels of serum IgG2 (6,460 milligrams per liter; normal range, 1,5006,400 mg/L), IgG4 (15,700 mg/L; normal range, 80-1,400 mg/L), and total immunoglobulin E (IgE) (322 kilounits per liter; normal range, 0-60 kU/L). The test results were all negative for antinuclear antibodies, anti-doublestranded DNA antibodies, and anti-extractable nuclear antigen antibodies including anti-Sjögren-syndrome–related antigen A (SSA) and anti–Sjögrensyndrome–related antigen B (SSB). We conducted a sialogram and computed tomography (CT) scan. The sialogram of the left submandibular gland displayed no punctate dilation or obstruction in the gland. The CT scan revealed swelling in the left submandibular gland (Figure 2) and bilateral lacrimal gland. The CT images also showed a round, hyperdense lesion (measuring 2 x 2 square centimeters), which was not apparent clinically, in the left parotid gland. Incisional biopsy results of the patient’s labial glands in the lower lip were nonspecific; however, histopathologic examination of biopsies from the patient’s left parotid and submandibular glands showed pronounced inflammation and fibrosis in both. The inflammatory infiltration consisted mainly of lymphocytes and plasmocytes, accompanied by lymph follicle formation with irregular germinal centers. We noted a storiform fibrosis, rich in fibroblasts, mainly in the interlobular connective tissues. We also observed a collagen sheath in the periductal areas (Figure 3). The inflammation and fibrosis resulted in glandular parenchyma atrophy, although the lobular contour was preserved. Immunohistochemical results revealed diffuse infiltration of IgG4-positive plasma cells (Figure 4) with a high ratio (that is, 80%) of IgG4-positive and IgG-positive plasma cells in both the parotid and submandibular glands.
September 2015
ORIGINAL CONTRIBUTIONS
Figure 1. Facial view of the swelling in the left submandibular region (arrow).
Figure 2. Computed tomography scan indicating swelling in the left submandibular gland (arrow).
Figure 3. Histologic examination of a specimen from the left submandibular gland biopsy, revealing pronounced inflammation (upper left arrow) and fibrosis (lower right arrow), with collagen sheath (upper right arrow) in the periductal areas (hematoxylin and eosin, original magnification x200).
Figure 4. Immunohistochemical examination of a specimen from the left submandibular gland biopsy, revealing abundant infiltration of immunoglobulin G4–positive plasma cells (arrow) (immunoglobulin G4 antibody, original magnification x200).
CAN YOU MAKE THE DIAGNOSIS? A. Sjögren syndrome B. sarcoidosis C. sialosis (sialadenosis)
D. immunoglobulin G4–related disease E. mucosa-associated lymphoid tissue lymphoma
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ORIGINAL CONTRIBUTIONS
THE DIAGNOSIS D. immunoglobulin G4–related disease A comprehensive review of the patient’s medical history and current clinical and laboratory results, as well as radiographic and histopathologic results, led us to a diagnosis of IgG4-related disease (IgG4RD). Recognized as a disorder in 2010, IgG4RD is characterized by a hyper-IgG4 globulinemia and IgG4-producing plasma cell expansion in the affected organs, with fibrotic and sclerotic changes.1 Investigators have reported that IgG4RD can involve multiple organs or tissues, including but not limited to the lacrimal glands, salivary glands, pancreas, and kidneys.2 Clinical symptoms of diffuse or localized swelling or masses (that is, tumorlike swellings in some cases) vary, depending on the organ being affected. Two major presentations of this condition are type 1 autoimmune pancreatitis (that is, IgG4-related pancreatitis) and salivary gland disease, in which a patient may have a salivary gland enlargement (formerly known as Mikulicz disease), or sclerosing sialadenitis (formerly known as Küttner tumor). These conditions often resemble Sjögren syndrome (SS) but are clinicopathologically distinct.3 A patient with sclerosing sialadenitis can have concurrent oral and skin lesions, with the oral lesions clinically resembling oral squamous cell carcinoma.4 Some patients may experience serious complications, such as obstruction or compression symptoms, owing to organomegaly or hypertrophy, and organ dysfunction caused by cellular infiltration or fibrosis.5 IgG4RD is a syndrome of unknown etiology. When examining a patient with IgG4RD, a clinician may see multiple sites of bilateral enlargement of major salivary glands and lacrimal glands. The diagnosis of IgG4RD primarily is made on the basis of the morphologic appearance on biopsy. The critical histopathologic features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis.6 IgG4-positive plasma cell infiltration and the ratio of IgG4-positive plasma cells to IgG-positive plasma cells greater than 40% are of secondary importance.1,6 Other relevant histopathologic features are phlebitis without obliteration of the lumen and increased numbers of eosinophils that are neither sensitive nor specific for the diagnosis of IgG4RD.6 Approximately 60% to 70% of patients have an elevated level of serum IgG4 (> 135 milligrams per deciliter).3 Autoimmune pancreatitis, retroperitoneal fibrosis, tubulointerstitial nephritis, autoimmune hypophysitis, Riedel thyroiditis, and other autoimmune sclerosing diseases may be concomitant diseases. Before making a final diagnosis, clinicians also should investigate and exclude other etiologic factors, such as SS, sarcoidosis, sialadenosis, Wegener granulo-
696 JADA 146(9) http://jada.ada.org
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matosis, lymphoma, and HIV-related salivary gland disorders.1 IgG4RD can be treated with glucocorticoids. Generally, for reducing symptoms and preventing recurrence, prednisolone is recommended if whole-body complications are absent (30-40 mg per day) or present (50-60 mg per day).7-9 Once the disease is controlled, a maintenance dose of prednisolone (5-10 mg per day) is recommended, although there is a 30% to 40% chance of relapse. Glucocorticoids should be stopped if remission continues and if the patient has been on a maintenance steroid dosage regimen for 3 years.1 Because our patient had no systemic complications, she initially received a prednisolone regimen of 40 mg per day. We tapered the dose by 5 mg every 2 weeks until the dose was 30 mg per day, then we reduced the dose by 2.5 mg every 2 weeks and finally to 5 mg per day. The patient showed significant improvement at this dose for 3 months; her symptoms declined and her level of serum IgG4 dropped to 3,250 mg/L. We recommended that she continue this therapeutic strategy and take prednisolone at 5 mg per day for 3 years with a follow-up examination every 3 months. DIFFERENTIAL DIAGNOSIS
SS. SS is a chronic autoimmune disease characterized by lymphocytic infiltration that creates destructive lesions in the exocrine glands, primarily in the salivary and lacrimal glands. As an autoimmune disease, SS is second to rheumatoid arthritis in occurrence, with approximately 1% of the population affected; it is found more commonly in middle-aged women than men, at a ratio of approximately 9:1.10 The most common symptoms of SS are extreme fatigue, dry eyes, and dry mouth; other possible symptoms include swelling of the salivary glands, sialorrhea, and tooth loss.11 Enlargement of the parotid or other major salivary glands occurs in twothirds of patients with SS. Dentists play a key role in diagnosing and treating patients with SS because they are often the first practitioners to detect the symptoms.12 The diagnosis of SS is based primarily on 3 criteria: decreased lacrimation and salivation, serologic evidence of SS antibodies, and a labial salivary gland biopsy. Biopsy results that suggest a diagnosis of SS reveal pathognomonic focal aggregates of lymphocytes and parenchymal atrophy.13 Biopsy results offer a good diagnostic value with an elevated specificity and a sensitivity ranging from 63.5% to 93.7%.14 However, investigators have reviewed the accuracy and diagnostic benefits of the labial salivary gland biopsy for SS with mixed findings.15
ORIGINAL CONTRIBUTIONS
It is important to differentiate IgG4RD from SS because of the different therapeutic strategies used, especially when SS involves only the salivary and lacrimal glands and exhibits different clinical features. Swelling of the glands may be remarkable, but secretory dysfunction is unobtrusive in patients with IgG4RD. Serologically, patients with IgG4RD lack anti-SSA and anti-SSB antibodies, whereas they have elevated serum IgG4 levels. In addition, rates of allergic rhinitis and bronchial asthma, serum IgE concentrations, and eosinophil counts among white blood cells are higher in IgG4RD than in SS.1,16 Demographically, there is a higher prevalence of IgG4RD in men than women. Sarcoidosis. Sarcoidosis is a chronic systemic disorder of unknown etiology characterized by affected organs, an accumulation of epithelioid granulomas without caseation or staining for infectious agents, and derangement of tissue architecture.17 Sarcoidosis can affect multiple organs, especially the lungs, lymph nodes, skin, and eyes. Frequently the salivary glands are involved, and in some cases, xerostomia or bilateral parotid swelling is present.18,19 The salivary glands tend to be firm and slightly painful to touch, but they do not fluctuate in size during eating. Bilateral hilar lymphadenopathy is the classic finding on a patient’s chest radiograph. A serologic examination also may reveal anemia or other cellline deficiencies, elevated liver enzymes, hypercalciuria, and electrocardiogram abnormalities. The angiotensinconverting enzyme levels may be elevated, but this observation is not diagnostic. Histopathologic confirmation of noncaseating epithelioid cell granulomas is essential for diagnosis.13,20,21 Sialosis (sialadenosis). Sialosis is defined as an asymptomatic, noninflammatory, and nonneoplastic parenchymal salivary gland disease accompanied by a persistent, painless, and bilateral swelling of the salivary glands, commonly involving the parotid glands. There is no predilection of this condition by sex, and the peak occurrence is between 30 and 70 years of age.22 Sialosis has 2 origins: diabetes mellitus type 2 and chronic alcoholism. Sialosis of both etiologies is accompanied by xerostomia, or a sensation of dry mouth, with a decrease in the salivary flow.23 Histopathologic reports typically reveal a fatty infiltration of parenchyme with a decrease in the number of the acini structures and acinar hypertrophy.23 On a CT scan, a normal gland shows multiple irregular areas of hypodensity, reflecting the gland’s fatty content. For patients with alcoholic sialosis, clinicians must direct treatment at the dire aspect of the problem—liver damage. Medical care and alcohol abstinence can be expected to result in some decrease in any existing liver disease and mitigation of the parotid swellings, but the long-term prognosis varies.24 Caring for a patient’s diabetic condition will result in only a minimal improvement in gland size. Surgical reduction rarely is warranted. The known
benign course of this disease mandates a conservative “no-treatment” option, tinctured with a dose of reassurance for the patient.12 Mucosa-associated lymphoid tissue (MALT) lymphoma. Investigators have defined mucosaassociated lymphoid tissue lymphoma, a hematolymphoid malignancy, as nonencapsulated clusters of lymphocytes found throughout the mucosal tissue of the aerodigestive tract.25 MALT lymphoma is a distinct subtype of non-Hodgkin lymphoma and is described as a localized low-grade neoplasm that exhibits an indolent clinical course. MALT lymphomas arise in various extranodal sites and frequently are found in the gastrointestinal tract. Other autoimmune diseases, such as lymphoid interstitial pneumonitis, Hashimoto thyroiditis, and SS, also are associated with the development of MALT lymphoma.26-28 MALT lymphoma of the salivary glands is a rare disease found more often in women than men. Involvment of paired organs (for example, bilateral eyes or multiple salivary glands) is a common feature of MALT lymphoma. Treatment of MALT lymphoma includes but is not limited to surgery, radiation therapy, or a combination of both.28,29 CONCLUSION
IgG4RD is a syndrome of unknown etiology first recognized in 2010. Localized swelling is the most common sign of this disorder. To facilitate a better understanding of IgG4RD, we described a case with typical clinical and pathologic characteristics. However, the diagnosis of this disorder can be confused with the diagnoses of SS, sarcoidosis, sialadenosis, and MALT lymphoma. Clinicians should complete a comprehensive review of the patient’s medical history and clinical and histopathologic results along with the results of laboratory examinations to make a definitive diagnosis. n http://dx.doi.org/10.1016/j.adaj.2015.05.019 Copyright ª 2015 American Dental Association. All rights reserved.
Dr. Lv is a PhD candidate, Department of Oral Medicine, Peking University Hospital of Stomatology, Beijing, China. Dr. Huang is a resident, Department of Oral Medicine, Peking University Hospital of Stomatology, Beijing, China. Dr. Yu is a professor, Department of Oral and Maxillofacial Surgery, Peking University Hospital of Stomatology, Beijing, China. Dr. Gao is a professor, Department of Oral Pathology, Peking University Hospital of Stomatology, No. 22, Zhongguancun South St., Haidian District, 100081, Beijing, China, e-mail [email protected]. Address correspondence to Dr. Gao. Disclosure. None of the authors reported any disclosures. Diagnostic Challenge is published in collaboration with the American Academy of Oral and Maxillofacial Pathology and the American Academy of Oral Medicine. 1. Masaki Y, Kurose N, Umehara H. IgG4-related disease: a novel lymphoproliferative disorder discovered and established in Japan in the 21st century. J Clin Exp Hematop. 2011;51(1):13-20.
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ORIGINAL CONTRIBUTIONS
2. Sugiyama T, Jinbu Y, Matsumoto K, Itoh H, Noguchi T, Kusama M. Relapsed IgG4-related dacryoadenitis and sialoadenitis, so called Mikulicz’s disease: a case report. J Oral Maxillofac Surg Med Pathol. 2013;25(4):368-373. 3. Moutsopoulos HM, Fragoulis GE, Stone JH. Overview of IgG4-related disease. UpToDate. Available at: www.uptodate.com/contents/overviewof-igg4-related-disease. Accessed May 31, 2015. 4. Khurram SA, Fernando M, Smith AT, Hunter KD. IgG4-related sclerosing disease clinically mimicking oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;115(2):e48-e51. 5. Okazaki K, Umehara H. Are classification criteria for IgG4-RD now possible? The concept of IgG4-related disease and proposal of comprehensive diagnostic criteria in Japan. Int J Rheumatol. 2012; 2012:357071. 6. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25(9):1181-1192. 7. Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012; 22(1):21-30. 8. Yamamoto M, Nishimoto N, Tabeya T, et al. Usefulness of measuring serum IgG4 level as diagnostic and treatment marker in IgG4-related disease [in Japanese]. Nihon Rinsho Meneki Gakkai Kaishi. 2012;35(1): 30-37. 9. Kamisawa T, Shimosegawa T, Okazaki K, et al. Standard steroid treatment for autoimmune pancreatitis. Gut. 2009;58(11):1504-1507. 10. Hammi AR, Al-Hashimi IH, Nunn ME, Zipp M. Assessment of SS-A and SS-B in parotid saliva of patients with Sjogren’s syndrome. J Oral Pathol Med. 2005;34(4):198-203. 11. Mignogna MD, Fedele S, Russo LL, Muzio LL, Wolff A. Sjögren’s syndrome: the diagnostic potential of early oral manifestations preceding hyposalivation/xerostomia. J Oral Pathol Med. 2005;34(1):1-6. 12. Mathews SA, Kurien BT, Scofield RH. Oral manifestations of Sjogren’s syndrome. J Dent Res. 2008;87(4):308-318. 13. Mandel L, Khelemsky R. Asymptomatic bilateral facial swelling. JADA. 2012;143(11):1205-1208. 14. Guellec D, Cornec D, Jousse-Joulin S, et al. Diagnostic value of labial minor salivary gland biopsy for Sjogren’s syndrome: a systematic review. Autoimmun Rev. 2013;12(3):416-420. 15. Stewart CM, Bhattacharyya I, Berg K, et al. Labial salivary gland biopsies in Sjogren’s syndrome: still the gold standard? Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;106(3):392-402.
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16. Himi T, Takano K, Yamamoto M, Naishiro Y, Takahashi H. A novel concept of Mikulicz’s disease as IgG4-related disease. Auris Nasus Larynx. 2012;39(1):9-17. 17. Iannuzzi MC, Fontana JR. Sarcoidosis: clinical presentation, immunopathogenesis, and therapeutics. JAMA. 2011;305(4):391-399. 18. Piattelli A, Favia GF, Di Alberti L. Oral ulceration as a presenting sign of unknown sarcoidosis mimicking a tumour: report of 2 cases. Oral Oncol. 1998;34(5):427-430. 19. Batal H, Chou LL, Cottrell DA. Sarcoidosis: medical and dental implications. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;88(4): 386-390. 20. Kobak S, Sever F, Sivrikoz ON, Orman M. Sarcoidois: is it only a mimicker of primary rheumatic disease? A single center experience. Ther Adv Musculoskelet Dis. 2014;6(1):3-7. 21. Heinle R, Chang C. Diagnostic criteria for sarcoidosis. Autoimmun Rev. 2014;13(4-5):383-387. 22. Kim D, Uy C, Mandel L. Sialosis of unknown origin. N Y State Dent J. 1998;64(7):38-40. 23. Merlo C, Bohl L, Carda C. Gomez de Ferraris ME, Carranza M. Parotid sialosis: morphometrical analysis of the glandular parenchyme and stroma among diabetic and alcoholic patients. J Oral Pathol Med. 2010; 39(1):10-15. 24. Mandel L, Vakkas J, Saqi A. Alcoholic (beer) sialosis. J Oral Maxillofac Surg. 2005;63(3):402-405. 25. Konofaos P, Spartalis E, Katsaronis P, Kouraklis G. Primary parotid gland lymphoma: a case report. J Med Case Rep. 2011;5:380. 26. Ciccone E, Truini M, Grossi CE. Lymphoid complement of the human salivary glands: function and pathology. Eur J Morphol. 1998;36(suppl):252-256. 27. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011;117(19):5019-5032. 28. Vazquez A, Khan MN, Sanghvi S, et al. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue of the salivary glands: a population-based study from 1994 to 2009. Head Neck. 2015; 37(1):18-22. 29. Anacak Y, Miller RC, Constantinou N, et al. Primary mucosaassociated lymphoid tissue lymphoma of the salivary glands: a multicenter Rare Cancer Network study. Int J Radiat Oncol Biol Phys. 2012; 82(1):315-320.
DIAGNOSTIC CHALLENGE
Unilateral submandibular swelling Xin Lv, BDS; Yunhui Huang, DDS; Guangyan Yu, PhD; Yan Gao, PhD
694 JADA 146(9) http://jada.ada.org
THE CHALLENGE
A
60-year-old woman sought treatment at the Department of Oral Medicine at Peking University Hospital of Stomatology, Beijing, China. Her main symptom was a painless swelling of the left submandibular area that she had had for 2 months (Figure 1). Other symptoms included dry mouth and difficulty swallowing dry food. She did not complain of any other symptoms, such as fever, fatigue, reduced appetite, or weight loss. One year before visiting our department at a local hospital, the patient had undergone a partial thyroidectomy. Pathology results revealed a nodular adenomatoid hyperplasia and fibrosis of the thyroid. Shortly afterward, she began to complain of dry eyes and was diagnosed with xerophthalmia at a general hospital. She was not taking any medications and had no history of hypertension, diabetes mellitus, or other systemic disorders. Physical examination at admission revealed a diffuse, firm swelling of the left submandibular gland and an enlargement in the bilateral sublingual areas, which had a rubbery texture. There was no cervical lymphadenopathy. Her oral mucosa appeared moist, and her unstimulated whole salivary flow rate was measured as 2.0 milliliters for 10 minutes. Blood test results showed that her complete blood count was normal. Test results of serum proteins showed that the total immunoglobulin G (IgG) level in her serum was 21.73 grams per liter (normal range, 8.00-18.00 g/L), with elevated levels of serum IgG2 (6,460 milligrams per liter; normal range, 1,5006,400 mg/L), IgG4 (15,700 mg/L; normal range, 80-1,400 mg/L), and total immunoglobulin E (IgE) (322 kilounits per liter; normal range, 0-60 kU/L). The test results were all negative for antinuclear antibodies, anti-doublestranded DNA antibodies, and anti-extractable nuclear antigen antibodies including anti-Sjögren-syndrome–related antigen A (SSA) and anti–Sjögrensyndrome–related antigen B (SSB). We conducted a sialogram and computed tomography (CT) scan. The sialogram of the left submandibular gland displayed no punctate dilation or obstruction in the gland. The CT scan revealed swelling in the left submandibular gland (Figure 2) and bilateral lacrimal gland. The CT images also showed a round, hyperdense lesion (measuring 2 x 2 square centimeters), which was not apparent clinically, in the left parotid gland. Incisional biopsy results of the patient’s labial glands in the lower lip were nonspecific; however, histopathologic examination of biopsies from the patient’s left parotid and submandibular glands showed pronounced inflammation and fibrosis in both. The inflammatory infiltration consisted mainly of lymphocytes and plasmocytes, accompanied by lymph follicle formation with irregular germinal centers. We noted a storiform fibrosis, rich in fibroblasts, mainly in the interlobular connective tissues. We also observed a collagen sheath in the periductal areas (Figure 3). The inflammation and fibrosis resulted in glandular parenchyma atrophy, although the lobular contour was preserved. Immunohistochemical results revealed diffuse infiltration of IgG4-positive plasma cells (Figure 4) with a high ratio (that is, 80%) of IgG4-positive and IgG-positive plasma cells in both the parotid and submandibular glands.
September 2015
ORIGINAL CONTRIBUTIONS
Figure 1. Facial view of the swelling in the left submandibular region (arrow).
Figure 2. Computed tomography scan indicating swelling in the left submandibular gland (arrow).
Figure 3. Histologic examination of a specimen from the left submandibular gland biopsy, revealing pronounced inflammation (upper left arrow) and fibrosis (lower right arrow), with collagen sheath (upper right arrow) in the periductal areas (hematoxylin and eosin, original magnification x200).
Figure 4. Immunohistochemical examination of a specimen from the left submandibular gland biopsy, revealing abundant infiltration of immunoglobulin G4–positive plasma cells (arrow) (immunoglobulin G4 antibody, original magnification x200).
CAN YOU MAKE THE DIAGNOSIS? A. Sjögren syndrome B. sarcoidosis C. sialosis (sialadenosis)
D. immunoglobulin G4–related disease E. mucosa-associated lymphoid tissue lymphoma
JADA 146(9) http://jada.ada.org
September 2015 695
ORIGINAL CONTRIBUTIONS
THE DIAGNOSIS D. immunoglobulin G4–related disease A comprehensive review of the patient’s medical history and current clinical and laboratory results, as well as radiographic and histopathologic results, led us to a diagnosis of IgG4-related disease (IgG4RD). Recognized as a disorder in 2010, IgG4RD is characterized by a hyper-IgG4 globulinemia and IgG4-producing plasma cell expansion in the affected organs, with fibrotic and sclerotic changes.1 Investigators have reported that IgG4RD can involve multiple organs or tissues, including but not limited to the lacrimal glands, salivary glands, pancreas, and kidneys.2 Clinical symptoms of diffuse or localized swelling or masses (that is, tumorlike swellings in some cases) vary, depending on the organ being affected. Two major presentations of this condition are type 1 autoimmune pancreatitis (that is, IgG4-related pancreatitis) and salivary gland disease, in which a patient may have a salivary gland enlargement (formerly known as Mikulicz disease), or sclerosing sialadenitis (formerly known as Küttner tumor). These conditions often resemble Sjögren syndrome (SS) but are clinicopathologically distinct.3 A patient with sclerosing sialadenitis can have concurrent oral and skin lesions, with the oral lesions clinically resembling oral squamous cell carcinoma.4 Some patients may experience serious complications, such as obstruction or compression symptoms, owing to organomegaly or hypertrophy, and organ dysfunction caused by cellular infiltration or fibrosis.5 IgG4RD is a syndrome of unknown etiology. When examining a patient with IgG4RD, a clinician may see multiple sites of bilateral enlargement of major salivary glands and lacrimal glands. The diagnosis of IgG4RD primarily is made on the basis of the morphologic appearance on biopsy. The critical histopathologic features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis.6 IgG4-positive plasma cell infiltration and the ratio of IgG4-positive plasma cells to IgG-positive plasma cells greater than 40% are of secondary importance.1,6 Other relevant histopathologic features are phlebitis without obliteration of the lumen and increased numbers of eosinophils that are neither sensitive nor specific for the diagnosis of IgG4RD.6 Approximately 60% to 70% of patients have an elevated level of serum IgG4 (> 135 milligrams per deciliter).3 Autoimmune pancreatitis, retroperitoneal fibrosis, tubulointerstitial nephritis, autoimmune hypophysitis, Riedel thyroiditis, and other autoimmune sclerosing diseases may be concomitant diseases. Before making a final diagnosis, clinicians also should investigate and exclude other etiologic factors, such as SS, sarcoidosis, sialadenosis, Wegener granulo-
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matosis, lymphoma, and HIV-related salivary gland disorders.1 IgG4RD can be treated with glucocorticoids. Generally, for reducing symptoms and preventing recurrence, prednisolone is recommended if whole-body complications are absent (30-40 mg per day) or present (50-60 mg per day).7-9 Once the disease is controlled, a maintenance dose of prednisolone (5-10 mg per day) is recommended, although there is a 30% to 40% chance of relapse. Glucocorticoids should be stopped if remission continues and if the patient has been on a maintenance steroid dosage regimen for 3 years.1 Because our patient had no systemic complications, she initially received a prednisolone regimen of 40 mg per day. We tapered the dose by 5 mg every 2 weeks until the dose was 30 mg per day, then we reduced the dose by 2.5 mg every 2 weeks and finally to 5 mg per day. The patient showed significant improvement at this dose for 3 months; her symptoms declined and her level of serum IgG4 dropped to 3,250 mg/L. We recommended that she continue this therapeutic strategy and take prednisolone at 5 mg per day for 3 years with a follow-up examination every 3 months. DIFFERENTIAL DIAGNOSIS
SS. SS is a chronic autoimmune disease characterized by lymphocytic infiltration that creates destructive lesions in the exocrine glands, primarily in the salivary and lacrimal glands. As an autoimmune disease, SS is second to rheumatoid arthritis in occurrence, with approximately 1% of the population affected; it is found more commonly in middle-aged women than men, at a ratio of approximately 9:1.10 The most common symptoms of SS are extreme fatigue, dry eyes, and dry mouth; other possible symptoms include swelling of the salivary glands, sialorrhea, and tooth loss.11 Enlargement of the parotid or other major salivary glands occurs in twothirds of patients with SS. Dentists play a key role in diagnosing and treating patients with SS because they are often the first practitioners to detect the symptoms.12 The diagnosis of SS is based primarily on 3 criteria: decreased lacrimation and salivation, serologic evidence of SS antibodies, and a labial salivary gland biopsy. Biopsy results that suggest a diagnosis of SS reveal pathognomonic focal aggregates of lymphocytes and parenchymal atrophy.13 Biopsy results offer a good diagnostic value with an elevated specificity and a sensitivity ranging from 63.5% to 93.7%.14 However, investigators have reviewed the accuracy and diagnostic benefits of the labial salivary gland biopsy for SS with mixed findings.15
ORIGINAL CONTRIBUTIONS
It is important to differentiate IgG4RD from SS because of the different therapeutic strategies used, especially when SS involves only the salivary and lacrimal glands and exhibits different clinical features. Swelling of the glands may be remarkable, but secretory dysfunction is unobtrusive in patients with IgG4RD. Serologically, patients with IgG4RD lack anti-SSA and anti-SSB antibodies, whereas they have elevated serum IgG4 levels. In addition, rates of allergic rhinitis and bronchial asthma, serum IgE concentrations, and eosinophil counts among white blood cells are higher in IgG4RD than in SS.1,16 Demographically, there is a higher prevalence of IgG4RD in men than women. Sarcoidosis. Sarcoidosis is a chronic systemic disorder of unknown etiology characterized by affected organs, an accumulation of epithelioid granulomas without caseation or staining for infectious agents, and derangement of tissue architecture.17 Sarcoidosis can affect multiple organs, especially the lungs, lymph nodes, skin, and eyes. Frequently the salivary glands are involved, and in some cases, xerostomia or bilateral parotid swelling is present.18,19 The salivary glands tend to be firm and slightly painful to touch, but they do not fluctuate in size during eating. Bilateral hilar lymphadenopathy is the classic finding on a patient’s chest radiograph. A serologic examination also may reveal anemia or other cellline deficiencies, elevated liver enzymes, hypercalciuria, and electrocardiogram abnormalities. The angiotensinconverting enzyme levels may be elevated, but this observation is not diagnostic. Histopathologic confirmation of noncaseating epithelioid cell granulomas is essential for diagnosis.13,20,21 Sialosis (sialadenosis). Sialosis is defined as an asymptomatic, noninflammatory, and nonneoplastic parenchymal salivary gland disease accompanied by a persistent, painless, and bilateral swelling of the salivary glands, commonly involving the parotid glands. There is no predilection of this condition by sex, and the peak occurrence is between 30 and 70 years of age.22 Sialosis has 2 origins: diabetes mellitus type 2 and chronic alcoholism. Sialosis of both etiologies is accompanied by xerostomia, or a sensation of dry mouth, with a decrease in the salivary flow.23 Histopathologic reports typically reveal a fatty infiltration of parenchyme with a decrease in the number of the acini structures and acinar hypertrophy.23 On a CT scan, a normal gland shows multiple irregular areas of hypodensity, reflecting the gland’s fatty content. For patients with alcoholic sialosis, clinicians must direct treatment at the dire aspect of the problem—liver damage. Medical care and alcohol abstinence can be expected to result in some decrease in any existing liver disease and mitigation of the parotid swellings, but the long-term prognosis varies.24 Caring for a patient’s diabetic condition will result in only a minimal improvement in gland size. Surgical reduction rarely is warranted. The known
benign course of this disease mandates a conservative “no-treatment” option, tinctured with a dose of reassurance for the patient.12 Mucosa-associated lymphoid tissue (MALT) lymphoma. Investigators have defined mucosaassociated lymphoid tissue lymphoma, a hematolymphoid malignancy, as nonencapsulated clusters of lymphocytes found throughout the mucosal tissue of the aerodigestive tract.25 MALT lymphoma is a distinct subtype of non-Hodgkin lymphoma and is described as a localized low-grade neoplasm that exhibits an indolent clinical course. MALT lymphomas arise in various extranodal sites and frequently are found in the gastrointestinal tract. Other autoimmune diseases, such as lymphoid interstitial pneumonitis, Hashimoto thyroiditis, and SS, also are associated with the development of MALT lymphoma.26-28 MALT lymphoma of the salivary glands is a rare disease found more often in women than men. Involvment of paired organs (for example, bilateral eyes or multiple salivary glands) is a common feature of MALT lymphoma. Treatment of MALT lymphoma includes but is not limited to surgery, radiation therapy, or a combination of both.28,29 CONCLUSION
IgG4RD is a syndrome of unknown etiology first recognized in 2010. Localized swelling is the most common sign of this disorder. To facilitate a better understanding of IgG4RD, we described a case with typical clinical and pathologic characteristics. However, the diagnosis of this disorder can be confused with the diagnoses of SS, sarcoidosis, sialadenosis, and MALT lymphoma. Clinicians should complete a comprehensive review of the patient’s medical history and clinical and histopathologic results along with the results of laboratory examinations to make a definitive diagnosis. n http://dx.doi.org/10.1016/j.adaj.2015.05.019 Copyright ª 2015 American Dental Association. All rights reserved.
Dr. Lv is a PhD candidate, Department of Oral Medicine, Peking University Hospital of Stomatology, Beijing, China. Dr. Huang is a resident, Department of Oral Medicine, Peking University Hospital of Stomatology, Beijing, China. Dr. Yu is a professor, Department of Oral and Maxillofacial Surgery, Peking University Hospital of Stomatology, Beijing, China. Dr. Gao is a professor, Department of Oral Pathology, Peking University Hospital of Stomatology, No. 22, Zhongguancun South St., Haidian District, 100081, Beijing, China, e-mail [email protected]. Address correspondence to Dr. Gao. Disclosure. None of the authors reported any disclosures. Diagnostic Challenge is published in collaboration with the American Academy of Oral and Maxillofacial Pathology and the American Academy of Oral Medicine. 1. Masaki Y, Kurose N, Umehara H. IgG4-related disease: a novel lymphoproliferative disorder discovered and established in Japan in the 21st century. J Clin Exp Hematop. 2011;51(1):13-20.
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