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Pathology Quiz Case 1: Diagnosis

Pathology Quiz Case 1: Diagnosis Diagnosis: IgG4-related sialadenitis as a presenting symptom of IgG4-related disease IgG4-related sialadenitis, known previously in the literature as chronic sclerosing sialadenitis, or Küttner tumor, presents as unilateral or bilateral salivary gland enlargement that is inflammatory, extensively firm, and well defined.1-3 It most commonly affects the submandibular gland, although parotid gland involvement has been reported.2 It is typically diagnosed in middle-aged or elderly patients and is slightly more common in males.2,3 It is a rare disease with a differential diagnosis that includes sialolithiasis-associated sialadenitis,3 Sjögren syndrome, mucosa-associated lymphoid tumor, lymphoma, lymphoepithelial sialadenitis, and chronic sialadenitis, not otherwise specified.2 Although IgG4-related sialadenitis was thought to be a localized chronic inflammatory disease of unknown etiology for much of the past century, more recent studies have shown that it may be a feature of IgG4-related disease.1-5 IgG4-related disease classically presents with autoimmune pancreatitis and sclerosing lesions in various organs such as the liver, gallbladder, kidney, lung, and lymph nodes.1-4IgG4-related disease involvement of the head and neck has been much less commonly reported, with only 3 prior publications in the otolaryngology head and neck surgery literature (to our knowledge).1,6,7 IgG4-related sialadenitis was recently recognized as part of the spectrum of IgG4-related disease in both Asian and Western populations.1,2 IgG4-related sialadenitis is histologically characterized by an infiltrate of lymphocytes and polyclonal plasma cells; characteristic areas of cellular interlobular and periductal fibrosis made of fibroblasts, lymphocytes, and plasma cells; hyperplastic lymphoid follicles with large germinal centers; preserved lobular architecture; obliterative phlebitis; acinar atrophy; and absence of large lymphoepithelial lesions.1-3 The extent of involvement varies from lobule to lobule.1-3 IgG4-positive plasma cells can be identified imunnohistochemically and are characteristically abundant.1-3 In patients with extrasalivary gland manifestations of IgG4-related disease, a similar pattern of lymphoplasmacytic infiltration with fibrosis and high IgG4 reactivity is seen on biopsy of the pancreas, liver, lung, kidney, breast, bladder, and other affected sites.2,4 Staining for IgG4 is thus very valuable for distinguishing IgG4-related sialadenitis, a feature of IgG4-related disease, from other differential diagnoses. It was reported that IgG4 reactivity was higher on average in IgG4-related sialadenitis than in other inflammatory diseases affecting the salivary gland, including Sjögren syndrome.2 In the literature, there is no agreement on a threshold level of IgG4 for diagnosing either IgG4-related sialadenitis or IgG4-related disease presenting in extrasalivary sites. Proposed threshold levels of IgG4 for the diagnosis of autoimmune pancreatitis, a classic presentation of IgG4-related disease, range from 10 to 50 IgG4-positive plasma cells per high-power field.8 In addition to high IgG4 counts, a high ratio of IgG4 to IgG in tissue is further indicative of IgG4-related sialadenitis as opposed to other inflammatory conditions. In one study, the IgG4-IgG ratio ranged from 45.8% to 92.8% in patients with IgG4-related sialadenitis, compared with 0 to 4.9% in patients with sialolithiasis and Sjögren syndrome.5 Although IgG4 staining is a crucial step in diagnosis, it is important to note that common nonspecific inflammatory conditions such as rheumatoid synovitis, oral cavity lesions, and carcinoma-associated inflammatory response are associated with variable IgG4-positive plasma cell counts that are at times elevated to the same levels that are commonly seen in IgG4-related disease8; therefore, high IgG4 counts on biopsy are very suggestive but alone are not diagnostic of IgG4-related sialadenitis. Care must be taken to interpret high IgG4 counts in the context of other laboratory and clinical findings. Serum IgG and IgG4 levels are also frequently elevated, although the finding of elevated serum IgG4 levels is more variable than high IgG4 counts on biopsy; serum IgG4 levels may be normal, particularly in patients who lack the features of IgG4-related disease other than IgG4-related sialadenitis.3 Antinuclear antibody levels may be positive, but levels of anti–SS-A and anti–SS-B antibodies are characteristically negative,3 differentiating IgG4-related sialadenitis from Sjögren syndrome. An elastic stain is helpful for revealing obliterative phlebitis in IgG4-related sialadenitis,3 and the results of imaging in IgG4-related sialadenitis are usually negative for sialoliths.3 Salivary gland dysfunction, if any, is usually very mild in IgG4-related sialadenitis.3 Firm enlargement of the salivary gland may be the only symptom. In the head and neck, IgG4-related disease most frequently affects the salivary gland, but it may also affect the lacrimal gland (commonly in association with salivary gland involvement),6,7 thyroid, or macula and uvea of the eye.7 Rare laryngeal and temporal bone involvement, resulting in airway obstruction and hearing loss, respectively,7 has also been described. Therefore, IgG4-related disease involves a spectrum of diseases in which symptoms depend on the location and extent of involvement. The recognition of IgG4-related sialadenitis as a component of IgG4-related disease has important implications for treatment. IgG4-related disease is highly steroid sensitive; the administration of systemic corticosteroids causes remission, seen both by a dramatic improvement in symptoms (decreased salivary gland swelling in the case of IgG4-related sialadenitis) and by the quick normalization of IgG and IgG4 levels.1-3,5-7,9 However, with steroid therapy alone, patients with IgG4-related disease may experience a relapse after initial response and may require long-term steroid therapy, with associated morbidity.10 When administered in conjunction with steroids, steroid-sparing immunosuppressants such as mizoribine9 and rituximab10 have been found to improve control of IgG4-related disease and to enable successful steroid tapering.9,10 Further studies will be needed to establish the optimal steroid dosage and treatment regimen for patients with IgG4-related disease.1 One series reported that a regimen of 20 to 30 mg/d of prednisolone for 1 to 2 weeks was successful in treating patients with IgG4-related sialadenitis and manifestations of IgG4-related disease in other organs.1 Although the responsiveness of IgG4-related disease to steroid therapy has been clearly demonstrated in the literature, further studies on the long-term prognosis after steroid therapy should be performed; in the literature, to our knowledge, there are currently no established recommendations on the role of surveillance for patients with IgG4-related disease. Nonetheless, other than treatment with steroids, perhaps in conjunction with steroid-sparing agents, considering the systemic nature of the disease, we recommend that patients diagnosed as having IgG4-related sialadenitis or other presentations of IgG4-related disease be monitored for disease recurrence at the same site or at distant sites. Also, it has been suggested that long-standing IgG4-related disease may progress to malignancy.1 Salivary duct carcinoma can arise in the setting of IgG4-related sialadenitis, for example, although such reports are rare.1 More studies will be necessary to definitively establish an association between IgG4-related disease and malignancy.3 The present case highlights the importance of recognizing IgG4-related sialadenitis as a component of IgG4-related disease, which can present at a number of sites in the body, rather than as a localized inflammatory disease of the head and neck. The involvement of other organs, such as the lungs and lymph nodes, as in our patient, is not necessary for diagnosis but may further suggest IgG4-related disease. Staining for IgG and IgG4, as well as serologic tests for immunoglobulins, should be performed when the diagnosis of IgG4-related disease is suspected. Patients with characteristic features on biopsy and serologic testing should be referred to the rheumatology service to assist with diagnosis and management. Confirmed cases are effectively treated with steroids, and long-term follow-up is recommended. References 1. Ohta N, Kurakami K, Ishida A, et al. Clinical and pathological characteristics of IgG4-related sclerosing sialadenitis. Laryngoscope. 2012;122(3):572-57722241660PubMedGoogle ScholarCrossref 2. Geyer JT, Ferry JA, Harris NL, et al. Chronic sclerosing sialadenitis (Küttner tumor) is an IgG4-associated disease. Am J Surg Pathol. 2010;34(2):202-21020061932PubMedGoogle ScholarCrossref 3. Geyer JT, Deshpande V. IgG4-associated sialadenitis. Curr Opin Rheumatol. 2011;23(1):95-10121124091PubMedGoogle ScholarCrossref 4. Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol. 2003;38(10):982-98414614606PubMedGoogle ScholarCrossref 5. Kitagawa S, Zen Y, Harada K, et al. Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Küttner's tumor). Am J Surg Pathol. 2005;29(6):783-79115897744PubMedGoogle ScholarCrossref 6. Takano K, Yamamoto M, Takahashi H, Shinomura Y, Imai K, Himi T. Clinicopathologic similarities between Mikulicz disease and Küttner tumor. Am J Otolaryngol. 2010;31(6):429-43420015799PubMedGoogle ScholarCrossref 7. Masterson L, Del Pero MM, Donnelly N, Moffat DA, Rytina E. Immunoglobulin G4 related systemic sclerosing disease involving the temporal bone. J Laryngol Otol. 2010;124(10):1106-111020519036PubMedGoogle ScholarCrossref 8. Strehl JD, Hartmann A, Agaimy A. Numerous IgG4-positive plasma cells are ubiquitous in diverse localised non-specific chronic inflammatory conditions and need to be distinguished from IgG4-related systemic disorders. J Clin Pathol. 2011;64(3):237-24321233087PubMedGoogle ScholarCrossref 9. Nanke Y, Kobashigawa T, Yago T, Kamatani N, Kotake S. A case of Mikulicz's disease, IgG4-related plasmacytic syndrome, successfully treated by corticosteroid and mizoribine, followed by mizoribine alone. Intern Med. 2010;49(14):1449-145320647666PubMedGoogle ScholarCrossref 10. Khosroshahi A, Carruthers MN, Deshpande V, Unizony S, Bloch DB, Stone JH. Rituximab for the treatment of IgG4-related disease: lessons from 10 consecutive patients. Medicine (Baltimore). 2012;91(1):57-6622210556PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Otolaryngology - Head & Neck Surgery American Medical Association

Pathology Quiz Case 1: Diagnosis

JAMA Otolaryngology - Head & Neck Surgery , Volume 139 (2) – Feb 1, 2013

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Publisher
American Medical Association
Copyright
Copyright © 2013 American Medical Association. All Rights Reserved.
ISSN
2168-6181
eISSN
2168-619X
DOI
10.1001/jamaoto.2013.1268b
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Abstract

Diagnosis: IgG4-related sialadenitis as a presenting symptom of IgG4-related disease IgG4-related sialadenitis, known previously in the literature as chronic sclerosing sialadenitis, or Küttner tumor, presents as unilateral or bilateral salivary gland enlargement that is inflammatory, extensively firm, and well defined.1-3 It most commonly affects the submandibular gland, although parotid gland involvement has been reported.2 It is typically diagnosed in middle-aged or elderly patients and is slightly more common in males.2,3 It is a rare disease with a differential diagnosis that includes sialolithiasis-associated sialadenitis,3 Sjögren syndrome, mucosa-associated lymphoid tumor, lymphoma, lymphoepithelial sialadenitis, and chronic sialadenitis, not otherwise specified.2 Although IgG4-related sialadenitis was thought to be a localized chronic inflammatory disease of unknown etiology for much of the past century, more recent studies have shown that it may be a feature of IgG4-related disease.1-5 IgG4-related disease classically presents with autoimmune pancreatitis and sclerosing lesions in various organs such as the liver, gallbladder, kidney, lung, and lymph nodes.1-4IgG4-related disease involvement of the head and neck has been much less commonly reported, with only 3 prior publications in the otolaryngology head and neck surgery literature (to our knowledge).1,6,7 IgG4-related sialadenitis was recently recognized as part of the spectrum of IgG4-related disease in both Asian and Western populations.1,2 IgG4-related sialadenitis is histologically characterized by an infiltrate of lymphocytes and polyclonal plasma cells; characteristic areas of cellular interlobular and periductal fibrosis made of fibroblasts, lymphocytes, and plasma cells; hyperplastic lymphoid follicles with large germinal centers; preserved lobular architecture; obliterative phlebitis; acinar atrophy; and absence of large lymphoepithelial lesions.1-3 The extent of involvement varies from lobule to lobule.1-3 IgG4-positive plasma cells can be identified imunnohistochemically and are characteristically abundant.1-3 In patients with extrasalivary gland manifestations of IgG4-related disease, a similar pattern of lymphoplasmacytic infiltration with fibrosis and high IgG4 reactivity is seen on biopsy of the pancreas, liver, lung, kidney, breast, bladder, and other affected sites.2,4 Staining for IgG4 is thus very valuable for distinguishing IgG4-related sialadenitis, a feature of IgG4-related disease, from other differential diagnoses. It was reported that IgG4 reactivity was higher on average in IgG4-related sialadenitis than in other inflammatory diseases affecting the salivary gland, including Sjögren syndrome.2 In the literature, there is no agreement on a threshold level of IgG4 for diagnosing either IgG4-related sialadenitis or IgG4-related disease presenting in extrasalivary sites. Proposed threshold levels of IgG4 for the diagnosis of autoimmune pancreatitis, a classic presentation of IgG4-related disease, range from 10 to 50 IgG4-positive plasma cells per high-power field.8 In addition to high IgG4 counts, a high ratio of IgG4 to IgG in tissue is further indicative of IgG4-related sialadenitis as opposed to other inflammatory conditions. In one study, the IgG4-IgG ratio ranged from 45.8% to 92.8% in patients with IgG4-related sialadenitis, compared with 0 to 4.9% in patients with sialolithiasis and Sjögren syndrome.5 Although IgG4 staining is a crucial step in diagnosis, it is important to note that common nonspecific inflammatory conditions such as rheumatoid synovitis, oral cavity lesions, and carcinoma-associated inflammatory response are associated with variable IgG4-positive plasma cell counts that are at times elevated to the same levels that are commonly seen in IgG4-related disease8; therefore, high IgG4 counts on biopsy are very suggestive but alone are not diagnostic of IgG4-related sialadenitis. Care must be taken to interpret high IgG4 counts in the context of other laboratory and clinical findings. Serum IgG and IgG4 levels are also frequently elevated, although the finding of elevated serum IgG4 levels is more variable than high IgG4 counts on biopsy; serum IgG4 levels may be normal, particularly in patients who lack the features of IgG4-related disease other than IgG4-related sialadenitis.3 Antinuclear antibody levels may be positive, but levels of anti–SS-A and anti–SS-B antibodies are characteristically negative,3 differentiating IgG4-related sialadenitis from Sjögren syndrome. An elastic stain is helpful for revealing obliterative phlebitis in IgG4-related sialadenitis,3 and the results of imaging in IgG4-related sialadenitis are usually negative for sialoliths.3 Salivary gland dysfunction, if any, is usually very mild in IgG4-related sialadenitis.3 Firm enlargement of the salivary gland may be the only symptom. In the head and neck, IgG4-related disease most frequently affects the salivary gland, but it may also affect the lacrimal gland (commonly in association with salivary gland involvement),6,7 thyroid, or macula and uvea of the eye.7 Rare laryngeal and temporal bone involvement, resulting in airway obstruction and hearing loss, respectively,7 has also been described. Therefore, IgG4-related disease involves a spectrum of diseases in which symptoms depend on the location and extent of involvement. The recognition of IgG4-related sialadenitis as a component of IgG4-related disease has important implications for treatment. IgG4-related disease is highly steroid sensitive; the administration of systemic corticosteroids causes remission, seen both by a dramatic improvement in symptoms (decreased salivary gland swelling in the case of IgG4-related sialadenitis) and by the quick normalization of IgG and IgG4 levels.1-3,5-7,9 However, with steroid therapy alone, patients with IgG4-related disease may experience a relapse after initial response and may require long-term steroid therapy, with associated morbidity.10 When administered in conjunction with steroids, steroid-sparing immunosuppressants such as mizoribine9 and rituximab10 have been found to improve control of IgG4-related disease and to enable successful steroid tapering.9,10 Further studies will be needed to establish the optimal steroid dosage and treatment regimen for patients with IgG4-related disease.1 One series reported that a regimen of 20 to 30 mg/d of prednisolone for 1 to 2 weeks was successful in treating patients with IgG4-related sialadenitis and manifestations of IgG4-related disease in other organs.1 Although the responsiveness of IgG4-related disease to steroid therapy has been clearly demonstrated in the literature, further studies on the long-term prognosis after steroid therapy should be performed; in the literature, to our knowledge, there are currently no established recommendations on the role of surveillance for patients with IgG4-related disease. Nonetheless, other than treatment with steroids, perhaps in conjunction with steroid-sparing agents, considering the systemic nature of the disease, we recommend that patients diagnosed as having IgG4-related sialadenitis or other presentations of IgG4-related disease be monitored for disease recurrence at the same site or at distant sites. Also, it has been suggested that long-standing IgG4-related disease may progress to malignancy.1 Salivary duct carcinoma can arise in the setting of IgG4-related sialadenitis, for example, although such reports are rare.1 More studies will be necessary to definitively establish an association between IgG4-related disease and malignancy.3 The present case highlights the importance of recognizing IgG4-related sialadenitis as a component of IgG4-related disease, which can present at a number of sites in the body, rather than as a localized inflammatory disease of the head and neck. The involvement of other organs, such as the lungs and lymph nodes, as in our patient, is not necessary for diagnosis but may further suggest IgG4-related disease. Staining for IgG and IgG4, as well as serologic tests for immunoglobulins, should be performed when the diagnosis of IgG4-related disease is suspected. Patients with characteristic features on biopsy and serologic testing should be referred to the rheumatology service to assist with diagnosis and management. Confirmed cases are effectively treated with steroids, and long-term follow-up is recommended. References 1. Ohta N, Kurakami K, Ishida A, et al. Clinical and pathological characteristics of IgG4-related sclerosing sialadenitis. Laryngoscope. 2012;122(3):572-57722241660PubMedGoogle ScholarCrossref 2. Geyer JT, Ferry JA, Harris NL, et al. Chronic sclerosing sialadenitis (Küttner tumor) is an IgG4-associated disease. Am J Surg Pathol. 2010;34(2):202-21020061932PubMedGoogle ScholarCrossref 3. Geyer JT, Deshpande V. IgG4-associated sialadenitis. Curr Opin Rheumatol. 2011;23(1):95-10121124091PubMedGoogle ScholarCrossref 4. Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol. 2003;38(10):982-98414614606PubMedGoogle ScholarCrossref 5. Kitagawa S, Zen Y, Harada K, et al. Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Küttner's tumor). Am J Surg Pathol. 2005;29(6):783-79115897744PubMedGoogle ScholarCrossref 6. Takano K, Yamamoto M, Takahashi H, Shinomura Y, Imai K, Himi T. Clinicopathologic similarities between Mikulicz disease and Küttner tumor. Am J Otolaryngol. 2010;31(6):429-43420015799PubMedGoogle ScholarCrossref 7. Masterson L, Del Pero MM, Donnelly N, Moffat DA, Rytina E. Immunoglobulin G4 related systemic sclerosing disease involving the temporal bone. J Laryngol Otol. 2010;124(10):1106-111020519036PubMedGoogle ScholarCrossref 8. Strehl JD, Hartmann A, Agaimy A. Numerous IgG4-positive plasma cells are ubiquitous in diverse localised non-specific chronic inflammatory conditions and need to be distinguished from IgG4-related systemic disorders. J Clin Pathol. 2011;64(3):237-24321233087PubMedGoogle ScholarCrossref 9. Nanke Y, Kobashigawa T, Yago T, Kamatani N, Kotake S. A case of Mikulicz's disease, IgG4-related plasmacytic syndrome, successfully treated by corticosteroid and mizoribine, followed by mizoribine alone. Intern Med. 2010;49(14):1449-145320647666PubMedGoogle ScholarCrossref 10. Khosroshahi A, Carruthers MN, Deshpande V, Unizony S, Bloch DB, Stone JH. Rituximab for the treatment of IgG4-related disease: lessons from 10 consecutive patients. Medicine (Baltimore). 2012;91(1):57-6622210556PubMedGoogle ScholarCrossref

Journal

JAMA Otolaryngology - Head & Neck SurgeryAmerican Medical Association

Published: Feb 1, 2013

Keywords: sialadenitis,immunoglobulin g4,immunoglobulin g,steroids,sjogren's syndrome,biopsy,sialolithiasis,inflammatory disorders

References