Original Research—Sinonasal Disorders
Perplexing Lesions of the Sinonasal Cavity and Skull Base: IgG4-related and Similar Inflammatory Diseases
Otolaryngology– Head and Neck Surgery 2014, Vol. 151(3) 496–502 Ó American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0194599814533648 http://otojournal.org
Rachel B. Cain, MD1, Thomas V. Colby, MD2, Vijayan Balan, MD3, Naresh P. Patel, MD4, and Devyani Lal, MD1
No sponsorships or competing interests have been disclosed for this article.
Abstract Objective. IgG4-related disease (IgG4RD) causing sinonasal and skull base pathology is uncommonly described. We present a series of suspected IgG4RD patients, with a pertinent review of the literature to highlight diagnostic challenges. Study Design. Case series. Setting. Academic tertiary care center. Subjects and Methods. Case series of patients with IgG4RD or suspected IgG4RD involving the sinonasal cavity and skull base. Results. We present 4 patients with atypical sinonasal and/or skull base disease who were noted to have IgG4-positive plasma cell infiltration on immunohistochemistry of biopsy specimens. IgG4RD, a recently described entity affecting multiple organs, is characterized by lymphoplasmacytic infiltration and often elevated serum IgG4. IgG4RD can masquerade as malignancy or infection but responds to glucocorticosteroid and immunosuppressant therapy. IgG4RD has been infrequently reported presenting as sinonasal or skull base lesions, and definitive diagnostic criteria for these regions are not established. In our series, IgG4RD was suspected in all 4 patients, but only 1 met all current criteria for definitive diagnosis. All 4 patients, however, responded to corticosteroid therapy, and 1 was placed on long-term azathioprine. Conclusion. IgG4RD is rarely described in the sinonasal cavity and skull base, and specific diagnostic criteria for such disease have not been defined. We present a series of patients with IgG4-positive plasma cell inflammatory pathology who were suspected to have IgG4RD. Our series highlights diagnostic challenges associated with these patients. Tumefactive and destructive sinonasal-skull base lesions with a plasma cell-rich infiltrate should incite suspicion of IgG4RD, and immunohistochemistry for IgG4-positive plasma cells should be performed.
Keywords IgG4-related disease, IgG4, tumefactive fibroinflammatory lesion, plasma cell related inflammation, autoimmune pancreatitis
Received January 27, 2014; accepted April 9, 2014.
Introduction IgG4-related disease (IgG4RD) is a fibroinflammatory systemic condition characterized by tumefactive lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and often (but not always) elevated serum IgG4 concentrations.1 The entity was recently characterized in 2003, when patients with autoimmune pancreatitis were noted to have extrapancreatic manifestations.2 Involvement of numerous organ systems with IgG4RD has been described, including the pancreas, biliary tree, salivary glands, periorbital tissues, kidneys, lungs, lymph nodes, meninges, aorta, breast, prostate, thyroid, pericardium, and skin. Exocrine tissue seems preferentially affected.3 Histopathological features are similar across organs. The spectrum of IgG4RD may include Mikulicz syndrome, Kuttner tumor, Reidel thyroiditis,1 and eosinophilic angiocentric fibrosis of the upper respiratory tract,4 which all share similar pathologic features. The clinical presentation of IgG4RD is variable and dependent on the organ systems involved. Single-organ and multi-organ disease is possible. After the pancreaticobiliary system, the head and neck is the next most common site for involvement by IgG4RD.4 The classic tumefactive lesions of IgG4RD have been found in lymph nodes, salivary, lacrimal and thyroid glands, the upper aerodigestive tract, periorbital tissues,4 pituitary gland, paranasal sinuses,5-7 middle ear space and mastoid,8-10 and nasolacrimal duct.3 Chronic sclerosing sialadenitis of the submandibular and parotid glands (Kuttner tumor) is a common manifestation of IgG4RD, resulting in unilateral or bilateral swelling.4,11 1
Department of Otolaryngology, Mayo Clinic, Phoenix, Arizona, USA Department of Laboratory Medicine & Pathology, Mayo Clinic, Phoenix, Arizona, USA 3 Department of Hepatology, Mayo Clinic, Phoenix, Arizona, USA 4 Department of Neurologic Surgery, Mayo Clinic, Phoenix, Arizona, USA 2
Presented at Triological Combined Sections Meeting; January 24-26, 2013; Scottsdale, Arizona, USA. Corresponding Author: Devyani Lal, MD, Department of Otolaryngology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, Arizona 85054, USA. Email: [email protected]
Cain et al Radiologically, these tumefactive lesions appear iso- to hypointense on T2-weighted magnetic resonance imaging (MRI) with homogeneous enhancement. The adjacent bone often shows remodeling with erosion or sclerosis.12 Fludeoxyglucose positron emission tomography (FDG-PET) is effective for evaluating the presence of systemic lesions, with the uptake of FDG decreasing after steroid therapy.7 Autoimmunity, inflammatory, or infectious stimuli have been postulated as inciting factors for the type 2 helper T (Th2)-cell immune response associated with IgG4RD. Th2 cytokines interleukin (IL)-4, IL-5, IL-10, IL-13, IL-17 and transforming growth factor b (TGF-b) are subsequently overexpressed.1,11,13 Eosinophilia and elevated serum IgE levels are seen in approximately 40% of IgG4RD patients.14 These mediators cause influx of inflammatory cells and the characteristic fibrosis that results in subsequent organ damage.1 Most patients with IgG4RD respond quickly to glucocorticosteroid therapy. Oral glucocorticoids are first-line therapy, with a gradual taper over 3 to 6 months.1 Steroid-sparing agents used after steroid-induced remission include azathioprine, mycophenolate mofetil, cyclophosphamide, bortezomib,15 methotrexate,1 and mizoribine.16 B-cell depletion with rituximab, which appears to target the IgG4 subclass alone, is a particularly interesting therapeutic option.15,17,18 However, there have been no clinical trials evaluating any of these agents in IgG4RD. Definitive diagnosis of IgG4RD can only be made via histopathological analysis. However, diagnostic criteria for IgG4RD are not universally agreed upon and may differ for each region. Many sets of criteria have been proposed, some of which differ between affected organ systems. Distinct morphologic features of IgG4RD include a dense lymphoplasmacytic infiltrate in a matted and irregularly whorled (storiform) pattern, obliterative phlebitis, and a mild-to-moderate eosinophil infiltrate. Granulomas and neutrophils are rarely present. Immunohistochemical staining for IgG4 must demonstrate the presence of IgG4-positivity in more than 10 to 50 plasma cells per high power field (hpf). The infiltrate in IgG4RD is a mixture of non-clonal T and B lymphocytes, which distinguishes IgG4RD from lymphoma (characterized by a clonal lymphocyte population). Elevated serum IgG4 concentration is a feature exhibited by many patients with IgG4RD; however, approximately 30% of patients with IgG4RD diagnosed by histopathology/ immunohistochemistry have normal serum IgG4 concentrations.19 Furthermore, the significance of elevated serum IgG4 remains unclear, as it seems to have little prognostic implication for steroid-responsiveness or disease relapse.19-21 Organ-specific diagnostic criteria have been suggested for IgG4-related dacrocystitis/sialadenitis,22 IgG4-related pancreatitis,23 and IgG4-related kidney disease.24 The precise features of IgG4RD in these sites have been described in only a handful of small studies and case reports.5-7,9,10,25,26 As of yet, no site-specific diagnostic criteria have been proposed for IgG4-related rhinosinusitis or skull base inflammation. At the first international symposium on IgG4RD in 2011, the most current set of diagnostic criteria were proposed using a 3-tiered algorithm (Figure 1).27
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Figure 1. Diagnostic terminology proposed in a consensus statement by the Organizing Committee of the 2011 International IgG4-related Disease Symposium (adapted from Deshpande et al).27
Although there are a few case series from Japan and 1 from the United Kingdom describing sinonasal IgG4RD, sinonasal or skull base involvement has not been described in patients from the United States. We present 4 patients presenting with atypical inflammatory sinonasal or skull base lesions who were suspected to have IgG4RD on the basis of impressive numbers of IgG4-positive plasma cells infiltrating biopsy specimens. Their clinical course and radiological findings were initially suspicious for malignancy, skull base osteomyelitis, or autoimmune pathology. After a careful and thorough workup by way of immunohistopathology and laboratory tests, malignancy and infection were ruled out. Herein, we present the detailed description of these patients and a pertinent discussion of the literature to highlight diagnostic challenges.
Methods This study was deemed exempt by the Mayo Clinic Institutional Review Board. The medical records of 4 patients who were suspected to have IgG4RD were retrospectively reviewed. Pathological specimens from each patient were analyzed.
Results: Case Series Case 1 A 60-year-old Caucasian male presented with nasal congestion, cervical lymphadenopathy, retro-orbital pain, and vision changes. Six months previously he had undergone a partial pancreatectomy for a pancreatic head mass, which was found to be autoimmune pancreatitis. He also had previous excisional biopsies for cervical lymphadenopathy, which showed follicular hyperplasia. He was referred to our department after MRI revealed a unilateral cavernous sinus enhancing soft tissue mass (Figure 2A). Given this mysterious clinical picture, the histopathology slides from his previous surgeries were retrieved and reviewed. The pancreatectomy specimen showed focal lymphoplasmacytic infiltrate and marked sclerosis, consistent with IgG4 associated autoimmune pancreatitis (Figure 3). An immunologic panel revealed elevated serum IgG subclass 4 (IgG4) at 195 mg/dL. This patient
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Figure 2. Patient 1: (A) Pretreatment and (B) posttreatment T1-weighted gadolinium-enhanced MRI. A: Enhancing mass in right cavernous sinus (arrow). B: Resolution without recurrence (arrow) 2 years after initiating treatment.
Figure 3. Patient 1: Medium power hematoxylin and eosin (H&E) stain of pancreas showing replacement of normal pancreatic tissue by storiform fibrosis and focal chronic inflammation including plasma cells.
qualified for the diagnosis of IgG4RD, meeting all defined criteria. He was started on prednisone 40 mg daily, with rapid resolution of his symptoms. Repeat MRI after 1 month of prednisone showed a marked decrease in size of the previously noted cavernous sinus mass with minimal residual enhancement. This mass was therefore determined to be an inflammatory pseudotumor secondary to IgG4RD. He was transitioned from prednisone to azathioprine and has continued to do well without relapse. Surveillance MRI 2 years later showed complete resolution of the cavernous sinus mass (Figure 2B).
Case 2 A 66-year-old Caucasian male with a history of insulindependent diabetes, pericarditis, and atrial fibrillation presented with a 9-month history of daily headaches, vertigo, hearing loss, nausea, vomiting, and night sweats. He had a previous extensive workup without a diagnosis. He was admitted for intractable headache. A repeat MRI showed a diffuse enhancing infiltrative process involving the central skull base with bilateral involvement of the nasopharynx, parapharyngeal tissue, mastoid, clivus, and petrous apices
(Figure 4A). Initial differential included lymphoma, nasopharyngeal carcinoma, osteomyelitis, metastasis, or granulomatous process. Positron emission tomography/computed tomography (PET/CT) showed a metabolically active infiltrative petroclival and nasopharyngeal process with a maximum standardized uptake value (SUV) of 9.3 (Figure 4B). Pathology of nasopharyngeal biopsies showed nonspecific chronic inflammatory infiltrate. There was no clonal B-cell population on flow cytometry. The patient went to the operating room for clival biopsies taken via an endoscopic transnasal, transsphenoidal approach utilizing CT-guided localization. Pathology revealed sclerosis and inflammation with polyclonal plasmacytosis and up to 35 IgG4-positive plasma cells per hpf, with an IgG4/ IgG1 ratio of approximately 20%. IgG subclass analysis found elevated serum IgG4 at 153 mg/dL. While IgG4RD was highly suspected, he did not meet all current criteria for definitive diagnosis. Obscuring the clinical picture, culture of clival specimens grew Staphylococcus lugdunensis. The patient completed a 3-month course of intravenous antibiotics without resolution of his symptoms. Dexamethasone 4 mg twice daily was then initiated after the patient was hospitalized for dehydration from vomiting. Shortly after initiation of steroids, the patient’s symptoms resolved. Antibiotic therapy was stopped and he continued to do well on dexamethasone 4 mg every other day. Posttreatment MRI showed significant improvement in the petroclival infiltrative process.
Case 3 A 62-year-old Caucasian woman presented with massive destruction of the nasal septum and ethmoid sinuses causing multiple episodes of epistaxis requiring transfusion. Lymphoma, vasculitis, or granulomatous disease was suspected. Serology was significant for elevated erythrocyte sedimentation rate (ESR), but perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) and cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) were negative. Initial sinonasal biopsies showed nonspecific inflammation. She had multiple subsequent biopsies for progression of disease with destruction of the lamina papyracea and medial maxillary wall. Further histopathological review revealed
Cain et al
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Figure 4. Patient 2: (A) Pretreatment gadolinium-enhanced T1-weighted MRI shows enhancement of bilateral petrous apices and fluid in mastoids. (B) PET/CT with metabolic activity of central skull base and nasopharynx.
acute and chronic inflammation, reactive bone formation, and fibrosis. There was no evidence of granulomatous inflammation, giant cells, or vasculitis. Immunohistochemical staining showed increased numbers of IgG4-positive cells, approaching 50/hpf. However, other features consistent with IgG4RD, such as perivenular lymphocytic cuffing and storiform fibrosis, were not present. Flow cytometry ruled out lymphoma, and Gomori methenamine silver stain was negative for fungal organisms. While IgG4RD was highly suspected, she did not meet current criteria for definitive diagnosis. A complete Rheumatologic panel for autoimmune disease or evidence of cocaine use was nonspecific on repeat testing, with the only abnormalities being elevated ESR and C-reactive protein. Given the exclusion of other known conditions, a diagnosis of possible IgG4RD was postulated due to the presence of increased IgG4-positive plasma cells on immunohistochemistry, despite not all diagnostic criteria for IgG4RD being met. Simultaneously during this workup, the patient was also found to have optic neuritis, and prednisone 20 mg daily was started. She showed regression of optic neuritis and now continues to do well on this regimen without progression of sinonasal destruction.
Case 4
Figure 5. Patient 4: CT shows a lesion causing premaxillary destruction (arrow) with involvement of the nasal septum. Corresponding MRI (not illustrated) showed enhancement of the lesion with gadolinium.
A 79-year-old Caucasian male with stable monoclonal gammopathy of undetermined significance, allergic rhinitis, and atopy presented with a 4-year history of unilateral epistaxis. Nasal cautery had been attempted twice prior. However, he continued to have right-sided epistaxis and presented for evaluation. Nasal endoscopy revealed friable nasal septal mucosa on the right with copious crusting and a normal left nasal cavity. A 2-month trial of medical management with topical tobramycin/budesonide nasal irrigations, mupirocin ointment, and nasal emollient was unsuccessful. Occult malignancy, autoimmune disease, or other inflammatory condition was suspected. A biopsy revealed only inflamed squamous mucosa. CT and MRI showed a lytic, enhancing mass replacing the anterior inferior nasal septum with
erosion of the premaxilla (Figure 5). The patient was taken to the operating room for endoscopic biopsy, during which the thickened abnormal portion of nasal septum was excised. Histopathology showed chronic inflammation with stellate band-like fibrosis and sheets of plasma cells (Figure 6A). Despite the patient’s history of an IgG lambda monoclonal gammopathy, immunohistochemistry did not support plasmacytoma or plasma cell myeloma (Figure 6B). However, an immunoperoxidase stain for IgG4 showed IgG4-positivity in 30-50 plasma cells/hpf (Figure 6C). Congo red stain was negative for amyloid. While IgG4RD was suspected given the histological features and exclusion
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Figure 6. Patient 4: (A) Nasal biopsy: H&E stain with inflammation, plasma cells, fibrosis. (B) Predominance of IgG-positive plasma cells on immunohistochemical staining. (C) IgG4 stain reveals 30-50 IgG4-positve cells/hpf.
of other diagnoses, he did not meet currently defined criteria for IgG4RD. The patient opted to forego systemic glucocorticosteroid therapy due to concerns of adverse effects. He was therefore maintained on daily budesonide nasal irrigations (0.5 mcg in 240 mL normal saline) with resolution of epistaxis and without endoscopic progression of mucosal disease or septal destruction. Oral steroid therapy is being reserved for disease progression. Nasal steroid sprays were not used because of the patient’s previous problems with mucosal erosion and bleeding.
Discussion Tumefactive lesions in the sinonasal cavity and skull base necessitate a broad differential, including neoplasm, vasculitides, autoimmune disease, Castleman’s disease, and granulomatous conditions. We propose that IgG4RD or similarly presenting conditions be considered in the differential diagnosis of inflammatory diseases with destructive or atypical features in the sinonasal cavity and skull base when more common and better defined entities have been excluded. When a new disease is characterized, it is important to consider where such cases had been grouped previously. The term tumefactive fibroinflammatory lesion was coined by Wold and Weiland28 in 1983 to describe head and neck masses with histology similar in appearance to Riedel thyroiditis, sclerosing mediastinitis, retroperitoneal fibrosis, and sclerosing cholangitis.28 Subsequently, Olsen et al29 presented 12 patients with tumefactive fibroinflammatory lesions in the neck, parotid, antrum, nasal cavity, tongue, nasopharynx, or buccal space with clinical and histologic features consistent with those found in IgG4RD, also noting that the lesions resolved with steroids.29 It is likely these previously described ‘‘tumefactive fibroinflammatory lesions’’ may also fit within the IgG4RD spectrum. The sinonasal cavity is an extremely rare site of IgG4RD manifestation. Our literature review showed no previous cases of sinonasal IgG4RD in patients from the United States, with almost all such previous reports describing Japanese patients. Sinonasal mucosal involvement has been described to result in a clinical picture of chronic rhinosinusitis with nasal obstruction, discharge, crusting, and hyposmia.7,25 Tumor-like masses from IgG4RD in the maxillary sinus and nasal septum have also been implicated in case
reports.5,6 Many patients with IgG4RD additionally demonstrate allergic features such as atopy, eczema, asthma, and peripheral eosinophilia.1 The patients in our series showed some features similar to those previously described in the literature.5-7,25 All patients had rather atypical case presentations and clinical features. Data from several studies suggest that men are predominantly affected with IgG4RD, and most patients are older than 50 years of age.30,31 Such description is consistent with the patient characteristics in our series. In addition, tumefactive disease was also noted on radiological imaging, with bony erosion in some. On immunohistochemistry, all of our patients showed rich tissue infiltration with IgG4-positive plasma cells. Two of our patients had elevated serum IgG4 levels and 2 did not. In all, only 1 of our patients met all diagnostic criteria for IgG4RD as most recently defined (Figure 1).27 ‘‘Comprehensive diagnostic criteria’’ were developed in Japan for use by general physicians in making the diagnosis of IgG4RD regardless of organ system affected.32 These criteria necessitate immunohistochemical findings consistent with a ratio of IgG4/IgG-positive cells .40% and infiltration of .10 IgG4-positive plasma cells/hpf, along with tumefactive masses and elevated serum IgG4 concentrations 135 mg/dL.32 These ‘‘comprehensive diagnostic criteria’’ were replaced at the first international symposium on IgG4RD in 2011, when a 3-tiered diagnostic algorithm was proposed (Figure 1).27 A requirement for definitive or probable diagnosis according to this algorithm is tissue IgG4/IgG-positive cell ratio .40%, which was not present in cases 2 through 4 in our series (all had a ratio of IgG4/ IgG-positive cells approximately 10%-25%). Using this algorithm, case 1 in our series falls into the category of Histologically Highly Suggestive of IgG4-related Disease, while cases 2, 3, and 4 are in the category of Insufficient Histopathological Evidence of IgG4-related Disease. The sinonasal mucosa has distinct immunological and histopathological character. It is exposed to many inhaled irritants and stimulants that modify the inflammatory profile even in the normal state. We must make note that lymphoplasmacytic inflammation is a common feature of many subtypes of chronic rhinosinusitis (CRS) though the specific IgG4 staining pattern is not well described.33 That being said, it is possible that our 3 patients with sinonasal
Cain et al inflammation could indeed fall into an ‘‘endotype’’ of CRS.33 However, all patients in our case series had very atypical sinonasal or skull base disease, some with destructive features, that was otherwise inexplicable after extensive work-up. As noted, 3 patients in our series did not satisfy criteria of IgG4/IgG-positive cells .40%, although they all demonstrated increased number of IgG4-positive cells and all responded to glucocorticosteroid therapy. The basis for choosing the ratio of IgG4/IgG-positive cells .40% is not clearly defined and is somewhat arbitrary in the context of sinonasal mucosa. The current diagnostic criteria may accommodate further refining as more data regarding this rare disorder emerge. Furthermore, application of the current criteria to inflammatory sinonasal disease may not be without problems due to the unique immunological characteristics of normal and diseased sinonasal mucosa. Our 3 patients who do not meet current criteria may indeed fit within the IgG4RD spectrum or have a similar but distinct plasma cell–related disorder. Nevertheless, it is important to present these patients to highlight the diagnostic quandaries that may arise in practice. Recognizing that IgG4-positive plasma cell–related inflammatory disorders can present with very atypical and destructive features could be helpful to similar patients. The definitive diagnosis of IgG4RD is not readily made, as this is a relatively unknown entity for otolaryngologists. The diagnosis in case 1 was picked up quickly due to classic pancreatic manifestations of IgG4RD, but the other 3 patients presented more difficult diagnostic challenges. We therefore emphasize the need to disseminate knowledge of this rare disorder. We also now employ IgG4 immunohistochemical stains in clinically suspicious cases so as not to delay diagnosis and treatment. However, it cannot be overstated that malignancies, lymphoma, and infections must be ruled out prior to entertaining the diagnosis of IgG4RD using stringent pathological/immunohistochemical and serological analysis. We highlight the need for refining current diagnostic criteria for IgG4RD in the context of sinonasal and skull base lesions. As CRS is also associated with lymphoplasmacytic inflammation, delineating the spectrum from normal to ‘‘common-variety’’ CRS to IgG4RD is important in this context. Refinement of IgG4RD diagnostic criteria as it pertains to the sinonasal cavity and skull base may lead to earlier diagnosis and initiation of glucocorticosteroid therapy or steroid-sparing immunosuppressive agents.
Conclusions Otolaryngologic IgG4RD is rare and may be an underrecognized condition. We present 4 cases of suspected IgG4RD. While only 1 patient met currently described criteria for IgG4RD, all patients had a marked response to glucocorticosteroid therapy. All presented diagnostic challenges. We propose IgG4RD and IgG4-positive plasma cell inflammatory disorders be considered when one encounters tumefactive and destructive lesions of the sinonasal cavity or skull base. A high index of clinical suspicion and IgG4 immunohistochemical
501 stains can assist in diagnosing such patients with otherwise undefined inflammatory conditions. There is also a need to define specific diagnostic criteria for sinonasal IgG4RD. Author Contributions Rachel B. Cain, primary author, data acquisition and analysis, literature review, final approval; Thomas V. Colby, data acquisition and analysis, literature review, revision, final approval; Vijayan Balan, data acquisition and analysis, revision, final approval; Naresh P. Patel, data acquisition, revision, final approval; Devyani Lal, conception, data acquisition and analysis, revision, final approval.
Disclosures Competing interests: None. Sponsorships: None. Funding source: None.
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502 14. Kamisawa T, Anjiki H, Egawa N, Kubota N. Allergic manifestations in autoimmune pancreatitis. Eur J Gastroenterol Hepatol. 2009;21:1136-1139. 15. Khosroshahi A, Stone JH. Treatment approaches to IgG4-related systemic disease. Curr Opin Rheumatol. 2011;23:67-71. 16. 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;49:1449-1453. 17. Khosroshahi A, Bloch DB, Deshpande V, Stone JH. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease. Arthritis Rheum. 2010;62:1755-1762. 18. Stone JH. IgG4-related disease: nomenclature, clinical features, and treatment. Semin Diagn Pathol. 2012;29:177-190. 19. Sah RP, Chari ST. Serologic issues in IgG4-related systemic diseases and autoimmune pancreatitis. Curr Opin Rheumatol. 2011;23:108-113. 20. Kamisawa T, Shimosegawa T, Okazaki K, et al. Standard steroid treatment for autoimmune pancreatitis. Gut. 2009;58:1504-1507. 21. Ghazale A, Chari ST, Zhang L, et al. Gastroenterology. 2008; 134:706-715. 22. Masaki Y, Sugai S, Umehara H. IgG4-related diseases including Mikulicz’s disease and sclerosing pancreatitis: diagnostic insights. J Rheumatol. 2010;37:1380-1385. 23. Shimosegawa T, Chari ST, Frulloni L, et al. International consensus diagnostic criteria of autoimmune pancreatitis: guidelines of the International Association of Pancreatology. Pancreas. 2011;40:352-358. 24. Kawano M, Saeki T, Nakashima H, et al. Proposal for diagnostic criteria for IgG4-related kidney disease. Clin Exp Nephrol. 2011;15:615-626.
Otolaryngology–Head and Neck Surgery 151(3) 25. Moteki H, Yasuo M, Hamano H, Uehara T, Usami S. IgG4related chronic rhinosinusitis: a new clinical entity of nasal disease. Acta Otolaryngol. 2011;131:518-526. 26. Ikeda R, Awataguchi T, Shoji F, Oshima T. A case of paranasal sinus lesions in IgG4-related sclerosing disease. Otolaryngol Head Neck Surg. 2010;142:458-459. 27. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25: 1181-1192. 28. Wold LE, Weiland LH. Tumefactive fibro-inflammatory lesions of the head and neck. Am J Surg Pathol. 1983;7:477-482. 29. Olsen KD, DeSanto LW, Wold LE, Weiland LH. Tumefactive fibroinflammatory lesions of the head and neck. Laryngoscope. 1986;96:940-944. 30. Frulloni L, Lunardi C, Simone R, et al. Identification of a novel antibody associated with autoimmune pancreatitis. N Engl J Med. 2009;361:2135-2142. 31. Raina A, Yadav D, Krasinskas AM, et al. Evaluation and management of autoimmune pancreatitis: experience at a large US center. Am J Gastroenterol. 2009;104:2295-2306. 32. Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22:21-30. 33. Akdis CA, Bachert C, Cingi C, et al. Endotypes and phenotypes of chronic rhinosinusitis: a PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2013;131:1479-1490.
Perplexing Lesions of the Sinonasal Cavity and Skull Base: IgG4-related and Similar Inflammatory Diseases
Otolaryngology– Head and Neck Surgery 2014, Vol. 151(3) 496–502 Ó American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0194599814533648 http://otojournal.org
Rachel B. Cain, MD1, Thomas V. Colby, MD2, Vijayan Balan, MD3, Naresh P. Patel, MD4, and Devyani Lal, MD1
No sponsorships or competing interests have been disclosed for this article.
Abstract Objective. IgG4-related disease (IgG4RD) causing sinonasal and skull base pathology is uncommonly described. We present a series of suspected IgG4RD patients, with a pertinent review of the literature to highlight diagnostic challenges. Study Design. Case series. Setting. Academic tertiary care center. Subjects and Methods. Case series of patients with IgG4RD or suspected IgG4RD involving the sinonasal cavity and skull base. Results. We present 4 patients with atypical sinonasal and/or skull base disease who were noted to have IgG4-positive plasma cell infiltration on immunohistochemistry of biopsy specimens. IgG4RD, a recently described entity affecting multiple organs, is characterized by lymphoplasmacytic infiltration and often elevated serum IgG4. IgG4RD can masquerade as malignancy or infection but responds to glucocorticosteroid and immunosuppressant therapy. IgG4RD has been infrequently reported presenting as sinonasal or skull base lesions, and definitive diagnostic criteria for these regions are not established. In our series, IgG4RD was suspected in all 4 patients, but only 1 met all current criteria for definitive diagnosis. All 4 patients, however, responded to corticosteroid therapy, and 1 was placed on long-term azathioprine. Conclusion. IgG4RD is rarely described in the sinonasal cavity and skull base, and specific diagnostic criteria for such disease have not been defined. We present a series of patients with IgG4-positive plasma cell inflammatory pathology who were suspected to have IgG4RD. Our series highlights diagnostic challenges associated with these patients. Tumefactive and destructive sinonasal-skull base lesions with a plasma cell-rich infiltrate should incite suspicion of IgG4RD, and immunohistochemistry for IgG4-positive plasma cells should be performed.
Keywords IgG4-related disease, IgG4, tumefactive fibroinflammatory lesion, plasma cell related inflammation, autoimmune pancreatitis
Received January 27, 2014; accepted April 9, 2014.
Introduction IgG4-related disease (IgG4RD) is a fibroinflammatory systemic condition characterized by tumefactive lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and often (but not always) elevated serum IgG4 concentrations.1 The entity was recently characterized in 2003, when patients with autoimmune pancreatitis were noted to have extrapancreatic manifestations.2 Involvement of numerous organ systems with IgG4RD has been described, including the pancreas, biliary tree, salivary glands, periorbital tissues, kidneys, lungs, lymph nodes, meninges, aorta, breast, prostate, thyroid, pericardium, and skin. Exocrine tissue seems preferentially affected.3 Histopathological features are similar across organs. The spectrum of IgG4RD may include Mikulicz syndrome, Kuttner tumor, Reidel thyroiditis,1 and eosinophilic angiocentric fibrosis of the upper respiratory tract,4 which all share similar pathologic features. The clinical presentation of IgG4RD is variable and dependent on the organ systems involved. Single-organ and multi-organ disease is possible. After the pancreaticobiliary system, the head and neck is the next most common site for involvement by IgG4RD.4 The classic tumefactive lesions of IgG4RD have been found in lymph nodes, salivary, lacrimal and thyroid glands, the upper aerodigestive tract, periorbital tissues,4 pituitary gland, paranasal sinuses,5-7 middle ear space and mastoid,8-10 and nasolacrimal duct.3 Chronic sclerosing sialadenitis of the submandibular and parotid glands (Kuttner tumor) is a common manifestation of IgG4RD, resulting in unilateral or bilateral swelling.4,11 1
Department of Otolaryngology, Mayo Clinic, Phoenix, Arizona, USA Department of Laboratory Medicine & Pathology, Mayo Clinic, Phoenix, Arizona, USA 3 Department of Hepatology, Mayo Clinic, Phoenix, Arizona, USA 4 Department of Neurologic Surgery, Mayo Clinic, Phoenix, Arizona, USA 2
Presented at Triological Combined Sections Meeting; January 24-26, 2013; Scottsdale, Arizona, USA. Corresponding Author: Devyani Lal, MD, Department of Otolaryngology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, Arizona 85054, USA. Email: [email protected]
Cain et al Radiologically, these tumefactive lesions appear iso- to hypointense on T2-weighted magnetic resonance imaging (MRI) with homogeneous enhancement. The adjacent bone often shows remodeling with erosion or sclerosis.12 Fludeoxyglucose positron emission tomography (FDG-PET) is effective for evaluating the presence of systemic lesions, with the uptake of FDG decreasing after steroid therapy.7 Autoimmunity, inflammatory, or infectious stimuli have been postulated as inciting factors for the type 2 helper T (Th2)-cell immune response associated with IgG4RD. Th2 cytokines interleukin (IL)-4, IL-5, IL-10, IL-13, IL-17 and transforming growth factor b (TGF-b) are subsequently overexpressed.1,11,13 Eosinophilia and elevated serum IgE levels are seen in approximately 40% of IgG4RD patients.14 These mediators cause influx of inflammatory cells and the characteristic fibrosis that results in subsequent organ damage.1 Most patients with IgG4RD respond quickly to glucocorticosteroid therapy. Oral glucocorticoids are first-line therapy, with a gradual taper over 3 to 6 months.1 Steroid-sparing agents used after steroid-induced remission include azathioprine, mycophenolate mofetil, cyclophosphamide, bortezomib,15 methotrexate,1 and mizoribine.16 B-cell depletion with rituximab, which appears to target the IgG4 subclass alone, is a particularly interesting therapeutic option.15,17,18 However, there have been no clinical trials evaluating any of these agents in IgG4RD. Definitive diagnosis of IgG4RD can only be made via histopathological analysis. However, diagnostic criteria for IgG4RD are not universally agreed upon and may differ for each region. Many sets of criteria have been proposed, some of which differ between affected organ systems. Distinct morphologic features of IgG4RD include a dense lymphoplasmacytic infiltrate in a matted and irregularly whorled (storiform) pattern, obliterative phlebitis, and a mild-to-moderate eosinophil infiltrate. Granulomas and neutrophils are rarely present. Immunohistochemical staining for IgG4 must demonstrate the presence of IgG4-positivity in more than 10 to 50 plasma cells per high power field (hpf). The infiltrate in IgG4RD is a mixture of non-clonal T and B lymphocytes, which distinguishes IgG4RD from lymphoma (characterized by a clonal lymphocyte population). Elevated serum IgG4 concentration is a feature exhibited by many patients with IgG4RD; however, approximately 30% of patients with IgG4RD diagnosed by histopathology/ immunohistochemistry have normal serum IgG4 concentrations.19 Furthermore, the significance of elevated serum IgG4 remains unclear, as it seems to have little prognostic implication for steroid-responsiveness or disease relapse.19-21 Organ-specific diagnostic criteria have been suggested for IgG4-related dacrocystitis/sialadenitis,22 IgG4-related pancreatitis,23 and IgG4-related kidney disease.24 The precise features of IgG4RD in these sites have been described in only a handful of small studies and case reports.5-7,9,10,25,26 As of yet, no site-specific diagnostic criteria have been proposed for IgG4-related rhinosinusitis or skull base inflammation. At the first international symposium on IgG4RD in 2011, the most current set of diagnostic criteria were proposed using a 3-tiered algorithm (Figure 1).27
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Figure 1. Diagnostic terminology proposed in a consensus statement by the Organizing Committee of the 2011 International IgG4-related Disease Symposium (adapted from Deshpande et al).27
Although there are a few case series from Japan and 1 from the United Kingdom describing sinonasal IgG4RD, sinonasal or skull base involvement has not been described in patients from the United States. We present 4 patients presenting with atypical inflammatory sinonasal or skull base lesions who were suspected to have IgG4RD on the basis of impressive numbers of IgG4-positive plasma cells infiltrating biopsy specimens. Their clinical course and radiological findings were initially suspicious for malignancy, skull base osteomyelitis, or autoimmune pathology. After a careful and thorough workup by way of immunohistopathology and laboratory tests, malignancy and infection were ruled out. Herein, we present the detailed description of these patients and a pertinent discussion of the literature to highlight diagnostic challenges.
Methods This study was deemed exempt by the Mayo Clinic Institutional Review Board. The medical records of 4 patients who were suspected to have IgG4RD were retrospectively reviewed. Pathological specimens from each patient were analyzed.
Results: Case Series Case 1 A 60-year-old Caucasian male presented with nasal congestion, cervical lymphadenopathy, retro-orbital pain, and vision changes. Six months previously he had undergone a partial pancreatectomy for a pancreatic head mass, which was found to be autoimmune pancreatitis. He also had previous excisional biopsies for cervical lymphadenopathy, which showed follicular hyperplasia. He was referred to our department after MRI revealed a unilateral cavernous sinus enhancing soft tissue mass (Figure 2A). Given this mysterious clinical picture, the histopathology slides from his previous surgeries were retrieved and reviewed. The pancreatectomy specimen showed focal lymphoplasmacytic infiltrate and marked sclerosis, consistent with IgG4 associated autoimmune pancreatitis (Figure 3). An immunologic panel revealed elevated serum IgG subclass 4 (IgG4) at 195 mg/dL. This patient
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Figure 2. Patient 1: (A) Pretreatment and (B) posttreatment T1-weighted gadolinium-enhanced MRI. A: Enhancing mass in right cavernous sinus (arrow). B: Resolution without recurrence (arrow) 2 years after initiating treatment.
Figure 3. Patient 1: Medium power hematoxylin and eosin (H&E) stain of pancreas showing replacement of normal pancreatic tissue by storiform fibrosis and focal chronic inflammation including plasma cells.
qualified for the diagnosis of IgG4RD, meeting all defined criteria. He was started on prednisone 40 mg daily, with rapid resolution of his symptoms. Repeat MRI after 1 month of prednisone showed a marked decrease in size of the previously noted cavernous sinus mass with minimal residual enhancement. This mass was therefore determined to be an inflammatory pseudotumor secondary to IgG4RD. He was transitioned from prednisone to azathioprine and has continued to do well without relapse. Surveillance MRI 2 years later showed complete resolution of the cavernous sinus mass (Figure 2B).
Case 2 A 66-year-old Caucasian male with a history of insulindependent diabetes, pericarditis, and atrial fibrillation presented with a 9-month history of daily headaches, vertigo, hearing loss, nausea, vomiting, and night sweats. He had a previous extensive workup without a diagnosis. He was admitted for intractable headache. A repeat MRI showed a diffuse enhancing infiltrative process involving the central skull base with bilateral involvement of the nasopharynx, parapharyngeal tissue, mastoid, clivus, and petrous apices
(Figure 4A). Initial differential included lymphoma, nasopharyngeal carcinoma, osteomyelitis, metastasis, or granulomatous process. Positron emission tomography/computed tomography (PET/CT) showed a metabolically active infiltrative petroclival and nasopharyngeal process with a maximum standardized uptake value (SUV) of 9.3 (Figure 4B). Pathology of nasopharyngeal biopsies showed nonspecific chronic inflammatory infiltrate. There was no clonal B-cell population on flow cytometry. The patient went to the operating room for clival biopsies taken via an endoscopic transnasal, transsphenoidal approach utilizing CT-guided localization. Pathology revealed sclerosis and inflammation with polyclonal plasmacytosis and up to 35 IgG4-positive plasma cells per hpf, with an IgG4/ IgG1 ratio of approximately 20%. IgG subclass analysis found elevated serum IgG4 at 153 mg/dL. While IgG4RD was highly suspected, he did not meet all current criteria for definitive diagnosis. Obscuring the clinical picture, culture of clival specimens grew Staphylococcus lugdunensis. The patient completed a 3-month course of intravenous antibiotics without resolution of his symptoms. Dexamethasone 4 mg twice daily was then initiated after the patient was hospitalized for dehydration from vomiting. Shortly after initiation of steroids, the patient’s symptoms resolved. Antibiotic therapy was stopped and he continued to do well on dexamethasone 4 mg every other day. Posttreatment MRI showed significant improvement in the petroclival infiltrative process.
Case 3 A 62-year-old Caucasian woman presented with massive destruction of the nasal septum and ethmoid sinuses causing multiple episodes of epistaxis requiring transfusion. Lymphoma, vasculitis, or granulomatous disease was suspected. Serology was significant for elevated erythrocyte sedimentation rate (ESR), but perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) and cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) were negative. Initial sinonasal biopsies showed nonspecific inflammation. She had multiple subsequent biopsies for progression of disease with destruction of the lamina papyracea and medial maxillary wall. Further histopathological review revealed
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Figure 4. Patient 2: (A) Pretreatment gadolinium-enhanced T1-weighted MRI shows enhancement of bilateral petrous apices and fluid in mastoids. (B) PET/CT with metabolic activity of central skull base and nasopharynx.
acute and chronic inflammation, reactive bone formation, and fibrosis. There was no evidence of granulomatous inflammation, giant cells, or vasculitis. Immunohistochemical staining showed increased numbers of IgG4-positive cells, approaching 50/hpf. However, other features consistent with IgG4RD, such as perivenular lymphocytic cuffing and storiform fibrosis, were not present. Flow cytometry ruled out lymphoma, and Gomori methenamine silver stain was negative for fungal organisms. While IgG4RD was highly suspected, she did not meet current criteria for definitive diagnosis. A complete Rheumatologic panel for autoimmune disease or evidence of cocaine use was nonspecific on repeat testing, with the only abnormalities being elevated ESR and C-reactive protein. Given the exclusion of other known conditions, a diagnosis of possible IgG4RD was postulated due to the presence of increased IgG4-positive plasma cells on immunohistochemistry, despite not all diagnostic criteria for IgG4RD being met. Simultaneously during this workup, the patient was also found to have optic neuritis, and prednisone 20 mg daily was started. She showed regression of optic neuritis and now continues to do well on this regimen without progression of sinonasal destruction.
Case 4
Figure 5. Patient 4: CT shows a lesion causing premaxillary destruction (arrow) with involvement of the nasal septum. Corresponding MRI (not illustrated) showed enhancement of the lesion with gadolinium.
A 79-year-old Caucasian male with stable monoclonal gammopathy of undetermined significance, allergic rhinitis, and atopy presented with a 4-year history of unilateral epistaxis. Nasal cautery had been attempted twice prior. However, he continued to have right-sided epistaxis and presented for evaluation. Nasal endoscopy revealed friable nasal septal mucosa on the right with copious crusting and a normal left nasal cavity. A 2-month trial of medical management with topical tobramycin/budesonide nasal irrigations, mupirocin ointment, and nasal emollient was unsuccessful. Occult malignancy, autoimmune disease, or other inflammatory condition was suspected. A biopsy revealed only inflamed squamous mucosa. CT and MRI showed a lytic, enhancing mass replacing the anterior inferior nasal septum with
erosion of the premaxilla (Figure 5). The patient was taken to the operating room for endoscopic biopsy, during which the thickened abnormal portion of nasal septum was excised. Histopathology showed chronic inflammation with stellate band-like fibrosis and sheets of plasma cells (Figure 6A). Despite the patient’s history of an IgG lambda monoclonal gammopathy, immunohistochemistry did not support plasmacytoma or plasma cell myeloma (Figure 6B). However, an immunoperoxidase stain for IgG4 showed IgG4-positivity in 30-50 plasma cells/hpf (Figure 6C). Congo red stain was negative for amyloid. While IgG4RD was suspected given the histological features and exclusion
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Figure 6. Patient 4: (A) Nasal biopsy: H&E stain with inflammation, plasma cells, fibrosis. (B) Predominance of IgG-positive plasma cells on immunohistochemical staining. (C) IgG4 stain reveals 30-50 IgG4-positve cells/hpf.
of other diagnoses, he did not meet currently defined criteria for IgG4RD. The patient opted to forego systemic glucocorticosteroid therapy due to concerns of adverse effects. He was therefore maintained on daily budesonide nasal irrigations (0.5 mcg in 240 mL normal saline) with resolution of epistaxis and without endoscopic progression of mucosal disease or septal destruction. Oral steroid therapy is being reserved for disease progression. Nasal steroid sprays were not used because of the patient’s previous problems with mucosal erosion and bleeding.
Discussion Tumefactive lesions in the sinonasal cavity and skull base necessitate a broad differential, including neoplasm, vasculitides, autoimmune disease, Castleman’s disease, and granulomatous conditions. We propose that IgG4RD or similarly presenting conditions be considered in the differential diagnosis of inflammatory diseases with destructive or atypical features in the sinonasal cavity and skull base when more common and better defined entities have been excluded. When a new disease is characterized, it is important to consider where such cases had been grouped previously. The term tumefactive fibroinflammatory lesion was coined by Wold and Weiland28 in 1983 to describe head and neck masses with histology similar in appearance to Riedel thyroiditis, sclerosing mediastinitis, retroperitoneal fibrosis, and sclerosing cholangitis.28 Subsequently, Olsen et al29 presented 12 patients with tumefactive fibroinflammatory lesions in the neck, parotid, antrum, nasal cavity, tongue, nasopharynx, or buccal space with clinical and histologic features consistent with those found in IgG4RD, also noting that the lesions resolved with steroids.29 It is likely these previously described ‘‘tumefactive fibroinflammatory lesions’’ may also fit within the IgG4RD spectrum. The sinonasal cavity is an extremely rare site of IgG4RD manifestation. Our literature review showed no previous cases of sinonasal IgG4RD in patients from the United States, with almost all such previous reports describing Japanese patients. Sinonasal mucosal involvement has been described to result in a clinical picture of chronic rhinosinusitis with nasal obstruction, discharge, crusting, and hyposmia.7,25 Tumor-like masses from IgG4RD in the maxillary sinus and nasal septum have also been implicated in case
reports.5,6 Many patients with IgG4RD additionally demonstrate allergic features such as atopy, eczema, asthma, and peripheral eosinophilia.1 The patients in our series showed some features similar to those previously described in the literature.5-7,25 All patients had rather atypical case presentations and clinical features. Data from several studies suggest that men are predominantly affected with IgG4RD, and most patients are older than 50 years of age.30,31 Such description is consistent with the patient characteristics in our series. In addition, tumefactive disease was also noted on radiological imaging, with bony erosion in some. On immunohistochemistry, all of our patients showed rich tissue infiltration with IgG4-positive plasma cells. Two of our patients had elevated serum IgG4 levels and 2 did not. In all, only 1 of our patients met all diagnostic criteria for IgG4RD as most recently defined (Figure 1).27 ‘‘Comprehensive diagnostic criteria’’ were developed in Japan for use by general physicians in making the diagnosis of IgG4RD regardless of organ system affected.32 These criteria necessitate immunohistochemical findings consistent with a ratio of IgG4/IgG-positive cells .40% and infiltration of .10 IgG4-positive plasma cells/hpf, along with tumefactive masses and elevated serum IgG4 concentrations 135 mg/dL.32 These ‘‘comprehensive diagnostic criteria’’ were replaced at the first international symposium on IgG4RD in 2011, when a 3-tiered diagnostic algorithm was proposed (Figure 1).27 A requirement for definitive or probable diagnosis according to this algorithm is tissue IgG4/IgG-positive cell ratio .40%, which was not present in cases 2 through 4 in our series (all had a ratio of IgG4/ IgG-positive cells approximately 10%-25%). Using this algorithm, case 1 in our series falls into the category of Histologically Highly Suggestive of IgG4-related Disease, while cases 2, 3, and 4 are in the category of Insufficient Histopathological Evidence of IgG4-related Disease. The sinonasal mucosa has distinct immunological and histopathological character. It is exposed to many inhaled irritants and stimulants that modify the inflammatory profile even in the normal state. We must make note that lymphoplasmacytic inflammation is a common feature of many subtypes of chronic rhinosinusitis (CRS) though the specific IgG4 staining pattern is not well described.33 That being said, it is possible that our 3 patients with sinonasal
Cain et al inflammation could indeed fall into an ‘‘endotype’’ of CRS.33 However, all patients in our case series had very atypical sinonasal or skull base disease, some with destructive features, that was otherwise inexplicable after extensive work-up. As noted, 3 patients in our series did not satisfy criteria of IgG4/IgG-positive cells .40%, although they all demonstrated increased number of IgG4-positive cells and all responded to glucocorticosteroid therapy. The basis for choosing the ratio of IgG4/IgG-positive cells .40% is not clearly defined and is somewhat arbitrary in the context of sinonasal mucosa. The current diagnostic criteria may accommodate further refining as more data regarding this rare disorder emerge. Furthermore, application of the current criteria to inflammatory sinonasal disease may not be without problems due to the unique immunological characteristics of normal and diseased sinonasal mucosa. Our 3 patients who do not meet current criteria may indeed fit within the IgG4RD spectrum or have a similar but distinct plasma cell–related disorder. Nevertheless, it is important to present these patients to highlight the diagnostic quandaries that may arise in practice. Recognizing that IgG4-positive plasma cell–related inflammatory disorders can present with very atypical and destructive features could be helpful to similar patients. The definitive diagnosis of IgG4RD is not readily made, as this is a relatively unknown entity for otolaryngologists. The diagnosis in case 1 was picked up quickly due to classic pancreatic manifestations of IgG4RD, but the other 3 patients presented more difficult diagnostic challenges. We therefore emphasize the need to disseminate knowledge of this rare disorder. We also now employ IgG4 immunohistochemical stains in clinically suspicious cases so as not to delay diagnosis and treatment. However, it cannot be overstated that malignancies, lymphoma, and infections must be ruled out prior to entertaining the diagnosis of IgG4RD using stringent pathological/immunohistochemical and serological analysis. We highlight the need for refining current diagnostic criteria for IgG4RD in the context of sinonasal and skull base lesions. As CRS is also associated with lymphoplasmacytic inflammation, delineating the spectrum from normal to ‘‘common-variety’’ CRS to IgG4RD is important in this context. Refinement of IgG4RD diagnostic criteria as it pertains to the sinonasal cavity and skull base may lead to earlier diagnosis and initiation of glucocorticosteroid therapy or steroid-sparing immunosuppressive agents.
Conclusions Otolaryngologic IgG4RD is rare and may be an underrecognized condition. We present 4 cases of suspected IgG4RD. While only 1 patient met currently described criteria for IgG4RD, all patients had a marked response to glucocorticosteroid therapy. All presented diagnostic challenges. We propose IgG4RD and IgG4-positive plasma cell inflammatory disorders be considered when one encounters tumefactive and destructive lesions of the sinonasal cavity or skull base. A high index of clinical suspicion and IgG4 immunohistochemical
501 stains can assist in diagnosing such patients with otherwise undefined inflammatory conditions. There is also a need to define specific diagnostic criteria for sinonasal IgG4RD. Author Contributions Rachel B. Cain, primary author, data acquisition and analysis, literature review, final approval; Thomas V. Colby, data acquisition and analysis, literature review, revision, final approval; Vijayan Balan, data acquisition and analysis, revision, final approval; Naresh P. Patel, data acquisition, revision, final approval; Devyani Lal, conception, data acquisition and analysis, revision, final approval.
Disclosures Competing interests: None. Sponsorships: None. Funding source: None.
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