Atypical IgG4‐related disease limited to the sino‐nasal cavity: A case report

Abstract Given the overlapping clinical features of sino‐nasal immunoglobulin 4‐related disease (IgG4‐RD) to rhinitis or rhinosinusitis, this paper aims to delineate this rare, isolated manifestation significant to physicians for their daily practice and researchers contributing to this field.


| BACKGROUND
We are presenting a case report about sino-nasal immunoglobulin 4-related disease (IgG4-RD) in a middle-aged Southeast Asian man without systemic disease.
IgG4-related disease (IgG4-RD) refers to a group of immune-mediated inflammatory disorders with overlapping characteristic features clinically and on histopathology. 1,2 This systemic condition tends to be benign and chronic inflammatory sclerosing in nature is infiltrated by positively staining IgG4-positive plasma cells. [3][4][5][6] This infiltrate also leads to fibrosis organized in a storiform pattern with mildto-moderate tissue eosinophilia or that which is obliterative in nature. 7 Two common findings associated with this disease are allergic conditions and tumefactive lesions, which can manifest highly destructive behavior involving bony invasion, nerve infiltration, and bone marrow infiltration. 1,3,4,8 In terms of treatment, there is a favorable prognosis if treated early with prednisone. 3,4,9 Moreover, a prospective, openlabel clinical trial and case series reported the effectiveness of rituximab for IgG4-RD even without adjunctive glucocorticoid therapy. 10 Typically, multiple organs are involved and could include the lacrimal gland, salivary gland, thyroid gland, pancreas, biliary tract, and retroperitoneum. 4,6,7,11,12 On the other hand, IgG4-RD presenting as an isolated sino-nasal lesion is extremely rare in the literature. 3,13 Facial pain, epistaxis, and the clinical symptoms of chronic rhinosinusitis were commonly described in the sino-nasal mucosal presentation of this IgG4-RD. 14 Furthermore, in the first systematic review of IgG4-RD presentation in the head and neck that reviewed 484 patients, who majority were from Asia, however, none were reported from the Middle East or India. 15 This case report is about sino-nasal IgG4-RD in a middle-aged Southeast Asian man without systemic disease.

| CASE PRESENTATION
A 38-year-old Indian male patient, with no known comorbidities, was referred to the ENT outpatient clinic due to persistent right-side nasal pain and frequent nasal bleeding that stops with conservative measures, the patient did not have visual symptoms, he denied any systemic symptoms as arthralgia, fever, weight loss, or generalized weakness, the patient gave a history of endoscopic sinus surgery in the right nasal side done abroad 6 months prior to the presentation, and histopathology showed sino-nasal IgG4-related disease.
The physical examinations showed absent inferior nasal turbinate, crusts, and adhesions in the right nasal cavity with a clear left nasal cavity.
The lesion evaluated radiologically by Sinus CT (computed tomography) scan with contrast, Sinus MRI (magnetic resonance imaging) with contrast (Figures 1,2) which showed evidence of previous right uncinectomy, medial maxillectomy, and right inferior turbinectomy, with mass occupying the right maxillary sinus and destruction of lamina papyracea without signs or orbital herniation.
The patient was referred to the rheumatology team to check for rheumatologic manifestations and systemic involvement, clinically patient did not have any complaints, blood workup showed high blood levels of IgG4 257.00, reference range (3.00-201.00), total IgE of 976.00 Reference range (0.00-114.00), and blood flow cytometry showed a low level of CD19 count of 1.00 reference range (107.00-698.00).
The patient underwent FDG PET CT scan (fluorodeoxyglucose-positron emission tomography-computed tomography; Figure 3) that showed increase metabolic activity in the walls of right maxillary sinus with no signs of distant metabolic activity, and the patient was cleared from rheumatological point of view and diagnosed as isolated right sinomaxillary IgG4 disease.
The patient underwent mass debulking and excision ( Figure 4) then he was followed by rheumatology team where he received three doses of rituximab (each dose of 1 gram) and low dose prednisolone 5 mg daily for 3 months then tapered to 2.5 mg over the same period, the patient is following with rheumatology team on 3-month bases and disease progression is followed clinically and with lab tests.
The patient was followed by the ENT team on regular basis every 3 months, he did not give any history of recurrent epistaxis, and physical examination showed no signs of local recurrence.

| HISTOPATHOLOGY
Sections of the nasal biopsy show upper respiratory mucosa overlying fibrotic soft tissue infiltrated by numerous plasma cells and scattered small lymphocytes. Note the significantly increased IgG4 to IgG ratio.

| DISCUSSION
Currently, the majority of the patients reported in the literature come from the United States and Japan. 15 Interestingly, a recent cross-sectional study that gathered cases of IgG4-RD head and neck presentation among patients from America, Europe, and Asia reported a predilection for female patients and patients of Asian descent. 16 It is common among middleaged, elderly men above 50 years old. 6 Our patient happens to come from Southeast Asia. It would be worth investigating what etiology puts certain populations at risk or whether a higher index of clinical suspicion exists in certain parts of the world compared to other regions. 15 A literature review that investigated eight patient cases showed that IgG4-RD frequently involved the maxillary sinus; six of those had a local extension to the sino-nasal area. After urgently ruling out common malignant sino-nasal tumors like squamous cell carcinoma and lymphoma, this disease must be high in differential not to delay diagnosis and treatment. 17 Currently, no definitive diagnostic criteria for IgG4-RD affecting the sino-nasal cavity are established; rather, a 3-tiered diagnostic algorithm in a consensus statement was proposed during the first international symposium on IgG4-RD in 2011. 18 This statement declares that the diagnosis of IgG4-RD is highly suggestive or probable depending on which histopathology features are met, including "dense lymphoplasmacytic infiltration with increased IgG4-positive plasmacytosis, fibrosis, often storiform in character, and obliterative phlebitis." 19 Our patient falls under the category of "histologically highly suggestive of IgG4-RD" after the meeting. 13 Symptoms mimicking rhinitis or rhinosinusitis including facial pain due to pressure, bloody nasal discharge, and nasal obstruction may prompt prescription of steroid sprays in the clinic, possibly delaying or missing investigating for IgG4-RSD, which is only an emerging disease in the literature. 15 Moreover, despite the diagnosis of rhinosinusitis, there are cases reported of a patient with rhinosinusitis complicated with IgG4-RD (Table 1), so this differential must always be kept in mind. 20

| CONCLUSION
We hope this case report promoted broader recognition of IgG4-RD among physicians and researchers, also highlighting the extremely rare manifestation of IgG4-RD in the sino-nasal cavity. While ruling out malignancy, lymphoma and infection are critical before considering IgG4-RD, and investigations such as histopathology and serology should not be delayed maximizing patient outcome given studies have shown good prognosis with early intervention. In terms of demographic, it would be interesting to learn more about patient cases from different parts of Asia who may contribute to this reported predisposition for head and neck manifestations of IgG4-RD. 16,17

ACKNOWLEDGMENTS
We thank the patient for letting us to share his case, open access fund provided by Qatar National Library.

CONFLICT OF INTEREST
None declared.

AUTHOR CONTRIBUTIONS
HAS and MZS: involved in manuscript writing. KS, AAA, and AS: involved in data collection and manuscript writing.

PATIENT CONSENT
Consent obtained from the patient is available upon request.

DATA AVAILABILITY STATEMENT
All data generated or analyzed during this study are included in this published article.