# Outologic Manifestations of IgG4-Related Disease: Literature Review and Report of Two Cases
## 5 Discussion  
Since the first diagnosis of IgG-RD as autoimmune pancreatitis more than two decades ago [3], various patterns have been identified in different locations of the body. Occasionally the process is limited to a single organ, but the fibrotic and inflammatory process can be multiple organs, as well. Due to unspecified inflammatory and infiltrative pathophysiology nature, there is commonly misdiagnosis of infections, autoimmune conditions, and space-occupied lesions [27]. Regarding the head and neck region, the disease is reported practically in almost every organ, from the clivus, through meninges to the orbits. A systematic review recently published, identified 184 cases of IgG4-RD in the skull and skull base [11]. Disease involving the mastoid bone was reported in ten cases (5.3%), making it the most frequent location affected in the anatomical region of the ear. The first case of otologic manifestations was reported in 2010 by [PERSON] et al. [9], and since then an ongoing number of cases have been reported. [PERSON] et al. [28] reviewed the literature and identify 22 cases of IgG-RD with 5 cases involved the mastoid. According to these case studies, otological IgG4-RD consists of progressive hearing loss, otolgia, tinnitus, and vertigo. Recurrent mastoiditis, secretory otitis media, otorrhoea, and facial numbness, have been the main clinical symptoms. IgG4-RD may mimic multiple conditions, including infections, malignancies, and autoimmune diseases [2]. Thus, differential diagnosis may be broad and include not only imaging studies but serology investigations as well, including human immunodeficiency virus (HIV) testing, anti-nuclear antibody (ANA) titers, and antineutrophil cytoplasmic antibody (ANCA) titers, in purpose to rule out other conditions [24]. The gold standard for IgG4-RD diagnosis is histopathology. The key morphologic features of IgG4-RD are threefold: a dense lymphoplasmacytic infiltrate, storiform-type fibrosis, and obliterative phlebitis [2]. In the consensus statement on the pathology of IgG4-RD, an attempt has been made to create criteria for pathological diagnosis in various organs such as the pancreas, lungs, lymph nodes, and salivary glands. Specific criteria regarding the ear and its components were not given, since cases are quite rare. Secondary in importance, IgG4 immunostaining and calculating per HPF and measurement of IgG4/IgG ratio are recommended, with a comprehensive cutoff value when plasma cell ratio is over 40% [29]. In both cases reported here, IgG4/IgG ratio was lower than 20%, illustrating the certainty of such ratio on definitive diagnosis. IgG4 levels in serum are not mandatory for IgG4-Rd diagnosis. There are cases where the levels are increased, but the sensitivity and specificity of the immunoglobulin levels are still in doubt [1]. Even though not mandatory, taking IgG4 levels in the serum along with the levels in HPF and IgG4/IgG ratio from the histological examination could have been valuable in the diagnosis process in our cases. IgG4-RD lesions are well visualized on MRI and/or CT scan, particularly in cases with bone involvement, such as in the mastoid bone. In postcontrast imaging studies, IgG4-RD lesions are typically' nonspecific- homogenously enhancing, which does not reliably distinguish between IgG4-RD and another inflammatory or tumor process in the bone and its surroundings [30]. To date, there is a lack of randomized controlled trials examining the appropriate treatment for IgG-RD, especially in cases of solely organ involvement. Glucocorticoids are usually the first line of therapy. In 2010, a consensus statement from 17 medical centers in Japan proposed initial treatment with prednisolone for 14 to 30 days [31]. In this study we reported two cases of IgG-RD involving the mastoid bone and the middle ear, showing characteristic histopathological features of the disease.