IgG4-related disease (IgG4-RD) presents a diagnostic challenge due to its varied symptoms, lack of specific tests, and symptom overlap with other conditions. (1,2) This underscores the need for interdisciplinary collaboration. Accurate diagnosis often demands input from radiologists and experienced physicians, typically rheumatologists. IgG4-RD usually appears as an enhancing soft tissue mass or diffuse infiltrative process on imaging. (3) Rarely can a surgical pathologist make a standalone diagnosis of IgG4-RD. The expertise of a trained radiologist and the insight of an experienced treating physician, often a rheumatologist, are essential in guiding the pathologist to an accurate diagnosis. It is wise to remember that the mere elevation of serum or tissue IgG4 does not equate to IgG4-RD. (4)

In 2019, the American College of Rheumatology and the European League Against Rheumatism introduced a three-step classification system for IgG4-RD. (5)These classification criteria consist of a 3-step process. 1) To qualify, a patient must have characteristic symptoms in one of 10 key specified organs (; 2) numerous clinical, serologic, radiologic, and pathologic exclusion criteria must be absent; 3) meet specific clinical, serologic, and pathologic criteria while scoring 20 or higher on additional weighted criteria. Initially designed for research, the system has demonstrated high specificity (98%) and acceptable sensitivity (82%) for IgG4-RD and shows promise as a diagnostic framework (Table 1).

IgG4-RD can involve every part of the head and neck (table 2). Over the past two decades, there has been an effort to link various inflammatory diseases with IgG4-Related Disease (IgG4-RD). Some of these associations have been substantiated, while others remain marginally connected to IgG4-RD (Figure 1). This review focuses on the contentious aspects of IgG4-related head and neck diseases. Like other articles in this Seminar issue, we also discuss conditions that mimic IgG4-RD. Other comprehensive reviews on this topic are available for further reading, including one by one of the authors.(6)

IgG4-RD often targets glands like the major salivary and lacrimal glands, causing painless, symmetrical swelling. (6,7) Submandibular gland involvement is common across ages and genders. Previously called Mikulicz disease (a disease phenotype characterised by the bilateral enlargement of the orbital, parotid, sublingual and submandibular glands), this presentation is now recognised as classic IgG4-RD (table 3). Sicca symptoms like dry eyes and mouth are less severe than in Sjögren syndrome, a condition often mistaken for IgG4-RD. Orbital symptoms are covered separately. Bony destruction is uncommon but can resemble conditions like granulomatosis with polyangiitis when it occurs.

In 2019, Wallace and colleagues identified four distinct clinical phenotypes of IgG4-RD. (5) Their group was the first to identify that the patients with otherwise diverse clinical presentations could be segregated into four mutually exclusive, homogeneous groups: Group 1 (pancreatobiliary), group 2 (retroperitoneal fibrosis/aorta), group 3 (head and neck limited), and group 4 (head and neck and systemic). Of note, the third group is significantly more likely to be younger, female, and Asian when compared with the other three groups. The fourth group has significantly higher serum IgG4 levels. The second group has significantly lower serum IgG4 levels. Although each IgG4-RD phenotype has a unique distribution of organ involvement, it is important to note that the salivary glands can be affected by any phenotype. The clinical and treatment implications of the phenotype designations are yet to be fully determined

Imaging for IgG4-related sialadenitis is often inconclusive.(3) CT scans and MRIs usually show diffusely enlarged salivary glands with occasional superficial enhancement of the parotid glands. This appearance contrasts with Sjögren's syndrome, which displays a "salt-and-pepper" appearance on scans. Doppler ultrasound is the preferred imaging method for IgG4-related sialadenitis, revealing specific vascular patterns distinct from Sjögren's syndrome. PET scans with fludeoxyglucose/CT may indicate abnormal FDG uptake in affected glands but lack specificity. This type of PET scan is helpful for disease staging and evaluating treatment response in IgG4-RD.

A submandibular gland biopsy typically shows classic histological features of IgG4-RD, and a core biopsy can often provide a definitive diagnosis (Figure 2, Figure 3).

The classic histopathological features of IgG4-RD include 1) dense lymphoplasmacytic infiltrate, 2) storiform fibrosis, and 3) obliterative phlebitis (Figure 2). Although we emphasise that these individual features appear straightforward, the devil lies in the details.

A dense lymphoplasmacytic infiltrate implies that lymphocytes and plasma cells dominate the histological background. In addition, eosinophils are often prominent and can be present in sufficient numbers to raise the possibility of a hypersensitivity disorder, fungal and parasitic infections. Histiocytes tend to be invisible on the hematoxylin and eosin stain, although an immunohistochemical stain for histiocytes may highlight these cells.

Storiform fibrosis resembles a coir mat or cartwheel, with columns of fibroblasts and inflammatory cells emanating from a centre. However, in practice, significant variability exists in what constitutes storiform fibrosis. (8) In one study, storiform fibrosis was noted in 15% of the nonspecific sialadenitis group and 29% of the sialolithiasis with sialadenitis group. (8)

Another characteristic, although a relatively under-utilised feature, is the presence of ‘cellular inflamed stroma’. The presence of inflammatory cells, plump fibroblasts and myofibroblasts renders the stroma a cellular and active appearance in contrast to a more common paucicellular, quiescent stroma seen in fibrosis of many other fibroinflammatory lesions.

Obliterative phlebitis is the most characteristic feature of IgG4-RD and is a ubiquitous feature of salivary gland involvement. The clues to Identifying obliterative phlebitis and the mimics of obliterative phlebitis are Illustrated in prior reviews by one of the authors. (9,10)

The histological features are often subtler in biopsies from the parotid and minor salivary glands. Obliterative phlebitis is rarely observed, and storiform fibrosis is less pronounced. Therefore, the diagnosis in these cases usually relies more on IgG4 and IgG immunostaining.

Immunohistochemistry involving IgG4 and IgG is essential for diagnosing IgG4-related sialadenitis. Typically, a count of over 100 IgG4-positive cells per high-power field (HPF) is required, though this number is often exceeded. However, elevated IgG4 cell counts alone do not confirm (IgG4-RD. For instance, a study (8) examining 165 submandibular gland samples from sialadenitis and sialolithiasis patients found ≥70 IgG4+ cells/HPF IgG4+ cells in 19 samples. Despite this, only two patients had IgG4-RD. This finding highlights the non-specific nature of IgG4-positive cells in such diagnoses. A diffuse IgG4 infiltrate, as opposed to isolated clusters, is more indicative of IgG4-RD.

The IgG4/IgG ratio serves as a more accurate marker; in the mentioned study, only 4 of 19 samples with ≥70 IgG4+ cells/HPF and nonspecific sialadenitis or sialolithiasis had an IgG4/IgG ratio above 40%, with two evidencing IgG4-RD. Pathologists, however, face challenges in cell counting due to the high background in IgG staining. In-situ hybridisation staining can alleviate this issue, but it is not widely available (11).

The American College of Rheumatology and the European League Against Rheumatism emphasise the significance of IgG4 counts and the IgG4 to IgG ratio in their classification criteria.

In the authors' experience, chronic non-specific sialadenitis—often associated with calculi—is frequently misdiagnosed as IgG4-RD. Table 4 outlines key features that can help differentiate the two conditions. Morphological appearance plays a crucial role in this distinction.

Lymphoepithelial sialadenitis features lymphocyte infiltration of epithelial cells, forming lymphoepithelial lesions, significant lymphoid infiltration, and germinal centres. The condition lacks fibrosis and has few IgG4-positive cells.

In all IgG4-RD cases, low-grade lymphoma should be considered. A useful guideline for those unfamiliar with hematopathology is that IgG4-RD has sparse and well-circumscribed B-cell lymphoid aggregates; the T-cells are diffusely distributed. Large sheets of B-cells may indicate low-grade lymphoma. Combining B-cell and T-cell markers (CD20 and CD3) can serve as effective screening tools to rule out lymphoma. Note that lymphomas can also develop in the context of IgG4-RD.

Sjogren's syndrome is characterised by a predominantly lymphocytic inflammation involving the salivary glands, particularly the minor salivary glands. Plasma cells are generally not obvious. Other characteristic features of IgG4-related disease, including obliterative phlebitis are not seen in Sjogren's syndrome. Of note, only rare scattered IgG4 positive plasma cells identified in the IgG4 to IgG ratio is invariably less than 10%.

Granulomatosis with polyangiitis (GPA) (formerly Wegener's granulomatosis) is commonly linked with necrosis, vasculitis, granulomas, and giant cells. However, we have observed numerous GPA cases featuring storiform-type fibrosis and lacking traditional features associated with GPA. Additionally, some GPA cases show elevated IgG4-positive cell counts, overlapping with IgG4-RD. Therefore, clinical correlation and serum c-ANCA testing are essential for accurately differentiating the two conditions.

Neoplasms associated with high concentrations of IgG4-positive cells can pose diagnostic challenges. In salivary glands, increased IgG4+ plasma cells are linked with the sclerosing variant of mucoepidermoid carcinoma. (12) To avoid misdiagnosis, focus on histological characteristics: Cords and islands of epidermoid cells and mucous cells and lack of storiform-type fibrosis and obliterative phlebitis. Furthermore, imaging for IgG4-related sialadenitis usually does not reveal a well-circumscribed mass lesion.

Labial salivary gland biopsy represents a more convenient but less sensitive and specific alternative than major salivary gland biopsy for diagnosing IgG4-RD. (13) In one recent study analysing labial gland biopsies from IgG4-RD patients, only 42% showed the typical diffuse lymphoplasmacytic infiltration and abundant IgG4+ plasma cells expected in IgG4-RD. (13) Moreover, none of the biopsies demonstrated storiform fibrosis or obliterative phlebitis. However, around half of the IgG4-RD cases did exhibit an elevated IgG4/IgG ratio greater than 40%, contrasting with Sjögren's syndrome patients, where 0% had an elevated ratio. In another study, the sensitivity of labial salivary gland biopsy for diagnosing IgG4-RD was 55.6%, while specificity was 100%. (14) So, while labial salivary gland biopsy lacks sensitivity as a standalone test for IgG4-RD, an elevated IgG4/IgG ratio may provide supportive information to help distinguish IgG4-RD from mimic conditions like Sjögren's. Routine IgG4 staining in minor salivary gland biopsy in patients with xerostomia is not recommended. (15)

In summary, labial salivary gland biopsy has limitations for diagnosing IgG4-RD but may have some utility when interpreted carefully in the appropriate clinical context.

The involvement of the lacrimal gland is covered in the orbital section of this issue of the Seminars in Diagnostic Histopathology

IgG4-RD can present as a locally invasive and destructive sinonasal mass, most commonly affecting the maxillary sinus, nasal cavity, and septum. (16, 17, 18, 19, 20) On CT, there is an enhancing soft tissue mass with erosion and destruction of the sinus walls or septum. (21) The imaging differential diagnosis includes malignancies like lymphoma or squamous cell carcinoma due to the aggressive appearance. A second pattern is diffuse mucosal thickening; imaging shows diffuse sinus opacification and mucosal thickening, resembling chronic rhinosinusitis. One key clinical aspect of IgG4-related nasal and paranasal sinus disease is its potential to cause adjacent bone erosion, leading to nasal collapse or palatal perforation.

Serum IgG4 has a low specificity for IgG4-related rhinosinusitis. 43/288 (14.9%) patients with rhinosinusitis had elevated serum IgG4 levels > 135 mg/dL, and none of these patients had clinical or histological features of IgG4-RD. (22)

Histologically, the features mirror those discussed earlier. (23) However, diagnosing this condition is notably more challenging than IgG4-related sialadenitis. In a study of 23 patients, Suzuki et al. studied nasal manifestations of IgG4-related disease, only half the cases showed histological features of IgG4-RD.(24) Only 13 patients had >50 IgG4+ cells/HPF, and 12 patients had a ratio >40%, although it is unclear how many had isolated nasal disease versus systemic IgG4-RD. This highlights some of the challenges in diagnosing IgG4-related chronic rhinosinusitis. Given the number of entities that can mimic this disease, the authors urge caution before making this diagnosis.

Fibrosis underlying an ulcer may raise the possibility of IgG4-related disease. However, the granulation-tissue-like appearance should rule out the possibility of IgG4-RD.

In chronic rhinosinusitis, the mucosa is usually edematous and polypoidal, featuring inflammatory cells like lymphocytes, plasma cells, and macrophages. Eosinophils are common in allergic cases. Spindled cells are generally absent, except for isolated stellate fibroblasts, and storiform fibrosis is not observed. Notably, a high number of IgG4-positive plasma cells can be present, similar to levels in IgG4-RD, posing a diagnostic challenge.(25)

Non-invasive fungal rhinosinusitis may be associated with increased IgG4-positive cells. (25) The average IgG4+ cells in fungal rhinosinusitis in one series was 47/HPF, which was not significantly different from the 80/HPF seen in IgG4-related chronic rhinosinusitis. However, only 20% of fungal rhinosinusitis biopsies had an IgG4+/IgG+ ratio greater than 40%, compared to 90% in IgG4-related rhinosinusitis. Identifying fungal elements would rule out a diagnosis of IgG4-related disease. (25)

The sinonasal involvement in granulomatosis with polyangiitis (GPA) often manifests with extensive, erosive lesions and bloody crusting, contrasting with the less erosive disease typically seen in IgG4-related disease. The characteristic histopathological features of GPA include necrotising inflammation, giant cells, granulomas, and vasculitis. (26) However, some GPA cases exhibit nonspecific findings like eosinophils and neutrophilic microabscesses. We have encountered challenges differentiating GPA from IgG4-related disease in cases where GPA biopsies show storiform-type fibrosis (Figure 4) and increased IgG4+ cells but lack the classic GPA features. In these scenarios, detecting c-ANCA autoantibodies and antibodies against proteinase 3 can be essential to distinguish GPA from IgG4-related disease. While the histopathology may occasionally be ambiguous, the serological markers provide key evidence supporting the diagnosis of GPA over IgG4-related disease when clinical suspicion for GPA is high.

Most inflammatory myofibroblastic tumours consist of atypical spindle-shaped cells and lymphocyte infiltration, making them easily distinguishable from IgG4-RD. However, some display sparse spindle neoplastic cells and a dense lymphoplasmacytic infiltrate, resembling IgG4-RD, with increased IgG4-positive plasma cells (Figure 5). Genetic alterations like ALK, ROS, and NTRK fusions can be screened via immunohistochemistry. Yet, the lack of reactivity for these markers does not rule out an inflammatory myofibroblastic tumour for two reasons: 1) Immunohistochemistry for ROS and NTRK are relatively insensitive markers of the corresponding genetic alteration, and 2) many inflammatory myofibroblastic tumours, especially in adults, lack known genetic fusions.

A pathologist should consider lymphoma when diagnosing IgG4-RD, particularly in the nasal region, where ruling out Extranodal NK/T-Cell Lymphoma, Nasal Type is crucial. Characteristic histology shows angiocentric growth, necrosis, and polymorphous lymphocytic infiltration. The NK/T-cell phenotype (Immunophenotype is typically CD20-, CD3+, cytotoxic markers positive) aids diagnosis. Nasal Type consistently tests positive for EBER, whereas IgG4-RD tests negative for this marker.

Oral plasma cell mucositis is an inflammatory condition of the oral cavity and upper aerodigestive tract unrelated to IgG4-RD. Bateman and coworkers studied oral plasma cell mucositis and other non-specific chronic oral mucosal ulceration and inflammation and identified > 100 IgG4+ plasma cells per HPF in half the cases. (27) These conditions are distinct from IgG4-RD, highlighting the importance of a comprehensive diagnostic approach beyond IgG4 cell count alone. Elevated IgG4 cells can be found in various diseases with chronic inflammation, like syphilitic mucosa inflammation, illustrating the necessity of a broader diagnostic lens to avoid misinterpretation based solely on IgG4 cell count.