Immunoglobulin G4-related disease (IgG4-RD) manifestations in the head-and-neck: A narrative review with a focus on imaging

Abstract

Immunoglobulin G4-related disease (IgG4-RD) is an autoimmune fibrosclerotic inflammatory condition with distinctive histopathological findings affecting various organ systems. The disease can be tumefactive or “mass-like” in morphology, or less commonly, infiltrative. Many historic and well-known disease entities are manifestations of IgG4-RD in different organs. Radiologists need to be aware of this multifaceted disorder and its systemic nature. We searched Pubmed and Embase using the keywords “head and neck,” “IgG4-related disease,” and “imaging.” We included the relevant review articles published in the English language from 1997 to 2021, whose major area of discussion was IgG4-RD manifestations in the head-and-neck. Filters applied for inclusion were: “full text,” “humans,” “English,” “cancer,” article type: “review,” “meta-analysis,” “systematic review,” and “guideline.” In this review article, we have discussed the wide spectrum of manifestations of this disease at different head-and-neck subsites to familiarize radiologists with this interesting disease entity.

INTRODUCTION

IgG4-related disease (IgG4-RD) is an autoimmune, multisystemic fibroinflammatory condition.^[1] It affects a variety of organ systems and manifests as “mass-like” lesions or infiltrative disease, the latter being less common. The histopathological features of the disease can be used to make a diagnosis. Autoimmune pancreatitis is the most well-known IgG4-RD. Hamano and colleagues discovered considerable IgG4-positive plasma cell infiltration, fibrosis, and obliterative phlebitis in autoimmune pancreatitis, along with elevated blood IgG4 levels.^[2,3] Many extra-pancreatic lesions, including interstitial pneumonia, sclerosing sialadenitis, sclerosing cholangitis, mediastinal fibrosis, and retroperitoneal fibrosis have since been found to have a similar histopathologic appearance and raised serum IgG4 levels. These conditions can occur with or without concomitant autoimmune pancreatitis.^[4] The presence of IgG4-positive plasma cells in Mikulicz disease lesions was reported by Yamamoto et al. in 2005. Mikulicz disease was classified as a new type of IgG4-RD.^[5,6] The classification of IgG4-RD was established by an international symposium in 2011 and is now universally accepted.^[7] Following this, IgG4-RD has been discovered in essentially every organ system and tissue type.^[8] Multiple historically popular eponymous conditions are actually the manifestations of IgG4-RD within different organ systems. IgG4-RD symptoms include Mikulicz disease, Küttner pseudotumor, and Riedel’s thyroiditis, which all occur in the head-and-neck region. IgG4-RD in the head-and-neck is common and can arise as part of a systemic disease or on its own. Head-and-neck, orbit, and salivary glands are the sites most commonly affected.^[9] Other manifestations include enlargement of the lacrimal glands, inflammatory pseudotumors, thickening of the dura mater/pachymeningitis, or lesions in the pituitary and thyroid glands.^[9] A cross-sectional study of 114 IgG4-RD cases by Zen and Nakanuma^[10] and a review of the literature by Ferry and Deshpande^[11] showed that IgG4-RD of the head-and-neck shows female preponderance. Though the incidence of malignancy in IgG4-RD has not been clearly documented, there have been a few case reports.^[12,13] The aim of this review article is to familiarize radiologists with the manifestations of this multisystemic disease in the head-and-neck region.

METHODS

We searched Pubmed and Embase using the following keywords: “head and neck,” “IgG4-related disease,” and “imaging.” The reference lists of each of the shortlisted articles were also searched for additional relevant studies. We conducted a comprehensive search of the published abstracts of IgG4-RD and its manifestations in the head-and-neck region. We included relevant review articles published in the English language from 1997 to 2021, whose major area of discussion was IgG4-RD manifestations in the head-and-neck region. Filters applied for inclusion were: “full text,” “humans,” “English,” “cancer,” article type: “review,” “meta-analysis,” “systematic review,” and “guideline.” We excluded articles which dealt with non-human studies, articles for which the complete text was not available, and those that were not in English. The search strategy is outlined in Figure 1.

Figure 1: Search strategy for identifying articles relevant to imaging in IgG4-related disease in head-and-neck

ETIOLOGY AND PATHOGENESIS

Even though IgG4-RD is commonly recognized as an inflammatory disease, it is not known for certain whether it is triggered by autoimmune, allergic, or other pathways.^[1] The production of mature plasma cells in IgG4-RD is assumed to be triggered by an immune response to an unidentified antigen, which is regulated by cytokines secreted by activated type 2 helper T (Th2) cells and results in a significant fibrotic reaction.^[1,14] Excess circulating B lymphocytes and plasmablasts (immature plasma cells) are found in patients with IgG4-RD, which serves as a biomarker for active disease.^[15,16] The majority of existing evidence supports a link between atopy, sinusitis, asthma, and IgG4-RD.^[17,18]

CLINICAL FEATURES

IgG4-RD is characterized by a subacute onset and a slow progression, with painless enlargement of numerous organs. Infiltrative lesions can also be seen in the orbit, skin, and meninges. Fever and nocturnal sweats are not commonly associated with this disease.^[17,19,20] A major manifestation of systemic disease is weight loss and tiredness.^[8] Many organs can be involved in a synchronous or metachronous manner, and it is important to remember that head-and-neck involvement does not necessarily have to be accompanied by systemic disease. Figure 2 illustrates the various organ manifestations of IgG4-RD, as well as their historical eponymous names.

Figure 2: Diagrammatic representation of the various organ manifestations of IgG4-related disease with the corresponding historic eponymous names of few of these entities (details of the entities from Stone et al. Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations. Arthritis Rheum 2012)

IgG4-RD IN THE HEAD-AND-NECK REGION

IgG4-RD can involve any subsite in the head-and-neck. The most common sites are the salivary glands, lacrimal glands, orbits, thyroid gland, lymph nodes, sinonasal canals, and pituitary stalk.^[21] IgG4-RD entities have now been identified, including idiopathic orbital lymphoid hyperplasia, orbital inflammation (inflammatory pseudotumor), Küttner tumor, Mikulicz disease, Riedel thyroiditis, Hashimoto thyroiditis, and pituitary hypophysitis.^[21] As multiorgan involvement is common in IgG4-RD, when a lesion is confirmed in the head-and-neck region, it is important to evaluate for other organ systems’ involvement. The diagnosis of IgG4-RD is supported when multiple organs are involved. The pancreas, bile ducts, gallbladder, kidneys, retroperitoneum, mesentery, lungs, gastrointestinal system, and blood vessels are the most commonly affected organs beyond the head-and-neck, in descending order of frequency.^[21] Mikulicz syndrome is characterized by painless, symmetrical enlargement of the submandibular, sublingual, parotid, and lacrimal glands on both sides.^[22,23] The salivary glands are affected unilaterally or bilaterally by Küttner tumors, with the submandibular glands being the most commonly afflicted.^[24,25] Unilateral lesions resemble malignant salivary gland tumors, while bilateral lesions must be distinguished from lymphoma and the acute phase of Sjögren syndrome. The lacrimal glands in the orbits are the most typically affected by IgG4-RD.^{[22,23,26,27]} In IgG4-RD, lacrimal gland involvement is frequently bilateral and accompanied by salivary gland involvement.^[22,23] The lacrimal gland may be involved unilaterally, hence, distinguishing IgG4-RD from infectious dacryoadenitis or lacrimal gland cancers is difficult on imaging alone. IgG4-RD of the nasal cavity and paranasal sinus is uncommon; however, it may occur as a part of the multiorgan disease.^[28] The differential diagnosis of IgG4-RD includes Wegener granulomatosis, lymphoma, and fungal disease.^[29,30] Recently, it has been found that IgG4-RD, Riedel, and Hashimoto thyroiditis are related pathologies.^[26,31] Hashimoto thyroiditis is currently divided into two subgroups: IgG4 thyroiditis and non-IgG4 thyroiditis. Riedel thyroiditis is an IgG4-related thyroiditis.^[32] Hypophysitis is inflammation of the pituitary gland.^[33,34] The typical histopathologic findings help in determining the pathophysiology (e.g., granulomatous, lymphocytic, xanthomatous, necrotizing, or IgG4 plasmacytic infiltration). Pachymeningitis is a rare condition associated with IgG4-RD. Germinoma, sarcoidosis, Langerhans cell histiocytosis, and tuberculosis are among the differential diagnoses for sellar or suprasellar lesions in IgG4-RD. Laryngeal involvement as a primary feature of IgG4-RD is extremely rare. Only 14 cases of primary laryngeal IgG4-RD have been reported.^[35] The cervical, hilar, mediastinal, peripancreatic, paraaortic, and mesenteric lymph nodes are frequently affected.^[36,37] On computed tomography (CT), enlarged lymph nodes, with uniform attenuation and enhancement may be seen. On T2-weighted magnetic resonance imaging (MRI), lymphomatous involvement can present as low signal intensity, making it difficult to differentiate it from other pathologic conditions. Lymph nodes can range in size from a few mm to 2 cm. Because of the generic shape of the affected nodes, it is difficult to distinguish between IgG4-RD and sarcoidosis, lymphoma, metastases, or inflammatory reactive nodes. IgG4-related orbital disease, mainly the sclerosing subtype, now accounts for a significant proportion of idiopathic orbital inflammation (IgG4-ROD). IgG4-ROD is believed to impact the extraocular muscles (up to 90%).^[38] Figures 3-6 illustrate the CT and MRI findings in confirmed cases of IgG-RD involving the right and left orbits, as well as the nasopharynx and left nasal cavity.

Figure 3: Contrast-enhanced MRI of the orbits shows a confirmed case of IgG4-related orbital disease in a 33-year old woman who presented with a headache. Soft tissue involved the right lateral (marked with a yellow asterisk) and superior rectus muscle, posteriorly reaching up to the orbital apex, extending into the superior orbital fissure with intracranial extension along the right cavernous sinus. Axial images of the lesion demonstrate (a) T1 hypointense, (b) T2 intermediate signal, (c) homogeneous enhancement. (d) Coronal T2 STIR image shows hyperintense bulky right lateral rectus muscle

Figure 4: Contrast-enhanced MRI of the orbits of a confirmed case of IgG4-related orbital disease in a 16-year-old male with left orbital swelling. The image shows an intraconal soft tissue mass along the medial aspect of the left orbit (marked with a yellow asterisk). There was no intraocular or intracranial extension. The lesion appears (a) T1 isointense, (b) T2 intermediate, and (c) STIR hyperintense, and shows (d) mild homogeneous post-contrast enhancement

Figure 5: Contrast-enhanced CT and MRI of the paranasal sinuses and neck of a confirmed case of IgG4-related disease involving the nasopharynx in a 64-year-old man who presented with 10-day history of a change in the voice. The image shows an infiltrative soft tissue lesion (marked with yellow asterisk) with the epicenter in the nasopharynx. Posteriorly, it is eroding the clivus. There is extension into the right jugular foramen. (a) Coronal reformat of the contrast enhanced CT shows a homogeneously enhancing mass in the nasopharynx. (b) It shows increased metabolic activity on FDG-PET. (c) The lesion is T1 hypointense, (d) T2 intermediate, and shows (e and f) restricted diffusion, (g) avid homogeneous post-contrast enhancement, and (h) coronal STIR image shows hyperintense right nasopharyngeal infiltrative lesion

Figure 6: Contrast-enhanced MRI of paranasal sinuses and neck of a confirmed case of IgG4-related disease involving the nasal cavity in a 31-year-old male with left nasal mass and epistaxis shows a soft tissue mass (marked with a yellow asterisk) occupying the left nasal cavity. The mass is (a) T1 hypointense, (b) T2 hyperintense, (c) bright on STIR, and (d) shows heterogeneous post-contrast enhancement

DIAGNOSIS OF IgG4-RD

For the diagnosis of IgG4-RD, one or more of the following criteria should be present: (a) typical histopathologic appearance, (b) typical radiological findings with elevated blood IgG4 levels, and (c) good response to corticosteroid therapy.^[22] IgG4-RD has diffuse lymphoplasmacytic infiltration, occasional eosinophilic infiltration, obliterative vasculitis, and patchy fibrosis on histopathological analysis. An IgG4/IgG plasma cell ratio (IgG4/IgG ratio) of more than 30% is used to differentiate IgG4-RD from non-IgG4-related inflammatory diseases.^[10] For making a diagnosis of IgG4-RD, a complete clinical history, physical examination, laboratory, and radiographic examination are required.

IMAGING IN IgG4-RD

Ultrasound imaging is helpful for the evaluation of the superficial organs of the head-and-neck region with IgG4-RD involvement like the salivary and thyroid glands. Image-guided percutaneous biopsy of target organs is also possible. On routine CT or MRI scans, enhancing focal mass lesions or diffuse infiltrative disease is seen. CT scans are helpful in assessing the extent of bone involvement in the area. MRI allows for more precise soft tissue evaluation. On diffusion-weighted imaging (DWI), mild apparent diffusion coefficient (ADC) reduction is seen in these lesions.^[38] The tissue celularity and fibrosis determine the extent of diffusion restriction. IgG4-RD lesions are avid on 2-[18F]-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET), which helps in identifying asymptomatic multifocal disease and monitoring treatment response.^[38] CT, MRI, and (18)F-FDG-PET/CT are helpful in making the diagnosis of IgG4-RD with multiorgan involvement.^[22] FDG-PET/CT is helpful for follow-up as increased metabolic activity is noted during active illness with a reduction after corticosteroid therapy. IgG4-related pathology should be considered in the differential diagnosis when several foci of pathologic uptake are found in commonly affected locations. However, FDG-PET/CT alone is not enough to differentiate between IgG4-RD and malignancy.

TREATMENT

Even though IgG4-RD responds well to glucocorticoids, up to 40-45% of patients may relapse.^[39,40] Rituximab, a monoclonal anti-CD20 antibody, is effective in recurrent disease or disease refractory to steroid therapy. Rituximab can be used if urgent treatment is warranted especially if steroids are contraindicated or after failure of the first-line therapy in less aggressive cases.^[41] Retroperitoneal fibrosis, aortitis, proximal biliary strictures, tubulointerstitial nephritis, pancreatic enlargement, pericarditis, and pachymeningitis are among the IgG4-RD cases which need rapid management. Because the untreated disease can cause irreversible damage, many cases necessitate prompt therapy with a combination of moderate-to-high doses of glucocorticoids and additional mechanical treatments in certain organs (e.g., stenting of the biliary tract or ureter). Prednisone at a dose of 30-40 mg/day is the usual first line of treatment. The initial oral prednisolone dose which is recommended for induction of remission is 0.6 mg/kg/day. This dose is administered for 2-4 weeks. It is then tapered by 5 mg every 1-2 weeks, depending on the clinical manifestations, biochemical blood tests, and imaging findings. The dose is tapered to a maintenance dose of 2.5-5 mg/day over a period of 2-3 months. The cessation of steroid therapy is decided based on the disease activity in each case. Termination of maintenance therapy can be considered within 3 years in cases with radiological and serological improvement.^[42] Rituximab may be used instead of glucocorticoid therapy if glucocorticoid therapy is not feasible.^[41] Some patients will require a combination of glucocorticoids and a steroid-sparing immunosuppressive medication since glucocorticoids alone will eventually fail to control the disease and persistent glucocorticoid toxicities may emerge. Some individuals require maintenance therapy after completing successful induction therapy. Japanese consensus guidelines for autoimmune pancreatitis suggest low-dose steroid maintenance therapy (prednisolone 2.5-5 mg/day) for people who are at high risk of relapse.^[42] During the remission maintenance period, a steroid-sparing medication is added in the event of a relapse. Azathioprine, mycophenolate mofetil, 6-mercaptopurine, methotrexate, tacrolimus, and cyclophosphamide are common steroid-sparing treatments; however, there is little research on their effectiveness in IgG4-RD.^[41] If left untreated, IgG4-RD can become refractory, a result of progression to extensive fibrosis.^[1] IgG4-RD can cause significant morbidity and hence a timely and accurate diagnosis is essential.

CONCLUSION

Immunoglobulin G4-related disease is a multisystemic fibro-inflammatory condition that presents with tumefactive or infiltrative lesions with typical histopathological findings. The salivary glands and orbit are the most frequently involved areas in the head-and-neck region. Radiologists need to be cognizant of the multisystemic nature of IgG4-RD and its presentation at each head-and-neck subsite with relevant differential diagnoses. IgG4-RD is sensitive to glucocorticoids and rituximab in the initial stages but can become refractory if there is a delay in diagnosis.

Financial support and sponsorship

Nil.

Conflicts of interest

Vanita Noronha and Kumar Prabhash are members of the editorial board of Cancer Research, Statistics and Treatment. As such, they may have had access to information and/or participated in decisions that could be perceived as influencing the publication of this manuscript. However, they had recused themselves from the peer review, editorial, and decision-making process for this manuscript, to ensure that the content is objective and unbiased.