KeywordsInflammatory disorders, Lymphoproliferative disease, Orbit, Salivary gland, Thyroid, Pachymeningitis, IgG4
IgG4-related disease (IgG4-RD) is a relatively recently recognized fibroinflammatory condition of unknown etiology characterized by elevated serum IgG4, plasmacytic infiltration, multifocal tumefactive fibrosis, and clinical improvement by steroid therapy.
The association between autoimmune (sclerosing) pancreatitis and elevated serum IgG4 was first described by Hamano et al. in 2001, but it wasn’t until 2003 that the systemic nature of IgG4-RD was discovered. After the pancreas, the head and neck is thought to be the second most common site of involvement by IgG-RD. Recent years have been marked by a cascade of research implicating IgG4-RD in multiple previously established conditions. In the head and neck these include hypertrophic pachymeningitis (HP) in the skull base, Küttner tumor (2005), Mikulicz disease (2006), fibrous subtype of Hashimoto (2009), Riedel thyroiditis (2010), and a subset of idiopathic orbital inflammatory disease (2007).
IgG4-RD was originally described in Japan, and 74% to 86.6% of all reported cases are Japanese. However, it has likely been underreported in the western world, with IgG4-RD now described in nearly all ethnic groups across all continents. A recent review of cases at a North American institution showed 80% to be of Caucasian ethnicity.
Including all subsites, IgG4-RD in the head and neck has an almost 1 : 1 gender ratio, which is in contrast to systemic manifestations of IgG4-RD that favor males with a reported ratio of 1.3 to 3.2 : 1. The average age at presentation is 60.4 years, although there are case reports of IgG4-RD in children.
The most common subsites within the head and neck are the salivary glands and the orbits. Discrepancy exists in the literature as to which is more common. One study reviewing 799 cases of systemic IgG4-RD found that salivary gland involvement was more common (40% vs. 29%), whereas another study reviewing 730 cases of IgG4-RD with only head and neck manifestations found that orbital involvement was more common (22% vs. 53%). Less common subsites in the head and neck include thyroid, dura, pituitary hypophysis, temporal bones, paranasal sinuses, cervical lymph nodes, and larynx ( Fig. 40.1 ).
Histologically, IgG4-RD is characterized by a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. It remains unclear whether IgG4-RD is of autoimmune, allergic, or other etiology and IgG4 plasma cells in tissue, the hallmark of the disease, may be pathogenic or simply a response to an unknown inflammatory process. Elevated serum IgG4 is often detected, but nearly 50% of biopsy proven and clinically active systemic IgG4-RD may have normal serum IgG4 levels. Two different diagnostic criteria have been proposed.
According to the international symposium on IgG4-RD in Boston (2011), two-thirds of histologic features are diagnostic of “highly suggestive of IgG4-RD.” With fewer criteria, “probable IgG4-RD” can still be diagnosed if other serologic or radiographic evidence of IgG4-RD are present. Exceptions for “highly suggestive” are made for dacryoadenitis (one-third of histologic features), and oral mucosa and lymph nodes (reliant on IgG4 cell number and ratio).
Dense lymphoplasmacytic infiltrate
Fibrosis, usually storiform in character
According to the Japanese criteria (2012), characteristic diffuse or localized swelling or masses in single or multiple organs ( Table 40.1 ), in addition to both criteria, is diagnostic of “definite IgG4-RD.” Combined with only one criterion it is diagnostic of “possible IgG4-RD.”
Elevated serum IgG4
Marked lymphocyte and plasmacyte infiltration, fibrosis, and elevated IgG4/IgG cell ratio on histology
|Head and neck||Mikulicz disease|
|Orbital inflammatory pseudotumor|
|Fibrotic subtype Hashimoto thyroiditis|
Temporal Evolution: Overview
In general, IgG4-RD is characterized by relapsing-remitting, but slowly progressive, mass-like and fibrotic soft-tissue lesions, which can be focal or diffuse and typically are described as firm if palpable. The diagnosis is often delayed by months to years, likely due to the often-painless nature, relative sparing of glandular function, and lack of systemic symptoms until late in the disease. However, a minority of patients will present with fulminant disease at the outset. Once the abnormality is recognized, diagnostic delay is common, often arising from confusion with neoplastic processes due to the mass-like appearance of the lesion on imaging and clinical exam.
IgG4-RD characteristically exhibits rapid response to steroids and other immunosuppressive regimens, but this is not specific and should not be used to differentiate IgG4-RD from other pathologies. Although as many as 32% to 40% of cases will show relapse or treatment failure with initial therapy, full remission with medical treatment has been reported in up to 90% of cases. Despite this, surgery is common, either to treat local mass-effect or due to suspicion of neoplasm.
Temporal Evolution: in Greater Depth
Küttner Tumor (Localized Salivary)
The natural history of Küttner tumor is often insidious and slow growing, with more than 70% of patients presenting with a painless salivary gland mass often months to years after initially noticing it (median symptom duration ~20 months). Ultrasound is more specific than magnetic resonance imaging (MRI), classically showing a hypoechoic lesion “resembling cirrhosis” in the liver. However, even with characteristic imaging features and benign or indeterminate pathology on fine-needle aspiration (FNA), patients will almost always proceed to surgery due to concern of neoplasm. Upon excision recurrence is extremely rare. As a result of the recent correlation with IgG4-RD, steroids have been used to treat some cases, with good response demonstrated.
Mikulicz Disease (Diffuse/Multiglandular Salivary)
Mickulicz disease characteristically presents with painless swelling of the parotid, submandibular, lacrimal, and (in up to 50% of cases) sublingual glands. Involvement of glands need not be synchronous or sequential, often persists for a period of more than 3 months, and may evolve over years. Computed tomography (CT) and MRI will demonstrate either generalized or segmental enlargement of the affected glands, usually with a homogeneous appearance. Salivary gland function is normal to only mildly decreased with good response to steroids and rituximab. This is in stark contrast to Sjögren syndrome (SS), which demonstrates recurrent and short-lived glandular swelling without treatment, severe sicca symptoms, poor response to glucocorticoids, and progression to irreversible glandular damage in its end-stage.
IgG4-related orbital disease (IgG4-ROD) tends to present insidiously with painless proptosis and diplopia. It usually follows a relapsing remitting course and most commonly shows bilateral enlargement of the lacrimal glands on imaging, but also often involves other orbital adnexal structures. Both IgG4-ROD and non-IgG4-related idiopathic orbital inflammatory disease typically respond to glucocorticoids. However, the relapse rate upon stopping glucocorticoids tends to be higher in IgG4-ROD (67% vs. 30%) and relapse occurs earlier (mean recurrence at 1 month vs. 5 months). For this reason, some authors suggest that IgG4-ROD may need ongoing maintenance therapy.
Thyroid (Riedel Thyroiditis)
Riedel thyroiditis is generally a slowly progressive condition presenting with firm (“rock hard”), fixed, and usually painless enlargement of the thyroid often with local tissue infiltration and mass effect. It can cause hypoparathyroidism, tracheal compression, and recurrent laryngeal nerve involvement. Delay in diagnosis is common, ranging from 10 months to 2 years after goiter. It has been reported to occasionally stabilize or even regress after presentation, but commonly patients will undergo surgery to relieve compressive symptoms and exclude a neoplasm. However, complete resection is difficult and postoperative complications, such as vocal cord paralysis, are as common as 39% even in expert hands, leading some authors to suggest that surgical management may not be the best option. Due to the rarity of the condition, medical management is not well established. However, glucocorticoid therapy has been reported to result in a dramatic reduction in size of the mass, with the resolution of symptoms, such as recurrent laryngeal nerve involvement, in some cases.
HP can present with focal neurologic deficits (related to mechanical compression of neurologic or vascular structures) or diffuse symptoms such as headache, seizure, and cognitive decline. The most common clinical history is of chronic headache and multiple cranial neuropathies, although rapid progression of symptoms can occur in some situations. On CT and MRI linear or focal mass-like dural thickening and enhancement are noted, which can involve cranial nerves and can sometimes erode bone. This fibro-inflammatory dural thickening tends to be hypointense on T2-weighted imaging, avidly enhancing after administration of intravenous gadolinium, and can demonstrate radiotracer accumulation on F18 and C11 PET. Treatment is largely empirical due to limited evidence, but glucocorticoid and steroid-sparing agents (i.e., rituximab) have shown clinical and radiologic response. As with IgG-RD elsewhere in the body, early response to glucocorticoids is characteristic (often within 2 weeks), but is not specific and should not be used to differentiate IgG-RD from other causes. Additionally, the relapse rate upon steroid withdrawal is relatively common. In at least one case, resistance to traditional immunosuppression for over 1 year was overcome by a trial of intrathecal rituximab, which demonstrated clinical and radiologic improvement after 1 month.
Diagnosis and Differential
Küttner Tumor (Localized Salivary)
Küttner tumor (chronic sclerosing sialadenitis) is a focal fibroinflammatory condition of the salivary glands first described by Küttner in 1896 and was recognized as a manifestation of IgG4-RD in 2005. Much of the literature is based on case reports, with Küttner tumors only representing 4.6% of a series of 152 surgically managed salivary gland disorders. However, it may be underreported with another series showing it as a cause of as many as 43% of surgically managed submandibular tumors. The submandibular gland is most commonly affected (85.7%), followed by the parotid gland (14.3%). Although lesions can be bilateral, the term Küttner tumor is reserved for involvement of only a single salivary anatomic site (i.e., the submandibular glands or parotids glands), whereas Mikulicz disease refers to the involvement of multiple glands of varying size, including the lacrimal glands (see below).
More than 70% of patients present with a painless mass often months to years after the initial symptoms (median symptom duration ~20 months). Ultrasound typically shows a geographic hypoechoic lesion sometimes described as resembling cirrhosis in the liver. It may contain a dilated duct and is usually hypervascular on Doppler. CT and MRI are less specific, showing a mildly enhancing lesion, which may be hypointense on T2-weighted imaging ( Fig. 40.2 ) similar to lymphoma.
The primary differential diagnosis is that of a benign or malignant primary salivary gland neoplasm, MALT lymphoma, and chronic inflammatory sialadenitis. Percutaneous core biopsy under ultrasound is key to making the diagnosis of this medically treatable disease, as FNA will often be negative.
Mikulicz Disease (Diffuse Salivary and Lacrimal)
In 1892, a Polish surgeon published a single case of bilateral painless enlargement of the lacrimal, submandibular, and parotid glands. Subsequently, investigators made a distinction between “Mikulicz syndrome” secondary to a range of systemic diseases (i.e., sarcoid, lymphoma and tuberculosis), and idiopathic Mikulicz disease. For a time, due to histologic similarities, Mikulicz disease was thought to be a subtype of SS. However, in 2006, Mikulicz disease was recognized as falling under IgG4-RD, distinguishing it as an entity separate from SS.
Mikulicz disease is characterized clinically by painless swelling of the parotid, submandibular, lacrimal, and (in up to 50%) the sublingual glands, often persisting for months to years. CT and MRI typically demonstrate enlargement of the affected glands, either generalized ( Fig. 40.3 ) or segmental. The glandular parenchyma usually appears homogeneous, although ultrasound can show uniformly sized hypoechoic nodules, particularly in the submandibular gland.