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The many facets of dacryoadenitis

Mombaerts, Ilse

Current Opinion in Ophthalmology: July 2015 - Volume 26 - Issue 5 - p 399–407
doi: 10.1097/ICU.0000000000000183
OCULOPLASTIC AND ORBITAL SURGERY: Edited by Richard C. Allen
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Purpose of review To review the spectrum of lacrimal gland inflammation, with particular reference to the old condition, idiopathic dacryoadenitis, and the new, immunoglobulin G4 (IgG4)-related dacryoadenitis.

Recent findings Idiopathic dacryoadenitis remains the most common inflammatory lesion of the lacrimal gland, for which surgical treatment is successful. There is mounting evidence that the presence of IgG4-positive plasma cells in a lacrimal gland specimen is nonspecific, for being found in other inflammatory lacrimal gland lesions, even lymphoproliferative ones. To identify IgG4-related dacryoadenitis, particularly when there is no documented disease elsewhere, the criteria have been strengthened toward abundant IgG4-positive plasma cell counting.

Summary The gold standard of diagnosis of noninfectious lacrimal gland inflammation is tissue biopsying, which is commonly therapeutic in the case of idiopathic dacryoadenitis. Although it was initially suggested that IgG4-related dacryoadenitis is a possible cause of idiopathic dacryoadenitis, it becomes obvious that it has more resemblance to the lymphoproliferative tumors.

Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium

Correspondence to Ilse Mombaerts, Department of Ophthalmology, University Hospitals Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium. Fax: +32 16 33 26 67; e-mail: Ilse.Mombaerts@uzleuven.be

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INTRODUCTION

Approximately, half of the lacrimal gland mass lesions bear the histologic diagnosis of dacryoadenitis [1,2]. When interpreting the results of a biopsy, it is important to understand the architecture of the normal lacrimal gland. It contains immunoglobulin (Ig) A plasma cells, T cells, and a few B cells, occasionally organized in periductal lymphoid aggregates, with interlobular fibrosis [3]. It belongs to the lymphoid tissue system referred to as mucosa-associated lymphoid tissue (MALT). With aging, increased focal infiltration by T and B cells, increased periductal and interacinar fibrosis along with acinar atrophy, dilated ducts and interlobular fatty infiltration becomes evident [4].

The lacrimal gland is often a primary target of the immune system, as a result of an autoimmune disorder, or unique to the lacrimal gland, as in the poorly understood idiopathic lesions. By contrast, the inflammation can originate from the immune response to an infection or a neoplastic process. In clinical practice, dacryoadenitis is a source of obscurity for it often lacks the inflammatory signs, and presents with enlargement only, and a source of confusion for it can be the symptom of a neoplastic lesion. This review discusses the main causes of lacrimal gland inflammation, classified as infectious, idiopathic, autoimmune, and lymphoproliferative. They differ across the age and sex groups, although many conditions can affect all (Fig. 1). There is no role for a diagnostic corticosteroid trial in any of these causes.

FIGURE 1

FIGURE 1

Box 1

Box 1

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INFECTIOUS DACRYOADENITIS

In acute onset painful lacrimal gland inflammation, an infectious origin is considered first. The causative organisms are more often viral than bacterial, particularly in children and young adults [5,6]. Most commonly it is caused by Epstein–Barr virus (mononucleosis), less often by mumps, adenovirus, herpes zoster, herpes simplex, rhinovirus, or cytomegalovirus [5,7]. It usually presents with regional lymphadenopathy, occasionally generalized, and in 25% of cases with fever [5]. Both lacrimal glands are simultaneously affected in, approximately, 40% of patients, particularly in mononucleosis and mumps [5,8,9]. The disease takes 4–6 weeks to resolve, and the benefit of oral antiinflammatory or antiviral treatment is uncertain.

Acute suppurative bacterial dacryoadenitis is less common. It is usually caused by Staphylococcus aureus, including the methicillin-resistant variant, followed by skin flora, Streptococcus and Haemophilus influenzae[6,10,11]. Other bacteria, such as Pseudomonas, Moraxella, diphtheroids, Gonococcus, Micrococcus, Schistosoma, Mycobacterium tuberculosus, and Klebsiella pneumoniae have been implicated as very rare causes [8,12–14]. It may develop from adjacent skin infection, from hematogenous spread, or from cellulitis secondary to sinusitis, and rarely in association with lacrimal ductal cysts or stones [12,15,16]. It manifests as unilateral lacrimal gland swelling, purulent conjunctival discharge, and pouting of the lacrimal ductules. Roughly, half of the cases are complicated by lacrimal gland abscess formation, displayed on imaging as a low-density area in the contrast enhanced enlarged lacrimal gland [10,17]. There is usually no fever, unless in a lacrimal gland abscess associated with sinusitis [18–20]. Treatment includes systemic broad spectrum antibiotics, with surgical drainage in the case of a persistent abscess [15,17].

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IDIOPATHIC DACRYOADENITIS

Idiopathic, or nonspecific, dacryoadenitis represents the most common histologic diagnosis in lacrimal gland lesions [1,21]. It is a poorly understood disorder, characterized by a lacrimal gland mass that causes inflammation, fibrosis, and damage. Its cause remains elusive, despite an increased comorbidity of autoimmune diseases that are not known to be related to lacrimal gland disease [22▪]. Both a humoral and cell-mediated immunity have been implicated in the pathophysiology, the latter with site-specific wound healing and associated with the sclerotic subtype [23,24]. There is also evidence for an innate immune response to microbial inducers, but bacterial or abundant viral antigens have not been identified so far [25–27].

The clinical onset is acute to subacute. About 70% of patients present with pain and eyelid erythema, and 50% with a dry eye [22▪]. In 20% of patients, both lacrimal glands are affected, either simultaneously or sequentially [22▪]. On imaging, the lacrimal gland is diffusely enlarged and contrast enhanced, with possible extension into the adjacent extraocular muscles or orbital fat (Fig. 2). Histologically, the component of fibrosis, in varying amounts, is a requisite of the diagnosis, and should be differentiated from the fibrotic senile changes in a normal lacrimal gland. The lymphoplasmacytic infiltrate embodies lymphocytes – more T than B cells –, and plasma cells – even IgG4-positive –, with or without lymphoid follicles with germinal centers, mixed up with neutrophils and eosinophils, and occasionally histiocytes and macrophages. In 70% of cases, there is evidence of gland destruction, in the form of atrophy of acini, and, in more advanced disease, also of the ducts [23,28]. Predominant fibrosis with a paucity of inflammatory cells, defined as idiopathic sclerosing dacryoadenitis, accounts for 28% of the cases [22▪,28].

FIGURE 2

FIGURE 2

Despite responsive to high-dose corticosteroid treatment, it is complicated with a high recurrence rate on tapering or cessation. Debulking or excision of the mass is effective in 80% of patients, even when corticosteroid dependent. With a relapse rate of 8%, debulking is 74% effective as a permanent cure [22▪]. Repeated intralesional or perilesional injections with corticosteroids are a valuable alternative to avoid the adverse effects of systemic use [29]. In the relapsing or refractory cases, the second-line regimen is orbital radiotherapy, although less effective in the sclerosing subtype, or methotrexate [28]. On rare occasions with high morbidity, rituximab is used [22▪].

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AUTOIMMUNE DACRYOADENITIS

The lacrimal gland is often targeted in autoimmune disease, frequently as the first or only presentation. Lacrimal gland enlargement in thyroid eye disease (TED) will not be discussed here, as it is rather related to proptosis than to inflammation [30,31].

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Sarcoidosis dacryoadenitis

Around 20–25% of patients with enlarged lacrimal glands without a history of sarcoidosis, have a histology suggestive for the disease [32,33]. Conversely, of the patients with systemic sarcoidosis, 5% have, and 0.6% present primarily with enlarged lacrimal glands [34,35]. Of note, bilateral lacrimal gland sarcoid-like lesions have been reportedly linked to interferon-α and ribavirin treatment for hepatitis C infection [36,37].

It presents as a painless, palpable mass or upper eyelid swelling, in 36% bilaterally, and in 19% associated with a dry eye [33]. On imaging, the lacrimal gland is diffusely enlarged, with homogenous enhancement, occasionally involving the adjacent orbital fat or lateral rectus muscle [33,34]. The histopathological finding of discrete well formed nonnecrotizing granulomas consisting of collections of epithelioid and multinucleated histiocytes, surrounded by no, or scant inflammation, is the hallmark of the disease. There is little fibrosis, if at all. Serologic testing for angiotensin converting enzyme (ACE) is of limited value. ACE is present in 81% of systemic lacrimal gland disease, and in about 70% of limited lacrimal gland disease [32,33]. Remarkably, it is also demonstrated, at lower levels, in 26% of the nonsarcoidal lacrimal gland lesions [32].

Observation, intralesional corticosteroid injections, surgical excision, or debulking are considered for localized disease [33,34]. Lacrimal gland sarcoidosis responds well to systemic corticosteroid therapy, which is indicated in systemic disease, with the addition of methotrexate as corticosteroid sparing agent.

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Sjögren's dacryoadenitis

Dry eye syndrome is one of the leading diagnostic criteria to define Sjögren's syndrome, largely resulting from inflammation of the accessory conjunctival lacrimal glands. In a radiologic study, 17% of the patients with Sjögren's syndrome displayed enlarged lacrimal glands, which was not clinically associated with worse lacrimal gland function [38]. Whereas Sjögren's syndrome confers an increased risk of lymphoma particularly in the head and neck region, in the lacrimal gland the risk is only 0.4% and involves the MALT subtype [39].

Sjögren's dacryoadenitis presents as a slow onset, painless lacrimal gland swelling with eyelid redness, in 57% bilaterally and in 64% with a dry eye [40]. On imaging, 46% of the enlarged lacrimal glands have blurred margins as evidence of orbital spread [40]. Cyst formation within the gland is extremely rare [41]. Histologic analysis demonstrates lymphoplasmacytic infiltration, lymphoid follicles with germinal centers, acinar atrophy, and fibrosis. Of the plasma cells, the relative proportion of IgA-positive plasma cells is lower than in a normal gland [40]. Residual ducts and surrounding myoepithelial cell proliferation form the socalled epimyoepithelial islands. Importantly, 21% of the enlarged lacrimal glands display monoclonality, which cannot be distinguished on imaging [40,42]. Serologic testing for autoantibodies anti-Sjögren's syndrome-related antigen A (anti-SSA) (Ro) or anti-Sjögren's syndrome-related antigen B (anti-SSB) (La), antinuclear antibodies (ANA), or rheumatoid factor is not highly disease-specific, and often negative [40].

In localized disease, observation is warranted for the polyclonal lesions, and orbital radiotherapy for persistent lacrimal gland enlargement, monoclonal lesions, or orbital spread [40,43]. Corticosteroids, hydroxychloroquine, methotrexate, and azathioprine are indicated for significant systemic disease.

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Granulomatosis with polyangiitis dacryoadenitis

Granulomatosis with polyangiitis (GPA), formerly Wegener granulomatosis, accounts for 9% of dacryoadenitis biopsies [44]. The lacrimal gland can be the initial anatomic location of GPA, particularly in the limited form [45]. Of orbital GPA, 5% involve the lacrimal gland [46,47].

The clinical presentation is that of a painless or painful lacrimal gland mass, often bilaterally [45,48]. The ipsilateral eyelid swelling may have a brawny discoloration [35]. On imaging, the glands are diffusely enlarged, often combined with sinus and midline disease [49]. The classic histopathological features such as vasculitis, collagen necrosis, and granulomatous inflammation with or without giant cells, are often present rather as a spectrum than as a triad, likely due to the relative small samples, which do not contain vessels [49,50]. Secondary diagnostic features include granular degeneration, necrosis or mummification of collagen, and a rich polymorphous inflammatory infiltrate consisting of neutrophils, eosinophils, lymphocytes, plasma cells – even IgG4 positive –, and macrophages [44,48,50,51]. Antineutrophil cytoplasmic antibody (ANCA), reactive against proteinase 3, serology is diagnostically useful, when identified [52]. However, ANCAs are linked to disease severity, with less elevated to absent levels in limited orbital GPA [53].

The treatment of lacrimal gland GPA is that of systemic GPA, using a combination of systemic corticosteroids with cytotoxic agents (methotrexate, azathioprine, or cyclophosphamide, or mycophenolate mofetil). Rituximab is indicated in the refractory cases [54].

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Immunoglobulin G4-related dacryoadenitis

IgG4-related dacryoadenitis was first described, along with salivary gland swelling, as an extrapancreatic lesion in autoimmune pancreatitis [55]. It is now recognized as part of the spectrum of IgG4-related disease (IgG4-RD). The inflammation is assumed to be driven by stimulation of unknown antigens, as in autoimmune disease [56,57]. Roughly, half of the patients have a history of allergic asthma, rhinitis, or sinus disease [58▪]. Systemic disease, in the form of salivary, parotid gland, or lymph node enlargement, autoimmune pancreatitis, or retroperitoneal fibrosis, is present in 46–75% of patients [57,58▪]. Like in Sjögren's syndrome, there is evidence of association with lymphoma, particularly MALT, especially in the older age group [57,59–63].

IgG4-related dacryoadenitis presents as painless swelling, bilaterally in a varying incidence of 50–93% of patients, and with a dry eye in only 8% [57,58▪,64▪,65▪▪,66]. Imaging studies show a homogenous and smooth lacrimal gland swelling, often massively enlarged. In about 65% of cases, there is a patterned combination with tendon-sparing enlarged extraocular muscles – most commonly and most dramatically the lateral rectus muscle –, orbital nerves – particularly the infraorbital –, or an infiltrative orbital fat mass [58▪,65▪▪,67,68,69▪▪,70▪▪]. Ipsilateral sinus disease is common. Histologic evidence includes lymphoplasmacytic infiltration with lymphoid follicles, often with reactive germinal centers, loss of acini, and periductal and interlobular fibrosis [57,71,72]. Immunohistochemically, the IgG4-positive plasma cells are diffusely increased both in absolute number and relative number to the IgG-positive plasma cells [57,73] (Fig. 3). Monoclonality is revealed in 0.8% of the lesions [57]. The literature should be interpreted with caution, as the inclusion criteria tend to largely deviate from those of the original reports [74]. In 2012, more stringent plasma cell count criteria have been defined, leading to rediagnosing a significant number of IgG4-related dacryoadenitis as reactive lymphoid hyperplasia and a few as idiopathic dacryoadenitis [73,75▪▪]. Other organ involvement and elevated serum IgG4 level are considered diagnostic evidence in the cases with a histologically less suggestive diagnosis. Serum IgG4, however, can be deceptively normal due to the prozone phenomenon [76]. It is also nonspecific as found to be raised in a variety of other pathological processes, including chronic sinusitis, Sjögren's syndrome, and TED [77▪▪,78,79]. Elevated plasmablast count in the serum is a promising new biomarker for IgG4-RD [80].

FIGURE 3

FIGURE 3

The treatment of IgG4-related dacryoadenititis is empirical. Low-dose systemic corticosteroids are usually given first, but half of the cases relapse during the taper or after a course. Rituximab, alone or in combination with radiotherapy, is used for relapsing or generalized disease [66]. The lacrimal gland lesions can regress spontaneously, and success is reported with surgical debulking or excision [57,59,81].

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Rare autoimmune dacryoadenitis

Lymphoplasmacytic dacryoadenitis has been associated with alopecia areata as another manifestation of autoimmune disease [82]. The literature reports a few cases of lymphoplasmocytic dacryoadenitis in autoimmune hypophysitis and reactive arthritis from Chlamydia trachomatis urethritis, granulomatous dacryoadenitis in regional enteritis (Crohn), and vasculitic dacryoadenitis in Behçet's syndrome [83–87]. All of these patients presented in a similar way to the more common autoimmune dacryoadenitis, that is, bilaterally and without pain, except that they were of younger age [2].

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LACRIMAL GLAND LYMPHOPROLIFERATIVE TUMOR

Lymphoproliferative tumors account for 7% of the biopsies for orbital and lacrimal gland inflammation [53]. Lacrimal gland lymphoma represents 24% of the lacrimal gland tumors in patients aged 60 year or older, with increasing incidence over the last decades [1,88,89]. It concerns most frequently reactive lymphoid hyperplasia, MALT and follicular lymphoma [90–94]. Japan has a higher incidence of ocular adnexal MALT lymphoma, of which 10% is IgG4 producing [60].

Inflammatory symptoms such as eyelid erythema are present in 15%, and pain or irritation in 26% of the cases [91]. Dry eye is not reported. Bilateral lacrimal gland lymphoma occurs in the region of 24% of the cases, and is associated with systemic disease [91,92,94,95]. Imaging studies show a smoothly enlarged and enhanced lacrimal gland, with surrounding inflamed soft tissue (Fig. 4).

FIGURE 4

FIGURE 4

Treatment implies radiotherapy or tumor removal in localized unilateral disease, although, in the case of reactive lymphoid hyperplasia, observation after the biopsy may be sufficient [90,95]. Localized bilateral lacrimal gland disease, more aggressive histologic subtypes, and systemic disease is treated in accord with the chemotherapy, immunotherapy, and radiotherapy protocols.

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OTHER NEOPLASTIC TUMORS

Epithelial lesions such as pleomorphic adenoma and adenoid cystic carcinoma, and metastasis of the lacrimal gland occasionally exhibit inflammatory signs too [43,96].

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Lacrimal gland biopsy: safety and guidelines

Surgery of the lacrimal gland may cause damage and hence interfere with its function. Acini are arranged into lobules and drained by ducts. The ducts from the orbital lobe pass through those from the palpebral lobe, which empty into the superolateral conjunctival fornix. Thus, the preferred surgical route is transcutaneously, with the biopsies taken from the tumoral involved orbital lobe unless only affecting the palpebral lobe (Fig. 5). However, it is of interest that dacryoadenitis often exhibits gland damage, in the form of a dry eye or acinar atrophy, and that debulking surgery in idiopathic dacryoadenitis does not increase nor worsen it [22▪].

FIGURE 5

FIGURE 5

Prior to the biopsy, the administration of systemic or intralesional administration of corticosteroids should be avoided, as it may alter the clinical and pathological presentation and representivity [97]. However, corticosteroids did not affect the IgG4 priority of plasma cells [98]. To establish morphology, large tissue samples are required, to be fixed in formalin for histology, immunohistochemistry, immunophenotyping, and molecular genetic studies. The other samples are submitted as fresh tissue in isotonic saline for flow cytometry or other ancillary tests.

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CONCLUSION

This review emphasizes the principal role of the tissue biopsy as diagnosticum in noninfectious lacrimal gland inflammation. The discovery of IgG4-related dacryoadenitis, marked by abundant tissue infiltration of IgG4-positive plasma cells, has hardly reduced the group of idiopathies as was initially anticipated. It clinically resembles rather a lymphoproliferative than autoimmune lacrimal gland lesion. The benefit of a lacrimal gland biopsy largely outweighs its risks. In the case of a firm, fibrotic lesion, a minimum of three large incisional biopsies are recommended: one for fixing in formalin, one for fresh submission, and one for the cure. Indeed, in idiopathic, and some other benign causes of dacryoadenitis, biopsy-related debulking surgery is a worthy first-line therapeutic choice.

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Acknowledgements

I thank Rita Van Ginderdeuren, MD, for reviewing the pathology slides presented in the figures. I apologize to the many authors whose work could not be marked as papers of special interest because of the imposed limitation to include only recent publications of significance for this review.

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Financial support and sponsorship

None.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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Large case series of IgG4-related ophthalmic disease, showing a high prevalence of dacryoadenitis.

65▪▪. Tiegs-Heiden CA, Eckel LJ, Hunt CH, et al. Immunoglobulin G4-related disease of the orbit: imaging features in 27 patients. AJNR Am J Neuroradiol 2014; 35:1393–1397.

Large imaging study demonstrating the frequent association of extraocular muscle enlargement with dacryoadenitis. This is the first report on the specific feature of tendon-sparing lateral rectus muscle enlargement in orbital IgG4-RD.

66. Plaza JA, Garrity JA, Dogan A, et al. Orbital inflammation with IgG4-positive plasma cells: manifestation of IgG4 systemic disease. Arch Ophthalmol 2011; 129:421–428.
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Large study on the radiologic feature of infraorbital enlargement, both in IgG4-dacryoadenitis and reactive lymphoid hyperplasia. This is the first study to highlight the clinicoradiologic similarities between orbital IgG4-RD and reactive lymphoid hyperplasia.

70▪▪. McNab AA, McKelvie P. IgG4-related ophthalmic disease. Part II: clinical aspects. Ophthal Plast Reconstr Surg 2015; 31:167–178.

Refreshing review delineating the patterns and protean manifestations of IgG4-related ophthalmic disease.

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Large retrospective histopathological review on the impact of the more stringent 2012 consensus diagnostic criteria to define IgG4-related dacryoadenitis. It concludes that IOI is less often from IgG4-RD origin than previously considered.

76. Khosroshahi A, Cheryk LA, Carruthers MN, et al. Brief Report: spuriously low serum IgG4 concentrations caused by the prozone phenomenon in patients with IgG4-related disease. Arthritis Rheumatol 2014; 66:213–217.
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Large study on serum IgG4 concentrations in patients with and without IgG4-RD. As a diagnostic test for IgG4-RD, elevated serum IgG4 has both a poor specificity and a low-positive predictive value.

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Keywords:

dacryoadenitis; idiopathic; immunoglobulin G4-related disease; inflammation; lacrimal gland

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