Purpose
To review the clinical and histologic features of idiopathic dacryoadenitis, and to assess prognostic factors associated with disease recurrence, treatment recalcitrance, and incomplete treatment response.
Design
Retrospective interventional case series.
Methods
setting : Tertiary referral centers. patients : Seventy-nine cases of biopsy-confirmed idiopathic dacryoadenitis. observation procedures : The following data were reviewed: age, sex, laterality, symptom onset, clinical presentation, histopathology, treatment response, and recurrence. main outcome measures : Rates of treatment recalcitrance, incomplete treatment response, and recurrence.
Results
Idiopathic dacryoadenitis patients had a mean age of 50 years, 57% were female, and 16% of cases were bilateral. Fifty-two percent had inflammation extending to adjacent structures on imaging. Twenty percent were recalcitrant to treatment, 17% had an incomplete treatment response, and 15% of patients had a recurrence during a mean follow-up time of 64 months. Risk factors for an incomplete treatment response were male sex ( P = .01) and inflammation extending to extraocular muscle ( P = .01). A clinical presentation of “classic” dacryoadenitis was a risk factor for treatment recalcitrance ( P = .02). Bilateral cases were younger than unilateral cases ( P = .004) and had an increased risk of recurrence ( P = .05). Sclerosing cases were associated with an insidious onset of symptoms ( P = .009), but neither histopathology nor the speed of symptom onset was associated with a poor prognosis.
Conclusion
Thirty-seven percent of idiopathic dacryoadenitis had a poor response to treatment and 15% of cases recurred. The prognostic factors identified in this study have not been reported previously and may inform management.
Idiopathic orbital inflammation is a common subtype of orbital inflammatory disease and a diagnosis of exclusion. It is defined by what it is not; excluded are cases with a specific pathogen, specific histopathology, or a constellation of local and/or systemic findings that identify them as a distinct entity. Idiopathic orbital inflammation presents as dacryoadenitis in up to 50% of cases and is the most common cause of lacrimal gland disease, accounting for up to 30% of lacrimal gland biopsies. Many of the specific entities excluded from idiopathic orbital inflammation are themselves idiopathic (eg, sarcoidosis, IgG4-related disease); however, from here on, our use of the term “idiopathic dacryoadenitis” will relate only to the subset of dacryoadenitis attributed to idiopathic orbital inflammation.
Even though dacryoadenitis is a common manifestation of idiopathic orbital inflammation, there is relatively little published data relating specifically to this entity, as most studies have not subclassified cases according to disease location. Nevertheless, some useful discoveries have been made. These include the following: follicular and sclerosing cases have different immunohistochemical profiles (suggesting a different pathophysiology) ; risk factors for developing idiopathic orbital inflammation include high body mass index, lower socioeconomic status, and bisphosphonate use ; and factors portending a poor prognosis include sclerosing histology, chronicity, and orbital apex inflammation. It is not known whether these findings hold true for idiopathic dacryoadenitis.
Unfortunately, research into idiopathic orbital inflammation has been hampered by the lack of a precise definition for it, the lack of a systematic and comprehensive system for classifying cases, and the recent discovery of new disease entities that account for a significant proportion of cases previously included in it (eg, IgG4-related disease). Accordingly, published studies have employed different inclusion and exclusion criteria and have adopted different definitions for important disease endpoints such as recalcitrance and treatment failure. In addition, most published studies have not listed tissue biopsy as an inclusion criterion. Of those that do, only 1 has excluded IgG4-RD, a diagnosis that was recently found to account for 23%–36% of idiopathic orbital inflammation. The result is an assortment of studies that, although useful individually, are largely incompatible with one another and cannot be amalgamated for meta-analysis.
Recently, Bijlsma and associates reviewed all published classification systems for idiopathic orbital inflammation. They proposed and validated a “best practice classification system” based on histopathology and disease location. They found this classification system easy to apply, biologically plausible, and comprehensive, and found it to have high inter- and intrarater reliability.
The primary aims of this study were to determine the rate of incomplete treatment response, treatment recalcitrance, and disease recurrence, and to identify prognostic factors associated with these endpoints. Secondary aims were to report the clinical and histologic features of idiopathic dacryoadenitis by meticulously subclassifying cases.
Methods
This study was a twin-center, retrospective interventional case series. Consecutive cases with a histologic diagnosis of idiopathic dacryoadenitis presenting to the Royal Adelaide Hospital between 1999 and 2014 inclusive, or to the Royal Victorian Eye and Ear Hospital between 1997 and 2012 inclusive, were retrieved. Pathologists (D.K., P.M., N.S.) retrospectively reviewed all specimens, including an assessment of IgG and IgG4 immunostaining. Human Research Ethics Committee approval was obtained for this study for the Royal Adelaide Hospital and Royal Victorian Eye and Ear Hospital.
Patients were included in the study if they fulfilled the diagnostic criteria for idiopathic dacryoadenitis, as listed in Table 1 . We excluded cases with biopsy features suggestive of IgG4-related ophthalmic disease, defined here as >10 IgG4+ cells/high-power field (hpf) and IgG4+/IgG+ ratio >40% in the setting of other histopathology features supportive of the diagnosis (storiform fibrosis, phlebitis, or an eosinophil-rich infiltrate). Diagnostic criteria for IgG4-related ophthalmic disease are still being refined and various thresholds for IgG4 staining have been proposed (>10, >100, and most recently >50 IgG4+ cells/hpf). However, these criteria have not been validated, and bona fide cases of IgG4-related ophthalmic disease with very low levels of IgG4 staining have been reported. We therefore chose to use a threshold of just 10 IgG4+ cells/hpf to ensure that all cases that may be IgG4-related disease were excluded.
Inclusion criteria:
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Exclusion criteria:
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A chart review was undertaken for all cases. The following information was retrieved: demographic information (age, sex); medical history (atopic or autoimmune disease); presenting features; radiology data (imaging modality; orbital and extraorbital structures involved); management data (treatment, response); and follow-up data (recurrence, complications, duration of follow-up).
Each case was categorized according to 6 parameters ( Table 2 ). The histology criterion was taken directly from the “best practice classification system for idiopathic orbital inflammation.” The other 5 criteria were a synthesis of parameters that have previously been used in published literature on idiopathic dacryoadenitis. Data were analyzed using Fisher exact test (2-tailed) and Student t test (2-tailed). Statistical significance was defined as P < .05.
| Parameter | Description |
|---|---|
| Laterality (L) | |
| Unilateral (L U ) | Orbital inflammation confined to 1 orbit |
| Bilateral (L B ) | Synchronous or metachronous involvement of both orbits |
| Symptom onset (O) | |
| Acute (O A ) | Symptoms reach maximal level in <14 days |
| Insidious (O I ) | Symptoms reach maximal level in ≥14 days |
| Clinical presentation (P) | |
| “Classic” dacryoadenitis (P C ) | Moderate inflammation and mass effect centered in the superotemporal orbit. Moderate swelling and erythema confined to the upper eyelid and temporal bulbar conjunctiva. Typically associated with mild to moderate discomfort. |
| Quiet mass effect (P Q ) | Orbital mass effect that is painless or associated with mild discomfort only, and without eyelid or conjunctival erythema. |
| Orbital cellulitis (P O ) | Presentation resembling orbital cellulitis. Pain with marked erythema and preseptal swelling extending beyond the orbital rim, which may cause a near-complete mechanical ptosis. |
| Histopathology (H) | |
| Lymphoid/“classic” (H L ) | Chronic inflammatory cell infiltrate with small, well-differentiated lymphocytes, admixed with plasma cells, neutrophils, eosinophilic granulocytes, and occasionally histiocytes and macrophages. Increased connective tissue with variable amounts of tissue edema and fibrosis. |
| Sclerosing (H S ) | Interstitial connective tissue is disproportionately great and inflammatory infiltrate is paucicellular. Includes fibrosis (loosely attached immature collagen bundles with multiple fibroblasts) and sclerosis (more hyalinized connective tissue with few fibroblasts). |
| Not otherwise specified (H NOS ) | Impossible to classify elsewhere (eg, predominant eosinophilic specimens). |
| Treatment response (T) | |
| Excellent (T E ) | Complete clinical remission achieved at last follow-up and case does not fulfill definition for recalcitrance |
| Recalcitrance (T R ) | >12 weeks of consecutive corticosteroid therapy or ≥2 treatment courses or modalities (oral corticosteroids, intraorbital corticosteroids, radiotherapy, immunosuppression) required before complete clinical remission achieved |
| Incomplete (T I ) | Complete clinical remission not achieved at last follow-up |
| Recurrence (R) | |
| None (R 0 ) | No recurrence and >12 months follow-up |
| Recurrent (R 1 ) | Relapse of idiopathic dacryoadenitis requiring treatment, occurring after a period of quiescence while off treatment lasting ≥4 weeks |
| Unclassified (R X ) | Not fulfilling criteria for R 0 or R 1 |
Results
Two hundred and seventy-three lacrimal gland biopsy cases were retrieved; 194 cases were excluded, resulting in 79 cases of biopsy-confirmed idiopathic dacryoadenitis included for analysis. Excluded cases either were not inflammations (134 cases) or were specific inflammations (54 cases), or had missing clinical data (6 cases). Fifteen cases were excluded on the grounds of IgG and IgG4 staining: these cases all had an IgG4+/IgG+ ratio >40% with a cell count numbering >100 (n = 7), 51–100 (n = 3), or 10–50 (n = 5) IgG4+ cells/hpf. All cases had been investigated with complete blood picture, serum biochemistry, liver function tests, antinuclear antibody (ANA), extractable nuclear antigens (ENAs), antineutrophil cytoplasmic antibody (ANCA), and serum angiotensin-converting enzyme (ACE) level. Additional investigations performed in some cases included rheumatoid factor, anti-Ro and anti-La antibodies, thyroid function tests, thyroid autoantibodies, mumps virus serology, Epstein-Barr virus serology, mycobacterium tuberculosis testing, and syphilis testing.
Presenting Features
The characteristics of the cohort are presented in Table 3 . The mean age was 50 years (range, 11–86 years) and 4 subjects were children (all unilateral cases). Fifty-seven percent of subjects were female and 61% of cases had an acute onset of symptoms. Thirteen cases (16%) were bilateral; 10 cases were bilateral from disease onset whereas 3 cases began unilaterally and became bilateral after a variable delay (4 months, 60 months, 140 months). Patients with a clinical presentation of “classic” dacryoadenitis (P C , 53 of 79, 67%) or quiet mass effect (P Q , 18 of 79, 23%) often reported that their periorbital swelling tended to fluctuate. Swelling was worse in the mornings and was often first noticed by the patient upon awakening. Other clinical features at presentation included ipsilateral dry eye syndrome (27 cases, 22%), a recent history of a flu-like illness (4 cases, 5%), and concomitant posterior scleritis (1 case). Symptom onset occurred evenly throughout the months of the year; no seasonal trends were observed. The median interval between symptom onset and lacrimal gland biopsy was 33 days for lymphoplasmacytic cases and 72 days for sclerosing cases.
| Parameter | All Cases (N = 79) |
|---|---|
| Age, mean (SD) | 49.6 (19) |
| Male sex | 34 (43%) |
| Clinical presentation (P) | |
| “Classic” (P C ) | 53 (67%) |
| Quiet mass effect (P Q ) | 18 (23%) |
| Orbital cellulitis (P O ) | 8 (10%) |
| Laterality (L) | |
| Unilateral (L U ) | 66 (84%) |
| Bilateral (L B ) | 13 (16%) |
| Onset (O) | |
| Acute onset (O A ) | 48 (61%) |
| Insidious onset (O I ) | 31 (39%) |
| Histology (H) | |
| Lymphoid/“classic” (H L ) | 56 (71%) |
| Sclerosing (H S ) | 23 (29%) |
| Not otherwise specified (H NOS ) | 0 |
| Treatment response (T) | |
| Excellent (T E ) | 50 (63%) |
| Recalcitrant (T R ) | 16 (20%) |
| Incomplete (T I ) | 13 (17%) |
| Recurrence (R) | |
| None (R 0 ) | 55 (69%) |
| Recurrent (R 1 ) | 10 (13%) |
| Unclassified (R x ) | 14 (18%) |
| Follow-up: mean, months Cohort: >12 months follow-up (n = 68): | 54.2 64.0 |
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