- Email: [email protected]
Surgical Debulking for Idiopathic Dacryoadenitis
Surgical Debulking for Idiopathic Dacryoadenitis A Diagnosis and a Cure Ilse Mombaerts, MD, PhD,1 J. Douglas Cameron, MD,2 Waruttaporn Chanlalit, MD,3,4 James A. Garrity, MD4 Purpose: Idiopathic inflammatory tumor of the lacrimal gland, also called idiopathic dacryoadenitis, generally is treated with high-dose, long-term systemic corticosteroids, despite their limited success, high recurrence rate, and incidence of drug-induced side effects. This study describes the outcome of patients with idiopathic dacryoadenitis who were managed with surgical debulking. Design: Retrospective case series from 2 tertiary referral centers. Participants: Forty-six patients (46 lacrimal glands). Methods: Review of the clinical records, radiologic scans, and histopathologic specimens, with additional immunoglobulin G4 immunostaining. Main Outcome Measures: Clinical signs and symptoms at 2 months after the surgery and off medications. Results: Before referral, 41% (19 of 46) of the patients had received systemic high-dose corticosteroids, after which they all showed recurrence, of whom 26% (5 of 19) became dependent on corticosteroids. At referral, all patients underwent debulking surgery of the inflammatory lacrimal gland mass for diagnostic and therapeutic reasons. Additionally, intralesional or systemic low-dose corticosteroids were given during the operation or the first postoperative days in 54% (25 of 46) of the patients. At 2 months after the debulking surgery, a full clinical recovery was seen in 80% (37 of 46) of the patients. A recurrence occurred in 8% (3 of 37) of the patients 4 months and 2.2 and 4.6 years later. Surgical failure (20%; 9 of 46) was correlated with prior corticosteroid treatment (P ¼ 0.002, Fisher exact test), but not with sclerosing inflammation present in 28% (13 of 46). The median follow-up time was 7.2 years (range, 0.7e18 years). Conclusions: Debulking biopsy procedures for idiopathic dacryoadenitis, in addition to being diagnostic, may be therapeutic. Ophthalmology 2014;121:603e609 ª 2014 by the American Academy of Ophthalmology.
Idiopathic orbital inflammation (IOI), formerly known as orbital pseudotumor, is a poorly understood disorder presenting as an orbital mass composed of nonspecific inflammation and fibrosis, without an identifiable local or systemic cause.1 When the IOI is located solely in the lacrimal gland, it is also called idiopathic dacryoadenitis. It develops over days to weeks, often associated with pain, upper eyelid swelling and redness, restricted eye movements, and proptosis, for which treatment is required. High doses of systemic corticosteroids with a slow taper generally are accepted as the standard treatment, despite their limited sensitivity, high recurrence, and high systemic morbidity rate.2,3 Because the description of immunoglobulin G4 (IgG4)-related sclerosing disease, a subset of patients with the initial diagnosis of idiopathic dacryoadenitis have been relabeled as IgG4-related dacryoadenitis.4 However, this disease presents in a lymphoma-like way with painless, often bilateral, lacrimal gland masses and is, when active, markedly responsive to systemic corticosteroids.4,5 Optimal treatment of a noninfectious inflammatory lacrimal gland mass should be based on histopathologic diagnosis. When idiopathic dacryoadenitis is suspected, then 2014 by the American Academy of Ophthalmology Published by Elsevier Inc.
during the surgical intervention for the incisional biopsy, debulking or excision of the mass can be attempted. Previously, we have reported on the benefit of surgery in the treatment of patients with idiopathic dacryoadenitis.6,7 This study examined the outcome of therapeutic surgery in 46 new patients with idiopathic dacryoadenitis, with a slight modification to the technique.
Methods This double-center study was a retrospective review of all patients (n ¼ 78) with the diagnosis of idiopathic dacryoadenitis treated at the Mayo Clinics and at the University Hospitals Leuven between 1986 and 2008. The data were collected from the clinical charts. All patients were examined, were operated on, and were followed up by the authors (I.M., J.A.G.). The orbital digital imaging scans and histopathologic specimens were reviewed. The study was conducted according to the tenets of the Declaration of Helsinki and was approved by the institutional review board and ethics committee of both clinical centers. Informed consent for retesting the pathologic specimens was obtained as outlined in the approved institutional review board protocol. Patients eligible for inclusion in the study had to fulfill the diagnostic criteria of isolated idiopathic dacryoadenitis, as listed in ISSN 0161-6420/14/$ - see front matter http://dx.doi.org/10.1016/j.ophtha.2013.09.010
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Ophthalmology Volume 121, Number 2, February 2014 Table 1. Criteria for Diagnosis of Idiopathic Dacryoadenitis 1. (Sub-)Acute onset of 1 or more of the following symptoms and signs: Orbital pain Upper eyelid swelling/redness Superolateral (epi)scleritis Limited abduction/elevation Proptosis 2. Radiologically enlarged lacrimal gland(s): Possible adjacent orbital or upper eyelid spill-over Possible adjacent lateral/superior rectus muscle enlargement Possible adjacent bone thickening 3. Mixed lymphoplasmacytic infiltrate with fibrosis: Possible lacrimal gland acini and duct atrophy If plasma cells are immunoglobulin G4 positive, count should be 100 per high-power field 4. Without associated viral disease (mumps, Epstein-Barr) or systemic disease (sarcoidosis, granulomatosis with polyangiitis, lymphoproliferative hematologic disorder, immunoglobulin G4-related sclerosing disease)
Table 1. Patients whose scans showed an additional orbital mass, eyelid mass, or extraocular muscle enlargement not in continuity with the lacrimal gland mass were excluded. During the followup, patients who received anti-inflammatory drugs for autoimmune diseases, who developed a lacrimal gland-related autoimmune disease, and who had a follow-up of less than 6 months after initial success of the surgery were excluded. The surgical intervention comprised the following, with the patient under general or local anesthesia. The approach was a lateral orbitotomy without bone flap. The skin incision was in the lateral upper eyelid skin crease. In the suborbicularis plane, the dissection was carried down to the lateral orbital rim, where the periosteum was incised and reflected off the bone. The orbital periosteum was separated from the lateral orbital wall. In the case of local anesthesia, an additional anesthetic injection was given between the periosteum and the orbital lobe of the lacrimal gland. From this vantage point, the orbital lobe could be inspected directly and showed a tumor consisting of firm, white tissue. Large debulking biopsies were taken from the abnormally firm-feeling tissue, with the surgery remaining limited to the orbital lobe (Fig 1). If a well-delineated mass was present, it was removed entirely. At closure, the periosteum and skin were reapproximated. The removed tumoral tissue was stored in formaldehyde and fresh media for histopathologic examination. The histopathologic slides were re-examined for the purpose of this study. The paraffin blocks were recut and stained for IgG4 with a mouse monoclonal antibody (clone MRQ-44). Patients whose specimens had a IgG4-positive plasma cell count of more than 100 per high-power field were excluded because of a possible diagnosis of IgG4-related sclerosing dacryoadenitis.8 Treatment outcome was considered a success when complete relief of the symptoms (i.e., orbital pain, upper eyelid swelling and redness, restricted eye movements, proptosis) was achieved within 2 months after the surgery and the patient was not taking any medications. All patients with surgical failure, defined as no or partial improvement or worsening of the symptoms that occurred within 2 months of follow-up, were included because they required additional treatment. Recurrence was defined as recurrence of symptoms after initial full clinical recovery and completion of therapy. Corneal dryness was analyzed as a separate sign and symptom because it was not considered a criterion of surgical success or failure. The follow-up data were obtained from the chart review. If the follow-up was less than 6 months after initial success, the authors
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(I.M., J.A.G.) contacted the patient and referring physician to ask about recurrent attacks, dry eye symptoms, new diseases, and use of anti-inflammatory medications since the last visit.
Results Thirty-two patients (41%; 32/78) were excluded for the following reasons: additional inferior rectus or medial rectus involvement or other orbital mass (n ¼ 12), histopathologic review showing sarcoid-like lesions (n ¼ 7), histopathologic slides that could not be retrieved or were inconclusive (n ¼ 3), follow-up less than 2 months after initial surgical success (n ¼ 3), chronic use of antiinflammatory drugs for dermatomyositis (n ¼ 2), rheumatoid arthritis (n ¼ 1), inflammatory bowel disease (n ¼ 1), systemic lupus erythematosus and Sjögren’s syndrome (n ¼ 1), and development of IgG4-related sclerosing disease (n ¼ 1) or granulomatosis with polyangiitis (n ¼ 1) during the follow-up. The study included 46 patients with idiopathic dacryoadenitis (27 from the Mayo Clinic, 19 from the University Hospitals Leuven), of whom 26 were white American, 19 were white European, and 1 was black American. The patients’ characteristics are outlined in Table 2, and the presenting signs and symptoms, along with the imaging findings, are presented in Table 3. Bilateral idiopathic dacryoadenitis presented in 4 patients simultaneously and in 5 consecutively with a 4-, 9-, 15-, and 17-month and a 10-year interval, respectively. None of the patients had optic neuropathy. Twenty-four percent (11 of 46) of the patients had a history of 1 or more autoimmune disease(s) that were not lacrimal gland related, like Graves’ hyperthyroidism without orbitopathy (n ¼ 5), rheumatoid arthritis (n ¼ 2), diabetes mellitus (n ¼ 2), scleroderma (n ¼ 1), and multiple sclerosis (n ¼ 1). They did not receive antiinflammatory drugs for the autoimmune disease during the period between the lacrimal gland debulking and the last follow-up. A total of 50 lacrimal glands were operated on: on the right site in 23 patients, on the left site in 19 patients, and consecutively bilaterally in 4 patients. In the latter, the second affected site was excluded to avoid double-paired measurements. The 5 bilateral patients who were operated on unilaterally received an intralesional injection of 40 mg triamcinolone at the contralateral site (n ¼ 3) or were not treated (n ¼ 2), for it was considered a mild disease at that site. The surgery was performed with the patient under general anesthesia, except for 8 patients who were under local anesthesia (17%; 8 of 46). The orbital lobe mass was debulked, except in 3 patients who received a total excision of the tumoral mass. Additional perisurgical treatment was administered in 54% (25 of 46) of the patients: an injection with 40 to 80 mg triamcinolone at the lacrimal gland region at the end of the operation (n ¼ 18), a short course of low-dose oral methylprednisolone (n ¼ 3), or a combination of both (n ¼ 4). Improvement of clinical symptoms was noted from the immediate postoperative days, evolving to a full clinical recovery at 2 months after surgery in 80% (37 of 46) of the patients, at which stage they were all no longer taking any medications (Fig 1). This included 4 corticosteroid-dependent patients (Fig 2). Twenty percent (9 of 46) of the patients had insufficient improvement at 2 months after surgery. Failure of surgery was statistically significantly correlated with prior corticosteroid treatment (P ¼ 0.002, Fisher exact test), but not with duration of disease at time of the surgery (P > 0.05, t test), nor with age, gender, or additional perisurgical corticosteroid treatment (P > 0.05, Fisher exact test). The failures required treatment with 20 to 25 Gy orbital radiation (4 patients), rituximab 375 mg/m2 given 4 times (n ¼ 2), repeated intralesional 0.5 mg dexamethasone injections (n ¼ 2), or orbital radiation with methotrexate 15 mg/week and intralesional 40 mg triamcinolone injection (n ¼ 1). A recurrence occurred in 8% (3 of 37) of the
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Figure 1. Preoperative, intraoperative, and postoperative photographs of a 66-year-old woman with right idiopathic dacryoadenitis. Preoperative (A) clinical photograph and (B) axial bone window computed tomography scan of a patient with a 2-month history of upper eyelid swelling and dull orbital pain. The lacrimal gland is smoothly enlarged. The adjacent orbital bone is normal. (C), Intraoperative view at the end of the surgical debulking, performed under local anesthesia. Note the firm white tissue, which is the residual lacrimal gland inflammatory tumor (arrows). Postoperative (D) clinical photograph and (E) axial magnetic resonance imaging (MRI) scan. There was a full clinical recovery at 2 months after surgery. The MRI scan, obtained at 9 months after surgery, shows the remaining palpebral lobe of the lacrimal gland.
patients with initial full recovery, at an interval of 4 months, 2.2 years, and 4.6 years after the initial remission. They were treated successfully with rituximab (n ¼ 2) or orbital radiation (n ¼ 1). Two of these recurrent patients had been dependent on corticosteroids before the surgery. Thirty-seven percent (17 of 46) of the patients had a postoperative scan for reason of control of the asymptomatic side, or subsequent contralateral affection, taken at a mean of 7 months (range, 48 dayse1.4 years) after the surgery. It revealed a small residual lacrimal gland mass at the operated side in
41% (7 of 17) of the cases, which was not treated further and had disappeared completely on follow-up scans approximately 2 years later (Figs 1 and 2). After surgery, a mild corneal dryness was seen in 41% (19 of 48) of the eyes with lacrimal gland surgery, of which 16% (3 of 19) had received preoperative or postoperative radiation therapy. There was no correlation between corneal dryness and orbital radiation (P > 0.05, Fisher exact test). The dry eye was managed successfully with ocular lubricants or punctal occlusion in 2 cases. A
Table 2. Patient Characteristics and History of Treatment before Surgery
Table 3. Clinical and Radiologic Findings at Presentation, in Descending Order, of 46 Patients with Idiopathic Dacryoadenitis
Gender ratio (female/male) 1.9 (30/16) Median age, range (yrs) 51, 11e76 Bilateral (simultaneously or sequentially) 20% (9/46) Median duration of symptoms, range 76 days, 7 dayse3.6 yrs Median follow-up, range (yrs) 7.2, 0.7e18 Prior incisional biopsy* 15% (7/46) 41% (19/46) Prior systemic corticosteroidsy Recurrent 74% (14/19) Dependent 26% (5/19) Additional orbital radiation, methotrexate, or both 7% (3/46) 37% (17/46) Prior oral broad-spectrum antibioticsz *Showing no pathology, mainly taken transconjunctivally. Received subsequently systemic corticosteroids. y High dose (0.5e1 mg/kg daily) and slow taper (6 wks). Initial favorable response. z No favorable response.
% (No.) Upper eyelid swelling Upper eyelid erythema Pain Corneal dryness Proptosis Limited abduction/elevation Autoimmune comorbidity Adjacent orbital or eyelid extension Adjacent lateral ( superior) rectus enlargement (Epi)scleritis superolaterally Salivary gland comorbidity
91 69 67 50 43 24 24 22 20 20 9
(42) (33) (31) (9)* (20) (11) (11) (10) (9) (9) (4)
In the case of simultaneous bilaterality (n ¼ 4), only the worst affected side was included. *Examined before surgery in a subset of 19 patients.
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Figure 2. Magnetic resonance imaging (MRI) scans of a 30-year-old woman with idiopathic dacryoadenitis of the right side. She had a 2-year history of severe orbital pain with periorbital swelling, which became corticosteroid dependent. She demonstrated a recurrence after radiation therapy and withdrawal of methotrexate. Preoperative (A) axial and (B) coronal MRI scans. There is a large lacrimal gland mass with enlarged adjacent rectus muscles. Postoperative (C) axial and (D) coronal MRI scans obtained 6 months after the surgical debulking procedure with intraoperative intralesional triamcinolone. There is a small residual lacrimal gland mass, although the patient is free of symptoms and medication.
subset of 18 patients underwent preoperative screening for dry eye at the site of the dacryoadenitis and showed a prevalence of 50% (9 of 18); the dry eye neither worsened nor recovered after surgery. In the remaining 50% (9 of 18) of the patients, new dryness did not develop after surgery. The histopathologic findings consisted of a mixed lymphoplasmacytic infitrate, along with fibrovascular scarring and lacrimal gland destruction, in a varying degree. Phase 1 involved immature fibrous tissue with retention of normal ducts and acini (14 of 46; 30% of the specimens); phase 2 featured immature fibrous tissue proliferation with atrophy of acini, although with preservation of ducts (22 of 46; 48%); and phase 3 was composed of a well-organized fibrous tissue with atrophy of both acini and ducts (10 of 46; 22%; Fig 3). Some specimens showed all 3 phases simultaneously in the same sample, in which case they were labeled according to the most severe phase. Predominant fibrosis with a sparse inflammatory infiltrate, labeled as sclerosing inflammation, was seen in 28% (13 of 46) of the patients and was not related to the histopathologic phase (P > 0.05, Fisher exact test). There was no correlation between the histopathologic phase (analysis of variance [ANOVA]) or sclerosis (t test) and duration of disease (ANOVA) at time of the biopsy (P > 0.05, respectively, analysis of variance and t test), nor with prior corticosteroid treatment, preoperative corneal dryness, surgical failure, or surgical recurrence (P > 0.05, Fisher exact test). Pain, sclerosis, and surgical failure were not correlated to each other (P > 0.05, Cochran-MantelHaenszel test). Twenty percent (9 of 46) of the specimens showed an elevated count of IgG4-positive plasma cells between 10 and 100 per high-power field (mean, 47 per high-power field), which was not significantly associated with the presence of sclerosis (P > 0.05, Fisher exact test).
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Discussion To our knowledge, to date, this is the largest series on isolated, biopsy-proven idiopathic dacryoadenitis with a long-term follow-up (range, 7 monthse18 years). We found an 80% success and 8% recurrence rate after surgery of the lacrimal gland inflammatory mass. Before surgery, there was a 100% response rate in the subset of patients who received high-dose, long-term corticosteroids, of whom 74% recurred and 26% became dependent. Previous studies on histopathologically proven idiopathic dacryoadenitis show a lower corticosteroid response rate of 55% to 79% and recurrence rate of 42% to 78%.2,3 This may reflect our referral bias as tertiary centers. Surgical failure in this study was correlated to prior corticosteroid treatment. The high success, low recurrence, and absence of complications after surgery makes the surgical option superior to a treatment with systemic corticosteroids. Therefore, we recommend surgery, and not corticosteroids, as primary treatment of idiopathic dacryoadenitis. A clinical trial with systemic corticosteroids is discouraged before the surgery, for the following reasons: limited sensitivity and specificity as a diagnostic tool and potential adverse effect on the pathologic accuracy of the biopsy.2,9 Lacrimal gland inflammation is a condition that requires a biopsy for diagnosis, except in the case of a known infection or systemic-related disease.10 If the biopsy results show a predominantly mixed lymphoplasmacytic infiltrate with varying degrees of fibrosis, with or without lacrimal
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Figure 3. Photomicrographs of samples obtained from the same patient shown in Figure 2. A, Extensive sclerosis (stain, hematoxylineeosin; original magnification, 20). B, Lymphoplasmacytic infiltration involving the lacrimal gland. Note the preservation of ducts (arrows; stain, hematoxylineeosin; original magnification, 200). C, Perineural (arrows) lymphoplasmacytic infiltration with sclerosis, which may explain pain (stain, hematoxylineeosin; original magnification, 200).
gland destruction, the diagnosis may fit idiopathic dacryoadenitis. If the plasma cells show positive results for IgG4, then additional, recently strengthened, criteria are required to achieve the diagnosis of the autoimmune disease IgG4-related sclerosing dacryoadenitis.8,11 None of our specimens fulfilled these criteria. Nevertheless, the initial diagnosis of idiopathic dacryoadenitis requires vigilance and should be rejected when a lacrimal glandassociated systemic disease develops during the follow-up, as happened in 2 of our patients in whom IgG4-related sclerosing disease and granulomatosis with polyangiitis developed and who were hence excluded from the study. Interestingly, twice as many women were affected, and a 24% comorbidity of autoimmune disorders not known to be related to lacrimal gland disease was present, which was increased when compared with a prevalence of 3% in the general population.12 The literature on IOI has been biased because biopsies are performed because of atypical presentation or lack of response to corticosteroids.13 The current study involves all surgical cases with idiopathic dacryoadenitis, of whom 59% had not been treated before referral. Pain was absent in approximately 30% of the patients and was not a predictor for surgical failure. Pain may be caused by sclerosis adjacent to the lacrimal nerve, as was demonstrated histopathologically in 1 of our patients (Fig 3). Therapeutic surgery for inflammatory orbital masses is not a new concept. In the 1950s and 1960s, before the era of
steroid therapy and radiologic scans, complete excision was the preferred treatment for anteriorly located orbital inflammatory tumors.14 In 1983, Amemiya et al reported on the successful outcome of 7 patients after surgical excision via lateral orbitotomy for lacrimal gland inflammatory tumors resistant to systemic antibiotic and corticosteroid treatment.15 Others describe the beneficial effect of debulking surgery, alone or in combination with oral corticosteroids and orbital radiation, in patients with nonsclerosing and sclerosing IOI.16e18 The reason why surgery, even simply debulking surgery, may lead to improvement of the inflammation in IOI is not well known. Proinflammatory cytokines are produced early at the site of the surgical trauma and mediate an acute inflammatory response leading to increased microvascular permeability as a start of the wound healing.19 This may help to reduce the inflammation in IOI. Another possible mechanism is that by surgically decreasing the volume of the inflammatory mass, the disease has converted into a mild self-limited condition. A good response after surgery is determined when clinical signs and symptoms disappear, despite a potential residual lacrimal gland mass on radiologic imaging, as was the case in 41% of our patients. With histopathologic diagnosis established, however, it is safe to leave untreated the asymptomatic residual mass, because it likely consists of fibrous tissue. Repeated intralesional injections with intermediateacting steroids (triamcinolone) or long-acting steroids
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Ophthalmology Volume 121, Number 2, February 2014 (dexamethasone) have been used successfully in histopathologically confirmed idiopathic dacryoadenitis as an alternative to systemic corticosteroids for reduced systemic morbidity.20 We have restricted their use to a single injection in a few cases during surgery to attenuate postoperative swelling; in a few bilateral cases to treat the mild, nonoperated contralateral side; and in a few surgical failures. However, whether this treatment alone would have been beneficial cannot be judged in this study, because diagnostic surgical biopsies were performed in all patients. Intralesional steroid injection does carry the small, but real, risk of intravascular injection with subsequent retinal artery embolization. Over the years, we have modified the surgical goal from resecting the entire lacrimal gland mass toward debulking only, confined to the orbital lobe, for the concern of a dry eye. Although each component of the tear fluid is necessary, the major source remains the main lacrimal gland. The excretory ducts of the orbital lobe pass through the palpebral lobe and empty, along with those of the latter lobe, into the superior conjunctival fornix.21 It therefore is believed that the orbital lobe is less essential in the lacrimal gland function and can be biopsied aggressively without detriment. However, because the lacrimal nerve enters via the posterior edge of the lacrimal gland, a damaged orbital lobe may endanger the palpebral lobe function via denervation. Pre-existing dry eye was unaltered by the surgery and new dry eye was not encountered. Hence, we believe that debulking surgery, when restricted to the affected parts of the lacrimal gland, does not interfere with dryness. The inflammatory tumor likely disables the lacrimal gland function by destroying the acinic and tubular structures.22 However, the latter finding was not significantly related to dryness. Because some specimens showed multiple stages of fibrosis and lacrimal gland destruction simultaneously, defining severity of disease may be the result of sampling variability. In summary, incisional biopsy procedures for inflammatory dacryoadenitis, in addition to being diagnostic, may be therapeutic. Although dryness is not often experienced as such in the entire clinical picture at the time of presentation of the disease, it should be explained to the patient before proceeding to the operation that, if present, corneal dryness is the only symptom that will not recover.
References 1. Harris GJ. Idiopathic orbital inflammation: a pathogenetic construct and treatment strategy: The 2005 ASOPRS Foundation Lecture. Ophthal Plast Reconstr Surg 2006;22:79–86. 2. Mombaerts I, Schlingemann RO, Goldschmeding R, Koornneef L. Are systemic corticosteroids useful in the management of orbital pseudotumors? Ophthalmology 1996; 103:521–8.
3. Swamy BN, McCluskey P, Nemet A, et al. Idiopathic orbital inflammatory syndrome: clinical features and treatment outcomes. Br J Ophthalmol 2007;91:1667–70. 4. Takahira M, Kawano M, Zen Y, et al. IgG4-related chronic sclerosing dacryoadenitis. Arch Ophthalmol 2007;125: 1575–8. 5. Cheuk W, Yuen HK, Chan JK. Chronic sclerosing dacryoadenitis: part of the spectrum of IgG4-related sclerosing disease [letter]? Am J Surg Pathol 2007;31:643–5. 6. Garrity JA, Henderson JW, Cameron JD. Henderson’s Orbital Tumors. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:343–51. 7. Mombaerts I, Schlingemann RO, Goldschmeding R, et al. The surgical management of lacrimal gland pseudotumors. Ophthalmology 1996;103:1619–27. 8. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012;25: 1181–92. 9. Borenstein SH, Gerstle T, Malkin D, et al. The effects of prebiopsy corticosteroid treatment on the diagnosis of mediastinal lymphoma. J Pediatr Surg 2000;35:973–6. 10. Rose GE. A personal view: probability in medicine, levels of (un)certainty, and the diagnosis of orbital disease (with particular reference to orbital “pseudotumor”). Arch Ophthalmol 2007;125:1711–2. 11. Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol 2012;22:21–30. 12. Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997;84:223–43. 13. Yuen SJ, Rubin PA. Idiopathic orbital inflammation: distribution, clinical features, and treatment outcome. Arch Ophthalmol 2003;121:491–9. 14. Henderson JW. Orbital Tumors. 3rd ed. New York: Raven Press; 1994:396–400. 15. Amemiya T, Mori H, Koizumi K. Clinical and histopathological study of chronic dacryoadenitis. Graefes Arch Clin Exp Ophthalmol 1983;220:229–32. 16. Chaoui Z, Mellal Z, Boulanouar A, et al. Inflammatory pseudotumor of the lacrimal gland. Apropos of 2 cases [in French]. J Fr Ophtalmol 1999;22:562–5. 17. Chen YM, Hu FR, Liao SL. Idiopathic sclerosing orbital inflammationda case series study. Ophthalmologica 2010;224:55–8. 18. Hsuan JD, Selva D, McNab AA, et al. Idiopathic sclerosing orbital inflammation. Arch Ophthalmol 2006;124:1244–50. 19. Menger MD, Vollmar B. Surgical trauma: hyperinflammation versus immunosuppression? Langenbecks Arch Surg 2004;389:475–84. 20. Leibovitch I, Prabhakaran VC, Davis G, Selva D. Intraorbital injection of triamcinolone acetonide in patients with idiopathic orbital inflammation. Arch Ophthalmol 2007;125:1647–51. 21. Jones SI, Jakobiec FA. Diseases of the Orbit. Hagerstown, MD: Harper & Row; 1979:581–5. 22. Obata H, Yamamoto S, Horiuchi H, Machinami R. Histopathologic study of human lacrimal gland: statistical analysis with special reference to aging. Ophthalmology 1995;102: 678–86.
Footnotes and Financial Disclosures Originally received: April 18, 2013. Final revision: August 22, 2013.
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Accepted: September 8, 2013. Available online: October 28, 2013.
Manuscript no. 2013-631.
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Idiopathic Dacryoadenitis Surgery
1
Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium.
2
Departments of Ophthalmology and Laboratory Medicine and Pathology, University of Minnesota School of Medicine, Minneapolis, Minnesota.
3
HRH Princess Maha Chakri Sirindhorn Medical Center, Srinakharinwirot University, Bangkok, Thailand.
4
Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota.
Supported in part by an unrestricted grant to the Department of Ophthalmology and Visual Sciences, University of Minnesota School of Medicine, from Research to Prevent Blindness, Inc., New York, New York. Correspondence: Ilse Mombaerts, MD, PhD, Department of Ophthalmology, University Hospitals Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium. E-mail: Ilse. [email protected].
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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Idiopathic orbital inflammation (IOI), formerly known as orbital pseudotumor, is a poorly understood disorder presenting as an orbital mass composed of nonspecific inflammation and fibrosis, without an identifiable local or systemic cause.1 When the IOI is located solely in the lacrimal gland, it is also called idiopathic dacryoadenitis. It develops over days to weeks, often associated with pain, upper eyelid swelling and redness, restricted eye movements, and proptosis, for which treatment is required. High doses of systemic corticosteroids with a slow taper generally are accepted as the standard treatment, despite their limited sensitivity, high recurrence, and high systemic morbidity rate.2,3 Because the description of immunoglobulin G4 (IgG4)-related sclerosing disease, a subset of patients with the initial diagnosis of idiopathic dacryoadenitis have been relabeled as IgG4-related dacryoadenitis.4 However, this disease presents in a lymphoma-like way with painless, often bilateral, lacrimal gland masses and is, when active, markedly responsive to systemic corticosteroids.4,5 Optimal treatment of a noninfectious inflammatory lacrimal gland mass should be based on histopathologic diagnosis. When idiopathic dacryoadenitis is suspected, then 2014 by the American Academy of Ophthalmology Published by Elsevier Inc.
during the surgical intervention for the incisional biopsy, debulking or excision of the mass can be attempted. Previously, we have reported on the benefit of surgery in the treatment of patients with idiopathic dacryoadenitis.6,7 This study examined the outcome of therapeutic surgery in 46 new patients with idiopathic dacryoadenitis, with a slight modification to the technique.
Methods This double-center study was a retrospective review of all patients (n ¼ 78) with the diagnosis of idiopathic dacryoadenitis treated at the Mayo Clinics and at the University Hospitals Leuven between 1986 and 2008. The data were collected from the clinical charts. All patients were examined, were operated on, and were followed up by the authors (I.M., J.A.G.). The orbital digital imaging scans and histopathologic specimens were reviewed. The study was conducted according to the tenets of the Declaration of Helsinki and was approved by the institutional review board and ethics committee of both clinical centers. Informed consent for retesting the pathologic specimens was obtained as outlined in the approved institutional review board protocol. Patients eligible for inclusion in the study had to fulfill the diagnostic criteria of isolated idiopathic dacryoadenitis, as listed in ISSN 0161-6420/14/$ - see front matter http://dx.doi.org/10.1016/j.ophtha.2013.09.010
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Ophthalmology Volume 121, Number 2, February 2014 Table 1. Criteria for Diagnosis of Idiopathic Dacryoadenitis 1. (Sub-)Acute onset of 1 or more of the following symptoms and signs: Orbital pain Upper eyelid swelling/redness Superolateral (epi)scleritis Limited abduction/elevation Proptosis 2. Radiologically enlarged lacrimal gland(s): Possible adjacent orbital or upper eyelid spill-over Possible adjacent lateral/superior rectus muscle enlargement Possible adjacent bone thickening 3. Mixed lymphoplasmacytic infiltrate with fibrosis: Possible lacrimal gland acini and duct atrophy If plasma cells are immunoglobulin G4 positive, count should be 100 per high-power field 4. Without associated viral disease (mumps, Epstein-Barr) or systemic disease (sarcoidosis, granulomatosis with polyangiitis, lymphoproliferative hematologic disorder, immunoglobulin G4-related sclerosing disease)
Table 1. Patients whose scans showed an additional orbital mass, eyelid mass, or extraocular muscle enlargement not in continuity with the lacrimal gland mass were excluded. During the followup, patients who received anti-inflammatory drugs for autoimmune diseases, who developed a lacrimal gland-related autoimmune disease, and who had a follow-up of less than 6 months after initial success of the surgery were excluded. The surgical intervention comprised the following, with the patient under general or local anesthesia. The approach was a lateral orbitotomy without bone flap. The skin incision was in the lateral upper eyelid skin crease. In the suborbicularis plane, the dissection was carried down to the lateral orbital rim, where the periosteum was incised and reflected off the bone. The orbital periosteum was separated from the lateral orbital wall. In the case of local anesthesia, an additional anesthetic injection was given between the periosteum and the orbital lobe of the lacrimal gland. From this vantage point, the orbital lobe could be inspected directly and showed a tumor consisting of firm, white tissue. Large debulking biopsies were taken from the abnormally firm-feeling tissue, with the surgery remaining limited to the orbital lobe (Fig 1). If a well-delineated mass was present, it was removed entirely. At closure, the periosteum and skin were reapproximated. The removed tumoral tissue was stored in formaldehyde and fresh media for histopathologic examination. The histopathologic slides were re-examined for the purpose of this study. The paraffin blocks were recut and stained for IgG4 with a mouse monoclonal antibody (clone MRQ-44). Patients whose specimens had a IgG4-positive plasma cell count of more than 100 per high-power field were excluded because of a possible diagnosis of IgG4-related sclerosing dacryoadenitis.8 Treatment outcome was considered a success when complete relief of the symptoms (i.e., orbital pain, upper eyelid swelling and redness, restricted eye movements, proptosis) was achieved within 2 months after the surgery and the patient was not taking any medications. All patients with surgical failure, defined as no or partial improvement or worsening of the symptoms that occurred within 2 months of follow-up, were included because they required additional treatment. Recurrence was defined as recurrence of symptoms after initial full clinical recovery and completion of therapy. Corneal dryness was analyzed as a separate sign and symptom because it was not considered a criterion of surgical success or failure. The follow-up data were obtained from the chart review. If the follow-up was less than 6 months after initial success, the authors
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(I.M., J.A.G.) contacted the patient and referring physician to ask about recurrent attacks, dry eye symptoms, new diseases, and use of anti-inflammatory medications since the last visit.
Results Thirty-two patients (41%; 32/78) were excluded for the following reasons: additional inferior rectus or medial rectus involvement or other orbital mass (n ¼ 12), histopathologic review showing sarcoid-like lesions (n ¼ 7), histopathologic slides that could not be retrieved or were inconclusive (n ¼ 3), follow-up less than 2 months after initial surgical success (n ¼ 3), chronic use of antiinflammatory drugs for dermatomyositis (n ¼ 2), rheumatoid arthritis (n ¼ 1), inflammatory bowel disease (n ¼ 1), systemic lupus erythematosus and Sjögren’s syndrome (n ¼ 1), and development of IgG4-related sclerosing disease (n ¼ 1) or granulomatosis with polyangiitis (n ¼ 1) during the follow-up. The study included 46 patients with idiopathic dacryoadenitis (27 from the Mayo Clinic, 19 from the University Hospitals Leuven), of whom 26 were white American, 19 were white European, and 1 was black American. The patients’ characteristics are outlined in Table 2, and the presenting signs and symptoms, along with the imaging findings, are presented in Table 3. Bilateral idiopathic dacryoadenitis presented in 4 patients simultaneously and in 5 consecutively with a 4-, 9-, 15-, and 17-month and a 10-year interval, respectively. None of the patients had optic neuropathy. Twenty-four percent (11 of 46) of the patients had a history of 1 or more autoimmune disease(s) that were not lacrimal gland related, like Graves’ hyperthyroidism without orbitopathy (n ¼ 5), rheumatoid arthritis (n ¼ 2), diabetes mellitus (n ¼ 2), scleroderma (n ¼ 1), and multiple sclerosis (n ¼ 1). They did not receive antiinflammatory drugs for the autoimmune disease during the period between the lacrimal gland debulking and the last follow-up. A total of 50 lacrimal glands were operated on: on the right site in 23 patients, on the left site in 19 patients, and consecutively bilaterally in 4 patients. In the latter, the second affected site was excluded to avoid double-paired measurements. The 5 bilateral patients who were operated on unilaterally received an intralesional injection of 40 mg triamcinolone at the contralateral site (n ¼ 3) or were not treated (n ¼ 2), for it was considered a mild disease at that site. The surgery was performed with the patient under general anesthesia, except for 8 patients who were under local anesthesia (17%; 8 of 46). The orbital lobe mass was debulked, except in 3 patients who received a total excision of the tumoral mass. Additional perisurgical treatment was administered in 54% (25 of 46) of the patients: an injection with 40 to 80 mg triamcinolone at the lacrimal gland region at the end of the operation (n ¼ 18), a short course of low-dose oral methylprednisolone (n ¼ 3), or a combination of both (n ¼ 4). Improvement of clinical symptoms was noted from the immediate postoperative days, evolving to a full clinical recovery at 2 months after surgery in 80% (37 of 46) of the patients, at which stage they were all no longer taking any medications (Fig 1). This included 4 corticosteroid-dependent patients (Fig 2). Twenty percent (9 of 46) of the patients had insufficient improvement at 2 months after surgery. Failure of surgery was statistically significantly correlated with prior corticosteroid treatment (P ¼ 0.002, Fisher exact test), but not with duration of disease at time of the surgery (P > 0.05, t test), nor with age, gender, or additional perisurgical corticosteroid treatment (P > 0.05, Fisher exact test). The failures required treatment with 20 to 25 Gy orbital radiation (4 patients), rituximab 375 mg/m2 given 4 times (n ¼ 2), repeated intralesional 0.5 mg dexamethasone injections (n ¼ 2), or orbital radiation with methotrexate 15 mg/week and intralesional 40 mg triamcinolone injection (n ¼ 1). A recurrence occurred in 8% (3 of 37) of the
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Figure 1. Preoperative, intraoperative, and postoperative photographs of a 66-year-old woman with right idiopathic dacryoadenitis. Preoperative (A) clinical photograph and (B) axial bone window computed tomography scan of a patient with a 2-month history of upper eyelid swelling and dull orbital pain. The lacrimal gland is smoothly enlarged. The adjacent orbital bone is normal. (C), Intraoperative view at the end of the surgical debulking, performed under local anesthesia. Note the firm white tissue, which is the residual lacrimal gland inflammatory tumor (arrows). Postoperative (D) clinical photograph and (E) axial magnetic resonance imaging (MRI) scan. There was a full clinical recovery at 2 months after surgery. The MRI scan, obtained at 9 months after surgery, shows the remaining palpebral lobe of the lacrimal gland.
patients with initial full recovery, at an interval of 4 months, 2.2 years, and 4.6 years after the initial remission. They were treated successfully with rituximab (n ¼ 2) or orbital radiation (n ¼ 1). Two of these recurrent patients had been dependent on corticosteroids before the surgery. Thirty-seven percent (17 of 46) of the patients had a postoperative scan for reason of control of the asymptomatic side, or subsequent contralateral affection, taken at a mean of 7 months (range, 48 dayse1.4 years) after the surgery. It revealed a small residual lacrimal gland mass at the operated side in
41% (7 of 17) of the cases, which was not treated further and had disappeared completely on follow-up scans approximately 2 years later (Figs 1 and 2). After surgery, a mild corneal dryness was seen in 41% (19 of 48) of the eyes with lacrimal gland surgery, of which 16% (3 of 19) had received preoperative or postoperative radiation therapy. There was no correlation between corneal dryness and orbital radiation (P > 0.05, Fisher exact test). The dry eye was managed successfully with ocular lubricants or punctal occlusion in 2 cases. A
Table 2. Patient Characteristics and History of Treatment before Surgery
Table 3. Clinical and Radiologic Findings at Presentation, in Descending Order, of 46 Patients with Idiopathic Dacryoadenitis
Gender ratio (female/male) 1.9 (30/16) Median age, range (yrs) 51, 11e76 Bilateral (simultaneously or sequentially) 20% (9/46) Median duration of symptoms, range 76 days, 7 dayse3.6 yrs Median follow-up, range (yrs) 7.2, 0.7e18 Prior incisional biopsy* 15% (7/46) 41% (19/46) Prior systemic corticosteroidsy Recurrent 74% (14/19) Dependent 26% (5/19) Additional orbital radiation, methotrexate, or both 7% (3/46) 37% (17/46) Prior oral broad-spectrum antibioticsz *Showing no pathology, mainly taken transconjunctivally. Received subsequently systemic corticosteroids. y High dose (0.5e1 mg/kg daily) and slow taper (6 wks). Initial favorable response. z No favorable response.
% (No.) Upper eyelid swelling Upper eyelid erythema Pain Corneal dryness Proptosis Limited abduction/elevation Autoimmune comorbidity Adjacent orbital or eyelid extension Adjacent lateral ( superior) rectus enlargement (Epi)scleritis superolaterally Salivary gland comorbidity
91 69 67 50 43 24 24 22 20 20 9
(42) (33) (31) (9)* (20) (11) (11) (10) (9) (9) (4)
In the case of simultaneous bilaterality (n ¼ 4), only the worst affected side was included. *Examined before surgery in a subset of 19 patients.
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Figure 2. Magnetic resonance imaging (MRI) scans of a 30-year-old woman with idiopathic dacryoadenitis of the right side. She had a 2-year history of severe orbital pain with periorbital swelling, which became corticosteroid dependent. She demonstrated a recurrence after radiation therapy and withdrawal of methotrexate. Preoperative (A) axial and (B) coronal MRI scans. There is a large lacrimal gland mass with enlarged adjacent rectus muscles. Postoperative (C) axial and (D) coronal MRI scans obtained 6 months after the surgical debulking procedure with intraoperative intralesional triamcinolone. There is a small residual lacrimal gland mass, although the patient is free of symptoms and medication.
subset of 18 patients underwent preoperative screening for dry eye at the site of the dacryoadenitis and showed a prevalence of 50% (9 of 18); the dry eye neither worsened nor recovered after surgery. In the remaining 50% (9 of 18) of the patients, new dryness did not develop after surgery. The histopathologic findings consisted of a mixed lymphoplasmacytic infitrate, along with fibrovascular scarring and lacrimal gland destruction, in a varying degree. Phase 1 involved immature fibrous tissue with retention of normal ducts and acini (14 of 46; 30% of the specimens); phase 2 featured immature fibrous tissue proliferation with atrophy of acini, although with preservation of ducts (22 of 46; 48%); and phase 3 was composed of a well-organized fibrous tissue with atrophy of both acini and ducts (10 of 46; 22%; Fig 3). Some specimens showed all 3 phases simultaneously in the same sample, in which case they were labeled according to the most severe phase. Predominant fibrosis with a sparse inflammatory infiltrate, labeled as sclerosing inflammation, was seen in 28% (13 of 46) of the patients and was not related to the histopathologic phase (P > 0.05, Fisher exact test). There was no correlation between the histopathologic phase (analysis of variance [ANOVA]) or sclerosis (t test) and duration of disease (ANOVA) at time of the biopsy (P > 0.05, respectively, analysis of variance and t test), nor with prior corticosteroid treatment, preoperative corneal dryness, surgical failure, or surgical recurrence (P > 0.05, Fisher exact test). Pain, sclerosis, and surgical failure were not correlated to each other (P > 0.05, Cochran-MantelHaenszel test). Twenty percent (9 of 46) of the specimens showed an elevated count of IgG4-positive plasma cells between 10 and 100 per high-power field (mean, 47 per high-power field), which was not significantly associated with the presence of sclerosis (P > 0.05, Fisher exact test).
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Discussion To our knowledge, to date, this is the largest series on isolated, biopsy-proven idiopathic dacryoadenitis with a long-term follow-up (range, 7 monthse18 years). We found an 80% success and 8% recurrence rate after surgery of the lacrimal gland inflammatory mass. Before surgery, there was a 100% response rate in the subset of patients who received high-dose, long-term corticosteroids, of whom 74% recurred and 26% became dependent. Previous studies on histopathologically proven idiopathic dacryoadenitis show a lower corticosteroid response rate of 55% to 79% and recurrence rate of 42% to 78%.2,3 This may reflect our referral bias as tertiary centers. Surgical failure in this study was correlated to prior corticosteroid treatment. The high success, low recurrence, and absence of complications after surgery makes the surgical option superior to a treatment with systemic corticosteroids. Therefore, we recommend surgery, and not corticosteroids, as primary treatment of idiopathic dacryoadenitis. A clinical trial with systemic corticosteroids is discouraged before the surgery, for the following reasons: limited sensitivity and specificity as a diagnostic tool and potential adverse effect on the pathologic accuracy of the biopsy.2,9 Lacrimal gland inflammation is a condition that requires a biopsy for diagnosis, except in the case of a known infection or systemic-related disease.10 If the biopsy results show a predominantly mixed lymphoplasmacytic infiltrate with varying degrees of fibrosis, with or without lacrimal
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Figure 3. Photomicrographs of samples obtained from the same patient shown in Figure 2. A, Extensive sclerosis (stain, hematoxylineeosin; original magnification, 20). B, Lymphoplasmacytic infiltration involving the lacrimal gland. Note the preservation of ducts (arrows; stain, hematoxylineeosin; original magnification, 200). C, Perineural (arrows) lymphoplasmacytic infiltration with sclerosis, which may explain pain (stain, hematoxylineeosin; original magnification, 200).
gland destruction, the diagnosis may fit idiopathic dacryoadenitis. If the plasma cells show positive results for IgG4, then additional, recently strengthened, criteria are required to achieve the diagnosis of the autoimmune disease IgG4-related sclerosing dacryoadenitis.8,11 None of our specimens fulfilled these criteria. Nevertheless, the initial diagnosis of idiopathic dacryoadenitis requires vigilance and should be rejected when a lacrimal glandassociated systemic disease develops during the follow-up, as happened in 2 of our patients in whom IgG4-related sclerosing disease and granulomatosis with polyangiitis developed and who were hence excluded from the study. Interestingly, twice as many women were affected, and a 24% comorbidity of autoimmune disorders not known to be related to lacrimal gland disease was present, which was increased when compared with a prevalence of 3% in the general population.12 The literature on IOI has been biased because biopsies are performed because of atypical presentation or lack of response to corticosteroids.13 The current study involves all surgical cases with idiopathic dacryoadenitis, of whom 59% had not been treated before referral. Pain was absent in approximately 30% of the patients and was not a predictor for surgical failure. Pain may be caused by sclerosis adjacent to the lacrimal nerve, as was demonstrated histopathologically in 1 of our patients (Fig 3). Therapeutic surgery for inflammatory orbital masses is not a new concept. In the 1950s and 1960s, before the era of
steroid therapy and radiologic scans, complete excision was the preferred treatment for anteriorly located orbital inflammatory tumors.14 In 1983, Amemiya et al reported on the successful outcome of 7 patients after surgical excision via lateral orbitotomy for lacrimal gland inflammatory tumors resistant to systemic antibiotic and corticosteroid treatment.15 Others describe the beneficial effect of debulking surgery, alone or in combination with oral corticosteroids and orbital radiation, in patients with nonsclerosing and sclerosing IOI.16e18 The reason why surgery, even simply debulking surgery, may lead to improvement of the inflammation in IOI is not well known. Proinflammatory cytokines are produced early at the site of the surgical trauma and mediate an acute inflammatory response leading to increased microvascular permeability as a start of the wound healing.19 This may help to reduce the inflammation in IOI. Another possible mechanism is that by surgically decreasing the volume of the inflammatory mass, the disease has converted into a mild self-limited condition. A good response after surgery is determined when clinical signs and symptoms disappear, despite a potential residual lacrimal gland mass on radiologic imaging, as was the case in 41% of our patients. With histopathologic diagnosis established, however, it is safe to leave untreated the asymptomatic residual mass, because it likely consists of fibrous tissue. Repeated intralesional injections with intermediateacting steroids (triamcinolone) or long-acting steroids
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Ophthalmology Volume 121, Number 2, February 2014 (dexamethasone) have been used successfully in histopathologically confirmed idiopathic dacryoadenitis as an alternative to systemic corticosteroids for reduced systemic morbidity.20 We have restricted their use to a single injection in a few cases during surgery to attenuate postoperative swelling; in a few bilateral cases to treat the mild, nonoperated contralateral side; and in a few surgical failures. However, whether this treatment alone would have been beneficial cannot be judged in this study, because diagnostic surgical biopsies were performed in all patients. Intralesional steroid injection does carry the small, but real, risk of intravascular injection with subsequent retinal artery embolization. Over the years, we have modified the surgical goal from resecting the entire lacrimal gland mass toward debulking only, confined to the orbital lobe, for the concern of a dry eye. Although each component of the tear fluid is necessary, the major source remains the main lacrimal gland. The excretory ducts of the orbital lobe pass through the palpebral lobe and empty, along with those of the latter lobe, into the superior conjunctival fornix.21 It therefore is believed that the orbital lobe is less essential in the lacrimal gland function and can be biopsied aggressively without detriment. However, because the lacrimal nerve enters via the posterior edge of the lacrimal gland, a damaged orbital lobe may endanger the palpebral lobe function via denervation. Pre-existing dry eye was unaltered by the surgery and new dry eye was not encountered. Hence, we believe that debulking surgery, when restricted to the affected parts of the lacrimal gland, does not interfere with dryness. The inflammatory tumor likely disables the lacrimal gland function by destroying the acinic and tubular structures.22 However, the latter finding was not significantly related to dryness. Because some specimens showed multiple stages of fibrosis and lacrimal gland destruction simultaneously, defining severity of disease may be the result of sampling variability. In summary, incisional biopsy procedures for inflammatory dacryoadenitis, in addition to being diagnostic, may be therapeutic. Although dryness is not often experienced as such in the entire clinical picture at the time of presentation of the disease, it should be explained to the patient before proceeding to the operation that, if present, corneal dryness is the only symptom that will not recover.
References 1. Harris GJ. Idiopathic orbital inflammation: a pathogenetic construct and treatment strategy: The 2005 ASOPRS Foundation Lecture. Ophthal Plast Reconstr Surg 2006;22:79–86. 2. Mombaerts I, Schlingemann RO, Goldschmeding R, Koornneef L. Are systemic corticosteroids useful in the management of orbital pseudotumors? Ophthalmology 1996; 103:521–8.
3. Swamy BN, McCluskey P, Nemet A, et al. Idiopathic orbital inflammatory syndrome: clinical features and treatment outcomes. Br J Ophthalmol 2007;91:1667–70. 4. Takahira M, Kawano M, Zen Y, et al. IgG4-related chronic sclerosing dacryoadenitis. Arch Ophthalmol 2007;125: 1575–8. 5. Cheuk W, Yuen HK, Chan JK. Chronic sclerosing dacryoadenitis: part of the spectrum of IgG4-related sclerosing disease [letter]? Am J Surg Pathol 2007;31:643–5. 6. Garrity JA, Henderson JW, Cameron JD. Henderson’s Orbital Tumors. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:343–51. 7. Mombaerts I, Schlingemann RO, Goldschmeding R, et al. The surgical management of lacrimal gland pseudotumors. Ophthalmology 1996;103:1619–27. 8. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012;25: 1181–92. 9. Borenstein SH, Gerstle T, Malkin D, et al. The effects of prebiopsy corticosteroid treatment on the diagnosis of mediastinal lymphoma. J Pediatr Surg 2000;35:973–6. 10. Rose GE. A personal view: probability in medicine, levels of (un)certainty, and the diagnosis of orbital disease (with particular reference to orbital “pseudotumor”). Arch Ophthalmol 2007;125:1711–2. 11. Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol 2012;22:21–30. 12. Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997;84:223–43. 13. Yuen SJ, Rubin PA. Idiopathic orbital inflammation: distribution, clinical features, and treatment outcome. Arch Ophthalmol 2003;121:491–9. 14. Henderson JW. Orbital Tumors. 3rd ed. New York: Raven Press; 1994:396–400. 15. Amemiya T, Mori H, Koizumi K. Clinical and histopathological study of chronic dacryoadenitis. Graefes Arch Clin Exp Ophthalmol 1983;220:229–32. 16. Chaoui Z, Mellal Z, Boulanouar A, et al. Inflammatory pseudotumor of the lacrimal gland. Apropos of 2 cases [in French]. J Fr Ophtalmol 1999;22:562–5. 17. Chen YM, Hu FR, Liao SL. Idiopathic sclerosing orbital inflammationda case series study. Ophthalmologica 2010;224:55–8. 18. Hsuan JD, Selva D, McNab AA, et al. Idiopathic sclerosing orbital inflammation. Arch Ophthalmol 2006;124:1244–50. 19. Menger MD, Vollmar B. Surgical trauma: hyperinflammation versus immunosuppression? Langenbecks Arch Surg 2004;389:475–84. 20. Leibovitch I, Prabhakaran VC, Davis G, Selva D. Intraorbital injection of triamcinolone acetonide in patients with idiopathic orbital inflammation. Arch Ophthalmol 2007;125:1647–51. 21. Jones SI, Jakobiec FA. Diseases of the Orbit. Hagerstown, MD: Harper & Row; 1979:581–5. 22. Obata H, Yamamoto S, Horiuchi H, Machinami R. Histopathologic study of human lacrimal gland: statistical analysis with special reference to aging. Ophthalmology 1995;102: 678–86.
Footnotes and Financial Disclosures Originally received: April 18, 2013. Final revision: August 22, 2013.
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Accepted: September 8, 2013. Available online: October 28, 2013.
Manuscript no. 2013-631.
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1
Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium.
2
Departments of Ophthalmology and Laboratory Medicine and Pathology, University of Minnesota School of Medicine, Minneapolis, Minnesota.
3
HRH Princess Maha Chakri Sirindhorn Medical Center, Srinakharinwirot University, Bangkok, Thailand.
4
Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota.
Supported in part by an unrestricted grant to the Department of Ophthalmology and Visual Sciences, University of Minnesota School of Medicine, from Research to Prevent Blindness, Inc., New York, New York. Correspondence: Ilse Mombaerts, MD, PhD, Department of Ophthalmology, University Hospitals Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium. E-mail: Ilse. [email protected].
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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