Igg4-Related Chronic Sclerosing Dacryoadenitis

There were no corneal lesions. The The patient had 1 recurrent epi- Correspondence: Dr Pollard, De- dilated fundus examination find- sode of bilateral iritis 4 months later partment of Ophthalmology, Chil- ings were normal. Blood studies were and now has been clear for 2 years. dren’s Healthcare of Atlanta at Scot- negative for antinuclear antibodies tish Rite Children’s Hospital, James and rheumatoid factors and showed Comment. Cogan syndrome mainly H. Hall Eye Center, 5445 Meridian a normal complete blood count and affects young adults but can appear Mark Rd, Ste 200, Atlanta, GA 30342 negative angiotensin-converting en- from ages 3 to 40 years. Slightly more ([email protected]). zyme levels. males are affected than females. The Financial Disclosure: None re- We diagnosed bilateral atypical etiology is unknown, but in approxi- ported. Cogan syndrome in the patient. mately 20% of cases, the onset is pre- Funding/Support:Thisstudywassup- The bilateral iritis resolved with ceded by an upper respiratory in- ported by a grant from the James H. cycloplegics and topical steroid fection. In 41% of cases, the eye is Hall Eye Center, Atlanta, Georgia. drops. The patient has been re- affected first; in 43%, the ear is af- 1. Haynes BF, Kaiser-Kupfer MI, Mason P, Fauci AS. ferred for a cochlear implant. He fected first; and in 16% of cases, both Cogan syndrome: studies in thirteen patients, had another episode of bilateral iri- organs are affected at the same time. long-term follow-up, and a review of the tis 3 months later, which also re- literature. Medicine (Baltimore). 1980;59(6): The interval between ocular and ear 426-441. solved with topical cycloplegic and involvement can be as short as 3 2. Cobo LM, Haynes BF. Early corneal findings in Cogan’s syndrome. Ophthalmology. 1984;91 steroid eye drops. months in the typical syndrome or Case 2. A 10-year-old white boy (8):903-907. as long as 11 years in the atypical 3. Orsoni JG, Zavota L, Pellistri I, Piazza F, Cimino had a history of bilateral red eyes for syndrome. Making the diagnosis of L. Cogan syndrome. Cornea. 2002;21(4):356- 1 month at initial examination. One 359. Cogan syndrome is important, not 4. Garcı´a Berrocal JR, Vargas JA, Vaquero M, Ramo´n year prior to this eye examination, only because vision can be lost, but y Cajal S, Ramı´rez-Camacho RA. Cogan’s syn- he had acutely lost all of his hear- drome: an oculo-audiovestibular disease. Post- ing and had undergone a cochlear also because 10% of cases are com- grad Med J. 1999;75(883):262-264. plicated with aortic insufficiency, 5. Vinceneux P. Cogan’s syndrome. Orphanet implant in his right ear. Visual acu- 4 Encyclopedia. 2003;134:1-7. ity was 20/30 OD and 20/20 OS. He which can be life threatening. Poly- had bilateral iritis with posterior syn- arthralgias or arthritis can also ac- echiae in the left eye. There were no company the disease. corneal lesions and the dilated fun- Neurologic findings, such as epi- dus examination findings were nor- lepsy or encephalitis, can also be IgG4-Related Chronic mal. Blood studies were performed seen. Almost 90% of patients have Sclerosing Dacryoadenitis and levels of rheumatoid factor, fluo- severe hearing loss or total bilateral rescent treponemal antibody absorp- deafness. When deafness is not com- Recent evidence suggests that tion, angiotensin-converting en- plete, high-dose corticosteroids can Mikulicz disease is distinct from zyme, and complete blood count lead to hearing improvement in 50% Sjo¨gren syndrome and is an IgG4- were all normal. The iritis resolved of cases, but if deafness is already related systemic disease.1 Herein quickly with topical dilating and cor- total, the corticosteroids do not we report 4 cases of Mikulicz dis- ticosteroid drops. Six months later, help.5 ease in which the serum IgG4 con- the patient had another episode of The atypical form of Cogan syn- centrations were elevated and infil- bilateral iritis without corneal in- drome can be an overlooked cause tration of IgG4-stained plasma flammation, which also resolved of uveitis in children; the disease had cells with sclerosing fibrosis was with topical drops. At the 2-year fol- been undiagnosed in our patients pathologically observed in the lac- low-up, there was no recurrence. until their initial visit to our office. rimal gland. Case 3. A 13-year-old white boy One patient had seen 9 physicians had a history of red eyes off and on before we made the association be- Report of Cases. Three women for the past 2 years, which were tween uveitis and sensorineural (aged 46, 47, and 64 years) and 1 treated with topical antibiotic drops. hearing loss. Many articles on pedi- man (aged 66 years) were referred He had lost all hearing acutely dur- atric uveitis do not even mention with swelling of the lacrimal gland ing a 2-week period 18 months pre- atypical Cogan syndrome as a cause region (Table). Every patient had viously. He had received a success- of uveitis. While most cases of uve- experienced a chronic episode (3 ful left cochlear implant. Visual itis will not involve sensorineural months to 5 years) of progressive acuity was 20/30 OU and bilateral iri- hearing loss, the small percentage eyelid swelling. The 64-year-old tis was present. There were no cor- that will be seen with this serious woman (patient 3) had a history of neal lesions and the dilated fundus complication warrants a recommen- surgical resection of a subcutane- examination findings were also nor- dation to evaluate the patient’s hear- ous mass in the upper eyelid, which mal. Blood tests showed that levels ing status when no etiology for the was pathologically diagnosed as lym- of fluorescent treponemal antibody uveitis is found. phoid hyperplasia at a different hos- absorption, rheumatoid factor, com- pital 2 years prior to the initial visit. plete blood cell count, and angio- Zane F. Pollard, MD Magnetic resonance imaging de- tensin-converting enzyme were all Marc Greenberg, MD picted well-circumscribed masses in- normal. The iritis resolved with topi- Alice Bashinsky, MD cluding bilateral lacrimal glands in cal cycloplegic and steroid drops. Mark Bordenca, MD the lacrimal fossa (Figure 1). In ev-

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Patient No./ History of Salivary Gland Serum IgG Serum IgG4 IgG4:IgG Sex/Age, y Eyelid Swelling Swelling Concentration, mg/dLa Concentration, mg/dLa Ratio, % Medication 1/F/47 5 y Submandibular 2350 1000 43 Oral steroid 2/M/66 1 y Submandibular 1960 164 8 None 3/F/64 2 y Parotid submandibular 1820 486 27 Oral steroid 4/F/46 3 mo Submandibular 1350 209 15 Oral steroid

a To convert milligrams per deciliter to grams per liter, multiply by 0.01.

A B

C D

Figure 1. Magnetic resonance imaging before resection of the lacrimal gland. Bilateral masses including lacrimal glands are shown. A, Coronal T1-weighted image in case 1. B, Axial T1-weighted image in case 2. C, Coronal T1-weighted image with gadolinium enhancement in case 3. D, Axial T1-weighted image with gadolinium enhancement in case 4.

ery patient, swelling of the salivary section of the mass including the lac- CD3) in all of the cases. Monoclonal- glands (submandibular or parotid) rimal gland. ity was also not evident in the infil- was also observed (Table). No pa- Lacrimal glands resected from 4 trating plasma cells, which were tients showed symptoms or ophthal- cases pathologically showed severe composed of ␬-positive cells and mic findings of keratoconjunctivitis lymphoplasmacytic infiltration with ␭-positive cells (not shown). Im- sicca. Laboratory data ruled out sys- lymphoid follicles and irregular fi- munostaining of IgG4 showed that temic diseases causative of so-called brosis (Figure 2). Inflammatory numerous IgG4-positive plasma cells Mikulicz syndrome, such as sarcoid- cells consisted of mature lympho- infiltrated the lacrimal glands in all osis, leukemia, and lymphoma. Con- cytes and plasma cells without any of the cases (Figure 2). IgG4- centrations of the serum IgG (refer- atypia. Glandular tissue was atro- positive plasma cells were com- ence range, 870-1700 mg/dL; to phied and associated with interaci- monly observed in inflammatory convert milligrams per deciliter to nar and intra-acinar sclerosing areas among lymphoid follicles grams per liter, multiply by 0.01) and inflammation. Hyalinized dense fi- (Figure 2D and H). IgG4 (reference range,Ͻ135 mg/ brosis was also observed in cases 1 Based on these findings, we di- dL) were obtained prior to treat- and 2 (Figure 2A and C). Immuno- agnosed these cases as chronic scle- ment (Table). In all of the patients, staining revealed that the lympho- rosing dacryoadenitis, consistent the serum IgG4 concentration and the cytes were polyclonal and com- with Mikulicz disease related to ratio of IgG4 to IgG were elevated. All posed of B cells (positive for CD20 IgG4. No patients manifested evi- of the patients underwent partial re- and CD79␣) and T cells (positive for dence for IgG4-related sclerosing

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 salivary glands. Beginning with the A B report by Morgan and Castleman2 in 1953, Mikulicz disease had been considered to be a subtype of pri- mary Sjo¨gren syndrome owing to their resemblance pathologically. However, later studies suggested that these 2 diseases were distinctly different pathologically and clini- cally, ie, in Mikulicz disease, lacrimal gland acinar cells maintained

C D their function and were not pro- grammed for cell death.3 More re- cently, Mikulicz disease has been suggested to be a disorder involv- ing IgG4, the rarest subclass of IgG in healthy subjects. The serum level of IgG4 is elevated in patients with Mikulicz disease and prominent infiltration of IgG4-stained plasmacytes is observed pathologically, which are features not seen in Sjo¨- 1 E F gren syndrome. Moreover, it has been proposed that Mikulicz disease belongs to the clinical entity IgG4-plasmacytic endocrinopathy, which includes IgG4-related sclerosing diseases such as autoimmune pancreatitis, sclerosing chol- angitis, retroperitoneal fibrosis, and chronic sclerosing sialadenitis.4,5 These diseases are characterized by histopathological features that in- G H clude dense lymphoplasmacytic infiltration intermixed with fibrosis, obliterative phlebitis, and prominent infiltration of IgG4-positive plasma cells. In IgG4-related chronic sclerosing sialadenitis, marked lymphoplasmacytic infiltration is associated with the destruction and atrophy of the salivary gland.5 These histopathological features are iden- tical to those of the 4 cases of Miku- Figure 2. Histopathological analysis of the lacrimal gland lesions in case 1 (A and B), case 2 (C and D), case 3 (E and F), and case 4 (G and H). Hematoxylin-eosin staining with low magnification (original licz disease reported here. Another magnification ϫ10) showed lymphoplasmacytic infiltration with lymphoid follicle formations and stromal differential diagnosis would be ex- fibrosis (A, C, E, and G). Dense sclerosis was observed in cases 1 and 2 (A and C, respectively). Lacrimal tranodal marginal zone lymphoma glands were atrophic in all of the cases. Infiltration of many plasmacytes was detected with higher magnification (insets of A, C, E, and G, original magnification ϫ100). Immunostaining for IgG4 of the of the mucosa-associated lym- lacrimal gland with low (B and F, original magnification ϫ10) or high (D and H, original magnification phoid tissue, which could, how- ϫ100) magnification. Numerous IgG4-positive plasma cells were observed in the sclerosing inflammation, ever, be excluded in all of the cases especially in the areas among lymphoid follicle (B and D) and intraglandular (F and H) areas. on the basis of histological and im- munohistochemical findings of those lesions consisting of mature poly- disease in other organs except sali- swelling and salivary gland enlarge- clonal lymphocytes and plasma cells. vary glands. Oral prednisolone ment improved. In addition, IgG4 To our knowledge, no relationship (starting at 30 or 40 mg) was ad- levels improved after steroid treat- between IgG4-related chronic in- ministered to all but patient 2, who ment in 2 patients tested: 86 mg/dL flammation and lymphoma of the required the control of diabetes in case 3 and 36 mg/dL in case 4. mucosa-associated lymphoid tis- mellitus and had no further symp- sue has been reported. toms with the residual lacrimal Comment. Mikulicz disease is a dis- There was variability in the glands. In the 3 patients receiving order characterized by symmetri- amount of fibrosis and destruction steroids, the symptoms of eyelid cal enlargement of the lacrimal and of acinar subunits (Figure 2). Fibro-

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 sis is one of the characteristic patho- kawa 9208641, Japan (takahira ing scleral thinning and focal eleva- logical findings of IgG4-related dis- @kenroku.kanazawa-u.ac.jp). tion of the bulbar conjunctiva with ease irrespective of the organ of Financial Disclosure: None re- the appearance of a bleb along with origin. However, hyalinized dense fi- ported. dilatation of surrounding deep ves- brosis as observed in cases 1 and 2 sels (Figure 2). The anterior cham- is not typical for IgG4-related dis- 1. Yamamoto M, Takahashi H, Sugai S, Imai K. ber remained deep, and examina- Clinical and pathological characteristics of Miku- eases to our knowledge. We specu- licz’s disease (IgG4-related plasmacytic tion of the posterior segment yielded lated that this difference might de- exocrinopathy). Autoimmun Rev. 2005;4(4): normal findings. Intraocular pres- pend on anatomical characteristics 195-200. sure was 12 mm Hg in both eyes. Oral 2. Morgan WS, Castleman B. A clinicopathologic of the lacrimal gland (eg, tightly sur- study of Mikulicz’s disease. Am J Pathol. 1953; nonsteroidal anti-inflammatory drug rounded by muscles and bone) or 29(3):471-503. therapy was instituted. the duration of this disease. In ad- 3. Tsubota K, Fujita H, Tsuzaka K, Takeuchi T. Clinical appearance was un- Mikulicz’s disease and Sjo¨gren’s syndrome. dition, it is interesting that acinar Invest Ophthalmol Vis Sci. 2000;41(7):1666- changed 8 months later, however, in- subunits were considerably atro- 1673. traocular pressure was 11 mm Hg 4. Hamano H, Kawa S, Ochi Y, et al. Hydronephro- phied, although no patients showed sis associated with retroperitoneal fibrosis and OD and 2 mm Hg OS. The bleb was lacrimal dysfunction such as kera- sclerosing pancreatitis. Lancet. 2002;359(9315): Siedel test–negative. Gonioscopy of toconjunctivitis sicca. Similarly, pan- 1403-1404. the right eye demonstrated normal- 5. Kitagawa S, Zen Y, Harada K, et al. Abundant creas with autoimmune pancreati- IgG4-positive plasma cell infiltration character- appearing lightly pigmented mesh- tis usually shows normal exocrine izes chronic sclerosing sialadenitis (Kuttner’s work. Gonioscopy of the left eye pancreatic function irrespective of tumor). Am J Surg Pathol. 2005;29(6):783-791. demonstrated lightly pigmented tra- acinar atrophy.4 This discrepancy has becular meshwork, without evi- not been well documented until dence for a cyclodialysis cleft, cy- now, and further pathophysiologi- clodestruction, or other basis for cal examinations are mandatory for Spontaneous Filtration Bleb hypotony. Intraocular pressure dur- this issue. as a Consequence ing 15-month follow-up remained In all of the cases, we performed of Scleritis consistently asymmetric (range, 8-16 unilateral resection of the lacrimal mm Hg OD and 2-9 mm Hg OS). gland to make a diagnosis. How- Report of a Case. A 40-year-old During this period of observation, ever, surgery was also intended as woman with systemic lupus ery- the morphologic bleb features part of the treatment in case 2 be- thematosus was seen for evalua- remained stable without secondary- cause steroid therapy was undesir- tion of persistent redness and dis- complications from hypotony. able for the patient’s diabetes melli- comfort of variable intensity in the Ophthalmic treatment during this tus. The left eyelid swelling, his chief left eye during the previous 2 years. symptom, improved after surgery. Her best-corrected visual acuity was Thus, excisions of enlarged lacri- 20/30 OD and 20/40 OS, with intra- mal glands (occasionally bilateral) ocular pressure of 10 mm Hg in the may be an alternative treatment for right eye and 11 mm Hg in the left Mikulicz disease when steroid treat- eye. Slitlamp biomicroscopy showed ment is undesirable. mild dilatation of conjunctival and In conclusion, the 4 cases of episcleral vessels of the right eye. The Mikulicz disease reported here had left eye demonstrated diffusely di- chronic sclerosing inflammation of lated episcleral vessels with a flat, su- the lacrimal gland with IgG4- perotemporal perilimbal avascular stained plasma cell infiltration. These region with focal surrounding con- findings support the theory that junctival edema. Magnetic reso- Figure 1. Right eye. Note engorgement of both superficial vessels and the deeper scleral Mikulicz disease is within the clini- nance imaging performed to assess vascular plexus with a superotemporal cal spectrum of IgG4-related scle- for orbital venous outflow distur- perilimbal avascular patch. rosing diseases. bances was unrevealing. Topical cor- ticosteroid therapy (1% prednisolone acetate) with subsequent Masayuki Takahira, MD, PhD tapering resulted in limited clinical Mitsuhiro Kawano, MD, PhD improvement bilaterally. Yoh Zen, MD, PhD At follow-up examination 2 years Hiroshi Minato, MD, PhD later, the patient reported substan- Kazunori Yamada, MD tial left eye pain. Visual acuity in both Kazuhisa Sugiyama, MD, PhD eyes was unchanged. Examination of the right eye demonstrated engorge- Correspondence: Dr Takahira, ment of both superficial vessels and Department of Ophthalmology, the deeper scleral vascular plexus Figure 2. Left eye. Note underlying scleral Graduate School of Medical Sci- with a superotemporal perilimbal thinning and focal elevation of the bulbar ence, Kanazawa University, 13-1 avascular patch (Figure 1). The left conjunctiva with the appearance of a bleb along Takara-machi, Kanazawa, Ishi- eye demonstrated apparent underly- with dilatation of surrounding deep vessels.

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