Granulomatous Dacryoadenitis in Regional Enteritis (Crohn Disease) FREDERICK A. JAKOBIEC, ALIA RASHID, KATHERINE A. LANE, AND MICHAEL KAZIM PURPOSE:
To evaluate the clinical and immunopathologic features of 2 patients with bilateral dacryoadenitis associated with regional enteritis. DESIGN: Retrospective, clinicopathologic study. METHODS: Clinical records, photographs, and imaging studies were reviewed and microscopic sections of lacrimal gland biopsy samples were critically re-evaluated. The microscopic slides were stained with hematoxylin and eosin, special stains for organisms, and a range of immunohistochemical biomarkers, including CD3, CD4, CD5, CD8, CD20, CD68, CD138, CD1a, and immunoglobulins Ig G, IgG4, and IgA. RESULTS: Both patients were young women with a well-established diagnosis of regional enteritis. Histopathologic examination of biopsy samples disclosed moderate intraparenchymal fibrosis and lymphoplasmacytic infiltrates without lymphoid follicles. Small to medium intraparenchymal, noncaseating granulomas lacking multinucleated giant cells and, in 1 patient, CD68positive and CD1a-negative palisading granulomas in widened interlobular fibrous septa were detected. Vasculitis and IgG4 plasma cells were not observed. Additional immunohistochemical studies revealed that CD8 T lymphocytes (suppressor or cytotoxic subset) predominated over CD4-positive T lymphocytes (helper cells) surrounding the necrobiotic foci and were intermixed with the CD68-positive histiocytes in the absence of CD20 B lymphocytes. Special stains for organisms demonstrated negative results. CONCLUSIONS: Dacryoadenitis is the rarest form of ocular adnexal involvement in regional enteritis, which affects the orbit far more frequently than ulcerative colitis. It is a granulomatous process with the possibility of palisading necrobiotic foci. In contrast, ulcerative colitis causes an interstitial lymphocytic and nongranulomatous myositis. Sarcoidosis, Wegener granulomatosis, and
Accepted for publication Jul 11, 2014. From the David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts (F.A.J., A.R.); the Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts (F.A.J., A.R.); Ophthalmic Consultants of Vermont, South Burlington, Vermont (K.A.L.); and the Edward S. Harkness Eye Institute of the New York Hospital Presbyterian Medical Center, and Columbia University, New York, New York (M.K.). Inquiries to Frederick A. Jakobiec, David G. Cogan Ophthalmic Pathology Laboratory, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Suite 328, Boston, MA 02114; e-mail: Fred_Jakobiec@meei. harvard.edu
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pseudorheumatoid nodules must be ruled out. Treatment options entail a wide variety of agents with selection based on empirical considerations and tailored to the patient’s symptoms. (Am J Ophthalmol 2014;158:838–844. Ó 2014 by Elsevier Inc. All rights reserved.)
R
EGIONAL ENTERITIS (CROHN DISEASE) AND ULCERA-
tive colitis are the 2 main causes of noninfectious chronic inflammatory bowel disease.1,2 The former mostly affects the ileum (fistulas and segmental large bowel disease also can occur), whereas the latter affects the colon as acute cryptitis, although there may be associated so-called backwash ileitis. Regional enteritis differs in exhibiting noncaseating granulomas in the affected segments of the bowel in addition to a cryptitis and a polymorphic infiltrate composed of acute and chronic inflammatory cells in the mucosa. Transmural lymphocytic aggregates can eventuate in fistula formation. Erythema nodosum and pyoderma gangrenosum of the skin are extraintestinal manifestations encountered in 15% of patients with regional enteritis.1 Ocular complications that may be seen in up to 10% of patients consist of conjunctivitis, anterior uveitis or iritis, and episcleritis.1,3 In this article, 2 patients are described who already were diagnosed with regional enteritis and in whom bilateral lacrimal gland enlargements subsequently developed sequentially. The histopathologic and immunohistochemical findings found in this exceptional type of dacryoadenitis are documented.3,4
METHODS THIS CLINICOPATHOLOGIC, RETROSPECTIVE STUDY WAS
conducted under the auspices of the Massachusetts Eye & Ear Infirmary’s Institutional Review Board, in compliance with the rules and regulations of the Health Insurance Portability and Accountability Act and all applicable federal and state laws, and in adherence to the tenets of the Declaration of Helsinki. From the regular and consultation files of the David G. Cogan Ophthalmic Pathology Laboratory and hospital patient files of the Massachusetts Eye & Ear Infirmary, the clinical records, photographs, and imaging studies of 2 patients with a known diagnosis of regional enteritis in whom dacryoadenitis developed subsequently were retrieved and reviewed. All available microscopic slides
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and paraffin-embedded tissue blocks also were collected. Microscopic glass slides were stained with hematoxylin and eosin, acid-fast, Grocott methenamine silver, and Warthin-Starry silver. Additional sections were prepared from the blocks and immunostained for the following biomarkers: CD3 and CD5 for T lymphocytes, CD4 for T-helper cells, CD8 for T-suppressor or cytotoxic cells, CD20 for B lymphocytes, CD68 for histiocytes, CD1a for Langerhans cells (all of the preceding antibodies obtained from Leica Biosystems Newcastle Ltd, Newcastle upon Tyne, United Kingdom), CD138 for plasma cells (Thermo Fisher Scientific Inc, Cambridge, MA, USA), immunoglobulin (Ig) G and IgG4 (Cell Marque Corporation, Rocklin, CA, USA), and IgA (Dako Agilent, Carpinteria, CA, USA). The tissue sections were processed in the standard manner for immunoperoxidase staining using diaminobenzidine as a chromogen and hematoxylin as a counterstain. The immunopathologic findings were correlated with the routine microscopic features.
sedimentation rate, angiotensin converting enzyme, antinuclear cytoplasmic antibody, renal function, fluorescent treponemal antibody absorption test (FTA-Ab), and serum immunoglobulin electrophoresis, the results of which were within normal limits. The patient underwent a right lacrimal gland biopsy. At the time of biopsy, the gland was notably firm, rubbery, and alternately white and pink. Prominent surface vascularity, but with minimal bleeding from the gland itself, was evident during surgery. The patient has been followed up for 4 months after surgery and has manifested spontaneous resolution of her symptoms of bilateral facial swelling and headache after the right-sided lacrimal gland biopsy was performed. For financial reasons, the Lialda was discontinued and the patient was restarted on sulfasalazine, which resulted in the Crohn disease remaining in remission. A follow-up orbital magnetic resonance imaging scan at 3 months after surgery demonstrated interval reduction in the size and enhancement of both lacrimal glands. PATIENT 2:
CLINICAL HISTORIES PATIENT 1:
In April, 2014, a 32-year-old woman was referred for evaluation of bilateral upper eyelid and facial swelling. Her past medical history was significant for Crohn disease of the ileum and colon diagnosed 11 years earlier. She reported arthralgias, whereupon she had been treated with a regimen of azathioprine 100 mg 4 times daily, prednisone 5 mg 4 times daily, and sulfasalazine 3 g 4 times daily. Attempts to taper her off oral steroids were unsuccessful. In 2010 (7 years after initial diagnosis), she reported headache and active gastrointestinal bleeding. Her dose of Imuran was increased to 150 mg 4 times daily after colonoscopy revealed mild focal chronic ileitis and colitis. In October 2013, there was mild reactivation of disease in the ileum and colon and sulfasalazine was switched to mesalamine (Lialda, Shire, Wayne, PA, USA). Three weeks after this change, she reported right upper eyelid swelling accompanied by a dull retro-orbital ache with intact extraocular motility. Shortly after, lateral fullness of the left upper eyelid developed. She did not report diplopia and her vision was tested at 20/20 in both eyes. Examination demonstrated bilateral diffuse upper eyelid swellings, with an S-shaped configuration (Figure 1, Top left, upper panel). A palpable and moderately tender right lacrimal gland was detected. The remaining results of her ophthalmic examination were within normal limits. Magnetic resonance imaging revealed enlarged lacrimal glands with intermediate signal intensity on both T1- and T2-weighted images showing heterogeneous enhancement in postcontrast images (Figure 1, Top right, upper and lower panels). Further work-up included analysis of complete blood count with differential, erythrocyte
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A 35-year-old woman sought treatment from an ophthalmologist initially for left upper eyelid swelling, ocular pain to touch, and dry eyes. Subsequently, right upper eyelid swelling developed over 4 weeks. Her past medical history was significant for Crohn disease, which had been diagnosed definitively in 2012 by endoscopy and had been treated successfully with 6-mercaptopurine, permitting remission for 2 years. The eye symptoms had been treated with 60 mg prednisone daily. After the dosage reached 20 mg daily, there was a relapse of symptoms. At the patient’s most recent examination, visual acuity was 20/25 in each eye. Color vision and pupillary reactions were normal. There was no evidence of proptosis, limitation of eye movements, or resistance to retropulsion. Both upper eyelids were noted to be S-shaped with temporal ptosis (Figure 1, Top left, lower panel). The lacrimal glands were firm to the touch and easily palpable, with the right eye being more prominent. Mild episcleral injection was noted bilaterally. Magnetic resonance imaging examination revealed significant enlargement of the lacrimal glands bilaterally. The adjacent periorbital fat and extraocular muscles appeared normal. The results of serologic tests, which included complete blood count with differential, angiotensin converting enzyme, Lyme titers, antinuclear cytoplasmic antibody, Sjo¨gren syndrome antibody and thyroid function, all were within normal limits. A biopsy was performed of the right lacrimal gland. After the biopsy, she was started on 80 mg prednisone orally, and she demonstrated substantial improvement in the bilateral lid swelling by 10 days. 6-Mercaptopurine then was started, with a future plan of tapering off the prednisone while increasing the dose of 6-mercaptopurine. Three months later, the eyelid swelling and pain disappeared, with restitution of normal eyelid function and position, but there is still residual palpable lacrimal gland swelling.
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FIGURE 1. Clinical and microscopic features of dacryoadenitis in regional enteritis. (Top left) Upper panel depicts the clinical appearance of a 32-year-old woman (Patient 1) who initially sought treatment with a 3-week history of right upper eyelid swelling conferring an S-shaped deformity. The left upper eyelid swelled shortly thereafter. The lower panel illustrates similar findings in a 35-year-old woman (Patient 2) who first showed left upper eyelid swelling, followed shortly by right upper eyelid involvement. She also had mild bilateral epibulbar injection. (Top right) Upper panel is an axial magnetic resonance image after gadolinium injection showing oblong anteroposterior, enhancing enlargement of the gland with molding to the globe. Note the projection of the glands beyond the orbital rim into the eyelids, representing involvement of the palpebral lobes. The lower panel is a coronal image displaying superoinferior enlargement of the glands. Epithelial tumors are rounded and not oblong or bilateral. (Bottom left) Photomicrograph showing lacrimal acini separated by fibrous tissue containing small lymphocytes and plasma cells. The arrow points to an atrophic acinus. In the inset a small granuloma (arrows) is depicted. (Bottom right) Photomicrograph showing large nonnecrotizing granuloma (arrows) seen amidst lymphocytes and lacrimal glandular units. (Bottom left, and Bottom right: hematoxylin and eosin, 3200, and 3100, respectively.)
Visual acuity and extraocular motility remain intact and unchanged. Since surgery, the patient has been maintained on prednisone 60 mg daily with 6-mercaptopurine. Consideration is being given, in consultation with the patient’s rheumatologist, to substituting the prednisone with a nonsteroidal anti-inflammatory agent. HISTOPATHOLOGIC AND IMMUNOHISTOCHEMICAL FINDINGS: The formalin-fixed tissue excised from
Patient 1 was firm and white, measuring 8 3 3 3 2 mm and of the same character in Patient 2, measuring 7 3 2 3 2 mm. Fresh tissue for culturing microorganisms was not submitted because the surgeon did not suspect an infection. Histopathologic evaluation in both cases disclosed various degrees of replacement of the lacrimal gland lobules by collagenous tissue displaying a light to moderate mononuclear inflammatory infiltrate without evidence of lymphoid follicles (Figure 1, Bottom left). The infiltrate consisted of a dispersion of lymphocytes and plasma cells between acini and ducts along with histiocytes. Small (Figure 1, Bottom left, 840
inset) and medium (Figure 1, Bottom right) noncaseating granulomas of epithelioid cells with a mild lymphocytic mantle were observed in the lacrimal parenchyma. Multinucleated giant cells were not detected. Grocott’s methenamine silver staining for fungi, acid fast for tubercle bacilli, and Warthin-Starry silver for spirochetes demonstrated negative results. In the interlobular septa and only in Patient 1, there were round (Figure 2, Top left) or elongated (Figure 2, Top right) foci of necrobiosis in widened interlobular fibrous septa, but not in the glandular parenchyma. These necrobiotic areas manifested fibrillogranular degeneration or an amorphous coagulation of the collagen, which was either paler or more eosinophilic than the appearance of normal collagen. Palisading spindled histiocytes and admixed fibroblasts surrounded these abnormal regions of the extracellular matrix. An encircling lymphocytic infiltrate was not conspicuous. Immunohistochemical analysis revealed that the necrobiotic foci manifested a surround of CD68þ and CD1a histiocytes with a clear zone corresponding to the area of necrobiosis (Figure 2, Bottom left). These cells
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FIGURE 2. Microscopic and immunohistochemical features of dacryoadenitis in regional enteritis. (Top left) Focus of necrobiosis (arrows) is present in a widened collagenous septum with inflamed and moderately scarred lacrimal gland tissue on the left. (Top right) Necrobiotic focus is surrounded by palisading histiocytes (PH) and intermixed fibroblasts. The necrobiotic zone (arrows) has a fibrillogranular character. Lacrimal tissue is present below. (Bottom left) CD68 highlights the positively staining spindled histiocytes surrounding a nonstaining central focus of necrobiosis. The inset demonstrates a small intraparenchymal granuloma that is positively immunostained for CD68. (Bottom right) CD8 suppressor or cytotoxic T lymphocytes are intermixed with the histiocytes surrounding the necrobiotic center. CD4 T-helper cells were much less numerous. (Top left and Top right: hematoxylin and eosin, 3100; Bottom left, immunoperoxidase reaction, 3100 [inset 3100]; Bottom right, diaminobenzidine chromogen, 3200, hematoxylin counterstain.)
were also responsible for the intraparenchymal granulomas (Figure 2, Bottom left, inset) and were dispersed moderately throughout the lobular fibroinflammatory zones. CD8þ T lymphocytes of the suppressor or cytotoxic subset outnumbered CD4 cells of the helper subset among the palisading histiocytes (Figure 2, Bottom right) and also among the nonnecrotizing granulomas. CD20þ B lymphocytes were totally absent from the palisading granulomas. The relatively well preserved lobules of the lacrimal gland as well as those undergoing early fibrotic replacement exhibited a mixture of T lymphocytes (CD8 > CD4), CD20 B lymphocytes, and CD138-positive plasma cells (labeled with both the immunoglobulins IgG and IgA) Ig G4 cells were not observed. This cellular composition parallels the lymphocytic populations of the undisturbed normal lacrimal gland.5
DISCUSSION REGIONAL ENTERITIS CAN BE ASSOCIATED WITH A
clinical and radiographic picture of idiopathic orbital inflammation (pseudotumor) in the forms of scleritis, myositis, and VOL. 158, NO. 4
dacryoadenitis.1,3,4,6 Orbital inflammation is seen much less commonly in ulcerative colitis. In the orbit, ulcerative colitis so far exclusively has assumed the form of myositis that has not yet been biopsied7–9; in nonocular muscle, it takes the form of a nongranulomatous, patchy, mononuclear lymphocytic infiltrate.10,11 In a review of 14 published cases of orbital involvement in regional enteritis,12 3 patterns were detected: myositis, the most common; dacryoadenitis and scleritis combined with myositis; and isolated dacryoadenitis, the rarest. In this series, when the sex was known, young females predominated over males in a ratio of 6 to 1. In 6 cases, the orbital disease preceded the diagnosis of regional enteritis, whereas in the other 8 cases, the diagnosis had already been made. Seven of 12 cases were bilateral when laterality was specified, but involvement of the orbits can be dysynchronous. There are also 2 separate published cases of bilateral epiphora and regional enteritis. The first concerned a 41-year-old woman known to have regional enteritis for 5 years who underwent dacryocystorhinostomy.13 Histopathologic evaluation of the excised portion of the lacrimal sac disclosed nongranulomatous chronic inflammation. The second report described a 16year-old boy with a 2-year history of epiphora and granulomatous cheilitis. The concurrent onset of abdominal pain
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and diarrhea led to a colonoscopy with biopsy that established the diagnosis of regional enteritis. The tissue obtained from a dacryocystorhinostomy microscopically revealed granulomatous inflammation.14 In instances of orbital myositis with bowel disease, the typical muscle swellings with tendon involvement noted on computed tomography scanning were adequate for the diagnosis, and therefore patients generally did not undergo biopsy. In contrast to localized idiopathic orbital inflammation (pseudotumor), there was more frequent involvement of the medial, lateral, and inferior rectus muscles, rather than the usual medial and superior rectus–levator complex.6,12,15 Graves disease can be closely simulated, requiring appropriate serologic tests to rule out this disorder. In 1 patient with known regional enteritis, an isolated, atypical, massive swelling of the superior rectus belly was discovered. Biopsy revealed necrosis and suppurative inflammation in the muscle surrounded by a palisading granuloma.16 Biopsy of an inflamed gastrocnemius muscle associated with regional enteritis also has revealed granulomatous inflammation.17 In 2 previous cases of dacryoadenitis, 1 patient was a 32-year-old woman with unilateral lacrimal gland disease and no known systemic disorder.3 A biopsy revealed necrotizing granulomatous inflammation, and regional enteritis eventually emerged. The second patient was a 32-year-old woman known to have regional enteritis who sought treatment for rapid onset of bilateral dysynchronous dacryoadenitis.4 This patient experienced increasing lateral upper eyelid swelling over 1 to 2 weeks with moderate pain. Her lacrimal glands were not biopsied, and the symptoms subsided with oral prednisone therapy. Characteristic computed tomography scan findings of inflammation were present in these 2 cases, and just as in our patients, consisted of oblong enlargements of the lacrimal glands (as opposed to rounded enlargements typical of epithelial tumors), protrusion of the mass beyond the orbital rim signifying palpebral lobe involvement, and the absence of any contiguous bone changes.18 Our 2 patients were young women with already established diagnoses of regional enteritis. Small and medium noncaseating granulomas were discovered in biopsies in both cases within the lobules of the lacrimal parenchyma. The granulomas may be very small and widely separated, and thus easily overlooked; their detection can be facilitated by obtaining sections at different levels of the tissue and performing CD68 or CD163 immunostaining. In Patient 1, the biopsy disclosed widened fibrous interlobular septa that additionally exhibited multiple foci of necrobiosis (altered collagen that appeared fibrillogranular or amorphous, and either more or less eosinophilic than normal collagen) surrounded by palisading granulomas. Immunohistochemistry analysis demonstrated that T lymphocytes of the suppressor or cytotoxic subset, but not B lymphocytes or CD138 plasma cells, were intermixed with the CD68þ 842
histiocytes forming the palisading granulomas. T cells also predominated over B lymphocytes within the small aggregates of CD68þ histiocytes that composed the noncaseating granulomas within the lacrimal parenchyma. The affected tissues were moderately fibrotic and displayed a lymphoplasmacytic infiltrate without demonstrable lymphoid follicles or vasculitis. CD8-positive suppressor or cytotoxic T lymphocytes were found intermixed with the epithelioid histiocytes to the complete exclusion of CD20þ B lymphocytes. No IgG4 plasma cells were found, thus ruling out a role for IgG4–mediated fibroinflammatory disease.19,20 The lymphocytic profile of the relatively uninvolved lacrimal lobules recapitulated the normal standing population of lacrimal gland lymphocytes, including a T-cell predominance with a generous admixture of B-lymphocytes and plasma cells sporting IgG and IgA.5 Necrobiosis can be seen in necrobiotic xanthogranuloma, in which there may be cholesterol clefts and typically a palisading granuloma. Patients with this finding are at risk of a monoclonal gammopathy or a lymphoproliferative neoplasm developing.21–24 Pseudorheumatoid nodules (also called granuloma annulare) can be encountered at the orbital rim in young individuals as well as exceptionally in the episclera and the deep orbit; they are not harbingers of a systemic disease.25–28 In Wegener granulomatosis, the lacrimal gland can be involved with palisading granulomas around necrobiotic foci, but there also tends to be more advanced fibrosclerosis, an acute and chronic inflammatory infiltrate often displaying eosinophilic leukocytes, perivascular collagenous onion skinning, and vasculitis leading to mummification of the collagen (loss of nuclei). Concomitant surrounding sinus disease and antineutrophil cytoplasmic antibody positivity is associated.29 The granulomas in sarcoidosis are larger, display multinucleated giant cells (typically absent in the granulomas associated with regional enteritis), are surrounded by more pronounced fibrosis, and fail to display necrobiosis. Staining results for acid-fast bacilli, spirochetes for syphilis (Warthin-Starry silver), and fungi for the genus Aspergillus or mucormycosis (Grocott’s methenamine silver) were negative.30–32 A distinctive feature of tuberculous and syphilitic dacryoadenitis is adjacent periostitis of the palpebral orbital bony rim leading to osteolysis.33 Infections of the gland have also included schistosomiasis.34 Simultaneous bilateral infections of the lacrimal glands furthermore would be most unusual. The reason for the granulomatous dacryoadenitis in regional enteritis is elusive, but may revolve around antigenic overlaps between the bowel and lacrimal tissues (such a mechanism has been postulated in cases with uveitis35). Alternatively, it is also theoretically possible that a bowel antigen could localize hematogenously to the lacrimal glands location and incite a T-cell response with an accompanying granulomatous reaction pattern.
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A range of therapies has been used for dacryoadenitis in regional enteritis. Surgical resection of the inflamed ileum can lead to abatement of the orbital inflammation.36 Even a subtotal excisional biopsy can assist in resolution of the lacrimal gland inflammation, as occurred in Patient 1. If the bowel disease is under control, increasing the dose of prednisone may be curative. The use of acetylsalicylic acid alone has been shown in some cases to be able to arrest the disease.4 Stress management seems to be helpful in some patients in reducing the frequency and severity of ocular inflammatory attacks.37 If the patient concurrently experiences exacerbation of the bowel symptoms, then increasing the doses
of chemotherapeutic medicines may be required. However, the use of a more intensive regimen for recalcitrant disease may have to be instituted that includes infliximab. This agent is a chimeric mouse and human monoclonal antibody that prevents tumor necrosis factor a, a cytokine produced mainly by activated macrophages that are present in the granulomas of regional enteritis, from binding to its target cell receptor. Pulsed intravenous chemotherapy also can be introduced.38,39 Because of the apparent role of T lymphocytes in mediating the granulomatous dacryoadenitis of regional enteritis, consideration should be given to cyclosporin in the future treatment of this condition.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and none were reported. Involved in Conception and design of study (F.A.J., A.R.); Data collection (F.A.J., A.R., K.A.L., M.K.); Analysis and interpretation of data (F.A.J., A.R.); Provision of materials, patients, or resources (F.A.J., K.A.L., M.K.); Literature search (F.A.J., A.R.); Writing (F.A.J., A.R.), critical revision (F.A.J., A.R.), and final approval (F.A.J., A.R., K.A.L., M.K.) of article.
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12. Culver EL, Salmon JF, Frith P, Travis SP. Recurrent posterior scleritis and orbital myositis as extra-intestinal manifestations of Crohn’s disease: case report and systematic literature review. J Crohns Colitis 2008;2(4):337–342. 13. Mauriello JA Jr, Mostafavi R. Bilateral nasolacrimal duct obstruction associated with Crohn’s disease successfully treated with dacryocystorhinostomy. Ophthal Plast Reconstr Surg 1994;10(4):260–261. 14. Greninger DA, Yoon MK, Bloomer MM, Keyser R, Kersten RC. Extraintestinal Crohn disease causing bilateral nasolacrimal duct obstruction. Ophthal Plast Reconstr Surg 2012;28(2):e55–e56. 15. Ramalho J, Castillo M. Imaging of orbital myositis in Crohn’s disease. Clin Imaging 2008;32(3):227–229. 16. Leibovitch I, Galanopoulos A, Selva D. Suppurative granulomatous myositis of an extra-ocular muscle in Crohn’s disease. Am J Gastroenterol 2005;100(9):2136–2137. 17. Menard DB, Haddad H, Blain JG, Beaudry R, Devroede G, Masse S. Granulomatous myositis and myopathy associated with crohn’s colitis. N Engl J Med 1976; 295(15):818–819. 18. Yeo JH, Jakobiec FA, Abbott GF, Trokel SL. Combined clinical and computed tomographic diagnosis of orbital lymphoid tumors. Am J Ophthalmol 1982;94(2):235–245. 19. Wallace ZS, Khosroshahi A, Jakobiec FA, et al. IgG4-related systemic disease as a cause of ‘‘idiopathic’’ orbital inflammation, including orbital myositis, and trigeminal nerve involvement. Surv Ophthalmol 2012;57(1):26–33. 20. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012;366(6):539–551. 21. Plotnick H, Taniguchi Y, Hashimoto K, Negendank W, Tranchida L. Periorbital necrobiotic xanthogranuloma and stage I multiple myeloma. Ultrastructure and response to pulsed dexamethasone documented by magnetic resonance imaging. J Am Acad Dermatol 1991;25(2 Pt 2):373–377. 22. Robertson DM, Winkelmann RK. Ophthalmic features of necrobiotic xanthogranuloma with paraproteinemia. Am J Ophthalmol 1984;97(2):173–183.
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31. Green WR, Font RL, Zimmerman LE. Asperillosis of the orbit. Report of ten cases and review of the literature. Arch Ophthalmol 1969;82(3):302–313. 32. Schmoll C, Macrae M, Mulvihill A, Murray R, Cunningham S, McKenzie K. Tuberculous dacryoadenitis in a Scottish teenager. Br J Ophthalmol 2009;93(2):137–138. 274. 33. van Assen S, Lutterman JA. Tuberculous dacryoadenitis: a rare manifestation of tuberculosis. Neth J Med 2002;60(8): 327–329. 34. Jakobiec FA, Gess L, Zimmerman LE. Granulomatous dacryoadenitis caused by Schistosoma haematobium. Arch Ophthalmol 1977;95(2):278–280. 35. Bhagat S, Das KM. A shared and unique peptide in the human colon, eye, and joint detected by a monoclonal antibody. Gastroenterology 1994;107(1):103–108. 36. Young RS, Hodes BL, Cruse RP, Koch KL, Garovoy MR. Orbital pseudotumor and Crohn disease. J Pediatr 1981;99(2):250–252. 37. Boerner CF. Orbital inflammation and inflammatory bowel disease. Ophthalmology 1992;99(2):169. 38. Garrity JA, Coleman AW, Matteson EL, Eggenberger ER, Waitzman DM. Treatment of recalcitrant idiopathic orbital inflammation (chronic orbital myositis) with infliximab. Am J Ophthalmol 2004;138(6):925–930. 39. Suelves AM, Arcinue CA, Gonzalez-Martin JM, Kruh JN, Foster CS. Analysis of a novel protocol of pulsed intravenous cyclophosphamide for recalcitrant or severe ocular inflammatory disease. Ophthalmology 2013;120(6):1201–1209.
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Biosketch Frederick A. Jakobiec, MD, DSc is the Director of the David G. Cogan Laboratory of Ophthalmic Pathology at the Massachusetts Eye and Ear Infirmary in Boston, Massachusetts. Dr Jakobiec is the Henry Willard Williams Professor Emeritus of Ophthalmology and Pathology, the past Chairman of Ophthalmology at the Harvard Medical School, and the past Chief of Ophthalmology at the Infirmary. His main clinical and pathologic interests are in ocular and adnexal tumors and idiopathic inflammations.
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To evaluate the clinical and immunopathologic features of 2 patients with bilateral dacryoadenitis associated with regional enteritis. DESIGN: Retrospective, clinicopathologic study. METHODS: Clinical records, photographs, and imaging studies were reviewed and microscopic sections of lacrimal gland biopsy samples were critically re-evaluated. The microscopic slides were stained with hematoxylin and eosin, special stains for organisms, and a range of immunohistochemical biomarkers, including CD3, CD4, CD5, CD8, CD20, CD68, CD138, CD1a, and immunoglobulins Ig G, IgG4, and IgA. RESULTS: Both patients were young women with a well-established diagnosis of regional enteritis. Histopathologic examination of biopsy samples disclosed moderate intraparenchymal fibrosis and lymphoplasmacytic infiltrates without lymphoid follicles. Small to medium intraparenchymal, noncaseating granulomas lacking multinucleated giant cells and, in 1 patient, CD68positive and CD1a-negative palisading granulomas in widened interlobular fibrous septa were detected. Vasculitis and IgG4 plasma cells were not observed. Additional immunohistochemical studies revealed that CD8 T lymphocytes (suppressor or cytotoxic subset) predominated over CD4-positive T lymphocytes (helper cells) surrounding the necrobiotic foci and were intermixed with the CD68-positive histiocytes in the absence of CD20 B lymphocytes. Special stains for organisms demonstrated negative results. CONCLUSIONS: Dacryoadenitis is the rarest form of ocular adnexal involvement in regional enteritis, which affects the orbit far more frequently than ulcerative colitis. It is a granulomatous process with the possibility of palisading necrobiotic foci. In contrast, ulcerative colitis causes an interstitial lymphocytic and nongranulomatous myositis. Sarcoidosis, Wegener granulomatosis, and
Accepted for publication Jul 11, 2014. From the David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts (F.A.J., A.R.); the Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts (F.A.J., A.R.); Ophthalmic Consultants of Vermont, South Burlington, Vermont (K.A.L.); and the Edward S. Harkness Eye Institute of the New York Hospital Presbyterian Medical Center, and Columbia University, New York, New York (M.K.). Inquiries to Frederick A. Jakobiec, David G. Cogan Ophthalmic Pathology Laboratory, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Suite 328, Boston, MA 02114; e-mail: Fred_Jakobiec@meei. harvard.edu
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pseudorheumatoid nodules must be ruled out. Treatment options entail a wide variety of agents with selection based on empirical considerations and tailored to the patient’s symptoms. (Am J Ophthalmol 2014;158:838–844. Ó 2014 by Elsevier Inc. All rights reserved.)
R
EGIONAL ENTERITIS (CROHN DISEASE) AND ULCERA-
tive colitis are the 2 main causes of noninfectious chronic inflammatory bowel disease.1,2 The former mostly affects the ileum (fistulas and segmental large bowel disease also can occur), whereas the latter affects the colon as acute cryptitis, although there may be associated so-called backwash ileitis. Regional enteritis differs in exhibiting noncaseating granulomas in the affected segments of the bowel in addition to a cryptitis and a polymorphic infiltrate composed of acute and chronic inflammatory cells in the mucosa. Transmural lymphocytic aggregates can eventuate in fistula formation. Erythema nodosum and pyoderma gangrenosum of the skin are extraintestinal manifestations encountered in 15% of patients with regional enteritis.1 Ocular complications that may be seen in up to 10% of patients consist of conjunctivitis, anterior uveitis or iritis, and episcleritis.1,3 In this article, 2 patients are described who already were diagnosed with regional enteritis and in whom bilateral lacrimal gland enlargements subsequently developed sequentially. The histopathologic and immunohistochemical findings found in this exceptional type of dacryoadenitis are documented.3,4
METHODS THIS CLINICOPATHOLOGIC, RETROSPECTIVE STUDY WAS
conducted under the auspices of the Massachusetts Eye & Ear Infirmary’s Institutional Review Board, in compliance with the rules and regulations of the Health Insurance Portability and Accountability Act and all applicable federal and state laws, and in adherence to the tenets of the Declaration of Helsinki. From the regular and consultation files of the David G. Cogan Ophthalmic Pathology Laboratory and hospital patient files of the Massachusetts Eye & Ear Infirmary, the clinical records, photographs, and imaging studies of 2 patients with a known diagnosis of regional enteritis in whom dacryoadenitis developed subsequently were retrieved and reviewed. All available microscopic slides
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and paraffin-embedded tissue blocks also were collected. Microscopic glass slides were stained with hematoxylin and eosin, acid-fast, Grocott methenamine silver, and Warthin-Starry silver. Additional sections were prepared from the blocks and immunostained for the following biomarkers: CD3 and CD5 for T lymphocytes, CD4 for T-helper cells, CD8 for T-suppressor or cytotoxic cells, CD20 for B lymphocytes, CD68 for histiocytes, CD1a for Langerhans cells (all of the preceding antibodies obtained from Leica Biosystems Newcastle Ltd, Newcastle upon Tyne, United Kingdom), CD138 for plasma cells (Thermo Fisher Scientific Inc, Cambridge, MA, USA), immunoglobulin (Ig) G and IgG4 (Cell Marque Corporation, Rocklin, CA, USA), and IgA (Dako Agilent, Carpinteria, CA, USA). The tissue sections were processed in the standard manner for immunoperoxidase staining using diaminobenzidine as a chromogen and hematoxylin as a counterstain. The immunopathologic findings were correlated with the routine microscopic features.
sedimentation rate, angiotensin converting enzyme, antinuclear cytoplasmic antibody, renal function, fluorescent treponemal antibody absorption test (FTA-Ab), and serum immunoglobulin electrophoresis, the results of which were within normal limits. The patient underwent a right lacrimal gland biopsy. At the time of biopsy, the gland was notably firm, rubbery, and alternately white and pink. Prominent surface vascularity, but with minimal bleeding from the gland itself, was evident during surgery. The patient has been followed up for 4 months after surgery and has manifested spontaneous resolution of her symptoms of bilateral facial swelling and headache after the right-sided lacrimal gland biopsy was performed. For financial reasons, the Lialda was discontinued and the patient was restarted on sulfasalazine, which resulted in the Crohn disease remaining in remission. A follow-up orbital magnetic resonance imaging scan at 3 months after surgery demonstrated interval reduction in the size and enhancement of both lacrimal glands. PATIENT 2:
CLINICAL HISTORIES PATIENT 1:
In April, 2014, a 32-year-old woman was referred for evaluation of bilateral upper eyelid and facial swelling. Her past medical history was significant for Crohn disease of the ileum and colon diagnosed 11 years earlier. She reported arthralgias, whereupon she had been treated with a regimen of azathioprine 100 mg 4 times daily, prednisone 5 mg 4 times daily, and sulfasalazine 3 g 4 times daily. Attempts to taper her off oral steroids were unsuccessful. In 2010 (7 years after initial diagnosis), she reported headache and active gastrointestinal bleeding. Her dose of Imuran was increased to 150 mg 4 times daily after colonoscopy revealed mild focal chronic ileitis and colitis. In October 2013, there was mild reactivation of disease in the ileum and colon and sulfasalazine was switched to mesalamine (Lialda, Shire, Wayne, PA, USA). Three weeks after this change, she reported right upper eyelid swelling accompanied by a dull retro-orbital ache with intact extraocular motility. Shortly after, lateral fullness of the left upper eyelid developed. She did not report diplopia and her vision was tested at 20/20 in both eyes. Examination demonstrated bilateral diffuse upper eyelid swellings, with an S-shaped configuration (Figure 1, Top left, upper panel). A palpable and moderately tender right lacrimal gland was detected. The remaining results of her ophthalmic examination were within normal limits. Magnetic resonance imaging revealed enlarged lacrimal glands with intermediate signal intensity on both T1- and T2-weighted images showing heterogeneous enhancement in postcontrast images (Figure 1, Top right, upper and lower panels). Further work-up included analysis of complete blood count with differential, erythrocyte
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A 35-year-old woman sought treatment from an ophthalmologist initially for left upper eyelid swelling, ocular pain to touch, and dry eyes. Subsequently, right upper eyelid swelling developed over 4 weeks. Her past medical history was significant for Crohn disease, which had been diagnosed definitively in 2012 by endoscopy and had been treated successfully with 6-mercaptopurine, permitting remission for 2 years. The eye symptoms had been treated with 60 mg prednisone daily. After the dosage reached 20 mg daily, there was a relapse of symptoms. At the patient’s most recent examination, visual acuity was 20/25 in each eye. Color vision and pupillary reactions were normal. There was no evidence of proptosis, limitation of eye movements, or resistance to retropulsion. Both upper eyelids were noted to be S-shaped with temporal ptosis (Figure 1, Top left, lower panel). The lacrimal glands were firm to the touch and easily palpable, with the right eye being more prominent. Mild episcleral injection was noted bilaterally. Magnetic resonance imaging examination revealed significant enlargement of the lacrimal glands bilaterally. The adjacent periorbital fat and extraocular muscles appeared normal. The results of serologic tests, which included complete blood count with differential, angiotensin converting enzyme, Lyme titers, antinuclear cytoplasmic antibody, Sjo¨gren syndrome antibody and thyroid function, all were within normal limits. A biopsy was performed of the right lacrimal gland. After the biopsy, she was started on 80 mg prednisone orally, and she demonstrated substantial improvement in the bilateral lid swelling by 10 days. 6-Mercaptopurine then was started, with a future plan of tapering off the prednisone while increasing the dose of 6-mercaptopurine. Three months later, the eyelid swelling and pain disappeared, with restitution of normal eyelid function and position, but there is still residual palpable lacrimal gland swelling.
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FIGURE 1. Clinical and microscopic features of dacryoadenitis in regional enteritis. (Top left) Upper panel depicts the clinical appearance of a 32-year-old woman (Patient 1) who initially sought treatment with a 3-week history of right upper eyelid swelling conferring an S-shaped deformity. The left upper eyelid swelled shortly thereafter. The lower panel illustrates similar findings in a 35-year-old woman (Patient 2) who first showed left upper eyelid swelling, followed shortly by right upper eyelid involvement. She also had mild bilateral epibulbar injection. (Top right) Upper panel is an axial magnetic resonance image after gadolinium injection showing oblong anteroposterior, enhancing enlargement of the gland with molding to the globe. Note the projection of the glands beyond the orbital rim into the eyelids, representing involvement of the palpebral lobes. The lower panel is a coronal image displaying superoinferior enlargement of the glands. Epithelial tumors are rounded and not oblong or bilateral. (Bottom left) Photomicrograph showing lacrimal acini separated by fibrous tissue containing small lymphocytes and plasma cells. The arrow points to an atrophic acinus. In the inset a small granuloma (arrows) is depicted. (Bottom right) Photomicrograph showing large nonnecrotizing granuloma (arrows) seen amidst lymphocytes and lacrimal glandular units. (Bottom left, and Bottom right: hematoxylin and eosin, 3200, and 3100, respectively.)
Visual acuity and extraocular motility remain intact and unchanged. Since surgery, the patient has been maintained on prednisone 60 mg daily with 6-mercaptopurine. Consideration is being given, in consultation with the patient’s rheumatologist, to substituting the prednisone with a nonsteroidal anti-inflammatory agent. HISTOPATHOLOGIC AND IMMUNOHISTOCHEMICAL FINDINGS: The formalin-fixed tissue excised from
Patient 1 was firm and white, measuring 8 3 3 3 2 mm and of the same character in Patient 2, measuring 7 3 2 3 2 mm. Fresh tissue for culturing microorganisms was not submitted because the surgeon did not suspect an infection. Histopathologic evaluation in both cases disclosed various degrees of replacement of the lacrimal gland lobules by collagenous tissue displaying a light to moderate mononuclear inflammatory infiltrate without evidence of lymphoid follicles (Figure 1, Bottom left). The infiltrate consisted of a dispersion of lymphocytes and plasma cells between acini and ducts along with histiocytes. Small (Figure 1, Bottom left, 840
inset) and medium (Figure 1, Bottom right) noncaseating granulomas of epithelioid cells with a mild lymphocytic mantle were observed in the lacrimal parenchyma. Multinucleated giant cells were not detected. Grocott’s methenamine silver staining for fungi, acid fast for tubercle bacilli, and Warthin-Starry silver for spirochetes demonstrated negative results. In the interlobular septa and only in Patient 1, there were round (Figure 2, Top left) or elongated (Figure 2, Top right) foci of necrobiosis in widened interlobular fibrous septa, but not in the glandular parenchyma. These necrobiotic areas manifested fibrillogranular degeneration or an amorphous coagulation of the collagen, which was either paler or more eosinophilic than the appearance of normal collagen. Palisading spindled histiocytes and admixed fibroblasts surrounded these abnormal regions of the extracellular matrix. An encircling lymphocytic infiltrate was not conspicuous. Immunohistochemical analysis revealed that the necrobiotic foci manifested a surround of CD68þ and CD1a histiocytes with a clear zone corresponding to the area of necrobiosis (Figure 2, Bottom left). These cells
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FIGURE 2. Microscopic and immunohistochemical features of dacryoadenitis in regional enteritis. (Top left) Focus of necrobiosis (arrows) is present in a widened collagenous septum with inflamed and moderately scarred lacrimal gland tissue on the left. (Top right) Necrobiotic focus is surrounded by palisading histiocytes (PH) and intermixed fibroblasts. The necrobiotic zone (arrows) has a fibrillogranular character. Lacrimal tissue is present below. (Bottom left) CD68 highlights the positively staining spindled histiocytes surrounding a nonstaining central focus of necrobiosis. The inset demonstrates a small intraparenchymal granuloma that is positively immunostained for CD68. (Bottom right) CD8 suppressor or cytotoxic T lymphocytes are intermixed with the histiocytes surrounding the necrobiotic center. CD4 T-helper cells were much less numerous. (Top left and Top right: hematoxylin and eosin, 3100; Bottom left, immunoperoxidase reaction, 3100 [inset 3100]; Bottom right, diaminobenzidine chromogen, 3200, hematoxylin counterstain.)
were also responsible for the intraparenchymal granulomas (Figure 2, Bottom left, inset) and were dispersed moderately throughout the lobular fibroinflammatory zones. CD8þ T lymphocytes of the suppressor or cytotoxic subset outnumbered CD4 cells of the helper subset among the palisading histiocytes (Figure 2, Bottom right) and also among the nonnecrotizing granulomas. CD20þ B lymphocytes were totally absent from the palisading granulomas. The relatively well preserved lobules of the lacrimal gland as well as those undergoing early fibrotic replacement exhibited a mixture of T lymphocytes (CD8 > CD4), CD20 B lymphocytes, and CD138-positive plasma cells (labeled with both the immunoglobulins IgG and IgA) Ig G4 cells were not observed. This cellular composition parallels the lymphocytic populations of the undisturbed normal lacrimal gland.5
DISCUSSION REGIONAL ENTERITIS CAN BE ASSOCIATED WITH A
clinical and radiographic picture of idiopathic orbital inflammation (pseudotumor) in the forms of scleritis, myositis, and VOL. 158, NO. 4
dacryoadenitis.1,3,4,6 Orbital inflammation is seen much less commonly in ulcerative colitis. In the orbit, ulcerative colitis so far exclusively has assumed the form of myositis that has not yet been biopsied7–9; in nonocular muscle, it takes the form of a nongranulomatous, patchy, mononuclear lymphocytic infiltrate.10,11 In a review of 14 published cases of orbital involvement in regional enteritis,12 3 patterns were detected: myositis, the most common; dacryoadenitis and scleritis combined with myositis; and isolated dacryoadenitis, the rarest. In this series, when the sex was known, young females predominated over males in a ratio of 6 to 1. In 6 cases, the orbital disease preceded the diagnosis of regional enteritis, whereas in the other 8 cases, the diagnosis had already been made. Seven of 12 cases were bilateral when laterality was specified, but involvement of the orbits can be dysynchronous. There are also 2 separate published cases of bilateral epiphora and regional enteritis. The first concerned a 41-year-old woman known to have regional enteritis for 5 years who underwent dacryocystorhinostomy.13 Histopathologic evaluation of the excised portion of the lacrimal sac disclosed nongranulomatous chronic inflammation. The second report described a 16year-old boy with a 2-year history of epiphora and granulomatous cheilitis. The concurrent onset of abdominal pain
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and diarrhea led to a colonoscopy with biopsy that established the diagnosis of regional enteritis. The tissue obtained from a dacryocystorhinostomy microscopically revealed granulomatous inflammation.14 In instances of orbital myositis with bowel disease, the typical muscle swellings with tendon involvement noted on computed tomography scanning were adequate for the diagnosis, and therefore patients generally did not undergo biopsy. In contrast to localized idiopathic orbital inflammation (pseudotumor), there was more frequent involvement of the medial, lateral, and inferior rectus muscles, rather than the usual medial and superior rectus–levator complex.6,12,15 Graves disease can be closely simulated, requiring appropriate serologic tests to rule out this disorder. In 1 patient with known regional enteritis, an isolated, atypical, massive swelling of the superior rectus belly was discovered. Biopsy revealed necrosis and suppurative inflammation in the muscle surrounded by a palisading granuloma.16 Biopsy of an inflamed gastrocnemius muscle associated with regional enteritis also has revealed granulomatous inflammation.17 In 2 previous cases of dacryoadenitis, 1 patient was a 32-year-old woman with unilateral lacrimal gland disease and no known systemic disorder.3 A biopsy revealed necrotizing granulomatous inflammation, and regional enteritis eventually emerged. The second patient was a 32-year-old woman known to have regional enteritis who sought treatment for rapid onset of bilateral dysynchronous dacryoadenitis.4 This patient experienced increasing lateral upper eyelid swelling over 1 to 2 weeks with moderate pain. Her lacrimal glands were not biopsied, and the symptoms subsided with oral prednisone therapy. Characteristic computed tomography scan findings of inflammation were present in these 2 cases, and just as in our patients, consisted of oblong enlargements of the lacrimal glands (as opposed to rounded enlargements typical of epithelial tumors), protrusion of the mass beyond the orbital rim signifying palpebral lobe involvement, and the absence of any contiguous bone changes.18 Our 2 patients were young women with already established diagnoses of regional enteritis. Small and medium noncaseating granulomas were discovered in biopsies in both cases within the lobules of the lacrimal parenchyma. The granulomas may be very small and widely separated, and thus easily overlooked; their detection can be facilitated by obtaining sections at different levels of the tissue and performing CD68 or CD163 immunostaining. In Patient 1, the biopsy disclosed widened fibrous interlobular septa that additionally exhibited multiple foci of necrobiosis (altered collagen that appeared fibrillogranular or amorphous, and either more or less eosinophilic than normal collagen) surrounded by palisading granulomas. Immunohistochemistry analysis demonstrated that T lymphocytes of the suppressor or cytotoxic subset, but not B lymphocytes or CD138 plasma cells, were intermixed with the CD68þ 842
histiocytes forming the palisading granulomas. T cells also predominated over B lymphocytes within the small aggregates of CD68þ histiocytes that composed the noncaseating granulomas within the lacrimal parenchyma. The affected tissues were moderately fibrotic and displayed a lymphoplasmacytic infiltrate without demonstrable lymphoid follicles or vasculitis. CD8-positive suppressor or cytotoxic T lymphocytes were found intermixed with the epithelioid histiocytes to the complete exclusion of CD20þ B lymphocytes. No IgG4 plasma cells were found, thus ruling out a role for IgG4–mediated fibroinflammatory disease.19,20 The lymphocytic profile of the relatively uninvolved lacrimal lobules recapitulated the normal standing population of lacrimal gland lymphocytes, including a T-cell predominance with a generous admixture of B-lymphocytes and plasma cells sporting IgG and IgA.5 Necrobiosis can be seen in necrobiotic xanthogranuloma, in which there may be cholesterol clefts and typically a palisading granuloma. Patients with this finding are at risk of a monoclonal gammopathy or a lymphoproliferative neoplasm developing.21–24 Pseudorheumatoid nodules (also called granuloma annulare) can be encountered at the orbital rim in young individuals as well as exceptionally in the episclera and the deep orbit; they are not harbingers of a systemic disease.25–28 In Wegener granulomatosis, the lacrimal gland can be involved with palisading granulomas around necrobiotic foci, but there also tends to be more advanced fibrosclerosis, an acute and chronic inflammatory infiltrate often displaying eosinophilic leukocytes, perivascular collagenous onion skinning, and vasculitis leading to mummification of the collagen (loss of nuclei). Concomitant surrounding sinus disease and antineutrophil cytoplasmic antibody positivity is associated.29 The granulomas in sarcoidosis are larger, display multinucleated giant cells (typically absent in the granulomas associated with regional enteritis), are surrounded by more pronounced fibrosis, and fail to display necrobiosis. Staining results for acid-fast bacilli, spirochetes for syphilis (Warthin-Starry silver), and fungi for the genus Aspergillus or mucormycosis (Grocott’s methenamine silver) were negative.30–32 A distinctive feature of tuberculous and syphilitic dacryoadenitis is adjacent periostitis of the palpebral orbital bony rim leading to osteolysis.33 Infections of the gland have also included schistosomiasis.34 Simultaneous bilateral infections of the lacrimal glands furthermore would be most unusual. The reason for the granulomatous dacryoadenitis in regional enteritis is elusive, but may revolve around antigenic overlaps between the bowel and lacrimal tissues (such a mechanism has been postulated in cases with uveitis35). Alternatively, it is also theoretically possible that a bowel antigen could localize hematogenously to the lacrimal glands location and incite a T-cell response with an accompanying granulomatous reaction pattern.
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A range of therapies has been used for dacryoadenitis in regional enteritis. Surgical resection of the inflamed ileum can lead to abatement of the orbital inflammation.36 Even a subtotal excisional biopsy can assist in resolution of the lacrimal gland inflammation, as occurred in Patient 1. If the bowel disease is under control, increasing the dose of prednisone may be curative. The use of acetylsalicylic acid alone has been shown in some cases to be able to arrest the disease.4 Stress management seems to be helpful in some patients in reducing the frequency and severity of ocular inflammatory attacks.37 If the patient concurrently experiences exacerbation of the bowel symptoms, then increasing the doses
of chemotherapeutic medicines may be required. However, the use of a more intensive regimen for recalcitrant disease may have to be instituted that includes infliximab. This agent is a chimeric mouse and human monoclonal antibody that prevents tumor necrosis factor a, a cytokine produced mainly by activated macrophages that are present in the granulomas of regional enteritis, from binding to its target cell receptor. Pulsed intravenous chemotherapy also can be introduced.38,39 Because of the apparent role of T lymphocytes in mediating the granulomatous dacryoadenitis of regional enteritis, consideration should be given to cyclosporin in the future treatment of this condition.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST and none were reported. Involved in Conception and design of study (F.A.J., A.R.); Data collection (F.A.J., A.R., K.A.L., M.K.); Analysis and interpretation of data (F.A.J., A.R.); Provision of materials, patients, or resources (F.A.J., K.A.L., M.K.); Literature search (F.A.J., A.R.); Writing (F.A.J., A.R.), critical revision (F.A.J., A.R.), and final approval (F.A.J., A.R., K.A.L., M.K.) of article.
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31. Green WR, Font RL, Zimmerman LE. Asperillosis of the orbit. Report of ten cases and review of the literature. Arch Ophthalmol 1969;82(3):302–313. 32. Schmoll C, Macrae M, Mulvihill A, Murray R, Cunningham S, McKenzie K. Tuberculous dacryoadenitis in a Scottish teenager. Br J Ophthalmol 2009;93(2):137–138. 274. 33. van Assen S, Lutterman JA. Tuberculous dacryoadenitis: a rare manifestation of tuberculosis. Neth J Med 2002;60(8): 327–329. 34. Jakobiec FA, Gess L, Zimmerman LE. Granulomatous dacryoadenitis caused by Schistosoma haematobium. Arch Ophthalmol 1977;95(2):278–280. 35. Bhagat S, Das KM. A shared and unique peptide in the human colon, eye, and joint detected by a monoclonal antibody. Gastroenterology 1994;107(1):103–108. 36. Young RS, Hodes BL, Cruse RP, Koch KL, Garovoy MR. Orbital pseudotumor and Crohn disease. J Pediatr 1981;99(2):250–252. 37. Boerner CF. Orbital inflammation and inflammatory bowel disease. Ophthalmology 1992;99(2):169. 38. Garrity JA, Coleman AW, Matteson EL, Eggenberger ER, Waitzman DM. Treatment of recalcitrant idiopathic orbital inflammation (chronic orbital myositis) with infliximab. Am J Ophthalmol 2004;138(6):925–930. 39. Suelves AM, Arcinue CA, Gonzalez-Martin JM, Kruh JN, Foster CS. Analysis of a novel protocol of pulsed intravenous cyclophosphamide for recalcitrant or severe ocular inflammatory disease. Ophthalmology 2013;120(6):1201–1209.
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Biosketch Frederick A. Jakobiec, MD, DSc is the Director of the David G. Cogan Laboratory of Ophthalmic Pathology at the Massachusetts Eye and Ear Infirmary in Boston, Massachusetts. Dr Jakobiec is the Henry Willard Williams Professor Emeritus of Ophthalmology and Pathology, the past Chairman of Ophthalmology at the Harvard Medical School, and the past Chief of Ophthalmology at the Infirmary. His main clinical and pathologic interests are in ocular and adnexal tumors and idiopathic inflammations.
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