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, CD68-positive 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 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.
Regional enteritis (Crohn disease) and ulcerative colitis are the 2 main causes of noninfectious chronic inflammatory bowel disease. 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. Ocular complications that may be seen in up to 10% of patients consist of conjunctivitis, anterior uveitis or iritis, and episcleritis. 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.
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 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.
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 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
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, Sjögren 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. 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 × 2 mm and of the same character in Patient 2, measuring 7 × 2 × 2 mm. Fresh tissue for culturing micro-organisms 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, 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 CD68+ and CD1a− histiocytes with a clear zone corresponding to the area of necrobiosis ( Figure 2 , Bottom left). These cells were also responsible for the intraparenchymal granulomas ( Figure 2 , Bottom left, inset) and were dispersed moderately throughout the lobular fibroinflammatory zones. CD8+ 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. CD20+ 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.
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 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.
