Author Affiliations: David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary (Drs Jakobiec and Stacy), Department of Ophthalmology, Harvard Medical School (Drs Jakobiec, Stacy, and Hatton), and Ophthalmic Consultants of Boston (Dr Hatton), Boston.
Graves disease1 and, much more rarely, Hashimoto thyroiditis2 have well-established associations with proptosis. Less appreciated is that sclerosing inflammation of the lacrimal gland can be associated with Riedel struma (invasive fibrous thyroiditis that preferentially affects young women), both of which can also be components of multifocal fibrosclerosis (MFFS).3- 6 To our knowledge, no studies exist to date on the comparative immunopathologic features of these 2 involved glands, including the possible presence of IgG4-positive plasmacytes that would provide a link to the newly characterized fibrosing entity of IgG4-related disease.7- 10
A 38-year-old woman developed a tender left upper eyelid mass (Figure 1A) without proptosis over 6 months. Computed tomographic scanning showed unilateral enlargement of the left lacrimal gland (Figure 1B). Her serum IgG4 level was 55.4 mg/dL (reference range, <140 mg/dL; to convert to grams per liter, multiply by 0.01), and antineutrophil cytoplasmic antibody testing results were negative. Riedel thyroiditis lacking palpable nodularity had been diagnosed by biopsy 10 months earlier after causing dysphagia (Figure 1C). Workup disclosed elevated liver enzyme levels and a right upper lobe lung nodule. Biopsies of the common bile duct, ampulla of Vater, and a subpleural mass contained infiltrates of polyclonal lymphocytes, plasmacytes, and scattered eosinophils without granulomas; only the lung lesion displayed fibrosis. IgG4-positive plasmacytes were identified in small numbers in all 3 sites. The patient was treated with steroids, levothyroxine sodium, and tamoxifen citrate with moderate improvement.
Sclerosing dacryoadenitis and Riedel thyroiditis. A, The left upper eyelid mass (arrow) without skin erythema represents a palpebral lobe of the lacrimal gland and appeared over 6 months. B, The top panel of an axial computed tomographic scan displays diffuse oblong enlargement of the lacrimal gland without bone destruction (arrow), and the bottom panel fails to reveal an adjacent bony fossa (arrow) in coronal projection. C, The massively enlarged, nonnodular, rock-hard thyroid gland was biopsied (scar at bottom) 11 months before the lacrimal gland was biopsied. D, The lacrimal gland biopsy reveals keloidal bands of longitudinal collagen above and surviving ductules on the bottom left (hematoxylin-eosin, original magnification ×100). Inset, Concentric lamellations of periodic acid–Schiff–positive basement membrane material are seen around ductules (original magnification ×100). E, A follicle is present within a lymphoid aggregate in the thyroid gland. Note the characteristic keloidal collagen bands on the left that were also present in the lacrimal gland (hematoxylin-eosin, original magnification ×100). F, Blue-staining fibrosis engulfs red-staining cervical striated muscle fibers, indicating invasion of the thyroid gland capsule (Masson trichrome, original magnification ×400).
The lacrimal gland was biopsied when the patient was receiving 20 mg of prednisone daily. It manifested surviving ductules without acini in the midst of fibrosis (Figure 1D). Lymphoid follicles were focally observed in the thyroid gland biopsy (Figure 1E); fibrosclerosis invaded striated muscle (Figure 1F). Longitudinal keloidal bands in the lacrimal and thyroid glands (Figure 1D and E) stained positive with periodic acid–Schiff and strikingly positive with trichrome (Figure 1D [inset] and F); in the lacrimal gland, they fused with basement membranes around ductules (Figure 1D [inset]).
The infiltrates were polyclonal, composed of T cells (CD3/5+) (Figure 2A) and B cells (CD20+) (Figure 2B) with approximately equal κ and λ light chain expression. In the fibrotic area of both glands, IgA-positive plasmacytes were present (mean, 23/high-power field [HPF] in the lacrimal gland and 21/HPF in the thyroid gland) (Figure 2C and D). A small lobule of nonsclerosed lacrimal tissue contained more numerous interstitial IgA-positive cells. IgG4-positive plasmacytes were sparse in both the sclerosed thyroid and lacrimal glands (8/HPF each) (Figure 2E and F) but more apparent where there was follicle formation in the thyroid gland (73/HPF) (Figure 2F [inset]). (In fibrotic regions, having >30 IgG4-positive cells/HPF is considered significant.9)
Immunophenotypic features of inflamed glands (immunoperoxidase reaction, diaminobenzidine chromogen). A, Dispersion of CD3+ T lymphocytes predominates in sclerosing regions of the lacrimal gland (original magnification ×100). B, Small aggregates of CD20+ lymphocytes without follicular organization are seen in the scarred lacrimal gland (original magnification ×100). C, Dark-staining cells are IgA-positive plasmacytes in the lacrimal gland. Note the presence of IgA-positive staining in the luminal secretion of a surviving ductule (arrow). There is nonspecific background staining (original magnification ×200). D, IgA-positive plasmacytes are dispersed within the fibrotic mass replacing the thyroid gland (original magnification ×200). E, Sparse dark-staining IgG4-positive plasmacytes are seen in the lacrimal gland in the interstitium around faintly counterstained ductules (original magnification ×200). F, IgG4-positive cells are also lightly scattered in the fibrosclerotic thyroid tissue (original magnification ×200). Inset, Greater prominence of these cells is seen in a lymphoid aggregate (original magnification ×200).
Multifocal fibrosclerosis can affect many sites: orbital fat and muscles; parotid, lacrimal, and thyroid glands; mediastinum and retroperitoneum; and bile duct and pancreas.8- 10 Riedel invasive thyroiditis creates a hard mass, invades the gland's capsule,11 and is associated with MFFS in 34% of cases.12 Of all cases of MFFS, however, Riedel thyroiditis is an element of the syndrome in a much smaller subset of patients.3,13 In our patient and others described with Riedel thyroiditis,3- 6 the orbital disease preferentially occurs in the lacrimal gland. In orbital fibroinflammatory disease that is localized9 or part of MFFS but without associated thyroiditis,10,13 men are more often affected; furthermore, microscopically the fibrosis is concentrically arranged around blood vessels in muscle and fat rather than longitudinally arranged as keloidal bands as in the lacrimal and thyroid glands of our patient's biopsies.
We have confirmed the presence of IgA-positive plasmacytes in Riedel thyroiditis, whereas IgG-positive cells typify Hashimoto disease.11 We also found IgA-positive plasmacytes in the fibrotic lacrimal gland.14 A normal IgG4 serum level and a low IgG4-positive plasmacytic tissue density in both glands were possibly caused by the administration of prednisone therapy as IgG4-related fibrosclerosis is known to be corticosteroid responsive.10
From the clinical perspective, Riedel thyroiditis should be considered when proptosis or globe displacement is caused by a lacrimal gland swelling accompanied by an extremely firm, smooth enlargement of the thyroid gland. Our case and those previously reported3- 6 have documented that a clinically apparent thyroid mass usually precedes the onset of dacryoadenitis.
Correspondence: Dr Jakobiec, David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, 243 Charles St, Ste 321, Boston, MA 02114 (firstname.lastname@example.org).
Financial Disclosure: None reported.
Funding/Support: Dr Stacy is supported in part by the Heed Foundation.
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