Sjögren Syndrome

Sjögren syndrome is an autoimmune-mediated inflammation of the lacrimal and salivary glands that rheumatologists are frequently asked to evaluate; in these cases, the entire differential diagnosis must be considered, including malignant or lymphoproliferative processes. Ocular and oral dryness are common symptoms, particularly in elderly patients who frequently experience glandular age-related atrophy. Other common causes of ocular dryness include anticholinergic drugs, nonautoimmune gland dysfunction from blepharitis, or mechanical factors. Likewise, oral sicca may be caused by medications or chronic viral infections such as human immunodeficiency virus (HIV) and hepatitis C, following radiation therapy, as part of graft-versus-host disease, or as a result of infiltrative diseases such as sarcoidosis. Sjögren syndrome is characterized by lymphocytic infiltration, enlargement, and dysfunction of glandular tissue and is associated with the presence of antinuclear antibodies, anti-Ro and anti-La antibodies, rheumatoid factor, as well as extraglandular features in 25% and lymphoma in 2.5%. It is primary in 70% of cases or otherwise secondary to rheumatoid arthritis and other connective tissue diseases. The histology of Sjögren syndrome is coined benign lymphoepithelial sialadenitis (also known as myoepithelial sialadenitis [MESA]). Pathologic features include lymphocytic infiltration, parenchymal atrophy, and foci of epithelial proliferation. These findings may be localized initially, but, late in the disease, may involve the entire gland while preserving its architecture. Ductal hyperplasia, together with foci of lymphocyte infiltration, constitutes the lymphoepithelial lesion and results in ductal luminal obliteration. T cells (with occasional B cells) primarily constitute the lymphoid infiltrate. B cell clonal expansion is found in 50% of MESA by molecular genetics. Although, in some cases, this may represent the earliest manifestation of lymphoma, much uncertainty regarding this continuum remains, and malignant progression may require additional oncogenic mutations. A high index of suspicion for the development of salivary gland lymphoma should be maintained for the lifetime of a patient with Sjögren syndrome.

Salivary Gland Lymphoma

Salivary gland lymphomas represent 1.7% to 7% of all salivary gland tumors and are usually primary and only rarely secondary to extraglandular nodal disease. The characteristic patient is a woman in her 60s presenting with unilateral glandular enlargement. Although patients with Sjögren syndrome have an increased risk of salivary gland lymphoma, most patients with salivary gland lymphoma do not have an underlying autoimmune disease. Most salivary gland lymphomas are non-Hodgkin B cell lymphomas, primarily extranodal marginal zone B cell lymphoma and, less commonly, follicular or diffuse large B cell lymphomas. Marginal B cell lymphomas of the salivary glands are typically mucosa-associated lymphoid tissue (MALT) lymphomas. Most MALT lymphomas are associated with a predisposing factor such as infection or an autoimmune disease resulting in the formation of lymphoid tissue at sites where it is not normally present. In a series of 9 salivary MALT lymphomas, half the patients had a diagnosis of Sjögren syndrome. Most of the patients were women, had localized disease with good prognostic factors, and had presented with asymptomatic glandular enlargement of the parotid gland. In all cases, fine-needle aspiration and radiologic imaging were not diagnostic, only raising the suspicion for a lymphoproliferative process. Blind biopsies of parotid masses should be avoided to prevent injury to the facial nerve and avoid seeding of malignant cells. Diagnosis was established in all from surgical excision. Diagnostic features of MALT include broad strands of marginal zone B cells around lymphoepithelial lesions as well as the presence of monoclonal Ig expansion by immunohistochemistry. Differentiation from reactive lymphoid proliferation is difficult, especially because 20% of salivary gland MALT lymphomas are found in the setting of MESA.

IgG4-RSD

In 2003, Kamisawa and colleagues first recognized that autoimmune pancreatitis is characterized by infiltration with IgG4-positive plasma cells that can be detected beyond the pancreatic tissue and heralds a systemic disease, which they coined IgG4-related autoimmune disease. Since then, the field has expanded into a new concept of IgG4-RSD. IgG4-RSD can cause sialadenitis and dacryoadenitis and seems to encompass the poorly characterized old entities of Kuttner tumor and Mikulicz disease.

Kuttner tumor, also known as chronic sclerosing sialadenitis, was originally described by Kuttner as a hard swelling of 1 or more submandibular glands that may also involve the parotid and minor salivary gland. Patients are often middle-aged to elderly men who present with asymptomatic enlargement of salivary glands, unilateral or bilateral, with preserved to slightly reduced salivary gland function. Researchers from Japan reported on the presence of abundant IgG4 plasma cells in 12 patients with sclerosing sialadenitis and first proposed its association with IgG4-RSD. About half of these patients had extrasalivary systemic lesions with either pancreatic, lacrimal, prostate, or bile duct infiltration. More than 45% of infiltrating IgG-positive plasma cells were IgG4 positive in these patients, compared with less than 5% in sialolithiasis and Sjögren control patients. IgG4 serum levels were not measured in this series. A more recent study confirmed similar findings in a Western population of patients with chronic sclerosing sialadenitis, again supporting the finding that Kuttner tumor may belong within the spectrum of IgG4-RSD. Unlike MESA, lymphoepithelial lesions are not detected in Kuttner tumor. Instead, histology reveals marked lymphoplasmacytic infiltration with large germinal centers, obliterative phlebitis, acinal atrophy, and interlobular fibrosis with activated fibroblasts.

Mikulicz disease presents with bilateral and persistent enlargement of the lacrimal and salivary glands. It has been rarely reported in the Western literature since Morgan and Castleman defined it as a subset of Sjögren syndrome. Differences from Sjögren syndrome include a balanced gender distribution, mild keratoconjunctivitis sicca, the lack of positive antinuclear antibody or anti-Ro/La antibodies, reported positive response to corticosteroids with recovery of glandular function, and the lack of apoptosis and acinar destruction typical of Sjögren syndrome. Yamamoto and colleagues reported on 7 patients meeting the definition of Mikulicz disease and described increased serum IgG4 levels and the presence of IgG4-positive plasma cells infiltrating around the acinar and ductal cells, defining a new concept of Mikulicz disease as an IgG4-related plasmacytic disease. Presence of greater than 50 IgG4-positive plasma cells per high-power field and an IgG4/IgG-positive plasma cell ratio of greater than 50% have been proposed as the histologic requirement for the diagnosis of IgG4-associated sialadenitis.

Chronic sclerosing dacryoadenitis secondary to infiltration of the lacrimal glands by IgG4-positive plasma cells has recently been recognized in the spectrum of IgG4-related systemic disease. In a series reviewing 112 cases with ocular adnexal lymphoproliferative disorders, 21 patients were identified as having IgG4-positive plasma cell infiltration. Most of these patients had lacrimal gland infiltration and none had conjunctival involvement. Histology of the glands was similar to that of chronic sclerosing sialadenitis of the submandibular glands with lymphoplasmacytic infiltration with lymphoid follicle formation, acinar atrophy, periductal fibrosis, and sclerosis, but lacking the obliterative phlebitis described in other organs. Several cases of MALT lymphoma arising in a background of IgG4 plasma cell infiltrative disease have also been reported.

The pathogenesis of IgG4-RSD is poorly understood and the role of IgG4 antibodies in the inflammatory cascade is unknown. IgG4 normally represents only 3% to 6% of total IgG and levels are tightly regulated, increasing slightly with age and male gender. IgG4 differs from other IgG subtypes. The covalent bindings of its heavy chains are loose, resulting in alterations of the Fab arm specificity and in functionally monovalent antibodies, which do not bind complements or cross-link identical antigens. Tissue-infiltrating and circulating plasma cells are polyclonal and therefore not of neoplastic origin. IgG4 antibodies in IgG4-RSD are not antigen specific, thus arguing against an autoimmune disease. The mainstay of treatment of IgG4-RSD remains corticosteroids based on retrospective experience, with little long-term follow up.

Salivary Gland Cancer

Sialadenosis or isolated salivary gland enlargement may present to the rheumatologist for evaluation of Sjögren syndrome. If unilateral, the possibility of a primary salivary gland tumor must be entertained. Salivary gland neoplasms are rare and represent about 5% of all head and neck tumors, or 0.5% of all malignancies. They typically present in the sixth decade of life and, for the most part, occur equally in men and women. Eighty percent of salivary gland neoplasms arise in the parotid gland, and most of those turn out to be benign pleomorphic adenomas, which comprise 50% of all tumors, followed by papillary cystadenoma, also known as Warthin tumor. The most common malignant salivary gland tumor is the mucoepidermoid carcinoma, which represents 10% of all salivary gland tumors. Pathogenesis of salivary gland tumors is not well understood. Factors implicated in nonsalivary head and neck tumors, such as smoking, are not known risk factors for the development of salivary gland tumors, whereas radiation therapy seems to be. Warthin tumor is the exception because it may be multifocal and bilateral, is more common in men, and is associated with smoking. Salivary gland neoplasm should be suspected in a patient presenting with an enlarging painless mass. Minor salivary gland tumors may present with a persistent oral ulceration. Evaluation should include imaging with ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) to assess disease extent and guide fine-needle aspiration biopsy and help plan surgical excision, which is required for accurate diagnosis and management. Prognosis of malignant tumors is based primarily on tumor size, with patients with tumors less than 4 cm doing well regardless of histologic type.

Primary Intraocular Lymphoma

Primary intraocular lymphoma (PIOL), a rare ocular neoplasm, is frequently misdiagnosed as uveitis, vitritis, or chorioretinitis, and must be suspected in patients with vitritis or posterior uveitis that is refractory to or recurs after steroid therapy. In a series of 40 patients with a uveitis masquerade syndrome, 16 had an intraocular malignancy, of which 13 were intraocular lymphoma. Immunodeficiency from transplant antirejection therapy, HIV disease, or inherited immune deficiencies should raise the clinical suspicion PIOL. Diagnosis was delayed from 1 to 29 months in 1 series, and is challenging for several reasons: it may initially be responsive to steroid therapy; although common, central nervous system (CNS) involvement may not occur for years following initial ocular presentation, so a normal CNS evaluation does not exclude ocular lymphoma ; and cytologic evaluation early in the course may be unrevealing because some of the infiltrating leucocytes may be reactive to the malignant cells. PIOL typically presents in the fifth to seventh decade. Ocular symptoms are present in 80%, most often blurred vision but also eye pain, floaters, or a foreign-body sensation. Eighty percent of patients may present with bilateral involvement even in the absence of bilateral ocular symptoms. Fundus examination reveals vitritis universally with clumps of white cells without significant anterior chamber flare, and may be the only finding in 30%. The classic pathognomonic feature is described as round or oval, yellow-white, dome-shaped masses in the subpigment epithelial space but may also include chorioretinitis and retinal vasculitis. Ocular ultrasound may help support slit lamp findings as well as detect retrobulbar involvement in some cases. Fluorescein angiography may reveal granularity, blockage, and late staining at the level of the retinal pigment epithelium and, less commonly, pathognomonic hypofluorescent pigment epithelial detachment. Other features include lack of perivascular staining and lack of cystoid macular edema, as seen in the setting of other causes of vitritis. Additional evaluation should include pars plana vitrectomy or chorioretinal biopsy, if necessary. These tests are more likely to be sensitive if steroids are withheld before the procedure. Non-Hodgkin B cell lymphoma is the most common type PIOL, followed by angiotropic T cell lymphoma. Although only a small sample volume with a low number of malignant cells is obtained from vitrectomy, cytologic review and processing of fresh sample for immunohistochemistry and polymerase chain reaction analysis may increase the sensitivity of the test. An intravitreous interleukin (IL)-10/IL-6 ratio greater than 1.0 may suggest lymphoma. Head MRI and cerebrospinal fluid examination are necessary to assess for CNS involvement, which may already be present at the time of ocular presentation or may develop in up to 80% of patients. HIV testing is also essential. Intravitreally injected methotrexate and, possibly, intravitreally injected rituximab are important adjuncts to therapy. Because ocular lymphoma is usually associated with disease that extends beyond the eye, systemic chemotherapy is associated with an improved progression-free survival. Given its initially indolent ocular presentation and partial response to steroids, PIOL can easily be mistaken for idiopathic uveitis and must be considered and excluded before embarking on steroid-sparing immunosuppressant therapy.

Leukemia

The typical ocular manifestations of acute leukemia are described as leukemic retinopathy and orbital infiltration, but may rarely include uveitis masquerade syndrome. Most case reports describe children presenting with anterior uveitis as a first sign of CNS or bone marrow relapse with acute lymphoblastic leukemia.

Periocular Lymphoma

Several cases of periocular or adnexal ocular lymphoma presenting as refractory uveitis or scleritis have been reported in the literature. Periocular lymphoma represents about 1% to 2% of all non-Hodgkin lymphomas and is primarily a disease of older adults. The orbit is most commonly involved, followed by the conjunctivae, lacrimal glands, and the eyelids. It typically presents with a painless, salmon pink, diffuse or well-defined mass associated with proptosis, visual disturbance, periorbital edema, or redness. More than 70% to 90% of ocular adnexal lymphomas are primary and not secondary to systemic lymphoma. Most are low-grade B cell–type lymphomas. The most common histologic type is the extranodal marginal zone lymphoma of MALT and has been associated with cytogenetic abnormalities including trisomies and molecular translocations. Chlamydia psittaci has been implicated in the pathogenesis of ocular MALT but detection rates are highly variable among geographic regions. Systemic lymphoma develops in one-third of patients within 10 years, especially when the initial orbital presentation is bilateral. Therefore, a thorough evaluation and ongoing vigilance are required.

Retinoblastoma

Retinoblastoma may present as orbital inflammation in a subset of children and should be considered in the differential diagnosis of uveitis in children. Classically, retinoblastoma presents with leukocoria, strabismus, or reduced vision in children at a mean age of 18 months, with findings of a well-defined yellow-white retinal mass with evident calcifications on imaging. In a series of 1507 patients eventually diagnosed with retinoblastoma in one tertiary care center, 2% of cases presented with a diffuse infiltrative pattern mimicking ocular inflammation. The mean age was 4 years. Of those patients, 9% had been referred for evaluation of uveitis. Most presented with a white hypopyon, conjunctival injection, and vitritis, with either a lack or subtle presence of intralesional calcifications. Orbital cellulitis has also been reported as an initial presentation of diffuse retinoblastoma. Diagnosis should be made clinically by an experienced examiner because needle biopsy may lead to tumor cell seeding and future metastasis. Treatment consists of enucleation with or without chemotherapy.

Primary Ocular Melanoma

The eye is the second most common melanoma site. Primary ocular melanoma (POM) represents about 4% of all melanomas and is the most common primary ocular malignancy in adults, primarily affecting middle-aged white patients. Ninety-five percent of all ocular melanomas localize to the posterior uveal tract (ciliary body or choroid) and 5% to the iris. Most cases are sporadic. Fifty percent of cases are associated with metastasis, typically to the liver, and a 50% mortality at 10 years is reported and directly correlates with initial tumor size. Treatment consists of enucleation and local irradiation. Typically, POM presents with a painless mass. However, of 450 consecutive enucleations for malignant melanoma of the choroid or ciliary body, 5% initially presented with clinical signs of ocular inflammation. Close to half of those patients had episcleritis and the others had uveitis, endophthalmitis, or panophthalmitis. Cases presenting as scleritis have also been reported in the literature. These cases may initially respond to corticosteroid treatment, delaying the diagnosis. Furthermore, the choroidal mass may be plaquelike and difficult to detect. A high index of suspicion and close monitoring of mass enlargement with sequential examination, fundus photography, and orbital ultrasound are therefore recommended.

Primary Intraocular Lymphoma

Primary intraocular lymphoma (PIOL), a rare ocular neoplasm, is frequently misdiagnosed as uveitis, vitritis, or chorioretinitis, and must be suspected in patients with vitritis or posterior uveitis that is refractory to or recurs after steroid therapy. In a series of 40 patients with a uveitis masquerade syndrome, 16 had an intraocular malignancy, of which 13 were intraocular lymphoma. Immunodeficiency from transplant antirejection therapy, HIV disease, or inherited immune deficiencies should raise the clinical suspicion PIOL. Diagnosis was delayed from 1 to 29 months in 1 series, and is challenging for several reasons: it may initially be responsive to steroid therapy; although common, central nervous system (CNS) involvement may not occur for years following initial ocular presentation, so a normal CNS evaluation does not exclude ocular lymphoma ; and cytologic evaluation early in the course may be unrevealing because some of the infiltrating leucocytes may be reactive to the malignant cells. PIOL typically presents in the fifth to seventh decade. Ocular symptoms are present in 80%, most often blurred vision but also eye pain, floaters, or a foreign-body sensation. Eighty percent of patients may present with bilateral involvement even in the absence of bilateral ocular symptoms. Fundus examination reveals vitritis universally with clumps of white cells without significant anterior chamber flare, and may be the only finding in 30%. The classic pathognomonic feature is described as round or oval, yellow-white, dome-shaped masses in the subpigment epithelial space but may also include chorioretinitis and retinal vasculitis. Ocular ultrasound may help support slit lamp findings as well as detect retrobulbar involvement in some cases. Fluorescein angiography may reveal granularity, blockage, and late staining at the level of the retinal pigment epithelium and, less commonly, pathognomonic hypofluorescent pigment epithelial detachment. Other features include lack of perivascular staining and lack of cystoid macular edema, as seen in the setting of other causes of vitritis. Additional evaluation should include pars plana vitrectomy or chorioretinal biopsy, if necessary. These tests are more likely to be sensitive if steroids are withheld before the procedure. Non-Hodgkin B cell lymphoma is the most common type PIOL, followed by angiotropic T cell lymphoma. Although only a small sample volume with a low number of malignant cells is obtained from vitrectomy, cytologic review and processing of fresh sample for immunohistochemistry and polymerase chain reaction analysis may increase the sensitivity of the test. An intravitreous interleukin (IL)-10/IL-6 ratio greater than 1.0 may suggest lymphoma. Head MRI and cerebrospinal fluid examination are necessary to assess for CNS involvement, which may already be present at the time of ocular presentation or may develop in up to 80% of patients. HIV testing is also essential. Intravitreally injected methotrexate and, possibly, intravitreally injected rituximab are important adjuncts to therapy. Because ocular lymphoma is usually associated with disease that extends beyond the eye, systemic chemotherapy is associated with an improved progression-free survival. Given its initially indolent ocular presentation and partial response to steroids, PIOL can easily be mistaken for idiopathic uveitis and must be considered and excluded before embarking on steroid-sparing immunosuppressant therapy.

Leukemia

The typical ocular manifestations of acute leukemia are described as leukemic retinopathy and orbital infiltration, but may rarely include uveitis masquerade syndrome. Most case reports describe children presenting with anterior uveitis as a first sign of CNS or bone marrow relapse with acute lymphoblastic leukemia.

Periocular Lymphoma

Several cases of periocular or adnexal ocular lymphoma presenting as refractory uveitis or scleritis have been reported in the literature. Periocular lymphoma represents about 1% to 2% of all non-Hodgkin lymphomas and is primarily a disease of older adults. The orbit is most commonly involved, followed by the conjunctivae, lacrimal glands, and the eyelids. It typically presents with a painless, salmon pink, diffuse or well-defined mass associated with proptosis, visual disturbance, periorbital edema, or redness. More than 70% to 90% of ocular adnexal lymphomas are primary and not secondary to systemic lymphoma. Most are low-grade B cell–type lymphomas. The most common histologic type is the extranodal marginal zone lymphoma of MALT and has been associated with cytogenetic abnormalities including trisomies and molecular translocations. Chlamydia psittaci has been implicated in the pathogenesis of ocular MALT but detection rates are highly variable among geographic regions. Systemic lymphoma develops in one-third of patients within 10 years, especially when the initial orbital presentation is bilateral. Therefore, a thorough evaluation and ongoing vigilance are required.

Retinoblastoma

Retinoblastoma may present as orbital inflammation in a subset of children and should be considered in the differential diagnosis of uveitis in children. Classically, retinoblastoma presents with leukocoria, strabismus, or reduced vision in children at a mean age of 18 months, with findings of a well-defined yellow-white retinal mass with evident calcifications on imaging. In a series of 1507 patients eventually diagnosed with retinoblastoma in one tertiary care center, 2% of cases presented with a diffuse infiltrative pattern mimicking ocular inflammation. The mean age was 4 years. Of those patients, 9% had been referred for evaluation of uveitis. Most presented with a white hypopyon, conjunctival injection, and vitritis, with either a lack or subtle presence of intralesional calcifications. Orbital cellulitis has also been reported as an initial presentation of diffuse retinoblastoma. Diagnosis should be made clinically by an experienced examiner because needle biopsy may lead to tumor cell seeding and future metastasis. Treatment consists of enucleation with or without chemotherapy.

Primary Ocular Melanoma

The eye is the second most common melanoma site. Primary ocular melanoma (POM) represents about 4% of all melanomas and is the most common primary ocular malignancy in adults, primarily affecting middle-aged white patients. Ninety-five percent of all ocular melanomas localize to the posterior uveal tract (ciliary body or choroid) and 5% to the iris. Most cases are sporadic. Fifty percent of cases are associated with metastasis, typically to the liver, and a 50% mortality at 10 years is reported and directly correlates with initial tumor size. Treatment consists of enucleation and local irradiation. Typically, POM presents with a painless mass. However, of 450 consecutive enucleations for malignant melanoma of the choroid or ciliary body, 5% initially presented with clinical signs of ocular inflammation. Close to half of those patients had episcleritis and the others had uveitis, endophthalmitis, or panophthalmitis. Cases presenting as scleritis have also been reported in the literature. These cases may initially respond to corticosteroid treatment, delaying the diagnosis. Furthermore, the choroidal mass may be plaquelike and difficult to detect. A high index of suspicion and close monitoring of mass enlargement with sequential examination, fundus photography, and orbital ultrasound are therefore recommended.