Case 3 -

Idiopathic Sclerosing Orbital Inflammation (Orbital Pseudotumor) Diva R. Salomao Mayo Clinic Rochester, MN

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Clinical History A previously healthy 47-year-old woman came to our institution for evaluation of a right orbital mass which was incidentally found during work-up for shortness of breath. A CTA to exclude pulmonary embolism incidentally revealed an orbital mass confirmed later by dedicated orbital imaging. Although at first, this orbital mass seemed to be asymptomatic, on further questioning the patient reported intermittent short lived blurry vision and episodic discomfort near the right temple for the past year. She denied any discrete ocular pain, diplopia, limitation of ocular movements or noticed proptosis. On clinical examination, a 4 mm proptosis was present and there was tenderness to palpation over the superior temporal aspect of the right orbit which appeared full but was not discolored. The clinical differential diagnosis based on the infiltrative appearance of the mass on MRI included lymphoma, favored due to the lack of symptoms, but also idiopathic orbital inflammation and sarcoidosis, given the history of cough. Case 3 - Figure 1 HE 100 X – Marked collagenized fibrosis with aggregates of small lymphocytes. The vessels in the middle of the field are not involved by the inflammation. Case 3 - Figure 2 HE 100 X – The process involves lacrimal gland tissue in addition to orbital soft tissues Case 3 - Figure 3 HE 200 X – Lacrimal gland involvement by marked fibrosis and chronic inflammation predominantly by lymphocytes Case 3 - Figure 4 HE 200 X – The process is causing acinar atrophy and replacement of the lacrimal gland tissue by fibrosis and inflammation Case 3 - Figure 5 CD 3 – The lymphocytic infiltrate is represented by a number of CD3+ T-cells Case 3 - Figure 6 CD 20 – The lymphocytic infiltrated shows numerous CD20+ B-cells that were polyclonal for Kappa and Lambda immunoglobulin light chain Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: Tissue biopsy was sent to the pathology laboratory for frozen section preliminary diagnosis and also permanent sections. Gross examination revealed several small fragments of whitish firm tissue measuring in aggregate 2.8 x 2.5 x 0.7 cm. Frozen section examination demonstrated extensive fibrosis and lymphocytic infiltrate involving the lacrimal gland and adjacent orbital soft tissues. Tissue was sent to the flow cytometry laboratory and immunostains were also requested in order to rule out a low-grade lymphoproliferative disorder. Permanent sections performed in the formalin fixed tissue revealed extensive collagenized fibrosis and aggregates of small lymphocytes involving the lacrimal gland tissue and causing acinar atrophy. There was no evidence vasculitis, areas of necrosis or granulomas. By flow cytometry studies (CD3, CD5, CD7, CD10, CD19, CD20, CD23, CD45 and kappa and lambda immunoglobulin light chains) the lymphoid infiltrate was represented by a mixture of T-cells with no phenotypic abnormalities and B- cells which had polytypic expression of kappa and lambda immunoglobulin light chains. On immunohistochemistry (CD3, CD20, IgG, IgG4, kappa and lambda immunoglobulin light chains), similar results were obtained. In addition, there was a small population of polytypic IgG positive plasma cells, without significant IgG4 positivity. Differential Diagnoses: The differential diagnosis in this particular case, based on the histopathologic findings of lymphocytic infiltrate and background fibrosis involving lacrimal gland tissue and adjacent soft tissues included mainly low-grade lymphoma and idiopathic orbital inflammation. Vasculitis, granulomas or tissue necrosis was not seen. Flow cytometry and immunohistochemical studies revealed a polyclonal process consistent with non specific inflammation. Final Diagnosis: Idiopathic sclerosing orbital inflammation (orbital pseudotumor) Case Discussion: By definition, idiopathic orbital inflammation (IOI) is a diagnosis made after excluding lesions with identifiable local or systemic etiology. The differential diagnosis for IOI includes infectious processes, inflammatory responses to trauma or foreign body, thyroid orbitopathy, vasculitis (Wegener's granulomatosis), sarcoidosis, lymphoproliferative disorders and tissue reaction around a neoplasm. Infection must be always considered. The orbit is usually affected by contiguous spread from paranasal sinusitis, commonly starting in the ethmoid sinus. However, infectious processes in the orbit can also be seen in the setting of septicemia. Life threatening fungal infections such as mucormycosis and aspergillosis may occur in diabetic and immunocompromised patients. Therefore, an infectious etiology should always be excluded by clinical history, cultures, serological tests and special stains when necessary. Thyroid orbitopathy, Graves's orbitopathy, is an important consideration in the work-up of patients with IOI. Thyroid orbitopathy accounts for more than 50% of cases of proptosis. Men and women are equally affected. Graves's disease has usually a slower and more insidious course than IOI and it tends to be bilateral. The characteristic clinical manifestations are lid retraction, eyelid lag, proptosis, restrictive extraocular myopathy and optic neuropathy, Radiographic findings include enlargement of extraocular muscles and increased orbital fat volume. Histologically, the inflammation is restricted to the body of the extra-ocular muscles and represented mostly by lymphocytes, plasma cells and mast cells. A background of tissue edema with deposition of mucopolysaccharides is present and it can be demonstrated by Alcian blue stain. The clinical and serological findings are very important in order to support the histological diagnosis. Wegener's granulomatosis is a necrotizing, granulomatous inflammation and vasculitis that may also affect the respiratory and renal systems with ocular involvement in 50% of the cases. Bilateral eye pain, proptosis, redness and ocular motility dysfunction are common clinical features. Ocular and orbital manifestations of Wegener's granulomatosis include conjunctivitis, marginal ulcerative keratitis, scleritis, uveitis, optic neuropathy, dacryadenitis and nasolacrimal duct obstruction. Histological features include necrotizing, granulomatous inflammation and vasculitis. Serum levels of antineutrophil cytoplasmic antibodies (c- ANCA) are elevated in 90% of patients with active Wegener's granulomatosis. However, it is important to note that c- ANCA may not be positive in the limited form. Systemic work-up including pulmonary and renal functions are important to exclude Wegener's granulomatosis. Sarcoidosis is characterized by systemic granulomatous inflammation involving the lung, hilar lymph nodes, eyes and shin. Ocular involvement occurs in 25 to 50% of patients, and it may involve the lacrimal gland, extraocular muscles, orbital fat, optic nerve and uveal tract. Conjunctival granuloma or solitary orbital granuloma may also be found. Clinical features include pain, proptosis, oculomotor dysfunction, uveitis, and vision loss. Noncaseating epithelioid granulomas are the classical histological finding. Neoplasm is also an important consideration especially in patients with a solitary orbital lesion. In the adult population, metastatic lesions and lymphoma are high in the differential diagnosis. Breast, lung, prostate and kidney are common primary sites, and the possibility of chronic inflammatory reaction around a true neoplasm should be considered. Histologically, low-grade lymphomas are the main differential diagnosis as some cases of IOI may reveal prominent lymphoid infiltrate and/or follicular hyperplasia. Hence follicular lymphoma, extranodal marginal zone lymphoma and small lymphocytic lymphoma the most commonly considered in this differential. Immunophenotyping by flowcytometry or immunohistochemistry is usually needed to exclude a clonal process. As in this case, the diagnosis of idiopathic orbital inflammation (IOI) is the result of correlating the clinical and radiological findings (orbital mass) with the finding of a non-specific chronic inflammation in the biopsy. The presence of marked background fibrosis in this case characterized this process as idiopathic sclerosing orbital inflammation, considered a subtype of IOI. Review of the Literature/Treatment Options (if applicable): Idiopathic orbital inflammation (orbital pseudotumor) was first described by Birch-Hirschfeld in 1905 to report inflammatory conditions that caused a mass effect in the orbit and therefore produced a false clinical impression of a neoplasm. With time, several other diseases, such as Graves' orbitopathy, which were at first lumped under the umbrella term "orbital pseudotumor", were better categorized and received recognition in the medical literature as specific entities separate from idiopathic orbital inflammation. In fact, since its first description, the history of orbital inflammatory pseudotumor, or IOI, has been defined by what it is not. Several synonyms have been used, inflammatory pseudotumor, non specific orbital inflammation, however the term idiopathic orbital inflammation is the one most accepted nowadays. Although inflammatory processes of the orbit are relatively common, idiopathic orbital inflammation (IOI) represents only 5% to 20% of these cases in various studies. As the name implies, the pathogenesis of IOI has remained elusive. An immune-mediated process is thought to be responsible for this inflammatory response in the orbit. However, numerous unanswered questions remain, such as is there an antigenic stimulus? Why the lesion is localized to the orbit? Idiopathic orbital inflammation may occur in patients of any age, although more frequently observed in middle-aged women. The classical clinical presentation of this space- occupying infiltrating orbital process is of an acute or subacute onset with pain, discomfort on movement of the globe, proptosis, and inflammatory signs such as swelling and erythema. Presentation varies according to the specific location and degree of inflammation, fibrosis, and mass effect. Therefore, the disease can be further divided according to which orbital structure is predominantly involved: myositis (one or more extra-ocular muscles), dacryoadenitis (lacrimal gland), peri-scleritis, trochleitis, or perineuritis (outer dural sheath of the optic nerve), which ultimately determines the specific constellation of findings in each patient. Unilateral presentation is typical, but bilateral presentations are not uncommon. The acute form is the most striking and the easiest to distinguish from other orbital conditions such as thyroid related-orbitopathy or orbital lymphoma. This form is extremely responsive to systemic steroids. In the chronic form, patients become symptomatic from proptosis, diplopia or visual decrease that develops over a period of months to years. Pediatric IOI is characterized by a number of features that differ from the adult presentation. Bilateral manifestation, as well as uveitis, disc edema and eosinophilia, appear to be more common in the pediatric population. Pediatric cases are uncommon, accounting for only 6% to 17% of the total incidence. Radiological imaging studies allow tissue characterization and localization and have become invaluable diagnostic tools in the management of patients with a suspected orbital mass. Computed tomography (CT) is the most common imaging mode used in the work-up of these patients. IOI is typically seen on CT scans as a focal or diffuse mass, usually poorly demarcated and enhancing with contrast. Magnetic resonance imaging is used, either alone or in combination with CT, in patients with suspected extra- orbital or intracranial extensions. Although IOI is typically confined to the orbit, extra-orbital involvement may occur in rare cases through the superior orbital fissure into the cavernous sinus and the intracranial space, or through the inferior orbital fissure into the pterygopalatine fossa or infratemporal fossa. Bone destruction is rare. The histopathologic spectrum of idiopathic orbital inflammation is wide and diverse. Some cases are characterized by non specific chronic inflammation, mostly by lymphocytes and some plasma cells, histiocytes, occasional eosinophils with admixed background fibrosis. Other cases are characterized by a denser lymphocytic infiltrate which raises the possible diagnosis of lymphoma. Cases with marked lymphoid hyperplasia have been referred in the past by the name orbital pseudolymphomas. At the other end of the spectrum, some cases are characterized by dense collagenized connective tissue as the predominant component with scant inflammatory infiltrate (sclerosing form). The dense collagenization observed in the sclerosing form was first considered to be the end stage of the histological continuum of IOI. However, there is enough evidence that this is a separate subtype of IOI, characterized by insidious, frequently progressive course replacing and damaging orbital structures through entrapment. It tends to be more aggressive than the non sclerosing forms and to have poor therapeutic outcomes. Therapeutic approaches to IOI have included observation, nonsteroidal inflammatory drugs, radiation, surgical excisions, corticosteroids, immunosuppressants and immunobiologic agents. Systemic steroid therapy with a slow taper has been the established first-line treatment for symptomatic patients. However, the low-cure and high recurrence rates have raised the question if alternative treatment modalities such as non-steroidal anti- inflammatory drugs should be tried prior to starting the steroid therapy, which might be reserved to unresponsive cases. Radiation and pulse chemotherapy including cyclophosphamide and chlorambucil combined with prednisone have been reported as alternative treatment modalities for refractory cases or for patients who can not tolerate the corticosteroid side effects. Surgical excision has been proposed as a treatment alternative for more localized lesions. Conclusion(s): Orbital inflammatory processes may be caused by a wide range of specific and nonspecific causes. The inflammation may be classified according to the site of involvement and by the nature of the underlying pathology (vasculitis, granulomatous, non specific inflammation). The diagnosis of idiopathic orbital inflammation is a diagnosis of correlation of clinical sign and symptoms, with the presence of a space-occupying lesion radiographically and the finding of non specific chronic inflammation in the biopsy. More importantly, the diagnosis of idiopathic orbital inflammation requires the exclusion of all other specific causes of inflammation in the orbit by clinical, radiographic and morphological investigation. References: Ahn Yuen SJ, Rubin PAD. Idiopathic orbital inflammation: distribution, clinical features and treatment outcome. Arch Ophthalmol 2003; 121:491-9 Beannan PA. A review of sclerosing idiopathic orbital inflammation. Curr Opin Ophthalmology 2007; 18 (5):402-404 3. Birch-Hirschfeld A. Die Krankheiten der orbita. In Graefe A, Saemisch T (eds): Handbuch der Gesamten augenheilkunden. Vol 9, part 1, 1-1048. Berlin, Julius- Springer 1930 4. Harris GJ. Idiopathic orbital inflammation: A pathogenetic construct and treatment strategy: The 2005 ASOPRS Foundation Lecture. AM Soc of Ophthalm Plastic and Reconst Surg 2006, 22(2):79-86 Hsuan JD, Seha D, McNab AA, Sullivan TJ, Saled P, O'Donnel BA. Idiopathic sclerosing orbital inflammation. Arch Ophthalmol 2006; 124:1244-1250 6. Kennerdell JS, Dresner SC. The nonspecific orbital inflammatory syndrome. Surv Ophthalmol 1984; 29: 93-103 7. Mahr MA, Salomao DR, Garrity JA. Inflammatory pseudotumor with extension beyond the orbit. Am J Ophthalmol 2004; 138:396- 400 McCarthy JM, White VA, Harris G, Simons KB, Kennerdell J, Rootman J. Idiopathic sclerosing inflammation of the orbit: immunohistologic analysis and comparison with retroperitoneal fibrosis. Mod Pathol. 1993 Sep; 6(5):581-7 Mombaerts I, Goldschemeding R, Schlinagermann RO, Koornneef L. What is orbital pseudotumor? Surg Ophthalmol 1996; 41(1): 66-78 Rootmann J, McCarthy M, White V, Harris G, Kennerdall J. Idiopathic sclerosing inflammation of the orbit. A distinct clinicopathologic entity. Ophthalmology 1994; 101:570-584 Rubin PAD, Foster CS. Etiology and management of idiopathic orbital inflammation. Am J Ophthalmol 2004; 138 (6):1041-1043 Shields J, Shields C, Scartozzi R. Survey of 1264 patients with orbital tumors and simulating lesions. The 2002 Montgomery Lecture, part 1, Ophthalmology 2004; 11 (5): 997-1008 Swamy BN, McCluskey P, Nemet A, Crouch R, Martin P, Benger R, Ghabriel R, Wakefield D. Idiopathic orbital inflammatory syndrome: Clinical features and treatment outcomes. Br J Ophthalmol 2007; 91:1667-1670 Zbrowsha B, Ghabrial R, Seba D, McCluskey P. Idiopathic orbital inflammation with extra orbital extension: case series and review. Eye 2006; 20:107-113 Wilson MW, Shergy WJ, Haik BG. Infliximab in the treatment of recalcitrant idiopathic orbital inflammation. Ophthal Plast Reconst Surg 2004; 20:381-3 Weber AL, Romo LV, Sabates NR. Pseudotumor of the orbit, clinical, pathologic and radiologic evaluation. Radiol Clin North Am 1999; 37:151-168 Yuen SJA, Rubin PAD. Idiopathic orbital inflammation. Distribution, clinical features and treatment outcome. Arch Ophthalmol 2003; 121:491-499