Companion Meeting - USCAP 2016 Annual Meeting American Association of Ocular Oncologists and Pathologists Sunday, March 13, 2016
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2 Companion Meeting - USCAP 2016 Annual Meeting American Association of Ocular Oncologists and Pathologists Sunday, March 13, 2016 Inflammatory and Benign Orbital Lesions Inflammatory processes of the orbit account for more than half of the orbital diseases. Many of these are of infectious etiology, mostly related to extension of an infection in the adjacent sinuses and are treated without the need of a tissue biopsy. However, many of the other inflammatory processes involving the orbit are of non-infectious etiology and are often biopsied. These can be divided in lesions restricted to the orbit or systemic, extra-orbital diseases involving the orbital soft tissues. Herein, we aim to provide a practical approach to the inflammatory orbital lesions from the pathologist point of view. PRACTICAL APPROACH TO DIFFERENTIAL DIAGNOSIS ORBITAL INFLAMMATORY LESIONS Determine the predominant histological finding in each case Fibrosis Lymphoid Infiltrate Foamy histiocytes Necrosis Granulomas Vasculitis Acute inflammation Based on predominant histological features- establish differential diagnosis list Correlate with clinical and radiological findings Orbital cellulitis It is defined by inflammation of the orbital soft tissues posterior to the orbital septum. It most frequently results from the extension of an infection involving periorbital tissues such as sinuses, eyelids or lacrimal sac. It can also occur by direct inoculation of the orbit following trauma or surgery or by hematogenous spread from bacteremia. Orbital cellulitis is more common in children than adults, with a median age of presentation 7-12 years. In children, it has been reported twice as often in males than females, but in adults, it seems that there is no sex predilection, except for cases caused by methicillin-resistant Staphylococcus aureus, which are more common in female patients. In fact, it has been noted an increase in the frequency of 1
3 orbital cellulitis due to by methicillin-resistant Staphylococcus aureus due to community acquired S. aureus infections in USA. The etiology is variable. Bacterial infections are most often due to Streptococcus sp., Staphylococcus aureus and Haemophilus influenza. Mucor and Aspergillus species are the most common fungal causes. These can carry high mortality rate in immunocompromised patients. Correlation with culture results is crucial before starting treatment. Tissue is obtained when the diagnosis is not well-established clinically, or the patient has an unusual clinical presentation, or when tissue debridement is required to drain a non-resolving abscess. Orbital cellulitis can result in orbital/ocular and intracranial complications including visual loss in 11% of the cases. Permanent visual loss may be due to corneal damage, destruction of intraocular tissues, optic neuritis or CRVO. Intracranial complications include meningitis, cavernous sinus thrombosis and intracranial abscess. Prompt diagnosis and treatment reduces the rate of complications. Thyroid-related orbitopathy Thyroid eye disease usually presents in middle age patients, but can occur in any age including children. Between 30-50% of patients with thyroid dysfunction will develop Grave s orbitopathy. These samples seldom come to histopathology examination, representing the minority of all orbital inflammatory lesions examined in any ophthalmic pathology laboratory. The process usually involves the extraocular muscles particularly the inferior and medial rectus. The orbital and preseptal fat can also be involved. Histopathology is characterized by an increase of glycosaminoglycans, mostly hyaluronic acid, affecting the body of the muscle. This stains positive with Alcian blue and colloidal iron. A modest inflammatory infiltrate by lymphocytes, plasma cells, mast cells and histiocytes can also be seen. Idiopathic Orbital inflammation (inflammatory pseudotumor) Idiopathic orbital inflammation (IOI) represents approximately 5% to 20% of the orbital inflammatory lesions. As its name implies, the etiology and pathogenesis of IOI remain elusive, with no recognizable local cause and, to date, no known association with an underlying systemic disease. Morphologically, IOI is characterized by nonspecific features and varying degrees of lymphoplasmacytic infiltrate on a background of fibrosis. IOI is often a diagnosis of exclusion both clinically and morphologically. In some cases, stromal collagenization is the predominant feature. Often referred to as idiopathic sclerosing orbital inflammation, these cases have been compared with inflammatory processes associated with marked fibrosis occurring in other sites, such as sclerosing mediastinitis and idiopathic retroperitoneal fibrosis. In other cases, the intensity of the lymphocytic infiltrate raises suspicion for malignant lymphoma. A close mimicker of lymphoma clinically and morphologically, IOI has been referred to as pseudolymphoma in the past. However, immunophenotyping by immunohistochemistry or flow cytometry excludes clonality and confirms the polytypic nature of the plasma cells and lymphocytes. The presence of necrosis, vasculitis or granulomas should exclude the diagnosis of idiopathic orbital inflammation. One important consideration is to exclude the possibility of a non-diagnostic 2
4 biopsy, such as tissue reaction around a neoplasm or another lesion. Radiological correlation to determine the site of the biopsy is crucial in those cases. Orbital involvement by IgG4-related Disease IgG4-RD is an inflammatory disorder that affects mainly middle aged and older adults. It may have localized or widespread involvement, including sclerosing lesions in extranodal sites. It is characterized by elevated serum IgG4 levels and tissue infiltration by IgG4 positive plasma cells. A recent consensus document on IgG4-RD requires the presence of a dense lymphoplasmacytic infiltrate and storiform-type fibrosis as well as > 100 IgG4+ plasma cells /hpf in most anatomic sites and an IgG4 to IgG ratio 40%. Despite the recommendation, the cutoff for IgG4 RD in ophthalmic sites has been lower, ranging from positive cells/ hpf. Orbital IgG4 RD affects both sexes roughly the same, and bilateral involvement is observed in near 50% of the cases in most studies. Mostly, it involves lacrimal gland and orbital soft tissues; concomitant involvement of extra-orbital sites has been described. Histologically, it is characterized by fibrosis, lymphoplasmacytic and eosinophilic infiltrates, and frequently lymphoid hyperplasia. Obliterative phlebitis and storiform fibrosis which are seen in extraorbital sites are rarely seen in the orbital biopsies. The differential diagnosis includes lymphoid hyperplasia, idiopathic orbital inflammation and low-grade lymphomas, mostly extra-nodal marginal zone (MALT) lymphoma. Immunostains for IgG and IgG4 as well as a battery of immunostains to prove/exclude clonality are essential to establish the correct diagnosis. Of note is the fact that many xanthogranulomatous inflammatory lesions involving the orbit have been reported to have an increased number of IgG4 positive cells. Therefore, the diagnosis of IgG4-RD in the orbit requires careful clinicopathological correlation. Systemic Diseases with Orbital Involvement Granulomatosis with polyangiitis (Wegener s granulomatosis) Ocular symptoms may be the first manifestation in 16% of patients with Wegener's granulomatosis, while overall approximately half of patients will eventually develop ocular involvement. Orbital involvement has been reported in 45-70% of patients, and in rare occasions it may precede the detection of the systemic disease. The histological diagnosis is characterized by the presence of necrobiotic coagulative necrosis, a large number of neutrophils and eosinophils, forming small clusters and intermixed with the necrosis; associated with histiocytic granulomatous reaction around the large areas of necrosis and small vessel vasculitis. Early lesions might not show the full-blown picture (vasculitis, geographic necrosis and granulomatous inflammation) and are characterized by small neutrophilic microabscesses. The differential diagnosis is mainly with idiopathic orbital inflammation, in which one should not observe the presence of vasculitis or necrosis. Granulomatosis with polyangiitis is part of a group of autoimmune disorders known as antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, which also includes microscopic polyangiitis, Churg-Strauss syndrome and renal-limited vasculitis. These disorders are characterized by the presence of necrotizing small-vessel vasculitis with the presence of serum autoantibodies directed against neutrophil cytoplasmic constituents, in particular protein 3 (PR3) and myeloperoxidase (MPO). 3
5 Sarcoidosis The eye may be affected by sarcoidosis in a variety of ways, with the most frequent site being the uveal tract. Optic nerve and optic nerve head involvement have been reported in about 5% of patients with sarcoidosis. Evidence suggests that patients with retinal and optic nerve involvement are at increased risk to have or to develop CNS involvement. Although CNS involvement is rare, 2% of all patients, CNS complications account for 25% of death caused by sarcoid. The diagnosis of sarcoidosis is often made in a biopsy from the lacrimal gland. The typical lesion is characterized by well-circumscribed epithelioid granulomas with little or no necrosis, and few Langhans giant cells. Giant cells may contain asteroid or Schaumann s bodies. A sparse lymphocytic infiltrate might be seen in the periphery of these granulomas, the reason these are referred as naked granulomas. The differential diagnosis of sarcoidosis includes mainly granulomatous infectious processes such as tuberculosis and fungus infection. Therefore, special stains and tissue cultures for microorganisms must be obtained on routine basis. Sinus histiocytosis with Massive Lymphadenopathy (Rosai Dorfman Disease) RDD can involve any part of the eye or orbit, but infiltration of the intraconal space orbital soft tissue is the most common ocular manifestation. Proptosis is the most common symptom; blurred vision, diplopia, dry eye and epiphora can also be seen. RDD is one of the non-langerhans cell benign histiocytosis, where predominantly the sinuses or interfollicular area are infiltrated with distinctive histiocytes. The hallmark of RDD is the presence of lymphophagocytosis or emperipolesis, where viable lymphocytes are located in vacuoles of intact histiocytes. Plasma cells, neutrophils and red blood cells may also be seen within the cytoplasmic vacuoles. The involved histiocytes are activated macrophages that express S100 protein, HAM 56, α 1 antitrypsin, α 1 chymotrypsin, lysozyme and CD30, but are negative for CD1a. The histopathologic features of RDD in extranodal sites are similar to the nodal disease except for that fibrosis tends to be more prominent and emperipolesis less evident. The differential includes non-specific sinus histiocytosis (lacks emperipolesis and histiocytes are S100 negative), Langerhans cell histiocytosis (positive for S100 and CD1a), hemophagocytic syndromes, storage disorders, necrobiotic granuloma, lymphoproliferative disorder, leprosy and metastatic melanoma. SELECTED REFERENCES 1. Andrew N, Kearney D, Selva D. Applying the consensus statement on the pathology of IgG4- related disease to lacrimal gland lesions. Mod Pathol. 2013;26: Andrew NH, Sladden N, Kearney DJ, et al. An analysis of IgG4-related disease (IgG4-RD) among idiopathic orbital inflammations and benign lymphoid hyperplasias using two consensus-based diagnostic criteria for IgG4-RD. Br J Ophthalmol. 2015;99: Bergin DJ, Wright JE. Orbital cellulitis. Br J Ophthalmol 1986; 70: Blomquist PH. Methicillin-resistant Staphylococcus aureus infections of the eye and orbit. Trans Am Ophthalmol Soc 2006; 104: Chang SY, Keogh K, Lewis JE, et al. Increased IgG4-positive plasma cells in granulomatosis with polyangiitis: a diagnostic pitfall of IgG4-related disease. Int J Rheumatol. 2012;2012: Chen TD, Lee LY. Rosai-Dorfman disease presenting in the parotid gland with features of IgG4- related sclerosing disease. Arch Otolaryngol Head Neck Surg. 2011;137:
6 7. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25: Ferry JA, Klepeis V, Sohani AR, Harris NL, Preffer FI, Stone JH, Grove A, Deshpande V. IgG4- realted Orbital Disease and its mimics in a Western Population. Am J Surg Pathol 2015; 39: Gupta D, Hemment B, Marsha. T. A complex orbit. Orbit 2008; 27(4): Herbort CP, Rao NA, Mochizuki M. International criteria for the diagnosis of ocular sarcoidosis: results of the first international workshop in ocular sarcoidosis (IWOS). Ocul Immunol Inflamm 2009; 17(3): Jannette JC, Falk RJ: Small-vessel vasculitis. NEJM 1997; McKinley SH, Yen Mt, Miller AM et al. Microbiology of pediatric orbital cellulitis. Am J Ophthalmol 2007; 144: Obenauf CD, Shaw HE, Snyder CF, Klintworth GK. Sarcoidosis and its ophthalmic manifestations. Am J Ophthalmol 1978; 86 (5): Plaza JA, Garrity JA, Dogan A, et al. Orbital inflammation with IgG4-positive plasma cells: manifestation of IgG4 systemic disease. Arch Ophthalmol. 2011;129: Prabhakaran VC, Bhatnagar A, Sandilla J, Olver J, Leibovitch I, Ghabrial R, Goldenberg RA, Selva D. Orbital and adnexal Rosai Dorfman Disease. Orbit 2008; 27: Rutar T, Zwick OM, Cockerham KP et al. Bilateral blindness from orbital cellulitis caused by community-acquired methicillin-resistant Staphyloccocus aureus. Am J Ophthalmol 2005; 140: Sato Y, Ohshima K, Ichimura K, et al. Ocular adnexal IgG4-related disease has uniform clinicopathology. Pathol Int. 2008;58: Singh K, Rajan KD, Eberhart C. Orbital necrobiotic xanthogranuloma associated with systemic IgG4 disease. Ocul Immunol Inflamm. 2010;18: Ugurlu S, Bartley GB, Gibson LE. Necrobiotic xanthogranuloma: long-term outcome of ocular and systemic involvement. Am J Ophthalmol 2000; 129: Vemuganti GK, Naik MN, Honavar SG. Rosai Dorfman disease of the orbit. Journal of Hematology and Oncology 2008; June: Verdijk RM, Heidari P, Verschooten R, et al. Raised numbers of IgG4-positive plasma cells are a common histopathological finding in orbital xanthogranulomatous disease. Orbit. 2014; 33: 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: Yuen SJA, Rubin PAD. Idiopathic Orbital inflammation. Distribution, Clinical Features and Treatment Outcome. Arch Ophthalmol 2003; 121:
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