Adult Orbital Xanthogranulomatous Disease
Evening Specialty Conference: Ophthalmic PathologySunday, March 22, 2015
Lynn SchoenfieldAssociate Professor, Ohio State University Wexner Medical Center
No financial disclosures
Goals
Be familiar with the rare entity of Adult orbital xanthogranulomatous disease (AOXGD)
Know the 4 subtypes List the differential diagnosis Know what clinical and
histopathologic/immunohistochemical features are important in the diagnosis
Case
46 year old male with 9 year history of diplopia, proptosis, and papilledema
Orbit MRIs: diffuse intraconal masses with encasement of optic nerves bilaterally, L>R
Brain MRI: non-specific lesions, particularly involving the brain stem
PMH:– Malignant melanoma of right shoulder 2 years prior (in
2011) with previous dysplastic nevi in various locations– Pericardial effusion– Renal function deteriorating– Denies bone pain
Case - PMH
Dyslipidemia
Hypertension
Obesity
Laboratory findings
HgB = 10.4 g/dl Serum protein = 6.1 g/dl BUN = 39 mg/dl, Creatinine = 1.97 mg/dl,
Estimated GFR decreased Calcium = 9.9 mg/dl ALT = 8 U/L Cholesterol = 212 mg/dl, Triglycerides = 479
mg/dl Normal immunoglobin levels; specifically normal
IgG4 No paraproteinemia
Histopathology
Histopathology – Pertinent Immunohistochemical Stains
Negative for– S-100– CD1a– MelanA– AE1/3
CD3 and CD20 (kappa and lambda light chains showed polyclonal population)
Only occasional IgG4 positive plasma cells
Histiocytic Disorders(Histiocyte Society Writing Group – 1987)
Class I: Langerhans cell histiocytosis –histiocytosis X spectrum
Class II: Histiocytoses of mononuclear phagocytes other than Langerhans cells
Class III: Malignant histiocytic disorders
Adult orbital xanthogranulomatous disease (AOXGD)
Type II - Non-Langerhans type of histiocytosis
Rare and poorly understood heterogeneous group of syndromes
AOXGD
Age range: 17-85 (usually middle age) No sex preference, except for Erdheim
Chester disease (male>female, 3:1) Clinically:
– Bilateral firm, indurated, rubbery, yellow masses: subcutaneous, subconjunctival, or periocular
– CT scan demonstrating preseptal anterior or diffuse intraconal orbital infiltration
ECD
AOXGD: 4 Subtypes
Adult onset xanthogranuloma (AOX) Adult onset asthma and periocular
xanthogranuloma (AAPOX) Necrobiotic xanthogranuloma (NBX) Erdheim-Chester disease (ECD)
Histopathology
– Sheets of foamy histiocytes (xanthoma cells)
– Fibrosis– Touton giant cells– Dispersed aggregates of lymphocytes– Necrobiosis of collagen (in necrobiotic
xanthogranuloma)
Histopathology
Xanthoma cells:– cytoplasm positive for lipid stains (Oil
red-O or adipophilin – Lack atypia and high mitotic rate (or Ki-
67)– Positive by IHC for CD68, CD163, XIIIa– Negative for CD1a and usually S-100– Negative for IHC markers for
melanoma, carcinoma, etc.
Adult onset xanthogranuloma (AOX)
Solitary lesion
Adult onset juvenile xanthogranuloma (JXG) of the orbit
No systemic findings
Adult onset asthma and periocular xanthogranuloma (AAPOX)
Syndrome described by Jakobiec et al in 1993 based on small number of cases
In addition to asthma, patients may have lymphadenopathy and increased IgG levels (polyclonal)
Necrobiotic xanthogranuloma (NBX)
Subcutaneous skin lesions in eyelids and anterior orbit (and sometimes throughout body or internally)
Skin lesions have strong propensity to ulcerate and then become fibrotic
Frequent systemic findings:– Paraproteinemia and multiple myeloma
NBX
Erdheim Chester disease (ECD)
Most devastating subtype
Dense, progressive fibrosclerosis of orbit and internal organs– Bone involvement common– Mediastinum, pericardium, pleura,
retroperitoneum, and perinephric region
Erdheim-Chester Disease
Frequency of clinical and radiologic features:– Bone pain (50%)– Periaortic infiltration (60%)– Pericardial involvement (45%)– Exophthalmos (27%)– Diabetes insipidus (27%)– Xanthelasma (19%)– “Hairy kidney” appearance on CT– CNS involvement (15-25%)– Pulmonary involvement (22%)– Death (60%)
Orbital involvement in AOXGD
Anterior orbit/adnexal:– AOX– AAPOX– NBX
Diffuse or intraconal orbit:– ECD
Differential Diagnosis
Adult xanthogranulomatous disease Langerhans histiocytosis Extranodal Rosai-Dorfman disease Inflammatory pseudotumors including inflammatory
myofibroblastic tumor and IgG4 related sclerosing disease Juvenile xanthogranuloma (JXG) Lymphoma RA Sarcoid Infection Melanoma Metastatic carcinoma
Breast
Diagnosis
May not be apparent until the disease process evolves
Sometimes overlap of subtypes as well as syndromes (ECD with LCH or ECD with Rosai-Dorfman disease)
Erdheim-Chester Disease
Treatment: Interferon αCyclophosphamideVemurafenib (BRAF inhibitor) in severe
multisystem disease when BRAFV600E
mutation existsSteroids
Recent update on patient’s condition
Treated with cyclophosphamide and prednisone
FDG PET/CT: soft tissue prominence around origin of great vessels and pericardium, as well as around kidneys; also increased FDG uptake of long bones
Stroke/Carotid artery stenosis
Summary
AOXGD is a non-Langerhans type of xanthogranulomatous disease (type II), typically affecting middle age adults
May or may not be part of systemic disease Several disease entities should first be ruled out
(metastasis, melanoma, inflammatory processes, etc.)
Histopathologic findings alone cannot be used alone to subclassify the 4 subtypes (except perhaps if necrobiosis is present)
Clinical correlation required because of the non-specific findings
References
1. Guo J and Wang J. Adult orbital xanthogranulomatous disease. Arch Pathol Lab Med. 2009;133:1994-1997 2. Sivak-Callcott JA, Rootman J, Rasmussen SL, et al. Adult xanthogranulomatous disease of the orbit and ocular adnexa: new
immunohistochemical findings and clinical review. Br J Ophthalmol. 2006;90:602-608. 3. Haroche J, Arnaud L, Cohen-Aubart F, Hervier B, Charlotte F, Emile JF, Amoura Z. erdheim-Chester disease. Curr
Rheumatol Rep. 2014;16:412-419. 4. Dalia S, Jaglal M, chervenick P, Cualing H, Sokol L. Clinicopathologic characteristics and outcomes of histiocytic and
dendritic cell neoplasms: The Moffitt Cancer Center experience over the last twenty five years. Cancers 2014;6:2275-2295. 5. Jakobiec FA, Mills MD, Hidayat AA, et al. Periocular xanthogranulomas associated with severe adult-onset asthma. Trans
Am Ophthalmol Soc. 1993;91:99-125. 6. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N
Engl J Med. 2011;364:2507-2516. 7. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. A newly recognized benign clinicopathological
entity. Arch Pathol. 1969;87:63-70. 8. Vemuganti GK, Naik MN, Honavar SG. Rosai Dorfman disease of the orbit. Journal of Hematology and Oncology. 2008;1-7. 9. Yalan B, Huo Z, Meng Y, Wu H, Yan J, Zhou Y, Liu X, Song L. Extranodal Rosai-Dorfman disease involving the right atrium
in a 60 year old male. Diagnostic Pathology 2014;9:115. 10. Foucar E, Rosai J, Dorfman RF. The ophthalmologic manifestations of sinus histiocytosis with massive lymphadenopathy.
Am J Ophthalmol. 1979;87:354-367. 11. Sanchez R, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. An analysis of 113 cases with special
emphasis on its extranodal manifestations. Lab Invest. 1977;36:21-22. 12. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): Review of
the entity. Semin Diagn Pathol 1990;7:19-73. 13. Yamamoto H, Yamaguchi H, Aishima S, Oda Y, Kohashi K, Oshiro Y, Tsuneyoshi M. Inflammatory myofibroblastic tumor
versus IgG4-related sclerosing disease and inflammatory pseudotumor. A comparative clinicopathologic study. Am J Surg Pathol. 2009;9:1330-1340.
Thank you
?