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

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