Statistics from Altmetric.com
We report three cases of adult lacrimal gland xanthoganulomatous disease that demonstrate the spectrum of this disorder and provide insight into immune dysfunction.
A 23 year old asthmatic female had 1 year of bilateral, painless, lacrimal gland masses from polyclonal B cell (CD 20+) infiltration (fig 1A, B) The patient was asymptomatic for 18 months after external beam radiation (25 Gy in 10 fractions). While 7 months pregnant, painless lacrimal gland enlargement recurred, as firm, yellow, nodular masses (fig 1C). A second biopsy showed foamy histiocytes, Touton giant cells, and lymphoid infiltrate without necrobiosis (fig 1D). The orbital masses have remained stable 2 years after corticosteroids and surgical debulking. Systemic involvement included breast MALT type lymphoma 4 years after presentation.
A 49 year old Brunei male had 10 years of bilateral, yellow, mildly steroid responsive, superolateral orbital masses (fig 2A). Previous biopsy showed benign, polyclonal lymphocytic proliferation in the lacrimal gland and eyelid xanthoma. Second eyelid and lacrimal gland biopsy demonstrated xanthomatous infiltrate involving obicularis and lymphocytes with some germinal centres, s100 negative, KP1 positive foamy histiocytes and Touton giant cells, respectively (fig 2B–D). Orbital findings improved with Solumedrol (3 g over 3 days), ciclosporin, and cyclophosphamide. The patient was lost to follow up after 6 months. Systemic associations included asthma, sinusitis, and polyclonal paraproteinaemia (increased α1 and α2, β globulin, and IgM).
A 52 year old white female had 2 months of bilateral, yellow, lacrimal gland masses and dry eye (confirmed by Schirmer’s testing) (see fig 3A–C). Lacrimal gland biopsy demonstrated foamy histiocytes, Touton giant cells, chronic inflammation, bands of fibrosis, and necrobiosis. The lacrimal gland masses resolved at 2 years after treatment with Solumedrol (3 g over 3 days), methotrexate, pulsed cyclophosphamide, and topical 0.05% ciclosporin (Restasis) (fig 3E–F). She is maintained on prednisone 40 mg per day, methotrexate 17.5 mg per week, and Restasis twice a day. Systemic associations included asthma, cervical, axillary, hilar lymphadenopathy, iliac, sacral, L4 sclerosis, and xanthogranulomatous disease of the breast for which she underwent mastectomy 3 months before presentation (fig 3D).
Adult xanthogranulomatous disease is a class II histiocytic disorder1 syndromically classified as adult onset xanthogranuloma (AOX), adult onset asthma and periocular xanthogranuloma (AAPOX),2 necrobiotic xanthogranuloma (NBX),3 and Erdheim-Chester disease (ECD).4 AOX is a solitary lesion.5,6 AAPOX has B cell mediated findings including adult onset asthma, lymphadenopathy, and paraproteinaemia.3 Ulcerative skin lesions, paraproteinaemia/myeloma, and silent internal organ disease characterise NBX.3,7,8 ECD is typified by lethal, retroperitoneal and bony sclerosis.4
All our cases had asthma. Case 2 had elevated serum protein. Case 3 had lymphadenopathy, salivary gland enlargement, and bony sclerosis. Cases 1 and 3 had breast masses: MALT type lymphoma postdated orbital disease in case 1; xanthogranulomatous disease preceded orbital involvement in case 3. The first two cases could be classified as AAPOX. Case 3 had necrobiosis suggesting NBX, but had clinical features of AAPOX and lacked skin ulcers. These findings demonstrate the adult xanthogranulomatous syndromes are not mutually exclusive.
Xanthogranuloma histology consists of non-Langerhans, lipid laden histiocytes, Touton giant cells, and varying degrees of lymphocytic infiltrate, fibrosis, and necrosis (necrobiosis). This infiltration replaced the normal lacrimal gland architecture causing mass effect and loss of tear production. This same process affected the breast in case 3.
The immune cascade leading to this histopathological appearance is unknown. Our previous work found a predominance of CD8 (cytotoxic) T cells in areas of fibrosis and lipophage accumulation. We postulated that CD8 cells activated histiocytes and fibroblasts. Relevant to this hypothesis, it is fascinating that polyclonal B cell (CD20+) infiltration, without gland destruction or foamy histiocytes, preceded the development of xanthogranuloma in cases 1 and 2 and in one case from the literature6 (fig 1B). An additional report was initially diagnosed as Sjögren’s syndrome, but lacked histology.9 Moreover, case 1 developed a monoclonal proliferation of B cells in the breast 1 year after the orbital xanthogranuloma.
Our cases are unusual because the orbital xanthogranuloma were limited to the lacrimal gland, which is devoid of fat. We found four similar reports (table 1). Perhaps immune dysregulation leads to tissue destruction, and the resultant cell membrane fatty acids are scavenged by malfunctioning histiocytes.
The best treatment for xanthogranulomatous disease is unknown. Our patients had some response to steroids, with cases 2 and 3 responding to B cell (cyclophosphamide and methotrexate) and T cell (ciclosporin) suppressors.
These cases raise questions regarding the pathogenesis of non-Langerhans histiocytosis and demonstrate that histopathological and clinical findings must be used for diagnosis in the spectrum of disorders that is xanthogranulomatous disease.