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Adult xanthogranulomatous disease of the orbit and ocular adnexa: new immunohistochemical findings and clinical review
  1. J A Sivak-Callcott1,
  2. J Rootman2,3,
  3. S L Rasmussen5,
  4. R A Nugent4,
  5. V A White2,3,
  6. D Paridaens6,
  7. Z Currie7,
  8. G Rose7,
  9. B Clark8,
  10. A A McNab9,
  11. F V Buffam2,
  12. J M Neigel10,
  13. M Kazim11
  1. 1Department of Ophthalmology, West Virginia University Eye Institute, Morgantown, WV, USA
  2. 2Department of Ophthalmology and Visual Sciences, University of British Columbia and the Vancouver General Hospital, Vancouver, British Columbia, Canada
  3. 3Department of Pathology, University of British Columbia and the Vancouver General Hospital, Vancouver, British Columbia, Canada
  4. 4Department of Radiology, University of British Columbia and the Vancouver General Hospital, Vancouver, British Columbia, Canada
  5. 5Calgary Laboratory Services and the Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada
  6. 6Department of Oculoplastic, Lacrimal and Orbital Surgery, Rotterdam Eye Hospital, Rotterdam, Netherlands
  7. 7Moorfields Eye Hospital, London, UK
  8. 8Division of Pathology, Institute of Ophthalmology, University of London, UK
  9. 9Orbital, Plastic and Lacrimal Clinic, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
  10. 10Department of Ophthalmology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ, USA
  11. 11Departments of Ophthalmology and Surgery, Edward S. Harkness Eye Institute, Columbia University, New York, NY, USA
  1. Correspondence to: Jennifer A Sivak-Callcott MD, Department of Ophthalmology, West Virginia University Eye Institute, One Stadium Drive, Morgantown, WV 26505, USA; jsivak{at}hsc.wvu.edu

Abstract

Background/aims: Adult xanthogranulomatous disease involving the ocular tissues is rare and poorly understood. Adult onset xanthogranuloma (AOX), adult onset asthma and periocular xanthogranuloma (AAPOX), necrobiotic xanthogranuloma (NBX), and Erdheim-Chester disease (ECD) are the four syndromes within this disorder, which is diagnosed by characteristic histopathology. Experience with eight cases prompted a multi-institutional effort to study the histopathology, immunohistochemistry, clinical findings, and systemic associations in this disorder.

Methods: 22 cases, including histopathological slides, were compiled. Published reports were identified by an English language Medline search (1966–2005) and review of reference citations. Each case in this series and the literature was classified as one of four syndromes and then analysed for age onset, sex, skin xanthoma, orbital location, immune dysfunction, internal organ and bone lesions, treatment, and outcome. The histopathology in each of these cases was reviewed by two pathologists. Immunhistochemical stains (CD3, CD4, CD8, L26) were performed in 14 cases where unstained slides were available.

Results: 137 cases were compiled. There was no sex or age difference between syndromes. AOX, AAPOX, NBX affect the anterior orbit, ECD tends to be diffuse and intraconal. Skin lesions are found in all the syndromes. Immune dysfunction was noted in all cases of AAPOX and NBX; 11% of NBX and all ECD patients had internal organ disease. Treatment included surgery, corticosteroids, other chemotherapeutic agents, radiotherapy, and combinations of these. No AOX or AAPOX deaths occurred; 66% of ECD patients died. All 22 cases had xanthoma cells; most had Touton giant cells. Lymphocytes were present in all cases and occurred as aggregates (mostly in AAPOX) or diffuse populations mixed with fibroblasts (mostly in ECD). Immunohistochemistry revealed the majority of these to be CD8+. Necrosis was most marked in NBX.

Conclusion: Adult xanthogranuloma of the orbit is rare, making prospective evaluation or meta-analysis impossible. The best treatment is unknown but seems to be with multiagent chemotherapy guided by histopathological, immunohistochemical, and systemic findings.

  • AAPOX, adult onset asthma and periocular xanthogranuloma
  • AOX, adult onset xanthogranuloma
  • ECD, Erdheim-Chester disease
  • MGUS, monoclonal gammopathy of undetermined significance
  • NBX, necrobiotic xanthogranuloma
  • xanthogranuloma
  • CD-8 cell
  • necrobiotic
  • Erdheim-Chester disease
  • AAPOX, adult onset asthma and periocular xanthogranuloma
  • AOX, adult onset xanthogranuloma
  • ECD, Erdheim-Chester disease
  • MGUS, monoclonal gammopathy of undetermined significance
  • NBX, necrobiotic xanthogranuloma
  • xanthogranuloma
  • CD-8 cell
  • necrobiotic
  • Erdheim-Chester disease

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Adult xanthogranulomatous disease involving the ocular or orbital tissues is rare and constitutes a group of entities with varying manifestations that are poorly understood. These are non-Langerhans histiocytic disorders (type II) that are diagnosed histopathologically by the presence of foamy histiocytes, Touton giant cells, and varying degrees of fibrosis and, in some entities, necrosis. Personal experience with eight cases prompted us to organise a multi-institutional effort to study the histopathology, immunohistochemistry, clinical findings, and systemic associations of this group of disorders, which included a comprehensive review of the English language literature.

METHODS

Clinical case series and review of published articles

Twenty two cases were collected, eight from the University of British Columbia and 14 from other institutions; eight of the latter have been previously reported. Based on systemic associations, there are four syndromes that comprise the disorder of adult xanthogranuloma1–3:

  • Adult onset xanthogranuloma (AOX) (solitary lesion without systemic findings)

  • Adult onset asthma and periocular xanthogranuloma (AAPOX)

  • Necrobiotic xanthogranuloma (NBX)

  • Erdheim-Chester disease (ECD).

We classified each case as one of these four syndromes and then analysed for onset age, sex, location of the orbital/adnexal lesion, skin xanthomas, internal organ involvement, bone lesions, immune dysfunction (including asthma, paraproteinaemia, lymphadenopathy, and other lymphoproliferative disorders), treatment, and outcome.

A search was conducted using the Medline database (1966–2005) for English language publications, and all identified articles and their reference citations were reviewed. Each case of orbital xanthogranulomatous disease was classified and analysed in the same fashion as our case series. Data obtained from reported cases and from our cases were then pooled and analysed.

Statistical analysis

For each syndrome, the mean age and standard deviation were determined and analysed using nominal logistic regression. A p value <0.05 was considered significant. The sex distribution of all the cases was analysed using the χ2 test.

Histopathology and immunohistochemistry

Haematoxylin and eosin as well as Masson’s trichrome stained slides were obtained for all 22 cases and reviewed by two pathologists. All slides were specifically evaluated for foamy histiocytes, Touton giant cells, lymphocytic infiltrate, and presence of fibrosis and necrosis. The immunohistochemical examination focused on the lymphocyte population and included CD3 (T cell), CD4 (T helper cell), CD8 (T suppressor cell, cytotoxic), and L26 (B cell). This was performed on 14 of the cases where additional unstained slides were available.

RESULTS

Clinical case series and review of published reports

Between this case series and published reports, 137 cases of adult xanthogranulomatous disease of the orbit and adnexa were compiled, including eight classified as AOX, 21 as AAPOX, 72 as NBX, and 36 as ECD (table 1). Four cases of periocular xanthogranuloma were unclassifiable and were not included in this analysis.4,5 Nominal logistic regression using the pooled data revealed no significant difference in the mean age of patients with each syndrome (p = 0.059). The average age of patients with NBX in this study was similar to that of reported series.6,7 There was no sex preference (χ2 observed = 6.34, p = 0.095) (table 1).

Table 1

 Number, mean age, and sex distribution of patients with orbital xanthogranuloma

Patients classified as AOX, AAPOX, and NBX typically had preseptal and anterior orbital involvement (table 2, figs 1, 2, 4). Intraconal involvement was evident in two cases of AOX, one of AAPOX, and one of NBX (fig 3). In contrast, all but one patient with ECD had diffuse intraconal disease (fig 5). Eyelid skin lesions were noted in all syndromes: four of eight AOX (50%), 20 of 21 AAPOX (95%), 53 of 62 NBX (85%), and 15 of 36 ECD (42%). Overall, 72% (92 of 127) had periocular skin manifestations (table 3). Evidence of immune dysfunction was denoted by the presence of asthma, lymphadenopathy, paraproteinaemia or other lymphoproliferative lesions including multiple myeloma, lymphoma, and chronic lymphocytic leukaemia (table 4). All AAPOX and NBX cases had evidence of immune dysfunction. In AAPOX, the dysfunction tended to be asthma and reactive (benign) lymphadenopathy; other lymphoproliferative disorders included our case of Burkitt’s lymphoma and one report of non-Hodgkin’s lymphoma. In NBX, immune dysfunction was usually paraproteinaemia, either monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma.8 Other lymphoproliferative disorders in NBX included a single case each of non-Hodgkin’s lymphoma, Hodgkin’s disease and lymphosarcoma.6,7,9 By our criteria, there was no evidence of immune dysfunction in AOX and only one case of ECD had evidence of immune dysfunction.10

Table 2

 Anatomical location of ocular adnexal/orbital lesions

Table 3

 Periocular skin findings

Table 4

 Systemic findings associated with orbital xanthogranuloma.

Figure 1

 Adult onset xanthogranuloma. (A) Clinical photograph of a 42 year old white male with 8 year history of bilateral, yellow, palpable, firm, rubbery masses restricting lid elevation. He was treated with surgical debulking and had no evidence of systemic disease. (B) Computed tomography scan showing homogeneous infiltration of the preseptal and anterior orbital tissues including the lacrimal gland. Reproduced with permission.

Figure 2

 Adult onset asthma and periocular xanthogranuloma. (A) Clinical photograph of a 46 year old white male with 3 year history of bilateral, rubbery, yellow lid lesions, and facial fullness. Associated findings included three separate lymph node biopsies showing reactive change, 20 years earlier, adult onset asthma diagnosed 15 years earlier, submandibular and cervical lymphadenopathy (arrow), allergic sinusitis with nasal polyps, and autoimmune thyrotoxicosis. The patient was treated with 2000 cGy in 10 fractions to both orbits with worsening condition. Ciclosporin 250 mg/day and prednisone 10 mg/day led to improvement, but 1 year later he developed Burkitt’s lymphoma. (B) During bone marrow suppressive treatment he had resolution. (C) He has done well when maintained on prednisone 8 mg/day at 2 year follow up. (D and E) Computed tomography scan at initial presentation showing bilateral infiltration of the extraocular muscles, lacrimal glands, and lids and at 2 year follow up. Reproduced with permission.

Figure 3

 Adult onset asthma and periocular xanthogranuloma. (A) Clinical photograph of a 74 year old Indian male with bilateral, progressive proptosis, firm, periocular xanthogranuloma, limited ocular movements, and decreased vision. Associated findings included adult onset asthma. (B) The patient had return of vision and reduction in lesion size after corticosteroid and ciclosporin treatment. (C) CT scan showed diffuse, irregular anterior and extraconal infiltrates. Reproduced with permission.

All ECD cases had internal organ dysfunction, including pericardial or pleural effusions, retroperitoneal involvement, perinephric and mediastinal infiltrations, diabetes insipidus, brain and dural masses and hepatosplenomegaly (table 4). Eight of 71 (11%) patients with NBX had clinically identifiable internal organ lesions, including one patient with pancreatitis in our series. One AAPOX case had a low testosterone level. No patient with AOX had known internal organ disease.11,12 Bone lesions were present in 29 of 33 (89%) patients evaluated for such; all had ECD (table 4).

The treatment modalities employed were surgery, administration of corticosteroids and/or other chemotherapeutic agents, radiation, and combinations of these. Surgery alone was effective in AAPOX (6/8, 75%) and one case of NBX, whereas corticosteroids were useful in some cases of AAPOX (2/2), NBX (8/24, 33%), and ECD (7/24, 29%). Other immunosuppressive agents were beneficial in 31 of 52 cases (60%). In our series, the most frequent beneficial agents were ciclosporin and cyclophosphamide. In some reports, management, including cyclophosphamide, melphalan, chlorambucil, vincristine, vinblastine, interferon, etoposide, methotrexate, etanercept, gammaglobulin, clofazimine, and doxorubicine, led to improvement. Radiation was effective in four of six (67%) NBX cases. Despite treatment, two of our patients died (one each with NBX and ECD). Of patients reported in the literature, those with NBX had a 90% survival rate at 15 years6 whereas 21 of the 32 (66%) patients with ECD died. No death was reported among patients with AOX or AAPOX. Based on immunohistochemical evidence of T cell influx, two of our patients were treated successfully in a novel way using corticosteroids, cyclophosphamide (B cell suppression), and ciclosporin (T cell suppression).

Histopathology and immunohistochemistry

All cases studied histopathologically had xanthoma cells and most had Touton giant cells infiltrating the tissue. In cutaneous specimens, the infiltrate extended deeply into subcutaneous tissue and orbicularis muscle. The lesions were poorly circumscribed, especially when xanthoma cells were admixed with inflammatory cells and fibroblasts (fig 6).

Lymphocytes were observed in all cases and occurred in two patterns: aggregates or a diffuse population admixed with proliferating fibroblasts. The lymphoid aggregates varied in size and number, from large and numerous to absent, and were most abundant in AAPOX (fig 6B). They had typical germinal centres; small “burnt out” or ill defined germinal centres were not a feature. Secondary follicles exhibited the usual immunohistochemical profile of B cells within germinal centres and a T cell rich population in the parafollicular zone.

The diffuse population of lymphocytes was intimately admixed with proliferating fibroblasts. This population was seen in all the syndromes but was most frequent in ECD, which had more areas of fibrosis and fewer follicles than the other syndromes. Immunohistochemistry showed the majority of these diffuse lymphocytes to be CD8 positive suppressor cells with little evidence of influx of CD4 helper/inducer cells or B cells (table 5, fig 6D–E). Other inflammatory cells, especially eosinophils and plasma cells were seen but were never the dominant population. Angiocentric inflammation was not present in any case.

Table 5

 Stromal immunohistochemistry of 14 patients diagnosed with orbital xanthogranuloma

Necrosis was most marked in the cases of necrobiotic xanthogranuloma, represented by geographic areas of necrosis surrounded by a palisade of epithelioid histiocytes, and seen only in one case of AAPOX (fig 6C).

DISCUSSION

In 1987, the Histiocyte Society Writing Group classified histiocytic disorders into three categories: class I (Langerhans cell histiocytosis-histiocytosis X spectrum), class II (histiocytoses of mononuclear phagocytes other than Langerhans cells) (table 6), and class III (malignant histiocytic disorders).13 Adult xanthogranulomatous disease, which falls within class II, is uncommon, generally affects middle aged individuals without sex predilection (table 1), and can present as subcutaneous, subconjunctival and periocular xanthochromic infiltrates with varying mass formation.

Table 6

 Non-Langerhans disorders of histiocytes

Adult ocular adenexa/orbit xanthogranuloma are often associated with other systemic manifestations. These are the basis for classification into the four syndromes: adult onset xanthogranuloma (AOX), adult onset asthma with periocular xanthogranuloma (AAPOX), necrobiotic xanthogranuloma (NBX) and Erdheim-Chester disease (ECD). NBX is the most frequently reported followed by ECD, AAPOX, and AOX (table 1).

AOX is an isolated xanthogranulomatous lesion without systemic involvement (figs 1 and 6A). There are two reports of this condition that were termed adult onset juvenile xanthogranuloma of the orbit.12 Juvenile xanthogranuloma is a separate non-Langerhans histiocytic disorder that occurs as a self limited, corticosteroid sensitive and usually focal subcutaneous disease of childhood11,14 (table 6).

AAPOX is a syndrome (periocular xanthogranuloma associated with asthma) that was described by Jakobiec et al.1 In addition to asthma, cases of APPOX in our series had lymphadenopathy and often increased IgG levels (polyclonal), suggesting an underlying stimulation and proliferation of B cell populations (figs 2, 3, 6B). Our search for reported cases identified four additional cases with associated asthma and one with an increased IgG level (polyclonal) and lymphadenopathy.15–17

NBX is characterised by the presence of subcutaneous skin lesions in the eyelids and anterior orbit, which also may occur throughout the body. Although skin lesions are seen in all the syndromes, those in NBX have a strong propensity to ulcerate and fibrose. Frequent systemic findings include paraproteinaemia and multiple myeloma2,6–9,18–25 (figs 4, 6C). Internal organ involvement occurs in NBX, but is often found only at autopsy.8

Figure 4

 Necrobiotic xanthogranuloma. (A and B) Clinical photograph of a 69 year old white female with 1 year history of yellow, subcutaneous and subconjunctival infiltrates, pain, diplopia, tearing, and blurred vision. Associated findings included elevated IgG at 31.7 g/l (8–18 g/l) and a similar leg lesion. She was initially treated with prednisone 40 mg/day and then maintained on 5 mg/day without change for 6 years. (C) Computed tomography scan showed prominent, enhancing, soft tissue masses around each globe, a thickening medial rectus muscle, and increased fat density on the right. Reproduced with permission.

ECD, the most devastating of the adult xanthogranulomas, is characterised by dense, progressive, recalcitrant fibrosclerosis of the orbit and internal organs, including the mediastinum, pericardium and pleural, perinephric,26,27 and retroperitoneal spaces. While the orbit/adenexal xanthogranuloma tends to be anterior in AOX, AAPOX, and NBX, it is often diffuse in ECD and leads to visual loss (fig 5, table 2). Bone involvement is common and death frequent despite aggressive therapies3,10,28–43 (figs 5, 6D–E).

Figure 5

 Erdheim-Chester disease. (A) Clinical photograph of a 67 year old Asian female with 4 month history of bilateral, progressive, painless vision loss, proptosis, and decreased extraocular movements. Associated findings included long bone sclerosis and hypertension secondary to retroperitoneal/perinephric fibrosis. The patient was treated with methylprednisolone, 1 g every other day for three doses, followed by prednisone 40 mg/day and cyclophosphamide 100 mg/day. She had initial improvement in vision but then declined to no light perception on the right and hand motions on the left. The patient died 4 months after presentation. (B) Contrasted computed tomography scan showing bilateral, intraconal, homogeneous, mildly enhancing masses with smooth margins. The extraocular muscles are obscured, and the optic nerves are displaced superomedially and appear thin. Reproduced with permission.

Figure 6

 Pathology. (A) Haematoxylin and eosin stain (20× magnification) of case of AOX showing foamy histiocytes and Touton giant cells (arrow). (B) Haematoxylin and eosin stain (10× magnification) of AAPOX case with prominent follicle formation. (C) Haematoxylin and eosin stain (10× magnification) of NBX case demonstrating necrobiosis (arrow). (D) Haematoxylin and eosin stain (10× magnification) of ECD case demonstrating foamy histiocytes and Touton giant cells with lymphocytic infiltrate and fibrosis. (E) CD8 stain (20× magnification) of ECD case showing predominance of CD8+ cells.

While the majority of published cases were able to be classified as one of the four syndromes, there are four published reports that fall between AOX and AAPOX/NBX These patients had periocular xanthogranuloma and other blood dyscrasias including thrombocytopenia, paraproteinaemia and monoclonal gammopathy of undetermined significance.4,5

The xanthogranulomas have a histopathological appearance that is common to all forms, and thus they cannot be subclassified on histopathological grounds alone. The histopathological hallmarks are the presence of non-Langerhans lipid laden histiocytes and Touton giant cells (fig 6). Non-Langerhans histiocytes tend to be s100, MAC387, and LeuM1 negative, and positive for Ln3 and KiM1p.44 Lymphocytic infiltration, fibrosis, and necrosis are also present but these can vary within the same specimen and between cases and, moreover, change with time and treatment. Although these features are common to all adult xanthogranuloma, certain features can suggest a specific syndromic association. For instance, necrosis (necrobiosis) with pallisading epitheliod histiocytes is most often seen in NBX whereas large lymphoid aggregates with germinal centers are often found in cases of AAPOX (fig 6C and B). ECD exhibits florid fibrosis with fewer follicles and more dispersed lymphocytes and lipid laden histiocytes (fig 6D). These histopathological differences may correlate with the associated findings in each of the syndromes. NBX tends to have clinical ulcerative lesions, which correlates with necrobiosis. AAPOX is associated with lymphadenopathy and B cell dysfunction (including asthma and paraproteinaemia) and histologically has B cell lymphoid aggregates. The fibrosclerosis seen ECD is responsible for the internal organ and orbital mass effect seen clinically.

While clinical and histopathological description are useful academic endeavours, ultimately, we hope to positively affect the treatment of patients with adult xanthogranuloma. But, the rarity of this disease precludes prospective investigation or meta-analysis, making the outcome of therapy extremely difficult to evaluate because of conflicting reports and the multiple modalities used in all these syndromes. Current treatment regimens are often ineffective, especially in ECD. Two of our patients, with NBX and ECD respectively, died; 21 of 32 reported patients with ECD died between 3 months and 15 years after diagnosis.3,10,28–39,41–43 The best results seem to have been obtained with multiagent chemotherapy, with or without radiation or surgery. While comprehensive examination establishes the degree of the disease, a thorough understanding of the histopathology and immunohistochemistry are necessary to guide therapy.

To this end, we found the dominant diffuse lymphocytic infiltrate was T cells (CD3 positive) with a subset of CD8 (cytotoxic) cells in areas of fibrosis and lipophage accumulation (fig 6E). In other disorders (such as Graves’ disease, myelofibrosis, parabronchiolitis, sclerosing orbital inflammation and retroperitoneal and mediastinal fibrosis),45–58 granulomatous inflammation with fibroplasia appears to be activated by T cells; therefore, we treated two of our patients with ciclosporin and cyclophosphamide. In addition, there may be a rationale for systemic B cell suppression in the management of AAPOX and NBX. Myra et al have had a unique case of ECD with a monocytosis with specific cytokine activation that responded to cladribine, a purine analogue toxic to monocytes.59 Further developments in immunohistochemistry, selective immunotherapeutic and chemotherapeutic agents, and a better characterisation of the histiocytes may lead to better treatment options. Because the best reported results were obtained with multiagent chemotherapy, and because of our success with ciclosporin combined with cyclophosphamide and our new immunohistochemical findings, we recommend that clinical features be correlated with histopathological B and T cell findings when choosing an immunosuppressive agent for treatment.

CONCLUSION

The diagnosis of adult xanthogranulomatous disease is based on characteristic histopathological findings. Because this disease is so rare, a prospective evaluation of treatment will not be possible. Nevertheless, our understanding of xanthogranulomatous disease will be advanced by comprehensive assessment for systemic manifestations, and histopathological study of tissue specimens. New treatments may be guided by complete histopathological and immunohistochemical examination including study of B and T cell populations and perhaps cytokines. These syndromes emphasise the importance of the systemic context in the study of orbital disorders.

REFERENCES

Footnotes

  • The authors have no financial conflict of interest with the subject matter or materials discussed in this manuscript.

  • Presented at the Vancouver Orbital Symposium—Graves’ Orbitopathy and Orbital Disease: Present Status and Future Challenges, 15–17 March 2002, Vancouver, British Columbia, Canada.