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Correspondence
Association of systemic characteristics and histological variations in a case study of adult-onset asthma and periocular xanthogranuloma
  1. Toshinobu Kubota1,
  2. Suzuko Moritani2,
  3. Shu Ichihara2,
  4. Hiroko Terasaki3
  1. 1 Department of Ophthalmology, National Hospital Organization, Nagoya Medical Center, Nagoya, Japan
  2. 2 Department of Pathology, National Hospital Organization, Nagoya Medical Center, Nagoya, Japan
  3. 3 Department of Ophthalmology, Nagoya University Medical School, Nagoya, Japan
  1. Correspondence to Dr Toshinobu Kubota, Department of Ophthalmology, National Hospital Organization, Nagoya Medical Center, 4-1-1, Sannomaru, Naka-ku, Nagoya-shi, Aichi-ken 460-0001, Japan; ganiky{at}nnh.hosp.go.jp

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Introduction

Ocular adnexal histiocytic disorders, including adult-onset asthma and periocular xanthogranuloma (AAPOX), necrobiotic xanthogranuloma and Erdheim-Chester disease, have common histological characteristics, such as the presence of foamy histiocytes (xanthoma cells) and Touton giant cells.1–3 Additionally, AAPOX presents lymphoid aggregation with prominent T cells and other histological variations with prominent B cells and plasma cells.2–5 AAPOX is also associated with unique systemic disorders, including adult-onset asthma, systemic lymphadenopathy, salivary gland enlargement and elevated serum levels of IgG.1–6 The causal relationships between the systemic characteristics and histological variations have not been determined.

To investigate the relationship between the systemic and histological associations of AAPOX in more detail, we studied four patients with AAPOX. We compared the clinicopathological features of AAPOX with those of ocular adnexal IgG4-related lymphoplasmacytic infiltrative disorder (IgG4-related ophthalmic disease).7

Case reports

Procedures used in this study conformed to the tenets of the Declaration of Helsinki, and were approved by the Ethics Committee at Nagoya Medical Center, Nagoya, Japan.

Case 1

A 38-year-old man presented with bilateral swollen eyelids that had gradually worsened over 9 years (figure 1). He had had autoimmune pancreatitis 10 years earlier and asthma 4 years earlier. He had received oral prednisolone, and 5 mg of oral prednisolone was given every other day before our initial examination. The laboratory data showed that the serum level of IgG4 was 525 mg/dL (reference range, 4.8–105 mg/dL). CT imaging showed that the lesions had bilateral periocular and left superior rectus muscle involvements (figure 1). Systemic evaluations showed no abnormalities. Periocular biopsy samples showed xanthoma cells and lymphoplasmacytic infiltrations with IgG4-positive plasma cells (figure 1). The histological IgG4:IgG ratio was 0.5. His eyelid swellings partially responded to the subsequent treatment with 30 mg/day of prednisolone.

Figure 1

External photograph, CT image, and biopsy samples of periocular lesions from Case 1. (A) External photograph showing bilateral yellow and indurated eyelid masses. (B) CT image showing that the lesions have infiltrated into bilateral periocular regions, lacrimal glands and left superior rectus muscle. (C and D) Histology shows foamy histiocytes, collagen fibres, and lymphoplasmacytic infiltrations (C); lymphoid aggregation is also observed (D). H&E staining, original magnification 200×. (E and F) Immunostaining for CD138 reveals plasma cells infiltrating the lesions (E); immunostaining for IgG4 reveals IgG4-positive plasma cells also infiltrating the lesions (F). Immunoperoxidase staining, original magnification 200×.

Case 2

A 41-year-old man presented with bilateral swollen eyelids that had gradually worsened over 3 years. He was diagnosed with asthma 7 years previously, and he had cervical lymphadenopathy 3 years earlier. Biopsy samples from the cervical lymph node revealed IgG4-related lymphadenopathy (figure 2). He had received oral prednisolone, and a dose of 7.5 mg/day of prednisolone was given before our initial examination. The laboratory data showed the serum level of IgG4 was 145 mg/dL. CT imaging showed bilateral periocular involvement. Periocular biopsy samples contained xanthoma cells, Touton giant cells, and lymphoid aggregation with prominent T cells (figure 2). Although prednisolone (7.5–15 mg/day) had been given, his eyelid swelling continued to worsen during the 2-year follow-up period.

Figure 2

Biopsy samples of the cervical lymph node and periocular lesion from Case 2. (A) Low magnification of histology of the cervical lymph node (H&E staining, original magnification 40×) shows different sizes of lymphoid follicles. (B) High magnification (original magnification 100×) shows a lymphoid follicle with the germinal centre containing tangible body macrophages surrounded by a clear mantle zone. These findings are indicative of reactive lymphoid hyperplasia of the lymph node. (C and D) Immunostaining for IgG4 (C) and IgG (D) reveal IgG4-positve plasma cells at the germinal centre (progressive transformation of the germinal centre type). Immunoperoxidase staining, original magnification 100×. The histological IgG4:IgG ratio is 1.0. (E and F) Histology of the periocular lesion illustrating foamy histiocytes (E, H&E staining, original magnification 200×) and lymphoid aggregation (F, H&E staining, original magnification 100×). (G and H) Immunostaining for T cell markers CD4 (G) and CD8 (H). Immunoperoxidase staining, original magnification 100×.

Case 3

A 48-year-old woman with a history of asthma had experienced painless, bilateral, periocular mass lesions for 6 months. The laboratory data showed that the serum level of IgG4 was 179 mg/dL. Periocular biopsy samples showed xanthoma cells and Touton giant cells. Prednisolone (30 mg/day) with a slow taper and maintenance dose (2–7 mg/day) had been administered for 5 years. The periocular masses had initially decreased; however, they eventually worsened during the follow-up period.

Case 4

A 34-year-old woman with a history of adult-onset asthma had been diagnosed with AAPOX 7 years earlier and was referred to our hospital. She had received oral prednisolone, and a dose of 5 mg/day of prednisolone was given before our initial examination. The laboratory data showed that the serum level of IgG4 was 270 mg/dL at the initial examination. Periocular biopsy samples showed xanthoma cells, Touton giant cells and lymphoid aggregation. Oral ciclosporin (300 mg/day) was administered for 2 months as a second line of treatment. However, her eyelid swellings did not improve.

Discussion

Our results showed that two of the patients with AAPOX had systemic IgG4-related diseases, and four patients had elevated serum levels of IgG4. IgG4 serum levels and IgG4-related systemic conditions in patients with AAPOX have not been previously published. The published cases of AAPOX show that most patients have adult-onset asthma, and several also have systemic lymphadenopathy, salivary gland enlargement and elevated serum levels of IgG.1–6 IgG4-related ophthalmic disease is associated with adult-onset asthma, systemic lymphadenopathy, salivary gland enlargement and elevated serum levels of IgG.7 Thus, these systemic characteristics overlap with those of the systemic conditions associated with IgG4-related ophthalmic disease.7 These data suggest that the systemic characteristics of AAPOX may be closely correlated with the IgG4-related conditions.

Histological variations in the published cases consisted of the prominent lymphoplasmacytic infiltration of B cells and plasma cells into the periocular and systemic lesions.4 ,5 Patients with these histological variations were closely associated with systemic lymphadenopathy, salivary gland enlargement and an elevated serum level of IgG.4 ,5 The histological variations in our cases showed prominent B cell lymphoplasmacytic infiltrations and IgG4-positive plasma cells. In addition, the patient in Case 1 with IgG4-positive plasma cells had a history of autoimmune pancreatitis, an IgG4-related condition and a high serum IgG4 level. These data suggest that the cause of the histological variations of AAPOX may be correlated with the IgG4-related systemic conditions.

The previously published cases and our cases were characterised by chronic onset and bilateral, periocular, lacrimal gland, and extraocular muscle involvement.1–6 These symptoms and anatomical locations are similar to those of IgG4-related ophthalmic disease.7 Therefore, AAPOX from IgG4-related ophthalmic disease should be differentiated, though IgG4-related diseases are diagnosed in other organs.

In conclusion, AAPOX may often be associated with IgG4-related diseases. The systemic characteristics and histological variations of AAPOX may be closely correlated with the IgG4-related conditions rather than necrobiotic xanthogranuloma and Erdheim-Chester disease.

References

Footnotes

  • Contributors Analysis and interpretation: TK, SM and SI. Writing article: TK. Critical revision of the article: TK, SM, SI and HT.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics Committee at Nagoya Medical Center, Nagoya, Japan.

  • Provenance and peer review Not commissioned; externally peer reviewed.