Are You Confident of the Diagnosis?
Characteristic findings on physical examination
Annular elastolytic giant cell granuloma (AEGCG) is characterized by smooth-surfaced annular plaques with raised red borders and central hypopigmentation, occurring mostly on sun-exposed areas of the head, neck, and upper extremities. (Figure 1) Papular and reticulated variants have also been described. Lesions are usually asymptomatic. A history of excessive sun exposure is typically associated. The term actinic granuloma (of O’Brien) is often used for the typical lesions of AEGCG on sun-damaged skin. Involvement of non-exposed areas may also occur in AEGCG. Occasionally the plaques arise adjacent to scars from previous thermal burn injuries.
Expected results of diagnostic studies
Diagnosis is confirmed by punch biopsy. The dermis contains numerous foreign body type multinucleated giant cells, admixed with other inflammatory cells (Figure 2). A key feature is elastophagocytosis, ie, the presence of fragmented elastic tissue fibers within giant cells (Figure 3). Zones of absent elastic tissue fibers are adjacent to zones of granulomatous inflammation. Necrobiosis, mucin deposition, and lipid deposition are not seen. Severe solar elastosis is often present in the background.
Granuloma annulare (GA) is the main entity in the differential diagnosis, both clinically and histopathologically. The relationship between GA and AEGCG is controversial, and some consider AEGCG to be a form of GA. Individual lesions of AEGCG are clinically very similar to GA, but AEGCG is more likely to occur in a photo-distributed pattern.
The histopathologic differences are most helpful in distinguishing the two entities. GA routinely demonstrates necrobiosis and mucin deposition, while AEGCG lacks both of these features. These histopathologic features, rather than elastophagocytosis, are most helpful in distinguishing AEGCG from GA. Elastophagocytosis is not specifically diagnostic of AEGCG. The phenomenon may be seen in biopsies of GA and other granulomatous cutaneous disorders.
The clinical differential diagnosis also includes other entities with annular lesions, such as tinea corporis, subacute lupus erythematosus, erythema annulare centrifugum, annular secondary syphilis, and elastosis perforans serpiginosa. These entities can generally be distinguished without difficulty from AEGCG by the histopathologic features. The histopathologic differential diagnosis of AEGCG includes mid-dermal elastolysis, cutis laxa, granulomatous mycosis fungoides, and granulomatous infections. These entities may typically be distinguished from AEGCG by the clinical features. To rule out granulomatous infections, special stains and/or cultures may be needed.
Who is at Risk for Developing Annular Elastolytic Giant Cell Granuloma?
Adults, age 40 to 70 years, are primarily affected. The female-to-male ratio is 2:1. AEGCG is rare in children and infants. Predisposing factors include excessive chronic sun exposure in many but not all cases. Prior thermal burn injuries are occasionally associated.
What is the Cause of Annular Elastolytic Giant Cell Granuloma?
Etiology and pathogenesis are unclear. A cell-mediated immune response may be directed against damaged elastic tissue fibers, but this theory is debated.
Systemic Implications and Complications
There usually are no systemic implications. AEGCG has rarely been reported (mostly in single isolated cases) to be associated with diabetes mellitus, necrobiosis lipoidica, giant cell temporal arteritis, sarcoidosis, acute myelogenous leukemia, adult T-cell leukemia, primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma, monoclonal gammopathy, gastric carcinoma, relapsing polychondritis, cutaneous amyloidosis, giant molluscum contagiosum, alcoholic cirrhosis, and perforating pseudoxanthoma elasticum. It is currently unclear whether AEGCG is related to any of these disorders or whether the associations are coincidental. Mid-dermal elastolysis has rarely been reported to follow AEGCG.
Treatment options are summarized in Table I.
|Medical Treatment||Surgical Procedures||Physical Modalities|
|Tacrolimus ointment||Narrow band ultraviolet B|
Optimal Therapeutic Approach for this Disease
Treatment of AEGCG is difficult. Published descriptions of successful treatments are limited mostly to anecdotal case reports.
For patients with a single lesion or very few lesions of AEGCG, intralesional triamcinolone 3mg/mL is a reasonable first choice. Lidocaine cream 4% may be considered as a topical anesthetic prior to injection.
If intralesional injection is not feasible or not tolerated, topical calcineurin inhibitors are a second consideration (tacrolimus ointment 0.1% twice daily or pimecrolimus cream 1% twice daily). In prescribing topical calcineurin inhibitors, it should be noted that these medications carry an FDA black box warning, indicating that long0term safety has not been established, particularly with regard to a potential association with malignancy.
As a result, it is reasonable to discuss these concerns with the patient and to explain that therapy for AEGCG with tacrolimus ointment is off-label. In discussion with the patient, it can be determined whether the potential benefits of therapy outweigh the theoretical risks.
For small lesions in cosmetically appropriate areas, excision may be an option. For unresponsive or extensive lesions, systemic medications, such as pentoxifylline, antimalarials, or oral retinoids may be considered.
Among systemic medications, pentoxifylline (400mg by mouth three times daily) is a leading consideration due to its relatively good safety profile. Oral antimalarials (hydroxychloroquine 200mg twice daily, chloroquine 250-500mg daily, or quinacrine 100-200mg daily) could alternatively be considered. For AEGCG, oral retinoid regimens include acitretin 25mg daily or isotretinoin 0.5mg/kg/day.
Published reports describe successful treatment of AEGCG with phototherapy, including narrow band ultraviolet (UV) B and psoralen plus UVA (PUVA). Narrowband UVB phototherapy offers greater convenience and less risk of inducing skin cancers, in comparison to PUVA.
Finally, cyclosporine could be considered for particularly difficult cases of AEGCG. Recommended dosing for cyclosporine varies with the specific brand: 2.5mg/kg/day for Neoral and 2.5-5mg/kg/day for Sandimmune.
Reports in the literature suggest that a period of up to 6 months may be needed to assess a response to a systemic therapy. Therapeutic efficacy is, however, difficult to assess because spontaneous resolution, even rapid regression, may occur in untreated patients. The unpredictable benefit of therapy would need to be weighed carefully against the potential risk of adverse effects, particularly with systemic treatments such as cyclosporine.
The timing of follow-up depends mostly upon the potential risks of the selected therapy. Topical and intralesional treatments may require follow-up on a monthly basis to assess response to treatment. Higher-risk systemic medications may require close laboratory monitoring and more frequent follow-up.
Unusual Clinical Scenarios to Consider in Patient Management
In the setting of widespread lesions, intralesional corticosteroids are impractical for the treatment of every lesion. In this situation, intralesional corticosteroids may be directed to the few most cosmetically troublesome areas, regardless of whether systemic therapy is pursued. Alternatively, topical corticosteroids may also be considered in combination with systemic therapy.
What is the Evidence?
O’Brien, JP. “Actinic granuloma: an annular connective tissue disorder affecting sun- and heat-damaged (elastotic) skin”. Arch Dermatol. vol. 11. 1975. pp. 460-6. (Comprehensive description of the clinical and histopathologic features of actinic granuloma (common subtype of annular elastolytic giant cell granuloma) from 1975 by Dr. John O'Brien, for whom the entity is named.)
Limas, C. “The spectrum of primary cutaneous elastolytic granulomas and their distinction from granuloma annulare: a clinicopathological analysis”. Histopathology. vol. 44. 2004. pp. 277-282. (Detailed report of 20 patients with AEGCG. The results support the view that AEGCG is a separate entity, distinct from granuloma annulare.)
Rongioletti, F, Baldari, M, Burlando, M, Parodi, A. “Papular elastolytic giant cell granuloma: Report of a case associated with monoclonal gammopathy and responsive to topical tacrolimus”. Clin Exp Dermatol. vol. 35. 2010. pp. 145-8. (Case report of a 43-year-old woman with a papular variant of elastolytic granuloma. Widespread papules were present on the trunk for 3 years. She had a concurrent IgG lambda monoclonal gammopathy, for which she received no specific treatment. For the AEGCG, tacrolimus ointment 0.1% was applied twice daily. Marked improvement was noted after 2 months of treatment.)
Ratnavel, RC, Grant, JW, Handfield-Jones, SE, Norris, PG. “O'Brien's actinic granuloma: response to isotretinoin”. J R Soc Med. vol. 88. 1995. pp. 528P-9P. (Case report of an elderly man with enlarging disfiguring plaques of AEGCG on the face and neck. Previous treatments with intralesional and topical corticosteroids had not been beneficial. The initiation of isotretinoin 0.5 mg/kg/day PO was associated with resolution of the newest lesions of AEGCG and improvement of longstanding lesions. After 12 weeks of treatment, isotretinoin was discontinued due to liver enzyme elevation and lethargy. Eight weeks after stopping treatment, he developed 2 new lesions of AEGCG.)
Stefanaki, C, Panagiotopoulos, A, Kostakis, P, Stefanaki, K, Petridis, A. “Actinic granuloma successfully treated with acitretin”. Int J Dermatol. vol. 44. 2005. pp. 163-6. (Case report of an elderly man with expanding lesions of actinic granuloma (common variant of annular elastolytic giant cell granuloma) on the forehead and nose. Treatment with acitretin 25 mg by mouth daily was associated with remarkable improvement. The lesions nearly resolved after 1 year of acitretin.)
Ventura, F, Vilarinho, C, daLuz Duarte, M, Pardal, F, Brito, C. “Two cases of annular elastolytic giant cell granuloma: different response to the treatment”. Dermatol Online J. vol. 16. 2010. pp. 11(Description of two patients with AEGCG on the back and extremities. The first patient, an elderly woman, experienced complete resolution of lesions after 3 weeks of betamethasone dipropionate cream. The second patient, an elderly man, failed treatment with topical corticosteroids and PUVA. Subsequent treatment with hydroxychloroquine 400 mg by mouth daily was associated with improvement by 4 months. The treatment was discontinued due to early retinopathy. Cyclosporine 200 mg by mouth daily was then initiated. The patient experienced complete clearing over the next 7 months.)
Rubio, FA, Robayna, G, Pizaro, A, de Lucas, R, Herranz, P, Casado, M. “Actinic granuloma and vitiligo treated successfully with pentoxifylline”. Int J Dermatol. vol. 37. 1998. pp. 958-60. (Case report of an elderly man with widespread actinic granuloma (variant of AEGCG) and vitiligo. Pentoxifylline (400mg by mouth three times daily) was associated with marked improvement of his AEGCG lesions over a 6-month period. The medication was subsequently discontinued due to gastrointestinal side effects, and the AEGCG lesions rebounded.)
Takata, T, Ikeda, M, Kodama, H, Ohkuma, S. “Regression of papular elastolytic giant cell granuloma using narrow-band UVB irradiation”. Dermatol. vol. 21. 2006. pp. 77-9. (Case report of an elderly Japanese man with papular elastolytic giant cell granuloma involving the dorsal hand and back. Localized narrow-band UVB was administered to the hand at 100 mJ/cm2 and was repeated four times on a weekly basis at 200mJ/cm2. The hand lesions nearly resolved. The localized narrow-band UVB was then similarly administered directly to the back lesions over 6 weeks and was associated with complete resolution of the back lesions.)
Lee, LW, Lee, MW, Choi, JH, Moon, KC, Koh, JK. “Annular elastolytic giant cell granuloma in an infant: improvement after treatment with oral tranilast and topical pimecrolimus”. J Am Acad Dermatol. vol. 53. 2002. pp. S244-6. (Case report of an 8-month-old infant boy with widespread AEGCG on the extremities and trunk. Concurrent administration of pimecrolimus 1% cream twice daily for 4 months and oral tranilast 5 mg/kg/day for 3 months was associated with resolution of lesions. Tranilast is an anti-allergic drug that inhibits release of chemical mediators from mast cells and affects the release of cytokines by monocytes and macrophages.)
Kelly, BJ, Mrstik, ME, Ramo-Caro, FA, Iczkowski, KA. “Papular elastolytic giant cell granuloma responding to hydroxychloroquine and quinacrine”. Int J Dermatol. vol. 43. 2004. pp. 964-6. (Case report of an elderly man with widespread lesions of elastolytic giant cell granuloma (papular variant) on the trunk, extremities, and face. Initial treatment with hydroxychloroquine 200 mg by mouth twice daily was associated with a 75% improvement. The hydroxychloroquine was discontinued due to ophthalmologic side effects. The skin lesions rebounded within 6 months after the discontinuation of therapy. Quinacrine 100 mg by mouth daily was then started and was associated with a noticeable improvement in his lesions within 3 months.)
Igawa, K, Maruyama, R, Katayama, I, Nishioka, K. “Anti-oxidative therapy with oral dapsone improved HCV antibody positive annular elastolytic giant cell granuloma”. J Dermatol. vol. 24. 1997. pp. 328-31. (Case report of an elderly man with AEGCG on the neck and upper extremities. He was noted to have a history of positive Hepatitis C serology. Treatment with dapsone 50 mg daily was associated with improvement of AEGCG lesions in 1 month and complete resolution in 14 months.)
Can, B, Kavala, M, Turkglu, Z, Zindanci, I, Topalog, F. “Successful treatment of annular elastolytic giant cell granuloma with hydroxychloroquine”. Int J Dermatol. vol. 52. 2013. pp. 501-518. (Case report of a female patient with AEGCG that was unresponsive to multiple treatments over a 10-year period. Her skin lesions resolved after five months of treatment with oral hydroxychloroquine 400 mg daily.)
ElKhoury, J, Kurban, M, Abbbas, O. “Elastophagocytosis: underlying mechanisms and associated cutaneous entities”. J Am Acad Dermtol. vol. 70. 2014. pp. 934-944. (This review examines the postulated mechanisms of elastophagocytosis in AEGCG and other cutaneous disorders.)
Marmon, S, O’Reilly, KE, Fischer, M, Meehan, S, Machler, B. “Papular variant of annular elastolytic giant-cell granuloma”. Dermatol Online J. vol. 18. 2012. pp. 23(Case report of a female patient with a rare papular variant of AEGCG.)
Arora, S, Malik, A, Patil, C, Balki, A. “Annular elastolytic giant cell granuloma: A report of 10 cases”. Indian Dermatol Online J. vol. 6. 2015; Dec. pp. S17-20. (Case series of 10 patients with annular elastolytic giant cell granuloma, treated with hydroxychloroquine 200 mg twice daily and photo protection. Skin lesions resolved in all patients within 4-6 months.)
Errichetti, E, Stinco, G, Avellini, C, Patrone, P. “Annular elastolytic giant cell granuloma treated with topical pimecrolimus”. Indian J Dermatol Venereol Leprol. vol. 80. 2014; Sep-Oct. pp. 475-6. (Case report of a 63-year-old man with annular elastolytic giant cell granuloma of the scalp. The lesion resolved after 3 weeks of therapy with pimecrolimus cream twice daily.)
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- Are You Confident of the Diagnosis?
- Who is at Risk for Developing Annular Elastolytic Giant Cell Granuloma?
- What is the Cause of Annular Elastolytic Giant Cell Granuloma?
- Systemic Implications and Complications
- Treatment Options
- Optimal Therapeutic Approach for this Disease
- Patient Management
- Unusual Clinical Scenarios to Consider in Patient Management