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Histologic Features Mimicking Mycosis Fungoides Induced by Imiquimod, 5% A Potential Pitfall for Dermatopathologists FREE

Davide Altamura, MD1; Francesco Simonacci, MD1; Torkan Hirbod, MD1; Evdokia Arkoumani, MD2; Roberto Verdolini, MD, FRCP1
[+] Author Affiliations
1Department of Dermatology, The Princess Alexandra Hospital Trust, Harlow, Essex, England
2Department of Pathology, The Princess Alexandra Hospital Trust, Harlow, Essex, England
JAMA Dermatol. 2014;150(11):1236-1237. doi:10.1001/jamadermatol.2014.929.
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Published online

Imiquimod is a topical immune response modifier with potent antiviral and antitumor effects. It induces an immune-mediated response, demonstrated by changes in the lymphocytic infiltrate and locally produced cytokines.1,2

REPORT OF A CASE

A man in his 80s presented with a keratotic, erythematous, and partially eroded plaque on the vertex of the scalp measuring 14 × 22 mm (Figure, A). He had a medical history of multiple actinic keratoses and epidermal neoplasms on sun-exposed areas and comorbidities including arterial hypertension and diabetes type 2. Clinical examination of the lesion on the scalp revealed a degree of induration; no locoregional lymphadenopathies nor further skin lesions were identified.

Place holder to copy figure label and caption
Figure.
Clinical and Histopathologic Images Illustrating the Present Case

A, Growing and eroded skin lesion on the scalp of a man in his 80s; the photograph shows an erythematous, eroded, and partially keratotic plaque on a background of actinic changes of the skin. B, Histopathologic findings of a punch biopsy specimen taken from the excoriated plaque on the scalp (hematoxylin-eosin, original magnification ×20). The image shows the presence of a dense infiltrate of atypical lymphocytes in the upper dermis; collections of lymphocytes resembling Pautrier microabscesses are seen in the epidermis.

Graphic Jump Location

Based on the clinical features, a clinical diagnosis of hypertrophic actinic keratosis was favored, and the patient was treated with imiquimod, 5%, cream applied once daily, 5 d/wk. After 4 weeks of treatment, the lesion appeared reduced in size but still moderately hypertrophic, excoriated, and inflamed. Because squamous cell carcinoma with early infiltration could not be completely ruled out, a punch biopsy was performed, and the patient was asked to continue the therapy for a further 4 weeks.

Rather surprisingly, histologic analysis showed very little epidermal change. Instead, a dense polymorphous infiltrate of atypical lymphocytes with cerebriform nuclei in the upper dermis with an intraepidermal collection of neutrophils was noted. Focally there were collections of cells resembling Pautrier microabscesses. Immunohistochemical staining revealed the lymphoid cell infiltrate to be positive for CD3, CD4, CD5, and CD7 and negative for CD56 and Epstein-Barr virus–encoded small RNA). A significant amount of CD8 and CD30 small and large T cells were also identified (Figure, B). The overall histopathologic findings were fully consistent with mycosis fungoides.

However, analysis with polymerase chain reaction (PCR) gene rearrangement showed no evidence of monoclonal T-cell receptor expansion. Six weeks later, the lesion appeared clinically regressed. During the subsequent 18 months of clinical follow-up, the patient developed further actinic and bowenoid keratoses on sun-exposed areas of his body but no skin eruptions suggestive of cutaneous T-cell lymphoma and no lymphadenopathies. His scalp, in particular, remains clear of any further lesions.

DISCUSSION

Topical imiquimod is an active imidazoquinoline immunomodulator agent currently indicated as nonablative treatment for superficial basal cell carcinomas, actinic keratoses, and genital warts.3 Imiquimod, 5%, in cream has also shown efficacy against many other tumor entities and primary cutaneous lymphomas such as mycoses fungoides.46 The basic mechanism of its action is explained by the production and release of proinflammatory cytokines leading to the activation of antigen-presenting cells and induction of apoptosis, but several secondary effects on the molecular and cellular level may also be explained.13

In the present case, we found a discrepancy between the clinical picture of hypertrophic actinic keratosis and the histopathologic findings of mycosis fungoides. We believe that the topical application of imiquimod, 5%, in cream may have induced the histologic picture observed and then promoted the resolution of what was originally an actinic keratosis. Our hypothesis was supported by the clinical features of the skin lesion treated with imiquimod, the patient’s history of severe actinic skin damage, and the absence of monoclonal T-cell receptor expansion found by PCR analysis.

In conclusion, we hypothesize that imiquimod, 5%, for treatment of actinic keratoses or epithelial skin neoplasms could induce histopathologic changes mimicking mycosis fungoides, and this phenomenon may represent a potential diagnostic pitfall for the dermatopathologist.

ARTICLE INFORMATION

Corresponding Author: Davide Altamura, MD, Department of Dermatology, The Princess Alexandra Hospital Trust, Hamstel Road, Harlow, Essex CM20 1QX, England (davide.altamura@pah.nhs.uk).

Published Online: August 13, 2014. doi:10.1001/jamadermatol.2014.929.

Conflict of Interest Disclosures: None reported.

REFERENCES

Torres  A, Storey  L, Anders  M,  et al.  Immune-mediated changes in actinic keratosis following topical treatment with imiquimod 5% cream. J Transl Med. 2007;5:7.
PubMed   |  Link to Article
Schön  MP, Schön  M.  Imiquimod: mode of action. Br J Dermatol. 2007;157(157)(suppl 2):8-13.
PubMed   |  Link to Article
Wagstaff  AJ, Perry  CM.  Topical imiquimod: a review of its use in the management of anogenital warts, actinic keratoses, basal cell carcinoma and other skin lesions. Drugs. 2007;67(15):2187-2210.
PubMed   |  Link to Article
Buettiker  UV, Yawalkar  NY, Braathen  LR, Hunger  RE.  Imiquimod treatment of lentigo maligna: an open-label study of 34 primary lesions in 32 patients. Arch Dermatol. 2008;144(7):943-945.
PubMed   |  Link to Article
Adams  S, Kozhaya  L, Martiniuk  F,  et al.  Topical TLR7 agonist imiquimod can induce immune-mediated rejection of skin metastases in patients with breast cancer. Clin Cancer Res. 2012;18(24):6748-6757.
PubMed   |  Link to Article
Coors  EA, Schuler  G, Von Den Driesch  P.  Topical imiquimod as treatment for different kinds of cutaneous lymphoma. Eur J Dermatol. 2006;16(4):391-393.
PubMed

Figures

Place holder to copy figure label and caption
Figure.
Clinical and Histopathologic Images Illustrating the Present Case

A, Growing and eroded skin lesion on the scalp of a man in his 80s; the photograph shows an erythematous, eroded, and partially keratotic plaque on a background of actinic changes of the skin. B, Histopathologic findings of a punch biopsy specimen taken from the excoriated plaque on the scalp (hematoxylin-eosin, original magnification ×20). The image shows the presence of a dense infiltrate of atypical lymphocytes in the upper dermis; collections of lymphocytes resembling Pautrier microabscesses are seen in the epidermis.

Graphic Jump Location

Tables

References

Torres  A, Storey  L, Anders  M,  et al.  Immune-mediated changes in actinic keratosis following topical treatment with imiquimod 5% cream. J Transl Med. 2007;5:7.
PubMed   |  Link to Article
Schön  MP, Schön  M.  Imiquimod: mode of action. Br J Dermatol. 2007;157(157)(suppl 2):8-13.
PubMed   |  Link to Article
Wagstaff  AJ, Perry  CM.  Topical imiquimod: a review of its use in the management of anogenital warts, actinic keratoses, basal cell carcinoma and other skin lesions. Drugs. 2007;67(15):2187-2210.
PubMed   |  Link to Article
Buettiker  UV, Yawalkar  NY, Braathen  LR, Hunger  RE.  Imiquimod treatment of lentigo maligna: an open-label study of 34 primary lesions in 32 patients. Arch Dermatol. 2008;144(7):943-945.
PubMed   |  Link to Article
Adams  S, Kozhaya  L, Martiniuk  F,  et al.  Topical TLR7 agonist imiquimod can induce immune-mediated rejection of skin metastases in patients with breast cancer. Clin Cancer Res. 2012;18(24):6748-6757.
PubMed   |  Link to Article
Coors  EA, Schuler  G, Von Den Driesch  P.  Topical imiquimod as treatment for different kinds of cutaneous lymphoma. Eur J Dermatol. 2006;16(4):391-393.
PubMed

Correspondence

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