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Case Report/Case Series |

Cutaneous Granulomatous Eruption and Successful Response to Potent Topical Steroids in Patients Undergoing Targeted BRAF Inhibitor Treatment for Metastatic Melanoma

June J. Park, BS1; Elena B. Hawryluk, MD, PhD2; Steven R. Tahan, MD3; Keith Flaherty, MD4; Caroline C. Kim, MD5,6
[+] Author Affiliations
1University of Illinois College of Medicine, Chicago
2Department of Dermatology, Harvard Medical School, Boston, Massachusetts
3Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
4Massachusetts General Hospital Cancer Center, Division of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston
5Pigmented Lesion Clinic, Department of Dermatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
6Cutaneous Oncology Program, Department of Dermatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
JAMA Dermatol. 2014;150(3):307-311. doi:10.1001/jamadermatol.2013.7919.
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Importance  Targeted BRAF inhibitor therapy (vemurafenib, dabrafenib) is an effective, novel treatment for patients with metastatic melanoma with the V600E BRAF mutation. This therapy is associated with squamous cell carcinomas and keratoacanthomas. Granulomatous eruptions have not been previously reported.

Observations  Two patients with melanoma developed cutaneous granulomatous eruptions during targeted BRAF inhibitor therapy. In case 1, after 2 months of treatment with dabrafenib and trametinib (MEK inhibitor), a papular eruption concerning for progression of disease prompted cessation of treatment. After the histopathologic diagnosis of granulomas, the patient was treated with clobetasol ointment with resolution within days and resumption of therapy. In case 2, after 5 months of vemurafenib treatment, the patient developed a granulomatous eruption, which resolved 3 weeks after cessation of therapy.

Conclusions and Relevance  We report 2 cases of cutaneous granulomatous eruptions on treatment with targeted BRAF inhibitors, a previously unreported association. Although additional investigations are necessary to better elucidate the pathogenic mechanisms, our report includes a treatment plan that prevents unnecessary discontinuation of therapy. Given the Food and Drug Administration approval of vemurafenib for metastatic melanoma, clinicians should be aware of this possible cutaneous reaction and treatment option to optimize patient management.

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Figure 1.
Photographs of Lower Extremity of Patient in Case 1

A, Multiple erythematous and light brown 1 to 5-mm papules on the right inner knee. A biopsy of the papule circled in purple ink revealed metastatic melanoma. B, Multiple new inflamed, erythematous papules and plaques (left and middle arrowheads) in the area of original metastatic disease 2 months after initiation of BRAF inhibitor therapy. The initial biopsy site is still healing. The new biopsy site of a papule of the right medial thigh is circled in purple ink (right arrowhead). The other biopsy site of a similar papule on the right anterior lower leg is not seen on this photograph. C, Resolution of inflamed plaques, and fewer, smaller, less erythematous and indurated papules after 2 weeks of topical clobetasol treatment, revealing overall improvement of disease after BRAF inhibitor therapy.

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Figure 2.
Biopsy of Right Medial Thigh

Biopsy of the site shown in Figure 1B revealed granulomatous inflammation around degenerated collagen in mid-reticular dermis. No melanoma cells were identified by level sections stained with hematoxylin-eosin (H&E) and melanoma antigen recognized by T cells (MART-1) immunostain (original magnification, ×40). B, Higher magnification reveals granulomas with hybrid sarcoidal and foreign body type features encircling an edematous and degenerated focus of the reticular dermis (H&E, original magnification, ×100).

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Figure 3.
Punch Biopsy of Right Anterior Lower Leg

A, Biopsy revealed metastatic melanoma with a granulomatous response in the mid-reticular dermis. The granulomas are well formed with hybrid sarcoidal and foreign body type features (hematoxylin-eosin, original magnification, ×100). B, Immunohistochemical stain for melanoma antigen recognized by T cells (MART-1) highlights numerous melanocytic cells within the granulomatous area (MART-1 immunostain, original magnification, ×100).

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Figure 4.
Punch Biopsy of Lower Extremity of Patient in Case 2

A, Biopsy revealed granulomas present in the reticular dermis with predilection to form around blood vessels (hematoxylin-eosin [H&E], original magnification, ×40). High magnification reveals loosely arrayed granulomas composed of histiocytes, Langerhans-type multinucleated giant cells, and lymphocytes (H&E, original magnification, ×200).

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