Cutis Verticis Gyrata in Association With Vemurafenib and Whole-Brain Radiotherapy

Case Report 1

A 33-year-old man presented to an outside hospital with a 2-month history of lower back pain, fever, chills, and anorexia. Physical examination revealed subcutaneous nodules on the chest, abdomen, and back. Cross-sectional imaging demonstrated multiple masses throughout the paraspinal tissue, vertebrae, liver, and subcutis. A magnetic resonance imaging scan of the brain showed four brain metastases ranging from 2 to 12 mm in size. An excisional biopsy of a subcutaneous lesion revealed metastatic melanoma characterized by a BRAF^V600E mutation.

The patient initiated external-beam whole-brain radiotherapy (WBRT, 30 Gy over 10 daily fractions with 6 MV photons) and vemurafenib at a dose of 960 mg orally twice per day. After seven of 10 fractions of WBRT (21 Gy), the patient developed pain and erythema of the ears and scalp, resulting in a diagnosis of grade 2 radiation dermatitis. The patient temporarily stopped WBRT and received topical emollients. Vemurafenib was continued without a dose reduction. After slight improvement in his symptoms, WBRT was reinitiated to complete the 10 fractions. The patient subsequently noted recurrence and worsening of his symptoms, which reached their maximum severity approximately 3 weeks after completion of WBRT. Photographs (Figs 1A and 1B) of his head and neck demonstrate a severe confluent erythematous and hyperkeratotic plaque limited to the radiation field. Tortuous skin folding and thickening of the scalp with induration of the ears, not observed previously, are also notable.

Fig 1.

The patient received treatment with topical corticosteroids, retinoids, and antibiotics with slow improvement of this toxicity. Two months later, the patient presented to our Center for further evaluation. Physical examination revealed resolution of the previously noted hypertrophic scalp changes. However, the confluent erythematous and hyperkeratotic plaque persisted. Cross-sectional imaging demonstrated a partial response to vemurafenib therapy. We recommended continuation of vemurafenib and prescribed a topical corticosteroid (alclometasone) for the patient's scalp. One month later, he had a continued clinical response to vemurafenib with complete resolution of his scalp eruption.

Case Report 2

A 53-year-old woman with a history of stage IIIB (T2bN1aM0) cutaneous melanoma (American Joint Committee on Cancer staging system, edition 7) originating on the trunk was treated initially with wide local excision, completion lymph node dissection, and a clinical trial with an adjuvant DNA vaccine. The patient did well clinically and was without radiographic evidence of disease for nearly a decade. Two months before presentation at our center, she complained of fatigue, unintentional weight loss, confusion, and an unsteady gait. Cross-sectional imaging showed extensive pulmonary, splenic, hepatic, mesenteric, and osseous masses that were consistent with widespread metastatic disease. A magnetic resonance imaging scan of the brain demonstrated a left posterior orbital metastasis and innumerable bilateral brain metastases ranging from 1 to 28 mm in size. A computed tomography–guided liver biopsy confirmed the presence of metastatic melanoma.

The patient completed a course of WBRT with the radiation portal including the left posterior orbital metastasis (35 Gy over 14 daily fractions with 6 MV photons) concurrent with temozolomide. After progression of disease, she then presented to our center for further therapeutic options. While tumor sequencing for a BRAF mutation was in progress, the patient received one dose of ipilimumab. Once a BRAF^V600E mutation was identified, the patient began receiving vemurafenib at a dose of 960 mg orally twice per day. This treatment was begun 3 weeks after the completion of WBRT. Within 3 weeks of initiating vemurafenib, the patient complained of scalp pain, swelling, and redness. Physical examination of the head and neck demonstrated diffuse erythema and hyperkeratosis limited to the radiation field (Figs 1C and 1D). A diagnosis of grade 1 radiation recall was made, with furrowing and ridging of the scalp. She continued vemurafenib with several dose reductions. Her rash persisted, but did not worsen, and was treated with topical salicylic acid. The patient ultimately died as a result of her disease approximately 11 weeks after the initiation of therapy.

Discussion

Herein we present two cases of a cutaneous eruption of the scalp that occurred in the context of vemurafenib and WBRT. Both patients developed a cutaneous reaction that was characterized by pain, erythema, hyperkeratosis, and hypertrophy of the scalp. The observed tortuous skin folding and convoluted furrowing that resembles the sulci and gyri of the cerebrum is descriptively termed cutis verticis gyrata (CVG).¹

CVG is an uncommon and typically innocuous dermatologic condition that occurs either in isolation (ie, primary essential CVG) or in association with a number of medical conditions (ie, primary nonessential or secondary/acquired CVG).² On histopathologic examination, the appearance of CVG is variable and depends on the underlying etiology. In isolated cases of CVG, dermal biopsy may reveal normal skin architecture. In patients with acquired CVG, dermal collagen thickening and hypertrophy of the sebaceous structures (as in acromegaly), inflammation and edema, and, in some cases, malignant conditions (leukemia and sarcoma) are observed on pathologic review.^2–4 Irrespective of the underlying cause, the galea aponeurotica limits the soft tissue expansion and/or overgrowth of the scalp, which in turn leads to the unique and characteristic cerebriform pattern. Spontaneous resolution of acquired CVG can occur with treatment of the underlying medical cause; however, in many patients, the cutaneous changes are permanent.

Dermatologic adverse events occurring with the RAF kinase inhibitors vemurafenib and dabrafenib are common and include rash, photosensitivity, alopecia, and hyperproliferative cutaneous eruptions (ie, verrucae, papillomas, hyperkeratosis, keratoacanthomas, and squamous cell carcinomas).⁵ The mechanistic basis for the development of hyperproliferative skin lesions, particularly squamous cell carcinoma, is thought to be the result of paradoxical activation of extracellular signal-regulated kinases (ERK) signaling in BRAF wild-type cells in response to RAF kinase inhibition.^6–9 This in turn leads to cellular hyperproliferation of BRAF wild-type cells. Like RAF kinase inhibition, radiotherapy can also cause multiple dermatologic complications. Acute radiation-induced skin changes include erythema, mild edema, and dry and moist desquamation, and occur within days to weeks of treatment.¹⁰ Ionizing radiation induces direct DNA damage in developing keratinocytes, which leads to inflammation, cell cycle arrest, and apoptosis.¹¹ To our knowledge, such dramatic cutaneous reactions characterized by erythema, hyperkeratosis, and CVG have not been reported with WBRT or with the RAF kinase inhibitors alone.

The molecular effects of concurrent RAF kinase inhibition and radiotherapy on BRAF mutant melanoma are incompletely understood; preclinical data suggest that RAF inhibitors are radiosensitizers.^12,13 Little is known about their effects on normal tissue. It is possible that RAF inhibitor therapy can enhance the cutaneous toxicity of radiation therapy. RAF inhibitors paradoxically increase ERK signaling and cellular proliferation in BRAF wild-type keratinocytes.^8,9 Additionally, ionizing radiation increases ERK signaling in a number of cell lines through the activation of receptor tyrosine kinases, RAS, and the preferential activation of CRAF.¹⁴ Concomitant radiotherapy and RAF inhibitor therapy may each activate the mitogen-activated protein kinase pathway in keratinocytes, leading to hyperkeratosis and hypertrophy within the radiation field.

In summary, we present these cases to familiarize medical and radiation oncologists with CVG and to point out the need for further evaluation of the effects of RAF inhibition and radiotherapy, particularly with concomitant administration. The clinical experience with RAF kinase inhibition and radiotherapy is limited, and presently, it is difficult to ascertain whether or not their combination will lead to improvement in outcomes or greater toxicity.^15–18 The potential for cutaneous toxicity that is associated with combination therapy certainly exists. As illustrated in the cases presented, such events (albeit likely rare) can be intolerable to patients, profoundly disfiguring, and affect quality of life. Our institutional practice is to discontinue RAF kinase inhibitors 5 to 7 days before the initiation of any form of radiotherapy. On completion of radiotherapy, we resume the RAF inhibitor as dictated by the clinical situation. We avoid concurrent radiotherapy with RAF inhibitors in routine clinical practice and recommend their combined administration only in the context of a clinical trial.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) and/or an author's immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Christopher A. Barker, RP Pharmaceuticals (C); Paul B. Chapman, Genentech (C), GlaxoSmithKline (C); Mario E. Lacouture, Genentech (C) Stock Ownership: None Honoraria: None Research Funding: Paul B. Chapman, Genentech, GlaxoSmithKline Expert Testimony: None Patents: None Other Remuneration: None