Journal of Clinical & Experimental Dermatology Research
Open Access

Erythema Nodosum-like Panniculitis Associated with the Use of Vemurafenib

Jorge Magdaleno Tapial^*, Cristian Valenzuela Oñate, Álvaro Martínez-Doménech, Daniela Subiabre Ferrer, Gemma Pérez Pastor, Pablo Hernández Bel and Víctor Alegre de Miquel ^*Correspondence: Jorge Magdaleno Tapial, Department of Dermatology, Hospital General Universitario de Valencia, Valencia, Spain, Email:

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Introduction

Melanoma is a type of skin cancer derived from melanocytes, whose I ncidence has grown during the last decade. Even though it represents only 4% of all skin cancers, it is responsible for 80% of deaths from skin tumors and one of the most important in terms of years of potential life lost [1]. However, the development of new targeted therapies directed specifically against malignant cells has brought hope to the treatment of melanoma patients. The first drugs developed against specific molecules were BRAF inhibitors, designed for the treatment of metastatic melanoma with positivity for V600E BRAF mutation, which occurs in 40-60% of melanomas, especially in those arising in areas without chronic sun exposure [2]. These drugs have been demonstrated to improve both overall and disease-free survival in these patients [3]. At the same time, a wide range of adverse events (AEs) have emerged from their use. We must be familiar with these AEs since they can cause significant morbidity and even force discontinuation of therapy. Some of them are quite frequent and are observed regularly in everyday practice, such as maculopapular rash, photosensitivity, xerosis, keratosis pilaris or epithelial neoplasms [4]. On the other hand, there are rare AEs that require an early diagnosis for adequate treatment, so knowledge of their existence is crucial for timely recognition and patient management. Examples of these are neutrophilic dermatosis such as Sweet syndrome, eccrine neutrophilic hydradenitis and neutrophilic panniculitis [5]. We present a case of erythema nodosum-like septal panniculitis in a patient receiving therapy with vemurafenib and cobimetinib.

Case Report

A 43-year-old male was diagnosed with melanoma of unkown primary after consulting for a painful right axillary lymphadenopathy. Fine needle aspiration biopsy of the lymphadenopathy demonstrated epithelioid melanoma metastatic cells. Complete study of the patient revealed no signs of primary melanoma but detected left inguinal adenopathies, two lung metastases and one splenic metastasis. The patient started on combined therapy with vemurafenib and cobimetinib.

One month later, the patient consulted in the Emergency Department for asthenia, malaise, high fever, and arthralgias that did not improve with non-steroidal antiinflammatory drugs (NSAIDs). Physical examination revealed infiltrated, erythematous, ill-defined and painful subcutaneous nodules on the proximal upper (Figure 1) and lower extremities. They were also present to a lesser extent in the abdomen. A punch biopsy was performed and the patient was treated with oral perdnisone 45 mg daily, with discontinuation of therapy for melanoma.

Figure 1: Subcutaneous nodules on the proximal upper and lower extremities.

Histological examination demonstrated a discrete superficial and deep perivascular inflammatory dermal infiltrate, associated with a dense neutrophilic infiltrate in the subcutaneous tissue septa, which in some areas extended partially into the lobules. There were multiple granulomatous-like structures composed by histiocytes encircling a clear central space and surrounded by a dense neutrophilic infiltrate, findings characteristic of Miescher's granulomas (Figure 2).

Figure 2: Findings characteristic of Miescher's granulomas.

The patient's symptoms and lesions resolved 2 weeks later, so steroid therapy was tapered down. One month later, both vemurafenib and cobimetinib were reintroduced, with subsequent reapparance of the same lesions. Adequate control was achieved with low-dose prednisone without requiring discontinuation of vemurafenib or cobimetinib.

Discussion and Conclusion

Neutrophilic panniculitis is a rare AE of BRAF inhibitor therapy, drugs used to treat metastatic melanomas with BRAF gene mutation. This type of panniculitis has also been described in children and adolescents with central nervous system tumors treated with vemurafenib [6]. So far, there have been over 20 cases reported of panniculitis associated with the use of BRAF inhibitors in metastatic melanoma (Table 1). This AE is mostly reported with BRAF inhibitors as monotherapy, and among these, it is more frequent with vemurafenib than dabrafenib. It has not been described in patients receiving MEK inhibitors exclusively. A recent report described a case of panniculitis associated to combined therapy with vemurafenib and cobimetinib that resolved and relapsed with the latter's removal and reintroduction, respectively [7]. This might be the first case of panniculitis associated to MEK inhibitor therapy, though it may also be a coincidental observation, as the majority of case reports describe resolution of lesions, either spontaneously or with NSAIDs, withour discontinuation of BRAF inhibitor therapy.

Table 1: Cases of panniculitis as associated to the use of BRAF inhibitors in patients with metastatic melanoma reported in the literature.

BRAF inhibitor-associated panniculitis is over two times more frequent in females than in males, and among patients treated with vemurafenib, it is more common in those with lung metastases. However, this last observation might be due to the high frequency of metastases in this location and have no pathogenic link to the development of panniculitis.

The majority of cases reported appeared early during therapy, between the 2^nd and 3^rd weeks of treatment. In the case series reported by Choy et al. lesions appeared later on (mean 48 days, range 3-195 days) [8]. Clinical presentation simulates erythema nodosum, with painful, erythematous nodules predominantly on the anterior aspect of the legs, although arm involvement is also frequent. They may be accompanied by systemic symptoms, usually with fever and arthralgias, in up to 60% of cases. Differential diagnosis should include subcutaneous metastasis of melanoma, so skin biopsy is required [8,9].

Histologic examination of reported cases reveal heterogeneous characteristics. These panniculitis are predominantly lobular and are composed of a neutrophilic infiltrate. Mixed septolobular panniculitis have been described in 4 patients, though the cases reported by Shina, et al. presented erythema nodosum-like panniculitis, similar to our case [10]. Pathology of our patient's lesions demonstrated a predominantly septal panniculitis, a dense neutrophilic infiltrate and multiple Miescher's radial granulomas. Though these are not pathognomonic, they are very typical of early erythema nodosum lesions. This is the first report of BRAF inhibitor-associated neutrophilic panniculitis with these histopathological findings.

These lesions usually resolve in a few days without requiring discontinuation of BRAF inhibitor therapy. However, as in our case, relapses after resuming therapy or increasing dose have been reported [11,12]. Treatment is symptomatic and usually analgesics and NSAIDs suffice, though some cases may require systemic corticosteroids, as did our patient. Some authors recommend using oral corticosteroids as initial treatment due to the intense pain these lesions can cause, which might even motivate discontinuation of therapy [13]. Each individual case must be carefully assessed before making the decision to interrupt BRAF inhibitor therapy [14].

In conclusion, we present a new case of BRAF inhibitor-associated erythema nodosum-like panniculitis presenting in a patient receiving combined therapy with vemurafenib and cobimetinib. Though the patient experienced a relapse after reintroducing therapy, avoiding a second discontinuation was possible due to adequate control with lowdose oral prednisone.

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