Abstract
An 8-year-old boy presented with his mother for evaluation of an erythematous rash 3 weeks after the start of dual BRAF-MEK inhibition with dabrafenib and trametinib for treatment of progression of low-grade glioma. Panniculitis has been reported as a rare adverse cutaneous event induced by BRAF inhibitors, MEK inhibitors, and the combined dual BRAF-MEK therapy. Based on the patient’s history, clinical presentation, and histopathological findings, a diagnosis of drug-induced neutrophilic panniculitis was made. This case describes neutrophilic panniculitis as a potential cutaneous manifestation of dual BRAF-MEK inhibitor therapy and describes the management of such side effects. Neutrophilic panniculitis is a relatively rare manifestation, characterized by neutrophilic inflammation in the subcutaneous tissue. Additionally, this case serves as a reminder to consider the cutaneous side effects of such therapies, given that MEK and BRAF inhibitors are increasingly used to treat primary brain tumors in the pediatric population. Routine inspection and early management may improve patients’ quality of life and enable continuation of anticancer therapy.
Keywords: BRAF inhibitor, BRAF-MEK, drug-induced neutrophilic panniculitis, low-grade glioma, MEK inhibitor
CASE SUMMARY
An 8-year-old boy with a history of BRAF-mutated progressive low-grade glioma, who previously completed carboplatin and vincristine therapy, presented to the dermatology clinic for evaluation of a tender rash located on bilateral medial thighs for 1 week. Three weeks before the cutaneous symptoms began, he was started on dual BRAF-MEK inhibition with dabrafenib and trametinib due to progression of his oncologic disease. The patient had no other significant medical history or medications.
On physical examination, the patient was found to have numerous erythematous, firm and tender plaques, measuring 0.2 to 0.5 cm, in the medial thighs bilaterally (Figure 1). The differential diagnosis included panniculitis versus erythema nodosum. A 5-mm punch biopsy performed from one of the nodules showed relatively normal-appearing epidermis and dermis and mixed inflammatory infiltrate composed of neutrophils with a background population of lymphocytes and histiocytes within the deep panniculus (Figure 2). The histological findings were consistent with neutrophilic lobular panniculitis.
Figure 1.
Firm, irregular, erythematous plaques tender to palpation in the medial thighs measuring 0.2 to 0.5 cm.
Figure 2.
Normal-appearing epidermis and dermis. Within the deep panniculus, there is mixed inflammatory infiltrate composed of neutrophils with a background population of lymphocytes and histiocytes.
The patient was started on meloxicam 7.5 mg nightly with some symptomatic improvement. At the 2-week follow-up appointment, the lesions were no longer painful to palpation and no new lesions had erupted. No dose reduction or discontinuation of BRAF-MEK inhibitor therapy was needed.
CLINICAL QUESTIONS
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A patient presents with mildly tender, erythematous nodules to bilateral thighs after recently starting a new targeted therapy regimen with a BRAF inhibitor and MEK inhibitor. What is the recommended management?
Discontinue targeted therapy
Decrease the dose of targeted therapy
Begin oral steroids and discontinue targeted therapy
Begin daily NSAID with continuation at current dose of targeted therapy
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What histological findings are most consistent with neutrophilic lobular panniculitis?
A dense, diffuse neutrophilic infiltrate invading the dermis
A lobular neutrophilic infiltrate involving the subcutaneous tissue
Septal panniculitis with a slight superficial and deep perivascular inflammatory lymphocytic infiltrate
Neutrophilic infiltration and granulomatous formation extending between the muscle bundles within the vessel wall
Correct answers are given at the end of the article.
DISCUSSION
Neutrophilic panniculitis has been reported in pediatric and adult patients who are undergoing treatment with BRAF inhibitors, including dabrafenib and vemurafenib, with or without MEK inhibitors.1 BRAF and MEK inhibitors were initially approved to treat metastatic BRAF V600E-mutated melanoma; however, approval has expanded to treat non–small cell lung cancer and thyroid disease. More recently, these drugs are being used to treat cases of low-grade gliomas in pediatric patients. A few cases of panniculitis have been documented in the literature as a side effect of BRAF and MEK inhibitors in children undergoing therapy for glioma, but the majority of case reports are related to the use of BRAF inhibitors as monotherapy in adults undergoing treatment for metastatic melanoma.1,2 One reported case was strictly induced by MEK inhibitors, specifically trametinib, which resolved after discontinuation of the medication. Dabrafenib, a BRAF inhibitor, has been reported to cause tender subcutaneous nodules in bilateral upper and lower extremities in a child after 3 weeks of therapy.1
Presentation and diagnosis
While the lesions can present clinically as tender erythematous plaques or nodules on bilateral lower limbs, as well as bilateral upper limbs, abdomen, back, and buttocks, the diagnosis relies on histological findings.3,4 The interval between the start of anticancer treatment and the appearance of panniculitis varies by case and by treatment regimen.3,5 Neutrophilic lobular panniculitis (NP) is a subclassification of neutrophilic dermatoses in which the inflammation predominates in the fat lobules, typically sparing the dermis and without vasculitis.4 A biopsy is essential for the diagnosis of NP, specifically a punch or excision biopsy, which will show a lobular infiltrate of neutrophils.
Management
The mechanism by which BRAF and MEK inhibitors cause panniculitis is not well understood, but some patients with this treatment-related side effect benefit from antiinflammatory medications.6 Initiation of treatment in NP is dependent on the patient’s symptoms. Early initiation of treatment with nonsteroidal antiinflammatory medications (NSAIDs) often provides symptomatic relief in mild cases.6 NSAIDS, including ibuprofen and meloxicam, are the first-line choice in management. In more severe cases or when symptoms persist despite NSAID therapy, systemic corticosteroids may be needed, with a short course of oral prednisone. Discontinuation or interruption of the targeted therapy is usually not necessary but may be considered in severe cases, such as severe systemic symptoms in addition to cutaneous manifestations or in the setting of impaired quality of life.7 Patients should have follow-up appointments to evaluate for symptomatic improvement, resolution, or progression of cutaneous symptoms. NP seems to be highly sensitive to oral steroids, and most patients need only conservative management in mild cases without the need for targeted therapy dose reduction or discontinuation.
CONCLUSION
With the increased use of MEK and BRAF inhibitors in the treatment of pediatric neurological tumors, clinicians should be aware of the adverse cutaneous effects of MEK inhibitors and BRAF inhibitors when used as monotherapy in addition to combination therapy, in order to avoid treatment discontinuation and compromise antitumor effect. Routine inspection and early management may improve quality of life and enable continuation of anticancer therapy.
ANSWERS FOR CLINICAL QUESTIONS
Question 1, d; Question 2, b.
Disclosure statement/Funding
The authors report no funding or conflicts of interest. The patient and parent consented to publication of this case.
References
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