BRAF inhibitor–induced necrotizing granulomatous lymphadenopathy: a case report of drug-induced sarcoid-like reaction

Abstract

BRAF inhibitors are a class of targeted therapies used in the treatment of malignant melanoma. They are the standard of care in the treatment of advanced BRAF-mutated malignant melanoma and are generally well tolerated. However, in rare cases, an adverse effect involving granulomatous lymphadenopathy may occur. This case report discusses a patient receiving BRAF inhibitor therapy who developed mediastinal lymphadenopathy with necrotizing granulomatous disease found on intranodal forceps biopsy.

KEY POINTS

• The case highlights a rare adverse effect of BRAF inhibitor therapy, commonly used for treating advanced BRAF-mutated malignant melanoma. The patient developed extensive mediastinal lymphadenopathy with necrotizing granulomatous disease, confirmed via intranodal forceps biopsy. This reaction, resembling a drug-induced sarcoid-like response, underscores the potential for granulomatous lymphadenopathy as a rare but significant complication of BRAF inhibitors.

• Discontinuation of BRAF inhibitor therapy, followed by a brief course of systemic steroid therapy (prednisone), led to a significant reduction in the size of mediastinal lymphadenopathy on follow-up imaging. This outcome suggests that holding BRAF therapy and concurrently administering systemic steroid therapy may be an effective management strategy for drug-induced necrotizing granulomatous reactions.

CASE SUMMARY

A 57-year-old woman with a past medical history of malignant melanoma of the right upper extremity was initially placed on BRAF inhibitor therapy (dabrafenib/trametinib) after resection but developed an erythematous bilateral lower-extremity rash and was converted to cobimetinib/vemurafenib. After initiating therapy, a surveillance positron emission tomography (PET)/computed tomography (CT) scan was performed, which demonstrated new and extensive fludeoxyglucose-avid mediastinal lymphadenopathy (Figure 1a, 1b), including a 2.7 cm right lower paratracheal lymph node. Following this finding, she underwent bronchoscopy with endobronchial ultrasound (EBUS), during which a fine-needle aspirate/intranodal forceps biopsy was performed. The results demonstrated necrotizing granulomatous disease without evidence of malignancy at station 4R (Figure 1c). Bronchoscopic cultures were negative for fungal or mycobacterial infection.

Figure 1.

(a) Pretreatment transverse chest CT showing a 2.7 cm lower paratracheal lymph node (arrow). (b) Transverse chest PET/CT indicating fludeoxyglucose-avid mediastinal lymphadenopathy (arrow). (c) Pathology image from intranodal forceps showing necrotizing granulomas. (d) Posttreatment transverse chest CT, with arrow indicating a 1.5 cm lower paratracheal lymph node.

A presumptive diagnosis of BRAF inhibitor necrotizing granulomatous reaction was made, and BRAF inhibitor therapy was discontinued after completion of a 1-year course. This was followed by a brief course of systemic steroid therapy with prednisone. Follow-up imaging with a chest CT demonstrated a significant interval decrease in size of lymphadenopathy, with the lower paratracheal lymph node size decreasing to 1.5 cm (Figure 1d). This is suggestive of BRAF inhibitor–associated necrotizing granulomatous disease.

CLINICAL QUESTIONS

1. Which of the following gene products does the BRAF oncogene produce?

   1. Receptor tyrosine kinase

   2. Nonreceptor tyrosine kinase

   3. Serine/threonine kinase

   4. Transcription factor

2. A 52-year-old African American woman presents to the pulmonary clinic for a new evaluation of cough. She reports a 1-year history of progressive dry cough with mild exertional dyspnea. She is a never-smoker without a prior history of pulmonary disease. Her primary care provider obtained a chest CT after a chest radiograph suggested mediastinal adenopathy. On review of her chest CT, bilateral hilar lymphadenopathy is demonstrated. What is the next best step in evaluation?

   1. Cervical mediastinoscopy

   2. EBUS-guided biopsy

   3. Surgical lung biopsy

   4. Observation

Answers are provided at the end of the article.

DISCUSSION

Melanoma is the deadliest form of skin cancer and results from the uncontrolled division of melanocytes. A common risk factor for the development of melanoma is a genetic mutation. More than half of the patient population with malignant melanoma has a mutation at the BRAF V600 gene.¹

BRAF inhibitors, such as vemurafenib, dabrafenib, and encorafenib, are a class of targeted therapies used in the treatment of melanoma patients with the BRAF V600 mutation.² The B-Raf proto-oncogene (BRAF) is part of the mitogen-activated protein kinases (MAPK) pathway and plays a key role in regulating cellular growth and survival.³ Activating mutations in the BRAF gene result in continuous downstream activation of the MAPK cascade, leading to uncontrolled cell proliferation and malignant transformation.⁴ Patients with this mutation have historically had a poor prognosis; however, BRAF inhibitor therapy targets these pathways, thereby interfering with the MAPK signaling pathway that regulates the proliferation and survival of these melanoma cells.¹ BRAF inhibitors are the standard of care in the treatment of advanced BRAF-mutated malignant melanoma and are generally well tolerated.

In rare cases, an adverse effect involving granulomatous lymphadenopathy may occur as a side effect of certain tyrosine kinase inhibitors.⁵ Recent literature has demonstrated an association between BRAF inhibitor therapy and sarcoidosis/sarcoid-like reactions. This case report discusses a patient on BRAF inhibitor therapy who developed mediastinal lymphadenopathy with necrotizing granulomatous disease.

Previous literature has documented the association between BRAF inhibitors and granuloma development, frequently described as “sarcoid-like reactions.”⁶ Skin rashes and papules are a common manifestation of granuloma development; however, pulmonary manifestations have also been documented with the use of BRAF/MEK inhibitors. EBUS is a minimally invasive technique that enables the diagnosis of mediastinal pathology.⁷ In this patient, EBUS demonstrated necrotizing granulomatous disease without evidence of malignancy. Optimal therapy for BRAF inhibitor-associated granulomatous lymphadenopathy is not clear. Systemic steroid therapy is occasionally used, but the efficacy of this therapy is unclear. With this patient, a trial of prednisone along with holding of the BRAF inhibitor therapy was performed with radiographic decrease in the size of mediastinal lymphadenopathy on follow-up CT. In clinical follow-up, this patient remains asymptomatic off systemic steroid and BRAF therapy.

Although cutaneous manifestations of noncaseating granulomas are well documented, the incidence of mediastinal necrotizing granulomatous disease appears much less frequently. While not completely understood, proposed pathophysiological mechanisms include upregulation of downstream MAPK proteins from RAF. Strong overexpression of MAP kinases has previously been observed in pyogenic granulomas, suggesting that cotreatment with dual BRAF and MEK inhibitors may be beneficial in preventing the development of necrotizing granulomatous reactions. In a somewhat paradoxical finding, the development of a granulomatous reaction in BRAF-inhibitor therapy may be a patient characteristic associated with a positive tumor response.

Evolution and management of necrotizing granulomatous disease involving the mediastinum can be challenging, as the differential diagnosis includes both infectious and neoplastic etiologies. In addition to tissue biopsy and culture to assess for infections (fungal and mycobacterial), laboratory evaluations for serum angiotensin-converting enzyme, hepatic and renal function, and calcium level may be useful in establishing a definitive diagnosis. An initial minimally invasive approach may be favorable, including diagnostic bronchoscopy for culture acquisition and EBUS-guided tissue sampling to facilitate histopathologic evaluation of mediastinal lymphadenopathy.

ANSWERS TO CLINICAL QUESTIONS

Question 1, c. When needed, proto-oncogenes will stimulate necessary cell proliferation. However, with a gain-of-function mutation in one allele of a proto-oncogene, the proto-oncogene will become an oncogene, allowing unregulated cell proliferation and increasing the risk of cancer. BRAF is an oncogene that encodes B-raf, a serine/threonine kinase involved in the MAPK pathway. About 60% of all melanomas involve the BRAF oncogene,⁸ with the V600E mutation being the most common mutation.

Question 2, b. EBUS-guided biopsy has a pooled diagnostic accuracy of 79% and is a minimally invasive test for establishing the diagnosis of sarcoidosis.⁹ EBUS–transbronchial needle aspiration should be performed in this patient to confirm the suspected diagnosis of sarcoidosis. If a diagnosis was not obtained by EBUS-transbronchial needle aspiration, then cervical mediastinoscopy could be considered. Cervical mediastinoscopy and surgical lung biopsy are incorrect as the next step in evaluation because they are invasive techniques without a significant increase in diagnostic accuracy. Observation is incorrect because a diagnosis needs to be established in this patient with progressive symptoms.

Disclosure statement/Funding

The authors report no funding or conflict of interest. The patient provided written permission to publish the case.

DISCLOSURE STATEMENT

The authors report no funding or conflict of interest. The patient provided written permission to publish the case.