|Year : 2022 | Volume
| Issue : 2 | Page : 138-142
BRAF/Mitogen-activated extracellular signal-related kinase inhibitors induced sarcoid-like reaction in patients with refractory localized conjunctival melanoma: A rare case report
Susan Kennedy1, Karina Kulakova1, John Crown2
1 National Ophthalmic Pathology Laboratory, Royal Victoria Eye and Ear Hospital; Research Foundation, Royal Victoria Eye and Ear Hospital, Dublin, Ireland; School of Biotechnology, Dublin City University, Dublin, Ireland
2 Department of Oncology, St. Vincent's University Hospital, Dublin, Ireland
|Date of Submission||20-Jun-2022|
|Date of Decision||11-Aug-2022|
|Date of Acceptance||04-Oct-2022|
|Date of Web Publication||06-Feb-2023|
Dr. Susan Kennedy
National Ophthalmic Pathology Laboratory, Royal Victoria Eye and Ear Hospital, Adelaide Road, Dublin 2
Source of Support: None, Conflict of Interest: None
We present a rare case of a patient with refractory localized conjunctival melanoma (CM) who was treated with BRAF/mitogen-activated extracellular signal-related kinase inhibitors in the absence of systemic metastasis. The patient had complete remission and developed a local sarcoid-like reaction. To our knowledge, this is the first report of this complication in a patient with locally advanced CM which emphasizes the local complication of BRAF inhibition.
Keywords: BRAF/mitogen-activated extracellular signal-related kinase inhibition, conjunctival melanoma, dabrafenib, sarcoid-like reaction, trametinib
|How to cite this article:|
Kennedy S, Kulakova K, Crown J. BRAF/Mitogen-activated extracellular signal-related kinase inhibitors induced sarcoid-like reaction in patients with refractory localized conjunctival melanoma: A rare case report. J Precis Oncol 2022;2:138-42
|How to cite this URL:|
Kennedy S, Kulakova K, Crown J. BRAF/Mitogen-activated extracellular signal-related kinase inhibitors induced sarcoid-like reaction in patients with refractory localized conjunctival melanoma: A rare case report. J Precis Oncol [serial online] 2022 [cited 2023 Mar 28];2:138-42. Available from: https://www.jprecisiononcology.com//text.asp?2022/2/2/138/369209
| Introduction|| |
Conjunctival melanoma (CM) is a rare tumor with an unpredictable course. The US incidence using the Surveillance, Epidemiology, and End Results database is 0.53 per 100,000. The European crude incidence is 0.46 per 100,000 with an overall 5-year survival of 83.5%. There is a local recurrence rate of up to 50% at 10 years and a metastatic rate of 25. There is no standard therapy for advanced CM. CM is a genetically distinct type of melanoma that has more similarities to cutaneous melanoma than uveal/mucosal melanoma.
The BRAF mutation was discovered in cutaneous melanoma in 2002 and occurs in up to 50% of CM, although not associated with a worse prognosis.,, The ability to specifically target the BRAF mutation therapeutically has revolutionized the treatment of metastatic BRAF mutant melanoma. Mitogen-activated extracellular signal-related kinase (MEK) inhibitors are now used in conjunction with BRAF inhibitors to prevent the reactivation of mitogen-activated protein kinase (MAPK). MAPK is involved in the mechanism of resistance to monotherapy with BRAF inhibitors. In January 2014, the combination of dabrafenib and trametinib (BRAF and MEK inhibitors, respectively) was Food and Drug Administration-approved. Since its approval, BRAF/MEK inhibition has become the standard of care for patients with unresectable or metastatic BRAF-mutant melanoma. It is generally well tolerated with limited adverse effects. A sarcoid-like reaction (SLR) is a known side effect of immune checkpoint inhibition therapy. We report a case of an SLR induced by treatment with dabrafenib and trametinib in a patient whose locally recurrent CM totally regressed during treatment.
| Case Report|| |
A Caucasian female in her 17th decade of life presented to an external hospital in 2017 with an 8-month history of right conjunctival irritation. On examination, she had densely pigmented conjunctival areas in her inferior and superior bulbar conjunctiva, with associated conjunctival injection. Her past medical history was notable for a remote history of breast carcinoma. This remains in remission up to the current date.
The patient underwent an incisional biopsy of the pigmented areas located in the inferior and superior conjunctiva. Histology identified conjunctival mucosa showing primary acquired melanosis (PAM) with atypia extending to the resection edge and invasive melanoma with associated lymphoid infiltrate extending to deep margin (approximately 0.45 mm in depth) and free of radial margins.
Further excision of the pigmented areas confirmed in situ and invasive malignant melanoma, maximum Breslow thickness of 3.4 mm in the bulbar conjunctiva and 1.2 mm in the upper tarsal plate. Several recurrences occurred over the next 2 years. These were treated with excision, cryo freeze, and local mitomycin C. There was a gap of 6–8 weeks before there was a further recurrence. This included pigmentation of the plica and both the bulbar and tarsal conjunctiva. A total of 14 procedures were carried out over the 2 years. Her left eye remained unaffected.
The patient was referred to the Royal Victoria Eye and Ear Hospital in 2019 to assist with a future treatment plan. On examination, her visual acuity was 6/36 OD. There were areas of flat pigmentation and some amelanotic areas along the limbus, with a suspicious amelanotic area in the superior fornix temporally and centrally in the upper tarsal conjunctiva. The patient underwent three biopsies of the 7–9 o'clock limbal conjunctiva and 10–1 o'clock limbal conjunctiva and central upper tarsal conjunctiva. They all demonstrated melanoma in situ with a microscopic focus of invasive melanoma at the 1 o'clock limbal area. A magnetic resonance imaging of the head and neck showed no evidence of metastatic disease. The patient was commenced on mitomycin C 0.04% for three cycles.
A COBAS® NRAS/BRAF Mutation Test of the invasive tumor revealed an activating BRAF V600E mutation. The treatment options presented to the patient to prevent further recurrences included proton beam radiotherapy, immunotherapy, and exenteration. In conjunction with medical oncology, a decision was made to commence immunotherapy with BRAF/MEK inhibition therapy using a combination of dabrafenib and trametinib. One month into her treatment course, she developed a local painful inflammatory reaction. Her C-reactive protein level was 15.6 (upper limit of normal <5). As a result, dabrafenib and trametinib dosage was decreased. Regular checkups showed no evidence of recurrence, no pigmentation, or lymphadenopathy. While the patient felt there was an improvement throughout the course, she was using lubricants very frequently – Hylo-Forte daily and Hylo Night for painful dry eyes.
Eight months after commencing treatment, she complained of severe ocular pain and a decrease in vision. On examination, her visual acuity was 6/60 OD with the development of symblepharon. This was followed by an emergency exenteration of her right eye a week later to attempt local control and symptom relief.
Detailed histopathology of the exenteration specimen showed no evidence of any residual melanocytic proliferation in the tarsal or bulbar conjunctiva. A florid coalescent granulomatous inflammation replaced much of the lacrimal gland. In addition, multiple conjunctival sarcoid-type nodules were present beneath the epithelium of both the bulbar and tarsal conjunctiva. The patient remains comfortable postexenteration. Her examination and most recent CT scan (2022) show no evidence of metastatic disease. She has given us permission to discuss her case.
| Discussion|| |
This case is an example of rapidly progressive conjunctival PAM with atypia in a patient who experienced numerous recurrences. Histopathology confirmed both in situ and invasive CM. The use of BRAF/MEK inhibition therapy was used to provide local control. While she did not experience any recurrences throughout the treatment, she developed a severe inflammatory reaction in the primary tumor location. The patient required exenteration to relieve pain and scarring and prevent the development of metastasis. The patient's chest X-ray was clear before the treatment and there was no clinical evidence of sarcoidosis. We postulate that the local SLR was induced by the BRAF/MEK inhibitors dabrafenib and trametinib acting at the tumor site. Mitomycin C may also have had a role in the symblepharon and pain due to dry eye.
There is no approved single standard treatment for refractory CM., Immunotherapy and molecular-targeted therapies have been used for unresectable skin or mucosal melanoma in stage 2 or higher stage disease. Their ability to target specific proliferative mechanisms and reduce resistance has revolutionized treatment options and overall patient outcomes. The combination of BRAF and MEK inhibitors is one such therapy. BRAF is part of the MAPK pathway and plays a key role in the regulation of cellular growth and survival. Activating mutations in the BRAF gene result in continuous downstream activation of the MAPK cascade including MEK, leading to uncontrolled cell proliferation and malignant transformation. BRAF inhibition provides significant antitumor activity in BRAF-mutated melanoma. A systematic Cochrane review reported that combinations of BRAF and MEK inhibitors have superior efficacy to chemotherapy, have a synergistic effect, and can delay the development of acquired resistance. Guidelines provided by American society of clinical oncology (ASCO) advise that combinations of dabrafenib and trametinib or nivolumab or pembrolizumab can be offered to patients with stage 3 or unresectable or metastatic melanoma of skin or mucosal site. Rossi et al. report on the use of these drugs specifically in BRAF-mutant metastatic CM. The ASCO guidelines note that switching between BRAF/MEK inhibitor combinations can be a reasonable strategy if patients develop toxicity. The COMBI-AD trial of dabrafenib and trametinib versus placebo for skin melanoma found significant improvement in relapse-free survival and overall survival with a minimum 3-year follow-up in patients with BRAF-mutant melanoma. However, severe treatment-related toxicity is higher with dabrafenib (41%) compared to nivolumab (14.4%) and pembrolizumab (14.7%). The discontinuation rate in the COMBI-AD trial was 26% compared to 8.1% in Checkmate and 10% in Keynote trials. There are approximately 20 reports,,,,,,,,,,,,,,, on sarcoid reactions following dabrafenib and trametinib to date, as seen in [Table 1]. The majority are confined to the skin, but granulomatous uveitis and vitritis requiring steroid therapy, nephritis, hepatitis, and fatal granulomatous carditis, and have been described. There are three reports of hilar and mediastinal node involvement and one report of salivary and mediastinal node involvement. Where detailed, these reports are posttreatment for cutaneous melanoma. In our patient's case, the reaction appears confined to the right conjunctiva, the primary tumor location, and the lacrimal gland without evidence of salivary gland involvement.
|Table 1: Cases of sarcoid-like reaction induced by a combination of dabrafenib and trametinib in patients|
Click here to view
Patients treated with MAPK inhibitors have increased TNF-alpha and IFN-gamma serum levels which are associated with granuloma formation. It has been hypothesized that granulomatous reactions could be a paradoxical autoimmune response to BRAF inhibition through CD8-positive T-cell infiltration and PDL1 expression.
| Conclusion|| |
We found this case very interesting because the literature is limited on the use of these drugs in progressive localized CM. We postulate that the synergistic effects of mitomycin C and BRAF/MEK inhibitors could both have contributed to severe ocular pain due to dry eye. The granulomatous reaction apparently confined to the site of the primary tumor and local lacrimal gland along with complete regression of atypical melanocytic hyperplasia (PAM) is intriguing and supports the use of carefully monitored and titrated treatment of BRAF/MEK inhibitors in rapidly progressive BRAF-mutant melanocytic neoplasia of the conjunctiva.
Declaration of patient consent
The authors certify that they obtained all appropriate patient consent forms in which the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published, and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Hu DN, Yu G, McCormick SA, Finger PT. Population-based incidence of conjunctival melanoma in various races and ethnic groups and comparison with other melanomas. Am J Ophthalmol 2008;145:418-23.
Virgili G, Parravano M, Gatta G, Capocaccia R, Mazzini C, Mallone S, et al.
Incidence and survival of patients with conjunctival melanoma in Europe. JAMA Ophthalmol 2020;138:601-8.
Shields CL, Markowitz JS, Belinsky I, Schwartzstein H, George NS, Lally SE, et al.
Conjunctival melanoma: Outcomes based on tumor origin in 382 consecutive cases. Ophthalmology 2011;118:389-95.e1.
Rossi E, Maiorano BA, Pagliara MM, Sammarco MG, Dosa T, Martini M, et al.
Dabrafenib and trametinib in BRAF mutant metastatic conjunctival melanoma. Front Oncol 2019;9:232.
Rossi E, Schinzari G, Maiorano BA, Pagliara MM, Di Stefani A, Bria E, et al.
Conjunctival melanoma: Genetic and epigenetic insights of a distinct type of melanoma. Int J Mol Sci 2019;20:5447.
Kaštelan S, Gverović Antunica A, Beketić Orešković L, Salopek Rabatić J, Kasun B, Bakija I. Conjunctival melanoma – Epidemiological trends and features. Pathol Oncol Res 2018;24:787-96.
Spendlove HE, Damato BE, Humphreys J, Barker KT, Hiscott PS, Houlston RS. BRAF mutations are detectable in conjunctival but not uveal melanomas. Melanoma Res 2004;14:449-52.
Larsen AC, Dahl C, Dahmcke CM, Lade-Keller J, Siersma VD, Toft PB, et al.
BRAF mutations in conjunctival melanoma: Investigation of incidence, clinicopathological features, prognosis and paired premalignant lesions. Acta Ophthalmol 2016;94:463-70.
Manzano JL, Layos L, Bugés C, de Los Llanos Gil M, Vila L, Martínez-Balibrea E, et al.
Resistant mechanisms to BRAF inhibitors in melanoma. Ann Transl Med 2016;4:237.
Grimes JM, Shah NV, Samie FH, Carvajal RD, Marr BP. Conjunctival melanoma: Current treatments and future options. Am J Clin Dermatol 2020;21:371-81.
Zeng Y, Hu C, Shu L, Pan Y, Zhao L, Pu X, et al.
Clinical treatment options for early-stage and advanced conjunctival melanoma. Surv Ophthalmol 2021;66:461-70.
Mandalà M, Voit C. Targeting BRAF in melanoma: Biological and clinical challenges. Crit Rev Oncol Hematol 2013;87:239-55.
Pasquali S, Hadjinicolaou AV, Chiarion Sileni V, Rossi CR, Mocellin S. Systemic treatments for metastatic cutaneous melanoma. Cochrane Database Syst Rev 2018;2:CD011123.
Seth R, Messersmith H, Kaur V, Kirkwood JM, Kudchadkar R, McQuade JL, et al.
Systemic therapy for melanoma: ASCO guideline. J Clin Oncol 2020;38:3947-70.
Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, et al.
Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med 2017;377:1813-23.
Green JS, Norris DA, Wisell J. Novel cutaneous effects of combination chemotherapy with BRAF and MEK inhibitors: A report of two cases. Br J Dermatol 2013;169:172-6.
Park JJ, Hawryluk EB, Tahan SR, Flaherty K, Kim CC. Cutaneous granulomatous eruption and successful response to potent topical steroids in patients undergoing targeted BRAF inhibitor treatment for metastatic melanoma. JAMA Dermatol 2014;150:307-11.
Jansen YJ, Janssens P, Hoorens A, Schreuer MS, Seremet T, Wilgenhof S, et al.
Granulomatous nephritis and dermatitis in a patient with BRAF V600E mutant metastatic melanoma treated with dabrafenib and trametinib. Melanoma Res 2015;25:550-4.
Garrido MC, Gutierrez C, Riveiro-Falkenbach E, Ortiz P, Rodriguez-Peralto JL. BRAF inhibitor-induced antitumoral granulomatous dermatitis eruption in advanced melanoma. Am J Dermatopathol 2015;37:795-8.
Ramani NS, Curry JL, Kapil J, Rapini RP, Tetzlaff MT, Prieto VG, et al.
Panniculitis with necrotizing granulomata in a patient on BRAF inhibitor (Dabrafenib) therapy for metastatic melanoma. Am J Dermatopathol 2015;37:e96-9.
Winkler JK, Buder-Bakhaya K, Ellert E, Herpel E, Martens UM, Enk A, et al.
Acute heart failure as a result of granulomatous myocarditis: Case report on a patient with metastatic melanoma treated with dabrafenib and trametinib. J Eur Acad Dermatol Venereol 2018;32:e31-2.
Rueda-Rueda T, Sánchez-Vicente JL, Moruno-Rodríguez A, Molina-Socola FE, Martínez-Borrego AC, López-Herrero F. Uveitis and serous retinal detachment secondary to systemic dabrafenib and trametinib. Arch Soc Esp Oftalmol (Engl Ed) 2018;93:458-62.
Dimitriou F, Frauchiger AL, Urosevic-Maiwald M, Naegeli MC, Goldinger SM, Barysch M, et al.
Sarcoid-like reactions in patients receiving modern melanoma treatment. Melanoma Res 2018;28:230-6.
Giet G, Lebas E, Rorive A, Arrese JE, Nikkels AF. Granulomatous reactions from tattoos following BRAF inhibitor therapy. Case Rep Dermatol 2019;11:101-7.
Huynh S, Lheure C, Franck N, Goldman-Lévy G, Aractingi S, Dupin N, et al.
Induced sarcoid-like reactions in patients with metastatic melanoma treated with dabrafenib and trametinib: A monocentric retrospective study. Melanoma Res 2020;30:317-20.
Boutros A, Schiavi C, Cecchi F, Spagnolo F, Guadagno A, Tanda ET, et al.
Case report: Immune-related toxicity during adjuvant treatment with BRAF plus MEK inhibitors in a melanoma patient. Front Immunol 2020;11:579523.
Tijtgat J, Schwarze JK, Awada G, Neyns B, Aspeslagh S. Sarcoid-like reaction in a BRAF V600E-mutated metastatic melanoma patient during treatment with BRAF/MEK-targeted therapy. Melanoma Res 2021;31:272-6.
Assan F, Schlemmer F, Assie JB, Mahevas M, Sustronck P, Ortonne N, et al.
Atypical systemic sarcoid-like granulomatosis in two patients treated with BRAF and MEK inhibitors. Eur J Dermatol 2019;29:556-7.
Lheure C, Kramkimel N, Franck N, Laurent-Roussel S, Carlotti A, Queant A, et al.
Sarcoidosis in patients treated with vemurafenib for metastatic melanoma: A paradoxical autoimmune activation. Dermatology 2015;231:378-84.
Pham JP, Star P, Phan K, Loh Y, Joshua AM, Smith A. BRAF inhibition and the spectrum of granulomatous reactions. J Am Acad Dermatol 2022;87:605-13.
Bala VM, Mitsogianni M, Laschos K, Pliakou E, Lazaridi E, Lampropoulou DI, et al.
Mediastinal and hilar sarcoid-like reaction in a patient treated with dabrafenib and trametinib for metastatic melanoma: A case report and review of the literature. Mol Clin Oncol 2022;16:99.
Wilmott JS, Haydu LE, Menzies AM, Lum T, Hyman J, Thompson JF, et al.
Dynamics of chemokine, cytokine, and growth factor serum levels in BRAF-mutant melanoma patients during BRAF inhibitor treatment. J Immunol 2014;192:2505-13.
Rubio-Rivas M, Moreira C, Marcoval J. Sarcoidosis related to checkpoint and BRAF/MEK inhibitors in melanoma. Autoimmun Rev 2020;19:102587.