Research
Case Report/Case Series
Cutaneous Granulomatous Eruption and Successful Response to Potent Topical Steroids in Patients Undergoing Targeted BRAF Inhibitor Treatment for Metastatic Melanoma June J. Park, BS; Elena B. Hawryluk, MD, PhD; Steven R. Tahan, MD; Keith Flaherty, MD; Caroline C. Kim, MD
IMPORTANCE Targeted BRAF inhibitor therapy (vemurafenib, dabrafenib) is an effective,
novel treatment for patients with metastatic melanoma with the V600E BRAF mutation. This therapy is associated with squamous cell carcinomas and keratoacanthomas. Granulomatous eruptions have not been previously reported. OBSERVATIONS Two patients with melanoma developed cutaneous granulomatous eruptions during targeted BRAF inhibitor therapy. In case 1, after 2 months of treatment with dabrafenib and trametinib (MEK inhibitor), a papular eruption concerning for progression of disease prompted cessation of treatment. After the histopathologic diagnosis of granulomas, the patient was treated with clobetasol ointment with resolution within days and resumption of therapy. In case 2, after 5 months of vemurafenib treatment, the patient developed a granulomatous eruption, which resolved 3 weeks after cessation of therapy. CONCLUSIONS AND RELEVANCE We report 2 cases of cutaneous granulomatous eruptions on treatment with targeted BRAF inhibitors, a previously unreported association. Although additional investigations are necessary to better elucidate the pathogenic mechanisms, our report includes a treatment plan that prevents unnecessary discontinuation of therapy. Given the Food and Drug Administration approval of vemurafenib for metastatic melanoma, clinicians should be aware of this possible cutaneous reaction and treatment option to optimize patient management. JAMA Dermatol. 2014;150(3):307-311. doi:10.1001/jamadermatol.2013.7919 Published online December 18, 2013.
I
n patients with advanced melanoma, mean survival time is 6 to 9 months and the 3-year survival rate is 10% to 15% historically. BRAF mutations are found in approximately 40% to 60% of melanomas, 90% of which possess a V600E point mutation.1,2 Vemurafenib, which is US Food and Drug Administration (FDA) approved for metastatic melanoma treatment, targets the driver oncogenic mutation BRAF V 6 0 0 E , a mediator in the MAPK/ERK (mitogenactivated protein kinase/extracellular signal–regulated kinase) signaling pathway that leads to cell proliferation and differentiation.2 Patients treated with vemurafenib have been reported to have a substantial overall response rate (53%) and improved median overall survival rate (15.9 months).3 However, responses to therapy may last less than 1 year, and mechanisms of resistance have recently been elucidated. 4 Ongoing clinical trials for patients with the BRAF V600E mutation include the use of MEK inhibitors together with targeted BRAF inhibition to address acquired resistance to BRAF inhibitors alone. Our 2 patients illustrate granulomas after the initiation of targeted BRAF inhibitor therapy. jamadermatology.com
Author Affiliations: Author affiliations are listed at the end of this article. Corresponding Author: Caroline C. Kim, MD, Department of Dermatology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Shapiro 2, Boston, MA 02215 (ckim3 @caregroup.harvard.edu).
Report of Cases Case 1 A woman in her 80s received a diagnosis of a 2.25-mm Breslow depth/Clark level IV nonulcerated superficial-spreading melanoma with 5 mitotic figures per high-power field on her right dorsal foot. She underwent a wide local excision and a sentinel lymph node biopsy that was negative for melanoma, and 1.5 years later, she presented with multiple pink and light brown papules 1 to 5 mm in diameter on her right leg, proximal and distal to the knee (Figure 1A). A punch biopsy confirmed metastatic melanoma, which was found to be positive for the BRAF V600E mutation, and she had no other disease on additional staging scans. The patient’s disease was staged as M1a stage IV melanoma given her distant subcutaneous disease, and she consented to and began treatment as a participant in a clinical trial of targeted BRAF inhibitor dabrafenib (GSK2118436; 75-mg oral pills twice daily) and MEK inhibitor trametinib (GSK1120212; 2-mg oral pills daily) therapy. After 1 month of treatment, the patient JAMA Dermatology March 2014 Volume 150, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Georgian Court University User on 05/14/2015
307
Research Case Report/Case Series
Granulomatous Eruptions With BRAF inhibitor Use
Figure 1. Photographs of Lower Extremity of Patient in Case 1 A
B
C
(right arrowhead). The other biopsy site of a similar papule on the right anterior lower leg is not seen on this photograph. C, Resolution of inflamed plaques, and fewer, smaller, less erythematous and indurated papules after 2 weeks of topical clobetasol treatment, revealing overall improvement of disease after BRAF inhibitor therapy.
A, Multiple erythematous and light brown 1 to 5-mm papules on the right inner knee. A biopsy of the papule circled in purple ink revealed metastatic melanoma. B, Multiple new inflamed, erythematous papules and plaques (left and middle arrowheads) in the area of original metastatic disease 2 months after initiation of BRAF inhibitor therapy. The initial biopsy site is still healing. The new biopsy site of a papule of the right medial thigh is circled in purple ink
Figure 2. Biopsy of Right Medial Thigh A
B
Biopsy of the site shown in Figure 1B revealed granulomatous inflammation around degenerated collagen in mid-reticular dermis. No melanoma cells were identified by level sections stained with hematoxylin-eosin (H&E) and melanoma antigen recognized by T cells (MART-1) immunostain (original magnification, ×40). B, Higher magnification reveals granulomas with hybrid sarcoidal and foreign body type features encircling an edematous and degenerated focus of the reticular dermis (H&E, original magnification, ×100).
had fewer and less pronounced papules in the area of her disease, demonstrating clinical response to treatment. However, after approximately 2 months of treatment, the patient presented with numerous new erythematous and violaceous, firm, 1 to 2-mm papules, as well as an erythematous, indurated 5-cm plaque around the areas of her known subcutaneous disease (Figure 1B). On the basis of the clinical appearance and distribution of the lesions, the eruption was concerning for progression of metastatic melanoma and her treatment was put on hold. Two 3-mm punch biopsies were performed, 1 biopsy on the right anterior lower leg revealing a perifollicular granulomatous inflammation (Figure 2) and the second biopsy on the right medial thigh revealing granulomatous inflammation surrounding a focus of melanoma cells highlighted by melanoma antigen recognized by T cells (MART-1) and microphthalmia transcription factor (MITF) immunostains (Figure 3). The patient was instructed to apply clobetasol ointment twice daily under occlusion with plastic wrap. One week later, 308
the patient had near-complete resolution of her new eruption revealing continued improvement of her in-transit disease, and the BRAF inhibitor and MEK inhibitor protocol treatment was resumed. After 2 weeks of topical steroid treatment, the eruption had resolved completely, and clobetasol treatment was discontinued (Figure 1C). The area of subcutaneous disease remains improved, and the patient continues to receive targeted treatment at this time after 9 months of therapy.
Case 2 A man in his 70s with a history of stage III melanoma of the right lower extremity developed a recurrence in the right groin 9 years later and underwent 1 year of high-dose interferon therapy. Five years later, he developed an enlarging right subpleural nodule with 3 enlarged hilar nodes, which on surgical resection was found to be consistent with metastatic melanoma. The patient initially consented and enrolled in a clinical trial of combined temozolamide and
JAMA Dermatology March 2014 Volume 150, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Georgian Court University User on 05/14/2015
jamadermatology.com
Granulomatous Eruptions With BRAF inhibitor Use
Case Report/Case Series Research
Figure 3. Punch Biopsy of Right Anterior Lower Leg A
B
A, Biopsy revealed metastatic melanoma with a granulomatous response in the mid-reticular dermis. The granulomas are well formed with hybrid sarcoidal and foreign body type features (hematoxylin-eosin, original magnification, ×100). B, Immunohistochemical stain for melanoma antigen recognized by T cells (MART-1) highlights numerous melanocytic cells within the granulomatous area (MART-1 immunostain, original magnification, ×100).
Figure 4. Punch Biopsy of Lower Extremity of Patient in Case 2 A
B
A, Biopsy revealed granulomas present in the reticular dermis with predilection to form around blood vessels (hematoxylin-eosin [H&E], original magnification, ×40). High magnification reveals loosely arrayed granulomas composed of histiocytes, Langerhans-type multinucleated giant cells, and lymphocytes (H&E, original magnification, ×200).
PARP (poly adenosine diphosphate ribose polymerase) inhibitor therapy, and the study medication therapy was stopped after 6 months because of progression of disease. His metastatic melanoma was determined to be positive for the BRAF V600E mutation, and he began treatment with vemurafenib on clinical trial (RO5185426; 960-mg oral pills twice daily). After 5 months of treatment, he presented with multiple asymptomatic scattered erythematous and violaceous papules scattered over his bilateral upper and lower extremities. A 4-mm punch biopsy of his right leg revealed granulomatous dermatitis with focal necrosis (Figure 4). The rash worsened over the next 3 weeks, during which the study protocol was discontinued because of progression o f m e l a n o m a s e e n o n r e p e at e d p o s it r o n e m i s s i o n tomographic/computed tomographic scan. A complete spontaneous resolution of cutaneous findings was observed approximately 3 weeks after the discontinuation of vemurafenib treatment while the patient was receiving supportive care only. He was subsequently transitioned to a regimen of ipilimumab for 6 months and then to a clinical trial of sorafenib/bortezomib for 8 months and experienced progression of disease with both study therapies. Approximately 2 years after first initiating vemurafenib treatment, the patient began rechallenge with vemurafenib (half the usual dose, ie, 480-mg dose twice daily due to general symptoms), and he did not have any recurrent granulomatous eruptions. However, his disease progressed again, and after receiving palliative therapy, he died almost 5 years after his diagnosis of stage IV disease. jamadermatology.com
Discussion Common adverse effects of targeted BRAF inhibitors include arthralgias, fatigue, nausea, and diarrhea; cutaneous effects reported include photosensitivity, follicular hyperkeratotic and/or keratosis pilaris–like rash, verruciform hyperkeratosis, squamous cell carcinomas (SCCs), keratoacanthomas, palmar-plantar erythrodysesthesia, erythema nodosum, and alterations of nevi.5 Squamous cell carcinomas and keratoacanthomas have been reported to develop in approximately 19% to 26% of patients within 2 to 36 weeks of the treatment.6 Squamous cell carcinomas in patients treated with vemurafenib have increased prevalence of HRAS mutations compared with sporadic SCC,7 which suggests a paradoxical activation of the MAPK signaling pathway induced by BRAF inhibitors, potentially by priming wild-type RAF to activate the MAPK pathway, particularly in the presence of an activating RAS mutation.8 The addition of an inhibitor of MEK, a kinase downstream of RAF, to targeted BRAF inhibition may mitigate tumor resistance and has been shown to reduce cutaneous adverse effects of BRAF inhibition, including a reduction in SCC.4,8 Although interferon and PARP inhibitors, which were used to treat the patient in case 2 prior to vemurafenib, are also known to induce immunomodulatory changes, the timing of onset of the granulomatous eruption after initiation of vemurafenib treatment and cessation of eruption after stopping the drug treatment suggests a correlation between granulomas and BRAF inhibition. To our knowledge, granulomatous erupJAMA Dermatology March 2014 Volume 150, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Georgian Court University User on 05/14/2015
309
Research Case Report/Case Series
Granulomatous Eruptions With BRAF inhibitor Use
tions in the setting of targeted BRAF inhibition have not been previously described. Granulomas are a pattern of inflammation defined as a collection of epithelioid histiocytes surrounded by giant cells and lymphocytes that develop during the body’s attempt to enclose foreign bodies or inciting agents. Tuberculosis, fungal infections, foreign material, cat-scratch disease, sarcoidosis, and Crohn disease are examples of infections and diseases with granulomatous reactions. The granulomatous inflammation is initiated by antigen-presenting cells, which activate T cells to secrete interleukin 2 (IL-2) and interferon γ, which activates additional T cells and macrophages, respectively. The activated macrophages transform into epithelioid histiocytes and giant cells. Several neoplasms, such as renal cell carcinoma and many others, including malignant lymphomas, renal cell carcinoma, nasopharyngeal carcinoma, seminoma of the testes, ovarian dysgerminoma, and melanoma have had reported associations with granulomas. Sarcoidal granulomatous reactions have also been described in patients with Hodgkin disease, non-Hodgkin lymphoma, and carcinomas. Although the pathophysiologic mechanism of granulomatous responses to neoplasms is unknown, it is hypothesized that the granulomas are caused by an aberrant cytokine release by tumor cells9 or may represent a nonspecific host response to the tumor.10 Interestingly, 2 reports have observed favorable clinical outcomes including fewer relapses and longer survival among patients with Hodgkin disease who developed granulomas, which was described as an unspecified “host response.”10,11 Similarly, Baselmans and colleagues12 reported regression of solid SL2 lymphosarcoma by a granulomatous inflammatory reaction, speculated to be IL-2 mediated. There is limited information in the literature regarding an association of granulomas and melanoma. In 1997, Robert and colleagues13 reported granulomatous reactions in 7 patients with melanoma: 3 patients with true sarcoidosis, 1 patient with tumor-associated granuloma at regional lymph node, and 3 patients with atypical tumor-associated granulomatoses believed to represent melanoma metastases. Tsunoda and colleagues14 reported a case of malignant melanoma associated with a cutaneous sarcoidal reaction, postulated to result from a T-cell–mediated immune response to a tumor. The sarcoidal granulomas resolved with treatment of the melanoma. Cutaneous and pulmonary sarcoidosis have been associated with interferon α therapy for melanoma, where authors hypothesize a similar tumor cytokine–induced and antigeninduced immune response as the pathogenesis of the reaction,15 although it is not clear whether the granulomas are an adverse effect of interferon treatment or tumor.
ARTICLE INFORMATION Accepted for Publication: August 28, 2013. Published Online: December 18, 2013. doi:10.1001/jamadermatol.2013.7919. Author Affiliations: University of Illinois College of Medicine, Chicago (Park); Department of Dermatology, Harvard Medical School, Boston, Massachusetts (Hawryluk); Department of Pathology, Beth Israel Deaconess Medical Center,
310
Although targeted BRAF inhibitors are not known to have activating effects on the immune system, we speculate that the granulomatous eruption during therapy may represent an immune response or activation against targets on melanoma cells perhaps unveiled by treatment. It is interesting that the second biopsy in case 1 revealed melanoma cells central to the granulomatous reaction (Figure 3B), suggesting that the reaction was incited by the melanoma cells. It is possible that such a response may represent a positive therapeutic response to targeted BRAF inhibition. This hypothesis poses an interesting clinical question: is it beneficial or necessary to treat this granulomatous cutaneous response in the setting of BRAF inhibitor therapy? Clinical trial protocols call for holding therapy in the setting of new-onset rash, and treatment of new-onset rashes during therapy is standard. It is possible that the granulomatous cutaneous reaction represents a positive therapeutic sign and may not need to be treated. This hypothesis requires further evaluation. The patient in case 1 continues to do well as a complete responder according to response evaluation criteria in solid tumors more than 1 year after diagnosis of metastatic disease. Although in case 2, the patient’s disease progressed after the onset of his granulomatous rash, it is still possible that his rash represented a positive response to treatment with vemurafenib, whether via a local response if there were cutaneous microscopic disease vs a systemic response to his visceral disease. The fact that he did not have the same rash on rechallenge of the drug is especially interesting in that this would argue against a drug-induced hypersensitivity-like reaction. It is notable that the patient survived almost 5 years after receiving a diagnosis of stage-IV disease. In case 1, the patient’s granulomatous eruption was treated as a noninfectious granulomatous eruption with clobetasol ointment under occlusion, which caused rapid improvement within days. The present case report, to our knowledge, is the first to describe granulomatous eruptions in the setting of targeted BRAF inhibitor therapy. We propose that granuloma formation represents immune activation toward possible melanoma regression. The cutaneous changes can be treated with potent topical steroids, thereby preventing any unnecessary discontinuation of therapy. Additional studies are warranted to explore the clinical importance of granulomatous eruptions in targeted BRAF inhibitor therapy and potential positive therapeutic outcomes. Given the FDA approval of vemurafenib as a firstline treatment for metastatic melanoma and ongoing clinical trials with other targeted BRAF inhibitors, clinicians should be aware of this possible cutaneous reaction and treatment option to help optimize patient management.
Harvard Medical School, Boston, Massachusetts (Tahan); Massachusetts General Hospital Cancer Center, Division of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston (Flaherty); Pigmented Lesion Clinic, Department of Dermatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (Kim); Cutaneous Oncology Program, Department of Dermatology, Beth Israel
Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (Kim). Author Contributions: Dr Kim and Ms Park had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Park, Tahan, Kim. Acquisition of data: All authors. Analysis and interpretation of data: Park, Tahan, Flaherty, Kim.
JAMA Dermatology March 2014 Volume 150, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Georgian Court University User on 05/14/2015
jamadermatology.com
Granulomatous Eruptions With BRAF inhibitor Use
Drafting of the manuscript: All authors. Critical revision of the manuscript for important intellectual content: Park, Tahan, Flaherty, Kim. Statistical analysis: Kim. Administrative, technical, or material support: Tahan, Flaherty, Kim. Study supervision: Kim. Conflict of Interest Disclosures: Drs Kim and Flaherty have served as consultants to Roche. Dr Flaherty has served as a consultant to GlaxoSmithKline. No other disclosures are reported. Funding/Support: Roche and GlaxoSmithKline funded the underlying clinical trials in which the patients in this report participated. Dr Kim was supported by the Kevin Reagan Memorial Fund and the Eleanor and Miles Shore/Beth Israel Deaconess Medical Center Department of Dermatology Fellowship. Role of the Sponsor: Roche and GlaxoSmithKline had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: Lauren Kovach, BA, Department of Dermatology, Beth Israel Deaconess Medical Center, provided administrative assistance. She was not compensated for her contribution.
jamadermatology.com
Case Report/Case Series Research
REFERENCES 1. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353(20):2135-2147. 2. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949-954. 3. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707-714. 4. Alcalá AM, Flaherty KT. BRAF inhibitors for the treatment of metastatic melanoma: clinical trials and mechanisms of resistance. Clin Cancer Res. 2012;18(1):33-39. 5. Manousaridis I, Mavridou S, Goerdt S, Leverkus M, Utikal J. Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management. J Eur Acad Dermatol Venereol. 2013;27(1):11-18. 6. Lacouture ME, Duvic M, Hauschild A, et al. Analysis of dermatologic events in vemurafenib-treated patients with melanoma. Oncologist. 2013;18(3):314-322. 7. Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366(3):207-215.
9. Brincker H. Sarcoid reactions in malignant tumours. Cancer Treat Rev. 1986;13(3):147-156. 10. Sacks EL, Donaldson SS, Gordon J, Dorfman RF. Epithelioid granulomas associated with Hodgkin’s disease: clinical correlations in 55 previously untreated patients. Cancer. 1978;41(2):562-567. 11. O’Connell MJ, Schimpff SC, Kirschner RH, Abt AB, Wiernik PH. Epithelioid granulomas in Hodgkin disease: a favorable prognostic sign? JAMA. 1975;233(8):886-889. 12. Baselmans AH, Koten JW, Battermann JJ, Van Dijk JE, Den Otter W. The mechanism of regression of solid SL2 lymphosarcoma after local IL-2 therapy. Cancer Immunol Immunother. 2002;51(9): 492-498. 13. Robert C, Schoenlaub P, Avril MF, et al. Malignant melanoma and granulomatosis. Br J Dermatol. 1997;137(5):787-792. 14. Tsunoda K, Onodera H, Akasaka T. Case of malignant melanoma associated with a sarcoid reaction. J Dermatol. 2011;38(9):939-942. 15. Suárez-García C, Pérez-Gil A, Pereira-Gallardo S, Codes-Villena M, García-Escudero A, Miguel Camacho F. Interferon-induced cutaneous sarcoidosis in melanoma. Melanoma Res. 2009;19(6):391-394.
8. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18): 1694-1703.
JAMA Dermatology March 2014 Volume 150, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Georgian Court University User on 05/14/2015
311
Case Report/Case Series
Cutaneous Granulomatous Eruption and Successful Response to Potent Topical Steroids in Patients Undergoing Targeted BRAF Inhibitor Treatment for Metastatic Melanoma June J. Park, BS; Elena B. Hawryluk, MD, PhD; Steven R. Tahan, MD; Keith Flaherty, MD; Caroline C. Kim, MD
IMPORTANCE Targeted BRAF inhibitor therapy (vemurafenib, dabrafenib) is an effective,
novel treatment for patients with metastatic melanoma with the V600E BRAF mutation. This therapy is associated with squamous cell carcinomas and keratoacanthomas. Granulomatous eruptions have not been previously reported. OBSERVATIONS Two patients with melanoma developed cutaneous granulomatous eruptions during targeted BRAF inhibitor therapy. In case 1, after 2 months of treatment with dabrafenib and trametinib (MEK inhibitor), a papular eruption concerning for progression of disease prompted cessation of treatment. After the histopathologic diagnosis of granulomas, the patient was treated with clobetasol ointment with resolution within days and resumption of therapy. In case 2, after 5 months of vemurafenib treatment, the patient developed a granulomatous eruption, which resolved 3 weeks after cessation of therapy. CONCLUSIONS AND RELEVANCE We report 2 cases of cutaneous granulomatous eruptions on treatment with targeted BRAF inhibitors, a previously unreported association. Although additional investigations are necessary to better elucidate the pathogenic mechanisms, our report includes a treatment plan that prevents unnecessary discontinuation of therapy. Given the Food and Drug Administration approval of vemurafenib for metastatic melanoma, clinicians should be aware of this possible cutaneous reaction and treatment option to optimize patient management. JAMA Dermatol. 2014;150(3):307-311. doi:10.1001/jamadermatol.2013.7919 Published online December 18, 2013.
I
n patients with advanced melanoma, mean survival time is 6 to 9 months and the 3-year survival rate is 10% to 15% historically. BRAF mutations are found in approximately 40% to 60% of melanomas, 90% of which possess a V600E point mutation.1,2 Vemurafenib, which is US Food and Drug Administration (FDA) approved for metastatic melanoma treatment, targets the driver oncogenic mutation BRAF V 6 0 0 E , a mediator in the MAPK/ERK (mitogenactivated protein kinase/extracellular signal–regulated kinase) signaling pathway that leads to cell proliferation and differentiation.2 Patients treated with vemurafenib have been reported to have a substantial overall response rate (53%) and improved median overall survival rate (15.9 months).3 However, responses to therapy may last less than 1 year, and mechanisms of resistance have recently been elucidated. 4 Ongoing clinical trials for patients with the BRAF V600E mutation include the use of MEK inhibitors together with targeted BRAF inhibition to address acquired resistance to BRAF inhibitors alone. Our 2 patients illustrate granulomas after the initiation of targeted BRAF inhibitor therapy. jamadermatology.com
Author Affiliations: Author affiliations are listed at the end of this article. Corresponding Author: Caroline C. Kim, MD, Department of Dermatology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Shapiro 2, Boston, MA 02215 (ckim3 @caregroup.harvard.edu).
Report of Cases Case 1 A woman in her 80s received a diagnosis of a 2.25-mm Breslow depth/Clark level IV nonulcerated superficial-spreading melanoma with 5 mitotic figures per high-power field on her right dorsal foot. She underwent a wide local excision and a sentinel lymph node biopsy that was negative for melanoma, and 1.5 years later, she presented with multiple pink and light brown papules 1 to 5 mm in diameter on her right leg, proximal and distal to the knee (Figure 1A). A punch biopsy confirmed metastatic melanoma, which was found to be positive for the BRAF V600E mutation, and she had no other disease on additional staging scans. The patient’s disease was staged as M1a stage IV melanoma given her distant subcutaneous disease, and she consented to and began treatment as a participant in a clinical trial of targeted BRAF inhibitor dabrafenib (GSK2118436; 75-mg oral pills twice daily) and MEK inhibitor trametinib (GSK1120212; 2-mg oral pills daily) therapy. After 1 month of treatment, the patient JAMA Dermatology March 2014 Volume 150, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Georgian Court University User on 05/14/2015
307
Research Case Report/Case Series
Granulomatous Eruptions With BRAF inhibitor Use
Figure 1. Photographs of Lower Extremity of Patient in Case 1 A
B
C
(right arrowhead). The other biopsy site of a similar papule on the right anterior lower leg is not seen on this photograph. C, Resolution of inflamed plaques, and fewer, smaller, less erythematous and indurated papules after 2 weeks of topical clobetasol treatment, revealing overall improvement of disease after BRAF inhibitor therapy.
A, Multiple erythematous and light brown 1 to 5-mm papules on the right inner knee. A biopsy of the papule circled in purple ink revealed metastatic melanoma. B, Multiple new inflamed, erythematous papules and plaques (left and middle arrowheads) in the area of original metastatic disease 2 months after initiation of BRAF inhibitor therapy. The initial biopsy site is still healing. The new biopsy site of a papule of the right medial thigh is circled in purple ink
Figure 2. Biopsy of Right Medial Thigh A
B
Biopsy of the site shown in Figure 1B revealed granulomatous inflammation around degenerated collagen in mid-reticular dermis. No melanoma cells were identified by level sections stained with hematoxylin-eosin (H&E) and melanoma antigen recognized by T cells (MART-1) immunostain (original magnification, ×40). B, Higher magnification reveals granulomas with hybrid sarcoidal and foreign body type features encircling an edematous and degenerated focus of the reticular dermis (H&E, original magnification, ×100).
had fewer and less pronounced papules in the area of her disease, demonstrating clinical response to treatment. However, after approximately 2 months of treatment, the patient presented with numerous new erythematous and violaceous, firm, 1 to 2-mm papules, as well as an erythematous, indurated 5-cm plaque around the areas of her known subcutaneous disease (Figure 1B). On the basis of the clinical appearance and distribution of the lesions, the eruption was concerning for progression of metastatic melanoma and her treatment was put on hold. Two 3-mm punch biopsies were performed, 1 biopsy on the right anterior lower leg revealing a perifollicular granulomatous inflammation (Figure 2) and the second biopsy on the right medial thigh revealing granulomatous inflammation surrounding a focus of melanoma cells highlighted by melanoma antigen recognized by T cells (MART-1) and microphthalmia transcription factor (MITF) immunostains (Figure 3). The patient was instructed to apply clobetasol ointment twice daily under occlusion with plastic wrap. One week later, 308
the patient had near-complete resolution of her new eruption revealing continued improvement of her in-transit disease, and the BRAF inhibitor and MEK inhibitor protocol treatment was resumed. After 2 weeks of topical steroid treatment, the eruption had resolved completely, and clobetasol treatment was discontinued (Figure 1C). The area of subcutaneous disease remains improved, and the patient continues to receive targeted treatment at this time after 9 months of therapy.
Case 2 A man in his 70s with a history of stage III melanoma of the right lower extremity developed a recurrence in the right groin 9 years later and underwent 1 year of high-dose interferon therapy. Five years later, he developed an enlarging right subpleural nodule with 3 enlarged hilar nodes, which on surgical resection was found to be consistent with metastatic melanoma. The patient initially consented and enrolled in a clinical trial of combined temozolamide and
JAMA Dermatology March 2014 Volume 150, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Georgian Court University User on 05/14/2015
jamadermatology.com
Granulomatous Eruptions With BRAF inhibitor Use
Case Report/Case Series Research
Figure 3. Punch Biopsy of Right Anterior Lower Leg A
B
A, Biopsy revealed metastatic melanoma with a granulomatous response in the mid-reticular dermis. The granulomas are well formed with hybrid sarcoidal and foreign body type features (hematoxylin-eosin, original magnification, ×100). B, Immunohistochemical stain for melanoma antigen recognized by T cells (MART-1) highlights numerous melanocytic cells within the granulomatous area (MART-1 immunostain, original magnification, ×100).
Figure 4. Punch Biopsy of Lower Extremity of Patient in Case 2 A
B
A, Biopsy revealed granulomas present in the reticular dermis with predilection to form around blood vessels (hematoxylin-eosin [H&E], original magnification, ×40). High magnification reveals loosely arrayed granulomas composed of histiocytes, Langerhans-type multinucleated giant cells, and lymphocytes (H&E, original magnification, ×200).
PARP (poly adenosine diphosphate ribose polymerase) inhibitor therapy, and the study medication therapy was stopped after 6 months because of progression of disease. His metastatic melanoma was determined to be positive for the BRAF V600E mutation, and he began treatment with vemurafenib on clinical trial (RO5185426; 960-mg oral pills twice daily). After 5 months of treatment, he presented with multiple asymptomatic scattered erythematous and violaceous papules scattered over his bilateral upper and lower extremities. A 4-mm punch biopsy of his right leg revealed granulomatous dermatitis with focal necrosis (Figure 4). The rash worsened over the next 3 weeks, during which the study protocol was discontinued because of progression o f m e l a n o m a s e e n o n r e p e at e d p o s it r o n e m i s s i o n tomographic/computed tomographic scan. A complete spontaneous resolution of cutaneous findings was observed approximately 3 weeks after the discontinuation of vemurafenib treatment while the patient was receiving supportive care only. He was subsequently transitioned to a regimen of ipilimumab for 6 months and then to a clinical trial of sorafenib/bortezomib for 8 months and experienced progression of disease with both study therapies. Approximately 2 years after first initiating vemurafenib treatment, the patient began rechallenge with vemurafenib (half the usual dose, ie, 480-mg dose twice daily due to general symptoms), and he did not have any recurrent granulomatous eruptions. However, his disease progressed again, and after receiving palliative therapy, he died almost 5 years after his diagnosis of stage IV disease. jamadermatology.com
Discussion Common adverse effects of targeted BRAF inhibitors include arthralgias, fatigue, nausea, and diarrhea; cutaneous effects reported include photosensitivity, follicular hyperkeratotic and/or keratosis pilaris–like rash, verruciform hyperkeratosis, squamous cell carcinomas (SCCs), keratoacanthomas, palmar-plantar erythrodysesthesia, erythema nodosum, and alterations of nevi.5 Squamous cell carcinomas and keratoacanthomas have been reported to develop in approximately 19% to 26% of patients within 2 to 36 weeks of the treatment.6 Squamous cell carcinomas in patients treated with vemurafenib have increased prevalence of HRAS mutations compared with sporadic SCC,7 which suggests a paradoxical activation of the MAPK signaling pathway induced by BRAF inhibitors, potentially by priming wild-type RAF to activate the MAPK pathway, particularly in the presence of an activating RAS mutation.8 The addition of an inhibitor of MEK, a kinase downstream of RAF, to targeted BRAF inhibition may mitigate tumor resistance and has been shown to reduce cutaneous adverse effects of BRAF inhibition, including a reduction in SCC.4,8 Although interferon and PARP inhibitors, which were used to treat the patient in case 2 prior to vemurafenib, are also known to induce immunomodulatory changes, the timing of onset of the granulomatous eruption after initiation of vemurafenib treatment and cessation of eruption after stopping the drug treatment suggests a correlation between granulomas and BRAF inhibition. To our knowledge, granulomatous erupJAMA Dermatology March 2014 Volume 150, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Georgian Court University User on 05/14/2015
309
Research Case Report/Case Series
Granulomatous Eruptions With BRAF inhibitor Use
tions in the setting of targeted BRAF inhibition have not been previously described. Granulomas are a pattern of inflammation defined as a collection of epithelioid histiocytes surrounded by giant cells and lymphocytes that develop during the body’s attempt to enclose foreign bodies or inciting agents. Tuberculosis, fungal infections, foreign material, cat-scratch disease, sarcoidosis, and Crohn disease are examples of infections and diseases with granulomatous reactions. The granulomatous inflammation is initiated by antigen-presenting cells, which activate T cells to secrete interleukin 2 (IL-2) and interferon γ, which activates additional T cells and macrophages, respectively. The activated macrophages transform into epithelioid histiocytes and giant cells. Several neoplasms, such as renal cell carcinoma and many others, including malignant lymphomas, renal cell carcinoma, nasopharyngeal carcinoma, seminoma of the testes, ovarian dysgerminoma, and melanoma have had reported associations with granulomas. Sarcoidal granulomatous reactions have also been described in patients with Hodgkin disease, non-Hodgkin lymphoma, and carcinomas. Although the pathophysiologic mechanism of granulomatous responses to neoplasms is unknown, it is hypothesized that the granulomas are caused by an aberrant cytokine release by tumor cells9 or may represent a nonspecific host response to the tumor.10 Interestingly, 2 reports have observed favorable clinical outcomes including fewer relapses and longer survival among patients with Hodgkin disease who developed granulomas, which was described as an unspecified “host response.”10,11 Similarly, Baselmans and colleagues12 reported regression of solid SL2 lymphosarcoma by a granulomatous inflammatory reaction, speculated to be IL-2 mediated. There is limited information in the literature regarding an association of granulomas and melanoma. In 1997, Robert and colleagues13 reported granulomatous reactions in 7 patients with melanoma: 3 patients with true sarcoidosis, 1 patient with tumor-associated granuloma at regional lymph node, and 3 patients with atypical tumor-associated granulomatoses believed to represent melanoma metastases. Tsunoda and colleagues14 reported a case of malignant melanoma associated with a cutaneous sarcoidal reaction, postulated to result from a T-cell–mediated immune response to a tumor. The sarcoidal granulomas resolved with treatment of the melanoma. Cutaneous and pulmonary sarcoidosis have been associated with interferon α therapy for melanoma, where authors hypothesize a similar tumor cytokine–induced and antigeninduced immune response as the pathogenesis of the reaction,15 although it is not clear whether the granulomas are an adverse effect of interferon treatment or tumor.
ARTICLE INFORMATION Accepted for Publication: August 28, 2013. Published Online: December 18, 2013. doi:10.1001/jamadermatol.2013.7919. Author Affiliations: University of Illinois College of Medicine, Chicago (Park); Department of Dermatology, Harvard Medical School, Boston, Massachusetts (Hawryluk); Department of Pathology, Beth Israel Deaconess Medical Center,
310
Although targeted BRAF inhibitors are not known to have activating effects on the immune system, we speculate that the granulomatous eruption during therapy may represent an immune response or activation against targets on melanoma cells perhaps unveiled by treatment. It is interesting that the second biopsy in case 1 revealed melanoma cells central to the granulomatous reaction (Figure 3B), suggesting that the reaction was incited by the melanoma cells. It is possible that such a response may represent a positive therapeutic response to targeted BRAF inhibition. This hypothesis poses an interesting clinical question: is it beneficial or necessary to treat this granulomatous cutaneous response in the setting of BRAF inhibitor therapy? Clinical trial protocols call for holding therapy in the setting of new-onset rash, and treatment of new-onset rashes during therapy is standard. It is possible that the granulomatous cutaneous reaction represents a positive therapeutic sign and may not need to be treated. This hypothesis requires further evaluation. The patient in case 1 continues to do well as a complete responder according to response evaluation criteria in solid tumors more than 1 year after diagnosis of metastatic disease. Although in case 2, the patient’s disease progressed after the onset of his granulomatous rash, it is still possible that his rash represented a positive response to treatment with vemurafenib, whether via a local response if there were cutaneous microscopic disease vs a systemic response to his visceral disease. The fact that he did not have the same rash on rechallenge of the drug is especially interesting in that this would argue against a drug-induced hypersensitivity-like reaction. It is notable that the patient survived almost 5 years after receiving a diagnosis of stage-IV disease. In case 1, the patient’s granulomatous eruption was treated as a noninfectious granulomatous eruption with clobetasol ointment under occlusion, which caused rapid improvement within days. The present case report, to our knowledge, is the first to describe granulomatous eruptions in the setting of targeted BRAF inhibitor therapy. We propose that granuloma formation represents immune activation toward possible melanoma regression. The cutaneous changes can be treated with potent topical steroids, thereby preventing any unnecessary discontinuation of therapy. Additional studies are warranted to explore the clinical importance of granulomatous eruptions in targeted BRAF inhibitor therapy and potential positive therapeutic outcomes. Given the FDA approval of vemurafenib as a firstline treatment for metastatic melanoma and ongoing clinical trials with other targeted BRAF inhibitors, clinicians should be aware of this possible cutaneous reaction and treatment option to help optimize patient management.
Harvard Medical School, Boston, Massachusetts (Tahan); Massachusetts General Hospital Cancer Center, Division of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston (Flaherty); Pigmented Lesion Clinic, Department of Dermatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (Kim); Cutaneous Oncology Program, Department of Dermatology, Beth Israel
Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (Kim). Author Contributions: Dr Kim and Ms Park had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Park, Tahan, Kim. Acquisition of data: All authors. Analysis and interpretation of data: Park, Tahan, Flaherty, Kim.
JAMA Dermatology March 2014 Volume 150, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Georgian Court University User on 05/14/2015
jamadermatology.com
Granulomatous Eruptions With BRAF inhibitor Use
Drafting of the manuscript: All authors. Critical revision of the manuscript for important intellectual content: Park, Tahan, Flaherty, Kim. Statistical analysis: Kim. Administrative, technical, or material support: Tahan, Flaherty, Kim. Study supervision: Kim. Conflict of Interest Disclosures: Drs Kim and Flaherty have served as consultants to Roche. Dr Flaherty has served as a consultant to GlaxoSmithKline. No other disclosures are reported. Funding/Support: Roche and GlaxoSmithKline funded the underlying clinical trials in which the patients in this report participated. Dr Kim was supported by the Kevin Reagan Memorial Fund and the Eleanor and Miles Shore/Beth Israel Deaconess Medical Center Department of Dermatology Fellowship. Role of the Sponsor: Roche and GlaxoSmithKline had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: Lauren Kovach, BA, Department of Dermatology, Beth Israel Deaconess Medical Center, provided administrative assistance. She was not compensated for her contribution.
jamadermatology.com
Case Report/Case Series Research
REFERENCES 1. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353(20):2135-2147. 2. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949-954. 3. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366(8):707-714. 4. Alcalá AM, Flaherty KT. BRAF inhibitors for the treatment of metastatic melanoma: clinical trials and mechanisms of resistance. Clin Cancer Res. 2012;18(1):33-39. 5. Manousaridis I, Mavridou S, Goerdt S, Leverkus M, Utikal J. Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management. J Eur Acad Dermatol Venereol. 2013;27(1):11-18. 6. Lacouture ME, Duvic M, Hauschild A, et al. Analysis of dermatologic events in vemurafenib-treated patients with melanoma. Oncologist. 2013;18(3):314-322. 7. Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366(3):207-215.
9. Brincker H. Sarcoid reactions in malignant tumours. Cancer Treat Rev. 1986;13(3):147-156. 10. Sacks EL, Donaldson SS, Gordon J, Dorfman RF. Epithelioid granulomas associated with Hodgkin’s disease: clinical correlations in 55 previously untreated patients. Cancer. 1978;41(2):562-567. 11. O’Connell MJ, Schimpff SC, Kirschner RH, Abt AB, Wiernik PH. Epithelioid granulomas in Hodgkin disease: a favorable prognostic sign? JAMA. 1975;233(8):886-889. 12. Baselmans AH, Koten JW, Battermann JJ, Van Dijk JE, Den Otter W. The mechanism of regression of solid SL2 lymphosarcoma after local IL-2 therapy. Cancer Immunol Immunother. 2002;51(9): 492-498. 13. Robert C, Schoenlaub P, Avril MF, et al. Malignant melanoma and granulomatosis. Br J Dermatol. 1997;137(5):787-792. 14. Tsunoda K, Onodera H, Akasaka T. Case of malignant melanoma associated with a sarcoid reaction. J Dermatol. 2011;38(9):939-942. 15. Suárez-García C, Pérez-Gil A, Pereira-Gallardo S, Codes-Villena M, García-Escudero A, Miguel Camacho F. Interferon-induced cutaneous sarcoidosis in melanoma. Melanoma Res. 2009;19(6):391-394.
8. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18): 1694-1703.
JAMA Dermatology March 2014 Volume 150, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a Georgian Court University User on 05/14/2015
311
