|Year : 2015 | Volume
| Issue : 3 | Page : 647
Vemurafenib-related sterile scrotal abscess in a patient with BRAFV600K-mutant advanced melanoma mimicking distant metastasis
Jennifer Gibbons Marsico1, Regulo Rodriguez2, Joachim Muller3, Markus Jorger1
1 Department of Medical Oncology, Cantonal Hospital, St.Gallen, Switzerland
2 Department of Pathology, Cantonal Hospital, St.Gallen, Switzerland
3 Department of Nuclear Medicine, Cantonal Hospital, St.Gallen, Switzerland
|Date of Web Publication||9-Oct-2015|
Dr. Jennifer Gibbons Marsico
Translational Research Fellow (Department Medical Oncology), Cantonal Hospital, St. Gallen, Rorschacherstrasse 95, CH-9007 St. Gallen
Source of Support: J. Gibbons.Marsico is supported by a fellowship grant funded by the European Society of Medical Oncology., Conflict of Interest: None
Background: Vemurafenib is a selective BRAF-inhibitor that has been approved for the use in patients with advanced BRAF-mutant melanoma. Major adverse events include skin rash, photosensitivity, pruritus, cutaneous squamous-cell carcinoma or keratoacanthoma. Observation: We present the case of a patient experiencing extensive sterile abscess of the scrotum after nine months of treatment with vemurafenib for oligometastatic (liver) BRAF-mutant melanoma. The scrotal lesion mimicked distant metastasis in a first round of clinical and radiological examinations, but was identified as sterile abscess after surgical exploration and complete excision. The patient went on to receive hemihepatectomy for melanoma supposedly confined to the liver, and continues receiving vemurafenib. Conclusions: We describe a remarkable case of probably vemurafenib-related sterile abscess. This adverse event is of substantial clinical relevance, as it mimicks metastatic melanoma and requires careful diagnostic evaluation and proper treatment to allow a favorable patient outcome.
Keywords: BRAF inhibition, melanoma, sterile infection, vemurafenib
|How to cite this article:|
Marsico JG, Rodriguez R, Muller J, Jorger M. Vemurafenib-related sterile scrotal abscess in a patient with BRAFV600K-mutant advanced melanoma mimicking distant metastasis. J Can Res Ther 2015;11:647
|How to cite this URL:|
Marsico JG, Rodriguez R, Muller J, Jorger M. Vemurafenib-related sterile scrotal abscess in a patient with BRAFV600K-mutant advanced melanoma mimicking distant metastasis. J Can Res Ther [serial online] 2015 [cited 2019 Nov 15];11:647. Available from: http://www.cancerjournal.net/text.asp?2015/11/3/647/136039
| > Introduction|| |
Melanoma accounts for less than 5% of all skin cancers. Still, melanoma represents the 5 th most common cancer among men and the 6 th most common among women. , Patients with metastatic melanoma have a poor prognosis with an overall survival of less than 1 year. Unfortunately, between 2% and 5% of patients present with metastatic disease at initial diagnosis, another 5-15% will eventually develop metastatic disease. , In the last few years, new targeted drugs such as ipilimumab and the BRAF-inhibitors vemurafenib and dabrafenib have been shown to result in a substantial improvement of the prognosis of patients with advanced melanoma.  The development of vemurafenib is based on the discovery of oncogenic BRAF-mutations in up to 60% of patients with both localized and metastatic melanoma. , Several activating BRAF-mutations have been described in melanoma, with the most common being a single aminoacid substitution at the valine 600 (V600) position of 15 exon. , Vemurafenib is a first-in-class, oral small-molecule BRAF-inhibitor that selectively targets cells harboring the classical V600E mutation as well as atypical BRAF-mutations.  The most common adverse events associated with the use of vemurafenib include rash, photosensitivity, pruritus, alopecia, cutaneous squamous-cell carcinoma, diarrhea, arthralgia, and nausea. ,, The most intriguing of these adverse effects is the wide spectrum of cutaneous toxicity, including verrucous papilloma, hand-foot skin reaction, hyperkeratotic follicular rash, photosensitivity, alterations in hair growth, xerosis, cystic lesions, milia, facial erythema, cheilitis, panniculitis, keratoacanthoma, nipple hyperkeratosis and radiodermatitis. , This is the first description of a possibly vemurafenib-related sterile abcess that is of high interest for clinicians, as it is potentially related to the drug's immunostimulatory effects, and mimicks metastatic tumor sites.
| > Case report|| |
A 46-year-old Caucasian male presented with superficial-spreading malignant melanoma (SSM) on the vertex scalp in July 2009, after having received incomplete local excision of the tumor (R1). The patient underwent re-excision with a 2 cm tumor-free margin as well as sentinel node biopsy (SNB). The latter did not reveal tumor metastases, resulting in an initial tumor stage of pT3a pN0, Breslow 3.38 mm, Clark level IV, M0. Three months later, the patient presented with cutaneous satellite metastasis that was completely resected in December 2010, and confirmed metastasis of the original tumor. A follow-up PET-TC scan in November 2011 showed two new liver metastases in segment VII [1.7 cm] and segment V/VI [1.8 cm], confirmed by fine-needle biopsy. In December 2011, melanoma was confirmed to carry the BRAFV600K mutation and the patient was started on systemic treatment with the experimental MEK-inhibitor MEK-162 within a clinical trial. However, MEK-162 had to be stopped after two months of treatment due to, a drug-related elevation of serum creatinine kinase (CK) CTC grade 2 (2640 U/l) and serous retinal detachment (SRD). In February 2012, the patient started treatment with oral vemurafenib 960 mg b.i.d at our institute. Two months later, dermatologic examination revealed keratoacanthoma on both the upper left leg and the occiput, as well as squamous-cell carcinoma of skin of the head (right parietal region), all requiring radical excision. Radiological restaging in September and December 2012 showed minor progression of liver metastases, but a new PET-TC scan in December 2012 also raised the suspicion of extrahepatic tumor spread with strong FDG-uptake alongside the right spermatic cord (SUV 13.7) [Figure 1]. On physical examination, there was a painless nodule of 4 × 3 cm adjacent to the right testicle, that was clearly growing according to the patient. Subsequently, the patient underwent a local biopsy to confirm scrotal metastasis. During surgery, extensive necrotic inflamation of the scrotum was found and surgically removed. Histopathologic examination showed extensive fibrino-granulocytic cell infiltration as part of chronic, unspecific inflammation, and without any signs of malignancy [Figure 2]. Postoperatively, the patient continued vemurafenib at the initial dose, and underwent right hemihepatectomy with complete resection of all liver metastases in January 2013. In March 2013, radiological restaging confirmed complete tumor remission, and the patient is presently continuing vemurafenib without further complications.
|Figure 1: PET-TC study showing focal FDG-uptake in liver segments VI and VII (SUV 15.6), as well as in liver segment VI (SUV 10.8) and subcapsular in segment V (SUV 6.9) (panel 1a). Strong additional FDG-uptake along the right spermatic cord (SUV 13.7), suggesting extrahepatic tumor spread (panel 1b and 1c).|
Click here to view
|Figure 2: Histopathological sections from local excision, showing abscess wall with granulocytic inflammation and signs of organization (panel 2a and b). No signs of malignancy.|
Click here to view
| > Discussion|| |
Vemurafenib is known for a wide spectrum of cutaneous adverse events. , No data however have been described about vemurafenib-related sterile abscesses to our knowledge. According to the Naranjo ADR probability scale,  the relation between sterile abscesses described in our patient and vermurafenib treatment has to be seen as "possible", corresponding to a Naranjo score of 4 points. No immunosuppressive or cytostatic drugs resulting in an increased risk of infections were administered to the patient, and vemurafenib was given at the recommended dose of 960 mg b.i.d. In fact, immunostimulatory effects related to the systemic treatment with vemurafenib or associated with the underlying malignant disease may have resulted in sterile infection as described in our patient. Actually, activation of the host immune system is a major mechanism contributing to the treatment of advanced-stage melanoma. The BRAF/MAP pathway is involved in the production of various immunosuppressive factors, even more in melanoma cell lines harboring BRAF mutations, in which this pathway is already constitutively activated.  More specifically, the MAP-kinase pathway is critical for cell signaling via lymphocyte immune receptors, lymphocyte activation and response to antigen encounter or cytokine stimulation.  Accordingly, successful treatment with specific BRAF inhibitors may result in unspecific immunostimulatory effects that potentially lead to sterile abscesses described in the present case. In fact, our patient also presented smaller relapsing local infections similar to relapsing folliculitis with intermittent discharge of pus. As presented, more extensive sterile abscess formation represents a difficult diagnostic challenge, in particular to make proper differential diagnosis and clearly discern it from metastatic disease. In this case, no interruption or dose reduction of vemurafenib was required, and the patient is presently continuing treatment following radical resection of oligometastatic melanoma in the liver. This is in full concordance with previous results of good clinical activity of vemurafenib in patients with BRAF-mutant advanced melanoma.  The importance of the proper identification and treatment of vemurafenib-related adverse events is helping to improve the quality of life in patients receiving vemurafenib, and finally improves treatment compliance and clinical outcome.
| > Acknowledgement|| |
J. Gibbons Marsico is supported by a fellowship grant funded by the European Society of Medical Oncology.
| > References|| |
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10-29.
Ravnan MC, Matalka MS. Vemurafenib in patients with BRAF V600E mutation-positive advanced melanoma. Clin Ther 2012;34:1474-86.
Khan KH, Godoy RB, Hameed H, Jalil A, Coyle VM, Mc Aleer JJ. Metastatic melanoma: A regional review and future directions. Tumori 2012;98:575-80.
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto PA, Larkin J, et al
. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al
. Mutations of the BRAF gene in human cancer. Nature 2002;417:949-54.
Greaves WO, Verma S, Patel KP, Davies MA, Barkoh BA, Galbincea JM, et al
. Frequency and spectrum of BRAF mutations in a retrospective, single-institution study of 1112 cases of melanoma. J Mol Diagn 2013;15:220-6.
Boussemart L, Routier E, Mateus C, Opletalova K, Sebille G, Kasmu-Kom N, et al
. Prospective study of cutaneous side-effects associated with the BRAF-inhibitor vemurafenib: A stduy of 42 patients. Ann Oncol 2013; 24:1691-7.
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al
. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.
Sumimoto H, Imabayashi F, Iwata T, Kawakami Y. The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med 2006;203:1651-6.
Comin-Anduix B, Chodon T, Sazegar H, Matsunaga D, Mock S, Jalil J, et al
. The oncogenic BRAF kinase inhibitor PLX4032/RG7204 does not affect the viability or function of human lymphocytes across a wide range of concentrations. Clin Cancer Res 2010;16:6040-8.
[Figure 1], [Figure 2]