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CASE REPORT
Year : 2020  |  Volume : 16  |  Issue : 1  |  Page : 170-172

Human papillomavirus-negative epithelial proliferations resembling condylomata acuminata in a patient receiving vemurafenib for Stage IV melanoma


1 Department of Dermatology, Netherlands Cancer Institute, Amsterdam; Department of Dermatology, MC Zuiderzee Hospital, Lelystad, Netherlands
2 Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
3 Department of Dermatology, Netherlands Cancer Institute, Amsterdam, Netherlands

Date of Submission05-Apr-2017
Date of Decision15-Aug-2017
Date of Acceptance03-Mar-2018
Date of Web Publication30-Oct-2018

Correspondence Address:
Marnix H Geukes Foppen
Department of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam
Netherlands
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_317_17

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 > Abstract 


With the discovery of v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors, new treatment possibilities arose against metastatic melanoma. A frequent adverse effect of BRAF inhibitor therapy is the induction of epithelial proliferations such as cutaneous squamous cell carcinoma and verrucous papilloma. Here, we describe a case in which a patient developed extensive anal epithelial proliferations resembling condylomata acuminata, after starting vemurafenib treatment. This adverse effect has rarely been reported in the literature. Interestingly, the lesions in our patient were negative for human papillomavirus, and mutations in BRAF, Neuroblastoma rat sarcoma viral oncogene homolog (NRAS), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Harvey rat sarcoma viral oncogene homolog (HRAS) were not detected. Different pathways can contribute to these epithelial proliferations resembling condylomata acuminata. We show the relevance of a detailed history at the beginning and during treatment, instructions, education, and dermatological follow-up (including the genital area) for patients treated with BRAF inhibitors. Condylomata acuminata can influence the quality of life and are treated, in an early stage, with cryotherapy, coagulation, imiquimod, and/or CO2 laser therapy.

Keywords: Condylomata acuminata, human papillomavirus, melanoma, vemurafenib


How to cite this article:
Peters MA, Geukes Foppen MH, Blank CU, Crijns MB. Human papillomavirus-negative epithelial proliferations resembling condylomata acuminata in a patient receiving vemurafenib for Stage IV melanoma. J Can Res Ther 2020;16:170-2

How to cite this URL:
Peters MA, Geukes Foppen MH, Blank CU, Crijns MB. Human papillomavirus-negative epithelial proliferations resembling condylomata acuminata in a patient receiving vemurafenib for Stage IV melanoma. J Can Res Ther [serial online] 2020 [cited 2020 Jun 6];16:170-2. Available from: http://www.cancerjournal.net/text.asp?2020/16/1/170/244452




 > Introduction Top


One of the most aggressive forms of skin cancers is melanoma. BRAF inhibitors, such as vemurafenib and dabrafenib, have shown high objective responses and an improvement in overall and progression-free survival.[1],[2] Unfortunately, this therapy is not devoid of side effects. Both benign and malignant skin tumors can occur during vemurafenib therapy. In this case report, we present human papillomavirus (HPV)-negative epithelial proliferations resembling condylomata acuminata beginning 1 week after the start of vemurafenib in a patient who never had condylomata acuminata before. To the best of our best knowledge, this is the first case report describing this phenomenon. We will discuss the relevance of HPV and Rat sarcoma (RAS) mutations in cutaneous side effects seen with BRAF inhibitors.


 > Case Report Top


At our outpatient clinic, we saw a 53-year-old male with a medical history of a nodular melanoma at the left flank in 2013. The melanoma was surgically removed, and re-excision with a margin of 2 cm around the previous scar was performed. The Breslow thickness was 2.1 mm and there was the presence of dermal mitoses. No ulcerations, microsatellites, or signs of regression were seen. BRAF and NRAS mutation analysis (high-resolution melting followed by sequential analysis) of the primary melanoma showed a mutation in exon 15 of the BRAF gene (p.V600E) and no NRAS mutation at codons 12, 13, and 61. In May 2014, our patient started with vemurafenib (960 mg b.i.d.) because of metastatic lesions in the brain. Directly after starting vemurafenib treatment, our patient developed a severe photosensitivity reaction. This was alleviated with protective measurements. In August 2014, he was referred to the dermatology department with multiple skin disorders. During the dermatological examination, we saw multiple seborrheic verrucae on the trunk and multiple hyperkeratotic papillomas on the scalp, ear, and back. Histopathology of these lesions showed squamous, partly verrucous, and partly keratoacanthoma-like proliferations. There was no evidence of malignancy. Multiple small yellow cysts were found on the back of the patients head. The patient also told us that, 1 week after receiving the first dose of vemurafenib, he noticed some perianal skin disorders which increased in number and became very uncomfortable. He had no history of genital warts and nor did his wife. Dermatological investigation of the genitals showed multiple (>20) sharp demarcated small verrucous papillomas perianal [Figure 1]. Histopathology of these skin lesions showed a papillomatous squamous cell proliferation with hyperkeratosis, parakeratosis, and vacuolated keratinocytes matching a condyloma acuminatum [Figure 2]a and b].
Figure 1: Multiple (>20) sharp demarcated small verrucous papillomas perianal

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Figure 2: (a) Histopathology of perianal lesion. Papillomatous squamous cell proliferation. (b) Histopathology of perianal lesion. Details of vacuolated keratinocytes with prominent keratohyalin granules

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The histopathology was revised by a dermatopathologist. Next-generation sequencing (Illumina TruSeq Amplicon - Cancer Panel v1.0 kit) on the perianal skin disorders showed no NRAS mutation (in codons 12, 13, and 61), no KRAS mutation, no HRAS mutation (in exons 2 and 3), and no BRAF mutation in codon 600. The polymerase chain reaction (PCR) and SPF10-LiPA genotyping test for HPV, using a probe that detects 25 subtypes including subtypes 6 and 11, were negative after testing twice. Due to multiple adverse events, for example, the increasing photosensitivity, many condylomata, and multiple keratoacanthoma, our patient switched to dabrafenib therapy (150 mg b.i.d.). In September 2014, our patient developed progressive brain metastases, and the treatment was discontinued. In October 2014, the patient had deceased.


 > Discussion Top


The incidence of cutaneous malignant melanoma has been increasing in the past decades. In an individual patient, malignant melanoma still has an unpredictable course. A review of the recent literature demonstrates that therapy with BRAF inhibitors is associated with the induction of new skin lesions ranging from benign proliferations to malignant squamous proliferative lesions.[3],[4],[5] BRAF inhibitors are thought to stimulate cells which are RAS mutated. However, it is unclear why a great number of, for example, squamous cell carcinomas in patients treated with vemurafenib are RAS wild type.[6]

Within our knowledge, this is the first case report of HPV-negative, BRAF-negative, and RAS-negative epithelial proliferations resembling condylomata acuminata in a patient receiving vemurafenib. Our findings suggest that the BRAF inhibitor vemurafenib is responsible for the growth of keratinocytes in the epithelium of our patient. Despite clinical and histopathological research, HPV was negative in our material. This suggests that the HPV subtypes studied are not involved in the pathogenesis of these epithelial proliferations resembling condylomata acuminata. This does, however, not rule out an infection with a nonstudied subtype HPV or a false-negative result. The latter is very unlikely since the screening for HPV was carried out twice with PCR and SPF10 LiPA genotyping test. This has a high performance in terms of sensitivity, reproducibility, and coverage of HPV types.[7] The fact that HPV potentially has no role in this pathway is consistent with other studies, whereas the role of the mitogen-activated protein kinases (MAPK) and phosphoinositide-3-kinase, catalytic, alpha polypeptide is very likely to induce cutaneous epithelial proliferations. The diversity of cutaneous lesions observed in patients treated with BRAF inhibitors may also reflect the presence of multiple pathways responsible for their growth. One of these possibilities is the MAPK pathway activation which has been observed with RAF inhibitors. In nonmutated BRAF cell lines, they can cause epithelial proliferation.[8] Many cutaneous side effects in patients with a BRAF inhibitor are described in the literature.[3],[4],[5],[9] Our finding of epithelial proliferations resembling condylomata acuminata in a patient receiving a BRAF inhibitor confirms the relevance of a detailed history at the beginning and during treatment, clear instructions, education, and dermatological follow-up (including the genital area). Not only HPV-negative but also HPV-positive proliferations can be induced. Condylomata acuminata can influence the quality of life and are treated, in an early stage, with cryotherapy, coagulation, imiquimod, and/or CO2 laser therapy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16.  Back to cited text no. 1
    
2.
Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: A multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012;380:358-65.  Back to cited text no. 2
    
3.
Boussemart L, Routier E, Mateus C, Opletalova K, Sebille G, Kamsu-Kom N, et al. Prospective study of cutaneous side-effects associated with the BRAF inhibitor vemurafenib: A study of 42 patients. Ann Oncol 2013;24:1691-7.  Back to cited text no. 3
    
4.
Holderfield M, Lorenzana E, Weisburd B, Lomovasky L, Boussemart L, Lacroix L, et al. Vemurafenib cooperates with HPV to promote initiation of cutaneous tumors. Cancer Res 2014;74:2238-45.  Back to cited text no. 4
    
5.
Anforth RM, Blumetti TC, Kefford RF, Sharma R, Scolyer RA, Kossard S, et al. Cutaneous manifestations of dabrafenib (GSK2118436): A selective inhibitor of mutant BRAF in patients with metastatic melanoma. Br J Dermatol 2012;167:1153-60.  Back to cited text no. 5
    
6.
Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 2012;366:207-15.  Back to cited text no. 6
    
7.
Dal Bello B, Spinillo A, Alberizzi P, Cesari S, Gardella B, Silini EM, et al. Validation of the SPF10 liPA human papillomavirus typing assay using formalin-fixed paraffin-embedded cervical biopsy samples. J Clin Microbiol 2009;47:2175-80.  Back to cited text no. 7
    
8.
Carnahan J, Beltran PJ, Babij C, Le Q, Rose MJ, Vonderfecht S, et al. Selective and potent Raf inhibitors paradoxically stimulate normal cell proliferation and tumor growth. Mol Cancer Ther 2010;9:2399-410.  Back to cited text no. 8
    
9.
Schrama D, Groesser L, Ugurel S, Hafner C, Pastrana DV, Buck CB, et al. Presence of human polyomavirus 6 in mutation-specific BRAF inhibitor-induced epithelial proliferations. JAMA Dermatol 2014;150:1180-6.  Back to cited text no. 9
    


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  [Figure 1], [Figure 2]



 

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