Correspondence  Clinical Letter

to the fields, many people are now seriously ill” (Figure 1b). Again, I sent a letter of disapproval to the editorial office, adding that my comments were not meant to question the general issue as to whether the chemicals used for soy growing in Argentina were harmful to humans or not. The managing editor Marc Schürmann thanked me for this “hint”, but preferred not to publish my opposing expert opinion. My criticism is this: the editors of both journals knew exactly what they were doing. Both “Stern” and “Süddeutsche Zeitung” misused this girl‘s ailment for the purpose of disinformation. What do Aixa‘s nevi have to do with genetic engineering and spraying of chemicals? From a scientific point of view: absolutely nothing. As dermatologists, we should protest against this form of journalism. For if we are silent, who will speak?

Clinical Letter Don‘t miss the base – keratoacanthoma-type squamous cell carcinoma with perineural invasion during BRAF inhibitor therapy for melanoma

DOI: 10.1111/ddg.12686

Dear Editors, Besides viral papillomas, well-differentiated squamous cell carcinomas, especially of the keratoacanthoma type, are the most common skin tumors to occur during therapy with BRAF inhibitors such as vemurafenib and dabrafenib [1, 2]. It is assumed that these tumors have a low risk for local recurrence or metastasis [1, 2]. Usually exophytic, these tumors are frequently treated with superficial curettage, thus – at times – not only preventing their complete removal but also their comprehensive histopathological evaluation. We present the case of a woman with metastatic melanoma (BRAF-V600E) who, while on vemurafenib, developed a keratoacanthoma-type squamous cell carcinoma with deep perineural invasion. The 80-year-old patient has been treated with vemurafenib since February 2014. As early as the fourth week of treatment, numerous hyperkeratotic tumors developed on the face, neck, and trunk, histologically corresponding to viral papillomas and well-differentiated squamous cell carcinomas. In treatment week 7, an asymptomatic hyperkeratotic nodule, 25×18×10 mm in size, occurred on

Rudolf Happle Department of Dermatology, Freiburg University Medical Center, Freiburg, Germany.

Correspondence to Dr. med. Rudolf Happle Department of Dermatology Freiburg University Medical Center Hauptstrasse 7 79104 Freiburg Germany E-mail: [email protected]

her forehead (right paramedian location), which was subsequently completely excised. Histology showed marked epidermal proliferation with a central crater-like keratin plug (Figure 1a, b). At the base, narrow tumor strands infiltrated the upper parts of the subcutis. Moreover, there was prominent perineural invasion of epithelial cell clusters in the subcutis (Figure 2a, b). Both tumor components were immunohistochemically positive for cytokeratin (CK) 5/6 and CK903 (34ßE12) (Figure 2c). Eight months after the excision, there was no evidence of clinical recurrence. Due to progressive nausea and weakness, the initial vemurafenib dose had to be reduced by 50%. The patient died due to progressive disease in the beginning of 2015. Verrucous hyperplasia and well-differentiated squamous cell carcinomas are frequently observed during BRAF inhibitor therapy. The suspected pathogenesis involves a paradoxical increase in the activity of the mitogen-activated protein kinase (MAPK) signaling cascade in those keratinocytes that already showed a RAS mutation prior to therapy [3, 4]. Clinically, these tumors are usually characterized by exophytic growth and a low risk for local recurrence. This is why they are frequently removed superficially, while BRAF inhibitor therapy is continued [1, 2]. To date, cases of metastasis have not been published, however, it is unclear whether this is due to the tumors’ biological behavior or a result of the close follow-up of patients on BRAF inhibitor therapy. There have been reports of aggressively growing squamous cell carcinomas following electrodissection and curettage as well as of clinically aggressive recurrences after apparently complete excision [5]. Histologically, the clinical aggressiveness possibly correlates with the deep invasion of some of the tumors resulting in a desmoplastic stromal response [5]. In addition,

© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1312

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Figure 1  Keratoacanthoma-type squamous cell carcinoma (hematoxylin-eosin stain, original magnification x 12.5 (a), x 40 (b)).

Figure 2  Perineural invasion of epithelial cells (hematoxylin-eosin stain x 40 (a), x 600 (b)). Positivity for cytokeratin 5/6 (immunohistochemistry x 600) (c).

cases of dermal spindle cell squamous cell carcinomas during BRAF inhibitor therapy have recently been published for the first time [6, 7].

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Perineural invasion is reported in approximately 5.95% of squamous cell carcinomas [8]. It occurs more often in tumors of the midface, recurrent tumors as well as dedifferen-

© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1312

Correspondence  Clinical Letter

tiated and large tumors. It is associated with more aggressive local growth, risk of recurrence, and increased morbidity and mortality [9]. Given the lack of data, there is no categorical recommendation for adjuvant radiation therapy in high-risk squamous cell carcinomas [10]. In keratoacanthoma, on the other hand, perineural infiltration has been described less frequently. According to the literature, it occurs in up to 4% of cases, particularly often in head and neck tumors [11]. Although larger case series have not shown any effect on clinical outcome, reports of aggressive and malignant disease courses with involvement of facial muscles and nerves as well as local recurrence and metastasis have been published [12, 13]. Apart from the size of the affected nerve, loss of adhesion molecules such as desmoglein 1 has been suggested as a histological predictor of clinically aggressive behavior [12, 13]. In case of extensive perineural invasion, the prognosis might possibly correspond to that of squamous cell carcinoma with perineural infiltration [13]. Superficial removal or even topical treatment methods prevent comprehensive histological evaluation of tumors. In our patient, superficial curettage would not have allowed for detection of perineural invasion in the dermis. Besides close dermatological follow-up, we consequently propose that there be a more careful assessment of suitable surgical methods for removing secondary tumors during BRAF inhibitor therapy as well as thorough histological examination. Histological evaluation of the entire lesion is essential to prevent inadequate treatment and avoid recurrences, which may possibly show a more aggressive biological behavior. Conflict of interest None.

Monica Schüürmann, Iris Pönitzsch, Jan ­Christoph Simon, Mirjana Ziemer Department of Dermatology, Venereology, und Allergology, University Medical Center Leipzig, Leipzig, Germany

Correspondence to Priv.-Doz. Dr. med. habil. Mirjana Ziemer Department of Dermatology, Venereology, und Allergology University Medical Center Leipzig Philipp-Rosenthal-Straße 23

References 1

Anforth R, Fernandez-Penas P, Long GV. Cutaneous toxicities of RAF inhibitors. Lancet Oncol 2013; 14: e11–e18. 2 Huang V, Hepper D, Anadkat M, Cornelius L. Cutaneous toxic effects associated with vemurafenib and inhibition of the BRAF pathway. Arch Dermatol 2012; 148: 628–33. 3 Oberholzer PA, Kee D, Dziunycz P et al. RAS mutations are ­associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J Clin Oncol 2012; 30: 316–21. 4 Zimmer L, Vaubel J, Livingstone E, Schadendorf D. Side effects of systemic oncological therapies in dermatology. J Dtsch ­Dermatol Ges 2012; 10: 475–86. 5 Sufficool KE, Hepper DM, Linette GP et al. Histopathologic characteristics of therapy-associated cutaneous neoplasms with vemurafenib, a selective BRAF kinase inhibitor, used in the treatment of melanoma. J Cutan Pathol 2014; 41: 568–75. 6 Cohen DN, Lumbang WA, Boyd AS et al. Spindle cell ­squamous carcinoma during BRAF inhibitor therapy for ­advanced melanoma: an aggressive secondary neoplasm of undetermined biologic potential. JAMA Dermatol 2014; 150: 575–7. 7 Ziemer M, Pönitzsch I, Simon JC, Schüürmann M. Spindle cell squamous cell carcinoma arising from verrucous hyperplasia during BRAF inhibitor therapy for melanoma. J Dtsch Dermatol Ges 2015; 13(4): 326–8. 8 Leibovitch I, Huilgol SC, Selva D et al. Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia II. Perineural invasion. J Am Acad Dermatol 2005; 53: 261–6. 9 Binmadi NO, Basile JR. Perineural invasion in oral squamous cell carcinoma: a discussion of significance and review of the literature. Oral Oncol 2011; 47: 1 005–10. 10 Jambusaria-Pahlajani A, Miller CJ, Quon H et al. Surgical monotherapy versus surgery plus adjuvant radiotherapy in high-risk cutaneous squamous cell carcinoma: a systematic review of outcomes. Dermatol Surg 2009; 35: 574–85. 11 Godbolt AM, Sullivan JJ, Weedon D. Keratoacanthoma with perineural invasion: a report of 40 cases. Australas J Dermatol 2001; 42: 168–71. 12 Basoglu Y, Metze D, Nashan D, Stander S. Keratoacanthoma with perineural invasion: an indicator for aggressive behavior? J Dtsch Dermatol Ges 2008; 6: 952–5. 13 Petrie M, Eliezri Y, Campanelli C. Keratoacanthoma of the head and neck with perineural invasion: incidental finding or cause for concern? Dermatol Surg 2010; 36: 1 209–13.

04103 Leipzig Germany E-mail: [email protected]

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Don't miss the base - keratoacanthoma-type squamous cell carcinoma with perineural invasion during BRAF inhibitor therapy for melanoma.

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