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the online version of this article ( doi:10.1007/s13555 - 014 - 0051 - 4 ) contains supplementary material , which is available to authorized users .
ingenol mebutate ( a macrocyclic diterpene ester , pep005 , 0.015% ) derives from the sap of the plant euphorbia peplus .
ingenol mebutate is currently an us food and drug administration ( fda ) and european medicines agency ( ema ) recognized field - directed treatment for actinic keratosis [ 1 , 2 ] .
ingenol mebutate activates a broad range of protein kinase c ( pkc ) (  ,  ,  ,  ,  ,  and  ) isoenzymes .
direct pro - apoptotic effects of this drug have been demonstrated in several malignant cells , including melanoma cell lines .
micromolar concentrations of ingenol mebutate are required to kill melanoma cells via pkc - independent secondary necrosis .
topical application of ingenol mebutate was revealed as being effective for human and murine melanoma in mouse models . in transformed keratinocytes
it has been demonstrated that ingenol mebutate does not mediate cytotoxicity by a simple lytic , necrotic mechanism , but activates distinct processes involving multiple cell organelles in a cell - type and differentiation - dependent manner . in vitro experiments
revealed epidermal cell death , acute inflammation , recruitment of neutrophils , hemorrhage , and eschar formation when ingenol mebutate was tested on keratinocytic cell lines and squamous cell cancer cell lines [ 5 , 6 ] .
currently , the action mechanism of ingenol mebutate is divided into three consecutive steps ; ( 1 ) a direct effect of the drug on the initial cancer accompanied by an in situ production of pro - inflammatory cytokines , ( 2 ) neutrophil infiltration , and ( 3 ) induction of tumor - reactive antibodies , diminishing potential relapses by antibody - dependent neutrophil cytotoxicity .
however , as far as the authors are aware , no published data are available on a potential effect of ingenol mebutate on in vivo melanoma .
melanoma in situ ( mis ) is the most superficial form of melanoma [ 7 , 8 ] .
there are different treatment options including topical immunotherapy by imiquimod , topical destructive treatment by cryotherapy , superficial radiotherapy and excisional or mohs surgery , all presenting their respective advantages and inconveniencies .
some patients do not qualify anymore for surgery for various reasons and topical treatments are then preferred .
this case report describes an elderly woman with two previous large excisions of thick melanoma on her cheek who refused further surgery for recurrent mis on the surgical scars .
a 91-year - old woman presented with 2 biopsy - proven recurrent miss in the direct vicinity of a scar on her right cheek ( fig .  1 ) . in 2011 , she was diagnosed with a superficial melanoma of the right cheek ( 0.14  mm depth , clark ii , ki67 : 10% , 1 mitosis / mm , with micro metastases ) arising from an mis and a nodular melanoma of the right cheek ( 4  mm depth , clark v , ki67 : 30% , > 5 mitoses / mm ) ( fig .  2 ) .
histology revealed a nodular melanoma ( 1 , 93  mm depth , clark iv , ki67 : 30% , 3 mitoses / mm , with micro metastases ) .
due to her age and her own wishes , no further staging examinations were performed .
two years later , she presented with 2 recurrent miss adjacent to the surgical scar ( fig .  2 ) .
a 4-mm punch biopsy confirmed the diagnosis of mis of the lentigo maligna melanoma type .
again the patient and her family refused categorically any further surgical intervention and the authors decided to attempt to treat these lesions with ingenol mebutate gel 0.015% , based on in vitro data on melanoma cell lines .
three consecutive daily applications were performed on the lesion area . on the day of the third application ,
a moderately crusting and oozing reaction was observed . according to the severity scale assessing ingenol mebutate toxicity ,
the composite score was 9/24 ( erythema : 1 , flaking or scaling : 2 , crusting : 4 , swelling : 2 , vesiculation  or postulation : 0 and erosion or ulceration : 0 ) . topical disinfection and topical antibiotic ointment were recommended and the crust disappeared after 1  week .
one month later , there was a clinical resolution of both lesions , with a slightly squamous , post - inflammatory erythema ( fig . 
4 ) and on using immunohistochemistry with nki - c3 , s100a , hmb45 and melan a ( dako , glostrup , denmark ) ( fig .  5 ) .
the local tolerance of the treatment was acceptable for the patient and no systemic signs were observed .
after 6  months of follow - up the patient was still free of mis recurrence.fig . 
4histology ( h / e 10 ) showing dermal fibrosis without any evidence of residual in situ melanomafig . 
5melan a immunostaining ( 20 ) revealing no evidence of recurrent melanoma in situ recurrent in situ melanomas in 2013 clinical aspect of the melanoma on the right cheek in 2011 clinical aspect 1  month after treatment with ingenol mebutate histology ( h / e 10 ) showing dermal fibrosis without any evidence of residual in situ melanoma melan a immunostaining ( 20 ) revealing no evidence of recurrent melanoma in situ
standard care for mis is surgical excision or mohs surgery respecting a margin of 59  mm of clinically non - involved healthy skin .
either the patient refuses excisional surgery or surgery is no longer recommended due to morbidity and/or cosmetic considerations .
furthermore , older age , multiple previous surgical procedures , medical comorbidities may preclude from surgery .
the non - invasive treatment options for mis include local radiation therapy and topical immunotherapy .
although published cure rates achieving 86% to 95% , it remains an uncommonly used treatment option for mis in poor candidates for surgery .
imiquimod is a synthetic imidazoquinoline amine and acts as a toll - like receptor ( tlr ) agonist on tlr7 and tlr8 [ 711 ] .
this topical immunomodulator increases , after binding to the tlr s , the endogenous production of interferon - alpha , exhibiting anticancer properties , interleukins ( ils ) 6 and 12 , as well as tumor necrosis factor alpha [ 7 , 8 ] .
a recent meta - analysis showed an average clearance rate of 91% with a histological proof .
however , the follow - up periods were usually short , the  negative biopsy  did not preclude persisting areas of mis and particular attention should be given to invasive melanoma progression after an initial superficial tumor clearing .
there is no standard recommendation on dosing and application protocols of imiquimod and adaptations are often required to minimize the local adverse reactions , consisting of moderate to severe erythema , crusting , and sometimes oozing , usually occurring after 23  weeks of treatment .
systemic effects may sometimes be observed in the form of flu - like symptoms with fever , headache , hyperesthesia , myalgia and fatigue . in sum ,
the long - term cure rates of imiquimod are questionable   and caution is advocated not to fail a subsequent diagnosis of residual or recurrent invasive melanoma .
this case report suggests that in some selected patients with mis , ingenol mebutate could be considered as an alternative treatment .
it could present the advantage over imiquimod not to display potential systemic flu - like symptoms .
furthermore , although cutaneous adverse effects are common for both agents , they are usually shorter in duration with ingenol mebutate .
further research on the  cytotoxicity / inflammation  mechanisms of action of ingenol mebutate on in vivo melanocytic tumors is warranted .
ingenol mebutate merits to be considered as an alternative treatment option for mis in selected patients , after other therapies have failed .
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backgroundtreatment options for melanoma in situ ( mis ) include imiquimod , radiation therapy , cryotherapy , excisional and mohs surgery . 
 ingenol mebutate is a new topical treatment option recognized for actinic keratosis . 
 although in vitro effectiveness has been demonstrated on melanoma cell lines , its therapeutic potential for in vivo melanomas is unknown.case reportin 2011 , a 91-year - old woman presented a thick melanoma of her cheek . 
 the lateral sections revealed persisting in situ melanoma , which were again excised . 
 she presented for follow - up and a recurrent mis was evidenced centered on the previous scar . 
 she refused further surgery and ingenol mebutate ( 0.015% gel ) was administered on three consecutive days . 
 one month later , a complete clinical resolution was observed . 
 histology and immunohistology revealed no residual mis.conclusionin this patient , ingenol mebutate was successful and well - tolerated as a topical , alternative therapy for mis after failure of other treatment options.electronic supplementary materialthe online version of this article ( doi:10.1007/s13555 - 014 - 0051 - 4 ) contains supplementary material , which is available to authorized users .