Cutaneous Oncology: Part 2

Actinic Keratoses

George Martin, MD

Unfortunately, field therapy for the treatment of AKs continues to remain underutilized in clinical practice even though we have a number of therapies available. Recent studies on dermatologist treatment practices demonstrate that 92% of patients treated for actinic damage are treated with cryotherapy alone; 7% with cryotherapy plus a prescription for a field therapy; and 1% of patients leave the office with a prescription for a field therapy alone. Why is field therapy underutilized? This is, in part, due to prolonged downtime, patient compliance issues, the costs of medication, and patient discomfort during therapy. Therapies such as ingenol mebutate and short duration 0.5% 5-FU and combination therapies have been developed to address the above noted issues.

Our expert panel (George Martin, Eggert Stockfleth, Ted Rosen, Neal Bhatia, Neil Swanson, and Marc Brown) reviewed various challenging clinical cases with AKs. Some of the recommendations and comments are as follows:

How does a dermatologist optimally treat AKs? For facial AKs, 5-FU remains the basis of field therapy in most clinical practices.  During phase III clinical trials, clearance rates in excess of 70% were measured 30 days following daily treatment for 1 week using 0.5% 5-FU.  Lengthening the therapy to 4 weeks results in better efficacy but is in Dr. Martin’s opinion not worth the additional downtime and patient local skin reactions. Dr. Martin protocol involves treating daily for seven days, then the patient has a rest period of 1 month, then he treats again for 2 weeks or longer depending on the desired clinical result.  What about 3.75 imiquimod?  The 2 week on-off-on for facial AKs results in significant downtime.  Investigator initiated studies are looking at using 3.75% imiquimod daily for 7 days followed by a 2 weeks rest and then instituting once weekly applications. Ingenol Mebutate has also proven to be efficacious as a full-face field therapy using a single tube application to cover the entire face.  Complete healing with excellent clinical responses have been observed in larger area therapies. Large controlled studies quantitating efficacy on full face and scalp, large surface areas on the trunk and extremities have not been completed. Be sure to have your patients refrigerate their ingenol mebutate as soon as possible after picking it up.

Actinic damage on the chest of women poses a great challenge to the practitioner. Because of permanent depigmentation when used on chest areas, imiquimod 3.75% should be avoided. While PDT has shown to be effective, it is off-label for use on the chest and does not have any well-controlled studies to support its use. Both ingenol mebutate and 5-FU are viable options for treatment of AKs on the chest. Ingenol mebutate 0.05% QD x 2 days results in a “chemical peel” like reaction but produces excellent AK clearance and cosmesis.

What about the management of a patient with significant AK damage on the dorsal hands and forearms? Combined use of 5-FU QD in the morning for seven days with 5% imiquimod QD in the evening for six days followed by three to four weeks of “rest” and repeating the cycle for a total of three cycles has proven effective. Using 0.5% 5-FU QD for ten days followed by ALA PDT (3 hour incubation) is also effective but painful. Ingenol mebutate .05% applied QD for two days, while approved by the FDA for treatment of the hands/forearms, lacks significant efficacy and might benefit from future clinical studies examining the efficacy and safety of a three to four day regimen. It is important to remember actinic damage is a chronic disease that requires vigilance and therapeutic intervention.

Cutaneous Oncology: Part 1

Viral Skin Carcinogenesis

Eggert Stockfleth, MD

Dr Stockfleth reviewed the latest data and the role of the human papillomavirus (HPV) in skin cancer.   HPV is a very stable, host-specific virus, which it is why it is referred to as “human” papillomaviruses.  HPV is a frequent virus in most everyone.  The most known strains of HPV are 16 and 18. HPV also has a very special DNA from the oncogenic type (E6 and E7). Currently, there are two prophylactic quadrivalent vaccines available, which harbor HPV 6, 11, 16 and 18.

It’s important to know that the target cell for HPV is the keratinocyte. HPV types can infect skin tumors and mucosa tumors.

Currently, there are over 150 human papillomavirus types. These types can be distinguished by either alpha type, the wart-associated types, or cutaneous types, which are mainly the beta- or gamma-PV types.

Genital HPV, as we know, is one of the most frequently transmitted diseases; however, don’t forget that most of us already have these viruses for life.

Cutaneous HPV

Transmission of cutaneous HPV is through skin contact. Yet, the virus is very stable so can remain for several days. Probably, the best known oncogenic HPV types for cutaneous HPV are types 5 and 8.

Cutaneous Squamous Cell Carcinoma

SCC is prevalent on 80% of sun-exposed areas in cutaneous HPV and the main risk factor is UV radiation (UVA and UVB).  Dr Stockfleth and colleagues found that 118 genes were identified as differentially expressed in skin cancer.

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There are multiple risk factors during skin carcinogenesis. With a functional immune system, your body can repair DNA image or lead to programmed cell death, i.e, apoptosis. Chronic UV exposure leads to a local down-regulation of immune response; therefore, leading to an increased risk of developing skin cancer. HPV blocks apoptosis and the repair mechanism which can lead to SCC.

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What are the criteria to define a causal role in disease by infectious agents?

Biology of HPV

  • Presence of HPV in (pre)cancer cells
  • Expression of  viral genes in (pre)cancer cells
  • Transforming properties (in vitro and in vivo models)


  • Relative Risk (RR) and Odds Ratio (OR)
What about cellular networks?

Research on cellular networks over the years has led researchers to look for the “guardian” genes.

A 2011 publication by Dr Stockfleth and colleagues, looked at the interaction of cutaneous HPV 23. Of note, HPV 23 and 38 are the most prevalent types of virus and play a role in development of skin cancer. These HPV subtypes (23 and 38) induced anti-apoptotic effects in UV-damaged cells through the expression of two oncogenic proteins E6 and E7 that lead to persistence and accumulation of further mutations.  Data from this paper suggest that cutaneous HPV23 E6 protein directly targets HIPK2 function; therefore, HIPK2 was identified as the guardian gene.

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Research is still ongoing regarding identification of other viruses, vaccination and treatment.