Skin Cancer Review

Julia Ernst, MS, Assistant Editor
Medical Resource Centers: 

Recent news, developments and research updates related to skin cancer.

Size of Tumors in Patients With Basal Cell Carcinoma Awaiting Mohs Surgery Remain Mostly Stable, New Study Finds

Skin Cancer ReviewA study published more than 40 years ago (Shanoff et al) has served as the basis for classifying basal cell carcinoma (BCC) growth rates as linear the first 2 years and unpredictable after that time period. Based on this information, and the lack of other prospective, long-term studies that examine growth rates for BCC, researchers from the Ramon y Cajal Hospital in Madrid, Spain performed a new study to confirm the findings of Shanoff et al and to further examine the growth rates for BCC in patients awaiting Mohs micrographic surgery (MMS).

Researchers examined 19 patients with BCC, measuring tumors 1 month after biopsy, at the consultation and immediately before the Mohs procedure. Mean time between both measures was 6 months. The researchers registered major (longest) and minor (shortest) diameters and an estimated area was calculated.

The results of the analysis varied, although most outcomes were positive. Among the 19 patients in the study, 4 BCCs (1 solid and 3 infiltrating) enlarged by 2 or more mm in diameter, 5 decreased in size (4 of which were solid) and the rest remained stable. According to the researchers, local immune responses have been studied as a possible explanation for this phenomenon, although one study suggested alterations in the stroma — like fibrosis — as a potential cause. Such alterations are more evident in larger tumors.

The researchers report that this study is the first prospective long-term study that includes the routine, high-risk BCCs derived for Mohs surgery.

“It illustrates that BCCs waiting a mean time of 6 months for MMS do not double their size but continue nearly stable (some of them decreased indeed), and therefore this waiting time would not have great consequences for the prognosis or surgical management,” the researchers write in the Journal of the European Academy of Dermatology and Venereology. “In addition, we concluded that growth of BCCs is not linear and therefore it is difficult to predict the effect of longer delays.”

Truchuelo M, Ríos-Buceta L, Béa-Arbedol S, Alcántara González J, Olasolo PJ. Basal cell carcinoma growth in patients waiting for Mohs surgery: A prospective study. J Eur Acad Dermatol Venereol. 2013 Jan;27(1):e141-143. doi: 10.1111/j.1468-3083.2012.04527.x. Epub 2012 Mar 26.

Skin Cancer ReviewUV Lamps in Nail Salons Do Not Increase Risk of Skin Cancer

Exposure to ultraviolet (UV) light emitted by lamps in nail salons to dry manicures does not raise an individual’s risk of developing skin cancer.

Dr. Alina Markova, of Massachusetts General Hospital in Boston, and Dr. Martin Weinstock, of Brown University in Providence, RI, looked at three UV nail lamps commonly used to dry manicures. They measured the light, in terms of its likely carcinogenic effect, and calculated the “UV dose” a user would receive during a 10-minute nail drying session. The doctors found that between 13,000 and 40,000 10-minute nail-drying sessions are needed before an individual receives a dose of UV equivalent to the amount received by a patient with psoriasis who underwent light treatment for the condition. According to the researchers, this is equivalent to about 250 years of weekly manicures.

The researchers discuss two previous studies to examine the link between exposure to UV nail lamps and risk of skin cancer, but state that both were faulty. One investigation used anecdotal evidence from two women and “the spectral irradiance cannot be calculated by using bulb wattage (bulb’s power requirements) and exposed to body surface area, but must be measured spectroradiometrically, as performed in our study.” In the second study to assess this association, the laboratory was hired by the nail salon industry and the study design was incorrect, according to the current study researchers. As a result of these issues, the conclusion in both studies that there is a link between exposure to nail salon lamps and skin cancer is not supported, the researchers of the current study conclude.

Writing in the Journal of Investigative Dermatology, the researchers conclude: “Although some sources of UVA and UVB contribute to the development of keratinocyte carcinoma (KC), UV nail lamps do not appear to significantly increase the lifetime risk of KC. Dermatologists and primary care physicians may reassure patients regarding the safety of these devices.”

Markova A, Weinstock MA. Risk of skin cancer associated with the use of UV nail lamp [published online ahead of print December 6, 2012]. J Invest Dermatol. doi: 10.1038/jid.2012.440.

Skin Cancer ReviewVirotherapy with Oncolytic Measles Virus is Effective against Melanoma

A new study from researchers in Germany demonstrates that virotherapy with an oncolytic measles virus was effective against melanoma.

The researchers engineered an oncolytic measles virus entering melanoma cells “through the high molecular weight melanoma–associated antigen (HMWMAA) and proved highly specific infection and spread in melanoma cells,” according to an article on the study in the Journal of Investigative Dermatology (JID). The virus was further enhanced “by inserting the FCU1 gene encoding the yeast-derived prodrug convertases cytosine deaminase and uracil phosphoribosyltransferase.”

The combination treatment of armed and retargeted MV-FCU1-αHMWMAA and the prodrug 5-fluorocytosine (5-FC) utilized by the researchers led to effective pro-drug conversion to 5-fluorouracil, extensive cytotoxicity to melanoma cells and excessive bystander killing of non-infected cells. According to the article in JID, “HMWMAA-retargeted MV showed antitumor activity in a human xenograft mouse model, which was further increased by the FCU1/5-FC pro-drug activation system.” The study also demonstrated susceptibility of melanoma skin metastasis biopsies to HMWMAA-retargeted MV.

The researchers conclude: “The highly selective, entry-targeted and armed oncolytic virus MV-FCU1-αHMWMAA may become a potent building block of future melanoma therapies.”

Kaufmann JK, Bossow S, Grossardt C, et al. Chemovirotherapy of malignant melanoma with a targeted and armed oncolytic measles virus [published online ahead of print December 6, 2012]. J Invest Dermatol. doi: 10.1038/jid.2012.459.

Skin Cancer ReviewVitiligo Patients are at a Decreased Lifetime Risk For Non-melanoma and Melanoma Skin Cancers

Patients with vitiligo may be at a decreased lifetime risk for non-melanoma skin cancer (NMSC) and melanoma.

The recent study in the British Journal of Dermatology examined the results of a questionnaire filled out by 1,307 patients with vitiligo and 788 controls. Patients with vitiligo were found to have a significant, three-fold lower lifetime probability of developing melanoma, both by univariate and multivariate analyses that adjusted for childhood sunburn and having more than 100 nevi. This supports adequate internal validity of the study design, according to the researchers. The team also found in a multivariate analysis that patients with vitiligo have a three-fold decreased probability of developing NMSC, adjusted for 8 independent NMSC risk factors.

The researchers cite several explanations for these findings. In regard to melanoma, the researchers write: “The anti-melanocyte immune response in patients with vitiligo may be responsible for the observed decrease in melanoma lifetime prevalence.” In regard to the decreased risk of NMSC, the researchers write: “The lower probability of NMSC in patients with vitiligo may relate to the observed decreased photodamage and increased levels of wild-type p53 expression in keratinocytes in the skin of patients with vitiligo.” The researchers add that the tumor-suppressor gene “may protect against actinic damage and the development of keratinocyte cancer.”

Because patients with vitiligo may be treated with phototherapy, the researchers also sought to determine if this treatment avenue would increase patients’ likelihood of developing skin cancer. In total, 911 of the 1,307 patients with vitiligo had a history of NB-UVB and/or PUVA treatment. No increased prevalence of NMSC or melanoma was seen in phototherapy-treated patients compared to vitiligo patients who had not received phototherapy.

Teulings HE, Overkamp M, Ceylan E, et al. Decreased risk of melanoma and non-melanoma skin cancer in patients with vitiligo: A survey among 1,307 patients and their partners. Br J Dermatol. 2013;168(1):162-171.

Researchers Identify Drug Combinations for Highly Resistant Forms of Melanoma

Skin Cancer ReviewResearchers at Yale University recently examined about 8,000 combinations of drug compounds used for cancer treatment and have identified a series of combinations that may lead to more effective, longer-lasting skin cancer treatment.

All of the drugs the researchers examined had either already been approved by the FDA or were similar to previously tested drugs. They targeted compounds that had potential activity against melanoma caused by BRAF and RAS genes, because of the high resistance of these specific types to treatment.

According to the results of the study in Cancer Discovery, “Results reveal several inhibitor combinations effective for melanomas with activating RAS or BRAF mutations, including mutant BRAF melanomas with intrinsic or acquired resistance to vemurafenib.” Inhibition of both EGF receptor and AKT sensitized treatment-resistant BRAF mutant melanoma cultures to vemurafenib.

The FDA approved vemurafenib (Zelboraf) in 2011, although problems arose when tumor resistance developed soon after the drug was approved. As a result, strategies for tackling this resistance are urgently needed, especially because vemurafenib demonstrated both improved rates of overall and progression-free survival in patients with advanced disease.

“We have used drug combinatorial screening to identify effective combinations for mutant BRAF melanomas, including those resistant to vemurafenib, and mutant RAS melanomas that are resistant to many therapies,” the researchers write in Cancer Discovery. “Mechanisms governing the interactions of the drug combinations are proposed, and in vivo xenografts show the enhanced benefit and tolerability of a mutant RAS-selective combination, which is currently lacking in the clinic.”

Held MA, Langdon CG, Platt JT, et al. Genotype-selective combination therapies for melanoma identified by high-throughput drug screening. Cancer Discov. 2012 Dec 27. [Epub ahead of print].

Circulating Tumor Cells in Blood of Melanoma Patients may have Prognostic Value

Skin Cancer ReviewPrevious studies have shown that the detection of circulating tumor cells in the blood of patients with breast, colorectal and prostate cancers correlates to disease progression and poor outcomes, although this correlation has not been established for melanoma. While studies show that the detection of such cells may be useful in patients with melanoma, none have thoroughly examined it, but a new study in the British Journal of Dermatology (BJD) may offer promising results in regard to this approach.

The study included 154 patients with primary cutaneous melanoma and 76 with metastatic melanoma. The majority of patients had Stage I disease (33.5%), with 16.5% at Stage 0, 17% at Stage II, 13% at Stage III and 20% at Stage IV. Blood samples were obtained from patients and polymerase chain reactions (PCR) were performed; multi-marker, quantitative, real-time PCR was used to detect circulating tumor cells.

Patients with melanoma were significantly more likely to express a melanoma cell marker in their blood, according to the study results in BJD. According to the authors, “The number of markers expressed by participants was important, with 83% of healthy controls expressing either no marker or just one marker, in contrast to patients with melanoma, who were highly likely to express two or more markers (72%, P=0.012).” In terms of specific markers, the researchers found that “MLANA, ABCB5, MCAM, PAX3d and TGFb2 were detected in 30% (n=68), 40% (n=90), 47% (n=108), 40% (n=91) and 66% (n=152) of patients with melanoma, respectively,” according to the article in BJD. The study also demonstrated that patients suffering from disease recurrence were more likely to express a greater number of markers and that surgical removal of tumors related to a decrease in the expression of certain markers.

The expression of the MCAM marker “was significantly more common in patients with a negative treatment outcome, with 43% expressing MCAM (n=17), while only 9% of samples from patients with a positive outcome expressed this marker (n=2; P=0.006),” according to the article in BJD. “The positive predictive value for MCAM expression as a marker of poor clinical outcome in patients with stage IV melanoma is 89.5%, while the negative predictive value is 46.5%.”

Taken together, these results show clearly “that circulating tumor cells are detectable at all stages of disease,” the authors write, adding that the detection of ABCB5-, MLANA- and MCAM-expressing tumor cells in the blood of patients with melanoma may specifically have prognostic value.

The authors continue: “Importantly, we demonstrated that a qRT-PCR multi-marker blood test provides a suitable method from which to develop further a reliable test for monitoring disease status without the need for specific isolation of circulating tumor cells.”

Reid AL, Millward M, Pearce R, et al. Markers of circulating tumour cells in the peripheral blood of patients with melanoma correlate with disease recurrence and progression. Br J Dermatol. 2013;168(1):85-92. doi: 10.1111/bjd.12057. Epub 2012 Nov 15.

Skin Cancer ReviewImmunohistochemical Analysis with Anti-Braf Antibody is Effective for Detecting Melanoma

A ctivating mutations in the BRAF gene are found in 50% of melanomas. An international team of researchers from Australia, Germany and Austria recently reported a new immunohistochemical (IHC) analysis that uses an anti-BRAF antibody to detect the presence of the BRAF V600E mutation in patients with advanced disease.

One hundred patients with stage IIIC unresectable or stage IV melanoma who had undergone tumor DNA BRAF mutation testing were enrolled. Paraffin-embedded, formalin-fixed biopsies were analyzed for BRAF mutation status by independent, blinded observers who used both conventional DNA molecular techniques and IHC with the novel BRAF V600E mutant-specific antibody, VE1.

The antibody demonstrated 97% sensitivity and 98% specificity for detecting BRAF V600E mutations, according to the study results in the American Journal of Surgical Pathology (AJSP). Of the BRAF-mutated cases, none of the non-V600E cases (including V600K) stained positive with the antibody (0/11).

There were 5 cases with discordant BRAF mutation results. Additional molecular analysis confirmed the BRAF results obtained via immunohistochemistry in 3 cases, which suggests, according to the AJSP abstract, that the initial molecular testing results were incorrect. Two patients would not have received a BRAF inhibitor on the basis of the initial false-negative mutation testing result, and two cases remained discordant.

As a result of the study, the researchers conclude: “The reported IHC method is an accurate, rapid, and cost-effective method for detecting V600E BRAF mutations in melanoma patients. Clinical use of the V600E BRAF antibody should be a valuable supplement to conventional mutation testing and allow V600E mutant metastatic melanoma patients to be triaged rapidly into appropriate treatment pathways.”

Long GV, Wilmott JS, Capper D, et al. Immunohistochemistry is highly sensitive and specific for the detection of V600E BRAF mutations in melanoma. Am J Surg Pathol. 2012 Jan;37(1):61-65.

Skin Cancer ReviewNew Study Will Investigate the Bystander Effect of PV-10

Researchers at the Moffitt cancer Center in Tampa, FL have initiated a trial with the drug-in-development PV-10 to investigate potential immune biomarkers in both tumor tissue and peripheral blood after intralesional PV-10 injection of melanoma tumors.

According to Craig Dees, PhD, the CEO of Provectus, the pharmaceutical company developing PV-10, “We believe that the mechanism by which PV-10 can cause regression of un-injected lesions is novel. Although this study is separate from our expected registration pathway (study of PV-10 in melanoma patients with loco-regional disease accessible to PV-10 treatment), this work is very important as it will help us to better understand the potential systemic benefit of PV-10 treatment, and suggest logical therapeutic combinations that may augment the apparent immune response to PV-10 treatment in cancer patients with substantial tumor burden.”

Provectus has already completed Phase II trials of PV-10 in metastatic melanoma.

Amod Sarnaik, MD, a member of the Experimental Therapeutics Program at Moffitt and a faculty member at the University of South Florida, is the principal investigator for the new study, which is expected to enroll as many as 15 patients.

According to Dr. Sarnaik, “These results should help elucidate the immunologic basis of the ‘bystander effect’ noted in previous clinical studies of PV-10 and help optimize PV-10 treatment, particularly in combination with other therapies. As Moffitt pursues its mission of contributing to the prevention and cure of cancer, we are pleased to spearhead this important clinical work.”

Skin Cancer ReviewRates of Non-Melanoma Skin Cancer Are Increased in HIV-Positive Patients

Patients with HIV are more likely to suffer from non-melanoma skin cancer (NMSC) than HIV-negative individuals, the results of a new study in the Journal of the National Cancer Institute (JNCI) show.

The group of researchers from the National Cancer Institute and Kaiser Permanente Northern California identified 6,560 HIV-positive and 36,821 HIV-negative non-Hispanic white males who were enrolled in and followed up at Kaiser Permanente Northern California from 1996 to 2008. The first biopsy-proven NMSCs diagnosed during follow-up were identified from pathology records, according to the article in JNCI.

Rates of NMSC incidence were 1,426 and 766 per 100,000 person years for HIV-positive and HIV-negative individuals, respectively, according to the article in JNCI, corresponding to an adjusted rate ratio of 2.1 (95% confidence interval [CI] = 1.9 to 2.3). The adjusted rate ratio for HIV-negative versus HIV-positive patients was 2.6 (95% CI = 2.1 to 3.2) for squamous cell carcinoma (SCC) and 2.1 (95% CI = 1.8 to 2.3) for basal cell carcinoma (BCC). The researchers also report a statistically significant trend of higher rate ratios with lower recent CD4 counts among HIV-positive patients compared to HIV-negative men for SCC [P (trend)<.001).

The researchers conclude: “HIV-positive subjects had a two-fold higher incidence rate of NMSCs compared with HIV-negative subjects. SCCs but not BCCs were associated with immunodeficiency.”

Silverberg MJ, Leyden W, Warton EM, Quesenberry CP Jr, Engels EA, Asgari MM. HIV infection status, immunodeficiency and the incidence of non-melanoma skin cancer [published online ahead of print January 4, 2013]. J Natl Cancer Inst. doi: 10.1093/jnci/djs529.

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