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Skin Cancer

Skin cancer is the most common type of cancer and accounts for half of all new cancers in Western populations. It occurs more often in people with light coloured skin who have had a high exposure to sunlight. The two most frequent types of skin cancer are Basal Cell Carcinomas and Squamous Cell Carcinoma (often grouped under "non-melanoma skin cancer"). The third most frequent skin cancer is Melanoma, this is a malignancy of the cells which give the skin it's colour (melanocytes). In addition there are a number of other, less common cancers starting in the skin including Merkel cell tumours, cutaneous lymphomas, and sarcomas (see the pages on sarcoma and lymphoma in this guide).

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Information for Patients and the Public
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Latest Research Publications
Prevention of Skin Cancer
Non Melanoma Skin Cancer
-- Basal Cell Carcinoma
-- Squamous Cell Carcinoma
Cutaneous T-cell Lymphoma
Dermatofibrosarcoma Protuberans
Merkel Cell Cancer

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  • PubMed search for publications about Skin Cancer - Limit search to: [Reviews]

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    MeSH term: Skin Neoplasms
    International US National Library of Medicine
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Loeb S, Folkvaljon Y, Lambe M, et al.
Use of Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction and Risk of Malignant Melanoma.
JAMA. 2015 Jun 23-30; 313(24):2449-55 [PubMed] Related Publications
IMPORTANCE: The target for the oral erectile dysfunction drugs, phosphodiesterase type 5 (PDE5) inhibitors, is part of a pathway implicated in the development of malignant melanoma. An increased risk of melanoma in sildenafil users was recently reported.
OBJECTIVE: To examine the association between use of PDE5 inhibitors and melanoma risk, including data on specific PDE5 inhibitors, number of prescriptions, and melanoma stage.
DESIGN, SETTING, AND PARTICIPANTS: Nationwide, population-based, nested case-control study in the Swedish Prescribed Drug Register, the Swedish Melanoma Register, and other health care registers and demographic databases in Sweden, including 4065 melanoma cases diagnosed from 2006 through 2012 and 5 randomly selected controls per case with matching year of birth.
EXPOSURES: Number of filled prescriptions for the PDE5 inhibitors sildenafil and vardenafil or tadalafil.
MAIN OUTCOMES AND MEASURES: Risk of melanoma; overall and by stage and risk of basal cell carcinoma in multivariable logistic regression analyses.
RESULTS: Of 4065 melanoma cases, 435 men (11%) had filled prescriptions for PDE5 inhibitors, as did 1713 men of 20,325 controls (8%). In multivariable analysis, there was an increased risk of melanoma in men taking PDE5 inhibitors (OR, 1.21 [95% CI, 1.08-1.36]). The most pronounced increase in risk was observed in men who had filled a single prescription (OR, 1.32 [95% CI, 1.10-1.59]; exposure rate, 4% for cases vs 3% for controls), but was not significant among men with multiple filled prescriptions (for 2-5 prescriptions: OR, 1.14 [95% CI, 0.95-1.37], 4% for cases and 3% for controls; for ≥6 prescriptions: OR, 1.17 [95% CI, 0.95-1.44], 3% for cases vs 2% for controls). PDE5 inhibitors were significantly associated with melanoma stage 0 (OR, 1.49 [95% CI, 1.22-1.83], 13% for cases vs 8% for controls) and stage I (OR, 1.21 [95% CI, 1.02-1.43], 12% for cases vs 10% for controls), but not stage II through IV (OR, 0.83 [95% CI, 0.63-1.09], 6% for cases vs 7% for controls). The risk estimates were similar for sildenafil and vardenafil or tadalafil. PDE5 inhibitor use was also associated with an increased risk of basal cell carcinoma (OR, 1.19 [95% CI, 1.14-1.25], 9% for cases vs 8% for controls). Men taking PDE5 inhibitors had a higher educational level and annual income, factors that were also significantly associated with melanoma risk.
CONCLUSIONS AND RELEVANCE: In a Swedish cohort of men, the use of PDE5 inhibitors was associated with a modest but statistically significant increased risk of malignant melanoma. However, the pattern of association (eg, the lack of association with multiple filled prescriptions) raises questions about whether this association is causal.

Andrei R, Zurac S, Socoliuc C, et al.
Problems of Differential Diagnosis in Melanoma Arising from Blue Naevus.
Rom J Intern Med. 2015 Jan-Mar; 53(1):95-101 [PubMed] Related Publications
Melanoma arising from blue naevus is an exceedingly rare variant of melanoma. Most of the cases are located in head and neck area, with scalp the most affected site. This type of melanoma develops on blue naevus or resembles blue naevus, most frequently cellular blue naevus. We present the case of a 52 years old female diagnosed with a pigmented melanoma of the scalp, with maximum tumoral thickness of 6.8 mm and invasion of the hypodermis, highly resembling cellular blue naevus. All criteria of malignancy were present: prominent nuclear pleomorphism, infiltrative pattern, tumoral necrosis, high mitotic rate (11 mitoses/mm2) with atypical mitosis and high Ki67 index. No lymph node or distant metastases were identified at presentation. Because of the rarity of cases, histopathological diagnosis can be difficult, differential diagnosis with blue naevi, atypical blue naevi or metastatic melanoma being the most challenging problems. Prognosis is given by tumoral thickness, frequently being more than 4 mm.

Socoliuc C, Zurac S, Andrei R, Stăniceanu F
Multiple Histological Subtypes of Dermatofibrosarcoma Protuberans Occurring in the Same Tumor.
Rom J Intern Med. 2015 Jan-Mar; 53(1):79-88 [PubMed] Related Publications
Dermatofibrosarcoma protuberans (DFSP) represents a low-grade cutaneous sarcoma which may have different histological aspects, presenting as a fibrosarcomatous, pigmented, juvenile, myxoid, atrophic, sclerosing or myoid lesion. Some of these subtypes may occur isolated or in association with one of the others creating hybrid lesions. We present the case of a 66 years old woman having a 4 cm diameter tumor located on the abdominal wall. Histopathological examination of the resection specimen revealed areas of typical DFSP associated with fibrosarcomatous transformation, myoid and myxoid areas. Also, focally, pleomorphic tumor cells and foreign-body type multinucleated giant cells were observed. Immunostains revealed CD34 positivity in typical DFSP and myxoid areas with negative staining of some of the tumor cells in fibrosarcomatous areas and negative staining of myoid areas. Smooth muscle actin was positive in myoid areas. The nature of myoid fascicles in DFSP is a matter of debate, being uncertain whether these represent a type of tumor differentiation or a reactive myoid proliferation. In this particular case, finding the association of myoid cells with blood vessel walls sustains their reactive nature. We present the morphological aspects of the different areas of the tumor with emphasis on differential diagnostic problems and clinical implications.

Guy GP, Thomas CC, Thompson T, et al.
Vital signs: melanoma incidence and mortality trends and projections - United States, 1982-2030.
MMWR Morb Mortal Wkly Rep. 2015; 64(21):591-6 [PubMed] Related Publications
BACKGROUND: Melanoma incidence rates have continued to increase in the United States, and risk behaviors remain high. Melanoma is responsible for the most skin cancer deaths, with about 9,000 persons dying from it each year.
METHODS: CDC analyzed current (2011) melanoma incidence and mortality data, and projected melanoma incidence, mortality, and the cost of treating newly diagnosed melanomas through 2030. Finally, CDC estimated the potential melanoma cases and costs averted through 2030 if a comprehensive skin cancer prevention program was implemented in the United States.
RESULTS: In 2011, the melanoma incidence rate was 19.7 per 100,000, and the death rate was 2.7 per 100,000. Incidence rates are projected to increase for white males and females through 2019. Death rates are projected to remain stable. The annual cost of treating newly diagnosed melanomas was estimated to increase from $457 million in 2011 to $1.6 billion in 2030. Implementation of a comprehensive skin cancer prevention program was estimated to avert 230,000 melanoma cases and $2.7 billion in initial year treatment costs from 2020 through 2030.
CONCLUSIONS: If additional prevention efforts are not undertaken, the number of melanoma cases is projected to increase over the next 15 years, with accompanying increases in health care costs. Much of this morbidity, mortality, and health care cost can be prevented.
IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Substantial reductions in melanoma incidence, mortality, and cost can be achieved if evidence-based comprehensive interventions that reduce ultraviolet (UV) radiation exposure and increase sun protection are fully implemented and sustained.

Kandolf-Sekulović L, Babović N, Jokić N, et al.
Clinicopathological characteristics, diagnosis and treatment of melanoma in Serbia--the Melanoma Focus Study.
Vojnosanit Pregl. 2015; 72(4):312-6 [PubMed] Related Publications
BACKGROUND/AIM: Treatment options for metastatic melanoma in Serbia are limited due to the lack of newly approved biologic agents and the lack of clinical studies. Also, there is a paucity of data regarding the treatment approaches in different tertiary centers and efficacy of available chemotherapy protocols. The aim of this study was to obtain more detailed data about treatment protocols in Serbia based on structured survey in tertiary oncology centers.
METHODS: Data about the melanoma patients treated in 2011 were analyzed from hospital databases in 6 referent oncology centers in Serbia, based on the structured survey, with the focus on metastatic melanoma patients (unresectable stage IIIC and IV).
RESULTS: A total of 986 (79-315 in different centers) patients were treated, with 320 (32.45%) newly diagnosed patients. There were 317 patients in stage IIIC/IV, 77/317 aged < 50 years. At the time of diagnosis 47.3% of patients were < 60 years of age (24.2% < 40 years, 23% 50-59 years, 52.6% > 60 years). At initial diagnosis 12.5% of patients were in stage III and 4.5% in stage IV. The most common type was superficial spreading melanoma (50-660), followed by nodular melanoma (23.5-50%). Apart from the regional and distant lymph node metastases, the most frequent organs involved in stage IV disease were distant skin and soft tissues (12-55%), lungs (19-55.5%), liver (10-60%), and bones (3-10%). The first line therapy in stage IV metastatic melanoma was dacarbazine (DTIC) dimethyl-triazenoimidozole-carboxamide in 61-93% of the patients, while the second line varied between the centers. Disease control (complete response + partial response + stable disease) was achieved in 25.7% of the patients treated with the first line chemotherapy and 23.1% of the patients treated with the second line therapy, but the duration of response was short, in first-line therapy 6.66 +/- 3.36 months (median 6.75 months). More than 90% of patients were treated outside the clinical trials.
CONCLUSION: Based on this survey, there is a large unmet need for the new treatment options for metastatic melanoma in Serbia. The development of national guidelines, and greater involvement in international clinical studies could lead to widening of treatment options for this chemotherapy resistant disease.

Larkin J, Chiarion-Sileni V, Gonzalez R, et al.
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
N Engl J Med. 2015; 373(1):23-34 [PubMed] Related Publications
BACKGROUND: Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] checkpoint inhibitor) have been shown to have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab plus ipilimumab was compared with ipilimumab alone in patients with metastatic melanoma.
METHODS: We assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression-free survival and overall survival were coprimary end points. Results regarding progression-free survival are presented here.
RESULTS: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group.
CONCLUSIONS: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).

Holm RP
Skin cancer prevention and screening.
S D Med. 2015; Spec No:75-7, 79-81 [PubMed] Related Publications
Skin cancer is the most common and recognizable of all cancers. The human dermis can turn malignant due to excessive solar exposure and chronic injury, with the influence of genetic risk and inherited pigmentation. Basal cell carcinoma, the most common skin cancer in lighter pigmented individuals, spreads locally, and usually appears pearly and often ulcerative. Squamous cell carcinoma, the most common skin cancer in darker pigmented people, metastasizes to lymph nodes 2-5 percent of the time, appears often scaly, smooth, nodular, ulcerative, or even pigmented. Malignant melanoma accounts for 2 percent of skin cancers, but for the vast majority of skin cancer deaths. All three can mimic each other. Solar or ultraviolet (UV) light exposure is the most common carcinogen; however, any chronic irritant can increase the risk, and efforts to avoid such exposure is apropos. Though not yet absolutely proven, skin cancer research strongly supports the following statements: sunscreen is protective, tanning devices are causative, and the routine screening of high-risk individuals is preventative. Authorities strongly recommend avoiding excess sun and UV light, using sunscreen, and keeping a watchful eye for unusual skin lesions.

Xu YG, Aylward J, Longley BJ, et al.
Eccrine Porocarcinoma Treated by Mohs Micrographic Surgery: Over 6-Year Follow-up of 12 Cases and Literature Review.
Dermatol Surg. 2015; 41(6):685-92 [PubMed] Related Publications
BACKGROUND: Eccrine porocarcinoma (EPC) has a poor prognosis after standard wide local excision (WLE), with 20% local recurrence, 20% regional and 12% distant metastatic rates. Mohs micrographic surgery (MMS) has been used as a promising treatment.
OBJECTIVE: To review the use of MMS for EPC and assess treatment outcomes.
MATERIALS AND METHODS: This was a retrospective case series of 12 EPC patients treated by MMS between 1984 and 2013 in the institution. Furthermore, a literature review revealed an additional 17 cases of EPC managed by MMS.
RESULTS: Of 29 cases of EPC treated by MMS, outcome was established in 27 cases. The patients had a significantly longer mean follow-up period of 6 years (range, 4-206 months), as compared with 19 months (range, 2-48 months) in reported cases. Two patients had regional lymph node metastasis after MMS. The regional metastatic rates to lymph nodes were 7% (2/27). There was no local recurrence, distant metastasis, or disease-specific death in the 27 cases studied.
CONCLUSION: To the best of the authors' knowledge, this is the single largest case series of EPCs treated by MMS and the authors' data demonstrated that MMS may be superior to the standard WLE.

Sekulic A, Migden MR, Lewis K, et al.
Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12-month update of efficacy and safety of vismodegib in advanced BCC.
J Am Acad Dermatol. 2015; 72(6):1021-6.e8 [PubMed] Related Publications
BACKGROUND: Primary analysis from the pivotal ERIVANCE BCC study resulted in approval of vismodegib, a Hedgehog pathway inhibitor indicated for treatment of adults with metastatic or locally advanced basal cell carcinoma (BCC) that has recurred after surgery or for patients who are not candidates for surgery or radiation.
OBJECTIVE: An efficacy and safety analysis was conducted 12 months after primary analysis.
METHODS: This was a multinational, multicenter, nonrandomized, 2-cohort study in patients with measurable and histologically confirmed locally advanced or metastatic BCC taking oral vismodegib (150 mg/d). Primary outcome measure was objective response rate (complete and partial responses) assessed by independent review facility.
RESULTS: After 12 months of additional follow-up, median duration of exposure to vismodegib was 12.9 months. Objective response rate increased from 30.3% to 33.3% in patients with metastatic disease, and from 42.9% to 47.6% in patients with the locally advanced form. Median duration of response in patients with locally advanced BCC increased from 7.6 to 9.5 months. No new safety signals emerged with extended treatment duration.
LIMITATIONS: Limitations include low prevalence of advanced BCC and challenges of designing a study with heterogenous manifestations.
CONCLUSION: The 12-month update of the study confirms the efficacy and safety of vismodegib in management of advanced BCC.

Gibson JF, Alpdogan O, Subtil A, et al.
Hematopoietic stem cell transplantation for primary cutaneous γδ T-cell lymphoma and refractory subcutaneous panniculitis-like T-cell lymphoma.
J Am Acad Dermatol. 2015; 72(6):1010-5.e5 [PubMed] Related Publications
BACKGROUND: The panniculitic T-cell lymphomas (TCLs) comprise 2 distinct entities, αβ subcutaneous panniculitis-like TCL (SPTCL) and the γδ cutaneous TCLs with pannicular involvement primary cutaneous γδ (PCGD)-TCL. Although outcomes for most patients with SPTCL are favorable, those with PCGD-TCLs generally have an inferior outcome, and treatment strategies have not been well defined. Allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to be a potentially curative strategy in aggressive TCLs and in refractory and advanced-stage mycosis fungoides.
OBJECTIVE: We sought to analyze the outcomes of HSCT for panniculitic cutaneous TCL.
RESULTS: Fourteen patients (4 SPTCL, 10 PCGD-TCL) presented with primarily pannicular T-cell infiltrates. Seven patients underwent allogeneic HSCT from matched-related donors and matched-unrelated donors of which 4 (57%) are alive (1 SPTCL, 3 PCGD-TCL) at 7.8, 6.9, 6.2, and 0.25 years. Two patients underwent autologous HSCT (1 SPTCL, 1 PCGD-TCL) and both are alive at a median follow-up of 1.91 years.
LIMITATIONS: This study is limited by its retrospective nature and small sample size because of the rarity of SPTCL and PCGD-TCL.
CONCLUSION: Aggressive therapy followed by allogeneic HSCT is a promising treatment modality for patients with PCGD-TCL.

Henn A, Michel L, Fite C, et al.
Sézary syndrome without erythroderma.
J Am Acad Dermatol. 2015; 72(6):1003-9.e1 [PubMed] Related Publications
BACKGROUND: Sézary syndrome is a cutaneous T-cell lymphoma characterized by erythroderma and leukemic involvement.
OBJECTIVE: We sought to define the clinical, biologic, and histopathologic features of Sézary syndrome without erythroderma.
METHODS: Features of patients with Sézary syndrome and normal-appearing skin or stage-T1 patches, fulfilling Sézary syndrome hematologic criteria and with histologically documented disease in normal-appearing skin were collected. Expression of Sézary syndrome molecular biomarkers in peripheral blood and skin lymphocytes were studied.
RESULTS: Five women and 1 man (median age: 71 years) were all referred for generalized pruritus. Four had no specific lesions; 2 had T1-stage patches. Histologic examination of normal-appearing skin from all patients showed lesions compatible with Sézary syndrome. Peripheral blood lymphocytes from 3 of 4 patients tested strongly expressed PLS3, Twist-1, and KIR3DL2. All normal-appearing skin biopsy specimens expressed programmed death-1. Median follow-up was 9 years. Although no patient developed erythroderma, tumors, or abnormal lymph nodes, specific skin lesions appeared in all patients during follow-up. Only 1 death, unrelated to Sézary syndrome, occurred.
LIMITATIONS: Retrospective design and small sample size are limitations.
CONCLUSION: Sézary syndrome without erythroderma is a rare entity that may have a better prognosis than classic Sézary syndrome.

March J, Hand M, Truong A, Grossman D
Practical application of new technologies for melanoma diagnosis: Part II. Molecular approaches.
J Am Acad Dermatol. 2015; 72(6):943-58; quiz 959-60 [PubMed] Related Publications
The criterion standard for diagnosing cutaneous melanoma continues to be histologic examination. However, classifying some melanocytic lesions by conventional microscopy can be problematic if they exhibit some architectural or morphologic characteristics of both nevus and melanoma. Moreover, histologic appearance does not always predict biologic behavior. There is therefore a need and opportunity to develop new technologies that can facilitate the histologic diagnosis of melanoma and potentially help distinguish lesions with a lesser or greater risk of metastasis. In part II of this 2-part continuing medical education article, we will review the molecular technologies currently available for facilitating melanoma diagnosis, including comparative genomic hybridization, fluorescence in situ hybridization, and epidermal genetic retrieval. Our goal is to provide the clinician with an up to date understanding of these molecular approaches so that they can be applied to their management of challenging melanocytic lesions.

March J, Hand M, Grossman D
Practical application of new technologies for melanoma diagnosis: Part I. Noninvasive approaches.
J Am Acad Dermatol. 2015; 72(6):929-41; quiz 941-2 [PubMed] Related Publications
Confirming a diagnosis of cutaneous melanoma requires obtaining a skin biopsy specimen. However, obtaining numerous biopsy specimens-which often happens in patients with increased melanoma risk-is associated with significant cost and morbidity. While some melanomas are easily recognized by the naked eye, many can be difficult to distinguish from nevi, and therefore there is a need and opportunity to develop new technologies that can facilitate clinical examination and melanoma diagnosis. In part I of this 2-part continuing medical education article, we will review the practical applications of emerging technologies for noninvasive melanoma diagnosis, including mobile (smartphone) applications, multispectral imaging (ie, MoleMate and MelaFind), and electrical impedance spectroscopy (Nevisense).

Aguayo RS, Rafel M, Santacana M, et al.
Erk1/2 activation in stromal fibroblasts from sporadic basal cell carcinomas.
Dermatol Surg. 2015; 41(6):677-84 [PubMed] Related Publications
BACKGROUND: Constitutive activation of the Erk pathway can lead to oncogenic transformation. However, the Erk pathway is not activated in human basal cell carcinomas (BCCs); although in animal models, this seems to be important.
OBJECTIVE: To help understand the role of Erk activity in BCC formation.
MATERIALS AND METHODS: The authors assayed the specific levels of phosphorylated Erk by immunohistochemistry in BCCs and normal skin biopsies. They have also analyzed Erk activation by immunoblot in fibroblasts isolated from BCC.
RESULTS: By immunohistochemical analysis, the authors have observed that 10 of BCCs (56%) did not show phosphor-Erk staining in tumor masses and 7 (40%) showed a gradient staining exhibiting phospho-Erk only in the epidermal side of tumor masses. Remarkably, 15 BCC samples (83%) showed phospho-Erk accumulation in stroma. Six of the 9 independent cultures of dermal fibroblasts isolated from BCC maintained Erk activation "in vitro."
CONCLUSION: The authors propose that there is a specific cell-type regulation of Erk activity in BCC, and this feature may be relevant during BCC formation. Stroma region from BCCs showed Erk activation and reduced proliferation. Conversely, Erk activation is barely detectable in proliferative BCCs.

Mochel MC, Piris A, Nose V, Hoang MP
Loss of BAP1 Expression in Basal Cell Carcinomas in Patients With Germline BAP1 Mutations.
Am J Clin Pathol. 2015; 143(6):901-4 [PubMed] Related Publications
OBJECTIVES: Patients with heterozygous germline mutations in BRCA1-associated protein 1 (BAP1), a tumor suppressor gene, develop a tumor predisposition syndrome (OMIM 614327) with increased risk of uveal and cutaneous melanomas, cutaneous atypical and epithelioid melanocytic lesions, lung adenocarcinoma, clear cell renal cell carcinoma, and other tumors. Early recognition of this syndrome is of clinical importance. In addition, screening for BAP1 mutation, loss, and inactivation by performing BAP1 immunohistochemistry on cutaneous lesions would be a simple method for screening patients suspected of having germline BAP1 mutations.
METHODS: We investigated BAP1 expression in seven basal cell carcinomas (BCCs) in two patients with germline BAP1 mutation and a family history of uveal melanoma. Six lesions were from the head and neck region and one from the shoulder. Thirty-one sporadic BCCs were included as controls.
RESULTS: All seven BCCs in the patients with germline BAP1 mutations exhibited loss of BAP1 nuclear staining, while 30 (97%) of 31 sporadic BCCs exhibited positive BAP1 nuclear staining.
CONCLUSIONS: Loss of BAP1 expression could be associated with the development of BCC in patients with germline BAP1 mutations. These results suggest that BCC may be a component of the expanding category of tumors associated with this syndrome.

Horna P, Kurant D, Sokol L, et al.
Flow cytometric identification of immunophenotypically aberrant T-cell clusters on skin shave biopsy specimens from patients with mycosis fungoides.
Am J Clin Pathol. 2015; 143(6):785-96 [PubMed] Related Publications
OBJECTIVES: To assess the ability of flow cytometry (FC) to detect putative neoplastic T-cell subsets on skin shave biopsy (SSB) specimens from patients with mycosis fungoides (MF) and to study the immunophenotype of skin-infiltrating tumor cells in MF.
METHODS: SSB specimens from patients with suspected MF were bisected and submitted for both FC and routine histopathology. Six-dimensional gating strategies were applied to identify putative neoplastic cells, independently from their expected immunophenotype.
RESULTS: Aberrant T cells were detected by FC in 18 of 33 SBB specimens, of which all had clinicomorphologic features of MF. Of the remaining 15 SSB specimens, six had clinicomorphologic features of MF and nine were diagnosed with benign inflammatory dermatoses. Unexpectedly, CD26 was aberrantly overexpressed in 11 (73%) and lost in three (20%) of 15 SSB specimens from patients with MF where this antigen was evaluated. Other detected aberrancies included CD3 dim- (13/18 [72%]), CD7 dim- (15/18 [83%]), and CD4-/CD8- (3/18 [17%]).
CONCLUSIONS: FC is capable of identifying putative neoplastic cells on SSB specimens from patients with MF. Bright homogeneous CD26 expression is a common and previously undescribed immunophenotypic aberrancy on MF skin infiltrates.

Di Giacomo AM, Margolin K
Immune checkpoint blockade in patients with melanoma metastatic to the brain.
Semin Oncol. 2015; 42(3):459-65 [PubMed] Related Publications
Metastatic disease to the brain is a frequent manifestation of melanoma and is associated with a very poor outcome. Systemic therapy with cytotoxic chemotherapy provide only a minimal benefit, while surgery and radiotherapy provide in some patients local control but they less frequently affect the overall outcome of melanoma brain metastases (MBM). The advent of active systemic drugs has revolutioned the care of metastatic melanoma, but this benefit has not been translated into intracranial activity. However, since 2010 the anti-CTLA-4 antibody ipilimumab and the BRAF inhibitors, dabrafenib and vemurafenib, have demonstrated initial signs of efficacy in active brain metastases. This chapter reviews the available data and rationale for ongoing and future trials of immune checkpoint-based combination therapy.

Weide B, Di Giacomo AM, Fonsatti E, Zitvogel L
Immunologic correlates in the course of treatment with immunomodulating antibodies.
Semin Oncol. 2015; 42(3):448-58 [PubMed] Related Publications
Monoclonal antibodies (Ab) targeting immune checkpoints like CTLA-4 or PD-1 have come of age in the treatment of metastatic melanoma and further approvals are expected for other malignancies like lung and renal cell cancer as well. However, the majority of patients still do not experience clinical benefit upon these therapies. Moreover, immune-related side effects and the costs of these therapies prompt the search for their precise mode of action and for biomarker discovery. Here, we describe different classes of immunologic correlates such as pharmacodynamic changes observed in all treated patients, correlates with response during treatment (surrogate markers) or at the time-point of tumor assessment, as well as predictive markers for response and for immune-related adverse events. This review gives an overview of available data about correlates analyzed in the serum, all in immune cell subsets in the peripheral blood or in tumor-infiltrating lymphocytes. We will discuss how to prospectively validate and integrate these parameters for routine assessment of patients in daily clinical practice and give an outlook on promising future directions of biomarker research.

Eggermont AM, Maio M, Robert C
Immune checkpoint inhibitors in melanoma provide the cornerstones for curative therapies.
Semin Oncol. 2015; 42(3):429-35 [PubMed] Related Publications
Immunotherapy has been revolutionalized by the concept of breaking tolerance. It represents a major paradigm shift that marks the beginning of a new era. The impact of the first checkpoint inhibitors, ie, anti-CTLA-4 (cytotoxic T lymphocyte antigen-4) and anti-PD-1/ anti-PD-L1 (programmed death-1 receptor and its ligand, PD-L1) is unprecedented. In only 5 years advanced melanoma has been transformed from an incurable disease into a curable disease, and we are only at the beginning of discovering its transversal impact throughout solid tumor oncology. In advanced melanoma response rates are about 12% for anti-CTLA-4 and about 40% for anti-PD-1, and are remarkably durable, hence their impact on survival. In melanoma anti-CTLA-4 (ipilimumab) was approved in 2011 and anti-PD-1 (pembrolimumab) in 2014. Another anti-PD-1 antibody (nivolumab) has been recently approved based on phase III trial results in metastatic melanoma without BRAF mutation. Ipilimumab already has been evaluated in the adjuvant setting (European Organization for Research and Treatment of Cancer [EORTC] 18071) and shown to significantly improve recurrence-free survival in stage III patients at high risk of relapse. An adjuvant trial to evaluate pembrolizumab in this population (EORTC 1325) was started in early 2015.

Delyon J, Maio M, Lebbé C
The ipilimumab lesson in melanoma: achieving long-term survival.
Semin Oncol. 2015; 42(3):387-401 [PubMed] Related Publications
The anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) antibody ipilimumab is the first treatment that significantly improved the survival rates of metastatic melanoma patients, marking a new era in the treatment of melanoma. During its development, a hallmark of ipilimumab therapy was the extended duration of response, achieved in 20% of patients. The follow-up of patients included in phase II and phase III trials and in expanded access programs revealed that the survival rates remained stable after 3 years. These results demonstrated that ipilimumab induces an effective anti-tumor immune response persisting after the completion of treatment, and suggested a potential remission in a subset of patients. In this article we review the development of ipilimumab and highlight the long-term results. This approach emphasizes the need to optimize the use of ipilimumab in the future, by identifying the patients most likely to achieve long term survival after ipilimumab therapy, and by developing combined therapeutic approaches involving cytotoxic agents, targeted therapies or other immunotherapies to achieve durable control in a larger proportion of patients.

Vemurafenib (Zelboraf) with longer follow-up. Metastatic melanoma: a few extra months of life, but many adverse effects.
Prescrire Int. 2015; 24(159):89-90 [PubMed] Related Publications
Further analysis of the unblinded trial described in the initial clinical evaluation suggests that vemurafenib prolongs survival by a median of about 4 months compared with dacarbazine. The adverse effects of vemurafenib are frequent and sometimes serious. More data are needed on renal and pancreatic toxicity and the risk of extracutaneous cancers.

Wang C, Luo Z, Chen J, et al.
Target therapy of unresectable or metastatic dermatofibrosarcoma protuberans with imatinib mesylate: an analysis on 22 Chinese patients.
Medicine (Baltimore). 2015; 94(17):e773 [PubMed] Related Publications
Dermatofibrosarcoma protuberans (DFSP) is a rare, plaque-like tumor of the cutaneous tissue occurring more on the trunk than the extremities and neck. More than 95% of DFSP present anomalies on the 17q22 and 22q13 chromosomal regions leading to the fusion of COL1A1 and PDGFB genes. Surgery is the optimal treatment for DFSP, but less effective in locally advanced or metastatic patients, as is the case with chemotherapy and radiotherapy. The aim of this study was to assess retrospectively the therapeutic activity and safety of imatinib on 22 Chinese patients with locally inoperative or metastatic DFSP at a single institution.In the collected data of 367 Chinese patients with DFSP, we analyzed retrospectively 22 patients with locally advanced or metastatic DFSP, all of whom received imatinib therapy at 1 center from January 2009 to October 2014. Patients were administered with imatinib at an initial dose of 400 mg and escalated to 800 mg daily after they developed imatinib resistance. The median follow-up time was 36 months, and the median treatment time was 15 months.The results showed that 10 locally advanced DFSP patients and 12 metastatic DFSP patients received imatinib therapy. Apart from 1 patient who developed primary imatinib resistance, 15 patients achieved partial remission (PR), and 6 patients achieved stable disease (SD). Both fibrosarcomatous DFSP and classic DFSP patients demonstrated similar response to imatinib. Median PFS was estimated to be 19 months. Median overall survival (OS) has not been reached, and estimated 1- and 3-year OS rates were 95.5% (21/22) and 77.3% (17/22), respectively. Four out of 10 patients with primarily unresectable DFSP received complete surgical resection after neoadjuvant treatment of imatinib.Imatinib therapy is well tolerated with a safety profile and is the therapy of choice in locally inoperative or metastatic DFSP. Neoadjuvant treatment of locally advanced or metastatic DFSP with imatinib improves surgical outcomes and may facilitate resection of difficult tumors.

Rogers-Vizena CR, Lalonde DH, Menick FJ, Bentz ML
Surgical treatment and reconstruction of nonmelanoma facial skin cancers.
Plast Reconstr Surg. 2015; 135(5):895e-908e [PubMed] Related Publications
LEARNING OBJECTIVES: After reading this article, the participant should be able to: (1) Identify the appropriate resection margins for common types of nonmelanoma skin cancer. (2) Discuss indications for secondary intention healing, skin grafting, and local flaps for reconstruction of facial skin cancer defects. (3) Describe at least one local flap for reconstruction of scalp, forehead, temple/cheek, periocular, nose, and lips.
SUMMARY: Current evidence for diagnosis and surgical treatment of nonmelanoma facial skin cancers is reviewed. In addition, reconstructive options for facial defects are discussed by anatomic location.

Walsh SB, Varma R, Raimer D, et al.
Utility of Wood's light in margin determination of melanoma in situ after excisional biopsy.
Dermatol Surg. 2015; 41(5):572-8 [PubMed] Related Publications
BACKGROUND: Margin evaluation of melanoma in situ (MIS) is difficult because of its ill-defined clinical borders. Wood's light examination is commonly used to help delineate MIS margin before excision.
OBJECTIVE: To prospectively study the accuracy of preoperative Wood's light examination for margin assessment of MIS.
MATERIALS AND METHODS: The authors evaluated 60 patients before excision of MIS under white light and Wood's light. Staged excision was performed using the square procedure technique. After achieving clear margins, they compared final wound size with expected wound size if surgical margins had been based on Wood's light examination.
RESULTS: Seven patients (11.7%) had Wood's light enhancement beyond the visible margin of the biopsy site. In all 7, increased wounding would have occurred if the surgical margins had been based on Wood's light examination. In 1 of the 7, use of the Wood's light examination would have reduced the surgical stages needed by 1 stage but would have increased the wound size by 83.3%.
CONCLUSION: Wood's light examination has limited utility if complete excisional biopsy of MIS is performed before treatment. In this study, surgical margin based on the Wood's light examination would have resulted in an increased average wound size and would not have reduced the number of stages needed when performing the square procedure.

Robert C, Schachter J, Long GV, et al.
Pembrolizumab versus Ipilimumab in Advanced Melanoma.
N Engl J Med. 2015; 372(26):2521-32 [PubMed] Related Publications
BACKGROUND: The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma.
METHODS: In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival.
RESULTS: The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%).
CONCLUSIONS: The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.).

Surace L, Lysenko V, Fontana AO, et al.
Complement is a central mediator of radiotherapy-induced tumor-specific immunity and clinical response.
Immunity. 2015; 42(4):767-77 [PubMed] Related Publications
Radiotherapy induces DNA damage and cell death, but recent data suggest that concomitant immune stimulation is an integral part of the therapeutic action of ionizing radiation. It is poorly understood how radiotherapy supports tumor-specific immunity. Here we report that radiotherapy induced tumor cell death and transiently activated complement both in murine and human tumors. The local production of pro-inflammatory anaphylatoxins C3a and C5a was crucial to the tumor response to radiotherapy and concomitant stimulation of tumor-specific immunity. Dexamethasone, a drug frequently given during radiotherapy, limited complement activation and the anti-tumor effects of the immune system. Overall, our findings indicate that anaphylatoxins are key players in radiotherapy-induced tumor-specific immunity and the ensuing clinical responses.

Pfister H
Association between betapapillomavirus seropositivity and keratinocyte carcinoma-prospects for prophylactic vaccination?
J Invest Dermatol. 2015; 135(5):1211-3 [PubMed] Related Publications
In this issue, Genders et al. (2015) demonstrate in a cohort of organ transplant recipients that betapapillomavirus seropositivity around transplantation significantly increases the risk of developing keratinocyte carcinomas. These results further substantiate an etiologic role of betapapillomaviruses in skin cancer and raise prospects of anti-viral immunotherapy.

Hunger RE, Angermeier S, Seyed Jafari SM, et al.
A retrospective study of 1- versus 2-cm excision margins for cutaneous malignant melanomas thicker than 2 mm.
J Am Acad Dermatol. 2015; 72(6):1054-9 [PubMed] Related Publications
BACKGROUND: Most guidelines recommend at least 2-cm excision margin for melanomas thicker than 2 mm.
OBJECTIVE: We evaluated whether 1- or 2-cm excision margins for melanoma (>2 mm) result in different outcomes.
METHODS: This is a retrospective cohort study on patients with melanomas (>2 mm) who underwent tumor excision with 1-cm (228 patients) or 2-cm (97 patients) margins to investigate presence of local recurrences, locoregional and distant metastases, and disease-free and overall survival.
RESULTS: In all, 325 patients with mean age of 61.84 years and Breslow thickness of 4.36 mm were considered for the study with a median follow-up of 1852 days (1995-2012). There was no significant difference in the frequency of locoregional and distant metastasis between the 2 groups (P = .311 and .571). The survival analysis showed no differences for disease-free (P = .800; hazard ratio 0.948; 95% confidence interval 0.627-1.433) and overall (P = .951; hazard ratio 1.018; 95% confidence interval 0.575-1.803) survival.
LIMITATIONS: The study was not prospectively randomized.
CONCLUSIONS: Our study did not show any significant differences in important outcome parameters such as local or distant metastases and overall survival. A prospective study testing 1- versus 2-cm excision margin is warranted.

Kauvar AN, Cronin T, Roenigk R, et al.
Consensus for nonmelanoma skin cancer treatment: basal cell carcinoma, including a cost analysis of treatment methods.
Dermatol Surg. 2015; 41(5):550-71 [PubMed] Related Publications
BACKGROUND: Basal cell carcinoma (BCC) is the most common cancer in the US population affecting approximately 2.8 million people per year. Basal cell carcinomas are usually slow-growing and rarely metastasize, but they do cause localized tissue destruction, compromised function, and cosmetic disfigurement.
OBJECTIVE: To provide clinicians with guidelines for the management of BCC based on evidence from a comprehensive literature review, and consensus among the authors.
MATERIALS AND METHODS: An extensive review of the medical literature was conducted to evaluate the optimal treatment methods for cutaneous BCC, taking into consideration cure rates, recurrence rates, aesthetic and functional outcomes, and cost-effectiveness of the procedures.
RESULTS: Surgical approaches provide the best outcomes for BCCs. Mohs micrographic surgery provides the highest cure rates while maximizing tissue preservation, maintenance of function, and cosmesis.
CONCLUSION: Mohs micrographic surgery is an efficient and cost-effective procedure and remains the treatment of choice for high-risk BCCs and for those in cosmetically sensitive locations. Nonsurgical modalities may be used for low-risk BCCs when surgery is contraindicated or impractical, but the cure rates are lower.

Campbell LB, Kreicher KL, Gittleman HR, et al.
Melanoma Incidence in Children and Adolescents: Decreasing Trends in the United States.
J Pediatr. 2015; 166(6):1505-13 [PubMed] Related Publications
OBJECTIVE: To assess trends in the incidence of melanoma in children and adolescents in the US from 2000-2010.
STUDY DESIGN: Using the Surveillance, Epidemiology, and End Results cancer registry data, we calculated age-adjusted incidence rates of melanoma in children and adolescents (age <20 years) from 2000-2010, as well as annual percent changes. We analyzed incidence trends using joinpoint regression models. We further stratified incidence rates and trends by age group, sex, race, and melanoma-specific characteristic (histology, anatomic site, Breslow depth, ulceration status, lymph node involvement, and presence of metastasis).
RESULTS: We included 1185 pediatric patients (age <20 years) diagnosed with melanoma from 2000-2010. In patients age <20 years overall, we found a significant decreasing incidence (11.58% per year) from 2004-2010. Overall, significant decreasing incidence trends were also noted in males, melanoma located on the trunk, melanoma located on the upper extremities, superficial spreading melanoma, and melanoma with good prognostic indicators. When further subdividing the pediatric population by age group, these significant decreasing incidence trends were most notable in adolescents (age 15-19 years), decreasing 11.08% per year from 2003-2010. Furthermore, in 15- to 19-year-olds, decreasing trends were found to be significant in melanoma located on the trunk, superficial spreading melanoma, and melanoma with good prognostic indicators.
CONCLUSIONS: Decreasing trends in melanoma incidence in the pediatric population from 2000-2010 stand in contrast to previous reports of increasing long-term incidence trends. Possible contributors to these decreasing trends include effective public health initiatives, decreased time spent outdoors, and increased sunscreen use.

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