Melanoma overdiagnosis: What do we know and what do we do?

BACKGROUND: Melanoma overdiagnosis occurs when melanomas, not destined to cause morbidity or death in a patient's lifetime, are identified and treated. OBJECTIVE: This study considers the causes and magnitude of melanoma overdiagnosis in Australia. We also speculate about a possible benefit of overdiagnosis in Australia; namely, a reduction in excess deaths in the geographical areas where melanoma is diagnosed most frequently. DISCUSSION: Overdiagnosis can arguably be mitigated by factors that reduce the number of lesions treated for each melanoma identified. Data from the Australian Cancer Atlas show that there is a reduction in excess deaths from melanoma in geographical areas where diagnostic rates are higher (Pearson correlation coefficient r=-0.5978, 95% CI: -0.6243 to -0.5699, P<0.0001); this being the strongest inverse correlation observed among the 20 cancer types in the Atlas. Is early diagnosis of actual life-threatening melanomas in these geographical regions impacting survival? Further research is planned.

Practitioner characteristics, diagnostic accuracy metrics and discovering-individual with respect to 637 melanomas documented by 27 general practitioners on the Skin Cancer Audit Research Database.

BACKGROUND AND OBJECTIVE: Knowledge of accuracy for melanoma diagnosis and melanoma discovering-individual in primary care is limited. We describe general practitioner (GP) characteristics and analyse defined diagnostic accuracy metrics for GPs in the current study comparing this with a previous study for GPs common to both, and we analyse the individual first discovering each melanoma as a lesion of concern. METHODS: The characteristics and diagnostic accuracy of 27 Australasian GPs documenting 637 melanomas on the Skin Cancer Audit Research Database (SCARD) in 2013 were described and analysed. The number needed to treat (NNT) and percentage of melanomas that were in situ (percentage in situ) were analysed as surrogates for specificity and sensitivity, respectively. The discovering-individual was analysed according to patient age and sex and lesion Breslow thickness. RESULTS: The average NNT and percentage in situ were 5.73% and 65.07%, respectively. For 21 GPs in both a 2008-2010 study and the current study, the NNT was 10.78 and 5.56, respectively (p = 0.0037). A consistent trend of decreasing NNT and increasing percentage in situ through increasingly subspecialised GP categories did not reach statistical significance. NNT trended high at ages and sites for which melanoma was rare. While the patient or family member was more likely to discover thick melanomas and melanomas in patients under 40 years, GPs discovered 73.9% of the melanomas as lesions of concern. CONCLUSIONS: GPs were the discovering-individuals for the majority of melanomas in the current study and their accuracy metrics compared favourably with published figures for dermatologists and GPs.

Characteristics, treatment and outcomes of 589 melanoma patients documented by 27 general practitioners on the Skin Cancer Audit Research Database.

BACKGROUND AND OBJECTIVE: General practitioners manage more melanomas than dermatologists or surgeons in Australia. Previously undescribed, the management and outcomes of melanoma patients treated by multiple Australasian general practitioners are examined. METHODS: The characteristics, management and outcomes of 589 melanoma patients, managed by 27 Australasian general practitioners and documented on the Skin Cancer Audit Research Database (SCARD), were analysed. RESULTS: Most patients (58.9%) were males with mean age at diagnosis of 62.7 years (range 18-96), and most melanomas were in situ or thin-invasive. Patients aged under 40 years had fewer melanomas, but a higher proportion (the majority) were invasive, compared with older patients (P < 0.0001). Most (55.9%) melanomas were diagnosed following elliptical excision biopsy, the rate of unintended involved margins being eightfold higher for shave biopsies. Wide re-excision was performed by the treating general practitioner for most (74.9%) melanomas, with thick melanomas preferentially referred to surgeons. The average Breslow thickness of invasive melanomas re-excised by general practitioners was 0.67 mm compared with 1.99 mm for those referred to other specialists (P < 0.0001). Of 205 patients with invasive melanoma, 14 progressed to metastatic disease, 50% of these being associated with nodular melanoma. Nine patients progressed to melanoma-specific death. The 5-year survival rate for patients with invasive melanoma was 95.2% (95% CI: 91.2-98.5%). CONCLUSIONS: Diagnostic and therapeutic management of a series of melanoma patients by Australasian general practitioners were closely aligned with current guidelines and 5-year survival with respect to invasive melanoma was at least as favourable as national population-based metrics.

Conventional type 1 dendritic cells (cDC1) as cancer therapeutics: challenges and opportunities.

INTRODUCTION: The use of dendritic cell (DC)-based cancer vaccines over three decades has shown them to be a safe therapeutic approach against a range of hematological and solid malignancies. However, underwhelming and inconsistent results from clinical trials have seen them move in and out of favor. The limitations of ex vivo generated monocyte-derived DC (MoDC) in these therapies provide a pointed explanation for the varying and somewhat disappointing clinical outcomes. The identification of a specialized role for the rare conventional type 1 dendritic cell (cDC1) subset in orchestrating tumor immunity via the initiation of CD8+ T cell responses has led to a new concept of targeting cDC1 as a therapeutic option to address the unmet need of enhancing the immune response in cancer patients. AREAS COVERED: This article reviews several current challenges and key opportunities associated with the development and use of next generation cDC1 cancer vaccines. EXPERT OPINION: Manipulation of cDC1 quantity and quality holds enormous potential to improve tumor immunogenicity, as already demonstrated in preclinical models. New technologies are rapidly advancing the understanding of cDC1 in human cancer patients and facilitating the generation of these extremely rare cells in vitro, providing feasible new approaches toward clinical translation.

Characteristics of 637 melanomas documented by 27 general practitioners on the Skin Cancer Audit Research Database.

BACKGROUND AND OBJECTIVE: Most melanomas (including melanomas in situ), in Australasia, are treated by general practitioners (GPs). Previously undescribed, the characteristics of a series of melanomas treated by multiple GPs are examined. PATIENTS AND METHODS: Six hundred and thirty-seven melanomas treated by 27 Australasian GPs during 2013 and documented on the Skin Cancer Audit Research Database (SCARD) were analysed by anatomical site, subtype, Breslow thickness, diameter, associated naevi and linked adverse outcomes. RESULTS: Most melanomas (59.7%) were on males, mean age at diagnosis being 62.7 years (range 18-96). Most (65.0%) were in situ, with a high incidence of lentiginous melanoma (LM) (38.8%) and 32% were naevus associated. Most LM (86.4%) were in situ, compared to 55% of superficial spreading melanoma (SSM) (P < 0.0001). There was male predominance on the head, neck and trunk and female predominance on extremities. There was no significant association between Breslow thickness and diameter, with small melanomas as likely to be thick as large melanomas, and melanomas ≤3 mm diameter, on average, more likely to be invasive than larger melanomas. There was a positive correlation between age and both melanoma diameter and Breslow thickness. Seven cases progressed to melanoma-specific death: Five nodular melanoma (NM) and two SSM, one of which was thin (Breslow thickness 0.5 mm). CONCLUSIONS: A large series of melanomas treated by Australasian GPs were predominantly in situ, with a high proportion of LM subtype. With implications for GP training, NM linked to death was over-represented and there was a novel finding that older patients had larger diameter melanomas.

Clinical and dermatoscopic characteristics of lichen planus-like keratosis in a West-Asian population.

BACKGROUND/OBJECTIVE: The clinical and dermatoscopic features of lichen planus-like keratosis have been described but the characteristics of this entity in a West-Asian population are not known. METHODS: We retrospectively analysed 82 histopathologically verified cases of lichen planus-like keratosis from 81 patients from Iran and Turkey. RESULTS: The majority of lichen planus-like keratoses were macules (61% n = 50), clinically pigmented (67.1% n = 55) and dermatoscopically multi-coloured (91.5% n = 75). The majority (63.4%) had a single dermatoscopic pattern, most frequently: structureless (35.4%), dots (14.6%) and angulated lines (8.5%). Of the lesions with more than one pattern (n = 30), the majority (n = 21) had asymmetry of pattern, the most common combinations being structureless plus dots (n = 8) and structureless plus angulated lines (n = 5). The most common structure was pigmented dots, most frequently grey and present in 70.7% of cases. Vessels were seen in 30.5% of lesions, being significantly more prevalent in non-pigmented, than pigmented, lichen planus-like keratoses (83.3% vs. 21.4% P < 0.001). When we compared lichen planus-like keratosis in the current study to that entity in a large North American study, the statistically significant differences in a West-Asian population included a greater frequency of pigmented variants, a lower incidence in females and a lower prevalence on the torso, in favour of the face. CONCLUSIONS: Lichen planus-like keratosis in a West-Asian population has clinical and dermatoscopic similarities to that entity in another studied population. The significant differences in gender association and anatomical site may be secondary to cultural factors.

Dermatoscopic features of pigmented intraepidermal carcinoma on the head and neck.

BACKGROUND AND OBJECTIVE: Pigmented intraepidermal carcinoma is characterized by dermatoscopic dots and structureless areas, including dots in linear arrangement and by coiled vessels. There are no studies describing the dermatoscopic features of pigmented intraepidermal carcinoma on the head and neck. We aim to characterize the clinical and dermatoscopic appearance of this entity. PATIENTS AND METHODS: We retrospectively analyzed 79 cases of pigmented intraepidermal carcinoma on the head and neck. RESULTS: Pigmented intraepidermal carcinoma on the head and neck was characterized dermatoscopically by multiple colors (98.7 %, n = 78), pigmented circles (48.1 %, n = 38), white circles (17.7 %, n = 14), angulated lines (41.8 %, n = 33) and structureless areas (86.1 %, n = 68). Dots in linear arrangement were present in 13.9 % (n = 11). Coiled vessels were present in 7.6 % (n = 6), the dominant vessel type being prominent serpentine vessels (29.2 %, n = 23), thicker and/or redder in color than surrounding vessels, most being in the angular arrangement of the dermal plexus (24.1 %, n = 19). CONCLUSIONS: Pigmented intraepidermal carcinoma on the head and neck differs from current published descriptions of pigmented intraepidermal carcinoma, reaching statistical significance with a lower incidence of coiled vessels and a higher incidence of pigmented circles, with evident similarities to pigmented actinic keratosis at that location.

Human CLEC9A antibodies deliver NY-ESO-1 antigen to CD141+ dendritic cells to activate naïve and memory NY-ESO-1-specific CD8+ T cells.

BACKGROUND: Dendritic cells (DCs) are crucial for the efficacy of cancer vaccines, but current vaccines do not harness the key cDC1 subtype required for effective CD8+ T-cell-mediated tumor immune responses. Vaccine immunogenicity could be enhanced by specific delivery of immunogenic tumor antigens to CD141+ DCs, the human cDC1 equivalent. CD141+ DCs exclusively express the C-type-lectin-like receptor CLEC9A, which is important for the regulation of CD8+ T cell responses. This study developed a new vaccine that harnesses a human anti-CLEC9A antibody to specifically deliver the immunogenic tumor antigen, NY-ESO-1 (New York esophageal squamous cell carcinoma 1), to human CD141+ DCs. The ability of the CLEC9A-NY-ESO-1 antibody to activate NY-ESO-1-specific naïve and memory CD8+ T cells was examined and compared with a vaccine comprised of a human DEC-205-NY-ESO-1 antibody that targets all human DCs. METHODS: Human anti-CLEC9A, anti-DEC-205 and isotype control IgG4 antibodies were genetically fused to NY-ESO-1 polypeptide. Cross-presentation to NY-ESO-1-epitope-specific CD8+ T cells and reactivity of T cell responses in patients with melanoma were assessed by interferon γ (IFNγ) production following incubation of CD141+ DCs and patient peripheral blood mononuclear cells with targeting antibodies. Humanized mice containing human DC subsets and a repertoire of naïve NY-ESO-1-specific CD8+ T cells were used to investigate naïve T cell priming. T cell effector function was measured by expression of IFNγ, MIP-1ß, tumor necrosis factor and CD107a and by lysis of target tumor cells. RESULTS: CLEC9A-NY-ESO-1 antibodies (Abs) were effective at mediating delivery and cross-presentation of multiple NY-ESO-1 epitopes by CD141+ DCs for activation of NY-ESO-1-specific CD8+ T cells. When benchmarked to NY-ESO-1 conjugated to an untargeted control antibody or to anti-human DEC-205, CLEC9A-NY-ESO-1 was superior at ex vivo reactivation of NY-ESO-1-specific T cell responses in patients with melanoma. Moreover, CLEC9A-NY-ESO-1 induced priming of naïve NY-ESO-1-specific CD8+ T cells with polyclonal effector function and potent tumor killing capacity in vitro. CONCLUSIONS: These data advocate human CLEC9A-NY-ESO-1 Ab as an attractive strategy for specific targeting of CD141+ DCs to enhance tumor immunogenicity in NY-ESO-1-expressing malignancies.