Dysplastic naevi with moderate to severe histological dysplasia: a risk factor for melanoma

BACKGROUND: The risk of malignant melanoma associated with histologically dysplastic naevi (HDN) has not been defined. While clinically atypical naevi appear to confer an independent risk of melanoma, no study has evaluated the extent to which HDN are predictive of melanoma. OBJECTIVES: To estimate the risk of melanoma associated with HDN. Secondarily, the risk associated with number of naevi and large naevi is estimated. METHODS: We enrolled 80 patients with newly diagnosed melanoma along with 80 spousal controls. After obtaining information on melanoma risk factors and performing a complete cutaneous examination, the most clinically atypical naevus was biopsied in both cases and controls. Histological dysplasia was then assessed independently by 13 dermatopathologists (0, no dysplasia; 1, mild dysplasia; 2, moderate dysplasia; 3, severe dysplasia). The dermatopathologists were blinded as to whether the naevi were from melanoma subjects or controls. Multivariate analyses were performed to determine if there was an independent association between the degree of histological dysplasia in naevi and a personal history of melanoma. RESULTS: In persons with naevi receiving an average score of > 1 (i.e. naevi considered to have greater than mild histological dysplasia), there was an increased risk of melanoma [odds ratio (OR) 2.60, 95% confidence interval (CI) 0.99-6.86] which persisted after adjustment for confounders (OR 3.99, 95% CI 1.02-15.71). Very few dermatopathologists reliably graded naevi of subjects with melanoma as being more dysplastic than naevi of control subjects. Among the entire group, the interobserver reliability associated with grading histological dysplasia in naevi was poor (weighted kappa 0.28). CONCLUSIONS: HDN do appear to confer an independent risk of melanoma. However, this result may add more to our biological understanding of melanoma risk than to clinical assessment of risk, because HDN assessed by a single pathologist generally cannot be used to assess risk of melanoma. Future studies should be directed at establishing reproducible, predictive criteria for grading naevi.     

The dermoscopic classification of atypical melanocytic naevi (Clark naevi) is useful to discriminate benign from malignant melanocytic lesions

BACKGROUND: The dermoscopic classification is a useful tool for handling patients with atypical naevi (Clark naevi). OBJECTIVES: To investigate if the dermoscopic classification of atypical naevi is of any value to discriminate benign from malignant melanocytic lesions. METHODS: Consecutive patients (n = 205) were included with 254 suspicious melanocytic lesions, confirmed by histopathology at the Pigmented Lesions Clinic of the Department of Dermatology, University Medical Center, University of Tuebingen, Germany. In this retrospective study, dermoscopic images of benign and malignant melanocytic lesions were classified according to the dermoscopic classification of atypical naevi (reticular, globular, homogeneous or combinations of two of these) and pigmentation (uniform, central hyper- or hypopigmentation, eccentric peripheral hyper- or hypopigmentation, or multifocal hyper- or hypopigmentation). The three-structure type (reticular, globular and homogeneous) was additionally defined. RESULTS: Reticular, homogeneous and reticular-homogeneous types were significantly more frequent in naevi than in melanomas, whereas the three-structure type was significantly more frequent in melanomas (P < 0.001). A sensitivity of 86.7%, specificity of 87.7% and diagnostic accuracy of 87.4% was obtained. Uniformly pigmented and centrally hyperpigmented types were significantly more frequent in naevi than in melanomas, whereas eccentric peripheral hyperpigmented and multifocal hyper- or hypopigmented types were significantly more frequent in melanomas (P < 0.001). CONCLUSIONS: The dermoscopic classification of atypical naevi (Clark naevi) is useful to discriminate benign from malignant melanocytic lesions. The three-structure type and eccentric peripheral hyperpigmentation were significantly more frequently found in malignant than in benign melanocytic lesions. The knowledge of these two dermoscopic types should be helpful for the management of patients presenting with multiple melanocytic lesions.     

The role of pattern analysis and the ABCD rule of dermoscopy in the detection of histological atypia in melanocytic naevi

BACKGROUND: Clinical features of melanocytic naevi correlate poorly with the presence, histopathologically, of architectural disorder and cytological atypia, making the detection of histological atypia by means of macroscopic appearance unreliable. OBJECTIVES: The aim of this study was to investigate the diagnostic effectiveness of dermoscopy in the non-invasive detection of histological atypia in naevi. METHODS: Observers blinded for histological diagnosis classified a series of 168 melanocytic naevi as common or atypical on the basis of their clinical features and on their dermoscopic profile. The diagnostic performance of both methods compared with the true (histopathological) diagnosis was assessed. RESULTS: Dermoscopy using pattern analysis showed better results than clinical examination in the non-invasive detection of naevi with architectural disorder with or without cytological atypia (diagnostic accuracy 45% vs. 28%). A statistically significant difference in the frequency of dermoscopic parameters between atypical and common naevi was found for atypical pigment network (39% vs. 17%, P = 0.001) and dermoscopic regression structures (13% vs. 2%, P = 0.008). Dermoscopic features, which best predicted histological atypia in naevi, were regression structures (white scar-like areas or peppering), irregular vascular pattern and grey-blue areas (positive predictive values 83%, 83% and 73%, respectively). In contrast, no statistically significant difference in the mean values of the ABCD score between common and atypical naevi was found. The best diagnostic performance of dermoscopy by means of the ABCD rule (cut-off point of 4.0 of total dermoscopy score) was not dissimilar to that of clinical diagnosis (diagnostic accuracy 30%). CONCLUSIONS: Dermoscopy by means of pattern analysis enhances the diagnostic accuracy of dermatologists in the prediction of histological atypia in melanocytic naevi as compared with clinical examination alone.     

Can early malignant melanoma be differentiated from atypical melanocytic nevus by in vivo techniques?

Background/aims: Differentiation between early (Breslow thickness less than 1 mm) malignant melanoma (MM) and atypical melanocytic nevus (AMN) remains a challenge even to trained clinicians. The purpose of this study is to determine the feasibility of reliable discrimination between early MM and AMN with noninvasive, objective, automatic machine vision techniques.
Methods: A data base of 104 digitized dermoscopic color transparencies of melanocytic lesions was used to develop and test our computer-based algorithms for classification of such lesions as malignant (MM) or benign (AMN). Histopathologic diagnoses (30 MM and 74 AMN) were used as the "gold standard" for training and testing the algorithms.
Results: A fully automatic, objective technique for differentiating between early MM and AMN from their dermoscopic digital images was developed. The multiparameter linear classifier was trained to provide 100% sensitivity for MM. In the blind test, this technique did not miss a single MM and its specificity was comparable to that of skilled dermatologists.
Conclusions: Reliable differentiation between early MM and AMN with high sensitivity is possible using machine vision techniques to analyze digitized dermoscopic lesion images.     

Improvement of malignant/benign ratio in excised melanocytic lesions in the 'dermoscopy era': a retrospective study 1997-2001

BACKGROUND: Because of the many limitations of studies based on the diagnostic setting of excised lesions, the impact of dermoscopy (epiluminescence microscopy, dermatoscopy) in melanoma screening during practice remains to be established. OBJECTIVES: We assumed that effects of the use of dermoscopy on some indicators of diagnostic performance in melanoma screening should be traceable retrospectively; therefore, we analysed the impact of routine dermoscopy use on the malignant/benign ratio in excised melanocytic lesions. METHODS: Preoperative and histological diagnosis of 3053 melanocytic lesions [319 melanomas (10.4%)] consecutively diagnosed and excised at the Department of Dermatology, University of Florence in the period 1997-2001 inclusive were retrieved. Six dermatologists who selected the lesions to excise and who performed preoperative diagnosis were divided into two groups according to their use of dermoscopy in routine activity (n = 2 dermoscopy users and n = 4 nonusers). The study period was divided into a predermoscopy period (1997), a shift phase (1998) and a dermoscopy period (1999-2001). RESULTS: During the study period, the malignant/benign ratio improved in dermoscopy users only (from 1 : 18 to 1 : 4.3, P = 0.037). No significant difference was found for nonusers (from 1 : 11.8 to 1 : 14.4). Dermoscopy users were more likely to have a melanoma diagnosed within a series of excised lesions than nonusers, even taking into account potential confounders such as sex, age and study period by means of multivariate analysis (odds ratio 1.55, 95% confidence interval 1.17-2.01). The percentage of 'problem' naevi (naevi with architectural disorder with or without cytological atypia and Spitz or Reed naevi) over the total number of excised lesions was higher in dermoscopy users than in nonusers (year 2001, 51.6% vs. 40.9%, P = 0.014). Similar findings were obtained after exclusion from the data set of lesions excised for cosmetic reasons. CONCLUSIONS: The adoption of dermoscopy in routine melanoma screening is followed by an improvement of the malignant/benign ratio in excised lesions, suggesting a more appropriate selection of pigmented lesions referred to surgery. Because of the possible limitations of a retrospective study design, future confirmation of this finding by means of a prospective, randomized study is advisable. The introduction of dermoscopy in routine practice may have major implications in large-scale melanoma screening with cost savings and a reduction of the dermosurgery workload.     

RAS and RAF mutations in banal melanocytic aggregates contiguous with primary cutaneous melanoma: clues to melanomagenesis

Background  Distinguishing banal melanocytic aggregates contiguous with malignant melanoma can be a histological challenge but is essential because of the potential for a spurious Breslow measurement.
Objectives  Our aim was to ascertain whether the histological distinction between the two relates to differences in the prevalence of mutations in genes significant in melanomagenesis.
Methods  Mutations in BRAF codon 600, NRAS1 codons 12/13, NRAS2 codons 60/61 and KRAS codons 12/13 were ascertained in 18 cases of primary cutaneous malignant melanoma contiguous with banal melanocytic aggregates using laser capture microdissection.
Results  Overall, 12 of 18 cases (67%) exhibited a mutation in at least one gene. BRAF  V600E appeared to be the most commonly mutated gene in both the melanocytic aggregate (seven of 18, 39%) and the melanoma (four of 18, 22%). Both populations demonstrated a similar BRAF genomic profile in 11 of 18 cases (61%) (two BRAF  V600E, nine BRAF -WT), a similar KRAS genomic profile in 14 of 18 cases (78%) (one KRAS  G12V, 13 KRAS- WT) and a similar NRAS2 genomic profile in 14 of 18 cases (all WT). Of interest, we noted a relatively high prevalence of KRAS mutations (five of 18, 28%). The frequency of KRAS mutations in the melanocytic aggregate (five of 18, 28%) was second to BRAF  V600E, while in melanoma, the frequency was also second to BRAF  V600E but equalled that of NRAS2 (1 of 18, 6%). No NRAS1 mutations were observed. BRAF and RAS mutations appeared to be mutually exclusive with only three of 18 cases (17%) demonstrating a mutation in both genes (melanocytic aggregate only).
Conclusions  Our findings hint towards the interpretation of banal melanocytic aggregates serving as precursor lesions.     

Case–control study to identify melanoma risk factors in the Belgian population: the significance of clinical examination

BACKGROUND: Although numerous studies have evaluated risk factors associated with cutaneous malignant melanoma (CMM), no such study has been carried out in Belgium. OBJECTIVES: To identify individuals who are at high risk of developing malignant melanoma in Belgium, which could enhance the efficacy of screening interventions and avoid unnecessary skin inspections. STUDY DESIGN/SETTING/SUBJECTS: We prospectively included patients who were diagnosed with invasive malignant melanoma between 1998 and 2001 at the Department of Dermatology in a case-control study. Controls were selected from the outpatient dermatology clinic. Participants were interviewed and clinically examined by a dermatologist. We asked questions concerning most known risk factors associated with malignant melanoma such as phenotypical and skin characteristics, and environmental and lifestyle exposures. To adjust for confounding variables and to estimate odds ratios (ORs) and 95% confidence intervals (CIs), a multivariate model was used. RESULTS: Although sunburn in childhood and substantial occupational solar exposure were modestly, but significantly, associated with malignant melanoma risk, clinical examination yielded several stronger risk factors. In a multivariate model, which adjusted for age, gender and skin phototype, phenotypical characteristics such as skin, hair and eye colour were significantly associated with the development of malignant melanoma. In the multivariate model, people with three or more atypical naevi were at more than 10-fold risk of developing a malignant melanoma (> or = 3 atypical naevi; adjusted OR = 11.40, 95% CI = 4.79-17.53) compared to those without an atypical naevus. The presence of one or more palpable naevi on the upper extremities or having solar lentigines increased the odds of developing malignant melanoma at least twofold. CONCLUSIONS: In Belgium, risk factors associated with malignant melanoma appear to be in accordance with previous studies. To assess peoples' risk profile, clinical skin examination is likely to yield the most important sporadic malignant melanoma risk factors. Therefore, focusing screening campaigns on individuals with predefined findings on skin self-examination may increase its efficacy.     

A blueprint for staging of murine melanocytic lesions based on the Cdk4 ( R24C/R24C ) ::Tyr- NRAS ( Q ) ( 61K ) model

It has been shown that gene mutations which drive the development of malignant melanoma (MM) in humans also lead to emergence of MM when engineered mice. However, little attention has been paid to the clinical and histopathological features of melanocytic lesions and their natural history in a given mouse model. This knowledge is crucial to enable us to understand how engineered mutations influence the initiation and evolution of melanocytic lesions, and/or for the use of mice as a preclinical model to test specific treatments. We recently reported the development of melanocytic proliferations along the spectrum of naevi to MM in a Cdk4 ( R24C/R24C ) ::Tyr- NRAS ( Q ) ( 61K ) mouse model. In this study, we followed the development of lesions over time using digital photography and dermoscopy with the aim to correlate the clinical and histopathological features of lesions developing in this model. We identified two types of lesions. The first are slow-growing dermal MMs that emanate from dermal naevi. The second did not emanate from naevi, grew rapidly, and appeared to be solely confined to the subcutaneous fat. We present a simple staging system for the MMs that progress from naevi, based on depth of extension into the dermis and subcutis. This represents a blueprint for documentation and follow-up of MMs in the live animal, which is critical for the proper use of murine melanoma models.     

Accuracy in skin cancer diagnosis: a retrospective study of an Australian public hospital dermatology department

Background/Objectives: Accurate identification of skin lesions is vital in ensuring malignancies are not missed and that they are treated early to avoid mortality. It is also important that appropriate lesions are submitted for biopsy to decrease the costs and morbidity associated with the unnecessary removal of benign lesions. This study attempted to assess current accuracy in skin cancer diagnosis. Methods: Histology reports for all biopsies and excisions performed in an 18‐month period at a public hospital dermatology department were reviewed. Dermatology registrars and consultants were involved in assessing lesions for biopsy. Calculations were made to quantify the sensitivity of melanoma diagnosis; naevi to melanoma ratio (NMR); biopsy to treatment ratio (BTR), and number needed to treat for melanoma (NNT). NNT was calculated as the number of pigmented lesions (seborrhoeic keratoses, naevi and melanoma) removed to identify one melanoma. Results: 6546 biopsies/excisions were performed, identifying 55 melanomas. The sensitivity of melanoma diagnosis was 76% and 11% of melanomas were thought to be dysplastic naevi. The NMR was 6.4. The BTR was 1.97, indicating that one in every 1.97 biopsies was identified as a non‐melanoma skin cancer. The NNT was 11.9. All dysplastic naevi and 91% of melanomas were biopsied using either shave or excision biopsy. Conclusions: These audits are important to ensure quality of care and could aid in identifying doctors and institutions that may benefit from further training in melanoma diagnostic algorithms. These figures can be used as a benchmark to measure the impact of new vectors in skin cancer diagnosis as they are introduced.     

CDKN2A and MC1R variants influence dermoscopic and confocal features of benign melanocytic lesions in multiple melanoma patients

Non‐invasive diagnostic tools are effective in the histomorphological study of melanocytic lesions. The role of melanoma susceptibility genes on melanocytic nevi histopathological features is not clear. The current study aimed to correlate genetic alterations and histomorphological features of melanocytic nevi. Clinical, dermoscopic and confocal features of 34 multiple melanoma patients and 34 controls were compared. Among patients with melanoma, carriers of CDKN2A mutations and/or MC1R variants, and wild‐type genes were also compared. In patients with melanoma, a lighter phototype (P = 0.051), a higher number of nevi (P < 0.01) and clinically atypical nevi (P < 0.01) were observed. At dermoscopy, these nevi showed a complex pattern (P = 0.011), atypical network (P = 0.018) and irregular pigmentation (P = 0.037); at confocal, an irregular meshwork pattern (P = 0.026) with atypical nests (P = 0.016) and an inflammatory infiltrate (P = 0.048) were observed. Among patients with melanoma genetically tested, CDKN2A G101W mutation carriers were more frequently younger (P = 0.023), with clinically atypical nevi (P = 0.050), with cytological atypia (P = 0.033) at confocal. G101W mutation and MC1R variants carriers showed hypopigmented nevi (P = 0.002) and, at confocal, roundish cells infiltrating the junction (P = 0.019). These data suggest an influence of CDKN2A mutation and MC1R variants in the development of dysplastic melanocytic lesions. Non‐invasive histomorphological evaluation, together with genetic studies, improves melanoma risk identification and early diagnosis, for a patient‐tailored management.     

Awareness and early detection of cutaneous melanoma: an analysis of factors related to delay in treatment

Factors associated with the detection of cutaneous melanomas and reasons for delay in diagnosis were investigated in 429 patients with histologically proven melanoma operated on between January 1993 and June 1996. Patients were interviewed using a standardized questionnaire. In 25% of patients, treatment was delayed for more than 1 year from the time they first noticed a suspicious pigmented lesion. Melanoma was detected by the patients themselves in 67% of women and 45% of men. The three predominant clinical symptoms of melanoma were change in colour (darker), increase in size and increase in elevation of a pigmented lesion. The role of sun exposure and of naevi as risk factors for melanoma, as well as the potential benefit of early treatment, were known by 87%, 66% and 82% of the patients, respectively. However, melanoma awareness had no impact on the time period between first observation of skin changes and treatment. Among the factors associated with delay in melanoma diagnosis, an initial incorrect diagnosis as a benign lesion by the physician first visited (in 18% of all cases) had the highest significance. Patients detecting their lesions themselves were treated significantly later than patients in whom others had remarked on changes in a naevus. Furthermore, melanomas of the head and neck were treated later than melanomas at other body sites. Further efforts to educate both the public and the medical profession are essential to ensure earlier treatment for cutaneous melanomas.