De novo intraepidermal epithelioid melanocytic dysplasia as a marker of the atypical mole phenotype -- a clinical and pathological study of 75 patients

BACKGROUND: We encountered a distinctive pattern of dysplastic intraepidermal melanocytic proliferation, which defies classification as a dysplastic melanocytic nevus, but in which the morphologic features fall short of a diagnosis of melanoma in situ. We designate such lesions as de novo intraepidermal epithelioid melanocytic dysplasia. METHODS: From 75 patients, 82 skin biopsies were encountered that showed this distinctive morphology. Hematoxylin- and eosin-stained histologic sections were studied and the features were correlated with personal and family histories of dysplastic nevi and melanoma. RESULTS: The diagnosis of de novo melanocytic dysplasia was made in 27 male patients and 48 female patients (mean age: 44 years). The histologic hallmark was a pagetoid (single-cell) array of moderately to severely atypical epithelioid melanocytes within the epidermis. Seventy-three lesions were located on sun-exposed skin and nine on sun-protected skin. In 41 patients, there was an atypical mole phenotype, whereas 20 patients had a prior or subsequent diagnosis of melanoma with five of 16 patients questioned revealing a family history of melanoma. CONCLUSIONS: De novo intraepidermal epithelioid melanocytic dysplasia is a distinct entity associated with an atypical mole phenotype and a personal and/or family history of melanoma.     

De novo intraepidermal epithelioid melanocytic dysplasia: an emerging entity

De novo intraepidermal epithelioid melanocytic dysplasia represents a distinctive form of intraepidermal melanocytic dysplasia. Although these lesions are atypical, they are not diagnostic of melanoma. They are considered a part of the atypical mole phenotype and may define a point in the natural course of melanomagenesis. Magro CM, Crowson AN, Mihm MC, Kline M. De novo intraepidermal epithelioid melanocytic dysplasia: an emerging entity of diagnostic and clinical importance.     

The number and distribution of nevus cell nevi in patients with malignant melanoma

Total-body cutaneous examination of 211 patients with malignant melanoma (MM) and 157 controls showed that patients with MM had significantly more nevi. Among MM patients, men had more nevi on the trunk than women, and women had more nevi on the lower extremities than men. Men had an MM distribution that was similar to their nevus distribution. Women, however, had proportionately more MM on the legs and fewer MM on the neck. The "nevus density," defined as the number of nevi per unit surface area of skin, was higher in male MM patients. The nevus density was highest on the head and neck, and lower on the lower extremities and anterior trunk. Patients with nodular melanoma had more nevi than those with superficial spreading melanoma. MM patients with a family history of many nevi had more nevi than those without such a history. Patients with a family history of MM did not show an increased number of nevi, but they had larger numbers of suggestive nevi removed than those without a family history of MM. We believe that many of these observations are consistent with the view that MM is caused by a genetic predisposition to an overactive melanocytic system in combination with an external stimulant, such as UV radiation.     

Monoclonal antibodies selected to discriminate between malignant melanomas and nevocellular nevi

Two monoclonal antibodies (MoAbs), PAL-M1 and PAL-M2, are described that were selected to discriminate between melanomas and nevocellular nevi (NN) in frozen sections. MoAb PAL-M1 reacted with all 15 melanoma metastases (MM), with 14 of 19 primary cutaneous melanomas (PCM), 9 of 35 dysplastic nevi (DN), and 2 of 26 NN. The 2 NN stained were removed from patients with the dysplastic nevus syndrome. MoAb PAL-M2 reacted with 9 of 15 MM, 5 of 19 PCM, 3 of 35 DN, and did not react with 26 NN after usual staining conditions. The proportion of melanocytic cells stained was low in DN and much higher in PCM and especially in MM. Staining in DN was restricted to intraepidermal or subepidermal nests of atypical melanocytes. In PCM, staining with PAL-M2 was observed only in tumors with a Breslow thickness of 0.76 mm or higher. PAL-M1 and PAL-M2 may be immunohistochemical markers for tumor progression in melanocytic proliferations.     

Age distribution and histologic patterns of dysplastic nevi

A total of 676 dysplastic moles collected from 487 patients over a 1-year period were reviewed together with demographic data. The associated nevus in 642 cases (95%) had a superficial, or "acquired," pattern within the papillary dermis, in comparison with the nevus in the remaining 34 cases (5%), which showed a deep, or "congenital," pattern. The dysplasia was graded in severity as mild, moderate, or severe (on a scale of 1 to 3). When patients with mild to severe dysplastic melanocytic nevi were compared with those patients showing atypical intraepidermal melanocytic hyperplasia (also called in situ malignant melanoma) or early invasive malignant melanoma associated with dysplasia, a progression of ages was noted. The average ages in the five diagnostic groups were as follows: 34.8 years, mild dysplasia (group 1); 35.1 years, moderate dysplasia (group 2); 41.5 years, severe dysplasia (group 3); 44.4 years, in situ malignant melanoma (group 4), and 46.9 years, early invasive malignant melanoma (group 5). Statistical analysis revealed that the two younger groups differed significantly in age from the three older groups. Men and women had an equal proportion of acquired and congenital pattern nevi, but men were older in each category and had more severe dysplasia, a greater tendency toward truncal lesions, and more regressive changes. Biopsy of trunk lesions was done in 275 cases (80%), of extremity lesions in 60 cases (17%), and in head and neck sites in 9 cases (3%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Analysis of protein tyrosine kinase expression in melanocytic lesions by tissue array

BACKGROUND: It has been proposed that melanoma progression involves a multistep process from benign nevi (BN), dysplastic nevi (DN), radial and vertical growth phase melanoma (MM) to metastatic melanoma (MMM). Protein tyrosine kinases (PTKs) may participate in this progression. METHODS: Tissue microarray blocks of 89 melanocytic lesions were evaluated by immunohistochemistry for the expression of selected PTKs: c-kit, c-abl, abl-related gene (ARG), platelet-derived growth factor receptors alpha (PDGFR-alpha) and beta (PDGFR-beta). RESULTS: Seventeen of 31 (55%) MMM lacked expression of c-kit versus 100% expression (18/18) in DN and 96% expression (22/23) in MM; similarly, only 59% (10/17) of BN showed expression of c-kit. PDGFR-beta expression levels were similar in BN, DN, and MM, but lower in MMM. There was a trend toward lower expression of abl and ARG from BN to MMM. There was a marked decrease in staining intensity of ARG from BN to DN, MM, and MMM. CONCLUSION: Our results support that BN is different from DN and MM and that these two are different from MMM. Metastasis appears to be associated with loss of c-kit and PDGFR-beta expression. Since malignant melanoma expresses PTK, it may be a candidate for treatment with anti-PTK, such as STI-571 (Gleevec).     

Ultrastructural discrimination between malignant melanomas and benign nevocytic nevi using high-resolution image and multivariate analyses

Prompted by the well-known difficulties of reliable and objective histologic differentiation between initial malignant melanoma (MM) and benign nevocytic nevi (NN), ultrastructural high-resolution image and multivariate analyses were evaluated for their diagnostic efficiency. Thirty-seven different features describing morphometry (area, circumference, and shape factor), amount of heterochromatin and euchromatin, chromatin homogeneity, and presence of smaller dark chromatin aggregations were determined by a MICROVAX 3500 computer in each of 1840 intraepidermal melanocytic nuclei of 17 MM and 20 NN. A strategy for the classification of cases based on the identification of markedly atypical melanocytic cells (MACS) was developed. MACS, selected in multivariate analysis with a linear combination of the eight most important features for cell classification, were found in 39.4% of the melanoma cells, but only in 0.3% of nevocytic nevus cells. The presence of MACS allowed a clear differentiation between MM and NN. All cases of MM had more than four MACS, whereas 17 cases of nevocytic nevi were MACS negative, and in each of the remaining three cases only one MAC was present. The percentage of MACS detected within intraepidermal parts of MM by using computerized high-resolution image analysis was found to be a highly efficient diagnostic marker. The new classification strategy has the potential of saving considerable time in subsequent studies, because preselected sampling and the calculation of only a few criteria have proven sufficient for correct classification of malignant melanomas.     

Origin of cutaneous melanoma in a congenital dysplastic nevus spilus

Cutaneous melanoma developed in contiguity with a congenital nevus spilus on the leg of a 79-year-old white woman. The unique features of the nevus spilus in this case were its relatively large size (diameter, 8 cm), irregular gross appearance, lifelong stability until the recent appearance of a tumor nodule, and the presence of intraepidermal melanocytic dysplasia appearing as multifocal elements within darkly pigmented speckles distributed throughout a lightly pigmented background of lentigo simplex. Based on this observation, we suggest that the presence of intraepidermal melanocytic dysplasia in nevus spilus may be a predisposing factor for the development of melanoma. The malignant potential of "dysplastic" nevus spilus requires further study.     

Seasonal variation in dysplastic naevi

There is a relationship between sunlight and the development of melanocytic neoplasms. Because the incidence and excision of melanocytic neoplasms varies according to season, we sought to determine if dysplasia and/or intraepidermal melanocytic expression differed in a cohort of dysplastic naevi (DN) removed in January compared with a similar cohort removed in August. The DN were graded based on the degree of dysplasia, and the number of intraepidermal melanocytes were counted after immunohistochemical staining with HMB-45 and Melan-A. There was no seasonal difference in the grading of the dysplastic naevi in either season (P = 0.08). Comparing 85 cases from August and 86 from January, there was a larger number of Melan-A-positive melanocytes in the August samples (P < 0.02), and a larger number of HMB-45-positive melanocytes in January (P < 0.01). This difference may be related to seasonal variations such as exposure to ultraviolet light exposure; however, there was no difference between the two groups in the degree of atypia seen.     

Clinical diagnosis of dysplastic melanocytic nevi: A clinicopathologic correlation

A prospective, community practice-based, clinicopathologic correlation was undertaken in 165 melanocytic nevi excised from a group of forty-three patients, each patient having previously had at least one clinically suspected and histologically confirmed dysplastic melanocytic nevus. Eighty-two percent of seventy-two lesions with histologic evidence of mild dysplasia had been diagnosed correctly as such clinically. The accuracy of clinical diagnosis of moderate dysplasia was low (20%); however, all cases of severe dysplasia with or without in situ melanoma were diagnosed correctly. In 75% of all cases in which dysplasia of any degree was diagnosed clinically, histologic evidence of dysplasia was found. In order to investigate further the clinical features of these nevi, 175 color enlargements of histologically confirmed dysplastic melanocytic nevi were examined. The following clinical features were found to be most common: ill-defined border (90%), irregularly distributed pigmentation (84%), maximum diameter greater than 5.0 mm (72%), erythema (64%), and accentuated skin markings (63%). Increasing darkness and confluence of pigmentation in these dysplastic melanocytic nevi correlated with increasing severity of dysplasia. We conclude that careful clinical examination of individual melanocytic nevi will separate severe dysplasia with or without in situ melanoma from low-grade (mild or moderate) dysplasia in a high percentage of nevi from patients with the dysplastic nevus syndrome. Clinical examination will yield a diagnosis of dysplasia in approximately 75% of nevi from such patients in whom histologic evidence of dysplasia is present. Clinical examination constitutes a practical and sufficiently reliable method for the assessment of melanocytic nevi in patients with the dysplastic nevus syndrome.     

Loss of claudin-1 expression in tumor-associated vessels correlates with acquisition of metastatic phenotype in melanocytic neoplasms

Claudins are a family of transmembrane proteins involved in cell-to-cell adhesion and are believed to be the main component of tight junctions. Recent studies have suggested that some metastatic solid tumors lack claudin expression. It is unknown whether claudins play a role in cutaneous melanoma. Immunohistochemical studies were performed on tissue microarrays containing 19 benign melanocytic nevi (BN), 21 dysplastic nevi (DN), 23 primary malignant melanomas (MMs), and 31 metastatic melanomas (MMMs) using a polyclonal anti-claudin-1 antibody. Immunoreactivity in tumor cells and associated vessels was graded by intensity and by percentage of reactive cells. Normal epidermis served as internal control (3+ labeling). Cases with at least 2+ labeling in more than 25% of the cells were considered positive. Claudin-1 expression was present in 37% of BN, 24% of DN, 26% of MM, and 3.2% of MMM. Tumor-associated vessels showed the following results: 11 of 19 (58%) in BN, 14 of 21 (67%) in DN, 17 of 23 (74%) in MM, and 6 of 31 (19%) in MMM. A significant loss of expression was noted between MMM and all other lesions in tumor cells and associated vessels. There was no significant difference between BN, DN, and MM. Within primary melanomas, there was a significant correlation between expression of claudin in tumor cells and Clark level/Breslow thickness. Also significant was a decreased expression of claudin in tumor vessels of lesions with higher Breslow thickness or Clark level. These data suggest that loss of claudin-1 may play a significant role in the acquisition of metastatic phenotype in cutaneous melanoma. Cohn ML, Goncharuk VN, Diwan AH, Zhang PS, Shen SS, Prieto VG. Loss of claudin-1 expression in tumor-associated vessels correlates with acquisition of metastatic phenotype in melanocytic neoplasms.     

Epidemiology of cutaneous melanoma and non-melanoma skin cancer in Schleswig-Holstein, Germany: incidence, clinical subtypes, tumour stages and localization (epidemiology of skin cancer)

BACKGROUND: Population-based figures on skin cancer are essential for a realistic assessment of the personal disease burden, prevention modes and the need for caring. The Robert Koch Institute in Germany estimates the incidence of melanoma skin cancer as seven cases in 100 000 persons (age-standardized by the European standard rate). Population-based studies presumably show higher incidence rates of 10-16 cases in 100 000 persons. Few data exist for non-melanoma skin cancer (NMSC) as this is not systematically registered in Germany. OBJECTIVES: To present the first population-based results from the Schleswig-Holstein (Germany) Cancer Registry on incidence, stage distribution, clinical types and localization of skin cancer and to compare the results with other studies. METHODS: The Cancer Registry of the Bundesland Schleswig-Holstein with 3500 registering institutions, 100 of which are dermatological institutions, investigates all notifiable incident cancer cases according to international standards. From the recorded data all melanoma and NMSC cases were identified and evaluated. RESULTS: Between 1998 and 2001, 1784 malignant melanoma (MM) and 12 956 NMSC cases underwent diagnostic and analytical evaluation. For MM, age-standardized incidence rates were 12.3 and 14.8 in 100 000 men and women, respectively, and the mean age of men was greater than that of women (56.6 vs. 54.9 years, P < 0.05). Superficial spreading melanoma was the most frequent clinical type (39.1%). The tumours were predominantly located on the trunk in men (46.8%) in contrast to leg and hip in women (39.5%). For NMSC, the age-standardized incidence rates were 100.2 and 72.6 in 100 000 men and women, respectively. More than 80% of all tumours were basal cell carcinoma. CONCLUSIONS: The first population-based data from Schleswig-Holstein on the characteristics (age, sex, histological subtypes, localization and stage) of skin tumours agree well with the existing literature and may thus be regarded as representative. However, markedly higher incidences for MM and NMSC in the north of Germany compared with other parts of the country were observed. As the incidence rates from the north of Germany fit well into the European geographical pattern, we assume no regional increase. Therefore, the official German estimates on cutaneous tumours may largely depend on regional factors and may not be regarded as representative for all regions in Germany.     

Trauma and melanoma formation: a true association?

BACKGROUND: Little is known about the role of mechanical trauma in the pathogenesis of malignant melanoma. In individual patients, traumatic events have been discussed as a causative factor for the induction of melanoma and diagnosis of melanoma following trauma may raise medico-legal questions. OBJECTIVES: To evaluate the relationship between traumatic single or recurrent events and melanoma characteristics. METHODS: Retrospective questionnaire in 369 melanoma patients. RESULTS: A large number of patients (337 of 369; 91.3%) denied an association between a possible traumatic event and melanoma formation. Thirty-two of 369 patients (8.7%) considered an association of trauma and melanoma formation likely. Of these 32 patients, 22 patients (13 men, nine women) reported a single event, and 10 patients (four men, six women) a persisting irritation. An irritation of a pre-existing melanocytic naevus was reported by two patients with histologically confirmed melanoma on acquired or congenital naevus. CONCLUSIONS: As most of the patients who mentioned a trauma in this study suffered from acral melanoma, or melanoma located on the extremities, a history of trauma should be expected more frequently at these body sites. A review of epidemiological, clinical and scientific research indicates that there seems to be no evidence for single or persistent traumatic events as a causative factor for melanoma formation.     

The Skin Cancer Quality of Life Impact Tool (SCQOLIT): a validated health‐related quality of life questionnaire for non‐metastatic skin cancers

Background Quality of life (QOL) issues in patients with non‐metastatic skin cancer are not satisfactorily demonstrated when using existing QOL questionnaires. Objective To construct and validate a 10 item disease‐specific QOL questionnaire, the Skin Cancer Quality of Life Impact Tool (SCQOLIT), for use in patients following treatment of non‐metastatic skin cancer. Methods The SCQOLIT was constructed and administered initially to 120 patients with non‐metastatic skin cancer, 60 with malignant melanoma (MM) and 60 with non‐melanoma skin cancer (NMSC) following treatment, then repeated in half this cohort at seven days, and the other half at three months. Data was collected on age, gender, skin cancer type and Breslow thickness. Statistical validation was undertaken. Results There were 113 valid SCQOLIT responses at initial completion (54 in the MM group, and 59 in the NMSC group). Initial SCQOLIT median scores (interquartile range [IQR], range) for the two groups were 10 (12, 0–28) MM, and 4 (5, 0–19) NMSC. Amongst the cohort readministered the SCQOLIT at three months (23 in the MM group, 25 in the NMSC group) median scores (IQR, range) were 6 (6, 0–26) MM and 3 (4, 0–20) NMSC. Conclusions The SCQOLIT is a validated disease‐specific QOL questionnaire for use in patients following treatment of non‐metastatic skin cancer. Higher SCQOLIT scores are observed in MM patients than NMSC patients, but diminish with time in the MM group. Patients with persistently elevated SCQOLIT scores merit additional attention.     

Metabolic risk factors and skin cancer in the Metabolic Syndrome and Cancer Project (Me-Can)

Background Little is known about the associations of metabolic aberrations with malignant melanoma (MM) and nonmelanoma skin cancer (NMSC). Objectives To assess the associations between metabolic factors (both individually and combined) and the risk of skin cancer in the large prospective Metabolic Syndrome and Cancer Project (Me‐Can). Methods During a mean follow‐up of 12 years of the Me‐Can cohort, 1728 (41% women) incident MM, 230 (23% women) fatal MM and 1145 (33% women) NMSC were identified. Most NMSC cases (76%) were squamous cell carcinoma (SCC) (873, 33% women). Hazard ratios (HRs) were estimated by Cox proportional hazards regression for quintiles and standardized z‐scores (with a mean of 0 and SD of 1) of body mass index (BMI), blood pressure, glucose, cholesterol, triglycerides and for a combined metabolic syndrome score. Risk estimates were corrected for random error in the measurements. Results Blood pressure per unit increase of z‐score was associated with an increased risk of incident MM cases in men and women [HR 1·17, 95% confidence interval (CI) 1·04–1·31 and HR 1·18, 95% CI 1·03–1·36, respectively] and fatal MM cases among women (HR 2·39, 95% CI 1·58–3·64). In men, all quintiles for BMI above the reference were associated with a higher risk of incident MM. In women, SCC NMSC risk increased across quintiles for glucose levels (P‐trend 0·02) and there was a trend with triglyceride concentration (P‐trend 0·09). Conclusion These findings suggest that mechanisms linked to blood pressure may be involved in the pathogenesis of MM. SCC NMSC in women could be related to glucose and lipid metabolism.     

Actin-binding protein fascin expression in skin neoplasia

BACKGROUND: Fascin containing actin bundles provide mechanical support to cellular protrusions and stress fibers. In cancers, some malignant cells (e.g. subsets of breast and ovarian carcinomas) express fascin. In skin cancer, the role of fascin is unknown. METHODS: Cases of 61 keratocytic neoplasms, 35 melanocytic neoplasms, nine extramammary Paget's disease (four with adenocarcinoma) and five sarcomas (angiosarcoma and atypical fibroxanthoma) were examined by immunohistochemistry, using monoclonal antihuman fascin antibody, clone 55 k-2 (Dako Corporation, Carpinteria, CA, USA). RESULTS: Fascin labeled all sarcomas and all keratinocytic neoplasms except for pagetoid pattern Bowen's disease. The regions of most intense fascin labeling were seen in the basal cells of infiltrative tumor margins. A minority of Merkel cell carcinomas exhibited weak or absent immunoreactivity. All melanocytic nevi except for some junctional nests of dysplastic melanocytic nevi expressed fascin. However, pagetoid cells of melanoma in situ and epithelioid cells of invasive melanoma weakly expressed or did not express fascin, whereas melanoma cells exhibiting spindle cell morphologies labeled intensely with fascin. Lastly, all cells of extramammary Paget's disease and most associated adenocarcinomas cells did not or were faintly labeled by fascin antibodies. Decreased or absent fascin expression was significantly associated with skin cancers with a high risk for metastasis (e.g. melanoma) vs. those with a low risk (e.g. basal cell carcinoma) (24% vs. 100% with > 50% immunoreactivity; p = 0.0001, chi-squared test). CONCLUSION: Fascin is expressed by skin tumors that locally infiltrate and replace surrounding tissues indicating a role for fascin in cell adhesion, cell motility and invasiveness. No or weak fascin expression is exhibited by cancers with pagetoid intraepidermal spread and by invasive tumors with a high risk of metastasis. Downregulation or loss of fascin's actin-bundling properties, probably associated with disorganization of cell-cell and cell-matrix contacts, may be a crucial step in the progression from locally invasive to widely disseminating cancers.     

Novel immune signatures associated with dysplastic naevi and primary cutaneous melanoma in human skin

Dysplastic naevi (DN) are benign lesions with atypical features intermediate between that of common melanocytic naevi (CMN) and malignant melanoma (MM). Debate remains over whether DN represent progressive lesions from CMN. Through gene expression profiling and analysis of molecular gene signatures, our study revealed progressive increases in immune activation and regulation, along with pathways implicated in melanomagenesis, from CMN to DN to MM. Using criteria of 1.5‐fold change and false discovery rate ≤0.05, we found differential expression of 7186 probes (6370 unique genes) with the largest difference detected between DN and MM from the standpoint of genomic melanoma progression. Despite progressive increases in the T‐helper type 1 (Th1)‐inducing gene (IL‐12), RT‐PCR indicated impaired Th1 or cytotoxic T‐cell response (decreased IFN‐γ) in MM. Concordantly, our results indicated progressive increases in molecular markers associated with regulatory T cells, exhausted T cells and tolerogenic dendritic cells, including detection of increased expression of suppressor of cytokine signalling 3 (SOCS3) in dendritic cells associated with MM. All together, our findings suggest that the increased immunosuppressive microenvironment of melanoma may contribute to unhampered proliferation of neoplastic cells. In addition, the detection of increased markers associated with tolerogenic dendritic cells in MM suggests that targeting these suppressive immune cell types may represent an alternative avenue for future immunotherapy.     

The Histogenesis of malignant melanoma in relation to pre-existing pigmented lesions

One hundred and twenty-nine eases of malignant melanoma seen at Bangour General Hospital over an eleven year period were reviewed clinically and histologically. In 51 patients (39.5%) there was a history of pre-existing pigmented lesion at the site of the melanoma. In 14 cases (10.8%) histology confirmed traces of a benign melanocytic naevus. The relationships between naevus cells and malignant melanocytes are described. The patterns most frequently observed were those of intradermal nevus cells in the deeper part of an invasive melanoma and of a compound naevus undergoing malignant change in its junctional component. From these histological observations a histogenetic sequence of events is postulated. In the 37 patients with a positive history of a preceding pigmented lesion but no histological traces of a naevus, the percentage incidence of Lentigo Maligna (LM) and Superficial Spreading Melanoma (SSM), as compared with the 78 patients with a negative clinical history, was significantly higher than the incidence of nodular melanoma (NM). Although LM and SSM are thought to have separate histogenesis and aetiology, they share an important clinical and histological factor, i.e. in both, the radial growth phase is preceded by a, more or less, prolonged stage of intraepidermal horizontal growth. It is postulated that this pre-existing lesion of atypical melanocytic proliferation rather than a hypothetical benign naevus is in most cases the precursor of an invasive melanoma.     

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.