Metamorphosis of melanoma. Trends in size and thickness of cutaneous melanoma over one decade at the Istituto Nazionale Tumori, Milan.

AIMS AND BACKGROUND: Messages about the description of the clinical features of cutaneous melanoma (CM) have remained unchanged since 1985, when the ABCD (Asymmetry, Border irregularity, Color variegation, Diameter >6 mm) rule for melanoma detection was formulated. Given the significant shift to the diagnosis of earlier-stage CMs over the past decades, it is reasonable to think that also the clinical aspects of the disease might have changed. The aim of this study was to examine trends in the presentation of CM over the last decade at our Institution, focusing on two characteristics of the disease: size and thickness. METHODS: A retrospective study was conducted including 1,603 primary invasive CMs seen and treated at the Unit for Melanoma Detection at our Institute between January 1997 and December 2006. RESULTS: The results showed a trend towards smaller CMs, with a difference of 3 mm in median size from the beginning to the end of the period. Detection of small (< or =6 mm) CMs increased at a rate of about 1.5% per year, with a current ratio of 25% with respect to all CMs. Thickness remained substantially unchanged over time. CONCLUSIONS: Physicians must be aware that the characteristics of melanoma have undergone a metamorphosis over the years and the ABCD signs cannot be relied on for adequate sensitivity to further the early detection of CM.

In vivo evaluation of melanoma thickness by multispectral imaging and an artificial neural network. A retrospective study on 250 cases of cutaneous melanoma.

AIMS AND BACKGROUND: Noninvasive diagnostic methods such as dermoscopy, sonography, palpation or combined approaches have been developed in an attempt to preoperatively estimate melanoma thickness. However, the clinical presentation is often complex and the evaluation subjective. Multispectral image analysis of melanomas allows selection of features related to the content and distribution of absorbers, mainly melanin and hemoglobin, present within the lesion. Hence, it is reasonable to assume that the same features might be useful to predict melanoma thickness. METHODS: A multispectral image system was used to analyze in vivo 1939 pigmented skin lesions. The lesion selection was based on clinical and/or dermoscopic features that supported a suspicion for melanoma. All the lesions were then subjected to surgery for the histopathological diagnosis, and 250 were melanomas. From the multispectral images of the melanomas, we selected 12 features, seven of which were used to train and test an artificial neural network on 155 and 95 melanomas, respectively. RESULTS: Sensitivity (i.e., melanoma > or = 0.75 mm thick correctly classified) and specificity (i.e., melanoma < 0.75 mm thick correctly classified) evaluated from the receiving operating characteristic curves ranged from 76 to 90% and from 91 to 74%, respectively. CONCLUSIONS: Our approach provides results similar to those obtained with other methods and has the advantage that it is not related to the expertise of the clinician. In addition, the physical interpretation of the selected features suggests a possible role of spectrophotometry as an objective method to study the natural history of the early phases of the disease.

Lack of terminally differentiated tumor-specific CD8+ T cells at tumor site in spite of antitumor immunity to self-antigens in human metastatic melanoma.

Activation of CTL-mediated antitumor immunity to self-epitopes expressed by neoplastic cells is thought to be prevented, at any stage of tumor progression, by tolerance mechanisms. In contrast, in 74 American Joint Committee on Cancer stages I-IV melanoma patients, we found that development of lymph node metastases is a key event triggering CD8(+) T-cell-mediated immunity to self-epitopes encoded by melanocyte differentiation antigens. This was shown by the increased peripheral precursor frequency to Melan-A/Mart-1, gp100, and tyrosinase epitopes in stage III and IV compared with stage I and II patients, and by accumulation of functional memory T cells directed to Melan-A/Mart-1(26-35) in tumor-invaded lymph nodes. However, in tumor-invaded lymph nodes of most patients, CD8(+) T cells directed to melanocyte differentiation antigens or to tumor-restricted antigens (MAGE-3 and NY-ESO-1 epitopes), showed a CCR7(+) CD45RA(+) CD27(+) CD28(+) perforin(-) "precursor" phenotype. Only in 7 of 23 cases antigen-specific CD8(+) T cells in invaded lymph nodes showed a predominant CCR7(-) CD45RA(-) CD27(+) CD28(-) perforin(+) "preterminally differentiated" phenotype. In the latter subset of patients, by immunohistochemistry in lymph node lesions, we found that CD8(+) T lymphocytes intermingling with the neoplastic tissue expressed a CCR7(-) CD45RO(+)/RA(-) phenotype, whereas CD4(+) lymphocytes did not infiltrate the tumor. Furthermore, perforin and granzyme B were expressed on a higher fraction of the CD8(+) cells surrounding the invading tumor compared with the lymphocytes infiltrating the neoplastic tissue. In addition, no evidence for tumor regression was found in such metastatic lesions, as documented by absence of neoplastic cell necrosis or apoptosis. These data indicate that neoplastic cells in the lymph nodes and/or increased tumor burden in metastatic disease activate CD8(+) T-cell-mediated antitumor immunity to self-epitopes. However, the paucity of terminally differentiated CD8(+) T cells at tumor site suggests that immunotherapy strategies may require not only the boosting of tumor immunity, but also effective means to promote CD8(+) T-cell differentiation in the neoplastic tissue.

SCCA2-like serpins mediate genetic predisposition to skin tumors.

Reasons for early onset skin cancer are poorly understood. Microarray analysis revealed overexpression of the Scca2 gene in the 12-O-tetradecanoylphorbol-13-acetate-treated skin of Car-S mice, or line phenotypically selected for high susceptibility to two-stage skin carcinogenesis, as compared with 12-O-tetradecanoylphorbol-13-acetate-treated skin of Car-R mice, which is resistant. A human skin squamous cell carcinoma cell line (NCI-H520) transfected with mouse Scca2 or a related gene, Scca2-rs1, both expressed in the skin, showed significantly increased tumor growth as compared with controls when injected in nude mice. Immunohistochemical analysis of samples from two independent series of Italian and Korean patients with squamous cell carcinoma of the skin indicated a significant association between SCCA2 protein expression and younger age at tumor onset. These findings provide evidence that SCCA2-like serpins mediate genetic predisposition to skin cancer in a mouse model and in humans.

Automated melanoma detection with a novel multispectral imaging system: results of a prospective study.

The aim of this research was to evaluate the performance of a new spectroscopic system in the diagnosis of melanoma. This study involves a consecutive series of 1278 patients with 1391 cutaneous pigmented lesions including 184 melanomas. In an attempt to approach the 'real world' of lesion population, a further set of 1022 not excised clinically reassuring lesions was also considered for analysis. Each lesion was imaged in vivo by a multispectral imaging system. The system operates at wavelengths between 483 and 950 nm by acquiring 15 images at equally spaced wavelength intervals. From the images, different lesion descriptors were extracted related to the colour distribution and morphology of the lesions. Data reduction techniques were applied before setting up a neural network classifier designed to perform automated diagnosis. The data set was randomly divided into three sets: train (696 lesions, including 90 melanomas) and verify (348 lesions, including 53 melanomas) for the instruction of a proper neural network, and an independent test set (347 lesions, including 41 melanomas). The neural network was able to discriminate between melanomas and non-melanoma lesions with a sensitivity of 80.4% and a specificity of 75.6% in the 1391 histologized cases data set. No major variations were found in classification scores when train, verify and test subsets were separately evaluated. Following receiver operating characteristic (ROC) analysis, the resulting area under the curve was 0.85. No significant differences were found among areas under train, verify and test set curves, supporting the good network ability to generalize for new cases. In addition, specificity and area under ROC curve increased up to 90% and 0.90, respectively, when the additional set of 1022 lesions without histology was added to the test set. Our data show that performance of an automated system is greatly population dependent, suggesting caution in the comparison with results reported in the literature. In our opinion, scientific reports should provide, at least, the median values of thickness and dimension of melanomas, as well as the number of small (6 mm) melanomas.

Automated segmentation of pigmented skin lesions in multispectral imaging.

The aim of this study was to develop an algorithm for the automatic segmentation of multispectral images of pigmented skin lesions. The study involved 1700 patients with 1856 cutaneous pigmented lesions, which were analysed in vivo by a novel spectrophotometric system, before excision. The system is able to acquire a set of 15 different multispectral images at equally spaced wavelengths between 483 and 951 nm. An original segmentation algorithm was developed and applied to the whole set of lesions and was able to automatically contour them all. The obtained lesion boundaries were shown to two expert clinicians, who, independently, rejected 54 of them. The 97.1% contour accuracy indicates that the developed algorithm could be a helpful and effective instrument for the automatic segmentation of skin pigmented lesions.

Automated melanoma detection: multispectral imaging and neural network approach for classification.

Our aim in the present research is to investigate the diagnostic performance of artificial neural networks (ANNs) applied to multispectral images of cutaneous pigmented skin lesions as well as to compare this approach to a standard traditional linear classification method, such as discriminant function analysis. This study involves a series of 534 patients with 573 cutaneous pigmented lesions (132 melanomas and 441 nonmelanoma lesions). Each lesion was analyzed by a telespectrophotometric system (TS) in vivo, before surgery. The system is able to acquire a set of 17 images at selected wavelengths from 400 to 1040 nm. For each wavelength, five lesion descriptors were extracted, related to the criteria of the ABCD (for asymmetry, border, color, and dimension) clinical guide for melanoma diagnosis. These variables were first reduced in dimension by the use of factor analysis techniques and then used as input data in an ANN. Multivariate discriminant analysis (MDA) was also performed on the same dataset. The whole dataset was split into two independent groups: i.e., train (the first 400 cases, 95 melanomas) and verification set (last 173 cases, 37 melanomas). Factor analysis was able to summarize the data structure into ten variables, accounting for at least 90% of the original parameters variance. After proper training, the ANN was able to classify the population with 80% sensitivity, 72% specificity, and 78% sensitivity, 76% specificity for the train and validation set, respectively. Following ROC analysis, area under curve (AUC) was 0.852 (train) and 0.847 (verify). Sensitivity and specificity values obtained by the standard discriminant analysis classifier resulted in a figure of 80% sensitivity, 60% specificity and 76% sensitivity, 57% specificity for the train and validation set, respectively. AUC for MDA was 0.810 and 0.764 for the train and verify set, respectively. Classification results were significantly different between the two methods both for diagnostic scores and model stability, which was worse for MDA.

Clinical and dermatoscopic diagnosis of small pigmented skin lesions.

Small pigmented skin lesions represent a new challenge for all physicians devoted to the early diagnosis of melanoma. The purpose of this prospective study was to establish the diagnostic value of the clinical and the dermatoscopic examinations in a population of 157 consecutive patients with 161 small (< or = 6 mm) pigmented lesions, recruited in a short time. Of these 161 lesions, 13 were thin melanomas (median thickness 0.49 mm). In this population, clinical evaluation produced a diagnostic sensitivity of 77% and a specificity of 74%. Dermatoscopy resulted in a sensitivity of 77% and in a specificity of 72%. Combining clinical and dermatoscopic evaluations all the melanomas were preoperatively recognised. The results of the present study stress the complementary role of clinical and dermatoscopic examinations. In particular, clinical evaluation remains of utmost importance in diagnosing melanoma. This concept must be stressed in the education and training of young dermatologists.

Micro-melanoma detection. A clinical study on 22 cases of melanoma with a diameter equal to or less than 3 mm.

BACKGROUND AND AIMS: Very small pigmented lesions may represent an extreme diagnostic challenge to the clinician. Our aim was to describe the clinical and dermoscopic features in a series of cutaneous melanomas with a maximum clinical diameter of 3 mm. METHODS: We conducted a retrospective study of the 924 primary melanomas seen and treated during a period of five years at the Unit for Melanoma Detection of the Istituto Nazionale Tumori of Milan, Italy. The size characteristics of the considered lesions allowed the identification of 22 (2.4%) cases of micro-melanoma (clinical diameter of 3 mm or less). Sixteen of these cases were subjected to dermoscopy. The clinical and dermoscopic features as well as the corresponding diagnoses were recorded. RESULTS: The typical lesion presents as a small, dark, often black macule, generally evenly colored, with well-defined borders; it may be asymmetric or symmetric in shape. These features prompted a correct clinical diagnosis in nearly half of the cases. Dermoscopy lead to a correct diagnosis in all cases subjected to the technique. CONCLUSION: Dermoscopy appears to be an efficient aid to the diagnosis of micro-melanomas, provided that clinicians are aware of this type of lesion and maintain the index of suspicion at a high level.

Narrower surgical margins might be sufficient in invasive horizontal growth phase melanoma.

BACKGROUND AND AIMS: The delineation of horizontal and vertical growth phases in primary cutaneous melanoma has contributed to our understanding of melanoma progression. Horizontal growth phase invasive melanomas are now believed to metastasize very rarely. Consequently, some of us have started to treat these lesions with very limited surgical margins, assuming that in terms of biological behavior this type of melanoma is more similar to an in situ than an invasive lesion. METHODS: Between January 1997 and December 2001 42 lesions of this type in 41 patients (24 women and 17 men) were treated in the outpatient clinic under local anesthesia. The excision margin was half a centimeter and the subcutaneous fat was cleared in most cases to the deep fascia, which was conserved. Loss was made good by direct tissue closure. All patients had undergone an excisional biopsy before definitive surgery. The size of the lesions ranged from 2 mm to 19 mm in maximum linear extent (median 7 mm). Lesion thickness ranged from 0.11 mm to 0.58 mm (median, 0.27 mm). RESULTS: The median follow-up was 47 months (range, 26-83). During this period none of the patients had locoregional or distant relapses. CONCLUSIONS: This preliminary report seems to corroborate the assumption that horizontal growth phase melanoma is not an aggressive lesion and might therefore be cured by non-aggressive surgery. The proper treatment of such lesions might be a surgical excision at half a centimeter distance from the biopsy scar. This approach may produce very good cosmetic results, while keeping the costs and required resources to a minimum.

Does melanoma behave differently in younger children than in adults? A retrospective study of 33 cases of childhood melanoma from a single institution.

OBJECTIVE: To ascertain whether childhood melanoma presents any peculiar clinical features or differences in prognosis with respect to adults, we retrospectively analyzed the data from 33 patients who were up to 14 years of age and treated for cutaneous melanoma at the Istituto Nazionale Tumori, Milan, over a 25-year period. METHODS: Primary lesions were amelanotic in half of the cases and raised in 73%. Lower extremities were the most common primary sites. Histologically, 9 cases were classified as nodular type, and median thickness was 2.5 mm. Nine children had nodal involvement at diagnosis, 2 in-transit metastases, and 1 distant spread. Surgery was the mainstay of treatment; 9 patients underwent lymph node dissection, 3 received chemotherapy, and 2 received radiotherapy. RESULTS: With a median follow-up of 122 months, 5-year event-free survival and overall survival were 60% and 70%, respectively. Age seemed to correlate with survival, event-free survival being 90% in children under 10 and 47% in older patients, although the initial microstaging seemed worse in the former. CONCLUSION: By comparison with adult cases, childhood melanoma can have a higher percentage of atypical clinical features (amelanotic and raised lesions), nodular histotype, and thick lesions. Although we have no data to support any suggestion of biological differences between young children and adolescents or adults, our findings give the impression that melanoma behaves differently in the younger age group.

Melanoma detection. A prospective study comparing diagnosis with the naked eye, dermatoscopy and telespectrophotometry.

BACKGROUND: Successful treatment of melanoma depends directly on early diagnosis. Such a diagnosis is based on clinical examination and dermatoscopy. Recently, automated instruments for melanoma detection are under development. OBJECTIVE: To prospectively evaluate the diagnostic possibilities provided by clinical and dermatoscopic examinations and by a computerized telespectrophotometric system (TS). METHODS: The study involves a consecutive series of 298 patients with 313 cutaneous pigmented lesions (66 melanomas and 247 non-melanoma lesions). Each lesion was subjected to the triple diagnostic evaluation, before surgery. Results were expressed in terms of sensitivity and specificity of each kind of evaluation. RESULTS: Clinical evaluation had sensitivity and specificity values of 86 and 77%, respectively, whereas dermatoscopy gave corresponding values of 91 and 74%. TS assessment resulted in a sensitivity of 80% and a specificity of 49%. Differences between clinical and dermatoscopic diagnoses lacked statistical significance (p = 0.22), whereas there was a significant difference comparing both clinical and TS evaluations (p < 0.01) and dermatoscopic and TS evaluations (p < 0.01). Combining clinical and dermatoscopic evaluations, a sensitivity of 97% was achieved. Addition of TS has not changed this figure. CONCLUSIONS: Results of this study confirm and stress the importance of dermatoscopy in the diagnosis of melanoma. Clinical evaluation coupled with dermatoscopy can be considered the cornerstone of such a diagnosis. Although TS is able to achieve interesting results, at present it cannot significantly compete with any of the other tested methods.