Recognition Of Melanoma Research Articles

Diagnosis and treatment of cutaneous melanoma: a practical guide.

During the past decades, a number of new scientific evidences have been provided allowing a better understanding of the nature of cutaneous melanoma. New scientific methods, such as dermoscopy, have been shown to improve the diagnostic accuracy of pigmented skin lesions and early recognition of melanoma. Aggressive approaches for the surgical treatment of melanoma have been shown to be useless and have been replaced by more conservative surgical protocols and by sentinel lymph node biopsy. In the advanced stage of melanoma, new chemotherapy protocols and immunotherapy have been proposed, whereas the role of vaccines is still under investigation. In this review, the authors present an up-to-date overview of the epidemiologic, clinical, histopathologic, and therapeutic aspects of melanoma that can be used as a practical guide for the management of this tumor.

Malignant melanoma: treatments emerging, but early detection is still key.

Although we are beginning to develop treatment options for malignant melanoma, earlier recognition of potential primary melanomas remains the most effective way to increase survival in this highly malignant disease. This article reviews prominent risk factors for melanoma, key physical findings in at-risk patients, new melanoma staging guidelines, and recent and emerging therapy options.

Clinical simulators of melanoma

A prominent dermatologist suggested that “no one should die of melanoma,”1 since this neoplasm arises on a readily accessible site; specifically, it is skin-deep and can be recognized in its early stages when simple excision is usually curative. In the same breath, “What is the hardest of all? That which you hold the most simple; seeing with your own eyes what is spread out before you” (Goethe, quoted by J. P. Eckermann, in Conversations with Goethe, May 18, 1824). This is true for all skin lesions but all the more so for malignant melanoma, and the bottom line is that diagnosing melanoma in its early stages is easier said than done. The diagnosis of melanoma has always been a real challenge for dermatologists and it will probably remain so in the third millennium as well. The ability of general practitioners (GPs) and dermatologists to diagnose pigmented skin lesions in general and melanoma in particular was evaluated in one Belgian study before and after a lecture on melanoma.2 It emerged that the recognition of melanoma was proportional to melanoma exposure in everyday practice and that thick melanomas were better recognized than thin ones by both groups of physicians. After the lecture on melanoma, the sensitivity of the GPs to recognize the lesion increased from 49% o 76%, but the diagnostic ability of dermatologists was superior to theirs both for discriminating between malignant and benign disease and for correctly identifying various lesions. The number of missed melanomas was highest for the earlystage melanomas, ie, 34% among the GPs and 13% among the dermatologists. A higher diagnostic accuracy of skin lesions on the part of dermatologists compared with several medical specialty groups has been reported by other studies.3–6 The differential diagnosis of malignant melanoma includes a wide variety of benign and malignant lesions that will be presented and discussed in the present article.

Digital dermoscopy analysis for automated diagnosis of pigmented skin lesions

Melanoma is increasing in frequency worldwide. In Italy the current incidence of this tumor is about 10–15 new cases per year per 100,000 population.1 Despite much research into the field of melanoma biology and treatment that has already been done, this tumor is still practically incurable when diagnosed in an advanced stage. Early diagnosis is therefore of utmost importance to reduce the mortality rate.2 Clinical recognition of melanoma is, however, not always easy. Conventional clinical criteria for early diagnosis of melanoma are summarized by the ABCDE formula: A stands for asymmetry, B for border irregularity, C for color variegation, D for diameter 5 mm, and E for evolution (morphologic changes of the lesion). Although ABCDE clinical criteria represent a simple and reliable guide for self-examination, they cannot always be considered an effective approach to reach high diagnostic accuracy for melanoma, since numerous benign, pigmented skin lesions (PSLs) may mimic melanoma by using this method. From a diagnostic viewpoint, accuracy has greatly been improved since dermatologists have started to use new techniques, such as epiluminescence light microscopy (ELM), which magnifies lesions and enable them to be examined down to the dermo-epidermal junction.3,4 By ELM, new morphologic features of melanoma can be visualized, facilitating early diagnosis in most cases.5,6 Many studies have provided specific epiluminescence diagnostic criteria, paving the way for a new semeiology of patterns, colors, pigmentation intensity, configuration, regularity, and margin and surface characteristics. Qualitative evaluation of the many morphologic characteristics of PSLs observable by ELM, however, is often extremely complex and subjective.7 With the aim of obviating the problem of qualitative interpretation of dermatoscopic features, methods and instruments based on mathematical analysis of PSLs have recently been developed (Table 1).8–12 These methods are based on computerized analysis of digital images that are obtained by ELM. An example is digital dermoscopy analysis (DDA), which gathers numerical data and enables PSL images to be described objectively.

Loss of single HLA class I allospecificities in melanoma cells due to selective genomic abbreviations.

Expression of human leucocyte antigen (HLA) Class I molecules is essential for the recognition of malignant melanoma (MM) cells by CD8(+) T lymphocytes. A complete or partial loss of HLA Class I molecules is a potent strategy for MM cells to escape from immunosurveillance. In 2 out of 55 melanoma cell cultures we identified a complete phenotypic loss of HLA allospecificities. Both patients have been treated unsuccessfully with HLA-A2 peptides. To identify the reasons underlying the loss of single HLA-A allospecificities, we searched for genomic alterations at the locus for HLA Class I alpha-chain on chromosome 6 in melanoma cell cultures established from 2 selected patients with MM in advanced stage. This deficiency was associated with alterations of HLA-A2 gene sequences as determined by polymerase chain reaction-sequence specific primers (PCR-SSP). Karyotyping revealed a chromosomal loss in Patient 1, whereas melanoma cell cultures established from Patient 2 displayed 2 copies of chromosome 6. Loss of heterozygosity (LOH) using markers located around position 6p21 was detected in both cases. By applying group-specific primer-mixes spanning the 5'-flanking region of the HLA-A2 gene locus the relevant region was amplified by PCR and subsequent sequencing allowed alignment with the known HLA Class I reference sequences. Functional assays using HLA-A2-restricted cytotoxic T-cell clones were performed in HLA-A2 deficient MM cultures and revealed a drastically reduced susceptibility to CTL lysis in HLA-A2 negative cells. We could document the occurrence of selective HLA-A2 deficiencies in cultured advanced-stage melanoma metastases and identify their molecular causes as genomic alterations within the HLA-A gene locus.

Diagnostic ability of general practitioners and dermatologists in discriminating pigmented skin lesions

Background: Early recognition of melanoma is the key in preventing metastatic disease. Objective: The aim of this study was to evaluate diagnostic ability of general practitioners (GPs) and dermatologists concerning pigmented skin lesions in general and melanoma in particular. We also investigated whether the diagnostic ability of GPs changed after a lecture on melanoma. Methods: A test set of 13 pigmented skin lesions on 35-mm color slides was presented to 160 GPs and 60 dermatologists during educational courses. Results: GPs correctly evaluated biologic behavior of the pigmented skin lesions in 72% of the evaluations. In 71% of these evaluations they correctly identified the lesions. The proportion of lesions correctly identified was positively correlated with the frequency of pigmented skin lesions in everyday practice. Dermatologists made a correct identification of the lesions in 88% of all evaluations, and they correctly evaluated biologic behavior in 94% of these. Recognition of melanoma was proportional to melanoma exposure in everyday practice. Thick melanomas were better recognized than thin melanomas in both physician groups. After a lecture on melanoma, sensitivity of GPs to recognize malignant disease increased from 72% to 84%, without a significant decrease in specificity. The proportion of lesions correctly identified also rose significantly (66% vs 52%). (J Am Acad Dermatol 2001;44:979-86.)

Epidemiology of Cutaneous Melanoma in Germany and Worldwide

Rising incidence rates of cutaneous melanoma have been observed during the last three decades. At the beginning of the 1970s 3 cases and in the 1990s 9 cases per 100,000 inhabitants and year were reported by the Saarland Cancer Registry in Germany. Other incidence studies from Germany in the 1990s even reported 10–12 cases per 100,000 inhabitants and year, which is more likely to be the representative melanoma incidence in Western Germany. In a worldwide comparison this is a medium incidence rate as compared to clearly higher incidence rates in the United States (10–20 cases per 100,000 inhabitants and year) and in Australia (40–60 cases per 100,000 inhabitants and year). In Europe the highest incidence rates have been reported from Scandinavia (about 15 cases per 100,000 inhabitants and year) and the lowest from the Mediterranean countries (about 5–7 cases per 100,000 inhabitants and year). Mortality rates likewise increased in Germany between 1970 and 1995 in males from 1.7 to 3.2 cases and in females from 1.6 to 2.0 cases per 100,000 inhabitants and year. In the 1990s, in Germany and in many other countries a leveling off of mortality rates was observed. 48,928 melanoma patients have been recorded by the Central Malignant Melanoma Registry from the German-speaking countries in the time period from 1983 to September 2000, and clinico-epidemiological analysis of cutaneous melanoma is based on this data material. While 2/3 of all melanoma patients in Germany were females in the 1970s, there is now a more balanced gender distribution with more than 45% of patients being males. Age distribution does not significantly change during the last three decades. Most melanomas are diagnosed in the age group between 50 and 60 years, 22% of all melanomas are diagnosed before the 40th year of age. A clear decrease of Breslow’s tumor thickness was found from the beginning of the 1980s to the mid-1990s with the median thickness decreasing from 1.3 to 0.8 mm. Lower Breslow’s tumor thickness at first diagnosis of cutaneous melanoma has only been reported from Australia. This development indicates improved early recognition of cutaneous melanoma which is presently the main factor for a more favorable prognosis.

Pathologic and Clinical Features Influencing Outcome of Thin Cutaneous Melanoma: Correlation with Newly Proposed Staging System

The incidence of malignant melanoma is increasing. Because of increased awareness, early recognition of malignant melanoma has become more common. In 1997, a new staging system for cutaneous melanoma was proposed, with reclassification of thin melanoma < 1 mm, with and without ulceration. This report evaluates the pathologic and clinical features of thin melanomas influencing recurrence and survival from a tertiary cancer center in an attempt to correlate findings with the proposed staging system. A review of the Roswell Park Cancer Institute tumor registry identified 352 patients with thin cutaneous melanomas (< 1.0 mm) seen during an 18-year period ending August 30, 1998. Overall survival was 93 and 87 per cent at 5 and 10 years, respectively. Disease-free survival was 94 and 93 per cent at 5 and 10 years, respectively. Local recurrence occurred in 3 per cent of patients, regional recurrence in 3 per cent, and metastatic disease in 3 per cent, for an overall recurrence of 7 per cent, with a median follow-up of 118 months. Only the presence of ulceration was a significant prognostic factor for recurrence by both univariate and multivariate analysis. Failure rates (any recurrence) by Clark levels I, II, and III/IV were 3, 5, and 10 per cent, respectively (P = 0.14). Failure rates by tumor thickness (mm), for 0.0-0.24, 0.25-0.49, 0.50-0.74, and 0.75-0.99 were 3, 4, 7, and 10 per cent, respectively (P = 0.49). Ten-year disease-free survival for ulceration versus no ulceration was 40 and 94 per cent, respectively (P < 0.0001). We conclude that thin cutaneous melanoma carries an excellent prognosis with appropriate treatment. Our findings support inclusion of ulceration in a new staging system. Lesions 0.76 to 0.99 mm and Clark level III and IV may warrant close observation as a separate subgroup.

Secondary prevention of malignant melanoma

Secondary prevention of melanoma covers early recognition of malignant melanoma and precursors. The aims of secondary prevention are: decrease of tumor thickness at the time of first detection and first therapy. decrease of melanoma mortality. Screening of high-risk-persons for melanoma is a fair strategy for Switzerland: easy to perform and also efficient.

Computer-Supported Diagnosis of Melanoma in Profilometry

Laser profilometry offers new possibilities to improve non-invasive tumor diagnostics in dermatology. In this paper, a new approach to computer-supported analysis and interpretation of high-resolution skin-surface profiles of melanomas and nevocellular nevi is presented. Image analysis methods are used to describe the profile's structures by texture parameters based on co-occurrence matrices, features extracted from the Fourier power spectrum, and fractal features. Different feature selection strategies, including genetic algorithms, are applied to determine the best possible subsets of features for the classification task. Several architectures of multilayer perceptrons with error back-propagation as learning paradigm are trained for the automatic recognition of melanomas and nevi. Furthermore, network-pruning algorithms are applied to optimize the network topology. In the study, the best neural classifier showed an error rate of 4.5% and was obtained after network pruning. The smallest error rate in all, of 2.3%, was achieved with nearest neighbor classification.

CLINICAL RECOGNITION OF MELANOMA AND ITS PRECURSORS

This article reviews the essential clinical features of cutaneous melanoma, as well as those of the more common benign pigmented lesions that need to be distinguished on clinical examination.

Malignant Melanomas of the Iris

The recognition of iris melanoma is important because a number of benign lesions clinically resemble these tumors. In this article, the epidemiological, clinical and histopathological features, treatment modalities, and prognosis of 41 iris melanoma patients, seen between 1964 and 1996 were evaluated. Of the patients, 20 were men and 21 women. Their mean age was 44.6 years. After determining the size, localization, and extension of the tumor, the management of choice was observation in 9, sector iridectomy in 15, iridocyclectomy in 6 and enucleation in 11 of the patients. During the follow-up, enucleation was also required in 6 and iridocyclectomy in 1 of the 7 patients who were in the observation or sector iridectomy group initially. Histopathologic examination revealed spindle cell in 27, mixed cell in 6 and epithelioid cell type melanomas in 2 of the 35 cases who underwent iridectomy, iridocyclectomy, and/or enucleation. The mean follow-up was 3.2 years and the mortality rate was found to be 2.4% during this period. One patient who died of metastases had epithelioid cell type melanoma.

Clinical Characteristics of Malignant Melanoma

Malignant melanoma represents a major public health concern. Its incidence is rising throughout the World; in Europe particularly, 13–21 people/100.000 are affected annually. Although the aetiology is multifactorial, excessive UV exposure (UVB 290–320 min.) appears to be one of the most important predisposing agent. Genetic predisposition plays also a fundamental role. Chromosome 9p has been implicated in familial melanoma via the inhibition of a cyclin-dependent kinase 4 which interferes with cell cycle. I he early detection and recognition of malignant melanoma is the key for possible cure. Technical aids like photography, computer based systems, epiluminescence or biopsy increase the sensitivity of formally trained clinicians.

Killer Cell Inhibitory Receptors for MHC Class I Molecules Regulate Lysis of Melanoma Cells Mediated by NK cells, γδ T Cells, and Antigen-Specific CTL

AbstractNK cells and T cells express killer cell inhibitory receptors (KIR) recognizing polymorphic MHC class I molecules. Although prior studies have established that MHC class I can protect normal and transformed hematopoietic cells from NK cell lysis, the role of MHC class I on the recognition of solid tumors has been controversial. In this study, we investigated whether interactions of KIR with their ligands on melanoma tumor cells could inhibit tumor cell lysis by NK and γδ T cell clones. Ligation of the NK cell receptor KIR3DL1 by HLA-Bw4 allotypes resulted in inhibition of cytotoxicity against HLA-B*4403-transfected melanomas as well as against melanomas endogenously expressing HLA-Bw4 allotypes. Similarly, interactions of KIR2DL2 or KIR2DL3 (KIR2DL2/3) with HLA-Cw3-related allotypes on melanomas resulted in decreased tumor cell lysis. We also investigated whether signaling via KIR affected melanoma recognition by CTL. Introduction of KIR3DL1 molecules into HLA-A*0201-restricted gp100-specific CTL resulted in inhibition of lysis of gp100+ melanomas co-expressing HLA-A*0201 and HLA-Bw4 allotypes. These results suggest that disrupting interactions of KIR with their ligands on tumor cells in vivo may enhance antitumor responses mediated by both innate and adaptive immune effector cells.

Epiluminescence microscopy in clinical diagnosis of pigmented skin lesions?

Melanoma is also one of the clearest cases of a cancer for which early detection and treatment are critical. The ABCD (Asymmetry, Border irregularity, Colour variegation, Diameter >6 mm) criteria for assisting the visual recognition of early melanoma were introduced in 1985. 1 Friedman RJ Rigel DS Kopf AW Early detection of malignant melanoma: The role of physician examination and self examination of the skin. Ca. 1985; 35: 130-151 Google Scholar However, there have since been limited attempts to develop non-invasive tools to improve early diagnosis. One such tool is epiluminescence microscopy (ELM), first described in 1987. 2 Steiner A Pehamberger H Wolff K Improvement of diagnostic accuracy in pigmented skin lesions by epiluminescent light microscopy. Anticancer Res. 1987; 7: 433-434 PubMed Google Scholar Also known as skin-surface microscopy and dermatoscopy, ELM is a non-invasive method that, by employing the optical properties of oil immersion, makes subsurface structures of the skin accessible for in-vivo examination. Initially designed to be used with complex microscopic equipment, ELM can now be easily used in the general clinical setting with an inexpensive hand-held otoscope-like unit.

DERMOSCOPY (EPILUMINESCENCE MICROSCOPY) OF PIGMENTED SKIN LESIONS: Current Status and Evolving Trends

Dermoscopy (epiluminescence microscopy) is a noninvasive technique that is designed for in vivo microscopic examination of pigmented skin lesions, particularly for the early recognition of malignant melanoma. Since its introduction, dermoscopy technique has undergone extensive improvements; the instruments have become more readily available; and the diagnostic indications, benefits, and limitations have been better delineated. This article offers a concise review of the technique of dermoscopy, assesses the current status, and makes some predictions for future applications.

MALIGNANT MELANOMA FROM THE DERMATOLOGIC PERSPECTIVE

Early recognition and treatment of thin cutaneous melanomas (stages Ia and Ib) have contributed to a decreased case-fatality rate during the past several decades. The only known preventable risk factor for melanoma is sun protection in childhood, which directly affects the number of melanocytic nevi developing in an adult. Additional risk factors, clinical features, and the malignant potential of precursor lesions are discussed. The four major clinicopathologic subtypes of melanoma are described with recommendations for appropriate biopsy techniques for suspected melanoma. Nationwide skin cancer screenings by dermatologists and greater public awareness of the warning signs of melanoma have enhanced detection of early melanoma and have promoted chances for a cure.

Neoplastic progression and prognosis in melanoma.

Most melanomas evolve through an initial stage known as radial growth phase (RGP), encompassing in situ and microinvasive malignancies in which the probability of cure approaches 100%. At the present time, despite a shift toward earlier recognition of melanoma, by the time of diagnosis roughly 70% of melanomas have evolved to a point, known as vertical growth phase (VGP) or tumorigenic melanoma, at which cure is not certain, and prognosis depends upon certain attributes of the neoplasm and the host. Attempts have been made to assemble these attributes into prognostic models to permit estimation of the probability of cure for individuals and for groups of patients. Attributes that have been identified as independent prognostic variables include thickness of the primary neoplasm, the numbers of mitotic figures, and the presence of tumor-infiltrating lymphocytes (TIL). Other biologically important prognostic variables are on the horizon, and some will likely be based on molecules (markers) expressed on neoplastic cells that show functional significance in mechanisms of metastasis.

Recognition of Human Renal Cell Carcinoma and Melanoma by HLA‐A2‐Restricted Cytotoxic T Lymphocytes is Mediated by Shared Peptide Epitopes and Up‐Regulated by Interferon‐γ

Cytotoxic T lymphocytes (CTL) have previously been isolated from peripheral blood of patients with renal cell carcinoma (RCC). The CD8-positive CTL line MZ1257-CTL-5 (CTL-5) has been shown to lyse autologous cultured RCC cells in an HLA-A2 restricted fashion. Allogeneic, HLA-A2-matched RCC and melanoma cell lines were also lysed by CTL-5, suggesting that melanoma and renal cancer share antigenic determinants. The aim of the study was to determine whether RCC and melanoma share peptide epitopes that are recognized by CTL-5 in the context of HLA-A2 molecules. Peptides were acideulated from various cell lines, separated by reversed phase high performance liquid chromatography (RP-HPLC), and assessed for their ability to reconstitute the CTL-5-defined epitope by pulsing the peptides on HLA-A2 positive antigen-processing mutant cell line CEM x 721.174.T2 (T2). Peptides eluted from allogeneic HLA-A2-matched RCC and melanoma cell lines exhibited the CTL-5-defined epitope in the same HPLC fractions as peptides derived from the autologous RCC line. Renal cancer and melanoma cells preincubated with interferon-gamma (IFN-gamma) resulted in an additional peak of reconstitution activity in both cell types. This second lytic peak was also observed when high amounts of autologous RCC cells were used for peptide preparation without IFN-gamma pretreatment, indicating that IFN-gamma increases the amount of MHC class I/peptide complexes per cell, rather than inducing a neo-epitope.

Recognition and Lysis of Human Melanoma by a CD3+, CD4+, CD8−T-Cell Clone Restricted by HLA-A2

Thein vitrocytotoxic response to human melanoma is characterized by CD3+CD8+T-cells which recognize shared peptide antigens presented in the context of HLA class-I-encoded gene products. We report here studies of a CD3+, CD4+, CD8−, HLA-A2-restricted, melanoma-specific cytotoxic T-cell clone derived by limiting dilution from a T-cell line induced in PBLs from a melanoma patient followingin vitrostimulation with an HLA-A2-matched melanoma cell line. The CD4+cytotoxic T-cell clone is lytic only for melanomas which share the HLA-A2 allele, and the cytotoxicity is blocked by antibody to the T-cell receptor and by antibody to HLA class I. The clone proliferates only following stimulation with HLA-A2-matched melanoma tumor cells. The data suggest that cytotoxic CD4+T-cells may play a significant role in immunity to melanoma, and HLA class-I-restricted recognition of melanoma may not necessarily require the CD8 molecule on the lytic T-cell.