Dermatoscopy of amelanotic and hypomelanotic melanoma

Amelanotic melanoma is a subtype of cutaneous melanoma without pigment. The clinical diagnosis is challenging because it may mimic benign or malignant melanocytic and non‐melanocytic neoplasms and inflammatory skin diseases. In synchrony with the improvement of the diagnosis of pigmented lesions, dermatoscopy may assist the clinician in the diagnosis of non‐pigmented skin neoplasms in general and of amelanotic melanoma in particular. We have searched the literature to extract the most relevant dermatoscopic clues to diagnose amelanotic and hypomelanotic melanomas by dermatoscopy. In addition we present eight consecutive cases and discuss their clinical and dermatoscopic characteristics in the light of published data.     

Tissue microarray analysis of ezrin, KBA.62, CD166, nestin, and p-Akt in melanoma versus banal and atypical nevi, and nonmelanocytic lesions

Multiple melanocytic markers are useful for differentiating between melanoma and nonmelanocytic lesions but generally do not distinguish melanoma from nevi and atypical melanocytic lesions. We sought to determine if several immunohistochemical markers recently described in the literature, including ezrin, KBA.62, p-Akt, CD166, and nestin, may be helpful in distinguishing these lesions. One hundred ten tissue microarray samples were scored for nestin and CD166 and 220 samples for ezrin, KBA.62, and p-Akt. We found that putative stem cell markers nestin and CD166 were both expressed in most melanomas (86% and 65% of samples, respectively), including desmoplastic melanoma, but were also expressed at similar levels in nevi (79% and 74%, respectively). In addition, these markers were not specific for melanocytic lesions. Ezrin was also expressed in both nevi and melanoma (81% each), including desmoplastic melanoma (75%), and in neural tumors. KBA.62 stained more cases of nevi versus melanoma (93% and 65%, respectively) and was positive in 53% of desmoplastic melanoma. However, it was also positive in several nonmelanocytic tumors. P-Akt expression was generally weak but was increased in nevi (75%) versus melanoma (43%), and was lost in desmoplastic melanomas (5%). Overall, only KBA.62 and p-Akt expression differed between melanoma and nevi, and none of these markers were completely specific for melanocytic tumors versus nonmelanocytic lesions.     

Modified dermoscopic algorithm for the differentiation between melanocytic and nonmelanocytic skin tumors

BACKGROUND: The use of dermoscopy (dermatoscopy, epiluminescence microscopy, surface microscopy) improves the clinical diagnostic accuracy of skin tumors by applying different algorithms or scores. The first step in the dermoscopic evaluation is the differentiation between melanocytic and nonmelanocytic skin tumors. OBJECTIVE: To evaluate the diagnostic accuracy of the established dermoscopic algorithm (EDA) and the modified dermoscopic algorithm (MDA) for melanocytic versus nonmelanocytic skin tumors. METHODS: Two hundred forty-nine patients with melanocytic and nonmelanocytic skin lesions were included. Dermoscopic images of the tumors were taken with 10-fold magnification, followed by surgery and histopathology at the departments of Dermatology at the universities of Tuebingen, in Germany, and Naples, in Italy. Each lesion was classified using the EDA and MDA. In the MDA, accessory nipples and dermatofibromas were considered in particular. RESULTS: With the EDA, 225 of 249 (90.4%) skin tumors were correctly classified in one of the six groups. With the MDA, 237 of 249 (95.2%) were correctly classified. Improvement was achieved in 12 (4.8%) better classified skin tumors. In both algorithms, no melanoma was classified as a nonmalignant melanocytic tumor. All melanomas were classified in the group of melanocytic tumors and one melanoma was classified in the group of basal cell carcinomas. CONCLUSION: Both dermoscopic algorithms for the differentiation between melanocytic and nonmelanocytic skin tumors were simple and effective when applied step by step. The MDA is an improvement on the EDA with the classification of accessory nipples and dermatofibromas.     

Adding dermatoscopy to naked eye examination of equivocal melanocytic skin lesions: effect on intention to excise by general dermatologists

Background. According to the literature, dermatoscopy can improve diagnostic accuracy for melanoma. However, a weak point of the studies in the literature is that most were carried out in a ‘privileged’ setting of dermatologists who are expert in dermato‐oncology, and who work in departments specializing in screening pigmented lesions. This study was set up to specifically evaluate whether the use of dermatoscopy by general dermatologists would also improve accuracy. Aim. To analyse the effect on intention to excise lesions (intervention yes/no) of adding either dermatoscopy (20 years after the advent of the method) or detailed lesion classification (melanoma yes/no) to clinical examination by the naked eye. More specifically, we evaluated whether the current practice of general dermatologists using dermatoscopy improves the sensitivity and specificity values, and thus the diagnostic accuracy. Methods. Eight general dermatologists examined separately clinical images and combined (clinical and dermatoscopic) images of 200 melanocytic lesions that had been excised (64 melanomas and 136 melanocytic naevi). Results. Focusing on intention to excise (intervention yes/no), addition of dermatoscopy to naked eye examination resulted in an increase in sensitivity for all observers (average gain + 4.5%) but an overall nonsignificant reduction in specificity (?4.5%, P = 0.10). Diagnostic accuracy, which increased when examination was focused on melanoma (yes/no) classification (+ 4.1%, P < 0.05) remained unchanged (?1.62%; P = 0.36). Conclusions. The effect of adding dermatoscopy to naked eye examination of melanocytic lesions on ‘general dermatologists’ changes according to the aim of the examination. Dealing with the intention to excise, the increase of sensitivity associated with dermatoscopy (lower risk of leaving a melanoma unexcised) is obtained at the expense of specificity (higher number of melanocytic naevi excised) without improving overall diagnostic accuracy.     

Dermatoscopy of "dysplastic nevi": a beacon in diagnostic darkness

The sequential progression model for melanocytic tumours from common nevus to malignant melanoma was proposed by Clark almost 30 years ago. The "dysplastic nevus" has frequently been considered a logical offspring of this concept and as a direct precursor of melanoma, analogous to the epithelial dysplasia-carcinoma sequence. Despite the use of modern molecular methods, there is no consensus as to if the dysplastic nevus represents a true precursor lesion of melanoma, a separate distinct type of nevus, or a diagnostic dilemma. Currently, the concept of melanocytic dysplasia remains subject to confusing definitions at all levels of the diagnostic process, i.e. clinical appearance, dermatohistopathology, and molecular biology. In this review, we collect evidence that nevi fulfilling Clark and Elder's classic histological criteria mostly represent "endpoints" of nevocytic evolution, whereas a minority of "dysplastic nevi" represent true melanoma precursors. The unsolved dilemma is that neither clinical, histopathological nor molecular criteria exist to make a distinction between dysplastic nevi and early melanomas. Our analysis of the current knowledge on dysplastic nevi shows that dermatoscopy remains the only quantifiable, easily applicable and reproducible diagnostic tool to approach the problem. Due to a "quantum leap" in optical resolution, objective scores can be established, e.g. the total dermatoscopy score (TDS) according to the ABCD rule, and documentation of changes over time are possible by digital image storage devices. Although dermatoscopy does not solve the dilemma of discriminating early, basically feature-less melanomas from dysplastic nevi, and it does not prove that dysplastic nevus is a distinct entity, it helps make melanocytic tumours with unclear malignant potential a manageable disease.     

Can automated dermoscopy image analysis instruments provide added benefit for the dermatologist? A study comparing the results of three systems

BACKGROUND: Instruments designed to provide computer program-driven diagnosis of dermoscopic images of lesions are now commercially available. Multiple publications tout the improved diagnostic accuracy of these instruments compared with that of clinicians. OBJECTIVES: Our aim was to evaluate the actual usefulness of these instruments for dermatologists practising in a pigmented lesion clinic. METHODS: Over a 4-month period we subjected lesions, which were being evaluated in one of our clinics, to automated computer diagnosis performed by three commercially available instruments. We intentionally included three groups of lesions: group 1 lesions were suspicious melanocytic lesions that were scheduled to be excised; group 2 lesions were nonmelanocytic lesions; group 3 lesions were clinically obvious melanomas. The automated diagnoses provided by the instruments were compared with the dermoscopy diagnosis of experienced physicians and with histopathology. RESULTS: We included a total of 107 lesions. One imaging system's computer algorithm was unable to analyse one third of the lesions. All three instruments' computer algorithms were able to identify the clinically obvious melanomas (group 3) correctly. However, all three systems tended to overdiagnose by incorrectly classifying most seborrhoeic keratoses (group 2) as potential malignant lesions. Concerning the suspect melanocytic lesions (group 1), which are precisely the lesions for which a dermatologist would welcome a second opinion, we found significant variability in the diagnostic accuracy of the instruments tested. However, all three systems providing computer-assisted diagnosis had a tendency to overdiagnose benign melanocytic lesions as potential melanomas. CONCLUSIONS: Although the image analysis systems tested by us correctly identified the clinically obvious melanomas, they were not able to discriminate between most dysplastic naevi and early malignant melanoma. Thus, for the moment these computer-assisted diagnostic imaging machines provide little to no added benefit for the experienced dermatologist/dermoscopist.     

The use of the dermatoscope to identify early melanoma using the three-colour test

BACKGROUND: There is continuing interest in pre-operative evaluation of cutaneous pigmented lesions with the aim of differentiating early melanoma, which requires excision from non-melanomatous pigmented lesions that may safely be left untreated. OBJECTIVES: To establish, in the setting of a specialist pigmented lesion clinic, if use of the hand-held dermatoscope can prevent unnecessary excision of benign melanocytic pigmented lesions. METHODS: The study was carried out by three dermatologists experienced in the use of the dermatoscope. Patients had been referred by primary care physicians to the pigmented lesion clinic and had melanocytic lesions considered by dermatologists to merit excision on clinical grounds. A set of 74 sequentially observed lesions referred for excision, 37 melanomas and 37 melanocytic naevi, was used as the initial set and, thereafter, a second set of 52 lesions comprising 32 melanomas and 20 melanocytic naevi was used to validate conclusions drawn from the original set. Clinical features such as appearance and history, and also dermatoscope features were included in the assessment. RESULTS: In both sets of lesions, the most powerful identifying feature of lesions subsequently shown on pathological examination to be melanoma was the presence of three or more colours seen in the lesion on dermatoscopy. In the initial set of lesions, the age of the patient, an irregular edge and largest diameter of the lesion also contributed to diagnosis; however, in the second set of lesions these variables contributed little additional discriminatory value. The sensitivity and specificity of the three-colour dermatoscopy test for melanoma vs. naevus were 92% and 51%, respectively. CONCLUSIONS: The use of the dermatoscope three-colour test could reduce excision of benign melanocytic naevi by 50%, and thus prevent both unnecessary minor surgical workload and patient morbidity.     

The dermatoscopic ABCD rule does not improve diagnostic accuracy of malignant melanoma

The dermatoscopic ABCD rule has been suggested to improve diagnostic performance regarding cutaneous malignant melanoma. Using this rule, a total dermatoscopy score is calculated from the presence of various dermatoscopic elements. A total dermatoscopy score above 4.75 signifies possible and 5.45 probable melanoma. We compared the diagnostic accuracy of dermatoscopy with and without the use of the ABCD rule. Furthermore, receiver operating characteristic analysis was performed for the ABCD rule. The area under the receiver operating characteristic curve was 0.854 (range 0.777-0.906) demonstrating that in 85.4% of the cases, cutaneous malignant melanomas were rated higher than the non-melanoma skin lesions. Sensitivity for the melanoma diagnosis was higher for simple dermatoscopy than when the ABCD rule was used (p<0.05). There was no difference in specificity when a total dermatoscopy score of 4.75 was used as cut-off point, but specificity was lower for simple dermatoscopy than when the total dermatoscopy score of 5.45 was used. Diagnostic accuracy was higher for simple dermatoscopy than for the ABCD rule (p<0.01). In conclusion, the dermatoscopic ABCD rule was not superior to simple dermatoscopy, and fewer malignant melanomas were identified with this rule.     

The effect of the sun on expression of beta-catenin, p16 and cyclin d1 proteins in melanocytic lesions

BACKGROUND: The tumour suppressor gene product, p16, is often inactivated during melanoma malignant progression. Although the importance of p16 in melanomas is well documented, its relationship with cyclin D1, beta-catenin and ultraviolet radiation (UVR) remains unclear. AIM: To determine the role of these cell cycle-related proteins and high-risk sun exposure in the biological behaviour of melanocytic lesions. METHODS: We used immunohistochemistry to examine 28 melanocytic naevi (MN; 9 congenital and 19 acquired types) and 24 primary cutaneous malignant melanomas (CMM; 19 nodular melanomas, 3 lentigo maligna melanomas, 1 acral lentiginous melanoma and 1 superficial spreading melanoma) for the presence of p16, cyclin D1 and beta-catenin. The melanocytic lesions were classified into two groups to examine the effects of UVR on these three proteins: high risk of sun exposure (chronically sun damaged; CSD), or low risk of sun exposure (nonchronically sun damaged; non-CSD). We evaluated the relationship between the production of these proteins and the histopathological and clinical characteristics of the lesions. RESULTS: Production of p16 was repressed in most CMM, but not in MN (P < 0.0001). Cyclin D1 was overproduced in CMM but not in MN, and beta-catenin was frequently overproduced both in MN and CMM. Overproduction of beta-catenin was not common in CSD melanocytic lesions, but was more frequent in non-CSD melanocytic lesions (P = 0.027). CONCLUSION: An immunohistochemical panel including melanocytic markers enriched by p16 and cyclin D1 could be used to differentiate some borderline melanocytic lesions. In addition, the Wnt/beta-catenin pathway was more frequently activated in non-CSD than in CSD melanocytic lesions.     

Comparison of classical dermatoscopy and acrylic globe magnifier dermatoscopy

Dermatoscopic asymmetry of melanocytic skin lesion is pivotal in most algorithms assessing the probability of melanoma. Larger lesions cannot be assessed by dermatoscopy and the Dermaphot in a single field of vision, but this can be performed using the acrylic globe magnifier. We examined the diagnostic accuracy of the acrylic globe magnifier and compared it with classical dermatoscopy. A total of 119 patients successively referred to our naevus clinics had Dermaphot and acrylic globe magnifier pictures taken. Lesions were excised and assessed by histopathology. Observers blinded to histopathology diagnoses, assessed dermatoscopic and acrylic globe magnifier photo-slides according to the dermoscopic risk stratification. The observed agreement over all categories between acrylic globe magnifier dermatoscopy and classical dermatoscopy was 94% and Cohen's kappa coefficient was 90% (95% confidence interval 83-97%). Sensitivity for melanoma, benign melanocytic naevi and basal cell carcinoma was 100%, 98% and 85%, respectively. Specificity was 95%, 94% and 100% for melanoma, naevi and basal cell carcinoma. Acrylic globe dermatoscopy enables a diagnostic accuracy similar to epiluminescence microscopy.     

SM5-1: a new monoclonal antibody which is highly sensitive and specific for melanocytic lesions

Abstract Antibodies such as HMB-45 and anti-S100 protein have been widely used as markers of malignant melanoma despite evidence that HMB-45 has a sensitivity of only 67–93% and S100 is nonspecific for melanoma. Using a subtractive immunization protocol in a mouse model of human melanoma, we have generated several monoclonal antibodies with putative specificity for melanoma. After initial screenings, the antibody SM5-1 was chosen because of its intriguing reactivity with melanocytic tumors in both frozen and paraffin sections. The immunohistochemical staining of SM5-1 was studied in paraffin-embedded specimens of 401 melanomas (n = 401; 250 primary melanomas, 151 metastases), melanocytic nevi of the skin (n = 16), nonmelanocytic neoplasms (n = 84). The results were compared with HMB-45 and anti-S100 staining. All antibodies reacted with nevi and 97–99% with primary melanomas. Whereas both SM5-1 and anti-S100 stained 96% (146/151) of melanoma metastases, HMB-45 correctly identified only 83% (126/151). All HMB-45-negative metastases were positive for SM5-1. Whereas neither SM5-1 nor HMB-45 stained any of 84 specimens from 40 different nonmelanocytic neoplasms, anti-S100 was positive in 21/84 (25%). While the staining pattern of SM5-1 was mostly homogeneous, small tumor areas in some metastases remained unstained. Staining with SM5-1 was also observed in perivascular dendritic cells, in plasma cells, some myofibroblasts and the secretion of eccrine sweat glands. Nonactivated epidermal melanocytes, keratinocytes, endothelial cells, smooth muscle cells and peripheral nerves were all negative for SM5-1. These results suggest that SM5-1 is highly specific, as well as sensitive, for melanocytic lesions and is useful in the immunohistochemical evaluation of melanoma. Received: 16 June 2000 / Revised: 28 July 2000 / Accepted: 29 September 2000     

Nevus associated malignant melanomas--diagnostic validation and prognosis

The diagnosis and prognosis of naevus-associated malignant melanomas are examined in the present study. For this purpose, 581 cases of primary malignant melanoma seen in the University Department of Dermatology, Berlin Steglitz, were histologically investigated for naevus association. A naevocytic association was proven in 135 (23%) of the malignant melanoma biopsies. Naevocytic malignant melanomas were found at a significantly higher rate (P less than 0.01) in patients under 50 years of age. The 5-year survival rate for naevocytic melanomas was not significantly different from that for other malignant melanoma types: around 80% in both groups. An immunohistological evaluation of the diagnosis of naevus-associated melanoma was also performed on the basis of specimens from 89 melanocytic lesions. The use of HMB-45 for diagnosis of melanocytic tumours made it possible to differentiate resting dermal naevus cells from malignant melanoma infiltrates in paraffin sections in the present study, thus simplifying the diagnosis of naevus-associated malignant melanomas. However, dysplastic naevi, junctional naevi and juvenile melanomas are also stained by HMB-45, which means that malignant melanomas associated with junctional melanocytic naevi still cannot be reliably identified even today.     

Comparison of pHH3, Ki-67, and survivin immunoreactivity in benign and malignant melanocytic lesions

Differentiating malignant melanoma from benign melanocytic lesions can be challenging. We undertook this study to evaluate the use of the immunohistochemical mitosis marker phospho-Histone H3 (pHH3) and the proliferation markers Ki-67 and survivin in separating malignant melanoma from benign nevi. Sixty-six melanocytic lesions (18 malignant melanomas, 8 Spitz nevi, 20 dysplastic nevi, and 20 compound nevi) were stained with antibodies to pHH3, Ki-67, and survivin. No pHH3 expression was detected in the dermis of compound and dysplastic nevi. Rare mitoses were observed in the superficial dermis in 3 of 8 Spitz nevi (37%). Staining for pHH3 was higher in malignant melanomas [average 25 per 10 high-power field (HPF), range 2-75 per 10 HPF] than in Spitz nevi (average 0.5 per 10 HPF, range 0-2 per 10 HPF) and was heterogeneously distributed in the malignant melanomas compared with a superficial dermal location in Spitz nevi. There was no cytoplasmic staining for survivin in any of the 66 melanocytic lesions and no nuclear staining in any of the benign ones. Survivin nuclear staining was present in 12 of 18 cases of malignant melanoma (67%) with an average index of 7% (range 0%-15%). In benign melanocytic lesions, the Ki-67 index was less than 5% (range 0%-4%) and staining was present close to the dermo-epidermal junction compared with an average index of 27% in melanomas (range 5%-50%) and a generally heterogeneous pattern of staining throughout the dermis. pHH3 and Ki-67 can be useful adjuncts to histopathology to separate malignant melanoma from benign nevi. pHH3 is especially useful to highlight mitoses and to rapidly assess the mitotic activity in melanocytic lesions.     

Digital dermatoscopic follow‐up of 1027 melanocytic lesions in 121 patients at risk of malignant melanoma

Objective  The aim of the presented prospective study was to use a digital dermatoscopic system to follow‐up patients with multiple melanocytic naevi, and to evaluate the frequency and character of dermatoscopic changes. Methods  We monitored selected melanocytic lesions with the use of a 6‐month follow‐up interval between check‐ups. We searched for changes in size, shape, symmetry, structure and colour. We defined the criteria for surgical excision and histopathological examination of changing lesions. We created a small group of excised unchanged atypical melanocytic naevi. Results  We completed dermatoscopic monitoring of 1027 melanocytic lesions in 121 patients at risk of developing malignant melanoma. The average total follow‐up interval was 21.0 months. We noticed a substantial enlargement of monitored lesions in 4.5% of cases, and there was a change of shape in 1.3% and change of asymmetry in 2.0%. The appearance of new structures, frequently being associated with malignant melanoma, was observed in 10 lesions, and it was predictive for the histopathological confirmation of this diagnosis in all cases. About 80% of monitored lesions remained unchanged. We excised 38 monitored lesions (seven melanomas in situ, four thin invasive melanomas and 27 melanocytic naevi). There was no melanoma excised in the group of unchanged atypical melanocytic lesions. Conclusion  Digital dermatoscopic follow‐up facilitates the recognition of thin malignant melanomas and helps to reduce the number of unnecessary excisions.     

Difficult early melanomas

There is a spectrum of melanocytic tumors from benign to malignant. The goal of the dermatologist is to identify and remove early melanomas because doing so can be lifesaving. At the same time, it is inappropriate to randomly remove benign nevi. Dermatoscopy is an additional tool that can be used to help discriminate features that may assist in the diagnosis of melanoma. Even with dermatoscopy, identification of an early melanoma can be difficult. It is important to consider all clinical information available when making a management decision.     

Application of fluorescence in situ hybridization as a diagnostic tool in melanocytic lesions,using paraffin wax‐embedded tissues and imprint‐cytology specimens

Background. Accurate histopathological diagnosis of certain melanocytic skin lesions as benign or malignant can be notoriously difficult. Recently, four‐colour fluorescence in situ hybridization (FISH) has emerged as an important tool for classifying these lesions. Aim. To evaluate the sensitivity and specificity of a melanoma FISH probe kit for accurate diagnosis of melanocytic tumours, and to validate its use with imprint‐cytology specimens from the cut surface of tumours. Methods. In total, 50 melanocytic skin lesions (31 malignant melanomas, 10 benign melanocytic naevi, and 9 histologically challenging benign melanocytic skin lesions) were evaluated. The samples comprise 47 tissue specimens embedded in paraffin wax, and three imprint‐cytology specimens from the cut surface of melanomas. FISH was performed using four locus‐specific identifier probes [Ras responsive element binding protein (RREB)1, myeloblastosis viral oncogene homologue (MYB), cyclin (CCN)D1 and centromere of chromosome (CEP)6], and results were compared with the clinical long‐term follow‐up and histopathological diagnosis data. Results. The melanoma FISH probe distinguished between naevi and melanomas with a sensitivity of 100% and a specificity of 94.1%. The most sensitive criterion was a gain in 6p25 (RREB1), seen in 100% of cases, followed by CEP6‐related MYB loss (48.1%), CCND1 gain (37%) and MYB gain (22.2%). More than three‐quarters (77.8%) of melanomas were positive for two or more criteria. Positive FISH results were also obtained for the imprint‐cytology specimens. Conclusions. FISH is a valuable diagnostic tool for differentiating between benign and malignant melanocytic lesions, providing a high degree of sensitivity and specificity. The probes displayed exceptional discriminative capacity in difficult or ambiguous lesions. To our knowledge, his is the first reported use of imprint‐cytology specimens for FISH diagnosis.     

Immunohistochemical markers of melanocytic lesions: a review of their diagnostic usefulness

We critically reviewed recent literature reports of 25 melanocytic immunohistochemical markers. This review organizes and summarizes the many new studies of old and novel melanocytic markers and identifies the most promising diagnostic immunohistochemical markers that can be used to distinguish melanocytic from nonmelanocytic lesions and benign melanocytic from malignant melanocytic lesions.     

The dysplastic nevus. Separate entity, melanoma precursor or diagnostic dilemma?

Today, 20 years after Clark and Elder postulated their tumor progression model of melanocytic lesions from common nevi to melanoma, there are still controversies surrounding this subject. Despite modem molecular biological developments, a consensus about the question, if the dysplastic nevus should be considered as a separate entity, melanoma precursor or just represent a diagnostic dilemma, still seems to be impossible. In addition, since the term melanocytic dysplasia is not precisely defined with regard to all diagnostic methods (clinical morphology, dermatoscopy, dermatopathology, molecular biology), there is considerable confusion. The question remains if a quite arbitrary classification of melanocytic lesions such as dysplastic nevus is useful at all. In daily practice, dermatologists should be aware of the fact that each suspicious melanocytic lesion could represent an early malignant neoplasia, regardless whether it is formally named dysplastic nevus or initial malignant melanoma. We conclude that solid dermatological experience plus novel tools of documentation represent the key factor to minimize patients' risk.