Strategies for early recognition of cutaneous melanoma—present and future

Cutaneous melanoma is a highly aggressive malignant tumor of skin melanocytes with an increasing incidence in most countries of the world, especially in the fair-skinned populations. Despite all preventive and therapeutic efforts, malignant melanoma is still the most lethal skin cancer. A delayed diagnosis results in an advanced stage and worsened prognosis. Once distant metastases are present, the five-year survival rate is less than 10 percent. At the same time, patients may be cured by an early diagnosis of cutaneous melanoma followed by a wide excision. Therefore, the early detection of melanoma at curable stages is crucial for the patients’ survival. Besides the investigation of pigmented lesions with the unaided eye, a wide range of examination techniques for improved diagnostic accuracy have been developed and validated in clinical trials. However, none of these techniques are able to provide a definite and final diagnosis or to replace an excisional biopsy of suspicious lesions followed by histological analysis. This review provides a concise overview of general principles as well as current and future strategies for an improved early diagnosis of cutaneous melanoma

and atypical nevi, skin type, presence of freckles, eye color, hair color, and the presence of non-melanoma skin cancer lesions should be considered [2]. The overall number of nevi induced by ultraviolet radiation in early infancy was shown to be an especially important predisposing risk factor for the development of melanoma [3]. Individuals with a high nevus count are endangered notably, whereby the risk of melanoma development increases almost linearly with rising numbers of melanocytic nevi on the whole body [4].
Although cutaneous melanoma is less common than other skin cancers, it causes the majority (approximately 90 percent) of deaths related to skin cancer. An advanced tumor thickness (Breslow's depth) is strongly associated with an increased mortality. Therefore, the early detection of melanoma at early and curable stages is critical for the patients' survival. In contrast to many other tumor entities, cutaneous melanoma may already develop metastases at a low tumor volume. Once distant metastases have occurred, the median survival is approximately nine months and the fiveyear survival rate is less than 10 percent. On the contrary, for thin melanomas with a tumor thickness of less than 0.76 mm, the ten year survival rate is 99.5 percent. These rates markedly decrease to 48 percent for lesions with more than 3 mm tumor thickness [5].
Until today, the most common method for detecting melanoma is visual diagnosis. To make a correct diagnosis, knowledge about the different melanoma subtypes is essential. The most frequent form of cutaneous melanoma is superficial spreading melanoma (SSM, Figure 1). It grows slowly and initially in a horizontal plane and subsequently, in more advanced cases, it will reach a vertical growth phase.
With naked eye examination, lesions are often sharply demarcated, polycyclic and multicolored. In contrast, nodular melanoma (NM), a much more aggressive form, exhibits an early vertical growth phase. NM emerges primarily and is then often detected late, at an advanced tumor thickness, or it develops secondarily within a SSM ( Figure 2). The nodes often grow rapidly, are vulnerable with a tendency to ulceration and bleeding, or might appear non-pigmented.
Lentigo maligna melanoma (LMM, Figure 3) characteristically occurs at older age and is localized in areas of chronically sun-exposed skin, like the face or dorsa of the hands.
Similar to SSM, it appears polycyclic, sharp-bounded and often shows multiple brown spots. A rare growth variant of cutaneous melanoma, the acral-lentiginous melanoma (ALM, Figure 4) is localized in palmoplantar skin but may also involve the nail unit. ALM represents the most common growth variant in dark-skinned (e.g., Asian) populations.
Due to the architecture of palmoplantar skin with parallel ridges and furrows, the margins are often not clearly defined and the pigmentation is incoherent.
Further melanoma subtypes are not classifiable or represent hybrid forms. Moreover, special forms like mucosal and ocular malignant melanoma exist.
In summary, the most effective approach to improve the prognosis of cutaneous melanoma is early recognition and surgical excision at curable stages. The identification and the screening of high-risk patients is an important prerequisite to further enhance efforts to lower the mean tumor-thickness at the time of diagnosis. Excisional biopsies of suspicious lesions with subsequent histopathologic examination of specimens will allow for a definite classification.   cheek. This LMM shows the typical localization in areas of chronically sun-exposed skin.
Note the macroscopically visible granular appearance of light brown to black colors.

Clinical examination with the unaided eye
The application of the clinical ABCD rule (Table 1) devised by Friedman et al in 1985 is a common method for the clinical diagnostics of cutaneous melanoma [6]. The criteria asymmetry, irregular margin, multiple colors and a diameter over 6 mm, cutaneous melanoma has to be considered. However, the ABCD rule is characterized by a low specificity as other benign skin lesions such as seborrheic keratosis may also fulfill the aforementioned criteria. Moreover, it is not applicable for pigmented lesions on the palms, soles or face due to the particular skin anatomy at these sites [7]. Small melanomas with a diameter of 6 mm or less or rare nonpigmented subtypes of melanoma will also not be detected by the ABCD rule. Certain dynamic changes within melanocytic lesions are also suggestive of cutaneous melanoma, for instance, asymmetrical changes in size, shape or color, or itching and bleeding. In consequence, the acronym was extended by the letter "E" for evolving or evolution to the ABCDE rule [8].
Before examination of selected nevi in more detail, it is useful to get an overview of recurrent and predominant patterns of a patient's nevi. Nevi in the same individual tend to resemble one another, so-called "signature lesions," indicating benign nevi on a regular basis. In contrast, melanomas often deviate from the individual's nevus pattern, so-called "ugly duckling sign" [9]. Recently, a high sensitivity for the early detection of melanoma with the help of the "ugly duckling sign" could be demonstrated [10].
Medical total body photography is often used in dermatology to support the clinical surveillance of high-risk patients. One method is the total body photography in standardized and reproducible positions. Photographically assisted follow-up images help clinicians and patients to detect new and changing pigmented lesions with the unaided eye [11,12]. In contrast to digital dermoscopy, which allows for monitoring of a few lesions only, full body photography permits monitoring of all lesions of a patient. Therefore, full body photography is a useful supplement to dermoscopy.

Dermoscopy
Dermoscopy (also known as epiluminescence microscopy, dermatoscopy, or amplified surface microscopy) allows for a significant improvement in the preoperative diagnostic accuracy of pigmented skin lesions. Dermoscopy is a non-invasive technique for the in vivo examination of melanocytic and non-melanocytic skin lesions. The handheld dermo-  More recently dermoscopes that emit polarized light to eliminate skin surface reflection entered the market. These instruments do not require skin contact and a liquid medium can be omitted (e.g., Dermlite™ 3 Gen).
The dermoscopic evaluation of a lesion is performed in two steps. This procedure for classification of pigmented skin lesions was agreed on at an international consensus meeting [14]. In the first step it has to be determined whether a melanocytic or non-melanocytic tumor is present. In case of a melanocytic lesion, the differentiation between benign or malignant/suspicious lesions follows in a second step. For this second step various algorithms were established and validated in clinical trials. Most algorithms (e.g., the ABCD rule of dermoscopy [15], the 7-point checklist of dermoscopy [16], or Menzies' scroring method [17]) use a number of criteria associated with the presence of melanoma as first described for the pattern analysis by Pehamberger et al [18]. Especially, three algorithmic methods (qualitative pattern analysis, the ABCD rule of dermoscopy, and the 7-point checklist) were shown to be valid and reliable in distinguish-ing benign and malignant melanocytic tumors. The pattern analysis is based on a detailed, qualitative assessment of numerous dermoscopic criteria, and a high rate of diagnostic accuracy could be obtained by experienced investigators after a significant degree of formal training (19). The ABCD-rule of dermoscopy uses a semiquantitative scoring system based on a complex evaluation of asymmetry, border, color, and different dermoscopic structures within the lesion [15]. The 7-point checklist ( Table 2) was developed as a quantitative scoring system with three major criteria (score of 2 points) and four minor criteria (score of 1 point). A minimum total score of 3 is required for the diagnosis of melanoma [16]. a specificity of up to 99% were documented for the detection of cutaneous melanoma by dermoscopy [23]. Among dermatologists, dermoscopy has become a routine examination technique in Europe and is with gaining acceptance worldwide.
When computer hardware became more and more available and affordable, digital dermoscopy devices were devel- 2. The 7-point checklist of dermoscopy. With the addition of criteria scores, a score of 3 or more points is suspicious for melanoma. The odds ratio is a measure to describe the strength of association between two variables, in this case between a dermoscopic structure and the possibility of malignancy.  [13]. Some digital dermoscopy devices even offer a computer-assisted diagnosis [24][25][26]. have not yet acquired melanoma-typical dermoscopic features, thus increasing the sensitivity [27][28][29]. With the help of sequential digital dermoscopy, incipient melanomas can be identified by detection of intralesional changes, for instance asymmetrically enlargement or architectural changes (Fig-Figure 5.   ure 11 A-C) [30,31]. This applies especially for melanomas without suspicious dermoscopic features, so-called "featureless melanoma." Another strategy of sequential dermoscopic follow-up is the short-term follow-up (three-month interval), which targets a restricted number of highly atypical nevi, which should be removed whenever dynamic changes become apparent [29,32]. Numerous systems for sequential digital dermoscopy imaging are commercially available (e.g., Molemax™, Fotofinder™, SolarScan™).

New innovative applications
The To implement the CLSM in the clinical setting, a consensus conducted as an online meeting for terminology in CLSM has been published [38].

Conclusion
Early detection of cutaneous melanoma is one of the most effective ways of reducing mortality rates from this disease.
In addition to the clinical assessment with the unaided eye, Above all, it has to be emphasized that none of the aforementioned examination techniques are currently able to