Dermatology: Practical and Conceptual Review | Dermatol Pract Concept 2018;8(3):16 231 DERMATOLOGY PRACTICAL & CONCEPTUAL www.derm101.com Sequential digital dermatoscopic imaging of patients with multiple atypical nevi Philipp Tschandl1 1 ViDIR Group, Department of Dermatology, Medical University of Vienna, Austria Key words: dermatoscopy, monitoring, melanoma, nevi, digital, screening Citation: Tschandl P. Sequential digital dermatoscopic imaging of patients with multiple atypical nevi. Dermatol Pract Concept. 2018;8(3):231-237. DOI: https://doi.org/10.5826/dpc.0803a16 Received: December 29, 2017; Accepted: March 3, 2018; Published: July 31, 2018 Copyright: ©2018 Tschandl. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: None. Competing interests: The authors have no conflicts of interest to disclose. All authors have contributed significantly to this publication. Corresponding author: Priv. Doz. Philipp Tschandl, MD, PhD, ViDIR Group, Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. Email: philipp.tschandl@meduniwien.ac.at. Introduction Dermatoscopy has progressed to a state-of-the art technique not only to distinguish melanoma from nevi [1,2], but also to diagnose all kinds of pigmented and nonpigmented skin tumors [3]. This is due to its proven increase in diagnostic accuracy compared to the unaided eye [4], an improve- ment that recently has also been shown to be present in nonpigmented lesions that are inherently more difficult to diagnose [5]. But there is a specific aspect of pigmented and nonpig- mented skin lesion diagnosis with dermatoscopy that stands apart, namely, screening high-risk patients. Why is this dif- ferent? Not only are these patients much more likely to be diagnosed with melanoma [6,7], they are also more difficult to diagnose [8]. This is partially because early melanoma can be featureless, but also because nevi on those patients can have a worrisome morphology. Some approaches have been proposed to tackle these problems. The morphologic differentiability can be overcome partly by comparing nevi clusters of the same pattern in a patient [9,10], which has become well known as the comparative approach set forth by Argenziano [11]. This comparative approach has its limitations though; for example, in an experimental setting, dermatologists were not able to dis- tinguish melanomas and nevi well in lesions of high-risk patients [8,12]. Total-body imaging is widely used for screening high-risk patients, but because pigmented skin lesions can change or occur, especially in young patients [13-15], it is most com- monly not applied solely but in combination with other diagnostic methods [16,17]. Patients with multiple atypical nevi are at higher risk of developing melanoma. Among different tech- niques, sequential digital dermatoscopic imaging (SDDI) is a state-of-the art method to enhance diag- nostic accuracy in evaluating pigmented skin lesions. It relies on analyzing digital dermatoscopic im- ages of a lesion over time to find specific dynamic criteria inferring biologic behavior. SDDI can reduce the number of necessary excisions and finds melanomas in an early—and potentially curable—stage, but precautions in selecting patients and lesions have to be met to reach those goals. ABSTRACT 232 Review | Dermatol Pract Concept 2018;8(3):16 most likely will not benefit from it at all; instead, it may even do harm, as recent literature shows a positive association of false positive findings with a number of monitored lesions in a patient [30]. Compliance An often-underestimated drawback is lack of patient compli- ance [29,31]; that is, patients do not show up for the follow- up appointments. The reason this is an issue is changed sensitivity at the baseline visit [32]. One basic mechanism of the increased diagnostic accuracy of digital dermatoscopic monitoring is that one increases specificity by leaving a lesion untouched in good faith, the lesion—on the patient—will come back after a specified interval. This increased specific- ity comes at the price of lower sensitivity, which can only be overcome by finding missed melanomas at a second examina- tion. Thus, the physician has to ensure the patient returns to the office. While the lack of compliance is not without dispute [33], an Italian group [28] found compliance was higher for shorter intervals and that long-term monitoring may be started with shorter periods. Lesions Previous studies have shown that in high-risk patients one cannot estimate at baseline which of the lesions on the patient is more prone to become a melanoma [8,12]. While other authors argue that only lesions with some sign of atypia should be followed over time [34], those results suggest a possible benefit in integrating inconspicuous lesions. One should not follow, though, that all lesions on a patient have to be monitored at every visit. Taking photographs of all lesions at every visit is not only impossible to do in a rea- sonable amount of time, but it may also decrease diagnostic accuracy as more monitored lesions per patient are positively correlated with false positive findings [30]. A survey showed that the majority of experts in the field in fact do not perform dermatoscopic monitoring of every single lesion on a patient [35], and indirect evidence indicates this is truly not neces- sary. In a retrospective analysis of our own high-risk center, where only a random subset of lesions is monitored at every visit with monitoring being stopped after no change has been seen for 2 (or 3) years, almost half of melanomas were in situ and mean invasion depth was well below 1 mm for 10 years [30]. Therefore, because we cannot estimate which pigmented skin lesion turns out to be a melanoma, selection of lesion monitoring has to be random and can be incremental to save resources (incremental SDDI, Figure 1). One cannot choose which lesions specifically should be monitored, but there are rules as to which lesions should not be. Important exclusion criteria are: (1) nodular (black, brown, gray, red or blue) lesions, as thick melanomas would progress to higher invasion depths more quickly [36,37]; A German group presented a rather innovative method in which they removed the skin of the entire back of a patient to reduce his melanoma risk [18]. Though seemingly promis- ing, this approach may not be a solution for usual high-risk patients: The removed nevi are most likely not the precursors of a potential melanoma [19], and possible melanoma risks due to germline mutations [20] would still be present. Finally, such an overwhelming surgical procedure defeats the purpose of a screening method, namely reducing invasive procedures. Rather, a noninvasive and more specific method has to be chosen for that purpose. One technique that fulfills those requirements, and overcomes some drawbacks mentioned previously, is digital dermatoscopic follow-up, or sequential digital dermatoscopic imaging (SDDI) [21,22]. By comparing 2 images of a lesion taken at different time points, additional information about the dynamics, and thus biologic behavior, can be obtained. This additional informa- tion has gained interest when being added as an additional “E” criterion to the classic “ABCDs” [23]. In a study of patients with a high risk of melanoma [24], about 20% to 50% of melanomas could only be detected with the help of digital follow-up, but not with a single dermatoscopic examination. In addition to monitoring multiple nevi, digital dermatoscopy is also used to enhance specificity on individual suspicious lesions. Here, a shorter interval (2-3 months [25]; short-term follow-up) is usually chosen [26] for single lesions and even small dermatoscopic changes are regarded as suspi- cious, whereas in the screening of patients with many nevi an interval of 6-12 months (long-term follow-up) is more common. In the following sections, general rules for practical application of SDDI are discussed. Selection Risk Factors The first consideration in applying digital dermatoscopic monitoring is the patient collective, as it has to meet certain criteria [27]. A previous report [24] has shown that digital dermatoscopy is particularly useful for patients with a familial atypical mole and multiple melanoma (FAMMM) syndrome and an atypical mole syndrome (AMS; >50 nevi and >3 atypical nevi) in a strict sense. Conversely, con- ventional dermatoscopy was sufficient for the detection of melanomas in patients with solely a large number of (inconspicuous) nevi: in this patient group, more than 80% of melanomas were diagnosed over a period of 10 years by means of a single dermatoscopic examination or other clini- cal information. In 2 additional studies with a shorter period of time, no melanoma was found in patients with low risk among the dermatoscopically monitored lesions [28,29]. Thus, there is no compelling evidence for applying digital dermatoscopic monitoring to low-risk patient groups. They Review | Dermatol Pract Concept 2018;8(3):16 233 for 2-3 years because a diagnosed single melanocytic nevus is at very low risk of transforming into a melanoma at 0.0005% to 0.003% per year [42]. Evaluation Melanocytic nevi generally grow symmetrically and fol- low 1 of 3 variants: a reticular pattern (slow growth), a surrounding rim of clods (moderate to fast growth), or peripheral pseudopodia and radial lines (fast growth) [43]. The following changes (summarized in Table 1 and Fig- ures 2-4 and adapted from Kittler et al [44]) have been associ- ated with melanoma in previous studies [45,46] and should lead to the removal of a lesion: (1) changed architecture; (2) asymmetric increase in size; (3) new colors, depigmentation, and focal color change; and (4) the appearance of melanoma criteria such as black dots or regression. (2) blue lesions [38], as monitoring cannot reliably evaluate changes in the dermis; (3) regressive lesions, as a potential melanoma may be completely regressed at follow-up; (4) lesions with a dermatoscopic clod pattern, as they show a faster growth [39]; and (5) spitzoid lesions [40], not includ- ing Reed nevi [41], as the latter can show fairly symmetric growth and stabilization. Lesions with these characteristics should be removed immediately, unless they are clearly benign at the baseline visit. Finally, what should lesions selected for SDDI look like? Ideally, they are medium-sized, flat, and show a dermato- scopic reticular pattern. But, as with any recommendation, the preceding recommendations are due to change with new findings, specifically in the advent of automated full-body imaging, where monitoring of every single lesion of a patient seems feasible in the future. Until then, it is justifiable to discard monitoring a single lesion if no change has occurred TABLE 1. Differentiation of Nevus and Melanoma with Follow-Up Images* Change Nevus Melanoma Change in size None or symmetrical growth Asymmetrical growth Change in color No change or even lighter/darker brown or erythema New colors, especially focally and depigmentation Change in structure No or subtle changes such as accentuation of existing structures Architecture changes and the appearance of new structures including classical melanoma criteria and regression and signs of regression *Adapted from Kittler et al [50]. Figure 1. Incremental SDDI. Because with current methods it is not feasible to image every lesion at every visit, we selected a random sample of new lesions at every visit (gray), which were imaged in subsequent visits (yellow), but were discarded from follow-up after showing no change for 2 years (green). With this method, we were able to map all lesions eventually, to suggest if one lesion has occurred in the last interval even without TBP (red). [Copyright: ©2018 Tschandl.] 234 Review | Dermatol Pract Concept 2018;8(3):16 and (4) age. First, with shorter intervals between 2 images, less change indicates a probable melanoma [26,48], whereas nevi generally change more slowly and in a limited fashion [39,49,50]. In con- trast, recurrence of a benign nevus may occur earlier than recurring melanoma [51]. Second, new checkpoint inhibitors such as dabrafenib [52] or vemurafenib [53] may lead to drastic changes in nevi. Notably, all criteria rely heavily on asymmetry (chaos), which is one of the most (interrater) reliable features in der- matoscopy [47], but evaluation of the necessary extent of change still relies on the subjective judgment of the exam- ining physician. Additionally, many additional factors have to be taken into account and these are (1) time, (2) medication, (3) anatomic location, Figure 2. A compound nevus (A) with peripheral clods showing (B) symmetrical growth after 1 year. Nevi with peripheral clods very commonly show symmetric enlargement over time [70]. [Copyright: ©2018 Tschandl.] Figure 3. This histopathologically verified lentigo maligna initially presented with only struc- tureless brown areas (A) at the baseline visit. (B) After 14 months of follow-up, the pigment has become darker, grown asymmetrically, and an additional pink structureless area can be seen. [Copyright: ©2018 Tschandl.] Figure 4. While this lesion (A) initially appears inconspicuous, after (B) 6 months it shows additional black dots and asymmetric growth. Histopathological evaluation re- vealed a superficially spreading melanoma with an invasion depth of 0.4 mm. [Copyright: ©2018 Tschandl.] Third, congenital nevi of the nail appa- ratus may show growth and involution [54]. Fourth, growing lesions raise more suspicion in older patients, as nevi are expected to change in younger patients to some extent [14,15]. General Considerations Effectiveness Regarding diagnostic accuracy, a meta- analysis has shown that by using SDDI, 54.6% of melanomas can be excised in situ. The number of lesions needed to monitor differs significantly between studies (31-1 008), most possibly reflecting different methods of execut- ing SDDI. Undeniably, this number is the lowest for short-term SDDI [21,48] because it is mainly used for increasing specificity (ie, avoiding excision of single suspicious lesions rather than scanning all lesions on a patient). It therefore does not have the identical purpose as long- term SDDI and is commonly combined with other screening methods such as total-body photography, conventional skin examination, and dermatoscopy [16,17]. The number of needed excisions (NNE) to find a melanoma under long- term SDDI is low (1:12; melanoma: benign nevi as diagnosed by histopa- thology), but here also short-term SDDI is lower (1:5) [21], as it includes only suspicious lesions, decreasing the pretest probability of false positive findings. The low NNE for any kind of SDDI is thought to be one of the main reasons the NNE has decreased in recent years in specialized centers [55]. For every screening method, not only diagnostic accuracy, but also immediate and follow-up costs have to be taken into account. Literature sug- gesting that even skin cancer awareness interventions can increase costs along- side even lower quality-adjusted life years [56] show the importance of being careful and constantly critical of popu- lation-wide decisions about any kind of screening method [57]. When limiting interventions to high-risk patients, there Review | Dermatol Pract Concept 2018;8(3):16 235 5. Sinz C, Tschandl P, Rosendahl C, et al. Accuracy of dermatos- copy for the diagnosis of nonpigmented cancers of the skin. J Am Acad Dermatol. 2017;77(6):1100-1109. doi: 10.1016/j. jaad.2017.07.022. 6. Fusaro RM, Lynch HT, Kimberling WJ. Familial atypical mul- tiple mole melanoma syndrome (FAMMM). Arch Dermatol. 1983;119(1):2-3. doi: 10.1001/archderm.1983.01650250006002. 7. Clark WH Jr, Reimer RR, Greene M, Ainsworth AM, Mas- trangelo MJ. Origin of familial malignant melanomas from heritable melanocytic lesions. The B-K mole syndrome. Arch Dermatol. 1978;114(5):732-738. doi: 10.1001/archderm. 1978.01640170032006. 8. Tschandl P, Hofmann L, Fink C, Kittler H, Haenssle HA. Mela- nomas vs. nevi in high-risk patients under long-term monitoring with digital dermatoscopy: do melanomas and nevi already differ at baseline? J Eur Acad Dermatol Venereol. 2017;31(6):972-977. doi: 10.1111/jdv.14065. 9. Grob JJ, Bonerandi JJ. 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Total-body photography (TBP): By comparing clinical images of 2 time points, TBP itself may reduce the number of excised lesions in pigmented lesion clinics [61,62] by detect- ing clinically new or changing lesions. Especially with the advent of high-resolution photography and automated detec- tion of new lesions [63], TBP has the ability to become even more important in screening a large number of patients. The evidence and use of TBP for screening are promising, but an in-depth review is beyond the scope of this review. Regarding digital dermatoscopy, TBP performs very well when combined with SDDI in screening programs, as both possibly detect distinct subsets of melanoma [16,17]. Reflectance confocal microscopy (RCM): To further reduce the number of unnecessary excisions, RCM has been applied as a “second-level” exam for doubtful lesions found by digital dermatoscopy [64]. 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