Dermoscopic Changes Observed in Slow-Growing Melanomas
Dermoscopic Changes Observed in Slow-Growing Melanomas
In the present study, we analysed the dermoscopic changes that occurred in a subset of melanomas characterized by slow growth (SGM). Briefly, we found that most of these melanomas had, at initial evaluation, the following dermoscopic findings: reticular, reticular–homogeneous or homogeneous global dermoscopic pattern; an overall disorganized pattern; light and/or dark brown colours; a pigmented network, typical dots or structureless areas. On follow-up, these SGM generally developed the following dermoscopic findings: a more homogeneous global dermoscopic pattern; more frequent disorganization of pattern; decreased prominence of the colour light brown, increased prominence of the colour dark brown, as well as the appearance of the colours red, white, grey, blue and black; loss of the dermoscopic structure of pigmented network, marked by the appearance of more structureless areas; and increased prominence as well as new appearance, at follow-up, of melanoma-specific dermoscopic structures such as negative network, BWS and blotches. Further, most SGM had minimal (i.e. ≤ 2 mm) or no change in size on follow-up; those melanomas that increased in size by > 2 mm also demonstrated the most changes in total number of dermoscopic structures and colours.
Many of the dermoscopic changes in melanomas presented in this study were not unexpected and, in fact, provide further evidence to support our current understanding of melanoma progression. One of the models developed to explain melanoma progression, in particular progression of the superficial spreading subtype of melanoma, was proposed by Scope et al., based on a review of findings from dermoscopy, reflectance confocal microscopy and histopathology studies of melanoma. Based on their dermoepidermal junction (DEJ) remodelling concept, Scope et al. theorized that melanoma progresses via three steps. In the first step, the neoplastic melanocytes proliferate within an undulating DEJ (i.e. with preserved rete ridges and dermal papillae); confluent junctional aggregates of neoplastic melanocytes are observed within the rete ridges, which appear widened and elongated and/or display bridging of adjacent rete ridges. In the second step, there is remodelling of the DEJ and superficial dermis; the neoplastic melanocytes proliferate along a DEJ that becomes progressively flattened. The flattening of the DEJ is associated with inflammation, fibroplasia and increased vascularity (also termed angiogenesis) in the superficial dermis, which are, in turn, probably induced by the neoplastic cells. The DEJ and superficial dermal remodelling may create a microenvironment that is more conducive for dermal invasion by malignant melanocytes; thus, the third step in the model is the development of an invasive nodule within or adjacent to the remodelled area.
Indeed, many of the observations made herein can be explained by this melanoma progression model. The main shift in global dermoscopic pattern was from reticular pattern (16% at baseline vs. 9% at follow-up) to reticular–homogeneous (31% at baseline vs. 40% at follow-up). Similarly, at initial evaluation, the majority (61%) of melanomas contained a pigmented network, a third of which showed an atypical network; structureless areas were seen in 40% of melanomas. At follow-up, in 54% of the melanomas that showed pigmented network at baseline, the network became less prominent or disappeared, while among melanomas with structureless areas at baseline, 49% showed increased prominence of these structureless areas (i.e. becoming more widespread within the lesion) at follow-up. Based on previous dermoscopic–histopathological correlation studies, pigmented network correlates with proliferation of melanocytes and presence of pigmented basal keratinocytes along preserved rete ridges (i.e. an undulating DEJ). Loss or blurring of network and appearance of more homogeneous areas on dermoscopy can be attributed to flattening of the DEJ and/or decreased pigmentation in melanocytes and basal keratinocytes. For example, brown structureless areas seen on dermoscopy have been shown by Annessi et al. to correlate with proliferation of melanocytes along a flattened DEJ. Thus, loss of network and increase in homogeneous areas at follow-up can be explained by progression from proliferation within an undulating DEJ (step 1 of the progression model) to proliferation along a flattened DEJ (step 2).
The most common structure present at baseline following the pigmented network and structureless areas are dots on a network (typical dots). On follow-up, 45% of lesions with typical dots at baseline exhibited a decrease in prominence or loss of this structure. According to Puppin et al., typical dots represent junctional nests of melanocytes, mostly along the side and tips of the rete ridges. We propose that the reduction in the observation of typical dots at follow-up is akin to the loss of the pigmented network; both result from loss of rete ridges as the DEJ undergoes remodelling during melanoma progression.
There was a striking increase in prominence of BWS on follow-up, with 11 (73%) of 15 melanomas showing an increase in prominence of BWS. Indeed, it has previously been demonstrated that the presence of BWS is significantly associated with melanoma. On histopathology, BWS overlying flat portions of the lesion is characterized by fibroplasias and presence of melanophages in the superficial dermis. According to the model by Scope et al., the higher prevalence of BWS may be suggestive of progression of melanomas to the second step. In addition, BWS may also represent regression of the lesion, particularly BWS over flat areas.
The increase in BWS also accounts for the substantial increase in prevalence of melanomas showing the colours blue, grey and white from baseline (6%, 18%, 3%) to follow-up (13%, 31%, 10%, respectively). Interestingly, an association between increase in stromal collagen (indicated by scar-like changes in areas showing BWS on dermoscopy or by the recently described finding of crystalline structures) and angiogenesis in melanoma has also been previously shown. This association may account for the concurrent increase in prevalence of melanomas showing the colour red, which represent increased vasculature, between baseline (29%) and follow-up (41%) images.
Among melanoma-specific criteria, the most common dermoscopic structure to appear at follow-up was a dark blotch. Most blotches were eccentric, irregular and/or asymmetrical. According to the virtual Consensus Net Meeting on Dermoscopy published in 2001, an asymmetrical blotch was deemed significantly associated with melanoma. Specifically, at initial consultation, 17% of melanomas displayed a dark blotch, while at follow-up, 34% of melanomas showed a dark blotch. Most often, blotches in melanoma are due to dense proliferation of pigmented melanocytes in the epidermis; a band of pigmented melanocytes in the underlying papillary dermis can also contribute to the homogeneous dark appearance of dermoscopically identified dark blotch. The increase in the frequency of dark blotches probably accounts for the increase in the colours dark brown and black from baseline (85%, 33%) to follow-up (95%, 45%, respectively). Another melanoma-specific criterion is the presence of a negative network; this structure became more prominent in over two-thirds of the lesions that showed it at baseline. The precise correlates of a negative network on histopathology are currently unknown. Although a negative network can be seen in Spitz naevi and rarely Clark's (dysplastic) naevi, it is highly specific for melanoma.
It is noteworthy to highlight that several of the findings in our study parallel those in one previous study. Specifically, Kittler et al. examined the role of sequential dermoscopic imaging in the identification of incipient melanoma and noted the following changes in melanomas monitored for more than 8 months: appearance of new colours in 32% of the lesions; darker overall pigmentation in 59% of the lesions; and disappearance of network lines in 10% of melanomas. Interestingly, loss of network can also occur in melanocytic naevi when imaged during long-term surveillance.
Our study has several limitations. Firstly, given the multicentre study design, it is worthwhile noting that the instruments used to capture images (dermatoscope, lens, camera, software), were likely not the same for every lesion; as a result, there were variations in image quality. Further, as the evaluations were sometimes several years apart, it is possible that change in technology may have made certain changes more prominent and others appear less so. Secondly, our series is limited in size. In fact, we chose not to present select data concerning certain dermoscopic structures [e.g. crystalline structures (shiny white lines) and black dots] because their relative frequency was low in this series. In addition, crystalline structures can be seen only with polarized dermoscopy, while most images in the current dataset were obtained with nonpolarized dermoscopy. Finally, the diagnosis of melanoma was rendered independently by the dermatopathologist at each medical centre, as per routine standard of practice. We are cognizant of the potential for discordant diagnoses (e.g. early melanoma vs. naevus with so-called severe dysplasia) in some of the cases, had they been reviewed by a panel of dermatopathologists. The potential for imperfect agreement among pathologists on the diagnosis of melanoma is a well-known issue in everyday practice.
In conclusion, the dermoscopic changes highlighted in this dataset of SGM are clinically relevant for physicians who follow pigmented lesions via dermoscopic monitoring. Physicians should pay particular attention to melanocytic lesions that, over time, become more disorganized, reveal a loss of network in favour of structureless areas, develop a negative network, and exhibit new colours such as dark brown, black, grey, blue, red and white; in addition, one should not rely solely on change in size. These observations also provide additional insights to our current understanding of melanoma progression.
Discussion
In the present study, we analysed the dermoscopic changes that occurred in a subset of melanomas characterized by slow growth (SGM). Briefly, we found that most of these melanomas had, at initial evaluation, the following dermoscopic findings: reticular, reticular–homogeneous or homogeneous global dermoscopic pattern; an overall disorganized pattern; light and/or dark brown colours; a pigmented network, typical dots or structureless areas. On follow-up, these SGM generally developed the following dermoscopic findings: a more homogeneous global dermoscopic pattern; more frequent disorganization of pattern; decreased prominence of the colour light brown, increased prominence of the colour dark brown, as well as the appearance of the colours red, white, grey, blue and black; loss of the dermoscopic structure of pigmented network, marked by the appearance of more structureless areas; and increased prominence as well as new appearance, at follow-up, of melanoma-specific dermoscopic structures such as negative network, BWS and blotches. Further, most SGM had minimal (i.e. ≤ 2 mm) or no change in size on follow-up; those melanomas that increased in size by > 2 mm also demonstrated the most changes in total number of dermoscopic structures and colours.
Many of the dermoscopic changes in melanomas presented in this study were not unexpected and, in fact, provide further evidence to support our current understanding of melanoma progression. One of the models developed to explain melanoma progression, in particular progression of the superficial spreading subtype of melanoma, was proposed by Scope et al., based on a review of findings from dermoscopy, reflectance confocal microscopy and histopathology studies of melanoma. Based on their dermoepidermal junction (DEJ) remodelling concept, Scope et al. theorized that melanoma progresses via three steps. In the first step, the neoplastic melanocytes proliferate within an undulating DEJ (i.e. with preserved rete ridges and dermal papillae); confluent junctional aggregates of neoplastic melanocytes are observed within the rete ridges, which appear widened and elongated and/or display bridging of adjacent rete ridges. In the second step, there is remodelling of the DEJ and superficial dermis; the neoplastic melanocytes proliferate along a DEJ that becomes progressively flattened. The flattening of the DEJ is associated with inflammation, fibroplasia and increased vascularity (also termed angiogenesis) in the superficial dermis, which are, in turn, probably induced by the neoplastic cells. The DEJ and superficial dermal remodelling may create a microenvironment that is more conducive for dermal invasion by malignant melanocytes; thus, the third step in the model is the development of an invasive nodule within or adjacent to the remodelled area.
Indeed, many of the observations made herein can be explained by this melanoma progression model. The main shift in global dermoscopic pattern was from reticular pattern (16% at baseline vs. 9% at follow-up) to reticular–homogeneous (31% at baseline vs. 40% at follow-up). Similarly, at initial evaluation, the majority (61%) of melanomas contained a pigmented network, a third of which showed an atypical network; structureless areas were seen in 40% of melanomas. At follow-up, in 54% of the melanomas that showed pigmented network at baseline, the network became less prominent or disappeared, while among melanomas with structureless areas at baseline, 49% showed increased prominence of these structureless areas (i.e. becoming more widespread within the lesion) at follow-up. Based on previous dermoscopic–histopathological correlation studies, pigmented network correlates with proliferation of melanocytes and presence of pigmented basal keratinocytes along preserved rete ridges (i.e. an undulating DEJ). Loss or blurring of network and appearance of more homogeneous areas on dermoscopy can be attributed to flattening of the DEJ and/or decreased pigmentation in melanocytes and basal keratinocytes. For example, brown structureless areas seen on dermoscopy have been shown by Annessi et al. to correlate with proliferation of melanocytes along a flattened DEJ. Thus, loss of network and increase in homogeneous areas at follow-up can be explained by progression from proliferation within an undulating DEJ (step 1 of the progression model) to proliferation along a flattened DEJ (step 2).
The most common structure present at baseline following the pigmented network and structureless areas are dots on a network (typical dots). On follow-up, 45% of lesions with typical dots at baseline exhibited a decrease in prominence or loss of this structure. According to Puppin et al., typical dots represent junctional nests of melanocytes, mostly along the side and tips of the rete ridges. We propose that the reduction in the observation of typical dots at follow-up is akin to the loss of the pigmented network; both result from loss of rete ridges as the DEJ undergoes remodelling during melanoma progression.
There was a striking increase in prominence of BWS on follow-up, with 11 (73%) of 15 melanomas showing an increase in prominence of BWS. Indeed, it has previously been demonstrated that the presence of BWS is significantly associated with melanoma. On histopathology, BWS overlying flat portions of the lesion is characterized by fibroplasias and presence of melanophages in the superficial dermis. According to the model by Scope et al., the higher prevalence of BWS may be suggestive of progression of melanomas to the second step. In addition, BWS may also represent regression of the lesion, particularly BWS over flat areas.
The increase in BWS also accounts for the substantial increase in prevalence of melanomas showing the colours blue, grey and white from baseline (6%, 18%, 3%) to follow-up (13%, 31%, 10%, respectively). Interestingly, an association between increase in stromal collagen (indicated by scar-like changes in areas showing BWS on dermoscopy or by the recently described finding of crystalline structures) and angiogenesis in melanoma has also been previously shown. This association may account for the concurrent increase in prevalence of melanomas showing the colour red, which represent increased vasculature, between baseline (29%) and follow-up (41%) images.
Among melanoma-specific criteria, the most common dermoscopic structure to appear at follow-up was a dark blotch. Most blotches were eccentric, irregular and/or asymmetrical. According to the virtual Consensus Net Meeting on Dermoscopy published in 2001, an asymmetrical blotch was deemed significantly associated with melanoma. Specifically, at initial consultation, 17% of melanomas displayed a dark blotch, while at follow-up, 34% of melanomas showed a dark blotch. Most often, blotches in melanoma are due to dense proliferation of pigmented melanocytes in the epidermis; a band of pigmented melanocytes in the underlying papillary dermis can also contribute to the homogeneous dark appearance of dermoscopically identified dark blotch. The increase in the frequency of dark blotches probably accounts for the increase in the colours dark brown and black from baseline (85%, 33%) to follow-up (95%, 45%, respectively). Another melanoma-specific criterion is the presence of a negative network; this structure became more prominent in over two-thirds of the lesions that showed it at baseline. The precise correlates of a negative network on histopathology are currently unknown. Although a negative network can be seen in Spitz naevi and rarely Clark's (dysplastic) naevi, it is highly specific for melanoma.
It is noteworthy to highlight that several of the findings in our study parallel those in one previous study. Specifically, Kittler et al. examined the role of sequential dermoscopic imaging in the identification of incipient melanoma and noted the following changes in melanomas monitored for more than 8 months: appearance of new colours in 32% of the lesions; darker overall pigmentation in 59% of the lesions; and disappearance of network lines in 10% of melanomas. Interestingly, loss of network can also occur in melanocytic naevi when imaged during long-term surveillance.
Our study has several limitations. Firstly, given the multicentre study design, it is worthwhile noting that the instruments used to capture images (dermatoscope, lens, camera, software), were likely not the same for every lesion; as a result, there were variations in image quality. Further, as the evaluations were sometimes several years apart, it is possible that change in technology may have made certain changes more prominent and others appear less so. Secondly, our series is limited in size. In fact, we chose not to present select data concerning certain dermoscopic structures [e.g. crystalline structures (shiny white lines) and black dots] because their relative frequency was low in this series. In addition, crystalline structures can be seen only with polarized dermoscopy, while most images in the current dataset were obtained with nonpolarized dermoscopy. Finally, the diagnosis of melanoma was rendered independently by the dermatopathologist at each medical centre, as per routine standard of practice. We are cognizant of the potential for discordant diagnoses (e.g. early melanoma vs. naevus with so-called severe dysplasia) in some of the cases, had they been reviewed by a panel of dermatopathologists. The potential for imperfect agreement among pathologists on the diagnosis of melanoma is a well-known issue in everyday practice.
In conclusion, the dermoscopic changes highlighted in this dataset of SGM are clinically relevant for physicians who follow pigmented lesions via dermoscopic monitoring. Physicians should pay particular attention to melanocytic lesions that, over time, become more disorganized, reveal a loss of network in favour of structureless areas, develop a negative network, and exhibit new colours such as dark brown, black, grey, blue, red and white; in addition, one should not rely solely on change in size. These observations also provide additional insights to our current understanding of melanoma progression.