Giant congenital nevi: a 20-year experience and an algorithm for their management.

A variety of treatment options exists for the management of giant congenital nevi. Confusion over appropriate management is compounded because not all giant congenital nevi are pigmented, and malignant potential varies between different types. The present study sought to define factors in the presentation of giant congenital nevi that could provide an algorithm for their management, with respect to both the extent of resection and subsequent reconstructive options.A retrospective review of all patients who presented with a congenital nevus of 20 cm2 or greater since 1980 was performed, distinguishing among nevi involving the head and neck, the torso, and the extremities. Sixty-one patients with giant congenital nevi were evaluated (newborn to age 16 years), of which 60 nevi in 55 patients have been operated on.Giant congenital nevi having malignant potential were pigmented nevi (53 patients) and nevus sebaceus (four patients). Those not having malignant potential were verrucous epidermal nevi (three patients) and a woolly hair nevus (one patient). Of the 60 giant congenital nevi operated on, expanded flaps were used in 25, expanded full-thickness skin grafts were used in 10, split-thickness or nonexpanded full-thickness skin grafts were used in 13, and serial excision was used in 30. After 1989, operations tended to use multimodality treatment plans, with an increased use of expanded full-thickness grafts and immediate serial tissue expansion. The use of serial excision, particularly in the extremities, also increased after 1989. Serial excision was the treatment of choice when it could be completed in two procedures or less, which occurred in more than 80 percent of cases using serial excision alone. Expanded flaps were the most common mode of reconstruction in the head and neck region and were used in 49 percent of these procedures. Serial excision was the most common form of treatment in the extremities, used in 50 percent of procedures. Tissue expansion in the extremities was infrequently used to provide an expanded flap (8 percent of procedures), whereas it was frequently used to provide expanded full-thickness skin grafts harvested from the torso (used in 31 percent of procedures).On the basis of these data, algorithms for the extent of resection and subsequent reconstructive options for giant congenital nevi were developed. Their management should be formulated relative to pigmentation, malignant potential, and anatomic location of the respective lesions.     

Pigmented Nevi—Induced Changes in the Junctional Component

The pigmented nevus represents a potentially more dynamic lesion than has been indicated by most published studies. New nevus cell clusters frequently appear in the epidermis over the residual portion of a nevus that remains after partial surgical excision. Even in relatively inactive nevi in adults, new junctional nevus cells may be induced by surgical trauma. This stimulated growth usually regresses by the time one year or more has elapsed. The growth of nevus cells is probably comparable to that induced in other cells by traumatic injury. There is no evidence to suggest that it is related to the development of melanoma in pigmented nevi.     

Treatment of a giant congenital hairy nevus of the ear

A split-thickness skin graft from the abdomen was successfully used to resurface the entire auricle following full-thickness excision of a congenital nevocellular nevus. We found no previous report describing the use of skin grafts to successfully resurface the entire ear and achieve an acceptable aesthetic result.     

Congenital malignant melanoma.

The diagnosis and management of a 3-day-old infant with an exophytic pigmented growth on her back and chest are discussed. At 3 days of age, the child underwent a complete surgical excision of this lesion with immediate coverage by partial-thickness skin grafts. Pathologically, the lesion proved to be a thoracolumbar congenital melanocytic nevus with multiple focal areas of malignant melanoma. The child is now 3 years past surgery and shows no evidence of recurrence or distant metastases. The importance of this case lies in the presence of overt malignant melanoma at birth within a giant congenital nevocytic nevus.     

Dermal nevus cells from congenital nevi cannot penetrate the dermis in skin reconstructs

Congenital nevi are composed of pigment cells bearing common features with melanocytes but showing altered differentiation which leads to nesting and dermal involvement. Using a dead de-epidermized dermis seeded with a combination of keratinocytes and various sources of pigment cells (normal melanocytes, dermal nevus cells from congenital nevi, Bowes melanoma cells), we have studied the formation of nests and the dermal migration of pigment cells together with their secretion profiles of matrix metalloproteinases (MMP). Dermal fibroblasts were also used as control cells in epidermal reconstructs. Besides their morphologic features, the absence of pigment donation to keratinocytes was the major characteristic of dermal nevus cells. A positive correlation was established between the increasing percentage of seeded nevus cells and the patchy pigmentation of reconstructs, as well as the clustering of cells in junctional nests. However, the presence of nevus cells in the dermis of reconstructs was never detected, whereas melanoma cells and dermal fibroblasts could invade the dermis during the time span of the experiments. MMP9 was never expressed in congenital dermal nevus cells but pro-MMP2 was constitutively expressed by all strains of congenital nevus cells and dermal fibroblasts. Melanocytes produced comparable amounts of both pro-MMP2 and pro-MMP9, and Bowes melanoma cells secreted a marginal level of pro-MMP2. In view of their three-dimensional behaviour and secretion of MMPs, we propose that dermal congenital nevus cells correspond to an intermediate status of differentiation between normal melanocytes and melanoma cells. Activation of MMPs by a cofactor or the activation of another signalling pathway seems necessary to induce the dermal passage of nevus cells.     

Giant congenital melanocytic nevus with vascular malformation and epidermal cysts associated with a somatic activating mutation in BRAF

Giant congenital melanocytic nevi may be symptomatically isolated or syndromic. Associations with capillary malformations are exceptional, and development of epidermal cysts has not been described. A 71‐year‐old patient with a giant congenital melanocytic nevus (CMN) of the lower back, buttocks, and thighs was asymptomatic except for unexpected hemorrhage during partial surgical excision years before. Blunt trauma at age 64 initiated recurrent, severe pain under the nevus; multiple large epidermal cysts then developed within it. Imaging and biopsy showed a large, non‐pulsatile venous malformation intermingled with the deep nevus. A low‐abundance, heterozygous BRAF c.1799T>A (p.V600E) mutation was present in both gluteal and occipital congenital nevi; additional mutations in NRAS, GNAQ, GNA11, HRAS, or PIK3CA were undetectable. This is the first demonstration of a recurrent BRAF mutation in multiple large congenital nevi from the same individual, confirming that this malformation can have multiple genetic origins. Early constitutive activation of BRAF can therefore cause unusual associations of giant nevi with vascular malformations, indicating that both pigment and endothelial cell physiology may be affected by mosaic RASopathies.     

Dysplastic nevus--risk factor or disguise for melanoma

Dysplastic nevus is an acquired or hereditary nevus that clinically seems atypical and pathohistologically dysplastic. The term of dysplastic nevus has changed through history and even until now the dermatologists and pathologists have not found the same conclusion for name and definition of dysplastic nevus. Epidemiology of dysplastic nevus is different depending on geographic lattitude, being three times higher in Australia than in Great Britain. Genetic factors play a role in etiology of dysplastic nevus but are still not well defined. UV radiation is indisputable main etiological factor in developing dysplastic nevus. Many studies confirm that children who have been using sun protection creams with SPF have less dysplastic nevi than those who did not. Nevus with geographic shape and muddy borders, dominately macular, red to brown colored and has 5 mm or more in diameter is clinically dysplastic nevus. ABCDE rules count for dysplastic nevus as well as for melanoma but prefferable diagnostic criteria for dysplastic nevus would be "ugly duckling sign". Pathohistologic analysis is the key in confirming the diagnosis of dysplastic nevus. Great experience and knowledge in dermatopathology field is essential for pathologists to make a distinction between dysplastic nevus and melanoma in situ. Likewise great experience in dermatooncology field is essential in differentiating dysplastic nevus from other nevi. Surgical excision is the only therapy that should be done for dysplastic nevus. Regular follow up is highly recommended for patients with dysplastic nevus and syndroma naevi dysplastic. Education about sun protection measures and self-examination techniques is essential for all patients with dysplastic nevi and their family.     

The usefulness of c-Kit in the immunohistochemical assessment of melanocytic lesions

C-Kit (CD117), the receptor for the stem cell factor, a growth factor for melanocyte migration and proliferation, has shown differential immunostaining in various benign and malignant melanocytic lesions. The purpose of this study is to compare c-Kit immunostaining in benign nevi and in primary and metastatic malignant melanomas, to determine whether c-Kit can aid in the differential diagnosis of these lesions. c-Kit immunostaining was performed in 60 cases of pigmented lesions, including 39 benign nevi (5 blue nevi, 5 intradermal nevi, 3 junctional nevi, 15 cases of primary compound nevus, 11 cases of Spitz nevus), 18 cases of primary malignant melanoma and 3 cases of metastatic melanoma. The vast majority of nevi and melanomas examined in this study were positive for c-Kit, with minimal differences between benign and malignant lesions. C-Kit cytoplasmatic immunoreactivity in the intraepidermal proliferating nevus cells, was detected in benign pigmented lesions as well as in malignant melanoma, increasing with the age of patients (P=0.007) in both groups. The patient's age at presentation appeared to be the variable able to cluster benign and malignant pigmented lesions. The percentage of c-Kit positive intraepidermal nevus cells was better associated with age despite other variables (P=0.014). The intensity and percentage of c-Kit positivity in the proliferating nevus cells in the dermis was significantly increased in malignant melanocytic lesions (P=0.015 and P=0.008) compared to benign lesions (compound melanocytic nevi, Spitz nevi, intradermal nevi, blue nevi). Immunostaning for c-Kit in metastatic melanomas was negative. Interestingly in two cases of melanoma occurring on a pre-existent nevus, the melanoma tumor cells showed strong cytoplasmatic and membranous positivity for c-kit, in contrast with the absence of any immunoreactivity in pre-existent intradermal nevus cells. C-Kit does not appear to be a strong immunohistochemical marker for distinguishing melanoma from melanocytic nevi, if we consider c-Kit expression in intraepidermal proliferating cells. The c-Kit expression in proliferating melanocytes in the dermis could help in the differential diagnosis between a superficial spreading melanoma (with dermis invasion) and a compound nevus or an intradermal nevus. Finally, c-Kit could be a good diagnostic tool for distinguishing benign compound nevi from malignant melanocytic lesions with dermis invasion and to differentiate metastatic melanoma from primary melanoma.     

The 'Abtropfung phenomenon' revisited: Dermal nevus cells from congenital nevi cannot activate matrix metalloproteinase 2 (MMP-2)

Since Unna's Abtropfung hypothesis, the process of migration of nevus cells in the dermis remains unknown. To investigate its mechanisms, we studied the role of gelatinases in dermal nevus cells obtained from congenital pigmented nevi, which are major actors in the remodeling of basement membrane proteins. Our previous studies have shown that dermal nevus cells express pro-matrix metalloproteinase (MMP)-2 exclusively and cannot return to the dermis when seeded together with keratinocytes on top of the dermis in a skin reconstruction model. To examine why MMP-2 was not in its active form, we used Western blot to study the expression of members of the MMP-2 activation pathway (membrane type 1-MMP and tissue inhibitor of metalloproteinase-2), which proved to be normally expressed. To induce the dermal passage of nevus cells artificially, we also tried to activate gelatinases with phorbol-12-myristate-13-acetate and epidermal growth factor, using epidermis reconstructed with nevus cells. No migration in the dermis could be triggered. We conclude that the absence of active MMP-2 is due to a functional blockade of its activation pathway and may prevent dermal nevus cells from reaching the dermal compartment in skin reconstructs. Furthermore, our findings reinforce the concept that dermal nevus cells originating from congenital nevi are in a quiescent status.     

The ‘Abtropfung Phenomenon’ Revisited: Dermal Nevus Cells from Congenital Nevi Cannot Activate Matrix Metalloproteinase 2 (MMP‐2)

Since Unna's Abtropfung hypothesis, the process of migration of nevus cells in the dermis remains unknown. To investigate its mechanisms, we studied the role of gelatinases in dermal nevus cells obtained from congenital pigmented nevi, which are major actors in the remodeling of basement membrane proteins. Our previous studies have shown that dermal nevus cells express pro‐matrix metalloproteinase (MMP)‐2 exclusively and cannot return to the dermis when seeded together with keratinocytes on top of the dermis in a skin reconstruction model. To examine why MMP‐2 was not in its active form, we used Western blot to study the expression of members of the MMP‐2 activation pathway (membrane type 1‐MMP and tissue inhibitor of metalloproteinase‐2), which proved to be normally expressed. To induce the dermal passage of nevus cells artificially, we also tried to activate gelatinases with phorbol‐12‐myristate‐13‐acetate and epidermal growth factor, using epidermis reconstructed with nevus cells. No migration in the dermis could be triggered. We conclude that the absence of active MMP‐2 is due to a functional blockade of its activation pathway and may prevent dermal nevus cells from reaching the dermal compartment in skin reconstructs. Furthermore, our findings reinforce the concept that dermal nevus cells originating from congenital nevi are in a quiescent status.     

An Ex Vivo Study of Congenital Pigmented Nevi in Epidermal Reconstructs

In order to study morphologic and functional characteristics of pigment cells in congenital pigmented nevi, autologous or heterologous reconstructs have been made using normal keratinocytes and nevus cells from the dermal-epidermal junction or from the dermis. All these cells, keratinocytes and nevus cells, were used as cell suspensions immediately after dissociation from the tissues or after subsequent brief cultivation in a serum-free medium. Reconstructed epidermis were cultured for 15 days at the air-liquid interface with or without ultraviolet (UV) B exposure. The reconstructs were examined macroscopically (formation of hyperpigmented macules), histologically (pigment cell nesting) and ultrastructurally (pigment structure and transfer). Typical nesting of nevus cells was observed in the dermal-epidermal junction or in the superficial dermis associated with macroscopically detectable small pigmented macules. UVB exposure induced an upward migration of nevus cells in the suprabasal layers of the epidermis. This tissue model can be considered as an excellent system for the ex vivo reproduction of pigmented nevi and as an assay of the sensitivity of nevus cells towards UVB irradiation.     

Comparison of image analysis with flow cytometry for DNA content analysis in pigmented lesions of the skin.

The DNA ploidy of 85 melanocytic skin lesions was determined by flow cytometry (FCM) and interactive image analysis (IA) using nuclear extracts of paraffin-embedded tissue. Of the 85 lesions analyzed, 43 were malignant melanomas in different stages of evolution, 15 were dysplastic nevi, 11 were Spitz nevi, and 16 were other types of nevi. Some of the last had features of congenital nevi. Within the melanoma category, there was 42% aneuploidy by FCM versus 56% by IA. Of those melanomas aneuploid by FCM, all but one were aneuploid by IA. All dysplastic nevi, 10/11 Spitz nevi and 15/16 other nevi were diploid by both methods. One of the 16 nevi from the "other types" category was tetraploid by IA but diploid by FCM. A single Spitz nevus was tetraploid by FCM but diploid by image analysis. While our results suggest that interactive IA is potentially a more sensitive method than FCM for detecting aneuploidy in cutaneous pigmented lesions, it remains to be shown whether this will translate into better prognostic assessment of the biologic behavior of melanocytic neoplasms than provided by flow cytometric ploidy analysis.     

Risk of melanoma arising in large congenital melanocytic nevi: a systematic review

Large congenital melanocytic nevi are cutaneous lesions regarded by many as premalignant; estimates of malignancy incidence range from 0 to 42 percent. Given the often complex and extensive nature of large congenital melanocytic nevi resection and reconstruction, the risk of malignant transformation is a crucial factor that surgeons and families must weigh when deciding whether or not to excise the lesion. The authors conducted a systematic analysis of data from the existing literature to critically evaluate the published studies and to establish a crude incidence rate for the risk of malignant melanoma transformation in large congenital melanocytic nevi. After a comprehensive literature search, they analyzed data from eight studies (containing a total of 432 large congenital melanocytic nevi patients) of sufficient scientific quality. Twelve patients (2.8 percent) in this sample developed cutaneous malignant melanoma during the reported follow-up periods. Using a subset of this data and comparing the incidence rates to those of the Surveillance, Epidemiology, and End Results population-based database using a standardized morbidity ratio, the authors found that the large congenital melanocytic nevi patients had an increased risk of melanoma (standardized morbidity ratio, 2599; 95 percent confidence interval, 844 to 6064) compared with the general population. Regarding treatment before developing melanoma in the 12 patients, 50 percent were observed before diagnosis, 17 percent had partial excision, 8.3 percent had dermabrasion, 8.3 percent had a chemical peel, and 17 percent did not have any treatment information. These combined data are clinically useful when consulting with the parents of children with large congenital melanocytic nevi and in the management of older patients with existing lesions. This study shows that there is a significantly increased risk of melanoma in large congenital melanocytic nevi patients. The data also reveal the need for a standardized definition of large congenital melanocytic nevi and a long-term, prospective outcomes study to determine the true lifetime risk of melanoma in patients with and without surgical excision.     

An ex vivo study of congenital pigmented nevi in epidermal reconstructs.

In order to study morphologic and functional characteristics of pigment cells in congenital pigmented nevi, autologous or heterologous reconstructs have been made using normal keratinocytes and nevus cells from the dermal-epidermal junction or from the dermis. All these cells, keratinocytes and nevus cells, were used as cell suspensions immediately after dissociation from the tissues or after subsequent brief cultivation in a serum-free medium. Reconstructed epidermis were cultured for 15 days at the air-liquid interface with or without ultraviolet (UV) B exposure. The reconstructs were examined macroscopically (formation of hyperpigmented macules), histologically (pigment cell nesting) and ultrastructurally (pigment structure and transfer). Typical nesting of nevus cells was observed in the dermal-epidermal junction or in the superficial dermis associated with macroscopically detectable small pigmented macules. UVB exposure induced an upward migration of nevus cells in the suprabasal layers of the epidermis. This tissue model can be considered as an excellent system for the ex vivo reproduction of pigmented nevi and as an assay of the sensitivity of nevus cells towards UVB irradiation.     

Cultured epithelial autografts for giant congenital nevi

Eight pediatric patients with giant congenital nevi confluent over 21 to 51 percent body surface area were treated by excision and grafting. The nevus was excised to the muscle fascia, and the open wound was grafted with cultured epithelial autografts and split-thickness skin grafts. The patients have been followed from 17 to 56 months. Seventeen operations were performed in the eight patients, excising a mean of 6.9 percent body surface area at each procedure. The mean duration of anesthesia was 3.7 hours, and the mean operative blood loss was 12.3 percent estimated blood volume. The mean "take" for the cultured epithelial autografts was 68 percent, and for the split-thickness skin grafts, 84 percent. Epithelialization of open wound areas adjacent to the grafts was somewhat slower for the cultured epithelial autografts than for the split-thickness skin grafts, but it led to a healed wound in all patients except one. Ten of the 17 areas grafted with cultured epithelial autografts resulted in small open wounds that required regrafting. Wound contraction under the cultured epithelial autografts and under split-thickness skin grafts was similar and depended more on the anatomic site grafted than on the type of graft employed. in 16 of 17 operations, the cultured epithelium remained as a permanent, durable skin coverage. The use of cultured epithelial autografts allowed a larger area of excision than would have been possible with split-thickness skin grafts alone and, therefore, a more rapid removal of nevus. Cultured epithelial autograft are an important new technique in the care of patients with giant congenital nevi.     

Allelic somatic mutations may explain vascular twin nevi

Summary Vascular twin nevi, i.e., telangiectatic nevus and nevus anemicus occurring together and adjacent to each other, can be explained as twin spots resulting from a somatic recombination. It is so far unclear, however, whether the postulated underlying autosomal recessive mutations are allelic. This problem can be approached by studying another cutaneous phenotype, phacomatosis pigmentovascularis. Within this diagnosis, several authors have reported the simultaneous occurrence of three different birthmarks, viz., a pigmentary nevus, a telangiectatic nevus and a nevus anemicus. These cases can also be explained as a twin-spot phenomenon, provided two of these nevi are considered allelic traits. The two vascular nevi are most probably allelic, whereas the pigmentary nevus may be a nonallelic component of this syndrome. In conclusion, phacomatosis pigmentovascularis provides circumstantial evidence suggesting allelism of somatic mutations giving rise to two different vascular nevi.     

Use of monoclonal antibody 225.28S in the study of nevus cells in culture

The aim of this work is to identify and purify cultured nevus cells. We used for our study monoclonal antibody 225.28S. This antibody reacts with a surface antigen which is expressed by nevus cells and melanoma cells, but it does not react with normal melanocytes. We studied 10 dermic nevi and we observed that antigenic determinant survives in cultured nevus cells. These results allowed us to employ the method of panning for purify cultured nevus cells.     

鉴别无色素性恶性黑色素瘤方法的探讨

无色素及少色素性恶黑鉴别诊断时,（１）组织化学铁反应,褪色素和黑色素银染对证实瘤细胞中黑色素是有帮助的,但不能从无色素性恶黑中检出黑色素。因此对无黑色素恶黑的诊断和鉴别诊断帮助不大。网状纤维染色良性病均有增加,而恶黑几乎没有增加或仅极少增加。因此网状纤维染色有助于良恶性的鉴别。（２）免疫组化Ｓ－１００１８例恶黑及６例良性痣均显示阳性,这对无色素恶黑的诊断是有价值的,但对色素痣的恶变帮助不大。１６例恶黑中１４例色素性与１０例无色素性恶黑ＨＭＢ４５均显示阳性,证明两者有共同抗原,总阳性率８７．５％,６例良性痣均为阴性,证明无ＨＭＢ４５抗原。结果提示ＨＭＢ４５免疫组化检测不仅对无色素及少色素性恶黑的诊断与鉴别诊断实用性大,还可以用于对恶黑与良性痣、良性痣恶变的鉴别。（３）本组４例无色素性恶黑电镜下均找到前黑色素小体。因此在其他方法诊断困难时,应用电镜检查对确诊具有决定性作用。     

Novel three‐way complex rearrangement of TRPM1‐PUM1‐LCK in a case of agminated Spitz nevi arising in a giant congenital hyperpigmented macule

The genetic anomalies associated with the agminated variant of Spitz nevus have so far been limited to HRAS G13R mutations, especially when arising within a nevus spilus. A previous report exposed the case of a man with a giant pigmented macule involving his upper right limb and trunk. Since childhood, Spitz nevi have been periodically arising, within the pigmented area. The histopathology of several lesions displayed the usual criteria of junctional, compound, or intradermal Spitz nevi with a diversity of cytomorphological and architectural features. Some lesions spontaneously regressed. Genetic studies confirmed in three lesions an identical translocation involving TRPM1, PUM1, and LCK. No mutations in HRAS, NRAS, BRAF, or other known fusion genes linked to Spitz nevus were detected. LCK break‐apart fluorescence in situ hybridization confirmed the rearrangement was present not only in the melanocytic proliferation but also in the surrounding non‐spitzoid melanocytes. This report expands the list of genetic alterations involved both in giant congenital macules and in agminated Spitz nevi, and also extends the concept of mosaicism in melanocytes to gene translocations.     

NRAS and BRAF Mutations in Melanoma-Associated Nevi and Uninvolved Nevi

According to the prevailing multistep model of melanoma development, oncogenic BRAF or NRAS mutations are crucial initial events in melanoma development. It is not known whether melanocytic nevi that are found in association with a melanoma are more likely to carry BRAF or NRAS mutations than uninvolved nevi. By laser microdissection we were able to selectively dissect and genotype cells either from the nevus or from the melanoma part of 46 melanomas that developed in association with a nevus. In 25 cases we also genotyped a control nevus of the same patients. Available tissue was also immunostained using the BRAF^V600E-mutation specific antibody VE1. The BRAF^V600E mutation was found in 63.0% of melanomas, 65.2% of associated nevi and 50.0% of control nevi. No significant differences in the distribution of BRAF or NRAS mutations could be found between melanoma and associated nevi or between melanoma associated nevi and control nevi. In concordant cases immunohistochemistry showed a higher expression (intensity of immunohistochemistry) of the mutated BRAF^V600E-protein in melanomas compared to their associated nevi. In this series the presence of a BRAF- or NRAS mutation in a nevus was not associated with the risk of malignant transformation. Our findings do not support the current traditional model of stepwise tumor progression.