Dysplastic changes in different types of melanocytic nevi. A unifying concept

We observed histopathologic changes previously described in dysplastic melanocytic nevi in association with a dermal component characteristic of other types of melanocytic nevi or overlapping with features of other varieties of nevi. In order to determine the frequency of these changes, we studied 2,164 cases of compound melanocytic nevi that fulfilled the histopathologic criteria for the diagnosis of compound dysplastic nevus, including architectural pattern, cytologic features, and mesenchymal changes. Of the 2,164 compound dysplastic melanocytic nevi, 1,895 (87.6%) had the histopathologic characteristics previously described for dysplastic nevus, 179 (8.3%) showed a dermal component with a congenital pattern, 67 (3.1%) demonstrated epidermal and dermal characteristics of Spitz's nevus, 8 (0.3%) had features of a combined blue nevus, 13 (0.6%) had a halo phenomenon and 2 (0.1%) showed dermal neuronevus. By considering these nevi as variants of dysplastic nevi, one may apply a unified conceptual basis for their nomenclature. In order to completely describe the appearance of the nevus, we named them by adding the term "dysplastic", to their main histopathologic subtype. Accordingly, six different varieties of dysplastic nevi were identified: 1) dysplastic nevus (original); 2) dysplastic nevus with a congenital pattern; 3) dysplastic Spitz's nevus; 4) dysplastic combined blue nevus; 5) dysplastic halo nevus; and 6) dysplastic neuronevus. In summary, we conclude that the histopathologic criteria previously reported for the diagnosis of dysplastic nevi may be found in association with a dermal component characteristic of other types of melanocytic nevi or may have overlapping features with other variants of nevi.     

Histologic spectrum of melanocytic nevi removed from patients > 60 years of age

BACKGROUND: The histology of melanocytic nevi removed from older patients often differs from that of nevi from younger adults. According to the literature, the most common nevus in older individuals is the intradermal nevus, and purely junctional nevi are rare and should alert the pathologist to a possible melanoma precursor. OBJECTIVE: To evaluate the histologic features of melanocytic nevi removed from patients > 60 year of age. METHODS: Biopsies of nevi (N=215) from 172 patients > 60 years (mean age 69+/-7 years) were examined retrospectively by three dermatopathologists, a consensus diagnosis was rendered, and the spectrum of histologic features was documented. RESULTS: Junctional melanocytic nevi were frequently diagnosed in older patients (21% of cases) and a lentiginous, often heavily pigmented growth pattern was common (12% of nevi). Severely atypical (dysplastic) changes were found in 6% of nevi removed from older patients. CONCLUSIONS: We conclude that benign junctional nevi are relatively common in older patients and that a lentiginous, heavily pigmented growth pattern, traditionally associated with younger individuals, is often seen in both junctional and compound nevi in this older age group. This pattern must be differentiated from dysplastic nevus and melanoma in situ, which they may clinically resemble.     

Clark's nevus

"Clark's nevi" is the name we apply to lesions that have been referred to in the past as dysplastic nevi or nevi with architectural and/or cytologic atypia. Our criteria for this histopathologic diagnosis include such architectural features as: (1) uneven distribution of melanocytes along the dermoepidermal junction; (2) irregularly spaced junctional nests that sometimes bridge between rete; and (3) ill-defined margins often characterized by a lentiginous growth pattern. If dermal nests are present, the junctional component usually extends laterally for some distance beyond the dermal nests. When there is cytologic atypia, it involves scattered melanocytes. Clark's nevi are of doubtful significance if few in number and occurring in a young patient in whom there is no family history of melanoma. When many are found in a patient with a family history of melanoma, their presence serves as a marker for dysplastic nevus syndrome (familial atypical mole-melanoma syndrome). When Clark's nevi develop in patients older than 40 or 50 years of age who have no family history of melanoma, their significance is less clear. However, they might signify a defect in those mechanisms that normally control formation and growth of melanocytic neoplasms.     

Benign melanocytic lesions: Risk markers or precursors of cutaneous melanoma?

Background: The role of benign melanocytic lesions as precursors and not only as risk markers for the development of cutaneous melanoma is controversial.Objective: The purpose of the study was to assess the frequency of the histologic association of benign melanocytic lesions with cutaneous melanoma of a maximum thickness of 1.00 mm. The possibility that the spatial association of benign lesions with melanoma may be co-incidental was also investigated.Methods: The study subjects representing 289 cases of cutaneous melanoma of maximum thickness 1.00 mm (or less) were examined histologically for the presence of an associated benign melanocytic lesion(s), including lentiginous melanocytic proliferation; junctional, compound, or intradermal nevus; dysplastic nevus; and congenital nevus contiguous with or adjacent to the melanoma. The effects of age, tumor thickness, level of invasion, histologic type, and anatomic site on the association of benign melanocytic lesions with melanoma were assessed. In the control subjects 40 basal cell carcinomas and 38 compound nevi (not dysplastic) randomly chosen and matched for age (±1 year) and site (head/neck, trunk, upper and lower limbs) with a melanoma case were examined to assess the proportion of these cases associated with benign lesions compared with the matched melanoma cases.Results: A nevus was associated with melanoma in 51% of cases (n = 147). Of these, 82 (56%) were dysplastic nevi, 61 (41%) were common acquired nevi, and 4 (3%) were congenital nevi. Lentiginous melanocytic proliferation was present in the epidermis adjacent to 219 melanomas (75%) and in 44% of these cases (n = 97) a coexisting nevus was also present.Conclusion: The results of this study lend further support to the concept of common acquired nevi and dysplastic nevi as precursors of cutaneous melanoma. In addition, lesions diagnosed clinically as simple lentigo and solar lentigo may be important as potential precursors of melanoma, particularly in the elderly.     

Melanocytic lesions of the genital area with attention given to atypical genital nevi

Melanocytic lesions of the genital area are rare. They arise mainly in the vulva, although they can also occur less frequently in the perineum, mons pubis and male genitalia and represent 10-12% of pigmented lesions of White women. These pigmented lesions include melanocytic nevi, lentigines, melanocytic nevi with architectural disorder and atypia of melanocytes (dysplastic nevi) and melanomas with microscopic features similar to those seen elsewhere on the body. There is a small subset of benign nevi named atypical melanocytic nevi of the genital type (AMNGT) that occur in young women, with distinctive histologic features in some cases overlapping morphologically with those of melanoma. Thus, it is important to distinguish AMNGT from melanomas in terms of prognosis and treatment. We retrieved 58 cases of genital pigmented lesions diagnosed at our hospital from 1986 to 2008 to evaluate their clinicopathologic features with especial consideration to those cases with atypical features. Thirty-two cases (55%) were common nevi, 10 (17%) lentigines, 6 (10%) melanomas, 3 (5%) dysplastic nevi and 1 blue nevus. Six cases (10%) corresponded to AMNGT and were taken from women with a median age of 21 years. All cases showed symmetry, and the melanocytic proliferation was well demarcated at the lateral margins. The junctional component was very prominent and formed by round or fusiform nests with common retraction artifact and/or cellular dyshesion or as a single cell proliferation with mild (33%) to moderate (67%) cytologic atypia, focal pagetoid spread (17%) and a benign-appearing dermal component (83%) with maturation and dense eosinophilic fibrosis in the superficial dermis. Neither nuclear atypia of melanocytes in the superficial dermis nor dermal mitoses were observed. AMNGT were excised, and no recurrences were recorded in the follow up (median 10.5 years). Therefore, it seems that there is no evidence that AMNGT are precursors of dysplastic nevi or melanomas.     

Architectural features in melanocytic lesions with cellular atypia

According to the quantity of single atypical melanocytes at the dermoepidermal junction 334 nevi were assigned to 3 groups: (1) with pronounced nuclear and cellular atypia (n = 73); (2) with moderate atypia (n = 127), and (3) without atypical melanocytes (n = 134). Three architectural features were almost exclusively observed in groups 1 and 2 with cellular and nuclear atypia: atypical localization of melanocytes in the epidermis, irregular distribution of melanocytes in the junctional zone and atypical nests of melanocytes. A combination of 2 or 3 of these features was seen in 76% of the nevi with pronounced cellular and nuclear atypia, in 28% of those with moderate atypia and in none of those without atypical melanocytes. Regarding 4 other criteria only minor but still statistically significant differences were found between the 3 groups of nevi. We conclude that these 4 other criteria, i.e. inflammatory infiltrate, lamellar and/or concentric fibroplasia, persisting lentiginous hyperplasia and dust-like pigment in melanocytes and nevus cells are not helpful for the diagnosis of a dysplastic nevus because of their low specificity. Minimal requirements for the diagnosis of a dysplastic nevus are suggested.     

Significant melanocytic lesions in infancy, childhood, and adolescence

Malignant melanoma is diagnosed yearly in approximately 300 persons under age 20 in the United States. Relatively recent advances in dermatology include the recognition of lesions felt to be potential precursors of malignant melanoma. Small congenital melanocytic nevi, present in 1 per cent of all newborn infants, may have a small but definite potential for developing malignant melanoma. Furthermore, despite inconclusive data, many leading dermatologists now advocate removal of these small congenital lesions. Giant congenital melanocytic nevi, with their strong predilection for undergoing malignant change, are removed surgically at an early age, often in multistaged procedures. Dermabrasion, once felt to have a role in the treatment of giant congenital nevi, does not remove the malignant potential of these lesions. The dysplastic nevus syndrome, recognized in 1976, identifies individuals at increased risk for developing melanoma. Adolescents who have the dysplastic nevus syndrome or who are members of families with the syndrome require close medical supervision and patient education. The benign Spitz nevus, with its histologic similarity to malignant melanoma, continues to challenge the dermatopathologist and clinician. These lesions--the Spitz nevus, dysplastic nevus, congenital melanocytic nevus, and malignant melanoma--must all be actively considered when regarding the many other benign melanocytic lesions found in infancy, childhood, and adolescence.     

Atypical Compound Nevus Arising in Mature Cystic Ovarian Teratoma (Dermoid Cyst)

Mature cystic ovarian teratomas (MCOT) are the most common ovarian neoplasm and contain components of one or more embryonic germ cell layers. Ectodermal components are most common. Rarely (1–3%), malignant transformation can occur in MCOT and are usually epidermoid, although multiple case reports of melanomas have been described. Four compound nevi and three blue nevi have also been reported; however, atypical (dysplastic) nevi have not been reported to our knowledge. A 28‐year‐old woman presented with a right ovarian mass. A 5 × 4 × 2.5 cm cystic ovarian mass was filled with hair and grumous keratinaceous debris. The lining was smooth with a 1 cm dark macule. Histologically, the mass was predominantly lined by epidermis and appendages. The pigmented lesion consisted predominantly of melanocytic nests irregularly disposed on sides and tips of distorted rete ridges, some with bridging between adjacent rete ridges, and junctional extension lateral to the small dermal component of nevus. Slight fibrosis invested some rete ridges. Moderate atypia was present. Although melanomas and melanocytic nevi have rarely been described previously in MCOT, we present the first atypical (dysplastic) compound nevus, to our knowledge. This case expands the spectrum of melanocytic lesions arising in MCOT.     

Melanocytic nevi with features of Spitz nevi and Clark's/dysplastic nevi ("Spark's" nevi)

Background: Nevi with cytologic characteristics of Spitz nevus and architectural features of Clark's/dysplastic nevus are not well recognized in the literature.
Methods: Twenty-seven nevi with characteristics of Spitz nevus and Clark's/dysplastic nevus are reviewed.
Results: The patients' mean age was 33 years, and 17/27(63%) patients were female. Lesions were most frequent on the trunk and lower extremities. Histopathologically, these nevi were composed of large, monomorphous spindled and/or epithelioid melanocytes. Spindle cells were often oriented parallel to the epidermis, with fused rete and lamellar fibroplasias. Lateral extension of the junctional component was a feature of compound lesions. An average of 10 years of clinical follow up in 12 patients revealed no recurrence or metastasis.
Conclusions: Recognition of this type of nevus is important to avoid confusion with malignant melanoma.     

The role of E-cadherin in nevogenesis: an experimental study using epidermal reconstructs

BACKGROUND: In the development of congenital nevi, how nevus cells migrate in the dermis remains unclear. As shown in an earlier study designed to investigate Unna's Abtropfung hypothesis, dermal invasion does not occur when nevus cells are seeded on epidermal reconstructs. In melanoma, the decrease of E-cadherin expression is associated with the dermal invasion of melanoma cells. OBJECTIVE: To study the expression of E-cadherin in dermal-cultured nevus cells from congenital nevi and its relevance to explain the absence of dermal invasion noted in epidermis reconstructed with cultured nevus cells. METHODS: Comparison of the immunohistochemical expression pattern of E-cadherin in congenital nevi in vivo and after culture in monolayers and in a three-dimensional system. RESULTS: E-cadherin was not expressed in vivo by dermal nevus cells, either isolated or in nests. However, in monolayer cultures, dermal nevus cells expressed E-cadherin. When these cells were used in reconstructed epidermis, nevus cells did not invade the dermis and they expressed E-cadherin when isolated and just weakly or not when grouped in junctional nests. CONCLUSIONS: The absence of dermal invasion of nevus cells could be due to the expression of E-cadherin in these cells in reconstructed epidermis. Our experiments suggest, a restoration of the control of keratinocytes, that nevus cells escape in the dermal compartment.     

The natural history of dysplastic nevi. A case history illustrating their evolution

A 31-year-old man with familial dysplastic nevus syndrome presented with numerous histologically confirmed dysplastic nevi. Seven years before this, all of his nevi, numbering over 150, had been "prophylactically" removed. Despite the removal of all visible nevi, many new nevocellular nevi and atypical nevi appeared during the subsequent seven years. This case illustrates the natural history of dysplastic nevi and suggests that removal of all nevi to prevent melanoma may be futile.     

Proliferation, apoptosis, and survivin expression in a spectrum of melanocytic nevi

BACKGROUND: Apoptosis is important for maintenance of tissue homeostasis and often dysregulated in cutaneous neoplasms. The apoptosis inhibitor survivin is expressed in melanoma and non-melanoma skin cancers and benign keratinocytic lesions. Its expression has not been studied in melanocytic nevi. OBJECTIVE: We determined the expression pattern of survivin in benign melanocytic nevi in comparison to markers of proliferation and apoptosis. METHODS: Six cases of each of the following melanocytic nevi were retrieved from a dermatopathology archive: compound dysplastic nevus, intradermal nevus, compound nevus, neurotized intradermal nevus, and Spitz nevus. Survivin expression was evaluated by in situ hybridization. Apoptotic and proliferation indices were calculated by counting immunoreactive cells in terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling and proliferating cell nuclear antigen immunostained sections, respectively. RESULTS: All nevi, regardless of histologic type, expressed survivin. Compound melanocytic lesions expressed survivin in both epidermal and dermal compartments. The apoptotic rate was low for dysplastic, compound, and Spitz nevi, and apoptotic cells were not identified in any neurotized nevus. The proliferative index was highest for Spitz nevi, while all other nevi demonstrated rare positive cells. CONCLUSIONS: Survivin is consistently expressed in benign melanocytic lesions, while apoptotic cells are rarely identified, suggesting the dysregulation of apoptotic pathways with the accumulation of cells in these neoplasms.     

Childhood melanoma

Pediatric melanoma is rare but increasing in incidence. Because early diagnosis and treatment improves prognosis, clinicians need to include it as a possible diagnosis when evaluating a pigmented lesion in a pediatric patient. Some risk factors for melanoma include xeroderma pigmentosum, giant congenital melanocytic nevi, dysplastic nevus syndrome, atypical nevi, many acquired melanocytic nevi, family history of melanoma, and immunosuppression. Definitive treatment is with surgical excision. Adjuvant therapies such as chemotherapy, immunotherapy, and radiation therapy can be used in advanced cases.     

Nevus lentiginoso atípico. Estudio clínico-patológico de 14 casos

BackgroundAtypical lentiginous nevus (of the elderly) is a peculiar form of dysplastic nevus. Clinically, this condition can resemble malignant melanoma and histologically, it has a lentiginous pattern with variable degrees of atypia and an absence of dermal nests. These features may lead to an erroneous diagnosis of lentigo maligna melanoma or lentiginous melanoma.Material and methodsWe reviewed 14 cases of atypical lentiginous nevus diagnosed at the dermatology department of Hospital General de Valencia in Valencia, Spain between December 2007 and March 2009. We studied the clinical and histopathologic features of the lesions after hematoxylin-eosin, Melan-A, and Ki-67 staining and compared our results to data reported in the literature.ResultsFour (28%) of the 14 patients (7 men, 7 women) were under 50 years of age. Clinically, most of the lesions (8/14) resembled atypical nevi and they were all located on the back. Histologically, they all had irregular lentiginous epidermal hyperplasia, with a proliferation of individual melanocytes only in the basal layer of the epidermis and an absence of dermal nests. Focal upward migration of melanocytes into the epidermis was present in just 4 cases. All the lesions had cellular atypia, which was moderate in 85% of cases. The Ki-67 proliferation index was low (<5%) in all the lesions analyzed.ConclusionsAtypical lentiginous nevi, which can be classified as atypical pigmented lesions with a lentiginous pattern, may clinically and histologically resemble melanoma. Our findings support earlier reports that both clinical and histologic findings may suggest a diagnosis of dysplastic nevus. All of the patients in our series are healthy and free of recurrence after 18 months or longer.     

Desmoplastic melanocytic nevi with lymphocytic aggregates

Desmoplastic melanocytic nevi can be difficult to distinguish from desmoplastic melanoma. The presence of lymphocytic aggregates in association with a sclerosing melanocytic proliferation is commonly regarded as a feature in support of a diagnosis of desmoplastic melanoma. However, the finding is not specific for melanoma. Herein we report six cases of sclerosing melanocytic nevi with associated lymphocytic aggregates. They occurred in five women and one man, ranging in age from 11 to 61 years. Three lesions were sclerosing Spitz nevi; one was an amelanotic sclerosing blue nevus, one an acquired intradermal sclerosing nevus, and one was a congenital compound melanocytic nevus with sclerosis of its dermal component. The lesions were interpreted as benign, i.e. melanocytic nevi, because of their histopathologic attributes (symmetric silhouette, benign cytologic features) and results from immunohistochemical studies (all lesions strongly expressed Melan-A and p16) and fluorescence in situ hybridization (FISH). Three lesions tested by FISH lacked copy number changes of 11p, 6q or 6p. None of the lesions recurred. The cases highlight that contextual information is essential for the diagnosis of desmoplastic melanoma and sclerosing nevus. The presence of lymphocytic aggregates per se does not prove that a sclerosing melanocytic proliferation is malignant.     

Eruptive post-chemotherapy in situ melanomas and dysplastic nevi

A 22-year-old white man without a personal or family history of atypical nevi had received chemotherapy for pre-B-cell acute lymphocytic leukemia at age 17 that included L-asparaginase, prednisone, methotrexate, mercaptopurine, daunorubicin, and cytoxan. Two to three months after completing maintenance chemotherapy, the patient reports he developed many moles, which remained stable for approximately 2 years. Upon examination, two dark, atypical appearing plaques with irregular borders and numerous pink papules of varying shapes and sizes were noted on his chest, back, and abdomen. Histology of specimens of both types of lesions revealed three moderately atypical compound dysplastic melanocytic nevi and three in situ melanomas. The lesions with only features of dysplastic nevi exhibited dermal fibrosis, cytologic atypia, junctional shoulders, lentiginous spread, and focal pigmentation. The lesions with in situ melanomas in addition demonstrated pagetoid spread, extension down adnexal structures, and more severe cytologic atypia. Malignant melanoma has been associated with chronic immunosuppression, and benign nevi have been reported to erupt after chemotherapy. We report an occurrence of multiple eruptive dysplastic nevi and in situ melanomas appearing shortly after completion of chemotherapy.     

Agminated atypical (dysplastic) nevi: case report and review of the literature.

BACKGROUND: Patients with the atypical mole syndrome have multiple dysplastic nevi that appear to be randomly distributed on certain preferred anatomical sites such as the upper back. These dysplastic nevi are thought to be acquired melanocytic nevi that begin appearing at puberty. To our knowledge, the presence of agminated atypical (dysplastic) nevi has not been reported. OBSERVATION: We describe a patient with the atypical mole syndrome who has more than 100 melanocytic nevi, many of which are clinically atypical and one of which proved to be a melanoma. Among his many melanocytic nevi is a cluster of approximately 50 nevi that are distributed in an area measuring 5 x 3 cm. The histopathologic features of these nevi are consistent with the diagnosis of "dysplastic nevus." CONCLUSIONS: To our knowledge, agminated atypical (dysplastic) nevi have not been described previously. The presence of agminated atypical (dysplastic) nevi in a patient with the atypical mole syndrome can be theorized to arise because of loss of heterozygosity.     

Cytoplasmic and nuclear expression of survivin in melanocytic skin lesions

Survivin, a member of the inhibitors of apoptosis protein family, regulates both cellular proliferation and apoptotic cell death. While the human survivin gene is highly expressed in the developing fetus, in adults its expression is restricted to highly proliferating normal tissues and neoplastic tumors tissues. In the present study, we compared the expression of survivin in melanoma and benign melanocytic lesions such as junctional, compound, dermal, congenital, blue and spitz nevi. This analysis reveals a heterogeneous expression of survivin with respect to both the intensity, frequency and cellular localization. In junctional, compound and blue nevi, survivin was present in nuclear localization, whereas in spitz nevi survivin was detectable in the cytoplasm. In dermal and congenital nevi, survivin was present in both localizations with predominance of the nuclear compartment. Interestingly, this distribution was similar to that observed in primary melanoma; whereas in metastatic melanoma the predominance of the nuclear localization of survivin was lost. Our data demonstrate that although survivin is expressed in a large number of benign nevi, the balance between its cytoplasmic and nuclear expression was immensely heterogeneous between lesions with suspected different developmental origins.