Cutaneous melanomas associated with nevi

OBJECTIVE: To determine the frequency of and the histologic and clinical factors associated with melanoma existing in histologic contiguity with a nevus. DESIGN: Pathology reports from melanomas collected from January 1, 1993, to December 31, 1997, were retrospectively reviewed. SETTING: Independent, community-based dermatopathology laboratory. PATIENTS: A total of 1606 patients with a histologic diagnosis of melanoma. INTERVENTION: None. MAIN OUTCOME MEASURES: Differences in histologic (subtype, Breslow thickness, and Clark level) and clinical (age, sex, and anatomic location) features between melanomas that are associated and unassociated with a nevus. RESULTS: Twenty-six percent of the melanomas reviewed were histologically associated with nevi (dysplastic nevi, 43.0%; and other nevi, 57.0%). Factors that were significantly associated with an increased likelihood of a melanoma being histologically contiguous with a nevus included younger age, superficial spreading subtype, truncal location, Breslow thickness, and Clark level. However, after multivariate analysis, only younger age (odds ratio, 1.27; 95% confidence interval, 1.19-1.37), superficial spreading subtype (odds ratio, 2.96; 95% confidence interval, 2.17-4.02), and truncal location (odds ratio, 3.26; 95% confidence interval, 2.55-4.19) remained significant. CONCLUSIONS: Most melanomas were not histologically contiguous with a nevus. Younger age, superficial spreading subtype, and truncal location are independent significant predicators of a melanoma being histologically associated with a nevus.     

Expression of activated Akt in benign nevi, Spitz nevi and melanomas

BACKGROUND: Activated Akt expression (p-Akt) is reportedly increased in many melanomas as compared with benign nevi. The purpose of this study was to evaluate and compare p-Akt immunohistological staining in benign nevi, Spitz nevi and primary melanomas. METHODS: Immunostaining for phosphorylated Akt was performed in 41 melanocytic lesions previously classified as benign intradermal nevus (14 lesions), Spitz nevus (9 lesions) or melanoma (18 lesions). Lesions were graded for intensity of p-Akt staining by two independent observers (0, no staining; 1, slightly positive; 2, moderately positive; 3, highly positive). Scores were averaged, and statistical analyses were performed. RESULTS: Benign nevi showed less staining (mean score 1.18) compared with Spitz nevi (mean score 2.11) and melanomas (mean score 2.19). This difference was statistically significant between benign nevi and melanomas (p = 0.0047) and benign nevi and Spitz nevi (p = 0.0271). No statistical difference was detected in staining between Spitz nevi and melanomas (p = 0.8309). CONCLUSIONS: Activated Akt expression is increased in Spitz nevi and melanomas as compared with benign intradermal nevi, but is unlikely to prove useful in differentiating between the former.     

G1 cell cycle regulators in congenital melanocytic nevi. Comparison with acquired nevi and melanomas

Background:  Congenital nevi are one of the known risk factors for the development of melanoma. However, the magnitude of the risk for both large and small congenital nevi is controversial.
Methods:  In order to elucidate the behavior of congenital nevocytes and to define any possible similarities or differences with common nevi and melanomas, we investigated the expression of Ki-67, Rb, p16, cyclin D1, p53 and p21/Waf-1 in 41 congenital nevi, 16 melanomas and 20 acquired common nevi by immunohistochemistry.
Results:  Congenital nevi highly expressed p16 (81.82 ± 9.98) but showed limited, if any, reactivity for Ki-67 (1.34% ± 0.89), Rb (0.76% ± 0.94), cyclin D1 (0.21% ± 0.29), p53 (0.54% ± 0.93) and p21 (0.0609% ± 0.32). No statistically significant difference was found between giant and nongiant congenital nevi and between congenital and common nevi for any of the markers. The expression of p16 was significantly higher in congenital nevi than in melanomas (p < 0.0001). On the contrary, the expression of Ki-67, p53, p21, Rb and cyclin D1 was significantly higher in melanomas (p < 0.0001).
Conclusion:  Our data regarding the immunohistochemical expression of Rb, p16, p53, cyclin D1 and Ki-67 in congenital nevi indicate that either the alteration of their expression is not an initiating event in melanoma formation or, alternatively, congenital melanocytic nevi may not be the first step in malignant transformation.     

Dysplastic melanocytic nevi in histologic association with 234 primary cutaneous melanomas

Dysplastic melanocytic nevi (DMN) are irregularly pigmented lesions characterized by (1) atypical melanocytic hyperplasia in a lentiginous epidermal pattern (AMHL), (2) one or more dermal mesenchymal changes, and (3) frequently a dermal nevocellular nevus. In order to determine an association between DMN and cutaneous melanoma, the dominant histologic feature of DMN (namely, AMHL) was sought in histologic contiguity with 234 primary melanomas. Of these 234 cases, 9 were lentigo maligna melanomas. Of the remaining 225 cases, 49 (21.8%) were associated with AMHL in the same histologic section as (but beyond the most lateral margin of) intraepidermal and invasive melanoma. AMHL was directly associated with the presence of dermal nevocellular nevi in histologic contiguity with melanoma, and a greater number of histologic slides with melanoma available for review. AMHL was inversely associated with nodular melanoma. Most of the AMHL cases were not associated with familial melanoma, but the total number of familial cases was low. The histologic association between AMHL and melanoma in one fifth of cases in this series supports the hypothesis that at least some cutaneous melanomas may have an origin in DMN.     

Genodermatoses associated with melanocytic nevi

Though melanocytic nevi are ubiquitous in the general population, they can also be key cutaneous manifestations of genetic syndromes. We describe genodermatoses associated with melanocytic nevi and discuss their clinical characteristics, cutaneous manifestations, underlying genetics, and, if applicable, guidelines for when genetic testing should be performed. We categorized these genodermatoses based on their association with congenital nevi, acquired nevi, or nevi whose first appearance is unknown. In many cases, the distinctive morphology or distribution of melanocytic nevi can be an important clue that an underlying genetic syndrome is present, allowing both the patient as well as family members to be screened for the more serious complications of their genetic disorder and receive education on potential preventative measures. As we continue to advance our understanding of how various genotypes give rise to the wide spectrum of phenotypes observed in these genodermatoses, we shall be able to better stratify risk and tailor our screening methods to clinically manage the heterogeneous manifestations of genodermatoses among these patients.     

Lectin-binding pattern of primary malignant melanomas and melanocytic nevi

A panel of six biotinylated lectins was applied in order to study the composition and distribution of plasma membrane carbohydrate residues in 83 primary cutaneous melanomas (MMs) and in 85 melanocytic nevi (MN) with the avidin-biotin peroxidase technique. No clear-cut differences between MN and MMs were observed with regard to the staining with lectins. In MN and MMs derived from different patients, the lectin-binding pattern was variable and heterogeneous even within the individual nevi or melanomas. It seems reasonable, therefore, to assume that the lectin-binding pattern cannot be regarded as a reliable histochemical marker for the differentiation of MN from MMs. Moreover, because the pattern reveals no statistically significant correlation with the thickness or the depth of invasion of MM, it seems to lack prognostic significance.     

Expression of neurotrophin receptor Trk-C in nevi and melanomas

BACKGROUND: Neurotrophins (NTs) are growth factors for neurons and other neural crest-derived cells. Their functions are mediated by 75-kDa low-affinity glycoprotein receptor (p75) NT receptor and a family of tyrosine kinase receptors (Trks) that includes Trk-A, -B, and -C. Signal transduction through the Trk receptors has been shown to regulate growth and apoptosis of tumors of neuronal origin. In addition, Trk oncogenes have been shown to be rearranged in some non-neuronal neoplasms. Recently, immunoexpression of NT-3 has been shown to be significantly higher in melanomas than in banal nevi on cryostat tissue. METHODS: Since the biologic function of NT-3 is mediated primarily through Trk-C, we investigated Trk-C immunoexpression on paraffin sections of 10 compound nevi and 63 melanomas. RESULTS: The expression of Trk-C was relatively low in compound nevi (30%). Trk-C expression was overall 62% in melanomas of various stages. Our data show that the expression of Trk-C increased as melanoma progressed from in situ (58%) to papillary dermal invasion (91%), and then declined in deeper (57%) and metastatic melanomas (31%). CONCLUSION: These findings suggest a possible role of Trk-C in the progression of early stages of melanoma.     

Mode of c-myc protein expression in Spitz nevi, common melanocytic nevi and malignant melanomas

The expression of c-myc protein was studied in formalin-fixed, paraffin-embedded sections of 16 compound Spitz nevi (SNs), 20 ordinary compound melanocytic nevi (MNs) and 30 malignant melanomas (MMs), using monoclonal antibody 9E10 and an immunoperoxidase technique. Nine (56%) SNs, 16 (80%) MNs and 23 (77%) MMs showed positive reactions in some of the tumor cells (P = non-significant). The staining reactions were mostly cytoplasmic, and moderate to strong in intensity. The frequencies of positively stained cells were higher in the MN and SN groups. Most of the lesions with a significant dermal component did not show stratification of staining with progressive descent into the dermis. Therefore, the mode of expression of c-myc in routinely processed specimens does not differentiate between SNs, MNs and MMs. One possible reason is that the increased expression of the c-myc protein is not sufficient alone to promote proliferation and malignant transformation in these types of tumors.     

Immunohistochemical expression of BCL-2 in melanomas and intradermal nevi

The BCL-2 gene is the prototype of a newly described family of oncogenes involved in tumorigenesis by blocking apoptosis, or programmed cell death. Overexpression of BCL-2 protein was originally described in follicular B-cell lymphomas bearing the 14;18 translocation. BCL-2 overexpression has also been described in other lymphomas and more rarely in neoplasms outside the lymphoid tissue. The aim of this paper is to determine the immunohistochemical expression of BCL-2 in intradermal nevi and primary invasive and metastatic melanoma. Formalin-fixed and paraffin-embedded tissues from 4 cutaneous melanoma metastases, 10 primary invasive melanomas, and 10 intradermal melanocytic nevi were immimolabeled with monoclonal antibodies directed against BCL-2 protein (Dako, clone 124) and Ki-67 antigen (Amac, clone MIB-1), after antigen retrieval techniques. Morphologically normal epidermal melanocytes expressed BCL-2, as did nevi and melanomas in virtually all cells. However, whereas the labeling in normal melanocytes and nevus cells showed a uniformly strong reactivity, melanoma cells showed a variable but mainly weak reactivity. Ki-67 antigen expression was restricted to melanomas. The widespread expression of BCL-2 suggests that this onco-protein cannot be involved in the malignant transformation of melanocytic cells. It seems likely that the decreased BCL-2 expression detected in melanomas may reflect one further step of tumor progression in melanocytic neoplasms.     

Immunohistochemical expression patterns of the microRNA-processing enzyme Dicer in cutaneous malignant melanomas, benign melanocytic nevi and dysplastic melanocytic nevi

Dicer is an essential cytosolic enzyme necessary for processing pre-microRNAs into mature microRNAs (miRNAs). Although a variety of malignancies have been attributed to perturbations in the miRNA machinery, there has been little research conducted on the role of miRNAs in cutaneous malignant melanoma and its premalignant lesions. In this small pilot study, we therefore investigated the distribution of Dicer by immunohistochemistry in cutaneous malignant melanomas, as well as in benign and dysplastic melanocytic nevi. Dicer was assessed in ten cutaneous malignant melanomas (CMM), benign melanocytic nevi (BMN), and dysplastic melanocytic nevi (DMN), by standard immunohistochemical staining. Semiquantitative analyses determined expression indices (EIs), which associate the conventional area fraction of labeled cells with immunostaining intensity scores, based on visual qualitative examination by two independent observers. Mean EI scores were significantly higher in the CMM group compared to those in the BMN group (p??0.05). For CMM we observed a significant correlation of Breslow tumor thickness and Dicer EI (r = 0.84, p = 0.022). For all three groups investigated, Dicer-positive staining was primarily located in the epidermis, specifically in melanocytes. By immunohistochemistry, Dicer staining was significantly higher in melanoma cells than in benign melanocytes. This preliminary study indicates that alterations in the miRNA machinery could exist and should be subject of further investigation.