Spitz nevi and atypical Spitz nevi/tumors: a histologic and immunohistochemical analysis.

A subset of Spitz nevi poses substantial diagnostic difficulty, even among experts, due to its resemblance to malignant melanoma. These lesions are termed atypical Spitz nevi/tumors and there is currently a lack of objective criteria for predicting their biologic behavior. We compared the expression of Ki-67, p21, and fatty acid synthase by immunohistochemistry in 10 atypical Spitz nevi, 28 typical Spitz nevi, 19 compound melanocytic nevi and 18 invasive malignant melanomas. There was a progressive increase in fatty acid synthase cytoplasmic expression with statistically significant differences observed between Spitz nevi and atypical Spitz nevi (P=0.003) and between atypical Spitz nevi and malignant melanoma (P<0.050). Ki-67 nuclear staining was lower in both typical and atypical forms of Spitz lesions than in malignant melanoma (P<0.001). The degree of P21 nuclear expression in atypical Spitz nevi was not significantly different than in Spitz nevi, but was significantly greater than expression in conventional nevi and approached significance after multiple comparisons corrections for malignant melanoma. Thus, a high level of P21 expression makes a tumor more likely to be a typical or atypical Spitz nevus than a malignant melanoma, especially when coupled with a low Ki-67 index and weak expression of fatty acid synthase. These immunohistochemical observations support the concept that atypical Spitz nevi are distinct lesions of borderline biologic behavior residing between Spitz nevi and malignant melanoma. The study also compared a large array of histologic features of 16 cases of typical Spitz nevi in children with 12 typical Spitz nevi in adults. The adult lesions were significantly more likely to be intradermal and to display dermal fibroplasia, but were histologically similar to their pediatric counterparts in all other respects.     

Utility of p16-Ki-67-HMB45 score in sorting benign from malignant Spitz tumors

When Spitz nevi have increased vertical thickness (>1.0 mm), show ulceration and deep seated mitoses, the differential diagnostic considerations of atypical Spitz tumor (AST) or a Spitzoid melanoma (SM) enter into consideration. While molecular genetic testing could be employed in the work up of atypical melanocytic proliferations, they are expensive and not available at all institutions. Recently, one study employed the combination of p16, Ki-67 and HMB45 (PKH) immunohistochemistry on adult melanomas and proposed a combination of the three markers with scoring of their result to support a diagnosis of melanoma. We report the utility of this antibody combination scoring in discriminating SM and AST in children. We retrospectively reviewed 30 Spitzoid lesions (7 SM, 9 AST and 14 Spitz nevi) from children. Slides from H&E staining and Immunohistochemistry for p16, Ki-67 and HMB45 were reviewed for all cases. The extent of immunohistochemical expression in the lesional cells was scored following published criteria as follows: p16 scored as 0, 1, 2, 3; Ki-67 scored as 0, 1, 2, 3, 4 and HMB45 scored as 0, 1 and 2. Thus, the total PKH score for the combination of the 3 antibodies for any case could vary from 0 to 9. The result of the immunohistochemical analysis of cases in our study revealed that the PKH score of Spitz nevus and AST was below 4 for each of the case and that of SM was >4 for each of the case. These results are significant as the previously published study found that the PKH score of equal/or >4 correlated with melanoma and less <4 correlated with benign nevi. Independently, the immunostains could be misleading as Ki-67 labeling index tended to be higher in young children (<2 years of age) and HMB45 was occasionally negative in both AST and SM, and p16 could be completely lost in AST.Our study replicates the findings of the published study of adult melanomas and nevi that showed a total PKH score of equal/or>4 is seen in melanoma. Although, the number of SM cases in our study are few, the PKH scoring pattern of malignant and benign cases was congruent with the adult study. We suggest routine use of PKH immunohistochemistry in the work up of atypical Spitzoid lesions in children.     

Sentinel lymph node biopsy for patients with diagnostically controversial Spitzoid melanocytic tumors?

The distinction of a Spitz nevus from melanoma can be very difficult. Pathologists may disagree on whether a Spitzoid melanocytic proliferation is benign or malignant, or acknowledge uncertainty about the diagnosis. As long as melanoma is suspected or strongly considered, a clinical management plan is often adopted as if the patient had melanoma, which may include sentinel lymph node (SLN) biopsy for staging. The findings of the sentinel node may resolve the diagnostic controversy about the primary tumor, but there is also the risk for more diagnostic confusion, uncertainty, and errors. We review the arguments in favor and against SLN biopsy for patients with diagnostically controversial Spitzoid melanocytic tumors, summarize current experience, and illustrate diagnostic pitfalls. Although SLN biopsy provides prognostic information helpful for clinical trials, we caution against performing the procedure as a diagnostic adjunct.     

BRAF and NRAS mutations in spitzoid melanocytic lesions.

BRAF mutations are common events in a variety of melanocytic nevi and primary cutaneous melanomas. We have previously found BRAF mutations in 82% of nevi, consisting of congenital, common acquired and dysplastic types, and 33% of primary cutaneous melanomas other than the spitzoid type, similar to other published reports. A small number of studies have evaluated Spitz nevi and have failed to detect any lesions possessing a BRAF mutation. Only one study included categories of atypical Spitz nevus and borderline lesions suspected to be spitzoid melanomas, along with classic Spitz nevi and spitzoid melanomas. We examined a spectrum of spitzoid lesions that included 48 Spitz nevi, some with atypical features, seven atypical (borderline) Spitz tumors, and 13 spitzoid melanomas. BRAF mutations were detected in 12 of 68 spitzoid lesions, of which two were spitzoid melanomas and 10 were Spitz nevi. Five of the 10 Spitz nevi with BRAF mutations were altered by more than usual cytologic atypia and/or architectural atypia overlapping with dysplastic nevi, or irritation/inflammation; one desmoplastic Spitz nevus had a BRAF mutation. These results indicate that a small subset of Spitz nevi, some with atypical histologic features, possess BRAF mutations. Therefore, the BRAF mutational status does not separate all Spitz nevi from spitzoid melanomas and non-Spitz types of melanocytic proliferations, contrary to previous reports.     

Melanocytic nevi simulant of melanoma with medicolegal relevance

A group of melanocytic benign nevi are prone to be misdiagnosed as nodular or superficial spreading melanoma. This review illustrates the most frequent forms of these nevi in direct comparison with their malignant morphologic counterparts. The nevi are: hyper-cellular form of common nevus to be distinguished from nevoid melanoma, Spitz nevus (vs spitzoid melanoma), Reed nevus (vs melanoma with features of Reed nevus), cellular atypical blue nevus (vs melanoma on blue nevus), acral nevus (vs acral melanoma), Clark dysplastic nevus (vs superficial spreading melanoma), desmoplastic nevi (vs desmoplastic melanoma), benign proliferative nodules in congenital nevi (vs melanoma on congenital nevi), epithelioid blue nevus (vs animal type melanoma) and regressed nevus (vs regressed melanoma). For each single ‘pair’ of morphological look-alikes, a specific set of morphological, immunohistochemical and genetic criteria is provided.     

Melanocytic nevi in children

Melanocytic nevi in children can be acquired or congenital. The vast majority are benign but diagnosis can be difficult. Nevi in newborns and nodular proliferations in giant congenital nevi can display histological features that lend to their misdiagnosis as melanoma. Acquired melanocytic nevi in children are often Spitz nevi or related nevi. These lesions are too often misdiagnosed as melanoma. On the other hand, clinicians and pathologists must be aware that melanoma does occur in childhood, albeit very rarely. It is exceptionally rare in prepubescent individuals. It can be associated with the following risk factors: giant congenital nevus, family history of melanoma, xeroderma pigmentosum, and immunosuppression. Melanoma in children younger than 10 years of age is extremely rare and has different clinical and histopathological features than those that arise in postpubescents, often being confused with a Spitz's nevus. Consequently, the diagnosis is often made too late. It should be emphasized that thickness is the main prognostic parameter in childhood melanoma and that early diagnosis is also crucial in this age group. The lesion must therefore be examined in a complete excision and not in a partial biopsy, and if atypical features are present it must be reviewed by an expert. On the other hand extreme caution should be exercised when diagnosing melanoma in children, as some benign lesions exhibit similar histologic features.     

Spitzoid malignant melanoma with lymph-node metastasis

Distinction of spitzoid malignant melanomas (SMM) from Spitz nevi may be difficult or even impossible on the basis of conventional histology. In this report, a patient suffering from a primary lesion diagnosed as a Spitz nevus and a metastatic malignant melanoma approximately 4 years thereafter is described. A diagnosis of SMM was made subsequently upon review of the primary lesion. In the present analysis, we used comparative genomic hybridization (CGH) to define markers characteristic of SMM. The primary lesion revealed deletions on chromosomes 6q and 9p. In the metastasis, additional deletions on chromosomes 10p and 10q and gains of chromosome 7 were found. To our knowledge, no chromosomal aberration on chromosome 6 was hitherto demonstrated in benign melanocytic nevi. Findings reported in the literature suggest that human melanoma metastasis suppressor gene maps to 6q. In contrast, losses on chromosome 9p seem to be an early event in the development of melanoma. However, they are not only found in melanomas but are occasionally present in Spitz nevi as well as in atypical nevi. The CGH result with deletion of 6q in this difficult to diagnose primary melanocytic lesion strongly supports the diagnosis of malignant melanoma. To demonstrate the reliability of loss on chromosome 6q as a marker of SMM, a larger number of lesions must be investigated.     

Immune-phenotypical markers for the differential diagnosis of melanocytic lesions

For specific subsets of melanocytic proliferations, there are morphologic limitations in the histological diagnosis, especially for borderline melanocytic tumors. In particular, Spitzoid proliferations can be difficult to diagnose. For these reasons, in the last years, clinic research has focusedattention on discovery of new diagnostic markers. Published gene expression and proteomic profiling data indicate new candidate molecules involved in melanoma pathogenesis, and useful in differential diagnosis of difficult melanocytic lesions. Recently, the diagnostic power of galectin-3 was demonstrated in series of melanocytic lesions, with a strong increasing of expression in malignant lesions compared with benign lesions. Similarly, the accumulation of Collagen XVII antibody was detected in vertical melanoma fronts and associated with invasive phenotype. Moreover, overexpression of cyclin D1 and p21 was detected in Spitz nevi compared with non-spitzoid melanomas; Ki-67 appears highly expressed in deep areas of non-spitzoid melanomas. In this review,werealizedan overviewofthe main molecular markersthat canbe a usefultoolfor the differential diagnosisofbenign, borderlineand malignant melanocytic lesions, related to their biological behavior, useful also for predicting the evolutionof the disease.     

Histologically ambiguous ("borderline") primary cutaneous melanocytic tumors: approaches to patient management including the roles of molecular testing and sentinel lymph node biopsy

It is well recognized that the pathologic diagnosis of melanocytic tumors can sometimes be difficult. For some atypical melanocytic tumors that do not display clear-cut features of malignancy, it may be difficult or impossible to exclude a diagnosis of melanoma; this includes those showing some resemblance to Spitz nevi, blue nevi, deep penetrating nevi, and possible nevoid melanomas. When there is uncertainty about whether a primary melanocytic tumor is a nevus or a melanoma, we recommend that a second opinion be sought from one or more experienced colleagues. If diagnostic uncertainty persists, the evidence for or against the various differential diagnostic considerations should be presented in the pathology report and a "most likely" or "favored" diagnosis given. Molecular testing of the primary tumor by using techniques such as comparative genomic hybridization or fluorescence in situ hybridization may assist in establishing a diagnosis of melanoma if multiple chromosomal aberrations are identified. However, these tests require further independent validation and are not widely available at present. Complete excision of the lesion is probably mandatory, but plans for further management should be formulated on a case-by-case basis. While the safest course of action will usually be to manage the tumor as if it were a melanoma (taking into account the tumor's thickness and other prognostic variables), this may not always be appropriate, particularly if it is located in a cosmetically sensitive site such as the face. In some cases, it may be appropriate for the surgical oncologist to convey the diagnostic uncertainty to patients and to present them with management choices so that they can decide whether they wish to be managed aggressively (as for a melanoma) or conservatively. While a sentinel lymph node biopsy may be recommended on the basis of the primary tumor characteristics, the clinical significance of lymph node involvement for these tumors is not yet clear, and it may not have the same prognostic implications as nodal involvement from an unequivocal "conventional" melanoma.     

High-resolution array-based comparative genomic hybridization for distinguishing paraffin-embedded Spitz nevi and melanomas.

Distinguishing between Spitz nevus and melanoma presents a challenging task for clinicians and pathologists. Most of these lesions are submitted entirely in formalin for histologic analysis by conventional hematoxylin and eosin-stained sections, and fresh-frozen material for ancillary studies is rarely collected. Molecular techniques, such as comparative genomic hybridization (CGH), can detect chromosomal alterations in tumor DNA that differ between these 2 lesions. This study investigated the ability of high-resolution array-based CGH to serve as a diagnostic test in distinguishing Spitz nevus and melanoma using DNA isolated from formalin-fixed and paraffin-embedded samples. Two of 3 Spitz nevi exhibited no significant chromosomal alterations, while the third showed gain of the short arm of chromosome 11p. The latter finding has previously been described as characteristic of a subset of Spitz nevi. The 2 melanomas showed multiple copy number alterations characteristic of melanoma such as 1q amplification and chromosome 9 deletion. This study has shown the utility of array-based CGH as a potential molecular test in distinguishing Spitz nevus from melanoma. The assay is capable of using archival paraffin-embedded, formalin-fixed material; is technically easier to perform as compared with conventional CGH; is more sensitive than conventional CGH in being able to detect focal alterations; and can detect copy number alterations even with relatively small amounts of lesional tissue as is typical of many skin tumors.     

S100A6 protein expression is different in Spitz nevi and melanomas.

The Spitz nevus is a benign melanocytic lesion that can be identified reliably in many cases by conventional histopathological criteria. However, there are subsets of Spitz nevi and of malignant melanoma that closely resemble each other and represent diagnostic challenges. S100 proteins are of interest because of their involvement in neoplastic processes and their genes are clustered in chromosome 1q21. Chromosome 1 contains mutations in several types of tumors, including melanomas. The expression of different S100 proteins (A2, A6 and A8/A9 or A12) was examined in 42 Spitz nevi, 105 melanomas, and 73 melanocytic nevi to test the hypothesis that their expression differs among these entities and may contribute to the distinction between these entities. The results showed an up-regulation of S100A6 protein in Spitz nevi, melanomas, and melanocytic nevi but with a different percentage of positivity and pattern of immunoreactivity. The differences between these three entities were statistically significant (P <.001). All 42 Spitz nevi (100%) showed strong and diffuse S100A6 protein expression, both in junctional and in dermal components of the nevi. Thirty-three percent of melanomas expressed S100A6 (35/105). The expression was mainly weak (30/35) and patchy in the dermal component and was negative or minimal in the junctional component. Fifty-six percent of different subtypes of melanocytic nevi (41/73) expressed S100A6, almost all of them weakly (40/41) and in the dermal component. Normal intraepidermal melanocytes were negative. The melanocytic cells in these three entities did not express S100A2, S100A8/A9 or A12. However, an up-regulation of S100A2 and S100A8/A9 or A12 proteins was observed in normal keratinocytes in the epidermis overlying Spitz nevi and melanomas, without differences. In summary, a simple immunohistochemical test for S100A6 protein differentiated between Spitz nevi, melanomas, and melanocytic nevi. This marker could be used when the distinction is very difficult or controversial in routine studies, especially when there is a junctional component. Further molecular analyses of the S100A6 protein and gene should be performed to study the underlying genetic bases for such differences.     

Subepidermal cleft formation as a diagnostic marker for cutaneous malignant melanoma

Cleft formation has been postulated as a clue to the histopathological diagnosis of malignant melanoma (MM). The frequency and reliability of clefts as a diagnostic criterion remain to be determined. We reviewed 503 cases of histologically proven MM searching for clefting between the epidermal layer and underlying MM. Cleft was defined as a separation of at least 0.3 mm in length. Conspicuous cleft formation was present in 120 (24%) of 503 MMs. The presence of clefts was not associated with age or sex of the patients, but showed a slight predilection for the back, a slightly higher prevalence in superficial spreading type of MM and for tumors with a Breslow thickness between 1 and 2 mm. Morphologically, clefts could be separated in 3 different types: linear (37.5%), single-nest (10.9%), and multi-nest (51.6%). In comparison, among 939 benign melanocytic lesions including 100 Spitz or Reed nevi, only 9 exhibited clefts longer than 0.3 mm (< 1%). One was an atypical compound nevus; all others were Spitz nevi, with the majority exhibiting an arched morphology above 1 or 2 large round nests. The relative frequency of cleft formation allowed a highly significant differentiation between MM and benign melanocytic lesions. Clefts are a reliable diagnostic criterion in favor of MM.     

Use of Bayes rule and MIB-1 proliferation index to discriminate Spitz nevus from malignant melanoma

Differentiating Spitz nevus from malignant melanoma is difficult and controversial. Despite helpful lists of differential diagnostic features, uncertainty about the diagnosis often provokes some to stain the tumor for MIB-1 antibody to Ki-67 and measure the proliferation index (PI) of the tumor. Of the many reports about MIB-1 PI in Spitz nevi and melanoma, none have consolidated the information to provide guidelines for the predictive probability that a lesion is a Spitz nevus, given that the MIB-1 PI falls into a certain interval. The present study used previously published data and exponential and gamma probability density functions to model statistical distributions of PI, respectively, in Spitz nevi and melanomas and Bayes rule to estimate the predictive probability that a lesion is a Spitz nevus, given an observed PI. Results indicate that PIs more than 10% favor a melanoma diagnosis and PIs less than 2%, Spitz nevus. PI values between 2% and 10% yield various predictive values for Spitz nevus, depending on the a priori probability that the lesion is a Spitz nevus. The algorithm tabulates guidelines for the predictive probabilities of Spitz nevus given an observed PI.     

Vascular endothelial growth factor expression in malignant melanoma: prognostic versus diagnostic usefulness.

Vascular endothelial growth factor (VEGF), an endothelial cell mitogen, plays a role in angiogenesis and progression in malignant melanoma. VEGF expression was examined in 62 biopsy specimens of melanocytic proliferations, including 45 malignant melanomas, 3 cellular blue nevi, 12 atypical compound nevi, and 2 Spitz nevi. The cases of malignant melanoma included 11 in situ melanomas, 18 Clark Level II, 9 Clark Level III, and 7 Clark Level IV tissue samples. All of the specimens were fixed in formalin and embedded in paraffin. Cytoplasmic immunoreactivity for VEGF was demonstrated in 19 (42%) of 45 melanoma samples, but there was no immunoreactivity for VEGF exhibited by any of the atypical compound melanocytic nevi, cellular blue nevi, or Spitz nevi (P < .009). Immunoreactivity for VEGF was found to be related to tumor thickness (as evidenced by Clark level [P < .03]) and to absence of regression (P < .04). Although VEGF is not a useful prognostic indicator for malignant melanoma, it may be useful as a discriminating factor between malignant melanoma and benign melanocytic lesions, and it may offer some insight into tumor growth.     

Sentinel lymph node biopsy in patients with "atypical Spitz tumors." A report on 12 cases

The distinction between Spitz nevus and melanoma is currently possible, applying a set of definite histological criteria. However, in certain lesions deviating from the stereotypical morphology of classic Spitz nevi ("atypical Spitz tumors"), the differentiation between benign and malignant cases appears problematic because objective criteria for a reliable diagnosis are lacking. We report the clinicopathologic findings of 12 patients with atypical Spitz tumors, who underwent sentinel node biopsy. All the tumors, composed of spindle and/or epithelioid cells, histologically showed features referable to Spitz nevi mixed to features generally found in malignant melanomas. Nine patients were females and three males, ranging in age from 2 to 48 years (mean, 23.2 years). The size of lesions ranged from 5 to 9 mm, the thickness from 1.12 to 5.70 mm. Nodal micrometastases were found in 4 (33.3%) patients. Among the patients with positive sentinel node, two showed minimal nodal involvements; one patient showed additional tumor deposits in one nonsentinel regional node. All patients are alive and free of disease with a follow-up of 2 to 90 months (mean, 26.3 months). Metastasizing and nonmetastasizing cases appeared clinically and histologically indistinguishable. The statistical analysis showed no significant difference between the two groups. Results suggested that all the reported cases may constitute a relatively homogeneous morphological group of lesions with a relevant metastatic potential that may be underdiagnosed.     

Dysplastic melanocytic nevus: Are molecular findings the key to the diagnosis?

The primary differential diagnosis of melanoma is dysplastic nevus. Until now, the final diagnosis is based on histological findings. With modern techniques, pathologists receive very early melanocytic lesions, which do not fit all malignant criteria. In those cases, even the concurrence between specialists and intraobserver agreement is not good. A molecular test could be developed to improve the accuracy of melanocytic lesions diagnosis and help in challenging lesions. The objective of this study is to provide a literary review looking for molecular markers that characterize dysplastic nevi and could help surgical pathologists differentiate them from melanoma. Articles from PubMed presenting case series of dysplastic nevi and melanoma genomic analyses were considered. The search was conducted in PubMed looking for papers written in English, published in the ten years preceding April 2020. This review confirmed the absence of a pathognomonic molecular marker of dysplastic nevi. This is a heterogeneous group of lesions with an uncertain risk to become a melanoma. The molecular heterogeneity of dysplastic nevi, the variation of histological diagnostic criteria among services, and the diverse molecular techniques applied are challenging features that might hamper definitive diagnoses. However, currently, there appears to be limited value for molecular testing in the diagnosis of dysplastic nevi.     

Spitz nevus and its histologic simulators

Spitz nevi continue to pose a considerable diagnostic challenge to the histopathologist. Key features of Spitz nevus and its variants are discussed and contrasted with the telltale signs of malignancy of "Spitzoid" melanomas. The importance of the histologic features of the deep, rather than superficial, part of the lesions is emphasized.     

Allelic imbalance in the diagnosis of benign,atypical and malignant Spitz tumours

To test the diagnostic usefulness of allelic imbalance (AI) analysis based on routinely paraffin-embedded tissue, a series of 55 benign Spitz naevi, Spitz tumours with uncertain malignant potential, and malignant Spitzoid melanomas was investigated. Laser microdissection was used to ensure representative sampling of lesional cells and to investigate AI in separate tumour areas of four melanomas. AI was found in 2/12 (17%) typical Spitz naevi, 3/9 (33%) atypical Spitz tumours, 12/17 (65%) atypical Spitz tumours suspicious for melanoma and 15/17 (88%) Spitzoid melanomas. Additional immunohistochemical staining for Ki-67 using the MIB-1 antibody revealed positive deeply situated lesional cells in 0/6 (0%) Spitz naevi, 1/8 (13%) atypical Spitz tumours, 5/14 (35%) atypical Spitz tumours suspicious for melanoma, and 7/14 (50%) Spitzoid melanomas, respectively. Two of the melanomas examined for AI in separate tumour areas showed intratumoural genetic heterogeneity. In view of the finding of AI and deeply situated Ki-67 positive cells not only in melanomas but also in Spitz tumours with uncertain malignant potential, these approaches appear to have no direct diagnostic applicability for the distinction between benign and malignant Spitz tumours. Further molecular studies will be required to determine whether Spitz tumours and Spitzoid melanomas are unrelated entities, or whether there is a true spectrum of tumour progression.     

Immunophenotype of tumor-infiltrating lymphocytes in atypical Spitzoid tumors according to the risk of progression

The aims of the study were to investigate and compare the immunophenotype of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in a series of benign, intermediate and malignant Spitzoid lesions showing marked inflammatory lymphoid component, to find out its possible relation with the prognosis of these lesions.Six out of 97 Spitz nevus (SN) (6 %), five out of 26 atypical Spitz tumors (AST) (16 %) and seven out of 37 Spitzoid melanomas (SM) (19 %) showed diffuse, intense inflammatory component and were included in the study. The biological risk of the tumors was assessed in all AST through the melanoma 4 probe-FISH assay and the 9p21 locus exploration. TILs were quantitatively immunophenotyped using CD3, CD4, CD8, CD20, TIA1, FOXP3 and PD1 antibodies. PD-L1 was assessed in tumoral cells and inflammatory cells adjacent to the tumor.No significant differences of TILs immunophenotype were found between SN, AST and SM. However, the classification of tumors according to the biological risk showed that grouped SN plus low-risk AST had a significantly higher number of T-cells CD8+ and TIA-1+, as well as a lower CD4/CD8 relation and B- lymphocyte number than high-risk of progression tumors (grouped high-risk AST plus SM). Immunoregulatory T-cell markers PD1 and FOXP3 only correlated with each other and with PD-L1 expression.In conclusion, The TILs immunoprofile differences between low-risk and high-risk of progression Spitzoid tumors, especially regarding CD8 and the cytotoxic immune response, can add prognostic information about these challenging tumors and impact the clinical management of patients.     

Expression of gamma-H2AX in melanocytic lesions

gamma-H2AX is a marker of activated DNA damage and is overexpressed in many malignancies and their precursor lesions. Previous studies have demonstrated the expression of gamma-H2AX in melanoma and dysplastic nevus, but its diagnostic and prognostic utility in a full range of melanocytic lesions has not been fully studied. In the current study, we investigated gamma-H2AX expression in a total of 162 melanocytic lesions. We found that gamma-H2AX was observed at higher levels (percentage and intensity of staining) in melanoma in situ (12/13), primary cutaneous melanoma (32/33; with the exception of desmoplastic melanoma), and metastatic melanoma (58/62), which was statistically different from that in benign nevus (7/9), dysplastic nevus (6/10), and Spitz nevus (5/9) considered together (P < .0001). Of note, desmoplastic melanoma (20/26) demonstrated weak or negative gamma-H2AX staining. The expression of gamma-H2AX did not show significant correlation with many melanoma prognostic factors, including Breslow depth, mitotic rate, and sentinel lymph node status. Except for desmoplastic melanoma, no difference in gamma-H2AX levels was observed among various melanoma subtypes. The overexpression of gamma-H2AX in melanoma as opposed to nevus indicates its possible role in melanomagenesis. Based on the overlap in subsets of nevi and melanomas, the potential clinical utility of this antibody remains uncertain until further studies have been carried out in a larger cohort of melanocytic lesions, including borderline cases.