The T1796A mutation of the BRAF gene is absent in Spitz nevi

BACKGROUND: BRAF, a serine/threonine kinase, is a component of the retrovirus-associated sequence (RAS)-RAF-extracellular-regulated protein kinase (ERK)-MAP kinase signal transduction pathway mediating signals from RAS to ERK. The T1796A single point mutation in exon 15 of the BRAF gene has recently been reported in a high percentage of malignant melanomas and benign melanocytic lesions such as congenital nevi, compound nevi, intradermal nevi and dysplastic nevi. The T1796A mutation has been shown to promote cell proliferation. METHODS: We screened 21 Spitz nevi and six spitzoid malignant melanomas for the presence of the T1796A BRAF mutation. RESULTS: The T1796A BRAF mutation could not be detected in any of the 21 Spitz nevi but was present in two of the six spitzoid malignant melanomas. CONCLUSIONS: Our results, in conjunction with data from a previous investigation, suggest that the melanocytic proliferation of Spitz nevi might be induced by components of the RAS-RAF-ERK-MAP kinase pathway different from BRAF, possibly combined with other genetic aberrations. The lack of the T1796A BRAF mutation might be of practical importance in distinguishing Spitz nevi from other melanocytic lesions simulating Spitz nevi as a part of a future complex diagnostic assay.     

Cdc7 expression in melanomas, Spitz tumors and melanocytic nevi

Background:  Cdc7 is a serine-threonine kinase required for initiation of DNA replication that may play a role in the development and progression of melanoma.
Materials and Methods:  Tissue microarrays containing 40 melanomas, 40 Spitz tumors and 30 nevi were constructed. Staining for Cdc7 was scored semiquantitatively according to intensity and extent, and the values were converted into composite scores.
Results:  Nodular melanomas, atypical Spitz tumors and superficial spreading melanomas had the highest scores (nodular melanomas, 3.67; atypical Spitz tumors, 2.78 and superficial spreading melanomas, 2.44). Typical Spitz nevi, dysplastic nevi and ordinary nevi had the lowest scores. Cdc7 expression in melanomas differed significantly from non-Spitz nevi (p < 0.001). The difference was also significant when invasive melanomas were compared with dysplastic nevi (p < 0.005) and when invasive melanomas were compared with non-atypical Spitz nevi (p < 0.001). However, there was no significant difference between invasive melanomas and atypical Spitz tumors (p = 0.69) or between dysplastic nevi and ordinary nevi (p = 0.73).
Conclusion:  Cdc7 expression differs significantly among cutaneous melanocytic neoplasms and can be evaluated by routine immunohistochemical methods. The results suggest that differences in Cdc7 expression may account for some of the differences between malignant melanomas and benign melanocytic nevi.     

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.     

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.     

Apoptosis, Fas and Fas-ligand expression in melanocytic tumors

Impaired regulation of apoptosis is known to be associated with the development of various forms of cancer. Fas binding to its ligand, Fas ligand (Fas-L), has been shown to trigger apoptosis in various cell types. Fas-L is expressed by melanoma cells and has been suggested to play a role in melanoma escape from immune surveillance. In the present study, we assessed apoptotic activity and examined Fas and Fas-L expression in malignant melanomas, Spitz nevi and ordinary melanocytic nevi. We evaluated apoptotic activity using terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling. Apoptotic activity was found to be minimal in melanomas and moderate in Spitz nevi. In contrast, common nevi demonstrated significant levels of apoptosis in the deep parts of the tumor. Fas was found to be expressed by all Spitz nevi, most melanocytic nevi and approximately half of the malignant melanoma specimens. Fas expression was also significantly more pronounced in Spitz nevus cells as compared with the two other tumors. The anti-Fas-L antibody was found to stain all three melanocytic tumors. Staining was shown to be stronger and more frequent in melanoma cells as compared to the nevus cells. Using the Spearman test, no significant correlation between Fas-L expression in melanoma cells and apoptosis in MM-infiltrating mononuclear cells was found, suggesting that Fas-L expression in melanoma cells may not be instrumental in their ability to escape immune mechanisms of defense. In contrast, increased levels of apoptosis in the deep parts of melanocytic nevi may reflect and possibly contribute to their benign nature.     

Cadherin expression pattern in melanocytic tumors more likely depends on the melanocyte environment than on tumor cell progression

BACKGROUND: Adhesion molecules have been assigned an important role in melanocytic tumor progression. By the loss of E-cadherin, melanocytes might escape the control of neighbouring keratinocytes. Although in vitro data support this hypothesis, there are yet no conclusive immunohistochemical results on cadherin expression in melanocytic tumors. OBJECTIVE: To gain detailed insight in the expression of cadherins and their cytoplasmic binding partners, the catenins, in various types of benign and malignant melanocytic neoplasms. METHODS: Immunohistochemical analysis of the expression of E-, P-, and N-cadherin and alpha-, beta-, and gamma-catenin in compound and dermal nevi, Spitz nevi, blue nevi, ultraviolet B (UVB)-irradiated nevi, and malignant melanomas of various tumor thickness. RESULTS: In both nevi and melanomas, E-cadherin expression in melanocytic cells decreased, following a gradient from junctional to deeper dermal localization. The pattern of E-cadherin expression was more heterogeneous in melanomas than in nevi. In some melanomas, E-cadherin was only weakly positive in the epidermal tumor cells. P-cadherin expression was similar to that of E-cadherin. N-cadherin expression in melanocytic lesions was a rare finding, however, a small percentage of melanomas showed expression in some cell nests. Some Spitz nevi exhibited strong N-cadherin immunoreactivity. Most melanocytic cells were alpha- and beta-catenin-positive and gamma-catenin-negative. UVB irradiation did not influence the expression of cadherins and catenins in melanocytic nevi in vivo. CONCLUSIONS: It is presumed that the gradual loss of E-cadherin expression represents a reaction of melanocytic cells to altered conditions in the dermal environment, e.g. lack of contact to keratinocytes, or new contact with dermal extracellular matrix molecules, respectively. Melanoma cells apparently are less dependent on these environmental factors and, therefore, show a more heterogeneous expression pattern. This might be of importance for the adaptation of the tumor cells to local requirements. However, in view of our results, a causative role of (loss of ) E-cadherin or (gain of ) N-cadherin for melanocytic tumor progression still remains to be proven.     

Comparison of pHH3, Ki-67, and survivin immunoreactivity in benign and malignant melanocytic lesions

Differentiating malignant melanoma from benign melanocytic lesions can be challenging. We undertook this study to evaluate the use of the immunohistochemical mitosis marker phospho-Histone H3 (pHH3) and the proliferation markers Ki-67 and survivin in separating malignant melanoma from benign nevi. Sixty-six melanocytic lesions (18 malignant melanomas, 8 Spitz nevi, 20 dysplastic nevi, and 20 compound nevi) were stained with antibodies to pHH3, Ki-67, and survivin. No pHH3 expression was detected in the dermis of compound and dysplastic nevi. Rare mitoses were observed in the superficial dermis in 3 of 8 Spitz nevi (37%). Staining for pHH3 was higher in malignant melanomas [average 25 per 10 high-power field (HPF), range 2-75 per 10 HPF] than in Spitz nevi (average 0.5 per 10 HPF, range 0-2 per 10 HPF) and was heterogeneously distributed in the malignant melanomas compared with a superficial dermal location in Spitz nevi. There was no cytoplasmic staining for survivin in any of the 66 melanocytic lesions and no nuclear staining in any of the benign ones. Survivin nuclear staining was present in 12 of 18 cases of malignant melanoma (67%) with an average index of 7% (range 0%-15%). In benign melanocytic lesions, the Ki-67 index was less than 5% (range 0%-4%) and staining was present close to the dermo-epidermal junction compared with an average index of 27% in melanomas (range 5%-50%) and a generally heterogeneous pattern of staining throughout the dermis. pHH3 and Ki-67 can be useful adjuncts to histopathology to separate malignant melanoma from benign nevi. pHH3 is especially useful to highlight mitoses and to rapidly assess the mitotic activity in melanocytic lesions.     

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.     

Cyclin D1 overexpression in Spitz nevi: an immunohistochemical study

The morphologic distinction between Spitz nevus and malignant melanoma can be difficult. Because cyclin D1 has been reported to be overexpressed in malignant melanomas, but not in common acquired nevi, we hypothesized that cyclin D1 might be a useful marker to distinguish Spitz nevi from malignant melanoma. Thus, we assessed for cyclin D1 expression in 11 Spitz nevi (10 compound and 1 intradermal) and 9 malignant melanomas (4 Clark stages I-III and 5 Clark stages IV-V) using an immunohistochemical method and routinely fixed and processed tissues. The cyclin D1 results were arbitrarily divided into three groups: 0% to 10%, >10% to 25%, and >25%. We confirmed the observations reported previously by others that cyclin D1 is expressed in malignant melanomas but not in common acquired nevi. Unexpectedly, a relatively high number of cyclin D1-positive cells (i.e., >10%) was also found in all cases of Spitz nevus. However, unlike malignant melanoma, the cyclin D1 positivity in Spitz nevi was present in a zonal pattern. In other words, the number of cyclin D1-positive cells decreased as the lesion extended more deeply, with the number of positive cells in the reticular dermis being less than that in the papillary dermis. Fluorescence in situ hybridization methods were used to assess amplification of 11q13, the locus harboring the cyclin D1 gene, in four cases of Spitz nevus; all were disomic. Using the antibody MIB-1, we compared cyclin D1 expression to the proliferation rate in Spitz nevi. Despite the high cyclin D1 positivity, all Spitz nevi had a relatively low number of MIB-1-positive cells (mean=3.2%), which was significantly lower than that of malignant melanomas (mean=15.3%) (p < 0.001). Thus, unlike malignant melanoma, there appears to be a dissociation between cyclin D1 overexpression and cell proliferation in Spitz nevi.     

Expression of polycomb group protein EZH2 in nevi and melanoma

BACKGROUND: Enhancer of zeste homolog 2 (EZH2), a polycomb group protein that regulates the cell cycle, has recently been implicated in the progression of several human cancers. We sought to determine the pattern of EZH2 expression in benign and malignant melanocytic tumors to see if EZH2 might play a role in melanoma pathogenesis and progression. METHODS: We identified and reviewed 11 compound nevi, 13 dysplastic nevi, 13 Spitz nevi, 9 in situ melanomas, 10 non-metastatic invasive melanomas and 19 melanomas metastatic to lymph nodes from the University of Michigan pathology archives. Sections immunostained with anti-EZH2 antibody were scored independently and blindly for staining intensity on a scale of 1-4 by three dermatopathologists. Results were analyzed and compared statistically. RESULTS: We observed an incremental increase in EZH2 expression from benign nevi to melanoma: scores of 1.18 and 1.08 for ordinary and dysplastic nevi, 1.7 and 1.78 for Spitz nevi and in situ melanoma, and 1.9 and 3.0 for invasive and metastatic melanoma, respectively. EZH2 expression for metastatic melanoma was significantly higher compared with invasive and in situ melanoma and benign nevi (p < or = 0.01). CONCLUSIONS: EZH2 protein levels increase incrementally from benign nevi to melanoma, which suggests that EZH2 may play a role in the pathogenesis and progression of melanoma.     

PTEN expression in normal skin, acquired melanocytic nevi, and cutaneous melanoma

BACKGROUND: Although various studies have shown mutations of the tumor suppressor gene, PTEN/MMAC1, in primary, metastatic, and cultured cutaneous melanoma specimens, little is known about the pattern of PTEN protein expression in early melanocytic tumor progression. OBJECTIVE: To further investigate the role of PTEN in melanocytic tumor development. METHODS: We assessed the level and distribution of PTEN in normal skin, 39 acquired melanocytic nevi, and 30 primary cutaneous melanomas, including lentigo malignas, by immunostaining. RESULTS: We found high levels of PTEN expression in cutaneous muscles, nerves, and muscular arteries, and moderate-to-high amounts of PTEN in the epidermis, follicular epithelium, and sebaceous and eccrine glands. PTEN staining in cutaneous lymphatics, dermal and periadnexal adventitial fibroblasts, and chondrocytes were variably absent. Junctional melanocytes and chondrocytes frequently exhibited preferential nuclear staining. We found uniformly strong PTEN expression in the cytoplasm of almost all benign and dysplastic nevi. However, there was some evidence of nuclear PTEN loss even in the benign melanocytic proliferations. In addition, out of 30 primary cutaneous melanomas and lentigo malignas, we detected diffuse expression of PTEN in 11 (37%) tumors, widespread loss of PTEN in 11 (37%) tumors and mixed PTEN expression in 8 (27%) lesions. In the primary cutaneous melanomas, PTEN was largely localized to the cytoplasm. CONCLUSIONS: The presence of PTEN in benign melanocytic tumors and the absence of PTEN in a significant proportion of primary cutaneous melanomas support a role for PTEN loss in the pathogenesis of melanoma.     

HMB-45 staining in benign and malignant melanocytic lesions. A reflection of cellular activation.

The antibody HMB-45 used as an immunohistochemical reagent has often been labeled as a marker for melanoma, even though some benign lesions have been noted to show positive staining reactions with this reagent. Biopsy specimens from 225 benign and malignant melanocytic lesions were examined after immunoperoxidase staining for S-100 protein and HMB-45. The lesions studied included common acquired nevi, spindle cell and epithelioid cell nevi (Spitz nevi), cellular blue nevi, deep penetrating nevi, congenital nevi, nevi from hormonally reactive areas (genital), malignant melanoma, and desmoplastic malignant melanoma. A positive reaction for HMB-45 was seen in the dermal component in a high percentage of each of these types of lesions except for the common acquired nevi and the desmoplastic malignant melanomas that were uniformly negative for HMB-45 in the dermal component. HMB-45 correlates with melanosome production and thus a melanocytic origin of HMB-45-positive cells. HMB-45 may correlate best with factors that stimulate melanocytic proliferation and production of melanosomes.     

IMP‐3 expression in melanocytic lesions

Background: Insulin‐like growth factor‐II mRNA‐binding protein 3 (IMP‐3 ), a member of the insulin‐like growth factor mRNA‐binding protein family, is expressed in several human malignancies, including melanomas. However, the expression of IMP‐3 has not been explored in melanoma in situ, various histologic subtypes of invasive melanomas and atypical Spitz tumors. Methods: IMP‐3 immunostain was performed in 157 melanocytic lesions. Results: Nearly all benign (8/8), dysplastic (8/8) and Spitz nevi (8/9) were negative for IMP‐3. Focal IMP‐3 positivity was observed in 5/12 melanoma in situ and 4/15 superficial melanomas (Breslow depth ≤1 mm). Half (10/20) of deep melanomas (Breslow depth >1 mm) and 25/52 metastatic melanomas demonstrated strong IMP‐3 staining. IMP‐3 expression differs significantly between non‐desmoplastic melanomas (superficial and deep) and benign or dysplastic or Spitz nevi (p = 0.0427, respectively). Four of 23 desmoplastic melanomas expressed IMP‐3 , which was significantly different from deep melanomas (p = 0.0109). IMP‐3 stained 7 of 10 atypical Spitz tumors. The difference between atypical Spitz tumors and Spitz nevi was statistically significant (p = 0.0256). Conclusion: A malignant circumstance, such as non‐desmoplastic melanoma or atypical Spitz tumor, can be inferred when IMP‐3 is expressed, suggesting potential diagnostic value of IMP‐3 in melanocytic lesions. Yu L, Xu H, Wasco MJ, Bourne PA, Ma L. IMP‐3 expression in melanocytic lesions.     

Distinctive eosinophilic cytoplasmic inclusion bodies in melanocytic nevi: an immunohistochemical and ultrastructural study

Background: We sought to further determine the histochemical, immunohistochemical and ultrastructural properties of eosinophilic cytoplasmic inclusion bodies in melanocytic nevi. Methods: Skin specimens from four patients with a known diagnosis of conventional melanocytic nevus (3) or Spitz nevus (1) and containing intracytoplasmic eosinophilic inclusion bodies were selected. In addition, melanomas (25), Spitz nevi (10) and blue nevi (4) were examined to determine the frequency of the inclusions. Results: Inclusions tended to be located in multinucleated melanocytes with abundant vacuolated cytoplasm. In conventional (hematoxylin and eosin‐stained) sections, the degree of density and eosinophilia of intracytoplasmic inclusions varied with size. Periodic acid‐Schiff, Fontana and Congo red stains showed no reactivity. All bodies were immunoreactive for ubiquitin but negative for tyrosinase, keratin and vimentin. Ultrastructurally, inclusion bodies were non‐membrane bound, ranged from 4 to 7 µm, and were comprised of radiating filamentous structures with or without an electron‐dense core. Electron probe x‐ray microanalysis revealed no significant peaks. None of additional melanomas, Spitz nevi and blue nevi that were evaluated showed similar inclusions. Conclusions: The inclusion bodies described herein bear no resemblance to other cytoplasmic inclusion bodies previously described in melanocytic lesions. There is no discernible relationship to melanosomes by ultrastructural analysis. We postulate a relationship with dysfunction of ubiquitin‐mediated protein degradation occurring in melanocytes. Shon W, Wada DA, Gibson LE, Flotte TJ, Scheithauer BW. Distinctive eosinophilic cytoplasmic inclusion bodies in melanocytic nevi: an immunohistochemical and ultrastructural study.     

Genome profiling of melanocytic tumors using multiplex ligation-dependent probe amplification (MLPA): Its usefulness as an adjunctive diagnostic tool for melanocytic tumors

BACKGROUND: The histopathology of melanocytic tumors sometimes presents diagnostic problems. Applicable parameters other than routine pathology are needed. OBJECTIVE: We assessed the feasibility of multiplex ligation-dependent probe amplification (MLPA), a novel PCR-based genome profiling method, in the classification of melanocytic tumors. METHOD: We extracted DNA from paraffin-embedded tissue sections of 24 primary melanomas, 14 Spitz nevi and 17 common melanocytic nevi. We analyzed the copy number gains or losses of a total of 76 genes spanning almost all chromosome arms using commercially available MLPA kits. RESULTS: Although four melanocytic nevi and three Spitz nevi did not yield sufficient DNA for reliable analysis due to small tumor size, the MLPA analysis was feasible and applicable to the remaining 88% of samples. We found multiple genetic aberrations in primary melanomas. The total number of aberrations in each tumor ranged from 1 to 32 (average, 12.04). All but two melanomas showed aberrations at more than three genetic loci. Seventeen (70.8%) of the 24 melanomas showed a copy number loss of either the CDKN2A or CDKN2B gene on chromosome 9p21. All the Spitz nevi and 7 (50%) of 14 common melanocytic nevi had copy number changes at one or two gene loci (average, 1.04). The receiver operator characteristic curve analysis showed that the threshold value of copy number aberrations corresponding to 98% specificity for melanoma was 2.42 and the sensitivity using this threshold value was 92.5%. CONCLUSIONS: MLPA could be used as an adjunctive diagnostic tool for melanocytic tumors.     

Expression of p-27 (kip1) in nevi and melanomas

Histopathologic criteria are usually sufficient for the accurate distinction of benign from malignant melanocytic lesions of the skin. A minority of cases, however, particularly Spitz nevi, continue to pose a vexing diagnostic challenge. Recent research, however, suggests that p27 (kip1), a cell cycle inhibitory protein, may prove helpful in predicting the biologic behavior of a diverse array of human neoplasms. We analyzed 63 melanocytic lesions of the skin (21 Spitz compound nevi, 21 compound nevi, 21 melanomas, and a variety of other benign and malignant cutaneous neoplasms as a control group) for expression of p27 (kip1). The distribution of immunoreactivity was analyzed by quantifying nuclear staining in each case without knowledge of the diagnosis or outcome. Clinical history and follow-up information were obtained by chart review. There was no difference in the expression of p27 between Spitz nevi (labeling index=38.4+/-4.0), compound nevi (labeling index=40.1+/-4.8), and melanoma (labeling index=42.3+/-5.1). Logistic regression failed to show any difference in p27 labeling index between the nevi and melanoma (p=0.736). These results indicate that antibodies to p27 are not useful in distinguishing between these melanocytic lesions.     

Differential expression of ras oncogene products among the types of human melanomas and melanocytic nevi

Ras oncogene expression of malignant melanoma and melanocytic nevus have been immunohistochemically analyzed on formalin-fixed and paraffin-embedded tissues from 26 melanomas and 24 melanocytic nevi with a monoclonal antibody that was generated against Harvey sarcoma virus-derived ras oncogene products (p21ras). We found distinct differences of p21ras expressions by the type of melanoma. Nodular melanoma, epithelioid cell type melanoma, and deeply invading melanoma revealed higher reactivity with anti-p21ras monoclonal antibody than the other types. The reactivity of melanomas appeared to correlate with the degree of malignancy of the melanoma. It was also demonstrated, however, that part of melanocytic nevi reacted with anti-p21ras monoclonal antibody with a relatively strong intensity. Melanocytic nevi with junctional activity and nevus cells located in the epidermis in compound nevi did not show the positive reaction in contrast to dermally located nevus cells that had relatively strong reactivity. The different p21ras expression among the type of tumors may represent the state of tumor cells differentiation with greater expression with more immaturity in the melanocyte lineage. p21ras expression does not appear to represent a marker of malignant transformation.     

A comparative immunohistochemical study of MART-1 expression in Spitz nevi, ordinary melanocytic nevi, and malignant melanomas

BACKGROUND: The histopathologic differential diagnosis of Spitz nevus (SN) from malignant melanoma (MM) may be difficult. OBJECTIVE: We attempted to elucidate the pattern of expression of a newly recognized melanocyte-specific melanosomal protein MART-1 in routinely processed specimens of SNs, MMs, and ordinary melanocytic nevi (MNs) and to see whether it can help to differentiate between them. METHODS: Twenty SN, 22 MM, and 27 ordinary MN were immunostained with anti-MART-1 monoclonal antibody (clone A103). RESULTS: All SNs, MNs, and MMs demonstrated cytoplasmic staining for MART-1 in some of their tumor cells, of which 17 of 20 (85%) and 24 of 27 (89%) of SN and MN, respectively, demonstrated positive stainings in more than half of their tumor cells, as compared with only 10 of 22 (45%) of the MM (P <.05). The majority of lesions in all 3 types of tumors showed a homogeneous mode of staining, although MM tended to show a more heterogeneous pattern. A consistent pattern of stratification of staining with progressive descent into the dermis was not demonstrated in these tumors. CONCLUSION: MART-1 does not differentiate between SN, MM, and ordinary MN in a consistent pattern, but it may be used as a marker for these tumors.