p53 immunoreactivity in human malignant melanoma and dysplastic naevi

Expression of the tumour suppressor protein, p53, was determined in 77 cutaneous melanocytic lesions, and in five lymph node metastases from malignant melanoma, in an immunohistochemical study employing CM-1, an antiserum raised against recombinant human p53 protein. Because wildtype p53 protein is rapidly degraded in normal cells, p53 immunoreactivity suggests the presence of an abnormally stable p53 protein. This may occur through either post-translational mechanisms or gene mutation. A highly significant correlation was found between p53 immunoreactivity and malignancy in melanocytic lesions (P<0.0001). Overall, p53 immunoreactivity was observed in 63% of tumour specimens examined, but not in benign melanocytic naevi, although occasional foci of weak nuclear p53 immunoreactivity were observed in a minority of dysplastic naevi and a solitary Spitz naevus. A significant correlation was also found between strong p53 immunoreactivity and malignant melanomas associated with a poor prognosis (P=0.008). These data suggest an important role for p53 tumour suppressor protein in the biology of human cutaneous malignant melanoma.     

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.     

Evaluation of tumour-infiltrating CD4+CD25+FOXP3+ regulatory T cells in human cutaneous benign and atypical naevi, melanomas and melanoma metastases

BACKGROUND: CD4+CD25+FOXP3+ regulatory T cells (Tregs) are thought to induce immunotolerance in melanoma. They have not yet been investigated in the entire spectrum of melanocytic cutaneous lesions within a tumour site. OBJECTIVES: To evaluate CD4+CD25+FOXP3+ Tregs among tumour-infiltrating lymphocytes in cutaneous melanocytic lesions. METHODS: We analysed 128 lesions (10 benign junctional common naevi, 10 benign compound common naevi, 10 compound Spitz naevi, 10 junctional atypical naevi, 20 compound atypical naevi, 20 radial growth phase melanomas, 30 vertical growth phase melanomas and 18 melanoma metastases). Tregs were identified by CD25-FOXP3 double immunostains. RESULTS: This study indicates that CD4+/CD25+FOXP3+ Tregs are present in all groups of lesions. Junctional atypical naevi, compound atypical naevi and radial growth phase melanomas showed the highest percentages of CD4+CD25+FOXP3+ Tregs (junctional atypical naevi vs. junctional common naevi, compound common naevi, compound Spitz naevi, melanoma metastases: P < 0.0001; junctional atypical naevi vs. vertical growth phase melanomas: P = 0.001; compound atypical naevi vs. junctional common naevi, compound common naevi: P < 0.0001; compound atypical naevi vs. compound Spitz naevi, melanoma metastases: P = 0.002; compound atypical naevi vs. vertical growth phase melanomas: P = 0.02; radial growth phase melanomas vs. junctional common naevi, compound common naevi, compound Spitz naevi, melanoma metastases: P < 0.0001; radial growth phase melanomas vs. vertical growth phase melanomas: P = 0.008). CONCLUSIONS: The strong prevalence of CD25+FOXP3+ Tregs both in junctional and compound atypical naevi and radial growth phase melanomas, suggests that they induce immunotolerance early during melanoma genesis, favouring melanoma growth. Their evaluation within a tumour site could be useful for prognostic and therapeutic purposes.     

An assessment of the value of Ag NOR staining in the identification of dysplastic and other borderline melanocytic naevi

One hundred and six melanocytic lesions were studied to determine the value of the so called Ag NOR technique in differentiating dysplastic naevi, Spitz naevi and spindle cell naevi of Reed from malignant melanoma and from 'banal' compound or intradermal naevi. In 79 cases Ag NOR counts were possible. The banal naevi (36) had a mean count of 1.54, (SD 0.3), and the unequivocally malignant superficial spreading melanomas (13), lentigo maligna melanomas (4) and secondary melanomas (4) had a mean count overall of 3.9 (SD 1.59). For dysplastic naevi (16) the mean Ag NOR count was 1.63 (SD 0.36) and for Spitz and spindle cell naevi (in toto 6) the figure was 1.72 (SD 0.55). The difference in Ag NOR counts between all types of naevi and all types of melanoma was highly statistically significant, but there was no difference between banal naevi and dysplastic, Spitz, and spindle cell naevi. Correlation of Ag NOR counts between three independent observers was good. This technique may, therefore, be a useful adjunct in separating true melanoma from borderline melanocytic naevi.     

BRAF, NRAS and HRAS mutations in spitzoid tumours and their possible pathogenetic significance

Background The relationships between so‐called spitzoid tumours have proven difficult to understand. Objectives To address three questions: does spitzoid tumour morphological similarity reflect molecular similarity? Does Spitz naevus progress into spitzoid melanoma? Are ambiguous spitzoid tumours genuine entities? Methods BRAF, NRAS and HRAS mutations were analysed using single‐strand conformational polymorphism analysis and sequencing. Results Both Spitz naevi and spitzoid melanoma had a lower combined BRAF and NRAS mutation frequency compared with common acquired naevi (P = 0·0001) and common forms of melanoma (P = 0·0072), respectively. To look for evidence of progression from Spitz naevi to spitzoid melanoma, HRAS was analysed in 21 spitzoid melanomas, with no mutations identified. The binomial probability of this was 0·03 based on an assumption of a 15% mutation frequency in Spitz naevi with unbiased progression. Under these assumptions, HRAS mutations must be rare/absent in spitzoid melanoma. Thus, Spitz naevi seem unlikely to progress into spitzoid melanoma, implying that ambiguous spitzoid tumours cannot be intermediate degrees of progression. In addition, the data suggest that HRAS mutation is a potential marker of benign behaviour, in support of which none of three HRAS mutant spitzoid cases metastasized. Conclusions First, the morphological similarity of spitzoid tumours reflects an underlying molecular similarity, namely a relative lack of dependence on BRAF/NRAS mutations. Second, Spitz naevi do not appear to progress into spitzoid melanoma, and consequently ambiguous spitzoid tumours are likely to be unclassifiable Spitz naevi or spitzoid melanoma rather than genuine entities. Third, HRAS mutation may be a marker of Spitz naevus, raising the possibility that other molecular markers for discriminating Spitz naevi from spitzoid melanoma can be discovered.     

Point mutations in the N-ras oncogene in malignant melanoma and congenital naevi

DNA from formalin-fixed and paraffin-processed samples from 100 melanocytic lesions (39 malignant melanomas, 18 cases of dysplastic naevi, and 43 congenital naevi) was extracted, and the sequences around codons 12/13 and 61 of the N-ras oncogene were amplified using the polymerase chain reaction. The amplified product was then analysed both by dot-blotting and by direct sequencing for point mutations. By the dot-blotting technique, mutations were seen in 18 of 100 lesions. These were in one of five distant metastases (20%), in one of three nodal metastases (33%), in four of 31 (13%) primary melanomas, in none of 18 dysplastic naevi, and in 12 of 43 (28%) congenital naevi, all at codon 61. On direct sequencing, nine of 18 mutations were confirmed, in two of 31 (6%) primary tumours, one distant metastasis, and six of 43 (14%) congenital naevi. Of the 23 superficial spreading melanomas examined, eight were on sun-exposed skin. A superficial spreading melanoma, in which the N-ras mutation at codon 61 was confirmed, was on non-exposed skin, and an unconfirmed mutation was from an exposed site. One of three nodular melanomas with a confirmed mutation was on a light-exposed site, and the other two nodular melanomas were from non-exposed areas. All four lentigo maligna melanomas were from exposed sites, and one of these had an unconfirmed mutation. The only acral lentiginous melanoma, which had no mutation, was from a sun-exposed area. Ten of the 43 congenital or early onset naevi were on sun-exposed sites; six unconfirmed and five confirmed mutations were from lesions on non-sun-exposed sites (5/33; 15%), and one confirmed mutation was from a lesion on a sun-exposed area (1/10; 10%). Our results do not, therefore, support the hypothesis that N-ras mutations are specifically associated with primary melanomas arising on continually sun-exposed skin. The overall pattern suggests that N-ras mutations in isolation in melanocytic lesions are not frequent. This is the first report of N-ras mutations in congenital/early onset melanocytic naevi, and shows a relatively high incidence in comparison with that observed in melanomas in this study.     

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.     

Expression of soluble adenylyl cyclase in acral melanomas

Soluble adenylyl cyclase (sAC) regulates melanocytic cells, and is a diagnostic marker for pigmented skin lesions. Because only a few studies on sAC expression in acral melanomas have been performed, we investigated the histopathological significance of sAC expression in 33 cases of acral melanoma, and assessed its diagnostic value in distinguishing melanoma in situ (MIS, n = 17) from acral invasive melanomas (n = 16) and melanocytic naevi (n = 11). Acral melanomas exhibited more marked nuclear immunopositivity compared with acral melanocytic naevi. sAC expression significantly correlated with the nuclear morphology of melanocytes and melanoma cells, namely, hyperchromatic nuclei and prominent nucleoli within vesicular nuclei. sAC expression was predominantly observed in the hyperchromatic nuclei of MIS and the prominent nucleoli invasive melanomas, respectively. In vitro culture models of melanocytes and melanoma cell lines exhibited sAC staining patterns similar to those of acral melanomas. Differentiation induction showed that nuclear and nucleolar expression varied depending on cell morphology. sAC immunostaining may be useful for the differential diagnosis of acral melanocytic lesions, and sAC expressed in the nucleus and nucleolus might be related to cytological and nuclear changes associated with invasion and progression of acral melanomas.     

Expression of endoglin in human melanocytic lesions

Angiogenesis plays an important role in progression of various tumours including malignant melanoma. It is possible that the immunostaining of angiogenic markers could differentiate benign and malignant melanocytic lesions or that the immunostaining pattern with angiogenic markers could vary with tumour thickness and thus be a prognostic marker. We were interested to see whether there was any correlation between endoglin (CD 105; EDG) expression with tumour thickness in primary cutaneous malignant melanomas (MM), any correlation between EDG expression and clinical outcome in patients with primary cutaneous MMs and any difference in staining pattern between cutaneous MMs and Spitz naevi which could be of diagnostic value. Tissue sections from 14 primary cutaneous MM lesions with a Breslow thickness of > 2 mm, 10 primary cutaneous MM lesions with a Breslow thickness of 1-2 mm, and six Spitz and 10 compound naevi were stained for EDG. EDG expression was compared with survival in patients with primary cutaneous MMs. Overall, EDG staining was positive in 96% of MMs and 94% of benign melanocytic naevi. Very strong (++++) and strong (+++) EDG staining was found in 58% of MMs and 56% of benign melanocytic lesions. EDG expression did not vary significantly with the thickness of the lesion in primary cutaneous melanoma. Survival of melanoma patients did not correlate with the degree of EDG expression. Therefore, expression of this marker alone is not sufficient to differentiate benign and malignant melanocytic lesions.     

DO ALL MELANOMAS COME FROM “MOLES”? A STUDY OF THE HISTOLOGICAL ASSOCIATION BETWEEN MELANOCYTIC NAEVI AND MELANOMA

Histological examination of 1101 melanomas (990 superficial spreading and 111 nodular melanomas) from 1098 people revealed that 23.3% showed an associated melanocytic naevus. Of these, 56.5% were classified histologically as common acquired, 37.7% as dysplastic and 5.8% as congenital. Of the superficial spreading melanomas, 25.7% showed an associated naevus. By contrast, only 2.7% of nodular melanomas showed histological evidence of a coexisting naevus. When the superficial spreading melanomas were analysed by level, the presence of a naevus varied from 31.3% of level I melanomas to 21.3% of level IV melanomas. When thickness was measured, an associated naevus was found in 27.0% of superficial spreading melanomas less than 1.0 mm thick, and 14.8% of melanomas with a thickness of 1.0 mm or greater. These data suggest that most melanomas do not arise in pre-existing naevi, and accordingly public educational programs for the early detection of melanoma should focus on looking for changes in previously normal skin as well as in pre-existing moles.     

Expression of p53 protein in malignant melanoma: clinicopathological and prognostic implications

In the present study, we investigated the expression of the tumour suppressor protein p53 in 1 primary and 43 metastatic malignant melanomas by immunohistochernistry, and correlated the findings with clinicopathological parameters such as histological melanoma subtype, thickness of primary melanomas (Breslow thickness) and patient outcome. In primary melanomas, the polyclonal anti-p5 3 antibody CM-1 detected immunoreactivity in 70% of the lesions, predominantly in the cytoplasm. Signals were observed in this cellular compartment in 57% of the melanomas, whereas in 32% nuclear p53 over-expression was detected. Immunohis-tochemistry, using the monoclonal antibody DO-1, revealed lower staining frequencies. However, both antibodies showed congruent results in approximately 80% of the cases. Overall, immuno-reactivity was observed in 73% of superficial spreading melanomas, but only in 52% of lentigo maligna melanomas. This difference (P<0.001) was mainly due to a lower frequency of cytoplasmic immunoreactivity (P<0.002). There was no difference with respect to cytoplasmic and nuclear immunoreactivity between thin (<1 mm thickness) and thicker primary melanomas. Staining frequencies detected in metastatic lesions seemed to be lower than in primary tumours. In 103 primary melanomas, follow-up data for at least 5 years were available. In 71% (54 of 76) of the primary melanomas which did not recur, and in 78% (21 of 27) of tumours with subsequent metastases, p53 over-expression was detected by CM-1. However, this difference was not statistically significant. The results of the present study indicate that immunoreactivity to anti-p53 antibodies is a common observation in malignant melanomas, with staining signals predominantly found in the cytoplasm of cells. The observation of similar staining frequencies in thin, thick and metastatic lesions indicates that p53 over-expression is an early event in the pathogenesis of malignant melanoma. However, the immunohistochemical detection of p53 in primary melanomas is not related to prognosis.     

Expression of galanin in melanocytic tumors

IntroductionGalanin is a neuropeptide with wide-ranging effects, especially within the endocrine and nervous systems. Galanin and its receptors are present in human skin. Galanin is expressed in different neural, endocrine and neuroendocrine tumors and, on the other hand, several neuropeptides, particularly α-MSH, seem to play a role in the pathogenesis of melanoma.ObjectiveTo investigate the expression of galanin in cutaneous melanomas and melanocytic nevi and correlate it with α-MSH expression and several prognostic factors for melanoma.Material and methodsWe performed an observational and retrospective study of the immunohistochemical expression of galanin and α-MSH in samples of cutaneous melanomas diagnosed in the last 5 years in the San Jorge Hospital, Huesca (Spain). Different types of melanocytic nevi were also analyzed.ResultsA total of 130 pigmented lesions were studied: 38 primary cutaneous melanomas, 6 cutaneous melanoma metastases and 86 melanocytic nevi. Immunostaining with galanin and α-MSH was significantly higher in melanomas than in melanocytic nevi (p < 0.001), although spindle cell and blue nevi showed significant expression of α-MSH. More than 50 % of nodular melanomas and 90 % of superficial spreading melanomas were positive for galanin and α-MSH, and the latter also showed the highest percentage of positive cells for galanin (mean 35.09 ± 28.16) as well as for α-MSH (mean 67.64% ± 35.38). A positive correlation of 71 % was found for immunostaining of both neuropeptides in melanomas. No significant correlation was observed between galanin expression and age, gender, location of the lesions, Breslow index, Clark level and mitotic index.ConclusionOur study shows the expression of galanin in cutaneous melanoma and its significant correlation with α-MSH immunostaining.     

Macrophages in melanocytic naevi

Summary Whereas the inflammatory infiltrates of malignant melanoma have been widely investigated, little is known about the infiltrates accompanying benign melanocytic naevi. Using monoclonal antibodies directed against HLA-DR antigens, the CD1 antigen, the transferrin receptor and functionally divergent macrophage subpopulations, frozen fresh material of 87 melanocytic naevi (MN), ten primary cutaneous melanomas (PCM) and ten samples of normal skin were studied. Compared with normal skin, abundant HLA-DR⁺ cells were found in the stroma of MN equivalent to the quantity present in PCM. In MN we found higher numbers of dermal CD1⁺ dendritic cells compared with PCM and normal skin. There were more macrophages that expressed the transferrin receptor or the antigens 27E10, RM3/1 and 25F9 in MN than in normal skin but fewer than in PCM. No significant differences were found between congenital MN (n=40), common acquired MN (n=27) and dysplastic MN (n=20) macrophage subpopulations. Also, no correlations were evident between macrophage infiltrates and naevus location or patients' age. Our data show that potential melanoma precursors among melanocytic naevi cannot be identified by the pattern of macrophage infiltrates.     

Absence of BRAF and HRAS mutations in eruptive Spitz naevi

Background Eruptive Spitz naevi have been reported rarely in the literature. In solitary Spitz naevi, BRAF and HRAS mutations, as well as increased copy numbers of chromosome 11p have been identified. Objectives To investigate the genetic changes underlying eruptive Spitz naevi. Methods We report on a 16‐year‐old boy who developed multiple disseminated eruptive Spitz naevi within a few months. We analysed BRAF, HRAS, KRAS and NRAS genes in 39 naevi from this patient for hotspot mutations. Furthermore, comparative genomic hybridization analysis was performed in three lesions. Results None of the Spitz naevi displayed a mutation in the analysed genes, and no chromosomal imbalances were observed. Conclusions Our results indicate that the typical genetic alterations described in solitary Spitz naevi appear to be absent in eruptive Spitz naevi. Yet unknown alternative genetic alterations must account for this rare syndrome.     

Contribution of monoclonal antibody HMB45 in the histopathologic diagnosis of melanoma]

We have tested the diagnostic value in malignant melanoma of HMB45, a monoclonal antibody available for use on paraffin-embedded tissue. MATERIAL AND METHOD. Tissues tested. The following pathological tissues were tested: 10 intradermal and 11 compound naevi; 6 spitz naevi; 20 dysplastic naevi; 10 blue naevi; 2 Bednar's tumours; 6 Sutton naevi; 15 melanonychias; 21 cutaneous and 11 ocular malignant melanomas (MM), and 3 achromic metastases. Control tissues were: vitiligo (20), carcinoma (5), malignant schwannoma of the orbit (1), soft tissue sarcoma (5) and malignant lymphoma (5). Antibodies. The antibodies used were antiprotein S100, antivimentin, anticytokeratin (KL1), monoclonal antileucocyte (CD45) antibodies and HMB45, a monoclonal antibody of the IgG 1 type obtained from lymph node metastases from pigmented malignant melanomas. RESULTS. None of the control tissues were stained by the HMB Ab. Intradermal naevi did not react positively. Compound naevi: the juntional cells were stained by HMB45 in 2/10 cases. Dysplastic naevi: HMB45 showed heterogeneous reactivity of junctional cells in 15/20 cases, and this correlated with the degree of atypia. Blue naevi: HMB45 stained the superficial and deep cells in 3/10 cases. Bednar's tumour: no cell was stained by HMB45. Spitz naevi: HMB45 gave an intensely positive reaction of junctional cells in 4/5 cases and a weaker reaction of dermal cells. Sutton naevi: the naevus cells were not stained by HMB45 in 5/6 cases. In simple melanocytic hyperplasia of the nail bed, only a few atypical cells were stained. In superficially spreading melanoma (SSM) all neoplastic cells were stained by HMB45 in proportion to their degree of atypia. Residual naevus cells were negative. The anti S100 and the antivimentin antibodies stained all neoplastic and naevus cells. In nodular melanoma (NM), HMB45 stained all neoplastic cells in proportion to their degree of atypia. The antivimentin Ab stained the neoplastic cells, and so did the anti-S100 Ab which also stained inflammatory cells. In acral-lentiginous melanoma (ALM), HMB stained the dermal tumoral cells moderately and the junctional cells more strongly. In ocular melanoma, HMB45 strongly stained the fusiform cells and less strongly the epithelioid cells. In achromic metastases from cutaneous malignant melanomas, HMB45 strongly stained the neoplastic cells but did not stain the peritumoral cells. DISCUSSION. The purpose of this study was to compare the value of HMB45 with that of other immunohistochemical staining methods A. Main data from the literature. (ABSTRACT TRUNCATED AT 400 WORDS)     

Expression of matrilysin (matrix metalloproteinase-7) in primary cutaneous and metastatic melanoma

BACKGROUND: Matrilysin (MMP-7), a member of the matrix metalloproteinase (MMP) family of proteins, is expressed in various types of malignant tumours. There have been no previous studies of the correlation between matrilysin expression and melanoma. OBJECTIVES: Protein expression of matrilysin was evaluated in human cutaneous melanomas, metastatic melanomas, acquired common melanocytic naevi and Spitz naevi, and the data were corrected with the clinicopathological factors. METHODS: We retrospectively investigated 18 primary melanomas, 15 metastatic melanomas, 10 common melanocytic naevi and five Spitz naevi samples at our clinic using immunohistochemistry (IHC). Both promatrilysin and active matrilysin were found in the melanoma tissue extracts by Western immunoblotting. In situ hybridization demonstrated that melanoma cells selectively express matrilysin mRNA. RESULTS: Of the melanoma samples, 29 of 33 (87 x 9%) were positive for matrilysin, including 14 of 18 (77 x 8%) primary cutaneous melanomas and 15 of 15 (100%) metastatic melanomas. In contrast, matrilysin was not expressed in common naevi or Spitz naevi. The matrilysin IHC staining score in primary melanomas was associated with the presence of metastases, tumour thickness and TNM staging (P=0 x 001, 0 x 025 and 0 x 021, respectively). The 5-year overall survival was 26.3% for matrilysin-positive cases and 100% for matrilysin-negative cases among melanoma specimen. CONCLUSIONS: We found matrilysin expression in primary melanomas and in metastatic melanomas. We further demonstrated that the matrilysin IHC staining score was associated with invasive depth of primary melanoma lesions and metastases. Our observations indicate that matrilysin may be associated with melanoma progression, and may enhance melanoma tumour cell invasion. Therefore, matrilysin may be potentially valuable as a prognostic indicator to predict the clinical behaviour of melanoma.     

Factor XIIIa in nodular malignant melanoma and Spitz naevi

The distribution of factor XIIIa-positive dermal dendritic cells was studied in a series of nodular malignant melanomas and compared with that seen in Spitz naevi. Two patterns of distribution were recognizable: (a) diffusely spread through the tumour and (b) located mainly at the periphery of the tumour. These did not correlate with the diagnosis of melanoma or Spitz naevus and the distribution appeared to be a function of growth pattern of the tumour. The diffuse pattern was the most common regardless of diagnosis and the distribution of factor XIIIa-positive cells is the same in malignant melanoma and Spitz naevi.     

Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis

Background There have been conflicting data regarding the prevalence and clinicopathological characteristics of BRAF and NRAS mutations in primary cutaneous melanoma. Objectives To solve this controversy, this study used a meta‐analysis to evaluate the frequencies of BRAF and NRAS mutations, and the relationship between these mutations and clinicopathological parameters of cutaneous melanoma. Methods Data from studies published between 1989 and 2010 were combined. The BRAF and NRAS mutations were reported in 36 and 31 studies involving 2521 and 1972 patients, respectively. The effect sizes of outcome parameters were calculated by odds ratios (OR). Results BRAF and NRAS mutations were reported in 41% and 18% of cutaneous melanomas, respectively. The mutations were associated with histological subtype and tumour site, but not with age and sex. The BRAF mutation was frequently detected in patients with superficial spreading melanoma (OR = 2·021; P < 0·001) and in melanomas arising in nonchronic sun‐damaged skin (OR = 2·043; P = 0·001). In contrast, the NRAS mutation was frequently evident in patients with nodular melanoma (OR = 1·894; P < 0·001) and in melanomas arising in chronic sun‐damaged skin (OR = 1·887; P = 0·018). Conclusions This pooled analysis shows that the incidences of BRAF and NRAS mutations in cutaneous melanomas differ according to histological type and tumour location based on the degree of sun exposure.     

Nestin is expressed in HMB‐45 negative melanoma cells in dermal parts of nodular melanoma

Nestin, a marker of neural stem cells, is expressed in the stem cells of the mouse hair follicle. The nestin‐expressing hair follicle stem cells can differentiate into neurons, glia, keratocytes, smooth muscle cells and melanocytes in vitro. These pluripotent nestin‐expressing stem cells are keratin 15 (K15)‐negative, suggesting that they are in a relatively undifferentiated state. Recent studies suggest that the epithelial stem cells are important in tumorigenesis, and nestin expression is thought to be important in tumorigenesis. In the present study, we examined the expression of the hair follicle and neural stem cell marker nestin, as well as S‐100 and HMB‐45, in melanoma. Nestin immunoreactivity was observed in the HMB‐45‐negative melanoma cells in all five cases of amelanotic nodular melanomas. Moreover, nestin immunoreactivity was observed in the dermal parts in seven of 10 cases of melanotic nodular melanomas. Especially, nestin immunoreactivity was observed in the HMB‐45‐negative melanoma cells in the dermal parts of all 10 cases of HMB‐45‐negative amelanotic and melanotic nodular melanomas. On the other hand, nestin expression was negative in 10 of 12 cases of superficial spreading melanoma. These results suggest that nestin is an important marker of HMB‐45‐negative melanoma cells in the dermal parts of patients with nodular melanoma.     

Pathologic Features of Pediatric Head and Neck Melanoma

Although malignant melanoma is rare in children, its incidence is steadily increasing, and it is potentially lethal. Few studies have examined head and neck melanoma in children, and even fewer have focused on the histopathologic features of melanoma within this anatomic region. To further the understanding of this entity, we examined pathology specimens from nine subjects age 18 years and younger with an original diagnosis of head or neck melanoma. The anatomic locations of these primary melanomas were the face and nose (n = 4), scalp and neck (n = 4), and ear (n = 1). The cases included seven superficial spreading melanomas, one unclassified (possible nodular) melanoma, and one melanoma in situ. No melanomas demonstrating desmoplastic or spindle cell morphologies were noted upon review. Breslow depth ranged from 0 to 2.9 mm (mean 1.3 mm, median 0.6 mm), with Clark level ranging from I to V. Pagetoid scatter was found in eight cases. Other notable features included regression (n = 5), ulceration (n = 1), and associated melanocytic nevus (n = 4). We did not observe any small cell variants; all nine cases had an epithelioid appearance. Nor was any melanoma‐associated mortality observed at last follow‐up (mean 60.4 mos, median 48 mos, range 2–174 mos). These histopathologic features were consistent with adult‐type melanoma, which is in agreement with other histopathologic studies of melanoma in children.