Benign Melanocytic Nevi Research Articles

P16 Expression: A marker of differentiation between childhood malignant melanomas and Spitz nevi

Childhood malignant melanomas frequently present as nodular melanomas with Spitzoid features. Spitz nevus and Spitzoid melanoma overlap clinically and histopathologically and there have been many attempts to differentiate between them. Spitz nevi differ from melanomas by their immunohistochemical pattern of expression of cell cycle and apoptosis regulators such as the p16 protein. The aim of this study was to evaluate in a childhood population the expression of p16 in nodular malignant melanoma of Spitzoid type, Spitz nevi, and a control group of benign compound melanocytic nevi. We performed immunohistochemical studies for expression of p16 in 6 Spitzoid malignant melanomas, 18 Spitz nevi, and 12 compound melanocytic nevi in children younger than 18 years. Statistical analysis was used to compare p16 expression, mitotic count/mm(2), and Ki-67 index of childhood nodular malignant melanomas and Spitz nevi. All the childhood melanoma cases were associated with loss of p16 without any correlation with their Breslow thickness whereas all the Spitz nevi and benign melanocytic nevi had strong positive nuclear and cytoplasmic expression of p16 staining. We found a statistically significant difference in p16 expression, mitotic counts, and Ki-67 index when comparing the Spitzoid melanomas with the Spitz nevi. This study is limited by the small number of malignant melanomas, which are known to be rare in childhood. p16 Expression in childhood nodular Spitzoid malignant melanomas and Spitz nevi, in conjunction with clinical and histopathological evaluation, may be a useful tool in differentiating between these two entities.

Abstract 3459: Expression of oncogene-induced senescence markers in pilocytic astrocytomaIs associated with younger age and longer survival

Abstract Pilocytic astrocytomas are the most common pediatric brain tumor. They are low grade neoplasms, and in some cases can spontaneously stop growing or regress. The recent discovery of constitutive BRAF activation in the majority of pilocytic astrocytomas, due either to gene duplication/fusion or point mutation, suggests a possible molecular basis for this relatively benign pathobiology. Oncogenic BRAF-induced senescence has previously been identified in benign melanocytic nevi and colonic polyps, but whether it also occurs in pilocytic astrocytomas is not clear. To investigate this, we examined the senescence marker acidic beta-galactosidase in low passage pilocytic astrocytoma cultures established from freshly resected tumors. Two of these cultures, tested at passages 2 to 3, were derived from tumors that contained KIAA1549:BRAF fusions, and both expressed the senescence marker in over half of the cells. Another culture tested at passage 3 was also strongly positive for acidic beta-galactosidase, but the genetic status of its parent tumor is not known. A final culture came from a pilocytic astrocytoma lacking the KIAA1549:BRAF fusion, or an activating V600E BRAF point mutation, and was negative for the senescence marker, but was tested at passage 10. To help confirm these effects in vivo, we immunostained a tissue microarray containing 78 pilocytic astrocytoma for p16 and p53, both of which have been implicated in oncogene-induced senescence in other tumor types. The majority of pilocytic astrocytoma expressed p16, but the 13% of tumors lacking this senescence marker were associated with significantly shorter overall survival (p = 0.0002). Patients whose pilocytic astrocytomas lacked p16 were also older (mean age 25 years) as compared to those with intermediate (mean age 12 years) or high expressing tumors (mean age 7 years). Immunohistochemical analysis of p53 revealed much weaker staining, and only 18 tumors were positive, but expression correlated positively with that of p16 (Spearman r = 0.45, p = 0.0001). Our data suggest that the low-grade phenotype of pilocytic astrocytomas may be due to oncogene-induced senescence driven by KIAA1549:BRAF fusions or BRAF V600E point mutations, and that expression of senescence markers in vivo is associated with younger age at presentation and better clinical outcomes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3459. doi:10.1158/1538-7445.AM2011-3459

Laser Eradication of Pigmented Lesions: A Review

Pigmented lesions include solar lentigines, seborrheic keratoses, dermatosis papulosa nigra, ephelides, café-au-lait macules, nevus spilus, Becker's nevus, postinflammatory hyperpigmentation, melasma, nevocellular nevi, congenital nevi, junctional and compound melanocytic nevi, nevus of Ota and Ito, Hori's nevus, and blue nevi. Advances in laser technology have resulted in the ability to treat pigmented lesions with greater safety and efficacy. To review the literature on the use of cutaneous laser treatments for pigmented lesions using Medline. The literature cited the use of various lasers to treat pigmented lesions, including argon, carbon dioxide, erbium-doped yttrium aluminum garnet, Q-switched, long-pulsed ruby, alexandrite, diode, and fractional lasers. For each lesion, we describe the efficacy of laser treatments, treatment intervals, and settings used for a variety of diagnoses. The treatment of pigmented lesions continues to evolve as new laser technology emerges and improvements in existing devices are made. The ability to treat pigmented lesions with greater efficacy and safety has resulted from recent advances in laser technology.

Mitotic Activity Within Dermal Melanocytes of Benign Melanocytic Nevi: A Study of 100 Cases With Clinical Follow-up

It is generally accepted that otherwise benign intradermal or compound melanocytic nevi may show mitotic activity within dermal melanocytes. However, it is not known whether there is any clinical significance to this finding. Our objective is to analyze and describe the clinicopathologic features of benign nevi with mitotic activity (NMA). To do this, we collected 100 consecutive NMA during the usual course of business in our private dermatopathology practice. These cases were seen between the years 2000 and 2008. We then collected clinical and pathologic data on these cases and compared the findings with 100 control nevi without mitotic activity (CN). We compared these nevi with regard to demographic features, clinical history provided by clinician, and clinical follow-up, as well as anatomic site and season of biopsy, type of nevus, and selected histologic features (ie, trauma). We also estimate the incidence of NMA and describe the amount and location of mitotic figures within the NMA. Our results indicate that the incidence of NMA is 0.91%. Most (80) NMA revealed only one mitotic figure, whereas some (20) NMA revealed more than one mitotic figure. Most NMA (89) showed mitotic activity in the upper portion of the nevus, whereas some (11) showed mitotic activity in the lower portion of the nevus. NMA patients were of younger age than the CN patients (P = 0.0019). Compared with CN, the NMA were more likely to be from the extremities (P = 0.0113) or head and neck (P = 0.0237) and less likely to be from the trunk (P < 0.001). The NMA were also more likely to show histologic features suggesting a congenital onset (P < 0.001) and were more likely to be Spitz nevi (P = 0.0185). Compared with the CN, the NMA were more often reexcised (P = 0.0073) and more often, there was residual nevus in the reexcision specimen (P = 0.13), although the latter finding was not statistically significant. Anecdotally, 2 of our NMA were identified adjacent to invasive melanomas; however, on clinical follow-up, we were unable to detect any increased incidence of melanoma.

Eczematous Nevus Sebaceus: A Report of Three Cases

Meyerson's phenomenon is a well-documented inflammatory reaction described in a variety of cutaneous lesions, including the original description in nevocellular nevi (1). Such an inflammatory reaction was subsequently described in melanocytic and a sundry of nonmelanocytic lesions alike, including vascular malformations (2-11). We present three cases of infants with nevus sebaceus on the scalp, which were obscured by an eczematous, eosinophilic reaction reminiscent of that first described by Meyerson. Two of the patients had concomitant atopic dermatitis, but one had no association. Recognition of this secondary feature is important in establishing the correct diagnosis.

Two Cases of Multiple Spitz Nevi

The occurrence of multiple Spitz nevi is rare, especially the disseminated variant. Multiple Spitz nevi may be confused with, and must be differentiated from, primary spitzoid melanoma and cutaneous melanoma metastases. Over the past decade, fluorescence in situ hybridization (FISH) has emerged as a tool for studying melanocytic neoplasms, helping to differentiate between melanoma and benign melanocytic nevi. We describe 2 cases of patients with multiple Spitz nevi and their FISH results. One case of disseminated Spitz nevi, in a 17-year-old female, showed balanced tetraploidy using FISH, while the other case, in a 51-year-old female with multiple Spitz nevi, showed normal diploid cells without significant gains or losses in chromosomes 6 or 11. Patients may present with multiple, even disseminated, Spitz nevi. This phenotype should not be confused with melanoma and/or cutaneous metastasis. The use of FISH studies in context with careful correlation of clinical features and dermoscopic and histologic findings can assist in the diagnostic workup.

Desmoplastic Nevus: An entity Distinct From Spitz Nevus and Blue Nevus

Desmoplastic (sclerotic) nevus is an infrequently reported poorly characterized benign melanocytic proliferation, with only 4 case series published to date. To better define this nevus, we examined the clinical and histologic features of 25 lesions. Desmoplastic nevus is seen in both children and adults and can be located on the face, trunk, or extremities. There is a female predominance. Clinically, it can resemble intradermal nevus, atypical nevus, melanoma, and pigmented basal cell carcinoma. These are generally small, symmetric, and well-circumscribed lesions, averaging 3.5 mm in diameter. The most distinctive features include predominantly compound growth, a zonal configuration with greater cellularity in the superficial portion of the lesion, and a mixture of melanocytic phenotypes including type A, B, and C nevus cells, ovoid and dendritic melanocytes, and Spitzoid melanocytes. A distinctive eosinophilic stroma which either resembles that of a dermatofibroma or neurofibroma is always present. Variable amounts of melanin pigment are found in both tumor cells and macrophages, but this is not a prominent feature. Mitotic activity is exceedingly rare (1 case), and pleomorphism is minimal. These lesions are distinct from typical compound nevus, Spitz nevus, epithelioid blue nevus, and desmoplastic melanoma, to which they are often compared. Strict application of these histologic features allows definitive diagnosis of desmoplastic nevus as a distinct form of a benign melanocytic nevus.

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). However, EI differences between BMN and DMN as well as between CMM and DMN were not significant (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.

Frequent Mitotic Activity in Banal Melanocytic Nevi Uncovered by Immunohistochemical Analysis

The presence and distribution of mitotic figures is an important discriminatory parameter in the assessment of melanocytic lesions. We evaluated the number and distribution of mitotic figures in 353 randomly collected melanocytic nevi of various subtypes by hematoxylin and eosin (H&E) staining and immunohistochemically with the 2 mitotic markers Phospho-Histone H3 Ser28 (PHH3) and MPM2. At least 1 mitotic figure was present in 19.5%, 31.3%, and 42.8% of H&E-, PHH3-, and MPM2-stained lesions, respectively. In common compound nevi, the mean number of dermal mitoses amounted to 0.024/mm dermal surface area in the H&E staining (PHH3: 0.061; MPM2: 0.087) and to 0.175/mm in Spitz nevi (PHH3: 0.325; MPM2: 0.45). Nevi exhibiting mitotic figures were significantly more frequent in the youngest age group (0-20 years) than in patients older than 50 years (P < 0.0001). In the upper half of the dermis, mitotic activity was roughly 3 times as frequent as compared with the lower half. Clusters of mitotic figures within the dermis were not observed. Mitotic activity in obviously benign melanocytic nevi is not rare even in the deep dermal part. More than 2 mitotic figures per lesion can usually be explained either by the nevus subtype, young patient age, traumatization, or inflammation. PHH3 and MPM2 are a valuable diagnostic adjunct in the evaluation of melanocytic tumors allowing more sensitive and faster recognition of mitotic figures and their distribution.

A Case of Nevocellular Nevus with Cutaneous Ossification, Nevus of Nanta

A Case of Nevocellular Nevus with Cutaneous Ossification, Nevus of Nanta

P47 Pigmented basal cell carcinoma masquerading as malignant melanoma – case report

Introduction Pigmented basal cell carcinoma (PBCC) is a rare BCC form, although the firmest malignant tumour. The frequency of this clinical type is approximately 2% in clinical material. Because of the specific look, it must be distinguished from the pigmented nevocytic nevus, blue nevus, angiokeratoma, pigmented seborrhoea keratosis, melanoachantoma and especially from melanoma. Female patient, M.B., age 62, housewife from the city, came to the medical examination because of the skin changes in the lumbar region in the form of pigmented prominence. This change lasts for a long time but a year ago it started to increase itself and it has got extremely dark colour. Occasionally scabs and itching are presented. The patient skin is photo type III. In the patient's lumbar region tumorous change is registered. It is slightly raised; discreetly nodular, asymmetric, unevenly dark brown to black colour, its size is 49×45 mm, without changed environment. In personal and family history there are no risk factors for skin tumours. Methods The results of the conducted dermoscopial examination are the following: suspicious pigment change to pigmented BCC and to a melanoma, too. To be sent to the surgeon for the purpose of surgery intervention and HP verification. Apart from slightly raised values of glycaemia, cholesterol and triglycerides, laboratory analyses, bleeding time and coagulation time are within the referent values. Results Lungs RTG: bo. Abdomen EHO: inside the gallbladder the signs of calculosis are present but all the rest is without pathological findings. Internist findings: Hypertensio arterialis, Hyperlipoproteinemia, Hyperglycaemia, Cholecystis chr, calculosa. Nalaz anesteziologa: Varices cruris. It is possible to do a surgery intervention with pre-operational trombo-embolic prevention. Redundancy list with surgery: Melanoma malignum cutis regio lumbalis. Op: Excisio MM in toto. Sutura directa. The wound heals per primam. Patho-histological finding: Ca basocellulare cutis. The resection was radical. Conclusion The patient shown, clinically even dermoscopically had the change of the type PBCC that is very suspicious to melanoma. Completed surgery intervention and pathohistological finding completely solved the diagnostic dilemma.

Abstract 3349: Immunoexpression of human melanoma stem markers during progressive stages of the disease

Abstract Introduction: Human Cutaneous melanoma is known as potentially lethal malignancy due to its inherent intrinsic resistance to various cancer therapeutic modalities. Ineffective chemotherapy may be linked to the existence of hyperpolarized CD133+ subpopulation of melanoma stem cells. Recently, this subpopulation has been shown to express a novel chemoresistance mediator ABCB5+ thus acquire aggressive and resistant cell phenotype to cancer therapy. The present exploratory study was undertaken to identify preferential expression of melanoma stem cell markers-CD133+ and ABCB5+ as well as their anchoring adhesion molecule CD166 and Nestin- a neural stem cell marker to define high risk population. Methods: 5µm thick paraffin embedded tissue sections from primary melanoma (n=40), lymph node (LN) metastasis (n=15), distant metastatic lesions (n=19), benign melanocytic nevi (n=11) were subjected for immunohistochemical staining for melanoma stem makers using monoclonal antibodies to CD133+, ABCB5, CD166 and Nestin. In addition, archival tissue sections were also included from patients with primary melanoma who had short disease-free survival (DFS) and developed metastasis within 6 months (n=8),as well as disease those with longer DFS of &amp;gt;24 months (n=13) in order to correlate expression of melanoma stem cell markers with different clinical outcome. Results: Using Fisher's exact test, the statistical analysis revealed significant difference in overexpression of ABCB5+ and CD133 stem cell markers in distant metastatic lesions compared to benign melanocytic nevi (p&amp;lt;0.007 and p&amp;lt;0.05 respectively). In addition, significant overexpression of the adhesion molecule- CD166 was found in primary melanoma compared with benign nevi (p&amp;lt;0.0012). Simultaneous overexpression of CD133+/ABCB5+ was also observed statistically significant in Lymph node and distant metastases (p&amp;lt;0.002 and p&amp;lt;0.026 respectively) when compared to benign nevi. Two cases of benign nevi that expressed ABCB5+ and CD133+ markers belonged to patients who had past history of melanoma. Greater percentage of cases of primary melanoma who had short DFS demonstrated overexpression of ABCB5+ compared to those who had longer DFS. However, they did not reach statistical significance probably due to the limited number of study cases. Furthermore, no significant difference in immunoexpression of all stem cell markers was observed in primary melanoma compared to distant metastases. Conclusions: CD133 stem cell population exhibiting chemoresistance mediator ABCB5+ may be distinct aggressive phenotypes of invasion and metastases which are uniquely associated with human cutaneous melanoma. These findings may have further diagnostic and therapeutic implication. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3349.

Microrna profiling analysis of differences between the melanoma of young adults and older adults

BackgroundThis study represents the first attempt to perform a profiling analysis of the intergenerational differences in the microRNAs (miRNAs) of primary cutaneous melanocytic neoplasms in young adult and older age groups. The data emphasize the importance of these master regulators in the transcriptional machinery of melanocytic neoplasms and suggest that differential levels of expressions of these miRs may contribute to differences in phenotypic and pathologic presentation of melanocytic neoplasms at different ages.MethodsAn exploratory miRNA analysis of 666 miRs by low density microRNA arrays was conducted on formalin fixed and paraffin embedded tissues (FFPE) from 10 older adults and 10 young adults including conventional melanoma and melanocytic neoplasms of uncertain biological significance. Age-matched benign melanocytic nevi were used as controls.ResultsPrimary melanoma in patients greater than 60 years old was characterized by the increased expression of miRs regulating TLR-MyD88-NF-kappaB pathway (hsa-miR-199a), RAS/RAB22A pathway (hsa-miR-204); growth differentiation and migration (hsa-miR337), epithelial mesenchymal transition (EMT) (let-7b, hsa-miR-10b/10b*), invasion and metastasis (hsa-miR-10b/10b*), hsa-miR-30a/e*, hsa-miR-29c*; cellular matrix components (hsa-miR-29c*); invasion-cytokinesis (hsa-miR-99b*) compared to melanoma of younger patients. MiR-211 was dramatically downregulated compared to nevi controls, decreased with increasing age and was among the miRs linked to metastatic processes. Melanoma in young adult patients had increased expression of hsa-miR-449a and decreased expression of hsa-miR-146b, hsa-miR-214*. MiR-30a* in clinical stages I-II adult and pediatric melanoma could predict classification of melanoma tissue in the two extremes of age groups. Although the number of cases is small, positive lymph node status in the two age groups was characterized by the statistically significant expression of hsa-miR-30a* and hsa-miR-204 (F-test, p-value < 0.001).ConclusionsOur findings, although preliminary, support the notion that the differential biology of melanoma at the extremes of age is driven, in part, by deregulation of microRNA expression and by fine tuning of miRs that are already known to regulate cell cycle, inflammation, Epithelial-Mesenchymal Transition (EMT)/stroma and more specifically genes known to be altered in melanoma. Our analysis reveals that miR expression differences create unique patterns of frequently affected biological processes that clearly distinguish old age from young age melanomas. This is a novel characterization of the miRnomes of melanocytic neoplasms at two extremes of age and identifies potential diagnostic and clinico-pathologic biomarkers that may serve as novel miR-based targeted modalities in melanoma diagnosis and treatment.

Melanocytic Tumors of Uncertain Malignant Potential

Several reports demonstrated the difficulties and lack of agreement in the histopathologic diagnosis of particular melanocytic tumors (atypical Spitz tumors, atypical blue nevi, deep penetrating nevi). These lesions are often referred to as "melanocytic tumors of uncertain malignant potential" (MELTUMP). We studied a large number of such tumors to find out whether repeatable histopathologic criteria for distinction of benign from malignant cases exist. Fifty-seven cases of MELTUMP were classified within 3 groups according to behavior as follows: (a) favorable (no evidence of metastatic disease after a follow-up of > or = 5 y), (b) unfavorable (tumor-related death and/or large metastatic deposits in the lymph nodes and/or visceral metastases), (c) borderline (small nodal deposits of tumor cells < or = 0.2 mm). There were no significant differences in tumor thickness and presence or absence of ulceration between the different groups. The only 3 histopathologic criteria that were statistically different between the groups of favorable and unfavorable cases were presence of mitoses, mitoses near the base, and an inflammatory reaction, all of them found more frequently in cases with unfavorable behavior. The major outcome of this study of a series of "MELTUMPs" suggests as a preliminary observation that these lesions as a group exist and that they may be biologically different from conventional melanoma and benign melanocytic nevi. The terminology remains highly controversial, reflecting the uncertainty in classification and interpretation of these atypical melanocytic tumors.

Pigmented Epithelioid Melanocytoid Tumor of the Ocular Adnexa

An 8-year-old girl with a history of microphthalmia in the right eye presented with a left medial upper eyelid mass with a dark blue-green nodule that could be seen through the skin but did not appear to involve the overlying epidermis. A biopsy demonstrated a pigmented epithelioid melanocytoid tumor with rare mitoses arising in association with a congenital nevus and positive margins. Due to the pathological findings, the patient underwent excision of the tumor with 5-mm margins and a sentinel lymph node biopsy. The re-excision of the upper eyelid margins demonstrated residual benign congenital melanocytic nevus, but did not reveal residual melanocytic lesion. The parotid sentinel node biopsy revealed benign and cytologically mature nevus nests in the capsule and septa, but there was no evidence of involvement with the pigmented epithelioid melanocytoid tumor. The patient underwent successful eyelid reconstruction and had no evidence of recurrence or metastasis after 2 years.

A Case of Nevocellular Nevus Showing Rapid Growth during Pregnancy, Needed to Required Differentiation from Malignant Melanoma

A Case of Nevocellular Nevus Showing Rapid Growth during Pregnancy, Needed to Required Differentiation from Malignant Melanoma

Metastatic adenocarcinoma of breast within a benign melanocytic nevus in the context of cutaneous breast metastatic disease

Metastatic breast cancer of skin may be seen in a number of forms. It is rare to find it in association with a benign melanocytic nevus. We describe a patient with metastatic adenocarcinoma of breast within a benign melanocytic nevus and delineate this occurrence within the context of reviewing cutaneous breast metastatic disease.

Dynamic Gene Expression Analysis Links Melanocyte Growth Arrest with Nevogenesis

Like all primary cells in vitro, normal human melanocytes exhibit a physiologic decay in proliferative potential as it transitions to a growth-arrested state. The underlying transcriptional program(s) that regulate this phenotypic change is largely unknown. To identify molecular determinants of this process, we performed a Bayesian-based dynamic gene expression analysis on primary melanocytes undergoing proliferative arrest. This analysis revealed several related clusters whose expression behavior correlated with the melanocyte growth kinetics; we designated these clusters the melanocyte growth arrest program (MGAP). These MGAP genes were preferentially represented in benign melanocytic nevi over melanomas and selectively mapped to the hepatocyte fibrosis pathway. This transcriptional relationship between melanocyte growth stasis, nevus biology, and fibrogenic signaling was further validated in vivo by the demonstration of strong pericellular collagen deposition within benign nevi but not melanomas. Taken together, our study provides a novel view of fibroplasia in both melanocyte biology and nevogenesis.

Molecular pathogenesis of malignant melanoma: a different perspective from the studies of melanocytic nevus and acral melanoma

The Clark model for melanoma progression emphasizes a series of histopathological changes beginning from benign melanocytic nevus to melanoma via dysplastic nevus. Several models of the genetic basis of melanoma development and progression are based on this Clark's multi-step model, and predict that the acquisition of a BRAF mutation can be a founder event in melanocytic neoplasia. However, our recent investigations have challenged this view, showing the polyclonality of BRAF mutations in melanocytic nevi. Furthermore, it is suggested that many melanomas, including acral and mucosal melanomas, arise de novo, not from melanocytic nevus. While mutations of the BRAF gene are frequent in melanomas on non-chronic sun damaged skin which are prevalent in Caucasians, acral and mucosal melanomas harbor mutations of the KIT gene as well as the amplifications of cyclin D1 or cyclin-dependent kinase 4 gene. Amplifications of the cyclin D1 gene are detected in normal-looking 'field melanocytes', which represent a latent progression phase of acral melanoma that precedes the stage of atypical melanocyte proliferation in the epidermis. Based on these observations, we propose an alternative genetic progression model for melanoma.

Expression of heat shock protein 105 and 70 in malignant melanoma and benign melanocytic nevi

Heat shock proteins (HSPs) restore immature proteins or denatured proteins, thus protecting cells. Also, the expression of some HSPs is elevated substantially in malignant tumors, but the expression of HSPs in association with melanoma has yet to be studied. Therefore, we examined the expression patterns of HSP 70 and 105 in melanoma, benign melanocytic nevi and normal human skin. Two specimens of malignant melanoma, two of benign melanocytic nevi and six of normal human skin were analyzed using Western blot analysis for expression of HSP 70 and 105. In another set, 16 specimens of malignant melanoma, 24 of benign melanocytic nevi and eight of normal human skin were analyzed for the expression of HSP 105 using immunohistochemical studies. The Western blot analysis showed that HSP 70 was overexpressed in all three types. But, the HSP 105 was hardly expressed in normal human skin and benign melanocytic nevi. However, in malignant melanoma, the HSP 105 was overexpressed, and immunohistochemical examination of HSP 105 showed a result similar to that of Western blot analysis. In our study, HSP 105 is thought to be a more relevant tumor-associated antigen in malignant melanoma than is HSP 70.