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.     

Staining of melanocytic neoplasms by melanoma antigen recognized by T cells

We stained benign melanocytic nevi and malignant melanoma with antibodies to melanoma antigen recognized by T cells (Mart-1) to determine if this was useful in differentiating benign from malignant melanocytic neoplasms. Forty-five primary malignant melanomas and 71 benign melanocytic nevi were stained with antibodies to Mart-1. Two cases of malignant melanoma metastatic to lymph node and three cutaneous metastases of malignant melanoma were also stained. The degree of staining was graded into diffuse positive staining, focal positive staining, and negative staining. Thirty-six of 45 primary malignant melanomas stained diffusely positive with antibodies to Mart-1. This included three of five desmoplastic malignant melanomas that showed positive staining. Four melanomas showed faint or focal positive staining. One of two metastases to lymph node showed strong positive staining and one showed no staining. All three cutaneous metastases showed diffuse positive staining. Sixty-one of 71 melanocytic nevi showed no staining or faint staining with antibodies to Mart-1. Ten of 71 melanocytic nevi showed strong positive staining. The majority of these were congenital nevi. Staining with antibodies to Mart-1 antigen was a useful marker of malignant melanoma. However, staining may also be seen in benign melanocytic neoplasms. The presence or absence of staining for Mart-1 antigen cannot be used to differentiate benign melanocytic nevi from malignant melanocytic tumors.     

Common acquired melanocytic nevi, dysplastic melanocytic nevi and malignant melanomas: an image analysis cytometric study

We used computerized image analysis cytometry in analyze 10 melanocytic lesions from each of the following categories: common acquired nevi, melanocytic nevi with architectural features of dysplasia, dysplastic melanocytic nevi (DMN) with slight atypia, DMN with moderate atypia, DMN with severe atypia, and superficial spreading melanomas. The nuclei of at least 50 consecutive nevomelanocytes in the most atypical zones were digitized at ×1000 under oil immersion, without knowledge of diagnosis by one observer. Grading of atypia was based on current practices as described in the literature. The results showed significant differences ( p < 0.05) in nuclear area and standard deviation of nuclear area between melanoma and DMN with severe atypia, and between DMN with severe atypia and all other categories of nevi. There were no differences among any lesions with respect to nuclear shape. No differences in nuclear area were found among DMN with moderate, or slight atypia, nevi with features of dysplasia, and typical nevi. These results show for the first time objective distinction of low-grade (slight-moderate atypia), and high-grade or severe atypia in pre-malignant nevomelanocytic lesions of the skin.     

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.     

Oestrogen receptor-beta expression in melanocytic lesions

Melanomas rarely occur before puberty, have a higher death rate for males, and tend to be more invasive during pregnancy. Prior to the discovery of a second oestrogen receptor (ERbeta), studies with the initial oestrogen receptor, ERalpha, showed no obvious role for oestrogen in the pathophysiology of benign or malignant melanocytic lesions. To investigate the specific immunostaining patterns of ERalpha and ERbeta, benign nevocytic nevi, dysplastic nevi with mild, moderate and severe cytological atypia, lentigo malignas and melanomas of varying depth (Clark) and thickness (Breslow) were studied. ERbeta but not ERalpha was the predominant oestrogen receptor we found in all types of benign and malignant melanocytic lesions. The most intense ERbeta immunostaining was seen in melanocytes in dysplastic nevi with severe cytological atypia and in lentigo malignas. ERbeta expression levels also correlated with the malignant tumor microenvironment; i.e., melanocytes in proximity with keratinocytes>deeper dermal melanocytes in contact with stroma>minimally invasive melanomas>Clark Level III/IV or thick melanomas (Breslow). Discovery that ERbeta expression varies in relation to the tumor microenvironment and increasing depth of invasion suggests its possible usefulness as a surrogate marker for neoplasia and prognosis in 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.     

Phosphoinositide 3-kinase is not overexpressed in melanocytic lesions

BACKGROUND: Although various studies have stressed the role of phosphatase and tensin homologue deleted on chromosome 10 (PTEN)-PI3K-AKT pathway in the progression of melanocytic lesions, little is known about the expression pattern of PI3K in these lesions. OBJECTIVE: To investigate the expression pattern of PI3K in benign and dysplastic nevi, primary melanomas, and metastatic melanomas and the role of PTEN and PI3K in melanocytic tumor progression. METHODS: Tissue microarrays were constructed using formalin-fixed, paraffin-embedded archival tissue blocks from 89 melanocytic lesions: 17 benign nevi, 18 dysplastic nevi, 23 primary melanomas, and 31 metastatic melanomas. Expression of PTEN and PI3K (p85 and p110 subunits) was evaluated immunohistochemically, and the number of cells and labeling intensity were assessed semiquantitatively. RESULTS: Both benign and dysplastic nevi showed strong cytoplasmic staining with PTEN, which was subsequently less in melanomas and completely lost in the metastatic lesions. Eleven of 17 (64%) benign nevi, seven of 10 (70%) dysplastic nevi, four of 23 (17%) primaries, and one of 31 (3%) visceral or lymph node metastasis showed strong positivity. Loss of PTEN expression from benign and dysplastic nevi to melanoma was statistically significant (p=0.001). Although few cells showed reactivity for phosphoinositide 3-kinase (PI3 kinase)-p85 subunit, strong positivity was not detected in the cytoplasm of benign, malignant, or metastatic lesions, except for a single visceral metastasis. Three of 13 (23%) nevi showed positivity for the p110 subunit. No positivity was observed in the dysplastic nevi. Two of 22 (9%) melanomas, one of 14 (7%) visceral metastasis, and three of 12 (25%) lymph node metastasis showed strong positivity. There was no statistical difference in PI3 kinase expression in benign and malignant melanocytic lesions (p=0.2). CONCLUSION: PI3K is not overexpressed in melanocytic lesions.     

Dysplastic melanocytic nevi in histologic association with 234 primary cutaneous melanomas

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

Comprehensive analysis of 112 melanocytic skin lesions demonstrates microsatellite instability in melanomas and dysplastic nevi, but not in benign nevi

INTRODUCTION: the length of DNA repetitive sequences (microsatellite instability (MSI)) represent distinct tumorigenic pathways associated with several familial and sporadic tumors. MATERIAL AND METHODS: To investigate the prevalence and frequency of MSI in melanocytic lesions, the polymerase chain reaction (PCR)-based microsatellite assay was used to examine formalin-fixed, paraffin-embedded tissues of 30 benign melanocytic nevi, 60 melanocytic dysplastic nevi (MDN), and 22 primary vertical growth phase cutaneous malignant melanomas (CMM). Twenty-four microsatellite markers at the 1p, 2p, 3p, 4q and 9p chromosomal regions were used. RESULTS: MSI was found at 1p and 9p in MDN and CMM but not in benign melanocytic nevi. The overall prevalence of MSI was 17/60 (28%) in MDN and 7/22 (31%) in CMM. The frequency of MSI ranged from 2/24 (9%) to 4/24 (17%) and was most commonly found at D9S162. There was a statistically significant correlation between degree of atypia and frequency of MSI (p<0.001) in MDN. There were two MSI banding patterns: band shifts and additional bands. CONCLUSIONS: The data presented revealed the presence of low-frequency MSI (MSI-L) at the 1p and 9p regions in both MDN and CMM. Whether the MSI-L pattern reflects a defect in mismatch repair genes is still to be determined.     

Intraepidermal distribution patterns of melanocytes in the melanocytic lesions on the sole: proposed criteria for histopathologic diagnosis of plantar malignant melanoma in situ

Eighty-eight melanocytic lesions on the soles of Japanese were histologically investigated. Increased numbers of solitary melanocytes above the basal layer of the epidermis were often found in the benign melanocytic nevi on the sole: in 5 lesions of 9 congenital melanocytic nevi, 22 of 65 acquired melanocytic nevi, and 1 of 5 dysplastic nevi. In addition, a moderate degree of nuclear atypia of proliferating melanocytes was frequently observed in the benign melanocytic nevi on the sole: in 3 lesions of 9 congenital melanocytic nevi, 17 of 65 acquired melanocytic nevi, and 2 of 5 dysplastic nevi. Therefore it cannot be said that increased numbers of solitary atypical melanocytes above the basal layer is a characteristic histologic feature of early malignant melanoma in situ. Combining the intraepidermal distribution patterns of melanocytes and maximum diameter of the lesion, we propose criteria for histopathologic diagnosis of plantar malignant melanoma in situ.     

Increased tenascin expression in melanocytic tumors

Tenascin is a large extracellular matrix glycoprotein which is widely distributed in normal, hyperplastic and neoplastic tissues. Its function is unknown but it has been associated with the epithelial-stromal interactions, such as cell adhesion and movement which take place, e.g. in morphogenesis, cellular proliferation and neoplasia. In this study, we investigated tenascin expression in 70 benign, dysplastic and malignant melanocytic tumors by using immunohistochemistry and monoclonal anti-tenascin L43DB7C8 antibody on paraffin sections. In all types of benign nevi, both intradermal, compound and functional, there was a moderate expression of tenascin at the dermoepidermal junction and in the papillary dermis. In dysplastic nevi, the fibrotic areas in the papillary clermis also showed a moderate staining for tenascin. Invasive malignant melanomas showed the strongest expression of tenascin. In addition to the staining at the dermo-epidermal junction and in the papillary clermis, there was a variable expression of tenascin in the reticular dermis. Intracyloplasmic tenascin was detected both in primary melanomas and melanoma metastases. In conclusion, we have shown that tenascin expression is moderately increased in benign and dysplastic melanocytic tumors and greatly increased in malignant melanomas and melanoma metastases. The function of tenascin may be related to the cellular-stromal interactions and it is possibly associated with the proliferation and spread of the melanocytic tumors.     

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 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.     

Monoclonal antibodies selected to discriminate between malignant melanomas and nevocellular nevi

Two monoclonal antibodies (MoAbs), PAL-M1 and PAL-M2, are described that were selected to discriminate between melanomas and nevocellular nevi (NN) in frozen sections. MoAb PAL-M1 reacted with all 15 melanoma metastases (MM), with 14 of 19 primary cutaneous melanomas (PCM), 9 of 35 dysplastic nevi (DN), and 2 of 26 NN. The 2 NN stained were removed from patients with the dysplastic nevus syndrome. MoAb PAL-M2 reacted with 9 of 15 MM, 5 of 19 PCM, 3 of 35 DN, and did not react with 26 NN after usual staining conditions. The proportion of melanocytic cells stained was low in DN and much higher in PCM and especially in MM. Staining in DN was restricted to intraepidermal or subepidermal nests of atypical melanocytes. In PCM, staining with PAL-M2 was observed only in tumors with a Breslow thickness of 0.76 mm or higher. PAL-M1 and PAL-M2 may be immunohistochemical markers for tumor progression in melanocytic proliferations.     

HMB-45 staining of dysplastic melanocytic nevi in melanoma risk groups

To evaluate the hypothesis that reactivity of the intradermal component of melanocytic nevi to the monoclonal antibody HMB-45 correlates with melanoma risk, dysplastic compound melanocytic nevi were examined for expression of the HMB-45 epitope in three subject groups differing in epidemiological risk for melanoma. The study groups consisted of 10 subjects with dysplastic nevi and a personal history of melanoma, 25 subjects with dysplastic nevi and a history of melanoma in one or more first degree relatives, and 15 population control subjects with sporadic dysplastic nevi. For each case, sections from one lesion, immunohistochemically processed for HMB-45 binding, were evaluated by two pathologists without knowledge of the clinical data. Of all dysplastic nevi, 98% showed diffusely positive cytoplasmic staining of the junctional nevomelanocytes and 90% had such positive staining of those cells within the superficial dermis. Nevus cells within the deeper dermis did not stain positively in any case. Furthermore, the data showed no differences in frequency, pattern, or intensity of HMB-45 reactivity between the subject groups. These observations indicate that evaluation of dysplastic nevi with the monoclonal antibody HMB-45, an apparent marker of proliferative or otherwise stimulated melanocytes, has no discriminating value for identifying subjects at increased historical risk for melanoma. The data, however, support the concept that so-called dysplasia within nevi, as defined by histologic criteria, actually represents the active or proliferative phase of melanocytic nevi.     

Human monoclonal antibodies that distinguish cutaneous malignant melanomas from benign nevi in fixed tissue sections

Human monoclonal antibodies were generated by fusing a nonsecretory variant of murine myeloma cells with lymphocytes obtained from the lymph nodes of patients with metastatic cutaneous malignant melanoma. Two human IgG monoclonal antibodies, designated 2-139-1 and 6-26-3, were extensively studied for their patterns of binding to cells in 64 specimens of formalin-fixed, paraffin-embedded tissue sections. These comprised: 23 cutaneous and 2 ocular melanomas; 4 specimens of lentigo maligna; 27 benign nevi; 2 basal and 2 squamous cell neoplasms of the skin; and 4 specimens of normal skin. A direct avidin-biotin-immunoperoxidase staining method was used. Under these conditions, the antibodies reacted with variable intensity to all 18 primary cutaneous malignant melanomas, 5 metastatic cutaneous melanomas, and both ocular melanomas. Antibody 2-139-1 reacted with 1 of 4 specimens and 6-26-3 with 3 of 4 specimens of lentigo maligna. Two of 5 dysplastic nevi reacted with both antibodies, each with a smaller proportion of cells than with melanomas. There was no reactivity with the 22 other nevi representing a spectrum of histologic types or with normal melanocytes. Basal cell and squamous cell carcinomas of the skin also were not stained. These human monoclonal antibodies appear to be useful in distinguishing malignant melanomas from benign nevi, with the exception of dysplastic nevi, and from basal and squamous cancers of the skin in routinely prepared tissue sections. They may also help to identify the cytoplasmic antigens that are immunogenic in humans.     

Number of melanocytic nevi as a major risk factor for malignant melanoma

A study of 121 melanoma patients and 139 control subjects from the University of California, San Francisco clinics was conducted among whites to examine the relationship between number of melanocytic nevi and cutaneous melanoma. Nevi that measured 2 mm or more in diameter were counted over the body by a dermatologist and a dermatology fellow. The average number of nondysplastic melanocytic nevi that were 2 mm or greater in diameter was 97 for melanoma patients and 36 for control subjects (p less than 0.001). Relative risks were 1.6 (p = 0.43) for 11 to 25 nevi, 4.4 (p = 0.01) for 26 to 50 nevi, 5.4 (p = 0.008) for 51 to 100 nevi, and 9.8 (p = 0.001) for more than 100 nondysplastic melanocytic nevi. Relative risks were 3.8 (p = 0.001) for 1 to 5 dysplastic nevi and 6.3 (p = 0.003) for 6 or more of these lesions. Report of blistering sunburns or of a previous skin cancer and having red or blond hair at the age of 20 were also independently associated with an increased risk of cutaneous melanoma. If confirmed in larger studies, the results presented on number of nevi and melanoma risk suggest a readily identifiable melanoma-prone group that could be followed to detect early malignant melanoma.     

Nestin expression in cutaneous melanomas and melanocytic nevi

BACKGROUND: Nestin is one of the intermediate filaments that are expressed in proliferating neural progenitor cells during development of the central nervous system (CNS) and peripheral nervous system. Postnatal re-expression of the protein occurs mainly under pathological conditions, including injury and neoplasia. In this study, nestin expression was detected in both benign and malignant melanocytic skin lesions and its diagnostic relevance was then evaluated. METHODS: Altogether 139 bioptic tissue samples consisting of 42 nodular melanomas, 32 superficial spreading melanomas, 12 metastatic melanomas, 10 dysplastic nevi and 43 common melanocytic intradermal and dermoepidermal nevi were analysed using indirect immunohistochemical staining. RESULTS: We demonstrated that nestin immunostaining was significantly increased in melanomas where it correlated with more advanced stages of the disease. CONCLUSION: We conclude that expression of the intermediate filament protein nestin might be an indicator of tumor dedifferentiation and more aggressive behaviour. Furthermore, we suggest that nestin might be a relevant marker of tumorous and non-tumorous angiogenesis.     

Expression of insulin-like growth factor-binding protein 2 in melanocytic lesions

BACKGROUND: Insulin-like growth factor-1 (IGF-1) is one of the most critical proteins required for the survival, migration, and growth of melanoma cells. IGF-binding protein 2 (IGFBP2), which binds and regulates the function of IGF-1, is upregulated in a dose-dependent manner in melanoma cells treated with IGF-1, suggesting a possible role of IGFBP2 in the pathogenesis of melanoma. METHODS: Tissue microarrays were constructed using formalin-fixed, paraffin-embedded archival tissue blocks from 94 melanocytic lesions: 20 benign nevi, 20 dysplastic nevi, 23 primary melanomas, and 31 metastatic melanomas. IGFBP2 expression was evaluated immunohistochemically using a polyclonal antibody against the C-terminus of IGFBP2. The number of cells and labeling intensity were assessed semiquantitatively. RESULTS: Positive IGFBP2 labeling was observed in 5.0% of benign nevi, which was significantly lower than in dysplastic nevi (35.0%), primary melanomas (52.2%), or metastatic melanomas (54.8%) (p < 0.05). Among the IGFBP2-positive cases, moderate-to-strong immunostaining was observed in 64.7% of metastatic melanomas and 33.3% of primary melanomas. But none of the dysplastic nevi had moderate-to-strong immunostaining (p < 0.05). CONCLUSIONS: Our study shows that IGFBP2 expression increases from benign and dysplastic nevi to primary and metastatic melanomas and suggests that it may play a role in melanoma progression.     

Increased intraepidermal melanocyte frequency and size in dysplastic melanocytic nevi and cutaneous melanoma. A comparative quantitative study of dysplastic melanocytic nevi, superficial spreading melanoma, nevocellular nevi, and solar lentigines

Dysplastic melanocytic nevi (DMN) are distinguished histologically by a hyperplasia of variably atypical intraepidermal melanocytes in a lentiginous epidermal pattern. In order to further characterize the intraepidermal melanocytes of DMN, 4 representative specimens each of DMN, acquired nevocellular nevi (NCN), solar lentigines (SL), and superficial spreading melanoma (SSM) were selected on the basis of predetermined criteria, confirmed in a blind histologic assessment, and compared in a quantitative morphologic study using 6 micron-thick hematoxylin and eosin stained sections of L-dihydroxyphenylalanine (dopa) preincubated vertical tissue slices of lesion and adjacent normal skin. The average melanocyte frequency, expressed as the percent of dopa-reactive perikarya among 600 consecutive basal unit cells, was significantly greater in DMN (60 +/- 23%) than in NCN (18 +/- 3%), SL (25 +/- 7%), and adjacent skin (14 +/- 3%), but similar to that in SSM (71 +/- 11%). The average mean diameter of 200 consecutive epidermal basal unit melanocytes was significantly larger in DMN (11 +/- 2 microns) than in NCN (7 +/- 0.4 microns), SL (6 +/- 0.1 microns), and adjacent skin (6 +/- 0.4 microns), but significantly smaller than in SSM (16 +/- 3 microns). The observed similarities of intraepidermal melanocytes in selected DMN and SSM, as well as distinct differences from melanocytes in selected NCN and SL, support the hypothesis that some varieties of DMN may represent potential precursors of cutaneous melanoma.