The use of elastin immunostain improves the evaluation of melanomas associated with nevi

Background:  Twenty to 30% of malignant melanomas are associated with melanocytic nevi; however, sometimes it is difficult to distinguish the melanoma from the nevus by routine histology. We have previously described distinctive patterns of elastic fibers in nevi and in melanomas.
Methods:  We analyzed elastic fiber patterns using elastin immunostain and elastic van Gieson (EVG) stain in 30 cases of invasive melanomas associated with nevi, 12 control melanocytic nevi and 14 control invasive melanomas.
Results:  Elastin immunostain was superior to EVG in showing the elastic fiber patterns. In nevi, the elastic fibers were preserved between nests and often around individual melanocytes. In contrast, melanomas had markedly decreased elastic fibers in the stroma and within the nests of melanocytes. The melanoma pushed down the pre-existing thin elastic fibers of the papillary dermis, forming a compressed layer at its base, which separated the melanoma from the nevus. On sun-damaged skin, the solar elastosis had similar elastin and EVG patterns. In three cases with dense inflammation, the layer of elastic fibers between melanoma and nevus was still present but less evident.
Conclusions:  The distinctive patterns of elastic fibers, best shown by the elastin immunostain, were helpful in evaluating melanomas associated with melanocytic nevi.     

Nevoid malignant melanoma

Summary Primary cutaneous malignant melanomas with histological features suggestive of benign nevocytic nevi were studied. From a total of about 3,500 cases, 33 patients with sufficient records, histological slides, and follow-up (at least 5 years for disease-free cases) were found; 15 of them had developed metastases, and 8 had died of disseminated melanoma. Some of the following histological characteristics were always observed: cellular atypia, mitoses, infiltration of adnexa, and in the deeper dermis, infiltrative growth, pigmented tumor cells, sharply demarcated tumor nests, and the absence of maturation. Tumor thickness was the most important prognostic criterion. Clinically, the tumors corresponded to nodular and superficial spreading melanomas. It is concluded that, in rare instances, malignant melanomas strongly resemble benign melanocytic/nevocytic nevi. Such cases do not appear to have a lower degree of malignancy and should be treated as normal malignant melanomas.     

Antiapoptotic bcl-2 and bcl-xL in advanced malignant melanoma

Apoptosis is an important cofactor in the pathogenesis of a plethora of malignancies. However, little is known about modulation of the expression of bcl gene family in melanocytic tumors. To determine the role of bcl-2, bcl-x and bax in melanocytic tumors we investigated the differential expression of these genes via RT-PCR in tissue samples from human benign nevi, primary melanomas and melanoma metastases in comparison with normal skin. Bcl-2 was strongly expressed in 14/16 metastases (87.5%), whereas only 7/13 primary melanomas (53%), 7/15 nevi (46%) and 7/16 normal tissue samples (43%) showed expression of bcl-2 (P < 0.05). There was a strong indication of a correlation between tumor thickness and bcl-2 expression in nodular malignant melanomas. Expression of bcl-x was found in 16/16 melanoma metastases (100%), 11/13 primary melanomas (84%), 12/15 nevi (80%) and 10/16 normal tissue samples (62%) (P < 0.05). Bcl-xL expression increased from primary melanoma to melanoma metastases, whereas bcl-xS showed a decreasing expression level during melanoma progression. No differences in bax expression were seen between melanoma metastases, primary melanoma, nevi and normal tissue. Immunohistochemical investigations of another 53 tissue samples showed similar results. Our results strongly indicate that bcl-2 and bcl-xL gene expression increases with progression of malignant melanoma. Bcl-2 and bcl-xL expression could reflect an increased malignant potential caused by an inhibition of apoptosis and growth advantage for metastatic melanoma cells.     

Adjuvant therapy of melanoma patients with gamma interferon

In a pilot study, 25 patients with high-risk malignant melanomas (a tumor thickness of more than 3 mm and/or a prognostic index of more than 13) and 15 patients with regional lymph-node metastases from malignant melanoma underwent standard surgical procedures. Afterwards, they were treated with gamma interferon in an adjuvant setting. Gamma interferon (200 micrograms) was given subcutaneously three times a week for 6 months. For three times a week for 6 months. For 25 patients, the follow-up has been 12 months or more; for 15 patients, it has been between 7 and 12 months. Tumor relapse occurred in 9 of 25 patients (36%) with high-risk primary tumors and in 5 of 15 patients (33%) with lymph-node metastases. Since these tumor-progression rates are in the same range as those in comparable patients, who did not undergo adjuvant therapy, one can conclude that the adjuvant gamma interferon regimen used is not effective in patients with high-risk malignant melanomas.     

DNA ploidy of malignant melanoma determined by image cytometry of fresh frozen and paraffin-embedded tissue

Image analysis of DNA content was performed from single nuclei of melanoma monolayer imprints made from fresh frozen tissue of 14 patients with primary malignant melanoma and 16 patients with local recurrences at the incision site and local or distant metastases. This procedure requires fewer cells and is an advantage when the quantity of tumor available is limited, especially in thin low Breslow depth cutaneous melanomas. Image analysis allowed reproducible measurement of DNA ploidy from 100 cells. The frequency of aneuploidy was similar in primary and metastatic melanomas. Three of 3 patients with euploid primary melanomas showed no evidence of recurrences or metastases, though one died of unrelated disease with short follow-up. The 4 patients with primary melanoma who developed metastases had aneuploid primaries; two of these patients died of metastatic disease. Three of 4 patients with euploid metastatic tumors were free of disease at last follow-up, and 1 patient died with stable disease. Nine of 12 patients with aneuploid tumors died of metastatic disease. The frequency of DNA ploidy in the present image analysis study correlated with previous flow cytometry studies. In 9 patients with primary tumors with a Breslow depth greater than 0.75 mm, the DNA content was also determined in nuclei obtained from formalin-fixed paraffin-embedded tissue. The frequency of aneuploidy was higher in fresh tissue (7 of 9) as compared with paraffin-embedded tissue of the same cases (4 of 9).     

Kl 67 immunostaining in melanocytic skin tumors. Correlation with histologic parameters

A total of 145 melanocytic tumors (nevus, 38; primary malignant melanoma, 72; metastatic malignant melanoma, 35) were stained with Ki 67 monoclonal antibody using a three-step immunoperoxidase technique. For each case, mean numerical density and maximum numerical density of Ki 67 positive nuclei (number per mm3) were quantitatively evaluated using interactive image analysis. Maximum numerical densities revealed highly significant differences. Within the group of primary malignant melanomas, there was a significant correlation between proliferative activity and maximum tumor thickness. Further, a 'Ki 67-prognostic index' was assessed in each case of primary malignant melanoma, calculating the product of the Breslow index and maximum numerical density/1000 (103 +/- 12; range 1-694). In a prospective, short-term evaluation of primary malignant melanomas, there was a significant difference concerning 'Ki 67-prognostic index' between disease-free survival and occurrence of metastases. After a follow-up time of 24 months, only 63% of the patients with a 'Ki 67-prognostic index' greater than 25 were disease-free, whereas no patient with a 'Ki 67-prognostic index' less than 25 was found to have metastases. We conclude: assessment of the maximum numerical density of Ki 67 reflects the degree of malignancy in melanocytic skin tumors; within primary malignant melanomas, maximum numerical density of Ki 67 positive cells correlates with well-established prognostic parameters (tumor thickness, level of invasion, mitotic rate); assessment of the 'Ki 67-prognostic index' may be of additional prognostic value for patients with primary malignant melanoma.     

Nerve growth and expression of receptors for nerve growth factor in tumors of melanocyte origin.

Nerve growth factor (NGF) stimulates growth and differentiation of sensory and sympathetic neurons. It is not known what role NGF plays in melanoma development, but nevus and malignant melanoma cells express NGF-receptor (NGF-R). We counted nerve fibers within melanocytic nevi, primary cutaneous melanomas, and cutaneous melanoma metastases using a monoclonal antibody (MoAb) as marker against a 200-kD glycoprotein that is expressed on human nerves. The expression of NGF-R was studied in serial cryostat sections using a MoAb against the NGF-R. Compared to normal skin, increased numbers of nerve fibers were found in 72 melanocytic nevi. In congenital nevi their number significantly increased with age. In 47 primary cutaneous melanomas the number of nerve fibers decreased in proportion to tumor thickness. In 33 cutaneous melanoma metastases no accumulation of nerve fibers was found. NGF-R was not expressed in normal skin melanocytes and in the majority of nevus cells in melanocytic nevi. Considerable numbers of NGF-R-positive nervus cells were found only in some congenital nevi and few acquired nevi with dysplastic features. By contrast, in primary and metastatic melanomas higher expression of NGF-R was observed. The increased number of nerve fibers in melanocytic nevi suggests that neurite-promoting factors are produced in situ. Production of such factors appears to be lost in malignant melanoma cells. The finding of an inverse correlation between an abundance of nerve fibers in NGF-R-poor nevi and a high expression of NGF-R in melanomas that show no evidence of nerve growth suggest a role of NGF and its receptor in malignant melanocytic tumors.     

Tissue microarray analysis of methylthioadenosine phosphorylase protein expression in melanocytic skin tumors

BACKGROUND: Using tissue microarrays, we investigated whether methylthioadenosine phosphorylase (MTAP) protein expression is associated with clinicopathologic variables in benign and malignant melanocytic skin tumors. OBSERVATIONS: Cytoplasmic MTAP expression was detected in 227 (72.1%) of 315 informative cases. Expression was significantly reduced in primary malignant melanomas and in melanoma metastases compared with benign nevi (P<.001 for both). No difference was noted in MTAP expression between primary malignant melanomas and melanoma metastases. In primary malignant melanomas, a Ki67-labeling index less than 5% was associated with MTAP expression (P = .04), suggesting that loss of MTAP expression is associated with proliferation. No other variables had significant associations with MTAP expression. Lymph node metastases demonstrated significantly higher MTAP expression compared with skin metastases (P = .01). In the overall cohort, MTAP expression was not associated with prognosis. Among 26 patients with MTAP-positive melanomas and tumor recurrence, 18 patients who received interferon therapy had a significant benefit compared with 8 patients who did not receive interferon therapy (P = .009). This was not seen in the patients with MTAP-negative tumors.Conclusion Methylthioadenosine phosphorylase protein expression may be a predictive marker of interferon therapy resistance in patients with melanoma and disease progression.     

Elastin-derived peptides upregulate matrix metalloproteinase-2-mediated melanoma cell invasion through elastin-binding protein

Type I collagen mediates melanoma cells invasion through upregulation of matrix metalloproteinases-1 and -2 (MMP-1 and -2) expression and activation. We investigated here the contribution of elastin-derived peptides (ED), degradation products of elastin, the main component of elastic fibers in melanoma cells invasion and MMP-1 and -2 expression. Our results evidenced fragmentation of elastin at the invasive front of melanoma, particularly in the most invasive tumors where those fibers nearly totally vanished. By electron microscopy, elastolysis was found to occur mainly at the periphery of melanoma cells, where close contact between elastic fibers and cells could be noticed. Therefore, we showed in vitro that plating melanoma cells high tumorigenic potential on ED-coated dishes, selectively enhanced MMP-2, as membrane-type MMP-1 (MT1-MMP) production and activation. Nevertheless, pro-MMP-2 activation was not observed owing to the parallel increase in tissue inhibitor of metalloproteinase (TIMP)-2 expression. The effects of ED on melanoma cells were found to be mediated by splicing form of beta-galactosidase (S-Gal) occupancy, as being suppressed by lactose. Supplementing collagen lattices with ED led to consistent activation of MMP-2 that can be attributed to TIMP-2 downregulation. Upregulation of MMP-2 activation by ED led to enhanced melanoma cells invasion through S-Gal occupancy. Immunohistochemistry studies, confirmed that S-Gal expression was more prominent at the melanoma invasion site associated with a strong expression of MMP-2 and MT1-MMP. We hypothesize that ED following interactions with S-Gal elastin receptor can favor melanoma cells invasion through a three-dimensional type I collagen matrix by upregulating MMP-2 activation.     

Keratinocytes influence the maturation and organization of the elastin network in a skin equivalent

Elastic fibers form a complex network that contributes to the elasticity of connective tissues. Alterations in the elastic fiber network are involved in several disease affecting organs in which compliance of the connective tissue is essential: skin, main vasculature, lung, joints, muscle, and ligament. The aim of our work was to study the deposition, maturation, and organization of elastic fiber components in a dermal equivalent model consisting of collagen-GAG-chitosan seeded with fibroblasts. The influence of keratinocytes was studied in parallel, thus constituting a skin equivalent model. These models were examined by transmission electron microscopy (TEM) and by immunohistochemistry to determine the staining patterns of fibrillin-1 and elastin proteins representative of the microfibrillar framework and of the elastic fibers, respectively. After 2 mo of fibroblast culture in the dermal equivalent, elastin was undetectable, whereas fibrillin-1 staining was weak and microfibrils were infrequently observed by TEM. In the skin equivalent, fibrillin-1 and elastin were detected by immunostaining 15 d after epidermization and TEM revealed the typical structure and organization of the elastic network in the dermis, with elastin deposition on the microfibrillar scaffold. This in vitro skin equivalent model is to our knowledge the first in which elastic fibers have been detected, thus demonstrating the influence of keratinocytes on the maturation and organization of the elastic network.     

Moesin and CD44 expression in cutaneous melanocytic tumours

The ERM (ezrin, radixin and moesin) family members, located just beneath the plasma membranes, are thought to be involved in the association of actin filaments with the plasma membrane. One of the family members, moesin, is reported to bind to CD44. Splice variants of CD44 are thought to be associated with tumour progression or differentiation. Our aim was to investigate immunohistochemically the expression of moesin together with CD44 on paraffin tissue sections of a series of melanocytic tumours. The material included 12 ordinary melanocytic naevi, six Spitz naevi, eight dysplastic naevi, six blue naevi, seven malignant melanomas in situ , 15 primary malignant melanomas, five metastatic melanomas to the skin and five lymph node metastases. In the normal skin and the melanocytic tumours the expression of moesin was largely similar to that of CD44 standard. Strong moesin staining was observed in benign melanocytic lesions and melanomas in situ . However, the expression was decreased in advanced malignant melanomas. The moesin labelling in melanoma cells was downregulated with the depth of dermal invasion. The immunoreactivity was also diminished in the skin metastases and the lymph node metastases of melanoma. These results suggest that in melanocytic tumours, the alternation in the expression of moesin may be involved in the progression of malignancy.     

CD44 and melanocytic tumors: a possible role for standard CD44 in the epidermotropic spread of melanoma

CD44 is a polymorphic family of cell membrane glycoproteins that mediate cell-matrix and cell-cell interactions involved in the mechanisms of tumor invasion and metastasis, and are subject to differential regulation during normal and malignant cell growth. We have investigated immunohistochemically the expression of CD44S and the variant isoforms CD44v3 and CD44v6 in paraffin-embedded tissue from 5 Spitz nevi, 3 compound melanocytic nevi, 2 blue nevi, 6 primary melanomas, 15 cutaneous metastases (three epidermotropic, nine dermal and three ulcerated) and 10 lymph node metastases of melanoma. Melanocytes were extensively positive for CD44S in primary melanomas and benign melanocytic proliferations. Among 15 cases of cutaneous metastases of melanoma, the three epidermotropic metastases, as well as one of the three ulcerated ones were positive for CD44S. CD44S expression was diminished or totally absent in six of the nine dermal metastases, in two of the ulcerated metastases and in seven of the ten lymph node metastases. CD44v3 and CD44v6 melanocytic expression was absent in all the lesions studied.
According to our results, selective retention of CD44S expression by melanocytes in epidermotropic metastases of melanoma seems to indicate that preservation of CD44S may contribute to the intraepidermal spread of melanoma.     

Volume of malignant melanoma is superior to thickness as a prognostic indicator. Preliminary observation

There are many clinical and histologic factors that are known to be valuable in predicting survival rates for patients with cutaneous malignant melanomas. Breslow thickness is considered to be the most reliable prognostic factor; however, thickness is a unidimensional measurement. A more accurate mensuration to predict biologic behavior might be one that takes into account the three-dimensional volume of the neoplasm. In a study of 35 primary malignant melanomas, the volumes of the dermal components of the tumors were calculated. Those patients with tumor volumes of 200 mm3 or less had a 91.4% 5-year disease-free survival rate, compared with survival rate of only 16.7% for those patients whose lesions had tumor volumes exceeding 200 mm3. On multivariate analysis, tumor volume exceeded thickness as a prognostic indicator. Thus, measurement of tumor volume proved to be of greater significance than thickness in predicting the outcome for patients with malignant melanomas.     

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.     

Elastic fiber pattern in regressing melanoma: a histochemical and immunohistochemical study

Background: Although histopathologic identification of regression of melanoma is usually straightforward, sometimes it can be difficult to distinguish it from scarring fibrosis. Therefore, this study investigates the elastic fiber pattern in melanomas associated with either regression or scars. Methods: We compared 33 invasive melanomas with the fibrosing stage of regression to 10 cases of invasive melanomas with scarring fibrosis. None of the regression cases had a prior surgical procedure. Elastic fiber patterns were evaluated with Verhoeff's elastic van Gieson stain (EVG) and elastin immunostain. Results: Elastin immunostain was superior to EVG in revealing the elastic fiber patterns. Both regression and scars had decreased to absent elastic fibers in the areas of fibrosis. However, areas of regression had a well‐defined compressed layer of thin elastic fibers pushed down from the papillary dermis to the base of the fibrosis. In contrast, the base of scars lacked this compressed elastic layer and had instead an abrupt transition to the thick elastic fibers of the spared reticular dermis. Conclusions: We have identified distinct changes of the elastic tissue network, which more accurately define the presence of regression in melanoma and distinguish it from scarring fibrosis Kamino H, Tam S, Roses D, Toussaint S. Elastic fiber pattern in regressing melanoma: a histochemical and immunohistochemical study.     

Stereologic estimation of volume-weighted mean nuclear volume as a predictor of prognosis in "thin" malignant melanoma.

At present, tumor invasion represents the most reliable prognostic factor for primary malignant melanoma. The 10-year survival rate of "thin" melanomas (Breslow less than 0.76 mm) is more than 95%, but approximately 5% of these low-risk tumors do metastasize. In an attempt to determine prognostic markers for "thin" melanomas we investigated the volume-weighted mean nuclear volume (Vv) of primary melanomas with tumor invasions below 0.76 mm in 32 patients. Ten of these patients had developed melanoma metastases within a mean follow-up period of 49 months; 22 patients who had not developed metastases and who were comparable with regard to clinical and histologic criteria as well as to follow-up period were selected as a comparison group. Vv was determined by computer-assisted image analysis (IBAS 20, Kontron, Germany) on hematoxylin-eosin-stained sections employing stereologic estimation of the volume-weighted mean nuclear volume. In addition, two-dimensional morphometric parameters (nuclear area and shape factors) as well as clinical (sex, age, location) and histologic characteristics (Breslow's thickness, Clark's level, and growth patterns) were recorded. The mean Vv (+/- SD) of primary melanomas with subsequent metastatic course was 273 microns 3 (+/- 81.3), whereas primary melanoma lesions without subsequent metastases exhibited a significantly lower Vv of 154 microns 3 (+/- 25.3) (p = 0.0008). On the other hand, two-dimensional morphometric and clinical and histologic parameters did not correlate with prognosis. Vv thus seems to represent a powerful and independent prognostic marker for "thin" primary melanomas. Assessment of Vv may provide a valuable tool in selecting patients with high-risk stage I, Breslow less than 0.76 mm, melanoma for adjuvant therapy.     

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.     

Syringotropic melanoma: a variant of melanoma with prominent involvement of eccrine apparatus and risk of deep dermal invasion

We report 7 cases which can be regarded as a syringotropic melanoma-a unique presentation of melanoma defined as melanoma spreading within the eccrine apparatus into the reticular dermis and/or subcutaneous tissue deeper than any (if present) associated invasive melanoma. Six patients were females, and 1 was a male. Their ages ranged from 32 to 85 years old (average 63). The lesions showed a wide site distribution, occurring on the extremities (4), trunk (2), and head and neck (1). Five melanomas were superficial spreading type; 1 was acral lentiginous type; 1 was unclassified. Four lesions (57%) invaded from within eccrine apparatus at a depth and anatomical level greater than that of an adjacent conventional invasive melanoma arising from the surface epidermis. In 1 lesion, which presented clinically as a pigmented macule, deep dermal syringocentric invasive tumor was the only site of invasion and tumorigenic growth. Thus, this variant of melanoma carries a significant risk of syringocentric deep dermal invasion, which may be unsuspected clinically but must be detected on histological examination to provide the most accurate prognosis and staging information.     

Morphological analysis of nevoid melanoma: a study of 20 cases with a review of the literature

Nevoid melanoma is a rare variant of melanoma characterized by deceptive morphologic features reminiscent of a benign melanocytic nevus. Twenty (13 nodular, 7 verrucous) nevoid melanomas were reviewed with the goal of identifying the predominant architectural patterns, cytologic features, and prognostic indicators. Although at scanning magnification, many lesions showed a strong resemblance to banal compound or dermal nevi, careful inspection in all cases demonstrated subtle pleomorphism and impaired maturation with depth, invariably accompanied by multiple dermal mitoses. Four tumors recurred and three metastasized, with subsequent death of the patients. Follow-up information for a period of at least 3 years was available in eight cases. In this group, mortality was 37.5%, the metastasis rate was 37.5%, and the local recurrence rate was 75%, with an average tumor thickness of 2.5 mm. We conclude that nevoid melanoma may be distinguished from a benign melanocytic nevus by a high index of suspicion, a careful analysis of architecture, and attention to cytologic features. Our data and a review of the literature do not support the notion that nevoid melanoma has a better prognosis than ordinary melanoma.