Tubulin expression in melanocytic skin tumors. An immunohistochemical study

The microtubulus system as a part of the cellular cytoskeleton contributes to cell movement. Microtubulus assembly and disassembly is considered to be essential for tumor invasion and serves as a target for tumor chemotherapy. Using immunohistochemical methods, we investigated the distribution of tubulin in normal skin and 34 melanocytic skin tumors. In normal skin, tubulin was strongly expressed in dermal nerves, melanocytes, fibroblasts within the papillary dermis and in myoepithelial cells. In melanocytic skin tumors, nevus cells and melanoma cells stained positive, particularly at the periphery of the lesions, where there were single cells and small nests. The main difference between benign and malignant melanocytic tumors was found in the stromal cells: In melanocytic nevi, the stromal fibroblasts were entirely tubulin negative; whereas, adjacent to the invasive edge in primary and metastatic malignant melanoma, the stroma fibroblasts were strongly positive. Our results show that tubulin is regularly expressed in melanocytic skin tumors and may serve as a prerequisite for cell movement. The pronounced expression of tubulin in fibroblasts surrounding malignant melanocytic skin lesions reflects a stromal alteration that might contribute to tumor invasion.     

Expression of nerve growth factor-receptor in normal skin and melanocytic tumor

Immunohistochemical localization of nerve growth factor (NGF) receptor in normal skin and melanocytic tumor was analysed using monoclonal antibody. In normal skin and fetal skin NGF receptor was good marker for cutaneous nerve sheath and schwann cells. In melanocytic lineage, the NGF receptor was not expressed in fetal, normal and dermal melanocyte and weakly positive in only small part of nevus cell nest. Positive staining was seen in primary and metastatic melanoma lesion and restricted to melanoma cell membrane. The distribution of the receptor suggests that the NGF-receptor may be involved in the control of proliferation and malignant transformation in melanocytic lineage.     

The intermediate filament peripherin is expressed in cutaneous melanocytic lesions

Peripherin is an intermediate filament involved in growth and development of the peripheral nervous system and is localized to neurons, some other cells derived from neural tube and neural crest, and some neuroendocrine cells (e.g. β cells of islets of Langerhans). Peripherin also has been demonstrated in neuroblastomas and cutaneous neuroendocrine (Merkel cell) carcinomas. The expression of peripherin by other cells derived from the neural crest is unknown. We evaluated by immunohistochemistry 74 cutaneous melanocytic lesions including primary invasive malignant melanoma (IMM), melanoma in situ (MIS), atypical nevus (nevus with architectural disorder and cytologic atypia of melanocytes) (AN), spindle and epithelioid cell nevus (Spit/nevus) (SN), blue nevus (BN), and common intradermal benign melanocytic nevus (BMN) for expression of peripherin. Peripherin was detected in a cytoplasmic distribution within tumor cells in 14/14 IMM and 8/10 MIS. For IMM, peripherin localised to both the intraepidermal and invasive dermal components. Peripherin was detected in 10/10 AN and 9/9 SN, being localized to the intraepidermal component and, focally, to the superficial dermal component of the lesions. The dendritic nevus cells in 15/15 BN also expressed peripherin. For most of the BMN, expression of peripherin was absent or limited to rare, scattered cells in the superficial portion of the lesions. Melanocytes in adjacent normal skin were not labeled in any of the lesions studied. These results indicate that expression of peripherin is common in both benign and malignant melanocytic lesions, but not in normal resting adult melanocytes. Among benign lesions, expression of peripherin in the dermal component is rare except in the dendritic cells of BN. These findings provide evidence that the expression of peripherin, a marker of neuronal differentiation, is maintained by IMM, MIS, and BN, but is lost in the normal maturational sequence of the dermal component of other melanocytic lesions.     

Immunohistochemical expression of cyclooxygenage-2 in melanocytic skin lesions

Background Several reports have shown expression of cyclooxygenase‐2 (COX‐2) in malignant skin tumors. COX‐2 has also recently been reported as a marker of malignant melanoma (MM). Objective Our aim was to investigate whether there is a difference in the immunohistochemical expression of COX‐2 between malignant and benign melanocytic lesions of the skin. Methods We selected 40 archival cases of MM including 10 cases of superficial spreading melanoma, 10 of lentigo maligna melanoma, 10 of nodular melanoma, and 10 of acral lentiginous melanoma. For comparison, we also selected 35 benign melanocytic lesions, which included 15 nonatypical nevi and 10 atypical nevi. The remaining 10 cases were Spitz nevi. COX‐2 immunohistochemical staining was performed, and intensities were assessed quantitatively. Results The MM group and the benign melanocytic nevi group showed a highly statistically significant difference in the intensity of COX‐2 expression (P < 0.0001). Staining intensity in the dermal component of MM cases also showed a tendency to increase with increasing tumor depth. By contrast, the intensity of the dermal component in the melanocytic nevi group decreased with increasing depth as the nevus cells matured from type A to type C cells. No statistical difference was noted between the MM and Spitz nevi cases (P = 0.20). Conclusions Malignant melanoma shows stronger immunohistochemical expression of COX‐2 than benign melanocytic nevi. Although COX‐2 cannot be used alone to differentiate MM from melanocytic nevi, it may serve as an aid in the differential diagnosis of melanocytic skin lesions.     

Expression of c-kit (CD117) in Spitz nevus and malignant melanoma

BACKGROUND: CD117, the receptor for kit-ligand, which is a growth factor for melanocyte migration and proliferation, has shown differential staining in various benign and malignant melanocytic lesions. The purpose of this study is to compare CD117 immunohistological staining in Spitz nevus versus malignant melanoma, to determine whether CD117 can aid in the diagnosis of these two lesions. METHODS: CD-117 immunohistological staining was performed in 22 clinically and pathologically diagnosed pigmented lesions including 9 cases of Spitz nevus, 10 cases of primary MM and 3 cases of metastatic melanoma. RESULTS: There was no significant difference in CD117 staining in either epidermis or dermis between Spitz nevi and primary melanomas. However staining of metastatic melanomas is less than dermal staining of primary MM and Spitz nevus. CONCLUSIONS: CD117 is unlikely a useful diagnostic tool in differentiating Spitz nevus from primary MM. On the other hand, CD 117 may be useful in differentiating metastatic melanoma from primary melanoma in patients who had a history of melanoma and who present with new dermal lesions.     

Increased expression of germinal center-associated nuclear protein (GANP) is associated with malignant transformation of melanocytes

BACKGROUND: Germinal center-associated nuclear protein (GANP) is a newly cloned molecule that is up-regulated in the germinal center B cells. Although GANP functions in the regulation of DNA repair during replication and survival of B cells, little is known about its expression in melanocytic cells. OBJECTIVES: To investigate whether GANP and phosphorylated-GANP (P-GANP) are expressed in cultured human melanocytes and melanoma cells and in benign and malignant melanocytic lesions. In addition, we aim to determine whether GANP and P-GANP are associated with malignant transformation of melanocytic lineage. METHODS: GANP and P-GANP expression in cultured melanocytic cells was analyzed by immunostaining and in vitro kinase assay. GANP and P-GANP expression in melanocytic lesions was analyzed by immunohistochemistry. RESULTS: GANP and P-GANP were up-regulated in cultured melanoma cells compared to melanocytes. GANP and P-GANP were restricted to nucleus of melanocytes but co-expressed in cytoplasm of melanoma cells. On the other hand, GANP and P-GANP were widely expressed at various levels in melanocytic nevi and melanoma lesions with nuclear and cytoplasmic staining pattern. Melanoma cells showed a stronger intensity of GANP and P-GANP than melanocytic nevus cells, however the staining intensity in primary melanoma lesions was not associated with any clinicopathological variables. Cytoplasmic GANP and P-GANP expression was associated with MCM3 and Ki67 expression. CONCLUSIONS: These data suggest, for the first time, that GANP and P-GANP are up-regulated in cultured melanoma cells compared to melanocytes and also they are widely expressed in benign and malignant melanocytic tumor cells.     

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

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

Desmoplastic melanocytic nevi with lymphocytic aggregates

Desmoplastic melanocytic nevi can be difficult to distinguish from desmoplastic melanoma. The presence of lymphocytic aggregates in association with a sclerosing melanocytic proliferation is commonly regarded as a feature in support of a diagnosis of desmoplastic melanoma. However, the finding is not specific for melanoma. Herein we report six cases of sclerosing melanocytic nevi with associated lymphocytic aggregates. They occurred in five women and one man, ranging in age from 11 to 61 years. Three lesions were sclerosing Spitz nevi; one was an amelanotic sclerosing blue nevus, one an acquired intradermal sclerosing nevus, and one was a congenital compound melanocytic nevus with sclerosis of its dermal component. The lesions were interpreted as benign, i.e. melanocytic nevi, because of their histopathologic attributes (symmetric silhouette, benign cytologic features) and results from immunohistochemical studies (all lesions strongly expressed Melan-A and p16) and fluorescence in situ hybridization (FISH). Three lesions tested by FISH lacked copy number changes of 11p, 6q or 6p. None of the lesions recurred. The cases highlight that contextual information is essential for the diagnosis of desmoplastic melanoma and sclerosing nevus. The presence of lymphocytic aggregates per se does not prove that a sclerosing melanocytic proliferation is malignant.     

Expression of the proliferation and apoptosis-associated CAS protein in benign and malignant cutaneous melanocytic lesions

We have examined the expression of the cellular apoptosis susceptibility protein, a nuclear transport factor that plays a role in apoptosis and cell proliferation, in benign and malignant melanocytic lesions. Tissue samples of 55 formalin-fixed, paraffin-embedded melanoma (primary n=32, metastatic n=23) and of 27 control cases (junctional dermal, compound, Spitz, Reed, blue nevi, balloon-cell nevus, lentigo maligna) were analyzed by immunohistochemistry with anti-cellular apoptosis susceptibility antibodies. The percentage of cellular apoptosis susceptibility-positive cells as well as the intensity on a four-point scale was evaluated. In normal skin, expression of cellular apoptosis susceptibility was primarily found in the basal cell layer of the epidermis. Benign melanocytic lesions that stained positive for cellular apoptosis susceptibility (13 of 27) showed a homogeneously distributed staining pattern with a mean of 5+/-12% cellular apoptosis susceptibility positive cells. Five out of 7 lentigo maligna melanoma, 11 out of 12 superficial spreading melanoma and all acrolentiginous (n=7) and nodular (n=6) melanoma showed immunoreactivity of medium (++) to high ( ) intensity. Vertical growth phases of primary cutaneous melanoma stained stronger than horizontally growing cell clusters. All metastases (n= 23) stained strongly positive, the staining pattern being inhomogeneous. Cellular apoptosis susceptibility detection in clinical stages according to UICC showed an increase from 43+/-34% cellular apoptosis susceptibility positive cells in stage I, to 53+/-26% in stage II, 68+/-24% in stage III and 72+/-24% in stage IV, respectively. Because the expression of cellular apoptosis susceptibility correlates predominantly with advanced stages of melanoma, staining with anti-cellular apoptosis susceptibility antibodies may be useful for diagnosis of melanoma and possibly as an immunohistochemical prognostic factor in cutaneous melanocytic lesions.     

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

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

Increased epidermal growth factor receptors in melanocytic lesions.

BACKGROUND: Epidermal growth factor receptors (EGF/R) have been reported to be absent in melanomas or, in contrast, to be markers for potential malignancy in melanocytic lesions. OBJECTIVE: Our purpose was to evaluate the literature discrepancies regarding the presence of EGF/R in melanocytic lesions and to determine whether EGF/R presence correlates with the potential for malignancy of melanocytic lesions. METHODS: An EGF/R-specific polyclonal antibody was used to study melanomas, dysplastic nevi, congenital nevi, and nevocellular nevi. RESULTS: All melanocytic cell types (nevus and melanoma cells) in the lesions studied had immunoreactive EGF/R. EGF/R immunoreactivity was also observed throughout the epidermal basal to granular cell layers overlying the melanocytic lesions, although dermal fibroblasts were negative. CONCLUSION: The pattern of increased immunoreactive EGF/R in both benign and malignant nevocellular lesions suggests that although EGF/R are not a specific marker of potential malignancy in melanocytic lesions, they may mediate or coordinate growth of keratinocytes and nevus cells.     

乙酰肝素酶mRNA和蛋白在恶性黑素瘤皮损及A375细胞株中的表达

目的探讨乙酰肝素酶mRNA和蛋白在恶性黑素瘤皮损及A375细胞株中的表达及意义。方法选择恶性黑素瘤30例、黑素细胞痣30例、恶性黑素瘤A375细胞株及15例正常皮肤组织,分别采用原位杂交、免疫组化法检测皮损及细胞株中乙酰肝素酶mRNA及蛋白的表达。结果A375细胞株及19例(19/30,63.33%)恶性黑素瘤皮损中乙酰肝素酶mRNA呈阳性表达,2例(2/30,6.67%)黑素细胞痣皮损中乙酰肝素酶mRNA表达阳性,正常皮肤组织中无1例呈阳性表达;恶性黑素瘤皮损中乙酰肝素酶蛋白的阳性表达率与黑素细胞痣、与正常对照组相比,差异均有显著性意义(χ12=19.200,P=0.000;χ22=25.714,P=0.000)。乙酰肝素酶蛋白在恶性黑素瘤、恶性黑素瘤A375细胞株、黑素细胞痣及正常皮肤组织的表达情况与mRNA相一致。结论乙酰肝素酶mRNA和蛋白的高表达可能与恶性黑素瘤的发生发展有关,有望作为治疗黑素瘤的靶点。     

Human malignant melanoma cells release a factor that inhibits the expression of smooth muscle alpha-actin

Smooth muscle alpha-actin (SMA) is a cytoskeletal protein expressed in vascular smooth muscle cells, pericytes, hair follicle dermal sheaths and myofibroblasts which appear in the process of wound healing and tumor growth. To examine the effect of malignant melanoma on the expression of SMA in these non-neoplastic cells, we carried out immunohistochemical staining and a cell culture study. Conditioned medium prepared from a melanoma cell line M14 was incubated with a rat fibroblastic cell line 3Y1, which had been shown to express SMA. Human cells that had migrated from nevus tissue were also cultured either with or without M14 conditioned medium. Immuno-histochemical staining of human melanoma tissues suggested that the expression of SMA was low in the vicinity of the tumor as well as within the tumor nodules. The conditioned medium from melanoma, but not the medium from control non-neoplastic cells, suppressed the expression of SMA both in the 3Y1 cells and human cells that migrated from the nevus. Preincubation of the medium with anti-platelet-derived growth factor allowed 76% recovery of SMA expression. These data thus imply that melanoma cells release a platelet-derived growth factor-like substance which has a suppressive effect on the contractile elements in non-neoplastic cells.     

Melanoma arising in a nevus of Ito: novel genetic mutations and a review of the literature on cutaneous malignant transformation of dermal melanocytosis

Dermal melanocytosis refers to a spectrum of benign melanocytic proliferations that includes Mongolian spot, nevus of Ota and nevus of Ito. These lesions most commonly occur in persons of Asian or African descent and are often present at birth or develop during childhood. Very rarely, dermal melanocytoses undergo malignant transformation. There have been only 13 reports in the literature of primary cutaneous melanoma arising in dermal melanocytoses. We report a case of a Chinese woman with melanoma arising in a congenital nevus of Ito. We performed targeted next‐generation sequencing of the tumor which revealed mutations of GNAQ and BAP1, suggesting that alterations in these two genes led to malignant transformation of the nevus of Ito. We also provide a summary of reports in the literature regarding primary cutaneous melanoma arising in the context of dermal melanocytosis.     

Proliferation, apoptosis, and survivin expression in a spectrum of melanocytic nevi

BACKGROUND: Apoptosis is important for maintenance of tissue homeostasis and often dysregulated in cutaneous neoplasms. The apoptosis inhibitor survivin is expressed in melanoma and non-melanoma skin cancers and benign keratinocytic lesions. Its expression has not been studied in melanocytic nevi. OBJECTIVE: We determined the expression pattern of survivin in benign melanocytic nevi in comparison to markers of proliferation and apoptosis. METHODS: Six cases of each of the following melanocytic nevi were retrieved from a dermatopathology archive: compound dysplastic nevus, intradermal nevus, compound nevus, neurotized intradermal nevus, and Spitz nevus. Survivin expression was evaluated by in situ hybridization. Apoptotic and proliferation indices were calculated by counting immunoreactive cells in terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling and proliferating cell nuclear antigen immunostained sections, respectively. RESULTS: All nevi, regardless of histologic type, expressed survivin. Compound melanocytic lesions expressed survivin in both epidermal and dermal compartments. The apoptotic rate was low for dysplastic, compound, and Spitz nevi, and apoptotic cells were not identified in any neurotized nevus. The proliferative index was highest for Spitz nevi, while all other nevi demonstrated rare positive cells. CONCLUSIONS: Survivin is consistently expressed in benign melanocytic lesions, while apoptotic cells are rarely identified, suggesting the dysregulation of apoptotic pathways with the accumulation of cells in these neoplasms.     

结缔组织增生性色素痣四例临床病理分析

目的 探讨结缔组织增生性色素痣的病理学特点及鉴别诊断.方法 对4例皮肤结缔组织增生性色素痣的临床表现、组织学表现、免疫组化及荧光原位杂交(FISH)特点进行分析.结果 4例结缔组织增生性色素痣中,男2例,女2例,年龄19 ～ 30岁,平均26.5岁;皮损位于四肢3例,外阴1例.组织学特点:均为皮内痣,病变左右对称,痣细胞呈上皮样和(或)梭形,聚集成团或单个散在分布于增生的纤维组织之间,均未见淋巴细胞聚集、坏死或溃疡.免疫组化显示,3例痣细胞为S100和Melan A阳性,2例为P16阳性;Ki-67阳性指数均小于5％;2例间质细胞为凝血因子FⅫ和CD34阴性.荧光原位杂交(FISH)显示结缔组织增生性色素痣在6p25(RREB1)、6q23 (MYB)、6p11.1-q11.1(Cep6)及11q13(CCND1)4个基因位点均无拷贝数异常.结论 结缔组织增生性色素痣是一种组织学独特的良性黑素细胞痣,ki-67 、S100、Melan A、凝血因子FⅩⅢ等免疫组化染色和黑素瘤FISH检测有助于其与皮肤纤维组织细胞瘤和黑素瘤鉴别.     

Overexpression of the cyclin-dependent kinase inhibitor p21WAF1/GIP1 in human cutaneous malignant melanoma

p2l^WAFI/CIPI (p21) is an inhibitor of cyclin-dependent kinases recently identified as the downstream effector of wild-type p53-me-diated cell cycle arrest. The gene coding for p21 may function as a negative regulator of melanoma growth, progression, and metastasis. Using immunohistochemistry and Western blotting, we investigated the expression of p21 in human melanocytic proliferations. Immunohistochemical staining was performed on 13 common acquired nevi, 12 dysplastic nevi, 23 primary malignant melanomas, and 12 metastatic melanomas. Common acquired nevi showed minimal p21 staining (1.8±0.3%, mean±SEM). The percentage of positive nuclei was slightly elevated in dysplastic nevi (8.9±1.7%). Both primary malignant melanoma (29±3%) and metastatic melanoma (33±5%) demonstrated a significantly increased number of p21-positive nuclei compared to benign lesions (p<0.001). p21 was strongly expressed even in actively proliferating lesions as confirmed by MIB-1 labelling, and although the majority of p21-positive cells likely represent a non-proliferating population, staining was occasionally observed in cells undergoing mitosis, suggesting abnormal function of this cell cycle inhibitor in malignant melanoma. Overexpression of p21 in metastatic melanoma compared to common acquired nevi was confirmed by Western blot analysis of human tumor samples. These findings suggest that increased p21 expression relative to benign nevi is not sufficient to control melanoma growth in vivo.     

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

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

Fibroblast activation protein: differential expression and serine protease activity in reactive stromal fibroblasts of melanocytic skin tumors

Growth and metastasis of solid neoplasms require the recruitment of a supporting tumor stroma. A highly consistent trait of tumor stromal fibroblasts in most epithelial cancers is the induction of fibroblast activation protein (FAP), a member of the serine protease family. Recently it was demonstrated that FAP has both dipeptidyl peptidase and collagenolytic activity capable of degrading gelatin and type I collagen. In this study, we describe the expression and enzyme activity of FAP in benign and malignant melanocytic skin tumors. FAP-positive fibroblasts were detected immunohistochemically in the reactive stroma of all melanocytic nevi tested. In primary and metastatic melanomas an upregulation of FAP expression in the reactive mesenchyme could be observed. Whereas 30% of the nevi revealed additional FAP expression on subsets of melanocytic cells, melanoma cells from primary and metastatic melanomas were FAP negative. This may indicate a possible role for FAP in the control of tumor cell growth and proliferation during melanoma carcinogenesis. Consistent with this in vivo expression pattern FAP enzyme activity could be detected by a specific immunocapture assay in extracts of melanocytic nevi and melanoma metastases, whereas no significant activity was detectable in normal adult skin. Strong protein expression of FAP was observed in patterned structures restricted to a subset of the melanoma metastases. Our findings that these FAP-positive structures showed no overlap with endothelial cell surface markers, nor with various melanoma antigens, suggest that FAP is a marker for specific stromal-cell-derived patterns in cutaneous melanoma metastases.