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It is often very difficult to confidently distinguish benign and malignant Spitz lesions, and a diagnosis of Spitz tumor of unknown malignant potential (STUMP) is rendered. To address this problem, we performed molecular genetic analysis in a large group of Spitz tumors (93 Spitz nevi and 77 STUMPs) and identified a subgroup of 24 lesions harboring a HRAS mutation. This subgroup lay predominantly in the dermis, had a relatively low cellularity, showed desmoplasia (with single cells interspersed between the collagen bundles), and had an infiltrating base. In 7 of these 24 cases (29%) melanoma had been the initial diagnosis, or an important differential diagnostic consideration, mainly based on the presence of multiple or deeply located mitotic figures, especially in adult patients. In our series none of the patients with the HRAS-mutated lesions developed recurrences or metastases (mean and median follow-up: 10.5 y). This was in accordance with the literature: review showed that no HRAS mutations had so far been reported in Spitzoid melanomas. We therefore conclude that HRAS mutation analysis may be a useful diagnostic tool to help differentiate between Spitz nevus and Spitzoid melanoma, thereby reducing the frequency of overdiagnosis of melanoma, and to help predict the biological behavior of a STUMP. Moreover, this might be a first step toward a more reproducible classification of Spitz tumors combining histological and genetic data.

Malignant transformation of giant congenital nevi (GCN) is very rare, but may already occur in childhood. Benign proliferative nodules in GCN may clinically and histologically mimic a malignant melanoma. We report a newborn infant with large proliferative nodules and multiple satellite nevi in a GCN of the bathing suit type. The diagnosis in our patient was based on the smooth transition of the pre-existing lesion and the nodule, the absence of strong atypical nuclei, the atypical mitotic figures, the ascension of melanocytes in the epidermis and the absence of necrosis. A review of the literature showed that the clinical and the histological features of benign (proliferative) nodules are variable. The awareness and the identification of this entity by clinicians and pathologist are imperative to prevent diagnostic errors.

This review intends to update current knowledge regarding molecular cytogenetics in melanocytic tumours with a focus on cutaneous melanocytic lesions. Advantages and limitations of diverse, already established methods, such as (fluorescence) in situ hybridization and mutation analysis, to detect these cytogenetic alterations in melanocytic tumours are described. In addition, the potential value of more novel techniques such as multiplex ligation-dependent probe amplification is pointed out. This review demonstrates that at present cytogenetics has mainly increased our understanding of the pathogenesis of melanocytic tumours, with an important role for activation of the mitogen-activated protein kinase (MAPK) signalling pathway in the initiation of melanocytic tumours. Mutations in BRAF (in common naevocellular naevi), NRAS (congenital naevi), HRAS (Spitz naevi) and GNAQ (blue naevi) can all cause MAPK activation. All these mutations seem early events in the development of melanocytic tumours, but by themselves are insufficient to cause progression towards melanoma. Additional molecular alterations are implicated in progression towards melanoma, with different genetic alterations in melanomas at different sites and with varying levels of sun exposure. This genetic heterogeneity in distinct types of naevi and melanomas can be used for the development of molecular tests for diagnostic purposes. However, at the moment only few molecular tests have become of diagnostic value and are performed in daily routine practice. This is caused by lack of large prospective studies on the diagnostic value of molecular tests including follow-up, and by the low prevalence of certain molecular alterations. For the future we foresee an increasing role for cytogenetics in the treatment of melanoma patients with the increasing availability of targeted therapy. Potential targets for metastatic melanoma include genes involved in the MAPK pathway, such as BRAF and RAS. More recently, KIT has emerged as a potential target in melanoma patients. These targeted treatments all need careful evaluation, but might be a promising adjunct for treatment of metastatic melanoma patients, in which other therapies have not brought important survival advantages yet.

Tumors are complex tissues composed of neoplastic cells, soluble and insoluble matrix components and stromal cells. Here we report that in melanoma, turn-over of type I collagen (Col(I)), the predominant matrix protein in dermal stroma affects melanoma progression. Fibroblasts juxtaposed to melanoma cell nests within the papillary dermis display high levels of Col(I) mRNA expression. These nests are enveloped by collagen fibers. In contrast, melanoma-associated fibroblasts within the reticular dermis express Col(I) mRNA at a level that is comparable to its expression in uninvolved dermis and reduced amount of collagen protein can be observed. To determine the significance of Col(I) expression in melanoma, we pharmacologically inhibited its transcription in a porcine cutaneous melanoma model by oral administration of halofuginone. When administered before melanoma development, it reduced melanoma incidence and diminished the transition from microinvasive toward deeply invasive growth by limiting the development of a tumor vasculature. Whereas invasive melanoma growth has been correlated with increased blood vessel density previously, our data for the first time demonstrate that the proangiogenic effect of Col(I) expression by fibroblasts and vascular cells precedes the development of invasive melanomas in a de novo tumor model., ((c) 2007 Wiley-Liss, Inc.)

Aims: To assess the type of problems encountered in diagnosing melanocytic lesions and to evaluate the contribution of expert review., Methods and Results: Data from 1887 lesions submitted for consultation to one of the expert pathologists of the Dutch Melanoma Working Group Pathology Panel between 1991 and 2004 were analysed. Referring pathologists can voluntarily submit lesions which are difficult to classify to the panel. Most cutaneous melanocytic lesions (n = 1217) were submitted with a presumed diagnosis by the referring pathologists. Relevant underdiagnoses of melanoma (in situ) and overdiagnoses of naevi were prevented in 12% (144/1217) and 15% (178/1217) of cases, respectively. Problematic melanocytic lesions were (i) spitzoid and dysplastic lesions, (ii) lesions with histological features that hampered the diagnosis such as regression, lymphocytic infiltrate, or a combination with other melanocytic lesions, and (iii) lesions with unusual clinical features, e.g. childhood melanoma. Remarkably, the features of the lesions that were submitted and the types of over- and under-diagnosis remained consistent from 1991 to 2004., Conclusions: A second opinion from an expert pathologist on problem-prone melanocytic lesions improves patient care, in our series in 27% of cases.

A definite diagnosis cannot be established based on histologic features alone in a large number of Spitz nevi and spitzoid melanomas. In a vast majority of common benign and malignant melanocytic lesions, B-RAF and N-RAS mutations were described, but these were not detected in Spitz nevi. In contrast, H-RAS mutations were frequently encountered in Spitz nevi, but only rarely in melanomas. To date, B-RAF mutation analysis has not been reported in atypical Spitz nevi, and there are only a few reports of it in spitzoid melanomas. We analyzed 96 formalin-fixed, paraffin-embedded spitzoid melanocytic lesions for hotspot mutations in B-RAF, N-RAS, and H-RAS genes to test the assumption whether mutation analysis would assist a more accurate diagnosis of spitzoid melanocytic lesions, which are notoriously difficult to classify. B-RAF or N-RAS mutations were observed in 31 of 36 (86%) spitzoid melanomas, and in 6 of 7 (86%) spitzoid melanoma metastases. In contrast, none of the 14 Spitz nevi and none of the 16 atypical Spitz nevi had mutations in any of the three genes. A B-RAF or N-RAS mutation was found in 8 of 23 (35%) spitzoid lesions suspected for melanoma. H-RAS mutations were detected in 4 of 14 (29%) Spitz nevi, in 3 of 22 (14%) atypical Spitz nevi, in 1 of 15 (7%) spitzoid tumors suspected for melanoma, but in none of the spitzoid melanomas. These results strongly indicate that Spitz nevi and spitzoid melanomas are genetically unrelated entities. Furthermore, we can conclude that mutation analysis may be useful as an additional diagnostic tool to distinguish between benign and malignant spitzoid lesions.

The histopathological diagnosis of cutaneous melanocytic lesions may be difficult to assess. Frequently encountered diagnostic problems include: 1) Dysplastic nevus or melanoma in situ?; 2) Melanoma in situ or superficial spreading melanoma?; 3) Lentigo maligna or lentigo maligna melanoma?; 4) Compound nevocellular nevus or nevoid melanoma?; and 5) Spitz nevus or Spitzoid melanoma? Moreover, less frequently encountered diagnostic challenges are discussed: 1) Deep penetrating nevus or nodular melanoma?; and 2) Cellular blue nevus or melanoma metastasis? In this contribution, these problems are discussed after a systematic approach involving a concise histopathological description of the classic lesions considered in the differential diagnoses, a presentation of the deviating histopathological features that give rise to the diagnostic problems, and finally diagnostic recommendations on the classification of the problematic lesions. We also briefly discuss the contribution of additional immunohistochemistry and molecular pathology in aiding to establish a correct diagnosis.

To test the diagnostic usefulness of allelic imbalance (AI) analysis based on routinely paraffin-embedded tissue, a series of 55 benign Spitz naevi, Spitz tumours with uncertain malignant potential, and malignant Spitzoid melanomas was investigated. Laser microdissection was used to ensure representative sampling of lesional cells and to investigate AI in separate tumour areas of four melanomas. AI was found in 2/12 (17%) typical Spitz naevi, 3/9 (33%) atypical Spitz tumours, 12/17 (65%) atypical Spitz tumours suspicious for melanoma and 15/17 (88%) Spitzoid melanomas. Additional immunohistochemical staining for Ki-67 using the MIB-1 antibody revealed positive deeply situated lesional cells in 0/6 (0%) Spitz naevi, 1/8 (13%) atypical Spitz tumours, 5/14 (35%) atypical Spitz tumours suspicious for melanoma, and 7/14 (50%) Spitzoid melanomas, respectively. Two of the melanomas examined for AI in separate tumour areas showed intratumoural genetic heterogeneity. In view of the finding of AI and deeply situated Ki-67 positive cells not only in melanomas but also in Spitz tumours with uncertain malignant potential, these approaches appear to have no direct diagnostic applicability for the distinction between benign and malignant Spitz tumours. Further molecular studies will be required to determine whether Spitz tumours and Spitzoid melanomas are unrelated entities, or whether there is a true spectrum of tumour progression., (Copyright 2002 John Wiley & Sons, Ltd.)