43 research outputs found
Genetic Alterations in melanocytic lesions -towards diagnostic use of molecular genetic analysis
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27367.pdf (Publisher’s version ) (Open Access)Melanoma is one of the most aggressive types of skin cancer and thick lesions. Obviously, a correct diagnosis is needed for an adequate therapy and proper information on the prognosis of the patient. But even a panel of expert pathologist cannot always arrive at a certain diagnosis; therefore, additional methods to support the diagnosis are needed. To find additional diagnostic markers we directed our efforts on routinely processed formalin-fixed paraffin-embedded tissue. We critically evaluate the various molecular techniques used to analyse genetic alterations on the DNA level in formalin fixed lesions and review the results published so far. Initially, Allelic Imbalance (AI) analysis showed some promise as a useful technique to analyse these gains and losses; however, only a few loci can be analyzed per experiment and gains cannot be distinguished from losses. Recently, a new technique to analyse gains and losses called Multiplex Ligation-dependent Probe Amplification (MLPA) was marketed; this technique solved the most important drawbacks from AI analysis. More recently, mutation of the BRAF gene in melanomas was reported, that could have diagnostic implications. We show a striking difference in frequency: no BRAF or NRAS mutations were detected in (atypical) Spitz naevi, whereas these genes were very frequent mutated in spitzoid melanomas. In borderline lesions a lower percentage was detected. In contrast to the AI findings these results suggest that these spitzoid lesions might not be part of a biologic spectrum but two separate subtypes. We showed that BRAF, NRAS and HRAS mutation analysis and MLPA provide additional information to arrive at correct diagnosis.RU Radboud Universiteit Nijmegen, 13 januari 2006Promotor : Ruiter, D.J. Co-promotor : Jeuken, J.W.M.156 p
Spitzoïde melanocytaire laesies: weinig consensus en veel controverses. Hoe krijgen we het spits?
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Analysis of mutations in B-RAF, N-RAS, and H-RAS genes in the differential diagnosis of Spitz nevus and spitzoid melanoma.
No full textA 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
Current diagnostic problems in melanoma pathology.
No full textItem does not contain fulltextThe 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
Benigne proliferatieve nodi in een ‘reuzen’-congenitale naevus naevocellularis
No full textGiant congenital naevi have a higher risk of malignant transformation compared to acquired naevi. Benign proliferative nodules in giant congenital naevi can have clinical and histological similarities with malignant melanoma. The diagnosis can be established by subtle histological differences and recognition
Loss of heterozygosity of gene THW is frequently found in melanoma metastases.
No full textItem does not contain fulltextWe have recently described a new member of the PMP22/gas3 family of plasma membrane proteins referred to as THW. This gene is located on chromosome 6q and preliminary data have indicated a possible tumor suppressor gene function. We have therefore investigated LOH for gene THW in a panel of cancer cell lines and in a series of primary human melanomas as well as in melanoma metastases. We have detected LOH for gene THW in cell lines derived from melanoma, breast, pancreas, cervical, prostate and colon carcinoma with different prevalence, whereas the ovary carcinoma cell lines (n = 3) were negative. For melanomas we found a prevalence of LOH for gene THW of 10-20% in primary tumors, whereas in melanoma metastases we found a score of 50%. These data and the fact that the recently identified murine homologue PERP of gene THW mediates cell death in murine fibroblasts support the possible tumor suppressor function of gene THW
Loss of heterozygosity of gene THW is frequently found in melanoma metastases.
No full textWe have recently described a new member of the PMP22/gas3 family of plasma membrane proteins referred to as THW. This gene is located on chromosome 6q and preliminary data have indicated a possible tumor suppressor gene function. We have therefore investigated LOH for gene THW in a panel of cancer cell lines and in a series of primary human melanomas as well as in melanoma metastases. We have detected LOH for gene THW in cell lines derived from melanoma, breast, pancreas, cervical, prostate and colon carcinoma with different prevalence, whereas the ovary carcinoma cell lines (n = 3) were negative. For melanomas we found a prevalence of LOH for gene THW of 10-20% in primary tumors, whereas in melanoma metastases we found a score of 50%. These data and the fact that the recently identified murine homologue PERP of gene THW mediates cell death in murine fibroblasts support the possible tumor suppressor function of gene THW
Benign proliferative nodules in giant congenital nevocytic nevus
No full textGiant congenital naevi have a higher risk of malignant transformation compared to acquired naevi. Benign proliferative nodules in giant congenital naevi can have clinical and histological similarities with malignant melanoma. The diagnosis can be established by subtle histological differences and recognition
Functional and morphologic analysis of the fluid-conducting meshwork in xenografted cutaneous and primary uveal melanoma.
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47821.pdf (Publisher’s version ) (Open Access)PURPOSE: In primary uveal and cutaneous melanoma lesions, extracellular matrix (ECM) is often deposited in arcs, loops, and network patterns. Based on prognostic relevance, these patterns appear to play a significant role in facilitating metastasis. It has been demonstrated that these patterns were capable of transmitting fluid. The current study was undertaken to elucidate further the functional role of these patterns in tumor perfusion and to examine the composition of the patterns by immunohistochemistry. METHODS: To study the role of these patterns in perfusion, fluorochrome-labeled bovine serum albumin, bovine insulin, and dextrans of different molecular sizes were injected intravenously into nude mice bearing subcutaneous human cutaneous melanoma xenografts. Distribution of the human melanoma cells and murine host cells was analyzed by DNA in situ hybridization. To elucidate the composition of these patterns, human uveal melanoma tissues were analyzed for expression of ECM components by immunohistochemistry. RESULTS: Small molecules (Stokes' radius <4.4 nm) crossed the vessel wall and spread along the ECM patterns within 2 to 10 minutes, whereas larger molecules (Stokes' radius approximately 5.8 nm) required 30 to 45 minutes to enter. Murine host cells were found exclusively in the ECM pattern compartment. In primary uveal melanoma, different types of collagen, ECM-associated heparan sulfate proteoglycans, and different types of cells were present in the patterns. CONCLUSIONS: The data suggest that the ECM deposited as arcs, loops, and network patterns, accommodate the transport of plasma-derived molecules, (e.g., nutrients), to the tumor lesion, thus enhancing tumor growth and progression, and facilitating infiltration of tumor tissue by host-derived cells
