Methods in molecular biology (Clifton, N.J.), 2015
Mouse models of melanoma have proven invaluable in the delineation of key molecular events involv... more Mouse models of melanoma have proven invaluable in the delineation of key molecular events involved in disease progression in humans and provide potential preclinical models for therapeutic testing (Damsky and Bosenberg, Pigment Cell Melanoma Res 25(4):404-405, 2012; Walker et al., Pigment Cell Melanoma Res 24(6):1158-1176, 2011). Here we concentrate on the clinicopathological analysis of melanocytic tumors.
We examined a combined (dermoscopic-pathological) approach to the telediagnosis of melanocytic sk... more We examined a combined (dermoscopic-pathological) approach to the telediagnosis of melanocytic skin lesions. A store-and-forward teleconsultation was simulated. Dermoscopic and histopathology images from 12 melanocytic lesions were stored in a telepathology workstation. A dermoscopy consultant, a histopathology consultant and an expert in dermoscopic-pathological correlation gave their diagnoses and comments on the images. The consensus diagnosis between two teleconsultants on the original histological slides was regarded as the gold standard. The diagnostic accuracy was 83% (including one false negative diagnosis of malignancy) for teledermoscopy and 100% for teledermatopathology. The combined approach detected one case that showed a much greater atypia on dermoscopy than on histopathology. In this case step-sections of the sample were deemed to be required for definite diagnosis. The combined approach was helpful in detecting macroscopic and microscope sampling errors of melanocytic lesions during teleconsultation.
We report on a systematic analysis of genotype-specific melanocyte (MC) UVR responses in transgen... more We report on a systematic analysis of genotype-specific melanocyte (MC) UVR responses in transgenic mouse melanoma models along with tumour penetrance and comparative histopathology. pRb or p53 pathway mutations cooperated with Nras(Q61K) to transform MCs. We previously reported that MCs migrate from the follicular outer root sheath into the epidermis after neonatal UVR. Here, we found that Arf or p53 loss markedly diminished this response. Despite this, mice carrying these mutations developed melanoma with very early age of onset after neonatal UVR. Cdk4(R24C) did not affect the MC migration. Instead, independent of UVR exposure, interfollicular dermal MCs were more prevalent in Cdk4(R24C) mice. Subsequently, in adulthood, these mutants developed dermal MC proliferations reminiscent of superficial congenital naevi. Two types of melanoma were observed in this model. The location and growth pattern of the first was consistent with derivation from the naevi, while the second appeared to be of deep dermal origin. In animals carrying the Arf or p53 defects, no naevi were detected, with all tumours ostensibly skipping the benign precursor stage in progression.
Journal of the American Academy of Dermatology, 2010
Early detection of basal cell carcinoma (BCC) is crucial to reduce the morbidity of this tumor. W... more Early detection of basal cell carcinoma (BCC) is crucial to reduce the morbidity of this tumor. We sought to investigate the variability and diagnostic significance of dermatoscopic features of BCCs. We conducted retrospective dermatoscopic analysis of 609 BCCs and 200 melanocytic and nonmelanocytic lesions, and assessment of interrater reliability of dermatoscopic BCC criteria. Lesions included nonpigmented (15.1%), lightly pigmented (33.2%), pigmented (42.7%), and heavily pigmented (9%) BCCs. Classic BCC patterns including arborizing telangiectasia (57.1%), blue/gray ovoid nests (47.5%), ulceration (39.2%), multiple blue/gray globules (26.1%), leaflike areas (15.9%), and spoke-wheel areas (9%) were significantly increased in pigmented BCCs compared with nonpigmented and heavily pigmented BCCs (P = .0001). Among nonclassic BCC patterns, we detected short fine superficial telangiectasia (10%) and multiple small erosions (8.5%), and described two new patterns named "concentric structures" (7.6%) and "multiple in-focus blue/gray dots" (5.1%). Dermatoscopic features suggestive of melanocytic lesions (eg, multiple brown to black dots/globules, blue/white veillike structures, and nonarborizing vessels) were observed in 40.6% BCCs and significantly increased in heavily pigmented BCCs (P < .0001). Expert observers provided an accurate (sensitivity: 97%) and reliable (K: 87%) dermatoscopic diagnosis of BCC, although a significant difference in terms of specificity (P = .0002) and positive predictive value (P = .0004) was found. Arborizing telangiectasia, leaflike areas, and large blue/gray ovoid nests represented reliable and robust diagnostic parameters. The study was retrospective. BCCs show a large spectrum of global and local dermatoscopic features; heavily pigmented BCCs show the most challenging combinations of dermatoscopic features.
Expression of cell surface molecules that mediate cell-matrix and cell-cell interactions largely ... more Expression of cell surface molecules that mediate cell-matrix and cell-cell interactions largely contributes to the ability of melanoma cells to migrate and spread beyond the primary site of the tumor. CD44, the principal cell-surface receptor for hyaluronate, and its numerous splice variants have been reported to play a crucial role in invasion and the metastatic process of different human neoplasms, including primary malignant melanoma (PMM). The aim of this study was to clarify which isoforms of CD44 (standard CD44 and CD44 variants) are distributed in PMM with a vertical tumor thickness of >1.4 mm. Staining of CD44 standard (CD44s) and splice variants was further examined for diagnostic and prognostic relevance in a panel of melanocytic skin lesions. Ten cases of PMM with Breslow >1.4 mm were analysed by immunohistochemistry using monoclonal antibodies specific for CD44s and the splice variants v3, v5, v6, v7, v7-8, and v10. In addition, using anti-CD44s, v5, and v6 antibodies, 55 melanocytic lesions, including dermal nevi (n=12), Clark nevi (dysplastic nevi) (CN; n=11), melanoma in situ (Mis; n=8), PMM (n=18), and cutaneous metastasis of malignant melanoma (cMMM; n=6) were assessed. Staining intensities were scored visually and evaluated by means of a staining index. In ten cases of PMM with a Breslow index >1.4 mm positive staining was ascertained for CD44s, v5 and for v6 in three cases. No staining was found for v3, v7, v7-8, and v10. Examination of CD44s, v5, and v6 in 55 melanocytic skin lesions revealed a high index for CD44s in all specimens and a weak staining of v5 in Mis; dermal nevi and CN did not stain for v5. However, in PMM and cMMM we found v5 to be strongly positive. The isoform v6 showed a variable index only in PMM, but without connection to established prognostic criteria. We conclude that CD44s and splice variants can not be regarded as indicators for tumor progression in malignant melanomas. However, v5 may potentially serve as a diagnostic marker for melanocytic skin lesions.
Methods in molecular biology (Clifton, N.J.), 2015
Mouse models of melanoma have proven invaluable in the delineation of key molecular events involv... more Mouse models of melanoma have proven invaluable in the delineation of key molecular events involved in disease progression in humans and provide potential preclinical models for therapeutic testing (Damsky and Bosenberg, Pigment Cell Melanoma Res 25(4):404-405, 2012; Walker et al., Pigment Cell Melanoma Res 24(6):1158-1176, 2011). Here we concentrate on the clinicopathological analysis of melanocytic tumors.
We examined a combined (dermoscopic-pathological) approach to the telediagnosis of melanocytic sk... more We examined a combined (dermoscopic-pathological) approach to the telediagnosis of melanocytic skin lesions. A store-and-forward teleconsultation was simulated. Dermoscopic and histopathology images from 12 melanocytic lesions were stored in a telepathology workstation. A dermoscopy consultant, a histopathology consultant and an expert in dermoscopic-pathological correlation gave their diagnoses and comments on the images. The consensus diagnosis between two teleconsultants on the original histological slides was regarded as the gold standard. The diagnostic accuracy was 83% (including one false negative diagnosis of malignancy) for teledermoscopy and 100% for teledermatopathology. The combined approach detected one case that showed a much greater atypia on dermoscopy than on histopathology. In this case step-sections of the sample were deemed to be required for definite diagnosis. The combined approach was helpful in detecting macroscopic and microscope sampling errors of melanocytic lesions during teleconsultation.
We report on a systematic analysis of genotype-specific melanocyte (MC) UVR responses in transgen... more We report on a systematic analysis of genotype-specific melanocyte (MC) UVR responses in transgenic mouse melanoma models along with tumour penetrance and comparative histopathology. pRb or p53 pathway mutations cooperated with Nras(Q61K) to transform MCs. We previously reported that MCs migrate from the follicular outer root sheath into the epidermis after neonatal UVR. Here, we found that Arf or p53 loss markedly diminished this response. Despite this, mice carrying these mutations developed melanoma with very early age of onset after neonatal UVR. Cdk4(R24C) did not affect the MC migration. Instead, independent of UVR exposure, interfollicular dermal MCs were more prevalent in Cdk4(R24C) mice. Subsequently, in adulthood, these mutants developed dermal MC proliferations reminiscent of superficial congenital naevi. Two types of melanoma were observed in this model. The location and growth pattern of the first was consistent with derivation from the naevi, while the second appeared to be of deep dermal origin. In animals carrying the Arf or p53 defects, no naevi were detected, with all tumours ostensibly skipping the benign precursor stage in progression.
Journal of the American Academy of Dermatology, 2010
Early detection of basal cell carcinoma (BCC) is crucial to reduce the morbidity of this tumor. W... more Early detection of basal cell carcinoma (BCC) is crucial to reduce the morbidity of this tumor. We sought to investigate the variability and diagnostic significance of dermatoscopic features of BCCs. We conducted retrospective dermatoscopic analysis of 609 BCCs and 200 melanocytic and nonmelanocytic lesions, and assessment of interrater reliability of dermatoscopic BCC criteria. Lesions included nonpigmented (15.1%), lightly pigmented (33.2%), pigmented (42.7%), and heavily pigmented (9%) BCCs. Classic BCC patterns including arborizing telangiectasia (57.1%), blue/gray ovoid nests (47.5%), ulceration (39.2%), multiple blue/gray globules (26.1%), leaflike areas (15.9%), and spoke-wheel areas (9%) were significantly increased in pigmented BCCs compared with nonpigmented and heavily pigmented BCCs (P = .0001). Among nonclassic BCC patterns, we detected short fine superficial telangiectasia (10%) and multiple small erosions (8.5%), and described two new patterns named "concentric structures" (7.6%) and "multiple in-focus blue/gray dots" (5.1%). Dermatoscopic features suggestive of melanocytic lesions (eg, multiple brown to black dots/globules, blue/white veillike structures, and nonarborizing vessels) were observed in 40.6% BCCs and significantly increased in heavily pigmented BCCs (P < .0001). Expert observers provided an accurate (sensitivity: 97%) and reliable (K: 87%) dermatoscopic diagnosis of BCC, although a significant difference in terms of specificity (P = .0002) and positive predictive value (P = .0004) was found. Arborizing telangiectasia, leaflike areas, and large blue/gray ovoid nests represented reliable and robust diagnostic parameters. The study was retrospective. BCCs show a large spectrum of global and local dermatoscopic features; heavily pigmented BCCs show the most challenging combinations of dermatoscopic features.
Expression of cell surface molecules that mediate cell-matrix and cell-cell interactions largely ... more Expression of cell surface molecules that mediate cell-matrix and cell-cell interactions largely contributes to the ability of melanoma cells to migrate and spread beyond the primary site of the tumor. CD44, the principal cell-surface receptor for hyaluronate, and its numerous splice variants have been reported to play a crucial role in invasion and the metastatic process of different human neoplasms, including primary malignant melanoma (PMM). The aim of this study was to clarify which isoforms of CD44 (standard CD44 and CD44 variants) are distributed in PMM with a vertical tumor thickness of >1.4 mm. Staining of CD44 standard (CD44s) and splice variants was further examined for diagnostic and prognostic relevance in a panel of melanocytic skin lesions. Ten cases of PMM with Breslow >1.4 mm were analysed by immunohistochemistry using monoclonal antibodies specific for CD44s and the splice variants v3, v5, v6, v7, v7-8, and v10. In addition, using anti-CD44s, v5, and v6 antibodies, 55 melanocytic lesions, including dermal nevi (n=12), Clark nevi (dysplastic nevi) (CN; n=11), melanoma in situ (Mis; n=8), PMM (n=18), and cutaneous metastasis of malignant melanoma (cMMM; n=6) were assessed. Staining intensities were scored visually and evaluated by means of a staining index. In ten cases of PMM with a Breslow index >1.4 mm positive staining was ascertained for CD44s, v5 and for v6 in three cases. No staining was found for v3, v7, v7-8, and v10. Examination of CD44s, v5, and v6 in 55 melanocytic skin lesions revealed a high index for CD44s in all specimens and a weak staining of v5 in Mis; dermal nevi and CN did not stain for v5. However, in PMM and cMMM we found v5 to be strongly positive. The isoform v6 showed a variable index only in PMM, but without connection to established prognostic criteria. We conclude that CD44s and splice variants can not be regarded as indicators for tumor progression in malignant melanomas. However, v5 may potentially serve as a diagnostic marker for melanocytic skin lesions.
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