Congenital Melanocytic Nevi, Associated Neoplasms, and Pediatric Melanoma

Barnhill, Raymond L.; Spatz, Alan

doi:10.1007/978-3-642-38385-4_6

Cited by 5 publications

(4 citation statements)

References 117 publications

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“…Rather, most nevi form later on in life, typically during the first and second decades. 17,18 Total nevus number in any given individual is thought to peak during the third decade of life. 19 This peak is due to reduced formation of new nevi (which becomes less common after 30 years of age) combined with the clinical regression of some existing nevi.…”

Section: Melanocytic Nevimentioning

confidence: 99%

Melanocytic nevi and melanoma: unraveling a complex relationship

2017

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Approximately 33% of melanomas are derived directly from benign, melanocytic nevi. Despite this, the vast majority of melanocytic nevi, which typically form as a result of BRAFV600E-activating mutations, will never progress to melanoma. Herein, we synthesize basic scientific insights and data from mouse models with common observations from clinical practice to comprehensively review melanocytic nevus biology. In particular, we focus on the mechanisms by which growth arrest is established after BRAFV600E mutation. Means by which growth arrest can be overcome and how melanocytic nevi relate to melanoma are also considered. Finally, we present a new conceptual paradigm for understanding the growth arrest of melanocytic nevi in vivo termed stable clonal expansion. This review builds upon the canonical hypothesis of oncogene-induced senescence in growth arrest and tumor suppression in melanocytic nevi and melanoma.

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Section: Melanocytic Nevimentioning

confidence: 99%

Melanocytic nevi and melanoma: unraveling a complex relationship

2017

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“…The staining patterns in nevi and melanomas could have important implications. First, our observations of tubulin β-3 staining gradient in nevi, in combination with: (i) the morphological (Barnhill, 2014;Lund and Stobbe, 1949) and (ii) antigen-expressing resemblance (Aso et al, 1988) of nevus cells of deeper dermis with Schwann cells, as well as the current knowledge of (iii) lack of tubulin β-3 expression in Schwann cells (Zeisel et al, 2018) and (iv) evidence for melanocytes that originate from Schwann cell precursors (Adameyko et al, 2009), could support the notion that some nevi might have a dual origin: a component resulting from intraepidermal melanocytes that would migrate downward into the dermis and a component resulting from schwann cells that would migrate upward (Masson, 1951). Second, our observations of worse prognosis for melanomas with areas of tubulin β-3 loss, in combination with (i) previous reports that the loss of tubulin β-3 expression in melanoma samples was associated with poor prognosis (Shimizu et al, 2016;Akasaka et al, 2009) and (ii) our findings in study I that depletion of tubulin β-3 induced a senescence-like phenotype of young melanocytes and melanoma cells in vitro (Orfanidis et al, 2017) suggest that poor prognosis in melanoma with loss of tubulin β-3 may be related to the induction of growth arrest in melanoma cells; however such detrimental effect of senescence in cancer biology is debatable (Schosserer et al, 2017).…”

Section: Importance Of the Findingsmentioning

confidence: 81%

Identification and clinical evaluation of senescence-associated markers to distinguish melanocytic nevi from melanomas

Orfanidis

2020

Linköping University Medical Dissertations

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Melanoma is a form of cancer that develops in melanocytes. While it represents only 5% of skin malignancies, it is the most aggressive and lethal. Benign proliferation of these cells form the melanocytic nevi. The definitive diagnosis of melanocytic nevi or melanoma lesions is histopathologic. However, it is estimated that a correct diagnosis is established by means of standard skin biopsy in only 83% of the melanocytic lesions; of the remaining cases 8% and 9% are overinterpreted (false positives) and under-interpreted (false negatives), respectively. This underscores the importance of additional diagnostic tests. Since cellular senescence is considered to be a tumor suppressive mechanism, immuno-histochemistry using senescence markers has been suggested for the evaluation of difficult melanocytic lesions; however, the routinely used senescence markers lack the ability to distinguish nevi from melanoma. The general aim of this thesis is therefore to identify novel senescence markers that may aid in melanoma diagnosis.In study I, we established a cellular model with nevus-mimicking characteristics consisting in primary melanocytes that become senescent. Transcriptomic analysis allowed expanding the set of senescence-associated markers that could distinguish nevi from melanoma and identifying tubulin β-3 as a potential diagnostic marker. Depletion of tubulin β-3 and pretreatment with tubulin destabilizing drugs in melanocytes and melanoma cells induced a senescence-like phenotype in vitro. In particular, reduced migration capacity and induction of cell cycle arrest in G2/M phase of the cell cycle was demonstrated.In study II, a potential inter-cellular signaling pathway between melanoma cells and stromal fibroblasts, that might facilitate melanoma invasion, was investigated. Ultraviolet (UV) radiation was shown, both in melanoma cells and fibroblasts, to promote the release and activation of TGF-β1 and subsequent increase in expression of the serine protease FAP-α, a protein that plays role in extracellular matrix degradation and therefore facilitates the invasion of melanoma cells. Such mechanism was not functional in senescent melanocytes.In study III, it was shown that tubulin β-3 immunostaining aids in the diagnosis of nevi and melanomas. The diagnostic criterium was the tubulin β-3 gradient within the melanocytic nevi that was no longer apparent in melanoma. Different patterns of tubulin β-3 immunostaining in melanoma were described, dermoscopy-immunohistochemistry associations were found, specific dermoscopic features highlighted, and the prognostic value of this tubulin β-3 marker was examined. The progression rate in patients whose melanomas had areas with loss of tubulin β-3 was 4 times higher than in patients without this feature, although statistical significance could not be reached (p=0.06).In conclusion, transcriptomic analysis expanded the set of senescence-associated markers that could distinguish nevi from melanoma and identified tubulin β-3 as novel immunohistochemistry marker shown to have diagn...

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“…Areas with neuroid differentiation with neurofibromatous tissue and vascular malformation, consistent with heterologous tissue, were also identified (Figure ). Biopsies from two pedunculated nodules on the right side of the abdomen and hip and one nodules each on the abdomen, right thigh, and right groin had the same histopathologic pattern of atypical melanocytic proliferation with a large number of mitoses, consistent with atypical nodular melanocytic proliferations . Initial reports had mitotic figures as low as 6/mm 2 , without apoptosis or necrosis.…”

Section: Case Reportmentioning

confidence: 88%

Aggressive melanoma in an infant with congenital melanocytic nevus syndrome and multiple, NRAS and BRAF mutation‐negative nodules

Carrillo

Vindenes

Kinsler

et al. 2018

Pediatric Dermatology

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We report the case of a newborn boy with multinodular NRAS and BRAF mutation-negative congenital melanocytic nevi and cerebral lesions compatible with congenital intraparenchymal melanosis. Histopathology from skin lesions showed atypical nodular melanocytic proliferation with marked melanocytic atypia and a large number of mitoses and apoptosis, indicating aggressive proliferation. The child developed several new subcutaneous tumors and multiple internal lesions, which were confirmed to be metastases, and died at 5 months of age. This case may represent an infantile melanoma developing from a giant congenital melanocytic nevus or a congenital melanoma.

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Congenital Melanocytic Nevi, Associated Neoplasms, and Pediatric Melanoma

Cited by 5 publications

References 117 publications

Melanocytic nevi and melanoma: unraveling a complex relationship

Melanocytic nevi and melanoma: unraveling a complex relationship

Identification and clinical evaluation of senescence-associated markers to distinguish melanocytic nevi from melanomas

Aggressive melanoma in an infant with congenital melanocytic nevus syndrome and multiple, NRAS and BRAF mutation‐negative nodules

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