Primary cutaneous melanoma. Optimized cutoff points of tumor thickness and importance of clark's level for prognostic classification

Büttner, Petra; Garbe, Claus; Bertz, Joachim; Burg, Günter; dʼHoedt, B; Drepper, H.; Guggenmoos-Holzmann, I.; Lechner, W.; Lippold, A.; Orfanos, Constantin E.; Peters, A.; Rassner, G.; Stadler, Rudolf; Stroebel, Waltraud

doi:10.1002/1097-0142(19950515)75:10<2499::aid-cncr2820751016>3.0.co;2-8

Cited by 148 publications

(56 citation statements)

References 25 publications

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“…In particular, if the tumor thickness exceeds 3.5 mm, it loses predictive power. 25 We conclude that in neuroectoderm-derived cancers, melanocytic tumors and glioblastomas, overexpression of the cell cycle controller pRb is limited to the malignant phenotype. pRb is markedly overexpressed in actively growing parts of malignant melanomas and coincident with hyperphosphorylation and possible pRb inactivation.…”

Section: Discussionmentioning

confidence: 86%

Overexpression and hyperphosphorylation of retinoblastoma protein in the progression of malignant melanoma

et al. 2005

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Mutation, absence or abnormal functioning of retinoblastoma protein are fundamental elements of uncontrolled growth in human cancer. In this study, we analyze the expression of retinoblastoma protein and phosphorylated retinoblastoma protein in melanocytic tumors in vivo. Real-time RT-PCR and immunohistochemistry (tissue microarrays and conventional histological sections) reveal that retinoblastoma protein is progressively upregulated in advanced and metastatic malignant melanomas in vivo. However, this increase is paralleled by increased retinoblastoma protein inactivation due to protein phosphorylation. Interestingly, retinoblastoma protein phosphorylation occurs not homogeneously, but with a 'growth zone'-related pattern. In superficial spreading melanomas a subepidermal-lateral maximum of phosphorylated retinoblastoma protein can be frequently observed. Accordingly, nodular vertically invasive melanomas are characterized by a strong staining of phosphorylated retinoblastoma protein in deep-dermal invading protrusions of the tumor. Furthermore, Kaplan-Meier analysis of 13 cases of advanced melanomas with long-time follow-up suggests a significant negative impact of retinoblastoma protein phosphorylation on survival of melanoma patients independent of tumor thickness. We conclude that the evaluation of phosphorylated retinoblastoma protein in melanocytic tumors could become a helpful adjunct in clinicopathological routine. The main principle of cell cycle homeostasis is the phosphorylation-dependent activation and deactivation of regulatory proteins upstream of retinoblastoma protein (pRb), which represents the central cycle-controlling element. At the G1/S transition, the antiproliferative function of active, hypophosphorylated pRb is mediated by its binding capacity to proproliferative transcription factors such as E2F, c-Myc, ATF-2 and c-Abl. 1 Surprisingly, with the exception of retinoblastoma, osteosarcoma and small cell lung carcinoma, the overall rate of pRbmutations in the vast majority of human cancers is either extremely low or not existent. 2 Also in malignant melanomas, the loss of cell cycle control is thought to be due to a lack of pRb activity and not to lack of expression or mutation. 3,4 Currently, the concept is arguably accepted that persistent inactivation and hyperphosphorylation of wild-type pRb in melanomas is caused by a sustained cyclindependent kinase (cdk) activity. [5][6][7] In uveal malignant melanomas, Brantley et al 8,9 have recently reported an increased pRb phosphorylation at Ser807/811. Since they have also detected a high cyclin D expression, the hypothesis of a functional inactivation of pRb due to cyclin-and cdk-dependent hyperphosphorylation was further substantiated.To the best of our knowledge, no detailed studies have been performed to elucidate the pRb phosphorylation status in in vivo samples of cutaneous melanocytic tumors. In particular, studies on the impact of hyperphosphorylated pRb on melanoma progression are still lacking. Therefore, in this study we analyze to...

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Section: Discussionmentioning

confidence: 86%

Overexpression and hyperphosphorylation of retinoblastoma protein in the progression of malignant melanoma

et al. 2005

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“…6 One German database showed that a Clark level III tumor had a 3.5 times greater risk of disease progression than did a level II tumor in melanomas r1.0 mm in thickness. 57 …”

Section: Thickness (Breslow)mentioning

confidence: 99%

Prognosticators of melanoma, the melanoma report, and the sentinel lymph node

2006

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Since the 1960s, the clinical characteristics of melanoma, its histopathology and its biological basis have been the subject of intense study at pigmented lesion clinics in North America, Europe, and Australia. More recently, the immense database of the Melanoma Committee of the American Joint Committee on Cancer (AJCC) has been exploited through complex mathematical models to measure the impact of various histologic features of primary melanomas and of sentinel lymph node deposits and to correlate these parameters with patient survival. The wealth of modern information available to pathologists and clinicians has become of vital interest to the prognostication of the individual patient with melanoma. The purpose of this review is to bring to the attention of anatomic pathologists the essential characteristics of the pathology report for primary cutaneous melanoma in the modern era.

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“…However, we did not observe significant changes in SOX2 expression at different stages of disease progression (Figure 1b). Breslow depth, which is defined as the total vertical height of the tumor, is one major important prognostic predictor of death from melanoma 29,30 . Therefore, we plotted SOX2 expression from human primary melanomas to Breslow thickness.…”

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confidence: 99%

Sox2 is dispensable for primary melanoma and metastasis formation

et al. 2017

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Tumor initiation and metastasis formation in many cancers have been associated with emergence of a gene expression program normally active in embryonic or organ-specific stem cells. In particular, the stem cell transcription factor Sox2 is not only expressed in a variety of tumors, but is also required for their formation. Melanoma, the most aggressive skin tumor, derives from melanocytes that during development originate from neural crest stem cells. While neural crest stem cells do not express Sox2, expression of this transcription factor has been reported in melanoma. However, the role of Sox2 in melanoma is controversial. To study the requirement of Sox2 for melanoma formation, we therefore performed CRISPR-Cas9-mediated gene inactivation in human melanoma cells. In addition, we conditionally inactivated Sox2 in a genetically engineered mouse model, in which melanoma spontaneously develops in the context of an intact stroma and immune system. Surprisingly, in both models, loss of Sox2 did neither affect melanoma initiation, nor growth, nor metastasis formation. The lack of a tumorigenic role of Sox2 in melanoma might reflect a distinct stem cell program active in neural crest stem cells and during melanoma formation.

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Primary cutaneous melanoma. Optimized cutoff points of tumor thickness and importance of clark's level for prognostic classification

Cited by 148 publications

References 25 publications

Overexpression and hyperphosphorylation of retinoblastoma protein in the progression of malignant melanoma

Overexpression and hyperphosphorylation of retinoblastoma protein in the progression of malignant melanoma

Prognosticators of melanoma, the melanoma report, and the sentinel lymph node

Sox2 is dispensable for primary melanoma and metastasis formation

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