cutaneous melanoma

Images

 Macroscopy

• https://twitter.com/JMGardnerMD/status/751416426834059265
• https://twitter.com/BellaMicheleang/status/877899577877176321

 Small cutaneous melanoma

• https://twitter.com/Dermpathl/status/881917255658872832

Digital cases

 UI:1827 - Malignant melanoma, solar damage.
 JRC:99 : Desmoplastic malignant melanoma.
 JRC:10632 : Spndle cell malignant melanoma.
 JRC:10642 : Cutaneous melanoma.
 JRC:10647 : Cutaneous melanoma.
 JRC:10650 : Cutaneous melanoma in a child.
 JRC:10651 : Cutaneous melanoma.

Definition: Melanoma, in its advanced stages, is the most deadly form of skin cancer due to its high metastatic potential and drug resistance.

Alterations in expression or activity of various genes and signaling pathways promote melanoma development.

Classification

 lentigo maligna melanoma (10–40%)
 superficial spreading melanoma (SSM) (30–60%)[1343]
 nodular melanoma (15–35%)
 acral lentiginous melanoma (5–10%)
 desmoplastic melanoma (and neurotropic melanoma) (rare)
 miscellaneous group (rare)

Variants

 neurotropic melanoma

Epidemiology

 A positive family history of the disease is among the most established risk factors for CMM; it is estimated that 10% of CMM cases result from an inherited predisposition. Mutations in CDKN2A and CDK4 genes have been shown to confer an increased risk of CMM and account for only 20%-25% of families with multiple cases.

Physiopathology

Most melanomas arise within the epidermis (melanoma in situ) and then invade across the basement membrane.

These melanoma cells escape from control by keratinocytes through five major mechanisms:

 (1) downregulation of receptors important for communication with keratinocytes such as E-cadherin, P-cadherin, and desmoglein, which is achieved through growth factors such as hepatocyte growth factor, platelet-derived growth factor, and endothelin-1 produced by fibroblasts or keratinocytes;
 (2) upregulation of receptors and signaling molecules important for melanoma cell-melanoma cell and melanoma cell-fibroblast interactions such as N-cadherin, Mel-CAM, and zonula occludens protein-1;
 (3) deregulation of morphogens such as Notch receptors and their ligands;
 (4) loss of anchorage to the basement membrane because of an altered expression of cell-matrix adhesion molecules;
 (5) increased elaboration of metal-loproteinases.

Types

 lentigo maligna melanoma (10–40%)
 superficial spreading melanoma (30–60%)
 nodular melanoma (15–35%)
 acral lentiginous melanoma (5–10%)
 desmoplastic (and neurotropic) melanoma (rare)
 miscellaneous group (rare)

• melanomas arising in blue nevi
• minimal deviation melanoma

Variants

 myxoid melanoma (11807440, 9711669)
 desmoplastic melanoma
 melanoma with ganglioneuroblastic differentiation (10328091)

Tumoral predisposition

 melanoma-prone families with germline mutations of CDKN2A (17492760)

Susceptibility loci

 CDKN2A mutations
 CDK4 mutations
 1p22 (12844286)

 SNP in ATM (rs1801516) (21983787)
 SNP in MX2 (rs45430) (21983787)
 SNP adjacent to CASP8 (rs13016963) (21983787)
 SNP at 1q21.3 (rs7412746) (21983785)

Deleted loci

 9p21: CDKN2A or p16(INK4) inactivation (MIM.600160)
 6p25
 6q23
 11q13

Gene amplifications

 CDK4 and MDM2 amplification by 12q14 amplification (16419059)

Prognosis

 tumor thickness

• Clark level system
   ulcerative state

Checklist

 Classification
 Level (Clark)
 Thickness (Breslow score)
 Growth mode
 Main cellular population
 Mitosis count (10 HPF)
 Ulceration
 Regression
 Inflammatory reaction
 Neurotropism
 Endovascular tumoral embols
 Permeation nodule
 Associated naevus
 Exeresis
 Margins

Prognostic factors

 Mitotic rate

• The mitotic rate has important prognostic significance.
• A rate greater than 6/mm2 was initially thought to be the significant level but the study of Azzola et al found that there were no significant survival differences for the stepwise increases in mitotic activity beyond 1 mitosis/mm2.
• The product of the thickness in millimeters and the number of mitoses per square millimeter (the prognostic index) may give prognostic information.
• The mitotic rate coulod be not an independent prognosticator because it is significantly associated with tumor thickness and ulceration.

Animal model

 Xiphophorus (17034900)

Protocols

 CAP protocol, June 2012. Based on AJCC/UICC TNM, 7th edition.

See also

 melanocytic tumors

Reviews

 Miller AJ, Mihm MC Jr. Melanoma. N Engl J Med. 2006 Jul 6;355(1):51-65. PMID: 16822996

 Smalley KS, Herlyn M. Towards the targeted therapy of melanoma. Mini Rev Med Chem. 2006 Apr;6(4):387-93. PMID: 16613575

 Smalley KS, Herlyn M. Targeting intracellular signaling pathways as a novel strategy in melanoma therapeutics. Ann N Y Acad Sci. 2005 Nov;1059:16-25. PMID: 16382039

 Meierjohann S, Schartl M. From Mendelian to molecular genetics: the Xiphophorus melanoma model. Trends Genet. 2006 Oct 9; PMID: 17034900

 Chudnovsky Y, Khavari PA, Adams AE. Melanoma genetics and the development of rational therapeutics. J Clin Invest. 2005 Apr;115(4):813-24. PMID: 15841168

 Chin L. The genetics of malignant melanoma: lessons from mouse and man. Nat Rev Cancer. 2003 Aug;3(8):559-70. PMID: 12894244

 Merlino G, Noonan FP. Modeling gene-environment interactions in malignant melanoma. Trends Mol Med. 2003 Mar;9(3):102-8. PMID: 12657431

 Satyamoorthy K, Bogenrieder T, Herlyn M. No longer a molecular black box—new clues to apoptosis and drug resistance in melanoma. Trends Mol Med. 2001 May;7(5):191-4. PMID: 11325619

References

 Fluorescence In Situ Hybridization (FISH) as an Ancillary Diagnostic Tool in the Diagnosis of Melanoma. Gerami P, Jewell SS, Morrison LE, Blondin B, Schulz J, Ruffalo T, Matushek P 4th, Legator M, Jacobson K, Dalton SR, Charzan S, Kolaitis NA, Guitart J, Lertsbarapa T, Boone S, Leboit PE, Bastian BC. Am J Surg Pathol. 2009 Jun 24. PMID: 19561450

 Kannengiesser C, Dalle S, Leccia MT, Avril MF, Bonadona V, Chompret A, Lasset C, Leroux D, Thomas L, Lesueur F, Lenoir G, Sarasin A, Bressac-de Paillerets B. New founder germline mutations of CDKN2A in melanoma-prone families and multiple primary melanoma development in a patient receiving levodopa treatment. Genes Chromosomes Cancer. 2007 Aug;46(8):751-60. PMID: 17492760

 Muthusamy V, Hobbs C, Nogueira C, Cordon-Cardo C, McKee PH, Chin L, Bosenberg MW. Amplification of CDK4 and MDM2 in malignant melanoma. Genes Chromosomes Cancer. 2006 May;45(5):447-54. PMID: 16419059