Fig. 24.23 Melanoma.(A)Lesionstendtobelargerthannevi,withirregularcontoursandvariablepigmentation.Macularareasindicatesuperficial(radial)growth,whileelevatedareasindicatedermalinvasion(verticalgrowth).(B)Radialgrowthphase,withspreadofnestedandsinglemelanomacellswithintheepidermis.(C)Verticalgrowthphase,withnodularaggregatesofinfiltratingtumorcellswithinthedermis.(D)Melanomacellswithhyperchromaticirregularnucleiofvaryingsizethathaveprominentnucleoli.Anatypicalmitoticfigureispresentinthecenterofthefield).Theinset showsasentinellymphnodecontainingatinyclusterofmetastaticmelanoma(arrow), detectedbystainingforthemelanocyticmarkerHMB-45.
Agents that selectively inhibit mutant BRAF and KIT have produced dramatic responses in patients with metastatic tumors with BRAF and KIT mutations, respectively, an encouraging development in a previously hopeless disease. More recently, immune checkpoint inhibitors have been shown to be effective at stabilizing metastatic disease and in some instances causing remarkable tumor regression and even clinical remissions. Immune checkpoint inhibitors are antibodies that interfere with the function of proteins found on the surface of T lymphocytes that abrogate cytotoxic T cell responsiveness. By blocking these pathways, checkpoint inhibitors reactivate the host T-cell response, which otherwise is held at bay. Current efforts are focused on building upon these successes by using combinations of different checkpoint inhibitors, as well as checkpoint inhibitors together with other targeted therapies such as BRAF inhibitors.
MELANOCYTICLESIONS,BENIGNANDMALIGNANT
Mostmelanocytic nevi haveactivatingmutationsinBRAF orlessoftenNRAS, butthevastmajorityneverundergoesmalignanttransformation.
Mostsporadicdysplastic nevi arebestregardedasmarkersofmelanomariskratherthanpremalignantlesions.Theyarecharacterizedbyarchitecturaldisorderandcytologicatypia.
Melanoma isahighlyaggressivemalignancy;tumorsonlyafewmillimetersinthicknesscangiverisetodeadlymetastases.
Inmostcases,melanomaprogressesfromanintraepithelial(insitu)toaninvasive(dermal)form.Characteristicsofthedermaltumorsuchasdepthofinvasionandmitoticactivitycorrelatewithsurvival.
Bastian BC: The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia, Ann Rev Pathol 9:239, 2014. [A modified classification of melanoma based on both clinical and genetic features. Such molecular classification schemes are critical for progress in targeted therapy.]
Cancer Genome Atlas Network: Genomic classification of cutaneous melanoma, Cell 161:1681, 2015. [A genomic study of cutaneous melanoma that highlights the different molecular subtypes and common pathogenic pathways.]
Elder DE: Dysplastic nevi: an update, Histopathology 56:112, 2010. [A balanced presentation of the histology and pathogenesis of dysplastic nevi and their relationship to melanoma.]
Epstein EH: Basal cell carcinomas: attack of the hedgehog, Nat Rev Cancer 8:743, 2008. [A succinct review of the epidemiology, clinical presentation, molecular pathogenesis, and novel treatment options for basal cell carcinoma.]
Nestle FO, Kaplan DH, Barker J: Psoriasis, N Engl J Med 361:496, 2009. [A discussion of the pathogenesis, clinical features, and targeted treatment options for psoriasis.]