International Journal of Molecular Sciences Review Melanoma Biomarkers and Their Potential Application for In Vivo Diagnostic Imaging Modalities 1,2, 3, 1 1 1,2 Monica Hessler y , Elmira Jalilian y, Qiuyun Xu , Shriya Reddy , Luke Horton , Kenneth Elkin 1,2, Rayyan Manwar 1,4 , Maria Tsoukas 5, Darius Mehregan 2 and Kamran Avanaki 4,5,* 1 Department of Biomedical Engineering, Wayne State University, Detroit, MI 48201, USA; [email protected] (M.H.); [email protected] (Q.X.); [email protected] (S.R.); [email protected] (L.H.); [email protected] (K.E.); [email protected] (R.M.) 2 Department of Dermatology, School of Medicine, Wayne State University School of Medicine, Detroit, MI 48201, USA; [email protected] 3 Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA; [email protected] 4 Richard and Loan Hill Department of Bioengineering, University of Illinois at Chicago, Chicago, IL 60607, USA 5 Department of Dermatology, University of Illinois at Chicago, Chicago, IL 60607, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-312-413-5528 These authors have contributed equally. y Received: 3 September 2020; Accepted: 12 December 2020; Published: 16 December 2020 Abstract: Melanoma is the deadliest form of skin cancer and remains a diagnostic challenge in the dermatology clinic. Several non-invasive imaging techniques have been developed to identify melanoma. The signal source in each of these modalities is based on the alteration of physical characteristics of the tissue from healthy/benign to melanoma. However, as these characteristics are not always sufficiently specific, the current imaging techniques are not adequate for use in the clinical setting. A more robust way of melanoma diagnosis is to “stain” or selectively target the suspect tissue with a melanoma biomarker attached to a contrast enhancer of one imaging modality. Here, we categorize and review known melanoma diagnostic biomarkers with the goal of guiding skin imaging experts to design an appropriate diagnostic tool for differentiating between melanoma and benign lesions with a high specificity and sensitivity. Keywords: melanoma; biomarkers; skin cancer; benign nevi; non-invasive 1. Introduction Melanoma is the fifth most common cancer type in the United States and is increasing in morbidity and mortality. Since 1975, the melanoma death rate has increased 16% while the incidence has quadrupled in both sexes, with male cases outnumbering female [1]. From 2007 to 2016, there has been a decrease in the incidence rate of 1.2% per year in individuals younger than 50 years of age, while the incidence rate is increasing by 2.2% per year for individuals >50 years old [2]. Although the average age of diagnosis is 63 and incidence increases with age, melanoma afflicts all demographics and is frequently diagnosed in individuals under the age of 30 [3]. The American Cancer Society anticipates 100,350 new cases of melanoma in 2020, with an estimated 6850 people ultimately succumbing to melanoma just this year [4]. Int. J. Mol. Sci. 2020, 21, 9583; doi:10.3390/ijms21249583 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 9583 2 of 27 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 27 Annually, estimates show that melanoma accounts for 65%–75% of skin cancer deaths despite Annually, estimates show that melanoma accounts for 65%–75% of skin cancer deaths despite comprising only 1% of all diagnosed skin cancers [3–6]. The thickness and invasion of the lesion in comprising only 1% of all diagnosed skin cancers [3–6]. The thickness and invasion of the lesion in the skin is associated with metastatic capacity and these features are the most established predictors the skin is associated with metastatic capacity and these features are the most established predictors of mortality at diagnosis, rendering early diagnosis essential to patient prognosis. See Figure1 for of mortality at diagnosis, rendering early diagnosis essential to patient prognosis. See Figure 1 for estimated time to metastasis of the different melanoma subtypes, emphasizing the importance of early estimated time to metastasis of the different melanoma subtypes, emphasizing the importance of and accurate diagnosis. early and accurate diagnosis. FigureFigure 1.1.Estimated Estimated timetime toto metastasismetastasis ofof melanomamelanoma subtypessubtypes(reproduced (reproducedfrom from“Prognostic “Prognosticfactors factors forformetastasis metastasis inin cutaneouscutaneous melanoma”melanoma” byby CherobinCherobin etet al.al. andand isis licensedlicensed underunder CCCC BY-NC-NDBY-NC-ND 3.03.0 fromfrom [ 7[7]]).). Kaplan–MeierKaplan–Meier curvecurve showingshowing thethe fourfour didifferentfferent majormajor subtypessubtypes ofof melanomamelanoma andand thethe timetime (in(in weeks) weeks) forfor the the development development ofof metastasis metastasis inin patients patients withwith primary primary cutaneouscutaneous melanomamelanoma inin thethe timespantimespan of of 1995–2012 1995–2012 [7]. [7]. This This emphasizes emphasizes the need the forneed the earlyfor the detection early detec and diagnosistion and of diagnosis melanoma. of melanoma. Patients with localized tumors (Breslow thickness < 0.8 mm) that undergo surgical excision can have aPatients 5-year survivalwith localized rate that tumors is >97% (Breslow [8]. The thickness survival < rate 0.8 dropsmm) that to 36% undergo with nodalsurgical metastasis excision and can tohave less a than5-year 10% survival for patients rate that with is >97% distant [8]. metastasis The survival [9]. rate There drops are to four 36% di ffwitherent nodal major metastasis subtypes and of melanomato less than including 10% for patie superficialnts with spreading distant metastasis (60%–70%), [9]. nodular There are (15%–30%), four different lentigo major maligna subtypes (10%), of andmelanoma acral lentiginous including superficial (5%) [10]. Otherspreading rare (60 variants%–70%), of nodular melanoma (15 include%–30%), desmoplastic, lentigo maligna spitzoid, (10%), melanomaand acral withinlentiginous blue nevus(5%) or[10] melanoma. Other rare in a variants congenital of nevus, melanoma pigmented include epithelioid desmoplastic, melanocytoma, spitzoid, andmelanoma other variants. within blue nevus or melanoma in a congenital nevus, pigmented epithelioid melanocytoma,Although lesions and other can variants. occur anywhere on the body involving both sun exposed and non-sun exposedAlthough areas, thelesions most can common occur locationsanywhere are on the the head, body neck, involving back, andboth lower sun exposed extremities and [ 11non]. It-sun is unsurprisingexposed areas, that the the most most common utilized diagnosticlocations are method the head, for cutaneous neck, back, melanoma and lower is a extremities full body skin [11]. exam It is byunsurprising a specialist that using the the most ABCDE utilized criteria diagnostic of asymmetry, method border for cutaneous irregularity, melanoma color variation, is a full body diameter skin (>exam6 mm), by anda specialist evolution, using accompanied the ABCDE by criteria dermoscopy of asymmetry, and mole mappingborder irregularity, techniques, color and ultimately variation, followeddiameter by (>6 biopsy mm), andand histopathologicevolution, accompanied analysisof by suspicious dermoscopy lesions and thatmole appear mapping diff erenttechniques, than other and molesultimately on the followed body [ 5by]. biopsy Physical and examination histopathologic relies analysis heavily of on suspicious physician lesions expertise that andappear experience; different therefore,than other effi molescacy is on variable the body with [5]. a sensitivity Physical ofexamination 57%–90% and relies a specificity heavily on of 59%–90%physician [11 expertise]. Currently, and theexperience; most reliable therefore method, efficacy for the is diagnosis variable ofwith malignant a sensitivity melanoma of 57% is– histopathology,90% and a specificity which of is 59 obtained%–90% [11]. Currently, the most reliable method for the diagnosis of malignant melanoma is histopathology, which is obtained through biopsy techniques. Skin biopsy is more invasive and can be painful, traumatic, costly, and holds some risk of infection, scarring, or delayed healing at more challenging Int. J. Mol. Sci. 2020, 21, 9583 3 of 27 through biopsy techniques. Skin biopsy is more invasive and can be painful, traumatic, costly, Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 3 of 27 and holds some risk of infection, scarring, or delayed healing at more challenging anatomic locations. Biopsy results also take time to get back to the patient, see Figure2 for an overview of the biopsy anatomic locations. Biopsy results also take time to get back to the patient, see Figure 2 for an process and timeline. overview of the biopsy process and timeline. FigureFigure 2. 2. MelanomaMelanoma d diagnosticiagnostic w workfloworkflow ( (reproducedreproduced from from [12]) [12]).. TheThe consequences consequences of of missing missing a a malignant melanoma melanoma are are grave. As As such, such, many many biopsies biopsies are are needlesslyneedlessly performed onon clinicallyclinically suspicious suspicious but but still still benign benign lesions lesions to to rule rule out out melanoma. melanoma. In fact,In fact, it has it hasbeen been shown shown that that for everyfor every positive positive case ofcase melanoma, of melanoma there, there are 15 are to 3015biopsies to 30