Actinic Keratoses: Reconciling the Biology of Field Cancerization with Treatment Paradigms

This Perspective briefly reviews the relationship between UV-induced mutations in habitually sun-exposed human skin and subsequent development of actinic keratoses (AKs) cancers. It argues that field therapy rather than AK-selective is more logical approach to cancer prevention hypothesizes treatment early process cancerization, even prior appearance AKs, may be effective preventing as well beneficial for better tolerated by at-risk individuals. Finally, encourages use rapidly advancing DNA analysis techniques quantify mutational burden sun-damaged its reduction various therapies. Actinic are a discrete stage progression normal invasive squamous cell carcinoma (SCC) result prolonged intermittent sun exposure (Criscione et al., 2009Criscione V.D. Weinstock M.A. Naylor M.F. Luque C. Eide M.J. 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Bhatia Kircik L.H. current insights into treatments.J Drugs 18: s161-s166PubMed frequent near-constant erythema, crusting scabbing, local adverse effects Roughly similar side effect profiles reported mebutate, 3% diclofenac, photodynamic either methyl aminolevulinate aminolevulinic acid, allowing differences protocols outcome measures among Whereas physicians find agents easier they shorter duration and/or less reactions treatment, characteristics nevertheless highly motivated advanced considered far short-term few AKs. above experience, appreciation dynamics suggests different huge societal States. underlying logic hypothetically expected results this Figure 1. schema assumes cumulative damage occurs essentially everyone infancy progresses variable rate throughout life determined intensity complexion, factors influencing (solid blue line 1). exponential assumption impair ability repair eliminate (Ziegler accelerating accumulation mutations. With minimal damage, skin’s adulthood. continues accumulate, (dyspigmentation, roughness, etc.) then gradually progress. By mid late adulthood, fair-skinned begin develop fields photodamage. per has range 0.025% 16% <1% Fuchs Marmur, 2007Fuchs Marmur kinetics carcinoma.Dermatol 33: 1099-1101Crossref (102) Glogau, 2000Glogau R.G. disease.J 23-24Abstract (398) 60% justifying If instituted when (the later Rx1 1), severity reduced, presumably through damaged (mutated) stem cells, temporary disappearance red Then, again resumes upward trajectory months. instead, given earlier initial treatment-associated improvement leads signs photoaging considerable delay instances, delays prevents malignancies remaining lifespan. Whether would favor repeated (Rx2 1) should logically depend effectiveness reactions. prospect years improved delayed eliminated however argue possibly intervention. Early intervention might encourage scrupulous protection, leading cancer-free lifespan, indicated slower (dashed lines There corollaries First, desirable document progressive AK-bearing cancer-bearing presumed decrease specific Recent advances sequencing methodologies noninvasive nonscarring sampling technique quantifying (Muradova 2020Muradova Patel Sell Bittencourt B.B. Ojeda Adelmann C.H. al.Noninvasive assessment markers (accessed July 2020)https://doi.org/10.1016/j.jid.2020.05.093Abstract (2) permit collection. Second, easier, (Touma 2004Touma Yaar Whitehead Konnikov Gilchrest B.A. short incubation, broad-area facial diffuse photodamage.Arch 140: 33-40Crossref (222) provide strong motivation compliance. Solid organ–transplant recipients increased developing presenting enormous challenge (Euvrard 2003Euvrard Kanitakis Claudy organ transplantation.N 1681-1691Crossref (1248) recent found 2–6 achieved standard (Heppt 2019Heppt M.V. Steeb Niesert Zacher Leiter U. Garbe al.Local interventions transplant recipients: review.Br 180: 43-50Crossref (14) However, problem progressing metastatic fatality (Lanz 2019Lanz Bouwes Bavinck J.N.B. Westhuis Quint K.D. Harwood C.A. Nasir al.Aggressive recipients.JAMA 155: 66-71Crossref (25) Lott 2010Lott D.G. Manz Koch Lorenz R.R. Aggressive behavior nonmelanotic solid recipients.Transplantation. 2010; 90: 683-687Crossref (86) unresolved. immediately transplantation measurement informative. Preferably, untreated arm, ethical proposal currently virtually who undergone will undergo yet experiencing Photographic documentation patients’ determine mildly impact important additional confirmation schema. prevalent condition reliable understanding decades, promoting rational traditional AK-specific modalities LN2 cryotherapy, lesions, paradigms do reflect biologic understanding. Even individuals, remain approach, nearly half AK-related costs. seemingly curious choice, fails treat majority cancerized field, malignancies, surely reflects long-established physician reimbursement policies arguable practice reserving disease. turn reluctance third-party payers reimburse concerns downtime related uncomfortable treatments. part decision-making likelihood disease lesser decreased lifetime (Figure morbidity Over past century, profound increase our expected, evolved incorporate knowledge base, attributable needed drugs, meaningful effectiveness. argued earlier, now poised benefit fully integration drug approval metrics. No datasets generated analyzed preparing perspective. Barbara Gilchrest: http://orcid.org/0000-0001-9906-1898 BAG paid consultant any company involved diagnosis served advisory board several. author grateful Kenneth Tsai helpful discussions research literature.