Cells to Surgery Quiz: April 2019

Abstract

Editorial note: Welcome to the Journal of Investigative Dermatology (JID) Cells to Surgery Quiz— In this monthly online-only quiz, the first question (“What is your diagnosis?”) relates to the clinical image shown, while additional questions concern the findings reported in a JID article by Behar et al. (2018) (https://doi:10.1016/j.jid.2018.05.028). Detailed answers and a list of relevant references are available following the Quiz Questions below. 1.What is your diagnosis?a.Pigmented basal cell carcinoma (BCC)b.Pigmented actinic keratosisc.Lentigo malignad.Lichenoid keratosise.Solar lentigo2.Which of the following statements is false regarding the treatment of actinic keratosis (AK)?a.The clinical clearance achieved with ingenol mebutate appears to be correlated with histologic clearance.b.Topical 5-fluorouracil (5-FU) is effective in more than 90% of patients with AK.c.Lesion-directed treatments, such as cryotherapy and surgical procedures, are the primary approach for isolated lesions.d.Treatment with imiquimod or photodynamic therapy generally resulted in better cosmetic outcomes than topical 5-FU and cryotherapy.e.Pulsed dye laser is the best laser choice for the treatment of AK.3.Behar et al. (2018) investigated the efficacy of a selective small molecule modulator of hexokinase 2 (HK2)’s interaction with the mitochondria (Comp-1) as a potential target for anticancer therapy for AK. Which statement is not consistent with their findings?a.Comp-1 selectively detached HK2 from the mitochondria (in vitro).b.Comp-1 reduced the mitotic index and increased apoptosis (in vivo).c.Comp-1 reduced apoptosis (in vivo).d.No systemic toxicities in minipigs were seen with the use of a topical ointment formulation of Comp-1 administered once daily for 28 days and 13 weeks.e.Comp-1 treatment resulted in a thinner epidermis. See the following pages for detailed answers. 1.What is your diagnosis?CORRECT ANSWER: b. Pigmented actinic keratosisActinic keratosis (AK), one of the most common skin lesions, results from the proliferation of atypical epidermal keratinocytes (Bickers et al., 2006Bickers D.R. Lim H.W. Margolis D. Weinstock M.A. Goodman C. Faulkner E. et al.The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology.J Am Acad Dermatol. 2006; 55: 490-500Abstract Full Text Full Text PDF PubMed Scopus (550) Google Scholar, Chung et al., 2013Chung H.J. McGuigan K.L. Osley K.L. Zendell K. Lee J.B. Pigmented solar (actinic) keratosis: an underrecognized collision lesion.J Am Acad Dermatol. 2013; 68: 647-653Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). AKs typically develop as solitary or multiple lesions on highly sun exposed areas, such as the balding scalp, neck, dorsal hands, dorsal forearms, and lower extremities. AKs present as several clinical variants, including classic, hypertrophic, atrophic, AK with cutaneous horn, pigmented, and actinic cheilitis (Goldberg and Mamelak, 2010Goldberg L.H. Mamelak A.J. Review of actinic keratosis. Part I: etiology, epidemiology and clinical presentation.J Drugs Dermatol. 2010; 9: 1125-1132PubMed Google Scholar). Although most AKs present without significant pigmentation, rare solar keratosis may present with a variable degree of pigmentation. Clinically, pigmented AKs (PAKs) present as scaly, hyperpigmented macules or patches. Lesions may be large, and in some cases, they exceed 1.5 cm (Goldberg and Mamelak, 2010Goldberg L.H. Mamelak A.J. Review of actinic keratosis. Part I: etiology, epidemiology and clinical presentation.J Drugs Dermatol. 2010; 9: 1125-1132PubMed Google Scholar). In dermatoscopy, PAKs commonly show brown or red pseudonetwork, surface scale, dots and globules, fine vessels, hyperpigmented follicular rim, annular granular pattern, atypical network, asymmetrically pigmented follicular ostia, and rhomboidal structure (Chung et al., 2013Chung H.J. McGuigan K.L. Osley K.L. Zendell K. Lee J.B. Pigmented solar (actinic) keratosis: an underrecognized collision lesion.J Am Acad Dermatol. 2013; 68: 647-653Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, Goldberg and Mamelak, 2010Goldberg L.H. Mamelak A.J. Review of actinic keratosis. Part I: etiology, epidemiology and clinical presentation.J Drugs Dermatol. 2010; 9: 1125-1132PubMed Google Scholar).Histopathologic criteria of PAK include cytologic atypia of the basal keratinocytes, parakeratosis that spared the follicular epithelium, increased amount of melanin in the epidermis and dermis, lack of nested melanocytes, and lack of pagetoid spread of melanocytes in the epidermis (Chung et al., 2013Chung H.J. McGuigan K.L. Osley K.L. Zendell K. Lee J.B. Pigmented solar (actinic) keratosis: an underrecognized collision lesion.J Am Acad Dermatol. 2013; 68: 647-653Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar).Discussion of incorrect answers:a.Pigmented basal cell carcinoma (BCC): Basal cell carcinoma (BCC) is a common skin cancer that occurs in adults, predominantly on the head and neck, followed by the trunk (Wang et al., 2018Wang Y.J. Tang T.Y. Wang J.Y. Huang Y.K. Wu Y.H. Genital basal cell carcinoma, a different pathogenesis from sun-exposed basal cell carcinoma? A case-control study of 30 cases.J Cutan Pathol. 2018; 45: 688-695Crossref Scopus (7) Google Scholar). Many subtypes of BCCs exist, including superficial, nodular, infiltrating, and pigmented types; approximately 7% of all BCCs are pigmented. Pigmented lesions may be produced by both nodular and superficial BCCs and may resemble melanoma or, less likely, a benign nevus. A pigmented BCC presents clinically as a brown, blue, or black macule, papule, or nodule with border irregularities and possible color variegation, found on sun-exposed areas. Also, it can have telangiectasia and/or a certain degree of translucency. A rolled edge with a depressed center (umbilication) may also be present (Menzies et al., 2000Menzies S.W. Westerhoff K. Rabinovitz H. Kopf A.W. McCarthy W.H. Katz B. Surface microscopy of pigmented basal cell carcinoma.Arch Dermatol. 2000; 136: 1012-1016Crossref PubMed Scopus (293) Google Scholar).On dermatoscopy, pigmented BCCs are characterized by the absence of a pigment network and the presence of blue-black globules, leaflike areas, spoke-wheel areas, and/or large ovoid nests. The rest of the dermoscopic features include those seen with nonpigmented BCCs, such as serpentine branched (or arborizing) vessels and ulceration. The infundibulocystic variant appears as bright red, sharply-in-focus vessels traversing the area, and blue globules and brown leaflike structures may also be seen (Menzies et al., 2000Menzies S.W. Westerhoff K. Rabinovitz H. Kopf A.W. McCarthy W.H. Katz B. Surface microscopy of pigmented basal cell carcinoma.Arch Dermatol. 2000; 136: 1012-1016Crossref PubMed Scopus (293) Google Scholar).On histopathologic examination, masses of basaloid cells in a fibrocellular stroma can be seen, as well as pigment in the tumor cells and in melanophages (Coleman et al., 2013Coleman C.I. Wine-Lee L. James W.D. Pigmented basal cell carcinoma: uncommon presentation in blue-eyed patients.JAMA Dermatol. 2013; 149: 995-996Google Scholar, Maloney et al., 1992Maloney M.E. Jones D.B. Sexton F.M. Pigmented basal cell carcinoma: investigation of 70 cases.J Am Acad Dermatol. 1992; 27: 74-78Abstract Full Text PDF PubMed Scopus (82) Google Scholar).c.Lentigo maligna: Lentigo maligna (LM) is a type of melanoma in situ that develops on sun-damaged skin, most commonly on the head and neck of older Caucasian males (Kallini et al., 2013Kallini J.R. Jain S.K. Khachemoune A. Lentigo maligna: review of salient characteristics and management.Am J Clin Dermatol. 2013; 14: 473-480Crossref PubMed Scopus (29) Google Scholar). Although LM usually occurs in older individuals, with a peak incidence between 65 and 80 years, the incidence of LM appears to be increasing in younger age groups (Farshad et al., 2002Farshad A. Burg G. Panizzon R. Dummer R. A retrospective study of 150 patients with lentigo maligna and lentigo maligna melanoma and the efficacy of radiotherapy using Grenz or soft X-rays.Br J Dermatol. 2002; 146: 1042-1046Crossref PubMed Scopus (153) Google Scholar). An increase in incidence has been reported from 2.2 per 100,000 per year between 1970 and 1989 to 13.7 per 100,000 per year between 2004 and 2007 in the United States (Mirzoyev et al., 2014Mirzoyev S.A. Knudson R.M. Reed K.B. Hou J.L. Lohse C.M. Frohm M.L. et al.Incidence of lentigo maligna in Olmsted County, Minnesota, 1970 to 2007.J Am Acad Dermatol. 2014; 70: 443-448Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar).LM typically presents as an asymmetric, hyperpigmented macule with irregular borders. Clinical features of LM include irregular shape; variable color (from light brown or tan to dark brown, black, pink, red, or white); variable size (from >1 to several centimeters); and nonscaly, smooth surface (Argenziano et al., 2003Argenziano G. Soyer H.P. Chimenti S. Talamini R. Corona R. Sera F. et al.Dermoscopy of pigmented skin lesions: results of a consensus meeting via the internet.J Am Acad Dermatol. 2003; 48: 679-693Abstract Full Text Full Text PDF PubMed Scopus (928) Google Scholar, Stolz et al., 2002Stolz W. Schiffner R. Burgdorf W.H. Dermatoscopy for facial pigmented skin lesions.Clin Dermatol. 2002; 20: 276-278Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar). It has a prolonged horizontal growth phase, with a tendency to grow centrifugally and remain confined to the epidermis (Witta et al., 2018Witta S. Bershow A. Farah R.S. Berg B. Goldfarb N. Dermoscopy findings of a one mm lentigo maligna.Dermatol Online J. 2018; 24: 18Google Scholar). Dermatoscopic findings of LM include asymmetric pigmented follicular openings, slate gray dots (also referred to as annular granular structures), a gray pseudo-network, and/or rhomboidal structures (Argenziano et al., 2003Argenziano G. Soyer H.P. Chimenti S. Talamini R. Corona R. Sera F. et al.Dermoscopy of pigmented skin lesions: results of a consensus meeting via the internet.J Am Acad Dermatol. 2003; 48: 679-693Abstract Full Text Full Text PDF PubMed Scopus (928) Google Scholar, Stolz et al., 2002Stolz W. Schiffner R. Burgdorf W.H. Dermatoscopy for facial pigmented skin lesions.Clin Dermatol. 2002; 20: 276-278Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, Witta et al., 2018Witta S. Bershow A. Farah R.S. Berg B. Goldfarb N. Dermoscopy findings of a one mm lentigo maligna.Dermatol Online J. 2018; 24: 18Google Scholar).Histologically, LM is a melanoma in situ characterized by an increased number of atypical melanocytes, often spindle shaped, arranged in single cells or in small nests along the dermoepidermal junction, often extending into the infundibular portion of hair follicles (Connolly et al., 2019Connolly K.L. Giordano C. Dusza S. Busam K.J. Nehal K. Follicular involvement is frequent in lentigo maligna: implications for treatment.J Am Acad Dermatol. 2019; 80: 532-537Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar).d.Lichenoid keratosis: Lichenoid keratosis (LK) or lichen planus-like keratosis is considered a regressing solar lentigo or seborrheic keratosis (Bugatti and Filosa, 2007Bugatti L. Filosa G. Dermoscopy of lichen planus-like keratosis: a model of inflammatory regression.J Eur Acad Dermatol Venereol. 2007; 21: 1392-1397Crossref PubMed Scopus (40) Google Scholar). Clinically, it appears as a nonpruritic, gray to brown papule or slightly indurated plaque. It mostly occurs on the sun-exposed trunk and upper extremities of adults, mainly females, between the ages of 50 and 70 years (Bugatti and Filosa, 2007Bugatti L. Filosa G. Dermoscopy of lichen planus-like keratosis: a model of inflammatory regression.J Eur Acad Dermatol Venereol. 2007; 21: 1392-1397Crossref PubMed Scopus (40) Google Scholar). On dermoscopy, LK shows a coarse or fine, gray to blue, granular pigmentation covering most of the lesion (Moscarella et al., 2011Moscarella E. Zalaudek I. Pellacani G. Eibenschutz L. Catricala C. Amantea A. et al.Lichenoid keratosis-like melanomas.J Am Acad Dermatol. 2011; 65: e85-e87Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). Fully or nearly fully regressed LK is characterized by diffuse brownish gray granules, which may coalesce to form globules, streaks, or even structures similar to rhomboids.Histologic variants of LK include classic, atrophic, early, bullous, and atypical (Morgan et al., 2005Morgan M.B. Stevens G.L. Switlyk S. Benign lichenoid keratosis: a clinical and pathologic reappraisal of 1040 cases.Am J Dermatopathol. 2005; 27: 387-392Crossref PubMed Scopus (59) Google Scholar). The classic type consists of epidermal acanthosis and hyperkeratosis with an intense lichenoid lymphocyte-predominant inflammatory infiltrate and flanking epidermal foci of lentigo (Bugatti and Filosa, 2007Bugatti L. Filosa G. Dermoscopy of lichen planus-like keratosis: a model of inflammatory regression.J Eur Acad Dermatol Venereol. 2007; 21: 1392-1397Crossref PubMed Scopus (40) Google Scholar, Morgan et al., 2005Morgan M.B. Stevens G.L. Switlyk S. Benign lichenoid keratosis: a clinical and pathologic reappraisal of 1040 cases.Am J Dermatopathol. 2005; 27: 387-392Crossref PubMed Scopus (59) Google Scholar). The atrophic or senescent type is defined by the presence of epidermal atrophy with a sparse papillary dermal lymphocyte infiltrate and variable papillary dermal fibroplasias and melanin incontinence (Bugatti and Filosa, 2007Bugatti L. Filosa G. Dermoscopy of lichen planus-like keratosis: a model of inflammatory regression.J Eur Acad Dermatol Venereol. 2007; 21: 1392-1397Crossref PubMed Scopus (40) Google Scholar). The early or interface type is defined by the presence of a slight acanthotic or normal epidermal thickness with variable degrees of epidermal pigmentation and an interface population of lymphocytes singly arrayed along the dermoepidermal junction. The bullous variant consists of more conspicuous numbers of apoptotic keratinocytes compared with the classic variant associated with intraepidermal blister formation and subepidermal vesiculation (Morgan et al., 2005Morgan M.B. Stevens G.L. Switlyk S. Benign lichenoid keratosis: a clinical and pathologic reappraisal of 1040 cases.Am J Dermatopathol. 2005; 27: 387-392Crossref PubMed Scopus (59) Google Scholar). The atypical variant consists of at least five atypical lymphocytes, which are found in the papillary dermis and aligned along the dermoepidermal junction associated with lichenoid infiltrate (Morgan et al., 2005Morgan M.B. Stevens G.L. Switlyk S. Benign lichenoid keratosis: a clinical and pathologic reappraisal of 1040 cases.Am J Dermatopathol. 2005; 27: 387-392Crossref PubMed Scopus (59) Google Scholar).e.Solar lentigo: Solar lentigo is also known as “old age” spots and is a proliferation of normal melanocytes secondary to chronic sun damage (Hodgson, 1963Hodgson C. Senile lentigo.Arch Dermatol. 1963; 87: 197-207Crossref PubMed Scopus (59) Google Scholar). These lesions occur most commonly in individuals with fair skin who have a history of chronic sun exposure. Clinically, solar lentigo lesions are well-defined, irregular, flat, oval, very small hyperpigmented macules localized over sun-exposed areas (Hodgson, 1963Hodgson C. Senile lentigo.Arch Dermatol. 1963; 87: 197-207Crossref PubMed Scopus (59) Google Scholar, Lallas et al., 2014Lallas A. Argenziano G. Moscarella E. Longo C. Simonetti V. Zalaudek I. Diagnosis and management of facial pigmented macules.Clin Dermatol. 2014; 32: 94-100Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). In dermoscopy, solar lentigo presents with an irregular outline; a sharply demarcated border; and fine lines that are parallel, short, straight, curved, or interrupted; they often form a reticular pattern, known as fingerprinting (Moreno-Ramirez et al., 2005Moreno-Ramirez D. Ferrandiz L. Camacho F.M. Are the ABCD signs useful for the management of solar lentigo?.Br J Dermatol. 2005; 153: 1083-1084Google Scholar, Wang et al., 2000Wang S.Q. Katz B. Rabinovitz H. Kopf A.W. Oliviero M. Rao B.K. Lessons on dermoscopy #11. Solar lentigo.Dermatol Surg. 2000; 26: 1173-1174Crossref PubMed Scopus (5) Google Scholar). A solar lentigo can also have a homogenous, diffuse tan-brown pigmentation devoid of structures. The borders can be well demarcated, scalloped, or moth-eaten (Moreno-Ramirez et al., 2005Moreno-Ramirez D. Ferrandiz L. Camacho F.M. Are the ABCD signs useful for the management of solar lentigo?.Br J Dermatol. 2005; 153: 1083-1084Google Scholar, Wang et al., 2000Wang S.Q. Katz B. Rabinovitz H. Kopf A.W. Oliviero M. Rao B.K. Lessons on dermoscopy #11. Solar lentigo.Dermatol Surg. 2000; 26: 1173-1174Crossref PubMed Scopus (5) Google Scholar). On histology, it shows elongated, fused rete ridges, with small budlike extensions, thin epidermis over the rete ridges, low epidermis with hyperpigmented basaloid cells, and strong dihydroxyphenylalanine-positive dendritic melanocytes (Hodgson, 1963Hodgson C. Senile lentigo.Arch Dermatol. 1963; 87: 197-207Crossref PubMed Scopus (59) Google Scholar).2.Which of the following statements is false regarding the treatment of actinic keratosis (AK)?CORRECT ANSWER: e. Pulsed dye laser is the best laser choice for the treatment of AK.Lasers choices that have been used for AKs include ablative laser resurfacing with carbon dioxide (CO2) and erbium:yttrium-aluminum-garnet (Er:YAG) lasers (Hantash et al., 2006Hantash B.M. Stewart D.B. Cooper Z.A. Rehmus W.E. Koch R.J. Swetter S.M. Facial resurfacing for nonmelanoma skin cancer prophylaxis.Arch Dermatol. 2006; 142: 976-982Crossref PubMed Scopus (84) Google Scholar; Ostertag et al., 2006Ostertag J.U. Quaedvlieg P.J. van der Geer S. Nelemans P. Christianen M.E. Neumann M.H. et al.A clinical comparison and long-term follow-up of topical 5-fluorouracil versus laser resurfacing in the treatment of widespread actinic keratoses.Lasers Surg Med. 2006; 38: 731-739Crossref PubMed Scopus (39) Google Scholar). A few uncontrolled studies have reported reductions in AKs after treatment with nonablative fractional lasers (Katz et al., 2011Katz T.M. Goldberg L.H. Marquez D. Kimyai-Asadi A. Polder K.D. Landau J.M. et al.Nonablative fractional photothermolysis for facial actinic keratoses: 6-month follow-up with histologic evaluation.J Am Acad Dermatol. 2011; 65: 349-356Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, Prens et al., 2013Prens S.P. de Vries K. Neumann H.A. Prens E.P. Non-ablative fractional resurfacing in combination with topical tretinoin cream as a field treatment modality for multiple actinic keratosis: a pilot study and a review of other field treatment modalities.J Dermatolog Treat. 2013; 24: 227-231Crossref PubMed Scopus (14) Google Scholar, Weiss et al., 2013Weiss E.T. Brauer J.A. Anolik R. Reddy K.K. Karen J.K. Hale E.K. et al.1927-nm fractional resurfacing of facial actinic keratoses: a promising new therapeutic option.J Am Acad Dermatol. 2013; 68: 98-102Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). CO2 lasers have proven to be effective in treating AK, causing a decrease in the p53 gene in the interfollicular epidermis 6 months after laser treatment; the absence of p53 decreased the risk of malignant progression (Sayan et al., 2018Sayan A. Sindel A. Ethunandan M. Ilankovan V. Management of seborrhoeic keratosis and actinic keratosis with an erbium:YAG laser—experience with 547 patients.Int J Oral Maxillofac Surg. 2018; (https://doi.org/10.1016/j.ijom.2018.08.008 (accessed 20 January 2019).)Google Scholar). In another study, CO2 lasers showed short-term efficacy in treating AK in the face and scalp. They were also shown to be inferior to photodynamic therapy (Dong and Goldenberg, 2018Dong J. Goldenberg G. Energy-based devices for actinic keratosis field therapy.Cutis. 2018; 101: 355-360Google Scholar). Although ablative lasers reduce the incidence and recurrence rate of AK, this treatment option is limited by downtime after laser treatment and patient discomfort. Nonablative lasers also reduce AK, but multiple treatments are required for optimal results (Dong and Goldenberg, 2018Dong J. Goldenberg G. Energy-based devices for actinic keratosis field therapy.Cutis. 2018; 101: 355-360Google Scholar, Gan et al., 2016Gan S.D. Hsu S.H. Chuang G. Konnikov N. Liang C.A. Ablative fractional laser therapy for the treatment of actinic keratosis: a split-face study.J Am Acad Dermatol. 2016; 74: 387-389Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). Although pulsed dye lasers show promising results, further studies are needed to determine their efficacy and safety for the treatment of AK (Dong and Goldenberg, 2018Dong J. Goldenberg G. Energy-based devices for actinic keratosis field therapy.Cutis. 2018; 101: 355-360Google Scholar).Discussion of incorrect answers:a.The clinical clearance achieved with ingenol mebutate appears to be correlated with histologic clearance: Ingenol mebutate gel was approved by the US Food and Drug Administration (FDA) in 2012 as a new topical field therapy treatment for AK (Costa et al., 2015Costa C. Scalvenzi M. Ayala F. Fabbrocini G. Monfrecola G. How to treat actinic keratosis? An update.J Dermatol Case Rep. 2015; 9: 29-35Crossref PubMed Scopus (50) Google Scholar, Lebwohl et al., 2012Lebwohl M. Swanson N. Anderson L.L. Melgaard A. Xu Z. Berman B. Ingenol mebutate gel for actinic keratosis.N Engl J Med. 2012; 366: 1010-1019Crossref PubMed Scopus (393) Google Scholar). Clinical studies have proven its efficiency in treating AK, due to its ability to induce cell death (Lebwohl et al., 2012Lebwohl M. Swanson N. Anderson L.L. Melgaard A. Xu Z. Berman B. Ingenol mebutate gel for actinic keratosis.N Engl J Med. 2012; 366: 1010-1019Crossref PubMed Scopus (393) Google Scholar) of tumor cells and induce an immune response by the activation of the protein kinase C (Martin and Swanson, 2013Martin G. Swanson N. Clinical findings using ingenol mebutate gel to treat actinic keratosis.J Am Acad Dermatol. 2013; 68: s39-s48Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). It is available in two concentrations, depending on treatment plan: (i) 0.015% concentration for topical application for AK in the face and scalp, applied once a day for 3 consecutive days, and (ii) 0.05% concentration for topical application for AK in the trunk and extremities, applied once a day for 2 consecutive days (Costa et al., 2015Costa C. Scalvenzi M. Ayala F. Fabbrocini G. Monfrecola G. How to treat actinic keratosis? An update.J Dermatol Case Rep. 2015; 9: 29-35Crossref PubMed Scopus (50) Google Scholar, Lebwohl et al., 2012Lebwohl M. Swanson N. Anderson L.L. Melgaard A. Xu Z. Berman B. Ingenol mebutate gel for actinic keratosis.N Engl J Med. 2012; 366: 1010-1019Crossref PubMed Scopus (393) Google Scholar). It effectiveness is attributed to the fast lesion resolution and the high adherence to the therapy due to its short duration (Lebwohl et al., 2012Lebwohl M. Swanson N. Anderson L.L. Melgaard A. Xu Z. Berman B. Ingenol mebutate gel for actinic keratosis.N Engl J Med. 2012; 366: 1010-1019Crossref PubMed Scopus (393) Google Scholar). Ingenol mebutate has shown good tolerability and excellent patient adherence in a clinical setting (Martin and Swanson, 2013Martin G. Swanson N. Clinical findings using ingenol mebutate gel to treat actinic keratosis.J Am Acad Dermatol. 2013; 68: s39-s48Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar), thus proving to be a good treatment choice for AK.b.Topical 5-fluorouracil (5-FU) is effective in more than 90% of patients with AK: 5-fluorouracil (5-FU) is an effective topical treatment for AK because it disrupts DNA and RNA synthesis (Dinehart, 2000Dinehart S.M. The treatment of actinic keratosis.J Am Acad Dermatol. 2000; 42: s25-s28Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar) and halts the growth of proliferating abnormal cells (Costa et al., 2015Costa C. Scalvenzi M. Ayala F. Fabbrocini G. Monfrecola G. How to treat actinic keratosis? An update.J Dermatol Case Rep. 2015; 9: 29-35Crossref PubMed Scopus (50) Google Scholar). 5-FU causes apoptosis of AK lesions but does not affect healthy skin cells (Werschler, 2008Werschler W.P. Consideration for the use of fluorouracil cream 0.5% for the treatment of actinic keratosis in elderly patients.J Clin Aesthet Dermatol. 2008; 1: 22-27PubMed Google Scholar). The FDA has approved the topical application of 5-FU twice a day over the affected area for a therapy duration of 2–4 weeks (Dinehart, 2000Dinehart S.M. The treatment of actinic keratosis.J Am Acad Dermatol. 2000; 42: s25-s28Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). It may also be applied over large areas to treat lesions at one time and to treat early AK lesions (Smith et al., 2004Smith S.R. Piacquadio D. Morhenn V. Atkin D. Fitzpatrick R. Short incubation PDT versus 5-FU in treating actinic keratosis.J Drugs Dermatol. 2004; 2: 629-635Google Scholar). Topical 5-FU is an ideal treatment for patients with multiple AK lesions who are compliant with the treatment regime (Dinehart, 2000Dinehart S.M. The treatment of actinic keratosis.J Am Acad Dermatol. 2000; 42: s25-s28Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). It has been the choice of treatment for AK because of its high cure rates (>90%) and its effectiveness at reducing and clearing AK lesions (Werschler, 2008Werschler W.P. Consideration for the use of fluorouracil cream 0.5% for the treatment of actinic keratosis in elderly patients.J Clin Aesthet Dermatol. 2008; 1: 22-27PubMed Google Scholar).c.Lesion-directed treatments, such as cryotherapy and surgical procedures, are the primary approach for isolated lesions: Lesion-directed therapies physically remove lesions; thus, they are effective for isolated AK lesions or for lesions that are few in number (Ceilley and Jorizzo, 2013Ceilley R.I. Jorizzo J.L. Current issues in the management of actinic keratosis.J Am Acad Dermatol. 2013; 68: s28-s38Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). This is accomplished with cryosurgery or surgical procedures, such as curettage (Costa et al., 2015Costa C. Scalvenzi M. Ayala F. Fabbrocini G. Monfrecola G. How to treat actinic keratosis? An update.J Dermatol Case Rep. 2015; 9: 29-35Crossref PubMed Scopus (50) Google Scholar). Cryosurgery is performed with liquid nitrogen to lower the temperature of the skin, destroying atypical AK cells (Dinehart, 2000Dinehart S.M. The treatment of actinic keratosis.J Am Acad Dermatol. 2000; 42: s25-s28Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). It is an effective treatment for patients with isolated lesions that are thin, scattered (Dinehart, 2000Dinehart S.M. The treatment of actinic keratosis.J Am Acad Dermatol. 2000; 42: s25-s28Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar), few in number, and well defined (Martin and Swanson, 2013Martin G. Swanson N. Clinical findings using ingenol mebutate gel to treat actinic keratosis.J Am Acad Dermatol. 2013; 68: s39-s48Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar) or for patients who are noncompliant with topical treatments (Costa et al., 2015Costa C. Scalvenzi M. Ayala F. Fabbrocini G. Monfrecola G. How to treat actinic keratosis? An update.J Dermatol Case Rep. 2015; 9: 29-35Crossref PubMed Scopus (50) Google Scholar). Cryosurgery has become the standard of care treatment option for AK (Dinehart, 2000Dinehart S.M. The treatment of actinic keratosis.J Am Acad Dermatol. 2000; 42: s25-s28Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar), as it is well tolerated by patients, is easy to use (Ceilley and Jorizzo, 2013Ceilley R.I. Jorizzo J.L. Current issues in the management of actinic keratosis.J Am Acad Dermatol. 2013; 68: s28-s38Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar), and has high cure rates (Costa et al., 2015Costa C. Scalvenzi M. Ayala F. Fabbrocini G. Monfrecola G. How to treat actinic keratosis? An update.J Dermatol Case Rep. 2015; 9: 29-35Crossref PubMed Scopus (50) Google Scholar, Dinehart, 2000Dinehart S.M. The treatment of actinic keratosis.J Am Acad Dermatol. 2000; 42: s25-s28Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). Surgical procedures involve the use of a curette or surgical blade to physically remove abnormal AK cells (Costa et al., 2015Costa C. Scalvenzi M. Ayala F. Fabbrocini G. Monfrecola G. How to treat actinic keratosis? An update.J Dermatol Case Rep. 2015; 9: 29-35Crossref PubMed Scopus (50) Google Scholar). A curette is effective for individual AK lesions, lesions that are closer to being invasive squamous cell carcinomas, or lesions that are resistant to other treatments, because it scrapes away abnormal cells (Dinehart, 2000Dinehart S.M. The treatment of actinic keratosis.J Am Acad Dermatol. 2000; 42: s25-s28Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). Lesion-directed therapies for the treatment of AK are quick and simple, and they clear abnormal tissue (Ceilley and Jorizzo, 2013Ceilley R.I. Jorizzo J.L. Current issues in the management of actinic keratosis.J Am Acad Dermatol. 2013; 68: s28-s38Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, Costa et al., 2015Costa C. Scalvenzi M. Ayala F. Fabbrocini G. Monfrecola G. How to treat actinic keratosis? An update.J Dermatol Case Rep. 2015; 9: 29-35Crossref PubMed Scopus (50) Google Scholar).d.Treatment with imiquimod or photodynamic therapy generally resulted in better cosmetic outcomes than topical 5-FU and cryotherapy: Imiquimod at the concentration of 3.75% was approved by the FDA in 2010 as a treatment for AK on the face and scalp and for a large surface area (Costa et al., 2015Costa C. Scalvenzi M. Ayala F. Fabbrocini G. Monfrecola G. How to treat actinic keratosis? An update.J Dermatol Case Rep. 2015; 9: 29-35Crossref PubMed Scopus (50) Google Scholar). Various concentrations of imiquimod are applied, following different regimens with periods of weeks to months (Lebwohl et al., 2012Lebwohl M. Swanson N. Anderson L.L. Melgaard A. Xu Z. Berman B. Ingenol mebutate gel for actinic keratosis.N Engl J Med. 2012; 366: 1010-1019Crossref PubMed Scopus (393) Google Scholar). Imiquimod is an effective treatment for AK because it disrupts tumor proliferation and stimulates apoptosis. Photodynamic therapy is another effective treatment for AK for patients who do not respond well to topical therapy or cryosurgery (Costa et al., 2015Costa C. Scalvenzi M. Ayala F. Fabbrocini G. Monfrecola G. How to treat actinic keratosis? An update.J Dermatol Case Rep. 2015; 9: 29-35Crossref PubMed Scopus (50) Google Scholar). It is a two-step, noninvasive treatment, whereby a precursor of a photosensitizing agent (Ceilley and Jorizzo, 2013Ceilley R.I. Jorizzo J.L. Current issues in the management of actinic keratosis.J Am Acad Dermatol. 2013; 68: s28-s38Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar), such as 5-aminolevulinic acid (Costa et al., 2015Costa C. Scalvenzi M. Ayala F. Fabbrocini G. Monfrecola G. How to treat actinic keratosis? An update.J Dermatol Case Rep. 2015; 9: 29-35Crossref PubMed Scopus (50) Google Scholar), is added to the affected area. Damaged cells absorb this precursor, causing an enzymatic conversion to a photosensitizer that, when illuminated with a red or blue light, initiates a tissue toxic photochemical reaction (Ceilley and Jorizzo, 2013Ceilley R.I. Jorizzo J.L. Current issues in the management of actinic keratosis.J Am Acad Dermatol. 2013; 68: s28-s38Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar) that destroys abnormal cells (Costa et al., 2015Costa C. Scalvenzi M. Ayala F. Fabbrocini G. Monfrecola G. How to treat actinic keratosis? An update.J Dermatol Case Rep. 2015; 9: 29-35Crossref PubMed Scopus (50) Google Scholar). The phototoxic reaction does not affect the dermis, thus providing an excellent cosmetic outcome (Ceilley and Jorizzo, 2013Ceilley R.I. Jorizzo J.L. Current issues in the management of actinic keratosis.J Am Acad Dermatol. 2013; 68: s28-s38Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, Costa et al., 2015Costa C. Scalvenzi M. Ayala F. Fabbrocini G. Monfrecola G. How to treat actinic keratosis? An update.J Dermatol Case Rep. 2015; 9: 29-35Crossref PubMed Scopus (50) Google Scholar).3.Behar et al. (2019) investigated the efficacy of a selective small molecule modulator of hexokinase 2 (HK2)’s interaction with the mitochondria (Comp-1) as a potential target for anticancer therapy for AK. Which statement is not consistent with their findings?CORRECT ANSWER: c. Comp-1 reduces apoptosis (in vivo).Comp-1 treatment induces apoptosis, which has been shown in two ways. Within 2 hours of treatment, a reduction of cytochrome C levels in the mitochondrial fraction was observed, as evaluated by Western blot and semiquantification. Also, within 6 hours of treatment, an increase in cellular levels of cleaved caspase-3 was observed. These two early events are in line with a caspase-dependent apoptotic mechanism.Discussion of incorrect answers:a.Comp-1 selectively detached HK2 from the mitochondria (in vitro): The activity of Comp-1 in a cell-free assay was evaluated using microscale thermophoresis analysis, which is based on the altered movement of a protein in a temperature gradient when bound to other molecules. The HK enzymes were first allowed to bind with VDAC1 to form the VDAC1/HK complexes. The addition of Comp-1 selectively dissociates HK2 from VDAC1 in a dose-dependent manner with a half maximal inhibitory concentration of 0.092 mmol/L.b.Comp-1 reduced the mitotic index and increased apoptosis (in vivo): Behar et al. (2018) evaluated the extent to which cells undergo active proliferation by using a semiquantitative histopathologic analysis of the epidermis layers on day 50. The analysis showed that Comp-1 significantly reduced the mitotic index in the treated skin.d.No systemic toxicities in minipigs were seen with the use of a topical ointment formulation of Comp-1 administered once daily for 28 days and 13 weeks: Unlike most other approved AK drugs, which cause significant skin irritation, under experimental conditions, Comp-1 was delivered with efficacy that avoided skin irritation. Good laboratory practice toxicology studies in minipigs with a topical ointment formulation of Comp-1 administered once daily for 28 days and 13 weeks established no systemic toxicities and minimal dermal reaction for doses of up to 20% and 15%, respectively.e.Comp-1 treatment resulted in a thinner epidermis: In mice, histopathologic analysis of the UVB-exposed skin showed epidermal thickening and the expected squamous cell carcinoma morphology of elongated keratinocyte cordlike structures toward the dermis. Comp-1 treatment resulted in a thinner epidermis, which was histologically similar to the skin of naive, non–UVB-exposed control mice.