Dermatology: Practical and Conceptual Review | Dermatol Pract Concept. 2024;14(3)S1:e2024147S 1 Clinical and Dermoscopic Diagnosis of Actinic Keratosis Claudio Conforti1, Luca Ambrosio1, Chiara Retrosi1, Carmen Cantisani2, Giovanni Di Lella1, Luca Fania1, Roberta Rotunno1, Iris Zalaudek3, Giovanni Pellacani2 1 Istituto dermopatico dell’Immacolata, IDI-IRCCS, Dermatological Research Hospital, Rome, Italy 2 Dermatology Clinic, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy 3 Dermatology Clinic, Maggiore Hospital, Piazza Ospitale 1, Trieste, Italy Key words: actinic keratoses, diagnosis, keratinocyte Citation: Conforti C, Ambrosio L, Retrosi C, et al. Clinical and Dermoscopic Diagnosis of Actinic Keratosis. Dermatol Pract Concept. 2024;14(3)S1:e2024147S. DOI: https://doi.org/10.5826/dpc.1403S1a147S Accepted: June 30, 2024; Published: July 2024 Copyright: ©2024 Conforti et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Carmen Cantisani, MD, Dermatology Clinic, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy. Email: carmencantisanister@gmail.com Introduction Actinic keratosis (AK) is the most common keratinocyte skin cancer (KC) mainly caused by chronic sun damage; over 80% of AKs arise on chronically sun exposed areas such as face, scalp, neck, forearms and hands [1,2]. In fact, the most important risk factors for the development of AKs is ultra- violet (UV) exposure, notably UVB rays, augmented by the length of exposure and a lighter skin phototype [3]. Rates of transformation of AKs into squamous cell carcinoma (SCC) vary from 0.0015% to 16% but no specific criteria have been linked to the risk of progression, therefore the treat- ment of AK is mandatory for all forms detected during the visit [4]. Studies demonstrated two pathways for the devel- opment of a SCC: a direct one, from AK stage I into SCC and another with a progressive model (from AK stage I to AK stage III and then transformation into SCC) [5]. As devel- opment of invasive AK directly from the cancer field cannot be ruled out, the ideal treatment should be able to eradicate AK lesions and reverse the underlying field cancerization [6]. The diagnosis of AK is based on the clinical and der- matoscopic features; the combination of clinical and der- matoscopic characteristics helped physicians to elaborate algorithms and systems of classification useful not only for the diagnosis but also for choosing the correct therapy and for monitoring the response to the treatment. The aim of this systematic review is to summarize the clinical and dermato- scopic clues for the diagnosis of AKs, including clinical clas- sification systems. Materials and Methods We searched the literature for studies published in the last 20 years between 2004 and 2024, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guidelines. We searched PubMed 2 Review | Dermatol Pract Concept. 2024;14(3)S1:e2024147S database using the term actinic keratosis in combination with the following terms: dermoscopic and/or dermatoscopic features, clinical features, classification, dermoscopic and/or dermatoscopic criteria. Eligibility was restricted to studies with more than thirty cases described. Reviews, meta- analyses, cohort studies, case series were eligible for inclu- sion. Only articles in English were selected. Letters and case reports without statistically relevant data were excluded from the analysis. Other potentially relevant articles were identified by manually checking the references of the in- cluded literature. The last search was run on 26th January 2023. Two investigators independently selected relevant articles according to predefined inclusion and exclusion criteria, as described above. Disagreements were solved by discussion, with a prior arrangement that any unsettled dis- crepancy would be determined by a third author. Clinical Diagnosis of AKs: Olsen Classification AK is clinically characterized by a squamous and erythem- atous macula or plaque; the degree of hyperkeratosis and symptomatology is variable. In fact, it can be asymptomatic, itchy and sometimes painful [7]. The first clinical classifica- tion of AKs is based on a three-stage model; the Olsen classi- fication is based on the distinction of AKs into three stages: grade I in which the AK is a small erythematous macula, not very visible and more easily appreciated on palpation; grade II with greater hyperkeratosis and erythema, whereby the lesion is easily diagnosed with the naked eye and also easily appreciated; otherwise grade III is characterized by the maximum of hyperkeratosis and the diagnosis is immediate [8]. This classification has been among the most widely ad- opted in both clinical practice and scientific studies but has as a major limitation: it does not evaluate the entire skin area but defines only the grade of individual observable ker- atosis. Moreover, based on a 3-stage model, it seems to be a progressive model up to the most severe degree of keratosis with higher risk of transformation into iSCC. As other stud- ies have shown, this is not true because even grade I AKs can evolve directly into iSCC, thus necessitating treatment of all forms. The aim of the original Olsen classification (elabo- rated in 1991) was not to establish a clinical classification of AKs but to evaluate the response of AKs to masopro- col; the original classification had as a main clue the grade of hyperkeratosis, explaining why it has three grades. No predictive values are associated with this classification, no correlation has been found between Olsen grade and rate of progression and Olsen grade do not correlate with his- tology (i.e Rowert-Huber classification). Finally, Olsen classification addressed only single lesions, not considering AKs as components of field of cancerization (FC) [8,9]. For all these reasons, according to some authors, its use should be dismissed. Dermatoscopic Features of AKs Non Pigmented AK The dermatoscope is certainly the quickest and most user- friendly tool for diagnosing AKs. They were first described by Zlaudek ed al in 2006 with the identification of four main dermatoscopic features: a pattern characterized by erythema surrounding hair follicles to form a “pseudonet- work,’’ yellowish-white scales; fine linear wavy vessels with a perifollicular distribution and follicles with yellowish ker- atotic plugs surrounded or not by a with halo. These fea- tures combined form a typical pattern, which later became famous over the years for ease of recognition, termed the “strawberry pattern’’ [10]. This pattern is, however, more characteristic of lesions located on the face. Reinehr et al. have described how the most frequent dermatoscopic fea- tures of non-facial actinic keratoses are represented by opaque white scales and erythema for non-pigmented le- sions, and homogeneous brown pigmentation for pigmented ones [11]. Rosettes, described as structures characterized by four white dots arranged like a 4-leaf clover visible under polarized light in actinic keratoses (AK) and squamous cell carcinomas (SCC), are actually quite nonspecific since they can also be identified in basal cell carcinomas (BCC), melanomas, and non-lesional photodamaged skin [12,13]. Dermatoscopy has also proven to be a valuable tool for the clinical and post-treatment follow-up of such lesions [14–17]. Pigmented AK Since the initial use of dermatoscopy in diagnosing AKs, it has been challenging to accurately identify pigmented AKs (pAKs), particularly when differentiating them from lentigo melanoma (LM) in cases of diagnostic uncertainty. In a 2005 study on two cases of pigmented actinic keratoses (pAK), Zalaudek et al. asserted that although dermatoscopy could be helpful in some instances, the principle that the diagnosis of a pigmented lesion cannot rely on a single criterion meant that histopathology remained the gold standard for diagnos- ing these lesions [18]. The same conclusion was reached in a subsequent study by Akay et al. on 89 facial pigmented skin lesions, includ- ing 67 pAK, aiming to define the dermatoscopic criteria that distinguish them from LM. The study identified up to eleven different dermatoscopic features in pAK, such as grey dots, annular-granular patterns, rhomboidal structures, and pseudonetworks [19]. Subsequently, Lallas et al. stud- ied 144 facial pigmented skin lesions, including 70 LM) and Review | Dermatol Pract Concept. 2024;14(3)S1:e2024147S 3 56 pAK, to determine if the limitations of dermatoscopy in differentiating these two types of lesions were due to previ- ous studies focusing exclusively on pigmented criteria with- out considering other possible characteristics. The results of their study indeed showed that features such as scales, red colors, and white circles were significantly associated with pAKs, whereas grey rhomboids, non-prominent follicles, and intense pigmentation were linked with LM (Figure 1) [20]. The most recently described criterion in the literature, useful for the differential diagnosis between pAK and LM, is the “inter grey halo,” as characterized by Nascimento et al. 21. This feature is described as a homogeneous circular struc- ture, either gray-blue or beige, which on one side surrounds the hair follicle and on the other forms the inner contour of the pigmented pseudonetwork. Histologically, this structure corresponds to an inverted cone of epidermis spared by the follicular keratin plug and the anaplastic, hyperpigmented epidermis of the pseudonetwork. Bowenoid AK Bowenoid actinic keratosis (AK) is a histological subtype of AK characterized by single-cell keratinization and full-layer atypia that does not involve the cutaneous adnexa [22]. Dermatoscopically, it is distinguished by regularly distrib- uted glomerular vessels on the surface of the lesion, unlike Bowen’s disease, where the vessels are typically arranged in clusters (Figure 1) [23]. Dermatoscopy Signs of Invasiveness in AK In 2012, based on Olsen’s clinical classification, the derma- toscopic features of nonpigmented AKs were analyzed to assess whether there were typical and/or pathognomonic cri- teria related to grades. It was shown that grade I AK showed mostly the erythematous pseudonetwork and white scales, grade II are characterized by the ‘‘strawberry’’ pattern while grade III are associated mostly with marked hyperkeratosis and follicular keratin plugs [24]. [Table 2] The most interesting finding was to have observed more hyperkeratosis dermatoscopically in the higher grades (II and III) which then reached the maximum presence in in situ squamous cell carcinoma (iSCC) [25]. Another criterion that aids in the diagnosis and assessment of progression, along with those previously mentioned, is the red starburst pattern. This pattern is characterized by the presence of peripheral radial lines or vessels in the context of typical actinic kera- tosis (AK) criteria. It is indicative of progression to invasive squamous cell carcinoma (iSCC) [24]. Papageorgiou et al. published a study evaluating the presence of dermatoscopic criteria indicative of early invasion, capable of differentiat- ing between early SCC and AK. Conducted on 45 AK cases and 50 early SCC cases, the study highlighted that the pre- dictive criteria for early SCC are dotted/glomerular vessels, hairpin vessels, and white structureless areas, while an ery- thematous background was identified as a negative predictor (Figure 2) [26,27]. Figure 1. Male kidney transplant patient presenting with a pinkish frontal macular lesion (A) der- matoscopically characterized by glomerular vessels evenly distributed over the surface (B) and cor- responding to a bowenoid AK on histopathology. Seventy-nine-year-old male with a pigmented hyperkeratotic patch of the left frontal region (C) characterized dermatoscopically by pigmented pseudonetwork, dilated yellowish-white follicular ostium, rosettes, and sharp margins (D) and cor- responding to a pigmented AK on histopathology. 4 Review | Dermatol Pract Concept. 2024;14(3)S1:e2024147S does not provide cellular details [28]. Several studies have described the morphological characteristics of actinic ker- atoses (AK) in Optical Coherence Tomography (OCT), in- cluding: disruption of the dermo-epidermal junction (DEJ), epidermal thickening, hyperkeratosis, white streaks and dots, rapid attenuation of light, lower penetration depth, and a dark band in the stratum corneum [29–33]. The most pre- dictive features described in the majority of published papers include architectural disarray, characterized by a complete or partial absence of the dermo-epidermal junction (DEJ); AK in other Non-Invasive imagine Techniques Optical Coherence Tomography (OCT) OCT operates as a noninvasive, in vivo imaging method uti- lizing interferometry principles. It employs infrared light for imaging, achieving an axial and lateral resolution around 15 micrometers, with a penetration depth between 500 and 1000 micrometers. This method allows for the visualization of skin layers, adnexal structures, and blood vessels, but it Table 2. Dermoscopic features of AK according to the grade Grade of AK Dermoscopic feature Histological correlation I Red pseudonetwork Atypical keratinocytes localized in the third of the epidermis II Strawberry pattern Atypical keratinocytes in the lower two-thirds of the epidermis III Yellow-White scales and follicular keratin plugs Atypia throughout the epidermis Figure 2. A 41-year-old male with an erythematous and hyperkeratotic macular lesion of the left malar region (A) dermatoscopically characterized by erythematous pseudonetwork, white scales, and (B) dilated follicular ostium corresponding to an AK on histology. Sixty-four-year-old male with an erythematous and hyperkeratotic maculo-papular lesion of the left malar region (C) character- ized dermatoscopically by erythematous pseudonetwork and dilated follicular ostium at the periph- ery associated with a central white structureless area (D) corresponding histologically to an SCC. Table 1. Clinical classification systems of AK Olsen classification AKASI score AK-FAS score Grades/Scores 3 18 4 Analysis of FC No Yes Yes Analysis of sun damage No No Yes Analysis Hyperkeratosis Yes No Yes Areas considered in the analysis Lesion-based classification Scalp and face Scalp and face FC: field of cancerization. Review | Dermatol Pract Concept. 2024;14(3)S1:e2024147S 5 portions and reduced image quality in the lower portions of lesions marked by this criterion. Greater lesion thickness, disrupted epidermal architecture, and non-outlined DEJ could assist instead in differentiating SCC from actinic kera- tosis AK [44]. Ruini and colleagues have shown that evaluat- ing AK with LC-OCT can non-invasively replicate the PRO histological classification, exhibiting strong correlation and interobserver agreement. As a result, this method facilitates the assessment of AK’s progression risk without requiring an invasive biopsy [45]. A study by Daxenberger et al. investi- gated the use of an artificial intelligence (AI) algorithm on LC-OCT images for diagnosing and grading AK. The per- formance of the AI algorithm was compared with that of a group of experts, demonstrating high concordance. Conse- quently, this suggests the potential to enhance the accuracy of diagnoses and improve the management of patients with this condition in clinical practice [46]. Numerous studies have been reported in the literature on the use of LC-OCT for monitoring AK after treatments such as cryotherapy [47] and tirbanibulin [48]. Reflectance Confocal Microscopy (RCM) Reflectance confocal microscopy (RCM) is a non-invasive imaging technique that enables the visualization of skin in the horizontal plane with cellular-level resolution. The im- aging depth of RCM extends approximately 200-300 mi- crometers, reaching down to the papillary dermis [49]. The primary features of AK as observed through RCM include hyperkeratosis with parakeratosis at the level of the stra- tum corneum and an irregular honeycombed pattern in the spinous-granular layers. Given that this technique provides images on a horizontal plane, it does not enable the assess- ment of the vertical invasion depth of these lesions [50]. Pellacani and colleagues reported a high concordance rate and strong interobserver correlation in the grading of kerat- inocyte atypia in AK when evaluated using RCM compared to histopathological examination [51]. Specifically, grade 1 actinic keratosis (AK) displays focal areas of atypical honey- combed patterns mixed with areas of normal honeycomb at the spinous layer level. Grade 2 AK shows widespread kera- tinocyte atypia across both the spinous and granular layers, featuring keratinocytes of various shapes and sizes. Grade 3 AK is characterized by a markedly atypical honeycombed pattern described as disarranged. Keratinocyte pleomor- phism increases proportionally with the AK grade [51,52]. Moscarella et al. outlined the principal features of pAK using RCM. These features include hyperkeratosis with paraker- atosis, atypical honeycombed pattern, increased epidermal thickness, intraepidermal dendritic cells, and bright, small dermal papillae with enlarged interpapillary spaces. Nota- bly, these observations were made in the absence of any fea- tures indicative of melanocytic lesions [53]. A confounding white streaks and dots, which histologically correspond to particularly dense areas of hyperkeratosis; epidermal thick- ening; and pronounced hyperkeratosis. The latter character- istic is not specific to actinic keratoses (AK) as it can also be found in other lesions and may compromise the quality of the images due to artifacts. These artifacts create shad- ows that obscure underlying portions of the tissue [29]. The basement membrane cannot be distinguished with this tech- nique, making it difficult to reliably determine early tumor invasion. he practical utility of Optical Coherence Tomogra- phy (OCT) for actinic keratoses (AK) also lies in its ability to non-invasively monitor the outcomes and effectiveness of various therapeutic approaches available for this condition, offering additional possibilities and information beyond what is possible with dermatoscopy alone. In this regard, numerous studies have been published on the use of OCT to evaluate the results of therapies such as ingenol mebu- tate [34,35], hybrid fractional ablative and nonablative laser resurfacing36, daylight photodynamic therapy after tailored pretreatment with ablative fractional laser or microderm- abrasion [37], cryosurgery [38], imiquimod [39], tirbanibu- lin [40], and fluorouracil [41]. Furthermore, this method is useful in the identification of both clinical and subclinical actinic keratoses, thereby serving as an important tool for precisely defining the field of cancerization in patients with significant photodamage [42]. Line-Field Confocal Optical Coherence Tomography (LC-OCT) Line-field confocal optical coherence tomography (LC-OCT) is a non-invasive optical imaging method that produces real- time vertical, horizontal, and three-dimensional section images. These images are comparable to traditional histol- ogy images and offer cellular resolution, with a penetration depth of approximately 500 micrometers [43]. This tech- nique can identify diverse skin structures and assess various conditions, such as the presence of atypical epidermal cells, the integrity of the dermo-epidermal junction in the vertical plane, the uniformity of the keratinocyte pattern, and the presence of dendritic cells in the horizontal plane. Cinotti and colleagues employed LC-OCT to identify and analyze key patterns in AK and SCC, aiming to distinguish specific criteria that could differentiate between these conditions. Notable features common to both AK and SCC included hy- perkeratosis, acanthosis, parakeratosis, erosion/ulceration, disrupted epithelial architecture, dyskeratotic keratinocytes, crowded cell nuclei, abnormal nuclei, tumor budding, and expanded blood vessels. Among these, dyskeratotic kerati- nocytes, atypical nuclei, and disorganized epithelial archi- tecture were particularly significant indicators [44]. Just as with OCT and RCM, excessive hyperkeratosis can lead to artifacts characterized by heightened reflectivity in the upper 6 Review | Dermatol Pract Concept. 2024;14(3)S1:e2024147S How to Improve Classification of AKs in Clinical Trials and Studies Considering the limitations of each classification and the low rate of reproducibility of some of them it seems inevitable to have classifications that cannot be compared with each other and with different analyzed characteristics. As already suggested by other authors, it would be necessary to always analyze the presence or absence of the field of cancerization and to evaluate the extent of the area of Aks [65]. Otherwise, focusing only on individual lesions does not allow the assessment of the disease burden and does not al- low the evaluation of the response to treatments accurately. Olsen’s classification, despite the limitations already mentioned, remains the most widely used but should be unused especially in scientific studies. Furthermore, Olsen’s classification has no predictive value for the development of SCC, unlike AKASI score, which has been associated with the incidence of iSCC. The use of AKASI in clinical trials would also allow the same score to be used during clinical practice to compare data with those in the literature. This method already appears to be in use for other dermatologic conditions such as psoriasis in which the PASI score is used both in research and during daily practice. Conclusions AKs are the most frequent tumors diagnosed during daily dermatological practice; their diagnosis is usually made by clinical evaluation, but in some cases the clinical aspect is not sufficient for a diagnosis of certainty. Dermatoscopy, already defined a silent revolution in dermatology because of its ease of use and being an inexpensive method [66], adds more specificity to the diagnosis through visualization of typical criteria, such as red pseudonetwork, the presence of large and white follicles, strawberry pattern and whitish scales. Several diseases in fact have a clinical presentation that can mimic AK: for example, irritated flat seborrheic keratosis, superficial basal cell carcinoma, lentigo melanoma, or even inflammatory pathologies such as psoriasis or cutaneous sar- coidosis [67]. The presence of dermatoscopic criteria helps to direct the diagnostic and the therapeutic process. Despite its easy use, the biggest limitation that can be observed in the classification systems previously described in this paper such as AKASI and AK-FAS, is the disregard of dermatoscopic parameters in classifications based on scores that only clini- cally evaluate AKs and the field of cancerization. It would be preferable in the future to integrate noninvasive diagnostics into the classifications systems in order to obtain objective and reproducible data based on a non-expensive and user- friendly diagnostic method. factor is the presence of intraepidermal dendritic cells, as this feature can also be observed in melanomas, making it chal- lenging to differentiate between the two conditions based solely on this characteristic. Another diagnostic challenge associated with RCM involves distinguishing between AK and SCC. Due to the limited penetration depth of RCM, it is difficult to assess deeper structures, which restricts the avail- able information for accurate differentiation between these conditions. Currently, the distinction between AK and SCC relies on the extent of keratinocyte atypia and epidermal dis- array, which appears widespread and full-thickness in SCC, but tends to be more localized and focal in AK [54,55]. RCM has also been used for the post-treatment follow-up of AK treated with various modalities such as fluorouracil [56], imiquimod [57], ingenol mebutate [58], shave biopsy [59], photodynamic therapy [60], daylight photodynamic therapy [61], and cryotherapy [62]. Field-Cancerization Based Classifications: AKASI and AK-FAS Score To evaluate not only the single AKs but the whole skin sur- rounding them, in 2017 the AKASI (AK Area and Severity Index) score was developed [63]. To calculate AKASI, four regions should be considered in the analysis: scalp, forehead, left face and right face. Within each region, according to the area affected by AKs, a score ranging from 1 (1-9% affected area) to 6 (90-100% affected area) is assigned. Other fea- tures considered are the distribution, erythema and thickness of AKs with a scale ranging from 0 (none) to 4 (maximum). Combining the area and the signs scores, a score ranging from 0 (no AKs) to 18 (most severe degree) is obtained. With this system, a global look on the affected area is achieved, quantifying the characteristics of sun damaged regions and obtaining an objective score for monitoring the efficacy of a treatment prescribed. This classification has a major lim- itation the restriction of the score only for the head, for this reason it cannot be used for AKs located in other areas, such as hands, forearms or chest. Also, in 2017 another score was developed, named AK- FAS (Actinic Keratosis Field Assessment Scale), to assess the severity of Aks [64]. This score is based on three criteria: hyperkeratosis, sun damage and AK area. Depending on percentage of area affected by AKs, a score from 0 (0% area affected) to IV (<50% area involved) is assigned. The scale has been vali- dated on photographs of twelve patients and the validation of the AK-FAS showed good reproducibility, helping to stan- dardize AK diagnosis, making it relevant to routine clinical practice but also for clinical trials and studies. Review | Dermatol Pract Concept. 2024;14(3)S1:e2024147S 7 combination of optical coherence tomography and reflectance confocal microscopy.  J Eur Acad Dermatol Venereol. 2016; 30(2):258-265. 18. Zalaudek I, Ferrara G, Leinweber B, Mercogliano A, D’Ambrosio A, Argenziano G. Pitfalls in the clinical and dermoscopic diag- nosis of pigmented actinic keratosis.  J Am Acad Dermatol. 2005;53(6):1071-1074. 19. Akay BN, Kocyigit P, Heper AO, Erdem C. Dermatoscopy of flat pigmented facial lesions: diagnostic challenge between pig- mented actinic keratosis and lentigo maligna. Br J Dermatol 163, 1212–7 (2010). 20. Lallas A, Tschandl P, Kyrgidis A, et al. Dermoscopic clues to differentiate facial lentigo maligna from pigmented actinic keratosis. Br J Dermatol. 2016;174(5):1079-1085. 21. Nascimento MM, Shitara D, Enokihara MM, Yamada S, Pellacani G, Rezze GG. Inner gray halo, a novel dermoscopic fea- ture for the diagnosis of pigmented actinic keratosis: clues for the differential diagnosis with lentigo maligna. J Am Acad Dermatol. 2014;71(4):708-715. 22. Reinehr CPH, Bakos RM. Actinic keratoses: review of clinical, dermoscopic, and therapeutic aspects. An Bras Dermatol 94, 637–657 (2019). 23. Zalaudek I, Kreusch J, Giacomel J, Ferrara G, Catricalà C, Argenziano G. How to diagnose nonpigmented skin tumors: a re- view of vascular structures seen with dermoscopy: part II. Nonme- lanocytic skin tumors. J Am Acad Dermatol. 2010;63(3):377-388. 24. Zalaudek I, Giacomel J, Schmid K, et al. Dermatoscopy of facial actinic keratosis, intraepidermal carcinoma, and invasive squa- mous cell carcinoma: a progression model. J Am Acad Dermatol. 2012;66(4):589-597. 25. Peris K, Micantonio T, Piccolo D, Fargnoli MC. Dermoscopic fea- tures of actinic keratosis. J Dtsch Dermatol Ges 5, 970–6 (2007). 26. Papageorgiou C, Lallas A, Manoli SM, et al. Evaluation of der- matoscopic criteria for early detection of squamous cell carci- noma arising on an actinic keratosis.  J Am Acad Dermatol. 2022;86(4):791-796. 27. Salafranca MÁ, Zaballos P. Dermoscopy of squamous cell carcinoma: from actinic keratosis to invasive forms. Actas Dermosifiliogr (2024) 28. Ulrich M, Stockfleth E, Roewert-Huber J, Astner S. Noninvasive diagnostic tools for nonmelanoma skin cancer. British Journal of Dermatology 157, 56–58 (2007). 29. Friis KBE, Themstrup L, Jemec GBE. Optical coherence tomog- raphy in the diagnosis of actinic keratosis—A systematic review. Photodiagnosis Photodyn Ther 18, 98–104 (2017). 30. Mogensen M, Joergensen TM, Nürnberg BM, et al. Assessment of optical coherence tomography imaging in the diagnosis of non-melanoma skin cancer and benign lesions versus normal skin: observer-blinded evaluation by dermatologists and pathol- ogists. Dermatol Surg. 2009;35(6):965-972. 31. Boone MALM, Norrenberg S, Jemec GBE, Del Marmol V. Imaging actinic keratosis by high-definition optical coher- ence tomography. Histomorphologic correlation: a pilot study. Exp Dermatol 22, 93–7 (2013). 32. Barton JK, Gossage KW, Xu W, et al. Investigating sun-damaged skin and actinic keratosis with optical coherence tomography: a pilot study. Technol Cancer Res Treat. 2003;2(6):525-535. 33. Korde VR, Bonnema GT, Xu W, et al. Using optical coherence tomography to evaluate skin sun damage and precancer. Lasers Surg Med. 2007;39(9):687-695. References 1. Lee, K. J. & Soyer, H. P. Cutaneous keratinocyte cancers of the head and neck: Epidemiology, risk factors and clinical, dermo- scopic and reflectance confocal microscopic features. Oral Oncol 98, 109–117 (2019). 2. Conforti, C., Beninati, E. & Dianzani, C. Are actinic keratoses really squamous cell cancer? How do we know if they would become malignant? Clin Dermatol 36, 430–432 (2018). 3. Spencer, J. Understanding actinic keratosis: epidemiology, biol- ogy, and management of the disease. J Am Acad Dermatol 68, S1 (2013). 4. Siegel JA, Korgavkar K, Weinstock MA. Current perspective on actinic keratosis: a review. Br J Dermatol. 2017;177(2):350-358. 5. Saenz-Sardà X, Carrato C, Pérez-Roca L, et al. Epithelial-to- mesenchymal transition contributes to invasion in squamous cell carcinomas originated from actinic keratosis through the differ- entiated pathway, whereas proliferation plays a more significant role in the classical pathway.  J Eur Acad Dermatol Venereol. 2018;32(4):581-586. 6. Fernandez Figueras MT. From actinic keratosis to squamous cell carcinoma: pathophysiology revisited. J Eur Acad Dermatol Venereol 31 Suppl 2, 5–7 (2017). 7. Filosa A, Filosa G. Actinic keratosis and squamous cell car- cinoma: clinical and pathological features. G Ital Dermatol Venereol 150, 379–84 (2015). 8. Olsen EA, Abernethy ML, Kulp-Shorten C, et al. A double-blind, vehicle-controlled study evaluating masoprocol cream in the treatment of actinic keratoses on the head and neck. J Am Acad Dermatol. 1991;24(5 Pt 1):738-743. 9. Sinclair R, Baker C, Spelman L, Supranowicz M, MacMahon B. A review of actinic keratosis, skin field cancerisation and the ef- ficacy of topical therapies. Australasian Journal of Dermatology 62, 119–123 (2021). 10. Zalaudek I, Giacomel J, Argenziano G, et al. Dermoscopy of facial nonpigmented actinic keratosis.  Br J Dermatol. 2006; 155(5):951-956. 11. Reinehr CPH, Garbin GC, Bakos, RM. Dermatoscopic Patterns of Nonfacial Actinic Keratosis: Characterization of Pigmented and Nonpigmented Lesions. Dermatologic Surgery 43, 1385–1391 (2017). 12. Liebman TN. Rosettes May Be Observed in a Range of Condi- tions. Arch Dermatol 147, 1468 (2011). 13. Cuellar F, Vilalta A, Puig S, Palou J, Salerni G. New Dermo- scopic Pattern in Actinic Keratosis and Related Conditions. Arch Dermatol 145, (2009). 14. Lee JH, Won CY, Kim GM, Kim SY. Dermoscopic features of actinic keratosis and follow up with dermoscopy: a pilot study. J Dermatol 41, 487–93 (2014). 15. Xiaoqin Y, Chan H, Long W, et al. Dermoscopic Monitor- ing for Treatment and Follow-Up of Actinic Keratosis With 5-Aminolaevulinic Acid Photodynamic Therapy. Technol Cancer Res Treat. 2018;17:1533033818820091. Published 2018 Dec 25. 16. Benati E, Longhitano S, Pampena R, et al. Digital follow-up by means of dermatoscopy and reflectance confocal microscopy of actinic keratosis treated with Imiquimod 3.75% cream.  J Eur Acad Dermatol Venereol. 2020;34(7):1471-1477. 17. Malvehy J, Alarcon I, Montoya J, Rodríguez-Azeredo R, Puig S. Treatment monitoring of 0.5% 5-fluorouracil and 10% sali- cylic acid in clinical and subclinical actinic keratoses with the 8 Review | Dermatol Pract Concept. 2024;14(3)S1:e2024147S line‐field confocal optical coherence tomography. Skin Research and Technology 30, (2024). 48. Thamm JR, Welzel J, Schuh S. AI-based and LC-OCT-guided follow-up of actinic keratoses under treatment with tirbanibulin 1. J Eur Acad Dermatol Venereol (2024) doi:10.1111/jdv.20059. 49. Shahriari N, Grant-Kels JM, Rabinovitz H, Oliviero M, Scope A. Reflectance confocal microscopy. J Am Acad Dermatol 84, 1–14 (2021). 50. Rishpon A, Kim N, Scope A, et al. Reflectance confocal microscopy criteria for squamous cell carcinomas and actinic keratoses.  Arch Dermatol. 2009;145(7):766-772. doi:10.1001 /archdermatol.2009.134 51. Pellacani G, Ulrich M, Casari A, et al. Grading keratinocyte atypia in actinic keratosis: a correlation of reflectance confocal microscopy and histopathology. J Eur Acad Dermatol Venereol. 2015;29(11):2216-2221. doi:10.1111/jdv.13215 52. Casari A, Chester J, Pellacani G. Actinic Keratosis and Non- Invasive Diagnostic Techniques: An Update. Biomedicines 6, (2018). 53. Moscarella E, Rabinovitz H, Zalaudek I, et al. Dermoscopy and reflectance confocal microscopy of pigmented actinic ker- atoses: a morphological study.  J Eur Acad Dermatol Venereol. 2015;29(2):307-314. doi:10.1111/jdv.12532 54. Aghassi D, Anderson RR, González S. Confocal laser micro- scopic imaging of actinic keratoses in vivo: a preliminary report. J Am Acad Dermatol 43, 42–8 (2000). 55. Peppelman M, Nguyen KP, Hoogedoorn L, van Erp PEJ, Gerritsen MJP. Reflectance confocal microscopy: non-invasive distinc- tion between actinic keratosis and squamous cell carcinoma. J Eur Acad Dermatol Venereol 29, 1302–9 (2015). 56. Ishioka P, Maia M, Rodrigues SB, Lellis RF, Hirata SH. In vivo Confocal Laser Microscopy for monitoring of actinic keratosis treatment: a comparison with histopathologic assessment after treatment with topical 5% 5-fluorouracil. J Eur Acad Dermatol Venereol. 2018;32(7):1155-1163. doi:10.1111/jdv.14716 57. Benati E, Longhitano S, Pampena R, et al. Digital follow-up by means of dermatoscopy and reflectance confocal microscopy of actinic keratosis treated with Imiquimod 3.75% cream.  J Eur Acad Dermatol Venereol. 2020;34(7):1471-1477. doi:10.1111 /jdv.16143 58. Estebaranz J, Franco A, Villegas R, Floristán U. Monitor- ing Ingenol Mebutate Gel Treatment of Actinic Keratoses by Reflectance Confocal Microscopy. Acta Dermato Venereol 97, 646–648 (2017). 59. Richtig E, Ahlgrimm-Siess V, Koller S, et al. Follow-up of ac- tinic keratoses after shave biopsy by in-vivo reflectance confo- cal microscopy--a pilot study.  J Eur Acad Dermatol Venereol. 2010;24(3):293-298. doi:10.1111/j.1468-3083.2009.03410.x60. 60. Mazur E, Reich A. Photodynamic Therapy is an Effective Treat- ment of Facial Pigmented Actinic Keratosis. Dermatol Ther (Heidelb) 13, 1265–1276 (2023). 61. Seyed Jafari SM, Timchik T, Hunger RE. In vivo confocal micros- copy efficacy assessment of daylight photodynamic therapy in ac- tinic keratosis patients. British J Dermatol 175, 375–381 (2016). 62. Curiel-Lewandrowski C, Myrdal CN, Saboda K, et al. In Vivo Reflectance Confocal Microscopy as a Response Monitoring Tool for Actinic Keratoses Undergoing Cryotherapy and Photo- dynamic Therapy. Cancers (Basel). 2021;13(21):5488. Published 2021 Oct 31. doi:10.3390/cancers13215488 63. Dirschka T, Pellacani G, Micali G, et al. A proposed scoring sys- tem for assessing the severity of actinic keratosis on the head: 34. Ruini C, Hartmann D, Bastian M, et al. Non-invasive monitor- ing of subclinical and clinical actinic keratosis of face and scalp under topical treatment with ingenol mebutate gel 150 mcg/g by means of reflectance confocal microscopy and optical coherence tomography: New perspectives and comparison of diagnostic techniques. J Biophotonics. 2019;12(7):e201800391. 35. Maier T, Cekovic D, Ruzicka T, Sattler EC, Berking C. Treat- ment monitoring of topical ingenol mebutate in actinic kerato- ses with the combination of optical coherence tomography and reflectance confocal microscopy: a case series. British Journal of Dermatology 172, 816–818 (2015). 36. Brown MM, Ortiz A. Hybrid Fractional Ablative and Nonabla- tive Laser Resurfacing of Actinic Keratoses. Dermatol Surg 45, 468–470 (2019). 37. Wenande E, Phothong W, Bay C, Karmisholt KE, Haedersdal M, Togsverd-Bo K. Efficacy and safety of daylight photodynamic therapy after tailored pretreatment with ablative fractional laser or microdermabrasion: a randomized, side-by-side, single-blind trial in patients with actinic keratosis and large-area field cancer- ization. Br J Dermatol. 2019;180(4):756-764. 38. Themstrup L, Banzhaf C, Mogensen M, Jemec GB. E. Cryosur- gery treatment of actinic keratoses monitored by optical coher- ence tomography: a pilot study. Dermatology 225, 242–7 (2012). 39. Banzhaf CA, Themstrup L, Ring HC, Mogensen M, Jemec GBE. Optical coherence tomography imaging of non‐melanoma skin cancer undergoing imiquimod therapy. Skin Research and Technology 20, 170–176 (2014). 40. Cantisani C, Musolff N, Azzella G, et al. Tirbanibulin 1% Oint- ment Effectiveness for Actinic Keratosis Treatment Evaluated by Dynamic Optical Coherence Tomography, Dermatol Ther 2024, 1018395, 7 pages, 2024. 41. Malvehy J, Alarcon I, Montoya J, Rodríguez-Azeredo R, Puig S. Treatment monitoring of 0.5% 5-fluorouracil and 10% salicylic acid in clinical and subclinical actinic keratoses with the combi- nation of optical coherence tomography and reflectance confocal microscopy. J Eur Acad Dermatol Venereol 30, 258–65 (2016). 42. Markowitz O, Schwartz M, Feldman E, et al. Defining Field Cancerization of the Skin Using Noninvasive Optical Coherence Tomography Imaging to Detect and Monitor Actinic Keratosis in Ingenol Mebutate 0.015%- Treated Patients.  J Clin Aesthet Dermatol. 2016;9(5):18-25. 43. Ogien J, Tavernier C, Fischman S, Dubois A. Line-field confocal optical coherence tomography (LC-OCT): principles and practi- cal use. Ital J Dermatol Venerol. 2023;158(3):171-179. 44. Cinotti E, Tognetti L, Cartocci A, et al. Line-field confocal op- tical coherence tomography for actinic keratosis and squa- mous cell carcinoma: a descriptive study.  Clin Exp Dermatol. 2021;46(8):1530-1541. 45. Ruini C, Schuh S, Gust C, et al. In-Vivo LC-OCT Evaluation of the Downward Proliferation Pattern of Keratinocytes in Actinic Keratosis in Comparison with Histology: First Impressions from a Pilot Study.  Cancers (Basel). 2021;13(12):2856. Published 2021 Jun 8. doi:10.3390/cancers13122856 46. Daxenberger F, Deußing M, Eijkenboom Q, et al. Innovation in Actinic Keratosis Assessment: Artificial Intelligence-Based Approach to LC-OCT PRO Score Evaluation. Cancers (Basel). 2023;15(18):4457. Published 2023 Sep 7. doi:10.3390/cancers 15184457 47. Pathak GN, Sanabria B, Caetano VD, Rafiq B, Rao BK. Eval- uation and treatment monitoring of actinic keratosis using Review | Dermatol Pract Concept. 2024;14(3)S1:e2024147S 9 66. Ring C, Cox N, Lee JB. Dermatoscopy. Clin Dermatol 39, 635–642 (2021). 67. Conforti C, Giuffrida R, de Barros MH, Resende FSS, Cerroni L, Zalaudek I. Dermoscopy of a single plaque on the face: an uncommon presentation of cutaneous sarcoidosis.  Derma- tol Pract Concept. 2018;8(3):174-176. Published 2018 Jul 31. doi:10.5826/dpc.0803a04 actinic keratosis area and severity index. J Eur Acad Dermatol Venereol. 2017;31(8):1295-1302. doi:10.1111/jdv.14267 64. Dréno B, Cerio R, Dirschka T, et al. A Novel Actinic Keratosis Field Assessment Scale for Grading Actinic Keratosis Dis- ease Severity.  Acta Derm Venereol. 2017;97(9):1108-1113. doi:10.2340/00015555-2710 65. Schmitz L, Broganelli P, Boada A. Classifying Actinic Keratosis: What the Reality of Everyday Clinical Practice Shows Us. J Drugs Dermatol 21, 845–849 (2022).