Cutaneous Squamous Cell Carcinoma Research Articles

European consensus-based interdisciplinary guideline for diagnosis, treatment and prevention of actinic keratoses, epithelial UV-induced dysplasia and field cancerization on behalf of European Association of Dermato-Oncology, European Dermatology Forum, European Academy of Dermatology and Venereology and Union of Medical Specialists (Union Européenne des Médecins Spécialistes).

A collaboration of multidisciplinary experts from the European Association of Dermato-Oncology, the European Dermatology Forum, the European Academy of Dermatology and Venereology, and the European Union of Medical Specialists was formed to develop European recommendations on AK diagnosis and treatment, based on current literature and expert consensus. This guideline addresses the epidemiology, diagnostics, risk stratification and treatments in immunocompetent as well as immunosuppressed patients. Actinic keratoses (AK) are potential precursors of cutaneous squamous cell carcinoma (cSCC) and display typical histopathologic and immunohistochemical features of this malignancy in an early stage. They can develop into cSSC insitu and become invasive in a low percentage of cases. AK is the most frequent neoplasia in white populations, frequently occurring within a cancerous field induced by ultraviolet radiation. Since it cannot be predicted, which lesion will progress to cSCC and when treatment is usually recommended. The diagnosis of AK and field cancerization is made by clinical examination. Dermatoscopy, confocal microscopy, optical coherence tomography or line-field confocal-OCT can help in the differential diagnosis of AK and other skin neoplasms. A biopsy is indicated in clinically and/or dermatoscopically suspicious and/or treatment-refractory lesions. The choice of treatment depends on patients' and lesion characteristics. For single non-hyperkeratotic lesions, the treatment can be started upon patient's request with destructive treatments or topical treatments. For multiple lesions, field cancerization treatment is advised with topical treatments and photodynamic therapy. Preventive measures such as sun protection, self-examination and repeated field cancerization treatments of previously affected skin areas in high-risk patients are advised.

Discoid lupus erythematosus and cutaneous squamous cell carcinoma

Discoid lupus erythematosus and cutaneous squamous cell carcinoma

Antihypertensive Medications and Risk of Melanoma and Keratinocyte Carcinomas: A Systematic Review and Meta-Analysis

Some anti-hypertensive medications are photosensitizing. The implications for skin cancer risk remain unclear, as results from prior studies are inconsistent and as new evidence is published. We performed a systematic review and meta-analysis to evaluate the association between anti-hypertensives and common skin cancers (cutaneous squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma), and to evaluate dose-response relationships. Forty-four articles met inclusion criteria, and 42 could be meta-analyzed. Increased risks were seen for BCC with calcium channel blockers (relative risk [RR] 1.17, 95% CI 1.11-1.22), diuretics (RR 1.06, 95% CI 1.03-1.10), and thiazides (RR 1.10, 95% CI 1.04-1.16); for SCC with calcium channel blockers (RR 1.08, 95% CI 1.01-1.14), diuretics (RR 1.29, 95% CI 1.17-1.43), and thiazides (RR 1.36, 95% CI 1.15-1.61); and for melanoma in angiotensin-converting-enzyme inhibitors (RR 1.09, 95% CI 1.03-1.14), calcium channel blockers (RR 1.08, 95% CI 1.03-1.12), and thiazides (RR 1.09, 95% CI 1.02-1.17). The quality of evidence was low or very low. We observed evidence for dose-response for thiazides with BCC, angiotensin-converting-enzyme inhibitors, diuretics, and thiazides with SCC, and angiotensin-converting-enzyme inhibitors, diuretics, and thiazides with melanoma. Our meta-analysis supports a potential causal association between some antihypertensives, particularly diuretics, and skin cancer risk.

Immune Checkpoint Inhibitor-Associated Remitting Seronegative Symmetrical Synovitis With Pitting Edema: Description of a New Entity by CanRIO.

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is characterized by symmetrical synovitis with pitting edema and negative rheumatoid factor (RF). It has been described in a setting of malignancy, suggesting a paraneoplastic association. With the increasing use of immune checkpoint inhibitors (ICIs) for the treatment of cancers and emergence of immune-related adverse events (irAEs), our objective was to identify and describe cases of ICI-associated RS3PE (ICI-RS3PE) and compare them to non-ICI-RS3PE. The Canadian Research Group of Rheumatology in Immuno-Oncology (CanRIO) network is a collaboration of Canadian rheumatologists with experience in the management of patients with rheumatic irAEs (Rh-irAEs). Standardized data on adult patients with Rh-irAE have been collected as part of retrospective and prospective cohorts. In this study, detailed information on all cases of ICI-RS3PE from both cohorts were extracted and analyzed. We identified 11 cases of ICI-RS3PE. The most frequently observed malignancy was nonsmall cell lung cancer (4 of 11), followed by malignant melanoma (2 of 11) and cutaneous squamous cell carcinoma (2 of 11). The median time to onset of ICI-RS3PE was 26 weeks from ICI start and 52 weeks from diagnosis of malignancy. Seven patients had stable cancer prior to onset of ICI-RS3PE, 3 had partial response, and 1 had complete response. All patients received glucocorticoids. Conventional synthetic disease-modifying antirheumatic drugs (csDMARD) were needed in 10 patients. ICI-RS3PE may be an independent Rh-irAE, separate from paraneoplastic RS3PE. The symptoms of ICI-RS3PE responded well to glucocorticoids, but concomitant treatment with csDMARDs may be necessary.

Integrating the 40-Gene Expression Profile (40-GEP) Test Improves Metastatic Risk-Stratification Within Clinically Relevant Subgroups of High-Risk Cutaneous Squamous Cell Carcinoma (cSCC) Patients.

The validated 40-gene expression profile (40-GEP) test independently stratifies risk of regional or distant metastasis for cutaneous squamous cell carcinoma (cSCC) tumors with high-risk clinicopathologic features. This study evaluated the stratification of risk by the 40-GEP test in a large cohort of tumors with one or more high-risk factors and in clinically relevant subgroups, including tumors within National Comprehensive Cancer Network (NCCN) high- and very-high-risk groups, lower-stage BWH T1 and T2a tumors, and patients > 65years old. This multicenter (n = 58) performance study of the 40-GEP included 897 patients. Kaplan-Meier analyses were performed to assess risk stratification profiles for 40-GEP Class 1 (low), Class 2A (higher) and Class 2B (highest) risk groups, while nested Cox regression models were used to compare risk prediction of clinicopathologic risk classification systems versus risk classification systems in combination with 40-GEP. Patients classified as 40-GEP Class 1, Class 2A, or Class 2B had significantly different metastatic risk profiles (p < 0.0001). Integrating 40-GEP results into models with individual clinicopathologic risk factors or risk classification systems (Brigham and Women's Hospital, American Joint Committee on Cancer Staging Manual, 8th Edition) and NCCN demonstrated significant improvement in accuracy for prediction of metastatic events (ANOVA for model deviance, p < 0.0001 for all models). The 40-GEP test demonstrates accurate, independent, clinically actionable stratification of metastatic risk and improves predictive accuracy when integrated into risk classification systems. The improved accuracy of risk assessment when including tumor biology via the 40-GEP test ensures more risk-aligned, personalized patient management decisions.

Real-World Experience of Immune-Checkpoint Inhibitors in Older Patients with Advanced Cutaneous Squamous Cell Carcinoma.

Older patients are often underrepresented in clinical trials owing to exclusionary comorbidities, which are more common with age. Chemotherapy is poorly tolerated in older comorbid advanced cutaneous squamous cell carcinoma (CSCC) patients; however, little is known on the efficacy and tolerability of immune-checkpoint inhibitors (ICIs) in this population. To our knowledge, this is the largest dedicated report on a cohort of older patients with advanced CSCC treated with immunotherapy to date. The aim was to report outcomes of ICI use in a real-world older cohort with advanced CSCC. A single-centre retrospective audit of all patients treated via an access scheme providing ICIs to patients with advanced CSCC was conducted. Participants were ≥ 70 years of age and had advanced CSCC not amenable to curative surgery or radiotherapy. Best overall response rate (ORR), 12-month overall survival (OS) and progression-free survival (PFS), and toxicity rates were assessed. A total of 53 patients were analysed. The median age was 81.8 years (range 70.1-96.8); 81% were male; 34% were immunocompromised; and 34% had an Eastern Cooperative Oncology Group (ECOG) performance status score of ≥ 2. The ORR was 57%, and 12-month OS and PFS were 63% (95% confidence interval [CI] 44-78) and 41% (95% CI 25-57), respectively. Thirty-two per cent developed an immune-related adverse event (irAE), but only two patients experienced a grade 3 irAE, with no treatment-related deaths. Higher ECOG score was associated with worse OS and PFS. No significant association was identified for increasing age, sex, Charlson Comorbidity Index score, or immunocompromised status. ICIs have demonstrated efficacy and have an acceptable safety profile among older patients with advanced CSCC, with comparable efficacy to what has been demonstrated in current clinical trials.

High response rate with extended dosing of cemiplimab in advanced cutaneous squamous cell carcinoma

BackgroundCemiplimab (Libtayo®), a human monoclonal immunoglobulin G4 antibody to the programmed cell death-1 receptor, is approved for the treatment of patients with advanced cutaneous squamous cell carcinoma (CSCC), who are...

129 Regional Experience of Cemiplimab, in Locally advanced and stage IV Head and Neck Cutaneous Squamous Cell Carcinomas

129 Regional Experience of Cemiplimab, in Locally advanced and stage IV Head and Neck Cutaneous Squamous Cell Carcinomas

Complete Resolution of Bulky Cutaneous Squamous Cell Carcinoma by Programmed Death-1 Inhibitor

Complete Resolution of Bulky Cutaneous Squamous Cell Carcinoma by Programmed Death-1 Inhibitor

The combined immunohistochemical expression of AMBRA1 and SQSTM1 identifies patients with poorly differentiated cutaneous squamous cell carcinoma at risk of metastasis: A proof of concept study.

Cutaneous squamous cell carcinoma (cSCC) incidence continues to increase globally with, as of yet, an unmet need for reliable prognostic biomarkers to identify patients at increased risk of metastasis. The aim of the present study was to test the prognostic potential of the combined immunohistochemical expression of the autophagy regulatory biomarkers, AMBRA1 and SQSTM1, to identify high-risk patient subsets. A retrospective cohort of 68 formalin-fixed paraffin-embedded primary cSCCs with known 5-year metastatic outcomes were subjected to automated immunohistochemical staining for AMBRA1 and SQSTM1. Digital images of stained slides were annotated to define four regions of interest: the normal and peritumoral epidermis, the tumor mass, and the tumor growth front. H-score analysis was used to semi-quantify AMBRA1 or SQSTM1 expression in each region of interest using Aperio ImageScope software, with receiver operator characteristics and Kaplan-Meier analysis used to assess prognostic potential. The combined loss of expression of AMBRA1 in the tumor growth front and SQSTM1 in the peritumoral epidermis identified patients with poorly differentiated cSCCs at risk of metastasis (*p < 0.05). Collectively, these proof of concept data suggest loss of the combined expression of AMBRA1 in the cSCC growth front and SQSTM1 in the peritumoral epidermis as a putative prognostic biomarker for poorly differentiated cSCC.

Neck management in metastatic cutaneous squamous cell carcinoma of the head and neck.

Optimal neck management remains unclear in head and neck cutaneous squamous cell carcinoma (HNcSCC) with parotid metastasis. Our goal was to compare the impact of different cervical treatments on HNcSCC with parotid metastasis. Patients were retrospectively included. The primary outcome variables were regional control (RC) and disease-specific survival (DSS). The impacts of observation, elective neck irradiation (ENI), and elective neck dissection (END) were analyzed using the Cox model and presented as hazard ratios (HRs) and 95% confidence intervals (CIs). In total, 268 patients were enrolled. In the Cox model for RC, compared with ENI, observation was associated with a significantly higher risk of regional recurrence (p = 0.001, HR = 2.50, 95%CI = 1.45-4.30). However, END showed a comparable influence on regional recurrence (p = 0.246, HR = 0.70, 95%CI = 0.38-1.28). In the Cox model for DSS, END demonstrated a similar HR of 0.62 (95%CI = 0.30-1.26) compared to ENI (p = 0.184). However, patients who underwent observation were associated with an additional nearly twofold risk of cancer-related mortality (HR = 2.85, 95%CI = 1.55-5.23). Subgroup analysis showed that ENI predicted comparable RC (p = 0.389) and DSS (p = 0.346) in patients with one or two metastatic parotid lymph nodes, but worse RC (p = 0.007) and DSS (p = 0.024) in patients with more than three positive lymph nodes. In HNcSCC with parotid metastasis, elective treatment of neck lymph nodes with END or ENI should always be performed.

3D modeling of normal skin and cutaneous squamous cell carcinoma. A comparative study in 2D cultures, spheroids, and 3D bioprinted systems.

The current cancer research and drug testing are primarily based on 2D cell cultures and animal models. However, these methods have limitations and yield distinct drug response patterns. This study addressed this gap by developing an innovativein vitrohuman three-dimensional (3D) normal skin model and a multicellular model of human cutaneous squamous cell carcinoma (cSCC) using 3D bioprinting technology. Comparative analyzes were performed between bioprinted 3D-cSCC model, consisting of HaCaT keratinocytes, primary normal human dermal fibroblasts and A431 cancer cells (tricellular), bioprinted 3D-A431 model composed of A431 cancer cells only (monocellular), A431 cancer cell spheroids, and conventional 2D models. The models were structurally characterized by light microscopy, immunofluorescence (LIVE/DEAD assay, confocal microscopy) and immunohistochemistry (hematoxylin/eosin, p63, vimentin, Ki67, epidermal growth factor receptor stainings). The spatial arrangement of the 3D models was analyzed using the ARIVIS scientific image analysis platform. All models were also functionally assessed by cetuximab (CTX) response testing with the MTS assay. 3D-cSCC models were maintained for up to 16 weeks. Morphological and histological examinations confirmed the presence of skin-like layers in the bioprinted 3D models of normal skin, and the intricate and diverse features of the bioprinted skin cancer model, replicating the criticalin vivocharacteristics. In both mono- and tricellular bioprinted tumor constructs, there was a gradual formation and continuous growth of spheroid-like clusters of cancer cells, significantly influencing the morphology of the models. Cancer cells in the 3D bioprinted constructs showed reduced sensitivity to CTX compared to spheroids and 2D cultures. This study underscores the potential of 3D multicellular models in elucidating drug responses and gaining a better understanding the intricate interplay of cellular components within the tumor microenvironment. Developing the multicellular 3D tumor model paves the way for new research critical to advancing fundamental cancer research and future clinical applications, particularly drug response testing.

Cutaneous Squamous Cell Carcinoma Outcomes in Solid Organ Transplant Recipients: A Matched Retrospective Cohort Study.

Solid organ transplant recipients with cutaneous squamous cell carcinoma (CSCC) have an increased risk of poor outcomes. However, a recent study demonstrated that immunosuppression is not an independent risk factor for these poor outcomes after controlling for primary tumor stage. To evaluate whether transplant status is an independent risk factor for poor outcomes in CSCC. A database of CSCCs treated at an academic center over 10 years was used to perform a retrospective cohort study comparing the risk of poor outcomes (local recurrence, regional and distant metastases, and disease-specific death) in solid organ transplant recipients and controls. Subjects were matched on age, tumor stage, sex, tumor site, and time to poor outcome. There were 316 tumors from 78 transplant patients and 316 tumors from 262 controls. On multivariate analysis, tumor stage and location on the head and neck were predictive of poor outcomes. There was no significant difference in the risk of poor outcomes in the transplant group versus the control group. Transplant status was not an independent risk factor for poor squamous cell carcinoma outcomes after controlling for stage, age, sex, site, and time to poor outcome.

T Cell Immunity in Human Papillomavirus-Related Cutaneous Squamous Cell Carcinoma-A Systematic Review.

Cutaneous squamous cell carcinoma (cSCC) is an invasive malignancy that disproportionately afflicts immunosuppressed individuals. The close associations of cSCC with immunosuppression and human papillomavirus (HPV) infection beget the question of how these three entities are intertwined in carcinogenesis. By exploring the role of T cell immunity in HPV-related cSCC based on the existing literature, we found that the loss of T cell immunity in the background of β-HPV infection promotes cSCC initiation following exposure to environmental carcinogens or chronic trauma. This highlights the potential of developing T-cell centred therapeutic and preventive strategies for populations with increased cSCC risk.

Transethosome‐Based Topical Administration Systems with Enhanced Penetration and Dual Actions for Treating EGFR‐Overexpressed Cutaneous Squamous Cell Carcinoma

AbstractEpidermal growth factor receptor (EGFR)‐overexpressing cutaneous squamous cell carcinoma (CSCC) necessitates more effective therapies due to its elevated metastasis risk compared to the conventional CSCC. While photodynamic therapy (PDT) is a promising way to treat CSCC, effectively administering photosensitizers to reach deeper skin malignancies remains a challenge. Herein, BE‐TEL is reported, a transethosome formulation designed to enhance skin and cutaneous tumor permeability, for targeted treatment of EGFR‐overexpressed CSCC. The formulation is co‐loaded with Erlotinib (Erb), a hydrophobic EGFR inhibitor, and BODIPY (BPY), a photosensitizer. Upon skin penetration and subsequent exposure to 660 nm light, BE‐TEL induces tumor cell apoptosis by reactive oxygen species (ROS) generation and EGFR pathway inhibition. ROS and Erb‐induced metabolic oxidative stress by upregulating the expression of NADPH oxidase 4 (NOX4) can enhance immunogenic cell death (ICD) and promote dendritic cell maturation for tumor‐specific immune response. Furthermore, the EGFR downregulation further mitigated the risk of metastasis and recurrence. In conclusion, BE‐TEL's superior penetration ability together with its combined PDT and EGFR targeted approach paves the way for an efficient strategy against EGFR‐overexpressed CSCC.

Parotid Gland Metastases of Cutaneous Squamous Cell Carcinoma of the Head: Occult Metastases Occurrence and Their Late Manifestation.

Cutaneous squamous cell carcinomas (cSCC) are malignant tumours with excellent prognosis unless nodal metastases develop. The aim of our study is to determine the prognostic significance of the clinical stage of parotid gland metastases and the incidence of occult cervical lymph node involvement in cSCC of the head. Our retrospective analysis includes 39 patients with cSCC parotid gland metastases, 15 of whom had concurrent cervical node involvement. In 32 patients, the lymph nodes manifested at stage N3b. A total of 26 patients were treated with parotidectomy, 9 patients received radiotherapy alone, and 4 received symptomatic therapy. The surgical treatment included either total conservative (21 cases) or superficial parotidectomy (5 cases) and neck dissection (therapeutic neck dissections in 11 cases and elective in 14 cases). In all cases, surgery was performed with sufficient tumour-free resection margins. Adjuvant radiotherapy was administered postoperatively in 16 patients. Occult metastases were present in 21% of cases after an elective neck dissection, but not in any case in the deep lobe of the parotid gland. The five-year overall survival and recurrence-free interval were 52% and 55%, respectively. Patients with the cN3b stage and G3 histological grade tend to have a worse prognosis, but not at a statistically significant level. The prognosis was not worse in patients with concurrent parotid and cervical metastases compared to those with metastases limited to the parotid gland only. The addition of adjuvant irradiation, in comparison to a single modality surgical treatment, was the only statistically significant prognostic factor that reduced the risk of death from this diagnosis (p=0.013). The extent of parotidectomy (partial vs. total) had no impact on either the risk of recurrence or patient prognosis. The combination of surgery with irradiation provides the best results and should be applied to all patients who tolerate the treatment. A partial superficial parotidectomy should be sufficient, with a minimum risk of occult metastasis in the deep lobe. Conversely, the relatively high incidence of occult neck metastases indicates that patients could likely benefit from elective neck dissection.

Creating an atlas of normal tissue for pruning WSI patching through anomaly detection

Patching whole slide images (WSIs) is an important task in computational pathology. While most of them are designed to classify or detect the presence of pathological lesions in a WSI, the confounding role and redundant nature of normal histology are generally overlooked. In this paper, we propose and validate the concept of an “atlas of normal tissue” solely using samples of WSIs obtained from normal biopsies. Such atlases can be employed to eliminate normal fragments of tissue samples and hence increase the representativeness of the remaining patches. We tested our proposed method by establishing a normal atlas using 107 normal skin WSIs and demonstrated how established search engines like Yottixel can be improved. We used 553 WSIs of cutaneous squamous cell carcinoma to demonstrate the advantage. We also validated our method applied to an external dataset of 451 breast WSIs. The number of selected WSI patches was reduced by 30% to 50% after utilizing the proposed normal atlas while maintaining the same indexing and search performance in leave-one-patient-out validation for both datasets. We show that the proposed concept of establishing and using a normal atlas shows promise for unsupervised selection of the most representative patches of the abnormal WSI patches.

Cancer Type and Histology Influence Cutaneous Immunotherapy Toxicities: A Multi-Institutional Cohort Study.

Cutaneous immune-related adverse events (cirAEs) are the most common toxicities to occur in the setting of immune checkpoint inhibitor (ICI) therapy. Identifying patients who are at increased risk of developing cirAEs may improve quality of life and outcomes. To investigate the influence of cancer type and histology on the development of cirAEs in the setting of ICI therapy and survival outcomes. This retrospective cohort study included patients between December 1, 2011, and October 30, 2020. They received ICIs from 2011-2020 with follow-up of outcomes through October 2021. We identified 3,668 ICI recipients who were seen at Mass General Brigham and Dana-Farber. Of these, 669 developed cirAEs. Records that were incomplete or categories of insufficient sample size were excluded from the study cohort. Multivariate Cox proportional hazards models were utilized to investigate the impact of cancer organ system and histology on cirAE development, after adjusting for demographics, Charlson Comorbidity Index, ICI type, cancer stage at ICI initiation, and year of ICI initiation. Time-varying Cox proportional hazards modeling was utilized to examine the impact of cirAE development on mortality. Compared to other non-epithelial cancers (neuroendocrine, leukemia, lymphoma, myeloma, sarcoma, and central nervous system malignancies), cutaneous squamous cell carcinoma (cSCC) (HR = 3.57, p < 0.001), melanoma (HR = 2.09, p < 0.001), head and neck adenocarcinoma (HR = 2.13, p = 0.009), genitourinary transitional cell carcinoma (HR = 2.15, p < 0.001), and genitourinary adenocarcinoma (HR = 1.53, p = 0.037) were at significantly higher risk of cirAEs in multivariate analyses. The increased risk of cirAEs translated into an adjusted survival benefit for melanoma (HR = 0.37, p < 0.001) and cSCC (HR = 0.51, p = 0.011). The highest rate of cirAEs and subsequent survival benefits were observed in cutaneous malignancies treated with ICIs. This study improves our understanding of patients who are at highest risk of developing cirAEs and would, therefore, benefit from appropriate counseling and closer monitoring by their oncologists and dermatologists throughout their ICI therapy. Limitations include its retrospective nature and cohort from one geography.

Pathophysiology, Histopathology, and Differential Diagnostics of Basal Cell Carcinoma and Cutaneous Squamous Cell Carcinoma-An Update from the Pathologist's Point of View.

Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) are the most frequently occurring non-melanocytic skin cancers. The objective of our study is to present the pathophysiology of BCC and cSCC and its direct relationship with the histopathological diagnostics and the differential diagnostics of these types of cancer, based on the morphological characteristics, immunohistochemical profile, and genetic alterations. The qualitative study was based on emphasizing the morphological characteristics and immunohistochemistry profiles of BCC and cSCC and the differential diagnostics based on the tissue samples from the Clinical Pathology Department of Mures Clinical County Hospital between 2020 and 2022. We analyzed the histopathological appearances and immunohistochemical profiles of BCC and cSCC in comparison with those of Bowen disease, keratoacanthoma, hyperkeratotic squamous papilloma, metatypical carcinoma, pilomatricoma, trichoblastoma, Merkel cell carcinoma, pleomorphic dermal sarcoma (PDS), and melanoma. Our study showed the importance of the correct histopathological diagnosis, which has a direct impact on the appropriate treatment and outcome for each patient. The study highlighted the histopathological and morphological characteristics of NMSCs and the precursor lesions in HE and the immunohistochemical profile for lesions that may make the differential diagnosis difficult to establish.

Field Cancerization Therapies for the Management of Actinic Keratosis: An Updated Review.

Field cancerization theory highlights that the skin surrounding actinic keratoses (AK) is also at increased risk for possible malignant transformation; thus, field-directed treatments may both reduce the risk of AK recurrence and potentially reduce the risk of development of cutaneous squamous cell carcinoma (cSCC). Photodynamic therapy (PDT) with either aminolevulinic acid (ALA) or methylaminolevulinate (MAL), as well as topical treatments such as 5-fluorouracil (5-FU), diclofenac gel, piroxicam, imiquimod, and ingenol mebutate, have all shown higher efficacy than vehicle treatments. PDT is widely recognized for its high efficacy; however, concerns for associated pain have driven new studies to begin using alternative illumination and pretreatment techniques, including lasers. Among topical treatments, a combination of 5-FU and salicylic acid (5-FU-SA) has shown to be the most effective but also causes the most adverse reactions. Tirbanibulin, a new topical agent approved for use in 2020, boasts a favorable safety profile in comparison with imiquimod, 5-FU, and diclofenac. Meanwhile, ingenol mebutate is no longer recommended for the treatment of AKs due to concerns for increased risk of cSCC development. Moving forward, an increasing number of studies push for standardization of outcome measures to better predict risk of future cSCC and use of more effective measures of cost to better guide patients. Here, we present an updated and comprehensive narrative review both confirming the efficacy of previously mentioned therapies as well as highlighting new approaches to PDT and discussing the use of lasers and novel topical treatments for treatment of AK.