Gene expression landscape of cutaneous squamous cell carcinoma progression.

BACKGROUND: Cutaneous squamous cell carcinomas (cSCCs) are the second most common human cancer and have been characterized by RNA sequencing (RNA-Seq); however, the transferability of findings from individual studies may be limited by small sample sizes and diverse analysis protocols. OBJECTIVES: To define the transcriptome landscape at different stages in the progression of normal skin to cSCC via a meta-analysis of publicly available RNA-Seq samples. METHODS: Whole-transcriptome data from 73 clinically normal skin samples, 46 actinic keratoses (AK) samples, 16 in situ SCC samples, 13 keratoacanthoma (KA) samples and 147 cSCC samples [including 30 samples from immunocompromised patients and 8 from individuals with recessive dystrophic epidermolysis bullosa (RDEB)] were uniformly processed to harmonize gene expression. Differential expression, fusion detection and cell-type deconvolution analyses were performed. RESULTS: Individual RNA-Seq studies of cSCC demonstrated study-specific clustering and varied widely in their differential gene expression detection. Following batch correction, we defined a consensus set of differentially expressed genes (DEGs), including those altered in the preinvasive stages of cSCC development, and used single-cell RNA-Seq data to demonstrate that DEGs are often - but not always - expressed by tumour-specific keratinocytes (TSKs). Analysis of the cellular composition of cSCC, KA and RDEB-cSCC identified an increase in differentiated keratinocytes in KA, while RDEB-cSCC contained the most TSKs. Compared with cSCC arising in immunocompetent individuals, cSCC samples from immunosuppressed patients demonstrated fewer memory B cells and CD8+ T cells. A comprehensive and unbiased search for fusion transcripts in cSCC and intermediate disease stages identified few candidates that recurred in >1% of all specimens, suggesting that most cSCC are not driven by oncogenic gene fusions. Finally, using Genotype-Tissue Expression (GTEx) data, we distilled a novel 300-gene signature of chronic sun exposure that affirms greater cumulative ultraviolet (UV) exposure in later stages of cSCC development. CONCLUSIONS: Our results define the gene expression landscape of cSCC progression, characterize cell subpopulation heterogeneity in cSCC subtypes that contribute to their distinct clinical phenotypes, demonstrate that gene fusions are not a common cause of cSCC and identify UV-responsive genes associated with cSCC development.

Cutaneous squamous cell carcinoma ('cSCC' for short) is a common type of skin cancer. Many studies have used a technology called 'RNA sequencing' to look for genes that behave differently from normal in cSCC. These genes may play a role in the development and progression of the disease. Small sample numbers and different methods have made it difficult to compare the results of different ­studies. This study re-analysed data from 11 other studies, giving a total of 306 cSCC specimens for us to compare. We also examined gene activity (or 'expression') in cSCC, as well as at earlier stages in the disease. We found a set of genes that were active during the progression from normal skin to cSCC. In this group, we identified genes controlled by exposure to sunlight, the leading risk factor for the development of skin cancer. We combined our findings with other data to determine which cells are present in the subtypes of cSCC. We found differences in the number of tumour, immune and stromal cells. Finally, we looked at cSCC and intermediate disease stages for 'gene fusions' (or 'hybrid genes' formed as a result of instability in the genome). These fusions can fuel tumour growth. Most specimens analysed had one gene fusion, but only a few were recurrent or exhibited features that would suggest disease. Our findings provide a reliable resource for researchers. They could also help with investigating potential treatment targets for cSCC.

Corrigendum: Differential Immunoexpression of Inhibitory Immune Checkpoint Molecules and Clinicopathological Correlates in Keratoacanthoma, Primary Cutaneous Squamous Cell Carcinoma and Metastases.

This Corrigendum relates to the following article: https://doi.org/10.2340/actadv.v104.13381.

Differential Immunoexpression of Inhibitory Immune Checkpoint Molecules and Clinicopathological Correlates in Keratoacanthoma, Primary Cutaneous Squamous Cell Carcinoma and Metastases.

Beyond established anti-programmed cell death protein 1/programmed cell death ligand 1 immunotherapy, T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) and its ligand CD155 are promising novel inhibitory immune checkpoint targets in human malignancies. Yet, in cutaneous squamous cell carcinoma, evidence on the collective expression patterns of these inhibitory immune checkpoints is scarce. Complete tumour sections of 36 cutaneous squamous cell carcinoma, 5 cutaneous metastases and 9 keratoacanthomas, a highly-differentiated, squamoproliferative tumour, with disparately benign biologic behaviour, were evaluated by immunohistochemistry for expression of programmed cell death ligand 1 (Tumor Proportion Score, Immune Cell Score), TIGIT, CD155 and CD8+ immune infiltrates. Unlike keratoacanthomas, cutaneous squamous cell carcinoma displayed a strong positive correlation of programmed cell death ligand 1 Tumor Proportion Score and CD115 expression (p < 0.001) with significantly higher programmed cell death ligand 1 Tumor Proportion Score (p < 0.001) and CD155 expression (p < 0.01) in poorly differentiated G3-cutaneous squamous cell carcinoma compared with keratoacanthomas. TIGIT+ infiltrates were significantly increased in programmed cell death ligand 1 Immune Cell Score positive primary tumours (p = 0.05). Yet, a strong positive correlation of TIGIT expression with CD8+ infiltrates was only detected in cutaneous squamous cell carcinoma (p < 0.01), but not keratoacanthomas. Providing a comprehensive overview on the collective landscape of inhibitory immune checkpoint expression, this study reveals associations of novel inhibitory immune checkpoint with CD8+ immune infiltrates and tumour differentiation and highlights the TIGIT/CD155 axis as a potential new target for cutaneous squamous cell carcinoma immunotherapy.

Mosaic Muir Torre Syndrome: Keratoacanthoma as a Piece of the Puzzle.

ABSTRACT: Lynch syndrome is an inherited condition, which increases the risk of numerous visceral malignancies and cutaneous tumors such as keratoacanthomas and sebaceous tumors. It is typically identified by immunohistochemistry of tissue taken from tumors or through genetic testing with next-generation sequencing. Diagnosing Lynch syndrome becomes more complex when the individual is mosaic for the relevant pathogenic variant. There are very few cases of this reported in the medical literature. It is even more unusual for the diagnosis to be made based on testing of a keratoacanthoma lesion. We report a case where immunohistochemistry of a keratoacanthoma helped make a diagnosis of mosaic Lynch syndrome. We will explore how mosaicism should be considered when a phenotype is strong, even if next-generation sequencing reports no pathogenic or likely pathogenic variant and how lesions such as keratoacanthomas can have a role in the early detection and treatment of future malignancies.

Diagnosing Common Benign Skin Tumors.

Patients commonly present to family physicians with skin findings, and distinguishing common benign skin tumors from potentially malignant tumors is important. Benign skin tumors can often be diagnosed by their history, distribution, and characteristic morphology. A biopsy or excision is indicated if there is diagnostic uncertainty or the lesion undergoes uncharacteristic or rapid change. A keratoacanthoma is a dome-shaped nodule with a central crater and can be difficult to distinguish from squamous cell carcinomas even with dermoscopy. Pilar cysts are typically benign, but rapidly growing types could have malignant qualities. Dermoid cysts, depending on their location, can have intracranial extension if untreated. Although dermatofibromas and seborrheic keratoses are benign, atypical presentations must be differentiated from melanomas. Sebaceous hyperplasia can mimic early basal cell carcinoma. Treatment options for cherry angiomas, acrochordons, slow-growing pilar cysts, and dermatofibromas should be individualized to skin type, lesion characteristics, and the patient's cosmetic preference. Generally, excision is the treatment of choice for keratoacanthomas, rapidly proliferating pilar cysts, and dermoid cysts. Cherry angiomas are treated with laser therapy and sebaceous hyperplasia with electrodesiccation. Common treatments for acrochordons and seborrheic keratoses are shave excision and cryotherapy. Pyogenic granulomas sometimes self-involute but bleed easily and often recur at the original site. They generally respond to shave excision and electrodesiccation. In patients with darker skin, treatment with cryotherapy and laser therapy should include discussions about hypopigmentation risk.

Strong association of TLR2 and TLR3 polymorphisms with keratoacanthoma and common warts: a case-control study.

AIM: To determine variations in allele and genotype frequencies between keratoacanthoma (KA) and common warts (CW), compared with the control group, in three single nucleotide polymorphisms (SNPs) within the TLR2, TLR3, and TLR9 genes. METHODS: This case-control study involved samples from 161 patients with KA, 152 patients with CW, and 469 controls. DNA was isolated from formalin-fixed paraffin-embedded tissue sections. Three SNPs - rs4696480 in TLR2, rs7657186 in TLR9, and rs35213 in TLR3 - were genotyped with TaqMan Genotyping Assays on the 7500 Real-Time PCR System. RESULTS: TLR2 rs4696480 and TLR3 rs7657186 were significantly overrepresented in KA and CW compared with controls (P<0.001). The association was stronger for CW than for KA, as evidenced by higher frequencies of the A allele and AA genotype for rs4696480. Both KA and CW patients had higher frequencies of the G allele and GG genotype for rs7657186 than controls. rs7657186 was moderately associated with KA and CW, with the G allele and GG genotype being more prevalent in CW cases, where no AA homozygotes were found. CONCLUSION: Genetic variants in TLR2 (rs4696480) and TLR3 (rs7657186) genes may affect KA and CW development, influencing immune responses and susceptibility to these skin lesions. Further research is required to elucidate TLR expression patterns and their role in KA development.

Multiple Keratoacanthoma-like Syndromes: Case Report and Literature Review.

Keratoacanthoma (KA) is a fast-growing skin tumor subtype that can be observed as a solitary lesion or rarely as multiple lesions in the context of rare genetic syndromes. Syndromes with multiple keratoacanthoma-like lesions have been documented as multiple self-healing squamous epithelioma (Ferguson-Smith syndrome), eruptive keratoacanthoma of Grzybowski, multiple familial keratoacanthoma of Witten and Zak Muir-Torre syndrome, and incontinentia pigmenti. The treatment approach of those entities is challenging due to the numerous lesions, the lesions' undefined nature, and the co-existence of other malignant skin tumors. Herein, we report a case of a 40-year-old woman who developed multiple treatment-resistant Ferguson-Smith-like keratoacanthomas with a co-existing large and ulcerated invasive squamous cell carcinoma and microcystic adnexal carcinoma on the scalp. Multiple keratoacanthomas on her extremities were successfully treated with oral acitretin (0.5 mg/kg/day) in combination with topical Fluorouracil (5-FU) 5%, while excision and plastic surgery restoration were performed to treat the ulcerated cancer lesion on her scalp. Due to the interesting nature of this rare syndrome, we performed a literature review including case reports and case series on multiple-KA-like lesions syndromes and focusing on diagnosis and therapy approaches. We also conducted a comparison of patient reports, which included assessing the clinical appearance of the lesions and evaluating the success and progress or the failure of various treatment approaches that were implemented.

Ungual Keratoacanthoma With Features of Regression.

ABSTRACT: Ungual keratoacanthoma (UKA) is an infrequent tumor. Different from keratoacanthoma in other parts of the skin, UKA rarely regresses, and grows aggressively with common destruction of the subjacent phalanx. Reported cases of UKA with features of regression are exceptional, and even dermatopathologists with reputed experience in nail pathology admit to having seen very few cases. We herein report a case of a 77-year-old man who presented a painful subungual lesion on the second finger of the right hand. An x-ray showed evidence of erosion of the subjacent distal phalanx. The patient was highly concerned about the lesion and rejected conservative treatment preferring amputation of the distal phalanx. The histopathologic examination revealed a UKA with features of regression.

The role of HPV in keratinocyte skin cancer development: A systematic review.

Keratinocyte skin cancers are the most frequent malignancy, accounting for approximately 30% of all cancers. Although beta genus HPV are the main etiologic agents for squamous cell carcinoma development in patients with epidermodysplasia verruciformis and organ transplant recipients, their role in non-melanoma skin cancer (NMSC) progression in the general population remains controversial. The aim of our review is to summarize current scientific data and to systematically analyse evidence regarding the role of HPV in keratinocyte skin cancers. A total of 2284 patients were included, of which 724 with actinic keratoses, 290 with Bowen's disease, 949 with cutaneous squamous cell carcinomas and 321 with keratoacanthomas. In the case of actinic keratoses, the majority were positive for beta (n = 372, 58.49%) and gamma HPV (n = 256, 40.25%) and only a few (n = 6, 0.94%) were positive for alpha subtypes. Similarly, most of the cutaneous squamous cell carcinomas were positive for beta (n = 248, 55.98%) and gamma HPV (n = 172, 33.82%) and 23 cases (2.42%) were positive for alpha subtypes. Bowen's disease lesions were mostly positive for beta (n = 43, 55.84%) and alpha HPV (n = 30, 38.96%), in contrast to the gamma genus (n = 4, 5.19%). Keratoacanthomas showed a high distribution among beta genus (n = 79, 50.31%) and an equal proportion between alpha (n = 39, 24.84%) and gamma (n = 39, 24.84%) genera. Studies published so far identifying HPV in keratinocyte skin cancers reflect the difference in detection methods rather than a type-specific tendency towards either actinic keratoses, Bowen's disease, squamous cell carcinoma or keratoacanthoma. On the other hand, recent evidence regarding the role of HPV vaccination in patients with non-melanoma skin cancer brings into perspective the idea of a beta-HPV vaccine or a combined alpha and beta-HPV vaccine that could be used as an adjuvant treatment measure in patients with recalcitrant non-melanoma skin cancer.

Dilute Intralesional 5-Fluorouracil for the Treatment of Squamous Cell Carcinomas and Keratoacanthomas: A Case Series.

BACKGROUND: Intralesional 5-fluorouracil (5-FU) is a promising, yet sparsely studied alternative to surgical treatment for nonmelanoma skin cancer (NMSC).1 Previous studies of intralesional 5-FU have reported concentrations ranging from 30 to 50 mg/mL. To the best of our knowledge, this case series represents the first reported use of intralesional 5-FU 10.0 mg/mL and 16.7 mg/mL for NMSC. METHODS: A retrospective chart review identified 11 patients who received intralesional 5-FU 10.0 mg/mL and 16.7 mg/mL for 40 cutaneous squamous cell carcinomas and 10 keratoacanthomas. We describe the characteristics of these patients and calculate the clinical clearance rate of dilute intralesional 5-FU therapy for NMSC at our institution. RESULTS: Dilute intralesional 5-FU successfully treated 96% (48/50) of the study lesions, providing complete clinical clearance in 82% (9/11) of patients across a mean follow-up time of 21.7 months. All patients tolerated their treatments well with no reported adverse effects or local recurrences. DISCUSSION: The use of more dilute preparations of intralesional 5-FU for NMSC may be a means of reducing cumulative dose and dose-dependent adverse reactions while maintaining clinical clearance. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.5058.

[Keratoacanthoma of the penis: A case report and literature review].

OBJECTIVE: To explore the clinical characteristics and treatment options of keratoacanthoma (KA) of the penis. METHODS: We report the diagnosis and treatment of a case of penile keratoacanthoma in our hospital and review the literature. RESULTS: The patient was admitted due to the discovery of a "new lesion on the glans for 4 months," diagnosed with a penile tumor, underwent tumor resection surgery, with histopathological examination revealing squamous epithelial hyperplasia, thickening, and excessive keratinization. The postoperative pathological diagnosis was penile keratoacanthoma. There was no recurrence or metastasis during follow-up. CONCLUSION: KA is a relatively rare benign tumor with potential malignant transformation, and close follow-up is necessary postoperatively.

NITROSAMINE CONTAMINATION WITHIN CARDIAC MULTIMEDICATION - SARTANS (VALSARTAN), CALCIUM CHANNEL BLOCKERS (AMLODIPINE AND NIFEDIPINE), AND ANTIARRHYTHMICS (PROPAFENONE) AS A SIGNIFICANT FACTOR IN THE DEVELOPMENT AND PROGRESSION OF MULTIPLE KERATINOCYTIC CANCERS: ADVANCEMENT ROTATION FLAP FOR KERATOACANTHOMA OF THE UPPER LIP AND UNDERMINING SURGERY FOR BCC OF THE SHOULDER AS AN OPTIMAL DERMATOSURGICAL APPROACH.

The data on the polycontamination of multimedication in polymorbid patients with a heterogeneous class of carcinogens/nitrosamines, NDSRIs (classified according to the FDA regulation to the companies of 2023 to those with a carcinogenic potency between 1 and 5), are one of the most important steps to clarify the concept of skin cancer nitrosogenesis/ pathogenesis. The FDA is the first regulatory institution in the world to courageously declare that a problem exists and should be addressed. The main and currently unexplained and somewhat controversial issue lies in 1) the sporadic nature of polycontamination in different geographical regions, and 2) the lack of official data from the established international, but also regional pharmaceutical market regulators on the results of the checks conducted for nitrosamine contamination of the respective batches. It is this that leads scientists to the idea of (albeit seemingly) speculative but entirely possible controlled contamination of the production in certain geographical regions. This (hypo)thesis is supported, albeit indirectly, by the fact that: a recent regional check for possible contamination of sartans in a particular geographical region was not indicative of the presence of any nitrosamines/NDSRIs. But this fact is indicative of several extremely important things: 1) contamination is not ubiquitous, its genesis is heterogeneous; 2) contamination could be completely avoided at production level in certain geographical regions; 3) ˝controlled contamination˝ or carelessness of a heterogeneous nature should be excluded by the relevant regulators. Regular inspection and certification of medicinal products in relevant geographical regions to exclude contamination with nitrosamines/NDSRIs would be the surest method to protect public health globally. The initial parameters of the restrictive processes for the availability of nitrosamines in medicines have been established by the most powerful regulator globally in the face of the FDA, with the hope being that manufacturers will find a short-term solution to the problem. We report another patient who simultaneously developed 2 cutaneous tumors under potentially/actually nitrosamine contaminated drugs such as: beta blockers- atenolol, calcium antagonists- nifedipine/amlodipine, sartans- valsartan and antiarrhythmics- propafenone. One of the tumors was localized in the upper lip area (keratoacanthoma) and the other in the right shoulder area (basal cell carcinoma). Successful surgical treatment of the tumors was performed in the form of upper lip advancement rotation flap and elliptical excision of the second lesion. The evolution/growth rate of the tumors in relation to the potential mutagens/carcinogens heterogeneous in their potency contained in the drugs is commented.

Eruptive keratoacanthomas associated with dupilumab therapy.

We would like to present the case of eruptive keratoacanthomas associated with dupilumab therapy, which occurred in an 85-year-old woman receiving biologic therapy for the treatment of atopic dermatitis. With the increasing prevalence of Dupilumab usage, this is an important potential complication of which clinicians should be aware.

Multiple eruptive squamoproliferative lesions during anti-PD1 immunotherapy for metastatic melanoma: Pathogenesis, immunohistochemical analysis and treatment.

Treatment with anti-PD1 inhibitors may enhance the risk for developing low grade squamoproliferative skin tumors. Immunohistochemical (IHC) analysis of the immune tumor microenvironment (TME) allows exploration of the pathogenesis and relationship with the PD1/PDL1 axis. Patients with eruptive keratoacanthoma (KA)-like lesions were recruited from the Melanoma Institute Australia, a tertiary referral specialist melanoma treatment center from January 2015 to August 2017. Clinicopathologic evaluation and IHC features of tumor cells (PDL1 expression) and peritumoral microenvironment (PD1, FOXP3, PDL1, CD4:CD8 expressing cells) in 12 eruptive KA-like lesions, were compared with solitary KAs in age and sex matched non-anti-PD1 treated controls. Four patients with repeated episodes of eruptive KA-like and lichenoid lesions developing 2-7 months after commencing pembrolizumab for AJCC stage IV melanoma, were recruited. Eruptive KA-like squamoproliferative lesions occurred in sun exposed sites and in areas of resolving, concomitant or delayed lichenoid reactions. Histologically, the lesions were well-differentiated squamoproliferative lesions resembling infundibulocystic squamous cell carcinoma or KA. IHC of cases and controls revealed low PDL1 expression of both squamous tumor cells and the TME immune cells. The numbers of immunosuppressive FOXP3 positive Tregs and PD1-expressing T-cells were higher in the cases than the controls but the CD4:CD8 ratio (2:1) was similar. The patients best responded to acitretin and were managed surgically if they demonstrated neoplastic features. Accelerated squamoproliferative growth in actinically damaged keratinocytes associated with lichenoid eruptions may be unmasked in patients treated with anti-PD1 immunotherapy potentially contributed to by a local cutaneous immunosuppressed TME.

Keratoacanthoma or cutaneous squamous cell carcinoma revealing a DNA mismatch repair default (Muir-Torre Syndrome).

Keratoacanthoma (KA) and well-differentiated cutaneous squamous cell carcinoma (cSCC) are hardly distinguishable clinically and histologically. They both can be seen in patients with hereditary non-polyposis colorectal cancer (HNPCC) or Lynch Syndrome, corresponding to DNA microsatellite instability. In our case, a young man had the excision of two rapidly growing skin tumours for which distinction between KA and cSCC was initially clinically and pathologically challenging. The diagnosis of well-differentiated cSCCs was made and the patient was treated with surgery. Ten years after the first cSCC, he was diagnosed with Muir-Torre syndrome, a variant of Lynch syndrome, with an heterozygote mutation of the MSH2 gene. This later diagnosis allowed to screen his family members for the same mutation and to adopt an appropriate follow-up regarding the risk of digestive tumours for him and his family. Furthermore, it is important to know that, in case of non-resectable cSCC occurring in this patient, immunotherapy using anti-PD1 antibody would probably be effective due to the known increased immunogenicity of MMR deficient tumours.

Treatment of Reactive Keratoacanthomas with Acitretin Following Multiple Excisions and Mohs Surgery for Recurrent Squamous Cell Carcinoma.

Surgical intervention is seen as the gold standard in the treatment of Squamous cell carcinoma. Yet, in cases of recurrence, repeated surgical procedures may unwittingly foment the rise of reactive keratoacanthomas at the surgical margins or edge of a newly placed skin graft.

Radiographic characteristics of canine subungual keratoacanthoma.

Subungual keratoacanthoma (SKA) is a rare benign nail bed tumor in dogs, and its radiographic characteristics have not been reported based on the authors' review of the literature. The purpose of this multicenter, retrospective, observational, descriptive study was to describe the radiographic features of SKA in dogs. Twelve dogs for a total of 12 digits with histologically confirmed SKA met the inclusion criteria. The radiographs of the manus or pes were reviewed by two veterinary radiologists and one veterinarian. The radiology reports were interpreted based on a consensus. In six dogs, there was lysis of both the middle phalanx (P2) and the distal phalanx (P3), whereas in the other six dogs, there was only lysis of P3. In all dogs with osteolysis of P2, the lysis involved the distal articular surface. Osteolysis of P3 was more severe in the ungual process than in the ungual crest in all dogs. The margins of the lytic regions of P2 and P3 were well defined and smoothly marginated in most dogs. Expansile changes in the P3 crest were observed in 83.3% (10/12 dogs), and the nail of the affected digit was enlarged and deformed in 91.6% (11/12 dogs). In summary, the radiographic features of canine SKA include severe pressure resorption of the P3 ungual process, expansile change of the P3 ungual crest, and nail enlargement and deformation. With these radiographic features, SKA should be considered as a differential diagnosis.

Radiographic features of subungual keratoacanthomas in dogs.

Subungual keratoacanthoma (SK) is a digital neoplasm that has rarely been reported in dogs and carries an excellent prognosis following surgical removal. Radiographic features of canine SK have only been briefly discussed in two prior case reports. Both articles described extensive distal phalangeal osteolysis, a feature more commonly associated with malignant digital neoplasms (e.g., subungual squamous cell carcinoma (SCC) or melanoma). This retrospective case series aimed to further characterize radiographic findings of histologically confirmed canine SK. Seven dogs met the inclusion criteria, with a total of seven affected digits. All seven digits (100%) had osteolysis of the distal phalanx's ungual process and crest, as well as regional soft tissue swelling. Osteolysis of the ungual process was severe in all cases, with complete destruction in six of seven digits (86%). Partial ungual crest geographic and expansile osteolysis was noted in four of seven digits (57%), while two digits (28%) had complete ungual crest destruction. Seven of seven digits (100%) had a radiographically thickened claw, and two of seven digits (28%) had associated lysis of the distal aspect of the middle phalanx. Based on these findings, an osteolytic subungual mass should not be considered pathognomonic for malignant neoplasia. Observing the imaging features previously described should prompt veterinarians to consider SK as a differential diagnosis.

A clinical and biological review of keratoacanthoma.

Keratoacanthoma (KA) is a common skin tumour that remains controversial regarding classification, epidemiology, diagnosis, prognosis and management. Classically, a KA manifests as a rapidly growing, well-differentiated, squamoid lesion with a predilection for sun-exposed sites in elderly people and a tendency to spontaneously regress. Historically, KAs have been considered a variant of cutaneous squamous cell carcinoma (cSCC) and are often reported as KA-type cSCC. However, the penchant for regression has led many to categorize KAs as biologically benign tumours with distinct pathophysiological mechanisms from malignant cSCC. The clinical and histopathological similarities between KA and cSCC, particularly the well-differentiated variant of cSCC, have made definitive differentiation difficult or impossible in many cases. The ambiguity between entities has led to the general recommendation for surgical excision of KAs to ensure a potentially malignant cSCC is not left untreated. This current standard creates unnecessary surgical morbidity and financial strain for patients, especially the at-risk elderly population. There have been no reports of death from a definitive KA to date, while cSCC has an approximate mortality rate of 1·5%. Reliably distinguishing cSCC from KA would shift management strategies for KAs towards less-invasive treatment modalities, prevent unnecessary surgical morbidity, and likely reduce associated healthcare costs. Herein, we review the pathophysiology and clinical characteristics of KA, and conclude on the balance of current evidence that KA is a benign lesion and distinct from cSCC.

Keratoacanthoma, committed stem cells and neoplastic aberrant infundibulogenesis integral to formulating a conceptual model for an infundibulocystic pathway to squamous cell carcinoma.

Keratoacanthomas (KAs) are distinctive tumors that are defined by their clinical and histopathological features. Their relationship and distinction from squamous cell carcinoma (SCC), however, remain controversial. All cytogenic and immunohistochemical markers that have been applied in this quest have failed. A close relationship of KAs to hair follicles has been recognized. The descriptive term infundibulocystic or infundibular SCC was introduced to define a more broad-based pathway encompassing KAs. The follicular infundibulum roles in respect to neoplasia and wound healing are important elements in understanding the pathogenesis of KAs. Mouse models for KA have provided insights into the relationship of KA to follicles and SCCs. These advances and together with the diverse clinical and histopathological aspects of KA have contributed to the formulation of a conceptual pathway. The central element is that ultraviolet (UV)-mutated or activated committed infundibular stem cells are driven by the combination of a mutated oncogenic RAS pathway linked with the Wnt/beta-catenin pathway responsible for stem cell maintenance, hair follicle development, wound healing and driving KA proliferation and terminal keratinization. The existence and activation of this mutated pathway may form the basis of the paradoxical emergence of KAs and SCCs in patients receiving BRAF and PD-1 inhibitor therapy.