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.

Patient and Tumour Characteristics of Keratoacanthoma in a Large, Community-based Cohort Study from Queensland, Australia.

Keratoacanthomas are common keratinocyte skin tumours. However, there is little community-based data published on the clinical features of keratoacanthoma. The aim of this study was to describe the patient and tumour characteristics of keratoacanthomas, as well as their treatment patterns. Data were obtained from the QSkin Sun and Health study, a prospective cohort of 40,438 randomly sampled and consented participants aged 40-69 years in Queensland, Australia. In 2010, a baseline survey collected data, including demography, phenotype, ultraviolet radiation exposure, medical history and lifestyle. Histopathological reports of keratoacanthomas arising until 30 June 2014 were reviewed. In total, 584 participants developed 738 keratoacanthomas; 18% of participants developed multiple tumours. Common patient characteristics were male sex (58%), age ≥60 years (76%), fair skin (80%), and previous history of actinic keratoses/keratinocyte cancers (89%). Keratoacanthomas were commonly located on the legs/feet (48%), and rarely on the the head/neck (7%). Excision was the most frequently used surgical method (71%) Evidence of histopathological regression was reported in 67% of keratoacanthomas, suggesting a potential for spontan-eous resolution in a significant proportion of keratoacanthomas.

Systematic review and meta-analysis of prevalence of dermatological toxicities associated with vemurafenib treatment in patients with melanoma.

BACKGROUND: Vemurafenib has been linked to dermatological adverse events in patients with melanoma, including an increased risk of rash, cutaneous squamous cell carcinoma, photosensitivity reaction and keratoacanthoma. However, there has been no systematic attempt to assess the dermatological toxicity data of vemurafenib associated with melanoma treatment. AIM: To evaluate the point prevalence of dermatological toxicities associated with vemurafenib treatment in patients with melanoma. METHODS: Searches were conducted of the electronic databases PubMed and EMBASE and of conference abstracts published by the American Society of Clinical Oncology. Eligible studies included prospective clinical trials and expanded-access programmes (i.e. outside a clinical trial) of patients with melanoma assigned to vemurafenib treatment. Outcomes included prevalence of dermatological toxicities treated with vemurafenib. Statistical analyses were performed using the R2.8.1 meta package. RESULTS: In total, 11 studies comprising 4197 patients were included in the meta-analysis. For patients assigned to vemurafenib, the overall prevalence of all-grade cutaneous squamous cell carcinoma (cSCC) was 18.00% (95% CI 12.00-26.00%), rash 45.00% (95% CI 34.00-57.00%), photosensitivity reaction (PR) 30.00% (95% CI 23.00-38.00%), keratoacanthoma (KA) 10.00% (95% CI 6.00-15.00%) and hand-foot skin reaction (HFSR) 9.00% (95% CI 4.00-20.00%), while the prevalence of high-grade events was: cSCC 16.00% (95% CI 11.00-23.00%), rash 12.00% (95% CI 3.00-38.00%), PR 4% (95% CI 2.00-8.00%) and KA 6.00% (95% CI 5.00-7.00%). CONCLUSION: The most frequent dermatological toxicities associated with vemurafenib treatment in patients with melanoma were cSCC, rash, PR and KA. These data may be useful for estimation of the efficacy and safety of the drug during clinical treatment and for reducing the prevalence of adverse reactions to vemurafenib treatment in patients with melanoma.

Cutaneous sebaceous tumours and Lynch syndrome: long-term follow-up of 60 patients.

BACKGROUND: Sebaceous neoplasms (SN) may appear sporadically in the general population but may also be part of the Muir-Torre variant of Lynch syndrome (MT-LS). There are few studies in southern Europe on the incidence of MT-LS in the population of patients with SN. AIM: To retrospectively review patients with SN and to analyse their clinical features and the incidence of MT-LS. METHODS: Patients with SN diagnosed between 1995 and 2015 were enrolled in the study. The diagnosis of MT-LS was made according to established clinical criteria and, whenever possible, was confirmed by germline mutation analysis. RESULTS: In 60 patients (32 men, 28 women, mean age 69.22 years), 96 SN were diagnosed: 65 adenomas (67.7%), 16 sebaceomas (16.7%) and 15 carcinomas (15.6%). Of the 60 patients, 50 (83.3%) had a single SN and 10 (16.7%) had multiple lesions. Patients diagnosed with MT-LS (12 patients, 20%) were younger (63.25 years vs. 70.71 years), and had a higher incidence of extrafacial SN (4/12 patients, 33.3%), and were significantly (P < 0.001) more likely to have multiple SNs (8/12, 75%) and keratoacanthomas (KAs) (6/12, 50%). CONCLUSION: Our study confirms that all patients with SN should be investigated, as 20% of our patients were diagnosed with MT-LS. The most specific features of SN associated with MT-LS in our study were the presence of multiple lesions and association with KAs.

Diffuse lichenplanopilaris and multiple squamous neoplasms.

Lichen planus is an inflammatory process that can affect the skin, mucosa, and hair follicles. An increased risk of squamous cell carcinoma has been noted in lichen planus of the mucosa. Rarely, in chronic, hypertrophic lichen planus of the skin, squamous cell neoplasms have been reported. We report a case of new onset lichen planopilaris with multiple squamous cell neoplasms.

Tattoos, inks, and cancer.

The introduction in the dermis of exogenous pigments and dyes to obtain a permanent design (tattooing) represents a unique in-vivo situation, where a large amount of metallic salts and organic dyes remain in the skin for the lifetime of the bearer. The potential local and systemic carcinogenic effects of tattoos and tattoo inks remain unclear. Several studies have shed light on the presence of potential carcinogenic or procarcinogenic products in tattoo inks. We extensively reviewed the literature and found 50 cases of skin cancer on tattoos: 23 cases of squamous-cell carcinoma and keratoacanthoma, 16 cases of melanoma, and 11 cases of basal-cell carcinoma. The number of skin cancers arising in tattoos is seemingly low, and this association has to be considered thus far as coincidental.

Squamous cell carcinoma arising in keratoacanthoma: a neglected phenomenon in the elderly.

Keratoacanthoma is a unique clinicopathologic entity with a behavior and clinical outcome that differs markedly from that of squamous cell carcinoma. The development of squamous cell carcinoma in a keratoacanthoma alluded to by Rook and Whimster in 1979 and by Reed in 1993 was confirmed by Sánchez Yus et al in 2000. We found this phenomenon in 5.7% of keratoacanthomas in a series of 3465 cases. Its incidence in patients older than 90 years was 13.9%. The incidence of perineural invasion in this series of keratoacanthomas was 0.2%.

PTH-independent hypercalcaemia and non-melanoma skin cancer.

BACKGROUND: Recently, it became more evident that skin is a target for neuroendocrine signals. AIMS: (1) To evaluate the relationship between tumour aggressiveness and hypercalcaemia in patients with non-melanoma skin cancer; (2) to identify clinical, functional, biological alterations caused by this setting; (3) calcium redistribution from extracellular fluids to intracellular compartments; (4) to describe several molecular aspects of hypercalcaemia development. MATERIALS AND METHODS: This study was conducted between January 2000 and May 2009 in Dermatoveneorological Center, Bucharest. From the 1232 cases that were investigated, there were 32 patients with keratoachantoma, 468 patients with basal cell carcinoma, 412 patients with squamous cell carcinoma and 320 healthy volunteers. All the patients were screened by clinical and paraclinical examinations (haematology, biochemistry, immunology). After biochemical confirmation of hypercalcaemia, patients had endocrine tests, electrocardiography and imagistic approaches. Total serum calcium was measured in extracellular fluids (serum, urine) by spectrophotometric methods. Ionized calcium was calculated depending on total serum calcium and total proteins. Corrected serum total calcium (cTCa) levels were calculated using albumin and total serum calcium levels. In tumour tissues and intact skin, calcium was assayed by physical methods of analysis: Instrumental Neutron Activation Analysis (INAA), Proton-Induced X-ray Emission (PIXE). Intact PTH was measured by ELISA. RESULTS: PTH-independent hypercalcaemia prevalence is low in SCC patients (1.21%). Hypercalcaemia manifestations are multiple including: digestive, renal, neuromuscular, and cardiovascular abnormalities. In these patients, intact PTH (iPTH) is normal, urinary calcium is decreased, serum albumin is reduced, and calcium concentration in tumour tissue is significantly increased compared to healthy tissue. CONCLUSIONS: PTH-independent hypercalcaemia has a low prevalence in SCC patients. Hypercalcaemia is correlated with susceptibility to develop metastases in SCC. A possible mechanism is PTHrp hypersecretion by malignant keratinocytes.

Keratoacanthomas: overview and comparison between Houston and minneapolis experiences.

Keratoacanthomas represent approximately 1% of skin malignancies treated in a Mohs practice in Houston, TX. The authors compared the age of onset, sex, location and month of prevalence of keratoacanthomas between Houston, TX and Minneapolis, MN. An earlier age of presentation was observed in men in Houston (65.9 years) versus in women (71.3 years) or in men and women in Minneapolis (71 years). There was a predominance of facial tumors in Texas males compared to females and tumors seen in Minneapolis. The tumors occurred more frequently during the winter months in Houston, TX versus June, November and December in Minneapolis, MN.

Assessment of Incidence Rate and Risk Factors for Keratoacanthoma Among Residents of Queensland, Australia.

Importance: Keratoacanthoma (KA) is a common and generally benign keratinocyte skin tumor. Reports of the incidence rates of KA are scant. In addition, the risk factors for KA are not well understood, although associations with UV radiation exposure and older age have been described. Objective: To investigate the incidence rate of KA and the risk factors for developing KA. Design, Setting, and Participants: The study included data from 40 438 of 193 344 randomly selected residents of Queensland, Australia, who participated in the QSkin Sun and Health (QSkin) prospective population-based cohort study. All participants completed a baseline survey between 2010 and 2011 and were ages 40 to 69 years at baseline. Histopathologic reports of KA were prospectively collected until June 30, 2014, through data linkage with pathologic records. Cox proportional hazards models were used to identify risk factors associated with KA while controlling for potential confounding variables. Data were analyzed from January 2 to April 8, 2020. Exposures: Demographic characteristics, phenotypes, UV radiation exposure, medical history, and lifestyle. Results: Among 40 438 participants (mean [SD] age, 56 [8] years; 18 240 men [45.1%]), 596 individuals (mean [SD] age, 62 [6] years; 349 men [58.6%]) developed 776 KA tumors during a median follow-up period of 3.0 years (interquartile range, 2.8-3.3 years). The person-based age-standardized incidence rate for KA in the age-restricted cohort was 409 individuals per 100 000 person-years (based on the 2001 Australian population). Risk factors after adjustment for potential confounders were older age (age ≥60 years vs age <50 years; hazard ratio [HR], 6.38; 95% CI, 4.65-8.75), male sex (HR, 1.56; 95% CI, 1.33-1.84), fair skin (vs olive, dark, or black skin; HR, 3.42; 95% CI, 1.66-7.04), inability to tan (vs ability to tan deeply; HR, 1.69; 95% CI, 1.19-2.40), previous excisions of keratinocyte cancers (ever had an excision vs never had an excision; HR, 6.28; 95% CI, 5.03-7.83), current smoking (vs never smoking, HR, 2.02; 95% CI, 1.59-2.57), and high alcohol use (≥14 alcoholic drinks per week vs no alcoholic drinks per week; HR, 1.42; 95% CI, 1.09-1.86). Conclusions and Relevance: This is, to date, the first large prospective population-based study to report the incidence rate and risk factors for KA. The high person-based incidence rate (409 individuals per 100 000 person-years) highlights the substantial burden of KA in Queensland, Australia. Furthermore, the study's findings suggest that older age (≥60 years), male sex, UV radiation-sensitive phenotypes, indications of high sun exposure (eg, previous keratinocyte cancer excisions), smoking, and high alcohol use are independent risk factors for the development of KA.

Keratoacanthoma and infundibulocystic squamous cell carcinoma.

One of the major controversies in dermatopathology is the relationship of keratoacanthoma to squamous cell carcinoma. Leaders in the field remain polarized in their views. Carcinomas with distinct follicular pattern of differentiation have been described in reference to the isthmus as trichilemmal carcinomas, to the follicular bulb as pilomatricomal carcinomas, and to the stem cell or rapidly amplifying cell compartment as basal cell carcinomas (trichoblastic carcinomas). We have employed the term infundibulocystic or infundibular squamous cell carcinoma to identify a subset of squamous cell carcinomas that demonstrate this pattern of differentiation. The recognition of infundibular squamous cell carcinoma is important in that well-differentiated examples are likely to have been diagnosed as keratoacanthoma, whereas moderately or poorly differentiated tumors would be more often reported as squamous cell carcinomas, leading to underrecognition of these infundibular variants of squamous cell carcinoma. The descriptive term infundibulocystic or infundibular squamous cell carcinoma may help to better define an alternative follicular-based pathway to squamous cell carcinoma distinct from the more common evolution from solar keratoses and also refine the classification of keratoacanthoma.

Epidemiology of skin cancer in the mature patient.

Epidermal cancers include keratinocyte cancer, melanocyte cancer, and Merkel cell carcinoma. These cancers account for the vast majority of new cancers diagnosed in Australia, North America, and Europe. Keratinocyte cancer is the most common epidermal cancer and accounts for 7 out of 8 new cancers diagnosed in Australia. Melanoma and Merkel cell carcinoma are less common than keratinocyte carcinoma but are more important causes of mortality in Australia. Keratinocyte cancer has also been demonstrated to be a marker of cancer-prone phenotype. Risk factors for epidermal cancer include intrinsic and environmental factors, in particular exposure to ultraviolet radiation and advanced age. Actinic keratosis has an approximate prevalence of 79% of men and 68% of women between 60 and 69 years of age, and has a low risk of malignant transformation into squamous cell carcinoma. Basal cell carcinoma is the most common malignancy in Caucasians worldwide, with the incidence increasing by 2% per year in Australia. Squamous cell carcinoma is the second most common epidermal cancer, with an incidence of approximately 1035 or 472 per 100,000 person-years in men and women, respectively. Primary risk factors for both basal cell carcinoma and squamous cell carcinoma include light skin color, UV radiation exposure, and chronic immunosuppression. Although the rate of melanoma is increasing, the mortality in Australia is reducing and is currently 9%. The overall incidence of melanoma in Australia is approximately 50 cases per 100,000 persons (62 for men and 40 for women). Keratinocyte carcinoma and melanoma are risk factors for developing further skin cancer and primary malignancy. This contribution reviews the incidence, prevalence, and risk factors associated with the development of epidermal cancer and premalignant epidermal neoplasia.

Sporadic and syndromic keratoacanthomas: diagnosis and management.

Keratoacanthomas are neoplasms of the skin and mucous membranes. Their nature continues to fuel controversies about the benign versus malignant nature of these tumors. The characteristics of keratoacanthomas (both the sporadic and syndromic types), the controversies about the benign versus malignant nature of keratoacanthomas, and current treatment options for keratoacanthomas are discussed.

Histopathologic analysis of epidermal skin tumours and tumour-like lesions in Ahmadu Bello University Teaching Hospital, Zaria.

OBJECTIVE: A histopathologic analysis of epidermal skin tumours and tumour-like lesions seen between 1991 - 2000 in the Department of Pathology, Ahmadu Bello University Teaching Hospital [A.B.U.T.H], Zaria is presented. PATIENTS AND METHOD: These tumours were classified according to World Health Organisation's International Histological Classification for Skin Tumours and were tabulated. RESULTS: A total of 350 such lesions comprising 9.9% of all cutaneous neoplasms seen within the study period were collected. Overall, they have a male to female ratio of 1.7:1. Malignant tumours constituted 72.5%; benign tumours 18.3% and tumour-like lesions 9.2%. The commonest malignant lesion was squamous cell carcinoma, which constituted 68.3% of all the lesions with a male to female ratio of 1.7:1. Epidermal cyst comprised 16.3% with a male to female ratio of 1.5:1. CONCLUSION: It is concluded that epidermal tumours and tumour-like lesions are not uncommon in Zaria and they show a male preponderance with squamous cell carcinoma being the commonest epidermal tumour and it also predominantly affects males.

Distribution of upper limb skin cancers in relation to arteriovenous fistula side in renal transplant recipients.

BACKGROUND: Renal transplant patients have an increased incidence of skin cancers, predominantly on sun-exposed surfaces. Clinical observation identified some patients with an increased number of viral warts, keratoses, and skin malignancies on the side of the arteriovenous fistula. METHODS: In a population of 980 patients who underwent transplantation in Oxford, we identified 68 patients with known fistula site who had developed cutaneous malignancies on the upper limbs. We compared the distribution of skin malignancies in relation to the side of the arteriovenous fistula with regard to histologically confirmed Bowen's disease, squamous cell carcinoma, basal cell carcinoma, and keratoacanthoma. RESULTS: No significant difference was found between the distribution of skin cancers, total malignancies or subgroups, in the fistula limbs compared with the nonfistula limbs. CONCLUSION: We have been unable to demonstrate that the presence of an arteriovenous fistula predisposes to the development of cutaneous malignancies.

Incidence and prediction of nonmelanoma skin cancer post-renal transplantation: a prospective study in Queensland, Australia.

BACKGROUND: Nonmelanoma skin cancer (NMSC) is a significant clinical problem after renal transplantation, particularly in areas of high UV light exposure. A single-center prospective study of a population of Queensland renal transplant recipients was performed with the aims of: (1) establishing NMSC incidence and tumor accrual post-renal transplantation, and (2) developing a clinically derived predictive index to identify transplant recipients at greatest risk. METHODS: Three hundred ten of 398 transplant recipients (78%) who underwent baseline assessment between July 1999 and April 2000 were reassessed a mean of 18 +/- 3.5 (SD) months later. A structured interview, full skin examination, biopsy of suspicious lesions, and review of medical and pathological records were used to determine the number and types of NMSC arising between the two assessments. Incidence (percentage of the population developing NMSC per year) and tumor accrual (number of tumors per person per year) were calculated. A clinically derived predictive index was generated using stepwise logistic regression models. RESULTS: Overall NMSC incidence was 28.1% and increased with duration of immunosuppression therapy: 18.8%, 24.8%, 33.3%, and 47.1% at less than 5, 5 to 10, 10 to 20, and greater than 20 years of immunosuppression therapy, respectively. Mean NMSC accrual was 1.85 +/- 3.84 tumors/person/y, increasing to 3.35 +/- 4.29 tumors/person/y after 20 years of immunosuppression therapy. Renal transplant recipients were stratified into categories of high and low NMSC risk by using predictive indices. CONCLUSION: Clinically derived predictive indices can allow NMSC risk stratification of an Australian transplant population and may provide an evidence-based and cost-effective approach to developing a targeted clinical NMSC surveillance program.

Keratoacanthoma in Kauai, Hawaii. The first documented incidence in a defined population.

BACKGROUND AND DESIGN: A prospective 5-year population-based incidence study was conducted on the island of Kauai, Hawaii, from 1983 through 1987 to investigate the frequency of keratoacanthoma in white residents. RESULTS: A total of 53 residents, 36 men and 17 women, were identified with an initial episode of keratoacanthoma during the 5-year study. The average annual incidence rate per 100,000 Kauai residents, standardized to the US white population, was 144 for men and 73 for women, with a combined rate of 104. The average patient age was 63.5 years. The limbs, particularly the hands and arms, were the most common anatomic site, with the trunk second. Only one patient developed a new subsequent keratoacanthoma, and no recurrent lesions were observed. Three patients had two keratoacanthomas when they first presented, and 13 patients had concurrent skin cancer. Sixty percent (32) of our patients developed skin cancer at one time or another. CONCLUSIONS: We report the first population-based keratoacanthoma incidence rates documented in the United States, which are almost equal to those of squamous cell carcinoma. Keratoacanthoma also shares many common epidemiological features with squamous cell carcinoma, such as increasing incidence in progressively older age groups.