3. Epidemiology and etiology – Actinic keratosis and squamous cell carcinoma of the skin
U. Leiter, J. Becker, E. Breitbart, T. Eigentler, C. Garbe, R. Greinert, K. Kraywinkel
3.1 Epidemiology of actinic keratosis
Hardly any reliable data on the epidemiology of AK exist. There are few data on the prevalence of AK; in Germany, the prevalence was calculated in 2014 in 90,800 workers based on data from the statutory health insurance funds. The prevalence for all age groups was 2.7% and increased with age (11.5% in the 60-70 age group). Men (3.9%) were more frequently affected than women (1.5%) [2]. In the Netherlands, the prevalence of AK in those over 45 years of age is 49% for men and 28% for women [3]. Green et al. showed that there is an increase in prevalence with age, so that it is already 20% in men over 60 years and as high as 52% in men over 70 years [4][5]. In the last decade a clear increase of AK could be determined. The reason for this, apart from etiological factors such as chronic UV exposure, is demographic change with higher proportions of an older population. It is estimated that 1.7 million people in Germany are currently undergoing dermatological treatment for AK. However, the number of patients who actually suffer from AK is much higher and will continue to increase in the coming years in line with the population structure [2]. Patients with occupational natural UV exposure (outdoor workers) are also significantly more likely to have AK than people who mainly work in offices [6]. This observation has led to the recognition of the presence of AK in certain occupational groups as an occupational disease (BK 5103).
3.2 Epidemiology of invasive squamous cell carcinoma
3.2.1 Incidence
SCC is the second most common skin tumor after basal cell carcinoma and represents 20% of all non-melanocytic skin tumors (NMSC) [7]. According to estimates by the Robert Koch Institute, approximately 29,300 men and 20,100 women developed SCC for the first time in Germany in 2014. The incidence of SCC is estimated to have increased 4-fold in Germany over the past 30 years [8][9][7]. The term “skin cancer epidemic” was coined to illustrate this phenomenon. It is likely that NMSC are currently not sufficiently recorded in full extent in most cancer registries in Germany also due to their predominantly outpatient therapy. Therefore, complete epidemiological data are not available and the above-mentioned estimates are still subject to greater uncertainty [10]. Internationally, the data situation is also severely limited; in many countries, NMSCs are not recorded at all in cancer registries.
An analysis of German Cancer Registry data for the periods from 1998 to 2010 for 14 German states shows a continuous increase in the age-standardized incidence of NMSC by a factor of 2.4–during this period, corresponding to an annual increase of 10.5% per year until 2003, after which the annual increase is 6.7% [10]. In the state of Schleswig-Holstein, a significant increase in the incidence of NMSC was observed in 2003-2004 from 81.5/100,000 to 111.5/100,000 (1998–2000). This represents an increase of 47% for women and 34% for men, which has been attributed to the skin cancer screening pilot project [11][12]. Due to this, detection rates improved and led to an increase in incidence rates. From 2008 onwards, mandatory skin cancer screening was introduced nationwide in Germany and a similar increase was observed in the course in other German states (47% in women and 40% in men) [11]. This may also be due to a certain extent to increased diagnosis of tumors that might never have been diagnosed. Because many NMSCs never cause symptoms, they are detected incidentally or only when the patient undergoes screening. This is especially true for older patients (> 60 years), 36% of whom participated in the screening program more often than others [13].
Table 4: Age-standardized incidence rate for SCC of the skin for regions with coverage judged to be sufficiently high and stable (per 100,000 persons and year, old European standard)
| Incidence - DMDR (direct method death rate; Europe old, age total) | |||
| 2009-2013 | 2014-2018 | Change | |
| Schleswig-Holstein | 38.3 | 40.8 | 6% |
| Hamburg | 30.1 | 26.0 | -13.9% |
| Lower Saxony | 35.0 | 41.0 | 17% |
| Bremen | 29.5 | 28.7 | -3% |
| North Rhine-Westphalia | 37.0 | 41.0 | 11% |
| Lower Bavaria/Upper Palatinate | 30.1 | 33.5 | 12% |
| Pooled | 35.7 | 39.5 | 11% |
| * for the incidence rate only the first squamous cell carcinoma of the skin (per person) is considered | |||
Another reason for the massive increase in NMSC may be due to the improvement of registration in cancer registries, whose results are probably increasingly converging. However, by definition, epidemiologic cancer registries do not reflect the entire disease burden of NMSC because only the first skin tumor in a given histology is counted as an incident case and all subsequent tumors of the same type are classified as recurrence [7]. However, the occurrence of multiple NMSC, basal cell carcinoma, or SCC is common [14]. An Australian study was able to show that 50% of patients develop further tumors, most of them within the first year after primary diagnosis [15].
Current data on the epidemiology of SCC were provided for this guideline by the Robert Koch Institute for Germany. Since data on the incidence of SCC over a longer period of time are not available from all federal states, data considered to be reliable were combined from a pool of different federal states such as Hamburg, Schleswig-Holstein, Bremen, Lower Saxony, Mecklenburg-Western Pomerania, Rhineland-Palatinate, and the administrative districts of Münster (North Rhine-Westphalia), Lower Bavaria, and Upper Palatinate (Bavaria). Based on this, incidence rates of SCC of the skin were presented over a 10-year period (2009-2018). The recorded age-standardized incidence rates currently range between 20/100,000 inhabitants and 37/100,000 inhabitants per year (old European standard), depending on the region.
Comparing the rates in 2009-2013 with the rates in 2014-2018 shows an increase in incidence rates of up to 42% in some states, and no increase was observed in some registries.
Table 5: Crude incidence rates as projected case numbers in Germany in 2014-2018
| Age group | Age-specific incidence rate for pooled registries, 2014-2018. | Population | Projected case numbers for 2018 | |||
| Men | Women | Men | Women | Men | Women | |
| 0-14 | 0.0 | 0.1 | 5,874,035 | 5,560,496 | 3 | 4 |
| 15-19 | 0.1 | 0.1 | 2,015,167 | 1,882,842 | 1 | 1 |
| 20-24 | 0.3 | 0.2 | 2,405,359 | 2,184,102 | 6 | 5 |
| 25-29 | 0.5 | 0.4 | 2,594,394 | 2,399,311 | 13 | 9 |
| 30-34 | 0.6 | 0.7 | 2,853,602 | 2,684,803 | 17 | 20 |
| 35-39 | 2.0 | 1.7 | 2,685,997 | 2,604,046 | 53 | 44 |
| 40-44 | 4.0 | 3.7 | 2,501,071 | 2,470,886 | 101 | 92 |
| 45-49 | 8.5 | 8.2 | 2,587,609 | 2,567,000 | 221 | 210 |
| 50-54 | 15.0 | 13.5 | 3,324,451 | 3,274,279 | 499 | 443 |
| 55-59 | 29.2 | 22.0 | 3,392,257 | 3,385,055 | 992 | 744 |
| 60-64 | 55.0 | 34.5 | 2,823,007 | 2,909,947 | 1,552 | 1,005 |
| 65-69 | 115.0 | 63.2 | 2,323,158 | 2,555,911 | 2,672 | 1,616 |
| 70-74 | 243.6 | 117.1 | 1,786,397 | 2,034,686 | 4,352 | 2,383 |
| 75-79 | 424.9 | 183.6 | 1,642,030 | 2,030,194 | 6,977 | 3,727 |
| 80-84 | 606.6 | 254.4 | 1,401,304 | 1,961,088 | 8,501 | 4,989 |
| 85 plus | 799.9 | 365.5 | 822,231 | 1,624,163 | 6,577 | 5,936 |
| total | 41,032,069 | 42,128,809 | 32,537 | 21,228 | ||
The risk of developing SCC increases with age even more significantly than for many other types of cancer. In 2016, 21% of people over 65 were diagnosed with SCC. As the number of older people in Germany continues to increase, a further increase can be expected due to demographic changes alone [7]. The number of people over 65 years of age will increase from 17.4 million (2016) to approximately 20 million in 2025, and thus the incidence rates for cutaneous SCC will also increase (see Figure 2).
European data show geographically determined differences. The highest incidence rates are reported in Wales (United Kingdom), the Netherlands, and Switzerland (age-standardized rate according to the European standard, 31.7/100,000, 22-35/100,000, and 28.9/100,000 population in 2012, respectively) [16][17]. Figure 3 shows the progression of age-standardized incidence rates in the Netherlands since 1989 and compares them with rates in Germany. In the United States, approximately 600,000 patients were treated with SCC in 2006, and an estimated 3,900-9,000 died from it.
The highest incidence rates of NMSC are reported in Queensland, Australia, and are 772 for men and 442/100,000 population per year for women [18]. In the Southern states of the US, mortality rates are reported to be similar to those for malignant melanoma, with up to 8,791 patients dying in 2012 [19]. SCC is more common in males than females and is 80% localized to the head and face, or to areas chronically exposed to UV light. The average age is 70 years [20]. SCC can metastasize primarily to the regional lymph nodes and form distant metastases. The rate is approximately 5%, in some subgroups up to 20%. If distant metastases are present, the prognosis is poor, with a median survival of less than 2 years. Therefore, early diagnosis and therapy of this tumor are critical [20].
3.2.2 Mortality
The mortality of NMSC is low and has remained largely stable in Germany over the last 25 years [10]. In 2015, 464 men and 350 women died from NMSC according to official cause of death statistics; the proportion of SCC is unknown due to the lack of mappability in ICD-10. Data from the Federal Statistical Office describe a mortality rate of 0.65 for men and 0.3 for women in 2011-2015; in 1991-1995, this was 0.62 for men and 0.27 for women. Various publications show a low rate of disease-specific compared to general causes of death [21][22][14].
3.2.3 Etiology and pathogenesis
The development of AK is predominantly caused by chronic UV exposure, especially to UV-B. A relationship between cumulative UV dose and the occurrence of AK has been demonstrated in numerous studies [6]. UV radiation induces a mutation of the tumor suppressor gene p53, which is considered to be causative for the development of AK. P53 plays a crucial role in cell cycle regulation and induces apoptosis of mutant cells. UV-B radiation leads to a characteristic „UV-typical“ transition from cytidine to thymidine in the tumor suppressor gene p53, resulting in a loss of function of the gene product p53. As a consequence, uncontrolled proliferation of degenerated cells occurs with subsequent appearance of AK [23].
UV radiation probably also leads to an activating mutation in codon 12 of the Ras oncogene H-Ras and thus influences the regulation of cell proliferation. This mutation leads to a permanent activation of the signaling pathway and thus to an increased cell proliferation. A corresponding mutation could be detected increasingly in AK and SCC of the skin. An association between AK or SCC and infections with human papilloma viruses (HPV) has been discussed repeatedly [24]. On the other hand, HPV DNA is also detected in normal skin and in hair follicles, which would accordingly also indicate a coincident association.
In mucocutaneous genital SCC, the etiologic relevance of HPV infection is better established, although again not the sole cause. One type of vulvar SCC occurs primarily in older women and develops from lichen sclerosus. The other type is more common in younger women and develops from vulvar intraepithelial neoplasia (VIN) caused by HPV infection. Penile SCC can also be divided etiologically into two groups. One type develops primarily in the presence of phimosis or chronic inflammation (balanitis), often due to poor hygiene. The second type develops from HPV infection, particularly serotypes 6, 11, 16, and 18. Similarly, scrotal SCC may be HPV-related or non-HPV-related.
For SCC of the vulva and penis, please refer to the respective current guidelines:
- Vaginal carcinoma: https://register.awmf.org/de/leitlinien/detail/032-042
- Penile carcinoma: https://www.leitlinienprogramm-onkologie.de/leitlinien/peniskarzinom/
The etiology of SCC is multifactorial and includes, in addition to a genetic or immunological predisposition, primarily exogenous trigger factors, first and foremost UV radiation. Due to its oncogenic potential, this was included in Group 1 of the established carcinogens by the WHO in 2009 [25] and plays a key role in the context of the newly established occupational disease BK 5103 of cutaneous SCC in Germany as cumulative „natural UV radiation“. Chemical carcinogens such as polycyclic aromatic hydrocarbons or arsenic are secured as full-fledged carcinogens in the induction of cutaneous SCC.
3.2.4 Risk factor immunosuppression
Epithelial skin tumors are by far the most common malignant neoplasms after organ transplantation and a typical long-term complication of chronic immunosuppression [26][27][28]. In the well-studied collective of organ transplanted patients, SCC are the most frequently diagnosed tumors with over 65-fold increased incidences [27]. In contrast, the incidence of basal cell carcinomas, which dominate the immunocompetent Caucasian population, is only increased by a factor of 10 after organ transplantation, and thus proportionally much less [27]. In addition, organ transplanted patients also show a significantly higher risk of developing AK. The incidence for the development of NMSC increases with the number of years under immunosuppression and is 40–60% after 20 years. In addition, there is a much more aggressive growth pattern of AK in organ transplant recipients with early progression to SCC [29].
The occurrence of a first invasive SCC, often on chronically UV-damaged skin on the ground of field cancerization typically represents an indicator lesion in organ transplant recipients of an at least 10-fold increased risk for the development of further SCC in often increasingly shorter time intervals [30][31]. In addition, SCC under immunosuppression typically show a more aggressive growth behavior, which is histologically characterized by a tendency to infiltrative tumor growth and perineural invasion and clinically by an increased metastasis rate of 5-8%, a higher local recurrence rate (up to 13.4%) and multifocal, often eruptive occurrence [26][27][30][32][33][28].
3.3 Prognostic factors for the transition from actinic keratosis to invasive squamous cell carcinoma
The data situation for reliable prognostic factors of the transition from AK to SCC is insufficient. At the moment, no reliable values for the probability of progression can be given. The following clinical factors are prognostically unfavorable:
- Immunosuppression
- Therapy resistance
- Field cancerization
Change note
The data situation for prognostic factors of the transition AK -> SCC is not sufficient. At the moment, no reliable values can be given for the probability of the transition from AK to SCC.Evidence tables (1)
Klassifikation AKExisting clinical and histological systems (e.g., classification according to Olsen, graduation into KIN 1-3, counting of lesions) are not sufficiently validated prognostically and thus dispensable in clinical practice.
Change note
Because existing clinical and histologic systems (e.g., classification according to Olsen or KIN 1-3) are not sufficiently prognostically validated, new classifications should be developed.Evidence tables (1)
Klassifikation AKBackground
AK is an epidermal malignant proliferation of keratinocytes ("in-situ carcinoma") of human skin, which is considered a precursor for SCC. AK occurs mainly in fair-skinned individuals in sun-exposed localizations. The main risk factor for the occurrence of AK is cumulative UV exposure from the sun and/or tanning beds [42]. Histologically, AK represents a dysplasia formed by keratinocytes that have atypical nuclei that are enlarged, irregular and hyperchromatic. To stratify the degree of epidermal dysplasia, 3-stage scales were proposed to describe the transition from AK to SCC.
Thus, the progressive stages of keratinocytic intraepidermal neoplasia (KIN) were divided into 3 stages. In KIN I, atypical keratinocytes are found in the lower third of the epidermis. This stage may then evolve to lesions occupying the lower two-thirds of the epidermis (KIN II) and subsequently penetrating the full thickness of the epidermis (KIN III) [38].
In a later classification with better clinicopathologic characterization, the progression stages of AK were termed early in-situ SCC of type AK I, AK II, and AK III. The purpose of this classification was to indicate that all forms of AK (AK I, AK II, and AK III) represent in-situ SCC at different stages of progression from the very beginning.
Again later, Stockfleth et al. suggested that all AK should be evaluated as intraepidermal SCC without being able to predict which cases have the potential for progression to invasive SCC [43]. However, this proposal was not universally accepted and recently AK were classified as premalignant and/or precancerous with KIN III/AK III as in situ SCC [38].
The classification and data for prognostic factors determining the transition from AK to SCC remain inadequate. Fernandez-Figueras et al. demonstrated that their data support both the hypothesis of a sequential progression ("classical pathway“) from AK to invasive SCC and a nonsequential sequence [38]. Histological evaluation of the epidermis of overlapping or adjacent epidermis of invasive SCC (196 biopsy specimens) showed that these cases were associated with the appearance of AK II and AK III in 17.9% and 18.4%, respectively, but were also associated with AK I in 63.8%. The authors therefore favor direct transformation of AK I to invasive SCC (so-called "differentiated pathway“).
Older data on progression from AK to SCC give estimates of 0.025% up to 16% for an individual lesion per year. Therefore, for a patient with 6-8 lesions, transformation rates of 0.15%-80% per year have been estimated. In one of the largest prospective studies by Criscione et al. in the follow-up of AK over 5 years, the risk of progression from AK to invasive SCC was shown to be 0.60% at year 1 and 2.57% at year 4 after initial diagnosis of AK [44].
The types of studies included vary. Study designs range from histological case descriptions, retrospective surveys, correlational studies, "nested case-control studies“, "retrospective case-controlled studies“, multicenter cohort studies, to a systematic review [45][46][47][48][49][50]. Other publications, mostly case-control studies, retrospective studies, or cohort studies with low evidence level ratings (3-4) failed to demonstrate differences in sex, age, and lesion location when analyzing prognostic factors and the time interval between AK and SCC transformation [46][49][50]. There was no correlation between epidermal thickness, degree of dysplasia and p53 expression. In immunosuppressed patients, an association between the size of AK-burdened areas and SCC risk was observed. In another study, 29% of 452 renal transplant patients were diagnosed with AK at baseline. In 13% of kidney transplant patients with AK without field cancerization, 7% developed SCC compared with 15% of patients with AK with field cancerization.
However, the systematic review also does not reach a „clear conclusion“ (because of inconsistent data), but summarizes that the absolute risk of developing SCC in an AK lesion on the head is 0.42. The time for progression of an AK lesion in the head to SCC is reported to be between 16-34 months [51].
Overall, there is a paucity of studies and inferred evidence for prognostic factors and transition probabilities from AK to SCC. A 2013 systematic literature review [34], which analyzed 24 studies, concluded: „In general, available data are limited. Important methodological limitations apply. Currently, reliable estimates of the incidence of AK development to invasive carcinoma are not possible and further studies are needed.” Recent studies by Dirschka et al. and Dreno et al. also indicate that the previous staging of AK, its progression to SCC, and necessary preventive therapies need to be reconsidered [52][53]. In their work, against the background of the occurrence of AK in a field cancerization, new assessment criteria for the stages of AK were developed (AK field assessment scale: AK-FAS; AK area and severity index: AKASI), which contribute to a new evaluation.
When assessing the data and study situation on the prognosis of AK transition to SCC, it is particularly noticeable that studies on the genetic, epigenetic and cellular level are too rarely performed and/or used to determine validated and clinically applicable parameters that ensure meaningful, evidence-based prevention and treatment of AK for the benefit of the affected individuals and with a balanced cost-benefit consideration for the health care system. This should be improved in the light of available modern molecular biological methods.
3.4 Prognostic factors for metastasis in invasive squamous cell carcinoma
Histopathologic factors (vertically determined tumor infiltration depth, desmoplasia, degree of differentiation, perineural growth) and clinical factors (localization, horizontal tumor diameter, comorbidities such as immunosuppression) are considered prognostic factors for metastasis or disease-specific survival.
Background
The following factors are considered prognostic for metastasis or disease-specific survival in cutaneous SCC:
- Vertical tumor thickness (>6 mm)
- Horizontal tumor diameter (≥ 2 cm)
- Histological differentiation (> grade 3)
- Desmoplasia
- Perineural growth
- Localization (lower lip, ear)
- Immunosuppression (iatrogenic or disease-related).
These apply to the following chapters on diagnosis, surgical and systemic therapy of SCC, and follow-up. The data on prognostic factors are based on manageably large collectives, which were usually analyzed retrospectively. Only a few publications show prospective data.
Cutaneous SCC is a tumor with a relatively low risk of metastasis, although the frequency of patients with metastatic SCC and thus the clinical relevance is relativized by the extremely high incidence. The risk of metastasis was 4% in a prospective cohort of 615 patients with a median follow-up of 43 months [20]. Local recurrence also occurred in 3% of patients. Metastases occurred in 4% of tumors that were between 2.1 mm and 6.0 mm thick and in 16% of tumors with tumor thickness greater than 6.0 mm. SCC with a vertical tumor thickness of 2.0 mm or less did not metastasize in this population. On multivariate analysis, the most important prognostic factors for metastasis were increased tumor thickness (HR 4.79; 95% CI 2.22-10.36; p<0.0001), immunosuppression (HR 4.32; 95% CI 1.62-11.52; p=0.0035), and localization to the ear (HR 3.61; 95% CI 1.51-8.67; p=0.0040). The risk of local recurrence depended on increased tumor thickness (HR 6.03; 95% CI 2.71-13.43; p<0.0001) and the presence of desmoplasia (HR 16.11; 95% CI 6.57-39.49; p<0.0001) [20].
In a large retrospective study, Schmults et al. identified a local recurrence rate of 4.6% [63] in 985 patients with 1,832 tumors and a median follow-up of 50 months. The rate of patients with local lymph node metastases was 3.7%. The case-related disease-specific mortality rate was 2.1%. In multivariate risk analyses, independent predictors of lymph node metastasis and disease-specific death were: horizontal tumor diameter of at least 2 cm (HR 7.0; 95% CI 2.2-21.6 and HR 15.9; 95% CI 4.8-52.3) and low differentiation (HR 6.1; 95% CI 2.5-14.9 and HR 6.7; 95% CI 2-7). Perineural invasion was significantly associated with disease-specific death (HR 3.6; 95% CI 1.1-12.0). Overall survival was associated with poor differentiation (HR 1.3; 95% CI 1.1-1.6) and invasion beyond adipose tissue (HR 1.7; 95% CI 1.1-2.8).
The observations from these large prospective and retrospective studies were also evident in other, smaller retrospective studies. Brinkman and colleagues examined prognostic factors in 131 patients with 155 SCC [54] in a retrospective analysis. Here, tumor differentiation grade was an independent prognostic factor for metastasis and overall survival. Metastasis-free survival was significantly higher in well-differentiated tumors (70%) than in moderately (51%) and poorly differentiated tumors (26%; p=0.012). Comparable percentages were found for overall survival (p=0.005).
Campoli et al. demonstrated in a retrospective analysis that perineural invasion was related to other prognostically relevant factors [55]. Here, perineural invasion was significantly associated with localization in the head and neck region (p=0.039), larger tumor diameter (p<0.001), thicker tumors (p<0.001), low tumor differentiation (p<0.001), presence of clinically detectable lymph nodes (p=0.012), and recurrent (p<0.001) and painful tumors (p<0.001). In addition, perineural invasion occurred significantly in association with thicker tumors (p<0.001).
In a publication by Haisma on SCC in the head and neck region, the following parameters were shown to be prognostic factors for metastasis to local lymph nodes [56]: tumor thickness >2 mm, horizontal tumor diameter >5 cm, low differentiation and localization to the ear.
In the retrospective analysis by Cherpelis and colleagues, horizontal tumor extent, vertical penetration of analogous anatomic structures (Clark level), degree of differentiation, presence of small tumor nests, infiltrative tumor strands, single cell infiltration, perineural invasion, acantholysis, and local recurrence were significantly associated with metastasis [57]. In contrast, tumor location, ulceration, inflammatory infiltrate, and Breslow absolute penetration depth did not correlate with metastatic development.
Ch’ng et al. showed in a multivariable model that the degree of differentiation correlated with disease-free survival (HR, 0.2; 95% CI 0.1-0.8; p=0.03), but not tumor-free cut margins, horizontal tumor diameter, or vertical tumor thickness [Ch'ng, S. et al. 2013]. A number of other publications confirmed the above risk factors in increasingly smaller collectives [66][60][61][62][64].
Evidence tables
Klassifikation AK
|
Study |
Aims |
Design |
Population |
Outcomes |
Results |
Comments and methodological assessment |
LoE |
|
Chen et al 2013 |
To assess the reliability of four different methods used to quantify AKs and to investigate whether a consensus meeting affects the reliability. |
Single-blinded, cross-sectional study of 12 experienced dermatologist raters counting AKs on the face and ears of nine subjects before and after a consensus meeting
To compare the degree of agreement of (i) AK count of discrete lesions > 0.25 cm (big), (ii) AK count of discrete lesions < 0.25 cm (small); (iii) total count, irrespective of size, and (iv) the body surface area method |
N=12 board-certified dermatologists 67% were women Mean age: 47 years ± 9
N=9 consecutive subjects with extensive AKs on their face and ears were invited to participate in a research kick-off meeting for AK assessment, 100% male |
intraclass correlation coefficient (ICC) among raters for pre- and post-consensus evaluations |
total count’ method had the greatest ICC for both pre- (0.18, P=0.04) and post-consensus (0.66, P≤ 0.0001) assessments.
Total count was also the only pre-consensus ICC for which the null hypothesis of no association among assessments was rejected. |
Small sample size
No histological confirmation of AK was obtained
Patients with AK to be rated were only male |
2 |
|
Cockerell 2000 |
To propose criteria for grading keratinocytic intraepidermal (malignant) neoplasia. |
Modification of an existing classification system based on a literature review à expert review/opinion |
- |
Classification system |
Proposed criteria for grading keratinocytic intraepidermal (malignant) neoplasia.
Grade I: Clinical: Flat, pink macule or patch on solar-damaged skin; background mottling; no roughness or hyperkeratosis. Histologic: Focal atypia of basal keratinocytes of lower one third of the epidermis.
Grade II: Clinical: Pink to red papule or plaque with rough, hyperkeratotic surface; variable induration. Histologic: Focal atypia of keratinocytes of at least the lower two thirds of the epidermis; focal hyperkeratosis, alternating orthokeratosis and parakeratosis with sparing of acrotrichia and acrosyringia; prominent acanthosis and buds of keratinocytes into the upper papillary dermis; may see some involvement of upper acrotrichia and acrosyringia.
Grade III: Clinical: Red, scaly indurated plaques on sun-damaged skin; may be pigmented. Histologic: Diffuse atypical keratinocytic proliferation involving the full thickness of the epidermis diffusely; parakeratosis, acanthosis, papillomatosis, the involvement of adnexal structures. |
No validation with real-world data of the system
No inter-rater reliability or other measure were investigated
Only expert review |
5 |
|
Cockerell et al 2005 |
To propose a classification for AK analogous to that used for cervical intraepithelial neoplasia. |
Modification of an existing classification system based on a literature review à expert review/opinion |
- |
Classification system |
Criteria for grading keratinocytic intraepidermal (malignant) neoplasia.
Grade I: Clinical: Flat, pink macule or patch on solar-damaged skin; background mottling; no roughness or hyperkeratosis. Histologic: Focal atypia of basal keratinocytes of lower one third of the epidermis.
Grade II: Clinical: Pink to red papule or plaque with rough, hyperkeratotic surface; variable induration. Histologic: Focal atypia of keratinocytes of at least the lower two thirds of the epidermis; focal hyperkeratosis, alternating orthokeratosis and parakeratosis with sparing of acrotrichia and acrosyringia; prominent acanthosis and buds of keratinocytes into the upper papillary dermis; may see some involvement of upper acrotrichia and acrosyringia.
Grade III: Clinical: Red, scaly indurated plaques on sun-damaged skin; may be pigmented. Histologic: Diffuse atypical keratinocytic proliferation involving the full thickness of the epidermis diffusely; parakeratosis, acanthosis, papillomatosis, involvement of adnexal structures. |
No validation with real-world data of the system
No inter-rater reliability or other measure were investigated
Only expert review |
5 |
|
Dirschka et al 2017 |
To develop and perform an initial pilot validation of a new easy-to-use quantitative tool for assessing AK severity on the head. |
1. review of other severity scoring systems in dermatology, in particular the psoriasis area and severity index (PASI)
2. Initial validation was performed by 13 physicians assessing AK severity in 18 AK patients and two controls using a physician global assessment (PGA) and AKASI.
To determine an AKASI score, the head was divided into four regions (scalp, forehead, left/right cheek ear, chin and nose). In each region, the percentage of the area affected by AKs was estimated, and the severities of three clinical signs of AK were assessed: distribution, erythema and thickness. |
N=18 patients with AK on the head [mean age (range): 73 years (60–80); 10 men and eight women] and two controls without AK (62-year old man and 70-year-old woman)
N=13 physicians were involved in the rating |
AKASI & PGA scores Correlation between AKASI and PGA (Pearson correlation coefficient) |
AKASI & PGA scores mean (SD) PGA score was 0.08 (0.27) for the controls and 1.74 (0.80) for the patients. The mean (SD) AKASI score was 0.11 (0.38) for the controls and 4.75 (2.51) for the patients
strong correlation between AKASI and PGA scores (Pearson correlation coefficient: 0.86). AKASI was able to discriminate between different PGA categories: mean (SD) AKASI increased from 2.88 (1.18) for ‘light’ to 5.33 (1.48) for ‘moderate’, 8.28 (1.89) for ‘severe’, and 8.73 (3.03) for ‘very severe’ PGA classification. The coefficient of variation for AKASI scores was low and relatively constant across all PGA categories. |
This work was funded by Centroderm GmbH.
An initial 30-min training on AKASI was provided, and the physician participants were provided with a handout containing detailed instructions on AKASI.
Small-medium sample size of both patients and physicians. |
2 |
|
Dréno et al 2017 |
To develop, test, and validate an Actinic Keratosis Field Assessment Scale (AK-FAS) based on photographic clinical cases. |
Development: initial draft of the AK-FAS was based on a combination of Olsen criteria for AK. This draft was then dynamically modified in a face-to-face meeting on 15 July 2016.
Validation: 108 standardized photographs of patients representing the full range of AK severity were collected.
Six investigators (involved in the development) and 2 untrained investigators independently rated each photograph according to 3 criteria (AK-FAS scale): AK area (total skin area affected by AK lesions), hyperkeratosis and sun damage. |
The final AK-FAS was tested separately on face and scalp areas (on 66 and 30 photographic cases, respectively) by 6 trained (testing) and 2 untrained investigators (validation). |
Inter-rater reproducibility |
Validation of the AK-FAS by investigators
Inter-rater reproducibility: For face and scalp combined, the inter-rater κ scores were 0.69, 0.71 and 0.51, respectively substantial agreement for 2 criteria (AK area and hyperkeratosis) and moderate agreement for the third criteria (sun damage)
Intra-rater reproducibility: good for all criteria (AK area, hyperkeratosis and sun damage) substantial agreement range for all investigators for AK area, almost perfect or substantial agreement range for all but one of the investigators for hyperkeratosis and moderate agreement range for the majority of the investigators for sun damage
Validation of the AK-FAS by untrained investigators κ scores of 0.59, 0.54 and 0.38, respectively, for AK area, hyperkeratosis and sun damage, indicating moderate agreement (good reproducibility) for AK area and hyperkeratosis, and fair agreement for sun damage; s imilar results were obtained for the face and scalp analysed separately
àValidation of the AK-FAS showed good reproducibility for AK area and hyperkeratosis, even for dermatologists untrained on use of the scale. |
Assessment for each area was repeated (with at least 1 h between assessments) to allow evaluation of inter- and intra-rater agreement.
The order of the photographic cases was randomly changed in the repeat assessment, in order to minimize grading by memory. The investigators had not previously seen any of the cases provided by their colleagues and were not allowed to confer during the assessment.
This study was funded by LEO Pharma. |
2 |
|
Fernández-Figueras et al 2015 |
To evaluate the prevalence of classic and differentiated pathways in the development of cutaneous iSCC. |
The epidermis adjacent to and overlying iSCC, assumed to be representative of pre-existing lesions, was histologically studied in 196 skin biopsy specimens showing iSCC by three pathologists. |
N=196 skin biopsy specimens showing iSCC (79 women and 117 men) mean age:77.3 years (±10.1) Most lesions (108 out of 196) were located on the face.
mean diameter of the selected biopsy specimens was 19.30 mm [median, 17 mm ± 13.01 mm; interquartile range (IQR), 10.00–27.50 mm]. The mean width of iSCC areas was 9.05 mm (median, 7 mm; ±7.17 mm; IQR, 3.50–13.00 mm). The anatomic level of infiltration was II in two cases (1.0%), III in 14 cases (7.1%), IV in 127 cases (64.8%), and V in 53 cases (27.0%). The mean maximum depth of infiltration was 3.83 mm (median, 3.00 mm; ±2.85 mm; IQR 2.00–5.00 mm). |
Features of the epidermis overlying iSCCs and at the edge of iSCCs, distributed according to the degree of involvement and the presence of ulceration (number of cases and corresponding percentages of total)
Adnexal involvement by atypical cells (proliferative AK) according to the thickness of atypical changes in the epidermis overlying iSCCs |
AK I, AK II and AK III lesions overlying iSCC were present in 63.8%, 17.9% and 18.4% of cases respectively. The corresponding percentages in the epidermis adjacent to iSCC were 77.9%, 6.6% and 8.3% respectively (stage could not be assessed in 8.1% of cases). Focal epidermal ulceration overlying iSCC was seen in 32% of AK I, 28.6% of AK II and 33.3% of AK III instances.
Adnexal involvement by atypical keratinocytes (proliferative AK) was present more frequently in cases with overlying AK I (39/125, 31.2%) than with AK II (8/35, 22.9%) and AKII I (5/36, 13.9%). |
Almirall has provided financial support for this study but has not participated in the elaboration and discussion of results.
Baseline characteristics of included participants were unbalanced. |
2 |
|
Fernández-Figueras et al 2018 |
To demonstrate that follicular extension of an AK is associated with the depth of invasion (Breslow) of iSCC. |
retrospective histologic review of 193 biopsy specimens of iSCC with an associated AK by three dermatopathologists
assessment of the presence and depth of follicular extension of atypical keratinocytes in the AK, using tumour (Breslow) thickness and the follicular unit level (infundibular, isthmic and subisthmic), as well as iSCC being present directly adjacent to the follicular basalis |
N=193 biopsy specimens |
Follicular extension
|
Follicular extension was present in 25.9% of the cases (50 cases), usually extending into the lower follicular segment. . In 12 of them, the atypia reached the upper portion of the follicle (infundibulum), and in three of them (25%), there was evidence of invasive squamous cell carcinoma (iSCC) originated from the follicular basalis. In 33 cases, the atypical cells reached the isthmic portion, and in 21 of them (63.6%), iSCC originated from the follicular basalis. In five cases, the atypical cells reached the isthmic portion and in all of them iSCC originated from the follicular basalis.
The iSCC was present directly adjacent to the follicular basalis in 58% of the cases (29 cases), correlating highly with the depth of follicular extension (infundibular: 3/12; isthmic: 21/33; subisthmic 5/5). |
all biopsy specimens smaller than 3 mm and larger than 2.5 cm in size and those specimens with poor architectural preservation (i.e. superficial or fragmented specimens and tumours with extensive exulceration) were excluded |
2 |
|
Ianhez et al 2013 |
To evaluate the actinic keratoses counting by various raters and suggest approaches to increase the reliability. |
Cross-sectional study: forty-three patients were evaluated by four raters (inter- and intra-rater assessment) on the face and forearms.
rating: two board-certified dermatologists and two residents of Dermatology |
N=43 patients Age: 63.1 years (range: 50–80 years) 25 females
mean actinic keratoses counts on the face and forearms were 7.7 and 9.1 |
Inter-rater agreement
Intra-rater agreement |
The overall agreement among the raters for the facial and forearm actinic keratoses was 0.74 and 0.77. The intra-rater assessment showed high rates of agreement for the face (ICC = 0.93) and forearms (ICC = 0.83).
The intra-rater agreement for 0–5, 6–10 and 11–20 counted lesions were: 0.66, 0.29 and 0.30. |
All evaluators received a specific training session on counting AKs for the study. |
2 |
|
Jiyad et al 2017 |
To provide a detailed evaluation of the consistency of AK counts on digital photographs with clinical examination in renal transplant recipients, using defined areas of skin. |
Skin sites of renal transplant recipients were examined clinically and on digital photographs by independent dermatologically-trained examiners. |
N=28 patients with 138 skin sites
Mean age: 57 ± 9 years, the majority were male (67%)
mean ± SD length of time since transplantation was 9 ± 7 years
number of AKs per skin site ranged from 0 to 14 and overall 305 AKs were diagnosed in total across all skin sites
mean ± SD number of AKs on any single skin site was 2 ± 3 |
Specificity, sensitivity, and Kendall’s tau-b correlation coefficient were calculated based on exact photographic AK counts as well as counts with ± 1 AK tolerance. |
When 138 skin sites with 305 clinical AK counts were examined for total count ± 1 AK, the sensitivity and specificity of photography was 95% and 100%, respectively.
There was a significant positive correlation between AK counts on photographs and clinical examination (Tb = 0.537) and correlation was even higher for total count ± 1 AK (Tb = 0.758).
àmoderate to strong concordance between AK counts on digital photographs and clinical examination |
Blinding was performed |
2 |
|
Röwert-Huber et al 2007 |
To propose a system that classifies an AK as an SCC, in conjunction with an atypia grading system. |
Review based on existing classification systems; modification of the existing system of Cockerell
Expert opinion |
- |
- |
The authors recommend an AK classification system that describes these lesions as squamous cell carcinomas (SCCs), using the terminology ‘early in situ SCC Type AK I’, ‘early in situ SCC type AK II’ and ‘in situ SCC type AK III’. |
No validation of the system; only expert opinion |
4 |
|
Schmitz et al 2018a |
To determine the association between chronically UV-induced tumours such as basal cell carcinomas or squamous cell carcinomas and AKASI. |
retrospective analysis of patients who had undergone oncological surgery due to UV-induced tumours and who were assessed for AKASI and Physician’s global assessment (PGA) before surgery. AKASI assessment and PGA were performed by one investigator.
Statistical analysis of the correlation between AKASI, PGA and invasive carcinomas |
N=210 patients were included Median age: 77 years (42–95) 66.2% were male 61.9%: FST II 52.4%: history of NMSC
N=626 lesions Histological evaluation revealed AKs in 298 (46.9%), BD in 88 (13.8%), SCC in 32 (5.0%), BCC in 118 (18.6%) and other tumours such as seborrhoeic keratosis in 104 (16.4%) cases |
AKASI
PGA
Statistical differences
Correlation (Spearman) |
patients exclusively presenting AKs (n = 106) showed a median (range) AKASI of 4.6 (0–15.5) and PGA of 2.0 (0–4.0)
Patients with solely noninvasive tumours (n = 43) such as AKs and BD had a median (range) AKASI of 5.0 (0.6–11.2).
Significantly higher AKASI in patients with SCC compared to patients with non-invasive lesions like AK and Bowen disease (BD) (P=0.0275).
Spearman’s coefficient of rank correlation between AKASI and PGA indicates that these measures of AK severity were strongly correlated (P < 0.0001; r = 0.90; 95% CI 0.865–0.920). |
Large sample size; retrospective design
AKASI and PGA have been evaluated by only one investigator |
2 |
|
Schmitz et al 2018b |
To determine whether there is a correlation between the commonly used histological classification scheme for AK lesions proposed by Röwert-Huber and basal epidermal growth patterns of AK.
To investigate accompanying factors such as vascular density, inflammation and involvement of adnexal structures. |
Retrospective analysis of histologically confirmed AK lesions occurring on the head/face from patients seen in routine practice
Determination of histological grade (AK I-III), basal growth patterns of atypical keratinocytes (crowding, budding and papillary sprouting) and accompanying parameters by two investigators independently from each other. |
N=246 lesions were included
Median age: 79 (56– 94) years 92.3% male 30.9% of lesions located on the scalp |
histological grade (AK I-III)
basal growth patterns of atypical keratinocytes (crowding, budding and papillary sprouting)
accompanying parameters
correlation of basal growth patterns and histological AK grades |
Of the 246 lesions included, 28.0% were histologically classified as AK I, 46.7% as AK II and 25.2% as AK III.
Approximately 26.4% of the basal growth patterns were classified as crowding (pro I), 49.6% as budding (pro II), 17.9% as papillary sprouting (pro III) and 6.1% without basal directed growth.
No significant correlation of the histological AK IIII grading and underlying growth patterns was observed (P = 0.4666). However, adnexal structure involvement (OR = 2.37; 95% CI 1.21–4.65), infiltration (OR = 2.53; 95% CI 1.31–4.90) and increased number of vessels (OR = 2.56; 95% CI 1.42–4.65) were independent positive predictive markers for pro II and pro III basal growth patterns. |
- |
2 |
|
Schmitz et al 2019a |
To investigate a possible relationship between basal growth patterns of AKs adjacent to iSCC. |
Retrospective study
Histological assessment of the epidermis overlying and adjacent to iSCCs
Determination of the histological grade (AK I–III), basal growth pattern (PRO I–III) and accompanying parameters such as adnexal involvement.
Assessments were performed by two investigators independently from each other. |
N= 307 iSCC lesions were included 73.6% male Median age: 81 (76–86)
Tumour thickness (mm), median: 1.9 (IQR 1.1–3.9) 59.6% of patients with a history of more than one iSCC
Most of the tumours were well differentiated (85.3%) and invaded into the reticular dermis (75.9%) |
histological grade (AK I–III), basal growth pattern (PRO I–III) and accompanying parameters |
Among 307 lesions, 52.4% of AKs were histologically classified as AK grade I, 38.1% as AK II and 6.8% as AK III (v2-test, P < 0.001). Only 2.6% of adjacent epidermal samples did not show any atypical keratinocytes. The epidermis adjacent to iSCCs was classified as having a PRO I basal growth pattern in 25.7%, PRO II in 31.9% and PROIII in 39.4% of cases. Only 2.9% of AKs showed no basal growth (v2-test, P < 0.001). In total 118 AKs (48.8%) showed extension into adnexal structures. These AKs were graded as PRO I in 18.6% of cases, PRO II in 30.5% and PRO III in 50.8%. The epidermis above iSCCs could be assessed only for upwards-directed growth and showed no significant differences in the three AK grades (P = 0.42). |
adjacent and overlying AKs were assessed, but the investigators were not able to evaluate the original AK from which the iSCC had originated. Changes at the mutational level most probably lead to the final progression of this distinct subtype of AK. |
2 |
|
Schmitz et al 2019b |
To compare the inter-rater reliability of the established classification of upwards directed growth of AKs (AK I–III) and the recently established classification of basal growth pattern of AKs (PRO I–III). |
Retrospective study
Histological images of 54 AKs were classified by 21 independent dermatopathologists with regard to basal proliferation (PRO I–III), histological grade (AK I–III) and assumed risk of progression into invasive carcinoma. |
N=54 AKs
Raters: 21 expert dermatopathologists, thereof 12 dermatologists (57.1%) and nine pathologists (42.9%) mean age: 43.4 (±9.6) years and a mean experience in dermatopathology of 10.9 (±8.6) years |
Classification of AK images with regard to basal proliferation (PRO I–III), histological grade (AK I–III) and assumed risk of progression into invasive carcinoma
Inter-rater reliability |
16.7% of AK (9/54) were classified as AK I, 66.7% (36/54) as AK II, and 16.7% (9/54) as AK III. With regards to basal growth pattern, 25.9% (14/54) were classified as PRO I, 42.6% (23/54) as PRO II, and 31.5% (17/ 54) as PRO III. We observed a highly significant inter-rater reliability for PRO-grading (P < 0.001) which was higher than for AK-grading (Kendall’s W coefficient: AK = 0.488 vs. PRO = 0.793). We found substantial agreement for assumed progression risk for AKs with worsening basal proliferation (k = 0.759) compared to moderate agreement (k = 0.563) for different AK-gradings. |
- |
2 |
|
Schmitz et al 2016 |
Determine whether there is a correlation between the commonly used clinical classification scheme for AK lesions proposed by Olsen et al. with that of the histological classification system developed by Roewert-Huber et al. |
Retrospective analysis
One AK lesion from patients in three pivotal clinical studies and routine practice was assessed clinically and histologically. A match in grading was defined as Olsen grade 1 being classified histologically as AK I, Olsen grade 2 as AK II and Olsen grade 3 as AK III.
Patient population for this study came from three randomized clinical trials (ALA-AK-CT002, ALA-AK-CT003 and ALA-AK-CT007) and routine clinical practice. |
N=892 patients Mean age: 71.6±7.3 83.4% male 64.0% of lesions located on face/forehead |
Classification of AK according to Olsen and Röwert-Huber
correlation between clinical and histological classification |
29.0% of lesions were classified as Olsen grade 1, 59.6% as Olsen grade 2 and 11.3% as Olsen grade 3; 19.2% were histologically classified as AK I, 69.6% as AK II and 11.2% as AK III.
Only 480 lesions (53.8%) had a matching clinical and histological classification. Of these matches, most were ‘Olsen grade 2 = AK II’ (83.1%).
The Spearman’s rank correlation coefficient for clinical and histological classification was r=0.0499 (P=0.137). |
- |
2 |
|
Sinnya et al 2015 |
To compare the inter-observer agreement between trained observers for AK counts based on photographs compared with clinical AK counts. |
Clinical AK counting was carried out in 2 sessions by 4 dermatologically trained clinicians with 6 months or more of dermatological experience and a senior consultant dermatologist with over 25 years of experience, whose counts served as practical reference standard.
The observers repeated counting from the same photographic images, 2 weeks later. |
N=6 patients (n=3 immunocompetent, n=3 OTRs) 84% male Mean age: 60 years±15 |
Agreement of AK counts: interclass and intraclass correlation coefficients (ICC) |
ICC for agreement across 5 observers for the photographic AK counts was 0.63 (95% CI 0.48–0.78) compared with 0.79 (95% CI 0.68–0.88) for clinical counts
ICC for agreement between photographic AK counts and clinical counts ranged from 0.66 (95% CI 0.48–0.81) to 0.84 (95% CI 0.73–0.91) across the 5 observers
interclass correlation coefficient for agreement between AK counts based on the same photographs but counted on 2 separate occasions ranged from 0.86 to 0.99 |
Small sample size;
Reference standard was the assessments of the senior consultant |
3 |
|
Yantsos et al 1999 |
To propose a classification system for AK. |
Expert review/opinion |
- |
Classification system |
Criteria for Grading KIN
Grade I: Clinical: Undetectable or fiat, pink macule or patch on solar damaged skin; background mottling; no roughness or hyperkeratosis. Histological: Focal atypia of basal keratinocytes of lower one-third of the epidermis.
Grade IIa: Clinical: Pink to red papule or plaque with rough, hyperkeratotic surface; minimal induration. Histological: Focal atypia of keratinocytes of the lower two thirds of the epidermis; alternating orfho and parakeratosis with sparing of acrotrichia and acrotrichia.
Grade IIb: Clinical: Similar to Ila but more induration, more hyperkeratosis and/or more erythema; all KIN lesions (other than KIN III) on lip and conjunctiva. Histological: Focal atypia of keratinocytes of at least the lower two-thirds of the epidermis; focal hyperkeratosis, often greater than Ila; one or more additional features such as acantholysis, the involvement of adnexal structures, prominent acanthosis and buds of keratinocytes into the upper papillary dermis present.
Grade III: Clinical: Red, scaly indurated plaques on sun-damaged skin; may be pigmented; seen on other sites such as mucosa in Bowenoid papulosis and erythroplasia of Queyrat; non sun-damaged skin in squamous cell carcinoma in situ induced by arsenic. Histological: Diffuse atypical keratinocytic proliferation involving the full thickness of the epidermis; parakeratosis, acanthosis, papillomatosis, involvement of adnexal structures. |
No validation of the system with real-world data or assessment of inter-rater reliability
Only expert opinion |
5 |
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