4. Status Quo Skin Cancer – Prevention of Skin Cancer

Version 2.1 · August 2021 · AWMF 032/052OL
Leitlinienprogramm Onkologie · Deutsche Krebsgesellschaft · Deutsche Krebshilfe · AWMF

4.1 The Etiology of Skin Cancer

4.1.1 The Causes of Basal Cell Carcinoma, Squamous Cell Carcinoma, and Malignant Melanoma

Revision by R. Greinert, B. Volkmer

4.1 · Consensus-based Statement · checked 2020

On the basis of current knowledge, ultraviolet (UV) radiation is considered to be the most significant risk factor in the etiology of skin cancer, even if not all details of the induction, promotion and progression of skin cancer in humans have been elucidated.

In 2009, the International Agency for Research on Cancer (IARC) classified solar and artificial ultraviolet radiation (UV radiation) used in tanning beds as a class 1 carcinogen (“carcinogenic to humans") [17]. This categorization was made without restriction to specific wavelength ranges (UVA, UVB) on the basis of the proven epidemiological and basic scientific evidence.

Fundamentals of the Biological Effects of UV Radiation

UV radiation covers the region of the electromagnetic spectrum that spans the wavelength range 100-400 nm. Historically, this wavelength range has been divided into UVC (100-200 nm), UVB (200-315 nm), and UVA radiation (315–400 nm) [18]. Solar UV radiation has a biological effect only through the UVB and UVA components, since UVC is absorbed by molecular oxygen in the Earth's stratosphere [18].

UV radiation can interact with a variety of cellular components (including membrane lipids, proteins, and intracellular photosensitive molecules such as flavins or porphyrins) [19], but mainly through the absorption of UV photons by nucleic acids [20].

UVB radiation can be absorbed directly by the DNA molecule. Photochemical processes then lead to dimerization reactions of adjacent pyrimidines on a DNA strand (cis-syn-cyclobutane pyrimidine dimers (CPD), or (6-4)-pyrimidone photoproducts ((6-4)-PP)) [21].

UVB and UVA radiation can further contribute to the formation of reactive oxygen species (ROS) via indirect reaction pathways in which the radiation energy is first absorbed by photosensitive molecules in the cell. ROS can then cause oxidative base damage, such as 8-oxo-7,8-dihydro-2‘-deoxyguanosine (8-oxo-dG) in DNA [22]; [21]. However, it has also been clear for some time that UVA radiation is also capable of producing CPDs in DNA [23]; [24]; [25]; [26].

DNA damage, such as CPDs and 8-oxo-dG, can be removed by efficient cellular repair systems (e.g. nucleotide excision repair (NER), base excision repair (BER)). If these repair pathways are defective or deficient (such as the NER in xeroderma pigmentosum patients, who have a greatly increased risk of skin cancer), mutations may occur in the genome. In this context, CPDs mainly lead to C→T or CC→TT mutations known as “UV-signature mutations,” whereas UVA-induced oxidative base damage can lead to less significant G G-T “fingerprint" mutations. In general, two models of UV-induced mutagenesis are proposed to explain the major occurrence of C-T mutations in UV-irradiated cells. One reaction pathway involves a defective lesion bypass involving translhesion polymerases (polζ, polκ) [27]; [28]. In the other reaction pathway, deamination of (methylated) CPDs occurs first, which is then followed by a defect-free lesion bypass by polη [29] ; [30]; [31]; [32].

The study of mutation profiles in skin tumours, especially those occurring in XP patients, has, in the past, proven the importance of UV-induced bipyrimidine photoproducts and oxidative DNA damage in skin cancer development. In addition, genes have been identified whose UV-dependent mutations affect elementary cellular response pathways associated with the development and progression of basal cell carcinoma (BCC), squamous cell carcinoma (spinocellular carcinoma), and malignant melanoma (MM).

The relationship between UV radiation and the development of skin cancers has been demonstrated in many epidemiological studies, in animal experiments, and in a large number of basic experimental studies [20]. New studies in the field of sequencing human tumour genomes additionally prove the connection between UV-induced DNA damage and MM on the molecular genetic level. For example, Pleasance et al. (2010) showed that the mutations found in the sequencing of a melanoma metastasis genome belonged predominantly to UV signatures [33].

Basal Cell Carcinoma (BCC)

BCC is the most common skin cancer worldwide. It develops primarily on so-called “sun terraces,” such as the nose and forehead, among other places. For this reason, it was initially assumed that its occurrence depends on the cumulative UV dose. However, a number of BCCs that should not be underestimated also occur on “sun-protected" parts of the body, e.g. the upper body. Recently, it has been assumed that intermittent UV exposure, such as sunburns in childhood and adolescence, is also (partly) responsible for BCC, similar to MM [34]; [35]; [36], [37], [38]; [39]; [40]; [41].

Intensive worldwide research results now also point to a significant genetic determinant for the development of BCC. For example, it has been shown that patients suffering from naevoid basal cell carcinoma syndrome (NBCC), who often develop multiple BCC at an early age [42]; [43], frequently have losses of chromosome 9q. These findings led to the identification of the localization of a possible tumour suppressor gene in the 9q22-q32 region, the PTCH gene [44]; [45]; [46]. They also led to further characterization of the important Sonic-Hedgehog-Patched-Smoothened response pathway, which is reported to be disrupted in up to 100% of sporadic BCCs [47].

In the skin, a signaling cascade dependent on the Sonic Hedgehog (SHH) gene is implicated in hair follicle growth and morphogenesis. The protein product encoded by the PTCH gene, PATCHED1, serves as a cell surface receptor for the secreted signaling molecule SHH. In the absence of SHH, Patched1 inhibits Smoothened protein (SMO), a G-protein coupled receptor. Upon binding of SHH to PATCHED1, SMO is released and initiates a signal transduction cascade that causes activation of the transcription factor Gli. Dysregulation of the Hedgehog-Patched-Smoothened response pathway can result from loss of function of PTCH or increased expression of SMO, which lead to increased levels of the transcription factor Gli and as a consequence induce BCC associated by inhibiting cell cycle arrest and differentiation [48] hair follicles [49]; [50]; [51]; [52]. In mouse models, disruption of the SHH-PTCH-SMO response pathway in hair follicle stem cells has been shown to be responsible for the development of BCC [53]; [54]. Mutations in PTCH or SMO have been found in the majority of all sporadic BCC [55]; [56]; [57]; [58]. Recent work has also reported the influence of WNT, NOTCH, mTOR, and Hippo, as well as the molecular response pathways involving these genes and altered miRNA expression profiles regulating [59].

UV-specific “signature mutations" (C→T, transition mutations) were found in the p53, PTCH and smoothened genes [49]; [60]; [61]; [62]; [63]; [64]; [65]; [66]; [67]; [57]. This finding must be taken as another important indication of the importance of UV exposure in the development of BCC. UV-induced p53 mutations in cells of the skin accumulate in “hot spots,” which differ from those in internal tumours. There is evidence that UV-specific mutations of the p53 gene may be specific for BCC [68].

A large body of recent work indicates that stem cells in the “bulge-region" of the hair follicle or interfollicular epidermal stem cells are important in the development of non-melanocytic skin cancers (NMSC, i.e., BCC, squamous cell carcinoma). Since stem cells and their differentiation or neoplastic transformation are essentially dependent on regulation by their microenvironment, intercellular communication and its signal-mediated response pathways are of great importance. In animal models and in vitro studies (also on human skin cells), the WNT, SHH, NOTCH and EGFR signal transduction pathways are particularly important in connection with BCC and squamous cell carcinoma (see review [69]).

In addition to the changes in the Hedgehog-Patched-Smoothened pathway described above, a striking feature of BCC genetics is that few numerical chromosomal aberrations can be detected in tumour cells [70]. However, BCC are characterized by marked intra-tumoural heterogeneity. In a cytogenetic analysis of 44 BCC, genetically unrelated subclones were found in 21 tumours and genetically related subclones in only 10 tumours [71]. The authors concluded that a large number of BCC are of multiclonal origin. They further demonstrated that a larger proportion of BCC were characterized by gain of chromosomes 18, X, 7, and 9, and that chromosomal losses frequently affected the distal regions of chromosomes 6q, 13q, 4q, 1q, 8q and 9p [71].

Squamous Cell Carcinoma (SCC)

SCC is the only skin cancer that has a known precursor: actinic keratosis (AK, also known as solar keratosis). AK represents a discrete, intraepidermal lesion that occurs on chronically sun (UV)-exposed areas, such as the face, scalp, lips, forearms, and hands, in fair-skinned middle-aged and older individuals. Cumulative UV exposure from the sun is considered to be the main reason for the occurrence of AK [72]; [73]. The incidence of AK therefore increases with age.

AK represents a precursor of squamous cell carcinoma [74]. In the literature, conversion probabilities, i.e. transition probabilities of AKs into invasive squamous cell carcinoma, can be found in a range from <1% up to 16% [75]; [76]; [77]; [78]. In individual cases, even up to 70% has been reported [79]. In a recent work by Criscione et al. (2009), which was prospectively designed and included more than 6,000 individuals with actinic keratosis, the transition probability AK to SCC is reported to be only 0.06%. However, six years after initial diagnosis of actinic keratosis, all occurring SCC were based on AK [80]. The presence of multiple actinic keratoses over a 10-year period has been reported to have a lifetime risk of developing SCC in the range of 6-10% [75]. AK, as a feature of increased UV exposure, is an important risk factor for the development of SCC.

The risk of developing NMSC or MM is six times greater for patients with AK than for those without this lesion

[81]. However, the underlying mechanisms for this increased risk of skin cancer are currently not fully understood.

Neither is it sufficiently well understood for AK how high the transition probability from AK to SCC or other skin cancer entities is (see above) [82]; [83], nor do robust molecular biological or molecular genetic findings exist so far that could prove which genetic alterations might drive the transition AK to SCC [84]; [85]. However, evidence that appears to support that malignant progression of AK into SCC occurs [86]; [87]; [88] is interpreted by some dermatologists and dermato-histopathologists in such a way as to classify AK per se as squamous cell carcinoma confined to an epidermal extension (carcinoma in-situ) [89]; [90]; [91]; [87]; [92]. However, in a recent paper, Feldmann and Fleischer, after reviewing the data in the literature, conclude that “presently there is insufficient evidence to support the concept that AK is frank squamous cell carcinoma" [82].

However, recent work demonstrates that this view needs to be preceded. AK itself can be divided into three successive, histologically differentiable stages: AK I, AK II and AK III. It has been shown that the majority of SCC arises from AK I cells (proliferating atypical keratinocytes in the basal cell layer of the epidermis). However, the gradual emergence of SCC via AK I, AK II and AK III (“classical reaction pathway") is also still relevant for a substantial fraction of SCC [93]. In this regard, reference is also made to the S3 guideline Actinic keratosis and squamous cell carcinoma of the skin (https://www.leitlinienprogramm-onkologie.de/leitlinien/aktinische-keratose-und-plattenepithelkarzinom-der-haut/).

Due to this uncertain categorization, there is currently no reason to include AK in the group of skin cancer entities to be screened in skin cancer screening.

For the etiology of SCC, a relatively well-described model exists in which early-occurring UV-specific mutations in the p53 gene during the tumour initiation phase favor the development of a precursor of squamous cell carcinoma, AK. It is assumed that in AK initially only one allele of the p53 gene is mutated. This prevents the p53-dependent apoptosis of UV-damaged cells (so-called “sunburn cells") of some of the cells. Since at the same time “neighboring" cells show normal apoptosis, p53 mutated cells have a “selection advantage" and can expand clonally to AK. If the second p53 allele mutates in these cells during the tumour promotion phase, the p53-dependent cell cycle checkpoint function is switched off. Uncontrolled cell growth occurs and invasive squamous cell carcinomas are formed by induction of further (possibly UV-related) mutations in other genes (e.g. ras) during the tumour progression phase [94]; [95]; [96].

p53 mutations occur in 75-80% of patients with AK in the white population (30-40% in Japanese and Koreans) [97] and in more than 90% of patients with in situ squamous cell carcinoma (i.e., squamous cell carcinoma still growing noninvasively) [98]. For the latter and also for the p53 mutations in AK, it has been shown that they are mainly caused by UV-induced dimerizations of adjacent DNA pyrimidines and lead to C-T and CC-TT base substitutions (tandem mutations) [98], which are accepted as “UV-signature-mutations" [99]. These mutations arise as a consequence of the misrepair/misreplication of UVB- and UVA-induced DNA damage, such as the cyclobutane-pyrimidine dimer and the pyrimidine(6-4)pyrimidone dimer [100]; [101]; [99]; [102]; [103]. This clearly supports the involvement of UV radiation in the etiology of squamous cell carcinoma. In the p53 gene, these mutations occur in specific “mutation hot-spots“ in the gene, located in regions where enzymatic repair of DNA damage by nucleotide excision repair (NER) is prevented or inhibited (“repair cold-spots“) [104]; [105].

A pioneering p53-dependent model for the development of SCC was established by studies in the hairless mouse and its variants in which the p53 DNA-binding domain (DBD) was replaced by the homologous human segment (Hupki mouse) [106]; [107]. UV-induced p53 mutations can be detected in this model by immuno-fluorescence detection of clonal “cell patches" (up to several thousand cells) in the epidermis. The origin of this clonal expansion of p53-mutated cells could be seen in the induction of single severely UV-damaged, non-apoptotic, persistent “CPD-retaining basal cells" (CRBCs), which have been detected in both mouse models and human epidermis [108]; [109]. CRBCs are likely interfollicular epidermal stem cells whose UV-induced damage is thought to be responsible for the development of squamous cell carcinoma [69]; [110]; [98]. Interfollicular epidermal stem cells, whose characterization and possible isolation is currently best described for the mouse epidermis, are characterized by the fact that they proliferate only rarely and therefore accumulate UV-derived DNA damage (“label-retaining cells,” such as CRBCs) [111]; [69]; [112]. Epidermal stem cells thus represent the “most suitable" target for the carcinogenic effects of UV radiation, as they can furthermore accumulate mutations due to their long residence time in the otherwise continuously renewing epidermis. This is consistent with early findings [113] and, with respect to skin cancer, new models for carcinogenesis [69]; [114]; [115].

Consistent with the dependence of squamous cell carcinoma on cumulative UV dose and the multistep nature of squamous cell carcinoma development (see above), squamous cell carcinoma, e.g. compared to BCC, exhibits much greater karyotypic complexity and cytogenetically documented heterogeneity. Nevertheless, some presumably squamous cell carcinoma-specific chromosomal aberrations could be detected in SCC. For example, loss of heterozygosity (LOH) of a “9q marker" was shown to occur frequently in SCC [116]; [117]. Moreover, LOHs in 3p, 13p, 17p, and 17q appear to be specific for SCC and its precursor, AK [118]. Using multiplex fluorescence in situ hybridization (m-FISH), it was further shown that complex chromosomal translocations are increased in cell lines derived from SCC [119], indicating a particular importance of genetic instability in the development of squamous cell carcinoma. In this context, it is important to point out that UVA radiation is able to induce DNA double-strand breaks via the induction of reactive oxygen species, which are known to be a necessary precursor lesion for the development of chromosomal aberrations [120]; [121]. Since 2015, multiple AKs (at least six individual AK lesions per year or confluent over an area of more than 4 cm² (field carcinogenization)) or a SCC are recognized as an occupational disease (OCD).

Malignant Melanoma (MM)

There is ample strong evidence that malignant melanoma (MM) occurs due to intermittent UV exposure and severe sunburns during childhood and adolescence [122]; [123]. MMs occur very frequently in fair-skinned individuals with red or blond hair (skin type I), who are prone to freckling, do not tan, and sunburn very easily (see Chapter 4.3). There is a link between the risk of developing MM and specific mutations in the melanocortin-1 receptor [124]; [125]. This receptor is responsible for the type of melanin produced in melanocytes after UV exposure. It is hypothesized that individuals with such receptor mutations are unable to form the photoprotective eumelanin and instead produce the photosensitizing (and therefore potentially mutagenic) pheomelanin [126].

There is strong evidence that MM is autosomal dominant heritable, as 5-12% of affected patients have one or more first degree relatives who also have MM. In these individuals with familial melanoma, the cancer appears early. It is often accompanied by multiple other (skin) tumours [127]; [128]; [129]; [130]; [131]. Genetic analysis of families with high incidence of melanoma led to the identification of susceptibility genes such as the cyclin-dependent kinase inhibitor CDKN2A (p16INK4A) and the genes for the cyclin-dependent kinases CDK4 and CDK6. It has been shown that p16INK4A, genetically encoded on chromosome segment 9p21, is mutated in 25-40% of familial melanomas. It is now considered certain that this gene represents a predisposition gene for MM [132]; [133]; [134]. p16INK4A inhibits the progression of cells through the G1 phase of the cell cycle by suppressing the binding of cyclin D1 to CDK4/6. This is required for phosphorylation of the retinoblastoma protein, which controls the regulated transition of cells from G1 phase to replication (S phase). Mutations in the INK4A gene, which encodes the inhibitor CDKN2A (p16), abolish this regulation and lead to uncontrolled cell division. Furthermore, germ cell mutations and sporadic mutations in the tumour CDK4 gene have been shown to prevent the binding of p16INK4A to CDK4 and thus abrogate the inhibitory function of p16INK4A [135].

The INK4A locus also encodes a structurally and functionally distinct protein, p14ARF, which acts as another tumour suppressor [136]. p14ARF activates the p53 response pathway as a result of oncogene-mediated signaling (such as by c-Myc or ras oncogene) by binding to the p53 negative regulator Mdm2. This prevents the degradation of p53 and allows the induction of cell cycle arrest or apoptosis. Since p14ARF has been shown to be mutated in cells from MM [137]; [138] and isolated germ cell mutations have been found in patients with MM [139]; [140], p14ARF also represents a candidate predisposition gene of MM. Recent studies show that mutations in the BRAF gene may be of major importance in the development of MM [141]; [142]; [143]; [144]; [145]; [146].

In models of melanoma progression, benign nevi (moles) are thought to be a possible precursor stage of MM [147]; [148]; [149]. It is suggested that p16INK4A controls the growth of nevi and that they have arisen by clonal proliferation from melanocytes, which probably cease proliferation due to cellular senescence [150]; [151]; [152]. This growth inhibition can be abolished, for example, by ras mutations detected in some forms of nevi [153]; [154]; [155]; [156] . Mutations in the BRAF gene may also contribute to this [157]; [158]; [159]; [160]; [161]. This can lead to the formation of dysplastic nevi and subsequently to the radial growth phase of MM [162]. Deficiencies in p16INK4A and in the retinoblastoma gene (RB) are thought to be necessary in these cells for this to occur. In a next step, nodular melanomas develop in a vertical growth phase, penetrating deep into the dermis and already capable of metastasis [163]. Recent studies using, e.g. NGS, could show that, depending on the mutation status, three molecular subtypes of malignant melanoma can be distinguished: BRAF (mut), RAS (mut), and non BRAF (mut)/non RAS (mut) [164].

The number of UV-induced benign nevi acquired in early childhood (0-6 years) is a significant (if not the primary) risk factor for the formation of MM [123]. MM not only arise from nevi, but a large number arise de novo, i.e. nevus-independently [165], so that the risk marker “number of benign nevi" must initially be regarded as no more than a significant indication of pigmentation disorders, which is then associated, in a way that has not yet been clarified, with an increase in risk for the development of MM. This suggests that different reaction pathways may be responsible for the formation of MM, even if UV radiation is causative for its initiation. For example, Maldonado et al. [166] demonstrated through an analysis of 115 patients with invasive MM that BRAF mutations occur far more frequently in melanomas arising on intermittently sun-exposed skin sites. They occurred very rarely in MM on chronically exposed skin sites. This suggests that different genetic alterations may be responsible for the formation of MM.

However, it is now accepted that 50–60% of all MM have BRAF mutations, 90% of which lead to valine glutamate mutations in codon 600 (BRAFV600). These BRAF mutations lead to kinase activation in the constitutive MAPK response pathway [167]. Thereby, phosphorylations of the tumour suppressor LKB1 (a serine/threonine protein kinase) lead to its negative regulation, thereby contributing to melanoma cell proliferation and attenuation of the apoptotic response to metabolic stress [168]; [169]; [170].

In contrast to SCC and BCC, UV-induced mutations in the p53 gene appear to be of secondary importance. Only about 20% of malignant melanomas have p53 mutations [171]. Evidence suggests that the involvement of p53 in the etiology of MM is complex [172] and needs further elucidation. It is possible that other mechanisms, such as the induction of genetic instability, play a more important role.

The etiology of MM is characterized by a high degree of UV-induced genomic instability, which increases as MM progresses to metastasis. Genomic instability manifests itself in the gain or loss of chromosomes (or chromosomal segments), the occurrence of chromosomal aberrations and LOH. Depending on the localization (eye or skin), two genetically distinct subtypes can be distinguished. Loss of chromosome 3 and 1p and gain of 8q are often observed in melanomas of the eye, while gain of 6p and loss of 6q appear to be specific to melanomas of the skin [173]. Studies using “Spectral Karyotyping" (SKY) on cell lines from melanoma metastases show that genomic instability at the chromosomal level in late stage melanoma metastasis can be so pronounced that almost every chromosome is involved in numerical or partially complex structural aberrations [174].

The gain of 7q associated with overexpression of c-MET (localized to 7q33-qter) appears to be a late event in melanoma progression. The tyrosine kinase receptor c-MET for hepatocyte growth factor (HGF) is found in both keratinocytes and melanocytes. Stimulation of the HGF-MET cascade not only supports cell proliferation and motility, but particularly disrupts the important adhesion between keratinocytes and melanocytes by down-regulating E-cadherin and desmoglein [175], thereby supporting melanoma progression.

LOH have been found in MM for a number of chromosomal loci: 1p, 3p, 3q, 6q, 9p, 9q, 11q, 17p, 17q, and 22q [176]. At these loci often map the localizations of tumour suppressor genes that play a particular role in the etiology of MM (e.g., 9p21 as the localization of CDKN2A). Moreover, LOH in chromosome 10q23 were found in 30% of metastatic melanomas [177] and in melanoma cell lines [178]. This LOH involves the PTEN phosphatase gene, another tumour suppressor gene that acts as a negative regulator of the phosphatidylinositol 3-kinase response pathway, which supports proliferation and cell survival [179].

A link between UV exposure and induction MM of the skin is always doubted, since malignant melanomas also occur on body sites that are usually not exposed to UV. However, if one takes a closer look at the literature on this subject, it turns out that in both men and women, only about 6% of all diagnosed melanomas occur in body regions (lower abdomen, buttocks, genito-anal, mucous membrane, occult) that typically have little UV exposure. In contrast, the vast majority of malignant melanomas (94%) localize to body regions that may be frequently or intermittently exposed to UV radiation, such as the face, head, neck, chest, back, upper arms, forearms, hands, thighs, lower legs, and feet [180].

However, the association between UV exposure and development of MM is strongly supported by recent studies. In 2010, Pleasance and co-workers catalogued for the first time the entire spectrum of somatic mutations in the whole genome of a melanoma metastasis [33]. They found that the majority (approximately 70%) of the single base substitutions detected were of the C-T type and approximately 70% of the dinucleotide substitutions were of the CC-TT type. Since it is known that these are “signature-mutations" for exposure to UV radiation, this finding represents important evidence for the connection between the development of MM and UV exposure.

4.1.2 The Clinical Course of BCC, SCC, and MM Considering the Histopathological Classification and TNM Classification (WHO Classification of Tumours)

E.W. Breitbart

4.1.2.1 The Basal Cell Carcinoma

BCC arises on clinically inconspicuous skin without a precursor. It is a slowly growing tumour, which is so discrete in its initial growth that it is hardly noticed. At this stage it is characterized by a grey-white induration of a few millimetres in size with a few telangiectasias. In most cases it is skin-coloured and grows slowly locally. The greatest danger with this tumour lies precisely in this slow unstoppable growth, which can grasp and destroy all local tissue structures. Metastasis is rarely described [181].

The BCC can occur on the whole integument, but it prefers in the frequency of its occurrence the areas exposed to UV radiation, such as the head, neck, forearms, and back of the hands. At a lower frequency, BCC can also be found on the upper body, arms and legs.

As it progresses, BCC develops a wide clinical range of variation.

Therefore, different appearance types are distinguished according to their growth and pigmentation development:

1. Nodular Basal Cell Carcinoma

Nodular BCC is the most common form of BCC. It usually develops in the UV-exposed areas of the head, neck, and nape of the neck and first appears as a small, sharply defined, dome-like, coarse consistency with a pearly cord-like border interspersed with telangiectasias. After a prolonged period of growth, a central depression develops, which is intermittently prone to hemorrhage, crusting, and oozing, and finally changes to a permanent slowly increasing ulceration.

In the absence of therapy and with progressive tumour growth, deep infiltrating tumours develop, destroying all tissue structures, historically known as ulcus rodens/ulcus terebrans.

2. Pigmented Basal Cell Carcinoma

Pigmented basal cell carcinoma is considered a variant of nodular basal cell carcinoma. The increased melanin deposition can lead to the fact that the classical criteria of the BCC, such as glassy surface with telangiectasia, as well as the pearl cord-like rim, can no longer be recognized. This may cause problems in the differential diagnosis between malignant melanoma and other pigmented changes, such as nevi, seborrheic warts, etc.

3. Superficial Basal Cell Carcinoma

Superficial basal cell carcinoma is also called trunk skin basal cell carcinoma because of its preferred location on the trunk. Because it clinically appears to occur multiply at one site, it is also often referred to as multicentric BCC.

Due to the fact that superficial BCCs differ from the other subtypes in both clinical and biologic behaviour, they are often misdiagnosed and confused with inflammatory dermatoses.

Clinically, they are sharply but irregularly circumscribed, reddish-brown, very flat changes that may resemble eczema on the skin. They may cause fine scaling, even itching, but may also crust over and show the typical pearly cord-like nodules in the marginal areas. They can become very large, but even very large tumours do not ulcerate.

4. Sclerodermiform Basal Cell Carcinoma

Sclerodermiform BCC is often overlooked because of its clinically discrete findings. This tumour is often recognizable only as a scar-like change that is slightly riddled with telangiectasias and feels gross on palpation. With further growth, it occasionally resembles a slightly raised scar. The particular problem of sclerodermiform BCC is that the often very delicate but extremely richly branched tumour cell clusters extend well beyond the border of the clinically recognizable central plaque, which is often somewhat raised and scarred with a yellowish appearance. This growth pattern is of particular importance in later therapy, as sclerodermiform BMCs tend to infiltrate even deeper anatomical structures very rapidly.

Histopathological Classification of Basal Cell Carcinomas

(according to WHO 2006 histological classification of keratinocytic skin tumours [182])

Superficial BCC,
Nodular BCC (solid, adenoid, and cystic),
Micronodular BCC,
Infiltrative BCC (non-sclerosing, sclerosing),
Fibroepithelial BCC,
BCC with adnexal differentiation (follicular, apocrine, eccrine),
Basosquamous carcinoma,
Keratotic BCC.

Mixed forms of these types are frequently found [183]. Collision tumors with squamous cell carcinoma are also possible.

4.1.2.2 The Squamous Cell Carcinoma

More than 90% of SCC develops on chronically UV-exposed skin such as the face, ears, lower lip, and back of the hand. It has a precursor, actinic keratosis (see chapter 4.1.1).

The AK appears in most cases as a sharply limited, faint redness with a very fine, firmly adherent scaling (sandpaper phenomenon). Over the course of time, brownish yellow cornifications form which can be scraped off without any problems. These hyperkeratoses continue to form until they become firmly adherent, inducing a fine light pain when an attempt is made to scrape them off, and then change into a clinically clearly visible, firmly adherent, brownish yellow keratosis, the cornu cutaneum. At the base of this cornification, the SCC often forms as a nodule that rapidly increases in size as it progresses, may rupture in the center, and may then develop weeping tumours of varying sizes.

This invasive growth leads to metastasis after prolonged persistence, initially to regional lymph nodes and later to other organs.

Squamous cell carcinomas arise primarily on chronically UV-damaged skin, but may also develop on X-ray-damaged skin. The chemical carcinogens arsenic and tar lead to squamous cell carcinoma, as do human papillomaviruses (HPV) 16 and 18.

Histopathological Classification of Squamous Cell Carcinoma

(according to WHO 2006 histological classification of keratinocytic skin tumours [182])

Acantholytic SCC,
Spindle cell SCC,
Verrucous SCC,
Pseudovascular SCC,
Adenosquamous SCC,
M. Bowen.

TNM classification of carcinomas of the skin (PEK and BZK) according to UICC (2017) (excluding eyelid, head and neck, penis, vulva, and perianal region) ([184]).

Classification applies only to carcinomas, excluding Merkel cell carcinomas. Histologic diagnostic confirmation and subdivision of cases by histologic type are required.

Procedures for determining T, N, and M categories are:

T categories: Clinical examination
N categories: Clinical examination and imaging techniques
M categories: Clinical examination and imaging procedures

Table 1: T category of skin cancer

T category of skin cancer (primary tumor)
TX	Primary tumour cannot be assessed
T0	No evidence of primary tumour
Tis	Carcinoma in situ
T1	Tumour 2cm or less in greatest extension
T2	Tumour > 2cm, but ≤ 4cm, in largest extension
T3	Tumour > 4cm in greatest extension or superficial bone invasion or perineural invasion or deep invasion*
T4a	Tumour with macroscopic bone invasion/ bone marrow invasion
T4b	Tumour with invasion of the axial skeleton including foramina and/or involvement of the vertebral foramen up to the epidural space
* A "deep invasion" is defined as invasion beyond the subcutaneous fat or >6mm (measured from the stratum granulosum of the adjacent epidermis to the base of the tumor). Perineural invasion as a criterion for T3 is defined as clinical or radiological involvement of named nerves without involvement of the foramina or skull base. In the case of multiple simultaneous tumors, the tumor with the highest T category is classified and the number of delineable tumors is indicated in parentheses, e.g. T2 (5).

Table 2: N Category of skin cancer

N category of skin cancer (regional lymph nodes)
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastases
N1	Metastasis(s) in a regional lymph node, 3cm or less in greatest extent
N2	Metastasis(s) in one lymph node, >3cm but not >6cm at greatest extent or in multiple lymph nodes, none >6cm at greatest extent
N3	Metastasis(s) in a lymph node, >6cm in greatest extent
Note: The regional lymph nodes correspond to the respective localization of the primary tumor.

Table 3: M Category of skin cancer

M category of skin cancer (distant metastases)
M0	No distant metastases present
M1	Distant metastases present
Note: Bilateral or contralateral lymph node metastases in non-melanoma carcinomas and not located in the head and neck skin are classified as distant metastases.

Table 4: Clinical stages of skin cancer

Clinical stages	T category	N category	M category
Stage 0	Tis	N0	M0
Stage I	T1	N0	M0
Stage II	T2	N0	M0
Stage III	T3 T1, T2, T3	N0 N1	M0 M0
Stage IV	T1, T2, T3 T4 Any T	N2, N3 Any N Any N	M0 M0 M1

4.1.2.3 Malignant Melanoma (MM)

Malignant melanomas often appear as brownish to reddish-bluish, blackish, greyish-white, often asymmetrical skin changes. However, they can also be completely pigment-free. MM occurs in a wide variety of clinical manifestations and can occur in all areas of the human skin, the hairy scalp, the mucous membranes of the eye, mouth, genitals, and also under the toenails and fingernails. In addition, in all organs of ectodermal origin, such as the meninges, bile, etc.

The different forms, the frequent asymmetry (which, however, does not necessarily have to be present), the discolourations, and the secondary changes such as oozing and crusting underline the extraordinary variety of this tumour in the clinical picture. Malignant melanoma has no defined precursor. The clinical diagnosis also requires many years of experience because of the extraordinarily high number of possible differential diagnoses.

According to their growth pattern, four main clinical types are distinguished:

Lentigo Maligna Melanoma (LMM), which requires chronically UV-damaged skin as a prerequisite and for this reason also occurs in UV-damaged areas,
Superficial Spreading Melanoma (SSM),
Nodular Melanoma (NM), and
Acrolentiginous Melanoma (ALM).

Depending on its vertical tumor growth, MM leads very rapidly to metastasis and is responsible for the highest mortality rate in skin cancer.

Histopathological Classification of Malignant Melanoma
(according to WHO 2006 histological classification of melanocytic tumours [182])

Superficial spreading melanoma,
Nodular melanoma,
Lentigo-maligna melanoma,
Acrolentiginous melanoma,
Desmoplastic melanoma,
Malignant blue nevus,
Melanoma on large congenital nevus,
Nevoid melanoma,
Spitzoid melanoma,
Persistent melanoma.

For malignant melanoma, a TNM classification and staging was proposed by the AJCC in 2018 (see the four tables below), which now underlies the classification of malignant melanoma.

Table 5: T category of primary tumor in malignant melanoma (2018).

T-stage	Tumor thickness
T1	≤ 1.00 mm	a: ≤ 0.80 mm + Ø ulceration b: > 0.80 mm or ulceration
T2	1,01-2,00	a: without ulceration b: with ulceration
T3	2,01-4,00	a: without ulceration b: with ulceration
T4	> 4.00 mm	a: without ulceration b: with ulceration

Table 6: N category of regional lymph nodes in malignant melanoma (2018).

N category

Number of metastatically affected lymph nodes (LK)

Extent of lymph node metastasis

1 LK

intralymphatic without LK

a: only microscopic metastasis(s) (clinically occult) +

b: only macroscopic metastasis(s) (clinically detectable)

c: satellite/intransit without LK

2-3 LK

intralymphatic with LK

a: only microscopic nodal metastasis(es) +

b: only macroscopic nodal metastasis(s)

c: satellite(s) or in-transit metastasis(s) without regional lymph node metastases

> 3 LK

LK packages ("matted")

Intransit with > 1 lymph node

Table 7: M category of distant metastases in malignant melanoma (2018).

M category	Type of distant metastasis	LDH
M1a	Metastases in skin, subcutis or lymph nodes beyond regional lymph nodes	Normal
M1b	Lung metastasis(s)	Normal
M1c	distant metastasis(s) of other localization or distant metastasis(s) of any site with elevated serum levels of lactate dehydrogenase (LDH)	Normal Elevated
The M1a category also includes the iliac lymph nodes. Source: WHO Classifications of Tumours, Pathology & Genetics, Skin Tumours

Table 8: Staging of malignant melanoma (2018).

Stage	Primary tumor(pT)	Regional lymph node metastases (N)	Distant metastases (M)
0	In situ tumours	None	None
IA	< 0.8 mm, no ulceration	None	None
IB	T1b: > 0.8 mm to 1.0 mm or all ≤ 1.0 mm + ulceration T2b: 1.01–2.0 mm, no ulceration	None None	None None
IIA	1.01–2.0 mm with ulceration 2.01–4.0 mm, no ulceration	None None	None None
IIB	2.01–4.0 mm with ulceration > 4.0 mm, no ulceration	None None	None None
IIC	> 4.0 mm with ulceration	None	None

4.2 Incidence, Prevalence, and Mortality of Skin Cancer

Revision: A. Waldmann, A. Korthals, I.-M. Hübner

In principle, population-related statements on the frequency and burden of disease can be made on the basis of data from epidemiological cancer registries. A nationwide registration of all new cancer cases has been realized in Germany with a reporting obligation of the treating physicians and the pathological institutions, whereby there are federal states with a long tradition of registration (such as Hamburg, new federal states, Saarland) and those in which the cancer registries have only recently started to collect data nationwide (e.g. Baden-Württemberg (since 2011), Hesse (since 2007)). International experience shows that it takes several years before cancer registration is established and full data can be expected. It follows that regional differences exist in the informative value of cancer registry data. This applies to both national and internationally available data. The differences are due, among other things, to the different reporting regulations (compulsory reporting, right to report, nationwide coverage, coverage of model regions, coverage of primary tumours with/without coverage of metastases and recurrences), the different completeness of the reports, and, not least, the quality of the reports (e.g. proportion of missing values for information on tumour size).

For the epidemiological cancer registries in Germany, and also for most international cancer registries, it can be stated that the recording of MM can currently be classified as good (systematic, high completeness), while the recording of non-melanocytic skin tumours (BCC, SCC) is not systematic in all federal states. Since the epidemiological cancer registries are incidence registries, only newly occurring cases are registered. With the introduction of nationwide clinical cancer registries according to § 65c SGB V, progression events such as metastases and recurrences are now also registered, although exceptions apply to non-melanocytic skin cancers (for example, they are excluded from the flat rate payment and are therefore not registered). If the burden of disease is to be estimated via cancer registries, the problem arises in the case of the non-melanocytic skin cancers in which multiple metachromic tumours of the same histology or recurrences frequently occur (multiple BCC occur in about 15% of the patients, multiple SCC in about 10%; [185]), but are not registered. However, these represent a high burden for the affected patients and the health care system.

4.2 · Consensus-based Recommendation · new 2020

In the clinical cancer registries, basal cell carcinomas (including multiple basal cell carcinomas occurring in one person) and squamous cell carcinomas should be included in the registration.

If this is not done, the goal of clinical cancer registration, i.e. to improve the care of people with cancer in Germany and (as far as possible) to record and evaluate all tumour diseases in Germany, cannot be fulfilled. It is also possible to initially limit this to model regions.

4.2.1 Malignant Melanoma

In Germany, population-based cancer registration is carried out at the level of the federal states. Based on these data, estimates of the incidence in Germany are published by the Society for Epidemiological Cancer Registries (GEKID) and the Centre for Cancer Registry Data (ZfKD) at the Robert Koch Institute (RKI). Currently, it is estimated that approximately 21,200 persons, of whom 51.4% are male, develop invasive MM in Germany each year (Table Current figures). MM is the fifth most common new cancer in men and women. The incidence of disease increases with age. Young women are more likely to develop MM than young men. This ratio and the rather high incidence at a young age compared to other tumour diseases are unusual. However, from the age of 60 years, the ratio reverses and the incidence in men increases to twice the incidence in women. The time course shows an almost continuous increase since the 1970s, a fivefold increase in incidence from about 5 to about 25 cases per 100,000 population. With the introduction of SCS in 2008, the incidence continues to rise, and more markedly than before [186].

Survival after MM has improved markedly over the past 20 years and is high compared with other cancers [187]; [188]; [189]. Currently, the five-year relative survival of all melanoma patients is estimated to be greater than 90% (Current Key Figures table) [187]; [186]; [189]. In contrast to the rising incidence, the age-standardized mortality rate has remained at a constantly low level over the last 30 years. Currently, about 3,070 people die of melanoma in Germany each year, of which 58.8% are men (table Current key figures) [190]. One of the main reasons for the constantly low mortality despite increasing incidence is probably the improved early detection of prognostically favorable melanomas.

In 2013, it is estimated that there were approximately 96,600 individuals living in Germany who had developed MM in the previous five years. The 10-year prevalence is 162,700 persons, which is 1.7 times higher [188]; [189]. Due to the increasing incidence and comparatively constant mortality, it can be assumed that the 5-year and 10-year prevalence will increase in the future.

In an international comparison, Germany, together with the other European countries, the USA, and Australia, is one of the countries with the highest incidence of melanoma ([191]). Within Europe, Germany is in the top third of melanoma incidence and prevalence (see figure Age-standardized melanoma incidence in Europe) [192]; International Agency for Research on Cancer). The mortality rate in Germany, on the other hand, is lower than in most other European countries (see figure Age-standardized melanoma mortality in Europe) and lower than in the USA and Australia/New Zealand (International Agency for Research on Cancer).

Table 9: Current key figures for malignant melanoma in Germany

Key figures	Men	Women
Incidence 2014*
New cases	10.910	10.310
Age-standardised rate (European standard) per 100,000	19,5	18,6
Mortality 2014**
Deaths	1.804	1.270
Age-standardized rate (European standard) per 100,000	2,9	1,7
Relative 5-year survival*
Total	91 %	94 %
Relative 5-year survival stage-specific (2007-2013)***
pT1	103,2 %	102,5 %
pT2	92,8 %	96,0 %
pT3	77,3 %	82,4 %
pT4	49,6 %	58,7 %
Prevalence*
5 years	47.600	49.000
10 years	78.200	84.500
Data sources: * [186] [189] [190] * [193]

While an increase in incidence has been observed in Germany over the last 30 years, various studies have been published in journals over the last 15 years describing either a slight decrease or stabilization in incidence. In a global analysis of melanoma incidence, Erdmann et al. 2012 showed that incidence continues to rise in most European countries, while in Australia, New Zealand, the USA, and Canada, as well as Israel and Norway, there are signs of stabilisation. This can be explained primarily by falling or stable incidence in the 25-44 age group [194].

The gender-specific differences and the incidence and mortality trends over time in Germany largely reflect differences and trends found in other industrialised countries. A special feature is evident for Australia/New Zealand, where MM is the fourth most common new cancer and the ninth most common cause of cancer-related death [195]. Incidence has been increasing in recent years (males: increase by a factor of 2.3 from 28 cases (1982) to 63 cases per 100,000 population (2014; age standardised to Australian population); females: increase by a factor of 1.6 from 26 to 42 cases per 100,000) [195] with a levelling off of the increase in the last decade). For melanoma mortality, a comparatively small upward trend has been observed over the last 30 years [195]. Age differentiated shows a slight decrease in mortality for persons < 60 years, stable rates for persons in the age group 55-79 years and an increase in melanoma mortality for persons 80 years and older until 2002 [196]; [197].

Age-specific melanoma incidence rates in 2014 differentiated by sex (Center for Cancer Registry Data at the Robert Koch Institute, 2019).

Time course of incidence rates in Saarland and Germany (smoothed; 3-years-floating means; old European standard; SL=Saarland, GER=Germany) (Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V., 2019; Saarland; Zentrum für Krebsregisterdaten am Robert Koch-Institut, 2019).

Age-standardized melanoma incidence in Europe in 2018 (world standard).

Age-standardized melanoma mortality in Europe in 2018 (world standard) (International Agency for Research on Cancer, 2010b).

Need for Research

A monitoring of the stage-specific incidences as well as the MM-mortality in Germany (and worldwide) could provide information on whether the early detection measure of the SCS by means of whole-body inspection in Germany leads to an increase of early stages and a decrease of late stages of melanoma and subsequently to a decrease of MM-mortality. To achieve this, it is necessary to reduce the currently high proportion of missing tumour stages among the cancer registry reports and, if possible, to register information on the tumour stage for all melanomas. Monitoring of melanoma mortality five to ten years after the introduction of the SCS could provide information on whether early detection will lead to a decrease in mortality. In a first analysis, Katalinic et al. were able to show that there was no decrease in mortality for Germany until 2013 (five years after the start of skin cancer screening), whereas such a decrease had been shown in the pilot region for skin cancer screening [198]; [199]. This difference is attributed to the different intensity or complexity of the screening program implemented [198].

The evaluation report on the SCS according to the cancer screening guideline of the G-BA from 2015 contains results on the number of participating physicians, the utilization by those entitled to benefits, as well as the incidence. However, it also impressively shows that questions regarding the benefit assessment of screening cannot be answered with the routine data [200].

It remains to be stated that the monitoring of mortality, incidence, and also of participation rates should be carried out regularly and that accompanying research seems to be absolutely necessary in order to be able to reliably assess the effectiveness of the screening and, if necessary, to make suggestions for optimising the screening programme.

Accompanying research has only been carried out in isolated cases so far. One example of this is the project to evaluate the nationwide SCS, which will be launched in 2019 and will use routine data from 2008 to 2016 to investigate, among other things, which group of people benefits most from the screening examinations [201].

4.2.2 Non-Melanocytic Skin Cancer (NMSC)

With about 137,700 registered new cases per year, non-melanocytic skin cancer occurs 6.5 times more frequently in Germany than malignant melanoma [186]; [189]. However, the actual number is probably significantly higher due to registration deficits [202]. Approximately 53.1% of all patients are men (table Current key figures for non-melanocytic skin tumours). In men, the level of estimated new cases is slightly higher than the incidence of prostate cancer (93/100,000 European Age Standardised Rate (EASR); 2014) [189], which is the most common tumour in men. The estimated incidence of NMSC in women is between that of the most common tumour (breast cancer; 114.6/100,000; EASR, 2014) and that of the tumour commonly cited as the second most common (colorectal cancer; 35.7/100,000; EASR; 2009) [189]. The incidence of the disease increases with age. In men aged 60 years or older, the incidence increases much more than in women. In the age group 85 years or older, the incidence in men is almost twice as high as in women (Figure Age-specific incidence rates of non-melanocytic skin cancer) [186]. Over time, the incidence has quadrupled (men) to quintupled (women) over the past 30 years. In contrast, mortality has remained at a constantly very low level over the last 30 years (Saarland; [189]). Currently, about 780 people die of NMSC in Germany each year; of these, 55.3% are men (Table Current key figures for non-melanocytic skin tumours) [190].

Table 10: Current key figures for non-melanocytic skin tumours in Germany

Key figures	Men	Women
Incidence 2014
New cases	73.163	64.357
Age-standardized rate (European standard) per 100,000	113,2	85,1*
Mortality 2014**
Deaths	435	351
Age-standardized rate (European standard) per 100,000	0,7	0,3
Data sources: * (Society of Epidemiological Cancer Registries in Germany e.V., 2014.) ** (Federal Statistical Office, 2012)

Age-specific incidence rates of non-melanocytic skin cancer in 2014 differentiated by sex (Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V., 2019).

In contrast to MM, the data situation for the non-melanocytic skin cancers is still to be regarded as incomplete. International comparative data on incidence and mortality are often available from studies or model regions and only rarely from epidemiological cancer registries. For New Hampshire, USA, an increase in the incidence of BCC from 1979/1980 to 1993/1994 of 235% in men and 350% in women and an increase in the incidence of SCC of 82% could be observed [185], also for younger Americans [Christenson, L. J. et al. 2005]. Canadian cancer registry data [203] as well as comparative data from Scotland [204] and Great Britain [205] also confirm the gender-specific differences and temporal incidence trends reported for Germany.

Need for Research

Compared to the data situation for melanoma, the data situation for the non-melanocytic skin cancers can be described as poor. In order to be able to reliably describe epidemiological trends in the future, a more stringent reporting of all incident non-melanocytic skin cancer types to the population-based cancer registries is required.

4.2.3 Effects of Skin Cancer Screening on Incidence and Mortality

Based on the data from the epidemiological cancer registries, temporal trends of new cancer cases can be described at the population level. A valid description of cancer incidence requires a high completeness of the registry, i.e. (as far as possible) all new cases of cancer are reported to the registry, as well as (as far as possible) complete information on tumour description such as histology, morphology and tumour spread. In the context of national health reporting, mostly only invasive new cases are described, whereas in the area-wide cancer registries according to § 65c SGB V, information on in situ tumours is also available. Thus, these cancer registries are able to describe not only the incidence of invasive but also that of in situ tumours.

In the period from 7/2003 to 6/2004, the SCREEN project was carried out in Schleswig-Holstein [206], hich was a model project for the skin cancer screening introduced throughout Germany in 2008. The effects of a SCS on the population-based incidence were investigated on the basis of data from the epidemiological cancer register of Schleswig-Holstein and Saarland (comparative region). Saarland served as the comparator region because no population-based SCS was conducted in this state during the SCREEN period.

The table "Age-standardized incidence rates of malignant melanoma" shows that in Schleswig-Holstein both the incidence of in situ and the incidence of invasive melanoma were significantly higher during the SCREEN period than in the period before the model project (1998-2000), whereas the incidence in Saarland increased only slightly over time. After the end of the model project (2005-2007), Schleswig-Holstein showed a slight decrease in the incidence of in situ melanoma and a significant decrease in the incidence of invasive melanoma, with only minor changes in Saarland during the same period [207].

Table 11: Age-standardized incidence rates of malignant melanoma

	Schleswig-Holstein (SH)			Saarland (SL)		p-value (comparison SH and SL)
	Women		Men	Women	Men	Women	Men
	Incidence rate, age standardized (European standard)
Before SCREEN Project (01/1998-12/2000)
MM (in situ) (ICD-10 D03)	5.7 (5.0; 6.4)		3.7 (3.2; 4.3)	2.4 (1.8; 3.2)	1.0 (0.6; 1.6)	<0.001	<0.001
MM (invasive) (ICD-10 C43)	16.8 (15.7; 18.0)		15.2 (14.1; 16.4)	9.2 (7.8; 10.6)	10.7 (9.3; 12.4)	<0.001	<0.001
SCREEN Project (07/2003-06/2004)
MM (in situ) (ICD-10 D03)	13.3 (11.5; 15.2)		7.7 (6.4; 9.2)	3.5 (2.1; 5.3)	3.1 (1.8; 4.8)	<0.001	<0.001
MM (invasive) (ICD-10 C43)	25.7 (23.2; 28.3)		19.2 (17.2; 21.5)	10.9 (8.4; 13.8)	11.8 (9.2; 14.9)	<0.001	0.003
After SCREEN Project before HKFP2 (01/2005-12/2007)
MM (in situ) (ICD-10 D03)	10.4 (9.5; 11.4)		6.6 (5.9; 7.3)	4.0 (3.1; 5.0)	3.6 (2.8; 4.6)	<0.001	<0.001
MM (invasive) (ICD-10 C43)	15.1 (14.0; 16.2)		15.1 (14.1; 16.3)	12.2 (10.6; 13.9)	11.5 (10.0; 13.1)	0.044	0.002
	Absolute differences in incidence rates, age-standardised (European standard) [observed incidence – preceding incidence as described above].
SCREEN Project
MM (in situ) (ICD-10 D03)		7.6 (5.6; 9.6)	4.0 (2.5; 5.5)	1.1 (-0.5; 2.7)	2.1 (0.6; 3.6)	<0.001	0.164
MM (invasive) (ICD-10 C43)		8.9 (6.1; 11.7)	4.0 (1.6; 6.4)	1.7 (-1.3; 4.7)	1.1 (-2.0; 4.2)	0.005	0.373
After SCREEN/Before HKFP
MM (in situ) (ICD-10 D03)		-2.9 (-5.0; -0.8)	-1.1 (-2.7; 0.5)	0.5 (-1.2; 2.2)	0.5 (-1.2; 2.2)	0.019	0.264
MM (invasive) (ICD-10 C43)		-10.6 (-13.3; -7.9)	-4.1 (-6.5; -1.7)	1.3 (-1.8; 4.4)	-0.3 (-3.4; 2.8)	<0.001	0.252
¹ Poisson based 95% confidence interval. ² Skin cancer screening program

In the figure "Time course of incidence" and the figure "Time course of incidence for non-melanotic skin tumours," the data from Schleswig-Holstein are compared with the estimates for Germany. Here it becomes clear that especially for women in Schleswig-Holstein, changes in melanoma incidence can be described with the implemented screening measures (starting with the field phase of SCREEN 1999/2000, implementation of SCREEN 2003/2004 and implementation of population-based screening from 2008).

Time course of incidence (EASR; age standardized according to European standard) for malignant melanoma in Schleswig-Holstein (dashed line) and Germany (solid line; each floating means) (Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V., 2019).

Time course of incidence (EASR; age standardized according to European standard) for non-melanotic skin tumors in Schleswig-Holstein (dashed line) and Germany (solid line; each floating means) (Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V., 2019).

Brunssen et al. [193] summarized in a systematic review the influence of screening measures on skin cancer-related incidence and mortality. A total of 15 international articles (from the USA, Australia, Belgium, France, and Germany) could be included by the systematic searches. The included studies vary considerably in their population due to different study designs (cohort studies, ecological studies, survey, case-control studies). As a result, the studies show an increase in incidence (in situ and invasive) after the start of screening (for melanoma: melanoma (in situ) from +1.6 per 100,000 (WASR) to +24.0 per 100,000 person-years (crude rate); for non-melanocytic skin cancer: from +16.5 per 100,000 (EASR) to +50.2 per 100,000 (EASR) and a decrease in melanoma incidence (invasive) as soon as screening is suspended again, to a level below the original level. There is also a stage shift with an increase in diagnoses to earlier stages and thinner melanomas (+0.3 per 100,000 (EARS) to +9.0 per 100,00 person-years (crude rate) and a decrease in thicker melanomas (e.g. melanoma >1.5mm = -9.8 per 100,00 person-years (crude rate)). Mortality analyses provide SCREEN (see above) with recorded melanoma mortality varying from -0.4 per 100,000 (crude rate) in persons up to 50 years of age to -3.7 per 100,000 (crude rate) in women over 70 years of age. Two other studies also reported fewer deaths than expected. However, the evidence of these results is limited due to the study design (mostly ecological studies).

Hübner et al. [208] also conducted an analysis of mortality rates in Germany for the years 1998 to 2017. As can be seen in Figure Age-Standardized Mortality, skin cancer-related mortality can be attributed primarily to melanoma and is significantly higher in men than in women.

Age-standardized mortality (per 100,000 women or men) of melanocytic (ICD-10 C43) and nonmelanocytic (ICD-10 C44) skin cancer by sex (Hübner et al., 2019, p. 989)

However, with regard to the question of the screening-induced reduction in mortality, the reduction in mortality observed since 2013 (annual change in age-standardized mortality rate –2.1% (95% CI: –4.0 to –0.2%) vs. +3.4% (95% CI: 1.3 to 5.4%) before 2013) and the discussion of possible causes of this reduction should be noted in particular. Thus, it is suspected by the authors and plausibilized with the help of trend analyses that both new therapies and skin cancer screening may have influenced this change (see figure below).

Age-standardized mortality (per 100,000 population) of melanocytic (ICD-10 C43) and non-melanocytic (ICD-10 C44) skin cancer for both sexes. Solid lines represent modeled trends in each case. Circles denote annual values in which these change. Vertical lines mark the onset of changes in care that should have an impact on mortality (Hübner et al., 2019, p. 919)

4.3 Risk Factors of Skin Cancer

Revision: B. Volkmer, R. Greinert

4.3.1 The Constitutional Risk Factors (Phenotypic or Genotypic) of Skin Cancer

With regard to the risk factors for NMSC and for MM, a distinction must be made between constitutional, acquired, and exposure risk factors. Purely constitutional risk factors include skin type in the case of non-melanocytic skin cancers (BCC, SCC). In MM, it is the skin type and large congenital nevi.

4.3 · Consensus-based Statement · modified 2020

Constitutional risk factors:
Non-melanocytic skin cancer (NMSC).
An important constitutional risk factor for non-melanocytic skin cancer (basal cell carcinoma and squamous cell carcinoma) is:

skin type.

Other risk factors (see 4.3.2, 4.3.4) can be acquired during the course of life.

Change note

3.2 Consensus-based statement Constitutional risk factors: Non-melanocytic skin cancer (NMSC) An important constitutional risk factor for NMSC (BZK and PEK) is skin type. All other risk factors may be acquired during life.

4.4 · Consensus-based Statement · checked 2020

Constitutional risk factors:

Malignant melanoma (MM)

The class of constitutional risk factors for MM includes

a) skin type and

b) large congenital naevus.

Other risk factors (see sections 4.3.2, 4.3.4, and 5.1) can be acquired during the course of life.

Non-Melanocytic Skin Cancer (NMSC)

From a large number of epidemiological, medical, and experimental studies, the most important constitutional risk factor for NMSCs can be identified as skin type. The risk of developing NMSC is higher for fair skin types (I, II) than for skin types III and IV (for skin types, see table Skin Types). Gallagher and coworkers report crude odds ratios (OR) of 5.1 (95% CI: 1.4-11.3) and 5.3 (95% CI: 1.7-10.6) for the occurrence of NMSC and ORs of 1.4 (95% CI: 0.5-3.0) and 2.2 (95% CI: 0.7-3.8) for the occurrence of PEC in two large studies [209]; [210] comparing skin types I and II with skin type IV.

Malignant Melanoma (MM)

a.) Skin Type

Skin type is an important constitutional risk factor for malignant melanoma. It has been shown that individuals with skin type I, II, or III are at significantly higher risk for MM than those who experience sunburn extremely rarely and already have very dark skin (skin type IV). Relative risks (RR) for skin type I, II and III (vs. skin type IV) have been reported in a meta-analysis with a RR of 2.09 (95% CI: 1.67-2.58), of 1.87 (95% CI: 1.43-2.36) and of 1.77 (95% CI: 1.23-2.56) [211].

b.) Congenital Nevi

According to the current international classification [212]

based on an expert consensus (EC), congenital, i.e. melanocytic nevi (CMN), already present at birth with a diameter of more than 20 cm up to 40 cm are designated as “large congenital nevi,” nevi above 40 cm as “giant nevi.” This classification is based on the maximum diameter of the nevus expected for adulthood.

Large congenital melanocytic nevi undoubtedly have a risk of malignant degeneration, which is particularly important in very large congenital nevi. Especially so-called “giant nevi" (> 40 cm in diameter) have an increased risk for the development of MM [213]; [214]; [215]. However, such nevi are extremely rare [216].

The risk of degeneration of congenital nevi correlates with size. On BMN up to 20 cm in diameter the development of melanoma has been described [217]

; however, the risk of degeneration is epidemiologically not demonstrably increased compared to “acquired,” non-congenital nevi. Especially until puberty, melanoma development on such BMN seems to be extremely rare. “Small" (up to 1.5 cm in diameter) and “medium-sized" CMN (1.5 to 20 cm) should therefore (like all nevi) be examined as part of the SCS and any changes recorded.

In contrast, “giant CMN,” which often show numerous so-called “satellite nevi" and in some cases a central nervous pigment cell proliferation, are a pathogenetically distinct entity based on NRAS mutations of the embryonic neural crest [218]. These BMN are associated with a significantly higher risk of developing cutaneous or even central nervous melanoma, starting in early childhood [213]. Typically, cutaneous melanomas arising on these nevi are a deep-seated, dermal, or subcutaneous nodule that can be palpated. These melanomas should be differentiated molecularly from so-called benign proliferative nodules [219].

Table 12: Skin types (Law on Protection against Non-Ionizing Radiation) ("Ordinance on Protection against Harmful Effects of Artificial Ultraviolet Radiation (UV Protection Ordinance - UVSV)," 2011).

Skin type	I	II	III	IV	V	VI
Description
Natural skin colour:	very fair	light	light to light brown	light brown, olive	dark brown	dark brown to black
Freckles/sunburn spots (lentigines):	very frequent	frequently	rarely	none	none	none
Natural hair colour:	reddish to reddish-blond	blond to brown	dark-blond to brown	dark-brown	dark-brown to black	black
Eye color:	blue, grey	blue, green, grey, brown	grey, brown	brown to dark brown	dark-brown	dark-brown
Reaction to the sun
Sunburn:	always and painful	almost always, painful	rarely to moderately	rarely	very rarely	extremely rare
Browning:	none	hardly to moderately	progressive	fast and deep	none	none
Erythema effective threshold irradiation:	200 Jm-2	250 Jm-2	350 Jm-2	450 Jm-2	800 Jm-2	> 1 000 Jm-2

4.3.2 The Acquired Risk Factors of Skin Cancer

4.5 · Consensus-based Statement · checked 2020

Acquired risk factors:
Non-melanocytic skin cancer (NMSC).

The main acquired risk factors for non-melanocytic skin cancer (basal cell carcinoma and squamous cell carcinoma) are:

a) actinic keratosis,

b) previous history of NMSC,

c) immunosuppression,

d) chronic radiation keratoses.

4.6 · Consensus-based Statement · checked 2020

Acquired risk factors:
Malignant melanoma (MM)

The main acquired risk factors for malignant melanoma are:

a) previous history of melanoma,

b) family history of melanoma,

c) number of acquired naevi,

d) clinically atypical naevi.

The probability of developing squamous cell carcinoma correlates with the UV dose to which a person has been exposed during his lifetime (cumulative dose).
For basal cell carcinoma, both cumulative UV exposure and intermittent UV exposure and sunburns seem to be of importance.
For malignant melanoma, intermittent UV exposures and sunburns (at any age) are of major importance.

Age-stratified analysis of epidemiological data for skin cancer (BCC, SCC and MM) (see Section 4.2) show that incidence increases with age. In the broadest sense, therefore, ageing can also be regarded as an acquired risk factor.

Non-Melanocytic Skin Cancer (NMSC)

For BCC and SCC, risk factors that may be acquired through UV exposure or other exposures during life include:
a.) actinic keratosis,
b.) self-history non-melanocytic skin cancer,
c.) immunosuppression,
d.) x-ray combination damage.

a.) Actinic Keratosis (AK)

AK represents a precursor of SCC [74]. In the literature, conversion probabilities of AKs into invasive SCC are found in a range from < 1% up to 16% [75]; [76]; [77]. In individual cases, even up to 70% have been reported [79]. The presence of multiple AKs over a 10-year period has been reported to have a lifetime risk of developing SCC in the range of 6-10% [65]. AK thus represents an important risk factor for NMSC, particularly SCC.

b.) Non-Melanocytic Skin Cancer (NMSC) in Self-History

Epidemiological studies show that individuals with NMSC or SCC in their own history have a significantly higher risk of developing non-melanocytic skin cancer again in later life [220]. The risk of developing a second SCC within five years of treatment of the first SCC is 30% [221]. TThe corresponding three-year risk is 18%, which is a 10-fold increased likelihood compared with the occurrence of a primary SCC in the general population. The three-year risk of developing a secondary BCC if the primary tumour was also a BCC is as high as 44%, which also corresponds to a 10-fold increased probability compared to the occurrence of primary BCC in the population [220]. The risk of developing a BCC in patients with a past SCC is approximately the same as that in individuals with a past BCC (approximately 40%). The risk of developing a SCC [222] as a second tumour if the initial tumour was a BCC is comparatively low (6%) [220]. Given these statistics, follow-up strategies (e.g. continuous risk group screening) are necessary for patients with SCC and BCC, since the presence of non-melanocytic tumours in the history represents a significant risk factor for the development of further non-melanocytic tumours.

c.) Immunosuppression

Organ transplant patients carry a significantly increased risk for the occurrence of non-melanocytic skin cancers, which is due to the use of immunosuppressive drugs [223]; [224]; [225]; [226]; [227]; [228]. SCC develops up to 65 times more frequently in transplant patients compared to controls [229]. Patients after heart transplantation seem to have the highest risk of developing SCC, followed by patients after kidney and liver transplantation [230]; [231]; [232]; [226]; [233]; [234]. The ratio of SCC to BCC after previous heart transplantation is approximately 3:1 to 4:1 in an Australian study, representing an inverse ratio to the incidence of SCC and BCC in the general population [235]. Compared to the normal population, SCC occurring in organ transplant recipients are more aggressive, metastasize more frequently, and result in approximately a tenfold increase in mortality (0.4-0.5/100,00 vs. 4.9/100,000) [Madeleine, M.M. et al. 2017].

Individuals with non-drug induced immunosuppression may also be at higher risk for non-melanocytic skin tumours. In general, HIV-infected individuals show a slightly increased incidence for SCC at younger ages compared to non-immunosuppressed individuals [236]. HIV-infected individuals with fair skin type and high UV exposure during leisure or gainful employment performed outdoors show an increased risk for SCC and BCC [237]; [238]; [239]. In addition, HIV patients appear to develop aggressive, fast-growing SCC associated with high risk of local recurrence and metastasis [236].

d.) X-Ray Combination Damage

Patients who have undergone radiation therapy with ionizing radiation (e.g. X-rays) are at risk of developing chronic radiation keratosis. This is a keratotic skin lesion that has been detected in radiotherapy patients or clinical staff who have been exposed to ionising radiation or worked with radioactive material for many years [240]. The X-ray combination damage is of importance given that BCC or SCC is more likely to develop. However, further findings show that exposure to therapeutic (ionizing) radiation is more likely to contribute to the formation of BCC and probably not to that of SCC [241]. The risk of SCC on the grounds of X-ray combination damage increases with UV exposure of individuals who easily suffer sunburn (skin type I, II) [242].

Malignant Melanoma (MM)

Many of the risk factors for malignant melanoma mentioned in this chapter were examined in studies used for three systematic reviews including meta-analyses [243]; [244]; [211]. These included studies published between 1966 and 2002 on risk factors for MM. After analysis of approximately 600 original papers using various inclusion criteria (only case-control, cohort, or cross-sectional studies were included; ecological studies, case studies, reviews, and editorials were excluded), pooled relative risks could be calculated for the number of acquired and atypical nevi, family history, skin type, freckles, skin colour, eye colour, and hair colour (Table Relative risks for malignant melanoma).

For MM, risk factors that may be acquired through UV exposure or other exposures during life include:

(a) history of MM
(b) family history of MM
(c) number of acquired nevi
(d) clinically atypical pigmented moles.

History of MM

The relative risk for a second melanoma after a MM in one's own history is high and is given as 8.5 [245]. This is approximately a factor of 4 higher than the relative risk of developing MM in the presence of MM in a 1st degree relative (RR = 2.2) [246]; [247]. Further studies show that approximately 3% of patients with MM are at high risk of developing MM again as a second primary tumor [248]; [249]. Standardized incidence ratios (compared to individuals who did not have a primary tumor) of 2-10 are reported [250]; [251]. Hübner et al. [252] give the risk of second melanoma in MM in the history based on data collected in the SCREEN project in Schleswig-Holstein with an odds ratio of 5.3 (95% CI: 3.6-7.6).

MM in Family History

Number of Acquired Nevi

A large number of studies demonstrate that the number of benign acquired nevi (nevus cell nevi, NCN) should be considered the quantitatively significant risk factor for melanoma development [255]; [256]; [257]; [258], [259]; [260]; [261]; [262]; [263]; [264]; [265]; [266].

Risk estimates reported in these studies range from 1.3-30. Twin studies show that nevus number is genetically controlled [267]; [268] and that it depends on constitutive factors such as skin type, hair color, and tendency to freckle [269]; [270]. A clear association has been demonstrated between severe sunburns (intermittent UV exposure) in childhood and the number of acquired benign nevi [123]; [271]; [258], [259]; [272]; [273]; [274]. Recent studies show that the predisposition to UV-induced formation of melanocytic nevi is particularly important in early childhood (0-6 years) [275] and, in the case of certain genetic predisposition, can already be caused by sub-erythemal UV exposure [276].

The listed studies prove the close connection between UV exposure and the development of melanocytic nevi, which are regarded as a decisive risk factor for the development of MM.

Clinically Atypical Pigmented Moles (Nevi)

Clinically atypical (dysplastic) pigmentary moles (nevus cell nevi) can occur all over the body. They are defined by their fuzzy and irregular borders and often variable colour components. The association between the presence of atypical nevi as risk markers for the development of MM has been widely documented.

In German-speaking countries, a multicenter study in 1994 described atypical melanocytic nevi as the second most important risk indicator for melanoma development next to the number of common melanocytic nevi. According to this study, the presence of few (1-4) atypical nevi is associated with a 1.6-fold increase in risk (compared to individuals without atypical nevi). When five or more atypical melanocytic nevi are detected, there is a significant 6-fold increase in risk for melanoma development. This finding has been interpreted to mean that at least five of these pigmentary moles must be present to identify at-risk individuals [258], [259]. However, Grob and coworkers [277] found that the presence of even one atypical pigmentary mole increased the relative risk for melanoma development three-fold. A relative risk of 3.8 was calculated for 1-5 atypical nevi, a value of 6.3 in the presence of six or more atypical nevi [278].

Approximately 40% of patients with sporadic MM (especially of the superficial spreading type) have atypical nevi, in contrast to 10-15% prevalence in the rest of the population [279].

Table 13: Relative risks for malignant melanoma (MM)

Risk factor	Reference	Relative risk (95 % CI)
Number of acquired nevi	101-120 vs. < 15	6,89 (4,63-10,25)
Number of atypical nevi	5 vs. 0	6,36 (3,80-10,33)
Melanoma in family history	yes vs. no	1,74 (1,41-2,14)
Skin type I	I vs. IV	2,09 (1,67-2,58)
Many freckles	high density vs. low density	2,10 (1,80-2,45)
Skin colour	light vs. dark	2,06 (1,68-2,52)
Eye colour	blue vs. dark	1,47 (2,80-2,55)
Hair colour	red vs. dark	2,02 (1,24-3,29)
Precancerous lesions and skin cancer lesions*		4,28 (2,8-6,55)
Actinic damage**		2,02 (1,24-3,29)
* actinic keratosis, PEK, BZK ** solar lentigines, elastosis
Source: [243]; [244]; [211]

4.3.3 UV Exposure as a Risk Factor

Data on the incidence of skin cancer as a function of latitude in Germany are not available. However, it will be difficult to prove clear causalities in the occurrence of any correlations between latitude-dependent UV exposure and the incidence of skin cancer, since the induction of cellular UV damage that can lead to skin cancer can also occur independently of geographical point of residence (e.g. during holidays, behaviour).

Furthermore, the form of the dose-response relationship for UV-induced skin cancers has not been sufficiently clarified. Only future research can reveal whether a threshold value or a linear dose-response relationship without a threshold value exists for the occurrence of certain skin diseases. This also applies to the possibility of quantitative information on the risk increase per dose (risk coefficients).

Non-Melanocytic Skin Cancers (NMSC)

In NMSC, UV exposure from natural or artificial radiation is the most important factor in disease development [122]; [95]; [280]. The fact that SCC and BCC usually develop on chronically UV-damaged skin or on body parts that are constantly exposed to light makes this connection clear. While the likelihood of developing SCC correlates with increasing lifetime acquired UV dose (cumulative dose) and occupational exposure [122]; [281]; [282], the UV dose-response relationship for BCC has not been fully elucidated. In addition to intermittent exposure [122]; [281], recent studies show that cumulative UV exposure, especially occupational, also plays a significant role [283]; [284]. Sunburns may also be responsible for BCC and possibly SCC [122].

Malignant Melanoma (MM)

Although the form of the dose-response relationship is largely unknown, as early as 1991 the "Consensus Development Conference on Sunlight, Ultraviolet Radiation, and the Skin" stated that the only established reason for the occurrence of melanoma--in the white population--was UV exposure from the sun [285]. The International Agency for Research on Cancer (IARC) also considered sun exposure to be the main cause of MM in humans as far back as 1992 (and again in 2012) [20].

However, other issues have arisen since then, mainly concerning the role of UV exposure patterns in the development of MM. In this regard, the literature distinguishes intermittent, chronic, and total UV sun exposure as well as sunburn. However, it is often difficult, especially retrospectively, to distinguish between these exposure patterns when reconstructing the "UV history" of individuals. Thus, it is difficult to separate interactions between sunburns, general sun exposure behaviour, individual tanning ability, and other phenotypic factors (eye colour, hair colour, skin type, etc.). UV radiation can act as an initiator, for example, through sunburn or intermittent exposure, but also as a promoter through subsequent chronic exposure [286]; [20]; [263]; [287]. Recent meta-analyses have shown that the number of acquired, UV-induced nevi is closely associated with melanoma risk and that their number is greater in individuals with high UV exposure [123]; [243]. Acquired UV-induced nevi thus occupy a central role in the causal chain between UV exposure and the development of MM

Gandini et al. [244] give in a meta-analysis (pooled) relative risks (RR) for different UV exposure patterns and their association with MM (Table Influence of UV exposure pattern).

Table 14: Influence of the UV exposure pattern on the relative risk for melanoma development

UV exposure pattern	RR for association with MM (95% CI)
Total (intermittent + chronic + sunburn)	1,34 (1,02-1,77)
Intermittent	1,61 (1,31-1,99)
Chronic	0,95 (0,87-1,04)
Sunburn	2,03 (1,73-2,37)
Source: [244]

Because the control groups in the individual studies were different, the control group with the lowest possible exposure was used to calculate the pooled RR in the meta-analysis.

Differences in the determination of risk estimators (e.g. odds ratio, rate ratio, risk ratio) between the analysed studies were ignored and each risk estimator for an association was transformed into logRR and associated variance according to a procedure from Greenland [288]. Four hundred thirty-eight studies (up to 2002) were found in the literature search, 87 of which appeared potentially suitable for meta-analysis and 57 eventually met the authors' inclusion criteria ([244]). The meta-analysis included 38,671 cases distributed among 32 studies in Europe, 19 in North America, two in Australia, and one each in New Zealand, Argentina, Brazil, and Israel. Fifty case-control studies, five cohort studies, and two embedded ("nested") case-control studies were included.

Despite the lack of well-designed cohort studies as well as systematically recorded UV exposures in case-control studies, and given the difficulties in retrospective surveys of UV exposure (recall bias) and in recruiting representative control groups, Gandini et al. [244] conclude in their meta-analysis that the vast majority of data support the importance of intermittent sun (UV) exposures for melanoma development. Particularly irregular and intense exposures (such as sunburns) significantly increase the risk of melanoma (Table Influence of UV exposure pattern).

However, the table "Influence of UV exposure pattern" also shows that a more regular (chronic) exposure may even be inversely associated with the occurrence of melanoma [244]. In particular, this is also shown in studies by Elwood and Jopson (1997) and Nelemans et al. (1995) [289]; [290]. Looking at the topographical distribution of cutaneous melanomas, studies in Lithuania, Finland, and Germany [291]; [292] find the highest incidence rates for MM on the trunk of the body in males, while females have the highest incidence for MM on the legs. This distributional property is also used as an argument that MM results from intermittent rather than chronic UV exposure.

However, the topographical comparison of incidence ignores the fact that the body areas being compared have very different body surface areas or melanocyte counts. The estimated body surface area of the trunk, for example, is 32% of the total body surface area, while the face, including lips and eyelids, accounts for about only 2.7%. If the topography-specific incidence rates are adjusted to the affected body surface (body surface adjusted rates, RSA), another interpretation possibility arises with regard to the predisposition of the skin areas to MM. The highest RSA is then found in women and men in the face, which is more likely to be classified as chronically UV-exposed.

Further studies are needed to clarify whether chronic UV exposure, possibly in conjunction with intermittent periods, is important for certain types of melanoma.

Other behavioural risk factors (e.g. tanning bed use) are addressed in Section 5.1 of this guideline.

4.3.3.1 UV Exposure as a Possible Exogenous Source of Damage to the Eyes

V. Kakkassery, L.Heindl

The mechanisms and data on skin carcinogenesis described above also apply to the eyelid skin. Due to the increased sun exposure, the eyelid is classified in most skin cancer guidelines as a high-risk zone for skin tumour development. In addition, further damage can occur directly to the eye following UV radiation exposure. Here, a distinction is made between acute damage to the eye and chronic damage to the eye from UV radiation.

Acute Ocular Surface Damage

Photokeratitis and photoconjunctivitis are acute UV radiation-induced damages (especially by UV-B and UV-C) of the conjunctival and corneal epithelium. In addition to artificial, non-sun-induced UV exposure (welding work, solar equipment, etc.), sun-induced UV exposure from about six hours onwards can also lead to swelling and exfoliation of the corneal and conjunctival epithelium [293]; [294]; [295]. This is associated with symptoms such as a temporary reduction in vision, very severe pain, tearing, and conjunctival swelling. Damages as well as complaints of this kind are self-limiting and have a recovalence time of approx. 8-12 hours [293]; [294]; [295]. Healing processes can be supported with caring and antibiotic eye ointments/drops.

Acute UV-Induced Retinopathy

Acute UV radiation-induced retinopathy, whether with natural or artificial UV radiation, can lead to thermal damage to the fovea. This damage is reversible or partially irreversible, depending on the temperature in the fovea centralis (visual fossa) [296]; [297]. The reversible damage can then also vary in visual recovery over time (period of up to six months after the damage). Visual impairment can then vary between 0.1 and 0.5 [296]; [297]. The damage can occur during sunbathing as well as when looking into the sun (in this case, of course, more frequently). Damages of the fovea show up by a typical yellowish-white spot at the fundus as well as in the optical coherence tomography defects in the area of the inner and outer segments of the photoreceptors [296]; [297]. Rare late consequences of sun-induced retinal damage can be the formation of choroidal neovascularization, which then significantly reduces the vision in the eye and which can be treated with intravitreal injections into the eye [296]; [297]. Protective factor for UV radiation-induced retinopathy may be an aging lens, so clear juvenile lenses are less protective accordingly [296]; [297].

Pterygium

Pterygium represents hyperplasia of the bulbar conjunctiva that grows over the cornea. It can cause astigmatism, dry eye, and vision loss by growing into the area of the imaging light path of the eye (depending on pupil width). It is generally accepted that UV radiation is a strong trigger of pterygium here and significantly favors progressive growth on the cornea, as studies in Australia as well as in the USA (Chesapeake Bay study), among others, have shown [298]; [299]; [300]; [301].

Pinguecula

Pinguecula is a hyaline-elastotic degeneration of the bulbar conjunctiva. In contrast to a pteryium, a pinguecula has hardly any disease value. Cosmetic aspects are more important. Studies in the Red Sea region as well as in the USA (Chesapeake Bay study) could also prove a connection between UV radiation and the frequent development of pinguecula [302]; [301].

Climatic Drop Keratopathy

Climatic droplet keratopathy is a formation of ball-like degenerations in the upper part of the corneal stroma directly below the Bowman's membrane (epithelial border) [303]. Massive UV-radiation leads to band-like opacities especially in the palpebral fissure area due to the remodelling of plasma proteins. Regional studies could prove the connection between climatic drop keratopathy and UV radiation [304]; [305]; [301].

Squamous Cell Carcinoma (Squamous Neoplasia) of the Ocular Surface

Squamous cell carcinomas (also called squamous neoplasms) of the conjunctiva develop via the precursors/progenitors of dysplasia and carcinoma in situ. [Pe'er, J. et al. 2015]. Alternatively, conjunctival intraepithelial neoplasia, with the grading of mild/moderate/severe (CIN I, II and III) is designated [Pe'er, J. et al. 2015], where CIN III is the carcinoma in situ. Studies in Uganda and Sudan as well as comparisons of incidences of squamous cell carcinoma of the ocular surface between Europe and North America compared to sub-Saharan countries in Africa demonstrate the association of UV radiation as well as the sun in the formation of neoplasms [307]; [308]; [309]; [310]; [311]; [312].

Conjunctival Melanomas/Pigmented Neoplasms of the Ocular Surface

Genetic patterns and alterations in conjunctival melanoma tissue suggest UV-induced damage to DNA [313]. However, these theoretical considerations have not yet been confirmed with data from cohort studies or similar, so it is unclear whether (and if so, at what dose) UV radiation exposure leads to pigmented neoplasia of the ocular surface.

Cataract

Evidence of the association between acceleration of age-related cataract development and UV radiation exposure has been widely demonstrated. Studies in the USA, in Australia, in India, in Nepal, and in Hong Kong could clearly prove this connection ([314]; [315]; [316]; [309]; [317]; [318]. The Chesapeake Bay Study and the Beaver Dam Eye Study from the USA reached the same conclusions [319]; [320]. Many other studies have demonstrated the connection between cataract development and UV radiation exposure.

Age-Related Macular Degeneration

The connection between age-related macular degeneration and UV radiation exposure is not clear. Several studies have failed to find an association, while other studies have found promotion of age-related macular degeneration by at least UV radiation from the sun.

In 1983 Hyman and colleagues found no association between macular degeneration and UV radiation exposure [321]. Similar findings were obtained by the Eye Disease Case-Control Study Group ([322]). Another Australian case-control study of 409 cases and 286 controls also saw no correlation between age-related macular degeneration and cumulative UV radiation exposure [323]. The Chesapeake Bay Watermann Study also failed to find a correlation between age-related macular degeneration and UV radiation exposure [324]. However, follow-up analyses of these data showed a long-term effect of blue light (but not UV radiation) on age-related macular degeneration [325]. TThe cohort study "Beaver Dam Eye Study" was able to demonstrate an association between age-related macular degeneration and sunlight exposure time [320]. However, this effect could not be seen with UV radiation exposure. A meta-analysis by Sui and colleagues suggests that there is an increased risk of age-related macular degeneration with increased UV radiation time [326].

Due to UV filtering by the natural lens, UV radiation-induced age-related macular degeneration is not currently thought to occur, but rather blue light-induced sun damage is suspected. This assumption is based on data from the Chesapeake Bay Waterman Study [325]. Especially in cataract-operated eyes with an artificial lens or without a lens, conclusions about possible damage to the macula by blue light could be suspected by pools of the Beaver Dam Eye Study and the Blue Mountains Eye Study in the comparison between the first operated eye and the subsequently operated eye [327]. Initial assumptions that blue light filter in artificial eye lenses has a protective effect could neither be proven nor disproven in a systemic review [328]. Currently, no recommendation for artificial blue light filter lenses in cataract surgery is given by professional societies.

4.3.4 Other Risk Factors for Skin Cancer

4.7 · Consensus-based Statement · checked 2020

Other risk factors that are described for non-melanocytic skin cancer are exposure to arsenic or tar, particularly in the work environment. HPV infections are discussed both as a sole risk factor for skin cancer and as a cofactor in combination with ultraviolet (UV) radiation.

Arsenic

Arsenic (in drinking water) is considered a risk factor for skin cancer (especially SCC and BCC). According to the IARC classification, arsenic belongs to class I carcinogens ("carcinogenic in humans"). It has been reported that arsenic may contribute to, among other things, numerical chromosomal aberrations and alteration of epigenetic regulation of tumour suppressor genes.

Limits for arsenic in drinking water are set at ≤ 10 µg/L. However, these are exceeded for nearly 100 million people mainly in Bangladesh, Taiwan, Mongolia, India, China, Argentina, Mexico, Canada, and the USA.

However, robust epidemiological studies on the contribution of arsenic-induced skin cancers to the overall incidence of skin cancer are not available.

Tar
Chronic exposure to tar and tar derivatives, particularly in occupational settings, is a risk factor for non-melanocytic skin cancer [329]; [330]. An increased risk due to the therapeutic use of tar has not yet been demonstrated [331].

HPV infection

HPV infections are discussed both as a sole risk factor for skin cancer (squamous cell carcinoma) and as a co-factor in combination with UV radiation. Extensive UV exposure at the site of skin biopsies has been described as a strong risk factor for the occurrence of HPV infections, and local immunosuppression may play an amplifying role [332]; [333].

However, since both the extent of UV exposure and the expression of HPV infection are difficult to quantify, large epidemiological studies are first needed to substantiate possible causal relationships between UV exposure and HPV infection and to quantify the number of HPV-associated squamous cell carcinomas in the total number of all occurring squamous cell carcinomas [332].

Hydrochlorotiazide

The use of the diuretic hydrochlorothiazide, which is found in many blood pressure lowering agents, also promotes the development of non-melanocytic skin cancer.

The diuretic hydrochlorothiazide (HCT), which is found in many blood pressure-lowering drugs, promotes the development of non-melanocytic skin cancers. In a Danish case-control study it was shown that the intake of HCT increases the risk of developing BCC by a factor of 1.29 (1.23-1.35), for PECC a factor of 3.98 (95% CI, 3.68-4.31) was determined [334]. Another study showed a factor of 3.9 (3.0-4.9) for SCC at the lip [335]. Both studies describe a dose effect.

4.3.5 Absolute and Relative Risks

For the listed constitutional risk factors, values for relative risks (RR) or lifetime risks are given in the literature in different studies. In the following table, some of these values are listed as examples for non-melanocytic skin cancer (table Skin Type as Risk Factor of Non-Melanocytic Skin Cancer) and for malignant melanoma (table Exemplary Constitutional Risk Factors of Malignant Melanoma):

Table 15: Skin type as a risk factor of non-melanocytic skin cancer

Risk factor	Relative risk (95% CI)
Skin type I vs. IV (BCC)	5.1 (1.4-11.3)
Skin type II vs. IV (BCC)	5.3 (1.7-10.6)
Skin type I vs. IV (SCC)	1.4 (0.5-3.0)
Skin type II vs. IV (SCC)	2.2 (0.7-3.8)
Sources: [209]; [210]

The presence of multiple actinic keratoses over a 10-year period is associated with a lifetime risk of developing squamous cell carcinoma (SCC) in the range of 6-10%.

The risk of developing another SCC within five years if there is a SCC in the patient's own history is 30%, and of developing a BCC is about 40%.

The risk of developing another BCC within three years in the case of a BCC in the patient's own history is 44%, and of developing a PECC is approximately 6%.

SCC develops up to 65 times more frequently in immunosuppressed transplant patients compared to controls. Immunosuppressed transplant patients develop more SCC than BCC (4:1).

For the listed constitutional risk factors, values for relative risks (RR) or lifetime risks are given in the literature in different studies. In the following, some of these values for malignant melanoma are listed as examples:

Table 16: Exemplary constitutional risk factors of malignant melanoma

Risk factor	Relative risk (95% CI)
Number of acquired nevi (100-120 vs. < 15)	6.89 (4.63-10.25)
Skin type (I vs. IV)	2.09 (1.67-2.85)
Family history of melanoma (yes vs. no)	1.74 (1.41-2.14)
Number of atypical nevi (5 vs. 0)	6.36 (3.80-10.33)
Melanoma in own history (yes vs. no)	8.5 (5.8-12.2)
Sources: [243]; [211]; [245]

The relative risks (RR) for the development of different skin cancer entities (BCC, SCC, and MM) depend on the UV exposure pattern. BCC does not depend on the cumulative UV dose (RR = 0.98, 95% CI 0.68-1.41), whereas SCC depends more strongly on the cumulative dose (RR = 1.53, 95% CI 1.02-2.23). MM occupies an intermediate position with respect to cumulative dose (RR = 1.2 95% CI 1.00-1.44). However, for MM, there is an increased risk with intermittent UV exposure (RR = 1.71, 95% CI 1.54-1.90) or sunburns at any age (RR = 1.91, 95% CI 1.69–2.17) [122].

4.4 Importance of Biomarkers for Primary and Secondary Prevention of Skin Cancer

R. Greinert, B. Volkmer

As an outlook into future developments in the field of primary and secondary prevention of skin cancer the increasing importance of biomarkers should be pointed out. Biomarkers are defined, according to WHO, as follows:

"…any substance, structure or process that can be measured in the body or its products and that can influence or predict the incidence or outcome of disease.” (WHO. International Program on Chemical Safety Biomarkers in Risk Assessment: Validity and Validation 2001. http://www.inchem.org/documents/ehc/ehc222.htm)

A distinction is now made between different categories of biomarkers, whereby there can be smooth transitions [336]; [337]; [338]; [339]:

Risk biomarkers
Diagnostic biomarkers
Prognostic biomarkers
Predictive biomarkers

Risk biomarkers indicate the potential risk for a disease, diagnostic biomarkers indicate the presence of a particular disease, prognostic biomarkers provide information about the course of a disease, and predictive biomarkers provide information about how a particular disease will respond to possible forms of therapy (e.g. "therapy-responder vs non-responder") [340]; [341]; [342].

Biomarkers are becoming increasingly important, especially in the context of their detection in liquid biopsies ("liquid biopsies") [343]; [344]; [345]. By this is meant that biomarkers in body fluids (such as blood, urine, cerebrospinal fluid, saliva, etc.) can be detected non-invasively after collection of the body fluids using a variety of methods [346]. New molecular-biological findings and isolation methods already make it possible to examine a large number of different biomarkers in liquid biopsies. These include, for example [346]:

Cell-free tumour DNA/RNA
Circulating tumor cells
Antibodies
Metabolites
Extracellular vesicles
Exosomes
Tumour-associated exosomes (TEX)
microRNAs (miRNAs)

Recently, the detection of exosomes and TEX as biomarkers has proven to be particularly promising, especially considering the miRNAs that are included as cargo in exosomes and TEX. The miRNAs are approximately 18-24 nucleotide long non-coding RNA segments that post-transcriptionally influence protein synthesis at all levels of cellular development and disease development [347]. They are particularly stable as cargo of exosomes and TEX in liquid biopsies and thus represent a suitable biomarker candidate for a variety of questions. Exosomes and TEX are small vesicles (50-120 nm in diameter) that are actively secreted by (tumour) cells to influence the micro- and macro-environment of disease- (tumour-) specific cells through the interaction of surface molecules they carry and through their (specific) cargo (e.g. miRNAs) that can be transferred into other cells [348]. They thus control, among other factors, the disease development, its course, and possibly also the therapy.

The importance of miRNAs, exosomes, and TEX as biomarkers in diagnostics, prognostics, and prediction of skin cancer has already been pointed out in a number of publications (e.g. [349]; [350]; [351]; [348]; [352]).

It must be noted, however, that until any form of biomarker can be used, which is already indicated in a large number of studies, a phase of consensual and large-scale validation must take place before a possible biomarker can enter clinical use or be used in any form in primary and secondary prevention.

References

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