4. Diagnostics – Actinic keratosis and squamous cell carcinoma of the skin
M. Flaig, M. Heppt, U. Hillen, T. Dirschka, S. Ihrler, C. Pfannenberg, L. Schmitz, J. Welzel
4.1 Classification, definition and nomenclature of actinic keratosis
The term "actinic keratosis" shall be used.
- Consensus
- Strong consensus (100%)
Multiple qualitative and quantitative factor integrating scores (e.g. AK-FAS, AKASI) improve standardized reporting of findings for actinic keratosis.
Evidence tables (1)
Klassifikation AKAK is a clinically and histomorphologically detectable skin lesion characterized by a proliferation (hyperplasia) of atypical epidermal keratinocytes that do not exhibit a basaloid phenotype. Multiple factors such as lesion number, size of affected area, or localization integrating scores (e.g., AK-FAS, AKASI) improve standardized clinical findings for AK both as baseline findings prior to therapy initiation and during the course to evaluate therapy response [67][53][52]. The cytomorphologic and genetic alterations of atypical keratinocytes resemble tumor cells of invasive SCC of chronically light-exposed skin. Currently, there is insufficient evidence that histomorphologic parameters translate into a clinical and/or therapeutically relevant consequence. In this respect, a detailed and extensive documentation of criteria beyond the mention of the diagnosis and subtype does not seem necessary or helpful.
The term "actinic keratosis“ has long been widely established in both clinical and histopathological usage. Basically, it is a common but, at its core, imprecise term, since changes designated by this diagnosis need not have an obligatory actinic (solar, sunlight-induced) genesis (e.g., arsenic or PUVA keratoses), nor need they be obligatorily accompanied by a clinically or histologically manifest keratosis (clinically keratotic scale, histomorphologically ortho- and/or hyperparakeratosis). Furthermore, the term does not describe histogenesis, as is usually the case in pathology. Synonyms include "solar keratosis", "senile keratosis", "in situ SCC of AK type", "keratinocytic intraepithelial neoplasia" and "squamous intraepithelial neoplasia". A common histomorphological feature of all of these is an obligatory atypia of keratinocytes of the surface covering epidermis. Cytomorphologically, the atypia of keratinocytes to be detected is manifested by nuclear hyperchromasia, nuclear pleomorphism, enlarged nuclei and high nuclear/cytoplasmic correlation. In addition, there are architectural criteria with alteration of the usual layering of the epidermis, increasing loss of polarity, which are manifested by an apparently random arrangement of intraepidermal keratinocytes and high cell density in the stratum basale ("crowding“).
The extent of histomorphologically detectable changes is highly variable. Thus, initial AK show only single atypical keratinocytes. However, hyperplasia may lead to displacement of keratinocytes appearing normal in the epidermis in varying proportions up to complete replacement. Frequently, although not obligatorily, hyperkeratosis is found over these atypical keratinocytic proliferates, which in the prototypical case shows an alternation of ortho- and parakeratotic portions ("pink and blue“). The epidermal band can appear narrowed, unchanged or acanthotic widened compared the surrounding epidermis. The appearance of rete ridges can be equally variable. These may be completely absent, small and plump in shape as in lentigo solaris or senilis, or hypertrophic and developed with bridging. These descriptive histomorphologic characteristics were used as the basis for a classification of basal proliferation patterns (PRO-I-III). PRO-I comprises hyperplasia of basal atypical keratinocytes ("crowding“), PRO-II initial plump rete ridges hyperplasia ("budding“), PRO-III ("papillary sprouting“) filiform reteridges hyperplasia exceeding the width of the overlying epidermis [68][69]. The decisive differentiating criterion for distinguishing AK from invasive SCC of the skin is evidence of endophytic proliferation of atypical keratinocytes crossing the basal membrane in non-traumatized skin.
In analogy to the diversity of clinical AK, the following variants are described histomorphologically:
- atrophic AK
- hypertrophic AK
- proliferative AK
- acantholytic AK
- pigmented AK
- lichenoid AK (with marked interface dermatitis, degenerating lymphocytic inflammatory reaction at the basal membrane zone, "interface“)
- bowenoid AK.
The latter refers to a variant in which there is polymorphism and atypia of the keratinocytes involved, as is typical in classic Bowen's disease. Frequently, several different manifestations of AK are found in close proximity in tissue samples. Sometimes the atypical keratinocytes can also be visualized in apical portions of adnexal epithelium. Often, but not always, a usually only sparse inflammatory infiltrate in the papillary dermis is associated with the appearance of the atypical keratinocytes. Almost always, actinic elastosis is found in the upper layers of the dermis.
The histomorphologic picture of AK ranges from the spectrum of merely actinically damaged skin with initial atypia of single keratinocytes to a complete replacement of the localized epidermis by atypical keratinocytes, which then corresponds to an epidermal carcinoma in situ, or in the case of high-grade atypia and polymorphism of keratinocytes, to Bowen's disease. To further classify this morphological spectrum, a three-tiered classification scheme (KIN I-III) has been proposed in analogy to the mostly HPV-induced intraepithelial neoplasms of the cervix uteri, corresponding to cervical, vulvar, penile, anal and perianal intraepithelial neoplasia according to the layers of the epidermis involved. This concept has always been controversially discussed and disputed, since invasive processes can arise from all stages; a three-stage classification system naturally has a very high interobserver imprecision and, moreover, no tangible clinical consequences have yet entered clinical routine. The same applies in principle to the three-level PRO classification [68][69][70][71].
Histomorphologically similar intraepidermal atypical proliferates occur in PUVA keratosis. In this case, the cytomorphological changes may be much less pronounced compared to classic AK. In the context of arsenic keratosis, the pronounced actinic elastosis is often absent in histomorphological analysis.
4.2 Classification, definition and nomenclature of cheilitis actinica
Cheilitis actinica is etiologically and morphologically the counterpart of actinic keratosis of the keratinizing squamous epithelium of the vermilion.
- Consensus
- Strong consensus (100%)
Evidence tables (1)
Klassifikation Cheilitis actinicaClinically, cheilitis actinica manifests mostly on the lower lip and is characterized by persistent dry scaling, leukoplakia, atrophy, blurred appearance of the lip red border, occasionally persistent swelling and erythema, persistent rhagades and ulcerations.
Mandatory histomorphological characteristics include actinic elastosis and a usually marked accompanying inflammatory infiltrate. Epithelial changes include cytological as well as architectural changes to individually varying degrees, which correspond to the usual epithelial dysplasia criteria: cellular and nuclear polymorphism, atypia, nuclear hyperchromasia, increased and enlarged nucleoli, basally accentuated stratification irregularities, loss of basal polarity, dyskeratoses, formation of plump or drop-shaped rete ridges. Analogous to other locations, evidence of endophytic proliferation of atypical keratinocytes crossing the basal membrane in non-traumatized skin corresponds to invasive growth and necessitates the diagnosis of invasive lip carcinoma.
Two- or three-stage classifications of cheilitis actinica have not gained acceptance due to lack of reproducibility and clinical consistency.
4.3 Classification, definition and nomenclature of squamous cell carcinoma in situ (Bowen's disease)
Bowen's disease is defined as an intraepidermal proliferation of highly atypical and polymorphic keratinocytes involving the entire epidermis. In this respect, Bowen's disease represents a special variant, which can progress into an invasive, then usually bowenoid differentiated (pleomorphic, low differentiated) squamous cell carcinoma ("Bowen's" carcinoma).
- Consensus
- Strong consensus (100%)
4.4 Classification, definition and nomenclature of invasive squamous cell carcinoma
4.4.1 Definition and nomenclature
Squamous cell carcinoma of the skin is a malignant neoplasm of the keratinocytes of the epidermis. The tumors can develop different degrees of differentiation (see also WHO/UICC classification).
- Consensus
- Strong consensus (100%)
Squamous cell carcinoma of the skin arises in most cases, but not necessarily, as a result of intraepidermal proliferation of atypical keratinocytes.
- Consensus
- Strong consensus (100%)
Invasive squamous cell carcinoma of the skin is said to occur when there is histomorphologically demonstrable disruption of the basal membrane beneath an intraepithelial keratinocytic proliferation in non-traumatized skin.
- Consensus
- Consent (87,5%)
The most important etiological factor is chronic UV exposure, especially in UV-sensitive individuals. Risk factors for the development of SCC include AK, older age, cumulative sun exposure and light pigmentation. The most important risk factor is the presence of AK [1]. The likelihood of a single AK progressing to invasive SCC cannot be accurately quantified (see Indications and Natural History). In addition to malignant transformation by UV radiation, other etiological factors may play a role. These include chronic wounds and inflammation such as leg ulcers, burns, scars, lichenoid disease, and bullous dermatoses. Arsenic exposure and X-rays may also promote malignant transformation. In immunosuppressed individuals, the incidence is greatly increased and the disease courses are less favorable. This is true for patients with iatrogenic immunosuppression after organ transplantation and for immunosuppression in malignant diseases and HIV infection. In immunosuppressed patients, malignant transformation is triggered by an increased rate of infection with carcinogenic HPV. Genetic syndromes with increased risk for SCC are albinism, xeroderma pigmentosum, Muir-Torre syndrome, epidermolysis bullosa hereditaria etc.
4.4.2 Classification and staging
The following variants of squamous cell carcinoma of the skin can be distinguished histomorphologically (some of these are reflected in the WHO/ UICC classification):
- Adenosquamous squamous cell carcinoma of the skin.
- Acantholytic (adenoid, pseudoglandular) squamous cell carcinoma of the skin
- Bowen's carcinoma/bowenoid differentiated squamous cell carcinoma of the skin
- Desmoplastic squamous cell carcinoma of the skin
- Keratoacanthoma-like squamous cell carcinoma of the skin/keratoacanthoma
- Lymphoepithelioma-like squamous cell carcinoma of the skin
- Pseudovascular (pseudoangiosarcomatous, pseudoangiomatous) squamous cell carcinoma of the skin
- Spindle cell (sarcomatoid) squamous cell carcinoma of the skin
- Verrucous squamous cell carcinoma of the skin (epithelioma cuniculatum)
- Consensus
- Strong consensus (100%)
Classification of squamous cell carcinoma of the skin should be based on histological and clinical parameters according to the currently used TNM systems of the UICC or AJCC.
- Consensus
- Strong consensus (100%)
A special variant of SCC is keratoacanthoma, which usually has a benign course. Clinical differentiation from SCC is uncertain. Although keratoacanthoma is usually identified as such due to its rapid growth progression and hemispherical growth form reliable clinical and/or histological differentiation is problematic and sometimes arbitrary. Characteristic features are the formation of a central horny plug, high degree of differentiation, marked symmetry and a broad-based infiltrative front. It may regress spontaneously. Primary therapy and histological workup as in the presence of SCC should be carried out. This is especially true for patient groups at increased risk of metastasis.
Verrucous SCC of the skin represents a particularly well-differentiated form for which invasive growth but rarely distant metastasis has been described. Epithelioma cuniculatum, oral florid papillomatosis and the so-called giant condylomata (Buschke-Löwenstein) are also assigned to this histological diagnosis (according to WHO / UICC classification). Not yet included in the international classification is desmoplastic SCC with high stromal content and narrow cell strands, which shows marked infiltrative growth that is sometimes perineural or perivascular. This type should be distinguished from the collective of common SCC with its high recurrence (approximately 25%) and metastatic (approximately 10%) potency. In patients treated with a selective BRAF inhibitor (e.g., vemurafenib, dabrafenib, encorafenib), keratoacanthomas have also been regularly described preferentially in chronically UV-exposed areas.
In addition, the WHO / UICC / AJCC classification can be used (see TNM classification of SCC and TNM classification of SCC of the head and neck). This is particularly useful for clinically very large SCC. However, at present classification for SCC of the skin does not appear to be well-developed, as it can convey differentiating information for only a very small proportion of tumors. Traditionally, a clinical classification is made into "low-risk" tumors of ≤20 mm and "high-risk" tumors of >20 mm tumor diameter (clinical parameter). Both classifications divide according to clinical and radiological parameters, respectively. In both classifications, the T1 category is defined by horizontal tumor extent (≤ 20 mm) and the T2 category (>20 mm). In the AJCC classification, the T1 category is further supplemented by means of 6 additional "high-risk“ factors, which are classified according to clinical and histological criteria. There are also differences in the T3 and T4 categories between UICC and AJCC. None of the classifications provide prognostic information such as the expected rate of metastasis.
More evidence for classification exists for histologically measurable vertical tumor thickness. A better estimate of the risk of metastasis is possible with this variable. The metastasis rate is 3-6% SCC depending on the collective [20]. A worsening of prognosis is observed in immunosuppressed patients after organ transplantation or after high-dose chemotherapy. Local recurrences are approximately 20 times more frequent in desmoplastic SCC than in common SCC. Local recurrences are considered a poor prognostic sign. It remains an open question whether the local recurrence itself contributes to this deterioration or represents a sign of the aggressive growth behavior of the tumor [20].
There are also differences in the N category between the UICC and AJCC classifications. Specifically, the AJCC divides the N2 category into three subgroups. In this approach, contralateral or bilateral metastasis results in upstaging. However, note that in the head and neck region, contralateral or bilateral lymphatic drainage is primary in 7% of cases. Micrometastasis, as found on sentinel lymph node biopsy, is considered only in the UICC classification (mi). No distinction is made between intranodal versus capsular lymph node metastasis. Staging does not correspond to evidence-based studies.
Table 6: TNM classification of SCC of the skin for the labial skin (excluding lip vermilion), trunk, upper extremities and shoulders, lower extremities, and hip and scrotum (8th edition, 2017)
| T category | |||
| TX | Primary tumor cannot be assessed | ||
| T0 | No evidence of primary tumor | ||
| Tis | Carcinoma in situ | ||
| T1 | Tumor 2 cm or less in greatest extension | ||
| T2 | Tumor more than 2 cm but not more than 4 cm at its maximum dimension | ||
| T3 | Tumor more than 4 cm at its maximal dimension or superficial bone invasion or perineural invasion or deep invasion* | ||
| T4a | Tumor with macroscopic bone invasion/ bone marrow invasion | ||
| T4b | Tumor with invasion of the axial skeleton including foramina and/or involvement of the vertebral foramen up to the epidural space | ||
|
*“deep invasion“ is defined as invasion beyond the subcutaneous fat or >6 mm (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 radiologic involvement of nameable 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). |
|||
| N category | |||
| NX | Regional lymph nodes cannot be assessed | ||
| N0 | No regional lymph node metastases | ||
| N1 | Metastasis(s) in a regional lymph node, 3 cm or less at its maximum dimension | ||
| N2 | Metastasis(s) in one lymph node, more than 3 cm but not more than 6 cm at its maximum dimension or in multiple lymph nodes, none more than 6 cm at its maximum dimension | ||
| N3 | Metastasis(s) in one lymph node more than 6 cm at its maximum dimension | ||
| M category | |||
| M0 | No distant metastases | ||
| M1 | Distant metastases | ||
| Stage classification | |||
| Stage 0 | Tis | N0 | M0 |
| Stage I | T1 | N0 | M0 |
| Stage II | T2 | N0 | M0 |
| Stage III | T3 | N0 | M0 |
| T1, T2, T3 | N1 | M0 | |
| Stage IV | T1, T2, T3 | N2, N3 | M0 |
| T4 | Any N | M0 | |
| Any T | Any N | M1 | |
Table 7: TNM classification of SCC of the head and neck according to AJCC / UICC (8th edition, 2017)
| T category | |||
| TX | Primary tumor cannot be assessed | ||
| T0 | No evidence of primary tumor | ||
| Tis | Carcinoma in situ | ||
| T1 | Tumor 2 cm or less in greatest extension | ||
| T2 | Tumor more than 2 cm but not more than 4 cm at its maximum dimension | ||
| T3 | Tumor more than 4 cm at its maximum dimension or superficial bone invasion or perineural invasion or deep invasion** | ||
| T4a | Tumor with macroscopic bone invasion/ bone marrow invasion | ||
| T4b | Tumor with invasion of the axial skeleton including foramina and/or involvement of the vertebral foramen up to the epidural space | ||
|
*“deep invasion“ is defined as invasion beyond the subcutaneous fat or >6 mm (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 radiologic involvement of named nerves without involvement of the foramina or skull base. |
|||
| N category (clinical) | |||
| N0 | No regional lymph node metastases | ||
| N1 | Metastasis(s) in a regional lymph node, 3 cm or less at its maximum dimension | ||
| N2 | Metastasis(s) as described below: | ||
| N2a | Metastasis(s) in solitary ipsilateral lymph node, more than 3 cm but not more than 6 cm at its maximum dimension, without extranodal spread | ||
| N2b | Metastases in multiple ipsilateral lymph nodes, none more than 6 cm at its maximum dimension, without extranodal spread | ||
| N2c | Metastases in bilateral or contralateral lymph nodes, none more than 6 cm at its maximum dimension, without extranodal spread | ||
| N3a | Metastasis(s) in one lymph node, more than 6 cm at its maximum dimension, without extranodal spread | ||
| N3b | Metastasis(s) in a single or multiple lymph nodes, clinically in extranodal spread***. | ||
|
***The presence of skin or soft tissue involvement (invasion) or clinical signs of nerve involvement is considered clinical extranodal spread. |
|||
| N category (pathological) | |||
| pN0 | No regional lymph node metastases | ||
| pN1 | Metastasis(s) in solitary ipsilateral lymph node, 3 cm or less at its maximum dimension, without extranodal spread | ||
| pN2 | Metastasis(es) as described below: | ||
| pN2a | Metastasis(s) in solitary ipsilateral lymph node, 3 cm or less at its maximum dimension, with extranodal spread or more than 3 cm but not more than 6 cm at its maximum dimension, without extranodal spread | ||
| pN2b | Metastases in multiple ipsilateral lymph nodes, none more than 6 cm at its maximum dimension, without extranodal spread | ||
| pN2c | Metastases in bilateral or contralateral lymph nodes, none more than 6 cm at its maximum dimension, without extranodal spread | ||
| pN3a | Metastasis(s) in one lymph node, more than 6 cm in greatest extent, without extranodal spread | ||
| pN3b | Metastasis(s) in one lymph node more than 3 cm at its maximum dimension with extranodal spread or in multiple ipsilateral, contralateral or bilateral lymph nodes with extranodal spread | ||
| M category | |||
| M0 | No distant metastases | ||
| M1 | Distant metastases | ||
| The pT categories correspond to the T categories. pM1 means that distant metastases were confirmed microscopically. | |||
| Stage classification | |||
| Stage 0 | Tis | N0 | M0 |
| Stage I | T1 | N0 | M0 |
| Stage II | T2 | N0 | M0 |
| Stage III | T3 | N0 | M0 |
| T1, T2, T3 | N1 | M0 | |
| Stage IV | T1, T2, T3 | N2, N3 | M0 |
| T4 | Any N | M0 | |
| Any T | Any N | M1 | |
4.5 Field cancerization
There is no generally accepted definition of field cancerization. Field cancerization includes an area of skin with multiple actinic keratoses surrounded by visible UV-related skin damage.
- Consensus
- Strong consensus (100%)
The concept of field cancerization was first established in 1953 by Slaughter et al. based on the histological evaluation of oral SCC and its environment [72]. It was shown that additional tumors often subsequently appeared in the initially clinically asymptomatic tumor environment. This was attributed to the pre-existing field-like spread of the tumors, which, however, initially remains subclinical. Meanwhile, the term field cancerization is attributed to genetic causes and used in the context of a variety of different tumor entities: head and neck, lung, vulvar, esophageal, cervical, breast, colon, bladder and skin tumors [73].
It is generally accepted that the environment of AK may also represent a "cancer field" and the term field cancerization is also used extensively in this regard [74]. A classification of the environment of AK as a "cancer field" has special significance for therapy: if subclinical changes are also present in the environment in addition to clinically visible AK, these would consequently have to be treated as well against the background of a possible clinical recurrence or tumor progression in the environment. In this context, therapy also distinguishes between lesional therapy ("lesion-directed“) and field-directed therapy ("field-directed“). Thus, if a tumor field can be characterized in the vicinity of AK, this will have an impact on the selection of the therapeutic procedure (see here) [75].
However, there is as yet no explicit definition that takes into account different aspects of field cancerization (genetic, immunological, molecular biological, histological and clinical characteristics).
On the genetic level, p53 mutations, for example, have been detected in the neighborhood of AK which are also characteristic for AK itself [76]. A variety of other immunological and molecular biological findings typical of AK are also detectable in the surrounding tissue, including increased COX2 expression, disturbances in the BRAF signaling pathway, and the highly variable expression of many individual genes [77][78][79]. Histologically, AK are characterized by atypical keratinocytes that are significantly more densely packed than in healthy skin. This phenomenon, referred to as "crowding“ (see here), is also observed histologically in clinically healthy surrounding skin [80]. Confocal laser scanning microscopy or high resolution optical coherence tomography are now able to visualize this structural atypia in the epidermis of the surrounding field in a non-invasive approach [74].
Genetic, immunological, molecular biological and histological findings as well as confocal laser scanning microscopy and high-resolution optical coherence tomography can thus help to characterize the tumor field. However, to date an explicit clinical definition has been lacking. Nevertheless, it is precisely the clinical definition of field cancerization in AK that would be of particular importance in clinical practice for the selection of the therapeutic procedure. Erlendsson et al. based the definition of field cancers in AK on clinical characteristics: field cancerization is rated as mild, moderate or severe based on the extent to which the surrounding skin shows mottled erythema ("mottled erythema“), pigmentation, telangiectasia, pallor, laxity and dry texture without evidence of AK itself. However, this definition has not yet been substantiated by clinical studies [81]. In a review of the definition of field cancerization in AK, it was emphasized that a unified clinical definition is still lacking. In this regard, a retrospective review highlighted telangiectasia, atrophy and pigmentary abnormalities as reliable or very reliable indicators of field cancerization in AK. An emery paper-like surface of the skin was considered to have moderate reliability for defining the field. In summary, as an expert opinion, field cancers in AK were defined as follows in this work:
"Field cancerization is defined clinically as an anatomic area with AK or adjacent to it and with visible sun-related skin damage characterized by at least two of the following signs: telangiectasia, atrophy, pigmentary abnormalities and sandpaper-like surface. It remains unclear whether visible AK is a prerequisite for field cancerization“ [82].
In this regard, for patients with these features and AK, field-directed therapy or field-directed therapy in combination with lesion-directed therapy is recommended. In case of clinical signs of field cancerization and absence of AK in the field, it is recommended to take educational or preventive measures and to arrange field monitoring by the patients themselves [82].
In conclusion, there is no clinically validated definition of field cancerization in AK. Genetic, immunological, molecular biological, and histological findings are impractical for therapy selection in the specific clinical situation and thus are more appropriate for scientific characterization of the field. Confocal laser microscopy or high-resolution optical coherence tomography can noninvasively visualize atypical keratinocyte clusters but has not been sufficiently widely used in treatment settings.
Thus, attempting a clinical definition, even in the absence of validation, seems reasonable and important for therapy selection in AK in clinical practice. In this regard, the clinical definition proposed in the work of Figueras Nart et al., based on clinical signs of UV damage, represents a feasible approach [82].
4.6 Importance of non-invasive diagnostic procedures
Diagnosis is made by clinical examination and inspection.
- Consensus
- Strong consensus (100%)
Dermatoscopy, confocal laser microscopy and optical coherence tomography can be used to diagnose actinic keratosis and squamous cell carcinoma of the skin when findings are clinically unclear.
- Consensus
- Strong consensus (100%)
Inspection and palpation are suitable to make a tentative diagnosis of AK. AK is characterized by a variable erythema with a variably pronounced keratosis. The clinical grading of AK does not correlate with the histological expression [37]. However, invasiveness cannot be assessed reliably by inspection and palpation [83].
Dermatoscopy is a suitable method to differentiate other diseases and tumors in case of unclear findings. Numerous studies have demonstrated that AK, pigmented AK, Bowen's disease and SCC show typical patterns, especially of the vessels, with dermatoscopy [84]. AK and SCC can thus be well differentiated from basal cell carcinoma. Dermatoscopy is also suitable for differential diagnosis between lentigo maligna, lentigo senilis and pigmented AK [85]. In addition, the degree of invasiveness correlates with vascular atypia, so dermatoscopy can also be used to assess invasiveness [86][87]. In one study, the sensitivity of dermoscopy in the diagnosis of AK was 98.7% compared with histology as the gold standard, and the specificity was 95% [84]. In pigmented lesions, both values are lower [88].
Other non-invasive imaging modalities include confocal laser microscopy and optical coherence tomography. There are numerous studies and an S1 guideline on the value of confocal laser microscopy for non-invasive diagnosis of AK [89]. It allows the diagnosis of subclinical AK and helps characterize a cancerized field. In confocal laser microscopy, light-damaged but clinically unaffected skin in a field cancerization often shows an atypical honeycomb pattern as a sign of subclinical AK, which returns to normal with topical therapy [90][91][92][93][94].
Likewise, optical coherence tomography is useful for diagnosing AK and SCC and for differentiating basal cell carcinoma. It shows a widened, irregular stratum corneum and an acanthotic epidermis in AK. In SCC, by definition, the basal membrane zone, which is still detectable in AK, is broken [95][96]. AK can be distinguished from basal cell carcinoma morphologically and by objective parameters such as epidermis thickness and signal intensity of the dermis [97]. Optical coherence tomography also allows diagnosis of multiple lesions in field cancerization. The measurement times for optical coherence tomography are so short that diagnosis of multiple lesions is possible within a short time. With confocal laser microscopy, this is also possible with the aid of a flexible handpiece. Numerous studies have used confocal laser microscopy and optical coherence tomography to visualize and quantify therapeutic effects in the topical treatment of AK [98][90][91][99][100][92][101]. The sensitivity of optical coherence tomography in detecting AK was 88%-93% depending on the investigator. Clinically manifest AK was detected in another study with a sensitivity of 100% (95% CI 88-100%). This value was 73% (95% CI 52-87%) for subclinical lesions [99]. A systematic review of the diagnostic performance of confocal laser microscopy reported a sensitivity of 91%-100% for AK and 100% for SCC [102]. Similar results were observed in another study, with epidermal pleomorphism in the stratum spinosum and granulosum showing the highest sensitivity and specificity for the diagnosis of AK [103].
4.7 When and how to obtain a histology specimen
Actinic keratosis does not require histological diagnosis if typical clinical findings are present.
- Consensus
- Strong consensus (100%)
In case of resistance to therapy and clinically unclear findings, a tissue sample shall be obtained.
- Consensus
- Strong consensus (100%)
If squamous cell carcinoma of the skin, cheilitis actinica or Bowen's disease is clinically suspected, histology shall also be performed to differentiate other benign or malignant neoplasia.
Preoperatively, the maximum diameter of the neoplasia should be documented for squamous cell carcinoma of the skin and Bowen's disease.
- Consensus
- Consent (94,7%)
Change note
If SCC or Bowen's disease is clinically suspected, histology should also be obtained to differentiate another benign or malignant neoplasm. Preoperatively, the maximum diameter of the neoplasia should be documented.Depending on the clinical situation, punch biopsies, shave excisions, or excisional biopsies are appropriate.
- Consensus
- Consent (94,7%)
If the clinical picture is clear for squamous cell carcinoma of the skin, complete resection can be carried out without prior biopsy.
- Consensus
- Consent (89,5%)
AK do not require histological diagnosis if typical clinical findings are present. Lesions that are clinically equivocal, have evidence of progression to SCC or whose biological behavior cannot be assessed should be biopsied. Histological diagnosis should also be carried out for AK that do not respond to adequate therapy.
Obtaining histology sample is required if SCC is clinically suspected. Depending on tumor size and therapeutic approach, a punch, incision or shave biopsy may be done or, alternatively, the tumor may be excised [104]. The clinical presentation of SCC of the skin can be diverse and most commonly resembles that of a hyperkeratotic plaque, a flat ulcer with a marginal mound or a keratotic nodule or nodule with or without ulceration. SCC may develop de novo or from AK precursor changes such as reddened or hyperkeratotic macules and plaques, AK or leukoplakia. Since the clinical appearance is variable and clinical-morphological overlaps with diverse entities are present, a differentiation between an early invasive SCC with breakthrough of the basal membrane of the skin and a hyperkeratotic AK is also not possible based on clinical picture alone; a histological examination should be initiated before therapy is started, especially to differentiate another benign or malignant neoplasia of the skin as well. If the overall clinical context is clear, primary therapy as in the presence of SCC is justifiable.
Although keratoacanthoma can usually be differentiated clinically from SCC of the skin because of its rapid growth progression and hemispherical growth form, neither clinical nor histological differentiation is certain. In this case, histologic examination and primary therapy should be carried out as in the presence of SCC. This is especially true for patient groups with an increased risk of metastasis.
AK and SCC that are potentially caused by occupational natural UV exposure and thus potentially fulfill the facts of an occupational disease 5103 according to the Occupational Diseases Ordinance represent a special consideration (see). In these cases diagnosis must meet the requirements for reporting a BK 5103: in the case of a SCC, the diagnosis is proven only by appropriate histological examination. In the case of multiple AK or field cancerization, histological confirmation is not required according to scientific justification, but is recommended at least for one of the AK present [105].
The value of cytological techniques has been investigated in several studies. Bilen et al. obtained cytological specimens in tumors suspected of malignancy on the head. False negative results were found in 1/19 cases and no false positive findings were detected. Limitations are presented by flat or ulcerated seborrheic keratoses, which can be confused with SCC and basal cell carcinoma. The authors further noted that the cytology of premalignant lesions bears strong resemblance to SCC and that obtaining meaningful cytology is often unsuccessful in crusted, hyperkeratotic, and hard lesions [106]. In another study of 50 basal cell carcinomas and 28 AK, the sensitivity of cytology for AK was 91% (Papanicolaou stain) and 83% (May-Grünwald-Giemsa stain), respectively. AK could be discriminated from basal cell carcinomas, but cytology does not reliably differentiate AK or carcinomata in situ from invasive SCC [107].
Vega-Memije et al. studied 30 SCC and found a high concordance of cytology with histological diagnosis and concluded that reliable diagnosis is possible by cytology, although cytology is not suitable to identify tumor subtypes or to determine aggressive tumor characteristics [108]. Currently, the value of cytodiagnosis of AK and SCC has not been sufficiently investigated and further studies are needed.
4.8 Parameters of a histological report
The following histomorphological variants should be designated when present:
- atrophic
- hypertrophic
- acantholytic
- pigmented
- lichenoid
- bowenoid
actinic keratosis.
- Consensus
- Strong consensus (100%)
The histology report for squamous cell carcinoma of the skin shall include the following in addition to the diagnosis:
- Histological tumor type (for specific subtypes of squamous cell carcinoma of the skin)
- Description of the histological depth extension in relation to the anatomical stratification (especially from level V, corresponding to infiltration of the subcutis)
- Measurement of the depth extension from an invasion depth of 2 mm (corresponds approximately to the diameter of a 10x field of view)
- If present, indication of the presence of perineural involvement, vascular invasion or poor differentiation
- Completeness of resection of the invasive tumor portion
- Consensus
- Strong consensus (100%)
In addition to the indication of histomorphological variants in the presence of AK or SCC, the components of the histology report of findings essentially result from the risk factors for recurrence and distant metastasis (see).
4.9 Diagnosis of spread in invasive squamous cell carcinoma
If the presence of squamous cell carcinoma of the skin is suspected, the initial examination shall include inspection of the entire skin.
- Consensus
- Strong consensus (100%)
There are virtually no robust prospective studies or observational studies on the diagnosis of spread. Most studies on the value of imaging techniques come from investigations from SCC of the head and neck region (head and neck squamous cell carcinoma, HNSCC).
4.9.1 Lymph node sonography
Locoregional lymph node sonography shall be carried out when locoregional metastases are suspected.
Locoregional lymph node sonography should be carried out when risk factors are present.
- Consensus
- Consent (94,7%)
Metastases of cutaneous SCC occur locoregionally as satellite, in-transit or locoregional lymph node metastases in approximately 80% of cases; locoregional filiae detected early have the option of R0 resection. Therefore, early detection of locoregional lymph node filiae is of particular importance. In a meta-analysis of 74 studies of melanoma, cost-effective lymph node ultrasonography was found to have the highest sensitivity and specificity (staging 60% and 97%, respectively, follow-up 96% and 99%) and the highest positive predictive value of 83% to 98% (risk-dependent) for detecting locoregional lymph node filiae [109].
Lymph node ultrasonography is also described as the most effective procedure in the diagnosis of HNSCC to detect locoregional lymph node metastases, showing a sensitivity of approximately 78% and specificity of 85% [110][111]. It is clearly superior to clinical examination by palpation [112]. In case of sonographic suspicion of the presence of parotidal and cervical metastases, the staging examination should be supplemented by fine needle cytology of the suspicious lymph nodes, a CT scan of the neck and thorax, and an MRI of the parotid gland [110]. In a meta-analysis comparing different imaging modalities (ultrasound, CT, MRI, PET) in the diagnosis of lymph nodes in clinically nodal-negative HNSCC, the positive predictive value for lymph node ultrasonography was 25% to 56% and the negative predictive value was 95% to 84% and was equivalent to the other modalities in accuracy [113]. Also, when compared with FDG PET/CT and software-based fusion PET/MRI, lymph node ultrasonography was found to be at least equivalent in detecting occult lymph node metastases from HNSCC tumors, although published PET data often refer to studies with inhomogeneous collectives (N-/N+) with varying levels of evidence [110][114]. Since cutaneous SCC of the neck and head also shows lymph node metastases at the same site, and studies of HNSCC frequently include cutaneous SCC, these observations can be applied to cutaneous SCC of the neck and head.
Although the accuracy of imaging techniques has steadily improved over the past decades, there remains limited sensitivity with respect to the detection of micrometastases with all methods. Moreover, lymph node ultrasonography is currently not available close to home in all regions.
4.9.2 Chest X-ray
Chest X-ray shall not be carried out as a standard of care when locoregional or distant metastasis of squamous cell carcinoma of the skin is suspected or demonstrated.
- Consensus
- Consent (94,7%)
X-ray chest examinations are clearly inferior to chest CT in detecting small pulmonary filiae [115][116]. X-ray thoracic examinations detect only 28-60% of pulmonary metastases diagnosed on CT thorax. One problem with chest X-ray examinations is the high number of false positive and false negative findings.
4.9.3 Abdominal sonography
Abdominal ultrasonography shall not be carried out as a standard of care when locoregional or distant metastasis of squamous cell carcinoma of the skin is suspected or demonstrated.
- Consensus
- Strong consensus (100%)
Abdominal ultrasonography can be used to detect parenchymal distant metastases and abdominal lymph node metastases; however, diagnostic accuracy is examiner- and patient-dependent and overall lower than that of MRI, CT, and PET/CT [117]. Limitations arise particularly in the diagnosis of deep-seated structures (e.g., retroperitoneal lymph nodes) and in obese patients. An advantage of abdominal ultrasonography is its easy practicability, wide availability, and lack of radiation exposure.
4.9.4 Cross-sectional imaging
If metastasis is suspected, cross-sectional imaging shall be carried out.
- Consensus
- Strong consensus (100%)
There have been no studies on the regular use of cross-sectional imaging in the diagnosis of spread in cutaneous SCC; therefore its use is reserved for the clarification of metastasis-sensitive findings; i.e. if clinical examination or lymph node sonography shows a suspicion of metastasis, cross-sectional imaging should be carried out. For cutaneous SCC, the NCCN guidelines recommend further cross-sectional imaging in patients at increased risk for metastasis such as presence of clinically positive lymph nodes, advanced local disease or perineural spread on histology, and in patients under immunosuppression. A retrospective study examining the impact of radiological staging on disease progression in cutaneous SCC in 108 patients showed that high-risk SCC (T2b, T3) who received multiple staging examinations (79% CT, 21% PET/CT, 19% MRI) during a median follow-up of 43 months had improved disease-free survival (p=0.028). No difference was seen in terms of distant metastasis-free or disease-specific survival [118].
Regarding the diagnosis of cervical lymph node metastases, CT, MRI and ultrasound show comparable accuracies. A meta-analysis comparing different imaging modalities (ultrasound, CT, MRI, PET) in the diagnosis of lymph node in nodal-negative HNSCC showed similar results in terms of pooled sensitivity and specificity. In advanced SCC, cross-sectional imaging should be carried out to exclude distant metastases [113]. In addition to high diagnostic accuracy, CT offers the advantages of standardized whole-body examination, general availability and patient- and examiner-independence compared with sonography. Functional imaging using FDG-PET/CT can detect distant metastases of a SCC in particular with high sensitivity and specificity due to their significantly increased glucose metabolism [119][120][121][122]. Several studies in HNSCC have shown that PET/CT in addition to conventional work-up increases staging accuracy, improves specificity of LK diagnosis, and detects more distant metastases than CT alone [123][120]. However, micrometastases in lymph node in clinically N0 patients remain a diagnostic problem even for PET/CT. In an analysis by Fujiwara et al. in 26 patients with high-risk cutaneous SCC, PET/CT showed high sensitivity (100%) and specificity (81%) in the detection of metastases, significantly higher than conventional CT with a sensitivity of 51% and specificity of 69% [124]. In 16% of patients, a false positive finding was seen, which was predominantly due to a strong inflammatory peritumoral infiltrate with mononuclear cells. However, this showed a significantly higher standardized uptake value (SUV) of the lymph node metastases compared with FDG uptake of the surrounding inflammatory infiltrate. These results were confirmed by another monocentric study of 23 patients, which showed a sensitivity of 100%, a positive-predictive value and an accuracy of 77.5% each for 18F-FDG-PET in initial staging. This examination was considered to have an important role not only in the detection of small soft tissue and lymph node metastases, but also in primary staging [125]. Another recent study by the same group of authors investigated the value of FDG-PET/CT for recurrence staging in 100 patients with cutaneous SCC. The study confirmed the superior sensitivity of the method, especially in the detection of small cutaneous/subcutaneous foci and lymph nodes, and was able to demonstrate PET/CT induced management change in 28% of patients [126].
Evidence tables
Klassifikation AK
|
Study |
Aims |
Design |
Population |
Outcomes |
Results |
Comments and methodological assessment |
LoE |
|
Chen et al 2013 |
To assess the reliability of four different methods used to quantify AKs and to investigate whether a consensus meeting affects the reliability. |
Single-blinded, cross-sectional study of 12 experienced dermatologist raters counting AKs on the face and ears of nine subjects before and after a consensus meeting
To compare the degree of agreement of (i) AK count of discrete lesions > 0.25 cm (big), (ii) AK count of discrete lesions < 0.25 cm (small); (iii) total count, irrespective of size, and (iv) the body surface area method |
N=12 board-certified dermatologists 67% were women Mean age: 47 years ± 9
N=9 consecutive subjects with extensive AKs on their face and ears were invited to participate in a research kick-off meeting for AK assessment, 100% male |
intraclass correlation coefficient (ICC) among raters for pre- and post-consensus evaluations |
total count’ method had the greatest ICC for both pre- (0.18, P=0.04) and post-consensus (0.66, P≤ 0.0001) assessments.
Total count was also the only pre-consensus ICC for which the null hypothesis of no association among assessments was rejected. |
Small sample size
No histological confirmation of AK was obtained
Patients with AK to be rated were only male |
2 |
|
Cockerell 2000 |
To propose criteria for grading keratinocytic intraepidermal (malignant) neoplasia. |
Modification of an existing classification system based on a literature review à expert review/opinion |
- |
Classification system |
Proposed criteria for grading keratinocytic intraepidermal (malignant) neoplasia.
Grade I: Clinical: Flat, pink macule or patch on solar-damaged skin; background mottling; no roughness or hyperkeratosis. Histologic: Focal atypia of basal keratinocytes of lower one third of the epidermis.
Grade II: Clinical: Pink to red papule or plaque with rough, hyperkeratotic surface; variable induration. Histologic: Focal atypia of keratinocytes of at least the lower two thirds of the epidermis; focal hyperkeratosis, alternating orthokeratosis and parakeratosis with sparing of acrotrichia and acrosyringia; prominent acanthosis and buds of keratinocytes into the upper papillary dermis; may see some involvement of upper acrotrichia and acrosyringia.
Grade III: Clinical: Red, scaly indurated plaques on sun-damaged skin; may be pigmented. Histologic: Diffuse atypical keratinocytic proliferation involving the full thickness of the epidermis diffusely; parakeratosis, acanthosis, papillomatosis, the involvement of adnexal structures. |
No validation with real-world data of the system
No inter-rater reliability or other measure were investigated
Only expert review |
5 |
|
Cockerell et al 2005 |
To propose a classification for AK analogous to that used for cervical intraepithelial neoplasia. |
Modification of an existing classification system based on a literature review à expert review/opinion |
- |
Classification system |
Criteria for grading keratinocytic intraepidermal (malignant) neoplasia.
Grade I: Clinical: Flat, pink macule or patch on solar-damaged skin; background mottling; no roughness or hyperkeratosis. Histologic: Focal atypia of basal keratinocytes of lower one third of the epidermis.
Grade II: Clinical: Pink to red papule or plaque with rough, hyperkeratotic surface; variable induration. Histologic: Focal atypia of keratinocytes of at least the lower two thirds of the epidermis; focal hyperkeratosis, alternating orthokeratosis and parakeratosis with sparing of acrotrichia and acrosyringia; prominent acanthosis and buds of keratinocytes into the upper papillary dermis; may see some involvement of upper acrotrichia and acrosyringia.
Grade III: Clinical: Red, scaly indurated plaques on sun-damaged skin; may be pigmented. Histologic: Diffuse atypical keratinocytic proliferation involving the full thickness of the epidermis diffusely; parakeratosis, acanthosis, papillomatosis, involvement of adnexal structures. |
No validation with real-world data of the system
No inter-rater reliability or other measure were investigated
Only expert review |
5 |
|
Dirschka et al 2017 |
To develop and perform an initial pilot validation of a new easy-to-use quantitative tool for assessing AK severity on the head. |
1. review of other severity scoring systems in dermatology, in particular the psoriasis area and severity index (PASI)
2. Initial validation was performed by 13 physicians assessing AK severity in 18 AK patients and two controls using a physician global assessment (PGA) and AKASI.
To determine an AKASI score, the head was divided into four regions (scalp, forehead, left/right cheek ear, chin and nose). In each region, the percentage of the area affected by AKs was estimated, and the severities of three clinical signs of AK were assessed: distribution, erythema and thickness. |
N=18 patients with AK on the head [mean age (range): 73 years (60–80); 10 men and eight women] and two controls without AK (62-year old man and 70-year-old woman)
N=13 physicians were involved in the rating |
AKASI & PGA scores Correlation between AKASI and PGA (Pearson correlation coefficient) |
AKASI & PGA scores mean (SD) PGA score was 0.08 (0.27) for the controls and 1.74 (0.80) for the patients. The mean (SD) AKASI score was 0.11 (0.38) for the controls and 4.75 (2.51) for the patients
strong correlation between AKASI and PGA scores (Pearson correlation coefficient: 0.86). AKASI was able to discriminate between different PGA categories: mean (SD) AKASI increased from 2.88 (1.18) for ‘light’ to 5.33 (1.48) for ‘moderate’, 8.28 (1.89) for ‘severe’, and 8.73 (3.03) for ‘very severe’ PGA classification. The coefficient of variation for AKASI scores was low and relatively constant across all PGA categories. |
This work was funded by Centroderm GmbH.
An initial 30-min training on AKASI was provided, and the physician participants were provided with a handout containing detailed instructions on AKASI.
Small-medium sample size of both patients and physicians. |
2 |
|
Dréno et al 2017 |
To develop, test, and validate an Actinic Keratosis Field Assessment Scale (AK-FAS) based on photographic clinical cases. |
Development: initial draft of the AK-FAS was based on a combination of Olsen criteria for AK. This draft was then dynamically modified in a face-to-face meeting on 15 July 2016.
Validation: 108 standardized photographs of patients representing the full range of AK severity were collected.
Six investigators (involved in the development) and 2 untrained investigators independently rated each photograph according to 3 criteria (AK-FAS scale): AK area (total skin area affected by AK lesions), hyperkeratosis and sun damage. |
The final AK-FAS was tested separately on face and scalp areas (on 66 and 30 photographic cases, respectively) by 6 trained (testing) and 2 untrained investigators (validation). |
Inter-rater reproducibility |
Validation of the AK-FAS by investigators
Inter-rater reproducibility: For face and scalp combined, the inter-rater κ scores were 0.69, 0.71 and 0.51, respectively substantial agreement for 2 criteria (AK area and hyperkeratosis) and moderate agreement for the third criteria (sun damage)
Intra-rater reproducibility: good for all criteria (AK area, hyperkeratosis and sun damage) substantial agreement range for all investigators for AK area, almost perfect or substantial agreement range for all but one of the investigators for hyperkeratosis and moderate agreement range for the majority of the investigators for sun damage
Validation of the AK-FAS by untrained investigators κ scores of 0.59, 0.54 and 0.38, respectively, for AK area, hyperkeratosis and sun damage, indicating moderate agreement (good reproducibility) for AK area and hyperkeratosis, and fair agreement for sun damage; s imilar results were obtained for the face and scalp analysed separately
àValidation of the AK-FAS showed good reproducibility for AK area and hyperkeratosis, even for dermatologists untrained on use of the scale. |
Assessment for each area was repeated (with at least 1 h between assessments) to allow evaluation of inter- and intra-rater agreement.
The order of the photographic cases was randomly changed in the repeat assessment, in order to minimize grading by memory. The investigators had not previously seen any of the cases provided by their colleagues and were not allowed to confer during the assessment.
This study was funded by LEO Pharma. |
2 |
|
Fernández-Figueras et al 2015 |
To evaluate the prevalence of classic and differentiated pathways in the development of cutaneous iSCC. |
The epidermis adjacent to and overlying iSCC, assumed to be representative of pre-existing lesions, was histologically studied in 196 skin biopsy specimens showing iSCC by three pathologists. |
N=196 skin biopsy specimens showing iSCC (79 women and 117 men) mean age:77.3 years (±10.1) Most lesions (108 out of 196) were located on the face.
mean diameter of the selected biopsy specimens was 19.30 mm [median, 17 mm ± 13.01 mm; interquartile range (IQR), 10.00–27.50 mm]. The mean width of iSCC areas was 9.05 mm (median, 7 mm; ±7.17 mm; IQR, 3.50–13.00 mm). The anatomic level of infiltration was II in two cases (1.0%), III in 14 cases (7.1%), IV in 127 cases (64.8%), and V in 53 cases (27.0%). The mean maximum depth of infiltration was 3.83 mm (median, 3.00 mm; ±2.85 mm; IQR 2.00–5.00 mm). |
Features of the epidermis overlying iSCCs and at the edge of iSCCs, distributed according to the degree of involvement and the presence of ulceration (number of cases and corresponding percentages of total)
Adnexal involvement by atypical cells (proliferative AK) according to the thickness of atypical changes in the epidermis overlying iSCCs |
AK I, AK II and AK III lesions overlying iSCC were present in 63.8%, 17.9% and 18.4% of cases respectively. The corresponding percentages in the epidermis adjacent to iSCC were 77.9%, 6.6% and 8.3% respectively (stage could not be assessed in 8.1% of cases). Focal epidermal ulceration overlying iSCC was seen in 32% of AK I, 28.6% of AK II and 33.3% of AK III instances.
Adnexal involvement by atypical keratinocytes (proliferative AK) was present more frequently in cases with overlying AK I (39/125, 31.2%) than with AK II (8/35, 22.9%) and AKII I (5/36, 13.9%). |
Almirall has provided financial support for this study but has not participated in the elaboration and discussion of results.
Baseline characteristics of included participants were unbalanced. |
2 |
|
Fernández-Figueras et al 2018 |
To demonstrate that follicular extension of an AK is associated with the depth of invasion (Breslow) of iSCC. |
retrospective histologic review of 193 biopsy specimens of iSCC with an associated AK by three dermatopathologists
assessment of the presence and depth of follicular extension of atypical keratinocytes in the AK, using tumour (Breslow) thickness and the follicular unit level (infundibular, isthmic and subisthmic), as well as iSCC being present directly adjacent to the follicular basalis |
N=193 biopsy specimens |
Follicular extension
|
Follicular extension was present in 25.9% of the cases (50 cases), usually extending into the lower follicular segment. . In 12 of them, the atypia reached the upper portion of the follicle (infundibulum), and in three of them (25%), there was evidence of invasive squamous cell carcinoma (iSCC) originated from the follicular basalis. In 33 cases, the atypical cells reached the isthmic portion, and in 21 of them (63.6%), iSCC originated from the follicular basalis. In five cases, the atypical cells reached the isthmic portion and in all of them iSCC originated from the follicular basalis.
The iSCC was present directly adjacent to the follicular basalis in 58% of the cases (29 cases), correlating highly with the depth of follicular extension (infundibular: 3/12; isthmic: 21/33; subisthmic 5/5). |
all biopsy specimens smaller than 3 mm and larger than 2.5 cm in size and those specimens with poor architectural preservation (i.e. superficial or fragmented specimens and tumours with extensive exulceration) were excluded |
2 |
|
Ianhez et al 2013 |
To evaluate the actinic keratoses counting by various raters and suggest approaches to increase the reliability. |
Cross-sectional study: forty-three patients were evaluated by four raters (inter- and intra-rater assessment) on the face and forearms.
rating: two board-certified dermatologists and two residents of Dermatology |
N=43 patients Age: 63.1 years (range: 50–80 years) 25 females
mean actinic keratoses counts on the face and forearms were 7.7 and 9.1 |
Inter-rater agreement
Intra-rater agreement |
The overall agreement among the raters for the facial and forearm actinic keratoses was 0.74 and 0.77. The intra-rater assessment showed high rates of agreement for the face (ICC = 0.93) and forearms (ICC = 0.83).
The intra-rater agreement for 0–5, 6–10 and 11–20 counted lesions were: 0.66, 0.29 and 0.30. |
All evaluators received a specific training session on counting AKs for the study. |
2 |
|
Jiyad et al 2017 |
To provide a detailed evaluation of the consistency of AK counts on digital photographs with clinical examination in renal transplant recipients, using defined areas of skin. |
Skin sites of renal transplant recipients were examined clinically and on digital photographs by independent dermatologically-trained examiners. |
N=28 patients with 138 skin sites
Mean age: 57 ± 9 years, the majority were male (67%)
mean ± SD length of time since transplantation was 9 ± 7 years
number of AKs per skin site ranged from 0 to 14 and overall 305 AKs were diagnosed in total across all skin sites
mean ± SD number of AKs on any single skin site was 2 ± 3 |
Specificity, sensitivity, and Kendall’s tau-b correlation coefficient were calculated based on exact photographic AK counts as well as counts with ± 1 AK tolerance. |
When 138 skin sites with 305 clinical AK counts were examined for total count ± 1 AK, the sensitivity and specificity of photography was 95% and 100%, respectively.
There was a significant positive correlation between AK counts on photographs and clinical examination (Tb = 0.537) and correlation was even higher for total count ± 1 AK (Tb = 0.758).
àmoderate to strong concordance between AK counts on digital photographs and clinical examination |
Blinding was performed |
2 |
|
Röwert-Huber et al 2007 |
To propose a system that classifies an AK as an SCC, in conjunction with an atypia grading system. |
Review based on existing classification systems; modification of the existing system of Cockerell
Expert opinion |
- |
- |
The authors recommend an AK classification system that describes these lesions as squamous cell carcinomas (SCCs), using the terminology ‘early in situ SCC Type AK I’, ‘early in situ SCC type AK II’ and ‘in situ SCC type AK III’. |
No validation of the system; only expert opinion |
4 |
|
Schmitz et al 2018a |
To determine the association between chronically UV-induced tumours such as basal cell carcinomas or squamous cell carcinomas and AKASI. |
retrospective analysis of patients who had undergone oncological surgery due to UV-induced tumours and who were assessed for AKASI and Physician’s global assessment (PGA) before surgery. AKASI assessment and PGA were performed by one investigator.
Statistical analysis of the correlation between AKASI, PGA and invasive carcinomas |
N=210 patients were included Median age: 77 years (42–95) 66.2% were male 61.9%: FST II 52.4%: history of NMSC
N=626 lesions Histological evaluation revealed AKs in 298 (46.9%), BD in 88 (13.8%), SCC in 32 (5.0%), BCC in 118 (18.6%) and other tumours such as seborrhoeic keratosis in 104 (16.4%) cases |
AKASI
PGA
Statistical differences
Correlation (Spearman) |
patients exclusively presenting AKs (n = 106) showed a median (range) AKASI of 4.6 (0–15.5) and PGA of 2.0 (0–4.0)
Patients with solely noninvasive tumours (n = 43) such as AKs and BD had a median (range) AKASI of 5.0 (0.6–11.2).
Significantly higher AKASI in patients with SCC compared to patients with non-invasive lesions like AK and Bowen disease (BD) (P=0.0275).
Spearman’s coefficient of rank correlation between AKASI and PGA indicates that these measures of AK severity were strongly correlated (P < 0.0001; r = 0.90; 95% CI 0.865–0.920). |
Large sample size; retrospective design
AKASI and PGA have been evaluated by only one investigator |
2 |
|
Schmitz et al 2018b |
To determine whether there is a correlation between the commonly used histological classification scheme for AK lesions proposed by Röwert-Huber and basal epidermal growth patterns of AK.
To investigate accompanying factors such as vascular density, inflammation and involvement of adnexal structures. |
Retrospective analysis of histologically confirmed AK lesions occurring on the head/face from patients seen in routine practice
Determination of histological grade (AK I-III), basal growth patterns of atypical keratinocytes (crowding, budding and papillary sprouting) and accompanying parameters by two investigators independently from each other. |
N=246 lesions were included
Median age: 79 (56– 94) years 92.3% male 30.9% of lesions located on the scalp |
histological grade (AK I-III)
basal growth patterns of atypical keratinocytes (crowding, budding and papillary sprouting)
accompanying parameters
correlation of basal growth patterns and histological AK grades |
Of the 246 lesions included, 28.0% were histologically classified as AK I, 46.7% as AK II and 25.2% as AK III.
Approximately 26.4% of the basal growth patterns were classified as crowding (pro I), 49.6% as budding (pro II), 17.9% as papillary sprouting (pro III) and 6.1% without basal directed growth.
No significant correlation of the histological AK IIII grading and underlying growth patterns was observed (P = 0.4666). However, adnexal structure involvement (OR = 2.37; 95% CI 1.21–4.65), infiltration (OR = 2.53; 95% CI 1.31–4.90) and increased number of vessels (OR = 2.56; 95% CI 1.42–4.65) were independent positive predictive markers for pro II and pro III basal growth patterns. |
- |
2 |
|
Schmitz et al 2019a |
To investigate a possible relationship between basal growth patterns of AKs adjacent to iSCC. |
Retrospective study
Histological assessment of the epidermis overlying and adjacent to iSCCs
Determination of the histological grade (AK I–III), basal growth pattern (PRO I–III) and accompanying parameters such as adnexal involvement.
Assessments were performed by two investigators independently from each other. |
N= 307 iSCC lesions were included 73.6% male Median age: 81 (76–86)
Tumour thickness (mm), median: 1.9 (IQR 1.1–3.9) 59.6% of patients with a history of more than one iSCC
Most of the tumours were well differentiated (85.3%) and invaded into the reticular dermis (75.9%) |
histological grade (AK I–III), basal growth pattern (PRO I–III) and accompanying parameters |
Among 307 lesions, 52.4% of AKs were histologically classified as AK grade I, 38.1% as AK II and 6.8% as AK III (v2-test, P < 0.001). Only 2.6% of adjacent epidermal samples did not show any atypical keratinocytes. The epidermis adjacent to iSCCs was classified as having a PRO I basal growth pattern in 25.7%, PRO II in 31.9% and PROIII in 39.4% of cases. Only 2.9% of AKs showed no basal growth (v2-test, P < 0.001). In total 118 AKs (48.8%) showed extension into adnexal structures. These AKs were graded as PRO I in 18.6% of cases, PRO II in 30.5% and PRO III in 50.8%. The epidermis above iSCCs could be assessed only for upwards-directed growth and showed no significant differences in the three AK grades (P = 0.42). |
adjacent and overlying AKs were assessed, but the investigators were not able to evaluate the original AK from which the iSCC had originated. Changes at the mutational level most probably lead to the final progression of this distinct subtype of AK. |
2 |
|
Schmitz et al 2019b |
To compare the inter-rater reliability of the established classification of upwards directed growth of AKs (AK I–III) and the recently established classification of basal growth pattern of AKs (PRO I–III). |
Retrospective study
Histological images of 54 AKs were classified by 21 independent dermatopathologists with regard to basal proliferation (PRO I–III), histological grade (AK I–III) and assumed risk of progression into invasive carcinoma. |
N=54 AKs
Raters: 21 expert dermatopathologists, thereof 12 dermatologists (57.1%) and nine pathologists (42.9%) mean age: 43.4 (±9.6) years and a mean experience in dermatopathology of 10.9 (±8.6) years |
Classification of AK images with regard to basal proliferation (PRO I–III), histological grade (AK I–III) and assumed risk of progression into invasive carcinoma
Inter-rater reliability |
16.7% of AK (9/54) were classified as AK I, 66.7% (36/54) as AK II, and 16.7% (9/54) as AK III. With regards to basal growth pattern, 25.9% (14/54) were classified as PRO I, 42.6% (23/54) as PRO II, and 31.5% (17/ 54) as PRO III. We observed a highly significant inter-rater reliability for PRO-grading (P < 0.001) which was higher than for AK-grading (Kendall’s W coefficient: AK = 0.488 vs. PRO = 0.793). We found substantial agreement for assumed progression risk for AKs with worsening basal proliferation (k = 0.759) compared to moderate agreement (k = 0.563) for different AK-gradings. |
- |
2 |
|
Schmitz et al 2016 |
Determine whether there is a correlation between the commonly used clinical classification scheme for AK lesions proposed by Olsen et al. with that of the histological classification system developed by Roewert-Huber et al. |
Retrospective analysis
One AK lesion from patients in three pivotal clinical studies and routine practice was assessed clinically and histologically. A match in grading was defined as Olsen grade 1 being classified histologically as AK I, Olsen grade 2 as AK II and Olsen grade 3 as AK III.
Patient population for this study came from three randomized clinical trials (ALA-AK-CT002, ALA-AK-CT003 and ALA-AK-CT007) and routine clinical practice. |
N=892 patients Mean age: 71.6±7.3 83.4% male 64.0% of lesions located on face/forehead |
Classification of AK according to Olsen and Röwert-Huber
correlation between clinical and histological classification |
29.0% of lesions were classified as Olsen grade 1, 59.6% as Olsen grade 2 and 11.3% as Olsen grade 3; 19.2% were histologically classified as AK I, 69.6% as AK II and 11.2% as AK III.
Only 480 lesions (53.8%) had a matching clinical and histological classification. Of these matches, most were ‘Olsen grade 2 = AK II’ (83.1%).
The Spearman’s rank correlation coefficient for clinical and histological classification was r=0.0499 (P=0.137). |
- |
2 |
|
Sinnya et al 2015 |
To compare the inter-observer agreement between trained observers for AK counts based on photographs compared with clinical AK counts. |
Clinical AK counting was carried out in 2 sessions by 4 dermatologically trained clinicians with 6 months or more of dermatological experience and a senior consultant dermatologist with over 25 years of experience, whose counts served as practical reference standard.
The observers repeated counting from the same photographic images, 2 weeks later. |
N=6 patients (n=3 immunocompetent, n=3 OTRs) 84% male Mean age: 60 years±15 |
Agreement of AK counts: interclass and intraclass correlation coefficients (ICC) |
ICC for agreement across 5 observers for the photographic AK counts was 0.63 (95% CI 0.48–0.78) compared with 0.79 (95% CI 0.68–0.88) for clinical counts
ICC for agreement between photographic AK counts and clinical counts ranged from 0.66 (95% CI 0.48–0.81) to 0.84 (95% CI 0.73–0.91) across the 5 observers
interclass correlation coefficient for agreement between AK counts based on the same photographs but counted on 2 separate occasions ranged from 0.86 to 0.99 |
Small sample size;
Reference standard was the assessments of the senior consultant |
3 |
|
Yantsos et al 1999 |
To propose a classification system for AK. |
Expert review/opinion |
- |
Classification system |
Criteria for Grading KIN
Grade I: Clinical: Undetectable or fiat, pink macule or patch on solar damaged skin; background mottling; no roughness or hyperkeratosis. Histological: Focal atypia of basal keratinocytes of lower one-third of the epidermis.
Grade IIa: Clinical: Pink to red papule or plaque with rough, hyperkeratotic surface; minimal induration. Histological: Focal atypia of keratinocytes of the lower two thirds of the epidermis; alternating orfho and parakeratosis with sparing of acrotrichia and acrotrichia.
Grade IIb: Clinical: Similar to Ila but more induration, more hyperkeratosis and/or more erythema; all KIN lesions (other than KIN III) on lip and conjunctiva. Histological: Focal atypia of keratinocytes of at least the lower two-thirds of the epidermis; focal hyperkeratosis, often greater than Ila; one or more additional features such as acantholysis, the involvement of adnexal structures, prominent acanthosis and buds of keratinocytes into the upper papillary dermis present.
Grade III: Clinical: Red, scaly indurated plaques on sun-damaged skin; may be pigmented; seen on other sites such as mucosa in Bowenoid papulosis and erythroplasia of Queyrat; non sun-damaged skin in squamous cell carcinoma in situ induced by arsenic. Histological: Diffuse atypical keratinocytic proliferation involving the full thickness of the epidermis; parakeratosis, acanthosis, papillomatosis, involvement of adnexal structures. |
No validation of the system with real-world data or assessment of inter-rater reliability
Only expert opinion |
5 |
Klassifikation Cheilitis actinica
|
Study |
Aims |
Design |
Population |
Outcomes |
Results |
Comments and methodological assessment |
LoE |
|
Câmara et al 2016 |
To evaluate comparatively the influence of histopathological features on epithelial dysplasia (ED) and the effectiveness in usage of WHO and binary grading systems in actinic cheilitis (AC). |
Cytological and architectural alterations established by WHO for ED were evaluated in 107 cases of AC.
Epithelial dysplasia was graded using WHO (no, mild, moderate, and severe ED) and binary systems (low risk and high risk for malignant transformation).
The comparisons were performed using kappa, chi-square, and phi coefficient tests (P < 0.05). |
Lower lip biopsies from 107 cases of AC were retrieved from Universidade Federal Fluminense.
Sample was composed of 60 males (56.1%) and 47 females (43.9%) with ages ranging from 21 to 86 years (mean of 59 years). There are only light-skinned types (phototypes I, II, or III) |
presence and grade of ED |
Most cases were classified as mild ED (44.5%) in the WHO system and as low risk for malignant transformation (64.5%) in the binary system. There was a positive correlation between WHO and binary systems (k = 0.33; P < 0.0002). Loss of basal cell polarity (P < 0.001) was associated with severity of ED grade in the WHO system. Anisonucleosis (P < 0.0001), nuclear pleomorphism (P < 0.0001), anisocytosis (P = 0.03), cell pleomorphism (P = 0.002) increased nuclear/cytoplasm ratio (P < 0.0001), increased nuclear size (P < 0.0001), increased number of mitotic figures (P = 0.0006), and dyskeratosis (P = 0.008) were associated with severity of ED grade in the binary system. |
No calibration exercises were attempted by the evaluators.
Unclear whether blinding was performed. |
3 |
|
Cavalcante et al 2008 |
To analyze the clinical and histological features of actinic cheilitis (AC). |
Clinical evaluation of 29 patients with AC, incisional biopsies for confirmation of clinical diagnosis. Histological features were analyzed, and dysplasia was classified as mild, moderate, or severe. The x² test was used for the following variables: gender, age, race, and smoking habits. The degree of dysplasia was related to these variables (Fisher’s test) to test for independence between them (P<0.05). |
N=29 patients 72.41% male, 75.86% were over age 40 years 93.10% were white 72.41% were nonsmokers |
Histological features
Classification of dysplasia (mild, moderate, severe)
Associations with baseline demographic features |
Clinical findings:
Dryness (100%), atrophy (72.41%), scaly lesions (65.52%), swelling of the lip (62.07%), erythema (58.62%), ulceration (58.62%), blurred demarcation between the lip vermilion border and the skin (58-62%), marked folds along with the lip vermilion (48.28%), white spots or plaque (41.3%)s, crusts (34.48%), blotchy areas (27.59%), and areas of pallor (17.24%).
Histological findings:
Dysplasia (100%), Elastosis (100%), inflammatory infiltrate (100%), vasodilatation (100%), Hyperplasia and/or acanthosis (86.21%), hyperparakeratosis (58.62%), hyperorthokeratosis (55.17%), epithelial atrophy (55.17%), granulosis (37.92%, hypergranulosis (37.93%), parakeratosis (17.24%), orthokeratosis (3.45%)
Dysplasia was mild in 10.34% of the patients, moderate in 27.59%, and severe in 62.07%.
Gender, age, race, or smoking habits were not related to the degree of dysplasia in the sample. |
Unclear whether blinding was performed. |
3 |
|
Pilati et al 2008 |
To determine the histopathologic findings in actinic cheilitis (AC) and lip squamous cell carcinomas (LSCC) to attempt to predict the evolution from AC to LSCC based on the comparison of two dysplasia classification systems. |
Histopathologic features were evaluated according to the World Health Organization classification of dysplasia and binary system of classification. Also, in LSCC, pattern, stage of invasion, and degree of keratinization were evaluated. A total of 58 cases of AC and 70 cases of LSCC were studied, and data correlation was performed using statistical analysis. |
N= 58 cases of AC |
Histological features according to the WHO classification and binary system classification |
presence of dyskeratosis and keratin pearls was found to be strongly associated with severe dysplasia and could represent higher proximity between the severe dysplasia in AC
changes related to the nuclei, such as hyperchromasia, nuclear pleomorphism, anisonucleosis, increase in the number and size of nucleoli, increased number of mitoses, and atypical mitoses, indicate progression in dysplasia spectrum |
Unclear whether blinding was performed. |
3 |
|
Poitevin et al 2017 |
To make a proposition of a clinical score to actinic cheilitis (Grade I starting from dryness of vermilion to endured ulcers representing Grade IV) and to assess its reproducibility. |
Fifty subjects were assessed
Obtained data were analyzed by means of descriptive statistics and by Kappa test to assess the interexaminer and the clinical Golden-Pattern concordance (95% CI).
AC Grade I. Dryness and desquamation on the vermilion of lips. AC Grade II. Atrophy on the vermilion’s border, presenting soft superficies and pallid areas with eruptions. Blurred limit between the lip’s vermilion border and the skin, or a dark line demarking that limit can be seen. This melanotic line should be different from ephelides or other pigmented lesions. AC Grade III. Rough and squamous areas on the drier parts of the vermilion and hyperkeratotic areas, especially when they spread to the wet lip’s mucosa (border between mucosa and semimucosa). AC Grade IV. Ulceration present in one or more sites of the lip’s vermillion or Leukoplakia, mainly in more traumatic places, due to the history of pipe or cigarettes consumption. These lesions could suggest that a malignization process would be in progress, especially when they are accompanied by endured areas on palpation. |
N=35 patients 20 men and 15 women, 32 Caucasians, 2 mixed ethnicities and 1 black. 28 were farmers, 2 were business people, 2 were homemakers and 3 were students
average age of 46.12 (18–74) years |
interexaminer and the clinical Golden-Pattern concordance |
During calibration, 15 patients were examined three times a week by each examiner (4) until Kappa test observed k= 0.8 or more. In the main experiment, the inter-examiner concordance was classified between good (k= 0.779; Po0.05) and very good (k= 0.925; Po0.05) from the 35 examined subjects. With the Golden-Pattern, it was considered very good (k= 0.812; Po0.05 to k= 0.925; Po0.05). |
Calibration: four examiners studied and discussed it before its application. The examiners were composed of two professors of oral medicine, one student finishing dental School and one dentist with 2 years of general dentistry practice.
The study was conducted in Brazil. |
2 |
|
Santana et al 2020 |
To summarize the results of published studies on immunohistochemical biomarkers in lip carcinogenesis, to evaluate if there is a marker that can distinguish the different histological grades of AC. |
Systematic review of retrospective studies that investigated immunohistochemical biomarkers in AC defined on standardised histological assessment
Systematic literature search in 5 databases until 25 April 2017: PubMed, Scopus, Web of Science, ScienceDirect and Scielo
Partial grey literature search was conducted as well.
Meta-analysis of protein Ki-67
Qualitative appraisal using the Critical Appraisal Tools from SUMARI. |
N=27 retrospective studies were included in the systematic review and n=3 in the meta-analysis
number of AC cases in each study varied from 10 to 70 |
type of histological grading performed; immunohistochemical biomarkers that were analyzed; expression of biomarkers in each subgroup |
Among the studied biomarkers, the ones that were most investigated were DNA repair proteins, with 12 antibodies assessed. The inflammatory markers were the second most assessed group. Other groups of proteins were also analyzed, including apoptosis markers, metalloproteins, cell cycle markers, growth factors, neural and muscle markers:
The proliferation marker Ki-67 was the most studied biomarker and we observed, through meta-analysis, that it was differently expressed between AC and lip cancer, but not in AC subgroups. Ki-67 mean expression was similar in control groups and was higher in LSCC than in AC.
N=5 articles used the binary classification system |
Most studies had a high risk of bias.
Studies from Brazil were overrepresented.
High heterogeneity among studies. |
2 |
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