2. Introduction – Actinic keratosis and squamous cell carcinoma of the skin

Squamous cell carcinoma of the skin (SCC) is the most common malignant skin tumor after basal cell carcinoma and is rising at an incidence rate of 80-100 per 100,000 population; in 1970-2012, age-standardized incidence rates (European age standard) increased 10-fold. Several times more common are actinic keratoses (AK), the precursors of SCC. An update and upgrade of the two existing German guidelines on AK and SCC are considered urgent for the following reasons:

• Increase in incidence and overall very high prevalence with many millions of people affected with AK nationwide in Germany
• Availability of new scientific evidence (e.g., newly published results of clinical trials with several new therapy approvals)
• Need for a systematic review of clinical studies regarding efficacy, side effects, and sustainability of a variety of therapeutic methods used in practice with classification according to the rules of evidence-based medicine
• Inclusion of topics that have not been considered so far:

- Non-invasive diagnostics (e.g,. optical coherence tomography (OCT), confocal laser scanning microscopy (CLSM)).

- UV-induced skin cancer as occupational disease (recognition of BK No. 5103 since 01.01.2015)

• Standardization of the classification

The aim of this S3 guideline on actinic keratosis and squamous cell carcinoma of the skin is to provide dermatologically and oncologically active physicians in practice and clinic with an accepted, evidence-based decision-making aid for the selection as well as implementation of appropriate measures for the diagnosis, therapy, and follow-up of these forms of fair skin cancer. The systematic presentation of study results regarding benefits and risks is intended to support physicians as well as patients in their decision making. The guideline is intended to set quality standards and thus improve the care of skin cancer patients in the long term.

 

In doing so, the guideline comments on the following questions:

Epidemiology and etiology

• Which prognostic factors are important in AK for the transition to SCC?
• Which prognostic factors are important for metastasis in SCC?

Diagnostics

• Which classification, definition, and nomenclature should be used to grade SCC? (clinical and histological)
• Which classification, definition, and nomenclature should be applied for the staging of AK? (clinical and histological)
• What is the definition of field cancerization (definition of terminology)?
• Which non-invasive diagnostic procedures are appropriate to diagnose AK and SCC?
• When, for which criteria, and how should histology be obtained?
• Which parameters should be components of the histological report of findings in AK and SCC?
• Which diagnostic of spread is indicated in patients with SCC at which stage?

Therapy of actinic keratosis

• Which forms of therapy are appropriate for the treatment of AK according to severity and clinical context?
• For which patients are which preventive therapies appropriate?

Therapy of squamous cell carcinoma

• What is the recommended therapy for the primary tumor?
• Is removal of the sentinel lymph node indicated? (In which cases?)
• For which patients is which lymph node dissection recommended?
• For which patients is adjuvant radiotherapy or postoperative radiotherapy (R1;R2) recommended?
• Which therapy is recommended for local or loco-regional recurrence?
• Which therapy is recommended for patients with distant metastatic stage (first- and second-line)?

Prevention and aftercare

• Which examinations are indicated for follow-up according to stage and at which intervals?
• Which measures are appropriate for primary prevention of SCC and AK?
• Which preventive measures are indicated specifically for at-risk groups?

Squamous cell carcinoma or/and actinic keratoses as occupational diseases

• Diagnostics in patients with occupationally increased UV exposure
• Notification of suspected occupational skin cancer

The S3 Guideline is primarily aimed at dermatologists, surgeons, radiologists and radiation therapists in clinics and practices, otorhinolaryngology specialists, oral and maxillofacial surgeons, and other medical specialties involved in the diagnosis and treatment of patients with AK or SCC.

The Guideline is also intended to provide information and guidance for primary care physicians (general practitioners), internists, gynecologists, urologists, internal oncologists, and other health care institutions (e.g., insurance companies and policy makers).

Furthermore, the guideline addresses patients with AK and/or SCC of the skin as well as patients who are at risk of developing these tumors, such as elderly patients with fair skin types, patients with UV-exposed skin, patients with occupationally high UV exposure, immunosuppressed patients (e.g. organ transplant patients, HIV-infected patients, patients with severe chronic inflammatory diseases).

A separate guideline on skin cancer prevention also exists (in German), see https://www.leitlinienprogramm-onkologie.de/leitlinien/hautkrebs-praevention/.

The S3 guideline is valid until the next update, the validity period is indicated for 5 years after the last update. Regular updates are planned.
Comments and advice for the update process are explicitly welcome and can be sent to the following address:

aktinische-keratose@leitlinienprogramm-onkologie.de

To classify the risk of bias of the identified studies, the 2011 version of the Oxford Centre for Evidence-based Medicine system listed in the table below was used in this guideline. This system provides for the classification of studies for different clinical questions (benefit of therapy, prognostic significance, diagnostic value).

 

Scheme of evidence grading according to Oxford (2011 version)

Question	Step 1 (Level 1*)	Step 2 (Level 2*)	Step 3 (Level 3*)	Step 4 (Level 4*)	Step 5 (Level 5)
How common is the problem?	Local and current random sample surveys (or censuses)	Systematic review of surveys that allow matching to local circumstances**	Local non-random sample**	Case-series**	n/a
Is this diagnostic or montitoring test accurate? (Diagnosis)	Systematic review of cross-sectional studies with consistently applied reference standard and blinding	Individual cross-sectional studies with consistently applied reference standard and blinding	Non-consecutive studies, or studies without consistently applied reference standards**	Case control studies, or “poor or non-independent reference standard**	Mechanism-based reasoning
What will happen if we do not add a therapy? (Prognosis)	Systematic review of inception cohort studies	Inception cohort studies	Cohort study or control arm of randomized trial*	Case-series or case control studies, or poor-quality prognostic cohort study**	n/a
Does this intervention help? (Treatment Benefits)	Systematic review of randomized trials or n-of-1 trials	Randomized trial or observational study with dramatic effect	Non-randomized controlled cohort/follow-up study**	Case-series, case-control studies, or historically controlled studies**	Mechanism-based reasoning
What are the COMMON harms? (Treatment Harms)	Systematic review of randomized trials, systematic review of nested case-control studies, n of-1 trial with the patient you are raising the question about, or observational study with dramatic effect	Individual randomized trial or (exceptionally) observational study with dramatic effect	Non-randomized controlled cohort/follow-up study (post-marketing surveillance) provided there are sufficient numbers to rule out a common harm. (For long-term harms the duration of follow-up must be sufficient)**	Case-series, case-control, or historically controlled studies**	Mechanism-based reasoning
What are the RARE harms? (Treatment Harms)	Systematic review of randomized trials or n-of-1 trial	Randomized trial or (exceptionally) observational study with dramatic effect
Is this (early detection) test worthwhile? (Screening)	Systematic review of randomized trials	Randomized trial	Non-randomized controlled cohort/follow-up study**	Case-series, case-control, or historically controlled studies**	Mechanism-based reasoning
* Level may be graded down on the basis of study quality, imprecision, indirectness (study PICO does not match questions PICO), because of inconsistency between studies, or because the absolute effect size is very small; Level may be graded up if there is a large or very large effect size. ** As always, a systematic review is generally better than an individual study.

 

In accordance with the AWMF regulations, the methodology of the German Guideline Program in Oncology provides for the assignment of recommendation grades by the guideline authors within the framework of a formal consensus process. Accordingly, moderated, nominal group processes or structured consensus conferences were conducted by the AWMF. During these processes, recommendations were formally voted on by the voting mandate holders (see Coordination and Editing section). The results of the respective votes (consensus strength) are assigned to the recommendations according to the categories in the table below.

In the guideline, for all evidence-based statements and recommendations, the level of evidence (see table "Scheme of evidence grading according to Oxford") of the underlying studies and, in the case of recommendations, additionally the strength of the recommendation (degree of recommendation) are shown. With regard to the strength of the recommendation, three grades of recommendation are distinguished in this guideline (see table "Scheme of recommendation grading"), which are also reflected in the wording of the recommendations in each case.

 

Scheme of recommendation grading

Grade of recommendation	Description	Expression
A	Strong recommendation	shall
B	Recommendation	should
0	Open recommendation	may/can

 

Consensus strength

Consensus strength	Percentage consensus
Strong consensus	> 95% of those eligible to vote
Consensus	> 75-95% of those eligible to vote
Majority agreement	> 50-75% of those eligible to vote
Dissent	< 50% of those eligible to vote

 

The decision criteria for determining the grades of recommendation are explained in the guideline report for this guideline.

The German Cancer Aid provided the financial means via the German Guideline Program in Oncology (GGPO). These funds were used for personnel costs, office supplies, literature procurement, and the consensus conferences (room rental, technical equipment, catering, moderator fees, travel expenses of participants). The guideline was developed in editorial independence from the funding organization.

All members submitted a written declaration of any conflicts of interest during the guideline process. The conflicts of interest disclosed in the AWMF form are listed in the guideline report for this guideline (https://www.leitlinienprogramm-onkologie.de/leitlinien/aktinische-keratosen-und-plattenepithelkarzinom-der-haut/). They were reviewed and evaluated by the coordinators and subsequently the procedure was decided by consensus in the guideline group.

The specific procedure and the consequences are also listed in the guideline report.