S3 guideline "actinic keratosis and cutaneous squamous cell carcinoma" - update 2023, part 2: epidemiology and etiology, diagnostics, surgical and systemic treatment of cutaneous squamous cell carcinoma (cSCC), surveillance and prevention.

Actinic keratosis (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline "actinic keratosis and cutaneous squamous cell carcinoma" was updated and expanded by the topics cutaneous squamous cell carcinoma in situ (Bowen's disease) and actinic cheilitis. The guideline is aimed at dermatologists, general practitioners, ear nose and throat specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings, as well as other medical specialties, policy makers and insurance funds involved in the diagnosis and treatment of patients with AK and cSCC. A separate guideline exists for patients and their relatives. In this part, we will address aspects relating to epidemiology and etiology, diagnostics, surgical and systemic treatment of cutaneous squamous cell carcinoma (cSCC), surveillance and prevention.

S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma - short version, part 1: diagnosis, interventions for actinic keratoses, care structures and quality-of-care indicators.

Actinic keratoses (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline "actinic keratosis and cutaneous squamous cell carcinoma" was developed using the highest level of methodology (S3) according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF). The guideline is aimed at dermatologists, general practitioners, ENT specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings as well as other medical specialties involved in the diagnosis and treatment of patients with AK and cSCC. The guideline is also aimed at affected patients, their relatives, policy makers and insurance funds. In the first part, we will address aspects relating to diagnosis, interventions for AK, care structures and quality-of-care indicators.

S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma (cSCC) - short version, part 2: epidemiology, surgical and systemic treatment of cSCC, follow-up, prevention and occupational disease.

Actinic keratoses (AKs) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guidelines for actinic keratosis and cutaneous squamous cell carcinoma were developed using the highest level of methodology (S3) according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF). The guidelines are aimed at dermatologists, general practitioners, ENT specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings as well as other medical specialties involved in the diagnosis and treatment of patients with AKs and cSCC. The guidelines are also aimed at affected patients, their relatives, policy makers and insurance funds. In the second part, we will address aspects relating to epidemiology, etiology, surgical and systemic treatment of cSCC, follow-up and disease prevention, and discuss AKs and cSCC in the context of occupational disease regulations.

Covering skin defects with a xenogeneic collagen matrix in comparison with a skin graft - A multicenter randomized controlled trial.

The objective of this study was to analyze, in a randomized controlled multicenter trial, whether a xenogeneic collagen matrix (XCM) could be used to cover skin defects. Patients with the need for skin excisions were recruited and randomized to treatment with a skin graft after a period of granulation or to treatment with an XCM. The results were evaluated by two independent observers on the Patient and Observer Scar Assessment Scale. On this scale, scars are ranked from 1 to 10 in six different categories. Results range from 6 to 60, with lower scores representing scars closer to normal skin. The results 6 months after reconstruction were used as primary endpoint and compared in a non-inferiority approach. A total of 39 wounds in the head and neck region were analyzed. The mean results were 16.55 (standard deviation 6.8) for XCM and 16.83 (standard deviation 8.21) in the control group. The result of the XCM was not significantly inferior to the result of the skin graft (p = 0.91). Within the limitations of the study, it seems that the use of xenogeneic collagen matrices is a viable alternative to other approaches in small skin defects, and therefore should be taken into account whenever the reduction of patient morbidity to a minimum is the priority. TRIAL REGISTRATION: This trial was registered in the German Clinical Trials Register under registration identification number DRKS00010930 and can be found under the following URLs: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00010930. https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00010930.

New Tumor Budding Evaluation in Head and Neck Squamous Cell Carcinomas.

BACKGROUND: Tumor budding (TB) is a histomorphological characteristic of the tumor invasion front and it has an impact on the tumor outcome prediction for head and neck squamous cell carcinoma (HNSCC) aetiopathology. PATIENTS AND METHODS: The average TB score (TB rel) of all tumor-positive marginal sections (n = 443) in the primary tumor was analyzed in the FFPE-fixed tumor slices of 66 patients with HNSCC, and they were compared with cryo-fixed sections. RESULTS: TB rel correlates with tumor aggressiveness (i.e., lymph node metastasis quantity, lymph node ratio, extra capsular growth, Pn1, pV1, grading). The TB scores often vary between the different tumor margins of FFPE sections in the same patient, and in many cases, they differ depending on the fixation method. CONCLUSION: Our data show that a randomly selected marginal cut cannot reliably mirror the TB score, and thus, they cannot predict the prognostic outcome. However, TB rel could be a tool that compensates for differences in TB score analysis. TB score determination in cryo sections seems to be inaccurate compared with TB determination in FFPE.

A potential new biomarker in HNSCC: metastasis suppressor protein 1 (MTSS1).

OBJECTIVE: Metastasis suppressor protein 1 (MTSS1) is a prognostic tumour marker in different malignant epithelial tumour entities and previously mainly the MTSS1 expression was analysed. This study evaluated the best analysis method as a prognosis and aggressiveness tumour marker in head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: MTSS1 expression, MTSS1 intensity, interpretation MTSS1 score and MTSS1 edging score were analysed in formalin-fixed paraffin-embedded tissue slices of 60 patients with proven HNSCC and correlated with clinical and pathological outcome parameters. RESULTS: A lack of MTSS1 expression showed tumour aggressiveness, but surprisingly, mainly MTSS1 intensity was correlated with a worse patient outcome. There was a significant correlation between higher MTSS1 intensity and an increased risk for lymph node metastasis (P = .027) and a significant increased risk for extracapsular growth (P = .016). Furthermore, disease-specific survival was worse in cases with higher MTSS1 intensity (P = .001). CONCLUSION: MTSS1 intensity has a high scientific potential for further studies and could potentially be used as a prognostic marker in diagnostic and therapeutic decision-making.

IMP3 Expression as a Potential Tumour Marker in High-Risk Localisations of Cutaneous Squamous Cell Carcinoma: IMP3 in Metastatic cSCC.

BACKGROUND: High IMP3 expression is correlated with a worse outcome. Until now, there have been no data about IMP3 expression and clinical outcome for high-risk localisation of squamous cell carcinoma of the skin (cSCC). METHODS: One-hundred twenty-two patients with cSCC of the lip and ear were included, and IMP3 expression in the tumours was immunohistochemically assessed in different evaluation approaches. Subsequently, subgroups were analysed in a matched pair approach and correlated with clinical pathologic parameters. In the following, different IMP3 analysis methods were tested for clinical suitability. RESULTS: We found a significant correlation between IMP3 expression and risk for lymph node metastasis, local relapse, and progression-free survival. CONCLUSIONS: On basis of our data, we suggest a prognostic benefit cutoff value for high (>50%) and low (<50%) IMP3 expression. Thus, IMP3 expression has a high scientific potential for further studies and could potentially be used as a prognostic marker in diagnostic and therapeutic decision-making.

Primary head and neck mucosal melanoma: Predictors of survival and a case series on sentinel node biopsy.

INTRODUCTION: Head and neck mucosal melanoma (HNMM) is a rare tumor with a poor outcome. The objective of this study was to assess outcome and prognostic factors for a cohort of patients treated in a head and neck cancer center. In addition, a case series on sentinel lymph node biopsy (SLNB) was included to evaluate it as a method for staging the node-negative neck. METHODS: A retrospective study design was chosen, and 50 patients who were treated from 1973 to 2015 in our institution for primary HNMM were included. The Kaplan-Meier method was used to estimate survival rates. Uni- and multivariate analyses were used to study the influence of possible risk factors on the patients' outcome. These risk factors included patient demographics, tumor characteristics, and treatment modalities. RESULTS: All patients were treated surgically and 50% received adjuvant treatment. The median disease specific survival (DSS) was 38 months, with a 5-year survival rate of 44%. Positive surgical margin (p = 0.004) and distant failure (p = 0.005) were associated with a worse DSS. The median disease-free survival (DFS) was 27 months, with a 5-year disease-free rate of 12%. Only tumor depth >5 mm (p = 0.002) was associated with a worse DFS. Five clinically node-negative patients received SLNB and only the two SLN-positive individuals suffered from distant failure. Radiotherapy, chemotherapy, and AJCC/UICC stage had no influence on any outcome measure. CONCLUSIONS: Positive surgical margin and distant failure are the only independent prognostic factors for DSS. Tumor depth can predict distant failure. SLNB may be a valuable staging tool for the node-negative neck.

Actinic Keratosis and Cutaneous Squamous Cell Carcinoma.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) and its precursors, actinic keratoses (AK), are common. Physicians of multiple specialties are confronted with their treatment. METHODS: This review is based on publications retrieved by a selective search in PubMed, as well as on the German guidelines on AK and cSCC, skin cancer prevention, and surgery with histologic guidance. RESULTS: Local treatments for AK include lesional cryotherapy, curettage, and laser ablation as well as field-directed treatments with topical agents, e.g., diclofenac plus hyaluronic acid, imiquimod, 5-fluorouracil, ingenol mebutate, and photodynamic therapy. These treatments can be administered in various sequences or combinations, depending on individual factors and the stage of the disease. The gold standard of treatment for cSCC is histologically confirmed complete resection; radiotherapy is an alternative. Locally uncontrollable or metastatic disease is treated with systemic drugs. The use of various chemotherapeutic agents, EGFR-directed therapies, and the PD-I inhibitor cemiplimab, either singly or in combination, has been described in uncontrolled trials and case series. Cemiplimab has a reported response rate of 47% and was recently approved for the treatment of advanced cSCC. CONCLUSION: There are many options for the treatment of AK and cSCC that must be considered in the interdisciplinary care of these entities.

Facial and midfacial symmetry in cleft patients: Comparison to non-cleft children and influence of the primary treatment concept.

PURPOSE: Patients with cleft lip, alveolus and palate (CLAP) may suffer from marked asymmetry with an impact on attractiveness and psychosocial aspects. The aim of this study was to assess symmetry in CLAP patients compared to non-cleft controls of similar age with regard to cleft type and treatment concept. MATERIALS AND METHODS: In CLAP patients with different cleft forms and in healthy non-cleft subjects (control group) a three-dimensional stereophotogrammetric face scan was performed and an objective 3D asymmetry index (AI) was calculated for the whole face, the midface, the upper lip and the nose. RESULTS: In total, 305 patients were included: 140 CLAP patients (90 male, 50 female, mean age 9.9 ± 3.6 years) and 165 controls (87 male, 78 female, mean age 8.7 ± 2.1 years). In general, CLAP patients showed significantly higher asymmetry than controls, with the most severe asymmetry found in unilateral complete CLAP. Patients treated according to an actual concept considering reconstruction of all affected muscular systems had a significant lower and more favourable AI than patients not treated according to this concept (p < 0.05). CONCLUSION: An adequate treatment concept is essential to achieve better results concerning symmetry in CLAP, but symmetry values of healthy non-cleft controls are not reached.

Risk factors for periimplantitis and implant loss in orbital implants.

BACKGROUND: After orbital exenteration a facial prosthesis is a viable option for rehabilitation. The aim of this study was to evaluate implant loss and peri-implantitis of solitary orbital implants with regard to risk factors. PATIENTS AND METHODS: Implant loss (primary outcome) and periimplantitis (secondary outcome) were reviewed retrospectively in patients who received orbital implants between 2006 and 2015 with a minimum follow-up time of 12 months. Potential risk factors were analyzed using univariate and multivariate statistics. RESULTS: 94 patients were included with 371 inserted implants and 326 implants remaining for final analysis. At the time of last follow-up 18.1% (59/326) of the implants were lost and 3.4% showed signs of periimplantitis but were still stable in situ. Daily smoking (p = 0.016, OR = 2.1), irradiation (p < 0.001, OR = 2.8) and daily alcohol abuse (p = 0.028, OR = 3.1) had a significant effect on periimplantitis and implant loss. Combining smoking and irradiation, implant failure was 46.9% versus 15.0% in patients without these risk factors (p < 0.001, OR = 5.0). Age, tumor entity, ASA Score, anticoagulation, chemotherapy, diabetes and implant position did not show a significant correlation for implant loss or - except for age - periimplantitis. Younger patients showed a higher risk of developing periimplantitis (p = 0.011). CONCLUSION: Orbital prostheses retained by solitary implants provide a solid option to reconstruct facial defects. Whereas in general high implant survival can be expected, they should be carefully considered in patients with the risk factors irradiation, smoking and alcohol abuse.

Computer-aided design of facial prostheses by means of 3D-data acquisition and following symmetry analysis.

The aim of this study was to investigate whether a method of designing digital models of facial prostheses was suitable for patients with orbital defects. 32 patients were included in a retrospective study. 23 of them already had a facial prosthesis. 3D-data of the faces were acquired optically using fringe projection technique without and with (if available) the facial prosthesis in place. The healthy side of the surface models was mirrored to reconstruct the defect area. By generating a NURBS-model, the edges of the virtual prostheses were adapted to the defect region. The CAD models were stored in STL format as templates for facial prostheses. Using an automatically calculated asymmetry index (AI), four situations of the digitized facial surface were analysed for symmetry: 1. with defect area excluded, 2. with mirrored healthy surface, 3. with digital CAD template, and 4. with manually produced facial prosthesis inserted (if available). Mean AI values were 6.05 ± 3.26 (situation 1), 4.79 ± 2.51 (situation 2), 5.12 ± 2.61 (situation), and 6.74 ± 2.77 (situation 4). Additionally, the CAD templates were rated by three anaplastologists. Ratings did not differ significantly. They partially agreed with the three statements "The CAD prosthesis fits harmoniously within the face", "The CAD prosthesis could be used for a wax pattern during conventional fabrication" and "The CAD prosthesis and the wax pattern reduce workload". The results indicate that the presented technique has the potential to increase facial symmetry and facilitate the technical procedure. However, symmetry alone is not a sufficient criterion for design of a facial prosthesis.

Influence of treatment concept, velopharyngoplasty, gender and age on hypernasality in patients with cleft lip, alveolus and palate.

OBJECTIVES: The aim of this study was to analyse cleft patients for hypernasality following velopharyngoplasty. PATIENTS AND METHODS: 95 subjects (43 females, 52 males) with cleft lip, alveolus and palate (4 - 25 years old) were analysed. Forty-three patients were treated according to the current protocol of the Cleft Palate/Craniofacial Malformations Centre of the Department of Cranio-Maxillofacial Surgery in Muenster ('MS+' group) and 52 patients were treated elsewhere according to different protocols. In 19 of the 95 patients a velopharyngoplasty had been performed. Hypernasality was judged perceptually and nasalance data was measured objectively using the NasalView system. RESULTS: Patients of the 'MS+' group showed significantly better results concerning hypernasality and nasalance data. Assessment of hypernasality and nasalance measurement showed no significant differences between subjects following velopharyngoplasty and those who had not had this operation. Gender and age did not correlate with hypernasality either. CONCLUSION: A functionally orientated treatment with early closure of lip and palate ensures optimal velopharyngeal function, optimal oro-nasal balance of resonance, low hypernasality and excellent nasalance data.

Treatment Outcome of the Transfacial Titanium Epiplating System for Total Nasal Defects.

BACKGROUND: Malignant tumors are the most frequent reason for acquired defects of the nose. Bone-anchored craniofacial prostheses represent a secure, uncomplicated, and cosmetically acceptable rehabilitative alternative to surgical reconstruction. The aim of this study was to determine a potential benefit of the Titanium Epiplating System (Fa. Medicon, Tuttlingen, Germany) as a grouped implant system in the anatomically difficult nasal region with limited bone supply. METHODS: Patients with complete nasal defects who received a transfacial Titanium Epiplating System between January of 2009 and December of 2013 for nasal prostheses were included. The Epiplating titanium plates are specially adapted to the nasal region and were modified individually. Implant survival, periimplantitis, clinical course, and risk factors for implant survival were assessed retrospectively, including univariate statistics. RESULTS: Fifty-three patients were included in this study. At the time of last follow-up, 51 of 53 Epiplating systems (96.2 percent) were stable in situ. One titanium plate had to be renewed because of a traumatic accident and one plate had to be removed because of disease recurrence. Periimplantitis occurred in 7.5 percent and could be treated successfully by either local or systemic antibiotic therapy without any loss of stability in bone anchorage. Only smoking significantly increased the risk of periimplantitis (p = 0.013), whereas age, irradiation, chemotherapy, and immunosuppression did not influence the outcome of therapy. The median healing time with use of the Titanium Epiplating System was 3.6 ± 2.7 months. CONCLUSIONS: The Titanium Epiplating System is a safe and uncomplicated system for bone-anchored retention of nasal prostheses. Good aesthetic results can be achieved. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Prediction model for lymph node metastasis and recommendations for elective neck dissection in lip cancer.

INTRODUCTION: In patients with squamous cell carcinoma (SCC) of the lip, occurrence of lymph node metastasis (LNM) is more frequent than in other cutaneous head and neck SCCs. The aim of this study was to identify predictive factors for LNM in SCC of the lip and to establish a prediction model identifying patients at high LNM risk. MATERIALS AND METHODS: Tumor characteristics of 326 patients with lip SCC were analyzed retrospectively to assess differences between the LNM group and controls. Using binary logistic and Cox regression analysis, a prediction model for LNM was calculated. RESULTS: Lymph node metastasis occurred in 26 (8%) patients. Regression analysis revealed tumor extent, tumor depth and grading as the most important factors in the correct classification of LNM in 94.2% of patients. A prediction model taking tumor depth and grading into account allowed for stratification of patients into high and low risk groups (sensitivity 92.3%, specificity 78.3%, negative predictive value 99.2%). CONCLUSIONS: Our new prediction model was able to identify patients with lip cancer who had a high risk of LNM with a good level of accuracy. This algorithm is easy to apply as part of the decision process for elective and selective lymph node dissection in SCC of the lip.