[Cutaneous squamous cell carcinoma]. / Kutanes Plattenepithelkarzinom.

Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers of the Caucasian population and accounts for 20% of all skin tumours. An S3 guideline of the German Guideline Program in Oncology has been available since 2019. The diagnosis is based on the clinical examination. Excision and histological confirmation is required for all clinically suspicious lesions to allow prognostic assessment and correct treatment. The therapy of first choice is complete excision with histological control of the surgical margin. In cSCC with risk factors such as tumor thickness >6 mm, sentinel lymph node biopsy may be discussed, but there is currently no clear evidence of its prognostic and therapeutic relevance. Adjuvant radiation therapy may be considered in cases of high risk of recurrence and should be tested in cases of inoperable tumors. The indication for electrochemotherapy should also be considered in the treatment of local or locoregional recurrence. The immune checkpoint inhibitor cemiplimab is approved for the treatment of inoperable or metastasized cSCC. In case of contraindications, chemotherapeutic agents, epidermal growth factor receptor (EGFR) inhibitors or palliative radiotherapy can be used. Since the evidence is low in these cases, a systemic therapy should be used preferentially within clinical studies. Follow-up care should be risk-adapted and includes a dermatological control, supplemented by ultrasound examinations in high-risk patients.

[Extramammary Paget's disease]. / Extramammärer Morbus Paget.

Extramammary Paget's disease (EPD) is a rare, slowly growing, cutaneous adenocarcinoma with an incidence of 0.1-2.4 per 1,000,000 inhabitants. Histologically, EPD is characterized by the presence of epidermal Paget's cells, similarly to mammary Paget's disease. The EPD is typically divided into primary EPD (type I) and secondary EPD (type II associated with colorectal carcinoma and type III associated with urogenital carcinoma). From a clinical point of view, EPD is unspecific commonly mimicking chronic inflammatory skin disorders. This unspecific clinical picture can impede and delay the diagnosis of EPD. The treatment of choice for local EPD is the micrographically controlled excision. The extent of the infiltration of adnexal structures should be histologically determined prior to topical therapies, such as imiquimod and superficial ablative therapy. The complete excision of the tumor can be challenging due to ill-defined borders. In the metastatic stage the EPD has a poor prognosis. Controlled clinical trials for systemic treatment are still lacking.

H1-antihistamine-refractory chronic spontaneous urticaria: it's worse than we thought - first results of the multicenter real-life AWARE study.

BACKGROUND: Most data on chronic spontaneous urticaria (CSU) originate from highly selected patient populations treated at specialized centres. Little is known about CSU patient characteristics and the burden of CSU in routine clinical practice. AWARE (A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation) is an ongoing global study designed to assess chronic urticaria in the real-life setting. OBJECTIVE: To describe the baseline characteristics of the first 1539 German AWARE patients with H1-antihistamine-refractory CSU. METHODS: This prospective non-interventional study included patients (18-75 years) with a diagnosis of H1-antihistamine-refractory CSU for > 2 months. Baseline demographic and disease characteristics, comorbidities, and pharmacological treatments were recorded. Quality of life (QoL) was assessed using the dermatology life quality index (DLQI), chronic urticaria QoL questionnaire (CU-Q2 oL), and angioedema QoL questionnaire (AE-QoL, in cases of angioedema). Previous healthcare resource utilization and sick leave data were collected retrospectively. RESULTS: Between March and December 2014, 1539 patients were assessed in 256 sites across Germany. The percentage of females, mean age, and mean body mass index were 70%, 46.3 years, and 27 kg/m2 , respectively. The mean urticaria control test score was 7.9, one in two patients had angioedema, and the most frequent comorbidities were chronic inducible urticaria (CIndU; 24%), allergic rhinitis (18.2%), hypertension (18.1%), asthma (12%), and depression (9.5%). Overall, 57.6% of patients were receiving at least one pharmacological treatment including second-generation H1-antihistamines (46.3%), first-generation H1-antihistamines (9.1%), and corticosteroids (15.8%). The mean DLQI, total CU-Q2 oL, and total AE-QoL scores were 8.3, 36.2, and 46.8, respectively. CSU patients reported frequent use of healthcare resources, including emergency services (29.7%), general practitioners (71.9%), and additional allergists or dermatologists (50.7%). CONCLUSIONS AND CLINICAL RELEVANCE: This study reveals that German H1-antihistamine-refractory CSU patients have high rates of uncontrolled disease, angioedema, and comorbid CIndU, are undertreated, have impaired QoL, and rely heavily on healthcare resources.

[Diagnostics of primary cutaneous lymphomas]. / Diagnostik kutaner Lymphome.

Primary cutaneous lymphomas can be diagnosed when the clinical symptoms, histology, immunohistology and molecular biological changes are characteristic of primary cutaneous T or B­cell lymphomas; however, in many cases not all of the changes are typical of a primary cutaneous lymphoma especially in the early stages; therefore, the diagnosis of a primary cutaneous lymphoma can be a challenge. This is especially true for the Sézary syndrome, which can initially prove to be difficult to differentiate from reactive erythroderma; therefore, the main focus of this review is the diagnostics of Sézary syndrome. The review also summarizes the clinical heterogeneity and describes the classical histological and immunohistochemical changes for the diagnosis of Sézary syndrome. Recent data from different multicenter, international studies by the cutaneous lymphoma task force of the European Organisation for Research and Treatment of Cancer (EORTC) on dermatological alterations of the skin and the detection of Sézary cells in blood are addressed. The detection of Sézary cells in the blood still remains a challenge despite improved molecular boiological and cytogenetic characterization of tumor cells. The latest studies of the EORTC group particularly identified CD158k, MYC, MNT, DNM, TWIST1, EPHA4 and PLS3 as valuable markers for the differentiation of reactive erythroderma but which are not yet part of the standard diagnostics of Sézary syndrome. Further studies are required to see if these markers can be used in the routine clinical application.

[Cutaneous squamous cell carcinoma]. / Kutanes Plattenepithelkarzinom.

Squamous cell carcinoma (SCC) of the skin accounts for 20 % of non-melanoma skin cancer and is one of the most frequent types of cancer in Caucasian populations. Diagnosis is based on the clinical features and should be histopathologically confirmed to adequately address the prognosis and treatment. Complete surgical excision with histopathological control of excision margins is the gold standard in the treatment of primary SCC. Sentinel lymph node biopsies (SLNB) can be considered in SCC with a tumor thickness of >6 mm but there is currently no evidence concerning prognostic and therapeutic effects. Radiotherapy can be discussed as an alternative to surgery for inoperable tumors or as adjuvant therapy for a high risk of recurrence. In SCC with distant metastases various chemotherapeutic agents are used; however, there is no standard regimen. The epidermal growth factor receptor (EGFR) inhibitors and immune checkpoint blockers can be discussed as treatment options, preferentially in clinical trials. There is no standard follow-up schedule for patients with SCC. A risk-adapted follow-up is recommended based on the risk of metastatic spread or development of new lesions primarily by dermatological control and supplemented by ultrasound investigations in high risk patients.

Segmentally arranged seborrhoeic keratoses with impending atypia and squamous cell carcinoma in an elderly woman.

Epidermal naevi (EN) are considered mosaic disorders. Postzygotic mutations are thought to occur during early embryogenesis. They are usually arranged along Blaschko's lines and tend to be noted either at birth or shortly thereafter. Skin tumours arising on EN are occasionally reported, with ongoing discussion as to whether these are collision tumours or a malignant transformation of the EN. We describe a 76-year-old woman with segmentally arranged seborrhoeic keratoses that showed impending atypia and, in one lesion, even overt malignant transformation. In biopsies from various lesions we found FGFR3 and PIK3CA hotspot mutations but there was no consistent pattern of mutations explaining the premalignant or malignant growth. So far it is unclear whether the precancerous changes as noted in this elderly patient can be taken as an unusual manifestation of one of the established types of EN, or whether this may represent a separate disorder that could be called 'SASKIA naevus'. The acronym would stand for segmentally arranged seborrhoeic keratoses with impending atypia.

Consensus on performing skin biopsies, laboratory workup, evaluation of tissue samples and reporting of the results in patients with suspected cutaneous graft-versus-host disease.

BACKGROUND: Histopathological diagnosis including selection of lesions, the determination of the best point of time for biopsy and workup is not trivial in cutaneous graft-versus-host disease (GvHD). OBJECTIVES: To develop interdisciplinary recommendations on performing, the laboratory work up and reporting of the results of skin biopsies in patients with suspected cutaneous GvHD. METHODS: A working group consisting of dermatopathologists, dermatologists, transplant-physicians and transplant-pathologists prepared recommendations for performing skin biopsies, laboratory workup and evaluation of tissue samples, and reporting of the results in patients with cutaneous GvHD. After achieving a consensus within the working group, a survey that comprised the core issues of the recommendations was electronically sent out to 72 alloHSCT centres within Germany, Austria, and Switzerland and their Departments of Pathology. The answers were discussed in a Consensus Conference and final recommendations were established. RESULTS: Twenty-five centres responded to the clinical and 17 centres to the histopathological survey. Questions addressed to the clinicians comprised the indication for skin biopsy in chronic GvHD (cGvHD) and acute GvHD (aGvHD) and the appropriate point of time for skin biopsy. Eighty-eight per cent agreed that the skin biopsy is generally indicated in patients with suspected cGvHD lacking diagnostic features. In contrast, with suspected aGvHD, only 62% of respondents felt that skin biopsy was necessary even if GvHD had not been confirmed in another organ. Although restricted due to the fact that immunosuppression is often applied in an emergency setting most centres supported skin biopsies before initiation of topical or systemic immunosuppression. The majority of pathologists agreed that in non-sclerotic GvHD a punch biopsy is adequate, whereas in sclerotic GvHD a scalpel biopsy is preferred. CONCLUSION: While a consensus on the need for biopsies in cGvHD was reached the value of skin biopsies in aGvHD and subsequent biopsies during therapy requires further evaluation.

[Kikuchi-Fujimoto's disease and adult-onset Still's disease. A rare co-occurence]. / Kikuchi-Fujimoto-Syndrom und adulter Morbus Still. Eine seltene Koinzidenz.

Kikuchi-Fujimoto's disease and adult-onset Still's disease are rare inflammatory conditions with overlapping clinical features. Adult-onset Still's disease causes high fevers, a typical salmon-colored rash, and joint pain. The principal symptom of Kikuchi's disease is cervical lymphadenopathy with typical histopathological features including extensive necrosis of the involved lymph nodes. Here, we report on a rare case of concurrent adult-onset Still's disease and Kikuchi-Fujimoto syndrome in a young Caucasian patient.

[Should metal alloy discs be used for patch testing in suspected metal implant intolerance reaction?]. / DKG-Stellungnahme zur Epikutantestung von Metalllegierungsplättchen bei Verdacht auf Metallimplantat-Unverträglichkeit.

Intolerance reactions to metal implants may be caused by metal allergy. However, prior to implantation, patch testing should not be done in a prophylactic-prophetic approach. Pre-implant patch testing should only be performed to verify or exclude metal allergy in patients with a reported respective history. In the case of implant-in particular arthroplasty-related complications like, for example, pain, effusion, skin changes, reduced range of motion, or loosening, orthopedic-surgical differential diagnostics should be performed first. Allergological workup of suspected metal implant allergy should be done with the DKG baseline series which contains nickel-, cobalt- and chromium-preparations. Various studies assessing the usefulness of metal alloy discs for patch testing proved that this approach does not give reliable information about metal allergy. Positive patch test reactions to the discs cannot be assigned to a specific metal within the disc alloy components. Furthermore, availability of such metal discs might be an invitation to uncritical testing. Accordingly, due to lack of benefit in comparison to patch testing with standardized metal salt preparations, we do not recommend patch testing with metal alloy discs.

Differential influence of vemurafenib and dabrafenib on patients' lymphocytes despite similar clinical efficacy in melanoma.

BACKGROUND: Since the majority of melanomas eventually become resistant and progress, combining selective BRAF inhibitors (BRAFi) with immunotherapies has been proposed to achieve more durable treatment responses. Here, we explored the impact of selective BRAFi on the hosts' immune system. PATIENTS AND METHODS: Clinical data, whole blood counts (WBC) and serum lactate dehydrogenase (LDH) of 277 vemurafenib- and 65 dabrafenib-treated melanoma patients were evaluated. The frequency and phenotype of lymphocyte subpopulations were determined by flow cytometry while T cell cytokine secretion was measured by multiplex assays. RESULTS: Progression-free survival (PFS) as well as overall survival (OS) were similar in patients treated with either BRAFi. High pretreatment LDH was associated with shorter PFS and OS in both groups. During therapy, peripheral lymphocytes decreased by 24.3% (median, P < 0.0001) in vemurafenib-treated patients but remained unchanged in dabrafenib-treated patients (+1.2%, P = 0.717). Differentiation of peripheral lymphocytes of vemurafenib-treated patients showed a significant decrease in CD4(+) T cells (P < 0.05). Within CD4(+) T cells obtained during treatment, an increase in CCR7(+)CD45RA(+) (naïve) and a decrease in CCR7(+)CD45RA(-) (central memory) populations were found (P < 0.01 for both). Furthermore, secretion of interferon-γ and interleukin-9 by CD4(+) T cells was significantly lower in samples obtained during vemurafenib treatment compared with baseline samples. CONCLUSION: While both compounds have comparable clinical efficacy, vemurafenib but not dabrafenib decreases patients peripheral lymphocyte counts and alters CD4(+) T cell phenotype and function. Thus, selective BRAFi can significantly affect patients' peripheral lymphocyte populations. Fully understanding these effects could be critical for successfully implementing combinatorial therapies of BRAFi with immunomodulatory agents.

Histopathological diagnosis of graft-versus-host disease of the skin: an interobserver comparison.

BACKGROUND: Histopathology is an important tool in diagnosing cutaneous graft-versus-host disease (GvHD). Minimum diagnostic criteria for active chronic GvHD have recently been defined. However, they are not specific and their interpretation is dependent on observer judgement. AIMS OF THE STUDY: i) to explore interobserver variability in the interpretation of histopathological changes in GvHD, and ii) to analyse the impact of detailed clinical data on histopathological diagnosis of GvHD. METHODS: Histopathological slides from 15 skin biopsies of GvHD and from dermatoses with histopathologically similar appearance were sent in two phases to four dermatopathologists experienced in cutaneous GvHD in France, Germany, Italy and Switzerland (first round of 'blind' review followed by a second round with complete clinical information provided). RESULTS: Interface dermatitis, especially vacuolar alteration, was the most inconsistently evaluated, particularly in cases with minor alterations. Interestingly, for vacuolar alteration and apoptotic keratinocytes, interobserver variability was lower in the adnexal epithelia than in the interfollicular epidermis. Complete clinical information resulted in increased diagnostic confidence and greater concordance on the final diagnosis, rising from 53% (first round, k = 0.345, fair agreement) to 80% (second round, k = 0.529, moderate agreement). The percentage of correct diagnoses increased from 33.3% to 80%. CONCLUSION: For the diagnosis of GvHD, histopathological analysis is of importance, but, for correct diagnosis, the correlation of pathological findings with clinical results is crucial. In cases of minor alteration, histopathologists should focus on the interpretation of vacuolar changes and apoptotic keratinocytes, possibly on the adnexal epithelia.

Guidelines on the use of extracorporeal photopheresis.

BACKGROUND: After the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi-disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease. MATERIALS AND METHODS: In order to provide recognized expert practical guidelines for the use of this technology for all indications the European Dermatology Forum (EDF) proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. RESULTS AND CONCLUSION: These guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion.

[Cutaneous squamous cell carcinoma: a review with consideration of special patient groups]. / Kutanes Plattenepithelkarzinom unter Berücksichtigung besonderer Patientengruppen.

The incidence of non-melanoma skin cancer (NMSC) is increasing. Squamous cell carcinoma of the skin (SCC) is a tumor of the elderly. Due to the increasing life expectancy, SCC will become more and more frequent in the future. Generally SCC has a favorable prognosis. Standard therapy is microscopically- controlled excision. Therapy of advanced and metastatic SCC is still challenging. Patients with regional lymph node metastasis have ten-year survival rates less than 20%; patients with distant metastases less than 10%. Immunosuppression has been shown to be one of the key prognostic factors for metastasis. The article reviews SCC and focusses on patients being at risk for an unfavorable course.

TERT promoter mutations in ocular melanoma distinguish between conjunctival and uveal tumours.

BACKGROUND: Recently, activating mutations in the TERT promoter were identified in cutaneous melanoma. We tested a cohort of ocular melanoma samples for similar mutations. METHODS: The TERT promoter region was analysed by Sanger sequencing in 47 uveal (ciliary body or choroidal) melanomas and 38 conjunctival melanomas. RESULTS: Mutations of the TERT promoter were not identified in uveal melanomas, but were detected in 12 (32%) conjunctival melanomas. Mutations had a UV signature and were identical to those found in cutaneous melanoma. CONCLUSION: Mutations of TERT promoter with UV signatures are frequent in conjunctival melanomas and favour a pathogenetic kinship with cutaneous melanomas. Absence of these mutations in uveal melanomas emphasises their genetic distinction from cutaneous and conjunctival melanomas.

Reliability and cost-effectiveness of complete lymph node dissection under tumescent local anaesthesia vs. general anaesthesia: a retrospective analysis in patients with malignant melanoma AJCC stage III.

BACKGROUND: Complete lymph node dissection (CLND) in melanoma patients with a positive sentinel lymph node (SLN) is currently being debated, as it is a cost-intensive surgical intervention with potentially high morbidity. OBJECTIVE: This clinical study seeks to clarify the effectiveness, reliability and cost-effectiveness of CLND performed under tumescent local anaesthesia (TLA) compared with procedures under general anaesthesia (GA). METHODS: We retrospectively analysed the data from 60 patients with primary malignant melanoma American Joint Committee on Cancer stage III who underwent CLND. RESULTS: Altogether 26 (43.3%) patients underwent CLND under TLA and 34 (56.7%) patients underwent CLND under GA. Fifteen of 43 (34.9%) patients had a complication, such as development of seromas and/or wound infections. The rate of complications was 25.0% (3/12) in the axilla subgroup and 28.6% (4/14) in the groin subgroup of the TLA group. In the GA group, the complication rate was 31.3% (5/16) in the axilla subgroup and 44.4% (8/18) in the groin subgroup. The costs for CLND were significantly less for the CLND in a procedure room performed under TLA (mean €67.26) compared with CLND in an operating room under GA (mean €676.20, P < 0.0001). CONCLUSIONS: In conclusion, this study confirms that TLA is an excellent, safe, effective and cost-efficient alternative to GA for CLND in melanoma patients.

Advantages of preoperative ultrasound in conjunction with lymphoscintigraphy in detecting malignant melanoma metastases in sentinel lymph nodes: a retrospective analysis in 221 patients with malignant melanoma AJCC Stages I and II.

BACKGROUND: Sentinel lymph node excision (SLNE) for the detection of regional nodal metastases and staging of malignant melanoma has resulted in some controversies in international discussions as it is a surgical intervention with potential morbidity. OBJECTIVE: The present retrospective study seeks to clarify the reliability of preoperative ultrasonography (US) in direct comparison to the result of SLNE and seeks to identify potential advantages of preoperative ultrasound if performed in conjunction with lymphoscintigraphy in detecting malignant melanoma metastases in sentinel lymph node (SLN). PATIENTS: We retrospectively analysed data from 221 patients with primary malignant melanoma with a Breslow index of ≥ 1.0 mm. RESULTS: Of the 221 patients, 77.4% (n = 171) had a negative SLN. In 50 patients (22.6%), the histopathological investigation of 71 excised lymph nodes resulted in a positive SLN. The US examination demonstrated a sensitivity of 13.6%, a specificity of 96.9%, a positive predictive value of 97.2% and a negative predictive value of 12.6%. SLNE alone shows a sensitivity of 94%, a specificity of 98.6%, a positive predictive value of 100% and a negative predictive value of 98.3%. Preoperative US in conjunction with dynamic lymphoscintigraphy, followed by SLNE, demonstrated a detecting ratio of 100% (n = 28) for micrometastases and 98.6% (n = 42/43) for macrometastases. CONCLUSION: In conclusion, this study confirms that preoperative US alone cannot replace the vital information obtained during dynamic lymphoscintigraphy. But preoperative US is an important component of the staging procedure in melanoma patients and has clear advantages when performed in conjunction with dynamic lymphoscintigraphy. Therefore, we recommend preoperative US before every SLNE.

Reliability and cost-effectiveness of sentinel lymph node excision under local anaesthesia versus general anaesthesia for malignant melanoma: a retrospective analysis in 300 patients with malignant melanoma AJCC Stages I and II.

BACKGROUND: Sentinel lymph node excision (SLNE) for the detection of regional nodal metastases and staging of malignant melanoma has resulted in some controversies in international discussions, as it is a cost-intensive surgical intervention with potentially significant morbidity. OBJECTIVE: The present retrospective study seeks to clarify the effectiveness and reliability of SLNE performed under tumescent local anaesthesia (TLA) and whether SLNE performed under TLA can reduce costs and morbidity. Therefore, our study is a comparison of SLNE performed under TLA and general anaesthesia (GA). PATIENTS: We retrospectively analysed data from 300 patients with primary malignant melanoma with a Breslow index of ≥1.0 mm. RESULTS: Altogether, 211 (70.3%) patients underwent SLNE under TLA and 89 (29.7%) patients underwent SLNE under GA. A total of 637 sentinel lymph nodes (SLN) were removed. In the TLA group 1.98 SLN/patient and in the GA group 2.46 SLN/patient were removed (median value). Seventy patients (23.3%) had a positive SLN. No major complications occurred. The costs for SLNE were significantly less for the SLNE in a procedures room performed under TLA (mean € 30.64) compared with SLNE in an operating room under GA (mean € 326.14, P<0.0001). CONCLUSION: In conclusion, SLNE performed under TLA is safe, reliable, and cost-efficient and could become the new gold standard in sentinel lymph node diagnostic procedures.