It was diverse, exciting and controversial – this year’s Skin Cancer Congress. The content ranged from hot topics, controversies in dermato-oncology and neoadjuvant therapy to rare skin tumors, side effect management and the availability of innovative therapies in oncology. In addition, interdisciplinary cooperation was given a large framework in order to generate the best possible treatment management for patients.
In recent years, immune checkpoint blockade (ICB) has revolutionized the treatment of patients with melanoma. The effectiveness of ICB is mainly attributed to the reactivation of CD8+ T cells, which can recognize antigens presented by MHC-I molecules on tumour cells. Despite the success of the therapy, ICB is limited by the occurrence of MHC-deficient tumor cells, which can escape recognition and destruction by CD8+ T cells. Current studies are therefore investigating the efficacy of CD4+ T cells, whose function is independent of MHC-I molecules. The clinical relevance of these resistance mechanisms of melanoma cells to immunotherapies was to be investigated in a current project [1]. For this purpose, the expression of MHC molecules and the infiltration of CD8+ T cells in cutaneous melanoma metastases were investigated using immunohistochemistry. A low expression of MHC-I was detected in a significant number of samples. In addition, a correlation of the expression of MHC-I with tumor-infiltrating CD8+ T cells was found. In an immunohistochemical analysis of MHC-II, expression was predominantly found in cells of the stroma and the immune system. Expression was particularly pronounced in the peripheral areas of the tumor and in association with infiltrating CD8+ T cells. Only in isolated cases was the expression of MHC-II on tumor cells themselves detected.
In a further, independent cohort of 20 melanoma metastases, the expression of MHC molecules was analyzed using single-cell RNA sequencing. Here, a transcriptional downregulation of MHC-I was detected in 4 of the samples. MHC-II was hardly expressed in melanoma cells. Interestingly, an association of low MHC-I expression on melanoma cells with poor treatment response to ICB was shown. In summary, the results show that a downregulation of MHC-I on melanoma cells is frequently observed, which promotes immune evasion.
Rare side effects of ICI
Vogt-Koyanagi-Harada syndrome (VKHD) is a rare multisystem disease that is based on a T-cell-mediated autoimmune reaction against melanocytes and presents clinically with uveitis, vitiligo and hair loss. More rarely, dysacusis and meningitis may also occur. VKHD can occur as a side effect of immune checkpoint inhibitor (ICI) therapy. This was the case in a 60-year-old female patient with metastatic melanoma with lymphonodal, subcutaneous and intramammary metastases who was treated with ipilimumab and nivolumab [2]. In the case of partial remission, treatment was discontinued after 30 doses of nivolumab. Therapy with pembrolizumab was initiated for new peritoneal metastases. One week after the second dose, a pronounced bilateral loss of visual acuity occurred. The ophthalmologic diagnosis was fulminant bilateral pan-uveitis with secondary macular edema, hypotomnia, optic disc swelling and retinal vasculitis. There were no indications of dysacusis. A lumbar puncture was refused. When incomplete VKHD was diagnosed, cortisone therapy with 1000 mg methylprednisolone /d. initiated over five days. The patient also received steroid eye drops and mydriatics. With slow regression of the findings, the prednisolone dose could be reduced to 100 mg i.v. /d. Following the recommendation of the interdisciplinary iTox Board, we initiated additional treatment with adalimumab 80 mg s.c.. Steroid reduction was performed on an outpatient basis. The patient is currently receiving a maintenance dose of 5 mg prednisolone p.o./d and adalimumab 40 mg s.c. every two weeks when her visual acuity has fully recovered. The current staging shows a partial remission.
In the case of VKHD, rapid initiation of high-dose immunosuppressive therapy is crucial in order to avoid chronification with secondary glaucoma or cataract and loss of vision. To date, 15 cases of VKHD with ICI have been described in the literature, including two cases with pembrolizumab. In 13 of these cases, treatment with high-dose corticosteroids was administered. Apart from the present case, only one patient received additional steroid-sparing substances (infliximab, vedolizumab). In 14/15 cases there was a complete regression of VKHD with unrestricted visual acuity. 13/15 patients showed a response to therapy. VKHD under ICI therefore has a favorable prognosis if it is detected early and treated quickly with high-dose immunosuppressants.
Atypical, metastasized dermatofibroma
Dermatofibromas are common, basically benign dermal tumors. However, there are rare histological variants with a high tendency to recur and cutaneous, lymphogenous or hematogenous metastasis. The clinical course of a patient with an atypical, metastatic dermatofibroma was presented in a case report [3]. A 46-year-old female patient presented to the Skin Tumor Center for the first time in June 2022. A history of multifocal recurrent, cell-rich atypical dermatofibroma on the right lower leg had been diagnosed. Several excisions of recurrent tumors, a flapplasty and a radiotherapy in the area of the right lower leg have already been performed. Cutaneous metastases in the area of the right leg as well as lymphogenous and pulmonary metastasis were found at the initial presentation. A reference histopathological examination confirmed the diagnosis. Due to the pronounced findings, chemotherapy with paclitaxel and radiotherapy of the right inguinal lymph node metastases was started. A presentation to the molecular tumor board revealed a RAC1 (p.P29S) and FGFR4 (p.G388R) mutation. This was followed by a change of therapy to imatinib, as paclitaxel did not show any therapeutic success. This resulted in a pronounced progression on the right leg with exophytically growing, constantly bleeding tumor nodules. Therefore, in January 2023, a therapy trial was carried out using extremity chemoperfusion of the right leg with melphalan and a TNF-α inhibitor. The tumor nodes initially regressed under this treatment. However, the tumors on the proximal right thigh grew again over time. After the costs were covered by health insurance, immunotherapy with nivolumab and ipilimumab was initiated in March 2023. After only two cycles, the discontinuation of immunotherapy was discussed with the patient due to massive tumor progression and the overall palliative situation. The case study demonstrates that atypical metastatic dermatofibroma is a rare subtype of dermatofibroma with a high tendency to recur and metastasize. Despite various therapeutic approaches, the serious course of the disease could not be prevented. If an atypical dermatofibroma is histologically suspected, reference pathological examinations are indicated. Early, radical surgical treatment and radiotherapy appear to make sense in order to prevent the disease from progressing.
Therapy of Kaposi’s sarcoma
Kaposi’s sarcoma (KS) is a rare malignant disease. Originating from lymphatic endothelial cells, it often manifests itself multilocularly, mainly on the skin and mucous membranes, less frequently in the area of lymph nodes and organs. In many cases, lesion-directed therapy can be carried out, but the approved therapy options are limited in the case of pronounced findings. In 2007, a 63-year-old patient was diagnosed with classic KS [4]. Initially, lesional therapies were carried out slowly. In 2017, progression occurred in the area of the feet and lower legs on both sides, so that percutaneous radiotherapy was initiated. This was followed in 2018 by systemic therapy with pegylated liposomal doxorubicin, which was discontinued due to palmar-plantar erythrodysesthesia. On initial presentation at the dermatology clinic at the end of 2019, brown-red to purple macules were present on the entire integument. Further diagnostics excluded mucosal, lymph node and organ involvement. A re-introduction of the pegylated liposomal doxorubicin was then initiated. After a total of seven doses, the skin findings showed progression, so that systemic therapy with the PD-1 antibody pembrolizumab was initiated. While the KS lesions clearly faded after only two months, one area on the abdomen showed a progressive, nodular and ulcerated appearance. The histopathological result after excision showed a malignant melanoma with a tumor thickness of 1.6 mm. Pembrolizumab therapy was continued and a complete remission was achieved in the further course. After seven months of therapy, the patient developed autoimmune hepatitis, which is why the therapy was discontinued. The complete remission is still ongoing.
Delyon J et al. published data from a multicenter Phase II study in 2022. Here, a total of 17 patients with KS received PD-1-directed therapy with a response rate of 71%. The case report presented here with a complete remission under therapy also underlines the good efficacy of PD-1 antibody therapy in KS. The aim is also to raise awareness of the occurrence of secondary cancers in this vulnerable patient group. Melanoma in particular is known for its ability to mimic. Accordingly, it is recommended that all suspected KS lesions should also be assessed dermatoscopically.
Prevention of skin tumors
Disseminated superficial actinic porokeratosis (DSAP) is a rare keratinization disorder that is considered a risk factor for the development of epithelial skin cancer. Treatment options include photodynamic therapy, topical imiquimod or topical retinoids, but treatment success is often frustrating. Mutations of enzymes of the mevalonate pathway, a part of cholesterol biosynthesis, lead to the accumulation of mevalonate and subsequent metabolites, which appear to be causative for the inflammatory changes typical of DSAP. The targeted topical therapy of this disorder with statins and cholesterol was first published in 2011 by Paller et al. successfully described for CHILD syndrome and published by Atzmony et al. transferred to DSAP in 2019. The aim of one study was to develop a simple and easy-to-use treatment regimen for patients with DSAP that effectively treats the disease while preventing the recurrence of skin tumors [5].
Over a period of 15 months, all patients presenting with refractory DSAP were treated with simvastatin 2%/cholesterol 2% cream and a long-term disease control regimen was established. The qualitative and quantitative assessment of the skin condition at the respective visits was carried out independently by two blinded dermatologists. Patients’ subjective satisfaction with the therapy was assessed using the TSQM. Demographic data and the development of new skin tumors during this period were also collected. During the observation period, 25 patients (16 female, 9 male) presented, seven of whom had a positive family history. Initially, treatment was given twice a day, but was reduced to once a day if there was a good tolerance and response. Over time, the therapy was switched to proactive therapy twice a week. All patients showed a response to the therapy. Patient satisfaction with the therapy was high. No new skin tumors developed during the observation period.
Thrombosis prophylaxis under ICI
Activation of the coagulatory system plays a crucial role in the spread of tumors such as melanoma, and is associated with cancer-related morbidity and mortality. While an increased risk of thromboembolic events has already been demonstrated in melanoma patients under immune checkpoint inhibition (ICI), there is still a lack of evidence on the influence of antithrombotic therapy on the course of the disease in melanoma patients treated with ICI. Data from 2258 melanoma patients who were recorded in the prospective multicenter skin cancer registry ADOREG and treated with ICI were evaluated. The primary endpoint of the study was progression-free survival (PFS) in first-line treatment of unresectable metastatic melanoma patients [6].
Melanoma patients treated with ICI who were treated with the non-steroidal anti-inflammatory drug acetylsalicylic acid (ASA), other platelet inhibitors or an oral anticoagulant due to previous thromboembolic events or cardiovascular comorbidities showed a significantly increased progression-free survival compared to patients without these concomitant therapies. The study indicates a protective effect of anticoagulant and antiplatelet concomitant medication in melanoma patients treated with ICI. When prescribing appropriate medication, the potential treatment-complementary effect can be included in the clinical decision-making process.
First real-world experiences in adjuvant therapy
The use of immune checkpoint inhibitors has revolutionized the treatment of melanoma in the distant metastatic, inoperable stage, but also in the adjuvant situation in recent years. Until now, the use of adjuvant immune checkpoint blockade was limited to treatment stages from stage III. Since July 2022, approval has been granted for adjuvant therapy with pembrolizumab from stage IIB, for which a significant reduction in the risk of distant metastases in particular has been demonstrated in the collective of all patients treated early. Valid factors that can be used to measure the benefit of early therapy for individual patients are still lacking in routine clinical practice. Therefore, a retrospective analysis of all stage IIB/C patients treated at the Skin Tumor Center since July 2022 was carried out, in which the patients’ willingness to undergo treatment was examined and psychosocial factors potentially underlying the patient-based treatment decision were identified [7].
Since July 2022, 14 patients have presented with stage IIB melanoma and six patients with stage IIC melanoma. All patients were offered adjuvant therapy with pembrolizumab, of which seven patients refused treatment. Among the treated patients, no significant influence of tumor stage, ECOG, distance to the treatment site, number of medications and mobility was found. However, a young patient age, male gender and the presence of a second tumor were identified as potential predictive factors. In the event of rejection, the most common reasons given by patients were their age and comorbidities. A disproportionately high number of patients requested time to think about the adjuvant treatment decision. The data provide an initial impression of the willingness of patients with stage IIB and IIC melanoma to undergo adjuvant immunotherapy. Overall, a rejection of the therapy was noted in over 30% of cases. This indicates that further patient education is necessary to improve acceptance of the therapy. Particular attention should be paid to psychosocial factors in the informed consent discussion.
Mucosal melanomas of the head and neck region
Melanomas of the mucous membranes (SHMM) in the head and neck area are rare and are often characterized by aggressive disease progression and a poor prognosis, especially in advanced stages. The aim was to present the necessary local radicality (primary tumor resection) and the locoregional lymph node management based on own data and a selective literature review [8]. Based on our own retrospective data, blood vessel invasion (BVI) and lymph vessel invasion (LVI) in particular should be evaluated as prognostic factors. A total of 75 patients with SHMM localizations in the conjunctiva, oral cavity and lips, nasal cavity and paranasal sinuses as well as naso- and oropharynx were included. Prognosis-relevant factors were R1 resection, distant metastasis, primary tumor location, tumor thickness (vertical invasion depth) and lymphatic or blood vessel invasion. There was no statistically significant correlation between the outcome and the safety margin for primary tumor resection. The double staining on BVI and LVI correlated significantly with the clinical outcome (survival, metastases). The cornerstone of SHMM therapy therefore remains the complete resection of the primary tumor. Selective lymph node dissection is sufficient, except in cases of proven metastasis in the locoregion, alternatively sentinel lymph node biopsy. The detection of blood and/or lymph vessel invasion is prognostically useful for identifying an increased risk profile.
ECT in cutaneous angiosarcoma
Cutaneous angiosarcoma (cAS) is a rare but highly aggressive malignant tumor with a poor prognosis. The therapy usually consists of surgery, radiotherapy and systemic therapy. Despite some phase II studies and approaches with neoadjuvant chemotherapy/radioimmunotherapy, the number of recurrences is high and the survival rate remains low. Electrochemotherapy (ECT) as an alternative or additional option in locoregional tumor control appears to be a possibility to effectively reduce the tumor burden and to sustainably support curative and prophylactic therapy approaches. As a result, it has found its way into the national S1 guideline for angiosarcoma on the basis of a small number of encouraging publications.
Based on a case series (n=5) over an observation period of >5 years, the significance and further importance of ECT as a fixed component in the treatment of cAS should be examined [9]. The retrospective data analysis includes response rates, recurrence-free time and side effects. Three patients received palliative care and three curative care. The objective response rate within one month was 100%. The palliative patients died after an average of 11.3 months. Two patients showed no signs of recurrence after 31 and 20 months respectively. These 2 pat. were treated with a combination of surgery, ECT and radioimmunotherapy.
All five cases showed an ORR of 100% and a clinical benefit (CBR) of significantly more than six months, even though two cases resulted in new lesions outside the treatment field. All patients benefited from an improved quality of life and effective tumor control with a very low side effect profile. In contrast to radiotherapy, ECT can also be used multiple times and appears to have proven itself not only in palliative situations, but also as an important integral component in the primary curative treatment of cAS.
Skin cancer prevention
Due to climate change and demographic developments, the incidence of skin cancer is expected to rise in the coming years. Preventive efforts to reduce the risk of skin cancer and promote early detection are therefore increasingly important. Under the leadership of the Arbeitsgemeinschaft Dermatologische Prävention e. V. (ADP) and the Arbeitsgemeinschaft für Berufs- und Umweltdermatologie e. V. (ADB), the S3 guideline on skin cancer prevention (AWMF register number 032/052OL, funded as part of the oncological guideline program) was published in 2021 in a completely updated and supplemented new version. With the participation of 44 specialist societies, 61 new recommendations were included at the highest level of evidence and 43 further recommendations were modified [10].
In the area of primary prevention, the topics of sunbed use and skin cancer risk are particularly noteworthy. New meta-analyses and primary studies on the association of tanning bed use with malignant melanoma and basal cell carcinoma were identified in systematic searches and an evidence-based strong recommendation to avoid tanning beds was made. In the area of early detection, the existing evidence on skin cancer screening is taken into account, on the basis of which the guideline group recommends screening. However, it is also emphasized that the currently available evidence on the effectiveness of nationwide skin cancer screening is still insufficient. In the new chapter “Climate change and UV radiation”, the guideline group recommends that prevention measures should focus on adaptation strategies to the health consequences of climate change to prevent UV and heat-related illnesses, particularly skin cancer. In this context, it is also important to protect people from unhealthy and unwanted exposure in their living environments as part of urban development and planning measures. For the prevention of occupational skin cancer, the guideline group recommends that targeted technical, organizational and personal protection and prevention measures should be integrated into the daily work routine of outdoor employees who are exposed to intensive UV radiation at work. The update of the S3 guideline “Prevention of skin cancer” is currently being continued in the form of a living guideline.
Congress: 33rd German Skin Cancer Congress (ADO)
Literature:
- Braun AD, Mengoni M, Rambow F,, et al:: Downregulation of MHC-I as an immune escape mechanism in melanoma. FV01. 33rd German Skin Cancer Congress (ADO Annual Meeting); September 06-09, 2023, Hamburg.
- Glaser AC, Grajewski R, Glauber A, et al: The Vogt-Koyanagi-Harada syndrome – a rare side effect of immune checkpoint inhibitor therapy. FV05. 33rd German Skin Cancer Congress (ADO Annual Meeting); September 06-09, 2023, Hamburg.
- Christ F, Baumert JE, Bergmann F, et al: Atypical, metastasized dermatofibroma. FV12. 33rd German Skin Cancer Congress (ADO Annual Meeting); September 06-09, 2023, Hamburg.
- Poch G, Schlaak M, Eigentler T: Efficacy of PD-1 antibodies in Kaposi’s sarcoma and fatal mimicry. FV31. 33rd German Skin Cancer Congress (ADO Annual Meeting); September 06-09, 2023, Hamburg.
- Ojak G, Crummenauer M, Wegener J, et al: Prevention of skin tumors by topical therapy of disseminated superficial actinic porokeratosis. FV36. 33rd German Skin Cancer Congress (ADO Annual Meeting); September 06-09, 2023, Hamburg.
- Zell T, Kött J, Zimmermann N, et al: Antithrombotic therapy as complementary medication in melanoma patients undergoing immunotherapy: an evaluation of the multicenter skin cancer registry ADOREG. FV37. 33rd German Skin Cancer Congress (ADO Annual Meeting); September 06-09, 2023, Hamburg.
- Bechtle L, Braun AD, Gaffal E, et al: First real-world experience with adjuvant immune checkpoint blockade of stage IIB and IIC melanoma – a unicenter experience report from the University Dermatology Clinic Magdeburg. eP084. 33rd German Skin Cancer Congress (ADO Annual Meeting); September 06-09, 2023, Hamburg.
- Wermker K: Mucosal melanomas of the head and neck region – blood and lymph vessel invasion as prognostic factors, outcome and clinical implications for the necessary surgical radicality. eP093. 33rd German Skin Cancer Congress (ADO Annual Meeting); September 06-09, 2023, Hamburg.
- Schepler H, Stege H, Grabbe S: The importance of electrochemotherapy (ECT) in the locoregional treatment of cutaneous angiosarcomas (cAS). eP121. 33rd German Skin Cancer Congress (ADO Annual Meeting); September 06-09, 2023, Hamburg.
- Hübner IM, Follmann, Breitbart EW: Prevention of skin cancer: Status quo and current recommendations from the S3 guideline Prevention of skin cancer. eP166. 33rd German Skin Cancer Congress (ADO Annual Meeting); September 06-09, 2023, Hamburg.
InFo ONKOLOGIE & HÄMATOLOGIE 2023; 11(5): 18–21
