GNAQ and GNA11 mutant nonuveal melanoma: a subtype distinct from both cutaneous and uveal melanoma.

BACKGROUND: GNAQ and GNA11 mutant nonuveal melanoma represent a poorly characterized rare subgroup of melanoma with a gene mutation profile similar to uveal melanoma. OBJECTIVES: To characterize these tumours in terms of clinical behaviour and genetic characteristics. METHODS: Patients with nonuveal GNAQ/11 mutated melanoma were identified from the prospective multicentre tumour tissue registry ADOREG, Tissue Registry in Melanoma (TRIM) and additional cooperating skin cancer centres. Extensive data on patient, tumour and treatment characteristics were collected retrospectively. Targeted sequencing was used to determine tumour mutational burden. Immunohistochemistry staining was performed for programmed death-ligand 1 and BRCA1-associated protein (BAP)1. Existing whole-exome cutaneous and uveal melanoma data were analysed for mutation type and burden. RESULTS: We identified 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma. Tumours had a lower tumour mutational burden and fewer ultraviolet signature mutations than cutaneous melanomas. In addition to GNAQ and GNA11 mutations (nine each), six splicing factor 3b subunit 1 (SF3B1), three eukaryotic translation initiation factor 1A X-linked (EIF1AX) and four BAP1 mutations were detected. In contrast to uveal melanoma, GNAQ/11 mutant nonuveal melanomas frequently metastasized lymphatically and concurrent EIF1AX, SF3B1 and BAP1 mutations showed no apparent association with patient prognosis. Objective response to immunotherapy was poor with only one partial response observed in 10 treated patients (10%). CONCLUSIONS: Our findings suggest that GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is both clinically and genetically distinct from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed. What is already known about this topic? The rare occurrence of GNAQ/11 mutations in nonuveal melanoma has been documented. GNAQ/11 mutant nonuveal melanomas also harbour genetic alterations in EIF1AX, SF3B1 and BAP1 that are of prognostic relevance in uveal melanoma. What does this study add? GNAQ/11 mutant nonuveal melanomas show metastatic spread reminiscent of cutaneous melanoma, but not uveal melanoma. GNAQ/11 mutant nonuveal melanomas have a low tumour mutational burden that is higher than uveal melanoma, but lower than cutaneous melanoma. What is the translational message? Primary GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is clinically and genetically distinct from both cutaneous and uveal melanoma. As metastatic GNAQ/11 mutant nonuveal melanomas respond poorly to available systemic therapies, including immune checkpoint inhibition, novel therapeutic approaches for these tumours are urgently needed. Linked Comment: Rafei-Shamsabadi. Br J Dermatol 2020; 183:806-807.

Clinical diversity and treatment approaches to blastic plasmacytoid dendritic cell neoplasm: a retrospective multicentre study.

BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive type of haematologic precursor malignancy primarily often manifesting in the skin. We sought to provide a thorough clinical characterization and report our experience on therapeutic approaches to BPDCN. METHODS: In the present multicentric retrospective study, we collected all BPDCN cases occurring between 05/1999 and 03/2018 in 10 secondary care centres of the German-Swiss-Austrian cutaneous lymphoma working group. RESULTS: A total of 37 BPDCN cases were identified and included. Almost 90% of the patients had systemic manifestations (bone marrow, lymph nodes, peripheral blood) in addition to skin involvement. The latter presented with various types of cutaneous lesions: nodular (in more than 2/3) and bruise-like (in 1/3) skin lesions, but also maculopapular exanthema (in circa 1/6). Therapeutically, 22 patients received diverse combinations of chemotherapeutic regimens and/or radiotherapy. Despite initial responses, all of them ultimately relapsed and died from progressive disease. Eleven patients underwent haematopoietic stem cell transplantation (HSCT; autologous HSCT n = 3, allo-HSCT n = 8). The mortality rate among HSCT patients was only 33.33% with a median survival time of 60.5 months. CONCLUSION: Our study demonstrates the clinical diversity of cutaneous BPDCN manifestations and the positive development observed after the introduction of HSCT.

[Role of stem cell transplantation in treatment of primary cutaneous T­cell lymphoma]. / Stellenwert der Stammzelltransplantation in der Therapie kutaner T­Zell-Lymphome.

BACKGROUND: Within the heterogeneous group of cutaneous T­cell lymphomas (CTCL) the therapeutic options for advanced and progressive forms are particularly limited. OBJECTIVE: The therapeutic value of hematopoietic stem cell transplantation in CTCL was analyzed. MATERIAL AND METHODS: A literature search using the keywords "hematopoietic stem cell transplantation" and "cutaneous T­cell lymphoma" was performed in PubMed. Studies between 1990 and 2017 were taken into account. The studies identified were analyzed for relevance and being up to date. RESULTS: After reviewing the currently available literature no prospective randomized studies were found. Wu et al. showed a superiority of allogeneic transplantation in a comparison of autologous and allogeneic stem cell transplantation for cutaneous lymphoma. The graft-versus-lymphoma effect plays a significant role in a prolonged progression-free survival after allogeneic transplantation. By using a non-myeloablative conditioning regimen, stem cell transplantation can also be an option for elderly patients. The most extensive long-term data after allogeneic stem cell transplantation were reported by Duarte et al. in 2014. CONCLUSION: Autologous stem cell transplantation does not currently represent a therapeutic option, whereas allogeneic stem cell transplantation for advanced cutaneous T­cell lymphoma, using a non-myeloablative conditioning scheme, does represent a therapeutic option. However, there is no consensus on the appropriate patients and the right timing. Morbidity and mortality of complications should be taken into account. Thus, this procedure is currently subject to an individual case decision.

Brentuximab vedotin in CD30+ cutaneous lymphoma: How do we treat, how shall we treat? A review of the literature.

Brentuximab vedotin is an antibody-drug conjugate that brings the antimicrotubule agent monomethyl auristatin E into CD30-expressing cells. Some prior studies demonstrated good efficacy in cutaneous lymphomas. The standard therapeutic scheme is 1·8 mg kg-1 every 3 weeks. The background of this work is the fact that cutaneous lymphoma has a different pathophysiology and a dynamic other than systemic lymphomas. The objectives of this review were to get an overview of the currently used therapeutic regimen, and to check whether dose reduction or modified time intervals could be of benefit in a similar way with less toxicity. Therefore, we conducted a systematic review of the literature indexed in PubMed and the Cochrane Central Register of Controlled Trials up to April 2016. The procedure was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The review showed that the currently used therapeutic regimen is 1·8 mg kg-1 every 3 weeks. No publications of dose-finding studies in CD30+ cutaneous T-cell lymphoma (CTCL) were found. Two cases of patients, treated with a dose < 1·8 mg kg-1 , have been published. Brentuximab vedotin seems to be a powerful treatment option in refractory CD30+ CTCL, and there is a trend that dose reductions, as well as prolonged treatment intervals, work without any loss of response and with fewer side-effects.

[Merkel cell carcinoma of the eyelid. An often unrecognized tumor entity : Clinical aspects and treatment strategies]. / Merkel-Zell-Karzinom des Augenlids ­ eine häufig verkannte Diagnose : Klinische Aspekte und Behandlungsmethoden.

Merkel cell carcinoma of the eyelid is an aggressive, highly malignant tumor of the skin. Totaling approximately 0.5 % of all tumors of the eyelid, it constitutes a relatively small group of lid tumors. Nevertheless Merkel cell carcinoma is of significance to the ophthalmologist. Because of its clinical presentation it can be easily confused as a chalazion, a hordeolum or the lesser aggressive basal cell carcinoma. This often leads to delayed treatment. In this article we describe clinical aspects, which aim to help the ophthalmologist suspect Merkel cell carcinoma earlier. Additionally we outline a diagnostic and therapeutic workup taking into consideration the special anatomy of the eyelid.

[Adjuvant therapy and interdisciplinary follow-up care of conjunctival melanoma]. / Adjuvante Therapie und interdisziplinäre Nachsorge des Bindehautmelanoms.

BACKGROUND: Despite microscopically controlled tumor excision, malignant melanomas of the conjunctiva have a propensity for local recurrence, lymphatic spread and distant metastases. OBJECTIVES: This review outlines the options of adjuvant therapy as well as the structure of interdisciplinary follow-up care for patients with conjunctival melanoma. METHODS: The study provides a PubMed literature review and own clinical results. RESULTS: In conjunctival melanoma complete tumor excision using a minimal touch technique should always be combined with adjuvant therapy, such as cryotherapy, radiotherapy, topical chemotherapy and/or immunotherapy. For locally circumscribed lesions of the bulbar conjunctiva adjuvant brachytherapy can be supplemented and for non-bulbar, extensive, diffuse or multilocular tumor growth, complementary adjuvant topical mitomycin C therapy or proton radiotherapy can be used. Novel adjuvant approaches include topical interferon alpha-2b immunotherapy, topical vascular endothelial growth factor (VEGF) inhibitors or in cases of BRAF mutations personalized therapy using selective BRAF inhibitors or in combination with mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK), MAPK/ERK (MEK) inhibitors. All patients should be integrated into an interdisciplinary follow-up care program including quarter yearly checkups in the first 5 years and psycho-oncological healthcare. CONCLUSION: Following microscopically controlled tumor excision, adjuvant treatment using cryotherapy, radiotherapy, topical chemotherapy and/or immunotherapy as well as interdisciplinary follow-up care are mandatory for the modern management of patients with conjunctival melanoma.

[Merkel cell carcinoma]. / Merkel-Zell-Karzinom.

Merkel cell carcinoma is a rare aggressive malignant neuroendocrine skin tumor, which can metastasize to lymph nodes early and often shows local recurrence. The prognosis depends on tumor size and disease stage. The majority of recurrences appear during the first 2 years after the primary diagnosis. The 5-year survival rate for primary tumor < 2 cm is 66-75 % and for primary tumors > 2 cm is 50-60 %. With lymph node metastases the 5-year survival rate is 42-52 %, while with distant metastases it drops to 17-12 %. Extensive staging inclusive sentinel lymph node biopsy is essential to assess the risk for distant metastasis and to allow the best recommendations for therapy. After surgical treatment with adequate safety margin, subsequent adjuvant radiation therapy of the tumor region and lymphatic draining basin is recommended to reduce the risk of local recurrence and lymphatic spread.

Assessment of clinical parameters associated with mutational status in metastatic malignant melanoma: a single-centre investigation of 141 patients.

BACKGROUND: Inhibitors of the mutated, constitutively activated BRAF protein have shown efficacy in the treatment of metastatic melanoma in clinical trials. Mutation analysis especially of the BRAF, NRAS and KIT genes is essential to identify patients suitable for targeted therapies and has been introduced into routine patient care. OBJECTIVES: To correlate mutational status with clinical parameters including age, skin type, number of melanocytic naevi, primary tumour location, chronic sun damage and exposure to ultraviolet (UV) irradiation. The overall aim was to define subgroups with an increased or decreased likelihood of gene mutations. Additionally, the impact of activating BRAF mutations on clinical course was investigated. METHODS: In a single-centre, retrospective approach, mutation analysis was performed on patients with metastatic malignant melanoma. Clinical parameters were correlated with molecular findings. The total sun-burden score was assessed using a validated standardized questionnaire. RESULTS: The analysis included 141 patients with metastatic melanoma. Forty-four per cent of patients had activating BRAF mutations and were significantly younger than patients with wild-type BRAF or with NRAS mutations. KIT mutations were detected in only 3% of the patients. BRAF-mutated melanomas developed preferentially in intermittently sun-exposed areas of the body, and patients had significantly more melanocytic naevi. Once patients had progressed into stage IV disease, survival times were identical for those with BRAF-mutated and BRAF wild-type tumours. CONCLUSIONS: Mutations of the BRAF gene are correlated with younger age, a higher number of melanocytic naevi and a tumour location in intermittently UV-exposed skin. Signs of chronic photodamage are not indicative of mutational status. Patients with metastatic melanoma with BRAF mutations showed a nonsignificant tendency to progress later to stage IV disease, but once metastases were present the prognosis was identical to that with BRAF wild-type tumours.

[Personalized therapy concepts for malignant melanoma]. / Personalisierte Therapiekonzepte beim malignen Melanom.

Metastatic melanoma is commonly regarded as one of the most difficult tumor entities to treat. Up to 2011 no systemic therapy had been able to achieve a prolongation of overall survival in controlled randomized trials. Cytotoxic chemotherapy resulted in objective remission in only a small subgroup of patients. The growing insight into the molecular pathology and the discovery of frequent mutations made it possible to define melanoma subgroups suitable for targeted therapies. In approximately 50% of melanomas activating mutations of the BRAF gene were identified and can be treated with specific inhibitors. Further mutations which can be approached by targeted therapies are found on the c-Kit and NRAS genes. Another promising approach is immunotherapy aimed to activate cytotoxic T cells. A monoclonal antibody directed against CTLA-4 was approved after convincing results in clinical trials and antibodies against PD-1 or PD-L1 are currently under clinical investigation. Through these achievements life prolonging therapies are available for melanoma patients for the first time.

Allogeneic stem cell transplantation for advanced primary cutaneous T-cell lymphoma: a systematic review.

Primary cutaneous T-cell lymphomas (CTCL) are non-Hodgkin lymphomas usually running an indolent course. However, some patients progress to tumor stages or leukemic phase for which no curative treatment is available. Although initial response rates are high, remissions are often short-lived. Recent reports suggest a potential curative role for allogeneic stem cell transplantation (alloSCT). We searched databases for genetically randomized controlled trials (RCT) comparing alloSCT with conventional therapy. Data extraction and quality assessment were performed following the guidelines of the Cochrane Collaboration. Primary outcome measures were overall survival, secondary criteria included time-to-progression and response rate. A total number of 2077 primary citations were screened for relevant studies. Detailed analysis revealed that no RCTs on this subject have been performed and no systematic meta-analysis could be carried out. Nevertheless, several retrospective analyses and case series addressed the question of alloSCT for patients with advanced CTCL or Sézary syndrome. In this review, we will discuss the currently available data.

Successful Treatment of a Panniculitis-Like Primary Cutaneous T-Cell Lymphoma of the α/ß Type with Bexarotene.

Subcutaneous panniculitis-like T-cell lymphoma (SPTL) of the α/ß type is a rare subtype of non-Hodgkin's lymphoma of the skin. Although these tumors usually run an indolent course, disease-related morbidity is often severe. Clinical findings include subcutaneous tumors located on the extremities or trunk, often accompanied by systemic symptoms like fever or fatigue. Due to the low incidence of SPTL, no standardized therapy has been defined so far and there is currently no curative therapy available for this type of non-Hodgkin's lymphoma. By sharing our experience with bexarotene therapy, we present a safe and potentially improved treatment for patients with SPTL. In the case presented, bexarotene was able to induce remission even after recurrence of disease.

Donor lymphocyte infusions combined with systemic PUVA/bexarotene as an effective bimodal immunologic approach in a patient with relapsed cutaneous T cell lymphoma after allogeneic stem cell transplantation.

One central challenge of allogeneic stem cell transplantation is the positive correlation between graft versus lymphoma effect (GvL) and graft-versus-host disease (GvHD). To date, specific targeting of GvL antigens with effector T cells and of GvHD antigens with specific regulatory T cells remains the subject of experimental research. In clinical reality, negative modulation of GvHD, e.g. by immunosuppression, reduces GvL and positive modulation of GvL, e.g. by donor lymphocyte infusions, often amplifies GvHD. Clinically feasible strategies to induce GvL while simultaneously reducing GvHD are urgently needed. Here, we report the case of an early relapsed primary cutaneous T cell lymphoma in tumor stage after allogeneic stem cell transplantation which was successfully treated with a parallel administration of donor lymphocyte infusions (DLI) and systemic PUVA and bexarotene which led to sustained complete remission without onset of acute GvHD. After termination of the treatment with PUVA/bexarotene subacute chronic GvHD occurred but was subsequently brought under control by extracorporeal photopheresis. We suggest that the combination of DLI and PUVA/bexarotene might be an interesting immunologic bimodal treatment option which warrants further investigation.

[Current therapy of non-melanoma skin cancer]. / Medikamentöse Therapie nichtmelanozytärer epithelialer Tumore.

Basal cell carcinoma, actinic keratosis as a carcinoma in situ and squamous cell carcinoma are classified as non-melanoma epithelial skin cancers. These forms of skin cancer are thought to be the most common cancers worldwide with rising incidences. In the past years new insights into the pathogenesis of non-melanoma skin cancers have been gained. Through knowledge of the pathologic pathways, new treatment options have become available. This review summarizes the recent advantages of treatment options of non-melanoma skin cancer.

UVA (UVA-1) therapy for the treatment of acute GVHD of the skin.

Long-wavelength UVA (340-400 nm UVA-1) phototherapy has been reported to be effective in atopic dermatitis, localized scleroderma and T-cell-derived skin diseases. We retrospectively investigated 70 patients with acute cutaneous GVHD after allogeneic haematopoietic cell transplantation or donor lymphocyte infusion. Complete and partial responses with a median duration of 10 months were achieved in 49 (70%) and 17 (24.3%) patients, respectively. Overall, 47 (67.1%) patients were not treated with systemic steroids. Furthermore, immunosuppression could be tapered in 24 (34.3%) patients while they were receiving UVA-1 treatment. Responses were seen irrespective of age or type of conditioning. Treatment was very well tolerated. After a median follow-up of 18 (range 10-60) months, three patients developed epithelial skin neoplasia. We conclude that UVA-1 therapy is feasible, well tolerated and can be an effective treatment for acute GVHD of the skin, thereby avoiding the use of systemic steroids and/or allowing a more rapid tapering of systemic immunosuppression in a substantial number of patients. The results of this retrospective analysis warrant larger, prospective studies and the effectiveness of UVA-1 therapy should be compared with other established treatment modalities.

[Mid-dermal elastolysis]. / Elastolyse der mittleren Dermis.

Mid-dermal elastolysis is a rare dermatosis of still unknown etiology with a characteristic mid-dermal loss of elastic tissue on histopatholoy. Papular and plaque-like wrinkling of the skin as well as inflammatory and non-inflammatory variants have been described. We present a 39-year-old patient with extended skin wrinkling of the trunk and upper extremities after extensive UV light exposure and describe the clinical and histopathological findings. Based on our case, differential diagnoses are discussed and the literature is reviewed.