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Purpose: The use of radiation therapy (RT) for non-melanoma skin cancer (NMSC) has been changing throughout the last century. Over the last decades, the use of radiotherapy has surged with the development of new techniques, applicators, and devices. In recent years, electronic brachytherapy (eBT) devices that use small x-ray sources have been introduced as alternative to radionuclide dependence. Nowadays, several devices have been incorporated, with a few series reported, and with a short follow-up, due to the recent introduction of these systems. The purpose of this work is to describe the clinical results of our series after two years follow-up with a specific eBT system. Material and methods: This is a prospective single-center, non-randomized pilot study, to assess clinical results of electronic brachytherapy in basal cell carcinoma using the Esteya (R) system. In 2014, 40 patients with 60 lesions were treated. Patient follow-up on a regular basis was performed for a period of two years. Results: Twenty-six patients with 44 lesions achieved two years follow-up. A complete response was documented in 95.5% of cases. Toxicity was mild (G1 or G2) in all cases, caused by erythema, erosion, or alopecia. Cosmesis was excellent in 88.6% of cases, and good in the rest. Change in pigmentation was the most frequent cosmetic alteration. Conclusions: This work is special, since the equipment's treatment voltage was 69.5 kV, and this is the first prospective study with long term follow-up with Esteya (R). These preliminary report show excellent results with less toxicity and excellent cosmesis. While surgery has been the treatment of choice, certain patients might benefit from eBT treatment. These are elderly patients with comorbidities or undergoing anticoagulant treatment as well as those who simply refuse surgery or might have other contraindications.

Graft-vs-host disease (GVHD) is a multisystem disease that arises as a complication of allogeneic hematopoietic stem cell transplant. It is due to recognition of the recipient's tissues by immune cells from the donor. The skin and mucous membranes are the organs most commonly affected. GVHD is classified as acute or chronic depending on the pathophysiology and clinical presentation. Acute GVHD typically presents with the triad of rash, diarrhea, and hyperbilirubinemia, and treatment is based on systemic corticosteroid and immunosuppressant therapy. The cutaneous manifestations of chronic GVHD are divided into sclerodermiform and nonsclerodermiform, and the mucous membranes and skin appendages may also be affected. The diagnosis is mainly clinical, but skin biopsy can help in doubtful cases. Treatment can be topical, systemic, or physical, depending on the size, site, and depth of the lesions and the involvement of other organs.

Purpose: Basal cell carcinoma (BCC) is a very common cancer in the Caucasian population. Treatment aims to eradicate the tumor with the lowest possible functional and aesthetic impact. Electronic brachytherapy (EBT) is a treatment technique currently emerging. This study aims to show the outcomes of two consecutive prospective pilot clinical trials using different radiation doses of EBT with Esteya (R) EB system for the treatment of superficial and nodular basal cell carcinoma. Material and methods: Two prospective, single-center, non-randomized, pilot studies were conducted. Twenty patients were treated in each study with different doses. The first group (1) was treated with 36.6 Gy in 6 fractions of 6.1 Gy, and the second group (2) with 42 Gy in 6 fractions of 7 Gy. Cure rate, acute toxicity, and late toxicity related to cosmesis were analyzed in the two treatment groups. Results: In group 1, a complete response in 90% of cases was observed at the first year of follow-up, whereas in group 2, the complete response was 95%. The differences with reference to acute toxicity and the cosmetic results between the two treatment groups were not statistically significant. Conclusions: Our initial experience with Esteya (R) EB system to treat superficial and nodular BCC shows that a dose of 36.6 Gy and 42 Gy delivered in 6 fraction of 7 Gy achieves a 90% and 95% clinical cure rate at 1 year, respectively. Both groups had a tolerable toxicity and a very good cosmesis. The role of EBT in the treatment of BCC is still to be defined. It will probably become an established option for selected patients in the near future.

Introduction and objectives Cutaneous chronic graft-vs-host disease (GVHD) is a common complication of hematopoietic stem cell transplantation. Phototherapy is a therapeutic option for patients with skin involvement and for those who require high doses of corticosteroids. We analyze the cases treated in our department and review the literature. Material and methods All patients with GVHD treated with phototherapy in the dermatology department of Hospital Universitario y Politecnico la Fe in Valencia, Spain between March 2011 and October 2014 were identified. Data were gathered retrospectively. Results There were 16 patients: 10 treated with psoralen–UV-A and 6 with narrowband–UV-B. Complete response was achieved in 9 patients and partial response in 7; 2 patients with partial responses relapsed after treatment. Ten patients were able to decrease their dose of corticosteroids during treatment, and a further 3 decreased the number of other immunosuppressant drugs. No serious adverse effects occurred. Conclusions Phototherapy is a good therapeutic option for patients with chronic GVHD with extensive cutaneous involvement, as well as for those who fail to respond to topical treatment or who have become steroid-dependent. The main benefits are that, as the treatment targets the skin, it reduces corticosteroid requirements and has a good safety profile. Treatment must be individualized and, in our experience, both the initial dose and the maximum dose per session can be lower than for other diseases.

Resumen Introduccion y objetivos La enfermedad injerto contra huesped (EICH) cronica cutanea es una complicacion frecuente tras un trasplante de progenitores hematopoyeticos. La fototerapia es una modalidad terapeutica para pacientes con afectacion cutanea o para aquellos que precisan altas dosis de corticoesteroides (CE). El objetivo de este estudio es revisar los casos tratados en nuestro servicio y hacer una revision de la literatura. Material y metodos Recogida de datos de manera retrospectiva de todos los casos tratados desde marzo de 2011 a octubre de 2014 en el Servicio de Dermatologia del Hospital Universitario y Politecnico la Fe de Valencia. Resultados Recogimos un total de 16 pacientes, 10 tratados con PUVA y 6 con UVB-BE. Nueve pacientes obtuvieron una respuesta completa y 7 una respuesta parcial, aunque 2 recidivaron tras el tratamiento. Diez pacientes pudieron disminuir la dosis de CE durante el tratamiento y 3 pudieron disminuir el numero de otros inmunosupresores. No se presentaron efectos adversos graves. Conclusiones La fototerapia es una buena opcion terapeutica para pacientes con EICH cronica con gran afectacion cutanea, para aquellos que no responden al tratamiento topico o para pacientes corticodependientes. Su mayor beneficio es el de ser un tratamiento dirigido a la piel que permite ahorrar CE y que presenta un buen perfil de seguridad. La pauta de tratamiento se realiza de manera individualizada y, segun nuestra experiencia, con dosis iniciales y dosis maximas por sesion menores que para otras enfermedades.

Resumen El melanoma mucoso es un subtipo infrecuente de melanoma que difiere del melanoma cutaneo en su biologia, clinica y manejo. El diagnostico suele realizarse de forma tardia debido a su localizacion en zonas de dificil acceso a la exploracion fisica y a la falta de signos especificos y tempranos. La cirugia es el tratamiento de eleccion en caso de enfermedad localizada. El papel de la biopsia selectiva de ganglio centinela y de la linfadenectomia permanece todavia incierta. La radioterapia se puede emplear como tratamiento adyuvante con el fin de controlar localmente la enfermedad. Existe un mayor porcentaje de mutaciones en c-KIT que en otros tipos de melanoma, lo que ha llevado a avances significativos en el tratamiento de la enfermedad metastasica con imatinib.

BackgroundPromoter methylation of tumour suppressor genes (TSGs) has recently been implicated in the pathogenesis of several types of cancer. Regarding melanoma, over 100 genes that contribute to its pathogenesis have been identified to be aberrantly hypermethylated. ObjectivesThis is a retrospective observational study that aims to analyse the prevalence of CpG island methylation in a series of primary melanomas, to identify the associations with the main clinicopathological features, and to explore the prognostic significance of methylation in melanoma survival. Materials and methodsDNA methylation was analysed using methylation-specific multiplex ligation-dependent probe amplification in a series of 170 melanoma formalin-fixed paraffin-embedded tumour samples. The relationship between the methylation status, known somatic mutations and clinicopathological features was evaluated. Disease-free survival (DFS) and overall survival (OS) were displayed by the Kaplan-Meier method. ResultsIn the entire cohort, one or more genes were detected to be methylated in 55% of the patients. The most prevalent methylated genes were RARB 31%, PTEN 24%, APC 16%, CDH13 16%, ESR1 14%, CDKN2A 6% and RASSF1 5%. An association between aberrant methylation and aggressive clinicopathological features was observed (older age, increased Breslow thickness, presence of mitosis and ulceration, fast-growing melanomas, advancing stage and TERT mutations). Furthermore, Kaplan-Meier survival analysis showed a correlation of methylation and poorer DFS and OS. ConclusionsAberrant methylation of TSGs is a frequent event in melanoma. It is associated with aggressive clinicopathological features and poorer survival. Epigenetic alterations may represent a significant prognostic marker with utility in routine practice. What's already known about this topic? Epigenetic aberrations have recently been implicated in the development and progression of many human cancers. Regarding melanoma, over 100 genes have been identified to be aberrantly hypermethylated. What does this study add? Aberrant methylation of tumour suppressor gene promoters is associated with aggressive clinicopathological features and poorer melanoma survival. What is the translational message? DNA methylation may represent a potential prognostic biomarker for the management of patients with melanoma in routine practice. Linked Comment:van Doorn. Br J Dermatol 2018; 179:250-251. Respond to this article

Purpose: Surface electronic brachytherapy (EBT) is an alternative radiotherapy solution to external beam electron radiotherapy and high-dose-rate radionuclide-based brachytherapy. In fact, it is also an alternative solution to surgery for a subgroup of patients. The objective of this work is to confirm the clinical efficacy, toxicity and cosmesis of a new EBT system, namely Esteya ® in the treatment of nodular and superficial basal cell carcinoma (BCC). Material and methods: This is a prospective single-center, non-randomized pilot study to assess the efficacy and safety of EBT in nodular and superficial BCC using the Esteya ® system. The study was conducted from June 2014 to February 2015. The follow up time was 6 months for all cases. Results: Twenty patients with 23 lesions were included. A complete response was documented in all lesions (100%). A low level of toxicity was observed after the 4 th fraction in all cases. Erythema was the most frequent adverse event. Cosmesis was excellent, with more than 60% of cases without skin alteration and with subtle changes in the rest. Conclusions: Electronic brachytherapy with Esteya ® appears to be an effective, simple, safe, and comfortable treatment for nodular and superficial BCC associated with excellent cosmesis. It could be a good choice for elderly patients, patients with contraindications for surgery (due to comorbidities or anticoagulant drugs) or patients where surgery would result in a more disfiguring outcome. A longer follow-up and more studies are needed to confirm these preliminary results. J Contemp Brachytherapy 2015; 7, 3: 231-238 DOI: 10.5114/jcb.2015.52140

Purpose: The purpose of this study is to compare high frequency ultrasonography (HFUS) and histpathologic assessment done by punch biopsy in order to determine depth of basal cell carcinoma (BCC), in both superficial and nodular BCCs prior to brachytherapy treatment. Material and methods: This study includes 20 patients with 10 superficial and 10 nodular BCCs. First, punch biopsy was done to confirm the diagnosis and to measure tumour depth (Breslow rate). Subsequently, HFUS was done to measure tumour depth to search for correlation of these two techniques. Results: Neither clear tendency nor significance of the punch biopsy vs. HFUS depth determination is observed. Depth value differences with both modalities resulted patient dependent and then consequence of its uncertainty. Conceptually, HFUS should determine the macroscopic lesion (gross tumour volume – GTV), while punch biopsy is able to detect the microscopic extension (clinical target volume – CTV). Uncertainties of HFUS are difficult to address, while punch biopsy is done just on a small lesion section, not necessarily the deepest one. Conclusions: According to the results, HFUS is less accurate at very shallow depths. Nodular cases present higher depth determination differences than superficial ones. In our clinical practice, we decided to prescribe at 3 mm depth when HFUS measurements give depth lesion values smaller than this value. J Contemp Brachytherapy 2014; 6, 4: 356–361 DOI: 10.5114/jcb.2014.47860

Graft-vs-host disease (GVHD) is a multisystem disease that arises as a complication of allogeneic hematopoietic stem cell transplant. It is due to recognition of the recipient's tissues by immune cells from the donor. The skin and mucous membranes are the organs most commonly affected. GVHD is classified as acute or chronic depending on the pathophysiology and clinical presentation. Acute GVHD typically presents with the triad of rash, diarrhea, and hyperbilirubinemia, and treatment is based on systemic corticosteroid and immunosuppressant therapy. The cutaneous manifestations of chronic GVHD are divided into sclerodermiform and nonsclerodermiform, and the mucous membranes and skin appendages may also be affected. The diagnosis is mainly clinical, but skin biopsy can help in doubtful cases. Treatment can be topical, systemic, or physical, depending on the size, site, and depth of the lesions and the involvement of other organs.

To the Editor: We have read with an interest the letter to the Editor titled “New technologies for non-melanoma skin cancer”. In this letter, the authors comment on our article [1] about the clinical implementation of a new system for skin brachytherapy (Esteya® electronic brachytherapy by Elekta, Stockholm, Sweden) and they asked for a reply to their letter. We would like to thank the authors for their interest in our publication and would like to respond to their letter. First of all we need to clarify that in our study we chose to exclude irregularly shaped lesions, lesions with a diameter > 2 cm, and lesions with a depth larger than 4 mm because of the design of the radiation therapy system that was used. Lesions included in our work using the specific features of the Esteya® device, in fact represent the vast majority of non-melanoma skin cancer primary presentations. The Esteya® electronic brachytherapy system (E-eBT) is delivered with a set of applicators up to 3 cm in diameter. When treating non-melanoma skin cancer, typically a margin of 0.5 cm is added to the GTV. Consequently, the maximum diameter of lesions to be treated is 2 cm. The system has a dose-gradient of about 8% per mm, therefore with lesions deeper than 0.4 cm, the overdose at the first skin layers will exceed 130% and this might impact cosmetic outcome. This is the reason we limited inclusion to lesions with a depth of 4 mm or less. Finally, E-eBT applicators are designed with a flat surface to allow full contact with the skin. Avoiding air gaps between applicator and skin is a prerequisite because of the significant impact of air gaps on the dose to the lesion. Nowadays, we have the possibility to use a new set of more precise applicators for treatment of lesions in difficult areas. When we say that irregular areas are not suitable for EBT, we only mean those locations that, despite applying some pressure, are not entirely in contact with the applicator. These cases should be treated with other types of brachytherapy/radiotherapy. In our experience there are only a few locations where one cannot get a flat surface by applying mild pressure. Only larger lesions in areas with angled surfaces result in bone or cartilage, for example impeding/preventing a flat surface being obtained; this can be on the inner canthus of the eye, or for example on the pinna, and on the peri-alar nose groove. We have, however, successfully treated several “difficult cases” of BCC located on for example the nasal tip, retroauricular region, and scalp with E-eBT. It is our experience that the vast majority of NMSC lesions can be treated with the Esteya® electronic brachytherapy system. We disagree with the authors of the letter stating that “NMSC often have irregular shapes and a diameter longer than 2 cm”, and “most cases of NMSC are recurrent and located in the periorbital area (i.e. inner canthus)”. In fact, most NMSC are small, usually less than 20 mm, and the majority of lesions are located on the face, especially on the nose. Both surgery and radiation therapy are very effective and recurrence is usually found in less than 10% of cases. There is, however, a bias of patients submitted to radiotherapy since only difficult cases and lesions that have failed other treatments are referred. Better communication and cooperation between dermatology and RT services will improve referral and benefit both patients and care givers. For the less frequent appearing lesions with dimensions and shapes that are outside of the range included in our study, other radiotherapy treatment solutions besides Esteya® electronic brachytherapy are available such as brachytherapy moulds, isotope based brachytherapy with interstitial-or flap applicators, and treatment with electrons. We have read with great interest the article of Pontoriero et al. [2] that the authors of the letter to the Editor referred to. In this article, Pontoriero et al. reported their experience treating a deeply invasive lesion on the inner canthus of the eye with the Cyberknife system. Although in their case report the patient seems to have a good clinical outcome, we do have some concerns with promoting this technology in general for skin cancer treatment around the eye based on this single case. We consider the risk of intrafraction-movement as high because of very long treatment time associated with the large number of beams. In addition, there are challenges associated with the dose build up in the first layers of the skin beam, the inverse planning calculation algorithm on the first fractions of millimeter of the skin, and the use of a bolus. Also, protecting the eye from radiation damage is not easy. In our opinion, more robust research is needed to prove this technique as safe and beneficial when other therapies, such as interstitial brachytherapy with more substantial evidences are available. That new sophisticated techniques such as “Cyber Knife®” – as Dr. Pontoriero described in his letter – or particulate radiation, as a proton beam therapy, etc., could be used in selected cases, complying properly the goals for treatment of theses tumors. But on the other hand, even when it is desirable, a good knowledge on the part of radiation oncologist specialist of the full potential of these new techniques is required. The cost and complexity of these techniques, together with the necessary investment in human resources to fit the goal of these treatments, as well as short follow up of every single case referred, become, at least in our opinion, the accurate approach as a non-elective treatment for non-melanoma skin cancer. In our practice, this type of lesions on the inner canthus use to be treated with an HDR interstitial implant, with catheters just subcutaneous, and the eyes protected with a lead sheet. Although it is small invasive procedure, in our hospitals we prefer it to IMRT because of the robustness, simplicity, eye protection, dose gradient through normal tissue, and guarantee of full coverage of the lesion. In our group, we have accumulated over years a great experience treating successfully this kind of difficult tumors with this approach. We want to express our gratitude to both the letter authors and the Journal Editor, to have the opportunity to include this discussion.

Although surgery is usually the first-line treatment for nonmelanoma skin cancers, radiotherapy (RT) may be indicated in selected cases. Radiation therapy as primary therapy can result in excellent control rates, cosmetics, and quality of life. Brachytherapy is a radiation treatment modality that offers the most conformal option to patients. A new modality for skin brachytherapy is electronic brachytherapy. This involves the placement of a high dose rate X-ray source directly in a skin applicator close to the skin surface, and therefore combines the benefits of brachytherapy with those of low energy X-ray radiotherapy. The Esteya electronic brachytherapy system is specifically designed for skin surface brachytherapy procedures. The purpose of this manuscript is to describe the clinical implementation of the new Esteya electronic brachytherapy system, which may provide guidance for users of this system. The information covered includes patient selection, treatment planning (depth evaluation and margin determination), patient marking, and setup. The justification for the hypofractionated regimen is described and compared with others protocols in the literature. Quality assurance (QA) aspects including daily testing are also included. We emphasize that these are guidelines, and clinical judgment and experience must always prevail in the care of patients, as with any medical treatment. We conclude that clinical implementation of the Esteya brachytherapy system is simple for patients and providers, and should allow for precise and safe treatment of nonmelanoma skin cancers.

Mucosal melanoma is a rare melanoma subtype that differs from the cutaneous form of the tumor in its biology, clinical manifestations, and management. Diagnosis is usually late due to a lack of early or specific signs and the location of lesions in areas that are difficult to access on physical examination. Surgical excision is the treatment of choice for localized disease. The value of sentinel lymph node biopsy and lymphadenectomy is still unclear. Radiotherapy can be used as adjuvant therapy for the control of local disease. c-KIT mutations are more common than in other types of melanoma and this has led to significant advances in the use of imatinib for the treatment of metastatic mucosal melanoma.

Epstein-Barr virus-positive (EBV) diffuse large B-cell lymphoma (DLCBL) of the elderly is a newly described lymphoproliferative disorder that arises in elderly patients without a predisposing immunodeficiency. Clinical features at presentation may include lymphadenopathy, B-symptoms and extranodal involvement. The main sites of extranodal involvement are the skin, lung, tonsil and stomach. Histopathological findings include atypical large lymphoid cells with variable amounts of reactive cells, such as small lymphocytes, plasma cells and histiocytes. The neoplastic cells are positive for CD20, and in situ hybridization for EBV-encoded RNA is positive in the majority of neoplastic cells. We present a new case of EBV-positive DLBCL in an 85-year-old man, who presented to our clinic with a 2-month history of asymptomatic cutaneous lesions involving his face and scalp.