S1-Guideline: Microscopically controlled surgery.

Microscopically controlled surgery (MCS) comprises various methods allowing histologically proven complete resection of malignant tumors while at the same time sparing the tumor-free tissue in the immediate vicinity as much as possible. All procedures subsumed under MCS have in common the marking of the excised tissue for topographical orientation, which provides an assignment of remaining tumor remnants. Indications for MCS are malignant skin tumors in problem localizations as well as aggressive subtypes of skin tumors. Established indications for MCS include basal cell carcinoma, cutaneous squamous cell carcinoma, Bowen's disease as well as Bowen's carcinoma, dermatofibrosarcoma protuberans, melanoma in chronically light-damaged skin as well as acral lentiginous melanoma and Merkel cell carcinoma. For other tumors such as extramammary Paget's disease and various cutaneous sarcomas, evidence exists that MCS has demonstrated benefits, such as local recurrence rates. In addition, MCS is indicated when it is foreseeable that a complex closure technique is required and complete resection of the tumor must be assured. Various methods of MCS have been described, including 3D histology, horizontal method and Mohs surgery. A close cooperation of qualified surgeons and (dermato)pathologists as well as laboratory staff is essential for the successful application of MCS.

Granuloma annulare - is it a paraneoplastic condition for malignant lymphoma?

In recent years, an association between granuloma annulare and the occurrence of malignant cutaneous lymphomas in the sense of a facultative paraneoplasia has been observed several times. The aim of the present work is to provide an overview of the currently available literature on granuloma annulare as well as an analysis of its association with cutaneous lymphomas. Using the example of two patients with granuloma annulare and associated cutaneous lymphomas, we would like to sensitize clinically active dermatologists and dermatopathologists to the possible association between these two diseases. Characteristic features and clinicopathological signs are discussed, which should raise suspicion of an associated malignant lymphoma. It is recommended to rule out an underlying cutaneous and/or extracutaneous lymphoma in unusual clinical constellations (for instance distribution pattern, subjective complaints, age at first manifestation, lack of response to conventional therapy), especially in the absence of other known clinical triggers of granuloma annulare such as insect bites, trauma or varicella-zoster infections, among others. However, in individual cases the criteria mentioned here justify lymphoma screening.

Current concepts of ectopic nodal inclusions with special emphasis on nodal nevi.

Nodal inclusions of ectopic tissue within lymph nodes are seen comparatively often in dermatopathology and general pathology. Glandular and nonglandular epithelium, as well as melanocytic nevi can be observed within lymph nodes and represent mostly incidental findings without any relevance. The main challenge in reporting these morphologic features is to differentiate such benign inclusions from metastatic settlements of distinct organ tumors. As sentinel node biopsy and lymph node dissection have become standard procedure in clinical oncology and have an immense clinical impact, the correct evaluation of these nodal inclusions is indispensable to avoid undertreatment or overtreatment of patients. In addition, the genesis of these inclusions has not yet been satisfactorily clarified. Two concepts have been laid out: the theory of benign metastases and the migration arrest theory. However, neither theory has so far been able to answer the following questions: Why do we find more nodal nevi in patients with melanoma who had a sentinel node biopsy than in patients without melanoma, and why do we not find nodal nevi in deep visceral lymph nodes? We present a comprehensive review of the current knowledge on nodal inclusions, proposing a concept for the pathogenesis of nodal nevi, to answer these questions.

Primary cutaneous diffuse large B-cell lymphoma, NOS and leg type: Clinical, morphologic and prognostic differences.

BACKGROUND AND OBJECTIVES: Primary cutaneous diffuse large B-cell lymphoma, NOS (PCLBCL/NOS) is a rare PCLBCL. Only few data are available for this tumor. The aim of this study was to identify clinical and/or immunohistochemical markers (in addition to Bcl-2) that characterize PCLBCL/NOS, assist in differentiating it from PCLBCL, leg type (PCLBCL/LT) and help to assess the clinical course/prognosis. PATIENTS AND METHODS: Bcl-2- PCLBCL/NOS) cases (n = 14 were compared with Bcl-2+ PCLBCL/LT cases (n = 29). RESULTS: PCLBCL/NOS patients were younger, predominantly male and had better survival rates than patients with PCLBCL/LT. Patients with PCLBCL/NOS presented more often with larger plaques limited to one or two contiguous body regions, whereas PCLBCL/LT cases often presented with disseminated lesions. Neoplastic cells had a higher proliferation rate (Ki67) in PCLBCL/LT patients. The tumor microenvironment of PCLBCL/NOS had a more prominent CD3+ infiltrate. Overall survival data for the whole cohort (n = 37) revealed that female gender and Bcl-2 expression correlated with a worse survival rate. Bcl-6 expression and centroblastic subtype correlated with better outcomes. None of the other markers studied (e.g. GCB/non-GCB subtype) correlated with survival rate. CONCLUSIONS: PCLBCL/NOS and PCLBCL/LT differ in their clinical behavior and outcomes. Bcl-2 still seems to be the best marker for discriminating between these two subgroups. Bcl-2, female gender and Bcl-6 represent prognostic markers for PCLBCL.

Dermatological manifestations of tuberous sclerosis complex (TSC).

Tuberous sclerosis complex (TSC) is a genetic multisystem disorder with prominent skin involvement that frequently occurs in early childhood. Dermatologic manifestations include facial angiofibromas, hypomelanotic macules, fibrous cephalic plaques, shagreen patches, and ungual fibromas. The International TSC Consensus Conference in 2012 provided guidelines for standardized baseline evaluation and follow-up. Detailed clinical dermatological evaluation at the time of diagnosis and annual skin examination is recommended for both pediatric and adult populations. The onset of dermatological manifestations is clearly age-related. However, dermatologists also have to assess for clinical manifestations beyond their own specialty. With advances in genetics and the advent of mTORC1 inhibitors, new specific therapeutic options have become available for TSC patients with skin manifestations. Early intervention is commonly recommended for symptomatic, rapidly evolving, disfiguring, or debilitating lesions. The consensus guidelines recommend "treatment as appropriate for the lesion and clinical context" and suggest the use of surgical excision, laser therapy, or topical mTORC1 inhibitors. Topical mTORC1 inhibitors present a useful option for TSC-associated skin lesions, particularly in medically complex patients. They may prevent or reduce the risks of subsequent surgeries and permanent scarring.

First report of an aneurysmal bone cyst presenting as subungual mass.

Painful subungual tumor masses in the toes usually emerge as glomus tumors or subungual exostoses. We present a patient with an aneurysmal bone cyst located subungually in whom the diagnosis was delayed due to inadequate diagnostic procedures, which led to marked destruction of the distal phalanx of the great toe of the right foot. After biopsy, the distal phalanx could not be preserved due to critical soft tissue involvement and the size of the process. Thus, we describe this rare entity to encourage clinicians to establish the diagnosis by biopsy of a tissue swelling of unclear origin and duration that does not resolve after a short time. Imaging examinations are useful in demonstrating periosteal involvement and extension of the lesion and can be helpful in the diagnostic algorithm. An interdisciplinary approach is a top priority to ensure optimal treatment.

On the significance of negative-pressure wound therapy with instillation in dermatology.

Methods used in the treatment of acute and chronic wounds undergo constant evolution, reevaluation, and innovation. While negative-pressure wound therapy (NPWT) is an established treatment modality, the combination of NPWT and instillation of normal saline as well as solutions with active antiseptic components for topical treatment of the wound bed represents a novel approach. The well-known effects of NPWT may thus be combined with those of local antisepsis. They include a decrease in wound area, induction of granulation tissue, and reduction in bacterial colonization. To date, studies have focused on NPWT with instillation for orthopedic/surgical indications, whereas clinical data in dermatosurgery is limited to case reports or small case series. There are as yet no randomized prospective studies investigating NPWT with instillation in the treatment of skin disorders. The goal of this review is to present the method of NPWT with instillation, to highlight its mode of action as well as possible complications and contraindications, and to review the recent literature. In summary, there is increasing evidence that both simple and complicated wounds may be effectively treated with NPWT with instillation, resulting in markedly accelerated tissue granulation and thus earlier defect closure.

Zum Stellenwert der Unterdruck-Instillationstherapie in der Dermatologie.

Die Methoden zur Behandlung akuter und chronischer Wunden unterliegen einer steten Weiterentwicklung, Reevaluierung und Anwendung innovativer Therapieformen. Die Vakuumtherapie zur Wundbehandlung gehört zu den etablierten Behandlungsmodalitäten. Ein innovatives Verfahren kombiniert die Vakuumtherapie mit der automatisierten, kontrollierten Zufuhr und Drainage wirkstoffhaltiger Lösungen zur topischen Wundbehandlung im Wundbett und auch wirkstofffrei durch Instillation physiologischer Kochsalzlösung (Unterdruck-Instillationstherapie). Hierdurch können die Effekte der konventionellen Vakuumtherapie mit denen der lokalen Antisepsis kombiniert werden. Hierdurch kommt es zu einer Reduktion der Wundfläche, einer Induktion von Granulationsgewebe sowie einer Reduktion der Keimbesiedelung der Wunden. Bisher publizierte Studien konzentrieren sich auf die Anwendung dieses Therapieverfahrens zur Behandlung orthopädisch-chirurgischer Krankheiten. Die Datenlage bezüglich der Vakuum-Instillationstherapie in der Dermatochirurgie beschränkt sich derzeit auf Fallberichte und Einzelfallerfahrungen. Randomisierte, prospektive Studien zum Vergleich der Vakuum-Instillationstherapie zur Behandlung dermatologischer Krankheitsbilder existieren bislang nicht. Ziele des vorliegenden Artikels sind die Vorstellung der Vakuumtherapie mit Instillation einschließlich ihres Wirkprinzips, deren mögliche Komplikationen, die Diskussion erdenklicher Kontraindikationen sowie eine Übersicht über die aktuell verfügbare Datenlage. Zusammenfassend scheint sich die Evidenz zu verdichten, dass mittels Unterdruck-Instillationstherapie sowohl einfache als auch komplizierte Wunden effizient behandelt werden können, was sich in einer deutlichen Beschleunigung der Wundgranulation mit konsekutiv früher möglichem Defektverschluss äußert.

Report on immediate irradiation of a rapidly growing sarcoma of the scalp prior to wound closure.

Cutaneous sarcomas are primarily treated with extensive surgery, and occasionally require adjuvant radiation therapy following complete wound healing. Thus, sarcoma surgery leads to large and deep wounds, and the initiation of adjuvant radiation therapy depends on the time required for defect closure. We present the case of a male patient with pleomorphic sarcoma of the temporal skin, which was treated with multiple wide and deep excisions, instant application of an Integra(®) bilayer, and immediate radiation therapy prior to wound closure. The objective was to investigate the usefulness of a dermal substitute (Integra(®) ) in accelerating the effect of adjuvant radiation therapy on scalp defects after tumor surgery. A ring-shaped skin area - at risk for recurrence - around the Integra(®) bilayer was irradiated with a total of 59.4 Gy. No necrosis, infection, or major radiotoxicity was observed, and a subsequent split skin graft following radiation therapy remained fully vital until complete healing. In conclusion, a combined procedure consisting of sequential tumor surgery and subsequent application of a dermal substitute in conjunction with immediate initiation of adjuvant radiation therapy is, in principle, possible, and may permit innovative therapeutic options in dermatooncology and dermatosurgery.

Improved patient-centered care with effective use of Integra® in dermatologic reconstructive surgery.

BACKGROUND: The incidence of skin tumors is increasing among elderly patients, and the multi-morbidities which occur in the elderly are a great challenge for dermatologic surgeons. The currently required safety margins for different types of melanomas and non-melanoma skin cancers lead to extensive and profound wounds. OBJECTIVE: To investigate the usefulness of a dermal substitute (Integra®) for routine use in surgery for dermatologic tumors. PATIENTS AND METHODS: In this retrospective study 20 patients underwent sequential surgeries for skin cancer. Wound closures were performed using Integra® (single layer) and immediate split-thickness skin graft. RESULTS: Twenty-two tumors (6 malignant melanomas, 10 squamous cell carcinomas, 2 pleomorphic sarcomas, 1 basal cell carcinoma, 2 Merkel cell carcinomas, and 1 trichoblastic carcinoma) were resected. The mean defect size was 41.4 cm(2) . All transplants were (65-100 %) vital; however, defects in the midface (cheek and infra-orbital area) often healed with esthetically disturbing, dense, pillow-like scars. CONCLUSIONS: With the use of Integra®, the duration of hospitalization was decreased, patients with multi-morbidities were effectively treated, and functionally- and esthetically-satisfactory outcomes were achieved. On the basis of these observations, we discuss points of handling those patients who require rapid and effective surgery and undergo dermatologic surgery using dermal substitutes.

[Micrographic controlled surgery in everyday dermatosurgery]. / Mikroskopisch kontrollierte Chirurgie im dermatochirurgischen Alltag.

Micrographic controlled surgery (MCS) has become established in dermatosurgery in recent years and includes various methods to enable the histologically proven complete resection of malignant cutaneous tumors, while at the same time sparing tumor-free tissue in the immediate vicinity as much as possible. MCS is of great importance in the surgical treatment of cutaneous malignancies in so-called problem locations and aggressive tumor subtypes. Indications for MCS include basal cell carcinoma, cutaneous squamous cell carcinoma, Bowen's disease and Bowen's carcinoma, melanoma in chronic light-damaged skin with acral lentiginous melanoma, dermatofibrosarcoma protuberans (DFSP), and Merkel cell carcinoma. However, other tumor entities are also treated using MCS, such as extramammary Paget's disease and various cutaneous sarcomas. All procedures subsumed under MCS have in common the marking of the surgical specimen for topographical orientation, which provides assignment of remaining tumor remnants. Various methods of MCS (3D histology, the horizontal method or Mohs surgery) are presented in this article. Furthermore, this article aims to raise awareness of the possibilities and limitations of micrographically controlled surgery.

Differential regulation of human papillomavirus type 8 by interferon regulatory factors 3 and 7.

The genus ß human papillomavirus (HPV) type 8 is associated with nonmelanoma skin cancer in patients with epidermodysplasia verruciformis, and evidence for its protumorigenic potential in the general population increases. To date, strategies to suppress genus ß HPV infections are limited. Interferon regulatory factors IRF-3 and IRF-7 play key roles in the activation of the innate immune response to viral infections. In this study, we show for the first time that both IRF-3 and IRF-7 regulate transcription of a papillomavirus, but with opposing effects. IRF-7, expressed in the suprabasal layers of human epidermis, increased HPV8 late promoter activity via direct binding to viral DNA. UV-B light-induced activation of the HPV8 promoter involved IRF-7 as a downstream effector. In contrast, IRF-3, expressed in all layers of human epidermis, induced strong HPV8 suppression in primary keratinocytes. IRF-3-mediated suppression prevailed over IRF-7-induced HPV8 transcription. Unlike the E6 oncoprotein of the mucosal high-risk HPV16, the HPV8 E6 protein did not bind to IRF-3 and only weakly antagonized its activity. Strong antiviral activity was also observed, when keratinocytes were treated with potent IRF-3 activators, poly(I:C) or RNA bearing 5' phosphates. In conclusion, we show that IRF-3 activation induces a state of cell-autonomous immunity against HPV in primary human keratinocytes. Our study suggests that local application of IRF-3-activating compounds might constitute an attractive novel therapeutic strategy against HPV8-associated diseases, particularly in epidermodysplasia verruciformis patients.