Tumor of follicular infundibulum - reappraisal in a series of 28 patients with critical review of the literature.

BACKGROUND AND OBJECTIVES: Tumor of follicular infundibulum (TFI) has been described as a neoplasm - isolated and multiple - and in association with other lesions. Its histopathologic definition is controversial. PATIENTS AND METHODS: We present a histopathologically analyzed series of 28 patients with TFI features. This has been supplemented by a search in MEDLINE on the literature on this subject. The corresponding figures given in these articles have been discussed and analyzed. RESULTS: Patients comprised 16 women and twelve men. TFI features were seen in five patients with nevus sebaceous, two trichofolliculomas, one dilated pore Winer, eight viral warts, one dermatofibroma, six seborrheic keratoses, three actinic keratoses, one invasive squamous cell carcinoma, and one basal cell carcinoma in association with a squamous cell carcinoma/actinic keratosis. After study of the literature especially of solitary cases of TFI, we interpret such cases mostly as variants of seborrheic keratoses with variable degree of infundibular, isthmic and/or sebaceous differentiation with or without regression. CONCLUSIONS: We regard TFI as an epithelial growth pattern which may occur in hamartomatous, inflammatory, infectious, reactive, or neoplastic conditions, in most solitary forms likely best classified within the histopathological spectrum of seborrheic keratoses.

Resection of Skin Cancer Resulting in Free Vascularized Tissue Reconstruction: Always a Therapeutic Failure?

The globally increasing incidence of cutaneous malignancies leads, in parallel, to increasing numbers of locally advanced skin cancer resulting in reconstructive surgery. Reasons for locally advanced skin cancer may be a patient's neglect or aggressive tumor growth, such as desmoplastic growth or perineural invasion. This study investigates characteristics of cutaneous malignancies requiring microsurgical reconstruction with the aim of identifying possible pitfalls and improving diagnostic and therapeutic processes. A retrospective data analysis from 2015 to 2020 was conducted. Seventeen patients (n = 17) were included. The mean age at reconstructive surgery was 68.5 (±13) years. The majority of patients (14/17, 82%) presented with recurrent skin cancer. The most common histological entity was squamous cell carcinoma (10/17, 59%). All neoplasms showed at least one of the following histopathological characteristics: desmoplastic growth (12/17, 71%), perineural invasion (6/17, 35%), or tumor thickness of at least 6 mm (9/17, 53%). The mean number of surgical resections until cancer-free resection margins (R0) were achieved was 2.4 (±0.7). The local recurrence rate and the rate of distant metastases were 36%. Identified high-risk neoplastic characteristics, such as desmoplastic growth, perineural invasion, and a tumor depth of at least 6 mm, require a more extensive surgical treatment without concerns about defect size.

The spectrum of melanocytic nevi and their clinical implications.

The magnitude of the topic of melanocytic nevi (MN) is directly related to its relevance in everyday clinical work. The different MN have different prognostic significance in regard to comorbidity and possible risk of transformation. In addition to the criteria of the ABCDE rule, relevant criteria in the assessment of an MN are the time of occurrence, the growth tendency, the distribution and the comparison with other MN of the respective individual. The present CME article provides an overview of the knowledge that has been gained with regard to the development and genetic background of MN and any risk of degeneration that may exist. In addition, certain clinical and/or dermatoscopic features may provide the clinician with a decision-making aid in the management of different MNs.

Vasculitides and occluding vasculopathies, challenges in recognizing histopathological patterns, and their solutions.

In this review, we propose a classification of vasculitides and occluding vasculopathies using the clinicopathological correlation as the basic process. We use an algorithmic approach with pattern analysis, which allows reliable reporting of microscopic findings. We first differentiate between small and medium vessel vasculitis. Second, we differentiate the subtypes of small- and medium-sized vessels. Finally, we differentiate vasculitides according to the predominant cell type into leukocytoclastic and/or granulomatous vasculitis. Regarding leukocytoclastic vasculitis as a central reaction pattern of cutaneous small/medium vessel vasculitides, its relation or variations may be arranged in a wheel-like order. With respect to occluding vasculopathies, the first two steps are identical to the algorithm of vasculitides, and we finally differentiate according to the time point of the coagulation/reorganization process and the involved inflammatory cells/stromal features. By visualizing the criteria in the style of bar codes, clinical and histological overlaps and differences may become more transparent.

Hide-and-seek: Neurotropes Plattenepithelkarzinom der periorbitalen Region - eine Fallserie und Übersichtsarbeit aktueller Literatur.

Das Plattenepithelkarzinom ist nach dem Basalzellkarzinom das zweithäufigste Malignom der Haut und wird vorwiegend an sonnenexponierten Stellen wie der Gesichtshaut diagnostiziert. Diese meist lokal destruktiv wachsende Malignität kann durchaus auch invasives Wachstumsverhalten, wie perineurale Ausbreitungsmechanismen, aufweisen. Das Plattenepithelkarzinom der periorbitalen Region ist in bis zu 14 % der Fälle mit perineuraler Invasion assoziiert. Vor allem in diesem Bereich birgt die anatomische Nähe zu den Hirnnerven das Risiko einer Progression Richtung zentrales Nervensystem, was mit einer schlechteren Prognose assoziiert ist. Der klinisch unauffällige Charakter dieser Entität resultiert oft in einer Verzögerung der definitiven Diagnosestellung, wodurch die vollständige Resektion und anschließende Rekonstruktion erschwert werden. Eine aufmerksame klinische Evaluierung kann bereits vor Erlangen histologischer Befunde Hinweise für ein perineurales Wachstum liefern. Neben fünf herausfordernden Fällen analysiert diese Arbeit Risikofaktoren, klinische als auch histologische Merkmale und Behandlungsoptionen des periorbitalen Plattenepithelkarzinoms mit perineuraler Invasion.

Hide-and-seek: Neurotropic squamous cell carcinoma of the periorbital region - a series of five cases and review of the literature.

Squamous cell carcinoma is the second most common malignancy of the skin after basal cell carcinoma and mainly found in sun-exposed areas such as the face. This mostly locally destructive malignancy may show invasive growth and insidious mechanisms of dissemination such as perineural invasion. Periorbital squamous cell carcinoma is associated with perineural invasion in up to 14 % of cases. Specifically in this region, the proximity to cranial nerves and therefore the associated risk of progression to the central nervous system are associated with poor prognosis. The clinically concealed character of this entity often leads to a delay in diagnosis and consequently makes complete resection and reconstruction demanding. Careful clinical evaluation often hints at perineural invasion before obtaining histology. Aside from presenting five challenging cases, this work analyzes risk factors, clinical as well as histological features, and treatment options for periorbital squamous cell carcinoma with perineural invasion.

Seborrheic Keratosis With Sebaceous Differentiation, a Series of 8 Cases and Critical Review of the Literature.

ABSTRACT: Seborrheic keratosis with sebaceous differentiation (SKSD) can sometimes raise uncertainty, confuse with other even malignant entities, and lead to overestimation of this harmless variant. Retrospective analysis of the cases diagnosed as SKSD and a search of the pertaining literature were conducted. Eight cases of SKSD were found. Histologically, these lesions show a flat to plate-like outgrowth of basaloid cells with solitary or clustered sebocytes at the bottom of the rete ridges and variable sebaceous ducts with luminal cuticula. The lesions differed in the outgrowth subpattern: flat/macular, acanthotic, or reticulated. No association was found with Muir-Torre syndrome, and no malignant transformation was seen in these lesions. Literature search revealed confusingly designated lesions that simply represented SKSD. SKSD can show several growth patterns as classic SK. This entity is either underreported or even underrecognized. This entity is benign; however, according to the literature, exclusion of an associating Muir-Torre syndrome should be warranted. The published literature about this lesion is confusing and inconsistent. We suggest the avoidance of confusing terminology and particularly the terminus epithelioma for such lesions.

High expression of mTOR signaling in granulomatous lesions is not predictive for the clinical course of sarcoidosis.

INTRODUCTION: Sarcoidosis is a systemic granulomatous disease with a variable clinical presentation and disease course. There is still no reliable biomarker available, which assists in the diagnosis or prediction of the clinical course. According to a murine model, the expression level of the metabolic checkpoint kinase mechanistic target of Rapamycin complex 1 (mTORC1) in granulomas of sarcoidosis patients may be used as a clinical biomarker. MATERIAL AND METHODS: This is a retrospective analysis of 58 patients with histologically confirmed sarcoidosis. Immunohistochemical staining of granulomas from tissue samples was evaluated for the expression of activated mTORC1 signaling, including phosphorylated mTOR, its downstream effectors S6K1, 4EBP1 and the proliferation marker Ki-67. Patients were categorized according to different clinical phenotypes, serum biomarkers, and immunomodulatory therapy. RESULTS: All patients showed activated mTORC1 signaling in granulomas, which correlated with its downstream effectors S6K1 and 4EBP1 but was not related to Ki-67 expression. The mTORC1 activity revealed an association neither to disease severity nor the necessity of treatment; however, p-mTOR inversely correlated with cumulative corticosteroid dosage. CONCLUSION: Our data confirm activation of the mTORC1 pathway in sarcoidosis, supporting the hypothesis that mTOR is a significant driver in granuloma formation. However, we could not find a relationship between the degree of mTOR activation and disease severity or the need for therapy.

Hyperspectral imaging as a diagnostic tool to differentiate between amalgam tattoos and other dark pigmented intraoral lesions.

The goal of this project is to identify any in-depth benefits and drawbacks in the diagnosis of amalgam tattoos and other pigmented intraoral lesions using hyperspectral imagery collected from amalgam tattoos, benign, and malignant melanocytic neoplasms. Software solutions capable of classifying pigmented lesions of the skin already exist, but conventional red, green and blue images may be reaching an upper limit in their performance. Emerging technologies, such as hyperspectral imaging (HSI) utilize more than a hundred, continuous data channels, while also collecting data in the infrared. A total of 18 paraffin-embedded human tissue specimens of dark pigmented intraoral lesions (including the lip) were analyzed using visible and near-infrared (VIS-NIR) hyperspectral imagery obtained from HE-stained histopathological slides. Transmittance data were collected between 450 and 900 nm using a snapshot camera mounted to a microscope with a halogen light source. VIS-NIR spectra collected from different specimens, such as melanocytic cells and other tissues (eg, epithelium), produced distinct and diagnostic spectra that were used to identify these materials in several regions of interest, making it possible to distinguish between intraoral amalgam tattoos (intramucosal metallic foreign bodies) and melanocytic lesions of the intraoral mucosa and the lip (each with P < .01 using the independent t test). HSI is presented as a diagnostic tool for the rapidly growing field of digital pathology. In this preliminary study, amalgam tattoos were reliably differentiated from melanocytic lesions of the oral cavity and the lip.

The Association of Residential Altitude on the Molecular Profile and Survival of Melanoma: Results of an Interreg Study.

Cutaneous melanoma (CM) incidence is rising worldwide and is the primary cause of death from skin disease in the Western world. Personal risk factors linked to environmental ultraviolet radiation (UVR) are well-known etiological factors contributing to its development. Nevertheless, UVR can contribute to the development of CM in different patterns and to varying degrees. The present study aimed at investigating whether altitude of residence can contribute to the development of specific types of CM and/or influence its progression. To this aim, 306 formalin-fixed and paraffin-embedded (FFPE) tissues from primary CM diagnosed in different geographical areas were submitted to B-RAF proto-oncogene serine/threonine kinase (BRAF) and N-RAS proto-oncogene GTPase (NRAS) mutational status detection and mRNA and miRNA profiling by qPCR. Genes were chosen for their functions in specific processes, such as immune response (CD2, PDL1, or CD274) and pigmentation (MITF, TYRP1, and TRPM1). Furthermore, four microRNAs, namely miR-150-5p, miR-155-5p, miR-204-5p, and miR-211-5p, were included in the profiling. Our results highlight differences in the gene expression profile of primary CM with respect to the geographical area and the altitude of residence. Melanoma-specific survival was influenced by the gene expression of mRNA and miRNAs and varied with the altitude of patients' residence. In detail, TYRP1 and miR-204-5p were highly expressed in patients living at higher altitudes, unlike miR-150-5p, miR-155-5p, and miR-211-5p. Since miRNAs are highly regulated by reactive oxygen species, it is possible that different regulatory mechanisms characterize CMs at different altitudes due to the different environment and UVR intensity.

Long-term outcome after hand and forearm transplantation - a retrospective study.

Between 2000 and 2014, five patients received bilateral hand (n = 3), bilateral forearm (n = 1), and unilateral hand (n = 1) transplants at the Innsbruck Medical University Hospital. We provide a comprehensive report of the long-term results at 20 years. During the 6-20 years follow-up, 43 rejection episodes were recorded in total. Of these, 27.9% were antibody-related with serum donor-specific alloantibodies (DSA) and skin-infiltrating B-cells. The cell phenotype in rejecting skin biopsies changed and C4d-staining increased with time post-transplantation. In the long-term, a change in hand appearance was observed. The functional outcome was highly depending on the level of amputation. The number and severity of rejections did not correlate with hand function, but negatively impacted on the patients´ well-being and quality of life. Patient satisfaction significantly correlated with upper limb function. One hand allograft eventually developed severe allograft vasculopathy and was amputated at 7 years. The patient later died due to progressive gastric cancer. The other four patients are currently rejection-free with moderate levels of immunosuppression. Hand transplantation remains a therapeutic option for carefully selected patients. A stable immunologic situation with optimized and individually adopted immunosuppression favors good compliance and patient satisfaction and may prevent development of DSA.

Defining chronic rejection in vascularized composite allotransplantation-The American Society of Reconstructive Transplantation and International Society of Vascularized Composite Allotransplantation chronic rejection working group: 2018 American Society of Reconstructive Transplantation meeting report and white paper Research goals in defining chronic rejection in vascularized composite allotransplantation.

OBJECTIVES: This report summarizes a collaborative effort between the American Society of Reconstructive Transplantation and the International Society of Vascularized Composite Allotransplantation to establish what is known about chronic rejection in recipients of vascularized composite allografts, with an emphasis on upper extremity and face transplants. As a picture of chronic rejection in hand and face vascularized composite allografts emerges, the results will be applied to other types of vascularized composite allografts, such as uterine transplantation. METHODS: The overall goal is to develop a definition of chronic rejection in vascularized composite allografts so that we can establish longitudinal correlates of factors such as acute rejection, immunosuppressive therapy, de novo donor-specific antibody and trauma/infection and other external factors on the development of chronic rejection. As Dr Kanitakis eloquently stated at the 2017 International Society of Vascularized Composite Allotransplantation meeting in Salzburg, "Before we can correlate causative factors of chronic rejection, we have to define what chronic rejection in VCA is." RESULTS: The first meeting report was presented at the sixth Biennial meeting of the American Society of Reconstructive Transplantation in November 2018. Based on collaborative efforts and descriptions of clinical cases of chronic rejection in vascularized composite allograft recipients, a working definition of chronic rejection in vascularized composite allografts with respect to overt functional decline, subclinical functional decline, histologic evidence without functional decline, and normal allograft function in the absence of histologic evidence of chronic rejection is proposed. CONCLUSIONS: It is the intent of this collaborative working group that these working definitions will help to focus ongoing research to define the incidence, risk factors and treatment regimens that will identify mechanisms of chronic rejection in vascularized composite allografts. As with all good research, our initial efforts have generated more questions than answers. We hope that this is the first of many updates.

[Lupus erythematosus-a clinico-pathological heterogeneous disease]. / Lupus erythematodes ­ ein klinisch-pathologisch heterogenes Krankheitsbild.

Lupus erythematosus (LE) is an autoimmune disorder where immune tolerance towards nucleic acids is lost and a hyperactivated type I interferon system drives chronic immune activation. Typically, signs, symptoms, and clinical disease course are very variable between patients. Cutaneous LE can be associated with or precede systemic involvement or be limited to the skin, necessitating careful examination and follow-up of patients. LE skin disease includes a wide range of manifestations and precise classification for clinical studies is challenging. In this review article we discuss common and rare manifestations of cutaneous lupus with its clinical presentation and histopathological characteristics.

Mechanical Irritation in Vascularized Composite Tissue Allotransplantation Triggers Localized Skin Rejection.

BACKGROUND: Mechanical and thermal stress has been observed to trigger skin rejection in hand-transplanted patients. This study aims to investigate this phenomenon. METHODS: Syngeneic and allogeneic orthotopic hindlimb transplantations were performed using male rats (Brown Norway to Lewis). Using a specially designed device, standardized mechanical skin irritation at a force of 5 N was applied to the planta pedis of the transplanted limb for 10 days, 4 times daily for 10 minutes. Biopsies, taken on day 10 and after a 5-day observational period, were assessed for macroscopic alterations using a standardized scale, by histopathology and immunohistochemistry, and for inflammatory protein expression using Luminex technology. RESULTS: Allogeneic animals displayed significant aggravated macroscopic skin alterations compared with naive (P < 0.0001) and syngeneic controls (P = 0.0023). Histopathology showed a trend toward higher rejection/inflammation grades in allogeneic animals compared with syngeneic controls. Minor skin alterations in syngeneic limbs recovered quickly; however, in allogeneic limbs, macroscopic skin alterations were significantly more pronounced (P < 0.0001) 5 days after irritation. Interleukin-1b and interferon-γ levels were upregulated in skin of allogeneic limbs. CONCLUSIONS: Mechanical skin irritation in vascularized composite allotransplantation can trigger localized skin inflammation consistent with rejection.

Erythema Nodosum, Early Stage-A Subcutaneous Variant of Leukocytoclastic Vasculitis? Clinicopathological Correlation in a Series of 13 Patients.

Erythema nodosum (EN) is considered to represent a septal panniculitis. In a period from January 2000 until June 2018, we clinically and histopathologically investigated 124 patients with EN, 13 (10.5%) of them in an early stage demonstrating features of a leukocytoclastic vasculitis (LCV) around postcapillary venules of the subcutaneous fat. Three of these patients presented with EN on the lower legs and Sweet syndrome on the head/neck, arms, or trunk. 19.3% and 70.2% of patients demonstrated "classic" features of subacute and chronic forms of EN, respectively. Histopathologically, in cases of early EN apart from septally accentuated vascular damage and neutrophils with nuclear dust, eosinophils were evident in 5 specimens as well, in one case even with flame figures as seen in Wells syndrome. The inflammation spilled over to the dermis and lobular panniculus in 12 and 10 specimens, respectively. From the same time period and for comparison, we investigated 497 cases of "classic" LCV. Depending on the degree of vascular damage and the presence of neutrophils and nuclear dust, 65.8% presented with acute, 18.9% with subacute, and 15.3% with late-stage disease. In the latter, only a few neutrophils but rather lymphocytes and macrophages were present. Four hundred forty patients revealed an involvement of the deep dermis; of those, in 342, a septal inflammation was present as well, whereas in 94, the process was purely dermal. The subcutis was missing for evaluation in 61 cases. These results indicate a closer relationship between EN and LCV than previously considered.

Bar Code Reader - an algorithmic approach to cutaneous occluding vasculopathies? part II medium vessel vasculopathies.

AIMS: Classifications of occluding vasculopathies (except vasculitis [1]) may exhibit some difficulties. Firstly, classifications may follow different principles, e.g. clinicopathologic findings, etiology or pathogenesis. Secondly, authors may not distinguish between vasculitis and occluding vasculopathies. Thirdly, occluding vasculopathies are systemic diseases. Organ-specific variations make morphologic findings difficult to compare. Moreover, subtle changes are recognized in the skin, but may be invisible in other organs. Our aim was to use the skin and subcutis as a tool and clinicopathological correlation as the basic process for classification. METHODS AND RESULTS: We first differentiate in the skin between small and medium vessel occluding vasculopathies. Here we focus on medium vessel-occluding vasculopathies. In the second step we differentiate the vessel subtypes. In the final step, we differentiate according to the time point of the coagulation/reorganization process and the involved inflammatory cells/stromal features. By applying the same procedure to the various entities and visualizing the findings in the style of bar codes, the overlaps and differences in the clinical picture as well as the histopathology become more apparent. CONCLUSIONS: Occluding vasculopathies are often not separate entities, but reaction patterns and epiphenomena. Distinguishing them from vasculitides is crucial because of the differences in pathogenesis, therapeutic approach and prognosis.

Bar code reader - an algorithmic approach to cutaneous occluding vasculopathies? Part I: small vessel vasculopathies.

AIMS: The classifications of occluding vasculopathies may present some difficulties. Firstly, classifications may follow different principles, e.g. clinicopathological findings, etiology or pathomechanism. Secondly, authors sometimes do not distinguish between vasculitis and vasculopathy. Thirdly, vasculopathies are often systemic diseases. Organ-specific variations make morphologic findings difficult to compare. Moreover, subtle changes may be recognized in the skin, but be invisible in other organs. Our aim was to use the skin and subcutis as tools and clinicopathological correlation as the basic process for classification. METHODS AND RESULTS: In the first step, we differentiate between small and medium vessel occluding vasculopathies in the skin, and focus in this part on small vessel occluding vasculopathies. In the second step, we differentiate among subtypes of small vessels. In the final step, we differentiate according to the time point of the coagulation/reorganization process and the involved inflammatory cells/stromal features. Applying the same procedure to the various entities and visualizing the findings with bar codes makes the similarities and differences more apparent, both clinically and with histopathology. CONCLUSION: Occluding vasculopathies are often not separate entities, but reaction patterns and epiphenomena. Distinguishing them from vasculitides is crucial because of differences in pathogenesis, therapeutic approach and prognosis.