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: 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.

The various clinical spectra of juvenile xanthogranuloma: imaging for two case reports and review of the literature.

BACKGROUND: Juvenile xanthogranuloma (JXG) belongs to the heterogeneous group of non-Langerhans cell histiocytosis and is caused by an accumulation and proliferation of macrophages. In the majority of cases JXG is a disorder of early childhood presenting during the first 2 years of life. The typical presentation is a solitary reddish or yellowish skin papule or nodule with spontaneous regression and no need for treatment. CASE PRESENTATION: Two infants with an atypical presentation of JXG, one with multiple blueberry muffin rash-like skin lesions and the other with severe multi-systemic involvement, are reported. Diagnosis was established by skin biopsy including histological work-up and immunostaining, where markers for macrophages (CD68 and CD163) exhibited significant reactivity. CONCLUSION: JXG is the most common of the non-Langerhans cell histiocytosis. The typical presentation is a solitary skin lesion. The purpose of this report is to familiarize paediatricians with an unusual variant of this entity in order to facilitate early diagnosis and raise awareness for possible visceral complications and associated medical conditions.

Amalgam tattoo versus melanocytic neoplasm - Differential diagnosis of dark pigmented oral mucosa lesions using infrared spectroscopy.

BACKGROUND: Dark pigmented lesions of the oral mucosa can represent a major diagnostic challenge. A biopsy is usually required to determine the nature of such intraoral discolorations. This study investigates the potential use of infrared spectroscopy for differential diagnosis of amalgam tattoos versus benign or malignant melanocytic neoplasms. MATERIALS AND METHODS: For this retrospective study, formalin-fixed paraffin-embedded tissue (FFPE) specimens of dark pigmented lesions concerning the oral mucosa or the lip were investigated using mid infrared spectroscopy. The samples were chosen from patients who had undergone a mucosal biopsy at the University Hospital Innsbruck (Austria) between the years 2000 and 2017. Principal component analysis was used for data exploration. Evaluation was based on the superimposition of the recorded spectra and the corresponding histologic slides. RESULTS: In total, 22 FFPE specimens were analyzed. Clear differences were found between amalgam and non-amalgam samples. A general weakening of the penetrating infrared radiation allowed for unspecific discrimination between these two classes. An overall accuracy in predicting the correct class of 95.24% was achieved. CONCLUSION: Infrared spectroscopy appears to be a suitable technique to differentiate between amalgam tattoos and melanocytic lesions in FFPE samples. It could potentially be applied in vivo, too, serving as a non-invasive diagnostic tool for intraoral dark pigmented lesions.

Erosive pustular dermatosis of the scalp: reappraisal of an underrecognized entity.

Erosive pustular dermatosis of the scalp (EPDS) is an inflammatory dermatosis of unknown etiology. Herein, we present a review of the disease and report our own clinical and histopathological experience in eleven patients. EPDS tends to spontaneously affect bald areas of the scalp in elderly individuals. A history of previous surgery at the same site - as observed in four of our patients - is common. Coronary artery disease, cerebrovascular insult, arterial hypertension, diabetes mellitus, and severe cases of cancer were frequent comorbidities. Most patients show an undulating clinical course despite topical anti-inflammatory treatment; in some individuals, the lesions heal with scarring. Histopathology reveals scaly crusts or erosions and granulation tissue-like changes in the dermis, evolving into a scar in more advanced stages. Apart from actinic/local damage, impaired immunity and microcirculation may be predisposing factors of the disease. Similar to pyoderma gangrenosum, EPDS must be considered in the context of nonhealing wounds in the elderly after the differential diagnoses mimicking EPDS have been ruled out. Given that previous or concomitant adjacent basal cell or squamous cell carcinoma is a common finding and that infiltrative variants extending beyond the clinically visible tumor may occur, histological mapping of the surrounding skin may be advisable in doubtful cases.

Langerhans cells and NK cells cooperate in the inhibition of chemical skin carcinogenesis.

Tissue immunosurveillance is an important mechanism to prevent cancer. Skin treatment with the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA), followed by the tumor promoter 12-O-tetra-decanoyl-phorbol-13-acetate (TPA), is an established murine model for squamous cell carcinoma (SCC). However, the innate immunological events occurring during the initiation of chemical carcinogenesis with DMBA remain elusive. Here, we discovered that natural killer (NK) cells and Langerhans cells (LC) cooperate to impair this oncogenic process in murine skin. The depletion of NK cells or LC caused an accumulation of DNA-damaged, natural killer group 2D-ligand (NKG2D-L) expressing keratinocytes and accelerated tumor growth. Notably, the secretion of TNFα mainly by LC promoted the recruitment of NK cells into the epidermis. Indeed, the TNFα-induced chemokines CCL2 and CXCL10 directed NK cells to DMBA-treated epidermis. Our findings reveal a novel mechanism how innate immune cells cooperate in the inhibition of cutaneous chemical carcinogenesis.

Hidradenoma Papilliferum: A Clinicopathologic Study of 264 Tumors From 261 Patients, With Emphasis on Mammary-Type Alterations.

Hidradenoma papilliferum (HP), also known as papillary hidradenoma, is the most common benign lesion of the female anogenital area derived from anogenital mammary-like glands (AGMLG). HP can be viewed conceptually as the cutaneous counterpart of mammary intraductal papilloma. The authors have studied 264 cases of HP, detailing various changes in the tumor and adjacent AGMLG, with emphasis on mammary-type alterations. In many HP, the authors noticed changes typical for benign breast lesions, such as sclerosing adenosis-like changes, usual, and atypical ductal hyperplasia. Almost in a third of cases, remnants of AGMLG adjacent to the lesion were evident, manifesting columnar changes reminiscent of those seen in breast lesions. This study shows that the histopathological changes in HP run a broad spectrum comparable with that in the mammary counterpart and benign breast disease.

Vasculitic wheel - an algorithmic approach to cutaneous vasculitides.

BACKGROUND: Previous classifications of vasculitides suffer from several defects. First, classifications may follow different principles including clinicopathologic findings, etiology, pathogenesis, prognosis, or therapeutic options. Second, authors fail to distinguish between vasculitis and coagulopathy. Third, vasculitides are systemic diseases. Organ-specific variations make morphologic findings difficult to compare. Fourth, subtle changes are recognized in the skin, but may be asymptomatic in other organs. Our aim was to use the skin and subcutis as a model and the clinicopathologic correlation as the basic process for classification. METHODS AND RESULTS: We use an algorithmic approach with pattern analysis, which allows for consistent reporting of microscopic findings. We first differentiate between small and medium vessel vasculitis. In the second step, we differentiate the subtypes of small (capillaries versus postcapillary venules) and medium-sized (arterioles/arteries versus veins) vessels. In the final step, we differentiate, according to the predominant cell type, into leukocytoclastic and/or granulomatous vasculitis. CONCLUSIONS: Starting from leukocytoclastic vasculitis as a central reaction pattern of cutaneous small/medium vessel vasculitides, its relations or variations may be arranged around it like spokes of a wheel around the hub. This may help establish some basic order in this rather complex realm of cutaneous vasculitides, leading to a better understanding in a complicated field.