[Bullous mycosis fungoides-clinical indicator for an aggressive course of disease]. / Bullöse Mycosis fungoides ­ ein klinischer Indikator für einen aggressiven Krankheitsverlauf.

Mycosis fungoides (MF) is defined as the most common cutaneous T­cell lymphoma (CTCL). The bullous form is considered one of its numerous variants. Only a few cases of this rare entity have been described. We report the case of a man with an aggressive course of bullous MF, which led to lethal outcome within a few weeks due to a fulminant sepsis.

Granulomatous Folliculotropic Secondary Syphilis: An Unusual Histopathological Clue.

ABSTRACT: Syphilis is a sexually transmitted disease that can present a wide variety of clinical and histopathological manifestations. We present the case of a 75-year-old patient with a persistent maculopapular rash on the trunk and extremities, in which the biopsy showed an exclusively perifollicular granulomatous infiltrate. In the immunohistochemical staining with anti-Treponema pallidum antibodies, spirochetes scattered within the perifollicular inflammatory infiltrate were identified. These findings together with the serological analysis allowed the diagnosis of secondary syphilis. Folliculotropic nonalopecic syphilis is rare, and the pathogenic mechanisms that cause this specific tropism are unknown. On the other hand, granulomatous inflammation is a pattern typically described in tertiary syphilis but also occasionally found in secondary syphilis. We present a case of secondary syphilis with the combination of both histopathological findings, an uncommon constellation for dermatopathologists to consider.

Hydrochlorothiazide and increased risk of atypical fibroxanthoma and pleomorphic dermal sarcoma.

BACKGROUND AND OBJECTIVES: Previous work has demonstrated that hydrochlorothiazide (HCTZ) is a risk factor for squamous cell carcinomas (SCC) and basal cell carcinomas (BCC) due to pro-photocarcinogenic effects. Atypical fibroxanthoma (AFX) and pleomorphic sarcoma (PDS), both ultraviolet-induced cancers, display a rare but rising cutaneous tumor entity. This study aimed to evaluate if the use of HCTZ is higher in patients with AFX/PDS than in patients with SCC/BCC and subsequently may be a risk factor for AFX/PDS-development. PATIENTS AND METHODS: In a retrospective study of four German skin cancer centers, AFX/PDS cases and SCC/BCC controls were sex and age matched (1:3) over a time-period of 7 years (2013-2019) to evaluate the use of HCTZ, immunosuppressive medication, second malignancies, and presence of diabetes mellitus. RESULTS: Overall, 146 AFX/PDS and 438 controls (SCC/BCC) were included in the study. The use of HCTZ was significantly higher in patients with AFX/PDS (44.5%) compared to patients with SCC/BCC (25.3%). Additionally, the presence of diabetes mellitus was significantly higher in AFX/PDS patients. CONCLUSIONS: This study demonstrates a significantly higher use of HCTZ in patients with AFX/PDS compared to SCC/BCC. This result suggests that HCTZ may be a risk factor for AFX/PDS. Additionally, diabetes mellitus or its comorbidities may be associated with an increased risk for AFX/PDS.

Applying an artificial intelligence deep learning approach to routine dermatopathological diagnosis of basal cell carcinoma.

BACKGROUND: Institutes of dermatopathology are faced with considerable challenges including a continuously rising numbers of submitted specimens and a shortage of specialized health care practitioners. Basal cell carcinoma (BCC) is one of the most common tumors in the fair-skinned western population and represents a major part of samples submitted for histological evaluation. Digitalizing glass slides has enabled the application of artificial intelligence (AI)-based procedures. To date, these methods have found only limited application in routine diagnostics. The aim of this study was to establish an AI-based model for automated BCC detection. PATIENTS AND METHODS: In three dermatopathological centers, daily routine practice BCC cases were digitalized. The diagnosis was made both conventionally by analog microscope and digitally through an AI-supported algorithm based on a U-Net architecture neural network. RESULTS: In routine practice, the model achieved a sensitivity of 98.23% (center 1) and a specificity of 98.51%. The model generalized successfully without additional training to samples from the other centers, achieving similarly high accuracies in BCC detection (sensitivities of 97.67% and 98.57% and specificities of 96.77% and 98.73% in centers 2 and 3, respectively). In addition, automated AI-based basal cell carcinoma subtyping and tumor thickness measurement were established. CONCLUSIONS: AI-based methods can detect BCC with high accuracy in a routine clinical setting and significantly support dermatopathological work.

Deep learning detection of melanoma metastases in lymph nodes.

BACKGROUND: In melanoma patients, surgical excision of the first draining lymph node, the sentinel lymph node (SLN), is a routine procedure to evaluate lymphogenic metastases. Metastasis detection by histopathological analysis assesses multiple tissue levels with hematoxylin and eosin and immunohistochemically stained glass slides. Considering the amount of tissue to analyze, the detection of metastasis can be highly time-consuming for pathologists. The application of artificial intelligence in the clinical routine has constantly increased over the past few years. METHODS: In this multi-center study, a deep learning method was established on histological tissue sections of sentinel lymph nodes collected from the clinical routine. The algorithm was trained to highlight potential melanoma metastases for further review by pathologists, without relying on supplementary immunohistochemical stainings (e.g. anti-S100, anti-MelanA). RESULTS: The established method was able to detect the existence of metastasis on individual tissue cuts with an area under the curve of 0.9630 and 0.9856 respectively on two test cohorts from different laboratories. The method was able to accurately identify tumour deposits>0.1 mm and, by automatic tumour diameter measurement, classify these into 0.1 mm to -1.0 mm and>1.0 mm groups, thus identifying and classifying metastasis currently relevant for assessing prognosis and stratifying treatment. CONCLUSIONS: Our results demonstrate that AI-based SLN melanoma metastasis detection has great potential and could become a routinely applied aid for pathologists. Our current study focused on assessing established parameters; however, larger future AI-based studies could identify novel biomarkers potentially further improving SLN-based prognostic and therapeutic predictions for affected patients.

Zunahme des atypischen Fibroxanthoms und pleomorphen dermalen Sarkoms: eine retrospektive Analyse vier deutscher Hauttumorzentren.

HINTERGRUND UND ZIELE: In den letzten Jahren konnten umfassende Erkenntnisse über die Pathogenese, Diagnostik und Behandlung von kutanen Sarkomen, insbesondere des atypischen Fibroxanthoms (AFX) und pleomorphen dermalen Sarkoms (PDS) gesammelt werden. Beide Entitäten zeigten innerhalb der letzten Dekade steigende Inzidenzraten. Die vorliegende Studie diente der Untersuchung, welchen Einfluss die neuen Erkenntnisse auf die Fallzahlen von AFX/PDS im Vergleich zu anderen Sarkom-Entitäten haben. PATIENTEN UND METHODIK: Diese retrospektive Studie wurde an vier deutschen Hauttumorzentren durchgeführt und alle von zertifizierten Dermatopathologen bestätigten histopathologischen Befunde von kutanen Sarkomen (AFX, PDS, Dermatofibrosarcoma protuberans, kutanes Leiomyosarkom, Angiosarkom und Kaposi-Sarkom) in einem Zeitraum von sieben Jahren (2013-2019) evaluiert. Zusätzlich wurde der Einsatz von immunhistochemischen Markern als diagnostische Hilfe (Panzytokeratin, S100, Desmin, CD34, CD10, Prokollagen-1, CD99, CD14 und CD68) erfasst. ERGEBNISSE: Insgesamt konnten 255 kutane Sarkome in die vorliegende Studie eingeschlossen werden. Die Zahl der kutanen Sarkome nahm kontinuierlich von 2013 bis 2019 zu (von 16 auf 52 Fälle im Jahr). Die Diagnose eines AFX/PDS konnte in 2019 4,6-mal häufiger als in 2013 gestellt werden. Das AFX stellte mit 49,3 % aller kutanen Sarkome den häufigsten Sarkom-Subtypen dar. Zusätzlich war der Anstieg von AFX/PDS mit dem Einsatz von Immunhistochemie assoziiert. Der Einsatz von spezifischen Immunhistochemischen Markern stieg von 57,1 % im Jahr 2013 auf 100 % in 2019. SCHLUSSFOLGERUNGEN: Diese retrospektive Studie von vier deutschen Hauttumorzentren demonstriert eine substanzielle Zunahme von AFX/PDS, wahrscheinlich infolge kürzlich etablierter beziehungsweise verbesserter diagnostischer und terminologischer Standards. Dieser Anstieg ist vermutlich mit dem vermehrten Einsatz von bestimmten immunhistochemischen Markern assoziiert. AFX/PDS treten wahrscheinlich häufiger auf als bisher vermutet und repräsentieren möglicherweise den häufigsten kutanen Sarkom-Subtyp.

Increase of atypical fibroxanthoma and pleomorphic dermal sarcoma: a retrospective analysis of four German skin cancer centers.

BACKGROUND AND OBJECTIVES: In recent years, considerable insight has been gained into the pathogenesis, diagnosis and treatment of cutaneous sarcomas, including atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS). Both entities have shown increasing incidence rates in the last decade. This study was initiated to evaluate how these new insights impact the number of diagnoses of AFX/PDS compared to other cutaneous sarcoma entities. PATIENTS AND METHODS: In a retrospective study of four German skin cancer centers, all histopathological reports of cutaneous sarcomas (AFX, PDS, dermatofibrosarcoma protuberans, cutaneous leiomyosarcoma, angiosarcoma, and Kaposi sarcoma) confirmed by board-certified dermatopathologists were analyzed during a time-period of seven years (2013-2019). Additionally, utilization of immunohistochemical markers (including pan-cytokeratin, S100, desmin, CD34, CD10, procollagen-1, CD99, CD14, and CD68) as an adjunct to diagnose AFX/PDS was recorded. RESULTS: Overall, 255 cutaneous sarcomas were included in the present study. The diagnosis of a cutaneous sarcoma has consequently risen from 2013 to 2019 (from 16 to 52 annual cases). The results of AFX/PDS revealed 4.6 times more diagnoses in 2019 than in 2013. Atypical fibroxanthoma represented the most common subtype, displaying 49.3 % of all diagnosed cutaneous sarcomas. Additionally, the increase of AFX/PDS was linked to the use of immunohistochemistry, with specific immunohistochemical markers used in 57.1 % of cases in 2013 compared to 100 % in 2019. CONCLUSIONS: This retrospective study of four German skin cancer centers demonstrates a substantial rise of AFX/PDS, possibly due to recently established diagnostic and terminology standards. This rise is probably linked to increased utilization of specific immunohistochemical markers. Atypical fibroxanthoma/PDS may be more common than previously thought and seems to represent the most frequent cutaneous sarcoma subtype.

Evaluation of a Deep Learning Approach to Differentiate Bowen's Disease and Seborrheic Keratosis.

Background: Some of the most common cutaneous neoplasms are Bowen's disease and seborrheic keratosis, a malignant and a benign proliferation, respectively. These entities represent a significant fraction of a dermatopathologists' workload, and in some cases, histological differentiation may be challenging. The potential of deep learning networks to distinguish these diseases is assessed. Methods: In total, 1935 whole-slide images from three institutions were scanned on two different slide scanners. A U-Net-based segmentation deep learning algorithm was trained on data from one of the centers to differentiate Bowen's disease, seborrheic keratosis, and normal tissue, learning from annotations performed by dermatopathologists. Optimal thresholds for the class distinction of diagnoses were extracted and assessed on a test set with data from all three institutions. Results: We aimed to diagnose Bowen's diseases with the highest sensitivity. A good performance was observed across all three centers, underlining the model's robustness. In one of the centers, the distinction between Bowen's disease and all other diagnoses was achieved with an AUC of 0.9858 and a sensitivity of 0.9511. Seborrheic keratosis was detected with an AUC of 0.9764 and a sensitivity of 0.9394. Nevertheless, distinguishing irritated seborrheic keratosis from Bowen's disease remained challenging. Conclusions: Bowen's disease and seborrheic keratosis could be correctly identified by the evaluated deep learning model on test sets from three different centers, two of which were not involved in training, and AUC scores > 0.97 were obtained. The method proved robust to changes in the staining solution and scanner model. We believe this demonstrates that deep learning algorithms can aid in clinical routine; however, the results should be confirmed by qualified histopathologists.

Genetic and methylation profiles distinguish benign, malignant and spitzoid melanocytic tumors.

Accurate classification of melanocytic tumors is important for prognostic evaluation, treatment and follow-up protocols of patients. The majority of melanocytic proliferations can be classified solely based on clinical and pathological criteria, however in select cases a definitive diagnostic assessment remains challenging and additional diagnostic biomarkers would be advantageous. We analyzed melanomas, nevi, Spitz nevi and atypical spitzoid tumors using parallel sequencing (exons of 611 genes and 507 gene translocation analysis) and methylation arrays (850k Illumina EPIC). By combining detailed genetic and epigenetic analysis with reference-based and reference-free DNA methylome deconvolution we compared Spitz nevi to nevi and melanoma and assessed the potential for these methods in classifying challenging spitzoid tumors. Results were correlated with clinical and histologic features. Spitz nevi were found to cluster independently of nevi and melanoma and demonstrated a different mutation profile. Multiple copy number alterations and TERT promoter mutations were identified only in melanomas. Genome-wide methylation in Spitz nevi was comparable to benign nevi while the Leukocytes UnMethylation for Purity (LUMP) algorithm in Spitz nevi was comparable to melanoma. Histologically difficult to classify Spitz tumor cases were assessed which, based on methylation arrays, clustered between Spitz nevi and melanoma and in terms of genetic profile or copy number variations demonstrated worrisome features suggesting a malignant neoplasm. Comprehensive sequencing and methylation analysis verify Spitz nevi as an independent melanocytic entity distinct from both nevi and melanoma. Combined genetic and methylation assays can offer additional insights in diagnosing difficult to classify Spitzoid tumors.

Review on the interactions of arsenic, iron (oxy)(hydr)oxides, and dissolved organic matter in soils, sediments, and groundwater in a ternary system.

High concentrations of arsenic (As) in groundwater threaten the environment and public health. Geogenically, groundwater As contamination predominantly occurs via its mobilization from underground As-rich sediments. In an aquatic ecosystem, As is typically driven by several underlying processes, such as redox transitions, microbially driven reduction of iron (Fe) oxide minerals, and release of associated As. Notably, dissolved As mobilized from soils and sediments exhibits high affinity for dissolved organic matter (DOM). Thus, high DOM concentrations can increase As mobility. Therefore, it is crucial to understand the complex interactions and biogeochemical cycling of As, DOM, and Fe oxides. This review collates knowledge regarding the fate of As in multicomponent As-DOM-Fe systems, including ternary complexes involving both Fe and DOM. Additionally, the release mechanisms of As from sediments into groundwater in the presence of both Fe and DOM have been discussed. The mechanisms of As mobilization/sorption at the solid-water interface can be affected by negatively charged DOM competing for sorption sites with As on Fe (oxy)(hydr)oxides and may be further modified by other anionic ubiquitous species such as phosphate, silicic acid, or sulfur. This review emphasizes the need for a comprehensive understanding of the impact of DOM, Fe oxides, and related biogeochemical processes on As mobilization to aquifers. The review identifies important knowledge gaps that may aid in developing applicable practices for preventing the spread of As contamination in aquatic resources and traditional soil management practices.

Deeply Supervised UNet for Semantic Segmentation to Assist Dermatopathological Assessment of Basal Cell Carcinoma.

Accurate and fast assessment of resection margins is an essential part of a dermatopathologist's clinical routine. In this work, we successfully develop a deep learning method to assist the dermatopathologists by marking critical regions that have a high probability of exhibiting pathological features in whole slide images (WSI). We focus on detecting basal cell carcinoma (BCC) through semantic segmentation using several models based on the UNet architecture. The study includes 650 WSI with 3443 tissue sections in total. Two clinical dermatopathologists annotated the data, marking tumor tissues' exact location on 100 WSI. The rest of the data, with ground-truth sectionwise labels, are used to further validate and test the models. We analyze two different encoders for the first part of the UNet network and two additional training strategies: (a) deep supervision, (b) linear combination of decoder outputs, and obtain some interpretations about what the network's decoder does in each case. The best model achieves over 96%, accuracy, sensitivity, and specificity on the Test set.

GNA14, GNA11, and GNAQ Mutations Are Frequent in Benign but Not Malignant Cutaneous Vascular Tumors.

Cutaneous vascular tumors consist of a heterogeneous group of benign proliferations, including a range of hemangiomas and vascular malformations, as well as heterogeneous groups of both borderline and malignant neoplasms such as Kaposi's sarcoma and angiosarcomas. The genetics of these tumors have been assessed independently in smaller individual cohorts making comparisons difficult. In our study, we analyzed a representative cohort of benign vascular proliferations observed in a clinical routine setting as well as a selection of malignant vascular proliferations. Our cohort of 104 vascular proliferations including hemangiomas, malformations, angiosarcomas and Kaposi's sarcoma were screened by targeted next-generation sequencing for activating genetic mutations known or assumed to be potentially relevant in vascular proliferations. An association analysis was performed for mutation status and clinico-pathological parameters. Frequent activating hotspot mutations in GNA genes, including GNA14 Q205, GNA11 and GNAQ Q209 were identified in 16 of 64 benign vascular tumors (25%). GNA gene mutations were particularly frequent (52%) in cherry (senile) hemangiomas (13 of 25). In angiosarcomas, activating RAS mutations (HRAS and NRAS) were identified in three samples (16%). No activating GNA or RAS gene mutations were identified in Kaposi's sarcomas. Our study identifies GNA14 Q205, GNA11 and GNAQ Q209 mutations as being the most common and mutually exclusive mutations in benign hemangiomas. These mutations were not identified in malignant vascular tumors, which could be of potential diagnostic value in distinguishing these entities.

Redox Dependence of Thioarsenate Occurrence in Paddy Soils and the Rice Rhizosphere.

In flooded paddy soils, inorganic and methylated thioarsenates contribute substantially to arsenic speciation besides the much-better-investigated oxyarsenic species, and thioarsenate uptake into rice plants has recently been shown. To better understand their fate when soil redox conditions change, that is, from flooding to drainage to reflooding, batch incubations and unplanted microcosm experiments were conducted with two paddy soils covering redox potentials from EH -260 to +200 mV. Further, occurrence of thioarsenates in the oxygenated rice rhizosphere was investigated using planted rhizobox experiments. Soil flooding resulted in rapid formation of inorganic thioarsenates with a dominance of trithioarsenate. Maximum thiolation of inorganic oxyarsenic species was 57% at EH -130 mV and oxidation caused nearly complete dethiolation. Only monothioarsenate formed again upon reflooding and was the major inorganic thioarsenate detected in the rhizosphere. Maximum thiolation of mono- and dimethylated oxyarsenates was about 70% and 100%, respectively, below EH 0 mV. Dithiolated species dominated over monothiolated species below EH -100 mV. Among all thioarsenates, dimethylated monothioarsenate showed the least transformation upon prolonged oxidation. It also was the major thiolated arsenic species in the rhizosphere with concentrations comparable to its precursor dimethylated oxyarsenate, which is especially critical since dimethylated monothioarsenate is highly carcinogenic.

Bilateral Facial Apocrine Fibrosing Hamartoma Mimicking Microcystic Adnexal Carcinoma.

An otherwise healthy 50-year-old woman was evaluated for the presence of 2 erythematous, and slightly pruritic plaques, involving both cheeks for 30 years. Left-side skin biopsy showed a diffuse proliferation of ductal structures horizontally arranged and involving the reticular dermis that resembled tubular adenoma embedded in a sclerotic stroma and surrounded by a peculiar periductal desmoplasia. Nuclear atypia or mitosis was not found. Contralateral biopsy showed identical findings. Differential diagnosis included microcystic adnexal carcinoma (MAC) and plaque-like syringoma and a peculiarly horizontally arranged tubular adenoma. We ruled out MAC as the lesions were long-standing, without infundibular cysts, solid strands, or perineural infiltration. Our case closely resembled those previously described as sweat duct proliferation associated with aggregates of elastic tissue and atrophoderma vermiculatum, although striking differences were observed, as our case did not present aggregates of elastic tissue, did not involve the papillary and superficial reticular dermis, and presented evidences of decapitation secretion as a sign of apocrine differentiation. We consider our case as a MAC simulator and we propose the descriptive name of bilateral facial apocrine fibrosing hamartoma.

Histopathological and Immunohistochemical Characteristics of Measles Exanthema: A Study of a Series of 13 Adult Cases and Review of the Literature.

Despite available vaccination, measles is one of the leading causes of death among young children in developing countries. In clinical practice, the spectrum of differential diagnoses of morbilliform exanthemas associated with fever is wide, and it can be hard to differentiate from other infectious eruptions, especially in adults or in atypical courses in immunocompromised patients. The goal of our study was to identify characteristic histomorphological and immunohistochemical patterns of measles exanthema through the study of 13 skin biopsy specimens obtained from 13 patients with this disease and a review of cases in the literature. Histopathological features of measles exanthema are quite distinctive and characterized by a combination of multinucleated keratinocytes, and individual and clustered necrotic keratinocytes in the epidermis with pronounced folliculosebaceous as well as acrosyringeal involvement. Immunohistochemical staining of skin biopsies with anti-measles virus (MeV) nucleoprotein and anti-MeV phosphoprotein can be of great value in confirming the diagnosis of measles. Both methods can serve as quick additional diagnostic tools for prompt implementation of quarantine measures and for providing medical assistance, even in patients in whom the clinician did not consider measles as a differential diagnosis of the rash due to the rarity of the disease in a putatively vaccinated community.

Black carbon yields highest nutrient and lowest arsenic release when using rice residuals in paddy soils.

Rice straw increasingly remains on the fields for nutrient supply to the next generation of crop plants. It can be applied either fresh or after burning to black carbon or ash. A central concern during rice cultivation is accumulation of carcinogenic arsenic and the question arises how much rice straw application contributes to nutrient versus arsenic supply in paddy fields. Laboratory incubation experiments were performed to assess the effect of rice straw, black carbon and ash on element mobilization. Our experiments showed initially higher silicon and phosphorus release from black carbon compared to fresh straw amendments. However, more re-sorption to soil lead to finally slightly lower pore water concentrations for black carbon versus fresh straw amendments. Highest arsenic, iron, manganese and dissolved organic carbon concentrations were observed after fresh rice straw application. Black carbon and ash application lead to only minor increases of arsenic compared to controls without amendments. Overall, for silicon and phosphorus the soil acts as sink while for iron and arsenic it was the main source. In summary, burning of rice straw to black carbon prior to application seems to yield a high increase in desired nutrient and a decrease in undesired arsenic mobilization in paddy soils.

Monothioarsenate Occurrence in Bangladesh Groundwater and Its Removal by Ferrous and Zero-Valent Iron Technologies.

In most natural groundwaters, sulfide concentrations are low, and little attention has been paid to potential occurrence of thioarsenates (AsVS n-IIO4- n3- with n = 1-4). Thioarsenate occurrence in groundwater could be critical with regard to the efficiency of iron (Fe)-based treatment technologies because previous studies reported less sorption of thioarsenates to preformed Fe-minerals compared to arsenite and arsenate. We analyzed 273 groundwater samples taken from different wells in Bangladesh over 1 year and detected monothioarsenate (MTA), likely formed via solid-phase zero-valent sulfur, in almost 50% of all samples. Concentrations ranged up to >30 µg L-1 (21% of total As). MTA removal by locally used technologies in which zero-valent or ferrous Fe is oxidized by aeration and As sorbs or coprecipitates with the forming Fe(III)hydroxides was indeed lower than for arsenate. The presence of phosphate required up to three times as much Fe(II) for comparable MTA removal. However, in contrast to previous sorption studies on preformed Fe minerals, MTA removal, even in the presence of phosphate, was still higher than that of arsenite. The more efficient MTA removal is likely caused by a combination of coprecipitation and adsorption rendering the tested Fe-based treatment technologies suitable for As removal also in the presence of MTA.