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The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.

The last 130,000 years of Earth’s history have been characterized by biodiversity losses due to increased anthropogenic pressure. In mammals, such losses particularly affected large-bodied megafauna (≥ 45 kg) and caused a downsizing of mammal communities. Theory and empirical evidence suggest that megafaunal losses severely altered ecological processes and disrupted ecosystem functioning. For instance, megaherbivores (≥ 1,000 kg) were the primary dispersers of plants that are considered evolutionary anachronisms today and megacarnivores (≥ 100 kg) used to dominate food webs all over the world, imposing top-down control effects that have been removed from degraded ecosystems.The unique ecological role of megafauna can partly be explained by scaling relationships of eco-physiological processes with body size. For example, the scaling of metabolism and movement ranges with body size determines megafauna to be keystone species for the flow of energy and nutrients. Yet, scaling relationships can explain only part of the ecological importance of megafauna. Species are part of large networks of biotic interactions, which connect organisms and create complex dynamics that shape ecosystems. Allometric scaling theory should therefore be integrated with network theory of biotic interaction to better investigate the ecological effects of Late Pleistocene and Holocene losses.By combining allometric scaling and network theory we can better understand the implications of megafaunal losses for ecosystem processes and functions. There is much to learn from such analysis of the past. For instance: How have ecosystems changed due to megafaunal losses following human impact? Which ecological processes and functions have been weakened or removed? How was the stability and resilience of ecosystems affected? Importantly, answering these questions can help protect the world's biodiversity, which is experiencing global changes due to anthropogenic activities, and to forecast possible disequilibria that can harm not only wildlife, but also human societies.In this thesis, I investigate how Late Pleistocene and Holocene megafaunal losses affected networks of biotic interactions. Specifically, I combined allometric scaling theory with network theory to examine losses of biotic connectivity, i.e. the connectivity among ecosystems promoted by wildlife, and the effects of human disturbances on species that exercise strong top-down control. I also studied how ecosystems can recover from past losses through rewilding, a novel restoration strategy that seeks to reintroduce species into their indigenous ranges and to replace extinct species with suitable functional analogues. In particular, I investigated rewilding opportunities for large (≥ 10 kg) terrestrial mammals worldwide as well as in protected areas and in regions with low human pressure using species distribution models. This gave a global assessment of the potential opportunities to rewild large mammals. I then expanded this approach to all terrestrial mammals and combined it with food web theory to assess the potential recoveries of trophic complexity through rewilding.Overall, I found that unique biotic interactions have been removed following megafaunal losses and that ecosystems have become increasingly disconnected and trophic complexity simplified as megafauna went extinct. Importantly, I found that such losses can be partly recovered through rewilding, if local acceptance and human-wildlife coexistence can be achieved. Notably, my results also show that megafauna have high charismatic value for human populations, which can help promote rewilding projects if societal factors allow.The findings from this thesis provide new theoretical support for the ecological consequences of megafauna extinctions, especially for the isolation and simplification of networks of biotic interactions worldwide. The results also support rewilding as a restoration strategy to promote recoveries from past ecological losses through species reintroduction and replacement of extinct species with functional analogues. In a time of widespread biodiversity changes and trophic downgrading as today, rewilding is a much needed approach to restore degraded ecosystems to self-sustaining biodiverse states.

Background: Anthropogenically driven biodiversity loss is predicted to increase in the future. Such losses decrease the complexity and resilience of ecological communities by hindering their capacity to recover from disturbances. A future-oriented approach to restore lost ecosystem function is trophic rewilding, the (re)introduction of missing keystone species to promote self-sustaining biodiverse ecosystems. A critical aspect in planning for future trophic rewilding is the selection of suitable release sites that match the biotic and abiotic needs of the focal species under future climates, with protection and restoration of reserves being an important consideration.Methods: Using current and estimated range maps of where large terrestrial mammals (≥10 kg) would live today without anthropogenic influences, we modelled climatic suitability under current and future climates. We then quantified the amount of climatically suitable habitat for large mammals within and outside current protected areas.Finding: We found that under current conditions ~22% of climatically suitable area could be restored with (re)introductions. For all reintroductions, current climatically suitable area was over ~220% of current range size. Under future climates the amount of climatically suitable habitat decreased ~50–65% from the current climatic suitability depending on emission scenario, although suitable habitat was still higher than current ranges. Most of the climatically suitable habitat was outside protected areas, which varied between only ~4–8% under both current and future climates, but, importantly, there remained climatically suitable habitat for all species in the future.Conclusion: Our results reveal substantial areas of climatically suitable habitat for the restoration of large terrestrial mammals through trophic rewilding under current and future climates, both within and outside protected areas, although emission scenario does impact the amount of available habitat.

During late Quaternary, humans caused mass extinctions of vertebrates, with a selective size-bias towards large mammals, likely causing losses of top-down trophic processes within ecosystems. Trophic rewilding is a restoration strategy that promotes self-sustaining ecosystems via (re)introduction of species to restore top-down processes, but the extent of restoration possible is poorly understood. Here, we used current and estimated range maps of where terrestrial mammals would live today without human influences together with climatic suitability ranges of these same species to simulate a rewilding scenario. We then used network analysis to investigate the impact of extinctions on top-down control and the restoration potential of trophic rewilding. Our results suggest that terrestrial ecosystems lost on average 44% of trophic levels’ species composition and 47% of the links among trophic levels. However, rewilding can restore trophic links to 80% of their pre-extinction level, highlighting the potential of trophic rewilding for restoring self-sustaining ecosystems.

Background/Question/MethodsThe current biodiversity crisis has reduced the connectivity among ecosystems, and humans have created barriers to the movement of animals responsible for these connections by fragmenting the landscape. Furthermore, the extinctions of species with large movement ranges may have removed the coupling interactions among ecosystems, resulting in a larger decrease of ecosystem connectivity even where the landscape has not been fragmented. However, how these extinctions have affected ecosystem connectivity has been overlooked so far, and the real impact of anthropogenic pressure on ecosystem connectivity may have been underestimated. To understand the implications of the extinctions of terrestrial mammals for ecosystem connectivity, we estimated the connectivity that ecosystems would have today in the complete absence of anthropogenic pressure through time, and we compared it to its current value. Then, we explored how much of the current connectivity would be lost if currently threatened species would go extinct. We considered a total of 4,395 terrestrial mammals, both extant and extinct (n = 322), that were alive during the Late Pleistocene, making our study the first global assessment of how ecosystem connectivity has changed because of species extinctions and range modifications due to anthropogenic pressure.Results/ConclusionsEcosystem connectivity has decreased worldwide following the extinctions and range modifications of terrestrial mammals, and it will continue to decrease if threatened species would go extinct. Particularly, ecosystem connectivity has been reduced in Europe, North America, and South America, which were more severely affected by human pressure that promoted the extinctions of megafauna (>44 kg) with large movement ranges. Africa and Asia, which conserve today a larger proportion of the original megafauna and relatively more intact connectivity, will be affected by future extinctions, and their ecosystem connectivity will continue to decrease if threatened species would go extinct. In general, most of the connectivity decrease is due to the extinctions and extirpations of megafauna. Nevertheless, ecosystem connectivity can be partly restored to its original value by re-introducing megafauna species in their natural geographic ranges. Overall, our results show that ecosystem connectivity has decreased worldwide because of anthropogenic extinctions and range modifications of terrestrial mammals, especially megafauna.

Table S2. Summary of the main studies on linear IgA bullous dermatosis including study design, patientsâ number, clinical features and laboratory findings. (DOCX 25 kb)

Table S1. Demographic data, clinical features, diagnostic findings, treatments and outcomes of 38 linear IgA bullous dermatosis patients. (DOCX 37 kb)

Psoriasis is a chronic inflammatory disease of the skin affecting approximately 2% of the world’s population. Systemic treatments, including methotrexate and cyclosporin, are associated with potential hepatotoxicity, due to either direct liver damage or immunosuppression or both immunomediated and a direct liver injury; therefore, treatment of patients with psoriasis poses a therapeutic challenge. The aim of this minireview is to help clinicians in the management of psoriatic patients who develop signs of liver dysfunction. To find relevant articles, a comprehensive search was performed on PubMed, EMBASE, and Cochrane with appropriate combinations of the following keywords being considered: viral hepatitis, nonalcoholic fatty liver disease, psoriasis, hepatotoxicity, drug toxicity, cholestasis, and autoimmune liver diseases.

Psoriasis is a skin inflammatory disease characterized by an increased body of comorbidities, including parodontopathy. Despite the visibility of skin lesions, prognostic biomarkers, related to disease monitoring and therapeutic effectiveness, are still missing. Although several markers have been studied, none of them has been identified as an independent prognostic factor. This concise review aims to summarize the current knowledge and results in saliva research applied to psoriasis. Combination of different markers could improve the prognostic prediction in patients with psoriasis. Future studies are needed to implement research on salivary biomarkers and their prognostic/therapeutic effects in the management of patients with psoriasis.

Activation of blood coagulation has been demonstrated in bullous pemphigoid (BP), a rare autoimmune blistering disease, potentially leading to a prothrombotic state. In order to evaluate the incidence of venous thromboembolism (VTE) in BP, a cohort study was carried out on 432 BP patients (59 % females; median age 76 years, interquartile range [IQR]: 68-82). At diagnosis, autoimmune bullous skin disorder intensity score (ABSIS) was calculated. VTE incidence was standardised with rates of the general population. Multivariable Cox proportional hazard model was used to estimate the hazard ratio of VTE according to ABSIS and concomitant risk factors. During a median follow-up of 4.2 years, 31 objectively-diagnosed VTE events were recorded. The incidence rate of VTE (per 1000 patient-years) was 17.2 overall (95 % confidence interval [CI]: 11.1-23.2), 56.7 (95 % CI: 33.0-80.4) during acute phase (22 VTE) and 6.3 (95 % CI: 2.8-11.3) during remission (9 VTE). The standardised incidence ratio was 4.06 (95 % CI: 2.73-5.65), higher during the acute phase (14.86, 95 % CI: 9.20-21.88) than during remission (1.48, 0.66-2.63). The adjusted hazard ratio of VTE was 2.74 (95 % CI: 1.07-7.04) for ABSIS > 48 vs ABSIS < 28, and 2.56 (95 % CI: 1.00-6.70) in patients with >= 2 concomitant risk factors. In conclusion, BP patients have a 15-fold increased VTE risk during acute phase, proportional to disease severity and heightened by concomitant risk factors. Activation of blood coagulation has been demonstrated in bullous pemphigoid (BP), a rare autoimmune blistering disease, potentially leading to a prothrombotic state. In order to evaluate the incidence of venous thromboembolism (VTE) in BP, a cohort study was carried out on 432 BP patients (59 % females; median age 76 years, interquartile range [IQR]: 68-82). At diagnosis, autoimmune bullous skin disorder intensity score (ABSIS) was calculated. VTE incidence was standardised with rates of the general population. Multivariable Cox proportional hazard model was used to estimate the hazard ratio of VTE according to ABSIS and concomitant risk factors. During a median follow-up of 4.2 years, 31 objectively-diagnosed VTE events were recorded. The incidence rate of VTE (per 1000 patient-years) was 17.2 overall (95 % confidence interval [CI]: 11.1-23.2), 56.7 (95 %CI: 33.0-80.4) during acute phase (22 VTE) and 6.3 (95 %CI: 2.8-11.3) during remission (9 VTE). The standardised incidence ratio was 4.06 (95 %CI: 2.73-5.65), higher during the acute phase (14.86, 95 %CI: 9.20-21.88) than during remission (1.48, 0.66-2.63). The adjusted hazard ratio of VTE was 2.74 (95 %CI: 1.07-7.04) for ABSIS > 48 vs ABSIS

Cutaneous vasculitides are a heterogeneous group of inflammatory disorders affecting skin blood vessels. They may be triggered by several factors, such as infection or drug, or may be related to underlying disease, notably connective tissue or malignancies. However, vasculitis occurs without any demonstrable triggering agents in a relevant number of patients. On the other hand, vasculitic skin lesions may manifest as a component of vasculitis affecting also internal organs; in someone of these patients, skin involvement occurs initially as the sole sign of disease, leading to consider cutaneous vasculitis a diagnosis of exclusion. In this review, we have focused on the most common variants of cutaneous vasculitis, including cutaneous small vessel vasculitis and urticarial vasculitis as well as Henoch-Schönlein purpura, a systemic form in which however skin involvement often predominates. We have also argued on livedoid vasculopathy, a cutaneous entity which, although nonfrankly vasculitic in origin, is frequently associated with connective tissue disease. Finally, we have analyzed the variety of cutaneous manifestations that may develop during the course of the main systemic vasculitides, such as Wegener's granulomatosis, Churg-Strauss syndrome and polyarteritis nodosa.

Autoinflammation has recently been suggested in the pathogenesis of neutrophilic dermatoses but systematic studies on their cytokine profile are lacking. Notably, amicrobial pustulosis of the folds (APF), classified among neutrophilic dermatoses, has been studied only in small case series. In our University Hospital, we conducted an observational study on 15 APF patients, analyzing their clinical and laboratory features with a follow-up of 9 months to 20 years. Skin cytokine pattern of 9 of them was compared to that of 6 normal controls. In all patients, primary lesions were pustules symmetrically involving the skin folds and anogenital region with a chronic-relapsing course and responding to corticosteroids. Dapsone, cyclosporine, and tumor necrosis factor blockers were effective in refractory cases. In skin samples, the expressions of interleukin (IL)-1β, pivotal cytokine in autoinflammation, and its receptors I and II were significantly higher in APF (P = 0.005, 0.018, and 0.034, respectively) than in controls. Chemokines responsible for neutrophil recruitment such as IL-8 (P = 0.003), CXCL 1/2/3 (C-X-C motif ligand 1/2/3) (P = 0.010), CXCL 16 (P = 0.045), and RANTES (regulated on activation, normal T cell expressed and secreted) (P = 0.034) were overexpressed. Molecules involved in tissue damage like matrix metalloproteinase-2 (MMP-2) (P = 0.010) and MMP-9 (P = 0.003) were increased. APF is a pustular neutrophilic dermatosis with a typical distribution in all patients. The disorder may coexist with an underlying autoimmune/dysimmune disease but is often associated only with a few autoantibodies without a clear autoimmunity. The overexpression of cytokines/chemokines and molecules amplifying the inflammatory network supports the view that APF has an important autoinflammatory component.

Exfoliative cheilitis is an uncommon chronic inflammatory condition that generally affects the vermilion of the lips. Its cause is still largely unknown an there is no effective treatment. Here we report of a case of exfoliative cheilitis possibly caused by mercury-containing dental amalgam in close proximity to dental titanium implant in a 41-year-old woman. By patch-testing, she was tested positive to thimerosal, palladium, gold, nickel, and copper. There was a strong temporal relation between last titanium dental implant and the onset of exfoliative cheilitis. Clinicians should be aware that exfoliative cheilitis might be associated with an allergy to intraoral dental metals and that titanium dental implant should not be implanted in the vicinity of the mercury-containing dental amalgam filling, even in presence of mercury amalgam as rootend filling material.

Background Wegener's granulomatosis (WG) is a rare granulomatous necrotizing vasculitis of small and medium vessels which has predilection for upper airways, lungs and kidney. However, any other organ, including the skin and oral cavity, can be involved. Although mucocutaneous lesions are relatively common, they have only rarely been reported as localized manifestation of the disease. Objectives Our aim was to evaluate the type and sites of skin and mucosal lesions, clinical course and response to treatment, histologic features and laboratory findings in localized WG. Methods The medical records of three patients (two women and one man) with localized WG followed up at our hospitals for a mean time of 10 years were studied. Results All patients presented with facial plaques infiltrating the nasal and palatal mucosae and cartilages and, in one case, perforating the palatal bone. Anti-neutrophil cytoplasmic antibodies, which are the marker for multisystem WG, were negative. The disease, refractory to various immunosuppressants, responded well, albeit incompletely, to prednisone plus cyclophosphamide. Limitations The limited number of patients is counterbalanced by the rarity of the disease. Conclusions Our cases may represent a rare distinctive subset of WG limited to the facial region and upper airway mucosa but showing a locally aggressive behaviour leading to cartilage and bony destruction. © 2011 European Academy of Dermatology and Venereology.

Vitiligo is a skin disorder characterized by loss of functional melanocytes. Keratinocytes contribute to melanocyte homeostasis, and keratinocyte alteration may play a role in melanocyte dysfunction in vitiligo. In particular, the release of melanogenic mediators and the level of functioning keratinocytes may affect melanocyte dysfunction in vitiligo epidermis. Keratinocyte-derived mediators involved in pigmentation, analysed by in situ hybridization, and epidermal apoptosis, detected by TUNEL assay and electron microscopy, were evaluated in lesional and perilesional skin biopsies from 15 patients with active vitiligo and in 5 control subjects. Among the melanogenic mediators, stem cell factor (SCF) and endothelin-1 (ET-1) mRNA were significantly reduced in lesional as compared to perilesional epidermis, whereas no difference was observed in mRNA of basic fibroblastic growth factor (bFGF) and granulocyte-monocyte colony stimulating factor (GM-CSF). The expression of mRNA for tumor necrosis factor (TNF)-α and interleukin-6 (IL-6), two pro-inflammatory cytokines with an inhibitory effect on pigmentation, was increased in the epidermis from vitiligo biopsies, whereas their expression was practically undetectable in the skin of control subjects. Apoptotic keratinocytes were more abundant in lesional vs. perilesional skin of vitiligo patients and were absent in the epidermis of control subjects. Changes in expression of keratinocyte-derived mediators observed in the present study are consistent with their differential functions in melanocyte regulation. In particular, increased TNF-α could contribute to keratinocyte apoptosis, which results in reduced release of melanogenic cytokines and ultimately in melanocyte disappearance.

Background: Granulomatous cutaneous T-cell lymphomas (CTCLs) are rare and represent a diagnostic challenge. Only limited data on the clinicopathological and prognostic features of granulomatous CTCLs are available. We studied 19 patients with granulomatous CTCLs to further characterize the clinicopathological, therapeutic, and prognostic features. Observations: The group included 15 patients with granulomatous mycosis fungoides (GMF) and 4 with granulomatous slack skin (GSS) defined according to the World Health Organization-European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas. Patients with GMF and GSS displayed overlapping histologic features and differed only clinically by the development of bulky skin folds in GSS. Histologically, epidermotropism of lymphocytes was not a prominent feature and was absent in 9 of 19 cases (47%). Stable or progressive disease was observed in most patients despite various treatment modalities. Extracutaneous spread occurred in 5 of 19 patients (26%), second lymphoid neoplasms developed in 4 of 19 patients (21%), and 6 of 19 patients (32%) died of their disease. Disease-specific 5-year survival rate in GMF was 66%. Conclusions: There are clinical differences between GMF and GSS, but they show overlapping histologic findings and therefore cannot be discriminated by histologic examination alone. Development of hanging skin folds is restricted to the intertriginous body regions. Granulomatous CTCLs show a therapy-resistant, slowly progressive course. The prognosis of GMF appears worse than that of classic nongranulomatous mycosis fungoides. ©2008 American Medical Association. All rights reserved.

Purpose Primary cutaneous B-cell lymphomas (PCBCLs) are a distinct group of primary cutaneous lymphomas with few and conflicting data on their prognostic factors. Patients and Methods The study group included 467 patients with PCBCL who were referred, treated, and observed in 11 Italian centers (the Italian Study Group for Cutaneous Lymphomas) during a 24-year period (1980 to 2003). All of the patients were reclassified according to the WHO–European Organisation for Research and Treatment of Cancer (EORTC) classification. Results Follicle center lymphoma (FCL) accounted for 56.7% of occurrences, followed by marginal-zone B-cell lymphoma (MZL; 31.4%); diffuse large B-cell lymphoma (DLBCL), leg type, was reported in 10.9% of patients. Radiotherapy was the first-line treatment in 52.5% of patients and chemotherapy was the first-line treatment in 24.8% of patients. The complete response rate was 91.9% and the relapse rate was 46.7%. The 5- and 10-year overall survival (OS) rates were 94% and 85%, respectively. Compared with FCL/MZL, DLBCL, leg type, was characterized by statistically significant lower complete response rates, higher incidence of multiple cutaneous relapses and extracutaneous spreading, shorter time to progression, and shorter OS rates. The only variable with independent prognostic significance on the OS was the clinicopathologic diagnosis according to the WHO-EORTC classification (DLBCL, leg-type, showed a significantly worse prognosis v FCL and MZL; P < .001), whereas the only variable with independent prognostic significance on disease-free survival was the presence of a single cutaneous lesion (P = .001). Conclusion Our study identifies a possible PCBCL subclassification and the extent of cutaneous involvement as the two most relevant prognostic factors in PCBCL. These data can be considered reasonably as the clinical background for an appropriate management strategy.

In the group of primary cutaneous T-cell lymphomas, T-cytotoxic and natural killer cell lymphomas have been recently recognized as distinct and rare clinicopathologic entities. Typically, cytotoxic granules associated proteins TIA-1, granulolysine and perform, and cytotoxic-natural killer (NK) cell markers CD8+, CD56+, CD94+, CD161+, NKp46+ are expressed by tumoral cells. Five T-cytotoxic and NK cutaneous lymphomas subtypes are actually recognized: subcutaneous panniculitis-like T-cell lymphoma, extranodal nasal and nasal-type NK-T cell lymphoma, blastic NK cell lymphoma, aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, cutaneous gamma-delta peripheral T-cell lymphoma. In this review, the most important clinical, histological, immunohistochemical and molecular data are analyzed together with differential diagnostic aspects between these entities. T-cytotoxic and NK cutaneous lymphomas pursue a very aggressive course, with poor outcome and high mortality rate, with few exceptions.

BACKGROUND. Cutaneous lymphomas expressing a cytotoxic or natural killer (NK) cell phenotype represent a group of lymphoproliferative disorders for which there is currently much confusion and little consensus regarding the best nomenclature and classification. METHODS. This study analyzes 48 cases of primary cutaneous lymphoma expressing cytotoxic proteins and/or the NK cell marker, CD56. These cases were collected for a workshop of the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Task Force, to better clarify the clinical, morphologic, and phenotypic features of these uncommon tumors. RESULTS. Several categories with different clinical and pathologic features were delineated: 1) aggressive, CD8+, epidermotropic, cytotoxic T-cell lymphoma; 2) mycosis fungoides, cytotoxic immunophenotype variant; 3) subcutaneous panniculitis-like T-cell lymphoma; 4) NK/T-cell lymphoma, nasal type; 5) CD4+, NK cell lymphoma; 6) blastoid NK cell lymphoma; (7) intravascular NK-like lymphoma; and 8) cytotoxic, peripheral T-cell lymphoma. CONCLUSIONS. Our data show that primary cutaneous cytotoxic/NK cell lymphomas include distinct groups of diseases, clinically, histologically, and biologically. Because the finding of a cytotoxic phenotype often has prognostic significance, the routine use of cytotoxic markers in the diagnosis and classification of cutaneous lymphomas should be expanded

Simple Summary Cutaneous and breast implant-associated anaplastic large-cell lymphomas are usually localized neoplasms with an indolent clinical course compared to systemic ALCL. However comparative analyses of the molecular features of these two entities have not yet been reported. We performed targeted RNA sequencing, which revealed that fusion transcripts, although infrequent, might represent additional pathogenetic events in both diseases. We also found that these entities display upregulation of the PI3K/Akt pathway and show enrichment in genes of the neurotrophin signaling pathway. These findings advance our knowledge regarding the pathobiology of cALCL and BI-ALCL and point to additional therapeutic targets. Abstract Cutaneous and breast implant-associated anaplastic large-cell lymphomas (cALCLs and BI-ALCLs) are two localized forms of peripheral T-cell lymphomas (PTCLs) that are recognized as distinct entities within the family of ALCL. JAK-STAT signaling is a common feature of all ALCL subtypes, whereas DUSP22/IRF4, TP63 and TYK gene rearrangements have been reported in a proportion of ALK-negative sALCLs and cALCLs. Both cALCLs and BI-ALCLs differ in their gene expression profiles compared to PTCLs; however, a direct comparison of the genomic alterations and transcriptomes of these two entities is lacking. By performing RNA sequencing of 1385 genes (TruSight RNA Pan-Cancer, Illumina) in 12 cALCLs, 10 BI-ALCLs and two anaplastic lymphoma kinase (ALK)-positive sALCLs, we identified the previously reported TYK2-NPM1 fusion in 1 cALCL (1/12, 8%), and four new intrachromosomal gene fusions in 2 BI-ALCLs (2/10, 20%) involving genes on chromosome 1 (EPS15-GNG12 and ARNT-GOLPH3L) and on chromosome 17 (MYO18A-GIT1 and NF1-GOSR1). One of the two BI-ALCL samples showed a complex karyotype, raising the possibility that genomic instability may be responsible for intra-chromosomal fusions in BI-ALCL. Moreover, transcriptional analysis revealed similar upregulation of the PI3K/Akt pathway, associated with enrichment in the expression of neurotrophin signaling genes, which was more conspicuous in BI-ALCL, as well as differences, i.e., over-expression of genes involved in the RNA polymerase II transcription program in BI-ALCL and of the RNA splicing/processing program in cALCL.

Mycosis fungoides (MF) is a rare neoplasm representing the most frequent form of primary cutaneous T-cell lymphoma (CTCL). Diagnosis of MF is generally complex, often requiring integration of clinical, histological, immunophenotypic and molecular data. Currently, there are no epidemiological data supported by registries or local studies on MF in Italy. Moreover, the clinical management of MF in Italy is heterogeneous, and differs according to the geographical area and experience of the physician who manages the disease. Considering the uncertainties in the current scenario for MF in Italy, a consensus project involving experts on CTCL was initiated to define the epidemiological impact of MF and obtain information about the current diagnostic and therapeutic pathway of this disease in Italy. The prevalence of MF in Italy was estimated to be 6,800 patients, 4,900 of whom with early stage of disease; the estimated incidence ranged between 270 and 330 new cases per year. Among the clinical figures involved in the multidisciplinary management of MF, dermatologists were recognised as a reference point for both diagnosis and therapeutic decisions. These findings suggest the importance of monitoring both the disease and its management; it is, therefore, interesting to set up regional registries for monitoring and recognition of rare tumor status for MF. The results further indicate the need to train physicians to favour more rapid diagnosis and simplify the pathway for referring patients to reference centres with adequate diagnostic and treatment standards. In light of the forthcoming introduction of new therapies, the development of a nationwide PDTA (Path of Diagnostic Therapeutic Care, in Italian defined as Percorso Diagnostico-Terapeutico Assistenziale) is also of substantial importance.

Blastic Plasmacytoid Dendritic Cell Neoplasm is a rare and aggressive hematological malignancy currently lacking an effective therapy. To possibly identify genetic alterations useful for a new treatment design, we analyzed by whole-exome sequencing fourteen Blastic Plasmacytoid Dendritic Cell Neoplasm patients and the patient-derived CAL-1 cell line. The functional enrichment analysis of mutational data reported the epigenetic regulatory program as the most significantly undermined (P

Breast implant-associated anaplastic large cell lymphoma is a new provisional entity in the revised World Health Organization classification of lymphoid malignancies, the pathogenesis and cell of origin of which are still unknown. We performed gene expression profiling of microdissected breast implant-associated anaplastic large cell lymphoma samples and compared their transcriptional profiles with those previously obtained from normal T-cells and other peripheral T-cell lymphomas and validated expression of selected markers by immunohistochemistry. Our results indicate that most breast implant-associated anaplastic large cell lymphomas exhibit an activated CD4+ memory T-cell phenotype, which is associated with CD25 and FoxP3 expression. Gene ontology analyses revealed upregulation of genes involved in cell motility programs (e.g., CCR6, MET, HGF, CXCL14) in breast implant-associated anaplastic large cell lymphomas compared to normal CD4+ T-cells and upregulation of genes involved in myeloid cell differentiation (e.g., PPARg, JAK2, SPI-1, GAB2) and viral gene transcription (e.g., RPS10, RPL17, RPS29, RPL18A) compared to other types of peripheral T-cell lymphomas. Gene set enrichment analyses also revealed shared features between the molecular profiles of breast implant-associated anaplastic large cell lymphomas and other types of anaplastic large cell lymphomas, including downregulation of T-cell receptor signaling and STAT3 activation. Our findings provide novel insights into the biology of this rare disease and further evidence that breast implant-associated anaplastic large cell lymphoma represents a distinct peripheral T-cell lymphoma entity.

Granulomatosis with polyangiitis (GPA) is a systemic necrotizing small vessel vasculitis associated with circulating anti-neutrophil cytoplasmic antibodies (ANCAs). Skin manifestations, mostly represented by palpable purpura, papulonodular lesions and livedo reticularis, are present in up to 50% of the cases. Ulcerations with undermined, raised erythematous–violaceous border resembling pyoderma gangrenosum (PG) have rarely been reported as skin involvement in GPA. The presence of circulating ANCAs with a cytoplasmic labelling pattern, the involvement of internal organs, particularly of the lung, and the absence on histology of a mainly neutrophilic infiltrate in early phases of the cutaneous lesions may be regarded as clues to rule out true PG and confirm the diagnosis of GPA skin ulcerations simulating PG. Herein, we describe two paradigmatic cases of such a unique presentation of GPA and a literature review focusing on clinicopathological features of GPA presenting with PG-like ulcerations in the skin has been provided. Moreover, referring to the scenario observed in these two cases, an easy-to-use working approach for the differential diagnosis between the two conditions has also been proposed.

Bullous pemphigoid is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. This disease typically affects the elderly and presents with itch and localized or generalized bullous lesions. In up to 20% of affected patients blister may be completely absent, and only excoriations, prurigo-like lesions, eczematous lesions, urticated lesions, and/or infiltrated plaques are observed. The disease is significantly associated with neurological disorders. The morbidity of bullous pemphigoid and its impact on the quality of life are significant. So far, a limited number of national treatment guidelines have been proposed, but no common European consensus has emerged. This guideline for the treatment of bullous pemphigoid has been developed by an Italian group of experts taking in account the Italian legislation and local pharmacological governance. Guidelines are adapted from the original article under the guidance of the European Dermatology Forum (EDF) in collaboration with the European Academy of Dermatology and Venereology (EADV). It summarizes evidence-based and expert-based recommendations (S2 level).

Purpose Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers. Patients and Methods Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS). Results Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%). Conclusion To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients.

Upon T cell receptor stimulation, CD4(+) T helper (Th) lymphocytes release extracellular vesicles (EVs) containing microRNAs. However, no data are available on whether human CD4(+) T cell subsets release EVs containing different pattern of microRNAs. The present work aimed at filling this gap by assessing the microRNA content in EVs released upon in vitro T cell receptor stimulation of Th1, Th17, and T regulatory (Treg) cells. Our results indicate that EVs released by Treg cells are significantly different compared with those released by the other subsets. In particular, miR-146a-5p, miR-150-5p, and miR-21-5p are enriched, whereas miR-106a-5p, miR-155-5p, and miR-19a-3p are depleted in Treg-derived EVs. The in vitro identified EV-associated microRNA signature was increased in serum of autoimmune patients with psoriasis and returned to healthy levels upon effective treatment with etanercept, a biological drug targeting the TNF pathway and suppressing inflammation. Moreover, Gene Set Enrichment Analysis showed an over-representation of genes relevant for T cell activation, such as CD40L, IRAK1, IRAK2, STAT1, and c-Myb in the list of validated targets of Treg-derived EV miRNAs. At functional level, Treg-derived (but not Th1/Th17-derived) EVs inhibited CD4(+) T cell proliferation and suppressed two relevant targets of miR-146a-5p: STAT1 and IRAK2. In conclusion, our work identified the miRNAs specifically released by different human CD4(+) T cell subsets and started to unveil the potential use of their quantity in human serum to mark the pathological elicitation of these cells in vivo and their biological effect in cell to cell communication during the adaptive immune response.

Categorization of primary cutaneous B‐cell lymphomas (PCBCL) other than marginal zone (MZL) represents a diagnostic challenge with relevant prognostic implications. The 2008 WHO lymphoma classification recognizes only primary cutaneous follicular center cell lymphoma (PCFCCL) and primary cutaneous diffuse large B‐cell lymphoma, leg type (PCDLBCL‐LT), whereas the previous 2005 WHO/EORTC classification also included an intermediate form, namely PCDLBCL, other. We conducted a retrospective, multicentric, consensus‐based revision of the clinicopathologic characteristics of 161 cases of PCBCL other than MZL. Upon the histologic features that are listed in the WHO classification, 96 cases were classified as PCFCCL and 25 as PCDLBCL‐LT; 40 further cases did not fit in the former subgroups in terms of cytology and/or architecture, thus were classified as PCDLBCL, not otherwise specified (PCDLBCL‐NOS). We assigned all the cases a histogenetic profile, based on the immunohistochemical detection of CD10, BCL6, and MUM1, and a “double hit score” upon positivity for BCL2 and MYC. PCDLBCL‐NOS had a clinical presentation more similar to PCFCCL, whereas the histology was more consistent with the picture of a diffuse large B‐cell lymphoma, as predominantly composed of centroblasts but with intermixed a reactive infiltrate of small lymphocytes. Its behavior was intermediate between the other two forms, particularly when considering only cases with a “non‐germinal B‐cell” profile, whereas “germinal center” cases resembled PCFCCL. Our data confirmed the aggressive behavior of PCDLBC‐LT, which often coexpressed MYC and BCL2. The impact of single factors on 5‐year survival was documented, particularly histogenetic profile in PCDLBCL and BCL2 translocation in PCFCCL. Our study confirms that a further group—PCDLBCL‐NOS—exists, which can be recognized through a careful combination of histopathologic criteria coupled with adequate clinical information.