Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive precursor cell hematological malignancy with a dismal prognosis, necessitating prompt and accurate diagnosis. However, its blastoid morphology and immunophenotype may lead to diagnostic confusion with a broad spectrum of hematological neoplasms. This systematic review delineates the critical morphological, immunophenotypic, and molecular features required to distinguish BPDCN from its mimics across common sites of involvement (skin, bone marrow, and lymph nodes). We reinforce the diagnostic criteria for BPDCN and provide an in-depth analysis of its differential diagnosis, structuring it into two groups: (A) hematological neoplasms with blastoid morphology (e.g., ALL/LBL, blastoid MCL, AML, myeloid sarcoma), and (B) myeloid malignancies with pDC-associated markers (e.g., AML with pDC-like phenotype, AML with pDC expansion, mature pDC proliferation). We emphasize the integration of immature and lineage-specific markers, and molecular data (e.g., ZRSR2, MYB/MYBL1, NPM1, FLT3, RUNX1, DNMT3, CCND1 status) to resolve diagnostic dilemmas. The aim is to provide a comprehensive diagnostic review and guide to standardize the workup and facilitate the early initiation of appropriate treatment for this challenging disease.

Abstract The PROspective Cutaneous Lymphoma International Prognostic Index Study ‘PROCLIPI’ (ClinicalTrials.Gov ID: NCT02848274) opened in 2015 at > 50 international expert centres for mycosis fungoides (MF) and Sézary syndrome (SS). The aim of the study was to determine a prognostic index to better stratify patients for survival. A prognostic index for advanced MF and SS has recently been published that stratifies patients with advanced MF/SS into risk groups with significantly different 5-year overall survival. A CLIPI for early-stage MF is urgently needed to allow dermatologists to identify patients at risk of progression to advanced stage and subsequently select treatments for improved survival, as PROCLIPI shows that 5-year overall survival varies between 72.4% and 95.4% in early-stage MF and SS. Prospectively collected predefined datasets were analysed, including clinical, pathological, genotypic, treatment and quality-of-life data, in patients with newly diagnosed MF or SS. In total, 2004 patients with early-stage disease (IA, n = 921; IB, n = 853; IIA, n = 154) were recruited across 52 sites, presenting at a median age of 57 years (interquartile range 43–68). In multivariate analysis, the presence of cutaneous plaques (P < 0.001), nodal enlargement (Nx–N2) (P < 0.001), age > 60 years (P = 0.02) and large cell transformation in skin (P < 0.001) were significant factors for progression and overall survival. Notably, plaques have a high correlation with disease progression and poor overall survival (83.2% 5-year survival) compared with patients with patch-only disease (94.9% 5-year survival). Early-stage MF is typically reported as a low-grade lymphoma, but data from PROCLIPI have found low 5-year survival rates coupled with a median age of diagnosis of 57 years. Thus there is a marked reduction in life expectancy for some patients. However, 5-year survival rates for patients with patch-only disease are comparable with those of the average 57-year-old individual in Europe. In addition to plaques, PROCLIPI has identified other significant factors associated with poor survival, enabling the identification of at-risk patients using markers such as nodal enlargement and large cell transformation in the skin. The data highlight the need for better stratification of patients with early-stage MF and SS to allow improved management.

Abstract Brentuximab vedotin (BV), a CD30+ antibody conjugate, was approved for CD30+ cutaneous T-cell lymphoma in 2018. Mogamulizumab, an anti-CCR4 monoclonal antibody was approved for refractory mycosis fungoides and Sézary syndrome. The overall survival (OS) benefit and optimal sequencing of these therapies remain unclear in relation to traditional systemic therapies – bexarotene and extracorporeal photopheresis (ECP) – used in advanced-stage disease. The PROCLIPI study (NCT02848274) was interrogated for patients with advanced-stage disease (2015–2025) receiving mogamulizumab, BV, bexarotene or ECP. Of 593 patients, 566 had recorded systemic therapy. Treatment groups overlapped because most had more than one modality. Extracted data included stage, treatment line, OS and best response [either complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD)]. Mogamulizumab was given to 72 patients with 52 completed courses. Rates of CR, PR, SD and PD were 31%, 37%, 15% and 17%, respectively, and the median OS was 64 months. BV was given to 83 patients with 69 completed courses. The rates of CR, PR, SD and PD were 12%, 35%, 41%, and 13%, respectively, and the median OS was 28 months. Bexarotene was used in 178 patients (CR, PR, SD and PD in 8%, 37%, 42% and 13%; median OS 48.5 months) and ECP in 153 (CR, PR, SD and PD in 3%, 40%, 46% and 11%; median OS 41 months). In survival analyses (n = 370), OS improved if a patient received mogamulizumab for any line vs. those who received other systemic (P = 0.008). Data for BV did not reach statistical significance. Monoclonal exposure improved OS (P = 0.04). B2 stage favoured mogamulizumab (P = 0.001). Treatment groups were not mutually exclusive. Mogamulizumab demonstrated the highest objective response. Patients receiving mogamulizumab for any line had longer OS, favouring its use in blood-dominant Sézary syndrome. BV produced durable responses, supporting its role in CD30+ large-cell transformation. Shorter OS in BV any line may reflect inadequacies in current staging, as tumour disease (IIB) had worse outcomes than erythrodermic disease (stage III/IV). Bexarotene and ECP remain important systemic therapies. These data inform phenotype-directed sequencing and underscore the need for prospective comparative studies.

In recent classifications several cutaneous lymphomas were reclassified as lymphoproliferative disorder (LPDs). These include primary cutaneous CD4+ small/medium T-cell LPD (PCSM-TCLPD), primary cutaneous acral CD8+ T-cell LPD (acral CD8+ TCLPD) and primary cutaneous marginal zone lymphoma/LPD (PCMZL/LPD). The latter is still classified as primary cutaneous marginal zone lymphoma (PCMZL) in the 5th edition of the World Health Organization classification. A survey was previously carried out among 30 cutaneous lymphoma centres on the effects of this new terminology on clinical management. The results revealed considerable heterogeneity and emphasized the need to develop uniform recommendations for management and treatment of these disorders. Our objective was to develop consensus recommendations for staging, treatment and follow-up in PCSM-TCLPD, acral CD8+ TCLPD and PCMZL/LPD. Two surveys with questions regarding staging, treatment and follow-up of cutaneous LPDs were distributed among 30 cutaneous lymphoma expert centres collaborating within the EORTC-CLTG, USCLC and ISCL. Consensus recommendations were formulated based on these surveys, an extensive literature search, two rounds of feedback and a final consensus meeting. Important changes compared with current practice and literature are as follows. (i) Staging examinations, other than thorough clinical examination of skin and peripheral lymph nodes, are not required in typical cases of PCSM-TCLPD and acral CD8+ TCLPD. (ii) Low-dose radiotherapy (4-8 Gy) can be used rather than dose ≥ 20 Gy for PCSM-TCLPD and acral CD8+ TCLPD, and 4 Gy can be used for PCMZL/LPD. The dose can be escalated to 20-24 Gy in the case of local failure. (iii) Intralesional corticosteroids are also recommended as initial treatment in all three LPDs. (iv) A limited follow-up period (2 years) is acceptable in PCSM-TCLPD and acral CD8+ TCLPD LPD. These EORTC/USCLC/ISCL consensus recommendations reflect the state-of-the-art management and treatment as agreed upon by major cutaneous lymphoma centres. They may contribute to uniform staging, treatment and follow-up policy in patients with cutaneous LPDs.

Malignant histiocytoses are rare histiocytic neoplasms that exhibit aggressive clinical and histopathological features. One of these entities, Langerhans cell sarcomas (LCS), shares some histopathological features with Langerhans cell histiocytosis but is distinguished by its overtly malignant cytologic features. The literature on LCS is mostly limited to short reports and a few reviews, while a complete revision of its nosology is lacking. This study aims to fill this gap in the knowledge on LCS, explore potential prognostic factors, and propose a clinical subclassification for better patient stratification, which could guide future treatment investigations. A systematic review of the literature was conducted following PRISMA guidelines. From each included patient, a complete set of clinical and pathological features was collected. Descriptive and association statistics, as well as survival analysis, were performed using R Studio. A cohort of 88 patients was analyzed, the majority being adult males with multisystem pictures often involving skin and lymph nodes. pERK pathway gene mutations were reported in around half. Overall prognosis was poor, even though the association with another hematological neoplasm displayed a significant negative prognostic impact (p = 0.0017). Moreover, in primary cases, a significant difference was observed dividing patients into single system vs multisystem (p = 0.012). Despite treatment modalities being highly heterogeneous, statistical analyses provided insights into the relevance of treating patients according to disease spread (e.g., treating localized masses with surgery alone leads to frequent complete remission, p = 0.0002). This study provides an extensive analysis of LCS nosology and prognostic factors, underscoring the importance of distinguishing LCS from LCH and other histiocytoses, as well as adopting a unified system to define disease spread and guide therapeutic management.

ABSTRACT:Advanced mycosis fungoides (MF) and Sézary syndrome (SS) have a poor overall survival (OS) of <5 years. Studies have found the current staging (IA-IVB) is inadequate for risk stratification. The PROCLIPI (Prospective Cutaneous Lymphoma International Prognostic Index) study was launched in 2015 at 46 international expert MF/SS centers, prospectively collecting predefined data sets in patients with newly diagnosed MF/SS, to determine a cutaneous lymphoma IPI (CLIPI). Five hundred fifty-two patients with advanced stage MF/SS were recruited. The 5-year OS was 50.0% for stage IIB, 64.8% for stage IIIA, 43.9% for stage IIIB, 50.8% for stage IVA1, 25.9% for stage IVA2, and 36.9% for stage IVB. Factors at diagnosis associated with a significantly worse survival were N3 status (P < .001), age >60 years (P < .001), raised serum lactate dehydrogenase (P = .005), and large-cell transformation in skin (P = .006). Modeling these 4 independent risk factors into a CLIPI found that there was a worse OS in high- vs low-risk (P < .001), high- vs intermediate-risk (P = .002) and intermediate- vs low-risk (P = .010) groups. Five-year OS was 63.3%, 44.7%, and 18.3% in the low-, intermediate-, and high-risk groups, respectively. In this advanced stage cohort there was a low 5-year survival and increasing stage was not associated with worsening survival. The use of CLIPI to stratify patients into risk groups has the potential to improve outcomes and aid optimal treatment selection. This trial was registered at www.ClinicalTrials.gov as #NCT02848274.

BackgroundPrimary cutaneous lymphomas are neoplasms of the immune system with a distinct tropism for the skin and an absence of extracutaneous manifestations at the time of diagnosis. Studies focusing on cutaneous lymphomas in children and adolescents remain scarce and often do not encompass the rare subtypes.ObjectivesTo address this knowledge gap by describing the clinical, histological and molecular characteristics of a large group of paediatric patients affected by primary cutaneous lymphoma. We also provided the Paediatric Primary Cutaneous Lymphoma Atlas that illustrates the clinicopathological spectrum of observed presentations, in the hope of supporting other physicians in the diagnostic process.MethodsRetrospective chart review of paediatric patients diagnosed with primary cutaneous lymphomas between 1980 and 2022 at the Paediatric Dermatology Unit of Fondazione IRCCS Ca ' Granda Ospedale Maggiore Policlinico, Milan.ResultsA total of 101 patients (58 males, 43 females) met the inclusion criteria. The most common subtypes were lymphomatoid papulosis (n = 48) and mycosis fungoides (n = 31). These were followed by primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorders (n = 7), primary cutaneous anaplastic large-cell lymphomas (n = 5), primary cutaneous marginal zone B-cell lymphomas (n = 3), primary cutaneous follicle centre lymphomas (n = 2), subcutaneous panniculitis-like T-cell lymphomas (n = 2), primary cutaneous peripheral T-cell lymphoma not otherwise specified (n = 1), primary cutaneous precursor B-lymphoblastic lymphoma (n = 1) and Sezary syndrome (n = 1). Clinical follow-up data covering a median of 70.8 months (range 1-324) were available for 74 patients, of whom three died due to cutaneous lymphoma.ConclusionsOur findings shed light on the peculiar aspects and long-term outcomes of paediatric cutaneous lymphomas, particularly emphasizing their distinctive features in comparison to their adult counterparts and exploring the less common subtypes. Further larger-scale studies are warranted to better characterize these entities and to achieve a more rapid and accurate diagnosis.

Background: Atopic Dermatitis (AD) is a prevalent inflammatory skin disease whose course is often complicated by the presence of concomitant anxiety and depressive disorders. Dupilumab has been demonstrated to be largely effective in AD. The aims of the present study were to (1) to verify the effectiveness of 2-year dupilumab treatment on the depressive and anxiety symptoms of patients affected by AD and (2) to identify predictors of the persistence of psychiatric symptoms despite maintenance treatment with dupilumab. Methods: A total of 331 patients with severe AD were assessed at baseline and at different times over 2 years by a large set of rating scales, including the Eczema Area and Severity Index (EASI), the Hospital Anxiety and Depression Scale (HADS), and the Dermatology Life Quality Index (DLQI). Paired sample t-tests were performed to verify the effectiveness of dupilumab on the severity of AD and mental health items. Two binary logistic regression models were then used to identify the predictors of the persistence of clinically significant depression and anxiety, defined by a score ≥ 8 on each sub-scale of the HADS. Results: After 2 years of treatment with dupilumab, the patients benefited, showing a significant improvement in both the dermatological disease and comorbid depression/anxiety (p < 0.001 for all scales). Overall, 17.5% and 13% of patients, respectively, reported residual depressive and anxiety symptoms after the 2-year treatment with dupilumab. The baseline predictors of the persistence of clinically significant depressive symptoms after the 2-year treatment with dupilumab were found to be a higher body mass index (BMI) (p = 0.012), a lower impact of dermatological disease on quality of life (p = 0.015), and more severe depressive symptoms (p < 0.01), while for anxiety, the only predictor was found to be female gender (p = 0.03). Conclusions: Using a multidisciplinary approach, at baseline, dermatologists should more closely monitor patients who are at a greater risk of maintaining residual psychiatric symptoms despite therapy, such as those with more severe depressive symptoms and those who are overweight.

Background Lymphomatoid papulosis (LyP) is a rare cutaneous T-cell lymphoproliferative disorder. Comprehensive data on LyP in the paediatric population are scarce.Objectives To characterize the epidemiological, clinical, histopathological and prognostic features of paediatric LyP.Methods This was a retrospective multicentre international cohort study that included 87 children and adolescents with LyP diagnosed between 1998 and 2022. Patients aged <= 18 years at disease onset were included. LyP diagnosis was made in each centre, based on clinicopathological correlation.Results Eighty-seven patients from 12 centres were included. Mean age at disease onset was 7.0 years (range 3 months-18 years) with a male to female ratio of 2 : 1. Mean time between the onset of the first cutaneous lesions and diagnosis was 1.3 years (range 0-14). Initial misdiagnosis concerned 26% of patients. LyP was most often misdiagnosed as pityriasis lichenoides et varioliformis acuta, insect bites or mollusca contagiosa. Erythematous papules or papulonodules were the most frequent clinical presentation. Pruritus was specifically mentioned in 21% of patients. The main histological subtype was type A in 55% of cases. When analysed, monoclonal T-cell receptor rearrangement was found in 77% of skin biopsies. The overall survival rate was 100%, with follow-up at 5 years available for 33 patients and at 15 years for 8 patients. Associated haematological malignancy (HM) occurred in 10% of cases (n = 7/73), including four patients with mycosis fungoides, one with primary cutaneous anaplastic large cell lymphoma (ALCL), one with systemic ALCL and one with acute myeloid leukaemia. If we compared incidence rates of cancer with the world population aged 0-19 years from 2001 to 2010, we estimated a significantly higher risk of associated malignancy in general, occurring before the age of 19 years (incidence rate ratio 87.49, 95% confidence interval 86.01-88.99).Conclusions We report epidemiological data from a large international cohort of children and adolescents with LyP. Overall, the disease prognosis is good, with excellent survival rates for all patients. Owing to an increased risk of associated HM, long-term follow-up should be recommended for patients with LyP. Lymphomatoid papulosis (LyP) is a rare cutaneous T-cell lymphoproliferative disorder. Comprehensive data on LyP in the paediatric population are scarce. This article helps to better characterize the epidemiological, clinical, histopathological and prognostic features of paediatric LyP. Lymphomatoid papulosis is a very rare skin condition caused by an abnormal increase in white blood cells (called 'lymphocytes') in the skin. The condition rarely affects children, so most of the scientific data published about this disease focuses on adults.This study involved 12 academic dermatology centres in Europe, the Middle East and North America, and gathered data from about 87 children who presented with symptoms of lymphomatoid papulosis before the age of 19 years. The aim of this study was to better describe this disease in the paediatric population and discuss its treatment options and evolution.We found that the presentation of the disease in children is roughly the same as in adults. Safe and effective treatment options exist. The disease is not life threatening, but it requires investigation by a dermatologist, both to make a careful diagnosis and to monitor it as sometimes associated cancers that originate from blood cells can occur, mostly on the skin.

Leading from a two-case series, including two patients receiving a diagnosis of epidermotropic T-cell lymphoma, featuring a mycosis fungoides (MF)-like clinical pattern and ALK expression and molecular alteration, we performed a critical appraisal of ALK+ primary cutaneous T-cell lymphomas (pcTCL). Considering our patients and the literature, 32 cases were retrieved, 7 of which featured an MF-like clinical picture over a 4-to-20-year period. MF-like cases show distinctive histology, comprising a predominantly epidermotropic infiltration of small-to-large, atypical-to-pleomorphic, with few anaplastic cells, negligible-to-intense CD30-expression, and a CD4+/cytotoxic granule+ phenotype. These features should prompt a search for ALK expression captured by the ALK D5F3 clone. Bona fide ALK+ pcTCL is very rare, and existent data suggest the presence of a broader pattern of disease, including instances mimicking MF and/or primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma. The major challenges in dealing with this subset include prodromal phases, misinterpreted as inflammatory dermatosis or parapsoriasis/early phase MF both clinically and histologically, while recognition of its ALK-driven biology is hampered both by the unusual clinic-pathologic pattern of the disease, which stands apart from the classical (i.e., nodal) picture of ALK+ anaplastic large cell lymphoma and by the low sensitivity of ALK1 clone. Data on its optimal management are far from being conclusive: An MF-like approach is currently chosen, but depending on CD30 and, most notably, ALK expression, a targeted therapy could be envisaged in advanced stages, as clinical response to ALK inhibition was documented in one patient.

Erdheim–Chester disease is a rare multisystem non-Langerhans cell histiocytosis. We report the case of a patient with BRAF wildtype Erdheim–Chester disease presenting with facial nodular xanthomas and developing systemic involvement 10 years later. The patient was successfully treated with a combination of anakinra and cobimetinib.

A 11-year-old Caucasian girl presented to our Dermatology Unit with a 2-month history of an erythematous nodule, localized to the medial portion of her left eyebrow, rapidly growing in the two weeks before presentation. The histopathological examination revealed a dermal multi-nodular epithelial neoplasm composed of clear cells, squamous cells, and glandular cells, characterized by cytologic atypia, high mitotic activity, and an infiltrative deep growth pattern. The immunohistochemical profile of the lesion was as follows: CKAE1/AE3+, EMA+, CK8/18+, CK7+, CK19+, AR negative, p63 focally +, Ki67 25%, rare cells GCDFP15+, p53+.

Rare subtypes of cutaneous T-cell lymphomas (CTCL) include four entities, primary cutaneous γδ T-cell lymphoma, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, and primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorders, primary cutaneous acral CD8+ T-cell lymphoma, which were previously considered provisional and are now included in the new 5th World Health Organization classification of hematolymphoid tumors as distinct entities. An updated summary of the clinical, histological, and genomic characteristics of these uncommon CTCL subtypes is given in this review, with a focus on the growing body of knowledge regarding their classification and possible treatment strategies.

Mogamulizumab is a first-in-class IgG1k monoclonal antibody that selectively targets the chemokine receptor type 4. The drug has received Food and Drug administration authorisation for mycosis fungoides and Sezary syndrome following failure of at least one previous course of systemic therapy and now is available in Europe. One of the most common treatment-related side effects observed has been the mogamulizumab-associated rash (MAR), which affects up to a quarter of patients and is the most frequent adverse event leading to drug discontinuation. The aim of this study is to perform a systematic review of the literature on patients diagnosed with MAR and other mogamulizumab-related cutaneous events to describe the clinical and histological characteristics, the management in clinical practice and to assess whether these events have prognostic implications. In total, 2073 records were initially identified through a literature search, 843 of which were duplicates. After screening for eligibility and inclusion criteria, 49 articles reporting mogamulizumab-associated cutaneous events were included. Totally, 1516 patients were retrieved, with a slight male prevalence as for the available data (639 males and 570 females, i.e. 52.9% vs. 47.1%). Regarding the reported clinicopathological findings of the cutaneous reactions, the five most common patterns were spongiotic/psoriasiform dermatitis (22%), eruptions characterized by the presence of papules and/or plaques (16.1%), cutaneous granulomatosis (11.4%), morbilliform or erythrodermic dermatitis (9.4%) and photodermatitis (7.1%). Our results highlight how the majority of the reported cutaneous adverse events on mogamulizumab are of mild-to-moderate entity and generally manageable in clinical practice, though prompt recognition is essential and case-by-case assessment should be recommended. Future research will need to focus on the MAR prognostic implications and to identify genomic and molecular markers for a more rapid and accurate diagnosis.

Intravascular large B-cell lymphoma (IVLBCL) is a rare aggressive extranodal non-Hodgkin lymphoma. The predominant, if not exclusive, growth of neoplastic cells within the lumina of small-sized vessels represents the hallmark of the disease. Diagnosis is challenging due to the absence of marked lymphadenopathy, the highly heterogeneous clinical presentation, and the rarity of the condition. Clinical presentation is characterized by variable combinations of nonspecific signs and symptoms (such as fever and weight loss), organ-specific focal manifestations due to altered perfusion, and hemophagocytic syndrome. The rarity of this entity and the paucity of neoplastic cells in biopsy samples hamper the study of recurrent molecular abnormalities. The purpose of this study was to explore the feasibility of a different approach to recover a sufficient amount of DNA of acceptable quality to perform next-generation sequencing studies. Here, we report the findings of whole-exome next-generation sequencing performed on a fresh-frozen cutaneous sample of IVLBCL, paired with the patient saliva used as germline DNA. To increase the cancer cell fraction, only the subcutaneous tissue was selected. With this approach, we obtained high-quality DNA and were able to identify oncogenic mutations specific for this entity and recapitulating its post-germinal center origin, even if the tumor fraction was low. Molecular studies performed on fresh-frozen cutaneous sample are feasible in IVLBCL, especially when analysis is restricted to the subcutaneous tissue. Wide adoption of this reproducible and cost-effective approach may foster further studies, which may be of help in supporting diagnosis, providing pathogenetic insights, and guiding treatment decisions.