Paediatric onset lymphomatoid papulosis: results of a multicentre retrospective cohort study, on behalf of the EORTC Cutaneous Lymphoma Tumours Group (CLTG).

BACKGROUND: Lymphomatoid Papulosis (LyP) is a rare cutaneous T-cell lymphoproliferative disorder. Comprehensive data on LyP in the paediatric population is scarce. OBJECTIVES: To characterize epidemiological, clinical, histopathological, and prognostic features of paediatric LyP. METHODS: This was a retrospective, multicentre international cohort study including 87 cases of children and adolescents with LyP diagnosed between 1998 and 2022. Patients aged ≤ 18 years old at disease onset were included. Diagnosis was made in each centre based on clinical-pathological correlation. RESULTS: Eighty-seven patients from 12 centres were included. The mean age at onset was 7.0 years (range 3 months-18 years) with a male to female ratio of 2:1. The mean time between onset of first cutaneous lesions and diagnosis was 1.3 years (range 0-14 years). Initial misdiagnosis concerned 26.4% of patients. Initially, LyP was most often misdiagnosed as Pityriasis lichenoides et varioliformis acuta (PLEVA), insect bites, or mollusca contagiosa. Erythematous papules or papulonodules were the most frequent clinical presentation. Pruritus was specifically mentioned for 20.7% of patients. The main histological subtype was type A in 55.1% of the cases. If analysed, monoclonal TCR rearrangement was found in 76.5% of the 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. A development of associated haematological malignancy (HM) occurred in 9.6% of the cases (7/73), including four mycosis fungoides (MF) cases, one primary cutaneous anaplastic large cell lymphoma (pc-ALCL), one systemic ALCL and one case of acute myeloid leukaemia. If we compare incidence rates of cancer with the world 0-19 years old population from 2001-2010, we estimate a significantly higher risk of associated malignancy in general, occurring before the age of 19 years old with incidence rate ratio of 87.49 (CI 86.01-88.99). CONCLUSIONS: We report epidemiological data from a large international cohort of children and adolescents with LyP. Overall the prognosis of the disease is good, with excellent survival rates for all patients. Due to increased risk of associated HM, a long-term follow-up should be recommended for LyP patients.

Paediatric cutaneous lymphomas including rare subtypes: A 40-year experience at a tertiary referral centre.

BACKGROUND: Primary 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. OBJECTIVES: To 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. METHODS: Retrospective 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. RESULTS: A 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 Sézary 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. CONCLUSIONS: Our 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.

Whole-exome sequencing is feasible on a fresh-frozen skin sample of intravascular large B cell lymphoma.

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.

A Microenvironment-Related Nine-Gene Signature May Predict Survival in Mycosis Fungoides Patients at Diagnosis.

Mycosis fungoides (MF) is the most common cutaneous lymphoma characterized by an indolent course. Prognosis is stage-based but this approach does not reflect the different outcomes within stages. Considering that tumor microenvironment is known to be involved in MF pathogenesis and progression, we decided to investigate 99 MF cases by using the PanCancer Immune Profiling Panel. We identified and validated a signature of 9 genes able to predict MF survival and distinguish a high-risk group with a worse outcome from a low-risk group of cases with a better outcome. At the molecular level, low-risk vs. high-risk cases reported a global upregulation of immune genes, enriched in cytokines, and a higher density of dendritic cells and mast cells, possibly associated with a more favorable clinical course.

Interleukin-17 vs. Interleukin-23 Inhibitors in Pustular and Erythrodermic Psoriasis: A Retrospective, Multicentre Cohort Study.

Pustular and erythrodermic psoriasis are rare and difficult-to-treat conditions. It has recently been shown that interleukin (IL)-17 inhibitors can be very effective among patients with these forms of psoriasis; however, the potential of IL-23 inhibitors is largely unknown. The aim of this multicentre, retrospective study was to compare the safety, effectiveness, and drug survival of IL-17 and IL-23 inhibitors among patients affected by these rare forms of psoriasis. The study involved 27 patients with erythrodermic psoriasis and 59 with pustular psoriasis (36 with generalised pustular psoriasis and 23 with palmoplantar pustular psoriasis) treated with an IL-17 or IL-23 inhibitor. The effectiveness of the two drug classes was assessed using the disease-specific Psoriasis Area Severity Index (PASI) and the Investigator Global Assessment, which were evaluated at different time points. There was a consistent trend towards a higher rate of PASI 100 responses in the patients treated with IL-17 inhibitors compared with those treated with IL-23 inhibitors, and the other efficacy outcomes showed a similar trend. There was no significant between-drug class difference in efficacy at any of the time points in the erythrodermic psoriasis cohort, whereas PASI 90 and PASI 100 response rates were significantly higher among the pustular psoriasis patients receiving IL-17 inhibitors at week 12 (IL-23 19% vs. IL-17 54% and IL-23 6% vs. IL-17 40%, respectively) and the percentage of responders to IL-17 inhibition was significantly higher at week 24 (IL-23 25% vs. IL-17 74%). In conclusion, it is therefore reasonable to assume that IL-17 and IL-23 inhibitors are both effective when treating pustular and erythrodermic psoriasis.

Disseminated superficial actinic porokeratosis following hydroxyurea treatment: A case report.

Porokeratosis encompass a group of acquired and familial, preneoplastic, keratinization disorders, clinically characterized by atrophic macules or patches with a peripheral keratotic rim, the cornoid lamella. Genetic background is recognized as crucial in its pathophysiology, while immunosuppression and ultraviolet radiation represent triggering factors. We report the case of a woman who developed disseminate superficial actinic porokeratosis following the intake of hydroxyurea for a polycythaemia vera. Clinical, dermoscopic and histopathology data are showed, and the role of drug as a second-hit mutation trigger is discussed.

Effectiveness and tolerability of chlormethine gel for the management of mycosis fungoides: a multicenter real-life evaluation.

Background: Topical chlormethine (CL) is recommended as a first-line treatment for early-stage mycosis fungoides (MF) and in 2017, the European Medicines Agency approved the CL gel formulation to treat adult patients. More recently, to increase patient compliance and adherence, clinicians have developed flexible protocols that allow the concomitant use of CL gel with topical corticosteroids in daily practice regimens. Therefore, sharing real-life data on CL gel use and side effects management may help improve the use of this agent. Objectives: To expand knowledge about the actual use of CL gel in patients with MF, the present study assessed the improvement of MF skin lesions after CL gel treatment and provided information on the management of cutaneous adverse events (AEs) in a real-life setting. Methods: This was an Italian retrospective study conducted among six dermatology referral centers. Patients ≥18 years affected by MF and in treatment with CL gel (160 µ/g), alone or in combination according to routine clinical practice, between December 2019 and December 2021 were considered. The study's primary aim was to evaluate the effectiveness of CL gel in terms of overall response rate (ORR) after 3 months of treatment. Results: A total of 79 patients (61% male) with different stages of MF (84% early stage) were included. CL gel was prescribed mainly in association with topical corticosteroids (66% of patients). ORR after 3 months of treatment was 42%, with no differences between early- and advanced-stage MF. Response rates improved over time up to 97% after 18 months of treatment. Overall, 66 AEs were reported in 67% of patients; most were hyperpigmentation (45%) and irritant contact dermatitis (37%). Six AEs led to treatment discontinuation, and five out of six (83%) patients who reported these events resumed treatment after interruption. No AEs were classified as severe. Conclusions: Our observations support the use of CL gel in patients with early- and advanced-stage MF, making it a valuable treatment option.

Vitiligo: Unmet Need, Management and Treatment Guidelines.

Vitiligo is a chronic depigmenting disorder characterized by characteristic, non-scaly, chalky-white skin macules and patches, due to the loss of skin pigment. Its exact pathogenesis is still not fully understood but it seems to be an autoimmune disease where the combination of genetic, environmental, and immune factors contributes to the destruction of melanocytes in the epidermis. Vitiligo is classified into different types based on its clinical characteristics and distribution patterns. The two main forms of vitiligo are non-segmental vitiligo (NSV) and segmental vitiligo (SV). NSV is the predominant form, characterized by symmetrical skin patches, that tend to evolve over time. In contrast, SV has unilateral or band-shaped lesions that progress rapidly but often stabilize early. Herein, current unmet needs in terms of psychosocial consequences and relative lack of valid therapeutic approaches are critically analyzed and put in perspective in the Italian prescribing scenario. Finally, available management guidelines are illustrated and briefly compared, to provide context for upcoming treatment options.

Cutaneous B-cell lymphomas: Update on diagnosis, risk-stratification, and management.

PCBCLs are a group of Non-Hodgkin's B-cell lymphomas originating in and usually confined to the skin, representing approximately one fourth of primary cutaneous lymphomas (PCL). Their current classification system has been the result of the joint World Health Organization (WHO) - European Organization for Research and Treatment of Cancer (EORTC) consensus in 2018. To date, several types of PCBCLs have been described in the scientific literature, with different clinical presentation and prognosis. Primary cutaneous follicle-center lymphoma (PCFCL) and primary cutaneous marginal zone lymphoma (PCMZL) are the most common forms, with a typical indolent course. On the contrary, primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT) is less common, yet more aggressive, with a reported 5-year overall survival of approximatively 50%. In this review, we outline the PCBCLs defining diagnostic criteria, report the features of the less common subtypes and summarize the noteworthy therapeutical options currently available in this field.

Primary Cutaneous Gamma-Delta T Cell Lymphomas: A Case Series and Overview of the Literature.

Primary cutaneous gamma-delta T cell lymphomas (PCGDTCLs) are rare and aggressive cutaneous malignancies that have been diagnostically challenging for dermopathologists and clinicians since their first published descriptions in 1991. Since then, the availability of immunostaining for T cell receptors γ and δ in formalin-fixed paraffin-embedded samples has greatly increased our knowledge of the gamma-delta phenotype by showing that it may also be present in the context of indolent entities, such as mycosis fungoides (MFs) and lymphomatoid papulosis, and this has raised questions concerning its diagnostic and prognostic implications. We here describe the histological and clinical differences between the dermo-epidermal and subcutaneous sub-groups of PCGDTCL observed in a cohort of 20 patients attending a single experienced centre, with particular focus on cases with an MF-like presentation, which are still less well defined than those of classic MF.

An expert consensus report on mycosis fungoides in Italy: epidemiological impact and diagnostic-therapeutic pathway.

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 recognized 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 favor more rapid diagnosis and simplify the pathway for referring patients to reference centers 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.

CCR4 in cutaneous T-cell lymphoma: Therapeutic targeting of a pathogenic driver.

New treatments are needed for patients with cutaneous T-cell lymphoma (CTCL), particularly for advanced mycosis fungoides (MF) and Sezary syndrome (SS). The immunopathology of MF and SS is complex, but recent advances in tumor microenvironment understanding have identified CCR4 as a promising therapeutic target. CCR4 is widely expressed on malignant T cells and Tregs in the skin and peripheral blood of patients with MF and SS. The interaction of CCR4 with its dominant ligands CCL17 and CCL22 plays a critical role in the development and progression of CTCL, facilitating the movement into, and accumulation of, CCR4-expressing T cells in the skin, and recruiting CCR4-expressing Tregs into the tumor microenvironment. Expression of CCR4 is upregulated at all stages of MF and in SS, increasing with advancing disease. Several CCR4-targeted therapies are being evaluated, including "chemotoxins" targeting CCR4 via CCL17, CCR4-directed chimeric antigen receptor-modified T-cell therapies, small-molecule CCR4 antagonists, and anti-CCR4 monoclonal antibodies. Only one is currently approved: mogamulizumab, a defucosylated, fully humanized, anti-CCR4, monoclonal antibody for the treatment of relapsed/refractory MF and SS. Clinical trial da1ta confirm that mogamulizumab is an effective and well-tolerated treatment for relapsed/refractory MF or SS, demonstrating the clinical value of targeting CCR4.

Italian expert-based recommendations on the use of photo(chemo)therapy in the management of mycosis fungoides: Results of an e-Delphi consensus.

BACKGROUND: Phototherapy is a mainstay for the treatment of MF. However, there is scarce evidence for its use, mostly due to the lack of a unified schedule. AIMS: The primary aim of this study was to establish the first structured, expert-based consensus regarding the indications and technical schedules of NB-UVB and PUVA for MF. The secondary aim was to determine the consensus level for each specific item. MATERIALS & METHODS: E-delphi study. Item-specific expert consensus was defined as the number of "Totally Agree" results to ≥80% of the panelists. Cronbach alpha index ≥0.7 was used as a measure of homogeneity in the responses among questions related to the same topic. RESULTS: Overall, there was a high homogeneity among responders (0.78). On specific topics, the highest grade was observed for technical items (0.8) followed by indications for early (0.73) and advanced stages (0.7). CONCLUSIONS: Items related to the most canonical indications of phototherapy and to treatment schedules showed the highest agreements rates. There is consensus about the use of standardized treatment schedules for the induction and consolidation phases for NB-UVB and PUVA in MF.

Phenotypical Markers, Molecular Mutations, and Immune Microenvironment as Targets for New Treatments in Patients with Mycosis Fungoides and/or Sézary Syndrome.

Primary cutaneous lymphomas encompass a wide spectrum of rare lymphoproliferative disorders originating in the skin, among which, mycosis fungoides (MF) is the most common subtype. The treatment of this disease is based on skin-directed therapies eventually in association with biologic response modifiers in the early phases, whereas in patients with the advanced stages, several therapeutic strategies can be used including mono and/or polychemotherapy and bone marrow transplantation. In recent years, the identification of specific markers (phenotypical, immunological, and molecular) has led to the development of several studies (including two randomized phase III trials). The results of these studies are modifying our therapeutic strategy toward a personalized treatment approach in which the clinical characteristics of the patients and tumor-node-metastasis-blood stage are considered together with the expression of specific markers (i.e., a CD30-positive expression for the use of brentuximab vedotin). This review will provide a comprehensive scenario of the main phenotypical, molecular, and immunological markers related to MF pathogenesis and disease evolution, which could represent the target for the development of innovative effective treatments in this disease.

CD30 expression in a case of intravascular large B-cell lymphoma, cutaneous variant.

Intravascular large B-cell lymphoma (IVLBCL) is one of the rarest B-cell non-Hodgkin lymphomas (NHL), with an aggressive clinical behavior and a poor prognosis; in fact, its treatment is still an unmet clinical need, with a 3-year overall survival (OS) rate of 60% to 81%, and a central nervous system relapse rate of 25%. It usually presents as a widespread disease at diagnosis, with multi-organ involvement. Previously considered as a diffuse large B-cell lymphoma variant, it now represents a different extranodal large B-cell lymphoma entity in the last WHO Classification of tumors of hematopoietic and lymphoid tissues. We hereby describe the case of an 84-year-old Italian woman with an IVLBCL, cutaneous variant, who suffered from early relapse after R-COMP chemotherapy regimen, and was therefore treated with a palliative metronomic chemotherapy. Interestingly, neoplastic cells showed CD30 expression at relapse. CD30 positivity has never been reported in this disease so far, and its expression is known to be involved in NF-kB activation. CD30 expression may be further studied as for prognostic and therapeutic significance; in fact, new therapeutic strategies, such as antibody-drug conjugate targeting CD30, are now available.