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Chronic active Epstein-Barr virus (EBV) disease (CAEBV) is characterized by high levels of EBV predominantly in T and/or natural killer cells with lymphoproliferation, organ failure due to infiltration of tissues with virus-infected cells, hemophagocytic lymphohistiocytosis, and/or lymphoma. The disease is more common in Asia than in the United States and Europe. Although allogeneic hematopoietic stem cell transplantation (HSCT) is considered the only curative therapy for CAEBV, its efficacy and the best treatment modality to reduce disease severity prior to HSCT is unknown. Here, we retrospectively assessed an international cohort of 57 patients outside of Asia. Treatment of the disease varied widely, although most patients ultimately proceeded to HSCT. Though patients undergoing HSCT had better survival than those who did not (55% vs 25%, P < .01), there was still a high rate of death in both groups. Mortality was largely not affected by age, ethnicity, cell-type involvement, or disease complications, but development of lymphoma showed a trend with increased mortality (56% vs 35%, P = .1). The overwhelming majority (75%) of patients who died after HSCT succumbed to relapsed disease. CAEBV remains challenging to treat when advanced disease is present. Outcomes would likely improve with better disease control strategies, earlier referral for HSCT, and close follow-up after HSCT including aggressive management of rising EBV DNA levels in the blood.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and clinically aggressive hematologic malignancy. Although BPDCN has long been recognized as a distinct clinical entity, the nomenclature for this disease [...], * Context.--Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcome. BPDCN diagnostically overlaps with entities such as acute myeloid leukemia, histiocytic/dendritic cell neoplasms, and natural killer/T-cell lymphomas. Unfortunately, large, patient-centered studies that comprehensively analyze clinical, pathologic, and other diagnostic features are lacking. As such, there is an incomplete understanding of this disease. Objective.--To better characterize BPDCN, a multicenter working group consisting of hematopathologists and dermatopathologists gathered in person and remotely to review the current understanding of BPDCN, discuss specific issues regarding the diagnosis and differential diagnosis, and perform a retrospective analysis of the literature. Data Sources.--The working group curated a database of published BPDCN patient cases (BPDCN Network literature database), and following careful discussion and review, 361 articles were identified, comprising a total of 1513 individually annotated patients. Conclusions.--By conducting an in-depth analysis, not only did we confirm known findings such as frequent skin involvement (84% of patients; 861 of 1028) and a male predominance among older patients (>60 years old; male to female ratio of 3.5:1; 617:177), but we also identified a number of underrecognized features, such as significant central nervous system involvement (38% of cases; 24 of 64), and a more equal male to female prevalence among patients younger than 40 years (male to female ratio of 1.25:1; 167:134). Furthermore, we were able to accurately summarize the immunophenotypic, cytogenetic, and molecular features of this disease. BPDCN is a complex disease with distinct morphologic, immunophenotypic, and molecular findings. Continual updates of the literature database generated here and further analysis can allow for prospective refinement of our understanding of this orphan disease. (Arch Pathol Lab Med. 2023;147:837-846; doi: 10.5858/ arpa.2021-0612-RA)

Introduction Epstein-Barr Virus (EBV) positive primary cutaneous marginal zone lymphoma (PCMZL) is uncommon and subsequent transformation is rare. Methods We report a patient with EBV positive PCMZL with subsequent transformation to plasmablastic lymphoma and review the literature for transformed PCMZL to assess clinical and pathologic characteristics. In the case we describe, the patient presented with multifocal PCMZL, developed large B cell transformation with plasmacytic differentiation, followed by plasmablastic transformation (PBL), and ultimately died of disease progression despite multiple lines of therapy. Past history was significant for psoriatic arthritis (multiple prior lines of immunomodulatory therapy). The lymphomas and non-involved bone marrow share the same somatic DNMT3A and TET2 mutations, suggesting clonal relatedness and an association with clonal hematopoiesis (CH). Results Eighteen cases comprised the cohort (seventeen cases from the literature and the case reported herein). Nearly half of the eighteen cases of PCMZL with transformation died of progressive disease (44%). Transformed cases were more commonly seen in patients with >2 sites at initial diagnosis. EBV was assessed in 5 patients, 3 were positive (all died of disease). Two patients with NGS studies demonstrated TET2 and DNMT3A mutations. Conclusions Transformation of EBV positive PCMZL appears to be a poor prognostic indicator, with our reported case being the first well defined case transformed to PBL, suspected to arise from myeloid-CH. [ABSTRACT FROM AUTHOR]

Background Patients with mycosis fungoides (MF)/Sézary Syndrome (SS) can experience impacted health-related quality of life (HRQoL). Objectives To validate the CTCL-S, a novel subscale of the Functional Assessment of Cancer Therapy–General (FACT-G), in patients with MF/SS. Methods Qualitative interviews were conducted with expert clinicians and patients with MF/SS. Thematic analysis identified the most common concerns, and 19 items were selected. Patients with MF/SS were recruited from a single centre. FACT-G, CTCL-S (collectively 'FACT-CTCL'), Skindex-29 and Visual Analogue Scale–Pruritis (VAS-itch) were administered. A subset repeated FACT-CTCL and VAS-itch after ≈2 weeks. Patient demographics and clinical characteristics were obtained via review of the electronic medical records. Psychometric properties were assessed. Internal consistency was estimated using Cronbach's α. Convergent and discriminant validity were assessed by comparing CTCL-S with disease stage, age, VAS-itch, FACT-G and Skindex-29. Exploratory factor analysis (EFA) was used to preliminarily assess CTCL-S dimensionality. Test–retest repeatability was summarized using intraclass correlation coefficient (ICC), within-subject standard deviation and within-subject coefficient of variation. Results Seventy-two patients completed the initial survey, and 35 repeated the FACT-CTCL and VAS-itch after ≈2 weeks. Two-thirds were men; most were White (78%). The majority (85%) had MF, 15% had SS and 75% early (stage IA–IIA) and 25% advanced (≥ stage IIB) disease. Preliminary EFA found a single predominant factor, supporting a hypothesis of unidimensionality of the CTCL-S. Internal consistency of the CTCL-S was high, with α = 0.95 [95% confidence interval (CI) 0.93–0.96]. There was no significant change in CTCL-S average test–retest scores [ICC 0.93 (P = 0.63)]. CTCL-S was significantly lower in advanced vs. early-stage disease [median (interquartile range) 34 (26–48) vs. 59 (44–68), P < 0.001] and strongly correlated with VAS-itch [Spearman's r (rs) –0.70, 95% CI –0.81 to –0.55], FACT-G (rs 0.77, 95% CI 0.65–0.85) and Skindex-29 (rs –0.90, 95% CI –0.94 to –0.84), supporting convergent validity. CTCL-S scores had little correlation with age (rs 0.19, 95% CI –0.05 to 0.41, P = 0.12), supporting discriminant validity. Conclusions The FACT-CTCL is a disease-specific instrument for assessing HRQoL with high reproducibility and good performance in a cohort of patients with MF/SS. [ABSTRACT FROM AUTHOR]

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of diseases characterized by abnormal neoplastic T-cell growth in the skin. Mycosis fungoides (MF), the most common CTCL, manifests as erythematous skin patches and/or plaques, tumours or erythroderma. The disease may involve blood, lymph nodes and rarely viscera. Sézary syndrome (SS) is a unique leukaemia/lymphoma syndrome related to MF, which presents with blood and skin involvement at diagnosis. The pathogenesis of MF/SS is not fully elucidated. The presence of skin lesions at distant sites underpins a hypothesis that MF/SS lesions may develop through haematogenous seeding. Phenotypic similarities between malignant and normal T cells led to the notion that disease-initiating mutations occur in specific subtypes of mature T cells, which are responsible for most CTCLs. However, this mature T-cell precursor model is not always consistent with clinical observations and research on MF/SS pathogenesis. Here, we review evidence supporting an alternative model of pathogenesis for MF/SS involving haematogenous seeding as a key process responsible for the initiation and progression of the disease. According to this hypothesis, malignant transformation occurs at an early stage of T-cell development (probably in bone marrow or thymus), yielding circulating neoplastic T cells which colonize the skin where the microenvironment is most permissive for proliferation and evolution. These mutated precursor cells seed the skin where they find a suitable niche to develop into clinically perceptible disease. Subsequently, malignant T cells can re-enter the bloodstream, re-seed pre-existing lesions and seed new areas of the skin, causing synchronous and convergent changes in the transcriptomic profile of lesions and tumours, and clinical disease progression – 'consecutive haematogenous seeding' captures this temporal phenomenon. This model radically changes the current understanding of CTCL pathogenesis, transforming it from a primarily cutaneous disease with secondary involvement of blood, to a systemic disease, where the spread of malignant cells through the blood to the skin is not a phenomenon of advanced disease but is an essential component of pathogenesis. This understanding of MF/SS could have several clinical implications, including standardizing our approach to assessing blood tumour burden, potential advances in prognosis and monitoring, and investigating combination treatments to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous T cell lymphomas (CTCLs) are a group of rare lymphoproliferative malignancies manifesting in the skin. Cutaneous T cell lymphomas are an incurable, disfiguring, and life-threatening disease. Emerging studies have implicated the surrounding cells of malignant T cells (tumor microenvironment) in the disease evolution. This has revealed that targeting the tumor microenvironment has therapeutic potential in cutaneous T cell lymphomas. This review provides a detailed insight into the contribution of the tumor microenvironment in cutaneous T cell lymphomas and the targeting strategies. Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin lymphomas, with mycosis fungoides and Sézary syndrome being the two common subtypes. Despite the substantial improvement in early-stage diagnosis and treatments, some patients still progress to the advanced stage with an elusive underpinning mechanism. While this unsubstantiated disease mechanism coupled with diverse clinical outcomes poses challenges in disease management, emerging evidence has implicated the tumor microenvironment in the disease process, thus revealing a promising therapeutic potential of targeting the tumor microenvironment. Notably, malignant T cells can shape their microenvironment to dampen antitumor immunity, leading to Th2-dominated responses that promote tumor progression. This is largely orchestrated by alterations in cytokines expression patterns, genetic dysregulations, inhibitory effects of immune checkpoint molecules, and immunosuppressive cells. Herein, the recent insights into the determining factors in the CTCL tumor microenvironment that support their progression have been highlighted. Also, recent advances in strategies to target the CTCL tumor micromovement with the rationale of improving treatment efficacy have been discussed. [ABSTRACT FROM AUTHOR]

Small bowel adenocarcinoma (SBA) is a rare primary gastrointestinal malignancy. We present a 60-year old man who developed a cutaneous metastasis of jejunal adenocarcinoma to his neck. This case highlights the clinicopathologic and immunophenotypic features of this uncommon cutaneous metastasis.