Development and psychometric properties of the Functional Assessment of Cancer Therapy-Cutaneous T-Cell Lymphoma (FACT-CTCL).

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 MF/SS patients. Thematic analysis identified the most common concerns, and 19 items were selected.MF/SS patients were recruited from a single center. FACT-G, CTCL-S (collectively "FACT-CTCL"), Skindex29, 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 record.Psychometric properties were assessed. Internal consistency was estimated using Cronbach's alpha (α). Convergent and discriminant validity were assessed by comparing CTCL-S to disease stage, age, VAS itch, FACT-G, and SkinDex29. 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 (wSD), 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 male, most were white (78%). The majority (85%) had MF, 15% 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 (α: 0.95 [95% CI: 0.93-0.96]). There was no significant change in CTCL-S average test-retest scores (ICC of 0.93 (p = 0.63)). CTCL-S was significantly lower in advanced vs early stage disease (median[IQR]: 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, -0.55), FACT-G (rs: 0.77, 95% CI: 0.65, 0.85), and Skindex29 (rs: -0.90, 95% CI: -0.94, -0.84), supporting convergent validity. CTCL-S scores had little correlation with age (rs: 0.19, 95% CI: -0.05, 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.

Updated cutaneous T-cell lymphoma TNMB staging criteria fail to identify Sézary syndrome patients with low blood burden.

Comparison of the 2007 EORTC/ISCL and the 2022 EORTC/ISCL/USCLC blood staging guidelines for cutaneous T-cell lymphoma at a single institution reveals the newer guidelines fail to detect a subset of Sézary syndrome patients with low blood burden.

Fifth Edition of the World Health Organization Classification of Tumors of the Hematopoietic and Lymphoid Tissues: Mature T-Cell, NK-Cell, and Stroma-Derived Neoplasms of Lymphoid Tissues.

This review focuses on mature T cells, natural killer (NK) cells, and stroma-derived neoplasms in the fifth edition of the World Health Organization classification of hematolymphoid tumors, including changes from the revised fourth edition. Overall, information has expanded, primarily due to advancements in genomic understanding. The updated classification adopts a hierarchical format. The updated classification relies on a multidisciplinary approach, incorporating insights from a diverse group of pathologists, clinicians, and geneticists. Indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract, Epstein-Barr virus-positive nodal T- and NK-cell lymphoma, and several stroma-derived neoplasms of lymphoid tissues have been newly introduced or included. The review also provides guidance on how the fifth edition of the World Health Organization classification of hematolymphoid tumors can be applied in routine clinical practice.

Lymphomatoid Papulosis With T-cell Receptor-Gamma Delta Expression: A Clinicopathologic Case-series of 26 Patients of an Underrecognized Immunophenotypic Variant of Lymphomatoid Papulosis.

Lymphomatoid papulosis (LyP) has several histopathologic presentations. LyP featuring gamma-delta (γδ) T-cell receptor expression may masquerade as and may be misdiagnosed as aggressive cutaneous T-cell lymphoma, particularly primary cutaneous γδ T-cell lymphoma (PCGDTL) or γδ mycosis fungoides. We performed a clinicopathologic analysis of the largest series of LyP featuring γδ T-cell expression. We identified 26 patients with a diagnosis of LyP with γδ T cells from our institutions, as well as through a comprehensive review of the literature, and characterized these cases. Most cases were treated with topical steroids or not treated at all. The majority of cases showed a CD4 - CD8 + phenotype and featured at least one cytotoxic marker. Histopathologic features included an intraepidermal or dermal infiltrate with large cells and frequent angiotropism. One case was initially misdiagnosed as PCGDTL, requiring further therapy. Our case series, the largest international cohort of γδ T cell predominant LyP cases, confirms marked clinicopathologic heterogeneity that may contribute to misdiagnosis, reasserting the need to identify classic clinical features, CD30 + T-cell components, and markers of cytotoxicity when dealing with this differential diagnosis. A limitation of this study includes somewhat limited follow-up, histologic, and immunophenotypic information for some cases.

Interstitial mycosis fungoides: A rare presentation of mycosis fungoides with overlapping granulomatous and folliculotropic features.

BACKGROUND: Interstitial mycosis fungoides (IMF) is a rare subtype of mycosis fungoides (MF) characterized by atypical lymphocytes infiltrating the reticular dermis between collagen bundles with limited epidermotropism and variable granulomatous features. METHODS: Retrospective single institution review of 31 cases of IMF including clinical characteristics, disease course and pathological features. RESULTS: Our cohort was predominately male (19; 61%, M:F 1.6:1) with a mean age at diagnosis of 43 years (range 11-85), mean signs/symptoms duration of 7 years prior to diagnosis, and 6 years mean follow-up duration. Clinically, patients often exhibited symmetric ill-defined patches/plaques involving intertriginous regions with tan-yellow hyperpigmentation and follicular-based papules, wrinkling, and alopecia. Lymphadenopathy was noted in seven patients. Fifteen (52%) patients were in near or complete clinical remission at the latest follow-up. T-cell receptor gene rearrangement was positive in 23/24 (96%) cases. Histopathologically, atypical cells were small-medium, CD4+ (29; 94%) or rarely CD4+/CD8+ (1; 3%) lymphocytes infiltrating the reticular dermis with thickened collagen bundles (27; 87%), multinucleated giant cells (12; 39%), and often tracing along adnexa with subtle folliculotropism (12/20; 60%). CONCLUSIONS: Our study demonstrates IMF is an indolent subtype of MF with distinct features, including frequent granulomatous and subtle follicular involvement resulting in alopecia.

Chemical exposures and demographic associations in cutaneous T-cell lymphoma: a large single institution physician validated cohort study.

Cutaneous T-cell lymphomas (CTCL) are a rare group of T-cell neoplasms which infiltrate the skin and can result in substantial morbidity and mortality. Risk factors for CTCL are still poorly understood though recent studies suggest chemical exposures may play a role in its development. To further characterize patient-centered risk factors for CTCL, especially compared with matched controls, we performed one of the largest prospective cohort survey studies to date to examine patient-reported exposures and health-related quality of life (HRQoL) in association with concurrent clinical disease characteristics. Patient demographics, lifestyle factors, and chemical exposures were collected via clinical data and surveys. Descriptive statistics, ANOVA, Chi-square tests and t tests were utilized to compare patient-reported exposures and HRQoL in patients with CTCL versus matched healthy controls (HC). Statistically significant differences were identified between patients and HC in terms of race (non-white race 22.4% in CTCL patients vs. 18.8% in HC, P = 0.01), and education level (high school or less 41.6% in CTCL patients vs. 14.3% in HC, P = 0.001), but not with Fitzpatrick skin type (P = 0.11) or smoking status (P = 0.28). Notably, 36.0% of the CTCL patients reported exposures to chemicals, a near threefold increased percentage when compared to HC (12.9%). Among various chemical exposures, 27.0% of the CTCL patients specifically reported industrial chemical exposure, a more than two-fold increased percentage when compared to HC (12.9%). Itch and pain were significantly associated with skin disease severity (as evaluated by CTCL-specific mSWAT score) in advanced stage disease (stages IIB-IVB) (r = 0.48 and 0.57, P < 0.05). Itch and body mass index (BMI) were weakly associated with skin disease severity in early-stage disease (stages IA-IIA) (r = 0.27 and 0.20, P < 0.05).

What's New in Cutaneous T-Cell Lymphoma-Associated Pruritus.

Cutaneous T-cell lymphomas are a heterogenous group of lymphomas that cause various skin manifestations. Severe pruritus occurs frequently in cutaneous T-cell lymphoma and negatively impacts patients' quality of life. The pathophysiology of cutaneous T-cell lymphoma-associated itch is complex and involves various immune cells, inflammatory cytokines, and neuroimmune interactions. Treating cutaneous T-cell lymphoma pruritus can be challenging, and there have been few randomized controlled studies evaluating the use of antipruritic treatments in these patients. Systemic therapies targeting the disease have also been shown to have some antipruritic effects. Furthermore, although biologic therapy has revolutionized the treatment of other pruritic skin conditions, the use of biologics in cutaneous T-cell lymphoma remains controversial.

Identifying and addressing unmet clinical needs in primary cutaneous B-cell lymphoma: A consensus-based paper from an ad-hoc international panel.

Primary cutaneous B-cell lymphomas (PCBCLs) are lymphoproliferative disorders that appear on the skin without evidence of extracutaneous manifestations at the time of diagnosis. There is a lack of evidence-based guidelines for their clinical management due to the availability of very few large scale studies and controlled clinical trials. Here we present and discuss a series of major unmet clinical needs (UCNs) in the management of PCBCLs by a panel of 16 experts involved in research and clinical practice of PCBCL. The Panel produced recommendations on the appropriateness of the clinical decisions concerning the identified clinical needs and proposed research for improving the knowledge needed to solve them. Recommendations and proposals were achieved by multiple-step formalized procedures to reach a consensus after a comprehensive analysis of the scientific literature. Recommendations and proposals lay in the domain of classification uncertainties of PCBCL, optimization of diagnosis, optimization of prognosis, optimization of staging and critical issues on therapeutic strategies with particular focus on new treatments. These recommendations are intended for use not only by experts but above all by dermatologists and hematologists with limited experience in the field of PCBCLs as well as general practitioners.

Epstein-Barr Virus-Associated Lymphomatoid Papules: A Sign of Immunosuppression Resembling Lymphomatoid Papulosis.

ABSTRACT: Epstein-Barr virus (EBV)-positive lymphoproliferative disorders associated with immunodeficiency constitute a spectrum of lymphoid and plasma cell proliferations that vary in cytomorphology, immunophenotype, and clinical behavior. CD30-positive cutaneous lymphocytic infiltrates with EBV expression and lymphomatoid papulosis-like presentations have been rarely reported. This retrospective study assessed the clinical and histopathological characteristics of EBV-positive cases with papulonodular morphologies and CD30 positivity seen by Northwestern Medicine Dermatopathology. Twelve patients (7M:5F, mean age 69 years) were presented with papular cutaneous lesions without antecedent patch/plaque disease. Nine cases were associated with known immunosuppression in the setting of transplant-related therapies (n = 4), hematopoietic malignancy (n = 2), post-transplant hematopoietic malignancy (n = 1), and autoimmune disease treatment (n = 2). Two patients had age-related immunosenescence. Four patients demonstrated EBV viremia; for 2 patients, this finding comprised the first sign of immunosuppression. Workup was negative for systemic lymphoma in all patients. Various treatment strategies were used, including observation (n = 3), discontinuation/reduction of immunosuppression (n = 3), rituximab (n = 4), and steroids (n = 4). At mean 30-month follow-up, 4 patients (33.3%) were alive, 3 with and 1 without disease. Eight patients (67.6%) had died, 3 after lesional resolution and 5 with recurrent disease. Biopsies revealed mixed lymphoid infiltrates composed of atypical CD30-positive T cells (n = 5) or B cells (n = 7) with variable EBV-encoded small RNA expression. These cases suggest clinicopathologic presentations resembling lymphomatoid papulosis with atypical, large CD30-positive, EBV-positive cells could comprise first sign of potentially serious immunodeficiency and should prompt evaluation for EBV viremia. These cases also broaden the current picture of immunodeficiency-associated lymphoproliferative disorders to include lymphomatoid papulosis-like clinical presentations.

PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma.

The PDCD1-encoded immune checkpoint receptor PD-1 is a key tumor suppressor in T cells that is recurrently inactivated in T cell non-Hodgkin lymphomas (T-NHLs). The highest frequencies of PDCD1 deletions are detected in advanced disease, predicting inferior prognosis. However, the tumor-suppressive mechanisms of PD-1 signaling remain unknown. Here, using tractable mouse models for T-NHL and primary patient samples, we demonstrate that PD-1 signaling suppresses T cell malignancy by restricting glycolytic energy and acetyl coenzyme A (CoA) production. In addition, PD-1 inactivation enforces ATP citrate lyase (ACLY) activity, which generates extramitochondrial acetyl-CoA for histone acetylation to enable hyperactivity of activating protein 1 (AP-1) transcription factors. Conversely, pharmacological ACLY inhibition impedes aberrant AP-1 signaling in PD-1-deficient T-NHLs and is toxic to these cancers. Our data uncover genotype-specific vulnerabilities in PDCD1-mutated T-NHL and identify PD-1 as regulator of AP-1 activity.

Expanding Our Knowledge of Molecular Pathogenesis in Histiocytoses: Solitary Soft Tissue Histiocytomas in Children With a Novel CLTC::SYK Fusion.

The histiocytoses comprise a histopathologically and clinically diverse group of disorders bearing recurrent genomic alterations, commonly involving the BRAF gene and mitogen-activated protein kinase pathway. In the current study, a novel CLTC :: SYK fusion in 3 cases of a histopathologically distinct histiocytic neoplasm arising as solitary soft tissue lesions in children identified by next-generation sequencing and fluorescence in situ hybridization is described. Morphologically, all 3 neoplasms were composed of sheets of cells with round-oval nuclei and vacuolated eosinophilic cytoplasm but, in contrast to classic juvenile xanthogranuloma (JXG), Touton giant cells were absent. A separate cohort of classic JXG cases subsequently profiled by fluorescence in situ hybridization were negative for the presence of a CLTC::SYK fusion suggesting that CLTC::SYK fusion-positive histiocytoma is genetically and histologically distinct from JXG. We postulate that the CLTC::SYK fusion leads to aberrant activation of the SYK kinase, which is involved in variable pathways, including mitogen-activated protein kinase. The identification of a novel CLTC::SYK fusion may pave the way for the development of targeted therapeutic options for aggressive disease.

Lifestyle, demographic and Skindex measures associated with cutaneous T-cell lymphoma: a single institution cohort study.

Cutaneous T-cell lymphoma (CTCL) risk factors and associated quality of life are poorly understood. Previous studies of CTCL risk factors explored patient comorbidities and lifestyle exposures, but not in conjunction with disease stage, subtype, severity, or health-related quality of life (HRQoL). We investigated lifestyle exposures and demographic factors associated with advanced-stage disease, increased disease severity, and poorer HRQoL outcomes in this single-center cohort study. A cohort survey study was conducted at Northwestern's Multidisciplinary Cutaneous Lymphoma specialty clinic between April 2019 and June 2021. REDCap surveys were administered to 140 patients with CTCL, investigating patients' demographics, lifestyle and chemical exposures. QoL was evaluated using the Skindex survey; pain and itch with ten-point Likert scales. Modified Severity Weighted Assessment Tool (mSWAT), disease stage, and disease subtype were confirmed upon enrollment in the study by a single board-certified dermatologist specializing in CTCL. Factors were compared by t test or Fischer's exact test. Median age was 63 years (range 14-92) with male-to-female ratio of 1.2:1. The most common diagnosis was CD4 + MF (n = 94, 67.1%). Common lifestyle exposures included smoking (past or current) (52.3%) and chemical exposure history (all sources [53.7%]; industrial only [33.0%]). History of chemical exposures were associated with advanced stage disease (p = 0.003) and worse QoL outcomes (p = 0.001). There were significant racial differences, respectively, in early (I-IIA) vs late (IIB-IV) stage disease (p = 0.003). Obesity, hygiene, smoking, recent sun exposure, education and atopy were not significantly associated with disease stage or severity. We provide an analysis of lifestyle and demographic factors in the context of CTCL disease severity, stage, and HRQoL. We identified race as a potential risk factor for advanced stage disease and both skin phototype and chemical exposures as a risk factor for increased disease severity as measured by mSWAT. QoL outcomes were multifactorial and significantly associated with history of chemical exposure, severe pain/itch, race, disease stage and subtype. An improved understanding of these associations may lead to better individualized care. As chemical exposure and race were found to be significant factors associated with advanced-stage disease, taking exposure histories and addressing racial disparities may improve care for CTCL patients.

Disease-Defining Molecular Features of Primary Cutaneous B-Cell Lymphomas: Implications for Classification and Treatment.

Primary cutaneous B-cell lymphoma-primary cutaneous follicle center lymphoma; primary cutaneous marginal zone lymphoma; and primary cutaneous diffuse large B-cell, leg type-is a heterogeneous group with a variety of clinical and histological presentations. Until recently, the molecular bases of these disease subtypes have been unclear. We and others have identified the specific genetic characteristics that distinguish these subtypes from their respective systemic counterparts. These molecular features can improve diagnoses, determine the likelihood of concurrent or future systemic disease, and enable the rational design of novel clinical trials.

Retrospective analysis of sepsis in cutaneous T-cell lymphoma reveals significantly greater risk in Black patients.

BACKGROUND: Sepsis is a leading cause of morbidity, mortality, and resource utilization among patients with cutaneous T-cell lymphoma (CTCL). OBJECTIVE: To characterize the demographic, clinical, and microbial attributes distinguishing patients with CTCL sepsis from other patients with non-Hodgkin lymphoma (NHL) sepsis and patients with CTCL in general. METHODS: Two-part retrospective cohort study at an academic medical center from 2001-2019 involving patients with CTCL (n = 97) and non-CTCL NHL (n = 88) admitted with sepsis, and a same-institution CTCL patient database (n = 1094). Overall survival was estimated by Kaplan-Meier analyses. RESULTS: Patients with CTCL sepsis were more likely to be older, Black, experience more sepsis episodes, die or be readmitted within 30 days of an inpatient sepsis episode, and develop Gram-positive bacteremia than patients with non-CTCL NHL sepsis. Staphylococcus aureus and Escherichia coli were the most frequently speciated organisms in CTCL (26%) and non-CTCL NHL (14%), respectively. No between-group differences were identified regarding sex, presence of central line, chemotherapy use, or disease stage. Compared with general patients with CTCL, patients with sepsis were Black and exhibited advanced-stage disease, higher body surface area involvement, and higher lactate dehydrogenase levels. LIMITATIONS: Single institution, retrospective nature may limit generalizability. CONCLUSION: Awareness of CTCL-specific risk factors is crucial for guiding sepsis prevention and improving patient outcomes.