Lymphatics doi: 10.3390/lymphatics4020029

Authors: Wei F. Chen Erica Tedone Clemente Yazan Mahafza Ryan Klatte Yazen Alfayez David C. F. Cheong Elise Kemp

Lymph node-to-vein anastomosis (LNVA) is an emerging physiologic treatment for fluid-predominant lymphedema that combines the efficacy of lymphatic bypass with reduced technical complexity. Despite its advantages, LNVA is limited by challenges in identifying suitable lymph nodes and recipient veins. This study evaluated whether three-dimensional stereolithography (SLA) could improve surgical planning, intraoperative navigation, and efficiency in robotic LNVA. A retrospective comparative study was conducted of 29 patients who underwent robotic inguinal LNVA between November 2024 and September 2025. Thirteen procedures were performed using standard robotic LNVA (control group), and sixteen were performed with the addition of SLA-assisted planning and navigation (study group). Patient-specific SLA models were created from contrast-enhanced CT data, segmented into lymph nodes, veins, arteries, and bony landmarks, and printed at 1:1 scale for incision planning and real-time intraoperative reference. Outcome measures included operative time, time to identification of target structures (TITS), surgeon-perceived operative difficulty (SPOD), and early patient-reported outcomes. Mean operative time was similar between groups (171 vs. 161 min), but TITS was significantly shorter with SLA (36 vs. 27 min; p = 0.021). Double LNVA was achieved in 69% of SLA cases compared with 8% of controls, without prolonging operative duration. SPOD was significantly lower in the SLA group (p < 0.001). All anastomoses were patent intraoperatively, and all patients reported symptom relief at one month. Model fabrication required approximately eight hours and averaged $270 per case. Stereolithography enhances robotic LNVA by providing a tangible three-dimensional roadmap that improves intraoperative orientation, reduces identification time, and enables multiple anastomoses without added operative burden. With modest cost and rapid production, SLA makes LNVA more precise, reproducible, and scalable—facilitating wider adoption and serving as a foundation for future outcome-based research.

Lymphatics doi: 10.3390/lymphatics4020028

Authors: Bingwen Eugene Fan Li Xian Amy Tan Yee Lin Tang Tong Tong Chuanhui Xu Khai Pang Leong Choon Guan Chua

In the original publication [...]

Lymphatics doi: 10.3390/lymphatics4020027

Authors: Kelly A. McGovern Katherine A. Ortmeyer Ryan Krouse Michael Brown Lydia Chen Kevin Guo Jeffrey Huang Jake Mlakar Edward Jim Delikatny Viktor Gruev Paul Zhang Sunil Singhal

Purpose: Lymph node (LN) excision is critical in oncologic surgery to provide important therapeutic and diagnostic information. LN evaluation helps in staging cancers, predicting prognosis and improving survival. The ultimate wish of a surgical oncologist would be to localize and dissect all pathologically positive LNs while avoiding the morbidity of removing true negative LNs. The goal of our study was to identify a reliable marker for clinical prediction of LNs with cancer cells from non-small cell lung cancer (NSCLC) versus LNs without. We identified epithelial cell adhesion molecule (EpCAM), a membrane protein normally expressed in epithelial tissues, including in lung. Patients and Methods: We used human specimens immunostained with anti-EpCAM monoclonal antibody. Results: EpCAM was expressed in NSCLC metastasis to LNs, as shown in 74 positive LNs from patients with resected primary NSCLC. Among pathologically negative LNs, regardless of PET avidity, EpCAM was absent; whereas among pathologically positive LNs, all PET uptake groups exhibited high EpCAM positivity. Together, these biomarkers had a 100% accuracy. There was no difference in expression between hilar and mediastinal LNs, nor between primary tumor histology. Conclusions: EpCAM may be useful for the surgical oncologist for preoperative or intraoperative detection of positive LNs from NSCLC.

Lymphatics doi: 10.3390/lymphatics4020026

Authors: Maria Gabriela Amaral Lima Ana Cláudia Souza da Silva Vanessa Maria da Silva Alves Gomes Nayara Priscila Dantas de Oliveira Vanessa Patrícia Soares de Sousa Diego Dantas

Background: Breast cancer–related lymphoedema (BCRL) is a frequent chronic complication associated with structural and functional changes in subcutaneous tissue. This study evaluated subcutaneous echogenicity, entropy, and thickness using ultrasound and examined their relationship with skin temperature measured by infrared thermography in breast cancer survivors. Results: Forty-five women were included (mean age 54.0 ± 7.6 years), of whom 44.4% had BCRL. After statistical adjustment, greater STT in the TB region of the homolateral limb compared with the contralateral limb remained supported, whereas other ultrasound differences were region-specific and exploratory. Participants with BCRL consistently exhibited lower Tmax across all ROIs, representing the most robust finding. Associations between ultrasound parameters and Tmax were limited and region-specific, with a statistically supported association observed only between ENT and Tmax in one forearm region. Methods: This cross-sectional exploratory study included women aged 40–70 years with a history of mastectomy. BCRL was diagnosed by indirect volumetry. Six regions of interest (ROIs) were assessed per limb (C1, C2, C3, TA in the forearm; C4 and TB in the upper arm). Ultrasound images were analysed using ImageJ version 1.54I to quantify subcutaneous tissue thickness (STT), echogenicity (ECHO), and entropy (ENT), while maximum skin temperature (Tmax) was extracted from thermographic images. Analyses accounted for repeated measurements within participants using generalized estimating equations, with adjustment for multiple comparisons. Conclusions: Ultrasonography and thermography capture partially overlapping but distinct structural and functional dimensions of tissue alteration in BCRL.

Lymphatics doi: 10.3390/lymphatics4020025

Authors: Claudia Simio Alessandra Vatteroni Cecilia Grandi

Extramedullary relapse (EMR) of acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) represents a clinically and biologically distinct entity compared with medullary relapse, characterized by marked heterogeneity, compartmental immune escape mechanisms, and generally poor prognosis. EMR arises at the intersection of clonal resistance, evolutionary disease adaptation, and heterogeneous distribution of the graft-versus-leukemia effect, resulting in evolutionary trajectories that are often dissociated between medullary and extramedullary compartments. In the absence of prospectively validated therapeutic algorithms, EMR management requires a structured and adaptive approach based on multidimensional assessment integrating leukemia biology, disease burden and anatomical distribution, bone marrow minimal residual disease (MRD) status, and immune reconstitution. Therapeutic strategies include local treatments, targeted agents, immunotherapies, and immunomodulatory interventions, applied within a dynamic sequence tailored to treatment response. Follow-up plays a central role as an active tool for prognostic stratification and clinical decision-making, enabling early detection of systemic progression and optimization of the timing of consolidative strategies, including second Allo-HSCT in selected patients. An integrated and biologically driven management of post-Allo-HSCT EMR is essential to improve outcomes in this high-risk clinical setting.

Lymphatics doi: 10.3390/lymphatics4020024

Authors: Shuyan Wei Judith Monzy Philip S. Brazio

Secondary lymphedema is a chronic, progressive condition characterized by limb swelling that arises after disruption of lymphatic channels from trauma or iatrogenic injury. In patients with complex soft tissue defects, reconstruction intended to restore the limb may inadvertently disrupt lymphatic drainage, highlighting the need for lymphatic-conscious surgical approaches. We present a retrospective case series of three patients with lower extremity soft tissue injuries who underwent flap-based reconstruction at our institution between 2021 and 2024. Reconstructive techniques, intraoperative decision-making, and postoperative lymphatic outcomes were analyzed over a follow-up period of 11 to 38 months. In the first two cases, disruption of established or new lymphatics during flap inset or repeated flap re-elevations may have contributed to the development of lymphedema. By contrast, indocyanine green (ICG) lymphography-guided flap planning and inset in the third case preserved lymphatic drainage pathways which could potentially lead to the development of lymphedema. Post-traumatic flap-based extremity reconstruction requires careful attention to native and transferred lymphatics to decrease the risk of secondary lymphedema. These cases draw attention to the concepts of preserving lymphatics, maintaining lymphatic axiality, and using ICG lymphography when planning flap-based reconstruction.

Lymphatics doi: 10.3390/lymphatics4020023

Authors: Ana Marta Pires Sérgio Chacim João Pedro Barreto Carla Azevedo José Mário Mariz Gabriela Martins

This brief report addresses intraclonal heterogeneity in multiple myeloma (MM) through a laboratory-based exploratory approach. We conducted a retrospective study of 49 patients with intact immunoglobulin MM and abnormal serum free light chain (sFLC) ratio at diagnosis, evaluating the molar relationship between sFLC and monoclonal protein (MP). The relative excess of sFLC showed wide variability, and higher values were associated with a trend toward less favorable outcomes, although not statistically significant. These findings suggest that the sFLC-to-MP relationship may reflect underlying biological features related to intraclonal heterogeneity and provide additional insight beyond conventional assessment.

Lymphatics doi: 10.3390/lymphatics4020022

Authors: Shahnur Ahmed Dylan Roth Luci A. Hulsman Rachel M. Danforth Ravinder Bamba Kandice K. Ludwig Mary E. Lester Karl Y. Bilimoria Carla S. Fisher Aladdin H. Hassanein

Breast lymphedema is characterized by skin thickening/swelling of the breast and is common following partial mastectomy and radiation. Oncoplastic reduction performed during partial mastectomy removes additional breast tissue compared to partial mastectomy alone to optimize breast contour. Recent literature has suggested oncoplastic reduction in patients with macromastia undergoing breast-conservation surgery is protective of breast lymphedema, decreasing rates from 11% to 3%. The purpose of this study is to assess the rates of breast lymphedema after partial mastectomy and oncoplastic reduction and identify risk factors. A single-center retrospective study was performed of breast cancer patients following partial mastectomy and oncoplastic reduction (2018–2023). Patients underwent contralateral breast reduction for symmetry. Breast lymphedema was assessed. Demographics data and risk factors were evaluated. This study included 158 patients who underwent partial mastectomy and oncoplastic reduction. Breast lymphedema incidence was 3.2% (5/158). Including contralateral non-cancerous breast symmetry reduction, lymphedema occurred in 3.6% (5/140) of irradiated breasts and 0% (0/176) of non-irradiated breasts (p = 0.0164). Among irradiated breasts, skin necrosis occurred in 11.4% (16/140) compared to 4.5% (8/176) of non-irradiated breasts (p = 0.031). Breast lymphedema developed 207.4 ± 37.6 days postoperatively and 101.6 ± 15.9 days following adjuvant radiation. Mean follow-up was 639 days. Breast lymphedema incidence following partial mastectomy and oncoplastic reduction was 3.6% in this series and occurs 3–4 months after radiation. Radiation was the only significant risk factor for developing breast lymphedema. This largest series on breast lymphedema after oncoplastic reduction corroborates that oncoplastic reduction may be protective.

Lymphatics doi: 10.3390/lymphatics4020021

Authors: Connor Frey

Introduction: Chimeric antigen receptor (CAR) T-cell therapies have revolutionized treatment for relapsed/refractory hematologic malignancies, targeting CD19 in B-cell neoplasms and BCMA in multiple myeloma, with response rates exceeding 80%. However, long-term risks, including therapy-related myeloid neoplasms, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), are emerging 6–24 months post infusion, potentially linked to lymphodepleting chemotherapy, clonal hematopoiesis expansion, and inflammatory milieus. This FAERS pharmacovigilance analysis quantified MDS/AML reporting across seven FDA-approved CAR-T products to detect antigen-specific signals unattainable in pivotal trials with limited follow-up. Methods: Adverse event reports from FAERS (1 January 2013–10 February 2025) were queried for tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, obecabtagene autoleucel, idecabtagene vicleucel, and ciltacabtagene autoleucel, focusing on MedDRA terms for MDS/AML. Duplicates and ambiguous cases were excluded. Disproportionality was assessed using reporting odds ratios (RORs; lower 95% CI >1 signaling significance), comparing CAR-T-event pairs to database background, with subgroup analyses by antigen target. Results: Among 14,093,557 reports, CAR-T products linked to 303 MDS (brexucabtagene autoleucel ROR 97.93 [72.18–132.87], n = 44; axicabtagene ciloleucel ROR 58.70 [50.34–68.44], n = 172) and 129 AML cases (axicabtagene ciloleucel ROR 22.89 [18.23–28.73], n = 76). Signals were consistent across CD19- and BCMA-directed agents, absent only for recently approved obecabtagene autoleucel. Conclusions: CAR-T therapies exhibit disproportionate MDS/AML reporting in FAERS, supporting class-wide late hematologic toxicity in pretreated patients with clonal hematopoiesis. Enhanced surveillance, baseline profiling, and marrow evaluation for cytopenias are warranted, balancing curative benefits.

Lymphatics doi: 10.3390/lymphatics4020020

Authors: Juliana H. Kim Sina Oh Alex Heglin Jaewon Yang Orhan K. Öz Robert C. Sibley

Lymphedema is a chronic condition marked by swelling in the body’s soft tissues due to impaired or damaged lymphatic function. Lymphedema is estimated to affect about 1 in 1000 in the United States and 1.4 per 1000 based on two European studies. Lymphedema diagnosis relies on clinical visual assessment by physicians, and the quantitative evaluation of lymphatic function is not widely employed due to the lack of standardized and validated metrics. Lymphoscintigraphy is considered the practical gold standard for evaluating lymphedema. With the emergence of advanced surgical therapies, there is a growing demand for quantitative evaluation metrics to objectively evaluate treatment response. To address this unmet need, we reviewed various methods of quantitative lymphoscintigraphy (qLSG) that were used for assessing lymphedema. We found that multiple qLSG approaches have been described. Moreover, the protocols vary widely in terms of tracer type, injection route, dosage, and exercise interventions. We compared the quantitative assessment strategies and highlighted the approaches that may help provide a more objective lymphedema diagnosis and follow-up.

Lymphatics doi: 10.3390/lymphatics4020019

Authors: Bingwen Eugene Fan Li Xian Amy Tan Yee Lin Tang Tong Tong Chuanhui Xu Khai Pang Leong Choon Guan Chua

We report a diagnostically challenging case of a 79-year-old man who presented with mediastinal lymphadenopathy, hepatosplenomegaly, and renal enlargement, raising suspicion for clinical lymphoma. However, the histological evaluation of a submandibular gland excision revealed fibrosis, a dense IgG4-positive plasma cell infiltrate (>100/HPF), and an IgG4:IgG ratio > 40%, supportive of IgG4-related disease (IgG4-RD) in the appropriate clinicopathologic context. This case illustrates an important but well-recognised diagnostic pitfall in which IgG4-RD may clinically and radiologically mimic lymphoma. PET-CT demonstrated multiorgan involvement with diffuse FDG uptake, but definitive diagnosis required the integration of clinical, radiologic, serologic, and pathologic findings. The patient’s laboratory profile, including hypocomplementemia and elevated inflammatory markers, supported the proliferative phenotype of IgG4-RD—recently proposed in the literature as a clinically distinct subgroup with systemic involvement and steroid responsiveness. Rather than representing a novel presentation, this case reinforces the importance of integrated assessment in distinguishing IgG4-RD from haematolymphoid malignancy. PET-CT served as a useful adjunct for identifying multiorgan disease and guiding diagnostic evaluation, but tissue evaluation remained essential to avoid misdiagnosis and inappropriate treatment. Recognition of this entity is vital to avoid misdiagnosis and inappropriate treatment.

Lymphatics doi: 10.3390/lymphatics4020018

Authors: Aurora M. Kareh Brielle Weinstein Nicholas J. Panetta

Lymphedema is a chronic, incurable disease affecting patients who undergo high-risk cancer treatments. Advances in microsurgical techniques have paved the way for the development of techniques that can prevent or treat this unrelenting condition. In this article we discuss microsurgical interventions for the prevention and treatment of lymphedema, as well as the role of robotics in lymphatic surgery.

Lymphatics doi: 10.3390/lymphatics4020017

Authors: Brian Tuckey Jay Shah John Srbely

Quantitative sensory testing (QST), including temporal summation of pain (TSP) and pressure pain threshold (PPT) assessments, was conducted to evaluate the diagnostic validity and immediate therapeutic efficacy of the manual therapy technique Fascial Counterstrain (FCS). A single patient with persistent lower back and referred leg pain was evaluated and treated by a certified FCS practitioner. A clinical diagnosis of left S1–S2 radiculitis (FCS criteria) was established and corroborated by elevated pre-treatment TSP and reduced PPT measures in the affected dermatomes, indicating nerve root irritation and central sensitization. Immediate post-treatment TSP and PPT assessments demonstrated near-complete normalization of wind-up in the involved S1 and S2 dermatomes, along with a substantial improvement in three-trial-average PPT measurements of the S1–S2 musculature from 2.4 kg/cm2 to 6.1 kg/cm2. This case report provides preliminary evidence supporting the diagnostic process and immediate post-treatment efficacy of FCS in patients with lower back pain and central sensitization.

Lymphatics doi: 10.3390/lymphatics4010016

Authors: Yimeng Zhao Weihua Yin Xingen Wang

Gastrointestinal indolent B-cell lymphomas (GI-iBCLs) are a group of low-grade, slowly progressive malignancies, accounting for approximately 1–4% of all gastrointestinal tumors. They represent the most common type of extranodal indolent B-cell lymphoma. Their clinical presentation often overlaps with that of benign inflammatory conditions, posing diagnostic challenges. In recent years, the incidence of GI-iBCL has been increasing in Asia and Europe, while advances in molecular pathology have facilitated more precise classification. This review systematically summarizes recent progress in understanding the epidemiology, clinical features, pathogenesis, pathological characteristics, treatment, and prognosis of GI-iBCLs, with a specific focus on mucosa-associated lymphoid tissue (MALT) lymphoma and duodenal-type follicular lymphoma (DTFL). We also discuss critical issues such as the risk of histological transformation, treatment optimization for refractory cases, the potential of molecular markers, and the evolving landscape of precision medicine.

Lymphatics doi: 10.3390/lymphatics4010015

Authors: Gabriel Saez Randy Khusial Kamron Hamedi Nathan Arreola Helen Khuu Heather Kissel

B cell maturation antigen (BCMA)-targeted chimeric antigen receptor T cell (CAR-T) therapy has transformed the treatment landscape for relapsed or refractory multiple myeloma (MM), with products such as idecabtagene vicleucel and ciltacabtagene autoleucel achieving high initial response rates, and in selected patient populations, durable treatment-free remission. However, a substantial proportion of patients still experience relapse, including antigen-positive progression, highlighting persistent limitations in long-term disease control across diverse clinical settings. An increasing body of evidence indicates that resistance to CAR-T therapy in MM is driven not only by tumor-intrinsic factors, but also by extrinsic pressures imposed by the bone marrow microenvironment (BMME). This review integrates current understanding of tumor-niche interactions that impair CAR-T persistence, trafficking, and effector function, including immunosuppressive cellular networks, inhibitory cytokine signaling, metabolic constraints, stromal adhesion, antigen modulation, and marrow remodeling. This review further examines emerging therapeutic strategies and next-generation CAR-T platforms.

Lymphatics doi: 10.3390/lymphatics4010014

Authors: Luis Viveros Cristín Olivares Patricia Huerta Claudia Cabezas Silvana Vásquez Mauricio Chandía

Bone marrow involvement in B-cell non-Hodgkin lymphoma is an adverse prognostic factor; therefore, its detection is necessary at the time of diagnosis and during follow-up. This study evaluates the concordance between flow cytometry (FC) and bone marrow biopsy (BMB) in detecting bone marrow involvement in B-cell non-Hodgkin lymphomas as well as their prognostic relevance in a Chilean cohort. A total of 202 samples from 172 patients with diffuse large B-cell (DLBCL), follicular (FL), marginal-zone (MZL), and mantle cell (MCL) lymphoma were retrospectively analyzed; all patients underwent simultaneous BMB and FC. Bone marrow involvement was identified in 29% of samples via BMB and in 40% via FC, with an overall concordance of 89% (kappa: 0.75), which was lower in mantle cell lymphoma. Eleven percent of cases showed BMB-FC+ discordance, generally associated with low tumor burden. In survival analyses, the BMB+/FC+ group exhibited shorter overall and progression-free survival, and concordant involvement was associated with a higher risk of mortality and progression, particularly among patients with an intermediate or high IPI. Involvement detected exclusively by FC did not have a significant prognostic impact. These findings support the role of FC as a complementary or alternative diagnostic tool in settings with limited resources, improving sensitivity for detecting bone marrow involvement without compromising clinical relevance.

Lymphatics doi: 10.3390/lymphatics4010013

Authors: Andrea Lorenzi Carmine Prizio Remo Accorona Vijay Kumar Srinivasalu Narayana Subramaniam

Cervical lymph node metastases are major prognostic determinants in head and neck squamous cell carcinoma (HNSCC), and neck dissection (ND) has long been central to regional control. As ND has evolved from radical to selective procedures, immune checkpoint inhibitors (ICIs) have emerged as a fourth treatment pillar, reframing tumor-draining lymph nodes (TDLNs) as active immune organs rather than passive conduits of metastatic spread. This narrative review synthesizes surgical, immunologic, and translational evidence on how ND and cervical irradiation interact with immunotherapy. It also examines the historical development of ND, the immunologic structure and function of cervical TDLNs, and the use of neoadjuvant, perioperative, and recurrent/metastatic immunotherapy in HNSCC. Preclinical and early clinical observations suggest that ablating or heavily irradiating non-involved nodal basins may attenuate ICI efficacy by disrupting antigen presentation, progenitor exhausted CD8+ T (Tpex) cell pools, and effector recirculation, supporting the conceptual model of an “immune desert neck.” The review critically appraises timing (pre- versus post-immunotherapy ND), response-adapted or de-escalated surgery, and imaging, tissue-based, and circulating biomarkers to guide individualized management. Current evidence does not support abandoning elective or therapeutic ND, but does highlight the need for biomarker-driven, lymphatic-sparing trials to redefine when ND is essential, modifiable, or potentially avoidable in immunotherapy-treated HNSCC.

Lymphatics doi: 10.3390/lymphatics4010012

Authors: Joanna Aldoori Rajeev Parameswaran Mechteld C. de Jong

Adrenocortical carcinoma (ACC) is a rare, aggressive endocrine malignancy with poor survival outcomes and high recurrence rates. Whilst surgical resection is the cornerstone of curative treatment, the role of lymphadenectomy remains debated. “Nodes of contention” in ACC management center on balancing accurate staging and potential oncologic benefit against added operative time, complexity, and morbidity. We reviewed the available published literature over the last 20 years, including retrospective series, to evaluate the prognostic and therapeutic significance of lymphadenectomy in ACC. Though systematic lymph node dissection improves staging accuracy and may identify patients at higher risk who could benefit from adjuvant therapy, evidence demonstrating a survival benefit is inconsistent. This is largely due to the rarity of the condition, heterogeneity in surgical approaches, and lack of standardized nodal templates. Concerns regarding increased operative morbidity further limit widespread adoption. This review synthesizes current evidence on nodal assessment in ACC and highlights gaps in prospective data. While nodal involvement is a strong prognostic factor, the therapeutic impact of lymphadenectomy remains unclear. Prospective, multicenter trials are urgently needed to define its role in ACC management.

Lymphatics doi: 10.3390/lymphatics4010011

Authors: Orsola Crespi François Rosset Umberto Santaniello Valentina Pala Cristina Sarda Martina Accorinti Pietro Quaglino Simone Ribero

Primary cutaneous lymphomas (PCLs) are a heterogeneous group of extranodal T- and B-cell neoplasms confined to the skin at diagnosis, characterised by distinct biological drivers, clinical behaviour, and therapeutic challenges compared with systemic lymphomas. Over the past decade, advances in genomic profiling, single-cell and spatial transcriptomics, and tumour microenvironment analysis have substantially refined the understanding of PCL pathogenesis, highlighting immune evasion, clonal heterogeneity, and compartment-specific disease dynamics as key determinants of outcome and treatment response. These insights have coincided with a rapidly evolving therapeutic landscape that includes immunomodulatory agents, targeted therapies, and ADCs, while also exposing persistent limitations related to diagnostic delay, response heterogeneity, resistance, and lack of validated predictive biomarkers. In this review, we provide a dermatology-focused synthesis of primary cutaneous lymphomas, integrating contemporary classification and clinicopathologic features with molecular pathogenesis and tumour microenvironmental insights of direct clinical relevance. We discuss current diagnostic and staging approaches, critically appraise established and emerging therapeutic strategies in cutaneous T- and B-cell lymphomas, and highlight unresolved clinical challenges and unmet needs, including biomarker integration, longitudinal disease monitoring, and translation of molecular advances into routine practice.

Lymphatics doi: 10.3390/lymphatics4010010

Authors: Andrew J. James Quinton L. Carr Colton H. Connor Brian J. Paul Christian Laurent Ryan Shapiro

Breast cancer-related lymphedema (BCRL) is a chronic and debilitating complication of breast cancer treatment, commonly associated with mastectomy, axillary lymph node dissection, and adjuvant radiation therapy. Though demographic and treatment-related risk factors for BCRL are well documented, emerging evidence suggests that certain genetic polymorphisms may predispose some patients to developing the condition. This review aims to summarize the current research regarding the genetic variants implicated in the development and severity of BCRL. Several candidate genes related to lymphangiogenesis, inflammation, immune cell activation, and lymphatic contractility have been identified. Unfortunately, the existing literature remains limited by the small number of manuscripts, modest sample sizes, and heterogeneous methodologies of available studies. However, further research may shed light on screening options and lead to more personalized treatment strategies to mitigate the incidence and severity of secondary lymphedema.

Lymphatics doi: 10.3390/lymphatics4010009

Authors: Alexandra Larson Vindhya Udhane Jennifer N. Adams Rakshitha Jagadish Anthony Acevedo Brett A. Domagala Samantha A. Vo Tarin Peltier Daniel Sanchez Viriya Keo Kala F. Schilter Qian Nie Honey V. Reddi

Cerebrospinal fluid (CSF) liquid biopsy has been recently recommended by the National Comprehensive Cancer Network (NCCN) as a molecular diagnostic tool for central nervous system (CNS) lymphoma that offers a minimally invasive method to detect key biomarkers when traditional diagnostics are limited by sensitivity or feasibility. This brief report describes the clinical use of two novel CLIA/CAP-approved CSF liquid biopsy tests from Belay Diagnostics, Summit™ and Vantage™, to aid in the diagnosis and management of CNS lymphoma. Results from both tests were reviewed for 50 CSF samples in the context of clinical information provided with the test order. Summit™ and Vantage™ detected clinically significant alterations in CNS lymphoma-associated genes such as MYD88, CD79B, and TP53 as well as MGMT methylation when other modalities (e.g., CSF cytology, MRI, or brain biopsy) were inconclusive. In several cases of suspected secondary CNS lymphoma, Summit™ detected pathogenic genomic variants as well as mild to high levels of aneuploidy, suggesting CNS involvement. Belay testing impacted management in 41 of 50 (82%) cases by informing CNS lymphoma diagnosis, stratification, or progression as well as therapeutic response with an overall false negative rate of 18% (2/11). This report contributes to the growing body of literature that demonstrates how comprehensive molecular profiling of CSF enhances detection and characterization of CNS lymphoma and offers a promising adjunct to conventional diagnostics.

Lymphatics doi: 10.3390/lymphatics4010008

Authors: Xiuyun Wu Jingxin Zhang

Therapy resistance remains a major cause of relapse and poor outcomes in acute lymphoblastic leukemia (ALL). Recent multi-omics studies in ALL have revealed that resistance arises from a combination of leukemia-specific genetic lesions, treatment-driven clonal evolution, and adaptive non-genetic programs. Genomic analyses have identified recurrent alterations associated with resistance to chemotherapy, tyrosine kinase inhibitors, and immunotherapies, while single-cell profiling has uncovered heterogeneous cell states that persist during treatment and contribute to minimal residual disease. Emerging epigenetic, proteomic, and metabolic data further indicate that reversible regulatory and signaling changes play a central role in leukemic persistence. Integrative analyses are beginning to define convergent resistance pathways and clinically relevant biomarkers, although longitudinal sampling and clinical translation remain limited. This review summarizes the current multi-omics landscape of therapy resistance in ALL and discusses opportunities to improve risk stratification and therapeutic strategies.

Lymphatics doi: 10.3390/lymphatics4010007

Authors: Aleksander Luniewski Sahil Chaudhary Adam Goldfarb Ifeyinwa E. Obiorah

The World Health Organization (WHO) and International Consensus Classification (ICC) systems have classified EBV-positive NK/T-cell neoplasms in adults and EBV-positive T/NK-cell lymphoid lymphoproliferative disorders (LPD) in children. Recent molecular profiling techniques have revealed the pathogenesis of these disorders, showing interactions among EBV-encoded proteins, host immune responses, and genetic alterations. Extranodal NK/T-cell lymphoma (ENKTL) shows molecular diversity, with various subtypes (TSIM, MB, and HEA) identified through a multiomics approach. Aggressive NK-cell leukemia (ANKL) has mutations in JAK/STAT, epigenetic regulators, and TP53 pathways. EBV-positive nodal T- and NK-cell lymphoma (ENTNKL) is a new entity, distinguished by primary nodal presentation and a unique molecular profile. Severe mosquito bite allergy (SMBA), hydroa vacciniforme lymphoproliferative disorder (HVLPD), and systemic chronic active EBV disease (CAEBV) are rare childhood EBV-driven LPDs defined by clinico-pathologic criteria, with largely unexplored genomic landscapes. Studies of CAEBV samples have found ENKTL-like driver mutations, including DDX3X and KMT2D, in EBV-infected NK/T cells, while KMT2D and chromatin modifier mutations were common in HVLPD. Comprehensive molecular sequencing of SMBA and Systemic EBV-positive T-cell lymphoma of childhood remains lacking. These findings suggest all EBV⁺ NK/T-cell LPDs exist on a biological continuum of viral oncogenesis. The integration of clinical, pathological, and molecular information aims to create a more accurate classification system, enabling better risk evaluation and tailored treatment strategies for patients with these complex disorders.

Lymphatics doi: 10.3390/lymphatics4010006

Authors: Stefano Ramirez-Gil Jose de Jesus Ley-Tomas Cecilia Belen Espinosa-Arce

Epstein–Barr virus (EBV) is a key oncogenic pathogen implicated in the development of lymphomas, particularly among HIV-positive and immunocompromised individuals. While the association between EBV and lymphoma is well established, the mechanisms underlying progression from infection to malignancy—especially in the head and neck region—remain incompletely understood. This review offers a comprehensive analysis of the pathophysiological pathways by which EBV and HIV contribute to lymphomagenesis, with an emphasis on latency patterns, immune evasion, and epigenetic “hit and run” oncogenesis. Notably, it integrates novel findings on the diagnostic implications of EBV latency proteins, explores HIV-mediated B-cell dysregulation, and evaluates the emerging landscape of targeted therapies, including monoclonal antibodies and lytic cycle inducers. By focusing specifically on head and neck lymphomas, this review underscores a clinically underrepresented domain and offers insights that may guide future diagnostics, surveillance, and treatment strategies in vulnerable patient populations. This review also highlights the pressing need for improved animal models and continued research into EBV-specific therapeutic targets.

Lymphatics doi: 10.3390/lymphatics4010005

Authors: Jingjing Pang Jianan Zhao Liam Flynn Juncheng Wei Long Nguyen Hoang Do Esteban Delgado Xiaolei Liu

The hepatic lymphatic system, long underappreciated, plays a critical role in liver physiology by maintaining interstitial fluid balance, removing metabolic waste, and facilitating immune surveillance. Emerging evidence indicates that lymphatic dysfunction contributes to the pathogenesis and progression of multiple liver diseases, including non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. This review summarizes current knowledge on hepatic lymphatic anatomy, physiology, and molecular regulation, highlights pathological alterations, and discusses potential therapeutic implications. A better understanding of the hepatic lymphatic system may enable the development of novel lymphatic-targeted strategies to improve liver health and treat liver disease.

Lymphatics doi: 10.3390/lymphatics4010004

Authors: Elaine Erika Tsuruda Marya Eduarda Paulino Natália Camargo Faraldo Rodrigo dos Santos Horta Alessandra Estrela-Lima Liz Marques de Mello Simone Carvalho dos Santos Cunha Martha Rocha Andresa Rosenfeld Rafaela Eduarda dos Reis Renee Laufer-Amorim Antony Rodrigues do Nascimento Filho Maria Carolina Mangini Prado Alana Carolina Capais Rodrigues Fernanda Barthelson Carvalho de Moura Carlos Eduardo Fonseca-Alves

Advances in veterinary medicine have contributed to increased life expectancy in companion animals, leading to a higher incidence of chronic and neoplastic diseases in cats. Epidemiological studies correlating demographic and clinical factors with lymphoma in cats are needed, particularly in South America. Data from 662 cats diagnosed with lymphoma were collected from veterinary centers located in all five Brazilian geographical regions and the Federal District. This study represents one of the largest epidemiological assessments of feline lymphoma in Brazil and highlights the broad distribution of the disease across diverse regions and age groups. The predominance of mixed-breed animals and the frequent association with retroviral infections underscore the need for early diagnostic protocols and targeted health strategies to address this issue. These findings contribute to a better understanding of feline lymphoma in Brazil and may support future efforts in disease prevention, early detection, and therapeutic planning for this disease.

Lymphatics doi: 10.3390/lymphatics4010003

Authors: Chase Atiga Haifaa Abdulhaq

Patients with Relapsed/Refractory Diffuse Large B-cell Lymphoma (R/R DLBCL) harbor a poor prognosis. Novel therapies, such as bispecific antibodies (BsAbs), provide an effective therapeutic option for such patients. BsAbs are studied both as monotherapy and combination therapy for patients with R/R DLBCL with promising results. Unlike cellular therapies, such as autologous stem cell transplant (ASCT) or chimeric antigen receptor therapy (CAR-T), BsAbs are more amenable to administration in a community setting, given the lower incidence and severity of key toxicities, such as cytokine release syndrome (CRS) and immune effector cell-associated neurologic syndrome (ICANS). Deployment of BsAbs in the community setting requires operational considerations and a multidisciplinary team approach. This review will discuss the currently approved BsAb treatment regimens and our community institution’s experience in implementing BsAbs.

Lymphatics doi: 10.3390/lymphatics4010002

Authors: Kristian M. Hargadon

Tumor-draining lymph nodes function paradoxically not only as key sites for the priming and coordination of anti-tumor CD8+ T cell responses but also as regional hubs through which invading tumor cells can seed distant metastases. The quality of tumor-specific CD8+ T cells elicited at this site is therefore a critical determinant of the outcome of anti-tumor immunity and cancer progression. Recent studies have demonstrated the significance of CD8+ T cell dysfunction within tumor-draining lymph nodes, highlighting it as an important means of tumor immune escape that may arise early in the course of cancer progression. This review aims to bring attention to emerging data on this topic, with particular focus given to the implications that lymph-node-resident CD8+ T cell dysfunction has both for cancer immunotherapy and for pre-metastatic niche formation during early stages of cancer progression.

Lymphatics doi: 10.3390/lymphatics4010001

Authors: Alison Ross Shakti Dahiya Paulina Cabada Aguirre Michael T. Lotze Jami L. Saloman Genia Dubrovsky

Diseases of the pancreas—such as pancreatic ductal adenocarcinoma (PDAC) and pancreatitis—have long been a challenge to treat. The study of lymphatics within the pancreas can provide some additional insights and offer new therapeutic targets. Here, we explore the development of pancreatic lymphatics and their connections to the nervous system and individual disease states, as well as the potential for therapeutic interventions. Lymphangiogenesis pathways in PDAC, driven by VEGF-C and other mediators, have been extensively explored, but specific therapeutic interventions are lacking. Furthermore, due to the emergence of PDAC with pancreatitis, insights could improve treatment in both settings. The role of neuroimmune interactions and control, as in other organ sites, appears as critical to both lymphatic and immune processes. With a better understanding of the lymphatic environment within the pancreas, we can develop more effective treatments for patients.

Lymphatics doi: 10.3390/lymphatics3040049

Authors: Haneen Al-Maghrabi Ghadeer Mokhtar Ahmed Noorsaeed

In the original publication [...]

Lymphatics doi: 10.3390/lymphatics3040048

Authors: Hirotada Otsuka Yusuke Tsunoyama Miki Koh Satoshi Soeta Naoko Nonaka

Aging is associated with chronic low-grade inflammation of exocrine glands, such as the lacrimal glands. Histamine, synthesized by histidine decarboxylase (HDC), is implicated in immune modulation; however, its role in age-related lacrimal gland inflammation remains unclear. To explore the role of histamine in age-related lacrimal gland inflammation, we compared wild-type and histidine decarboxylase knockout (HDC-KO) C57BL/6 mice at 6 weeks and 12 months of age (10 males and 10 females in each group). Histological and immunohistochemical analyses were performed to assess lymphocytic infiltration, mast cells, and the expression of cytokines and adhesion molecules. Gene expression levels were quantified using reverse transcriptase quantitative PCR (RT-qPCR). Aged wild-type mice showed significant upregulation of mRNA transcription of HDC and histamine H1 receptor, along with increased infiltration of B220-positive B cells and CD3-positive T cells in the lacrimal gland. The mRNA expression levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and ICAM-1 were elevated with age, whereas these changes were attenuated in HDC-KO mice. The mRNA expression of PPARγ, an anti-inflammatory factor, was upregulated in the aged HDC-KO mice. Mast cell numbers increased with age but did not differ according to sex. These findings suggest that histamine, via HDC and H1 receptor signaling, contributes to age-associated lacrimal gland inflammation by enhancing cytokine and ICAM-1 expression. HDC deficiency suppresses this inflammatory response, potentially through the upregulation of PPARγ. Thus, histamine may be a key mediator of age-related inflammation in the lacrimal gland and a potential therapeutic target.

Lymphatics doi: 10.3390/lymphatics3040047

Authors: Daniel Friedman Piers E. M. Patten Robbert Hoogeboom

Chronic lymphocytic leukemia (CLL) is an indolent malignancy with modest proliferation in the lymph nodes and accumulation of quiescent B cells in the peripheral blood. Targeted agents, including BTK inhibitors such as ibrutinib and the BCL2 antagonist venetoclax, have transformed therapy by disrupting proliferation, survival, and lymph node retention of CLL cells, yet CLL remains incurable. Recent studies reveal that CLL cells exist along a spectrum of proliferating, activated, and quiescent states, with dynamic transitions that shape intraclonal behavior. Whilst proliferation occurs mainly in lymph nodes, most emigrant cells in the peripheral blood become quiescent, with only a minority remaining activated. Quiescent, activated, and proliferating fractions display distinct phenotypes and CXCR4 and CD5 levels can be used to distinguish these states in the CLL life cycle. While proliferating and activated cells are more susceptible to BTK inhibition, quiescent subsets show greater sensitivity to BCL2 blockade. These functional differences, together with emerging evidence that phenotypic markers may correlate with residual disease activity, point to potential translational significance. Understanding how CLL cells switch between proliferative, activated and quiescent states will be important to uncover novel vulnerabilities and inform rational treatment strategies.

Lymphatics doi: 10.3390/lymphatics3040046

Authors: Elizabeth Reynolds David Rosas Emily Byrd Diana L. Farmer

Lymphatic malformations are rare congenital anomalies that range from small, self-limited lesions to large, rapidly expanding masses capable of causing serious perinatal complications, including hydrops fetalis, polyhydramnios, airway obstruction, and fetal demise. Although most lesions are managed expectantly or postnatally, in utero interventions have been attempted in highly select cases where lesions threaten pregnancy viability or safety of delivery. Reported approaches include the perinatal option of ex utero intrapartum therapy, intrauterine ultrasound-guided cyst aspiration for decompression, intrauterine intralesional sclerotherapy with agents such as OK-432, and more recently, maternal pharmacologic therapy targeting the mTOR pathways. This review summarizes the available literature describing prenatal management of these lesions, including procedural techniques, maternal and fetal outcomes, and emerging strategies. Together, these findings highlight the potential promise and the caution necessary in translating postnatal therapeutic advances for lymphatic malformations to the prenatal setting.

Lymphatics doi: 10.3390/lymphatics3040045

Authors: Pedro Cunha Ricardo Ribeiro Andreia Pizarro Jorge Mota José Carlos Ribeiro

The ADRENALINE pilot study explores the role of physical activity in health outcomes among patients with Chronic Lymphocytic Leukemia (CLL), focusing on disease markers, functional capacity, immune parameters, and quality of life. This baseline analysis includes treatment-naïve participants enrolled between September 2023 and August 2024, prior to randomization. Eleven patients (aged 47–78 years) underwent assessments of body composition, cardiovascular fitness, muscular strength, and immune profiling. Quality of life was evaluated using validated questionnaires (FACIT-F, EORTC QLQ-30/CLL17), and daily activity was objectively measured via accelerometry. Correlation analyses examined associations between physical activity, muscle strength, lean mass, and physical aptitude. Despite high self-reported physical function, participants demonstrated suboptimal body composition and cardiovascular fitness. Accelerometry revealed marked sedentary behavior, particularly among females, and overall activity levels were below current recommendations. Moderate-to-vigorous physical activity correlated positively with muscular strength and lean mass. Immune profiling identified a variability in key markers, warranting further investigation of their relationship with physical activity. These findings highlight the need for tailored interventions to increase activity and reduce sedentary time in CLL patients and support incorporating functional and immune monitoring into survivorship care.

Lymphatics doi: 10.3390/lymphatics3040044

Authors: Christian Omar Ramos Peñafiel Adolfo Martínez Tovar Daniela Pérez Sámano Rafael Cerón Maldonado Adán Germán Gallardo Rodríguez Carlos Martínez Murillo Irma Olarte Carrillo

In the original publication [...]

Lymphatics doi: 10.3390/lymphatics3040043

Authors: Mohamed Salih Makawi Stephen Ciaccio Asad Khan Alireza Nathani Ronaldo Ortiz-Pacheco

Lung cancer is the leading cause of cancer-related death worldwide. Lymph node involvement affects staging and, therefore, prognosis. Understanding lymph node drainage, metastatic patterns, and different sampling techniques contributes to the overall care of lung cancer patients. Non-small-cell lung cancer is the most common type of lung cancer; appropriate staging is vital to determine treatment modalities which includes surgery, radiation therapy, chemotherapy, or a combination of these. In this review, we aim to describe the pathogenesis of lymph node metastasis, current guidelines for lymph node sampling, patterns of lymph node spread, new and novel lymph node sampling techniques, and their diagnostic yields.

Lymphatics doi: 10.3390/lymphatics3040042

Authors: Michael Mazarei Shayan Mohammad Sarrami Darya Fadavi Meeti Mehta Anna Bazell Carolyn De La Cruz

Background: Lipedema is a progressive adipofascial disorder marked by painful nodular fat deposition that is often mistaken for obesity. While tumescent liposuction reduces limb volume with relative lymphatic safety, persistent large, painful lobules frequently remain, and excisional strategies risk iatrogenic lymphatic injury. We evaluated the application of intraoperative indocyanine green (ICG) lymphography to identify and preserve lymphatic channels during debulking surgery for symptomatic lipedema. Methods: We conducted a single-center case series (University of Pittsburgh Medical Center, July 2023–December 2024) of adults with lipedema refractory to conservative therapy who underwent a selective dermato-lipectomy (lobule/skin excision) with or without tumescent liposuction. Patients with clinical lymphedema or dermal backflow in ICG were excluded. Near-infrared ICG (SPY-PHI) was used for pre-incision mapping and real-time intraoperative guidance; lymphatic trajectories were marked and spared during lobule excision. Primary measures included dermal backflow patterns and lymph node transit time; secondary outcomes were complications and symptom burden (Lymphedema Life Impact Scale, LLIS) through ≥24 months. Results: Eight patients (five female/three male; mean age 49.5 ± 14.4 years; median BMI 52.65 kg/m2) underwent ICG-guided surgery. Preoperatively, linear lymphatic patterns were visualized up to the knee in all patients, but dermal backflow patterns could not be visualized in 83% from the level of the knee to the groin. Still, 67% demonstrated inguinal nodal uptake (mean transit 24 min), suggesting preserved lymphatic transport. All cases achieved intraoperative confirmation of intact lymphatic flow after debulking. The mean liposuction aspirate was 925 ± 250 mL per lower extremity; the mean excision mass was 2209 ± 757 g per lower extremity. Complications included two superficial cellulitis events (25%) and one wound dehiscence (12.5%); no hematomas or skin necrosis occurred. No patient developed clinical or imaging evidence of iatrogenic lymphedema during follow-up. Conclusions: Intraoperative ICG lymphography is a practical adjunct for lymphatic-sparing debulking of symptomatic lipedema, enabling real-time identification and preservation of superficial collectors while addressing focal lobules. This hybrid approach—targeted tumescent liposuction followed by ICG-guided superficial dermato-lipectomy—was associated with meaningful symptom improvement and a low morbidity in this early series.

Lymphatics doi: 10.3390/lymphatics3040041

Authors: Chi Sing Ng

Indolent lymphoproliferative diseases or disorders (LPDs) derived from T cells or Natural Killer (NK) cells may be neoplastic or non-neoplastic, which are often difficult to distinguish from each other and from their aggressive counterparts. The etiology and pathogenesis are mostly nebulous and may be related to infections or immune dysfunction. Indolent lymphomas differ from the high-grade aggressive counterparts by a prolonged clinical course of persistent or relapsing disease, histology, immunophenotype, and genetics. In recent decades, indolent lymphomas or LPD of T or NK cell derivation have been increasingly recognized, causing diagnostic and nosologic confusion. The issue is particularly challenging in the arena of indolent intestinal lymphomas and LPD, as evidenced by the myriad of names given to the indolent intestinal T- and NK-cell lymphomas and LPD. Confounding the picture are also reports of Epstein–Barr virus (EBV) positivity in various indolent non-intestinal LPD and, rarely, even in indolent intestinal T-cell lymphoma, which have been widely accepted to be typically EBV-negative. This review aims to curate current information and understanding of these diseases with the goal of resolving these issues. The recently described indolent T-lymphoblastic proliferation (iTLBP) and the re-classified indolent primary cutaneous CD4-positive small or medium T-cell LPDs and primary cutaneous acral CD8-positive T-cell LPDs also require greater awareness and recognition. It is important to diagnose these indolent entities in order to avoid over-treatment and unnecessary therapeutic intervention and to provide for accurate prognostic prediction and appropriate follow-up.

Lymphatics doi: 10.3390/lymphatics3040040

Authors: Nicolas Ulrich Edgar Seodam Kwak Kelsey Baron Archana Agarwal Anton Rets Anna Shestakova

Reactive intralymphovascular immunoblastic proliferation (ILVIP) is a rare and diagnostically challenging entity that can closely mimic intravascular large B-cell lymphoma (IVLBCL). We report the comprehensive clinicopathologic features of two patients with B-cell lineage ILVIP identified in bowel resection specimens. Both patients presented with small bowel obstruction requiring surgical intervention, and one patient was initially erroneously diagnosed with IVLBCL. Neither patient had systemic findings suggestive of lymphoma, such as lymphadenopathy, hepatosplenomegaly, or B symptoms. Histologic evaluation demonstrated focal ILVIP composed of intermediate-to-large B-lineage immunoblasts positive for CD45, CD79a, and MUM1 with polytypic light-chain expression, and negative for CD20, PAX5, CD138, Epstein–Barr virus, and HHV8. The immunoblasts showed a high proliferation index (80–100%) in both cases. Recognition of ILVIP in specimens resected for bowel obstruction in otherwise healthy patients is essential to avoid misinterpretation as intravascular lymphoma and prevent unnecessary treatment.

Lymphatics doi: 10.3390/lymphatics3040039

Authors: Masaya Aoki Go Kamimura Aya Harada-Takeda Toshiyuki Nagata Gen Murakami Kazuhiro Ueda

In the original publication [...]

Lymphatics doi: 10.3390/lymphatics3040038

Authors: Yasuhiro Tonoyama Yo-ichi Ishida

Clarifying the function of approximately 20,000 proteins encoded by the human genome is a key challenge in the fields of medicine and biology. However, many proteins remain uncharacterized. In this review, we introduce a challenge that uses adult T-cell leukemia/lymphoma (ATL) and proteomics to study human proteins of unknown function (PUFs). The characteristic properties of ATL cells are as follows: ATL cells (1) are infected with virus, (2) are derived from CD4+ T cells, (3) are generated via multi-stage carcinogenesis, (4) have flower-like nuclei, and (5) are highly infiltrative in the aggressive type. Given that ATL cells have contributed to impressive basic research, such as the discovery of HTLV-1 as a human cancer virus and interleukin-2 (IL-2) receptor α chain (IL-2Rα)/CD25, which is used for identifying regulatory T (Treg) cells, ATL cell lines could still be considered an attractive research tool. Furthermore, the “Unknome database” is useful for examining function-unknown degrees of proteins of interest using known scores based on Gene Ontology (GO) annotations and protein analysis through evolutionary relationships (PANTHER). Combining ATL proteomic data obtained by us with the “Unknome database” is expected to contribute not only to investigating the pathogenetic mechanism of ATL but also to clarifying the functions of PUFs.

Lymphatics doi: 10.3390/lymphatics3040037

Authors: Sudeep Kumar Ujjwal Adhikari Brijendra Singh

The lymphatic system is essential for maintaining the body’s fluid balance, lipid absorption, and immune regulation. The dysfunction of the lymphatic system is associated with a wide spectrum of disorders. These disorders include primary and secondary lymphedema, congenital malformations, and lymphatic neoplasms. In cancer patients, lymphatic remodeling is essential, which facilitates tumor progression and metastasis, while tertiary lymphoid structures (TLSs) develop during chronic inflammation and may be involved in anti-tumor immunity. This review highlights the immunological basis of lymphatic disorders, with a particular focus on cellular and molecular biomarkers that define disease states. The recent advances in molecular imaging techniques, such as ultrasonography (US), computed tomography (CT), and magnetic resonance lymphography (MRL), have improved and identified the diagnosis and therapeutic targets for lymphedema. Moreover, nanobiotechnology and nano-delivery tools have further enhanced the visibility of cancer cells by imaging. Artificial Intelligence (AI) in lymphatic systems have offered a new spectrum for disease prediction using forms of AI such as natural language processing (NLP), machine learning (ML), robotics-assisted approaches, fussy model (FM), and natural language processing (NLP)-based algorithms. Collectively, these advanced tools have improved diagnostic approaches and reveal exciting opportunities for future research and new therapeutic developments in patient care.

Lymphatics doi: 10.3390/lymphatics3040036

Authors: Meeti Mehta Michael Mazarei Shayan Mohammad Sarrami Carolyn De La Cruz

Introduction: Axillary reverse mapping (ARM) aims to reduce the risk of breast cancer-related lymphedema (BCRL) by preserving and limiting dissection of arm-draining lymphatics. The ideal type of dye and the location of injection, which maximize the sparing of lymphatics and improve outcomes of immediate lymphatic reconstruction (ILR), remain under-studied. The current literature reports inconsistent visualization of lymphatics using blue dye alone, whereas indocyanine green (ICG) near-infrared (NIR) lymphography has shown improved rates. However, optimized dual-dye workflows integrating breast–plastics co-surgery are lacking. Methods: A retrospective review of patients who underwent ILR following ALND for breast cancer between June 2021 and June 2023 was conducted. Patients who underwent ARM using our dual-dye technique were included, utilizing intradermal injections of indocyanine green (ICG) into the wrist and isosulfan blue (ISB) into the upper arm. Axillary reverse mapping channels were categorized by the type of dye used to visualize. Dye injection site, number of lymphatic channels visualized, channel diameter (mm), time-to-first channel, coordinates relative to fixed landmarks, ILR configuration, and pathologic findings were reviewed. Mann–Whitney U tests were used to compare channel visualization rates between types of dye. Results: Of 26 patients, 21 underwent dual-dye mapping and were included. A total of 115 ARM channels were identified: 99 (86%) via ICG and 29 (25%) via ISB. A total of 64 lymphaticovenous anastomoses were performed (mean: 2.46 per patient). Both dyes were identified in the axilla in only 11.7% of patients. At the end of the study, the lymphedema rate was 12%. Conclusions: We developed a reproducible dual-dye ARM technique for ALND with planned ILR, reducing lymphedema risk while maintaining oncologic safety. Dual-dye mapping reveals that proximal and distal lymphatics exhibit both overlapping and divergent drainage to axillary nodes. ICG’s higher axillary detection rate may reflect true anatomical differences or dye properties. These findings support the need for individualized lymphatic mapping during breast cancer surgery to guide preservation techniques and reduce the risk of BCRL.

Lymphatics doi: 10.3390/lymphatics3040035

Authors: Ethan L. MacKenzie Anne Huang Min-Jeong Cho Roman J. Skoracki Rohini L. Kadle

Lymphedema is a chronic, progressive, and debilitating disease of the lymphatic system with no current cure. Physiologic procedures, which address the underlying pathophysiology of lymphatic dysfunction, have gained traction in both treatment and prevention of lymphedema. This narrative review examines current physiologic lymphedema surgical techniques and emerging developments in this rapidly evolving field. While the two most common physiologic surgeries remain lymphovenous bypass (LVB) and vascularized lymph node transfer (VLNT), newer physiologic surgery techniques such as vascularized lymph vessel transfer (VLVT) and lymph node to vein anastomosis (LNVA) have been described in an effort to reduce donor site morbidity, with early promising clinical outcomes. The use of bioengineering with stem cells, pro-lymphangiogenic growth factors, and biomaterials such as Biobridge can be applied in conjunction with surgery to help promote lymphangiogenesis. Technological advances in robotic surgical systems and 3D exoscopes are helping to make supermicrosurgery more technically feasible and ergonomic, and increasing accessibility to lymphedema surgery. As our surgical armamentarium expands, treatment algorithms must be updated to determine how various surgical techniques can be combined and sequenced, how the indications for physiologic surgery can be expanded, and how surgical treatment can be tailored to the patient and disease process.

Lymphatics doi: 10.3390/lymphatics3040034

Authors: Vasisht Karri Samir Dalia

This review analyzed approximately 115 peer-reviewed studies published between 2010 and 2025, focusing on molecular subtyping and circulating tumor DNA (ctDNA)-guided approaches in Diffuse Large B-Cell Lymphoma (DLBCL). Evidence was synthesized from retrospective cohorts, prospective clinical trials, and translational studies, highlighting how molecular heterogeneity, clonal evolution, and the tumor microenvironment complicate classification and treatment. While molecular subtypes such as MCD, BN2, EZB, A53, and ST2 have improved prognostication, their routine use in clinical practice remains limited due to cost, complexity, and restricted access to sequencing platforms. Tumor-informed ctDNA assays show promise for minimal residual disease (MRD) monitoring and adaptive therapy, yet their predictive power for CAR-T therapy, bispecific antibodies, and checkpoint inhibitors is still incompletely understood. Overall, the literature converges on the need for integrated strategies combining ctDNA, molecular subtyping, and immune microenvironment analysis to personalize frontline therapy.

Lymphatics doi: 10.3390/lymphatics3040033

Authors: Patrick A. H. Ehm Christoph Rehbach

Acute lymphoblastic leukemia is the most common cause of cancer-related death in children and represents a poor prognosis for patients in high-risk groups. Current treatment protocols are based on intensive polychemotherapy, which is associated with a significant toxicity profile. Due to their higher specificity and lower toxicity, immunotherapies based on monoclonal antibodies, in particular antibody–drug conjugates (ADCs), are revolutionizing cancer therapy. However, reports on the potential efficacy of ADC-targeted therapy in ALL and its subgroups are limited. Gene expression data suggest that potentially new ADC antigens are highly abundant in ALL subgroups and represent promising targets for cancer therapy. In addition, the PI3K/AKT and RAS/MAPK signaling pathways are often persistently activated in ALL and recent data showed that active feedback loops following inhibition of these pathways can lead to redundancy of cell surface receptors that can potentially serve as antigens for ADC treatment. Therefore, we provide here an overview of the most interesting receptors of the various ALL subgroups and discuss the influence that feedback loops of the PI3K/AKT and RAS/MAPK signaling pathways may have on increasing protein expression of the aforementioned receptors, which could lead to targeted combination therapy approaches in the future.

Lymphatics doi: 10.3390/lymphatics3040032

Authors: Bruna Yukie Koizumi Marina Rayciki Sotomayor Carolina Coradi Ana Luiza Goulart Starck Anna Will Ribeiro Maikely Bruna Leite Maria Eduarda Pardal Simonato Rafael Gomes Paz Vinicius de Melo Tizzo Stefania Tagliari Longo Geise Ellen Broto Fausto Celso Trigo Carolina Panis

In the original publication [...]

Lymphatics doi: 10.3390/lymphatics3040031

Authors: Vignesh Krishnan Nagesh Ruchi Bhuju Ahmed S. Mohammed Emelyn Martinez Marina Basta Deepa Francis Shraboni Dey Maggie James Damien Islek Sanket Bhattarai Mohammed A. Saafan Shruthi Badam Adam Atoot

Gastrointestinal (GI) lymphomas are a diverse group of extranodal non-Hodgkin lymphomas primarily affecting the stomach, small intestine, and colon. They present with non-specific symptoms such as abdominal pain, weight loss, or GI bleeding, making early diagnosis challenging. Histologic subtypes vary, with mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBCL) being the most common. Diagnosis involves endoscopic evaluation with biopsy, cross-sectional imaging, and often PET-CT. Management is subtype-dependent, including antibiotics for H. pylori-associated MALT lymphoma, chemotherapy, immunotherapy, and occasionally surgery. A multidisciplinary approach is essential for optimal outcomes. Core Tip: Gastrointestinal lymphomas are rare but clinically significant malignancies with variable presentations. Accurate diagnosis and tailored treatment based on the histologic subtype and site are critical, requiring close collaboration among gastroenterologists, pathologists, oncologists, and radiologists.

Lymphatics doi: 10.3390/lymphatics3040030

Authors: Walid Kteiche Vasiliki Besa Stefanie Werther Dirk Theegarten Stefanie Bertram Enno Schmidt Anna Daniels Silke C. Hofmann

Background: Castleman’s disease (CD), also known as angiofollicular lymph node hyperplasia, describes a rare group of diseases manifesting with enlarged lymph nodes and various inflammatory symptoms. The association between Castleman’s disease, paraneoplastic pemphigus and bronchiolitis obliterans has been described in the literature and is depicted thoroughly in this case. Case Presentation: We present a case of severe bronchiolitis obliterans developing in a 17-year-old female with paraneoplastic pemphigus and unicentric Castleman’s disease. Conclusion: Surgical resection of unicentric Castleman’s disease remains the treatment of choice due to its efficacy in preventing the recurrence of associated morbidity caused by bronchiolitis obliterans and paraneoplastic pemphigus.

Lymphatics doi: 10.3390/lymphatics3040029

Authors: Yuki Asahi Tatsuhiko Yamada Masashi Kuroki Yuta Sato Yoshihiro Tanaka Manato Matsubara Saki Akita Rina Kato Ryota Iinuma Ryo Kawaura Hiroshi Okuda Kosuke Terazawa Kenichi Mori Hirofumi Shibata Natsuko Ueda Keishi Kohyama Hisakazu Kato Takenori Ogawa

Free jejunum is used for reconstruction after resection of advanced head and neck cancer. Postoperative transplanted mesenteric lymph nodes swelling is often experienced, but its clinical significance is unclear. This study included patients who underwent free jejunal reconstruction at Gifu University Hospital between March 2017 and November 2023. Regarding the size change of postoperative mesenteric lymph node and risk factors, the correlation with metastasis and prognosis was investigated. This study included 51 patients, of whom 16 cases (31.4%) had postoperative mesenteric lymph node swelling and 2 cases (3.9%) had metastasis. Only two cases with metastasis showed an increase in size of 5 mm or more. Many cases without extracapsular extension and cases of salvage surgery had postoperative mesenteric lymph node swelling (p = 0.0429, p = 0.0269). No correlation was found between postoperative mesenteric lymph node swelling and prognosis. However, because all cases with metastasis were included in cases of postoperative mesenteric lymph node swelling, this could be one factor in determining whether or not metastasis occurred. The transplanted mesenteric lymph node swelling is one of the important postoperative evaluation items, and additional evaluation such as PET-CT may be recommended.

Lymphatics doi: 10.3390/lymphatics3030028

Authors: Nicolas Giachetti Sarah Bellal Marianne Schwarz Jérôme Paillassa Aline Clavert Mathilde Hunault-Berger Firas Safa

Background: Lymphomatoid granulomatosis (LYG) is a rare and atypical EBV-induced B-cell lymphoproliferative disorder. Clinical manifestations are mainly respiratory, with nodular infiltrates, varying in number and size, being responsible for respiratory distress. Cutaneous, hepatic, or neurological involvement is also possible. Although pathogenesis is not clearly elucidated, quantitative or qualitative cellular immunodepression is thought to be a main factor. Here, we report a case of concomitant LYG and pulmonary tuberculosis. Case presentation: An 80-year-old female patient presented to the emergency unit for steadily increasing dyspnea, with workup revealing bilateral pulmonary nodules and mediastinal lymph node enlargement on chest imaging. Empiric antibiotic therapy was initially started with amoxicillin-clavulanate, which was later combined with azithromycin following respiratory deterioration. A CT-guided lung biopsy showed grade 2 LYG. Treatment with corticosteroids and weekly rituximab was initiated, leading to rapid improvement of respiratory symptoms. After the second dose of rituximab, sputum cultures that were initially collected were found to be positive for Mycobacterium tuberculosis. Rituximab was suspended, and antituberculous treatment was initiated. Rituximab was restarted once tuberculosis was controlled. Follow-up imaging later showed adequate control of both tuberculosis and LYG, with at least a partial remission of the latter. Conclusions: Our case highlights the importance of a complete diagnostic workup when a diagnosis of LYG is made, to avoid missing a concomitant pulmonary disease, such as tuberculosis, even when definite pathologic and clinical features of the former are present.

Lymphatics doi: 10.3390/lymphatics3030027

Authors: Thomas S. Maldonado Michael Barfield Ron Winokur Todd Berland Sandi Davis Vicky Ralph Nancy Chatham Stanley G. Rockson

Objective: Chronic edema, whether systemic or localized, is often underrecognized by providers due to limited awareness of its prevalence and debilitating impact. As result, patients suffering from this condition live with suboptimal management, diminished quality of life, and increased healthcare costs. Non-pneumatic compression devices (NPCDs) have been shown to be safe and more clinically effective in treating lymphedema (LED) than advanced pneumatic compression devices (APCD) in multiple published studies. In the latest study, the TEAYS trial, NPCDs showed superior clinical utility, better outcomes, and higher patient adherence than APCDs for managing lower extremity swelling. This sub-analysis of the TEAYS study focuses on outcomes for patients aged 65 and above diagnosed with lymphedema in the lower extremity. Methods: This trial was a randomized, crossover, head-to-head study across nine sites in the US in 2023. Patients were subjected to an initial 4-week washout period and then randomized to either the NPCD or a commercially available APCD. Patients used the randomly assigned initial device for 90 days followed by a second washout period before a 90-day use of the second device. Results: Analysis included a total of 71 patients with lower extremity lymphedema, 27 of whom were aged 65 or above, and this subset comprises the study cohort for the current study. These patients achieved statistically greater mean limb volume reduction (353.9 ± 99.17 mL) while on NPCD vs. APCD (−10.7 ± 125.59 mL). NPCD also showed significantly better improvement in overall quality of life (1.43 ± 0.45) vs. APCD (−0.10 ± 0.34). Statistically significant improvement in adherence was also observed while on NPCD (77%) vs. APCD (23%). No device-related adverse events were reported. Conclusions: For adults aged 65 and older with lower extremity lymphedema, non-pneumatic compression devices (NPCDs) demonstrated superior clinical outcomes—including greater limb volume reduction, improved mobility, higher adherence, and patient satisfaction—compared to advanced pneumatic compression devices (APCDs), supporting NPCDs as an effective, patient-preferred solution.

Lymphatics doi: 10.3390/lymphatics3030026

Authors: Varoon Phondge Maya Dornbrand-Lo Pooja Deshpande Alex K. Wong

Postoperative edema is a nearly universal consequence of aesthetic surgery, yet its clinical implications and potential progression to lymphedema remain underexplored. This review examines the prevalence, pathophysiology, diagnostic criteria, and management strategies for edema and lymphedema following aesthetic procedures. A comprehensive search of PubMed, Embase, and Cochrane databases identified studies involving adult patients undergoing aesthetic surgeries with documented postoperative edema or lymphedema. The review found that while edema is expected postoperatively and is generally self-limiting, persistent or disproportionate swelling may indicate early lymphedema. Risk factors include extensive liposuction, body contouring, and procedures involving lymphatic disruption. Despite its significance, lymphedema remains underdiagnosed due to a lack of standardized diagnostic criteria and low clinical suspicion. Emerging imaging modalities, such as indocyanine green lymphography, enhance early detection, while conservative treatments, such as manual lymphatic drainage, compression, and physical therapy, remain first-line interventions. Increased awareness among surgeons and incorporation of lymphatic-preserving techniques are vital to reducing morbidity. This review underscores the importance of distinguishing transient edema from chronic lymphedema and calls for further research to establish evidence-based guidelines for diagnosis, prevention, and management of postoperative lymphedema in aesthetic surgery.

Lymphatics doi: 10.3390/lymphatics3030025

Authors: Rafael Ríos-Tamayo

Systemic light-chain (AL) amyloidosis is a challenging, complex and heterogeneous disease. AL amyloidosis is classified under the category of plasma cell neoplasms and other diseases with paraproteins in the fifth edition of the World Health Organization classification of lymphoid tumors. Epidemiological information is limited, largely due to its low incidence and the lack of a global network of population-based specific registries. Despite recent advances, AL amyloidosis is still considered an incurable disease. The presence of a precursor disease, particularly monoclonal gammopathy of uncertain significance, is the main consolidated risk factor. Limited knowledge about other risk factors precludes the possibility of establishing preventive measures. A relevant percentage of AL amyloidosis patients fulfill the current diagnostic criteria of multiple myeloma. Incidence should be evaluated in the setting of population-based studies. On the one hand, incidence shows a slightly increasing pattern. On the other hand, survival is progressively increasing. Consequently, prevalence is also rising. Early mortality, commonly associated with advanced heart involvement, remains a serious drawback to improve the outcome. Epidemiology represents the first level of heterogeneity in AL amyloidosis. Both genomic and clinical epidemiological research in systemic AL amyloidosis have a crucial role in the global strategy to combat this multifaceted disease.

Lymphatics doi: 10.3390/lymphatics3030024

Authors: Adit Singhal David Mueller Benjamin Ascherman Pratik Shah Wint Yan Aung Edward Zhou Maria J. Nieto

Hodgkin’s Lymphoma (HL) affects approximately 8500 individuals annually in the United States. The 5-year relative survival rate has improved to 88.5%, driven by transformative advances in immunotherapy and precision oncology. The integration of Brentuximab vedotin (BV) and immune checkpoint inhibitors (ICIs) has redefined treatment paradigms. The phase III SWOG S1826 trial established nivolumab plus doxorubicin, vinblastine, and dacarbazine (N + AVD) as an emerging new standard for advanced-stage HL, achieving a 2-year progression-free survival (PFS) of 92% compared to 83% for BV plus AVD (HR 0.48, 95% CI: 0.33–0.70), with superior safety, particularly in patients over 60. In relapsed/refractory HL, pembrolizumab outperforms BV, with a median PFS of 13.2 versus 8.3 months (HR 0.65, 95% CI: 0.48–0.88), as demonstrated in the KEYNOTE-204 trial. Emerging strategies, including novel ICI combinations, minimal residual disease (MRD) monitoring via circulating tumor DNA (ctDNA), and artificial intelligence (AI)-driven diagnostics, promise to further personalize therapy. This review synthesizes HL’s epidemiology, pathogenesis, diagnostic innovations, and therapeutic advances, highlighting the role of precision medicine in addressing unmet needs and disparities in HL care.

Lymphatics doi: 10.3390/lymphatics3030023

Authors: Chaimae El Mahdaoui Hind Dehbi Siham Cherkaoui

Acute lymphoblastic leukemia (ALL) is a heterogeneous hematologic malignancy defined by the uncontrolled proliferation of lymphoid precursors. Accurate diagnosis and effective therapeutic strategies hinge on a comprehensive understanding of the genetic and molecular landscape of ALL. This review synthesizes the latest updates in cytogenetic and molecular classifications, emphasizing the 2022 World Health Organization (WHO) and International Consensus Classification (ICC) revisions. Key chromosomal alterations such as BCR::ABL1 and ETV6::RUNX1 and emerging subtypes including Ph-like ALL, DUX4, and MEF2D rearrangements are examined for their prognostic significance. Furthermore, we assess novel diagnostic tools, notably next-generation sequencing (NGS) and optical genome mapping (OGM). While NGS excels at identifying point mutations and small indels, OGM offers high-resolution structural variant detection with 100% sensitivity in multiple validation studies. These advancements enhance our grasp of leukemogenesis and pave the way for precision medicine in both B- and T-cell ALL. Ultimately, integrating these innovations into routine diagnostics is crucial for personalized patient management and improving clinical outcomes.

Lymphatics doi: 10.3390/lymphatics3030022

Authors: Anna-Carina Hund Jörg Larsen Gerald G. Wulf

Phosphatidylinositol-3-kinase (PI3K) inhibition has emerged as a therapeutic option against indolent lymphoma, including relapsed follicular lymphoma (FL). While inhibition of active signaling in the lymphoma cell represents the primary mode of action, PI3K inhibition also exerts immunomodulatory effects. Here we have analyzed 17 consecutive advanced treatment line FL patients treated with the delta-selective PI3K inhibitor idelalisib in a retrospective single-center observational study, with a specific focus on response and immune effects. Eleven patients achieved complete remission (CR) or partial remission (PR) with median response duration of 22 (11–88) months following a median idelalisib exposure of 15 (4–88) months. Disease response persisted in three patients for a median of 37 (21–63) months following cessation of idelalisib without another therapy being initiated. Autoimmune side effects occurred in eight of the eleven patients who responded, compared to none in six patients whose disease did not respond. In conclusion, a time-limited exposure to idelalisib may induce sustained remissions in a portion of patients with recurrent and/or refractory (r/r) FL, suggesting immunomodulatory effects of PI3K inhibition to be involved in the control of the disease.

Lymphatics doi: 10.3390/lymphatics3030021

Authors: Taru Goyal Saniya Sharma Rakesh Kumar Pilania Kajol Jawallia Sanchi Chawla Madhubala Sharma Monica Rawat Vaishali Thakur Urvi Arya Anoop Kumar Manpreet Dhaliwal Vignesh Pandiarajan Amit Rawat Surjit Singh

Kawasaki disease (KD), first identified in 1967 by Dr. Tomisaku Kawasaki, is an acute, self-limited vasculitis and remains the leading cause of acquired heart disease in children worldwide, particularly affecting those under the age of five. Clinically, it presents with persistent fever, mucocutaneous inflammation, skin rashes, and lymphadenopathy, with a marked tendency to involve the coronary arteries, potentially leading to serious complications such as coronary artery aneurysms. Despite extensive research spanning more than five decades, the precise etiology of KD remains unclear. However, accumulating evidence supports the significant role of genetic predisposition, highlighting the contribution of inherited factors in modulating immune responses and influencing disease susceptibility and severity. Emerging evidence highlights genetic susceptibility as pivotal, with genome-wide studies identifying polymorphisms in immune-related genes, such as ITPKC, CASP3, BLK, CD40, and ORAI1, which modulate disease risk and coronary complications. Epigenetic mechanisms, including DNA methylation and non-coding RNAs, bridge the gap between genetic and environmental factors, regulating immune responses and endothelial activation. Furthermore, emerging insights into autophagy-related processes provide a deeper understanding of the molecular mechanisms underlying the disease. This review aims to explore the current knowledge on the genetic landscape of KD, examine how these findings contribute to our understanding of its pathophysiology, and investigate the potential for genetically targeted therapeutic strategies in the future.

Lymphatics doi: 10.3390/lymphatics3030020

Authors: Jamie Rigney Kevin Zhang Michael Greas Yan Liu

There has been extensive research on the KSHV/HHV8 virus, which has led to a better understanding of viral transmission, pathogenesis, viral-driven lymphoid proliferation, neoplastic transformation, and how we might combat these processes clinically. On an extensive review of the literature, only two true KSHV/HHV8-positive lymphoid neoplasms are described: primary effusion lymphoma (PEL), which can also present as solid or extracavitary primary effusion lymphoma (EC-PEL) and diffuse large B-cell lymphoma (DLBCL). Two lymphoproliferative disorders have also been described, and while they are not true monotypic neoplasms, these lesions can transform into neoplasms: KSHV/HHV8-positive germinotropic lymphoproliferative disorder (GLPD) and multicentric Castleman disease (MCD). This review provides a somewhat concise overview of information related to KSHV/HHV8-positive lymphoid neoplasms and pertinent associated lymphoproliferative lesions.

Lymphatics doi: 10.3390/lymphatics3030019

Authors: Xiaocan Wu Hanna Liu Kejun Ying

Lymphoid neoplasms (LN), a diverse group of malignancies arising from lymphocytes, exhibit a striking increase in incidence with chronological age, suggesting a deep connection with the aging process. While chronological age remains a primary risk factor, the concept of biological age, reflecting an individual’s physiological state and susceptibility to age-related diseases, offers a more nuanced understanding of this relationship. Aging clocks, particularly epigenetic clocks based on DNA methylation, provide quantitative measures of biological age and have revealed associations between accelerated aging and increased cancer risk, including LN. Immunosenescence, the age-related decline in immune function characterized by thymic involution, altered lymphocyte populations, and chronic inflammation (inflammaging), appears to be a key mechanistic link between aging and LN development, potentially providing a more accurate predictor of cancer risk than mutation accumulation alone. Accelerated biological aging, measured by various clocks, correlates with LN risk and progression (e.g., in chronic lymphocytic leukemia), and may influence treatment tolerance and outcomes, particularly in older adults who are often burdened by frailty and comorbidities like sarcopenia. Integrating biological age assessments into clinical practice holds promise for refining diagnosis, prognosis, and personalizing treatment strategies (including guiding intensity and considering anti-aging interventions), and improving outcomes for patients with LN. This review synthesizes the current understanding of the intricate relationship between LN, immunosenescence, biological age, and aging clocks, highlighting clinical implications and key future research directions aimed at translating these insights into better patient care.

Lymphatics doi: 10.3390/lymphatics3030018

Authors: Amanda Fazzalari Ryoko Hamaguchi Candice Leach Justin Broyles Anna Weiss

Breast cancer-related lymphedema (BCRL) is a debilitating complication in breast cancer survivors, with axillary lymph node dissection (ALND) as the greatest independent risk factor. Beyond non-surgical therapies such as complete decongestive and compression therapy, there has been increased interest in immediate microsurgical reconstruction via immediate lymphatic reconstruction (ILR) anastomosing transected lymphatic vessels to a local venous recipient at the time of ALND to mitigate the risks of BCRL. This work provides a scoping review of the landscape surrounding ILR, spanning the updated literature investigating patient outcomes, current accepted best practices, and critical components of surgical techniques for a successful multidisciplinary approach. While limited by heterogeneity in the methods of lymphedema detection, a growing body of work demonstrates the protective effects of ILR. From the pioneering work by Boccardo et al. in 2009 and his introduction of Lymphatic Microsurgical Preventive Healing Approach (LYMPHA) using an intussusception-type end-to-end microanastmosis, to the first randomized control trial by Coriddi in 2023, which importantly employed relative upper extremity volume change as an outcome measure to circumvent the confounding effects of body size and BMI, the current literature supports ILR following ALND in the prevention of BCRL. Collaboration between the oncologic breast surgeon and reconstructive microsurgeon are central to the success of ILR. Critical components for operative success include preoperative and intraoperative lymphatic mapping, preservation of suitable venous targets, availability of supermicrosurgical instruments and sutures, as well as aptitude with a variety of microsurgical anastomotic techniques.

Lymphatics doi: 10.3390/lymphatics3030017

Authors: Chien-An A. Hu Christina Baum Yahui Xie

Cancer metastasis often accounts for the primary cause of cancer-related mortality, with the lymphatic system playing a pivotal role in the dissemination of malignant cells. While hematogenous vessel spread is commonly associated with distant organ metastasis, the lymphatic system serves as an early conduit for tumor cell invasion and dissemination. The process of lymphatic metastasis is a highly coordinated sequence of events that involves cancer cell invasion, intravasation into lymphatic vessels, survival, transport, and colonization of regional lymph nodes (LNs). Cancerous cells then establish micro-metastases at the colonized sites and expand in the new microenvironment, ultimately resulting in the generation of secondary tumors. Tumor-secreted factors, such as vascular endothelial growth factors (VEGF-C and VEGF-D), contribute to metastasis through lymphangiogenesis, the formation of new lymphatic vessels. In addition, cancer cells utilize pre-existing chemokine signaling pathways by expressing chemokine receptors, such as CCR7, which bind to chemokine ligands, such as CCL19 and CCL21, to facilitate targeted migration into the lymphatic vessels. LNs are often the initial sites for metastasis and therefore are indicators of distant organ involvement. It is well established that the location and extent of LN involvement provides significant prognostic information, although the optimal treatment approach for LN metastases remains a subject of debate. Understanding the mechanisms of lymphatic metastasis offers potential therapeutic targets to mitigate cancer progression.

Lymphatics doi: 10.3390/lymphatics3030016

Authors: Fathima Shehnaz Ayoobkhan Suryakumar Balasubramanian Arindam Bagga Tarun Parvataneni

Introduction: In the past decade, chimeric antigen receptor T-cell therapy (CAR-T) has revolutionized the treatment of relapsed refractory multiple myeloma (RRMM) and lymphoma, but it is associated with significant cardiovascular adverse effects. We aim to analyze the incidence, patterns, and outcomes of cardiac events in RRMM and lymphoma patients undergoing CAR-T therapy utilizing the FDA Adverse Event Reporting System (FAERS) database, paving the way for future research and being more vigilant in treating high-risk populations. Methods: We conducted a retrospective post-marketing pharmacovigilance inquiry using the FDA Adverse Event Reporting System (FAERS) database and the Medical Dictionary for Regulatory Activities (MEDRA). We examined the adverse effects associated with CAR-T and TCE since their FDA approval in US and non-US populations (accessed 5 January 2024), and we analyzed the incidence of cardiac events related to six CAR-T products: Idecabtagene vicleucel, Ciltacabtagene autoleucel, Axicabtagene ciloleucel, Tisagenlecleucel, Lisocabtagene maraleucel, and Brexucabtagene autoleucel since FDA approval. Cardiotoxicities were assessed, including coronary artery disease (CAD), myocardial infarction (MI), arrhythmia, heart failure, and hypotension. Results: Out of 12,949 adverse events, we identified 675 (5.2%) cardiac events irrespective of severity. Almost 440 (65%) cardiac events were associated with cytokine release syndrome (CRS). The most common cardiotoxic event was atrial fibrillation (122), followed by the development of heart failure (113), ventricular arrhythmia (108), hypotension (87), and bradyarrhythmia (41). The mortality rate was highest among Brexucabtagene autoleucel recipients (n = 26, 2.3%), followed by Tisagenlecleucel (n = 71, 2.1%) and Lisocabtagene maraleucel (n = 10, 2.1%). Conclusions: CAR-T therapy can result in fatal adverse events due to its cardiotoxic properties. Timely monitoring, such as screening echocardiography and electrocardiograms, can help identify the at-risk population and allow for early intervention—particularly in patients with high baseline cardiovascular risk or previous exposure to cardiotoxic agents—thereby improving outcomes by enabling risk stratification and supportive management.

Lymphatics doi: 10.3390/lymphatics3030015

Authors: Shahnur Ahmed Angad Sidhu Luci Hulsman Chilando M. Mulenga Aladdin H. Hassanein

Breast cancer-related lymphedema (BCRL) is the most common cause of secondary lymphedema in the Western world and occurs in up to one-third of breast cancer survivors following axillary lymph node dissection (ALND). Compression of the affected limb is a mainstay of therapy. Surgical management of BCRL involves excision of excess fibroadipose tissue and physiologic procedures to improve fluid retention in the limb. Once lymphedema is established, the inflammatory cascade and fibrosis render the disease hard to reverse. The purpose of this review is to elucidate existing management strategies for prevention of breast cancer-related lymphedema. A literature search was conducted using PubMed, Ovid, Embase, and Scopus. Articles that included management strategies for prevention of BCRL were selected for review. Immediate lymphatic reconstruction (ILR) is a microsurgical technique that connects disrupted axillary lymphatic vessels to nearby veins by lymphovenous anastomoses at the time of ALND and has been shown to reduce rates of lymphedema from 30% to 4–12%. BCRL remains incurable. Immediate lymphatic reconstruction has emerged as a preventative strategy to reduce rates of lymphedema in breast cancer patients.

Lymphatics doi: 10.3390/lymphatics3020014

Authors: Anthony McLoughlin Matthew J. Rees

The management of multiple myeloma (MM) in the elderly is challenging, exacerbated by age-related frailty and comorbidities. T-cell engagers (TCE) have been transformative to the treatment of relapsed MM, achieving deep and durable responses. This review evaluates the efficacy, toxicity, and other practical applications of approved and emerging TCEs in elderly MM patients. Broadly, approved monotherapy with TCEs produce overall response rates (ORR) of 60–70% in extensively treated populations. However, deeper and more durable responses have been observed with use in earlier lines of therapy or combined with conventional treatments. Cytokine release syndrome (CRS) and infection are the cardinal toxicities of TCEs. While CRS tends to be less severe than that observed with cellular immune therapies such as chimeric antigen receptor T-cell (CAR-T), the rate of severe infections appears to be higher, especially with BCMA-directed products, and strategies to mitigate this risk are being actively evaluated. TCEs offer logistical advantages over other cellular therapies, namely their off-the-shelf availability and simplified administration. TCEs are poised to redefine the care of elderly patients with MM and are being actively evaluated in this setting.

Lymphatics doi: 10.3390/lymphatics3020013

Authors: Masaya Aoki Go Kamimura Aya Harada-Takeda Toshiyuki Nagata Gen Murakami Kazuhiro Ueda

Background: Nodal dendritic cells (DCs) and CD169-positive macrophages, possibly monocyte-derived, cross-present cancer antigens earlier in the proximal node than in the distal node. Methods: We performed immunohistochemical and morphometric analyses to show differences in the distributions of DC-SIGN-, CD68-, and CD169-positive cells in the paratracheal, subcarinal, and hilar nodes from 25 non-small cell lung cancer patients without metastasis. Results: CD169-positive and DC-SIGN-positive cells were colocalized in the subcapsular and paracortical sinuses, whereas CD68-positive, self-renewal alveolar macrophages were present in the medullary sinus. This complementary distribution was more evident in nodes other than hilar nodes. In hilar nodes, the proportion of CD68-positive macrophages usually exceeds 50%. Notably, the proportion of the overlapped cluster between CD169-positive cells and DC-SIGN-positive cells, which likely corresponds to the cross-presentation activity, was almost the same between the hilar and “next-upstream” node (i.e., the paratracheal node for the upper lobe and the subcarinal node for the lower lobe). Monocyte-derived cells occupied a significantly larger area in the hilar nodes of patients with upper lobe cancer than in patients with lower lobe cancer (p = 0.002–0.009). Conclusion: The specific site occupying the lung hilum with collateral vessels seemed to determine the hilar node composite cells.

Lymphatics doi: 10.3390/lymphatics3020012

Authors: Nitya Devisetti Pushti Shah Farrah C. Liu

The lymphatic system, a complex and dynamic network comprising lymphatic vessels, lymph nodes (LNs), and associated lymphoid tissues, plays a pivotal role in regulating interstitial fluid balance and providing immune surveillance across the body. In cancer, however, the lymphatic system often transforms into a pathway for malignant cell dissemination, leading to lymphatic metastasis—a significant step in tumor progression associated with worse patient prognoses. Mechanistically, tumor cells exploit lymphangiogenic pathways to facilitate their entry and spread within the lymphatic network. Key mechanisms in this process include the upregulation of vascular endothelial growth factors C and D (VEGF-C/D), which promote lymphatic endothelial proliferation, vessel dilation, and increased permeability. This review seeks to provide an in-depth examination of the biological mechanisms underpinning lymphatic metastasis, explore its impact on cancer progression, and highlight current and emerging strategies aimed at managing metastatic disease.

Lymphatics doi: 10.3390/lymphatics3020011

Authors: Bruna Yukie Koizumi Marina Rayciki Sotomayor Carolina Coradi Ana Luiza Goulart Starck Anna Will Ribeiro Maikely Bruna Leite Maria Eduarda Pardal Simonato Rafael Gomes Paz Vinicius de Melo Tizzo Stefania Tagliari Longo Geise Ellen Broto Fausto Celso Trigo Carolina Panis

B-type acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. Despite significant advancements in treatment, chemotherapy resistance and relapse remain major challenges to be overcome. Oxidative stress markers, including lipoperoxides, have emerged as potential biomarkers in B-ALL patients under treatment. This study evaluated lipoperoxide levels in the peripheral blood of pediatric B-ALL patients during the induction phase of chemotherapy using high-sensitivity chemiluminescence and analyzed their association with clinical prognostic factors and patient outcomes, including definitive hospital discharge, disease relapse, and patient death. Lower lipoperoxide levels were observed in patients over 10 years old, those who achieved remission and were discharged from the hospital, and those with central nervous system (CNS) involvement. In contrast, significantly higher lipoperoxide levels were found in patients who relapsed, died, or had platelet counts exceeding 50,000/mm3. Receiver operating characteristic (ROC) curve analysis suggests that lipoperoxides may serve as potential biomarkers during the induction phase of chemotherapy, distinguishing B-ALL patients undergoing treatment from those not in treatment (sensitivity: 92.31%; specificity: 71.43%). These findings highlight the potential utility of lipoperoxides as prognostic biomarkers in B-ALL patients.

Lymphatics doi: 10.3390/lymphatics3020010

Authors: Chi Sing Ng

IgG4 is an unusual immunoglobulin (Ig) and is the least component of IgG in humans. It is often asymmetrical and heterobivalent with weak Fc (fragment crystallizable region)-dependent effector function and ineffective complement activation, thus playing an unclear role in immune functions. IgE is an uncommon Ig, being important mostly in allergy and type 2 immunity. There are two rare chronic Ig-related fibroinflammatory diseases, namely IgG4-related disease (IgG4RD) and Kimura disease (KD), characterized by prominent IgG4- or IgE-positive plasma cells in the affected tissues, with or without blood elevations of the same Ig. The etiology of these two Ig-related diseases is unclear, though it appears that the pathogenesis in both is related to polarized Ig heavy chain isotype switching, concomitant with other cellular, cytokine and chemotaxin interactions that culminates in the characteristic pathologic manifestations of inflammation and fibrosis. IgG4RD and KD, despite having overlapping and differing features, may be connected by the similar pathogenetic polarized Ig isotype switching.

Lymphatics doi: 10.3390/lymphatics3020009

Authors: Chi Sing Ng Jilong Qin

Disease eponyms can be confusing, difficult to remember, scientifically non-robust, and lacking in implications on and relationships with cell lineage, histogenesis, and pathogenesis. This review is geared toward revisiting hematolymphoid diseases with eponyms in light of recent advances in technology and science by searching the past fifty years of the literature using Scopus and Google Scholar with the keywords “eponyms, hematolymphoid, diseases, lymphoma, benign, malignant, lymph node, spleen, liver, bone marrow, leukemia”. With advances in science and technology, there is accumulation of information on the morphologic nuances and immunologic, immunophenotypic, and genetic features of various hematolymphoid eponymic diseases, thus shedding light on important issues of etiology and pathogenesis with implications on therapy in various non-neoplastic (Castleman, Evans syndrome Kikuchi–Fujimoto, IgG4-related diseases) and neoplastic (Hodgkin, Burkitt, NK/T-cell lymphomas, dendritic/histiocytic neoplasms, and Sezary syndrome) diseases. This contributes to modern nomenclature, classification, subtyping, prognostication, and discoveries on new treatment strategies of hematolymphoid eponymic diseases.

Lymphatics doi: 10.3390/lymphatics3010008

Authors: Frederic J. Bertino Kin Fen Kevin Fung

The central conducting lymphatics (CCL) and mesenteric lymphatic systems are responsible for lipid absorption, fluid regulation, and protein delivery into the bloodstream. Disruptions in these systems can result in debilitating conditions such as chylothorax, plastic bronchitis, post-operative lymphocele, protein-losing enteropathy (PLE), and chylous ascites. Advances in imaging techniques, including magnetic resonance lymphangiography (MRL), computed tomography lymphangiography (CTL), and fluoroscopic lymphangiography, allow for detailed anatomic and functional evaluation of the lymphatic system, facilitating accurate diagnosis and intervention by interventional radiologists. This review explores the embryology, anatomy, and pathophysiology of the lymphatic system and discusses imaging modalities and interventional techniques employed to manage disorders of the conducting lymphatics in the chest and abdomen. Thoracic duct embolization (TDE), percutaneous transhepatic lymphatic embolization (PTLE), and sclerotherapy are highlighted as effective, minimally invasive approaches to treat lymphatic leaks and obstructions and have shown high success rates in reducing symptoms and improving patient outcomes, particularly when medical management fails. This review seeks to demonstrate how anatomical imaging can facilitate minimally invasive procedures to rectify disorders of lymphatic flow.

Lymphatics doi: 10.3390/lymphatics3010007

Authors: Moyuru Hayashi Takuya Harada Jun Takai Satoshi Uemura Takashi Moriguchi Tomomi Watanabe-Asaka Yoshiko Kawai

The impaired repair of lymphatic vessels after tissue damage is an etiological hallmark of lymphedema. Previously, we demonstrated that lymphatic recanalization after the popliteal lymph node extirpation was delayed in Gata2 heterozygous mice. This impaired lymphatic vessel recanalization in Gata2 heterozygous mice was mitigated by administrating atelocollagen or crossing with heterozygous Gata3 deletion mice. To clarify the potential involvement of Gata3 heterozygosity in collagen gene expression within subdermal tissue, we conducted an RNAseq analysis and found 273 genes with up and 522 genes with down expression in Gata3 heterozygous mice, and these genes were categorized as collagen and extracellular matrix-related genes by GO analysis. We also found that Col6a1, a2, and a3, which compose type VI collagen, underwent a transient but significant upregulation during the lymphatic recanalization process. Histological analysis revealed that the collagen structure in the subdermal tissue exhibited thinner collagen fiber in Gata3 heterozygous deficient mice. These findings suggest that the altered collagen pattern in Gata3 heterozygous mice contributed to the enhanced lymphatic vessel recanalization in Gata2 heterozygous mice. The altered collagen expression pattern might play a role in shaping and maintaining the subcutaneous microenvironment.

Lymphatics doi: 10.3390/lymphatics3010006

Authors: Christian Omar Ramos Peñafiel Adolfo Martínez Tovar Daniela Pérez Sámano Rafael Cerón Maldonado Adán Germán Gallardo Rodríguez Carlos Martínez Murillo Irma Olarte Carrillo

Background/Objectives: The prognosis of acute lymphoblastic leukemia has significantly improved with the incorporation of innovative therapies such as immunotherapy, tyrosine kinase inhibitors, and CAR-T cell-based treatments. Drug resistance, mediated by genes such as ABCB1, has been associated with reduced treatment efficacy in various clinical scenarios. Although measurable residual disease (MRD) is the most reliable tool for monitoring treatment response in acute lymphoblastic leukemia, the relationship between ABCB1 expression and MRD remains unclear. Aims: To evaluate the expression of the ABCB1 resistance gene and explore its potential relationship with measurable residual disease. Methods: Prospective cohort where 57 patients with de novo diagnosis of acute lymphoblastic leukemia were admitted to the Hospital General de México “Dr. Eduardo Liceaga” between 2022 and 2024. Results: A total of 57 patients undergoing chemotherapy-based treatment were included, with a majority being male (n = 30, 52.6%) and a mean age of 32 years (range 18–71 years). Analysis of ABCB1 gene expression revealed that 35.1% (n = 20) had low expression, 40.4% (n = 23) had overexpression, and 24.6% (n = 14) showed absent expression. No statistically significant association was identified between MRD positivity and the presence of the Philadelphia chromosome (p = 0.171, 95% CI) or the ABCB1 high-risk group (high or absent expression) (p = 0.538, 95% CI). Conclusions: Although ABCB1 expression remains a valuable tool for understanding drug resistance in acute lymphoblastic leukemia, this study did not identify a significant relationship with MRD. MRD continues to be the most reliable prognostic factor in chemotherapy-based treatments for acute lymphoblastic leukemia, underscoring its importance in personalized medicine.

Lymphatics doi: 10.3390/lymphatics3010005

Authors: Hira Shaikh Zulfa Omer Koffi Wima Tara Magge Shimul A. Shah Tahir Latif

Post-transplant lymphoproliferative disorder (PTLD) is the most common malignancy in adults who receive solid organ transplantation (SOT), apart from skin cancer. It is a serious and potentially fatal complication of chronic immunosuppression (ISI) in SOT recipients. This report describes a 20-year (2001–2021) clinicopathological experience with 59 PTLD patients at an urban center. The median time from transplant to PTLD was 8.5 years and the most common types of transplants were kidney (41%) and liver (31%). Epstein–Barr encoding region (EBER) was positive in 51% tumors, and 50% patients had Epstein–Barr virus (EBV) viremia at diagnosis. Overall survival (OS) at 1 year and 5 years was 78% and 64%, respectively. OS was significantly (p < 0.05) shorter in males (hazard ratio [HR] 3.7), certain organ transplants (lung HR 10.4; liver HR 3.9 relative to kidney), PTLD diagnosed within 12 months of transplant (HR 4.1), multi-organ involvement at diagnosis (HR 7.1), vitamin D deficiency at diagnosis (HR 4.5), and low serum albumin level at diagnosis (HR 3.6). Our study highlights the prognostic factors of PTLD and corroborates improved PTLD outcomes in the past 20 years.

Lymphatics doi: 10.3390/lymphatics3010004

Authors: Nada Bochor Parshotam Gera

Lymphatic malformations (LMs) are benign, congenital vascular anomalies caused by abnormal lymphangiogenesis during embryology, often presenting as fluid-filled cystic lesions. Though LMs can affect any part of the body except the brain, they primarily manifest in the head and neck or axilla regions of children. With a prevalence of approximately 1 in 4000 births, LMs are commonly diagnosed by age two, with symptoms varying based on lesion location and size. This paper reviews the classification of LMs and discusses the de Serres staging system, which aids in assessing prognosis based on lesion site. Mutations in the (PIK3CA) gene are implicated in most cases, and LMs are also associated with syndromic conditions like Turner and Noonan syndromes. They are diagnosed by ultrasound (USS) or magnetic resonance imaging (MRI), while a histologic analysis can confirm lymphatic origin. Treatment options range from conservative approaches, such as observation, to sclerotherapy, pharmacotherapy, and surgery. Sclerotherapy, particularly with agents like OK-432, bleomycin, and doxycycline, has shown significant efficacy in reducing LM size and symptoms with minimal side effects. Pharmacological therapies, such as sirolimus, that target the mTOR pathway are also increasingly being used, with a good effect on the burden of disease. While surgical excision remains a choice for symptomatic or large lesions, minimally invasive approaches are often preferred due to lower morbidity. Emerging techniques include gravity-dependent sclerotherapy, electrosclerotherapy, alpelisib, everolimus, and Wnt/β-catenin pathway stimulators (e.g., tankyrase inhibitors, porcupine inhibitors). Computational atomistic molecular dynamics (MD) and density functional tight binding (DFTB) techniques may offer an experimental approach to future therapeutic targets. This paper highlights a multidisciplinary approach to LM management, emphasising individualised treatment based on lesion characteristics and patient needs.

Lymphatics doi: 10.3390/lymphatics3010003

Authors: Hanna Terhaar Mohammad Saleem Evan Liu Nabiha Yusuf

Introduction: Studies on the association between immune-mediated disorders and lymphoid disorders have been very limited, especially in diverse populations. The objective of this study is to evaluate the relationship between a variety of immune diseases and lymphoid malignancies. Methods: The NIH “All of Us” database was utilized to perform a cross-sectional analysis between lymphoid disorders and various immune diseases. The adjusted multivariable logistic regression analysis was performed in R to examine the association between lymphoid disorders such as leukemia, lymphoma, and plasma cell neoplasms against a variety of autoimmune diseases. Results: In the study cohort of 316,044 patients, we found significant associations between lymphomas and the aforementioned immune-mediated diseases, with the exception of dermatomyositis and scleroderma. Lymphoid leukemias showed significant associations (p < 0.001) with several autoimmune conditions, including psoriasis, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, and hyperthyroidism. In plasma cell neoplasms, significant associations were found in all but dermatomyositis, scleroderma, vitiligo, and atopic dermatitis (p < 0.001). Conclusions: In this population-level analysis, the majority of immune-mediated diseases were found to be significantly correlated with an increased incidence of lymphoid malignancies. As such, patients diagnosed with immune-mediated diseases should undergo close surveillance and early screening with the goal of early identification and treatment of lymphoid malignancies.

Lymphatics doi: 10.3390/lymphatics3010002

Authors: Hager Hisham El Khatib Kanz Abdulla Layla Khaled Nassar Mariam Gouda Ellabban Andreas Kakarougkas

Multiple myeloma is an incurable hematologic malignancy arising from plasma cells. The uncontrolled growth of monoclonal plasma cells leads to an abnormal overproduction of immunoglobulins. The recommended course of treatment for MM is according to disease progression and responses to therapeutic intervention, highlighting the necessity for multiple treatment options that alleviate different parts of MM. This comprehensive review provides insights into the current treatments and how to take preventative and prognostic measures. In advanced MM, osteoporosis is a common symptom that originates from a lack of regulation in osteoclast activity and bone resorption. Bisphosphonates such as zoledronic acid and pamidronate along with monoclonal antibodies such as denosumab hinder osteoclast function and aid in reducing the risk of fractures in patients with advanced MM. For targeted therapy approaches, proteasome inhibitors impede protein degradation pathways that cause an accumulation of misfolded proteins promoting cancer cell proliferation in patients with MM. CAR-T is another targeted therapy that can utilize T cells to target and isolate MM cells. Overall, this review highlights the frontrunners of treatments for those diagnosed with MM.

Lymphatics doi: 10.3390/lymphatics3010001

Authors: Josefa Oportus Lía Hojman Vicente Gonzalez Claudio Karsulovic

The soluble interleukin-2 receptor (sIL-2R) is a novel biomarker associated with a variety of immune-mediated diseases. It is produced through the proteolytic cleavage of the membrane-bound interleukin-2 receptor α-chain on activated T lymphocytes; hence, its increase reflects T-cell activation and immune dysregulation. Elevated sIL-2R levels are frequently documented in conditions such as rheumatoid arthritis, systemic lupus erythematosus, sarcoidosis, relapsing polychondritis, histiocytosis, hemophagocytic lymphohistiocytosis, lymphomas, and graft-versus-host disease, suggesting a potential role in monitoring disease activity and progression. However, sIL-2R levels may increase in the context of immune response to infections and malignancies, requiring careful interpretation. It is essential to determine whether elevated levels of this marker within specific ranges could suggest a specific entity, due to the implications this may have for the management of patients. This case-based review presents five patients with different immune-mediated diseases, highlighting how these different conditions can present with characteristic ranges of sIL-2R elevation. By integrating clinical findings with sIL-2R measurements, we emphasize the biomarker’s utility in guiding diagnosis, as well as monitoring disease activity and determining prognosis, which can enhance clinical decision-making and patient management in rheumatology and related fields.

Lymphatics doi: 10.3390/lymphatics2040020

Authors: Alejandro Soderini Ignacio Macció Alejandro Aragona Florencia Arrudi Baca Noel Patricio Mollar Vigh

The sentinel lymph node technique in early-stage cervical cancer—when to perform it, its process, as well as the surgical specimen—continues to be a challenge for gynecologists, oncologists, and pathologists in order to plan the therapeutic strategy. The objective of this paper is to describe the state of the art and provide a critical point of view about these topics.

Lymphatics doi: 10.3390/lymphatics2040019

Authors: William Grant Day Jon Heald Sierrah Grigsby Peter Beale Luke Pittman Christin B. DeStefano

Anti-CD19 chimeric antigen receptor (CAR) T-cell and anti-CD20 bispecific antibody therapies (BsAbs) are rapidly moving to earlier treatment lines for patients with B-cell non-Hodgkin lymphoma (B-NHL). The rapid pace of the advancement of these T-cell-engaging therapies is juxtaposed by a lack of a comprehensive understanding of the scope and kinetics of immunodeficiency following these treatments. We review emerging studies detailing the safety and efficacy of CD19 CAR-T and CD20 BsAbs in earlier lines for B-NHL, as well as a discussion of the limited knowledge of immune recovery following these treatments. We integrate the limited consensus prevention and management recommendations, advocating that the management of secondary immunodeficiency following these transformative therapies is an urgent unmet need in immune oncology research. A collaboration between hematologists/oncologists and immunologists in the management of these patients is critical to optimize patient care.

Lymphatics doi: 10.3390/lymphatics2040018

Authors: Mohanad Ghonim Mohamed Ghonim Ahmed K. Aly Ernesto Santos Amgad M. Moussa

Lymphatic complications are becoming increasingly identified in cancer patients. Chylous ascites, chylothorax, lymphoceles, and lymphorrhea are common in cancer patients and can occur due to traumatic injury during surgeries or infiltrative effects of the tumors themselves. Recently, some anti-neoplastic medications are also thought to result in lymphatic complications. Management options range from conservative options to minimally invasive interventions, to surgical interventions with no standardized management strategy. Imaging techniques such as dynamic contrast-enhanced magnetic resonance lymphangiography and intranodal computed tomography or fluoroscopic lymphangiography are becoming more valuable in diagnosis and treatment planning. Minimally invasive interventions are rapidly evolving and have become the first-line intervention in most cases. Current research, however, faces limitations due to study design and variability. Standardized reporting and prospective studies are needed to advance the field. This review summarizes some of the latest literature on lymphatic interventions in cancer patients and provides reporting recommendations for future studies on lymphatic interventions.

Lymphatics doi: 10.3390/lymphatics2040017

Authors: Erin N. McGinity William F. Bray Jay W. Granzow

Lymphedema surgeries have been proven effective in treating lymphedema and are not considered experimental or unproven. The medical literature consistently supports the safe and successful use of physiologic drainage lymphedema surgeries such as lymphaticovenous anastomosis (LVA), vascularized lymph node transfer (VLNT), and reductive surgeries such as suction-assisted protein lipectomy (SAPL) when performed by an experienced lymphedema surgery team to treat properly selected patients. Proper integration of lymphedema therapy is critical to achieving successful outcomes. We review effective lymphedema surgeries, their indications, patient selection, and the proper application of surgical treatments to achieve optimal results.

Lymphatics doi: 10.3390/lymphatics2040016

Authors: Justin Wang Robert M. Hoffman Yin Ye Jordan Dillard Sanford H. Barsky

Inflammatory breast cancer (IBC) is characterized by numerous tumor emboli within lymphatics. In a recent study, we observed tumor embolic budding both in vitro and in vivo within lymphovascular spaces and proposed this to account for the plethora of tumor emboli seen in IBC. These observations did not address, however, how lymphovascular invasion is initiated or the mechanisms involved. In the present study, using the well-characterized patient-derived xenograft (PDX), Mary-X, which exhibited florid lymphovascular invasion (LVI) in athymic mice (LVI) as defined by E-cadherin-positive tumor emboli within lymphatic channels distinguished by podoplanin and LYVE1 membrane and Prox1 nuclear immunoreactivities and spontaneous spheroidgenesis in vitro and human cases of IBC which showed similar LVI, we compared laser-captured microdissected emboli from Mary-X and from the cases of human IBC to non-embolic areas. Mary-X and IBC emboli expressed high levels of E-cadherin and no evidence of epithelial–mesenchymal transition (EMT). Mary-X spheroids expressed high levels of VEGF, especially VEGF-C, and stimulated both vascular and lymphatic endothelial haptotaxis. We then transplanted Mary-X serially into green, cyano, red, and nestin-green fluorescing protein (GFP-, CFP-, RFP-, and nestin-GFP) transgenic reporter mice in various combinations. Multicolor murine imaging studies indicated that reporter-labeled stroma initially encircled clumps of tumor cells and then served as a scaffold that supported nestin-GFP-labeled endothelial haptotaxis resulting in encircling lymphangiogenesis, confirmed by dual LYVE1 immunofluorescence. The present studies demonstrate a possible mechanism of a critical step of the tumor emboli formation of IBC.

Lymphatics doi: 10.3390/lymphatics2030015

Authors: Brian N. K. Ruliffson Stephen M. Larson Eleni K. Xhupi Diana L. Herrera-Diaz Catherine F. Whittington

Despite chronic fibrosis occurring in many pathological conditions, few in vitro studies examine how fibrosis impacts lymphatic endothelial cell (LEC) behavior. This study examined stiffening profiles of PhotoCol®—commercially available methacrylated type I collagen—photo-crosslinked with the photoinitiators: Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), Irgacure 2959 (IRG), and Ruthenium/Sodium Persulfate (Ru/SPS) prior to evaluating PhotoCol® permeability and LEC response to PhotoCol® at stiffnesses representing normal and fibrotic tissues. Ru/SPS produced the highest stiffness (~6 kilopascal (kPa)) for photo-crosslinked PhotoCol®, but stiffness did not change with burst light exposures (30 and 90 s). The collagen fibril area fraction increased, and dextran permeability (40 kilodalton (kDa)) decreased with photo-crosslinking, showing the impact of photo-crosslinking on microstructure and molecular transport. Human dermal LECs on softer, uncrosslinked PhotoCol® (~0.5 kPa) appeared smaller with less prominent vascular endothelial (VE)-cadherin (cell–cell junction) expression compared to LECs on stiffer PhotoCol® (~6 kPa), which had increased cell size, border irregularity, and VE-cadherin thickness (junction zippering) that is consistent with LEC morphology in fibrotic tissues. Our quantitative morphological analysis demonstrates our ability to produce LECs with a fibrotic phenotype, and the overall study shows that PhotoCol® with Ru/SPS provides the necessary physical properties to systematically study LEC responses related to capillary growth and function under fibrotic conditions.

Lymphatics doi: 10.3390/lymphatics2030014

Authors: Haneen Al-Maghrabi Ghadeer Mokhtar Ahmed Noorsaeed

Background: Some cases of classic Hodgkin lymphoma (CHL) display similarities to nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) in terms of architecture, leading to potential challenges in diagnosis. However, these difficulties can be overcome by conducting a thorough set of immunohistochemical examinations. Objective: To examine cases of T-cell-rich CHL that closely resemble the diagnosis of NLPHL, specifically pattern D, which can pose challenges in accurately determining the diagnosis even after conducting a thorough immunophenotypic assessment. Materials and methods: Histopathology slides of three cases of T-cell-rich CHL were retrieved and thoroughly examined to assess their clinical, immunomorphologic, and molecular features. Results: We present three cases containing cells that resembled lymphocyte predominant and Hodgkin Reed–Sternberg cells, expressing some B-cell antigens and CHL markers but all were lacking Epstein–Barr virus-encoded small RNA. All three cases were found in a background rich in T-cells with focal remaining follicular dendritic cell meshwork in one case. Only one case had few eosinophils while the other two had no background of eosinophils and plasma cells. Two patients presented with stage IIA and B-symptoms presented in one of them. Two patients were treated with four and six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), respectively. One patient planned to be treated with four cycles of ABVD plus Rituximab therapy. Conclusions: Some cases of Reed–Sternberg cells can show expression of both B-cell and CHL markers. This overlapping characteristic, which has not been extensively discussed in the existing literature, presents a unique challenge for treatment. Further research into these neoplasms may reveal valuable diagnostic and therapeutic implications.

Lymphatics doi: 10.3390/lymphatics2030013

Authors: Yuliya A. Veryaskina Sergei E. Titov Igor B. Kovynev Tatiana I. Pospelova Sofya S. Fyodorova Yana Yu. Shebunyaeva Sergei A. Demakov Pavel S. Demenkov Igor F. Zhimulev

Chronic lymphocytic leukemia (CLL) is the most common human leukemia. The disease is caused by abnormal proliferation and development of lymphocytes and their precursors in the blood and bone marrow (BM). Recent studies have shown that the CLL’s clinical course and outcome depend not only on genetic but also epigenetic factors. MicroRNAs (miRNAs) are involved in the development of hematological tumors, including CLL. The aim of this study is to identify the miRNA expression profile in CLL and determine the role of miRNAs in biological pathways associated with leukemogenesis in CLL. The following samples were used in this study: (1) samples obtained by sternal puncture and aspiration biopsy of BM (n = 115). They included samples from 21 CLL patients with anemia and indications for therapy and 45 CLL patients without anemia and with indications for therapy. The control group for the CLL BM samples consisted of patients with non-cancerous blood diseases (n = 35). (2) Lymph node (LN) samples (n = 20) were collected from CLL patients. The control group for the CLL LN samples consisted of patients with lymphadenopathy (n = 37). All cases were patients before treatment. We demonstrated a significant upregulation of miRNA-34a and miRNA-150 in CLL BM samples (p < 0.05) and downregulation of miRNA-451a in CLL LN samples (p < 0.05). We noted a dynamic increase in the levels of miRNA-150 and miRNA-34a in BM at various stages of tumor progression of CLL. We concluded that a dynamic picture of clinical manifestations of CLL closely correlates with changes in epigenetic characteristics of the tumor. Progression of the lymphoproliferative process and indications for cytoreductive therapy are associated with changes in the miRNA profile generated by cancer cells in different sites of clonal expansion.

Lymphatics doi: 10.3390/lymphatics2030012

Authors: Manlio Ferrarini Davide Bagnara Fabio Ghiotto Franco Fais

Chronic Lymphocytic Leukemia (CLL) is caused by the clonal expansion of CD5+ B lymphocytes in the circulation, peripheral lymphoid organs and bone marrow [...]

Lymphatics doi: 10.3390/lymphatics2030011

Authors: Tae Hyun Kim Sarah R. Adamson Pelicia Lim Kevin Tran Kevin Nguyen Derek Neoh Su Wen Loh Sally Ng

Lymphoedema is a potential adversity following axillary clearance, which is frequently performed in the setting of surgery for breast cancer or cutaneous malignancies of the upper limb. Often underestimated, lymphoedema can lead to debilitating symptoms which may decrease overall health-related quality of life. A retrospective cohort study was undertaken on 73 patients who underwent axillary clearance for breast and cutaneous malignancies from 2011 to 2021 at a tertiary centre in Melbourne, Australia. Bilateral upper limb circumference measurement was used to identify the prevalence of lymphoedema in this population. The lymphoedema quality of life (LYMQOL) questionnaire was used to assess the patient’s quality of life. Of 73 patients, 42 (58%) had lymphoedema; 33 (45%) were clinically detected as part of the study, and 9 were diagnosed with lymphoedema prior to our study. Patients with lymphoedema (n = 42) reported worse scores in all LYMQOL domains and the overall quality of life, but only the ‘appearance’ domain showed statistically significant differences in our cohort. These results demonstrate a substantial post-axillary clearance lymphoedema prevalence, without significant impacts on quality of life.

Lymphatics doi: 10.3390/lymphatics2020010

Authors: Susan Witt Thomas Dieterle Susan Gordon Narelle Campbell Neil Piller

Lymphoedema is a chronic and dynamic condition that requires the investment of time and resources to appropriately manage. It fluctuates in response to illness, activity, and age, as well as in response to environmental conditions. This qualitative study explored the impact of the climate and climatic variations on lymphoedema. Focus groups were completed with patients (n = 12) and therapists (n = 7) to explore, in depth, their experiences of managing lymphoedema throughout the year. The results suggested that heat and humidity definitely alter the severity of lymphoedema, and a range of individual strategies are required in order to control symptoms. Central to effectively managing lymphoedema is the notion that every body is different and every lymphoedema is different, and therefore understanding one’s own body, what it needs, and what resources are available is essential in maintaining lymphoedema in the face of climate change.

Lymphatics doi: 10.3390/lymphatics2020009

Authors: Susan Witt Jesús-Baltasar González-Rubino Rocío Martín-Valero María Jesús Vinolo-Gil Thomas Dieterle

Compression is the cornerstone of treatment for lymphoedema; however, in patients with Stage III lymphoedema that causes a significant alteration of limb shape and size, additional creative problem solving is required in order to find a solution that fits the person, their limb and their personal circumstances. Medical adaptive compression (MAC) systems provide solutions to complex situations. We present two cases of individuals who completed an inpatient rehabilitation stay for intensive treatment of their lymphoedema and were fitted with MAC devices to ensure long-term success.

Lymphatics doi: 10.3390/lymphatics2020008

Authors: Hala Al Kallas Pamela Cooper Shruti Varma Jenna Peplinski Yen-Hong Kuo Brianna Miller Noelle Aikman Mark Eliot Borowsky Ashley Haggerty Karim ElSahwi

Complex atypical endometrial hyperplasia (CAH) carries a high probability of cancer. The intraoperative evaluation of endometrial cancer in cases of CAH has not been reliable. The safety and sensitivity of sentinel lymph node (SLN) sampling has been validated. In our study, we aimed to evaluate the efficacy and safety of SLN sampling in CAH managed by the da Vinci robotic platform. A total of 113 patients with a preoperative diagnosis of CAH were included in this retrospective cohort study. All of them underwent a robot-assisted total laparoscopic hysterectomy and bilateral salpingo-oophorectomy, with 69 patients undergoing SLN sampling. A statistical analysis calculated the probability of cancer, the SLN map rate, and surgical complications. The predictors of cancer were evaluated. Descriptive statistics were used to summarize the results; comparative statistics were used to compare the cohorts; and logistical regression analysis was used to predict the risk. Forty-seven percent of the entire cohort was diagnosed with endometrial cancer. The median age was 63 years in the SLN cohort (N = 69) and 61 in the No-SLN cohort (N = 44) (p = 0.363). The median BMI was 34 Kg/m2 in the SLN cohort and 40 in the No-SLN cohort (p = 0.004). The bilateral SLN map was 92.8%, and the unilateral SLN map rate was 7.2%. There were no grade-3–4 complications in the SLN cohort, and four grade-3–4 complications in the No-SLN group (p = 0.021). A preoperative diagnosis of CAH bordering on or unable to rule out cancer was the only predictor of cancer. Sentinel lymph node sampling has a high map rate and low complications in CAH. We recommend a prospective study investigating the clinical benefit of the procedure.

Lymphatics doi: 10.3390/lymphatics2020007

Authors: Richaela Denlinger Julia H. Smith Joseph Lyle Ian Clapp Chandrika Janumpalli Sydney Amick Malgorzata Simm

The studies of thymic structure were performed predominantly in cohorts of younger individuals. Here, we established a cohort of body donors whose age at the time of death ranged from 57 to 103 to study the relationship between thymic structure and factors that, in the younger subjects, have shown to affect the organ’s anatomy, including the presence of the organ’s capsule, its weight, size of the left and right lobes, and a transverse diameter. We explored the relationships between these thymic parameters and the subjects’ age, sex, and cause of death (COD), asking how the thymus in the elderly differed from the organ’s macro-anatomy in a broader and younger human population, and whether age, sex, COD, and BMI could influence the thymic parameters in the elderly. Our analyses revealed that the thymic size but not thymic weight in the KYCOM cohort differed significantly from the younger individuals. The size of the thymus in males progressively decreased, but in females, the size of the right lobe increased. The encapsulated thymus was detected with a higher frequency in females than males. We found no associations between thymic parameters and the person’s COD, age, or sex. However, the person’s BMI was associated with thymic weight, suggesting that obesity may influence the aging of the immune system.

Lymphatics doi: 10.3390/lymphatics2020006

Authors: Bill S. Majdalany

For centuries, the lymphatic system was a known unknown [...]

Lymphatics doi: 10.3390/lymphatics2020005

Authors: Hyunjoo Lee Shabirul Haque Rashmi Gupta Jonathan E. Kolitz Steven L. Allen Kanti Rai Nicholas Chiorazzi Patricia K. A. Mongini

CLL B cells express elevated pro-survival BCL2, and its selective inhibitor, venetoclax, significantly reduces leukemic cell load, leading to clinical remission. Nonetheless, relapses occur. This study evaluates the hypothesis that progressively diminished BCL2 protein in cycling CLL cells within patient lymph node niches contributes to relapse. Using CFSE-labeled, purified CLL populations known to respond with vigorous cycling in d6 cultures stimulated with TLR9-activating ODN (oligodeoxynucleotide) + IL15, we show that BCL2 protein progressively declines during consecutive cell divisions. In contrast, MCL1 and survivin are maintained/slightly elevated during cycling. Delayed pulsing of quiescent and activated CLL cultures with selective inhibitors of BCL2 or survivin revealed selective targeting of noncycling and cycling populations, respectively, raising implications for therapy. To address the hypothesis that BCL2-repressive miRs (miR15a/miR16-1), encoded in Chr13, are mechanistically involved, we compared BCL2 protein levels within ODN + IL15-stimulated CLL cells, with/without del(13q), yielding results suggesting these miRs contribute to BCL2 reduction. In support, within ODN-primed CLL cells, an IL15-driven STAT5/PI-3K pathway (required for vigorous cycling) triggers elevated p53 TF protein known to directly activate the miR15a/miR16-1 locus. Furthermore, IL15 signaling elicits the repression of BCL2 mRNA within 24 h. Additional comparisons of del(13q)+ and del(13q)−/− cohorts for elevated p53 TF expression during cycling suggest that a documented miR15a/miR16-1-mediated negative feedback loop for p53 synthesis is active during cycling. Findings that robust CLL cycling associates with progressively decreasing BCL2 protein that directly correlates with decreasing venetoclax susceptibility, combined with past findings that these cycling cells have the greatest potential for activation-induced cytosine deaminase (AICDA)-driven mutations, suggest that venetoclax treatment should be accompanied by modalities that selectively target the cycling compartment without eliciting further mutations. The employment of survivin inhibitors might be such an approach.

Lymphatics doi: 10.3390/lymphatics2020004

Authors: Heather Barnhart

The foot and calf muscle pump, collectively known as the venous muscle pump, plays a crucial role in the circulatory system (veins, arteries, and lymphatics), particularly in the return of blood from the lower extremities to the heart. Further, the venous muscle pump is crucial to lymphatic health and essential in chronic edema/lymphedema management. This article will highlight the significance of the venous pump and review the functional anatomy and physiology of the foot and calf, integrating the connection to venous and lymphatic health. The complementary importance of mobility, exercise, and breathing will also be explored.

Lymphatics doi: 10.3390/lymphatics2010003

Authors: Yamna Jadoon Goutham Patil Chandravathi Loke Prarthna V. Bhardwaj

Hodgkin’s lymphoma (HL) is a monoclonal lymphoid neoplasm that is mainly characterized by multinucleated Reed–Sternberg cells on a background of non-neoplastic inflammatory cells. The incidence rate of Hodgkin’s lymphoma is 2.5 new cases per 100,000 people per year (1). Paraneoplastic syndromes are conditions that are related to malignancy; however, they are not a result of tumor invasion or compression of malignant tissues. These paraneoplastic syndromes can occur virtually at any point in the disease course, and paraneoplastic syndromes in HL and their various forms are not well studied. In this review article, we will be discussing paraneoplastic syndromes in general and then delve into specific syndromes seen in HL, followed by a brief discourse regarding their early recognition and timely management.

Lymphatics doi: 10.3390/lymphatics2010002

Authors: Himil Mahadevia Mirdhula Ananthamurugan Kashish Shah Atharva Desai Anuj Shrestha

Anti-CD20 monoclonal antibodies (mAbs) have revolutionized the treatment of lymphomas by improving the survival of patients, particularly in conjunction with chemotherapy. Until recently, the gold standard was based on the utilization of Rituximab (RTX) combined with chemotherapy. With our better understanding of monoclonal antibody (mAb) engineering, anti-CD20 mAb therapy has evolved to enhance clinical outcomes by improving pharmacokinetics, safety, activity and immunogenicity. Efforts to improve the on-targeting CD20 expressed on lymphomas through novel bioengineering techniques have led to the development of newer anti-CD20 mAbs that have accentuated complement-dependent cytotoxicity (CDC), antibody-dependent cell medicated cytotoxicity (ADCC), and/or a direct killing effect. There are several anti-CD20 monoclonal antibodies that have been evaluated for the treatment of lymphomas, some of which are now approved in addition to RTX.

Lymphatics doi: 10.3390/lymphatics2010001

Authors: Bouthaina Dabaja Susan Wu Nicholas J. Short

Radiation therapy is a key contributor to positive outcomes in hematological malignancies. However, this is contingent on minimizing the exposure of critical normal organs. The introduction of computed tomography (CT) for radiation treatment planning and the development of sophisticated dose calculation algorithms has transformed the radiation therapy field and made it possible to transition from conventional involved-field radiation to modern involved-site radiation therapy. Thanks to rapid advances in drug discovery, treatment strategies for many hematological malignancies have evolved to incorporate targeted and cellular therapies, in some cases even allowing the replacement of chemotherapy. As a result, new opportunities have been created for radiation to address relapses after more lines of therapy, identify disease-involving sanctuary sites, and bridge to the subsequent therapy. When considering radiation in patients receiving novel therapies, who may also be more heavily pretreated, respecting the critical and normal structures at all costs is imperative. In this document, we will describe modern techniques used to deliver state-of-the-art radiation therapy and practical considerations to ensure the accurate treatment of the target while avoiding normal organs at risk.

Lymphatics doi: 10.3390/lymphatics1030018

Authors: Paolo Strati Michael T. Spiotto

Radiotherapy and/or chemotherapy have been used for nearly 100 years to treat lymphoma. Recently, immunotherapy has been incorporated into the treatment of lymphomas. Here, we will review both the role of immunotherapy in lymphoma as well as the feasibility of incorporating immunotherapies with conventional lymphoma treatments, especially radiotherapy. Immunotherapy agents include checkpoint inhibitors that target the PD-1/PD-L1 axis, CTLA-4, or CD47. In addition, other immunotherapy agents such as bi-specific antibodies and CD19 CAR-T cell therapy are being implemented in various non-Hodgkin’s lymphomas. Extrapolating from observations in other disease sites and incorporating immunotherapy with conventional treatments of lymphoma, including radiotherapy, may have opposing effects. Radiotherapy may stimulate anti-tumor immune responses that synergize with immunotherapies. In contrast, radiotherapy, as well as chemotherapy, may also induce local and systemic immune dysfunction which reduces the efficacy of immunotherapies. With newer radiation treatment techniques and limited radiation fields, it is likely that the efficacy of immunotherapy can be maintained when included with conventional treatments. Therefore, there remains an unmet need to better understand the role of immunotherapy alone and in combination with current treatments in lymphoma patients.

Lymphatics doi: 10.3390/lymphatics1030017

Authors: Hans Theodor Eich Niklas Benedikt Pepper Michael Oertel

Radiation therapy has been proven to be highly effective in the treatment of lymphoma. With increasing rates of long-term survival, the reduction in toxicity has gained importance. The evolving understanding of the diseases’ biology, as well as technical and conceptual advances, allows for a precise and individualized application of irradiation. Smaller treatment fields and safety margins make it possible to spare healthy neighbouring tissue (organs at risk). The International Lymphoma Radiation Oncology Group (ILROG) has developed several guidelines to optimize radiotherapy treatment in lymphoma patients. Since its introduction in 2013, involved site radiotherapy (ISRT) has been adopted as the standard of care in most treatment regimens in adult lymphoma. This article serves as a summary of the current ILROG guidelines, also considering contemporary developments and possible future directions.