Lymphatics, Volume 4, Issue 1 (March 2026) – 16 articles

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article