Lymphatics, Volume 4, Issue 2 (June 2026) – 17 articles

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoproliferative disorders arising from mature T-cells and account for approximately 10% of all non-Hodgkin lymphomas. PTCL not otherwise specified (PTCL-NOS) is the most common subtype and is considered a diagnosis of exclusion after other PTCL subtypes have been ruled out. Therefore, PTCL-NOS exhibits extreme heterogeneity in its morphologic features, molecular characteristics, and clinical manifestations. Prognosis in PTCL is dismal with a 5-year overall survival (OS) of 20–30%. Diagnosis can be challenging, and efforts to improve risk stratification and optimize therapeutic management continue to evolve. This review systematically summarizes recent advances in the understanding of the epidemiology, classification, histopathology, diagnosis, and management of PTCL-NOS. We discuss emerging therapeutic options and future directions aimed at improving outcomes for this aggressive disease. Full article

Lymphoid neoplasms such as multiple myeloma (MM), indolent non-Hodgkin lymphoma, and chronic lymphocytic leukemia are increasingly managed as chronic, relapsing conditions characterized by prolonged surveillance, repeated treatment transitions, and cumulative self-management demands. These trajectories expose patients and caregivers to persistent illness uncertainty, fluctuating fear of progression, symptom and comorbidity burden, communication challenges, and treatment-related workload. This theory-informed framework development paper uses an overview of selected psycho-oncological, hematological, nursing, theoretical, and patient-reported outcome literature to propose the LUMINA framework: Longitudinal illness trajectory, Uncertainty fields, Multidimensional symptom and comorbidity load, Information and interaction context, Navigation work and self-management load, and Adaptive outcomes and alignment. LUMINA is intended as a hypothesis-generating conceptual structure to organize clinically relevant domains, clarify potential relationships among uncertainty, symptom burden, communication, navigation work, and adaptive outcomes, and guide future assessment, validation, and intervention research in chronic lymphoid neoplasms. The framework builds on prior theories of illness uncertainty, treatment burden, workload–capacity balance, fear of recurrence/progression, and lymphoma-specific qualitative work on uncertainty management and psychosocial adaptation. Potential research applications include structured assessment, shared decision-making research, and domain-matched supportive-care concepts; however, these applications remain theoretical and require empirical testing. Future studies should evaluate feasibility, acceptability, construct validity, domain overlap, predictive validity beyond quality of life, and the clinical utility of LUMINA-informed research profiles. Until such validation is available, LUMINA should be interpreted as a conceptual model rather than a validated clinical tool or care pathway. Full article

Acute myeloid leukemia (AML) presents significant challenges for CAR T-cell therapy due to its pronounced heterogeneity and the lack of leukemia-specific surface antigens. Frequently targeted antigens, such as CD33, CD123, and CLL-1, are also present on normal hematopoietic progenitors, resulting in on-target, off-tumor toxicity and restricting clinical translation. To address these challenges, logic-gated CAR T-cell strategies have been developed to enable combinatorial antigen recognition. These approaches incorporate engineered circuits, including AND, OR, and NOT gates, as well as synNotch receptors, split-CAR configurations, and inhibitory platforms (iCARs and Tmod), to improve discrimination between leukemic and normal cells. In AML, CAR T-cell efficacy and persistence are further affected by the immunosuppressive bone marrow and lymphoid microenvironment, which involves immune cell trafficking, cytokine signaling, and lymphatic immune regulation. Preclinical studies employing dual-target strategies, such as CD33/CD123 and CLL-1/CD123, have shown improved antileukemic efficacy with reduced hematopoietic toxicity. This review summarizes the molecular principles underlying logic-gated CAR-T systems and examines their translational application in AML. Additionally, it highlights emerging evidence connecting the regulation of lymphatic and immune microenvironments to CAR T-cell persistence, trafficking, and toxicity and discusses future strategies, such as single-cell antigen mapping, computational circuit engineering, and synthetic immune programming, to enhance the precision and clinical feasibility of next-generation AML immunotherapies. Full article

Head and neck lymphedema (HNL) is a common complication of head and neck cancer (HNC) treatment. Surgery and radiation, the backbones of HNC treatment, disrupt lymphatic networks through direct injury and fibrosis, leading to accumulation of lymphatic fluid in interstitial spaces. This causes swelling of external and internal structures, leading to decreased quality of life, cosmetic distress, social withdrawal, and functional deficits such as dysphagia, dysphonia, and reduced cervical mobility. In this narrative review, we provide a broad overview of the pathophysiology, assessment, and prevention of HNL. Key surgical factors include the extent of neck dissection, including specific levels removed. Radiation compounds surgical injury through lymphatic fibrosis in a dose-dependent manner. Emerging radiation de-escalation strategies may reduce HNL, though lymphedema is rarely studied as a trial endpoint. Moreover, assessment of HNL remains challenging due to the absence of a gold standard—patient-reported outcome measures, clinician-reported scales, and instrumental tests each capture distinct components of external and internal HNL. Currently, the cornerstone of HNL treatment is conservative management with complete decongestive therapy, which shows mixed efficacy and does not address internal HNL. Surgical options including lymphovenous anastomosis and vascularized lymph node transfer show early promise but remain limited to case reports and small series. Lymphatic imaging, particularly indocyanine green lymphography, represents a promising emerging modality for guiding personalized treatment planning, though application to the head and neck remains challenging. Ultimately, current management of HNL remains largely reactive, with a noticeable lack of preventative therapies. Future research may benefit from better defining surgical options, including HNL as an endpoint in radiation de-escalation trials, and validate emerging lymphatic imaging techniques in order to improve outcomes for HNC survivors. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article