Lymphatics, Volume 3, Issue 3 (September 2025) – 14 articles

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article