The lymphatic system serves dual roles in fluid homeostasis and immune surveillance, which functions as a key component of both the circulatory and immune systems. As part of the circulatory network, it maintains tissue fluid balance by draining ~2–4 l of protein-rich interstitial fluid on a daily basis through specialized vessels equipped with intrinsic contractility and unidirectional valves. Concurrently, its immune functions facilitate antigen presentation and lymphocyte trafficking via lymph node filtration (1). Lymphedema, which is pathologically defined as the abnormal accumulation of high-protein interstitial fluid (2), arises from either primary developmental abnormalities or secondary acquired damage. Primary lymphedema typically manifests through genetic mutations affecting lymphatic morphogenesis (2) and is diagnosed via combined lymphoscintigraphy findings and molecular testing (3). Secondary forms are identified via clinical history (including histories of surgery, radiation or filariasis) and imaging evidence of lymphatic obstruction, with CT/MRI indicating characteristic dermal backflow patterns (4–6).

Although the proportion of lymphoma-associated lymphedema in secondary lymphedema is relatively low (7), the association between lymphedema and lymphoma exhibits distinctive clinical features, including rapid unilateral progression, disproportionate truncal involvement and concurrent B symptoms. For the present study, the accumulation of 11 cases over 17 years reflects both the specialization in lymphatic disorders at Beijing Shijitan Hospital (managing >1,200 patients with lymphedema on an annual basis) and improved diagnostic sensitivity via advanced imaging protocols. The present case series addresses a key literature gap, as previous reports lacked standardized diagnostic criteria, of which only 4 out of 19 previous cases documented imaging correlates (Table I) (8–26). These findings establish essential clinical benchmarks to distinguish malignancy-related edema from benign edema.

From May 2007 to December 2024, a cohort of 11 patients suffering from lymphedema (either induced or exacerbated by lymphoma) received treatment at Beijing Shijitan Hospital (Beijing, China). Following the acquisition of approval from the institutional review board [approval no. sjtkyll-lx-2022(058)], a retrospective analysis of these 11 patients was conducted. In the present case report, a cohort of 11 patients diagnosed with lymphedema underwent a series of diagnostic evaluations, including laboratory tests (blood routine examination, blood tumor marker examination), ultrasonography, MRI, CT and radionuclide imaging. The imaging findings involved characterizations of ultrasound-assessed lymph node size (short-axis diameter >10 mm defined as being abnormal), vascularity and soft-tissue edema. CT was used to evaluate lymphadenopathy (axial diameter >15 mm), visceral/organ involvement and tumor masses. MRI was used to characterize soft-tissue infiltration and lymphatic obstruction patterns, as well as to differentiate between edema and neoplastic infiltration. Additionally, bone marrow aspiration and biopsy were performed to corroborate the diagnosis of malignancy (27).

The cohort of 11 patients included 8 men and 3 women. The distribution of lymphedema types included 1 patient with upper extremity lymphedema, 9 patients with lower extremity lymphedema (Fig. 1) and 1 patient with systemic edema. The ages of the patients with lymphoma ranged from 41 to 79 years, with a mean age of 61.0±12.5 years. The interval between the onset of lymphedema and the subsequent diagnosis of lymphoma varied from 1 to 24 months, with a median duration of 7 months. Additionally, these patients presented with various clinical symptoms, including weakness, weight loss, pain, the presence of a mass and lymphadenopathy. A detailed summary of the clinical features of each patient is provided in Table I.

In the present cohort, tumor markers were assessed in 6 patients, with 66.7% (4 out of 6) of the patients exhibiting abnormalities in at least one marker. The distribution of abnormal markers included CA125 (1 patient), urinary Igκ light chain (3 patients), serum β2-microglobulin (1 patient), urinary Igλ light chain (2 patients), serum Igκ light chain (2 patients) and urinary β2-microglobulin (1 patient). Individual patients often presented with multiple marker abnormalities (Table II). Additionally, the prevalence of anemia among patients diagnosed with malignant lymphedema was 45.5% (5 out of 11 patients). Several suspicious lesions were further evaluated via imaging modalities, which yielded positive detection rates of 100.0% for ultrasonography (7 out of 7 lesions), 100.0% for CT (8 out of 8 lesions) and 100.0% for MRI (2 out of 2 lesions). Representative imaging and pathology findings from Case 4 are shown in Fig. 2. Axial chest CT demonstrated a mass adjacent to the mediastinum involving the right lung hilum and upper lobe. Contrast-enhanced CT revealed this mass exhibited heterogeneous enhancement and was contiguous with a larger mediastinal mass, confirming their connection. Whole-body lymphoscintigraphy following foot injection showed mild left lower limb thickening, significant tracer retention at the left foot injection site suggesting impaired lymphatic drainage, and non-visualization (absence of uptake) in the left inguinal, iliac and para-aortic/lumbar nodal basins, indicating lymphatic obstruction in these regions. Histopathological examination of the dissected left supraclavicular lymph node (H&E stain) revealed effacement of nodal architecture with fibrosis, scattered lymph follicles, large cells and histiocyte-like cells. The morphology led to the diagnosis of ‘B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma’.

A total of 11 cases of lymphedema associated with malignant tumors were pathologically verified to have originated from the lymphatic tissue. The present cohort included 8 cases of mature B-cell lymphoma and 3 cases of mature T-cell lymphoma, as detailed in Table I and Fig. 2.

Furthermore, 11 patients underwent tumor and enlarged lymph node resection biopsies. A total of 6 patients were followed up until December 2024. Of note, 2 patients with vascular immune T-cell lymphoma died within 1 year after diagnosis. A total of 3 patients with diffuse large B-cell lymphoma were diagnosed and received chemotherapy (the specific details are unknown). These patients have survived for 7, 10 and 11 years. In addition, 1 patient with lymphoplasmacytic lymphoma has been receiving long-term oral treatment with traditional Chinese medicine (the specific details are unknown) and has survived for 14 years (Table I).

The clinical presentations of lymphoma can vary and a notable number of cases are identified at an advanced stage, which is primarily due to the constraints of existing diagnostic methodologies (28). In certain patients, lymphedema may be the initial manifestation of lymphoma, with lymphedema representing the sole clinical manifestation of lymphoma in certain cases. While no specific molecular biomarkers are universally established for the diagnosis of lymphedema, advancements in imaging and bioimpedance technologies have provided indirect markers for the assessment of lymphatic dysfunction (29,30). For instance, bioimpedance spectroscopy and the tissue dielectric constant are non-invasive tools that quantify extracellular fluid volume and detect subclinical lymphedema with high sensitivity (31). Additionally, serum biomarkers such as β2-microglobulin and urinary immunoglobulins (e.g., Igκ/λ light chains) have been observed in patients with malignancy-associated lymphedema, although these are non-specific and often linked to underlying conditions such as lymphoma (32). Emerging research also highlights the role of inflammatory cytokines (e.g., IL-6 and TNF-α) and lymphangiogenic factors (such as VEGF-C/D) in lymphatic remodeling, which may serve as potential molecular indicators in the future (33). The current study presented a series of lymphoma cases characterized by the presence of lymphedema. The analysis of the present study, in conjunction with previous studies, indicated that lymphedema could represent a potential manifestation of lymphoma, which potentially resulted from lymphatic or venous obstruction.

Previous studies have revealed a notable association between lymphedema and lymphoma, with lymphomas being the most prevalent neoplasms associated with immunodysregulation. It is posited that abnormal lymphoid proliferation may be causally linked to lymphatic stasis (11). Insufficient lymphatic drainage can disrupt the normal trafficking of lymphocytes and Langerhans cells, which are essential for the maintenance of immunocompetence, which leads to an immunologically susceptible state in the lymphedematous region and increases the risks of infection and oncogenesis (34). Several theories have been proposed to elucidate the underlying mechanisms involved in the aforementioned process. Futrell and Myers (35) emphasized the role of the immunological status in determining the response of animal hosts to tumors implanted in the skin, regardless of the integrity of the lymphatic system. Their findings revealed that, although tumor solutions did not induce malignancy when injected into areas with intact lymphatic vessels, malignant tumors developed when injections occurred in regions with compromised lymphatics (35). Furthermore, deficiencies in the lymphatic drainage system may hinder the early detection of tumor-specific antigens (36). Chronic stasis can lead to alterations in the local lymphatic protein composition, which are characterized by a decrease in the α-2 globulin fraction and an increase in the albumin-globulin ratio (37). This delay in protein transport from the interstitial space to the lymphatic space may modify the antigenic composition and/or regional immunological competence of the tissue. The relationship between elevated lymphocyte counts and lymphatic stasis remains complex and context-dependent. While chronic lymphatic stasis can lead to localized immune dysregulation, specific thresholds for lymphocyte proliferation in lymphedema are not well-defined in the literature. However, previous studies have suggested that persistent CD4⁺ T-cell infiltration in lymphedematous tissues contributes to chronic inflammation and fibrosis, which exacerbates lymphatic dysfunction (38). For instance, in cases of malignancy-related lymphedema, tumor-associated lymphocytes may infiltrate obstructed lymphatic pathways, although quantitative percentages are rarely reported. Further research is warranted to establish standardized values that associate lymphocyte counts with stasis severity. Additionally, systemic immunodeficiency or external factors, such as potential carcinogenic viral infections (e.g., HPV infection), may be evaluated and utilized to further elucidate the etiology of tumors (5,39).

In a study of 10 cases of lymphedema associated with lymphoma, Hawkins et al (25) demonstrated that unilateral leg edema was the sole presenting symptom in 7 cases. Similarly, Smith et al (7) reported that among 35 cases of lymphedema attributed to neoplasms, all 8 lymphoma cases presented with palpable inguinal lymph nodes, with 3 cases presenting with edema as the initial manifestation of the condition. Upon the diagnosis of lymphedema, clinicians should maintain a heightened clinical suspicion of lymphoma as a potential underlying cause.

In the present cohort of 11 patients, lymphedema predominantly affected the lower extremities (9 out of 11 patients), with a mean age of 61.0±12.5 years and a median delay of 7 months between lymphedema onset and lymphoma diagnosis. The key clinical manifestations of these patients included limb swelling, weakness, weight loss, lymphadenopathy and pain. These findings align with those of previous studies, such as that by Hawkins et al (25), which reported unilateral leg edema as the sole presenting symptom in 70% of patients with lymphoma-associated lymphedema. Similarly, Smith et al (7) noted that lymphedema secondary to malignancy often manifests acutely and asymmetrically, along with accompanying systemic symptoms such as fatigue and weight loss. Notably, the present case report revealed a greater proportion of lower extremity involvement (81.8%) compared with upper limb involvement (9.1%), which is consistent with a report by Tatnall and Mann (17), which described chronic limb lymphedema as a predisposing factor for non-Hodgkin's lymphoma. The present scenario contrasts with secondary lymphedema caused by breast cancer surgery, where upper limb involvement is predominant.

Lymphoma-induced lymphedema is frequently misdiagnosed initially because of its nonspecific presentation. In the present cohort, 66.7% of patients exhibited abnormal changes in tumor markers (including alterations in CA125 and β2-microglobulin) and 45.5% had anemia, which suggested systemic involvement. Furthermore, imaging modalities (such as CT, MRI and ultrasonography) achieved 100% detection rates for suspicious lesions, which thereby underscores their diagnostic utility. However, the case reported by González-Vela et al (11) was extremely prone to misdiagnosis: an 89-year-old male presented with multiple cutaneous lesions on his right limb, manifesting as chronic lymphedema. Upon skin examination, multiple purplish red, firm, slightly infiltrated nodules were found on his legs and instep of his foot. Biopsy of one of the nodules revealed a diffuse large B-cell lymphoma of the leg. CT scans of the patient's chest, abdomen, and pelvis did not show signs of lymph node enlargement. Bone marrow aspiration and biopsy results were normal. The patient underwent local radiotherapy and achieved significant clinical remission. The differentiation of lymphoma-associated lymphedema from lymphedema of other etiologies requires a comprehensive evaluation of the clinical presentation, imaging findings, biomarkers, pathological mechanisms and therapeutic responses. In our research, we found that lymphoma-induced lymphedema typically manifests with insidious, asymmetric lower extremity swelling (81.8% of cases) occurring over weeks to months, which is often accompanied by systemic symptoms such as weight loss, fever or lymphadenopathy. In addition, patients may exhibit acute-onset skin pigmentation changes or localized neuropathic symptoms, which represent features that are distinct from acute unilateral swelling with tenderness/cyanosis (which occurs in venous edema) or bilateral symmetry (which occurs in systemic causes such as heart failure). Additionally, imaging serves a key role. Specifically, the use of CT/MRI in lymphoma can reveal tumor-obstructed lymphatic pathways or malignant lymphadenopathy, whereas the use of positron emission tomography-CT can identify hypermetabolic lesions, which contrasts the venous duplex findings of thrombosis observed in venous edema or the hypoalbuminemia-driven fluid shifts observed with systemic causes. Furthermore, elevated serum biomarkers (such as β2-microglobulin and CA125) are observed in 66.7% of patients with lymphoma, which further distinguishes lymphoma from hypoproteinemia (low albumin levels) or a venous etiology (elevated D-dimer levels). Pathologically, lymphoma disrupts lymphatic integrity via direct tumor infiltration or cytokine-mediated dysfunction, which thus creates an immunocompromised microenvironment, whereas primary lymphedema stems from congenital lymphatic malformations. Therapeutically, lymphoma-associated edema responds poorly to conventional compression therapy and requires tumor-directed interventions (such as chemotherapy or radiotherapy), unlike venous edema (which is anticoagulation-responsive) or primary lymphedema (which is partially improved by using decongestive therapy). Notably, lymphoma rarely induces systemic edema, which is a feature that is absent in postoperative or primary lymphedema and thereby underscores the importance of screening for malignancy in atypical presentations (40,41).

In conclusion, based on the retrospective analysis of 11 patients with lymphoma presenting with lymphedema at our institution, this case series establishes that lymphedema frequently serves as an early and occasionally isolated manifestation of lymphoma, particularly affecting the lower extremities with asymmetric progression. Key findings include a median diagnostic delay of 7 months, frequent systemic biomarkers and universal detection of malignant lesions by cross-sectional imaging (CT/MRI/ultrasonography). Critically, lymphoma-induced lymphedema demonstrates poor response to conventional decongestive therapy but shows significant improvement with tumor-directed interventions (chemotherapy/radiotherapy). These observations underscore that unilateral lower limb edema-particularly when acute, therapy-refractory or accompanied by unexplained serologic abnormalities-warrants rigorous screening for occult lymphoma. Integrating targeted imaging and biomarker assessment into the diagnostic workflow is essential to reduce delays in lymphoma diagnosis and initiate timely oncologic management, thereby altering the natural history of this potentially misdiagnosed condition.