The study is a retrospective analysis of patients hospitalized between October 2015 and October 2025 whose lymphedema was the initial manifestation of what the authors classify as a paraneoplastic rheumatic syndrome, or PRS. These syndromes arise when an occult malignancy triggers immune-mediated symptoms that mimic rheumatic diseases, through humoral or cellular mechanisms distinct from direct tumor invasion or metastasis. Paraneoplastic polyarthritis, cancer-associated myositis and paraneoplastic vasculitis are recognized examples, but lymphedema as the opening act of such a process had not previously been reported as a series, according to the authors.

The six patients — three men and three women with a median age of 66 years at lymphedema onset — presented with swelling confirmed by lymphoscintigraphy in every case. Three had bilateral lower limb lymphedema, two had involvement of both upper and lower limbs, and one had bilateral upper limb and facial swelling. Crucially, the diagnostic workup excluded the obvious mechanical explanations: venous thrombosis, cardiac, renal or hepatic insufficiency and hypoalbuminemia were ruled out, and imaging and clinical review found no tumor invasion, lymph node compression, thoracic duct obstruction, intravascular tumor occlusion or treatment-related lymphatic injury.

None of the patients had a personal or family history of malignancy. On the rheumatologic side, the initial diagnoses spanned the spectrum of connective tissue disease. Two patients were diagnosed with leukocytoclastic vasculitis, confirmed by skin biopsy; two with undifferentiated connective tissue disease; one with Sjögren's syndrome under the 2002 International Classification Criteria; and one with anti-synthetase syndrome, supported by positive anti-aminoacyl-tRNA synthetase antibodies and a muscle biopsy.

The median interval from the onset of lymphedema to a rheumatic diagnosis was 5.5 months, ranging from one to 22 months — a window during which the true driver of disease remained hidden. Laboratory findings pointed to systemic inflammation in every patient. C-reactive protein was elevated in all six, with a median of 14.9 mg/L, and the erythrocyte sedimentation rate was elevated in four of six, with a median of 38 mm/h.

Antinuclear antibodies were positive in three patients, and two carried anti-ENA antibodies, including anti-SSA/Ro52. One patient tested positive for anti-YARS antibodies, a myositis-specific antibody, while rheumatoid factor and ANCA were negative across the board. Protein-losing enteropathy, documented by scintigraphy in two patients, indicated loss of lymphatic integrity in the ileum and ascending colon, and PET-CT in five patients revealed multiple lymphadenopathies in two — yet without any compressive or obstructive lesion to explain the swelling.

Treatment followed standard rheumatologic practice, and that is where the picture unraveled. All six patients received glucocorticoids, and four additionally received immunosuppressants such as hydroxychloroquine, mycophenolate mofetil, cyclophosphamide or cyclosporine. None achieved durable benefit.

Four showed suboptimal responses from the outset, and two initially improved but then progressed. The median interval from rheumatic diagnosis to therapy failure was just one month, and the median interval from therapy failure to a confirmed cancer diagnosis was also one month. Notably, both patients initially diagnosed with leukocytoclastic vasculitis, and the patient with anti-synthetase syndrome, were ultimately found to have lymphoma.

The authors argue that the lymphedema in these cases was predominantly immune-mediated rather than mechanical. Biopsy-proven leukocytoclastic vasculitis in two patients points to immune injury of capillary and lymphatic endothelium with increased vascular permeability, and the universal elevation of CRP suggests systemic immune dysregulation. The involvement spanned multiple lymphatic compartments — intestinal protein loss, chylous ascites in one patient, and lymphadenopathy on PET-CT — a pattern the authors interpret as widespread lymphatic activation or dysfunction driven remotely by the occult tumor.

In the patient with intravascular large B-cell lymphoma, the absence of any demonstrable vascular or lymphatic obstruction argues against microvascular tumor embolization as the principal mechanism, consistent with the known behavior of that disease, in which fever and systemic inflammation dominate while lymphadenopathy is typically absent. The temporal sequence strengthens the paraneoplastic interpretation: lymphedema appeared first, the rheumatic diagnosis followed, immunosuppression failed, and cancer emerged within weeks. Most telling is what happened when the tumors themselves were treated.

One patient with intravascular large B-cell lymphoma received six cycles of R-CHOP chemotherapy and achieved complete resolution of limb lymphedema; another, with lung adenocarcinoma, underwent surgery alone and saw marked improvement in swollen limbs. By contrast, the remaining four patients fared badly: the patient with gastric adenocarcinoma progressed on oral S-1 and died, the patient with peripheral T-cell lymphoma deteriorated before chemotherapy could begin and died, the NK/T-cell lymphoma patient received two cycles of L-GDP chemotherapy but died of progression, and the second lung adenocarcinoma patient, treated with surgery and immunotherapy, also died. Over follow-up ranging from one to 13 months, two patients improved significantly while four died.

The authors are candid about the limits of their evidence. The study is retrospective, single-center, and includes only six patients with no control group. Lymphedema was not systematically staged before lymphoscintigraphy using standardized tools such as ISL staging, the Stemmer sign or limb volume measurement, and retrospective adjudication relied on available imaging and histopathology — meaning microvascular tumor embolization cannot be entirely excluded, particularly in the intravascular lymphoma case.

With so few cases, the authors stress that the association between lymphedema and malignancy should be read as an important clinical clue rather than a definitive causal relationship. They also note that the link between anti-synthetase syndrome and cancer remains controversial, with some antibodies even proposed as protective; whether the anti-YARS antibody seen in their lymphoma patient heralds a paraneoplastic process is a question for future research. Even so, the clinical message is difficult to ignore.

Lymphedema can be an initial and isolated manifestation of an underlying malignancy operating through immune mechanisms, and a poor response to glucocorticoids or immunosuppressants should prompt a comprehensive workup for occult cancer, including PET-CT, lymphoscintigraphy and biopsy of suspicious lesions, ideally within a multidisciplinary team of rheumatologists, oncologists and lymphatic specialists. As prospective studies with larger cohorts and standardized lymphedema assessment are developed, this small series serves as a warning that swollen limbs with atypical rheumatic features — especially when immunosuppression fails — may be the immune system's first, distorted announcement of a cancer still hiding elsewhere.

Subject of Research: Lymphedema as the initial manifestation of paraneoplastic rheumatic syndromes masking occult malignancies

Article Title: Lymphedema as an initial manifestation of paraneoplastic rheumatic syndromes: a case series of six patients

Article References: Zhang, G.-H., Zhang, L.-L., Jiang, M.-N., Wang, W.-X., Zhong, K.-L., & Wang, Y.-H. (2026). Lymphedema as an initial manifestation of paraneoplastic rheumatic syndromes: a case series of six patients. Frontiers in Oncology, 16, Article 1964817. https://doi.org/10.3389/fonc.2026.1964817

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1964817

Keywords: lymphedema, paraneoplastic rheumatic syndromes, lymphoma, leukocytoclastic vasculitis, anti-synthetase syndrome, Sjögren's syndrome, lung adenocarcinoma, gastric adenocarcinoma, lymphoscintigraphy, immunosuppressive therapy, occult malignancy, case series