Rare Lymph Node Disorder Masqueraded as Cancer Spread in Breast Cancer Survivor

A 38-year-old woman who had already survived triple-negative breast cancer and a rare soft tissue tumor called angiomatoid fibrous histiocytoma faced a frightening possibility when new lymph nodes swelled in her neck: the cancer had returned. Instead, clinicians at the First Affiliated Hospital of Shandong First Medical University in Jinan, China, discovered something far less expected. Biopsy of a cervical lymph node revealed plasma cell-type Castleman disease, a rare lymphoproliferative disorder that can closely imitate metastatic cancer on scans. The case, published as a case report in Frontiers in Oncology, illustrates why newly detected lymphadenopathy in patients with complex oncological histories should never be presumed to be tumor recurrence or metastasis on the basis of imaging alone.

The patient’s medical history was itself unusual. She had been treated for left-sided triple-negative breast cancer with modified radical mastectomy and axillary lymph node dissection, followed by eight cycles of adjuvant chemotherapy and 25 fractions of radiotherapy. Because the initial treatment took place at another institution, the detailed chemotherapy regimen could not be retrieved. During seven years of routine postoperative surveillance, no local recurrence or distant metastasis was ever identified, and she reported no significant family history of malignancy or hereditary cancer-related conditions. Genetic counseling and germline testing were not performed during the current evaluation, so any potential hereditary predisposition remains unknown.

Seven years after her breast cancer surgery, a soft tissue mass in the left post-occipital region was excised at another hospital and diagnosed as angiomatoid fibrous histiocytoma, or AFH, a rare intermediate soft tissue tumor characterized by recurrent EWSR1-related gene rearrangements. Detailed surgical information about that lesion was unavailable. Roughly one year after the AFH excision, the patient noticed enlarged lymph nodes on the left side of her neck and sought medical attention. Imaging revealed multiple enlarged lymph nodes in the left cervical region together with newly detected nodular abnormalities in the left post-occipital area, all distributed within the same ipsilateral head and neck lymphatic drainage region. The nature of these lesions could not be determined from imaging alone.

Based on physical examination and ultrasonographic evaluation, the team selected the most prominent left level II cervical lymph node for excisional biopsy. Intraoperative frozen-section analysis showed no evidence of malignancy and did not support lymph node metastasis from breast cancer. Definitive histopathological examination then demonstrated abnormal lymph node architecture, with atypical lymphoid follicle formation and prominent interfollicular plasma cell proliferation. Immunohistochemical staining showed that CD3 and CD20 highlighted the T-cell and B-cell components respectively, while CD21 demonstrated the follicular dendritic cell network and CD38 marked increased plasma cell components. Both kappa and lambda light chains were expressed, indicating polyclonal rather than malignant plasma cell proliferation, and in situ hybridization for Epstein-Barr virus-encoded RNA was negative. The diagnosis was plasma cell-type Castleman disease.

To define the full extent of disease and assist classification, the patient underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography. The scan confirmed multiple nodal lesions in the left cervical and left post-occipital regions, with increased tracer uptake in some lesions, ranging from an SUVmax of 2.9 to 13.3. Critically, no definite abnormal lymphadenopathy was identified in the thorax, abdomen, or pelvis, suggesting the abnormalities were confined to the left head and neck drainage region. An ultrasound-guided core needle biopsy was then performed on a newly detected, metabolically active left post-occipital lymph node with an SUVmax of 13.3, a lesion distinct from the previously excised AFH mass. No AFH-like tumor component was found in the sampled tissue, and the histopathology showed Castleman disease-related changes concordant with the cervical node findings.

Laboratory and clinical evaluation added important context. The patient had no B symptoms such as fever, night sweats, or weight loss, and no skin rash, dyspnea, or peripheral neuropathy. Her complete blood count showed no anemia, thrombocytopenia, or leukocytosis. C-reactive protein was mildly elevated at 19.6 mg/L against a reference range of 0 to 3.48 mg/L, and serum interleukin-6 was increased at 29.448 pg/mL against a reference range of 0 to 9.99 pg/mL. Serum protein electrophoresis showed a mild increase in the gamma-globulin fraction without significant monoclonal immunoglobulin proliferation. Epstein-Barr virus DNA was undetectable, HIV markers were negative, serum IgG4 levels were normal, and autoimmune antibody testing showed no significant abnormalities. Given the regional lesion distribution, the absence of overt systemic inflammatory syndrome or multiorgan involvement, and these laboratory findings, the disease was classified as unicentric Castleman disease rather than multicentric disease.

The distinction matters because the two forms differ biologically. In multicentric Castleman disease, particularly the idiopathic form, systemic cytokine dysregulation is a prominent feature, with interleukin-6 contributing substantially to inflammatory manifestations in many patients. Unicentric disease is generally localized, and its pathogenesis remains incompletely understood. Increasing evidence points to abnormalities of the local lymph node stromal microenvironment, particularly involving follicular dendritic cells and other stromal cells, and recurrent activating PDGFRB mutations have been identified in CD45-negative stromal cells in a subset of unicentric cases. Although interleukin-6-related inflammatory abnormalities can occur in a minority of unicentric patients, especially those with plasmacytic histopathology, systemic inflammatory activity is generally less prominent than in multicentric disease, which fit this patient’s mild CRP and interleukin-6 elevations without systemic illness.

The relationship, if any, between AFH and Castleman disease remains speculative. AFH may exhibit prominent lymphoplasmacytic inflammation, and a subset of cases, particularly those harboring the EWSR1-CREB1 fusion, has been associated with excessive interleukin-6 production and paraneoplastic inflammatory manifestations. Rare reports have described Castleman-like lymph node changes in association with AFH; notably, an early case documented plasma cell-type Castleman-like lymphadenopathy that regressed substantially after resection of the primary AFH, supporting a reactive process, while a later report described true coexistence of the two entities. These observations suggest a possible cytokine-mediated or immune-related overlap, but no direct molecular link between AFH-associated EWSR1 rearrangements and Castleman disease has been established. The authors emphasize that the occurrence of unicentric disease after AFH in this patient should be regarded as an uncommon clinical observation rather than evidence of causation, and they note that the contribution of previous AFH-associated immune changes cannot be completely excluded because longitudinal pathological information about the original tumor was unavailable.

Management was individualized rather than dictated by default guidelines. Although complete surgical excision is the preferred treatment for resectable unicentric Castleman disease and may provide definitive disease control and long-term remission, the lesions in this patient involved multiple lymph nodes within the same left head and neck drainage region rather than a single isolated mass. Complete removal would have required more extensive surgery with potential additional morbidity. Given the absence of systemic inflammatory manifestations, organ involvement, or radiological progression, the team chose close surveillance, including regular clinical assessment, laboratory monitoring with complete blood count, liver and renal function, serum albumin, C-reactive protein, and interleukin-6 when necessary, plus contrast-enhanced CT or PET/CT to track lesion size, distribution, and metabolic activity. After six months of follow-up, the patient remained clinically stable with no radiological progression or newly developed systemic inflammatory manifestations, and long-term surveillance was planned with intervals adjusted to her condition.

The authors acknowledge important limitations. As a single case report, the study cannot establish any causal or biological relationship among angiomatoid fibrous histiocytoma, triple-negative breast cancer, and Castleman disease. The original AFH records, slides, and molecular data were unavailable, so the completeness of excision and margin status could not be assessed. The post-occipital lesion was sampled by core needle biopsy, meaning a very small focus of AFH in unsampled tissue cannot be excluded with absolute certainty. Detailed information about the previously treated breast cancer was unavailable, germline testing was not performed, and the ancillary work-up was incomplete: no quantitative kappa/lambda ratio, no tissue IgG4/IgG immunostaining, and no testing for human herpesvirus 8. Longer-term follow-up and additional well-documented cases will be needed to clarify the clinical course in this setting. Still, the central lesson stands: in patients with complex oncological histories, new lymphadenopathy demands careful integration of histopathology, lesion distribution, laboratory results, and clinical context before it is attributed to cancer recurrence.

Subject of Research: Unicentric Castleman disease mimicking metastatic lymphadenopathy in a patient with prior triple-negative breast cancer and angiomatoid fibrous histiocytoma

Article Title: Case Report: Unicentric Castleman disease mimicking metastatic lymphadenopathy in a patient with a history of triple-negative breast cancer and angiomatoid fibrous histiocytoma

Article References: He, M., Fu, J., & Wang, H. (2026). Case Report: Unicentric Castleman disease mimicking metastatic lymphadenopathy in a patient with a history of triple-negative breast cancer and angiomatoid fibrous histiocytoma. Frontiers in Oncology, 16, Article 1985669. https://doi.org/10.3389/fonc.2026.1985669

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1985669

Keywords: Castleman disease, unicentric Castleman disease, triple-negative breast cancer, angiomatoid fibrous histiocytoma, metastatic lymphadenopathy, lymphoproliferative disorders, PET/CT imaging, histopathology, interleukin-6, EWSR1 rearrangement, differential diagnosis, case report