Diagnostic delay and histopathological subtyping challenges in idiopathic multicentric Castleman disease, not otherwise specified: a case report of a three-hospital odyssey.

BACKGROUND: Castleman disease (CD) is a group of rare and heterogeneous lymphoproliferative disorders. Accurate diagnosis and subtyping remain challenging. This report describes a rare case of idiopathic multicentric Castleman disease, not otherwise specified (iMCD-NOS), highlighting the causes of misdiagnosis, diagnostic strategy, and critical features of clinical subtyping.

CASE PRESENTATION: A 53-year-old male presented with a 4-month history of persistent right submandibular lymphadenopathy. During this period, he experienced two febrile episodes (max temp 39.0 °C), each lasting 2 days, without associated respiratory symptoms. The fever resolved following intravenous antibiotic therapy at a local hospital, however, the lymphadenopathy did not improve and progressively enlarged. Core needle biopsy of the right submandibular lymph node at another municipal hospital revealed acute and chronic inflammation with fibrosis. He also reported occasional low-grade fever and night sweats, prompting admission to our hospital for further evaluation. On admission, physical examination revealed the largest lymph node measuring approximately 2.5 × 2.0 cm and purplish-red papules on the bilateral lower extremities. Laboratory findings revealed leukocytosis, eosinophilia, platelet (PLT) count: 296 × 109/L (Normal), elevated C-reactive protein (66.31 mg/L), and increased interleukin-6 (13.78 pg./mL). PET-CT demonstrated metabolically active lymphadenopathy involving the bilateral cervical, submandibular, supraclavicular, retroperitoneal, and pelvic regions, suggestive of a neoplastic process. Under general anesthesia, an excisional biopsy of a right cervical lymph node was performed. Histopathological examination revealed disrupted lymph node architecture, with the presence of both atrophic and hyperplastic follicles. A subset of follicles showed an "onion-skin" appearance, accompanied by hyaline degeneration of small vessel walls in the paracortical region. The borders between the paracortex and lymphatic sinuses were indistinct, and proliferation of lymphocytes and plasma cells was observed in the sinus areas. Immunohistochemistry demonstrated CD38 positivity in the cortex and medullary sinuses, CD138 positivity in the cortex and paracortex, as well as positive staining for IgG4 and IgG. The pathological diagnosis was mixed-type Castleman disease. In the light of the patient's multicentric lymph node involvement, systemic inflammatory symptoms, elevated inflammatory markers, and the exclusion of HHV-8 infection as well as features suggestive of TAFRO or IPL, a final diagnosis of iMCD-NOS was made. Given the rarity of the disease and the limited experience with its management in our department, the patient was referred to the Department of Hematology at Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. Following treatment with siltuximab plus prednisone, the patient's symptoms improved markedly, with resolution of fever and no recurrence of submandibular or cervical lymphadenopathy.

CONCLUSION: This case illustrates the diagnostic challenges of idiopathic multicentric Castleman disease-not otherwise specified (iMCD-NOS) and underscores the importance of excisional biopsy over core needle biopsy, systematic exclusion of differential diagnoses, and multidisciplinary collaboration. The patient's journey through three hospitals before diagnosis offers three key lessons for clinicians: (1) The possibility of Castleman disease should be considered when a triad of unexplained lymphadenopathy, systemic symptoms, and elevated inflammatory markers is present. (2) When multicentric lymphadenopathy coexists with systemic inflammation, excisional biopsy-rather than core needle biopsy-is essential for an accurate diagnosis. (3) Systematic exclusion of HHV-8 infection, TAFRO/IPL features, and other mimickers is mandatory for proper iMCD-NOS subtyping. Enhanced awareness of this disease, as provided by this report, may facilitate early recognition and reduce diagnostic delays.