A 55-year-old woman of East Asian ancestry presented with fever, drenching night sweats, 15 kg of unintentional weight loss over an 8-month period. CBC showed anemia with an Hb of 58 g/L (ref 115–165 g/L) with normal leukocyte and platelet counts of 7.3 × 109/L (ref 4–11 × 109/L) and 204 × 109/L (ref 150–400 × 109/L), respectively. HIV, Hepatitis B and C, CMV and EBV serology were negative, and esophagogastroduodenoscopy and colonoscopy were normal. On admission to hospital, computed tomography imaging demonstrated splenomegaly (18.7 cm) and enlarged retroperitoneal lymphadenopathy measuring up to 2.1 by 3.4 cm. Laboratory investigations demonstrated a normal lactate dehydrogenase (LDH) level at 127 U/L (ref 100–250 U/L), elevated C-reactive protein (CRP) of 85 mg/mL (ref < 5 mg/mL) and erythrocyte sedimentation rate (ESR) of 90 mm/h (ref 0–35 mm/h), serum ferritin 1150 ug/L (ref 20–400 ug/L), and polyclonal elevation of IgG 30.29 g/L (ref 6–16 g/L). Immunoglobulin subclasses demonstrated mildly elevated serum IgG4 level of 1.1 g/L (ref 0.039–0.864 g/L). Rheumatoid factor, anti-nuclear antibody (ANA), ANCA, and cryoglobulins were negative, and C3 and C4 levels were normal at 1.53 g/L (ref 0.8–1.8) and 0.35 g/L (ref 0.1–0.5 g/L) respectively. Vascular endothelial growth factor (VEGF) was 156 pg/mL (ref ≤ 96.2 pg/mL) and interleukin-6 (IL-6) was 241 pg/L (ref < 3.7 pg/mL). An initial bone marrow biopsy revealed a mildly hypercellular marrow with erythroid predominance and atypical paratrabecular lymphohistiocytic aggregates with focal MF-1 fibrosis in the paratrabecular areas. Megakaryocytes were not increased and demonstrated a normal interstitial distribution without clustering. Morphologically, megakaryocytes were unremarkable with no atypical or dysplastic forms identified. No increase in blasts or clonal lymphoid populations was noted, cytogenetics were normal, and a myeloid next generation sequencing panel was negative for any variants. Congo red staining for amyloid deposition was negative. Ancillary testing including special stains for AFB and fungal microorganisms (GMS, PAS-D, Giemsa) was negative, and EBV was negative by EBER ISH. No increase in IgG or IgG4 positive plasma cells was noted and HHV8 staining was negative. A percutaneous core retroperitoneal lymph node biopsy performed at the time was most consistent with a polymorphous lymphocytic infiltrate with no significant atypia. Molecular diagnostics for B cell clonal rearrangements were negative, and HHV8 was negative by LANA immunohistochemistry. On positron emission tomography-computed tomography (PET-CT) from initial presentation, the areas of sampled retroperitoneal adenopathy were FDG avid (SUV max of 17.0) and no hypermetabolic activity was noted in the enlarged spleen. The differential diagnosis included lymphoma, idiopathic multicentric Castleman disease (iMCD), immunoglobulin G4-related disease (IgG4-RD), and a histiocytic neoplasm. Two months later, she was readmitted to hospital with progressive splenomegaly now measuring up to 21 cm and associated left upper quadrant abdominal pain. A repeat bone marrow biopsy was performed which showed normocellular trilineage hematopoiesis without evidence of a lymphoproliferative disorder, plasma cell neoplasm, or increased blasts. Megakaryocytes were present in normal numbers with appropriate maturation and a normal distribution pattern, without clustering or dysplastic features. No fibrosis was noted on the repeat bone marrow biopsy. Over the following months, she experienced partial clinical, laboratory, and radiologic improvement without any systemic therapy. However, 1 year later, she re-presented with recurrent fatigue and severe anemia (Hb 57 g/L). Repeat PET-CT showed resolution of the previously avid retroperitoneal lymph nodes, but new FDG-avid aortocaval and supradiaphragmatic lymph nodes (SUVs ranging from 2.7–5.5), along with progression of sclerotic bone lesions. Her inflammatory markers including CRP (90.4 mg/L) and IL-6 (91.4 pg/mL) were again elevated. She developed transfusion-dependent anemia and persistent fevers as high as 39°C at home. An endobronchial ultrasound of the PET avid mediastinal lymph nodes and bronchial alveolar lavage were negative for malignant cells. She underwent diagnostic splenectomy and an excisional biopsy of a common hepatic artery lymph node. The enlarged spleen showed preserved architecture with discrete follicles containing regressed germinal centers, occasional sclerotic eosinophilic material, and intact CD21+ dendritic cell meshwork. The red pulp was expanded with vascular congestion, abundant CD68+ histiocytes with focal S100+ staining, scattered polytypic plasma cells, small CD3+ and CD5+ T-cells, occasional megakaryocytes, and two foci of trichrome-confirmed fibrosis. The common hepatic artery lymph node showed preserved architecture with discrete germinal centers and expanded sinuses containing CD68+ histiocytes (Figure 1A,B). Interfollicular and sinusoidal regions contained aggregates of CD138+ and MUM1+ polytypic plasma cells without light-chain restriction, and focal atrophic follicles with penetrating vessels and concentric marginal zones were present (Figure 1C,D). Immunohistochemistry confirmed polytypic kappa and lambda expression (Figure 1E,F) and showed IgG4-positive plasma cells and diffuse IgG positivity (Figure 1G,H). Stains for PASD, ZN, CD1a, and HHV8 were negative, and flow cytometry demonstrated no evidence of a lymphoproliferative disorder. With respect to iMCD histopathologic features, there were moderately increased regressed germinal centers (2/3), mild follicular dendritic cell predominance (1/3), mild vascular proliferation (1/3), moderately increased hyperplastic germinal centers (2/3), and moderately increased plasmacytosis (2/3) 1. Considering the combination of relapsing–remitting systemic inflammatory symptoms, anemia, polyclonal hypergammaglobulinemia, elevated IL-6, lymphadenopathy with Castleman-like follicles, and polyclonal plasmacytosis, the overall picture was most consistent with idiopathic multicentric Castleman disease-idiopathic plasmacytic lymphadenopathy (iMCD-IPL). The iMCD-IPL subtype of Castleman Disease is the hypergammaglobulinemia-dominant subtype of iMCD, presenting with subacute or chronic multicentric lymphadenopathy, anemia of inflammation, severe polyclonal hypergammaglobulinemia, normal or elevated platelets, and systemic inflammation with preserved organ function, driven by cytokine-mediated B-cell and plasma-cell activation 2. Although originally described predominantly in East Asian populations, it has become increasingly recognized in North America and Europe 2-4. First-line therapy for iMCD, including the IPL subtype, is IL-6 targeted therapy with siltuximab in the Western hemisphere, and tocilizumab in Japan 2, 5. Histopathologically, iMCD-IPL is characterized by expanded interfollicular zones containing dense, CD138+ sheets of mature plasma cells with plasmacytosis, accompanied by hyperplastic germinal centers 2, 3, 6. IL-6 immunostaining frequently highlights strong cytokine production within the interfollicular plasma cell infiltrates, supporting the IL-6-driven inflammatory characteristic of the disease 6. Increased IgG4-positive plasma cells may also be present, sometimes meeting thresholds for IgG4-RD 2. Recent spatial proteomic and single-nucleus transcriptomic analyses demonstrate that activated follicular dendritic cells and fibroblastic reticular cells secrete IL-6 and VEGF, driving B-cell activation, plasma cell differentiation, and stromal remodeling in iMCD 7. In addition, a recent study has shown that IL-6 in iMCD-IPL originates from plasma cells in lymph nodes, in contrast with the thrombocytopenia, anasarca, fever/reticulin fibrosis, renal dysfunction, organomegaly subtype of iMCD (iMCD-TAFRO), wherein the IL-6 originates from vascular endothelial cells 8, 9. Collectively, these features highlight the cytokine-driven, polyclonal nature of iMCD-IPL and suggest a predominantly microenvironment-mediated process arising from dysregulated stromal and endothelial cell signaling 10. After a clinicopathologic diagnosis of iMCD-IPL was confirmed, the patient was initiated on treatment with anti-IL6 blockade with Siltuximab at a dose of 11 mg/kg IV every 3 weeks. They experienced marked clinical and laboratory improvement on Siltuximab. Repeat abdominal imaging 3 months into treatment did demonstrate slight interval improvement in a marker lymph node to 1.2 from 1.5 cm, while hepatomegaly remained unchanged. Their energy levels improved, weight increased by 7 kg, hemoglobin improved from 87 to 127 g/L, and CRP normalized to 4.5 mg/mL within 12 weeks of treatment start; IgG and albumin levels subsequently normalized to 14.6 and 48 g/L, respectively. Treatment has been tolerated well with no significant adverse effects apart from hypertriglyceridemia managed with fibrate therapy. This case highlights the diagnostic challenge posed by iMCD-IPL, particularly when clinical and radiologic features evolve over time and initial biopsies are nondiagnostic. Recognition of this characteristic constellation of sheet-like interfollicular plasmacytosis with preserved nodal architecture, hyperplastic germinal centers, and IgG4 positivity is essential for distinguishing iMCD-IPL from mimickers such as IgG4-RD and Sjögren disease. Awareness of these clinical and histologic features, especially in patients with relapsing systemic inflammation and elevated IL-6, may help avoid diagnostic delay and guide appropriate evaluation and management. L.Y.C.C., C.S., and S.Q. drafted the manuscript. C.L., L.M., and C.H. contributed clinical and histological data and critically reviewed the manuscript. L.Y.C.C. conceptualized the project and critically revised the manuscript. All authors approved the final version. Luke Y.C. Chen's research is supported by a philanthropic gift from the Hsu & Taylor Family through the UBC & VGH Foundation. The authors have nothing to report. Written informed consent was obtained from the patient for publication of this case report and accompanying images. Luke Y.C. Chen has received honoraria from Recordati Rare Diseases. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Quon et al. (Mon,) studied this question.