The first report of adolescent TAFRO syndrome, a unique clinicopathologic variant of multicentric Castleman’s disease

A 15-year-old Japanese boy was referred to us with fever of unknown origin of 2 weeks’ duration. He had a systolic murmur and hepatosplenomegaly. The patient’s superficial lymph nodes were swollen, with a maximum diameter of 3.0 cm. Laboratory tests showed elevations in C-reactive protein (CRP; 17.8 mg/dL), soluble IL-2 receptor (2,467 IU/mL), lactate dehydrogenase (511 IU/L) and D-D dimer (5.6 μg/mL). The patient had decreased total protein (5.1 g/dL), albumin (1.8 g/dL), immunoglobulin G (729 mg/dL) and cholinesterase (48 IU/L). Complete blood cell count and serum levels of liver enzymes, blood urea nitrogen and creatinine (Cr) were within normal range. Urinalysis showed mild proteinuria of 0.4 mg/mg ∙ Cr without hematuria. Enhanced whole body computed tomography demonstrated systemic lymphadenopathy, hepatosplenomegaly, renal enlargement and anasarca (Figure 1A–C).Bone marrow biopsy revealed a hyperplastic marrow with megakaryocytic hyperplasia (Figure 2A) and mild reticulin fibrosis (Figure 2B). An 18-fluoro-deoxyglucose (FDG) positron emission tomography scan showed weak FDG uptake by the bilateral cervical and inguinal lymph nodes and spleen. Biopsies of the lymph nodes showed scattered lymphoid follicles with atrophic germinal centers and enlarged follicular dendritic cells, with surrounding concentric rings of small lymphocytes and penetrating vessels (lollipop-like appearance; Figure 2C). The interfollicular area was characterized by prominent vascularity and moderate numbers of mature plasma cells (Figure 2D). Immunological studies showed decreased numbers of B-cells and CD57+ T-cells in the germinal centers. Immunostaining for CD21 demonstrated tight/concentric and expanded/disrupted patterns of follicular dendritic cells (Figure 2E). These findings were compatible with the mixed type of Castleman’s disease.

Autoantibodies, serum M-protein and urine Bence-Jones protein were not detected in this patient. Blood culture and quantitative PCR examinations for cytomegalovirus, Epstein-Barr virus, human herpes virus type 8 (HHV-8) and human immunodeficiency virus (HIV) were all negative. There were no significant pathological findings of malignancy in lymph node or liver biopsies.Despite treatment with antibiotics and albumin, the disease progressed markedly to respiratory distress, oliguric renal failure, anemia and thrombocytopenia. Methylprednisolone pulse therapy at a dose of 1000 mg/day for 3 consecutive days was initiated on day 10 after admission, but the patient’s fever persisted and his CRP remained elevated. The patient was diagnosed with multicentric Castleman’s disease and treatment was initiated with weekly TCZ at a dose of 8 mg/kg, high dose intravenous immunoglobulin and 80 mg of prednisolone (PSL) daily. Weekly TCZ dramatically improved the patient’s symptoms and laboratory findings. However, anasarca persisted (Figure 1D–F). With removal of ascites, anasarca gradually disappeared.

One month after the initiation of TCZ therapy, the patient was forced to decrease his PSL dose because of steroid psychosis. In addition, he developed blisters over his entire body and was forced to discontinue treatment with TCZ because drug reaction or viral infection was suspected. Paraneoplastic pemphigus and pemphigoid, which are reported complications of Castleman’s disease [7‐9], were ruled out by negative antibody and immunofluorescence testing. We diagnosed the patient’s skin lesions as toxic epidermal necrolysis by pathology, but were unable to determine the cause.After treatment for multicentric Castleman’s disease was discontinued, the patient’s clinical symptoms reappeared with elevated cytokine levels. Restarting weekly TCZ resulted in improvement in these findings (Figure 3). During this treatment, the patient’s skin lesions also resolved. After cytokine levels normalized 4 months after admission, the patient was discharged. One year after disease onset, the patient continued treatment with 5 mg PSL daily and TCZ every 3 weeks without any signs of recurrence. His clinical symptoms completely matched those of TAFRO syndrome.

In the acute phase of the disease, the patient’s serum cytokine levels of IL-6, IL-7, IL-10, IL-12p70, IL-15, IL-16, soluble tumor necrosis factor receptors I and II (sTNF-R I/II), VEGF, neopterin, interferon gamma-induced protein 10 (IP-10), macrophage inflammatory protein 1β (MIP-1β), eotaxin-3 and monocyte chemoattractant protein 1 (MCP-1) were elevated (Table 1). After initiation of TCZ therapy, serum IL-6 levels increased because of IL-6 receptor blocking by TCZ (Figure 3). After repeated TCZ infusions, most of the serum and plasma cytokine/chemokine levels decreased, including IL-6. When TCZ therapy was discontinued because of steroid psychosis and toxic epidermal necrolysis, cytokine levels transiently increased. After restarting TCZ therapy, cytokine levels decreased once more (Figure 3).

Aspiration of ascites was performed twice with a total volume of 11.2 L removed. IL-6 and VEGF levels in the ascitic fluid were extremely high (Table 1).

Serum and plasma concentrations of IL-6, IL-18, tumor necrosis factor α (TNF-α), sTNF-R I/II, VEGF and neopterin were determined by using the following enzyme-linked immunosorbent assay (ELISA) kits: neopterin (IBL, Hamburg, Germany); IL-6, TNF-α, sTNF-R I/II and VEGF (R&D Systems Inc., Minneapolis, MN, USA); and IL-18 (MBL, Nagoya, Japan). Other cytokines/chemokines were determined by electrochemiluminescence immunoassay (MSD, Rockville, MD, USA).