Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV‐8‐negative multicentric Castleman disease

Abstract

Multicentric Castleman disease (MCD) describes a heterogeneous group of disorders involving systemic inflammation, characteristic lymph node histopathology, and multi-organ dysfunction because of pathologic hypercytokinemia. Whereas Human Herpes Virus-8 (HHV-8) drives the hypercytokinemia in a cohort of immunocompromised patients, the etiology of HHV-8-negative MCD is idiopathic (iMCD). Recently, a limited series of iMCD cases in Japan sharing a constellation of clinical features, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O) has been described as TAFRO syndrome. Herein, we report clinicopathological findings on 25 patients (14 males and 11 females; 23 Japanese-born and two US-born), the largest TAFRO syndrome case series, including the first report of cases from the USA. The median age of onset was 50 years old (range: 23-72). The frequency of each feature was as follows: thrombocytopenia (21/25), anasarca (24/25), fever (21/25), organomegaly (25/25), and reticulin fibrosis (13/16). These patients frequently demonstrated abdominal pain, elevated serum alkaline phosphatase levels, and acute kidney failure. Surprisingly, none of the cases demonstrated marked hypergammoglobulinemia, which is frequently reported in iMCD. Lymph node biopsies revealed atrophic germinal centers with enlarged nuclei of endothelial cells and proliferation of endothelial venules in interfollicular zone. 23 of 25 cases were treated initially with corticosteroids; 12 patients responded poorly and required further therapy. Three patients died during the observation period (median: 9 months) because of disease progression or infections. TAFRO syndrome is a unique subtype of iMCD that demonstrates characteristic clinicopathological findings. Further study to clarify prognosis, pathophysiology, and appropriate treatment is needed.

Cardiac arrest caused by rapidly increasing ascites in a patient with TAFRO syndrome: a case report

“…Although 96–100% of patients with TAFRO syndrome develop anasarca, the quantity of ascites and incidence of cardiac arrest due to ascites have not been reported 2, 5. In the present case, 4,000 mL of ascites was drained at the time of cardiac arrest, and 3,000–5,000 mL/day of ascites was continuously drained for 6 weeks despite immunosuppressive therapy.…”

“…In the present case, anasarca, thrombocytopenia, systemic inflammation, Castleman's disease‐like feature in lymph node, reticulin myelofibrosis in bone marrow, and renal insufficiency are consistent with the criteria. Lymph node findings partially met the new criteria 5. However, according to past cases, there is no contradiction in the pathological findings of TAFRO syndrome.…”

“…The mortality rate is 11–12% 2, 5. In some reports, the cause of death was multiple organ failure secondary to deteriorating TAFRO syndrome over a 2‐month period and septic shock associated with febrile neutropenia during an 8‐month observation period 2.…”

“…The diagnostic criteria for TAFRO syndrome were announced by two groups 2, 5. Both these criteria emphasize clinical findings, however, one requires the histological feature in lymph node, the other does not.…”

“…The diagnostic criteria, severity classification, and treatment strategy were recently announced by a Japanese group (Table 1). 2 The mortality rate is 11–12%, and death often occurs after a relatively long disease course 2, 5. The main causes of death are multiple organ dysfunction unresponsive to immunosuppressive agents and severe infection caused by an immunocompromised state.…”