TAFRO syndrome: current perspectives

Figures & data

Figure 1 Histopathological features of hyaline-vascular type in a patient with multicentric Castleman’s disease. Left inguinal node biopsy shows atrophic germinal centers and expansion of the interfollicular zone with vascular proliferation (hematoxylin and eosin stain).

Figure 2 Proposed classification distinguishes multicentric Castleman’s disease on the basis of human herpesvirus 8 status.

Note: Republished with permission of American Society of Hematology, from HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy, Fajgenbaum DC, Van Rhee F, Nabel CS, Blood, 123(19), 2014 copyright; permission conveyed through Copyright Clearance Center, Inc.¹⁶
Abbreviations: HHV8, human herpesvirus 8; HIV, human immunodeficiency virus; iMCD, idiopathic multicentric Castleman’s disease.

Table 1 Proposed diagnostic criteria for TAFRO-iMCD

1. Histopathological criteria

• Compatible with the pathological findings of lymph nodes as TAFRO-iMCD

• Negative LANA-1 for HHV8

2. Major criteria: 3 of 5 TAFRO symptoms

I. Thrombocytopenia

II. Anasarca

III. Fever

IV. Reticulin fibrosis

V. Organomegaly

Absence of hypergammaglobulinemia

Small volume lymphadenopathy

3. One or more of the minor criteria

Hyperplasia/normoplasia of megakaryocytes in bone marrow

High serum level of ALP without markedly elevated serum transaminase

Note: Republished with permission of American Journal of Hematology, Iwaki N, Fajgenbaum DC, Nabel CS, et al. Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease. Am J Hematol. 2016;91(2):220–226. © 2015 Wiley Periodicals, Inc.²²

Abbreviations: ALP, alkaline phosphatase; HHV8, human herpesvirus 8; iMCD, idiopathic multicentric Castleman’s disease; LANA-1, latency-associated nuclear antigen-1; TAFRO, thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly.

Table 2 Definition of Castleman–Kojima disease (TAFRO syndrome)

Blood count abnormalities: low platelet and/or red blood cell count

Thrombocytopenia

Microcytic anemia

Systemic inflammation

Polyserositis (pleuritis/peritonitis), inflammation of the tissue lining the lungs or abdominal cavities

Pleural effusions

Ascites

Renal dysfunction

Myelofibrosis

Immunological disorders

Rheumatoid factor, platelet-associated lgG, antithyroid antibody, and positivity on direct

Coombs test

Antinuclear antibody

Rare polyclonal hypergammaglobulinemia: <4.0 g/L

Laboratory data abnormalities

Elevated level of alkaline phosphatase and decreased level of lactate dehydrogenase

Elevated levels of interleukin-6 and the vascular endothelial growth factor in serum or effusion

Lymphadenopathy

Generally mild (<1.5 cm in diameter)

Histology of mixed-type and less frequently HV-type CD

Abbreviations: CD, Castleman’s disease; HV, hyaline vascular; TAFRO, thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly.

Table 3 Consensus diagnostic criteria for iMCD

I. Major criteria (both 1 and 2 are needed)

1. Histopathological lymph node features consistent with the iMCD spectrum (Figure 3). Features along the iMCD spectrum include (grades 2–3 for either regressive GCs or plasmacytosis is required at a minimum): regressed/atrophic/atretic germinal centers, often with expanded mantle zones composed of concentric rings of lymphocytes in an “onion-skin” appearance, FDC prominence, vascularity, often with prominent endothelium in the interfollicular space and vessels penetrating into the GCs with a “lollipop” appearance, sheet-like, polytypic plasmacytosis in the interfollicular space, hyperplastic GCs

2. Enlarged lymph nodes (≥1 cm in short-axis diameter) in ≥2 lymph node stations

II. Minor criteria (at least 2 of 11 criteria and at least 1 laboratory criterion are needed)

Laboratory

1. Elevated CRP (>10 mg/L) or ESR (>15 mm/h)

2. Anemia (hemoglobin, 125 g/L for male and <115 g/L for female)

3. Thrombocytopenia (platelet count < 150k/mL) or thrombocytosis (platelet count <400 k/mL)

4. Hypoalbuminemia (albumin <35 g/L)

5. Renal dysfunction (eGFR, 60 mL/min/1.73 m^2) or proteinuria (total protein 150 mg/24 h or 10 mg/100 mL)

6. Polyclonal hypergammaglobulinemia (total g globulin or immunoglobulin G.1.7 g/L)

Clinical

1. Constitutional symptoms: night sweats, fever (>38°C), weight loss, or fatigue (≥2 CTCAE lymphoma score for B-symptoms)

2. Large spleen and/or liver

3. Fluid accumulation: edema, anasarca, ascites, or pleural effusion

4. Eruptive cherry hemangiomatosis or violaceous papules

5. Lymphocytic interstitial pneumonitis

III. Exclusion criteria (must rule out all diseases that can mimic iMCD)

Infection-related disorders

1. HHV8 (infection can be documented by blood PCR; diagnosis of HHV8-associated MCD requires positive LANA-1 staining by IHC, which excludes iMCD)

2. Clinical EBV-lymphoproliferative disorders such as infectious mononucleosis or chronic active EBV (detectable EBV viral load not necessarily exclusionary)

Autoimmune/autoinflammatory diseases (requires full clinical criteria; detection of autoimmune antibodies alone is not exclusionary)

1. Systemic lupus erythematosus

2. Rheumatoid arthritis

3. Adult-onset Still’s disease

4. Juvenile idiopathic arthritis

Autoimmune lymphoproliferative syndrome and malignant/lymphoproliferative disorders (these disorders must be diagnosed before or at the same time as iMCD to be exclusionary):

1. Lymphoma (Hodgkin and non-Hodgkin)

2. Multiple myeloma

3. Primary lymph node plasmacytoma

4. FDC sarcoma

5. POEMS syndrome

Inflammation and adenopathy caused by other uncontrolled infections (eg, acute or uncontrolled CMV, toxoplasmosis, HIV, and active tuberculosis)

Note: Republished with permission of American Society of Hematology, from International, evidencebased consensus diagnostic criteria for HHV-8 – negative/idiopathic multicentric Castleman disease, Fajgenbaum DC, Uldrick TS, Bagg A, et a, Blood, 129(12), 2017, permission conveyed through Copyright Clearance Center, Inc. ²⁷

Figure 3 Histopathologic features of Castleman’s disease. Hypervascular subtype is characterized by the presence of regressed germinal centers and prominent FDC, whereas the plasmacytic subtype exhibits hyperplastic germinal centers and profuse plasmacytosis. The mixed subtype exhibits a combination of hypervascular and plasmocytic features. Vascularity is frequently observed in idiopathic multicentric Castleman’s disease but can be seen in either subtype as well. Republished with permission of American Society of Hematology, from International, evidencebased consensus diagnostic criteria for HHV-8 – negative/idiopathic multicentric Castleman disease, Fajgenbaum DC, Uldrick TS, Bagg A, et a, Blood, 129(12), 2017, permission conveyed through Copyright Clearance Center, Inc.²⁷

Abbreviation: FDC, follicular dendritic cell.

Abbreviations: CMV, cytomegalovirus; CRP, C-reactive protein; CTCAE, common terminology for adverse events; EBV, Epstein–Barr virus; eGFR, estimated glomerular filtration rate; ESR, erythrocyte sedimentation rate; FDC, follicular dendritic cell; GC, germinal center; HHV8, human herpesvirus 8; HIV, human immunodeficiency virus; iMCD, idiopathic multicentric Castleman’s disease; IHC, immunohistochemistry; LANA-1, latency-associated nuclear antigen; PCR, polymerase chain reaction; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes.

Figure 3 Histopathologic features of Castleman’s disease. Hypervascular subtype is characterized by the presence of regressed germinal centers and prominent FDC, whereas the plasmacytic subtype exhibits hyperplastic germinal centers and profuse plasmacytosis. The mixed subtype exhibits a combination of hypervascular and plasmocytic features. Vascularity is frequently observed in idiopathic multicentric Castleman’s disease but can be seen in either subtype as well. Republished with permission of American Society of Hematology, from International, evidencebased consensus diagnostic criteria for HHV-8 – negative/idiopathic multicentric Castleman disease, Fajgenbaum DC, Uldrick TS, Bagg A, et a, Blood, 129(12), 2017, permission conveyed through Copyright Clearance Center, Inc.²⁷

Abbreviation: FDC, follicular dendritic cell.

FajgenbaumDCVan RheeFNabelCSHHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapyBlood2014123192924293324622327

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IwakiNFajgenbaumDCNabelCSClinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman diseaseAm J Hematol201691222022626805758

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FajgenbaumDCUldrickTSBaggAInternational, evidence-based consensus diagnostic criteria for HHV-8 – negative/idiopathic multicentric Castleman diseaseBlood2017129121646165828087540

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