TAFRO Syndrome - Multicentric Lymphatic Overgrowth

Introduction

TAFRO syndrome was first identified in Japan and consisted of thrombocytopenia (a medical condition with reduced platelet counts), anasarca (a medical condition that leads to generalized body swelling), fever, reticulin fibrosis (refers to increased reticulin staining associated with malignant and benign conditions following tumor metastasis to the bone marrow) and organomegaly (abnormal enlargement of organ). Histopathology of TAFRO mimics idiopathic multicentric Castleman disease. TAFRO patients respond well to Glucocorticoids and Cyclosporine therapy. Mortality rates are often high in patients with TAFRO syndrome.

What Is TAFRO Syndrome?

TAFRO syndrome is a rare, newly recognized constellation of symptoms that includes anasarca (a medical condition that leads to generalized body swelling), thrombocytopenia (a medical condition with reduced platelet counts), reticulin fibrosis of bone marrow, organomegaly (abnormal enlargement of organ), and renal dysfunction. It was first identified as a variant of idiopathic multicentric Castleman disease (iMCD), which is a group of disorders associated with systemic inflammatory symptoms, multiple reactive proliferation of benign lymphocytes, and multiple organ impairments secondary to proinflammatory reported in Japan.

What Is Castleman Disease?

Castleman disease is a group of rare disorders that involves an overgrowth of cells in the body's lymphatic system. The lymphatic system is made up of lymph tissues and lymph nodes. Castleman disease has the potential to affect one or more lymph nodes or can involve multiple lymph nodes.

How Common Is Castleman Disease?

Castleman disease is rare and has been diagnosed in 6,500 to 7,700 individuals in the U.S. each year and was first reported in 1954.

What Are the Causes of Castleman Disease?

Castleman disease is associated with lymphoma (cancer of the lymphatic system) and is caused by infections such as human herpesvirus-8 (HHV-8).

What Are Different Types of Castleman Disease?

The different types of Castleman disease are:

• Unicentric Castleman Disease: Affects multiple or single lymph nodes in one region of the body and is also called localized Castleman disease.

• Multicentric Castleman Disease: It is the form where multiple lymph nodes are involved and are caused by human herpesvirus-8 (HHV-8) in people with human immunodeficiency (HIV).

What Are the Symptoms of Castleman Disease?

The symptoms of Castleman disease are:

• Pressure or full feeling in the abdomen or chest.

• Fever.

• A lump beneath the skin in the neck, armpit, and groin.

• Unexplained weight loss.

• Fatigue.

• Anemia (a medical condition associated with reduced red blood cells in the body)

• Appetite and weight loss.

• Enlarged liver or spleen.

• Abnormally large lymph nodes, typically in the armpit, neck, collarbone, and groin.

What Is the Difference Between TAFRO Syndrome and Idiopathic Multicentric Castleman Disease?

Histopathology of TAFRO syndrome mimics idiopathic multicentric Castleman disease; therefore, some researchers considered TAFRO syndrome a unique type of idiopathic multicentric Castleman disease. However, TAFRO syndrome and idiopathic multicentric Castleman disease differ from each other in terms of clinical features. Patients with idiopathic multicentric Castleman disease demonstrate multiple lymphadenopathies, polyclonal hyper gammopathy, severe inflammation, microcytic inflammation, and thrombocytosis, while in TAFRO syndrome, normal or hypogammaglobulinemia, small or unclear lymphadenopathy, pleural effusion (medical state associated with fluid-filled lungs), and ascites (a medical condition that leads to generalized body swelling) are seen. The research team of Japan combined TFRO and idiopathic multicentric Castleman disease in 2010.

What Is the Etiology of TAFRO Syndrome?

The etiology of TAFRO syndrome is unclear, although human herpesvirus-8 (HHV-8) is the known cause of cytokine storm in human immunodeficiency virus (HIV) positive multicentric Castleman disease (MCD) patients and in some human immunodeficiency (HIV) negative patient. Epstein Barr virus is also associated with multicentric Castleman disease (MCD).

How Is Tafro Syndrome a Subtype of Multicentric Castleman Disease?

A new variant of multicentric Castleman disease was proposed by Takai et al., whose features were seen in TAFRO syndrome. Typical human virus (HV) like changes were seen consistent with multicentric Castleman disease in lymph node biopsy. Patients suffering from TAFRO responded to immunosuppressive therapy with Cyclosporine and Glucocorticoids. Multicentric Castleman disease represented a group of systemic inflammatory diseases with autoimmune pathophysiology in response to immunosuppressive therapy.

What Is the Clinical Presentation of TAFRO Syndrome?

Clinical features and pathological characteristics of multicentric Castleman disease were analyzed by Iwaki et al. for 23 cases reported in Japan and two cases from the USA. Multicentric Castleman disease with TAFRO syndrome was characterized by an aggressive clinical course, severe thrombocytopenia, refractoriness to Corticosteroids, elevated levels of alkaline phosphatase, and frequency of anascra and normal gamma globulin levels.

What Is the Diagnostic Classification of TAFRO Syndrome?

The diagnostic classification of TAFRO syndrome includes three major categories and four minor categories, which are as follows:

1. Major Categories:

• Anasarca, including ascites (buildup of fluid in the abdomen), pleural effusion (refers to excessive accumulation and collection of fluid ), and general edema.

• Thrombocytopenia with platelet rates ≤100,000/μL, without myelosuppressive treatment.

• Systemic inflammation is characterized by a fever of unknown etiology above 37.5 degrees Centigrade and increased serum C-reactive protein concentration.

2. Minor Category:

• Castleman disease.

• Reticulin myelofibrosis (refers to bone marrow cancer that leads to disruption of the body’s normal production of blood cells) or an increased number of megakaryocytes present in the bone marrow.

• Mild organomegaly (enlargement of organs), including splenomegaly (enlargement of the spleen), hepatomegaly (enlargement of the liver), and lymphadenopathy (enlargement of lymph).

How to Diagnose TAFRO Syndrome?

TAFRO syndrome is a rare variant of idiopathic multicentric Castleman disease associated with ascites, thrombocytopenia, renal dysfunction, and organomegaly. If the person suffers from TAFRO syndrome, the following features can be seen :

• Chest and abdominal computed tomography (CT) scan revealed bilateral pleural effusion, splenomegaly, and multiple mildly enlarged lymph nodes, and splenomegaly.

• An excisional biopsy reveals inguinal lymph nodes with the expansion of interfollicular areas marking vascular proliferation, polytypic plasmacytosis, and the presence of few atrophic follicles.

• Bone marrow biopsy shows normocellular with increased megakaryocytes.

• Lymph node biopsy can be difficult to obtain from patients with TAFRO syndrome due to bleeding tendency, anasarca (a medical condition that leads to swelling of the whole body), and small or unclearness of the target lymph node).

Conclusion

TAFRO is a newly established variant of human herpesvirus-8 (HHV-8) with multicentric Castleman disease associated with an autoimmune etiology. The characteristics include an aggressive clinical course, higher frequency of anasarca, severe thrombocytopenia, and normal serum gamma globulin. Corticosteroids are considered the first-line drug of choice for the treatment of TAFRO syndrome.