TAFRO syndrome: A focused look at this rare subtype of Castleman disease!

Published Mar 17, 2022 • By Charlotte Avril

Castleman disease, a rare non-malignant lymphoproliferative disorder, can manifest itself through several distinct forms, implying the need for different care pathway and disease management depending on the form.

TAFRO syndrome is one of the uncommon types of Castleman's disease, which has only been characterized in the last decade.

What are the differences between the various subtypes of Castleman disease? What are the specifics of TAFRO syndrome?

We explain it all in our article!

TAFRO syndrome: A focused look at this rare subtype of Castleman disease!

What is Castleman disease? 

Described by Benjamin Castleman in 1954, Castleman disease (CD) may also be referred to as giant lymph node hyperplasia, angiofollicular lymph node hyperplasia or lymphoid hamartoma. It is a lymphoproliferative disorder, meaning that it causes the proliferation of so-called lymphoid cells, resulting in the immune system disorder. CD can be unicentric (located in a single lymph node group) or multicentric (involving several lymph node areas). The multicentric form is further subdivided into three categories: associated with human herpes virus type 8 (HHV-8), associated with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes) and idiopathic (iMCD), i.e. without a known cause.

CD is a rare disease: its incidence is about 15 million people per year for the unicentric form and 5 million people per year for the multicentric form.

To learn more about classification of CD, its symptoms and diagnosis, click below to read our article:
Castleman disease: Everything you need to know! 

What is TAFRO syndrome? In what way is it different from idiopathic-multicentric Castleman disease (iMCD)? 

Human herpesvirus 8 (HHV-8) infection has been identified as a major cause of multicentric Castleman disease (MCD) in immunocompromised patients, including human immunodeficiency virus (HIV)-positive individuals.

Although immunocompetent (with a functioning immune system) HHV-8-negative MCD patients have also been reported, the underlying causes remain unknown. Several experts speculate that MCD in immunocompetent individuals may be due to hypercytokinaemia (excessive production of cytokines, molecules involved in the immune response) as a result of infection with a virus other than HHV-8, inflammation or neoplastic disease (cancers or tumors).

Click below to read our article on CD associated with HHV-8:
Castleman disease and HIV: A focused look at the HHV-8 virus" 

In 2010, a distinct rare form of HHV-8-negative MCD was reported in Japan. Its diagnosis was established later and was based on a set of well-identified clinical symptoms and signs proposed by Masaki et al. in 2015.

These signs are divided into major diagnostic criteria:

  • Thrombocytopenia (T): a disorder caused by a decrease in the number of platelets (thrombocytes) in the blood, resulting in a coagulation disorder.
  • Anasarca (A): generalized edema under the skin (subcutaneous cellular tissue), caused by infiltration of serosity into the cellular tissue, mainly subcutaneous.
  • Fever (F) related to systemic inflammation.

And minor criteria, associated with a histological (study of the tissue) aspect typical of Castleman disease:

  • Reticulin fibrosis (R): a condition in which fibrous tissue progressively replaces blood stem cells in the bone marrow, causing the formation of abnormally shaped red blood cells, anemia and enlarged spleen.
  • Organomegaly (O): abnormal enlargement of an organ.
  • Kidney failure: a decrease in the function of the kidneys, which no longer filter the body's blood properly.

In addition to these criteria, there is a normal or slightly increased immunoglobulin level and a specific histology distinguished by the intensity of vascular lesions and the presence of fibrosis lesions.

Recent case reports and a systematic review suggest that TAFRO syndrome may have a unique pathogenesis among HHV-8-negative MCD subtypes.

TAFRO syndrome is thus sometimes considered a subtype of iMCD (TAFRO-iMCD), while iMCD without TAFRO syndrome is considered "not otherwise specified" (iMCD-NOS).

On the other hand, this syndrome, originally described in Japan, seems to be more common among the Asian population.

The individualisation of people with TAFRO syndrome among iMCD patients is still unknown to clinicians, however this issue is extremely important due to poor prognosis and excess mortality rates observed among these patients.

To learn more about the methods used to diagnose and identify the different subtypes of Castleman disease, do not hesitate to read our article Castleman disease and differential diagnosis 

How is TAFRO syndrome treated?

Treatment remains poorly codified due to the rarity of this subtype of Castleman disease. However, the treatment regimen for TAFRO syndrome appears to be the same as that for classic idiopathic multicentric Castleman's disease (iMCD), and includes corticosteroid therapy, tocilizumab, rituximab or chemotherapy (CHOP).

For a more detailed information on the treatments for the different subtypes of Castleman disease, click below to read our article
What are the treatment options for Castleman disease?” 

What are some of the current research avenues? 

Numerous studies were conducted in order to establish the specific characteristics of TAFRO syndrome

For example, in 2019, a study was carried out (Fujimoto et al.), collecting clinical data from more than 220 patients with iMCD, TAFRO syndrome and other iMCD- non otherwise specified (iMCD-NOS), and analyzing the differences between them. A lot of clinical signs differed in patients with TAFRO syndrome, compared to typical iMCD, indicating that the former is a distinct clinical entity. This study confirmed that the rates of fever, hydrops, renal failure and mortality were significantly higher in patients with TAFRO syndrome than in patients with iMCD-NOS. Indeed, more than 90% of patients with iMCD-NOS were still alive 10 years after diagnosis. Overall, these results indicate that TAFRO syndrome should be considered as a separate entity, requiring rapid diagnosis and intensive care.

There are several publications dedicated to the study of isolated cases of TAFRO syndrome, also seeking to characterize the distinctive symptoms and clinical signs of TAFRO syndrome. Only about 30 cases have been reported since 2010, mainly in Japan. For example, there was a case in Morocco, reported by the Mohamed VI University Hospital in Marrakech. Another case, recognised as an example of TAFRO syndrome and diagnosed in a 20-year-old man, was studied by Edenberg University.

If you'd like to know more about current and past research on Castleman disease,
don't hesitate to take a look at the this article:
Castleman disease - What is the current research?” 

Several studies have been carried out to identify the signalling pathways involved in TAFRO syndrome in order to develop and study new treatments.

A study carried out in 2020 and supported by the CDCN reveals potential new insights into the pathogenesis of TAFRO disease. It involved in-depth profiling analysis of blood samples from 15 iMCD-TAFRO patients in relapse and remission. This study builds on previous research that identified the activation of mTOR (a serine/threonine proteine kinase enzyme that regulates cell proliferation) as a possible new therapeutic target for iMCD. The researchers have identified a potential mechanism underlying the activation of mTOR in iMCD patients, which is another positive sign that blocking mTOR with the investigational drug sirolimus may help iMCD patients who do not respond to siltuximab.

There is an ongoing study for which researchers are currently recruiting volunteers: Castleman Disease Collaborative Network (CDCN) has partnered with the University of Pennsylvania and the University of Arkansas for Medical Sciences to conduct research on sirolimus for adults with iMCD who cannot benefit from anti-IL-6 therapies (siltuximab (Sylvant) and tocilizumab (Actemra)).

If you wish to have more information on medical research and the ways to contribute to it, do not hesitate to read our article on the subject: “Castleman disease: How to contribute to research? 

For more information:

Do not hesitate to visit the CDCN (Castleman Disease Collaborative Network) website for detailed information on the disease, treatments available, etc.  

You are also welcome to join the “Castleman disease” community on Carenity and share your own experience, find support and exchange useful information with other patients or carers. 

If you are interested in making your voice heard, let us know! You can share your experience as a Castleman disease patient (diagnosis, patient journey, etc.) with Carenity members.   

Would you like to share your story? If so, please email us at: contact@carenity.com 

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