November Case 2021

Aaron Victor, MD, PhD (Fellow), Sumire Kitahara, MD (Faculty)

TAFRO subtype of idiopathic Multicentric Castleman Disease (iMCD-TAFRO)

Multicentric Castleman Disease (MCD) encompasses three different clinical disorders: human herpes virus-8-associated MCD (HHV8-MCD); polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes-associated MCD (POEMS-MCD), and idiopathic MCD, which is further subdivided into iMCD-not otherwise specified (iMCD-NOS), and iMCD-thrombocytopenia, ascites, reticulin fibrosis, renal dysfunction, organomegaly (iMCD-TAFRO) (1, 2).

Formalized diagnostic criteria for iMCD were first published in 2017 in an effort to improve accuracy in diagnosis, exclude the numerous clinical mimics, and to guide appropriate treatment (3). Historically, Castleman disease (CD) had been classified as unicentric (UCD) or multicentric (MCD) based on the number of involved lymph node stations and by its histopathologic features, namely "hyaline vascular" or "plasmacytic" variants. These histologic features, however, typically exist on a spectrum. "Hyaline vascular", now referred to as "hypervascular (HV)" type, is characterized by regressed germinal centers and prominent vascularization. Plasmacytic (PC) type features include hyperplastic germinal centers with prominent plasmacytosis. The intermediate "mixed" type shows features of both.

iMCD-TAFRO, as its name suggests, is a non-HHV8-associated type of MCD that presents with the clinical findings associated with the TAFRO acronym--Thrombocytopenia, Ascites, (reticulin) Fibrosis, Renal dysfunction, and Organomegaly. The F in TAFRO is sometimes said to indicate Fever (4). The histologic features are typically "mixed", as in the above case, but may instead show predominantly HV features. iMCD may also be associated with a polyclonal hypergammaglobulinemia, hypoalbuminemia, lymphocytic interstitial pneumonitis, and eruptive cherry angiomata or violaceous papules (1,3-5). iMCD-TAFRO presents on average in the 5th decade and is slightly more common in men than in women (1,4,5). The pathogenesis of iMCD is unclear but seems to involve IL-6, VEGF, and mTOR signaling (1). The clinical course is usually very aggressive.

In the case presented, the underlying pathology was initially obscured by a superimposed pneumonia; however, once the infection was treated, the TAFRO features became more apparent. Histologic evaluation of an enlarged lymph node showed characteristic histologic features, establishing the diagnosis of iMCD-TAFRO. In fact, histologic evaluation is still a major diagnostic criterion along with identifying multicentricity of enlarged lymph nodes. However, as these histologic features alone may be nonspecific, evaluation for minor diagnostic criteria and exclusion of other diagnoses, as demonstrated in this case, are necessary to make the definitive diagnosis. A systematic approach to exclude infectious, autoimmune and malignant etiologies is necessary. Additional pitfalls could include Hodgkin lymphoma (classic or nodular lymphocyte predominant), plasma cell neoplasms, and IgG4-related disease, which were excluded in this case. The reader is guided to this reference for specific diagnostic criteria.

The patient received anti-IL-6 therapy (siltuximab) with high dose steroids, resulting in rapid clinical improvement. The following treatment algorithm shows the consensus guidelines for the treatment of iMCD (1,7).