Successful treatment of a Caucasian case of multifocal Castleman's disease with TAFRO syndrome with a pathophysiology targeted therapy - a case report

Abstract

Background: Castleman-Kojima disease (TAFRO Syndrome) is characterized by Thrombocytopenia, Anasarca, myeloFibrosis, Renal dysfunction, Organomegaly, multiple lymphadenopathy and histopathology pattern of atypical Castleman's disease (CD). Only few cases of this recently identified unique variant of Multicentric CD (MCD) are described in literature, all Japanese. It therefore poses serious diagnostic and therapeutic challenges.

Case description: We describe a 21 year old woman with fever, asthenia, bilateral pleural effusion, ascites, hypoalbuminemia, severe thrombocytopenia, anemia, renal failure and proteinuria, whereas microbiological tests, immune serology (except ANA) and bone marrow biopsy were all negative. A CT-scan showed multiple lymphadenopathy and tissue samplings of mediastinal lymph nodes was compatible with a mixed-type CD. The diagnosis of MCD with TAFRO syndrome was made, but after an initial improvement with high dose corticosteroid therapy, clinical and laboratory features worsened. Based upon the high serum IL-6 levels and the high number of CD20-lymphocytes in lymph nodes tissue, we started tocilizumab (partial benefit), followed by rituximab combined with CVP (cyclophosphamide, vincristine and prednisone) chemotherapy, achieving a complete response. A total of six cycles of R-CVP were administered monthly, followed by maintenance with monthly rituximab. A complete remission persists at the 12th month of follow-up.

Conclusions: In patients with massive immune system activation and lymphadenopathy it is mandatory to rule out Castleman-Kojima disease. In our patient a therapy aimed at the prominent pathophysiological abnormalities has been successful so far. However, since the rarity of TAFRO Syndrome, a multicenter registry is strongly desirable for a better understanding of the disease mechanisms, hopefully leading to evidence-based therapeutic choices.

Keywords: Castleman’s disease; Chemotherapy; Multicentric; PRES; Rituximab; TAFRO syndrome; Tocilizumab.

Figure 1

Histopathological findings. (A) The bone marrow appeared hypercellular with a marked expansion of granulopoiesis and a moderate increase of megakaryocytes (Periodic acid–Schiff (PAS), 20X). (B) On sections stained with the Gomori's silver impregnation technique, a diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen was evident. Fiber density was considered as grade 2 according to the European Consensus Criteria for grading myelofibrosis by Thiele et al. [2] (20X). (C,D) Multiple fragments of lymph node tissue were excised from the mediastinum of this patient. The architecture was preserved, showing CD20+ B-follicles and germinal centers with onion-skin appearance around prominent arterioles. The interfollicular areas showed abundant plasma cells with normal kappa:lambda ratio. Immunohistochemistry did not reveal aberrant B- or T-cell phenotype. Molecular testing was negative for B-cell or T-cell monoclonality. The search for HHV8 and EBV was also negative. The histology pattern was considered not diagnostic for malignant lymphoma and related to a lymphadenopathy with features resembling multicentric Castleman’s disease. The diagnosis was reviewed at the referral center of Bologna (Prof. Pileri) and confirmed.

Figure 2

CT images. (A, B) Contrast enhanced thoracic computed tomography (CT) before (A) and after (B) six months of chemotherapy, showing resolution of pleural effusion and the shrinking of axillar and mediastinal lymphnodes. (C, D) Contrast enhanced abdominal CT before (C) and after (D) six months of chemotherapy, showing the reduction of hepato-splenomegaly and celiac and perisplenic lymphadenopathy.

Figure 3

Patient’s disease course (12 months-follow-up). CT: computed tomography; MRI: magnetic resonance imaging; PET: positron emission tomography; TCZ: tocilizumab 8 mg/kg; R-CVP: rituximab 375 mg/m³, cyclophosphamide 750 mg/m³, vincristine 1.4 mg/m³ and prednisone 40 mg/m³; RTX: rituximab 375 mg/m³; Hb: hemoglobin; PLT: platelet counts; CRP: C reactive protein; IL6: interleukin 6.

Figure 4

New classification of MCD based on clinical and hystopatological features. Modified from: Kawabata H, et al. Castleman-Kojima disease (TAFRO syndrome): a novel systemic inflammatory disease characterized by a constellation of symptoms, namely, thrombocytopenia, ascites (anasarca), microcytic anemia, myelofibrosis, renal dysfunction, and organomegaly : a status report and summary of Fukushima (6 June, 2012) and Nagoya meetings (22 September, 2012). J Clin Exp Hematop 2013, 53(1):57–61. IPL: Idiopathic Plasmacytic Lymphadenopathy; POEMS: Polyneuropathy, Organomegaly, Endocrinopathy/Edema, M-protein, Skin abnormalities; TAFRO: Thrombocytopenia, Anasarca, myeloFibrosis, Renal dysfunction and Organomegaly.