TAFRO syndrome is a rare and aggressive inflammatory entity characterized by thrombocytopenia, anasarca, fever, renal failure, reticulin fibrosis, and organomegaly. This entity supposes a diagnostic and therapeutic challenge due to its significant overlap with Castleman\'s disease. However, distinct clinical and histological features warrant its classification as a separate subtype of idiopathic multicentric Castleman\'s disease (iMCD). While recent modifications have been made to the diagnostic criteria for iMCD, these criteria lack specificity for this particular condition, further complicating diagnosis. Due to its inflammatory nature, several complex molecular signaling pathways are involved, including the JAK-STAT pathway, NF-kB, and signal amplifiers such as IL-6 and VEGF. Understanding the involvement of immune dysfunction, some infectious agents, genetic mutations, and specific molecular and signaling pathways could improve the knowledge and management of the condition, leading to effective treatment strategies. The current therapeutic approaches include corticosteroids, anti-IL6 drugs, rituximab, and chemotherapy, among others, but response rates vary, highlighting the need for personalized strategies. The prognosis is uncertain due to diagnostic difficulties, emphasizing the importance of early intervention and appropriate targeted treatment. This comprehensive review examines the evolving landscape of TAFRO syndrome, including the pathophysiology, diagnostic criteria, treatment strategies, prognosis, and future perspectives.

Myelofibrosis is a rare myeloproliferative disorder. The detailed descriptions of myelofibrosis in children and adolescents is limited to a few case series and case reports describing fewer than 100 patients, thus suggesting the extreme rarity of this condition prior to adulthood. Though pediatric patients rarely present the typical features and outcomes usually observed in older people, pediatric myelofibrosis is not considered an independent entity. Here we aim to describe patients with pediatric myelofibrosis, showing different clinical and pathological features when compared to the World Health Organization 2016 Primary Myelofibrosis classification. We retrospectively collected and analyzed 14 consecutive pediatric myelofibrosis diagnosed in our Pediatric hematology outpatient clinic over a six-year period. According to clinical data and bone marrow biopsy findings, patients were classified into three subgroups: adult-like myelofibrosis, pediatric immune myelofibrosis, idiopathic myelofibrosis. Pediatric Immune Myelofibrosis was the predominant subgroup in our cohort (7/14). Pediatric Immune Myelofibrosis is characterized by peculiar bone marrow features (i.e., T lymphocyte infiltration) and a milder course compared to the other patients Pediatric Immune Myelofibrosis is a novel and distinct pathological entity. We suggest to carefully consider Pediatric Immune Myelofibrosis in case of bone marrow biopsies showing myelofibrosis that do not fulfill WHO criteria.

Multicentric Castleman disease (MCD) is an uncommon systemic lymphoproliferative disease. The diagnosis of this disease is typically challenging and requires collaboration between clinicians and pathologists. Moreover, it is important to exclude other diseases (such as malignancies, autoimmune diseases, and infectious diseases) that have similar clinical manifestations and pathological findings. Patients with untreated severe MCD have high mortality due to devastating cytokine storms. Thus, early diagnosis and prompt treatment is a key imperative. The diagnosis of MCD is based on the clinical signs of systemic inflammation, serological tests, and typical pathological features. In this review article, we provide an overview of MCD with a focus on the emerging evidence pertaining to its diagnosis and treatment.

TAFRO syndrome is a newly proposed disease that is characterised by thrombocytopenia, anasarca, fever, reticulin fibrosis (or renal dysfunction), and organomegaly. Generally, high doses of corticosteroids are recommended for the initial treatment of TAFRO syndrome; however, some patients experience prolonged refractory thrombocytopenia after initiating such therapies. If corticosteroid treatment alone is ineffective, additional immunosuppressive therapies such as cyclosporine A are recommended. Since long-term use of immunosuppressive therapies with TAFRO syndrome sometimes causes serious infection, it is important to recognise the time to recovery from thrombocytopenia. In this study, we investigated how long it took to recover from thrombocytopenia, to aid clinicians in decision-making regarding the need to strengthen treatment for prolonged thrombocytopenia. Here, we describe three of our patients with TAFRO syndrome exhibiting prolonged thrombocytopenia. We also investigated the median period to recovery from this complication (defined as the time to increase the platelet count above 50,000/µL) after the initiation of high-dose corticosteroid treatment in our 3 cases and 38 peer-reviewed cases. We found that it took our patients 61 days to recover from thrombocytopenia; in comparison, our investigation of the 38 peer-reviewed case reports revealed a median recovery time of 47.5 days among previously reported patients. We showed the time to recovery from thrombocytopenia in patients with TAFRO syndrome for the first time. Our findings ought to be useful for decision-making among clinicians regarding the administration of other immunosuppressive treatments in addition to corticosteroid.

OBJECTIVE: To evaluate whether a comprehensive histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in bone marrow trephine biopsies (BMBs) of primary myelofibrosis (PMF) patients may have prognostic implications.
RESULTS: Reticulin fibrosis, collagen deposition and osteosclerosis were graded from 0 to 3 in a series of 122 baseline BMBs. Then, we assigned to each case a comprehensive score [reticulin, collagen, osteosclerosis (RCO) score, ranging from 0 to 9] that allowed us to distinguish two groups of patients, with low-grade (RCO score 0-4) and high-grade (RCO score 5-9) stromal changes. Of 122 patients, 88 displayed a low-grade and 34 a high-grade RCO score. The latter was associated more frequently with anaemia, thrombocytopenia, peripheral blood blasts and increased lactate dehydrogenase levels. The RCO score was correlated strictly with overall mortality (P = 0.013) and International Prognostic Scoring System (IPSS) risk categories, and was able to discriminate the overall survival of both low- and high-grade patients (log-rank test: P < 0.001). Moreover, it proved to be more accurate than the European Consensus on Grading of Bone Marrow Fibrosis (ECGMF grade) in identifying high-risk patients with poor prognosis. Finally, a combined analysis of RCO scores and IPSS risk categories in an integrated clinical-pathological evaluation was able to increase the positive predictive value (PPV) for mortality in high-risk patients.
CONCLUSIONS: The comprehensive RCO score, obtained by histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis was prognostically significant and more accurate than ECGMF grade in identifying high-risk patients and improved PPV when applied in addition to IPSS.

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Primary myelofibrosis is a stem cell-derived clonal malignancy characterized by unchecked proliferation of myeloid cells, resulting in bone marrow fibrosis, osteosclerosis, and pathologic angiogenesis. Bone marrow fibrosis (BMF) plays a central role in the pathophysiology of the disease. This review describes current issues regarding BMF in primary myelofibrosis, including the pathophysiology and impact of abnormal deposition of excess collagen and reticulin fibers in bone marrow spaces, the modified Bauermeister and the European Consensus grading systems of BMF, and the prognostic impact of BMF on the overall outcome of patients with primary myelofibrosis. The impact of novel therapeutic strategies, including JAK-STAT inhibitors and allogeneic stem cell transplant, on BMF is discussed.

Recently, more than ten cases of thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome or Castleman-Kojima disease exhibiting such symptoms as thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly have been reported in Japan. We have found two cases of TAFRO syndrome and have reviewed another eighteen previously reported cases. Histological findings of the lymph nodes and levels of interleukin 6 (IL-6) and vascular endothelial growth factor in both serum/plasma and effusions are important characteristics for diagnosing this syndrome.

Fibrosis has been reported in some patients with immune thrombocytopenia (ITP) treated with thrombopoietin receptor agonists (TPO-RA). However, fibrosis has also been reported in patients with various stages of ITP, who were TPO-RA treatment-naïve. In our study, we looked for fibrosis in bone marrow trephine biopsies taken at initial diagnosis from 32 adult patients with ITP. Ten of the 32 evaluated samples (31·25%) showed increased reticulin (Grade 1-2 on Bauermeister scale and Grade 0-1 on the European Consensus scale), which showed a positive correlation with ethnicity (0·3%) but did not correlate with disease severity, any clinical features or co-morbidities.