Refractory Anemia with Ringed Sideroblasts Associated with Marked Thrombocytosis (RARS-t): A Clinicopathological Entity with Questionable Pathogenesis
Authors: Nayak Anupma , Goyal Abha , Brody Judith , Hsu Peihong , Savona Steven , Weiss Rita , Zervos George 
Published: April 2020

Abstract
Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-t) is a clinicopathological entity with features of both myelodysplastic syndrome and myeloproliferative disorder. The cases of RARS-t reported in literature are few and do not confirm whether this disease represents a variant of Refractory anemia with ringed sideroblasts (RARS), a variant of Essential Thrombocythemia (ET), or the simultaneous occurrence of two separate disorders (RARS and ET). Because of this ambiguity, RARS-t has been assigned to MDS/MPD- Unclassifiable subcategory as a provisional entity in the WHO (2001) classification. Recent studies have demonstrated association of RARS-t with JAK2 V617F mutation in up to 67% of cases, suggesting its proximity to MPD. In a few studies, presence of JAK2 mutation was related with better prognosis. Based on this evidence, there are chances that this provisional entity may be clubbed with the group of MPD disorders in the revised WHO classification. We present here 4 cases of RARS-t diagnosed within a period of 1 year (2007–2008) at our institution. Clinicopathological features of these cases are mentioned in the attached table (Table-1). Two of these cases were not associated with anemia at the time of presentation, however could be diagnosed as RARS-t based on the presence of dyserythropoetic features and &gt;15% ringed sideroblasts in marrow on iron stains. Other causes of reactive ring sideroblasts and thrombocytosis were ruled out in these cases. 2/4 cases were positive for JAK2 V617F mutation, however no correlation was found between the JAK2 positivity and the clinicopathological features including prognosis. All the 4 patients were given hydroxyurea and pyridoxine therapy. In contrast to other studies, one of our JAK2 positive cases had to be maintained on the transfusion support alone due to the multiple treatment failures. Our data adds to the literature supporting the association of RARS-t with JAK2 mutation. However, we do not agree with the notion that JAK2 positivity renders a better prognosis. Also, lack of any correlation of clinicopathological features in our cases with the JAK2 mutation drives us to think that it might be only a secondary association rather a primary pathogenesis event. Review of the literature reminds us that the pathogenetic events resulting in myelodysplastic component of this overlap syndrome have only been rarely addressed. In future, more studies focusing on the mutations responsible for genesis of ringed sideroblasts such as ALAS2, ABCB7, FECH and gene expression profiles of bone marrow progenitor cells are required for better understanding of this common but under reported entity.
Table 1
Case Age Sex Hb. (g/dL) Hct. MCV (fL) RS% Platelet (× 109/L) WBC (× 109/L) JAK2mutation Other cytogenetics Fibrosis Organomegaly Case#1 84 F 12.9 38.9 94.6 &gt;15% 709 8.3 Negative normal karyotype 1+ reticulin Absent Case#2 85 M 10.3 28.3 131 &gt;15% 1072 7.2 Negative normal karyotype 1+ reticulin Absent Case#3 68 M 6.9 25 101.3 &gt;15% 634 5.4 Positive normal karyotype 1+ reticulin Absent Case#4 63 M 13.7 41.5 78.7 &gt;15% 1272 17.7 Positive normal karyotype 1+reticulin Absent