Japanese Journal of Clinical Oncology Advance Access originally published online on February 21, 2008
Japanese Journal of Clinical Oncology 2008 38(3):230-232; doi:10.1093/jjco/hym174
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© The Author (2008). Published by Oxford University Press. All rights reserved
Isolated Erythrocythemia: A Distinct Entity or a Sub-type of Polycythemia Vera?
The First Department of Internal Medicine
(Hematology Division)
Tokyo Medical University
6-7-1 Nishi-shinjuku, Shinjuku-ku
Tokyo 160-0023, Japan
E-mail: ohyashik{at}rr.iij4u.or.jp
Department of Material and Life Science
Seikei University, Japan
Intractable Immune Disease Research Center
Tokyo Medical University
Japan
Chronic myeloproliferative disorders (CMPDs) are clonal hematopoietic disorders encompassing chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia and chronic idiopathic myelofibrosis. Since the hematological features of CMPD patients overlap with each other, it is proposed that a common biological mechanism may be present in CMPD. In 2001, the WHO classification proposed CMPD as a disease related to constitutive up-regulation of tyrosine kinase activity (1). More recently, the revised WHO-2008 reclassified CMPD as a subset of myeloproliferative neoplasms derived from hematopoietic stem cells (2). Five papers regarding up-regulation of Janus activating kinase-2 (JAK2) in CMPD appeared in 2005 (3–7): the JAK2 617V > F mutation occurs in the vast majority of patients with PV and 
30% of PV patients exhibit homozygous mutation as a result of uniparental disomy. In 2007, Scott et al. (8) demonstrated that JAK2 exon 12 mutations in PV and idiopathic erythrocytosis, suggesting the diversity of clonal erythrocytosis. These findings render us to consider whether monopathic erythrocytosis apart from JAK2 617V > F is a distinct clinical entity or not.
We used the JAK2 mutational status database in 33 reported patients with PV in our institute (9). The JAK2 617V > F mutation was determined using the sequence-specific primer-single molecule fluorescence detection (SSP-SMFD) assay (9,10). We found that this method could detect at least a 5% mixture of the T-specific population: wild-type JAK2: K2(T)%/K2(G)% ratio < 30; heterozygous JAK2 617V > F mutation: K2(T)%/K2(G)% ratio 30–230; homozygous JAK2 617V > F mutation: K2(T)%/K2(G)% ratio > 230 (9,10). The JAK2 exon 12 mutations were also determined, according to the description by Scott et al. (8), using the PCR and direct sequence method. To diagnose PV, we used the criteria proposed by the PV study group (PVSG) since long-term followed up patients were diagnosed based on the PVSG criteria, and reassessed by the WHO criteria and tried to categorize into two groups, as possible (1). The first category is ‘isolated erthrocythemia’ and the second one is ‘proliferative polycythemia’. When patients had neither palpable splenomegaly nor serum erythropoietin levels lower than the normal limit, they did not meet the WHO-PV criteria. In the same situation, when patients had a leukocyte count of >12 000 x 106/l or >400 x 109/l platelets, they were usually given the diagnosis of WHO-PV. Patients with ‘isolated erythrocythemia’ were thus defined as those PV patients with a leukocyte count of <12 000 x 106/l and a platelet count of <400 x 109/l at diagnosis: these hematologic levels were assigned to category B in criteria of the PVSG and the WHO. In contrast, PV patients without ‘isolated erythrocythemia’ were categorized as ‘proliferative polycythemia’. Therefore, in this report, we used the term ‘isolated erythrocythemia’ to mean monopathic erythrocytosis, but we could exclude secondary erythrocytosis.
Of the 33 PV patients given a diagnosis based on the PVSG criteria, we found 11 patients fitted the definition of ‘isolated erythrocythemia’ and four of them met the WHO criteria (Table 1), while all patients with ‘proliferative polycythemia’ satisfied the WHO criteria. The four patients in the group of ‘isolated erythrocythemia’ satisfied the WHO criteria because of the presence of palpable splenomegaly at diagnosis. The 11 patients with ‘isolated erythrocythemia’ were all male, and tended to younger than those with ‘proliferative polycythemia’ (P = 0.0774). Between these groups, there was no significant difference of hemoglobin and hematocrit levels (Table 1). Patients with ‘proliferative polycythemia’ had significantly higher levels of maximal leukocytes and maximal platelets, and a high frequency of requiring cytoreductive chemotherapy during their courses (P = 0.0009).
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No significant differences were determined in the occurrence of thrombosis (P = 0.3384) or palpable splenomegaly (P = 0.3245) between these groups, but a high frequency of anti-coagulant administration in ‘proliferative polycythemia’ group (P = 0.0321). Patients with ‘proliferative polycythemia’ tended to show detectable cytogenetic abnormalities (3/21 versus 0/9), suggesting an accumulation of genetic changes, in addition to JAK2 617V > F mutation. No patients with ‘isolated erythrocythemia’ showed evolution of myelofibrosis (0/11 versus 5/22: P = 0.0861) or acute leukemia, but without statistical significance (Table 1).
Of the 11 patients with ‘isolated erythrocythemia’, four patients met the WHO criteria and two of them had JAK2 617V > F, whereas none of the seven patients without the WHO criteria showed JAK2 617V > F mutation detected by the SSP-SMFD assay. In contrast, all 22 patients with ‘proliferative polycythemia’ had JAK2 617V > F mutation; 16 patients were determined to have heterozygous JAK2 617V > F and 6 were homozygous JAK2 617V > F (Table 1). None of the 33 PV patients showed MPL 515 mutation (data not shown). We also studied 7 of the 11 patients with ‘isolated erythrocythemia’ and failed to detect JAK2 exon 12 mutation.
In our study, 4 of 11 patients with ‘isolated erythrocythemia’ were given a diagnosis of WHO-PV because of the presence of splenomegaly and 2 of them had JAK2 617V > F, suggesting that the frequency of JAK2 617V > F mutation in PV depends on the diagnostic definition. Verstovsek et al. (11) stated that both technical differences and diagnostic differences are the main elements causing different frequencies of JAK2 617V > F mutation in PV patients. It is known that JAK2 617V > F-negative PV patients show lower leukocytes and platelets compared with those with JAK2 617V > F (3,5,6,9). Scott et al. found JAK2 exon 12 mutations in JAK2 617V > F-negative PV or ‘pure erythrocytosis’ and they found that patients with exon 12 mutations were significantly younger, with a low white-cell count, and a low platelet count (8), which agrees with our proposed category of ‘isolated erythrocythemia’. They further demonstrated a significantly high level of hemoglobin in PV patients without JAK2 617V > F but who had JAK2 exon 12 mutations (8). The PV patients with JAK2 617V > F tend to show pan-myelosis (4,5,9), thus indicating that the presence of JAK2 617V > F mutation might be sufficient to diagnose ‘proliferative polycythemia’. However, it is obscure whether the categorization of patients with non-WHO ‘isolated erythrocythemia’ should be classified as idiopathic erythrocytosis or as a spectrum of PV. Scott et al. reported that only 50% of patients (four of eight tested) showed a low serum erythropoietin level in their polycythemic patients with JAK2 exon 12 mutations, despite a higher level of red blood cell volume compared with those with JAK2 617V > F (8). Some of our patients with ‘isolated erythrocythemia’ were not given the WHO-PV diagnosis as a result of low but within normal range serum erythropoietin levels or a lack of palpable splenomegaly. Nevertheless, the low erythropoietin level, but not splenomegaly, is one of minor criteria of the revised WHO for the diagnosis of PV (2). This may indicate the possibility of underestimation of patients with polycythemia. We could not find out any clinico-hematologic difference, except for palpable splenomegaly, among patients with so-called ‘isolated erythrocythemia’ with or without JAK2 617V > F.
On the basis of the revised WHO criteria (2,12), the presence of JAK2 617V > F or other functionally similar mutations such as JAK2 exon 12 mutations may be one of the major criteria in diagnosing PV. It is still obscure whether all patients with isolated polycythemia show biological or functional similarity to those with JAK2 exon 12 mutations. Moreover, it is controversial whether the JAK2 617V > F mutation in PV patients is a primary event (13). The current clinical study supports the idea that ‘isolated erythrocythemia’ may be a distinct subset of polycythemia, and they usually do not progress to ‘proliferatative polycythemia’. Further analysis of detailed hematologic follow-up of monopathic erythrocytosis is required.
Thanks are due to Professor J. Patrick Barron of the International Medical Communications Center of Tokyo Medical University for his review of this manuscript, and Mr Tohru Makino and Kunio Hori, NovusGene (Tokyo) for their technical help. This work was supported in part by the ‘High-Tech Research Center’ Project from the Ministry of Education, Culture, Sports and Technology (MEXT) and by the ‘University-Industry Joint Research Project’ from MEXT. This work has been also supported by Foundation for Promotion of Cancer Research in Japan (JHO).
Conflict of interest statement
None declared.
References
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