Department of Laboratory Medicine
Contributions
Type: Publication Only
Background
According to WHO classification 2008, myeloproliferative neoplasm, unclassifiable (MPN-U) is defined as neoplasms that has MPN features but fails to meet the criteria of any specific MPN entities, or that has two or more characteristics of MPN entities. Accurate diagnosis of each MPN subgroup is important because each subgroup could show different clinical courses ; leukemic transformation rate at 20 years is estimated at <10% for polycythemia vera (PV) and <5% for essential thrombocythemia (ET) and fibrotic transformation rates are slightly higher (Tefferi A. Am J Hematol 2015;90:162). The prognosis of primary myelofibrosis (PMF) is significantly poor, compared with those of PV or ET.
Aims
The clinicopathologic characteristics of MPN-U are needed to be cleared so that we could assign MPN-U to specific subtypes, if possible. The purpose of this study was to identify characteristics of laboratory findings, bone marrow pathology, genetic aberrations and clinical course in MPN-U.
Methods
The study group included 8 patients diagnosed as having MPN-U based on WHO 2008 criteria from 2000 to 2014. Median follow up period was 59 months (range 8-91 months). The mutation analysis of JAK2, MPL and CALR was performed by real time PCR or direct Sanger sequencing. Whole genome single nucleotide polymorphism array (SNP-A) (SNP 6.0, Affymetrix, CA) based karyotyping and target exome sequencing (Ion AmpliSeq Comprehensive Cancer panel, Life Technologies) were performed according to manufacturer’s instructions.
Results
Five patients with thrombocytosis (450-991x106/L) and normal or mild leukocytosis(7.6-14.9x106/L) showed upper normal hemoglobin (16.1-17.4 g/dL in 2 men, 15.9-16.1 g/dL in 3 women), but, not met PV criteria of WHO 2008 (Hb >16.5 g/dL for women and 18.5 g/dL for men). Hypercellularity with trilineage proliferation for ages was found in 4 patients and megakaryocytic atypia was found in 1 patients. All patients showed normal karyotype and JAK2 V617F mutation. Of them, two patients showed one or more mutations in addition to JAK2 : 1 patient had JAK2, DNMT3A, and C-KIT; 1 patient JAK V617F and CSF1R. In the other hand, a 73-year old female patient with high hemoglobin (Hb 16.3 g/dL) had neither JAK2 V617F nor CALR mutation and the laboratory findings were as follows ; WBC 15x106/L, platelet 1,290x106/L, low levels of erythropoietin and panhyperplasia with megakaryocytic atypia. There was no one progression showing hemoglobin levels which met the criteria for typical PV during follow up period. Taken together, these patients didn’t meet the hemoglobin criteria for PV, but we can’t exclude the possibility of pre-PV phase.
In two patients developed myelofibrosis, the initial laboratory findings met neither the criteria of PMF nor ET fully. One patient (55-year old female) developing myelofibrosis at 33 months after initial diagnosis showed CALR mutation and copy neutral-loss of heterozygosity of 19p13.3-p13.12 region (including CALR gene) by SNP-A based karyotyping. The other laboratory findings were as follows: Hb 13.8 g/dL, WBC 6x106/L, platelet 1,626x106/L, increased LDH, normocellularity for ages and megakaryocytic atypia. The other patient (62- year old female) developing myelofibrosis at 6 months showed dual mutations of MPL and SF3B1, Hb 13.0 g/dL, WBC 17x106/L, platelet 930x106/L, increased LDH, hypercellularity for ages, but not significant megakaryocytic atypia. These findings suggested that these two patients may be prefibrotic stage of PMF at initial diagnosis.
Summary
This study suggests that MPN-U could include pre-PV or prefibrotic-PMF. Therefore, the pathologists need to assign a more specific diagnosis in MPN-U and further follow up study is recommended to provide a more precise classification in MPN-U patients.
Keyword(s): Genomics, Myelofibrosis, Myeloproliferative disorder, Polycythemia vera
Type: Publication Only
Background
According to WHO classification 2008, myeloproliferative neoplasm, unclassifiable (MPN-U) is defined as neoplasms that has MPN features but fails to meet the criteria of any specific MPN entities, or that has two or more characteristics of MPN entities. Accurate diagnosis of each MPN subgroup is important because each subgroup could show different clinical courses ; leukemic transformation rate at 20 years is estimated at <10% for polycythemia vera (PV) and <5% for essential thrombocythemia (ET) and fibrotic transformation rates are slightly higher (Tefferi A. Am J Hematol 2015;90:162). The prognosis of primary myelofibrosis (PMF) is significantly poor, compared with those of PV or ET.
Aims
The clinicopathologic characteristics of MPN-U are needed to be cleared so that we could assign MPN-U to specific subtypes, if possible. The purpose of this study was to identify characteristics of laboratory findings, bone marrow pathology, genetic aberrations and clinical course in MPN-U.
Methods
The study group included 8 patients diagnosed as having MPN-U based on WHO 2008 criteria from 2000 to 2014. Median follow up period was 59 months (range 8-91 months). The mutation analysis of JAK2, MPL and CALR was performed by real time PCR or direct Sanger sequencing. Whole genome single nucleotide polymorphism array (SNP-A) (SNP 6.0, Affymetrix, CA) based karyotyping and target exome sequencing (Ion AmpliSeq Comprehensive Cancer panel, Life Technologies) were performed according to manufacturer’s instructions.
Results
Five patients with thrombocytosis (450-991x106/L) and normal or mild leukocytosis(7.6-14.9x106/L) showed upper normal hemoglobin (16.1-17.4 g/dL in 2 men, 15.9-16.1 g/dL in 3 women), but, not met PV criteria of WHO 2008 (Hb >16.5 g/dL for women and 18.5 g/dL for men). Hypercellularity with trilineage proliferation for ages was found in 4 patients and megakaryocytic atypia was found in 1 patients. All patients showed normal karyotype and JAK2 V617F mutation. Of them, two patients showed one or more mutations in addition to JAK2 : 1 patient had JAK2, DNMT3A, and C-KIT; 1 patient JAK V617F and CSF1R. In the other hand, a 73-year old female patient with high hemoglobin (Hb 16.3 g/dL) had neither JAK2 V617F nor CALR mutation and the laboratory findings were as follows ; WBC 15x106/L, platelet 1,290x106/L, low levels of erythropoietin and panhyperplasia with megakaryocytic atypia. There was no one progression showing hemoglobin levels which met the criteria for typical PV during follow up period. Taken together, these patients didn’t meet the hemoglobin criteria for PV, but we can’t exclude the possibility of pre-PV phase.
In two patients developed myelofibrosis, the initial laboratory findings met neither the criteria of PMF nor ET fully. One patient (55-year old female) developing myelofibrosis at 33 months after initial diagnosis showed CALR mutation and copy neutral-loss of heterozygosity of 19p13.3-p13.12 region (including CALR gene) by SNP-A based karyotyping. The other laboratory findings were as follows: Hb 13.8 g/dL, WBC 6x106/L, platelet 1,626x106/L, increased LDH, normocellularity for ages and megakaryocytic atypia. The other patient (62- year old female) developing myelofibrosis at 6 months showed dual mutations of MPL and SF3B1, Hb 13.0 g/dL, WBC 17x106/L, platelet 930x106/L, increased LDH, hypercellularity for ages, but not significant megakaryocytic atypia. These findings suggested that these two patients may be prefibrotic stage of PMF at initial diagnosis.
Summary
This study suggests that MPN-U could include pre-PV or prefibrotic-PMF. Therefore, the pathologists need to assign a more specific diagnosis in MPN-U and further follow up study is recommended to provide a more precise classification in MPN-U patients.
Keyword(s): Genomics, Myelofibrosis, Myeloproliferative disorder, Polycythemia vera