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Distinguishing ET JAK2V617F from PV Table 1. Demographic and hematologic data of polycythemia vera (PV) and essential thrombocythemia (ETJAK2V617F) patients at diagnosis.
PV Patients (n = 83) ET Patients (n = 39) Men(n=45) Women(n=38) Men(n=12) Women(n=27)
Age median, range (yrs)
HCT mean ± SD (%)
HGB mean ± SD (g/dL)
RBC mean ± SD (x1012/L)
RCM mean ± SD (%)
Plasma volume mean ± SD (%)
SEV mean ± SD (mU/mL)
53.0 (28.0-80.0)
50.9±4.4 17.1±1.7 5.8±0.6 141.7±14.4 (n=28) 105.1±15.0
(n=41) 4.2±2.9
57.0 (27.0-78.0)
51.2±5.8
16.7±1.8
6.0 ± 0.9
149.4±24.5
(n=21) 99.4±15.3
(n=35) 2.8±1.6
53.5 (29.0-77.0)
43.5±4.4 14.9±1.6 4.9±0.8 91.8±15.9 91.2±9.4
(n=9) 5.8±2.1
51.0 (24.0-76.0)
42.8±2.2 14.4±0.8 4.8±0.4 96.1±14.8 (n=26) 99.1±11.5
(n=14) 5.6±3.0
n: number; yrs: years; HCT: hematocrit; HGB: hemoglobin; RBC: red blood cell count; RCM: red cell mass; SD: standard deviation; SEV: serum erythropoietin values.
HCT and HGB threshold values6 as surrogates for RCM to help diagnose and distinguish these diseases.7 These unconfirmed values were derived from a retrospective study and do not discriminate all cases of ETJAK2V617F from PV.2,7 For this reason, the WHO has advocated marrow biopsy and serum erythropoietin values (SEV), although it is not clear how frequently these tests are actually per- formed in clinical practices.
Since red cell values in ETJAK2V617F and PV can overlap, a proportion of both diseases may be misdiagnosed. Therefore, we decided to systematically study the sensi- tivity and specificity of distinguishing ETJAK2V617F with rel- atively high-normal red blood values from PV in patients when the RCM had been confirmed by isotope studies. Using a newly devised database-querying tool, we also determined the frequency of marrow biopsy and SEV testing, both of which we use at our own intuition.
Methods
The Institutional Review Board of Weill Cornell Medicine (WCM) approved this study. Signed informed consent was obtained in accordance with the Declaration of Helsinki.
The diagnosis of PV in our patients was established according to our previously published criteria which included JAK2V617F positivity, a Cr-51 isotope measured RCM≥125% of expected volume, and a marrow biopsy consistent with PV.4,8 The diagno- sis of ETJAK2V617F in our patients was established using JAK2V617F positivity, a Cr-51 isotope measured RCM<125% of expected volume, WHO 2007 criteria,1 and a marrow biopsy consistent with ET.8 ETJAK2V617F patients presenting with “high-normal” blood values (women: HCT>42.0%, HGB>14.0 g/dL; men: HCT>45.0%, HGB>15.0 g/dL) prompted an RCM study and were selected for this review.
We used a bioinformatics tool developed at WCM to search our electronic medical records for patients with an International Classification of Diseases (ICD) 9 or 10 code for PV or ET who had an RCM study performed from 2004-2017.9
Utilizing a receiver operating characteristic (ROC) analysis, we then determined threshold values for HCT, HGB, and RBC to establish limits of specificity and sensitivity. The ROC analy- sis calculates the optimal combination of sensitivity and speci- ficity thresholds within a range of values to determine which one is the most accurate for diagnosis. We then plotted these ROC-derived threshold values and the frequencies of red cell values obtained at the time of isotope studies to ascertain whether there was any overlap between ETJAK2V617F and PV.
Results
Of 157 patients who had an RCM study performed, 35 were excluded because of JAK2V617F and exon 12 negativ- ity; of the remaining 122 patients, 83 PV and 39 ETJAK2V617F patients met study requirements. Relevant demographic and hematologic data of these patients, including age, HCT, HGB, RBC, RCM, and plasma volume are shown in Table 1. The blood values were recorded at the time of isotope study and prior to any treatment, including phle- botomy. The median age for male and female PV patients was 53.0 (28.0-80.0) and 57.0 (27.0-78.0) years, respective- ly. The median age for male and female ETJAK2V617F patients was 53.5 (29.0-77.0) and 51.0 (24.0-76.0) years, respective- ly. For male PV patients, the mean HCT was 50.9±4.4%, the mean HGB 17.1±1.7 g/dL, and the mean RBC count 5.8±0.6x1012/L. For female PV patients, the mean HCT was 51.2±5.8%, the mean HGB 16.7±1.8 g/dL, and the mean RBC count 6.0±0.9x1012/L. For male ETJAK2V617F patients, the mean HCT was 43.5±4.4%, the mean HGB 15.4±1.6 g/dL, and the mean RBC count 4.9±0.8x1012/L. For female ETJAK2V617F patients, the mean HCT was 42.8±2.2%, the mean HGB 14.4±0.8 g/dL, and the mean RBC count 4.8±0.4x1012/L. The mean Cr-51 RCM of all 83 PV patients was 145.3±20.1%, greater than 125% above the expected value and thus establishing polycythemia;4 it was measured in 39 presumptive ETJAK2V617F and it was nor- mal in all of them (mean: 94.8±15.3%). These RCM values show a clear distinction because unlike in red cell values, there was no overlap in values. The mean plasma volume was measured in 49 of 83 PV patients and it was 102.7±15.4%. The mean plasma volume was measured in 38 of 39 ETJAK2V617F patients and was 96.6±11.5%. The dif- ference in plasma volume for all patients with PV and ETJAK2V617F was statistically significant (P=0.04) due to dif- ferences for male patients (P=0.01), but not for female patients (P=0.94). In addition, there was a weak correla- tion between HCT and plasma volume (r=-0.05). The mean serum erythropoietin value (SEV) was measured in 76 of 83 PV patients and was 3.5±2.5 mU/mL. The mean SEV was measured in 23 of 40 ETJAK2V617F patients and was 5.7±2.7 mU/mL.
Receiver operating characteristic (ROC) analyses were performed to determine optimal threshold values of HCT, HGB, and RBC to discriminate ETJAK2V617F from PV. The threshold values for distinguishing ETJAK2V617F from PV in men and women, respectively, are HCT: 49.3 and 47.9%, HGB: 16.8 and 15.3 g/dL, and RBC: 5.8 and 5.1x1012/L
haematologica | 2019; 104(11)
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