Page 1251 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 68 The Polycythemias 1097

TABLE World Health Organization Criteria for and TET2. Some of these tests can be performed by commercial
68.3 Polycythemia Vera 24 laboratories, but often one will have to contact an academic refer-
ence laboratory to complete such an extensive investigative effort
2016 WHO Diagnostic Criteria for PV (www.mayomedicallaboratories.com/articles/features/erythrocytosis/
Major criteria: testing).
1. Hemoglobin >16.5 g/dL in men, 16 g/dL in women, or PV must also be differentiated from the other MPNs, such as
hematocrit >49% (men), >48% women or increased RCM) a CML, ET, and PMF. Such classification has major prognostic impli-
2. BM biopsy showing hypercellularity for age with trilineage growth cations and influences important therapeutic decisions, including
(panmyelosis) including prominent erythroid, granulocytic, and the use of tyrosine kinase inhibitors. With the distinctive cytogenetic
megakaryocytic proliferation with pleomorphic, mature abnormalities and molecular genetic abnormalities that are unique to
megakaryocytes CML (Philadelphia chromosome, BCR-ABL gene fusion), these two
3. Presence of JAK2V617F or JAK2 exon 12 mutation disorders should not be difficult to differentiate. Occasional patients
Minor criteria: with an MPN have been shown to have both JAK2V617F as well as
1. Serum EPO level less than the reference range for normal BCR-ABL; whether this unusual occurrence that takes place in two
Diagnosis requires meeting either all three major criteria or the first two different clones and thereby represents two independent MPNs or
major criteria and the minor criterion a single clone and is caused by the predisposition of such patients
a More than 25% above mean normal predicted value. to acquire mutations in their hematopoietic cells is a subject of
BM, Bone marrow; EPO, erythropoietin; PV, polycythemia vera; RCM, red cell speculation.
mass; WHO, World Health Organization. Patients with PMF can present with abnormalities that are virtu-
Data from Arber DA, Orazi A, Hasserjian R, et al: The 2016 revision to the ally indistinguishable from those of patients with PV-related MF.
World Health Organization classification of myeloid neoplasms and acute
leukemia. Blood 127:2391, 2016. Almost 50% of PMF are JAK2V617F positive, but more than 90%
of patients with post-PV MF are JAK2V617F positive. The survival
of patients with the latter disorder is much shorter than that of
patients with the former condition. Unusual patients with PMF may
measurements do, however, remain an important diagnostic tool. actually develop PV after iron supplementation or the institution of
Elevation of EPO levels in the face of erythrocytosis is indicative of chemotherapy. ET with a borderline elevated hematocrit and PV
a hypoxic cause of secondary erythrocytosis, but extremely low levels with marked thrombocytosis can easily be confused. When the RBC
of EPO (<4 mIU/mL) are virtually diagnostic of PV. mass is used as a definitive diagnostic test, a distinction between
Incorporating a mutational screen into the algorithm for investi- ET and the erythrocytotic phase of PV is usually readily apparent.
gating a case of suspected polycythemia will help to streamline the This measurement is not widely available and can also be normal
diagnosis of PV, although the presence of a JAK2 mutation alone does or actually low in patients with PV who are iron deficient because
not distinguish PV from PMF or ET. Clinical criteria for the diagnosis of bleeding or excessive phlebotomy. Campbell and coworkers have
of PV have been defined by the World Health Organization (WHO), used sensitive PCR-based methods to assess the JAK2 mutational
which serves as a uniform platform with which to diagnose PV. It is states in 806 patients with ET. The mutation was present in more
important, however, for the clinician to realize that some patients than 50% of patients with ET. JAK2V617F-positive ET patients were
undoubtedly have an MPN disorder resembling PV but do not fulfill characterized by multiple features that resembled those of patients
all the diagnostic criteria of the PVSG or the WHO. The criteria for with PV, including higher hemoglobin levels, higher WBC counts,
the diagnosis of PV, including the use of the JAK2V617 assay and more prominent BM erythroid and granulocytic hyperplasia, a higher
histopathologic parameters, have been provided by the WHO (Table incidence of venous but not arterial thrombosis, low serum EPO
24
68.3). These criteria are the consensus of many experts working in levels, and lower serum ferritin levels. Surprisingly, JAK2V617F-
this field. negative patients who likely had calreticulin mutations had higher
There will always be unusual cases with clinical characteristics that platelet counts. Furthermore, JAK2V617F-positive ET patients
cannot be pigeonholed into a particular diagnostic category. If these had a higher probability of developing PV with long follow-up.
patients have serious symptoms, the individual physician must make Acquisition of homozygosity for the JAK2V617 caused by homolo-
treatment decisions on the basis of the risk–benefit ratio for that gous recombination is likely the critical event in the development
patient. of PV in JAK2V617F ET patients. Homozygosity for JAK2V617F
A particularly difficult dilemma occurs when evaluating patients occurs in at least 30% of patients with PV but is extremely
with isolated pure erythrocytosis. These patients have elevated RBC rare in ET.
masses, normal WBC counts, normal platelet counts, no evidence of
splenomegaly, and no evidence of any recognizable cause of secondary
erythrocytosis. Clearly, some of these patients have JAK2V617F- PROGNOSIS
positive PV or mutations of exon 12 JAK2, leading to isolated
erythrocytosis. The PFCPs are caused by truncation of the EPOR, The prognosis of a patient with PV depends on the nature and
characterized by increased sensitivity of erythroid progenitor cells severity of the complications that occur during the clinical course of
to EPO, and can be easily distinguished from PV. These patients that particular patient’s disorder. In addition, an individual patient’s
frequently present in childhood, and this disorder is characterized prognosis depends on the duration of the erythrocytotic phase or the
by isolated erythrocytosis that is associated with an increased risk of time to transition to post-PV MF or acute leukemia. Survival is also
thrombotic events. There is a strong family history of polycythemia. influenced by whether appropriate treatment is instituted during the
The BM progenitor cells are hypersensitive to EPO, yet no colonies erythrocytotic phase of the illness. Patients who have uncontrolled
form in the absence of EPO. The patient with profound erythrocyto- erythrocytosis are at an extremely high risk for the development of
sis who is negative for JAK2V617F as well as exon 12 JAK2 mutations thromboses. The median survival time from the onset of symptoms
and does not have erythrocytosis caused by smoking, cyanotic heart has been reported in a study that is over four decades old to be as
disease, an EPO-secreting tumor,, sleep apnea, or resides at a high short as 1.5 years in untreated patients, but this number seems
altitude remains a diagnostic dilemma. All patients should have a excessive because of the relatively large number of patients who are
good family and drug history, an arterial oxygen saturation study and diagnosed during routine examinations and are asymptomatic for
a carboxyhemoglobin measurement, and measurement or calculation prolonged periods of time. Determination of the optimal manage-
of p50, and quantitation of 2,3BPG and serum EPO levels. If these ment of patients with PV has been a difficult task because the disease,
studies are unrewarding, these patients should then be investigated when treated, is associated with a survival period of approximately
for mutations in the hypoxia-responsive element of the human 17 years. Studies of new potential therapeutic interventions therefore
EPO gene, HIF-2α and HIF-1α, VHL, PHD1,2,3, STAT5, LNK, require prospective studies with prolonged follow-up times before