Polycythemia Vera (PV)

 

Epidemiology and Etiology:

·       All of these must be excluded:

·       secondary erythrocytosis,

·       inheritable polycythaemia, and

·       other MPNs

·       0.7 to 2.6 per 100,000 in Europe and NA

·       Much lower in Japan

·       60 y. median age

·       Rare under 20 y

·       Unknown underlying cause mostly

·       Ionizing radiation maybe

·       Occupational exposure to toxins maybe

·       Genetic predisposition in some families

 

Common sites:

·       Blood

·       BM

·       Spleen (EMH in later stages)

·       Liver (EMH in later stages)

·       Organ damage as a result of vascular consequences of increased red cell mass

 

Gross features:

·        “spent” or post-polycythaemic myelofibrosis phase (post-PV MF)

·       hypersplenism

·        

 

Cytologic and Histologic features:

·       Panmyelosis

·       PB:

·       Mild to overt excess of normochromic, normocytic red blood cells

·       (may be iron deficiency changes if bleeding is present)

·       Neutrophilia maybe

·       Occasional immature granulocytes maybe in overt polycythaeimic phase

·       Basophilia maybe

·       No circulating blasts generally

·       Thrombocytosis

·       Disease progression / :

·       Leucoerythroblastic

·       Poikilocytosis

·       Teardrop-shpaed red blood cells

·       BM:

·       Hypercellular for patient’s age characteristically

·       35-100% cellularity (median 80%)

·       Submcortical marrow space shows increased cellularity (especially noteworthy since this area is normally hypocellular)

·       Panmyelosis (helps distinguish from ET)

·       Increased erythroid precursors and megakaryocytes is often most prominent

·       Erythropoiesis normoblastic

·       Granulopoiesis morphologically normal

·       Myeloblasts not increased

·       Megakaryocytes increased in number

·       Characteristic morphological abnormalities even in early phase

·       Hyperlobated nuclei

·       Significant pleomorphism with a mixture of different sizes

·       Majority exhibit normally folded or deeply lobulated nuclei

·       Lacking significant cytological abnormalities

·       Minority with bulbous nuceli and other nuclear abnormalities

·       Loose clusters or lying close to the bone trabeculae

·        “spent” or post-polycythaemic myelofibrosis phase (post-PV MF)

·       Bone marrow (BM) fibrosis (MF) (reticulin and collagen fibrosis is morphologic hallmark of this stage)

·       Hypocellular commonly (varies)

·       Erythropoiesis and granulopoiesis are decreased

·       Clusters of megakaryocytes, often with hyperchromatic and very dysmorphic nuclei, are prominent

·       significant myelodysplasia is unusual and most likely signals transformation to accelerated phase and/or MDS

·       Osteosclerosis maybe

·       Increase in immature cells maybe

·       > 10% blasts in PB or BM is unusual and most likely signals transformation to accelerated phase and/or MDS

·       > 20% blasts is considered AML

·       Reticulin normal (80%)

·       Increased reticulin and even borderline to mild collagen fibrosis in some

·       Lymphoid aggregates maybe (up to 20%)

·       Iron stain lacking (> 95%)

·       Extramedullary haematopoiesis (EMH) (post-PV MF / “spent” phase)

·        

 

Immunophenotype:

Marker:

Sensitivity:

Specificity:

 

 

 

·        No abnormal immunophenotype reported

 

Molecular features:

·       JAK2 mutation

·       V617F (> 95%)

·       Trilineage hyperplasia

·       Exon 12 mutation (mutually exclusive to V617F)

·       Isolated erythrocytosis

·       Homozygous, biallelic in 1/3

·       Gain of function

·       Not specific (other myeloid neoplasms)

·       LOH at 9p encompassing JAK2 (~35 %)

·       Karyotype abnormalities (20% at diagnosis) (80-90% at post-PV MF)

·       del(20)(q)

·       +8

·       +9

·       May occur in conjunction with activating JAK2 mutations

·       9p gains

·       del(13)(q) (10% of abnormal karyotypes)

·       interstitial with variable boundaries

·       q13q21 most frequent

·       RB1 at 13q14 is always deleted

·       1q gains

·       Additional chromosomal aberrations usually accompanying evolution to PPMF or AML:

·       1q duplication

·       therapy-related MDS/AML changes

·       del(5)(q)

·       del(7)(q)

·       del(17)(p)

·       no BCR-ABL1 fusion by definition

 

Other features:

·       Diagnostic criteria:

·       Both major criteria and one minor criterion, OR first major criterion with 2 minor criteria

·       Major criteria:

·       JAK2 V617F or other functionally similar mutation (eg. exon 12 mutation)

·       Hb > 18.5 g/dL (men) or 16.5 g/dL (women) OR one of the following:

·       Hb or haematocrit > 99th percentile of method-specific reference range for age, sex, altitude of residence

·       Hb > 17 g/dL (men) or 15 g/dL (women) if associated with a documented and sustained increase of at least 2 g/dL from an individual’s baseline value that cannot be attributed to correction of iron deficiency

·       Elevated red cell mas > 25% above mean normal predicted value

·       Minor criteria:

·       Hypercellular BM biopsy for age with trilineage growth (panmyelosis), with prominent erythroid, granulocytic, and megakaryocytic proliferation

·       Erythropoieitin (EPO) level below normal reference range

·       Endogenous erythroid colony (EEC) formation in vitro

·       Post-polycythaemic myelofibrosis (post-PV MF)

·       Required criteria:

·       Previous diagnosis of PV (defined as above) documented

·       Bone marrow fibrosis grade 2-3 (on 0-3 scale) or grade 3-4 (on 0-4 scale)

·       Additional criteria (2 required):

·       Anaemia or sustained loss of either phlebotomy (in the absence of cytoreductive therapy) or cytoreductive treatment requirement for erythrocytosis

·       Leukoerythroblastic peripheral blood picture

·       Increasing splenomegaly defined as EITHER:

·       Increase in palpable splenomegaly of > 5 cm from baseline (distance from the left costal margin)

·       Appearance of newly palpable splenomegaly

·       > 1 constiutional symptoms:

·       > 10% weight loss in 6 months

·       Night sweats

·       Unexplained fever > 37.5 oC

·       3 phases:

·       Prodromal, pre-polycythaemic phase (latent PV, pure idiopathic erythrocytosis)

·       Borderline to only mild erythrocytosis

·       Symptoms listed below

·       Overt polycythaemic phase

·       Significantly increased red cell mass

·       “spent” or post-polycythaemic myelofibrosis phase (post-PV MF)

·       Cytopenias, including anaemia

·       Ineffective haematopoiesis

·       Bone marrow (BM) fibrosis

·       Extramedullary haematopoiesis (EMH)

·       hyperspenism

·       low incidence of evolution to a MDS/pre-leukemic phase / AML

·       may clinically mimic ET but eventually evolve into an overtly polycythaemic stage

·       Major symptoms related to HTN or vascular abnormalities caused by increased red cell mass:

·       Venous or arterial thrombosis (DVT, MI, stroke) (20%)

·       Mesenteric, portal or splenic vein thrombosis

·       Budd-Chiari syndrome

·       May precede overt polycythemic phase

·       Headache

·       Dizziness

·       Visual disturbances

·       Paraesthesias

·       Pruritus

·       Erythromelalgia

·       Gout

·       Plethora

·       Palpable splenomegaly (full-blown polycythaemic stage) (70%)

·       Hepatomegaly (40%)

·       Median survival > 10 years

·       Most patients die from thrombosis or haemorrhage

·       MDS or AML in up to 20%

·       Risk increases following certain types of chemotherapy / cytotoxic agents

 

References:

·       Heim S, Mitelman F. Cancer Cytogenetics. 3rd ed. Wiley-Blackwell; 2009.

·       Gong JZ et al.  Laboratory Practice Guidelines for Detecting and Reporting JAK2 and MPL Mutations in Myeloproliferative Neoplasms: A Report of the Association for Molecular Pathology.  J Mol Diagn 2013;15:733-744.

·       Swerdlow SH et al.  WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (2008)