Polycythemia vera

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]; Shyam Patel [3]

Primary polycythemia occurs when excess red blood cells are produced as a result of an abnormality of the bone marrow. Often, excess white blood cells and platelets are also produced. Polycythemia vera is classified as a myeloproliferative neoplasm. Polycythemia vera arises from hematopoietic stem cells, which give rise to erythrocytes cells that are normally involved in delivering oxygen to the body tissue. The incidence of polycythemia vera is approximately 0.7 to 2.6 per 100,000 individuals in the US. Common risk factors in the development of polycythemia vera are history of thrombosis and old age ( 65 year old and older). If left untreated, patients with polycythemia vera may progress to develop headache, fatigue, and dyspnea. Common complications of polycythemia vera include bleeding, thrombosis, tinnitus , and splenomegaly. Prognosis is generally good with treatment, and the median survival for patients with polycythemia vera is around 10.9 to 27.8 years. People with polycythemia vera usually asymptomatic. Symptoms of polycythemia vera include headache, fatigue, and pruritis. Laboratory findings associated with the diagnosis of polycythemia vera include erythrocytosis, leukocytosis, andthrombocytosis. The mainstay of therapy for polycythemia vera is phlebotomy, hydroxyurea (alone or with phlebotomy), interferon-alpha and pegylated interferon-alpha, chlorambucil, and low-dose aspirin.

The first description of polycythemia vera dates back to the late 19th century. At that time, Louis Henry Vaquez and Sir William Osler were the first to describe this condition. Over the subsequent decades, the disease became better characterized. In the late 20th century, therapeutics were conceptualized, and it was found that hydroxyurea and interferon-alpha were effective in treating polycythemia vera. In 2005, a mutation in the JAK2 kinase (V617F) was found in multiple patients with myeloproliferative neoplasms (including polycythemia vera) by different researchers. The WHO developed diagnostic criteria for this condition in 2008. The WHO recently revised their criteria for the diagnosis of polycythemia vera in 2016.

Polycythemia vera is a subtype of myeloproliferative neoplasm. Myeloproliferative neoplasm may be classified according to the World Health Organization into eight subtypes: chronic myelogenous leukemia, chronic neutrophilic leukemia, polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic eosinophilic leukemia, mastocytosis, and myeloproliferative neoplasms, unclassifiable. The classification of polycythemia is subdivided into primary polycythemia (which is a clonal process caused by the JAK2 mutation) and secondary polycythemia (which is a reactive process due to a state of chronic hypoxia). There are numerous causes of secondary polycythemia, and most of these causes are cardiopulmonary in origin.

Normal physiology of red blood cell production involves the stimulation of the erythropoietin receptor on erythroid cells by the hormone erythropoietin. This process is normally tightly regulated. In polycythemia vera, there is autonomous production of red blood cells in an erythropoietin-independent manner due to an activating JAK2 mutation. The mutation is usually a point mutation (V617F). The JAK2 mutation causes hyperactivity of the red blood cell production process. Other mutations that are associated with the pathophysiology of polycythemia vera include mutations in TET2, SF3B1, and ASXL1. The resulting elevation of hemoglobin and red blood cell mass predisposes patients to thrombosis.

Polycythemia vera is caused by a mutation in the JAK2 gene (V617F mutation). This mutation occurs in more than 98% of cases of polycythemia vera. The JAK2 exon 12 mutation occurs in a small proportion of patients. There are no other causes of this disease.

Polycythemia vera must be differentiated from other myeloproliferative neoplasms, such as chronic myelogenous leukemia, essential thrombocythemia, and primary myelofibrosis. Polycythemia vera must also be differentiated from secondary polycythemia, which is usually due to chronic hypoxia. Each of these conditions have different etiologies, symptoms, laboratory abnormalities, physical exam findings, and treatments.

The incidence of polycythemia vera is approximately 0.7 to 2.6 per 100,000 individuals in the US.[1] The prevalence of polycythemia vera is 48 to 57 cases per 100,000 individuals in the United States. Males are more commonly affected than females. The life expectancy is variable but is typically more than 10 years for patients who have uncomplicated polycythemia vera and is significantly shorter in the case of post-PV myelofibrosis or post-PV acute myeloid leukemia.

Common risk factors in the development of polycythemia vera are old age (65 year old and older), family history, and Ashkenazi Jewish descent. After a patient is diagnosed with polycythemia vera, risk stratification involves assessment of age and thrombotic history. The risk assessment for development of post-PV myelofibrosis or post-PV acute myeloid leukemia include a variety of factors.

Screening for polycythemia vera is not a routine clinical practice. However, assessment of a complete blood count (CBC), which is done routinely, usually gives the first indication for the presence of polycythemia vera in a patient.

The natural history of polycythemia vera begins with symptoms such as headache, fatigue, and dyspnea. Common complications of polycythemia vera include thrombosis (such as deep vein thrombosis, pulmonary embolism, myocardial infarction, and stroke), bleeding, and splenomegaly. Prognosis is generally good with treatment, and the median survival for patients with polycythemia vera is around 10.9 to 27.8 years in the absence of complications. However, there is a variable risk for progression to myelofibrosis and acute myeloid leukemia, and these are the most devastating complications of the disease. Myelofibrosis and acute myeloid leukemia are part of the natural history of the disease.

The diagnosis of polycythemia vera is based on the World Health Organization criteria, which was initially proposed in 2008 then revised in 2016. In general, the diagnosis of polycythemia vera requires a combination of elevated hemoglobin, which include high levels of hemoglobin, presence of JAK2 V617F mutation, hypercellularity on bone marrow biopsy, low serum erythropoietin level, and endogenous erythroid colony formation in vitro.[1] The 2016 WHO criteria more accurately reflect the disease biology of polycythemia vera.

People with polycythemia vera usually asymptomatic. Symptoms of polycythemia vera include headache, fatigue, and pruritis. The symptomatology is highly variable between patients. Some patients can present with a minimal symptom burden that does not result in any change in quality of life, and other patients can have severe symptom burden.

Patients with polycythemia vera are usually well-appearing. Physical examination of patients with polycythemia vera is usually remarkable for skin bruising, fever, and splenomegaly.

Laboratory findings associated with the diagnosis of polycythemia vera include erythrocytosis, leukocytosis, and thrombocytosis. The most sensitive test for polycythemia vera is JAK2 V617F mutation testing in the peripheral blood. A specific finding in patients with polycythemia vera is low erythropoietin level.

Abdominal and chest CT scan may be helpful in the diagnosis of polycythemia vera. Findings on CT scan suggestive of polycythemia vera include enlarged lymph nodes, splenomegaly, and splanchnic venous thrombosis.

Brain MRI may be helpful in the detection of ischemic stroke in patients with polycythemia vera. Abdominal MRI can help with diagnosis of mesenteric thrombosis.

Abdominal ultrasound may be helpful in the diagnosis of myeloproliferative neoplasm. Findings on abdominal ultrasound suggestive of myeloproliferative neoplasm include splenomegaly, abdominal fluid, and hepatic lesions. Ultrasound of the extremities can assist with diagnosis of deep vein thrombosis, which is commonly associated with high-risk polycythemia vera.

Other imaging studies for polycythemia vera include PET scan, which helps to detect metastasis in bone marrow and to follow up medical treatment.

Other diagnostic studies for polycythemia vera include bone marrow aspiration and trephine biopsy. Erythropoietin levels can also be measured.

The mainstay of therapy for polycythemia vera is phlebotomy, aspirin, hydroxyurea (alone or with phlebotomy), interferon-alpha and pegylated interferon-alpha, chlorambucil. Some of these medications are targeted agents that work specifically in polycythemia vera, while others are non-specific therapies that can have numerous off-target adverse effects. Some of these treatments can modify the course of the disease, while others simply alleviate symptom burden.

Surgical intervention is a consideration in the management of polycythemia vera in case of splenomegaly, though surgery is not typically done.

There is no established method for primary prevention of polycythemia vera.

Secondary prevention strategy following polycythemia vera include low dose aspirin.

Template:Hematology

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ifeoma Odukwe, M.D. [2] Mohamad Alkateb, MBBCh [3], Shyam Patel [4]

The first description of polycythemia vera dates back to the late 19th century. At that time, Louis Henry Vaquez and Sir William Osler were the first to describe this condition. Over the subsequent decades, the disease became better characterized. In the late 20th century, therapeutics were conceptualized, and it was found that hydroxyurea and interferon-alpha were effective in treating polycythemia vera. In 2005, a mutation in the JAK2 kinase (V617F) was found in multiple patients with myeloproliferative neoplasms (including polycythemia vera) by different researchers. The WHO developed diagnostic criteria for this condition in 2008. The WHO recently revised their criteria for the diagnosis of polycythemia vera in 2016.

The history of polycythemia vera is presented chronologically.

• In 1892, Louis Henry Vaquez first described polycythemia vera as a disorder of hematopoietic hyperactivity.^{[1] [2]} He reported on a patient who had the polycythemia syndrome (elevated hemoglobin) without cardiopulmonary disease. Louis Henry Vasquez was the first person to suggest that the condition of elevated red blood cells could be divided into two categories:^[2]
  • Absolute erythrocytosis (due to elevated red blood cell mass)
  • Relative erythrocytosis (due to reduced plasma volume but not due to elevated red blood cell mass)

• In 1903, Sir William Olser reinforced the concept of polycythemia vera.^[1] He noted that in his clinical practice, patients with red blood cell elevation had a distinct clinical syndrome.^[2] He published a paper on these findings.

• In 1904, Wilhelm Turk, a Viennese physician, noted that all hematopoietic lineages, including white blood cells and platelets, were elevated in polycythemia vera. This suggested that polycythemia vera was not a condition exclusive to the erythroid lineage. This was the first suggestion that paved way for the idea that polycythemia vera was a disorder of the hematopoietic stem cell, as this cell gives rise to all lineages.^[2]

• In 1908, Sir William Osler described additional patients with polycythemia vera and wrote a second publication.

• In 1953, William Dameshek described myeloproliferative neoplasms as a group of disorders including polycythemia vera, essential thrombocythemia, and myelofibrosis.^[1] He postulated that polycythemia vera variably reflected bone marrow proliferative activity from an unidentified stimulus.

• From 1967 to 1997, the Polycythemia Vera Study Group created formal diagnostic criteria, brought to attention the value of therapeutic phlebotomy, and raised awareness about the use of hydroxyurea as a therapeutic intervention.^[3] Hydroxyurea was postulated to inhibit ribonucleotide reductase, which is necessary for cellular division and proliferation.

• In 1998, the anti-proliferative effects of interferon-alpha for polycythemia vera were described.^[1] Sustained hematologic responses by interferon-alpha were confirmed later via other studies.

• In 2005, multiple groups including those led by William Vainchenker, Ross Levine, Robert Kralovics, and Tony Green first described the JAK2 V617F mutation (in exon 14 of the JAK2 gene) in polycythemia vera.^[1][4] This is a gene encoding the Janus kinase 2 protein, and the mutation is a point mutation that converts valine to phenylalanine.

• In 2008, the World Health Organization (WHO) developed a classification for myeloproliferative neoplasms, including polycythemia vera. This classification included the JAK2 V617F mutation (or JAK2 exon 12 mutations) as a major criterion required for the diagnosis.^[1] The hemoglobin threshold for making a diagnosis of polycythemia vera was 18.5 g/dl in men and 16.5 g/dl in women. These hemoglobin values were deemed strong surrogate markers for an absolute increase in red blood cell mass, as hemoglobin is the main protein in red blood cells.

• In 2016, the WHO revised the classification scheme and diagnostic criteria for polycythemia vera. The diagnostic criteria now includes hemoglobin greater than 16.5 g/dl in men and 16 g/dl in women, bone marrow biopsy showing hypercellularity in all three cell lines (red blood cells, white blood cells, and platelets, and the presence of a JAK2 mutation (either V617F in exon 14 or a mutation in exon 12). These constitute the major criteria. The minor criteria is a subnormal erythropoietin level.

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ifeoma Odukwe, M.D. [2] Mohamad Alkateb, MBBCh [3]; Shyam Patel [4]

Polycythemia vera is a subtype of myeloproliferative neoplasm. Myeloproliferative neoplasm may be classified according to the World Health Organization into eight subtypes: chronic myelogenous leukemia, chronic neutrophilic leukemia, polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic eosinophilic leukemia, mastocytosis, and myeloproliferative neoplasms, unclassifiable. The classification of polycythemia is subdivided into primary polycythemia (which is a clonal process caused by the JAK2 mutation) and secondary polycythemia (which is a reactive process due to a state of chronic hypoxia). There are numerous causes of secondary polycythemia, and most of these causes are cardiopulmonary in origin.

Polycythemia vera is a subtype of myeloproliferative neoplasm. Myeloproliferative neoplasm may be classified according to the World Health Organization into eight subtypes:^{[1][2][3][4][5][6][7][8][9][10]}

• Polycythemia vera: This is a condition of elevated hemoglobin and red blood cell mass caused by the JAK2 mutation.
• Essential thrombocythemia: This is a condition characterized by persistent elevation in platelets which increases the risk for thrombosis and hemorrhage. It is associated with a variety of mutations, such as JAK2, CALR, or MPL. These mutations are mutually exclusive. This condition can progress to myelofibrosis, which carries a poor prognosis.
• Chronic myelogenous leukemia, BCR–ABL1–positive: This condition is a common cause of chronic leukemia. The peripheral blood of patients with chronic myelogenous leukemia commonly shows elevation of white blood cell precursors at all stages of maturation, including metamyelocytes, and band cells. Treatment involves oral tyrosine kinase inhibitors such as imatinib, dasatinib, bosutinib, nilotinib, or ponatinib.
• Chronic myelogenous leukemia, BCR–ABL1–negative (atypical CML): This a condition that carries a high risk for transformation into acute myeloid leukemia. It is frequently underdiagnosed since the BCR-Abl translocation is not found. Treatment considerations include allogeneic stem cell transplantation.
• Chronic neutrophilic leukemia: This is a condition characterized by elevation of neutrophil count and is commonly caused by a mutation in the colony-stimulating factor 3R (CSF3R) gene.
• Primary myelofibrosis: This is a highly lethal condition in which the bone marrow is replaced by reticulin fibrosis, resulting in ineffective erythropoiesis. The etiology of this disease is abnormal megakaryocyte proliferation and excess production of transforming growth factor-beta (TGF-beta), which stimulates collagen deposition and fibrosis.
• Chronic eosinophilic leukemia, not otherwise specified: This condition is of unknown etiology. There is clonal proliferation of erythropoetic precursors which results in elevated eosinophils in the blood, bone marrow or peripheral tissues.
• Mastocytosis: This condition is caused by mast cell proliferation and results in symptoms of coughing, wheezing, gastrointestinal upset, anaphylaxis, and diarrhea. Patients typically have high levels of histamine (a peptide released by mast cells). Treatment usually involves imatinib. In 2016, it was discovered that the tyrosine kinase inhibitor midostaurin could effectively treat mastocytosis, including patients who harbor the D816V mutation for which imatinib is ineffective.

• Cutaneous mastocytosis
• Systemic mastocytosis
• Mast cell leukemia
• Mast cell sarcoma
• Extracutaneous mastocytoma

• Myeloproliferative neoplasms, unclassifiable.

There are no subcategories within polycythemia vera.

Polycythemia vera is a subcategory of polycythemia in general. Classification of polycythemia in general includes primary polycythemia and secondary polycythemia. Secondary polycythemia is due to chronic hypoxia which results in compensatory increase in erythrocyte production. Secondary polycythemia is therefore characterized by a reactive increase in erythrocyte production, rather than clonal proliferation of erythrocytes.

• Primary polycythemia (polycythemia vera)
• Secondary polycythemia

• Congestive heart failure: This condition is defined as the inability of the circulatory system to meet the metabolic demands of exercising tissues.
• Chronic obstructive pulmonary disease: This is a group of disorders including chronic bronchitis and emphysema.
• Interstitial lung disease: This condition is due to destruction of the pulmonary parenchyma, resulting in fibrosis and scarring of the lung tissue. There are a variety of causes.
• Smoking: Cigarette smoking can cause a state of chronic hypoxia.
• Obstructive sleep apnea: This condition is due to physical impediment of the airways, resulting temporary cessation of breathing at night. This causes a state of chronic hypoxia.
• High altitude residence: Elevated heights carry low oxygen content.
• Erythropoietin-secreting tumors:

• Renal cell carcinoma: This is a malignancy of the kidney epithelial cells that sometimes produces the hormone erythropoietin.
• Hepatocellular carcinoma: This is a malignancy of the liver epithelial cells that sometimes produces the hormone erythropoietin.

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2] Ifeoma Odukwe, M.D. [3] Shyam Patel [4]

Normal physiology of red blood cell production involves the stimulation of the erythropoietin receptor on erythroid cells by the hormone erythropoietin. This process is normally tightly regulated. In polycythemia vera, there is autonomous production of red blood cells in an erythropoietin-independent manner due to an activating JAK2 mutation. The mutation is usually a point mutation (V617F). The JAK2 mutation causes hyperactivity of the red blood cell production process. Other mutations that are associated with the pathophysiology of polycythemia vera include mutations in TET2, SF3B1, and ASXL1. The resulting elevation of hemoglobin and red blood cell mass predisposes patients to thrombosis.

The normal physiology of polycythemia vera can be understood as follows:

• Under normal circumstances, erythrocytes are produced at a basal rate in response to erythropoietin. Erythropoietin is a hormone produced by the peritubular capillaries of the kidneys and serves as a signal for expansion of the erythrocyte pool. This process is normally tightly controlled. Janus kinase JAK2 is the receptor for erythropoietin, and this receptor (in the wild-type form) becomes activated when erythropoietin is present. JAK2 is a protein of the Janus kinase family, located on chromosome 9.^[1] JAK2 signals through STAT molecules, which are signal transducers and activators of transcription. Under conditions of low oxygen content, such as high altitude or smoking, erythropoietin production increases, and red blood cell production increases. This is the normal physiologic response to hypoxia, and this response serves to ensure adequate oxygen delivery to tissues.

• The presence of a JAK2 mutation within a hematopoietic stem cell and therefore within an erythroid precursor.^[1]
• The mutation that occurs is a point mutation that induces conversion of valine to phenylalanine at the 617th position within the JAK2 gene (JAK2 V617F).
• The JAK2 V617F point mutation is an activating mutation that results in autonomous activity of the JAK2 pathway, resulting in excess red blood cell production in an erythropoietin-independent manner.
• The JAK2 V617F mutation has been established to be positive in about 96% of people with polycythemia vera.^[2]
• There could also be a mutation in exon 12 of JAK2 which results in a smililar phenotype as JAK2 V617F. It is seen in about 2-3% of people with polycythemia vera.
• A very few patients with erythrocytosis and low erythropoetin (EPO) levels may have mutations in LNK (SH2B3), which is an inhibitor of the JAK-STAT signaling pathway.
• In addition to the JAK2 point mutation, epigenetic factors also contribute to the pathogenesis of polycythemia vera. This conclusion was made after it was determined that the same JAK2 activating mutation could contribute to the pathogenesis of essential thrombocythemia and primary myelofibrosis. In essential thrombocythemia, for example, the JAK2 mutation is found in ~50% of patients. These diseases have overlapping clinical features.^[2][3]
• On average, patients with polycythemia vera harbor 6-7 mutations. Besides the JAK2 mutation, other mutations occur in genes such as TET2 (found in 8.3% of patients), SF3B1 (involved in RNA splicing), DNMT3A (involved in epigenetic regulation), and ASXL1 (associated with a poor prognosis).^[2]
  

Genes involved in the pathogenesis of polycythemia vera include:^[2]

• JAK2 kinase (V617F)
• TET2
• SF3B1
• DNMT3A
• ASXL1

Conditions associated with polycythemia vera include:^[2]

• Myelofibrosis
• Secondary acute myeloid leukemia

• On microscopic histopathological analysis, characteristic findings of polycythemia vera include:^[4][5]

• Erythroid hyperplasia
• Granulocytic hyperplasia
• Increased number of atypical megakaryocytes of different sizes
• Monolobate to hyperlobate megakaryocyte nuclei with complex nuclear folding
• Megakaryocyte nuclear chromatin pattern: dispersed with prominent eosinophilic nucleoli to distinctly hyperchromatic
• Megakaryocytic clusters (greater than or equal to 3 megakaryocytes lying adjacent to each other with the absence of intervening cells)
• Normal or slightly increased bone marrow reticulin fibers
• Lymphoid nodules may be found in some patients

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Hannan Javed, M.D.[2] Zahir Ali Shaikh, MD[3] Mohamad Alkateb, MBBCh [4]; Shyam Patel [5]

Polycythemia vera must be differentiated from other myeloproliferative neoplasms, such as chronic myelogenous leukemia, essential thrombocythemia, and primary myelofibrosis. Polycythemia vera must also be differentiated from secondary polycythemia, which is usually due to chronic hypoxia. Each of these conditions have different etiologies, symptoms, laboratory abnormalities, physical exam findings, and treatments.

Polycythemia vera must be differentiated from a variety of other conditions include:^[1][2][3]

• Acute leukemia
• Essential thrombocythemia
• Chronic myeloid leukemia
• Primary myelofibrosis
• Secondary polycythemia

ABBREVIATIONS

N/A: Not available, NL: Normal, FISH: Fluorescence in situ hybridization, PCR: Polymerase chain reaction, LDH: Lactate dehydrogenase, PUD: Peptic ulcer disease, EPO: Erythropoietin, LFTs: Liver function tests, RFTs: Renal function tests, LAP: Leukocyte alkaline phosphatase, LAD: Leukocyte alkaline dehydrgenase, WBCs: White blood cells.

Myeloproliferative neoplasms (MPN)		Clinical manifestations		Diagnosis											Other features
		Symptoms	Physical examination	CBC & Peripheral smear									Bone marrow biopsy	Other investigations
				WBCs							Hb	Plat- elets
				Leuko-cytes	Blasts	Left shift	Baso- phils	Eosino- phils	Mono- cytes	Others
Chronic myeloid leukemia (CML), BCR-ABL1+[4][5]		Asymptomatic Constitutional Hyperviscosity and/or anemia related Bleeding Infection	Splenomegaly (46–76%) Purpura Anemia related Priapism	↑	<2%	+	↑	↑	↑	N/A	↓	NL	Hypercellurarity with ↑ granuloscytosis and ↓ erythrocytosis Fibrosis	FISH for t(9;22)(q34;q11.2) Reverse transcriptase quantitative PCR (RQ-PCR) for BCR-ABL	Granulocytic dysplasia is minimal/absent May present with blast crisis Absolute leukocytosis (median of 100,000/µL) Classic myelocyte bulge thrombocytopenia indicates advanced stage
Chronic neutrophilic leukemia (CNL)[6][7][8]		Asymptomatic Constitutional symptoms Bleeding Infection	Splenomegaly Heptomegaly Purpura Anemia related	↑	Minimal	+	NL	NL	NL	↑ LDH ↑ B12 levels	↓	↓	Uniforme and intense hypercellularity with minimal to none fibrosis Neutrophil toxic granulations and Dohle bodies	FISH Imaging for hepatosplenomegaly	Associationed with polycythemia vera and plasma cell disorders Leukocytosis with chronic neutrophilia
Polycythemia vera (PV)[9][10][11][12]		Constitutional Thromboembolism and bleeding Pruritus after a warm bath PUD related	Facial ruddiness Related to underlying cause Splenomegaly Renal bruit	NL or ↑	None	–	↑ or ↓	NL or ↑	NL	↓ Serum ferritin ↓ Folate levels ↑↑ B12 levels	↑↑	NL	Hypercellularity for age with tri-lineage growth Myelofibrosis (in up to 20% of patients)	Radioisotope studies Serum EPO levels LFTs RFTs Imaging studies	May transform into myelofibrosis or leukemia
Primary myelofibrosis (PMF)[13][14][15][16]		Constitutional Anemia related Bleeding Infection Abdominal Pain	Hepatosplenomegaly Petechiae & ecchymoses Abdominal distension Lymphadenopathy	↓	Erythroblasts	–	Absent	NL	NL	↑ LAP ↑ LAD ↑ Uric acid ↑ B12 levels	↓	↓	Variable with fibrosis or hypercellularity	JAK2 mutation CALR mutation MPL mutation	Bone marrow aspiration shows a dry tap Variable with leukocytosis or leukopenia
Essential thrombocythemia (ET)[17][18][19]		Headache Dizziness Visual disturbances Priapism Acute chest pain	Splenomegaly Skin bruises	NL or ↑	None	–	↓ or absent	NL	NL	N/A	↓	↑↑	Normal/Hypercellular	JAK2 mutation CALR mutation MPL mutation	Thrombosis Hemorrhage Pregnancy loss
Chronic eosinophilic leukemia, not otherwise specified (NOS)[20][21][22][23]		Constitutional Rash Rhinitis Gastritis Thromboembolism related	Hypertension Eczema, mucosal ulcers, erythema Angioedema Ataxia Anemia Lymphadenopathy Hepatosplenomegaly	↑	Present	+	↑	↑↑	↑	↑ B12 levels ↑ LDH	↓	↓	Hypercelluar with ↑ eosinophilic precursors, ↑ eosinophils, and atypical mononuclear cells	FISH Cytogenetic analysis of purified eosinophils and X-chromosome inactivation analysis	Heart failure Lung fibrosis Encephalopathy Erythema annulare centrifugam
MPN, unclassifiable		Similar to other myeloproliferative neoplasms	Similar to other myeloproliferative neoplasms	↑	Variable	±	↑ or ↓	↑ or ↓	↑ or ↓	May resemble other myeloproliferative neoplasms	↓	↑	↑ megakaryocyte proliferation with variable hypercellularity in granulocytic or erythrocytic cell lines	N/A	Similar to other myeloprolifeartive neoplasms but do not fulfil the criteria to be classified to a specific type
Mastocytosis[24][25][26][27]		Constitutional Pruritus & Flushing Urticaria & Blisters Hypotension & PUD Bleeding Bronchoconstriction	Mastocytosis exanthema Blistering Swelling Lymphadenopathy Bleeding Fibrosis	↑	None	–	NL	↑	NL	↑ Alkaline phosphatase ↑ LDH	↓	↓ or ↑	Multifocal dense infiltrates of mast cells with atypical morphology in >25 %	Cytogenetic analysis for c-KIT receptor mutations Serum tryptase levels 24-hour urine test for N-methyl histamine and 11-beta-prostaglandine	Skin most commonly involved Susceptibility to anaphylaxix Osteoporosis
Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1–JAK2[28][29][30][31]		Asymptomatic Constitutional Rash Cough & breathlessness Peripheral neuropathy/ encephalopathy	Fever Lymphadenopathy	↑	NL	–	NL	↑	↑	None	NL	↓	Myeloid expansion with eosinophilia	FISH shows t(8;13) and t(8;22)	May present or evolve into acute myeloid or lymphoblastic leukemia Leukocytosis (30 – 59 × 109/L
B-lymphoblastic leukemia/lymphoma[32][33]		Constitutional Anemia related Bleeding Infection Bone pain	Pallor Petechiae Organomegaly Lymphadenopathy	NL or ↑	>25%	N/A	↑ or ↓	↑ or ↓	↑ or ↓	Auer bodies	↓	↓	Hypercellular with blast infilterationwith or without myelodysplasia	Cytogenetic analysis Flow cytometry FISH	May present as extramedullary disease (Myeloid sarcoma)
Myelodysplastic syndromes (MDS)[34][35]		Constitutional Anemia related Bleeding Infection	Pallor Petechiae Organomegaly	↓	Variable	–	↓	↓	↓	Macro-ovalocytes Basophilic stippling Howell-Jolly body	↓	↓	Hypercellular/ normocellular bone marrow with dysplastic changes	Cytogenetic analysis Flow cytometry	Leukemia transformation Acquired pseudo-Pelger-Huët anomaly
Acute myeloid leukemia (AML) and related neoplasms[36][37]		Constitutional Anemia related Bleeding Bone pain Joint pain Infections	Infection related Pallor Leukemia cutis Bruising & petechiae Lymphadenopathy Hepatosplenomegaly	NL or ↑	↑	N/A	↑ or ↓	↑ or ↓	↑ or ↓	↑ Potassium ↑ Uric acid ↑ Phosphorus ↓ Calcium ↑ LDH	↓	↓	Increased immaturemyeloid cells with dysplasia	Cytogenetic analysis Flow cytometry FISH	Common in Down syndrome
Blastic plasmacytoid dendritic cell neoplasm[38][39][40][41]		Cutaneous symptoms (brown/purple nodular lesions) on face, scalp, lower limb & trunk	Brown/violaceous bruise like lesions Lymphadenopathy Splenomegaly	NL	↑		NL	NL	NL	Neutropenia	↓	↓	Malignant cells	Immunohistochemistry or flow cytometry for CD4 & CD56	TdT expression positive May develop chronic myelomonocytic leukemia (CMML)
Myelodysplastic /myeloproliferative neoplasms (MDS/MPN)	Chronic myelomonocytic leukemia (CMML)[42] [43][44]	Constitutional Anemia related Bleeding Infections Bone pain Leukemia Cutis	Organomegaly Bruising	↑	< 20%		NL	↑	↑↑	↑ LDH	↓	↓	Myelodysplastic and myeloproliferative feature	Cytogenetic analysis Flow cytometry	Overlapping of both, MDS and MPN Absolute monocytosis > 1 × 109/L (defining feature) MD-CMML:WBC ≤ 13 × 109/L (FAB)  MP-CMML:WBC > 13 × 109/L (FAB)
	Atypical chronic myeloid leukemia (aCML), BCR-ABL1-[45][46]	Asymptomatic Constitutional Hyperviscosity and/or anemia related Bleeding Infection	Splenomegaly (46–76%) Purpura Anemia related Priapism	↑	<20%	+	<2% of WBCs	N/A	N/A	N/A	↓	↓	Granulocytic hyperplasia with prominent dysplasia	Cytogenetic analysis Flow cytometry	Granulocytic dysplasia is prominent Absence of BCR-ABL or PDGFRA, PDGFRB, or FGFR1 rearrangements WBC > 13 × 109/L
	Juvenile myelomonocytic leukemia (JMML)[47][48]	Infections Anemia related	Hepatosplenomegaly Lymphadenopathy Rash	↑	↑	N/A	N/A	N/A	↑	↓ Serum Iron ↑ B12 levels	↓	↓	Hypercelluar with ↑ myeloid cells in stages of maturation	Cytogenetic analysis Flow cytometry	Polyclonal hypergammaglobulinemia
	MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)[49][50][51]	Constitutional Anemia related Thrombosis	Variable	NL or ↑	NL	–	NL	N/A	N/A	↑ Serum Iron	↓	↑	Hypercellularity with dyserythropoiesis and increased megakaryocytes	Cytogenetic analysis Flow cytometry	Large atypical megakaryocytes Ringed sideroblasts SF3B1 mutation
T-lymphoblastic leukemia/ lymphoma	T-lymphoblastic leukemia/ lymphoma[52][53][54]	Constitutional Anemia Related Bleeding Superior vena cava syndrome	Lymphadenopathy Mediastinal mass Pleural effusions Tracheal obstruction Pericardial effusions	↑	>25% blasts (Leukemia) <25% blasts (Lymphoma)	±	↑ or ↓	↑ or ↓	↑ or ↓	↑ LDH Positive for TdT	↓	↓	Hypercelluarity with increased T cells precursors	Cytogenetic analysisFlow cytometry FISH	May involve brain, skin, and testes.
	Provisional entity: Natural killer (NK) cell lymphoblastic leukemia/lymph[55]	Constitutional Anemia Related Bleeding Superior vena cava syndrome	Lymphadenopathy Mediastinal mass Pleural effusions Tracheal obstruction Pericardial effusions	↑	↑	±	↑ or ↓	↑ or ↓	↑ or ↓	↑ LDH	↓	↓	N/A	Cytogenetic analysis FISH Flow cytometry	Similar to T-cell lymphoblastic leukemia but may have more aggressive clinical course. Diagnosis is usually based on presence of CD56 expression, and T-cell-associated markers such as CD2 and CD7. B-cell markers are absent.
	Provisional entity: Early T-cell precursor lymphoblastic leukemia[56][57]	Constitutional Anemia Related Bleeding Superior vena cava syndrome	Lymphadenopathy Mediastinal mass Pleural effusions Tracheal obstruction Pericardial effusions	↑	↑	±	↑ or ↓	↑ or ↓	↑ or ↓	↑ LDH	↓	↓	Hypercelluarity with increased T cells precursors	Cytogenetic analysis FISH Flow cytometry	Similar to T-cell lymphoblastic leukemia but is more aggressive clinically and cell are characterized by cytometry as CD1a−, CD8−, CD5− (dim), and positivity for 1 or more stem cell or myeloid antigens. Gene expression indicates more immature cells as compared to other subtypes of T-cell neoplasms.

References

1. ↑ Tefferi A, Barbui T (2015). “Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management”. Am J Hematol. 90 (2): 162–73. doi:10.1002/ajh.23895. PMID 25611051.
2. ↑ Sanchez S, Ewton A (2006). “Essential thrombocythemia: a review of diagnostic and pathologic features”. Arch Pathol Lab Med. 130 (8): 1144–50. doi:10.1043/1543-2165(2006)130[1144:ET]2.0.CO;2. PMID 16879015.
3. ↑ Jabbour E, Kantarjian H (2014). “Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management”. Am J Hematol. 89 (5): 547–56. doi:10.1002/ajh.23691. PMID 24729196.
4. ↑ Savage DG, Szydlo RM, Goldman JM (January 1997). “Clinical features at diagnosis in 430 patients with chronic myeloid leukaemia seen at a referral centre over a 16-year period”. Br. J. Haematol. 96 (1): 111–6. PMID 9012696.
5. ↑ Thompson PA, Kantarjian HM, Cortes JE (October 2015). “Diagnosis and Treatment of Chronic Myeloid Leukemia in 2015”. Mayo Clin. Proc. 90 (10): 1440–54. doi:10.1016/j.mayocp.2015.08.010. PMC 5656269. PMID 26434969.
6. ↑ Szuber N, Tefferi A (February 2018). “Chronic neutrophilic leukemia: new science and new diagnostic criteria”. Blood Cancer J. 8 (2): 19. doi:10.1038/s41408-018-0049-8. PMC 5811432. PMID 29440636.
7. ↑ Maxson JE, Tyner JW (February 2017). “Genomics of chronic neutrophilic leukemia”. Blood. 129 (6): 715–722. doi:10.1182/blood-2016-10-695981. PMC 5301820. PMID 28028025.
8. ↑ Menezes J, Cigudosa JC (2015). “Chronic neutrophilic leukemia: a clinical perspective”. Onco Targets Ther. 8: 2383–90. doi:10.2147/OTT.S49688. PMC 4562747. PMID 26366092.
9. ↑ Vannucchi AM, Guglielmelli P, Tefferi A (March 2018). “Polycythemia vera and essential thrombocythemia: algorithmic approach”. Curr. Opin. Hematol. 25 (2): 112–119. doi:10.1097/MOH.0000000000000402. PMID 29194068.
10. ↑ Pillai AA, Babiker HM. PMID 30252337. Missing or empty |title= (help)
11. ↑ Tefferi A, Barbui T (January 2019). “Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management”. Am. J. Hematol. 94 (1): 133–143. doi:10.1002/ajh.25303. PMID 30281843.
12. ↑ Rumi E, Cazzola M (February 2017). “Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms”. Blood. 129 (6): 680–692. doi:10.1182/blood-2016-10-695957. PMC 5335805. PMID 28028026.
13. ↑ Cervantes F, Correa JG, Hernandez-Boluda JC (May 2016). “Alleviating anemia and thrombocytopenia in myelofibrosis patients”. Expert Rev Hematol. 9 (5): 489–96. doi:10.1586/17474086.2016.1154452. PMID 26891375.
14. ↑ Hoffman, Ronald (2018). Hematology : basic principles and practice. Philadelphia, PA: Elsevier. ISBN 9780323357623.
15. ↑ Michiels JJ, Bernema Z, Van Bockstaele D, De Raeve H, Schroyens W (March 2007). “Current diagnostic criteria for the chronic myeloproliferative disorders (MPD) essential thrombocythemia (ET), polycythemia vera (PV) and chronic idiopathic myelofibrosis (CIMF)”. Pathol. Biol. 55 (2): 92–104. doi:10.1016/j.patbio.2006.06.002. PMID 16919893.
16. ↑ Hoffman, Ronald (2018). Hematology : basic principles and practice. Philadelphia, PA: Elsevier. ISBN 9780323357623.
17. ↑ Schmoldt A, Benthe HF, Haberland G (1975). “Digitoxin metabolism by rat liver microsomes”. Biochem Pharmacol. 24 (17): 1639–41. PMID http://dx.doi.org/10.1182/blood-2007-04-083501 Check |pmid= value (help).CS1 maint: Multiple names: authors list (link)
18. ↑ Daniel A. Arber, Attilio Orazi, Robert Hasserjian, Jurgen Thiele, Michael J. Borowitz, Michelle M. Le Beau, Clara D. Bloomfield, Mario Cazzola & James W. Vardiman (2016). “The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia”. Blood. 127 (20): 2391–2405. doi:10.1182/blood-2016-03-643544. PMID 27069254. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
19. ↑ A. Tefferi, R. Fonseca, D. L. Pereira & H. C. Hoagland (2001). “A long-term retrospective study of young women with essential thrombocythemia”. Mayo Clinic proceedings. 76 (1): 22–28. doi:10.4065/76.1.22. PMID 11155408. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
20. ↑ Vidyadharan S, Joseph B, Nair SP (2016). “Chronic Eosinophilic Leukemia Presenting Predominantly with Cutaneous Manifestations”. Indian J Dermatol. 61 (4): 437–9. doi:10.4103/0019-5154.185716. PMC 4966405. PMID 27512192.
21. ↑ Hofmans M, Delie A, Vandepoele K, Van Roy N, Van der Meulen J, Philippé J, Moors I (2018). “A case of chronic eosinophilic leukemia with secondary transformation to acute myeloid leukemia”. Leuk Res Rep. 9: 45–47. doi:10.1016/j.lrr.2018.04.001. PMC 5993353. PMID 29892549.
22. ↑ Yamada Y, Rothenberg ME, Cancelas JA (2006). “Current concepts on the pathogenesis of the hypereosinophilic syndrome/chronic eosinophilic leukemia”. Transl Oncogenomics. 1: 53–63. PMC 3642145. PMID 23662039.
23. ↑ Kim TH, Gu HJ, Lee WI, Lee J, Yoon HJ, Park TS (September 2016). “Chronic eosinophilic leukemia with FIP1L1-PDGFRA rearrangement”. Blood Res. 51 (3): 204–206. doi:10.5045/br.2016.51.3.204. PMID 27722133.
24. ↑ Carter MC, Metcalfe DD, Komarow HD (February 2014). “Mastocytosis”. Immunol Allergy Clin North Am. 34 (1): 181–96. doi:10.1016/j.iac.2013.09.001. PMC 3863935. PMID 24262698.
25. ↑ Macri A, Cook C. PMID 29494109. Missing or empty |title= (help)
26. ↑ Lladó AC, Mihon CE, Silva M, Galzerano A (2014). “Systemic mastocytosis – a diagnostic challenge”. Rev Bras Hematol Hemoter. 36 (3): 226–9. doi:10.1016/j.bjhh.2014.03.003. PMC 4109736. PMID 25031064.
27. ↑ Valent P, Akin C, Metcalfe DD (March 2017). “Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts”. Blood. 129 (11): 1420–1427. doi:10.1182/blood-2016-09-731893. PMC 5356454. PMID 28031180.
28. ↑ Kumar, Kirthi R.; Chen, Weina; Koduru, Prasad R.; Luu, Hung S. (2015). “Myeloid and Lymphoid Neoplasm With Abnormalities of FGFR1 Presenting With Trilineage Blasts and RUNX1 Rearrangement”. American Journal of Clinical Pathology. 143 (5): 738–748. doi:10.1309/AJCPUD6W1JLQQMNA. ISSN 1943-7722.
29. ↑ Paolo Strati, Guilin Tang, Dzifa Y. Duose, Saradhi Mallampati, Rajyalakshmi Luthra, Keyur P. Patel, Mohammad Hussaini, Abu-Sayeef Mirza, Rami S. Komrokji, Stephen Oh, John Mascarenhas, Vesna Najfeld, Vivek Subbiah, Hagop Kantarjian, Guillermo Garcia-Manero, Srdan Verstovsek & Naval Daver (2018). “Myeloid/lymphoid neoplasms with FGFR1 rearrangement”. Leukemia & lymphoma. 59 (7): 1672–1676. doi:10.1080/10428194.2017.1397663. PMID 29119847. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
30. ↑ Ximena Montenegro-Garreaud, Roberto N. Miranda, Alexandra Reynolds, Guilin Tang, Sa A. Wang, Mariko Yabe, Wei Wang, Lianghua Fang, Carlos E. Bueso-Ramos, Pei Lin, L. Jeffrey Medeiros & Xinyan Lu (2017). “Myeloproliferative neoplasms with t(8;22)(p11.2;q11.2)/BCR-FGFR1: a meta-analysis of 20 cases shows cytogenetic progression with B-lymphoid blast phase”. Human pathology. 65: 147–156. doi:10.1016/j.humpath.2017.05.008. PMID 28551329. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
31. ↑ Paola Villafuerte-Gutierrez, Montserrat Lopez Rubio, Pilar Herrera & Eva Arranz (2018). “A Case of Myeloproliferative Neoplasm with BCR-FGFR1 Rearrangement: Favorable Outcome after Haploidentical Allogeneic Transplantation”. Case reports in hematology. 2018: 5724960. doi:10.1155/2018/5724960. PMID 30647980.CS1 maint: Multiple names: authors list (link)
32. ↑ Kamiya-Matsuoka C, Garciarena P, Amin HM, Tremont-Lukats IW, de Groot JF (December 2013). “B lymphoblastic leukemia/lymphoma presenting as seventh cranial nerve palsy”. Neurol Clin Pract. 3 (6): 532–534. doi:10.1212/CPJ.0b013e3182a78ef0. PMC 6082360. PMID 30107017.
33. ↑ Zhang X, Rastogi P, Shah B, Zhang L (September 2017). “B lymphoblastic leukemia/lymphoma: new insights into genetics, molecular aberrations, subclassification and targeted therapy”. Oncotarget. 8 (39): 66728–66741. doi:10.18632/oncotarget.19271. PMC 5630450. PMID 29029550.
34. ↑ Germing U, Kobbe G, Haas R, Gattermann N (November 2013). “Myelodysplastic syndromes: diagnosis, prognosis, and treatment”. Dtsch Arztebl Int. 110 (46): 783–90. doi:10.3238/arztebl.2013.0783. PMC 3855821. PMID 24300826.
35. ↑ Gangat N, Patnaik MM, Tefferi A (January 2016). “Myelodysplastic syndromes: Contemporary review and how we treat”. Am. J. Hematol. 91 (1): 76–89. doi:10.1002/ajh.24253. PMID 26769228.
36. ↑ Islam A, Catovsky D, Goldman JM, Galton DA (September 1985). “Bone marrow biopsy changes in acute myeloid leukaemia. I: Observations before chemotherapy”. Histopathology. 9 (9): 939–57. PMID 3864727.
37. ↑ Orazi A (2007). “Histopathology in the diagnosis and classification of acute myeloid leukemia, myelodysplastic syndromes, and myelodysplastic/myeloproliferative diseases”. Pathobiology. 74 (2): 97–114. doi:10.1159/000101709. PMID 17587881.
38. ↑ F. Julia, T. Petrella, M. Beylot-Barry, M. Bagot, D. Lipsker, L. Machet, P. Joly, O. Dereure, M. Wetterwald, M. d’Incan, F. Grange, J. Cornillon, G. Tertian, E. Maubec, P. Saiag, S. Barete, I. Templier, F. Aubin & S. Dalle (2013). “Blastic plasmacytoid dendritic cell neoplasm: clinical features in 90 patients”. The British journal of dermatology. 169 (3): 579–586. doi:10.1111/bjd.12412. PMID 23646868. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
39. ↑ Livio Pagano, Caterina Giovanna Valentini, Alessandro Pulsoni, Simona Fisogni, Paola Carluccio, Francesco Mannelli, Monia Lunghi, Gianmatteo Pica, Francesco Onida, Chiara Cattaneo, Pier Paolo Piccaluga, Eros Di Bona, Elisabetta Todisco, Pellegrino Musto, Antonio Spadea, Alfonso D’Arco, Stefano Pileri, Giuseppe Leone, Sergio Amadori & Fabio Facchetti (2013). “Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: an Italian multicenter study”. Haematologica. 98 (2): 239–246. doi:10.3324/haematol.2012.072645. PMID 23065521. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
40. ↑ Joseph D. Khoury (2018). “Blastic Plasmacytoid Dendritic Cell Neoplasm”. Current hematologic malignancy reports. 13 (6): 477–483. doi:10.1007/s11899-018-0489-z. PMID 30350260. Unknown parameter |month= ignored (help)
41. ↑ Shinichiro Sukegawa, Mamiko Sakata-Yanagimoto, Ryota Matsuoka, Haruka Momose, Yusuke Kiyoki, Masayuki Noguchi, Naoya Nakamura, Rei Watanabe, Manabu Fujimoto, Yasuhisa Yokoyama, Hidekazu Nishikii, Takayasu Kato, Manabu Kusakabe, Naoki Kurita, Naoshi Obara, Yuichi Hasegawa & Shigeru Chiba (2018). “[Blastic plasmacytoid dendritic cell neoplasm accompanied by chronic myelomonocytic leukemia successfully treated with azacitidine]”. [[[Rinsho ketsueki] The Japanese journal of clinical hematology]]. 59 (12): 2567–2573. doi:10.11406/rinketsu.59.2567. PMID 30626790.CS1 maint: Multiple names: authors list (link)
42. ↑ Patnaik MM, Tefferi A (June 2016). “Chronic myelomonocytic leukemia: 2016 update on diagnosis, risk stratification, and management”. Am. J. Hematol. 91 (6): 631–42. doi:10.1002/ajh.24396. PMID 27185207.
43. ↑ Parikh SA, Tefferi A (June 2012). “Chronic myelomonocytic leukemia: 2012 update on diagnosis, risk stratification, and management”. Am. J. Hematol. 87 (6): 610–9. doi:10.1002/ajh.23203. PMID 22615103.
44. ↑ Benton CB, Nazha A, Pemmaraju N, Garcia-Manero G (August 2015). “Chronic myelomonocytic leukemia: Forefront of the field in 2015”. Crit. Rev. Oncol. Hematol. 95 (2): 222–42. doi:10.1016/j.critrevonc.2015.03.002. PMC 4859155. PMID 25869097.
45. ↑ Dao KH, Tyner JW (2015). “What’s different about atypical CML and chronic neutrophilic leukemia?”. Hematology Am Soc Hematol Educ Program. 2015: 264–71. doi:10.1182/asheducation-2015.1.264. PMC 5266507. PMID 26637732.
46. ↑ Muramatsu H, Makishima H, Maciejewski JP (February 2012). “Chronic myelomonocytic leukemia and atypical chronic myeloid leukemia: novel pathogenetic lesions”. Semin. Oncol. 39 (1): 67–73. doi:10.1053/j.seminoncol.2011.11.004. PMC 3523950. PMID 22289493.
47. ↑ Aricò M, Biondi A, Pui CH (July 1997). “Juvenile myelomonocytic leukemia”. Blood. 90 (2): 479–88. PMID 9226148.
48. ↑ Hasle H (March 1994). “Myelodysplastic syndromes in childhood–classification, epidemiology, and treatment”. Leuk. Lymphoma. 13 (1–2): 11–26. doi:10.3109/10428199409051647. PMID 8025513.
49. ↑ Patnaik MM, Tefferi A (March 2017). “Refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis (RARS-T): 2017 update on diagnosis, risk-stratification, and management”. Am. J. Hematol. 92 (3): 297–310. doi:10.1002/ajh.24637. PMID 28188970.
50. ↑ Alshaban A, Padilla O, Philipovskiy A, Corral J, McAlice M, Gaur S (2018). “Lenalidomide induced durable remission in a patient with MDS/MPN-with ring sideroblasts and thrombocytosis with associated 5q- syndrome”. Leuk Res Rep. 10: 37–40. doi:10.1016/j.lrr.2018.08.001. PMID 30186759.
51. ↑ Bouchla A, Papageorgiou SG, Tsakiraki Z, Glezou E, Pavlidis G, Stavroulaki G, Bazani E, Foukas P, Pappa V (2018). “Plasmablastic Lymphoma in an Immunocompetent Patient with MDS/MPN with Ring Sideroblasts and Thrombocytosis-A Case Report”. Case Rep Hematol. 2018: 2525070. doi:10.1155/2018/2525070. PMC 6247723. PMID 30524760.
52. ↑ You MJ, Medeiros LJ, Hsi ED (September 2015). “T-lymphoblastic leukemia/lymphoma”. Am. J. Clin. Pathol. 144 (3): 411–22. doi:10.1309/AJCPMF03LVSBLHPJ. PMID 26276771.
53. ↑ Patel KJ, Latif SU, de Calaca WM (March 2009). “An unusual presentation of precursor T cell lymphoblastic leukemia/lymphoma with cholestatic jaundice: case report”. J Hematol Oncol. 2: 12. doi:10.1186/1756-8722-2-12. PMC 2663564. PMID 19284608.
54. ↑ Elreda L, Sandhu M, Sun X, Bekele W, Cohen AJ, Shah M (2014). “T-cell lymphoblastic leukemia/lymphoma: relapse 16 years after first remission”. Case Rep Hematol. 2014: 359158. doi:10.1155/2014/359158. PMC 4005062. PMID 24822133.
55. ↑ Sedick Q, Alotaibi S, Alshieban S, Naheet KB, Elyamany G (2017). “Natural Killer Cell Lymphoblastic Leukaemia/Lymphoma: Case Report and Review of the Recent Literature”. Case Rep Oncol. 10 (2): 588–595. doi:10.1159/000477843. PMID 28868017.
56. ↑ Jain N, Lamb AV, O’Brien S, Ravandi F, Konopleva M, Jabbour E, Zuo Z, Jorgensen J, Lin P, Pierce S, Thomas D, Rytting M, Borthakur G, Kadia T, Cortes J, Kantarjian HM, Khoury JD (April 2016). “Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype”. Blood. 127 (15): 1863–9. doi:10.1182/blood-2015-08-661702. PMC 4915808. PMID 26747249.
57. ↑ Haydu JE, Ferrando AA (July 2013). “Early T-cell precursor acute lymphoblastic leukaemia”. Curr. Opin. Hematol. 20 (4): 369–73. doi:10.1097/MOH.0b013e3283623c61. PMC 3886681. PMID 23695450.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ifeoma Odukwe, M.D. [2] Mohamad Alkateb, MBBCh [3] Shyam Patel [4]

The incidence of polycythemia vera is approximately 1.9 per 100,000 individuals per year in the US. The prevalence of polycythemia vera is 48 to 57 cases per 100,000 individuals in the United States. Males are more commonly affected than females.

• The incidence of polycythemia vera is about 1.9 per 100,000 individuals per year in the US. The incidence rate for men is 2.8 per 100,000 person-years, and is 1.3 per 100,000 person years for women.^[1]

• The prevalence of PV is estimated to be 44 to 57 cases per 100,000 persons, and approximately 148,000 persons are living with PV in the United States.^[2][3]

• The 15-year survival of patients with polycythemia vera is 65%.^[4]
• The mortality of polycythemia vera patients compared with the general population is 1.6-fold higher.

• The median age at diagnosis is 61 years but has been diagnosed in all age groups. The incidence increases with age.^[5]
• Younger patients have comparable rates of vascular complications compared to older patients. However, splanchnic vein thrombosis occur more frequently in younger patients.^[6]
• Younger patients are more likely to develop unusual complications such as mesenteric venous thrombosis. The rate of transformation to acute leukemia is similar as that of older adults.^[5]

• In ashkenazi jews, there is a high incidence of polycythemia vera.^[7]

• Males are more commonly affected with polycythemia vera than females. The male to female ratio is approximately 1.2 to 1.^[5]

Template:Hematology

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ifeoma Odukwe, M.D. [2] Mohamad Alkateb, MBBCh [3] Shyam Patel [4]

Common risk factors in the development of polycythemia vera are old age (65 year old and older), family history, and Ashkenazi Jewish descent. After a patient is diagnosed with polycythemia vera, risk stratification involves assessment of age and thrombotic history. The risk assessment for development of post-PV myelofibrosis or post-PV acute myeloid leukemia include a variety of factors.

Risk factors in the development of polycythemia vera are:^[1]

• Old age (65 years older)
  • mutations can accumulate in hematopoietic stem cells over time, resulting in a higher probability of a JAK2 mutation.
• Family history of polycythemia vera
  • First-degree relatives of patients with polycythemia vera have a 5 to 7-fold higher risk for development of a myeloproliferative neoplasm.
  • The cumulative risk of developing myelofibrosis is 6% at 10 years, 14% at 15 years, and 26% at 20 years from the initial diagnosis of polycythemia vera.^[2]
• Ashkenazi Jewish descent

High risk features of polycythemia vera include:

• Old age
• History of thrombotic event
• Presence of JAK2 mutation

The risk factors for the development of thrombosis include:^[3]

• Age >60 years
• History of prior thrombosis
• Leukocytosis
• Increased JAK2 V617F allele burden
• High risk gene expression profile

The risk factors for the transformation to myelofibrosis or secondary acute myeloid leukemia include:^[3]

• Older age
• Extended disease duration
• Leukocytosis
• Exposure to phosphorus-32, pipobroman, or chlorambucil

The risk factors associated with decreased survival include:^[3]

• Older age
• Leukocytosis
• History of venous thrombosis
• Abnormal karyotype

Template:Hematology

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2] Shyam Patel [3]

Screening for polycythemia vera is not a routine clinical practice. However, assessment of a complete blood count (CBC), which is done routinely, usually gives the first indication for the presence of polycythemia vera in a patient.

There is no role for screening for polycythemia vera. In order to diagnose a suspected case of polycythemia vera, JAK2 mutational analysis can be done from the peripheral blood. Cell-based quantitative assays for JAK2 V617F mutation may be helpful among patients with the following:^[1]

• Erythrocytosis
• Thrombocytosis
• Splanchnic vein thrombosis

The complete blood count (CBC), which includes quantitation of red blood cells, white blood cells, and platelets, is typically done routinely in people, and an elevated hemoglobin is sometimes the first laboratory indication for a diagnosis of polycythemia vera.

Template:Hematology

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Ifeoma Odukwe, M.D. [2] Mohamad Alkateb, MBBCh [3] Shyam Patel [4]

The natural history of polycythemia vera begins with symptoms such as headache, fatigue, and dyspnea. Common complications of polycythemia vera include thrombosis (such as deep vein thrombosis, pulmonary embolism, myocardial infarction, and stroke), bleeding, and splenomegaly. Prognosis is generally good with treatment, and the median survival for patients with polycythemia vera is around 10.9 to 27.8 years in the absence of complications. However, there is a variable risk for progression to myelofibrosis and acute myeloid leukemia, and these are the most devastating complications of the disease. Myelofibrosis and acute myeloid leukemia are part of the natural history of the disease.

• The symptoms of polycythemia vera usually develop in the sixth decade of life and start with symptoms such as headache and fatigue.
• The cumulative risk of developing myelofibrosis is 4.9 to 6.0% at 10 years, 6-14% at 15 years, and 26% at 20 years from the initial diagnosis of polycythemia vera. This is in comparison to the risk of post-essential thrombocythemia myelofibrosis, for which the risk is 0.8% to 4.9% at 10 years and 4-11% at 15 years.^[1][2]
• The cumulative risk of developing acute myeloid leukemia is 2.3-14% at 10 years, 5.5-18% at 15 years, and greater than 10% at 20 years from the initial diagnosis of polycythemia vera. This is in comparison to the risk of post-ET acute myeloid leukemia, for which the risk is 0.7-3% at 10 years and 2.1-5.3% at 15 years.^[1][2]

Common complications of polycythemia vera include:^{[1][3][4][5][6][7]}

• Thrombosis

• Arterial thrombosis
  • Most commmon type of thrombosis to occur in patients with polycythemia vera.
• Deep venous thrombosis
• Pulmonary embolism
• Myocardial infarction
• Stroke
• Budd-Chiari syndrome
• Splanchnic vein thrombosis

• Bleeding

• Epistaxis
• Gingival bleeding
• Menorrhagia
• Metrorrhagia
• Petechiae

• Splenomegaly
• Gout
• Peptic ulcer

• Clonal proliferation

• Myelofibrosis
• Acute myeloid leukemia

• Microvascular symptoms

• Hearing impairment
• Visual impairment
• Paresthesia
• Headache

• The median life expectancy for patients diagnosed with polycythemia vera exceeds 10 years.
• The prognosis of polycythemia vera is generally good with treatment. It will cause serious complications without treatment.^[8]
• Once myelofibrosis or acute myeloid leukemia ensues, the prognosis is very poor. Prognosis for post-PV myelofibrosis is adversely affected by older age, presence of leukocytosis, reticulin fibrosis, high JAK2 allele burden, splenomegaly, and history of venous thromboembolic events.^{[9] [2]}
• Post-PV acute myeloid leukemia, adverse risk factors include older age, leukocytosis, splenomegaly, reticulin, abnormal and complex karyotype, p53 mutation, and RUNX1 mutation.^[2]

• After transformation of polycythemia vera to myelofibrosis, the median survival is approximately 5.7 years.^[9]
• The median survival for patients with acute myeloid leukemia that has progressed from polycythemia vera is 5 months.^[9]
• High-risk patients with polycythemia vera have an average survival of 10.9 years. Low-risk patients have an average survival of 27.8 years.^[9]
• There is a 4.2-fold increase in the risk of death in the presence of any of the following risk factors^[2]:
  • Hemoglobin < 10 g/dl
  • Platelet count < 100,000/mcl
  • Leukocyte count > 30,000/mcl
• The 5-year survival rate is 17.3% for patients who develop post-PV myelofibrosis and have hemoglobin < 10 g/dl and age above 65 years.^[2]
• In elderly patients compared to younger patients, leukemic transformation contributes to more deaths, suggesting that age of onset of leukemia is an important prognostic risk factor for life expectancy.^[2]

Template:Hematology

Template:WikiDoc Sources