Myelofibrosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2], Sujit Routray, M.D. [3]

Myelofibrosis is a hematological disorder in which the bone marrow is replaced with collagenous connective tissue and progressive fibrosis, replacing the bone marrow with a scar tissue and hence disrupting the normal production of blood cells which leads to pancytopenia. It is also classified as a myeloproliferative disorder. The term myelofibrosis alone usually refers to primary myelofibrosis (PMF), also known as chronic idiopathic myelofibrosis (CIMF); the terms idiopathic and primary mean that the disease is of unknown or spontaneous origin. This is in contrast with myelofibrosis that develops secondary to polycythemia vera, essential thrombocythemia, leukemia, or lymphoma (secondary myelofibrosis). Myelofibrosis is a form of myeloid metaplasia, which refers to a change in cell type in the blood-forming tissue of the bone marrow, and often the two terms are used synonymously. Genes involved in the pathogenesis of myelofibrosis include JAK2, CALR, and MPL. Myelofibrosis must be differentiated from other diseases that cause diffuse bone sclerosis, such as sickle cell disease, hyperthyroidism, sclerosing bone dysplasia, osteoblastic metastases, and Paget’s disease.Myelofibrosis must be differentiated from other diseases that cause splenomegaly, such as anemia, CML, polycythemia rubra vera, cirrhosis, infections, neoplastic, and lipid storage disorders. The prevalence of myelofibrosis is approximately 1 per 100,000 individuals worldwide. Myelofibrosis is a disease that tends to affect the middle-aged and elderly population. The mean age at diagnosis is 60 years. Males are more commonly affected with myelofibrosis than females. The male to female ratio is approximately 1.5 to 1. Myelofibrosis usually affects individuals of the Ashkenazi Jews race. African American, Latin American, and Asian individuals are less likely to develop myelofibrosis. Common risk factors in the development of myelofibrosis may be age, other myeloproliferative disorders, radiation, or industrial chemical exposure. Myelofibrosis has a very indolent course. If left untreated, myelofibrosis may progress to develop acute myelogenous leukemia, thrombohemorrhagic events, and progressive marrow failure. Common complications of myelofibrosis include infections, bleeding, hepatic failure, heart failure, and gout. Prognosis is generally poor and the median survival for myelofibrosis is 3.5 years to 5.5 years, but patients younger than 55 years have a median survival of 11 years. According to the World Health Organization (WHO) diagnostic criteria for primary myelofibrosis, polycythemia vera, and essential thrombocythemia, the diagnosis of primary myelofibrosis is made when all three of the following major diagnostic criteria and at least two minor criteria are met. Symptoms of myelofibrosis include left upper quadrant abdominal pain, bruising, easy bleeding, pale skin, and frequent infections.^[1][2][3] Common physical examination findings of myelofibrosis include pallor, petechiae, lymphadenopathy, hepatomegaly, and splenomegaly. Laboratory findings consistent with the diagnosis of myelofibrosis include decreased red blood cells, normochromic normocytic anemia, tear-drop shaped RBCs, thrombocytopenia, and raised levels of lactate dehydrogenase. X-ray may be helpful in the diagnosis of myelofibrosis. Findings on x-ray suggestive of myelofibrosis include osteosclerosis at different sites of the body, which tends to be diffuse and devoid of architectural distortion. CT scan and MRI may be helpful in the diagnosis of myelofibrosis. Findings on CT scan suggestive of myelofibrosis include diffuse bone sclerosis. Findings on MRI suggestive of myelofibrosis include diffuse decrease bone marrow signal intensity. Bone marrow biopsy is the imaging modality of choice for myelofibrosis. A bone marrow biopsy will reveal collagen fibrosis that has replaced the bone marrow. Other diagnostic studies for myelofibrosis include JAK2 mutation analysis testing and bone scan. Red blood cell transfusion, danazol therapy, or thalidomide are recommended for patients who develop anemia. Ruxolitinib, an inhibitor of JAK1 and JAK2, can reduce the splenomegaly and the debilitating symptoms of weight loss, fatigue, and night sweats for patients with JAK2-positive or JAK2-negative primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis. Hydroxyurea, chemotherapy, radiotherapy, or splenectomy are recommended for patients who develop splenomegaly. Surgery is not the first-line treatment option for patients with myelofibrosis. Splenectomy is usually reserved for patients with massive splenomegaly unresponsive to conservative treatment. The only known cure is allogeneic stem cell transplantation, but this approach involves significant risks.Future and investigational therapies involve immunomodulatory drugs, histone deacetylase inhibitors, newer generation drugs of already existing medications and drugs targeting pathways other than the JAK/STAT. The goal is to limit the need for allogeneic stem cell transplantation.

The first description of primary myelofibrosis (PMF) is credited to a German surgeon, Gustav Heuck, who described the concept in 1879. Additional work and discoveries started to get documented at the beginning of the twentieth century. The substantial contribution came from Max Askanazy, a German pathologist and Herbert Assmann, an Internist from Germany. The condition was given several pseudonyms before the International Working Group for Myelofibrosis Research and Treatment decided in 2006 to use the term primary myelofibrosis (PMF).

Myelofibrosis is subclassified into primary and secondary types with the primary type being more common and a high proportion of the cases resulting from mutations in the Janus kinase 2 (JAK2) gene. It can be secondary to a variety of malignant, non-malignant, and hematologic conditions. It can also be secondary to malignancies, infections, toxins, autoimmune, and endocrine diseases.

Myelofibrosis, a myeloproliferative disorder, is characterized by the proliferation of megakaryocytes in the bone marrow, disrupted cytokine production, and reactive fibrosisresulting in bone marrow failure. The fibrosed and scarred bone marrow produces fewer and fewer normal functioning blood cells leading to pancytopenia and extramedullary hematopoiesis (EMH). It can mainly be associated with somatic mutation of the myeloproliferative leukemia virus (MPL) oncogene, the calreticulin (CALR) gene, or Janus kinase 2 (JAK2) gene but other genes can also be involved and it can also result in the setting of another primary insult.

Myelofibrosis is most commonly caused by somatic mutations in the myeloproliferative leukemia virus (MPL) oncogene, the calreticulin (CALR) gene, or Janus kinase 2 (JAK2) gene. Less common mutations in other genes have also been documented. It can also be the result of other primary disorders manifesting as a complication or part of the disease process.

Myelofibrosis must be differentiated from other diseases that cause diffuse bone sclerosis, such as sickle cell disease, hyperthyroidism, sclerosing bone dysplasia, osteoblastic metastases, and Paget’s disease. Myelofibrosis must be differentiated from other diseases that cause splenomegaly, such as anemia, CML, polycythemia rubra vera, cirrhosis, infections, neoplastic, and lipid storage disorders.

The prevalence of myelofibrosis is approximately 1 per 100,000 individuals worldwide. Myelofibrosis is a disease that tends to affect the middle-aged and elderly population. The mean age at diagnosis is 60 years. Males are more commonly affected with myelofibrosis than females. The male to female ratio is approximately 1.5 to 1. Myelofibrosis usually affects individuals of the Ashkenazi Jews race. African American, Latin American, and Asian individuals are less likely to develop myelofibrosis.

Common risk factors in the development of myelofibrosis may be age, other myeloproliferative disorders, radiation, or industrial chemical exposure.

There is insufficient evidence to recommend routine screening for myelofibrosis and there is no screening test currently available for the disease. Routine blood work can be used to check the blood cell counts which can further warrant a bone marrow biopsy.

The development of myelofibrosis is a a slow process and it does not cause early symptoms. A significant proportion of the patients can be asymptomatic and the diagnosis is usually made in the setting of an unrelated condition. The most overlapping and common findings encountered are anemia and splenomegaly presenting as weakness, easy fatigability, palpitations, and dyspnea in the case of anemia and early satiety with possible accompanying left upper quadrant discomfort if splenomegaly is present.

The disease has a progressive course and can result in pancytopenia as the bone marrow failure ensues. This can result in bleeding complications, easy bruising, increase in the susceptibility to infections, and worsening anemia. The bone marrow failure paves the way for extramedullary hematopoiesis (EMH) which mainly occurs in the reticuloendothelial tissues.

If left untreated, myelofibrosis can lead to severe complications, the most feared of which are acute leukemia, heart failure, and portal hypertension.

Diagnosis of myelofibrosis may be made based upon a thorough clinical evaluation, detailed patient history, and specialized tests. The World Health Organization (WHO) has set the criteria for diagnosing primary myelofibrosis (PMF). It has determined set rules for distinguishing the prefibrotic/early (pre-primary myelofibrosis) phase and the overtly fibrotic (overt primary myelofibrosis) phase. The World Health Organization (WHO) has also introduced a proposed revised criteria for primary myelofibrosis (PMF).

A significant proportion of patients with myelofibrosis can be asymptomatic. The hallmark of the disease is pancytopenia. A positive history of fatigue, recurring infections, and bleeding complications is suggestive of myelofibrosis. The most common symptom is fatigue which is prominent enough as it remarkably affects the quality of life. Fatigue, a result of anemia, leads to the associated complaints of weakness, palpitations, and dyspnea on exertion. Other nonspecific symptoms such as fever, night sweats, and weight loss can also be present at diagnosis.

Patients with myelofibrosis usually appear pale and chronically ill. Physical examination of patients with myelofibrosis is usually remarkable for splenomegaly, hepatomegaly, skin pallor, petechiae and ecchymoses, and lymphadenopathy.

Peripheral blood smear and bone marrow examination helps in making the diagnosis of myelofibrosis. Various tests performed to aid in reaching the diagnosis include complete blood count, peripheral blood smear and bone marrow examination, comprehensive metabolic panel, and leukocyte alkaline phosphatase (LAP) test. Laboratory findings consistent with the diagnosis of myelofibrosis include decreased red blood cells, normochromic normocytic anemia, tear-drop shaped RBCs, thrombocytopenia, and raised levels of lactate dehydrogenase.

There are no ECG findings associated with myelofibrosis.

X-ray may be

There are no echocardiography/ultrasound findings associated with myelofibrosis. However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of myelofibrosis, which include heart failure, splenic rupture, pulmonary hypertension, intestinal obstruction, splenomegaly, hepatomegaly, ureteral obstruction, and thromboticevents.

helpful in the diagnosis of myelofibrosis. Findings on x-ray suggestive of myelofibrosis include osteosclerosis at different sites of the body, which tends to be diffuse and devoid of architectural distortion.

CT scan may be helpful in the diagnosis of myelofibrosis. Findings on CT scan suggestive of myelofibrosis include diffuse bone sclerosis.

MRI may be helpful in the diagnosis of myelofibrosis. Findings on MRI suggestive of myelofibrosis include diffuse decrease bone marrow signal intensity.

There are no other imaging findings associated with myelofibrosis.

Other diagnostic studies for myelofibrosis include genetic testing, which demonstrates JAK2^V617F mutation, hybrid imaging, which demonstrates increased uptake of the radionuclides by the extramedullary hematopoietic foci, and bone scintigraphy and positron emission tomography (PET), both of which demonstrate fibrosis.

Red blood cell transfusion, danazol therapy, or thalidomide are recommended for patients who develop anemia. Ruxolitinib, an inhibitor of Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2), can reduce the splenomegaly and the constitutional symptoms of weight loss, fatigue, and night sweats for patients with Janus kinase 2 (JAK2)-positive or Janus kinase 2 (JAK2)-negative primary myelofibrosis (PMF), post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis. Hydroxyurea, chemotherapy, or radiotherapy are recommended for patients who develop splenomegaly.

Surgery is not the first-line treatment option for patients with myelofibrosis. Splenectomy is usually reserved for patients with massive splenomegaly unresponsive to conservative treatment. The only known cure is allogeneic stem cell transplantation, but this approach involves significant risks.

There are no established measures for the primary prevention of myelofibrosis. Avoidance of radiation may be helpful, as radiation exposure can induce bone marrow fibrosis.

There are no established measures for the secondary prevention of myelofibrosis.

Future and investigational therapies involve immunomodulatory drugs, histone deacetylase inhibitors, newer generation drugs of already existing medications and drugs targeting pathways other than the JAK/STAT. The goal is to limit the need for allogeneic stem cell transplantation.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2]

The first description of primary myelofibrosis (PMF) is credited to a German surgeon, Gustav Heuck, who described the concept in 1879. Additional work and discoveries started to get documented at the beginning of the twentieth century. The substantial contribution came from Max Askanazy, a German pathologist and Herbert Assmann, an Internist from Germany. The condition was given several pseudonyms before the International Working Group for Myelofibrosis Research and Treatment decided in 2006 to use the term primary myelofibrosis (PMF).

• In 1879, Gustav Heuck, a German surgeon, was the first to describe the notion of myelofibrosis. He explained the idea under the title of “Two cases of leukemia with peculiar blood and bone marrow findings”. Heuck described two patients with massive splenomegaly, increased number of morphologically abnormal leukocytes, and nucleated red blood cells. He observed that the clinical findings in these two patients were different from those described for chronic myelogenous leukemia (CML) because of the presence of bone marrow fibrosis and extensive extramedullary hematopoiesis (EMH). He also noted osteosclerosis in an autopsy report.^[1]
• In 1904, Max Askanazy, a German pathologist, reported a case with significant extramedullary hematopoiesis (EMH) of the liver and diffuse bone marrow fibrosis.^[2]
• In 1907, Herbert Assmann, an internist from Germany, described another case of extramedullary hematopoiesis (EMH) and bone marrow fibrosis which he went on and named “osteosclerotic anemia“. Later on, it was referred to as “Heuck–Assmann syndrome”.^[2]
• In 1914, Hans Hirschfeld, a German hematologist further elaborated the splenic pathology in primary myelofibrosis (PMF).
• In 1951, William Dameshek, an internationally renowned American hematologist, grouped together primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), polycythemia vera (PV), and essential thrombocythemia (ET) and classified them as “myeloproliferative disorders“.^[3][4]
• In 1975, Murray N Silverstein, an American hematologist, published his classic monograph and described most of the modern natural history and treatment of primary myelofibrosis (PMF).^[5]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2]

Myelofibrosis is subclassified into primary and secondary types with the primary type being more common and a high proportion of the cases resulting from mutations in the Janus kinase 2 (JAK2) gene. It can be secondary to a variety of malignant, non-malignant, and hematologic conditions. It can also be secondary to malignancies, infections, toxins, autoimmune, and endocrine diseases.

• Myelofibrosis may be classified according to etiology into two types:

• Primary
• Secondary

• The primary type is associated with:^[1][2][3]
  • Stem cell-derived clonal myeloproliferation
  • Mutations of the Myeloproliferative leukemia virus (MPL) oncogene, the calreticulin (CALR) gene, or Janus kinase 2 (JAK2) gene in 90% of patients
  • “Triple-negative” in 10% of patients
• The 2016 World Health Organization (WHO) revised classification of myeloproliferative neoplasms (MPNs) defines 2 stages of primary myelofibrosis (PMF):

• Prefibrotic/early (pre-primary myelofibrosis) phase, characterized by granulocytic/megakaryocytic proliferation and lack of reticulin bone marrow fibrosis.^[4][5]
• Overtly fibrotic (overt primary myelofibrosis) phase, characterized by bone marrow fibrosis, pancytopenia, higher blast count, extramedullary hematopoiesis (EMH), and unfavorable karyotype with a significantly shortened median survival.^[4]

• Myelofibrosis can be secondary to toxins exposure and multiple primary conditions such as:

• Malignancies and hematologic disorders (Hodgkin lymphoma, non-Hodgkin lymphoma, essential thrombocythemia (ET), polycythemia vera (PV), multiple myeloma (MM), thrombotic thrombocytopenic purpura [TTP], and malignancies with metastases to the bone)^{[6][7][8][9][10][11][12][13][14][15][6][16]}
• Toxins (Benzene, thorium dioxide, nitrosourea, and x- or γ-radiation)^{[17][18][19][20][21][22][23][24]}
• Infections (tuberculosis [TB], HIV infection, and dengue fever)^{[25][26][27][28]}
• Autoimmune diseases (systemic lupus erythematosus [SLE], multiple sclerosis [MS], and juvenile idiopathic arthritis)^[29][30][31]
• Endocrine disorders (primary hyperparathyroidism)^[32]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2]

Myelofibrosis, a myeloproliferative disorder, is characterized by the proliferation of megakaryocytes in the bone marrow, disrupted cytokine production, and reactive fibrosis resulting in bone marrow failure. The fibrosed and scarred bone marrow produces fewer and fewer normal functioning blood cells leading to pancytopenia and extramedullary hematopoiesis (EMH). It can mainly be associated with somatic mutation of the myeloproliferative leukemia virus (MPL) oncogene, the calreticulin (CALR) gene, or Janus kinase 2 (JAK2) gene but other genes can also be involved and it can also result in the setting of another primary insult. Associated conditions include malignancies, hematologic disorders, infections, autoimmune diseases, and endocrine disorders. Hepatomegaly, splenomegaly, and lymphadenopathy are the positive findings on gross pathology. On microscopic pathology, myelofibrosis is characterized by low RBC count, leukopenia – leukocytosis, basophilia, erythroblastosis, thrombocytopenia – thrombocytosis, micromegakaryocytes, splenic pulp changes, and abnormalities of platelets.

• Polyclonal mesenchymal cells of the bone marrow such as fibroblasts, osteoblasts, pericytes, endothelial cells, adipocytes, and reticular cells create a functional microenvironment, which maintains hematopoiesis. This maintenance takes place through cellular interactions via growth factors, adhesion molecules, cytokines, and extracellular matrix components along with the help of oxygen and calcium.^[1]
• Myelofibrosis is the result of pathologic interaction between hematopoietic progenitor and stromal cells leading to the activation and expansion of the stroma and the accumulation of reticulin and collagen fibers produced by mesenchymal cells.^[1]
• The development and progression of myelofibrosis involves the activation of Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway, which paves the way for the overproduction of abnormal megakaryocytes.^[2][3][4]
• The abnormally proliferated megakaryocytes produce cytokines such as platelet-derived growth factor (PDGF), transforming growth factor (TGF) beta, and basic fibroblast growth factor (bFGF) which are involved in the abnormal proliferation of fibroblasts, resulting in fibrosis.^{[5][6][7][8][9][10]}
• Myelofibrosis can result in the setting of somatic mutations in specific genes or it can also be secondary to other primary disorders.
• The somatic mutations driving the disorder can mainly involve the myeloproliferative leukemia virus (MPL) oncogene, the calreticulin (CALR) gene, or Janus kinase 2 (JAK2) gene.^[3][11]
• The fibrosis of bone marrow leads to extramedullary hematopoiesis (EMH) involving the reticuloendothelial organs such as the liver and spleen. Rarely, the extramedullary hematopoiesis (EMH) can also involve ectopic hematopoietic tissue which includes the skin, lymph nodes, lungs, gastrointestinal tract, peritoneum, central nervous system, genital, and urinary tracts.^{[12][13][14][14][15]}
• Extramedullary hematopoiesis (EMH) in the spleen of patients with primary myelofibrosis (PMF) can lead to abnormal angiogenesis in the organ and it has been documented that monocytes expressing the angiopoietin-2 receptor (Tie2) play a role in starting/maintaining this pathological angiogenesis.^[16]

• The main sites of extramedullary hematopoiesis (EMH) include the spleen and liver.^{[15][17][18][19][20]}
• Hematopoiesis can rarely also occur in the following locations:

• Genitourinary tract^[12][13][20]
• Central nervous system^{[21][22][23][12]}
• Lymph nodes^[19][12]
• Skin^[24]
• Peritoneum^[12]
• Gastrointestinal tract^[12]
• Lungs^[14][20]

• Development of myelofibrosis is the result of multiple genetic mutations.
• Genes involved in the pathogenesis of myelofibrosis include:^{[25][26][27][28][3][29][30][31][32][33][34][35]}

• Janus kinase 2 (JAK2)
• Calreticulin (CALR)
• Myeloproliferative leukemia virus (MPL) oncogene
• These mutations are found in approximately 90% of the patients.

• Additional sex combs-like 1 (ASXL1)
• Slicing factor, serine/arginine-rich 2 (SRSF2)
• Enhancer of zeste, drosophila, homolog 2 (EZH2)
• Neuroblastoma RAS viral oncogene homolog (NRAS)
• Kirsten rat sarcoma viral oncogene homolog (KRAS)
• Protein-tyrosine phosphatase, non-receptor type 11 (PTPN11)
• GATA-binding protein 2 (GATA2)
• Tumor protein p53 (TP53)
• Runt-related transcription factor 1 (RUNX1)

• Myelofibrosis belongs to a group of disorders collectively called myeloproliferative disorders. Other members of this group include chronic myelogenous leukemia (CML), polycythemia vera (PV), and essential thrombocythemia (ET).
• Myelofibrosis can be associated with a variety of medical conditions such as:

• Malignancies and hematologic disorders like:^{[36][37][38][39][40][41][42][43][44][45][46][47]}

• Hodgkin lymphoma
• Non-Hodgkin lymphoma
• Chronic lymphocytic leukemia (CLL)
• Essential thrombocythemia (ET)
• Polycythemia vera (PV)
• Multiple myeloma (MM)
• Malignancies with metastases to the bone

• Infections such as:^{[48][49][50][51][52]}

• Tuberculosis [TB]
• HIV infection
• Disseminated trichosporon infection
• Dengue fever

• Autoimmune diseases like:^{[53][54][55][56][57]}

• Systemic lupus erythematosus [SLE]
• Multiple sclerosis [MS]
• Sjogren’s syndrome
• Juvenile idiopathic arthritis

• Endocrine disorders such as:
  • Primary hyperparathyroidism^[58]
• Delta-storage pool deficiency (SPD)^[59]
• Ghosal syndrome^[60]
• Gray platelet syndrome^[61]
• Chromosome 14q32 duplication syndrome, 700-kb^[62]
• Revesz syndrome^[63]
• Dermatomyositis^[64]

• On gross pathology, extramedullary hematopoiesis (EMH), the characteristic finding, is manifested as:^{[65][66][67][68][33][69][70][71][72]}
  • Lymphadenopathy
  • Hepatomegaly
  • Splenomegaly

• Low red blood cell (RBC) count manifesting as anemia.^[73][65][74]
• Erythroblastosis^[75][76]
• Fish-shaped red blood cells (RBCs) on peripheral blood smear^[77]
• Micromegakaryocytes on the peripheral blood smear^[7]
• Fibroblast-like and myofibroblast-like reticulum cells on bone marrow study^[78]
• Teardrop cells^[79]
• Increased microvascular density, bizarre vessel architecture, and increased number of pericytes on bone marrow study^[80][81]
• Leukocytosis and thrombocytosis (in the initial stages)^{[82][83][84][85][86][87][88][89][90]}
• Leukopenia and thrombocytopenia (in the advanced stages)^{[82][83][84][85][86][87][88][89][90]}
• Basophilia^[91][92][93]

• Proplatelet (pseudopodia of megakaryocyte which extend into bone marrow sinuses to release platelets) formation^[94]
• CD14+ cells and monocytes expressing the angiopoietin-2 receptor (Tie2) lie close to the vessels in the spleen tissue^[16]
• Vessels with increased density, tortuous architecture, and increased branching on bone marrow study^[81]
• Thrombospondins (TSP) overexpression^[95]

• Micromegakaryocytes with mature cytoplasm containing alpha granules and the associated proteins^[7]
• Megakaryocytes in the peripheral blood with leukoerythroblastosis^[96]
• Significant atypicalities of the neutrophilic, basophilic, and megakaryocytic cell lines such as:

• Nuclear–cytoplasmic asynchrony^[97]
• Partial arrest of maturation

• Ultrastructural abnormalities in platelets such as:

• Hypoplasia of surface connecting system with few orifices^[98]
• Hyperplasia of the dense tubular system
• Considerable variety in the number of granules

• Splenic findings can consist of the following:

• No alteration in the basic structure^[99]
• Degenerative atrophic changes in the white pulp
• Erythropoietic and granulopoietic cells along with megakaryocytes in the sinuses and cords of the red pulp
• Cytoplasmic (degenerative in nature) and nuclear (nuclear blebs and loops) changes in the ,refhematopoietic cells

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2]

Myelofibrosis is most commonly caused by somatic mutations in the myeloproliferative leukemia virus (MPL) oncogene, the calreticulin (CALR) gene, or Janus kinase 2 (JAK2) gene. Less common mutations in other genes have also been documented. It can also be the result of other primary disorders manifesting as a complication or part of the disease process. Infections, malignancies, hematologic disorders, autoimmune diseases and exposure to certain toxins can also cause myelofibrosis.

There are no life-threatening causes of myelofibrosis, however complications resulting from untreated myelofibrosis is common.

Common causes of myelofibrosis include:

• Genetic mutations in:

• Myeloproliferative leukemia virus (MPL) oncogene^{[1][2][3][4][5][6][7][8][9][10][11]}
• Calreticulin (CALR) gene^{[1][2][3][4][5][6][7][8]}
• Janus kinase 2 (JAK2) gene^[9][10][11]

• Malignancies^{[12][13][14][15][16]}
• Hematologic disorders^{[16][17][18][19][20][21]}

• Infection^{[22][23][24][25]}
• Autoimmunity^{[26][27][28][29]}
• Toxins exposure^{[30][31][32][33][34][35][36][37]}
• Primary hyperparathyroidism^[38]

Common

Myelofibrosis is commonly caused by mutations in the following genes:

• Myeloproliferative leukemia virus (MPL) oncogene^{[1][2][3][4][5][6][7][8][9][10][11]}
• Calreticulin (CALR) gene^{[1][2][3][4][5][6][7][8]}
• Janus kinase 2 (JAK2) gene^[9][10][11]

Less Common

Myelofibrosis is less-commonly caused by mutations in the following genes:

• Additional sex combs-like 1 (ASXL1)^[39]
• Slicing factor, serine/arginine-rich 2 (SRSF2)^[39]
• Enhancer of zeste, drosophila, homolog 2 (EZH2)^[39]
• Neuroblastoma RAS viral oncogene homolog (NRAS)^[39]
• Kirsten rat sarcoma viral oncogene homolog (KRAS)^[39]
• Protein-tyrosine phosphatase, non-receptor type 11 (PTPN11)^[39]
• GATA-binding protein 2 (GATA2)^[39]
• Tumor protein p53 (TP53)^[39]
• Runt-related transcription factor 1 (RUNX1)^[39]

Cardiovascular	No underlying causes
Chemical/Poisoning	benzene, thorium dioxide, nitrosurea[30][31][32][33][34][35][36][37]
Dental	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	No underlying causes
Ear Nose Throat	No underlying causes
Endocrine	Primary hyperparathyroidism[38]
Environmental	benzene, nitrosurea[30][31][32][33][34]
Gastroenterologic	No underlying causes
Genetic	Mutations in multiple genes discussed above
Hematologic	Essential thrombocythemia (ET), Polycythemia vera (PV), and Multiple myeloma (MM)[16][17][18][19][20][21]
Iatrogenic	No underlying causes
Infectious Disease	tuberculosis (TB), HIV infection, and dengue fever[22][23][24][25]
Musculoskeletal/Orthopedic	No underlying causes
Neurologic	No underlying causes
Nutritional/Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	Hodgkin’s lymphoma, Non-Hodgkin lymphoma, and Bone metastases[12][13][14][15][40]
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal/Electrolyte	No underlying causes
Rheumatology/Immunology/Allergy	No underlying causes
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	x- or γ-radiation exposure

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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], Sujit Routray, M.D. [5]Sabawoon Mirwais, M.B.B.S, M.D.[6]

Myelofibrosis must be differentiated from other diseases that cause diffuse bone sclerosis, splenomegaly, anemia, leukopenia, thrombocytopenia, leukocytosis, thrombocytosis, and extramedullary hematopoiesis (EMH) such as sickle cell disease, hyperthyroidism, sclerosing bone dysplasia, osteoblastic metastases, Paget’s disease, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), polycythemia vera (PV), myelodysplastic syndrome, chronic myelomonocytic leukemia, acute panmyelosis, acute megakaryoblastic leukemia, cirrhosis, infections, neoplastic and lipid storage disorders.^{[1][2][3][4][5][6][7]}

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+[8][9]		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)[10][11][12]		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)[13][14][15][16]		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)[17][18][19][20]		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)[21][22][23]		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)[24][25][26][27]		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[28][29][30][31]		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[32][33][34][35]		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[36][37]		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)[38][39]		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[40][41]		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[42][43][44][45]		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)[46] [47][48]	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-[49][50]	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)[51][52]	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)[53][54][55]	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[56][57][58]	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[59]	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[60][61]	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.

Myelofibrosis must be differentiated from other diseases that cause diffuse bone sclerosis, anemia, leukopenia, thrombocytopenia, leukocytosis, or thrombocytosis:^{[2][3][4][6][7]}

Type of diseases	Diseases
Hematological	Sickle cell disease
Metabolic bone disorders	Hyperthyroidism Hypoparathyroidism Renal osteodystrophy
Congenital	Sclerosing bone dysplasia Osteopetrosis Pyknodysostosis
Malignancy	Lymphoma: infiltration Leukaemia: infiltration Osteoblastic metastases from: prostate cancer breast cancer
Other	Paget disease Fluorosis Mastocytosis Hepatitis C associated osteosclerosis

Myelofibrosis must also be differentiated from other diseases that cause splenomegaly and/or extramedullary hematopoiesis (EMH):^[1][5][6]

Type of diseases	Diseases
Hematological causes	Anemia Sickle cell disease Thalassemia Hereditary spherocytosis Pyruvate kinase deficiency Thrombotic thrombocytopenic purpura (TTP) Neoplastic/proliferative/redistribution of hematopoesis Leukemia (especially CML*) Polycythemia rubra vera (PRV) * Waldenstorm macroglobulinemia Osteopetrosis Idiopathic hypereosinophilic syndrome * = may cause massive splenomegaly
Hemodynamic	Portal hypertension in the setting of cirrhosis Congestive splenomegaly (Banti’s syndrome) Splenic vein obstruction Portal vein obstruction Right heart failure
Infections	Viral Infectious mononucleosis Acquired immunodeficiency syndrome (AIDS) Cytomegalovirus (CMV) viremia Disseminated Herpes simplex virus (HSV) infection Rubella infection Bacterial Miliary tuberculosis Tularemia Subacute bacterial endocarditis Typhoid fever Brucellosis Syphilis Abscess Fungal Histoplasmosis Candidiasis Parasitic disease Malaria Schistosomiasis Hydatid disease Leishmaniasis (kala-azar) Rickettsial disease Typhus
Storage/metabolic/infiltrative disorders	Glycogen storage diseases Mucopolysaccharidoses Hemochromatosis Amyloidosis Porphyria Sarcoidosis
Neoplastic	Lymphoma Metastases from primary malignancies such as: Breast carcinoma Lung carcinoma Colon carcinoma Ovarian carcinoma Melanoma Hemangioma Lymphangioma Angiosarcoma
Trauma	Hematoma Pseudocyst
Connective tissue disorders	Systemic lupus erythematosus (SLE) Rheumatoid arthritis Felty’s syndrome Juvenile rheumatoid arthritis Still’s disease

References

1. ↑ ^{1.0 1.1} Splenomegaly. Dr Henry Knipe and A.Prof Frank Gaillard et al. Radiopaedia 2016. http://radiopaedia.org/Italic textarticles/splenomegaly. Accessed on March 11, 2016
2. ↑ ^{2.0 2.1} Bae E, Park CJ, Cho YU, Seo EJ, Chi HS, Jang S, Lee KH, Lee JH, Lee JH, Suh JJ, Im HJ (December 2013). “Differential diagnosis of myelofibrosis based on WHO 2008 criteria: acute panmyelosis with myelofibrosis, acute megakaryoblastic leukemia with myelofibrosis, primary myelofibrosis and myelodysplastic syndrome with myelofibrosis”. Int J Lab Hematol. 35 (6): 629–36. doi:10.1111/ijlh.12101. PMID 23693053.
3. ↑ ^{3.0 3.1} Tefferi A (September 2014). “Primary myelofibrosis: 2014 update on diagnosis, risk-stratification, and management”. Am. J. Hematol. 89 (9): 915–25. doi:10.1002/ajh.23703. PMID 25124313.
4. ↑ ^{4.0 4.1} Tefferi A (February 2013). “Primary myelofibrosis: 2013 update on diagnosis, risk-stratification, and management”. Am. J. Hematol. 88 (2): 141–50. doi:10.1002/ajh.23384. PMID 23349007.
5. ↑ ^{5.0 5.1} Aumann K, Frey AV, May AM, Hauschke D, Kreutz C, Marx JP, Timmer J, Werner M, Pahl HL (November 2013). “[Differential diagnosis of myeloproliferative neoplasms. Quantitative NF-E2 immunohistochemistry for differentiating between essential thrombocythemia and primary myelofibrosis]”. Pathologe (in German). 34 Suppl 2: 201–9. doi:10.1007/s00292-013-1824-8. PMID 24196613.CS1 maint: Unrecognized language (link)
6. ↑ ^{6.0 6.1 6.2} Differential diagnosis of myelofibrosis. Dr Henry Knipe and Dr Yuranga Weerakkody et al. Radiopaedia 2016. http://radiopaedia.org/articles/myelofibrosis. Accessed on March 10, 2016
7. ↑ ^{7.0 7.1} Diffuse bony sclerosis: differential diagnosis. Dr Craig Hacking and Dr Yuranga Weerakkody et al. Radiopaedia 2016. http://radiopaedia.org/articles/diffuse-bony-sclerosis-differential-diagnosis. Accessed on March 10, 2016
8. ↑ 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.
9. ↑ 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.
10. ↑ 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.
11. ↑ 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.
12. ↑ 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.
13. ↑ 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.
14. ↑ Pillai AA, Babiker HM. PMID 30252337. Missing or empty |title= (help)
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16. ↑ 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.
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23. ↑ 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)
24. ↑ 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.
25. ↑ 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.
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29. ↑ Macri A, Cook C. PMID 29494109. Missing or empty |title= (help)
30. ↑ 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.
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32. ↑ 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.
33. ↑ 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)
34. ↑ 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)
35. ↑ 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)
36. ↑ 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.
37. ↑ 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.
38. ↑ 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.
39. ↑ 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.
40. ↑ 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.
41. ↑ 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.
42. ↑ 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)
43. ↑ 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)
44. ↑ 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)
45. ↑ 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)
46. ↑ 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.
47. ↑ 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.
48. ↑ 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.
49. ↑ 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.
50. ↑ 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.
51. ↑ Aricò M, Biondi A, Pui CH (July 1997). “Juvenile myelomonocytic leukemia”. Blood. 90 (2): 479–88. PMID 9226148.
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