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HLS Pathology 2

Hematopoeitic and Lymphatic System- White blood cell diseases

What is polycythemia? An increase in RBC mass above the normal level
What are the normal levels of hemoglobin? 16 g/dl in women 18 g/dl in men
What are the two main types of polycythemia? 1) Primary polycythemia (polycythemia vera) 2) Secondary polycythemia - more common
What is primary polycythemia? It is a neoplastic disease of the RBC line
Clinical characteristics of primary polycythemia? 1) Low erythropoietin 2) Splenomegaly 3) Plethora (redness of the skin due to congestion of RBCs in superficial veins) 4) Cyanosis 5) Itching 6) Gout 7) Thrombosis secondary to the high number and slow movement of the RBCs
Chronic hypoxia for any reason causes Secondary polycythemia
Secondary polycythemia might be due to: 1) Chronic lung disease 2) Chronic heart disease 3) Alcoholism: alcohol suppresses ADH secretion 4) Smoking 5) High altitude 6) Renal cell carcinoma
Surreptitious, which is the voluntary intake of erythropoietin or RBCs, is common in Athletes
What's the difference between Primary and secondary polycythemia? In secondary polycythemia, if you eliminate the underlying cause, patients will no longer have polycythemia and splenomegaly does not occur
Normally in the peripheral blood, the WBC count is Between 4,000-10,000 cell/microliter
Leukocytosis is an increase in the total number of WBCs above 10,000 cell/microliter
Leukopenia is: a decrease in the total number of WBCs below 4,000 cell/microliter
What are the causes of Leukopenia? 1) Neutropenia 2) Lymphopenia
We calculate the absolute neutrophil count (ANC) by multiplying the total WBC count by the percentage of neutrophils
If the ANC is below 1,500 cell/microliter This is absolute neutropenia
Neutropenia could be due to Decreased production Increased destruction
Decreased production could be due to: 1) Part of pancytopenia (more common) 2) Isolated Neutopenia 3) Congenital neutropenia
What happens in pancytopenia? there is a reduction of RBC, WBC and thrombocytes as well mainly due to bone marrow failure
Examples of cases in which decreased production occurs due to pancytopenia: 1) Aplastic anemia 2) Myelophthesic anemia 3) Megaloblastic anemia 4) Myelodysplastic syndrome 5) Chemotherapy
What occurs in isolated neutropenia? Only the Neutrophil count is decreasing RBCs and platelets are still normal
Examples of cases in which decreased production occurs due to isolated neutropenia: Neutropenia acquired secondary to drugs Antiepileptics Anti-psychotics Anti-hyperthyroidism drugs
Congenital Neutropenia (less common) is due to 2 syndromes: 1) Schwachman-diamond Syndrome 2) Chediak-Higashi syndrome
What is the mode of inheritance of these two syndromes? Both are autosomal recessive
Etiology of Schwachman-diamond Syndrome: A mutation in the gene SBDS
Etiology of Chediak-Higashi syndrome: A mutation in the gene is called LYST
Symptoms of patients with Schwachman-diamond Syndrome: Skeletal abnormalities and pancreatic failure Early in life during infancy Bone marrow is not producing neutrophils
Symptoms of patients with Chediak-Higashi syndrome: Abnormal lysosomal aggregation Bacterial infections early in life Platelet dysfunction (so they have a bleeding tendency) Albinos
Examples of cases in which increased destruction occurs: 1) Severe infections and sepsis 2) Immune-mediated 3) Cyclic neutropenia 4) Hypersplinism 5) Paroxysmal Nocturnal Hematuria
How do Sepsis and infections cause neutropenia? The bacteria overcome the neutrophils and destroy them, so the patient develops neutropenia, and this might result in death. Salmonella and Brucella are well-known for causing neutropenia
Immune-mediated: patients would have destruction of the neutrophils by Abnormal antibodies and it is common in auto-immune diseases, like rheumatoid arthritis
Etiology of cyclic neutropenia: a mutation in ELANE gene which causes abnormal elastase quantity
What is the mode of inheritance of cyclic neutropenia? Autosomal dominant
Pathology of cyclic neutropenia: Due to the increased number of elastase, and neutrophils would die prematurely
Hypersplenism results in: Destruction of cells which causes anemia, neutropenia and thrombocytopenia
Types of leukocytosis: 1) Reactive Leukocytosis 2) Neutrophelia 3) Eosinophila 4) Monocytosis 5) Lymphocytosis 6) Reactive Lymphadenitis
What is reactive leukocytosis? It is an increase in the number of WBCs in the blood
Most common cause of reactive leukocytosis: Infections
Condition where there is a left-shifted granulopoiesis, where immature WBCs go into the circulation: Leukemoid Reaction
The WBC count in Leukemoid reaction is: 50,000 or 100,000 cell/microliter or more
When does Leukemoid reaction occur? In very severe stress (patients in ICU) and in paraneoplastic syndrome in which patients have cancer and this cancer is functioning (produce leukotrienes and all the inflammatory mediators)
What is Neutrophilia? An increase in the count of neutrophils above the normal level Most common form of leukocytosis
Most common cause of Neutrophilia: Bacterial infections
Other causes of Neutrophilia: Burns, tissue necrosis (ex. Myocardial infarction) and steroids (activate myelogenesis)
In Reactive (non-neoplastic) neutrophilia, neutrophils are very active with prominent granules that are increased in number, and this is called Toxic granulation
What is eosinophilia? An increase in eosinophils in the peripheral blood
Causes of eosinophilia: Allergic diseases Parasitic infections Drug reactions (sensitivity to drugs) Cancers/malignancies (ex. Hodgkin lymphoma)
When does Monocytosis occur? In chronic infections (ex. Tuberculosis) Inflammatory bowel disease (there is a chronic inflammation in the GI system) Rheumatologic diseases
When does Lymphocytosis occur? Viral infection (most common) Tuberculosis Rheumatologic diseases
What is the difference between Reactive lymphadenitis and the other types of leukocytosis? Lymphadenitis is related to lymph nodes, while the other diseases are related to WBCs
What is reactive lymphadenitis? The increase in the size of lymph nodes secondary to the increase in the number of lymphocytes
Causes of reactive lymphadenitis: Infections, like viral infections and tuberculosis Autoimmune, like Rheumatoid arthritis
Enlargement of the Lymph nodes is clinically referred to as: Lymphadenopathy
In the acute setting of reactive lymphadenitis: The lymph nodes are painful The rapid increase in size will compress the nerves around it
Causes of acute reactive lymphadenitis: Bacterial and viral infections Usually, benign
In the chronic setting of reactive lymphadenitis: Painless Common in rheumatoud arthritis and lymphomas
The benign causes of chronic reactive lymphadenitis, which we classify between B and T cells: 1) Follicular hyperplasia 2) Paracortical (diffuse) hyperplasia
What is follicular hyperplasia? With increased B-cell proliferation, the number of germinal centers and follicles inside the lymph node will be increased, so the lymph node will be enlarged
When does follicular hyperplasia occur? 1) HIV infection 2) Toxoplasmosis (a parasite which causes increased number of B cells) 3) Rheumatoid arthritis and other rheumatologic diseases
What is paracortical diffuse hyperplasia? When T-cells proliferate, the paracortical area will expand and the lymph node will appear as if it has less germinal centers and it results in a diffused sheet-like appearance
When does paracortical diffuse hyperplasia occur? Viral infections Drug reactions (sensitivity) Post-vaccination
What is the difference in morphology between follicular and diffuse hyperplasia? In Reactive follicular hyperplasia, the follicles are in contact with each other While in Diffuse Hyperplasia, you cannot clearly see the germinal centers due to the proliferation of T cells
How are hematopoeitic malignancies classified? According to the cell of origin into: 1) Myeloid 2) Lymphoid (from the lymphocyte) 3) Histiocytic
Myeloid neoplasms are sub-classified into: 1) Myeloproliferative neoplasms 2) Myelodysplastic syndromes 3) Acute myeloid leukemia
What do the 3 sub-classifications of myeloid neoplasms have in common? There are mutations in the stem cells which cause neoplasms There is an increased number of cells in the bone marrow Tend to progress to acute myeloid leukemia Slow progression
Risk Factors for myeloid tumors: 1) Chemicals: benzene and pesticides (cause leukemia and myeloid neoplasms in cases of long exposure) 2) Radiation 3) Some congenital disease: most common one is fanconi anemia 4) Smoking 5) Paroxysmal Nocturnal Hematuria
Normal Cellularity of the Bone Marrow Promyelocytes: normally, they're up to 8% Monocytes: do not exceed 5% Lymphocytes: do not exceed 17% Plasma cells: do not exceed 3%
The number of myeloid cells is how much more erythroid cells? 3-4 times
When we examine bone marrow specimens, there are two types of specimens: 1) Aspirate smear: you swipe blood on a slide and examine it under the microscope, and you can visualize the cells individually 2) Bone Marrow Biopsy: using lower magnification you try to see how the tissue and its cells look like
Importance of aspirate smear: This smear contains all stages of maturation If it only had myeloblasts, it would be an indication of leukemia Also, if it had a lot of mature neutrophils, this could be an indication of CML
Importance of Bone marrow biopsy: In early life the bone marrow is very active and the cellularity can reach 100% To calculate normal cellularity of the bone marrow, we subtract the age from 100%.
What is Myeloproliferative neoplasm: A chronic disorder which means it stays for a long time, persists for years and is defined by hyperproliferation of neoplastic myeloid progenitors that retain the capacity of terminal differentiation
How do myeloproliferative neoplasms affect blood cells? The bone marrow is hypercellular Affects the stem cells (myeloid progenitors) which differentiate normally, so we see the terminal cells of each cell line Persistent peripheral blood cytosis( leukocytosis, polycytosis or thrombocytosis)
Difference between myeloproliferative neoplasms and Acute Myeloid Leukemia: AML shows many stem cells Myeloproliferative neoplasms produce terminal cells (the cells retain the capacity to differentiate)
Why do myeloproliferative neoplasms produce splenomegaly and hepatomegaly? Neoplastic blasts (stem cells) like to migrate due to increase in numbers, they escape from the bone marrow and go to the spleen and liver and they start proliferating there
What are the 4 main types of myeloproliferative neoplasm? 1) Chronic Myelogenous Leukemia 2) Polycythemia Vera 3) Primary Myelofibrosis 4) Essential thrombocythemia
What is the most common myeloproliferative neoplasm? CML
What genetic mutation occurs in CML? Translocation between chromosome 9 and 22 Chromosome 9 - ABL gene Chromosome 22 -BCR gene Fusion between ABL and BCR which creates a new gene (fusion gene) which is functioning and produces a tumor New chromosome- Philadelphia chromosome
What type of activity is present in this ABL-BCR fusion gene? tyrosine kinase activity
What are the clinical manifestations of CML? 1) Increase in WBC's ,exceed 100,000 cells/microL 2) Most cells mature normally 3) Thrombocytosis 4) Anemia, iron deficiency common - WBC's take in iron 5) Bone marrow hypercellular 6) Splenomegaly due to secondary extramedullary hematopoiesis
What do we see in the blood film? Increased number of WBC's , you see them compact and next to each other and this is not normal You see all the cell lines of cells in peripheral blood, and myeloblasts
What genetic mutation occurs in polycythemia vera? Janus kinase-2 (JAK-2) gene
What effect does the genetic mutation in polycythemia vera have on cells? Erythroid stem cells very sensitive to erythropoietin Erythropoietin is suppressed due to negative feedback inhibition Stem cells are sensitive to growth factors Hypercellular bone marrow Granulocytes + megakariocytes increased- panmyelosis
When a patient has polycythemia vera, the CBC shows: 1) here is increased haemoglobin concentration, in men above 18, in women above 16 2) Erythrocytosis, RBC count is more than 6,000 Patient have leukocytosis and thrombocytosis 3) Bone morrow is hypercellular and we see sheets of normoblasts
Clinical manifestations in patients with polycythemia vera: Plethora (redness of the skin) Cyanosis (hypoxia) Thrombosis due to increased number of erythrocyte which move slowly Itching Hypertension Uric acid accumulation causing Gout
What do we see in the blood film from a patient with polycythemia vera? Compact RBC's
What is primary myelofibrosis? Dense fibrosis in the bone marrow Increased numbers of myeloids and megakariocytes egakariocytes are predominant in primary myelofibrosis
Which cells are predominant in CML? Myeloids
Megakaryocytes in primary myelofibrosis are: Active They secrete GF B Activate the fibroblast in the bone marrow, when they are activated they secrete a lot of collagen, and the bone marrow will become fibrotic Cytopenia (leucopenia, anemia and thrombocytopenia)
Side effects in primary myelofibrosis: Spleen is producing erythroid and liver will have hematopoiesis, and this will cause spleenomegaly Jak-2 mutation (the gene which is affected in polycythemia vera) can be positive here
Blood film appearance in primary myelofibrosis: Change in the shape of RBCs because of fibrosis , they appear like tear drops Presence of early immature cells like: metamyelocyte and myelocytes Thrombocytosis platelets exceed 1000 and more Nucleated RBC's
Blood film after disease progression: Fibrosis in bone marrow Bone marrow becomes hypocellular Cytopenia Splenomegaly
What is Essential thrombocythemia? Chronic myeloprolefirative neoplasm that affects only megakaryocytes
Effect of essential thrombocythemia on blood: Thrombocytosis , number of platelets is more than 450 x10^9 /L Increased large mature megakaryocyte in the bone marrow NO fibrosis as in Primary myelofibrosis JAK-2 mutation present in 50% of the patients Thrombosis
Side effects of essential thrombocythemia: Hemorrhage Splenomegaly
Blood film of essential thrombocythemia at low magnification: megakaryocytes, they are large, crowded, close to each other. so in peripheral blood we see a lot of platelets(thrombocytosis)
Blood film of essential thrombocythemia at high magnification: one megakaryocyte has so many nuclear lobes (hyperlobulated nucleus)
Cells affected in CML; Myeloid and megakaryocytes
Cells affected in Polycythemia vera: Dominant one is erythrocyte but myelocytes and megakaryocytes also increase
Cells affected in Primary myelofibrosis: Megakaryocytes and myeloid cells with fibrosis
Cells affected in essential thrombocythemia: Only megakaryocytes
What is myelodysplastic syndrome? A group of clonal stem cell disorders (clonal means neoplastic) characterized by maturarion defect associated with ineffective hematopoiesis
Characteristics of MDS: Neutropenia Anemia Thrombocytopenia Hypercellular bone marrow
What are the hallmarks of MDS? Persistent peripheral cytopenia Morphologic dysplasia
How is MDS diagnosed? Mostly patients are idiopathic like in cancer they manifest without previous factors
How is MDS classified? 1) By the count of blasts 2) Extent of morphologic dysplasia
What are the categories in which MDS can be classified based on Blast count? < 6 % 6-10 % 11-19 % Above 19% (20% or more) means acute myeloid leukemia (AML)
What are the categories in which MDS can be classified based on extent of morphologic dysplasia? Erythroid Myeloid Megakaryocyte
If the number of blasts in MDS is between 6 –10 % we call it : Refractory anemia with excess blast 1 (RAEB-1)
If the number of blasts in MDS is between 11-19 % we call it : Refractory anemia with excess blast 2 (RAEB-2)
If the blast count is normal in MDS( less than 6%), we turn to: Morphologic dysplasia
If it is one cell line in MDS we call it : refractory cytopenia with unilinage dysplasia
If it is more than one cell line (2 or 3) in MDS we call it: Refractory cytopenia with multilinage dysplasia
In unicellular linage dysplasia in MDS we have one special type called: Refractory anemia with ring sideroblast
The prognosis in MDS is: Very good Patients live for a long time
Patients with refractory anemia with ring sideroblast commonly have: Cytopenia
Which stain do we use in normoblast dysplasia? Iron stain so you case see in the picture cells are red and this stain stained the iron with blue color
In blood film for normoblast dysplasia what do we see? Normoblast doesn't condensate Normoblast are not normal and they can't mature normally These condensate iron in the mitochondria around the nucleus as a ring Normoblast with multiple nuclei Hyposegmented neutrophils Megakaryocytes become shrunken
What are lymphoid neoplasms (lymphomas)? The malignant neoplasm of lymphocytes
In any lymphoma there is a possibility that malignant cells go out and circulate in the blood, this is called: Lymphoid leukemia
Generally, we classify lymphomas into: 1) Low grade lymphomas 2) High grade lymphomas
What is the difference between low and high grade lymphomas? Low grade lymphomas proliferate very slowly and the disease stays for a long period of time, for years High grade lymphomas are sharp, the symptoms progress rapidly, the tumor will increase in a short period of time
There is another classification specifically for B-lymphomas. What is it? 1) Hodgekins lymphoma 2) Non-Hodgekins lymphoma
Most common type of lymphomas in children and 1/3rd of B lymphomas in adult: Hodgekins lymphoma
Most common lymphomas in adults: Non-Hodgekins lymphoma
Risk factors for lymphomas: 1) Immune suppression 2) Chronic inflammation -proliferating T-cells increase chance of mutations 3) Viruses, like EBV and HPV
General scheme of normal lymphogenesis of B lymphocytes: B lymphocytes are produced and become immunocompetent in the bone marrow, then they circulate and go to the lymph nodes and in germinal centers they proliferate to produce B memory cells and plasma cells
General scheme of normal lymphogenesis of T lymphocytes: T lymphocytes are produced in the bone marrow and become immunocompetent in the thymus then they circulate to secondary lymphatic tissues where they become either cytotoxic T cells or helper T cells
What are the possible cells of origin for lymphocytes? Germinal centers The mantle cell Bone marrow Plasma cells (in B lymphomas) Thymus
Cancers which originate from immature nonfunctional cells are much worse than those which originate from: Mature functional cells
How is diagnosis of lymphoma done? 1) A mass larger than 2 cm 2) B-symptoms- fever, night sweating, weight loss, anorexia 3) Immune supression 4) High LDH 5) Microscopic architecture is abnormal 6) Overgrowth of B or T-cells
Lymphocytes express what CD cells? B lymphocytes express CD19 and CD20 T lymphocytes express CD2 and CD3 Cytotoxic T cells express CD8 Helper T cell express CD4
Special stain to identify CD cells: Immunohistochemical stain
Most common ALL in general and in children? B-acute lmphoblastic leukemia/lymphoma
The most common ALL in males, which occurs in adolescent age? T-acute lmphoblastic leukemia/lymphoma
Why can ALL be classified as both lymphoma and leukemia? It arises from the bone marrow and lymph nodes
In ALL, lymphoblasts exceed what percentage of cells in the bone marrow? 20%
Lymphoblasts exceeding 20% of the cells in bone marrow causes: myelopthistic anemia
Clinical features of ALL: 1) Fever caused by infection (result of neutropenia) 2) Fatigue because of anemia 3) Bleeding due to thrombocytopenia 4) Bone pain
Systemic involvement symptoms in ALL: 1) Generalized lymphadenopathy; lymph node enlargement. 2) Splenomegaly 3) Hepatomegaly 4) Brain involvement 5) Testicular involvement
Morphology of ALL: Lymphoblasts larger than lymphocytes Their size is larger than the size of RBCs by 2x or 3x The color of the immature nucleus of lymphoblast is faint and has no nucleoli, fine chromatin Cytoplasm is present, very minimal, usually empty, no granules
In AML the cells have: Cytoplasm, which is more abundant There are nucleoli (not present in lymphoblasts) Granules unlike the lymphoblasts
Chronic lymphocytic leukemia is also known as: Small lymphocytic lymphoma
Why is CLL considered the opposite of ALL? The malignant cell is a lymphocytic differentiated cells It is low-grade tumor because cells are small, round, mature and looking similar to normal lymphocytes The nucleus is dark
In CLL, which factor is upregulated? Bcl-2 , anti-apoptotic protein
What effect does the upregulation of Bcl-2 have? Cells will have longer life and persist for a longer time, so the number of cells will increase and this manifest as leukemia or lymphoma
What is the most common leukemia in the elderly? CLL
What are the clinical features of CLL? Hypogammaglobulinemia; immune system doesn't produce enough amount of immunoglobulins and patients will be immunosuppressed Hemolytic anemia: cold type autoimmune hemolytic anemia Indolent and mild course 10% of cases will become high-grade lymphoma
What is the treatment of CLL? No treatment is given unless the symptoms appear and the case become more progressive Chemotherapy work on mitotically active cells
Morphology of CLL: Diffuse effacement of nodal architecture Lymph node will appear like a solid mass Scattered larger cells called prolymphocyte-central nucleolus Dead cellscalled smudge (burst, destroyed These lymphocytes are fragile High level of LDH
What is the most common lymphoma in western countries? Follicular lymphoma
Why is it called follicular lymphoma? Arises from germinal centre of B-cells
General characteristics of follicular lymphoma Affects the elderly low-grade B-cell lymphoma
Genetic mutations of cells in follicular lymphoma: Translocation between chromosome 14 and chromosome 18 Bcl-2 on 18 IgH on 14 Overexpression of Bcl-2
Clinical features of follicular lymphoma: Generalized lymphadenopathy Indolent course High grade lymphoma in 40% of cases
Morphology of follicular lymphoma: Lymphoma cells proliferate to form abnormal, large, crowded follicles Small irregular (cleaved) dark cells, called centrocytes Large cells, called centroblasts
How to differentiate between follicular lymphoma and reactive follicular hyperplasia? Ee use special stain for Bcl-2 The cells of follicular lymphoma will be very bright after staining- cells are expressing Bcl-2 in large amount In reactive follicular hyperplasia the result will be negative which means the amount of Bcl-2 is normal
General characteristics of Diffuse Large B Cell Lymphoma: High grade Large lymphocytes Most common type of lymphoma in adults 50% of adult Non-Hodgkin Lymphomas
Causes of Diffuse Large B cell lymphoma: In most cases, this lymphoma arises de novo; idiopathic, without previous cause In minority, it arises as a transformation from low grade B-cell lymphoma (from CLL or Follicular lymphoma).
Morphology of diffuse large B cell lymphoma: The cells are very large Architecture is lost (effacement) Large nuclei, and nucleoli are very prominent
Created by: Ulaisl