Michael burton hematology Flashcards
Describe the structure of a lymph node
-Surrounded by a fibrous capsule that extends inwards to form trabeculae which gives structural support.
- Fibroblastic reticular cells produce reticular fibres which give more structural support and keep the sinuses open/patent.
1. Cortex
-The cortex contains inactive and activated B cells.
-Inactivated B cells are found in primary follicles, while activated B cells are found in the secondary follicles within the central germinal centre –> this is where they undergo activation, clonal expansion and begin differentiation into plasma cells.
2. Paracortex
- Contains mainly T cells + dendritic cells.
- This is where T cells are activated by antigen-presentation by dendritic cells.
- These activated T cells can migrate to the cortex to interact with B cells.
- Contains high endothelial venules which are lined with cuboidal endothelial cells allowing for entry of circulating lymphocytes into the node via adhesion molecules.
3. Medulla
- Contains medullary cords and sinuses
- This is where B cells undergo their final step of maturation into plasma cells/ antibody production.
Sinuses
- Sinuses traverse the lymph node towards the medulla where it can exit via efferent lymphatic vessels.
- They act to increase the surface area for interaction between potential pathogens and immune cells
- Subcapsular sinus –> radial sinus –> medullary sinus –> efferent vessel.
Describe the different types of reactive lymphadenopathy with causes of each
1. Follicular hyperplasia
- B cells are proliferating within secondary follicles in response to antigen stimulation.
-Bacterial infection in adjacent structure, HIV, RA, SLE
2. Interfollicular (paracortical) hyperplasia
- T cell proliferation in response to antigen stimulation
- Viral infections mostly; EBV, CMV, Vaccination
3. Sinusoidal hyperplasia
- Medullary sinuses are enlarged and filled with histocytes/macrophages
- Associated with drainage of nearby malignancies (node is not considered cancerous), hemolytic anemia, kikuchi disease.
Clinical features of acute leukemia (ALL/AML)
General to both
-Anemia; fatigue, pallor, tachycardia if severe
-Neutropenia; recurrent or persistent infections/ fever
-Thrombocytopenia; easy bleeding/bruising
-Hepatosplenomegaly due to leukemic infiltration
-Leukostasis; priapism, disseminated intravascular coagulation.
ALL
-Painless lymphadenopathy
-Bone pain
-Airway obstruction (stridor, difficulty breathing) due to mediastinal or thymic infiltration (primarily in T-cell ALL)
-Features of SVC syndrome
-Meningeal leukemia (or leukemic meningitis) → headache, neck stiffness, visual field changes, or other CNS symptoms
-Testicular enlargement (rare finding)
AML
-Leukemia cutis (or myeloid sarcoma): nodular skin lesions with a purple or gray-blue color
-Gingival hyperplasia
–Lymphadenopathy generally less common in AML–
What are the most common genetic abnormalities (karyotype) in ALL?
(1) Hyperdiploidy (> 50 chromosomes)
-Leukemic cells acquire extra chromosomes, often more than 50.
(2) Translocation between chromosome 12 and 21:
-This creates an abnormal fusion gene (ETV6-RUNX1) that affects cell growth regulation.
-This impairs differentiation and leads to uncontrolled proliferation of immature pre-B lymphoblasts.
This karyotype is associated with a good prognosis as it means the leukemic cells are better responsive to treatments
What is the Philadelphia chromosome and what are its implications in leukemia?
- Philadelphia chromosome is a genetic abnormality whereby there is a reciprocal translocation between chromosomes 9 and 22
- This creates the BCR-ALB-1 fusion gene which encodes for a highly active tyrosine kinase –> uncontrolled tyrosine kinase activity drives leukemia progression.
Implications
- Associated historically with a poorer diagnosis with high relapse rates.
- Requires a stringent treatment regimen involving tyrosine kinase inhibitors.
- High risk of CNS involvement may require prophylactic CNS treatment (e.g. intrathecal chemotherapy)
Briefly describe the pathophysiology of chronic lymphocytic leukemia
CLL involves proliferation of mature B cells, typically expressing the CD5 protein.
Mature B cells undergo malignant transformation, primarily due to genetic mutations, including chromosomal deletions, leading to the production of functionally incompetent B cells.
Tumor formation is driven by prolonged survival of these malignant B cells due to defective apoptosis, rather than by rapid proliferation.
Malignant transformation occurs in the bone marrow but can also involve the lymph nodes and spleen. If it primarily involves LN’s its referred to as small lymphocytic lymphoma (SLL).
As these CLL B cells accumulate, they gradually replace normal B cells in the bone marrow, lymph nodes, peripheral blood, and spleen, contributing to disease progression.
Overexpression of the anti-apoptotic protein BCL-2 within these malignant cells prevents programmed cell death, allowing for longer survival.
Hypogammaglobulinemia (reduced immunoglobulin production) results from impaired normal B-cell function, leading to increased susceptibility to infections.
The malignant B cells also disrupt immune regulation, inhibiting normal immune cell function (e.g., T cells and NK cells), contributing to overall immune dysfunction.
Paradoxically, CLL is associated with autoimmunity, as malignant B cells can lead to the production of autoantibodies against normal blood cells, increasing the risk of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP).
What is the difference between AML and CML in terms of cell of origin
AML arises from myeloblasts which are very immature, undifferentiated cells within the myeloid lineage of cells. These cells have not yet become committed to their final cell type i.e. monocyte or granulocyte. The key problem is a block in differentiation, leading to accumulation of blasts.
CML arises from more mature myeloid precursor cells. These cells are at a more mature stage of differentiation/committed to becoming granulocytes. Unlike AML, differentiation is not blocked—instead, too many mature granulocytes are produced.
What is the LAP score and what is its relevance in leukemia work up?
LAP Score (Leukocyte Alkaline Phosphatase Score) measures the alkaline phosphatase activity in mature neutrophils. It helps distinguish between Chronic Myeloid Leukemia (CML) and reactive leukocytosis (Leukemoid Reaction).
Neutrophils in CML are malignant and dysfunctional, so they lack normal alkaline phosphatase activity = LOW LAP score
In infections/inflammation, neutrophils are functionally normal, leading to increased alkaline phosphatase activity. = HIGH LAP score
Differentiate Hodgkins from Non-Hodgkins lymphoma in terms of pathology
Hodgkin’s lymphoma invovled malignant transformation of germinal centre B cells forming Reed-sternberg cells. It often begins in a single lymph node or a localized group of lymph nodes, and it tends to spread in a contiguous, orderly fashion from one node to the next. In early stages, the disease is frequently confined to one or a few lymph node regions. Over time, HL can spread to other parts of the lymphatic system or to other organs, but this spread typically follows a predictable pattern.
NHL is a heterogeneous group of lymphomas that can involve both B-cells and T-cells. It can start in lymph nodes as well but tends to present in a more widespread fashion, involving multiple lymph node groups at once or in a non-contiguous manner. NHL can also arise outside of the lymph nodes (extranodal sites), such as the spleen, bone marrow, gastrointestinal tract, skin, and other organs. Some types of NHL, especially aggressive ones, may involve extranodal tissues from the outset.
Describe the structure of splenic microcirculation
-Blood enters via the splenic artery which divides into trabecular and subsequently central arterioles.
-Central arterioles are surrounded by peri-arteriolar lymphoid sheath (PALS), a component of white pulp.
-PALS is lined with T cells and monitor blood for antigens.
-Adjacent to PALS are the lymphoid follicles (white pulp also), of which there are primary and secondary.
-Primary follicles contain inactive, naive B cells
-Secondary follicles contain activated B cells undergoing proliferation/class switching within the germinal centre.
-The marginal zone is the region between the red and white pulp and it contains macrophages, dendritic and specialised B cells which are responsible for removal of encapsulated bacteria.
-Red pulp is organised into open and closed circulation
-Closed circulation involves direct entry of RBC’s through splenic sinusoids, remaining within vessels, which then enter directly into venous circulation.
-Open circulation involves emptying of RBC’s into cords of billroth; these RBC’s must then squeeze through the fenestrated walls of the sinusoids to re-enter venous circulation –> damaged, old, abnormal RBCs are phagocytosed by macrophages at this stage.
-Splenic venules merge into larger veins –> splenic vein –> joins superior mesenteric vein –> portal
Name 5 functions of the spleen
- Blood filtration of old, abnormal RBCs
- Immune surveillance and antibody production
- Removal of encapsulated bacteria
- Fetal hematopoeisis until about 28 weeks.
- Storage of blood
- Iron recycling
MOA of Vincristine
Binds to beta-tubulin within the malignant cells, preventing its assembly with alpha-tubulin
This therefore inhibits microtubule polymerisation meaning the microtubules cannot grow or form the mitotic spindle.
This means that chromosomes cannot properly align nor separate and so are arrested in the M-phase of cell division
This prevents leukemic cell divison.
Causes peripheral neuropathy by affecting normal nerve microtubule function which is responsible for nerve cell transportation
MOA of Daunorubicin
Inserts itself into DNA and inhibits topoisomerase II.
Topoisomerase II is responsible for relieving the DNA supercoil and functions in cleaving and re-joining DNA strands during DNA replication.
Daunorubicin therefore prevents the resealing of double strand breaks leading to double strand break accumulation triggering leukemic cells apoptosis.
It is also known to generate free radicals which can contribute to DNA double strand breaks
Cardiotoxic –> Dilated cardiomyopathy
Asparaginase MOA
Catalyzes breakdown of circulating L-asparagine.
L-asparagine is needed by leukemic cells for protein synthesis, however because the lack the enzyme asparagine synthase, they rely on circulating L-asparagine for this.
Therefore by starving leukemic cells of this amino-acid, the cells undergo apoptosis.
MOA of Allopurinol
Allopurinol is a Xanthine oxidase inhibitor which prevents the conversion of hypoxanthine/xanthine to uric acid.
This help offset the otherwise high levels of uric acid produced during leukemic cell lysis (tumour lysis syndrome)
Steven Johnson Syndrome/ Nephrotoxicity
