Hematopoietic and Lymph Node Pathology

Normal Development

Red Blood Cell Maturation

&
Anemias

Differentiation of Hematopoietic Cells

Normal Development

1
 Bone Marrow Bone Marrow

Bone Marrow, RBC Precursors

RBC Expelling the Nucleus Myeloid Maturation

2
 Megakaryocyte

Anemia
Anemias
„ Acute
„ Not a disease in itself
„ Trauma
„ Just a symptom, like a fever „ Blood loss, either internal or external
„ Must Understand why. „ Reticulocytes 10-
10-15% in a week

„ Fix underlying cause „ Chronic

„ Unpredicted outcomes „ Time to adapt
„ GI bleeds, colon ca
„ Increased demands of pregnancy

Erythrocytes
Anemia Workup
„ Size
„ History, History & More History „ Anisocytosis (an/iso/cytosis)
„ Age, sex, medications, duration…. „ Shape
„ Physical „ Poikilocytosis (poikilo/cytosis)
„ Fragmented cells
„ Nailbeds, mucus membranes…..
„ Hemoglobin content of cells and whole blood
„ Lab „ HBG and HCT
„ CBC „ MCH & MCHC
RBC size, shape, HgB, RDW, MCV, MCHC
Mean volume of the RBCs (MCV)
„
„
„ Reticulocyte count
„ Uniformity (RDW)
„ Chemistries
Iron, B-
„ Cytoplasmic inclusions
„ B-12, Folate
„ Congenital problems
„ Bone marrow „ Sickle cell among others
„ Fancy stuff

3
 Anemias by Etiology Anemias by Etiology
„ Blood loss
„ Acute, no time to accommodate
„ Trauma „ Congenital
„ Massively bleeding ulcer or esophageal varices „ Hemoglobin
„ Chronic, slow with some adaptation
„ GYN loss „ Sickle cell
„ Ulcer „ Enzyme
„ Colon cancer
G6PD
„ RBCs are ‘normocytic’ „

„ Retic count better go up „ Membrane

„ History and Physical „ Spherocytosis

Sickle Cell Disease

Shperocytosis
„ Homozygous vs. heterozygous
„ Chronic anemia
„ Acute crisis
„ Microvascular occlusion
„ Infections
„ Relative malaria resistance for AS

Hemolytic Anemias Problems of RBC Production

„ Premature destruction
or removal of RBCs „ Genetic related
„ Genetic „ Nutritional deficits
„ SS „ Iron
„ Spherocytosis „ B12
„ Acquired „ Dietary or problems of absorption?
„ Antibody mediated „ Chronic gastritis
„ Intravascular „ Folic acid
„ Antibody mediated „ Chronic renal failure (no erythropoietin)
„ Free hemoglobin
„ Aplasia of RBC line in bone marrow
„ Extravascular

4
 Thalassemia
Nutrient Deficit
„ Genetic
„ Collection of problems of production of one of the
„ Inadequate dietary source? hemoglobin chains.
„ Beta and Alpha chains
„ Absorption?
„ Utilization?

Thalassemia Thalassemia
„ Microcytic
„ Small RBCs
„ Target cells
„ Mismatched
production of β
and α chains
„ Hemoglobin
globs in RBC
„ Reduced RBC
survival

B12 Deficiency Macrocytes and Megaloblasts

„ Dietary
„ Pernicious Anemia
„ Absorption
„ Binding factor missing
„ Chronic gastritis
„ Macrocytic anemia
„ Large cells
„ Delayed nuclear maturation
„ Neurological signs
„ Myelin production
„ Macrocyte
„ Large RBC
„ Megaloblast
„ Large BM precursor
„ Folic acid can have similar
look
„ CNS with B12 only
„ Be careful correcting B12
deficiency with folic acid.
„ Anemia corrects, but
neurological problems
progress.

5
 Folic Acid and B12 Microcytic Anemia
„ Small RBCs
„ Iron deficiency
„ Thalassemia

Iron Deficiency Anemia of Chronic Disease

„ Dietary?
„ Problem is of excessive drive to store iron.
„ Rarely in US
„ How much anyway? „ Chronic inflammation
„ Blood loss „ Arthritis
„ Chronic „ TB
„ GYN „ Even cancer
„ Colon cancer „ Most of incoming iron is sent to storage
„ RBCs are „ Part of the normal response to inflammation.
„ Microcytic „ In time anemia develops because of
„ Hypochromic „ Reduced iron for utilization
„ Lack iron for hemoglobin „ Not dietary lack or
production „ Failed absorption

Aplastic Anemia Over Production of RBCs

„ Believe it or not, it’s not a good thing.
„ Something kills „ Response to increased need
precursor in BM. „ High altitude living
„ Virus
„ Lung disease
„ Radiation
„ Emphysema
„ Chemotherapy
„ Over production of erythropoietin.
„ Renal disease
„ Tumors
„ Uncontrolled production at bone marrow level

6
 Hemolytic Disease of Newborn
„ Pregnant mother is Rh-, fetus is Rh+
„ If mom should have antibodies to the Rh
factor, they will cross the placenta.
„ Destruction of baby’s RBCs
„ Previous maternal exposure
„ Miscarriage
„ Previous delivery
„ Wrong transfusion
„ Treatment: Mom gets Rhogam

WBC Disorders WBC Disorders

„ Quantity
„ Do we have enough WBCs
„ Quality
„ If the number looks right, are the cells working?
„ Higher than expected number (leukocytosis)
„ Cell type
„ Reactive or
„ Neoplastic
„ Benign
„ Malignant
„ Leukopenia

Leukopenia Leukocytosis
„ Low WBC count „ High WBC count in peripheral blood
„ Under 3,000 per mm3 „ >12,000 per mm3
„ Causes „ Cell type?
„ Production problem „ Healthy Cells?
„ Sick BM „ Reaction to need
„ Replacement of BM space „ Pneumonia
„ Peripheral destruction „ Incr granulocytes; bacterial infection, necrosis
„ Autoimmune destruction „ Incr monocytes; TB, brucella, rickettsia
„ Sequestration of cells „ Incr lymphocytes; virus, tumor response
„ Large spleen „ Incr eosinophil; allergic, parasite
„ Rheumatoid arthritis

7
 Distinguish Malignant Proliferation Leukemia
„ Malignant proliferation of WBCs and/or precursors.
„ History and physical „ Classification
Cell line
„ Maturity of cells „

„ Granulocytes or Lymphocytes
„ Visual inspection of blood smear „ Cell population:
„ Flow cytometry „ Chronic, mature, slower developing
„ Acute, immature cells, rapidly developing
„ Nuclear maturity
„ The big three features: All three cell lines affected
„ Nucleoli „ RBC
„ Cellular inclusions „ WBC
Platelets
„ Chromosomal studies „

„ Causes
„ Bone marrow „ Chromosomal breaks, but why?
„ Viruses, chemical exposure, radiation…..

Leukemia Lymphocyte Maturation

„ Organs involved
„ BM
„ Blood
„ Nodes
„ Liver and Spleen
„ Brain……
„ Common presenting symptoms
„ Recurrent serious infections
„ Pneumonia
„ Bleeding tendency
„ Anemia
„ Fever with no obvious cause
„ Bone pain

Acute Lymphobalstic
Lymphoid Malignancies Leukemia

Children
„ ‘Solid’ vs. ‘Liquid’ „
„ Less common, but does
„ Leukemia occur in adults
„ Bone marrow predominately „ Precursor B leukemia
CD19, TdT +
„ Lymphoma „

„ Ig locus t(12:21)
„ Lymph nodes „ Marked BM replacement
„ Cell type and level of maturation „ Precursor T leukemia
CD1 and TdT +
„ Cell size „

„ Chromosomal breaks
„ CD typing „ Adolescent males
„ Where did it come from in the follicle? „ Mediastinal mass
„ +/-
+/- spleen and liver

8
 Acute Myelogenous Leukemia Acute Myelogenous
Leukemia

„ Myeloid line
„ Many subtypes
„ Level of maturation
determines what malignant
cells look like.
„ Adults
„ Aure rods ->
„ Adults
„ Rarely pure monocytic
„ Symptoms
„ Infections
„ Mouth ulcers
„ Gingival hypertrophy (mono)

Chronic Lymphocytic Chronic Lymphocytic Leukemia

Leukemia

„ Mature lymphocytes
„ High WBC count
„ B-Cells
„ Adult and older
„ Indolent course
„ Tissues
„ BM
„ Nodes
„ Liver and Spleen
„ May accelerate
„ Blast crisis
„ Richter’s syndrome

Chronic Myelocytic Ph’ Chromosome

Leukemia
„ Middle age and older
„ High WBC count
„ Stem cell is malignant
„ All phases present
„ Low LAP (cells don’t work)
„ Ph’ Chromosome
„ t(9:22)
„ Organs
„ BM
„ Spleen
„ Blast crisis
„ Soft tissue met
„ Chloroma

9
 Splenomegally in Chronic Granulocytic Leukemia Myelofibrosis Etc

„ Myelofibrosis
„ Scarring process
„ Reticulum fibers
„ Loss of marrow space
„ Extramedullary hematopoiesis
„ Metastatic cancer

Preleukemia

„ RBC abnormalities easiest to spot.

„ All cell lines have abnormal maturation.
„ Chromosomal abnormalities
„ Some end in leukemia
„ Most end with myelofibrosis

Bleeding Disorders Platelet Related Bleeding

„ Takes three things working for hemostasis „ Platelet problems
„ Platelets „ Petichae
„ Clotting proteins „ Bruises (purpura)

„ Vessels „ Quantity
„ 120,000-
120,000-400,000
„ The question is always „ Production
„ Quantity „ Destruction
„ Quality „ Quality
„ Aspirin
„ Renal failure

10
 Clotting Factor Related Bleeding Hemophilia A & B

„ Hematoma „ Hemophilia A
„ Deep muscle „ X-linked recessive
Boys express
„ Joint bleeds „

„ Factor VIII enzymatic

„ Bleeding gums „ Hemophilia B
„ Poor wound healing „ Christmas Disease
„ Quantity „ Factor IX
„ Can you make it „ Also X-
X-linked recessive
„ Genetics „ Not as severe as VIII
„ Liver disease
„ Quality

Von Willebrand’s
Generic Platelet Problems
„ Factor VIII, ‘structural’
„ Platelet binding „ Quantity (thrombocytopenia)
„ Collagen of damaged vessel „ Lack of bone marrow production
„ Platelet – platelet binding
„ Clinically, bleeding looks more
„ Autoimmune destruction (ITP)
like platelet abnormality. „ Heparin induced thrombocytopenia
„ Autosomal dominant „ Lack of stabilizing factor (TTP)
Multiple types
„
„ Type I
„ Quality
„ Most common „ Aspirin induced platelet dysfunction
„ Reduced quantity of vWF
„ Type II
„ Problem with multimeric form of
vWF

Disseminated Intravascular Coagulation

„ Runaway train
„ OB disaster
„ Sepsis and endothelial cell injury
„ Massive muscle injury

11
 Basic Node

Diseases of Lymph Nodes

Basic Node
Lymph Node Disorders
„ Reactive vs. Neoplastic
„ History & Physical Exam
„ Histological pattern
„ Nodal architecture recognizable?
„ Effaced?
„ Diagnostic inflammatory changes

Reactive Conditions Neoplastic Diseases

„ Classification is very important
„ Non-
Non-neoplastic reaction to „ Treatment options
„ Predicting outcome
„ Infections, necrosis, tumors „ Histological pattern
„ Histological pattern „
„
Hodgkin Lymphoma vs. Non-Non-Hodgkin Lymphoma
Cell type (where did it come from in the node?)
„ Follicular „ Degree of differentiation (grade)
„ Diffuse or Follicular
„ Sinusoidal „ Stage (extent of spread)
„ Specific patterns „ Know the difference between stage and grade
„ Systemic symptoms (so-
(so-called B symptoms)
„ Abscess „ Fever
„ Granuloma „ Night sweats
„ Weight loss

12
 Non-
Non-Hodgkin Lymphoma, SLL Non-
Non-Hodgkin Lymphoma, Follicular Pattern

„ Small cell lymphocytic lymphoma „ Nodal architecture is effaced

„ Tissue phase of CLL „ Nodular or follicular pattern
„ Diffuse replacement of nodal architecture „ ‘Centrocytic’ cells (from germinal centers)
Long- „ B-cell markers
„ Long-lived B-
B-cells (CD19, CD20)
„ Surface immunoglobulins
„ Surface immunoglobulins

Burkitt’s Lymphoma African Burkitt’s

„ Two types
„ American
„ Retroperitoneal
„ African
„ Jaw
„ EB virus association?
„ ‘Starry sky’ appearance
„ B-cell

Hodgkin’s Disease Hodgkin’s Disease

„ Distinguished from NHL by

„ Reed-
Reed-Sternberg cell ->
„ In its proper background
„ This is the malignant cell
„ The others are reactive
„ Bimodal age distribution
„ Distinctive patterns
„ Nodular sclerosis
„ Lacunar cells ->
„ Mixed-
Mixed-cellularity
„ Lymphocyte predominate

13
 Hodgkin’s Staging Multiple Myeloma
„ Stage I „ Plasma cell malignancy
„ Single node or single extranodal site (I-
(I-e) „ Term refers to holes in the bone
„ Stage II because of nest of plasma cells ->
„ Two or more nodal regions on the same side of the „ The replace marrow space.
diaphragm „ The cells make an intact, or
„ Stage III fragment, of immunoglobulin.
„ Both sides of the diaphragm „ Real problems with infections
„ No inflammatory cells
„ +/-
+/- Splenic involvement (III-
(III-s)
„ Bleeding
„ +/-
+/- Extranodal (III-
(III-e)
„ Protein coats platelets
„ Stage IV „ Renal failure
„ Multiple disseminated foci „ protein clogs tubules

Multiple Myeloma

„ Protein electrophoresis
„ Large amount of abnormal
protein in blood.
„ Immunoglobulin
„ Patient sample
„ Huge gamma band
„ All of it is kappa light chain

14