Leukemias and Lymphomas

Question 1

Leukemia vs. Lymphoma

Answer 1

Leukemia – a lymphoproliferative or myeloproliferative disorder diffusely involving hematopoietic cells in bone marrow.

Lymphoma – a lymphoproliferative disorder without diffuse involvement of the bone marrow; more like a solid proliferation, but can have many focal points

Question 2

Lymphoproliferative vs. Myeloproliferative

Answer 2

Lymphoproliferative disorder – a clonal (malignant) proliferation of lymphocytes such as B and T cells

Myeloproliferative neoplasm – a clonal (malignant) proliferation of non-lymphoid hematopoietic cells – typically granulocytic, monocytic, RBC precursors and/or megakaryocytes

Question 3

Plasma Cell Dyscrasias vs. Myelodysplastic Disorders

Answer 3

Plasma Cell Dyscrasias (Monoclonal Gammopathies) – clonal proliferation of plasma cells with or without production of monoclonal immunoglobulin; going “crazy”

Myelodysplastic disorders – a myeloid stem cell disorder in which ineffective cell production predominates aka defective hematopoiesis; instead of proliferation with release of cells into peripheral blood, the cells only mature so much (not fully) and proliferate and then fall apart in bone marrow

Question 4

Pathogenetic Factors

Answer 4

Radiation exposure.
Chemical/toxin/chemotherapeutic agent exposure.
Certain viral infections. (EBV)
Certain bacterial infections. (Helicobacter)
Inherited susceptibility (eg. loss of tumor suppressor gene function).

Sometimes clearing the body of the bacteria will get rid of the tumor

Question 5

Clinical Presentations

Answer 5

Lymphadenopathy.
Splenomegaly.
Leucocytosis or leucopenia.
Infectious disease.
Anemia.
Petechiae, purpura (thrombocytopenia).
“B” Symptoms – wt. loss, fever, night sweats

Question 6

Acute Leukemia

Answer 6

A rapidly progressing proliferation of immature cells in bone marrow. (blasts)
Uniformly fatal if not diagnosed early and aggressively treated with multi-agent chemotherapy and/or bone marrow transplantation.
Two major categories are acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML)

Lifespan without tx – 3-4 months
Survival rate is 95% after 5 years for ALL if tx

Question 7

ALL vs. AML

Answer 7

ALL has a peak incidence in childhood. It can also occur in adults.
AML has a bimodal incidence peak at about 20 and 60 years of age.
ALL and AML are treated with very different chemotherapeutic protocols, so correct diagnosis is essential.
AML blasts are MPO +. ALL blasts are MPO -
If you see auer rods on a wright strain in periphery or marrow = AML

Question 8

Chronic Leukemias

Answer 8

Involve proliferation of relatively mature cells.
Occur most often in adults.
Slow progression of disease over months or years

3-4 illnesses that are similar to chronic leukemia; two chronic categories
1. Chronic myeloproliferative diseases (CML)
2. Chronic lymphocytic leukemia (CLL)
Mature in pathway for the most part (not always all the way mature)
People seldom pass from chronic leukemia, and usually die from something else

Question 9

CLL vs. CML

Answer 9

Chronic lymphoproliferative disorders
Prototype: chronic lymphocytic leukemia (CLL)

Chronic myeloproliferative neoplasms
Prototype:chronic myelogenous leukemia (CML)

Question 10

Other Chronic Leukemias

Answer 10

Polycythemia Rubra Vera: high [Hb]. Thrombosis risk. Treatment – therapeutic phlebotomy.

Essential Thrombocythemia: megakaryocytes involved; goes into circulation; persistent thrombocytosis >600,000/uL. Thrombosis and bleeding risk.

Chronic Idiopathic Myelofibrosis: fibrosis of bone marrow cause by fibroblastic growth factor (FGF) released by megakaryocytes; cells do not go to circulation; dry tap marrow aspirate. End stage of other forms. Blood – leucoerythroblastosis

These three are interchangeable. If you start out having one, it can develop into another

Question 11

CLL

Answer 11

Rare before age 50 years.
Lymphocytosis and generalized lymphadenopathy.
Hypogammaglobulinemia.
Elevated lymphocytes and are fragile – may break during smear

Question 12

Chronic Myeloproliferative Disorders

Answer 12

Specific mutations in pleuripotential stem cells lead to autonomous proliferation.

CML – abl/bcr reciprocal translocation 9:22, creating the ‘Philadelphia chromosome’
Panmyelosis with granulocytes predominating, but proliferation of all cell lines
Polycythemia rubra vera – RBC predominance
Essential thrombocythemia – megakaryocytes; JAK2 mutations
Basophilia: basophil count may be elevated
JAK2 mutations, but not as common as the translocation

Question 13

CML

Answer 13

These patients have granulocytosis
WBC count is up
Peripheral smear can look like bone marrow because so many WBCs that are trying to get through capillaries creating low blood flow and lead to ischemia
Splenomegaly can occur from the above mechanism

Inatemib – CML treatment drug; specific antagonist to tyrosine kinase that are abnormal and not attack normal ones

Question 14

Hodgkin Lymphoma

Answer 14

Defined historically by the presence of Hodgkin and Reed Sternberg cells.
Occurs in young people and frequently involves lymph nodes in axilla, neck, and mediastinum
Lymph nodes are firm/solid and enlarged
Lymphoid cells in nodules surrounded by pink staining collagen fibers

Question 15

Reed Sternberg and Hodgkin’s Cells

Answer 15

Reed Sternberg Cells: have at least two nuclei each, and each nucleus has a prominent eosinophilic nucleolus = look like owls eyes
Hodgkin’s cells is like Reed Sternberg, but only one nucleus (large cell with prominent eosinophilic nucleus)

Both cells are neoplastic

Question 16

Non-Hodgkin Lymphoma

Answer 16

WHO Classification
         Pre B Cell (1)
         B Cell (12)
         Pre T Cell (1)
         T or NK Cell (12)
Specific lymphomas are defined by immunologic and clinical characteristics

Tdt + pre T and C cell lymphomas; others would be Tdt- because more mature

Question 17

Low Grade Non-Hodgkin Lymphomas

Answer 17

Slow disease progression.
Pathogenesis – often due to loss of apoptosis; cells proliferate slowly but are immortal.
Widespread disease (stage 4) common.
Tumors poorly responsive to standard chemotherapeutic agents

If lymphoma in lymph node, lymph node slowly gets bigger, and same with other areas – if spread through the body = lymphadenopathy below and above the diaphragm
Cells may go into the spleen and form masses in spleen = low grade
Lymphoma may progress and my compress another local structure and has to come out surgically, and not very susceptible to chemotherapeutic agents because only works on mitotic cells and these are fast maturing

Question 18

Follicular Lymphoma

Answer 18

Low Grade Non-Hodgkin Lymphomas
Lymph nodes have B cell aggregates
Lymph follicle inside lymphoma
Indicates not just reactive node, and that there is infection = population to expand and not normal follicles; subtle differences that indicate lymphoma
If have follicular lymphoma – low grade and occur in older people; may or may not cause symptom; have potential to become more aggressive

Question 19

Maltoma

Answer 19

Low Grade Non-Hodgkin Lymphomas
Helicobater pylori associated
Lymphoid proliferation formation a mass lesion in the stomach
Because there are not any normal lymphocytes in stomach, when you have the infection they mediate chronic inflammatory reaction in stomach = chronic gastritis
Inflammatory infiltrate and starts to proliferate and produce lymphoma = maltoma = mucosa associated lymphoid tumor “oma” to show cancer
Tx with antibiotics and give patients time and the tumor may go away because eradicating the disease

Question 20

High Grade Non-Hodgkin Lymphomas

Answer 20

Rapid progression.
Often diagnosed in an early stage.
Very responsive to multi-agent chemotherapy.
Recurrences common.
Overall, higher mortality rate than low grade lymphomas

Instead of being spread all over body even at stage 4, patients present with rapidly growing mass and at stage 1 at time of dx
Very responsive to chemo because stays in cell cycle because growing fast = a lot of mitoses; so effective that it can be a dramatic change
If it comes back, it will be resistant to the first type of chemotherapy so must use another one
Survival rate at 5 years is better for high grade vs. low grade

Question 21

Diffuse Lymphoma

Answer 21

High Grade Non-Hodgkin Lymphomas
Instead of follicular pattern, this is a diffuse pattern
Most lymphomas go through fibrous capsule

Irregular borders of nuclei and irregular folds within it
See mitotic figures = characteristic of high grade lymphoma
Does not metastasize often, stays in bone marrow
Tend to metastasize to other lymphoid tissues like the spleen
Metastasis to spleen = more likely a lymphoma
Diverse cocktail of chemotherapy of 3-4 agents to decrease chance of resistance or reoccurrence

CD15 and 45 = surface markers for Hodgkin’s; multiples of 15; 15, 30, and 45 only

Question 22

Myelodysplastic Disorders

Answer 22

Pleuripotential stem cell disorders with ineffective and dysplastic hematopoiesis.
Risk factors:
1) acquired disorder in the elderly,
2) years following chemotherapy.
Typical presentation: pancytopenia with a hypercellular bone marrow (all WBCs are low)

Anemia, thrombocytopenia, leukopenia = bone marrow failure = find no hematopoietic tissue and correlates well with pancytopenia; usually an aplastic anemia
No fat in bone marrow, but have thick rich bone marrow because ineffective hematopoiesis

Question 23

Dyserythropoiesis

Answer 23

Myelodysplastic disorder
Abnormal red blood cell shapes
Normoblast: segmented, clover leaf nucleus in the bone marrow of normoblast
Granulocytic precursors –usually hypergranulated
Pelger Huet: abnormal morphology is failure of neutrophils to segment; mature cytoplasm with granules and nucleus is round or dumbbell shape
Auer rods -can be seen in some forms of myelodysplastic disorders

Question 24

Ringed Sideroblasts

Answer 24

Iron doesn’t get incorporated into Hb formation so iron excess stays in normoblast and go into the mitochondrion = see basophilic granules
See within the bone marrow, unusual to find anywhere else

Question 25

Plasma Cell Dyscrasias

Answer 25

Localized or diffuse proliferation of clonal plasma cells.
When localized, plasma cells often form lytic lesions in affected bones that may lead to pathologic fractures.
Monoclonal immunoglobulins can interfere with normal Ab production, polymerize to form amyloid, and produce renal failure

Question 26

Monoclonal Gammopathy of Undetermined Significance (MGUS)

Answer 26

Plasma Cell Dyscrasia
Patients have autonomous clone of plasma cells making monoclonal protein and not many plasma cells; monoclonal protein concentration is low compared to multiple myeloma but risk factor for development for multiple myeloma

Question 27

Multiple Myeloma

Answer 27

Plasma Cell Dyscrasia
Multiple lytic bone lesions via plasma cells releasing cytokines
Bone marrow plasmacytosis.
Monoclonal immunoglobulin in serum and/or urine (free monoclonal light chains in urine are historically called Bence-Jones protein); plasma cells make same Ig and migrate to the same place

Plasmacytosis: bone marrow aspirate and see markedly elevated number of plasma cells (usually has 5%, but with this disorder will have 70-80% and almost no normal hematopoietic tissue present)

Question 28

Multiple Myeloma Bone Marrow

Answer 28

Granulocytic precursors
Big ones are plasma cells
Microscopic features of plasma cell: round, dark staining nucleus at edge of cell, blueish staining cytoplasm, and perinuclear Hof (corresponds to large well developed Golgi bodies)
Remember these are Ig factories, so these features correlate
Binucleate and large and looks immature – monoclonal Ig = plasmacytosis in bone marrow and lytic lesions = multiple myeloma
Population affected: elderly with CC of bone fractures because of lytic lesions; commonly in vertebral bodies and present with sudden onset of back pain and can compresses on spinal nerve and get radicular pain down their arms or legs
Tx: thalidomide for patients that have failed typical chemo

Question 29

Heavy Chain Disease

Answer 29

Plasma Cell Dyscrasia

Alpha heavy chain and gamma chain; only part of Ig that is manufactured by clone of plasma cells and associated with forms of lymphoma (GI tract one that is often associated)
Dense Jones proteins = light chains