Pathology of Bone Marrow

What are the two types of hematopoietic neoplasia?

• Myeloproliferative disorders

• Lymphoproliferative disorders

How to differentiate between the two types of hematopoietic neoplasia

• Myeloproliferative disorders

  • neoplastic proliferation of non-lymphoid blood cells (erythrocytes, granulocytes, monocytes, megakaryocytes)

  • neoplasia typically originates in bone marrow as these cells are produced in the bone marrow

• lymphoproliferative disorders

  • neoplastic proliferation of lymphoid cells

  • lymphocyte development occurs mainly outside of bone marrow → neoplasia originates both in bone marrow & outside of bone marrow

Classify the types of leukemia based on cell lineage & disease progression

• Myeloid progenitor

  • Neutrophils, monocytes, eosinophils, basophils

  • Dysplastic neutrophils/early myeloid precursors indicates myeloid neoplasia

• Lymphoid progenitor

  • dysplastic lymphocytes & plasma cells indicates lymphoid neoplasia

What are the common CBC changes associated with leukemia? Why do these changes occur?

Differentiate between the two main causes of lymphoid leukemia

Compare the prognoses of the two main causes of lymphoid leukemia using blood smear images

Distinguish between lymphoma & lymphoid leukemia based on clinical & pathological features

List the 4 key diagnostic features of plasma cell myeloma & apply them to make a diagnosis

Define myeloproliferative disease & discuss its incidence & clinical reference

What are two most common causes of non-regenerative anemia in domestic animals

• anemia of chronic disease/inflammation

• Anemia due to chronic kidney disease

what are diagnostic techniques for cell lineage confirmation?

• morphology assessment

  • Bone marrow aspiration & cytology

  • Peripheral blood smears → insufficient for Ddx alone

• cytochemical staining

  • Determines if leukemic cells originate from myeloid lineage (myeloid & lymphoid look similar at very young stages)

• immunophenotyping (flow cytometry or immunohistochemistry)

  • Useful for lymphoid cells

• PCR for clonality (PARR)

  • Detects clonality in lymphoid populations

• genetic & molecular testing

Classification of leukemias

• acute leukemia

  • Aggressive cancers that involve proliferation of immature blast cells

  • Blast cells = medium to large round blue cells

  • Rapid & severe course

  • Progression = days-weeks if left untreated

• Chronic leukemia

  • Proliferation of more mature cells that resemble normal, differentiated blood cells that can often be identified based on morphology alone

  • Progression = months-years

  • Some animals may be asymptomatic at diagnosis, may be found incidentally during routine blood testing

What is the most common chronic leukemia encountered in vet med?

chronic lymphocytic leukemia

Leukemic leukemia

marked increase in circulating neoplastic cells (high nucleated cell count)

Subleukemic leukemia

small numbers of malignant cells in circulation (normal or mildly increased nucleated cell count)

Aleukemic leukemia

no malignant cells detected in peripheral blood, diagnosis relies on bone marrow evaluation

What is the definition of leukemia?

cancer of circulating or bone marrow resident hematopoietic cells

Involves malignant hematopoietic cells found in the blood or bone marrow

Based on the predominant cell type seen in the image, would you suspect a myeloid or lymphoid neoplasm?

Lymphoid neoplasm

• predominance of small, mature lymphocytes

Based on the predominant cell type seen in the image, would you suspect a myeloid or lymphoid neoplasm?

myeloid in origin due to predominance of numerous segmented neutrophils

• chronic granulocytic leukemia

In acute leukemia, what would be expected cell maturity, cell appearance on blood smear, speed of clinical progression, & likely outcome if untreated?

• Cell maturity - immature blasts cells

• Cell appearance on blood smear - medium to large round cells, hard to identify lineage

• Speed of clinical progression - rapid (days to weeks)

• Likely outcome if left untreated - often fatal within weeks

In chronic leukemia, what would be expected cell maturity, cell appearance on blood smear, speed of clinical progression, & likely outcome if untreated?

• Cell maturity - more mature, differentiated cells

• Cell appearance on blood smear - smaller cells with more identifiable features (looks more like a lymphocyte or neutrophi)l

• Speed of clinical progression - slower (months to years)

• Likely outcome if left untreated - may remain stable for months-years, but progress to more significant disease

Are lymphoid or myeloid neoplasms more common in domestic species?

lymphoid

what are the different disorders of lymphoid neoplasms?

• lymphoma - forms solid tumors in organs (lymph nodes, spleen)

• Lymphoid leukemia - involves bone marrow, often spills over into blood

• Plasma cell neoplasia - multiple myeloma or plasmacytomas, arise from antibody-producing plasma cells

Where does primary lymphoid leukemia originate?

in the bone marrow

what are the two classifications of lymphoid leukemia?

• acute lymphoblastic leukemia

  • Large, immature lymphoblasts

• Chronic lymphocytic leukemia

  • Small, mature lymphocytes

CBC changes that can occur with acute lymphoblastic leukemia (ALL)

• lymphocytosis with immature cells

• Anemia

• Marked thrombocytopenia

• Blood smear - Large, immature lymphoblasts

prognosis of ALL

poor - limited survival time

Chemotherapy may induce temporary remission but is usually short lived

CBC findings of chronic lymphocytic leukemia (CLL)

• Blood smear - small, well-differentiated lymphocytes

• Marked lymphocytosis

• Moderate anemia, moderate thrombocytopenia

Prognosis of CLL

better than ALL

• treated dogs must have an MST (median survival time) of 1-3 years

• Treated cats must have MST of approximately 450 days

What would you expect to see in CBC for a dog diagnosed with advanced hematopoietic neoplasia? (WBC, RBC, Platelets)

WBC

• variable depending on the disease stage

  • Early stages = WBC may be increased

  • Advanced myelophthisis = leukopenia

RBC

• Decreased (non-regenerative anemia)

• Replacement of normal narrow with neoplastic tissue prevents normal RBC production = non-regenerative anemia

Platelets

• Decreased (thrombocytopenia)

• Platelet producing megakaryocytes are affected by bone marrow replacement = reduced platelet count, increased bleeding risk

What blood cell line would be affected first & which order would the impact occur

1. WBC (shortest lifespan)

2. Platelets (slightly longer lifespan = 5-10 days)

3. RBCs (longest lifespan, weeks)

4 key diagnostic features of plasma cell myeloma

• Radiographic evidence of osteopathic bone lesions

• Neoplastic plasma cells in bone marrow

• Monoclonal gammopathy → sharp spike in gamma region of serum protein electrophoretogram - represents excess production of single immunoglobulin class

• Bence-jones proteinuria → free immunoglobulin light chains may be filtered into urine & detected by urine protein electrophoresis

What is plasma cell myeloma & what does it commonly arise from?

malignant neoplasm of plasma cells

Commonly arises in bone activity involved in hematopoiesis (especially vertebrae, ribs, pelvis, & femur) → leads to multiple osteopathic lesions

other associated clinical features & lab abnormalities of plasma cell myeloma

• hyperglobulinemia → rouleaux formation, increased TP, interference with blood cross matching

• Hyperviscosity syndrome → cases with excessive IgM or IgA, may impair platelet function & clotting → bleeding tendency

• Myelophthisis → non regenerative anemia, granulocytopenia, thrombocytopenia

• Hypercalcemia → bone resorption due to osteolysis

Cutaneous plasmacytoma

• solitary, well-circumscribed dermal or SQ mass located in digits, head, limbs

• Usually benign, have a good prognosis

What is myeloproliferative disease?

• rare, non-lymphoid blood cancers originating from the colonial proliferation of stem cells in the bone marrow

• Affect various myeloid cell lines (granulocytes, monocytes, erythroid cells, megakaryocytes)

• Proliferation often extends beyond bone marrow to spleen, liver, & sometimes lymph nodes

what species is MPD most commonly seen in

cats but uncommon in animals

Accurate diagnosis of MPD

• unexplained leukocytosis or blast type cells on CBC

• Bone marrow aspirate, cytochemistry, immunophenotyping or molecular diagnositcs

• Challenging to diagnose due to vague & non specific clinical signs