Pathogenesis of Leukemias, Lymphomas, and Multiple Myelomas

Where are blood cells produced?

Bone marrow.

What do hematopoietic stem cells produce?

All mature blood cell types through myeloid and lymphoid lineages.

What is a blast cell?

An immature hematopoietic precursor cell.

What cells arise from the myeloid lineage?

Erythrocytes, platelets, granulocytes, and monocytes.

What cells arise from the lymphoid lineage?

B lymphocytes, T lymphocytes, and natural killer cells.

Where are B-cell follicles located in a lymph node?

Cortex.

Where are T cells predominantly located in a lymph node?

Paracortex.

What is leukopenia?

Decreased white blood cell count; neutropenia is the most common type.

What causes acquired neutropenia?

Autoimmune disease, drugs, infection, radiation, or hematologic malignancy.

What are congenital and acquired causes of lymphopenia?

Congenital: SCID. Acquired: HIV infection.

What are common causes of neutrophilia?

Acute infection, tissue injury, or medication reaction.

What are common causes of eosinophilia?

Allergic reactions, parasitic infections, and medications.

What conditions are associated with basophilia?

Allergic reactions, leukemias, and medication reactions.

What causes reactive lymphocytosis?

Viral infections, pertussis, and hypersensitivity reactions.

What causes monocytosis?

Chronic infections, autoimmune disease, or splenectomy.

What is reactive lymphadenitis?

Benign lymph node enlargement from antigen-driven cellular hyperplasia.

What organism causes cat scratch disease?

Bartonella henselae; causes necrotizing lymph node inflammation.

How do leukemia, lymphoma, and myeloma differ?

Leukemia primarily involves blood/marrow; lymphoma involves lymphoid tissues; myeloma involves plasma cells.

What factors contribute to leukemia and lymphoma development?

Genetic mutations, inherited factors, viruses, environmental agents, and prior cancer treatment.

What are the two major cancer-promoting mutation types?

Gain of function in proto-oncogenes; loss of function in tumor suppressor genes.

What translocation is associated with Burkitt lymphoma?

t(8;14), involving MYC and IGH.

What translocation is associated with mantle cell lymphoma?

t(11;14), involving CCND1 and IGH.

What translocation is associated with follicular lymphoma?

t(14;18), involving IGH and BCL2.

What translocation is associated with AML?

t(8;21), involving RUNX1 (AML1) and RUNX1T1 (ETO).

What translocation is associated with CML and some ALL cases?

t(9;22), producing BCR-ABL.

Which inherited disorders increase acute leukemia risk?

Bloom syndrome, Fanconi anemia, Li-Fraumeni syndrome, and NF1.

How does trisomy 21 affect acute leukemia risk?

Increases risk approximately 10-20-fold, according to the lecture.

What malignancy is associated with HTLV-1?

Adult T-cell leukemia/lymphoma.

What lymphomas are associated with EBV?

Burkitt, Hodgkin, and NK-cell lymphomas.

What lymphoma is associated with HHV-8?

Primary effusion lymphoma.

Why can previous chemotherapy or radiation cause leukemia?

Mutagenic injury to hematopoietic progenitor cells.

How are leukemias classified?

By lineage (myeloid vs. lymphoid) and maturity (acute vs. chronic).

What distinguishes acute from chronic leukemia?

Acute involves immature blasts with rapid onset; chronic involves more mature cells with slower progression.

What are the four major leukemia types?

AML, ALL, CML, and CLL.

Which leukemia predominantly affects young children?

ALL; peak incidence is ages 2-5 years.

Which acute leukemia predominantly affects older adults?

AML; mean diagnosis age is approximately 68 years in the lecture.

What causes fatigue, bleeding, and infections in acute leukemia?

Marrow dysfunction causing anemia, thrombocytopenia, and reduced functional leukocytes.

What additional clinical findings suggest acute leukemia?

Bone pain, lymphadenopathy, hepatosplenomegaly, and possible CNS symptoms.

Which acute leukemia more often involves the CNS and lymphoid organs?

ALL.

What cells proliferate in ALL?

Immature B- or T-lymphocyte precursors called lymphoblasts.

What proportion of ALL is B-cell lineage?

Approximately 85%.

What cells proliferate in AML?

Myeloid stem or precursor cells.

What does a blast look like on peripheral smear?

A large immature cell with a high nuclear-to-cytoplasmic ratio.

What finding strongly suggests AML rather than ALL?

Auer rods in myeloblasts.

What are Auer rods?

Lysosome-derived crystalline cytoplasmic inclusions in myeloid blasts.

How do myeloblasts differ from lymphoblasts?

Myeloblasts are larger with more cytoplasm, fine chromatin, and possible Auer rods.

What is the role of genetic testing in AML?

Classifies subtypes and may predict response to chemotherapy.

What three chemotherapy phases are listed for acute leukemia?

Induction, intensification, and maintenance.

When may stem cell transplantation be considered?

For chemotherapy-refractory acute leukemia.

What factors influence remission in acute leukemia?

Age, leukemia type, and disease characteristics at presentation.

What is the most common leukemia in adults?

CLL.

What cells proliferate in CLL?

Mature-appearing clonal B lymphocytes.

How does CLL commonly present?

Often asymptomatic; may cause fatigue, weight loss, or tissue infiltration.

What CBC finding suggests CLL?

Isolated lymphocytosis.

What peripheral smear finding is characteristic of CLL?

Small mature lymphocytes with smudge cells.

What are smudge cells?

Fragile lymphocytes disrupted during blood smear preparation.

How are CLL and SLL related?

They are related manifestations of the same B-cell neoplasm; SLL mainly involves lymphoid tissues.

What chromosomal changes are common in CLL?

Deletion 13q, deletion 11q, deletion 17p, and trisomy 12.

Which CLL abnormalities indicate poor prognosis in the lecture?

Deletion 11q, deletion 17p, and trisomy 12.

What is Richter transformation?

Transformation of CLL/SLL into aggressive diffuse large B-cell lymphoma.

What genetic abnormality causes CML?

BCR-ABL1 fusion from t(9;22), the Philadelphia chromosome.

What is the Philadelphia chromosome?

A shortened chromosome 22 resulting from reciprocal translocation with chromosome 9.

What is the mechanism of BCR-ABL in CML?

Constitutively active tyrosine kinase promotes proliferation and inhibits apoptosis.

Why are mature granulocytes elevated in CML?

BCR-ABL drives proliferation without blocking myeloid differentiation.

What peripheral blood findings suggest CML?

Leukocytosis with mature granulocytes and immature myeloid precursors.

What medication targets BCR-ABL?

Imatinib (Gleevec).

What is imatinib's mechanism of action?

Blocks the ATP-binding site of BCR-ABL tyrosine kinase.

What are the three clinical phases of CML?

Chronic phase, accelerated phase, and blast crisis.

What occurs during CML blast crisis?

Marked increase in immature blasts with aggressive clinical deterioration.

How can CML and CLL be distinguished on smear?

CML: granulocytes and myeloid precursors; CLL: mature lymphocytosis and smudge cells.

What are the two major categories of lymphoma?

Hodgkin lymphoma and non-Hodgkin lymphoma.

What is the age distribution of Hodgkin lymphoma?

Bimodal: ages 15-40 and over 55.

What is the hallmark cell of Hodgkin lymphoma?

Reed-Sternberg cell.

What is the classic appearance of a Reed-Sternberg cell?

Large binucleate or multinucleate cell with prominent owl-eye nucleoli.

Why do Hodgkin lymphoma lesions contain many reactive cells?

Reed-Sternberg cells release factors recruiting lymphocytes, granulocytes, and macrophages.

How does Hodgkin lymphoma typically spread?

Contiguously from one lymph node group to adjacent groups.

How does Hodgkin lymphoma commonly present?

Painless lymphadenopathy, often initially above the diaphragm.

What is the most common classic Hodgkin lymphoma subtype?

Nodular sclerosis.

What histologic finding characterizes nodular sclerosis Hodgkin lymphoma?

Fibrosis dividing tissue into nodules.

Which Hodgkin lymphoma subtype has the worst prognosis in the lecture?

Lymphocyte-depleted type.

What is the most important prognostic factor in Hodgkin lymphoma?

Stage, reflecting disease extent.

What treatment is listed for localized Hodgkin lymphoma?

Radiation therapy.

What treatment is listed for advanced Hodgkin lymphoma?

Combination radiation and chemotherapy.

Which B-cell lymphoma arises from germinal center cells and has t(14;18)?

Follicular lymphoma.

What is the usual clinical behavior of follicular lymphoma?

Indolent; may transform into diffuse large B-cell lymphoma.

What lymphoma is associated with chronic H. pylori infection?

Gastric MALT (marginal zone) lymphoma.

What is the usual behavior of marginal zone lymphoma?

Very indolent; may remain localized.

Which lymphoma arises from naïve mantle-zone B cells?

Mantle cell lymphoma.

What is the aggressiveness of mantle cell lymphoma?

Moderately aggressive.

What is the clinical behavior of diffuse large B-cell lymphoma?

Very aggressive.

Which aggressive lymphoma has MYC translocation and starry-sky histology?

Burkitt lymphoma.

What causes the starry-sky pattern in Burkitt lymphoma?

Tingible-body macrophages clearing apoptotic tumor cells.

What are the three clinical forms of Burkitt lymphoma?

Endemic, sporadic, and immunodeficiency-associated.

Which Burkitt lymphoma form is associated with EBV in children?

Endemic (African) form.

Which Burkitt lymphoma form commonly involves the abdomen?

Sporadic form.

Which Burkitt lymphoma form is associated with HIV?

Immunodeficiency-associated form.

What is a plasma cell dyscrasia?

Clonal plasma-cell expansion producing a monoclonal immunoglobulin or fragment.

What is MGUS?

Monoclonal serum immunoglobulin without other findings of multiple myeloma.

Why is MGUS clinically important?

Premalignant condition that can progress to myeloma or related disorders.

What is multiple myeloma?

Malignancy of terminally differentiated plasma cells involving bone marrow.