2.4 Hematologic Malignancies

Hematologic Malignancies: Diagnosis & Classification

Quick Answer: Leukemias are neoplastic proliferations of hematopoietic cells. They are divided into acute (rapid, immature blasts) and chronic (slow, mature cells), and further divided by lineage: myeloid or lymphoid. Identifying cell lineage through morphology, cytochemical stains, and immunophenotyping is critical for selecting the correct chemotherapy regimen.

Acute Leukemias vs. Chronic Leukemias

The fundamental distinction in leukemias involves the maturity of the neoplastic cells and the clinical onset of the disease.

Acute Leukemias

Acute Myeloid Leukemia (AML)

• Demographics: The most common acute leukemia in adults. Incidence increases with age.
• Morphology: Characterized by myeloblasts. These are large cells with moderate cytoplasm, delicate/fine chromatin, and prominent nucleoli.
• Diagnostic Hallmark: Auer rods. These are distinct, needle-like, red-staining inclusions in the cytoplasm of myeloblasts or promyelocytes. They are formed from the abnormal fusion of primary (azurophilic) granules. The presence of an Auer rod definitively confirms a myeloid lineage and entirely rules out lymphoid leukemia.
• WHO AML with Recurrent Genetic Abnormalities: The modern WHO classification prioritizes genetic lesions over morphology because they dictate prognosis and treatment. Key translocations include:
  • t(15;17)(q24;q21); PML-RARA: Defines Acute Promyelocytic Leukemia (APL / FAB M3). The marrow is packed with heavily granulated promyelocytes, often containing bundles of Auer rods ("faggot cells"). APL carries a very high risk of life-threatening Disseminated Intravascular Coagulation (DIC) due to the release of procoagulants from the granules. It is uniquely treated with emergency All-Trans Retinoic Acid (ATRA), which forces the malignant promyelocytes to mature.
  • t(8;21)(q22;q22); RUNX1-RUNX1T1: Often shows large myeloblasts with abundant cytoplasm, Auer rods, and prominent granulocytic maturation. Generally associated with a favorable prognosis.
  • inv(16)(p13.1q22); CBFB-MYH11: Classically presents with myelomonocytic blasts and abnormal, dysplastic eosinophils in the bone marrow (AML-M4Eo). Also associated with a favorable prognosis.

Acute Lymphoblastic Leukemia (ALL)

• Demographics: The most common childhood leukemia, peaking between ages 2-5 years.
• Morphology: Lymphoblasts are generally smaller than myeloblasts, with scant, agranular cytoplasm, condensed chromatin, and inconspicuous nucleoli.
• Diagnostic Markers: ALL cells are negative for myeloid stains but uniquely express TdT (Terminal deoxynucleotidyl transferase), an intranuclear DNA polymerase found only in primitive lymphoid cells.

Chronic Leukemias and Lymphoproliferative Disorders

Chronic Myeloid Leukemia (CML)

• Lineage: A classic Myeloproliferative Neoplasm (MPN) involving uncontrolled, dysplastic production of granulocytes.
• Peripheral Smear: Shows a massive leukocytosis with a "shift to the left" that includes the entire spectrum of granulocytic development: myeloblasts, promyelocytes, myelocytes, metamyelocytes, bands, and segmented neutrophils. Marked basophilia and eosinophilia are highly characteristic.
• Genetics: CML is driven almost exclusively by the Philadelphia chromosome, a reciprocal translocation t(9;22). This fuses the BCR gene on chromosome 22 with the ABL1 gene on chromosome 9, creating the BCR-ABL1 fusion gene—a constitutively active tyrosine kinase that promotes unregulated cell division. It is treated with targeted tyrosine kinase inhibitors like Imatinib (Gleevec).
• Diagnostic Assay: The Leukocyte Alkaline Phosphatase (LAP) score is characteristically very low in CML, distinguishing it from a severe infection (leukemoid reaction), which presents with a very high LAP score.

Chronic Lymphocytic Leukemia (CLL)

• Demographics: The most common leukemia in older adults (typically >60 years).
• Morphology: Characterized by a massive proliferation of small, mature-appearing, but functionally incompetent B-lymphocytes.
• Immunophenotype: Uniquely co-expresses the T-cell marker CD5 alongside mature B-cell markers like CD19, CD20, and CD23.
• Diagnostic Hallmark: Smudge cells. The neoplastic lymphocytes in CLL are unusually fragile and frequently rupture during the physical stress of making a peripheral blood smear. A drop of 22% bovine serum albumin (BSA) can be added to the blood before smearing to protect the cells, prevent smudge cell formation, and allow for an accurate WBC differential.

Burkitt Lymphoma

• Pathology: A highly aggressive mature B-cell non-Hodgkin lymphoma.
• Morphology: The tissue biopsy classically reveals a "starry sky" pattern, where tangible body macrophages (the stars) are interspersed amidst a dark background of rapidly dividing neoplastic B-cells (the sky).
• Genetics: Driven by the t(8;14) translocation, which moves the MYC oncogene on chromosome 8 next to the highly active IgH promoter on chromosome 14, leading to massive MYC overexpression and unchecked proliferation.

Multiple Myeloma

• Lineage: A malignant neoplasm of terminally differentiated plasma cells in the bone marrow.
• Pathology: The malignant plasma cells secrete vast quantities of a single monoclonal antibody (usually IgG or IgA), leading to hyperviscosity and end-organ damage.
• Diagnostic Hallmarks:
  • M-spike: A narrow, dense peak seen on serum protein electrophoresis (SPEP) representing the monoclonal immunoglobulin.
  • Bence Jones Proteinuria: Free light chains (kappa or lambda) that are small enough to be filtered by the kidneys, damaging the renal tubules and appearing in the urine.
  • Rouleaux Formation: Due to the massive increase in circulating immunoglobulins, red blood cells lose their zeta potential and stack together like coins on the peripheral smear.
  • CRAB Criteria: HyperCalcemia, Renal failure, Anemia, and Bone lytic lesions (punched-out lesions on x-ray).

Cytochemical Stains

Before the advent of modern flow cytometry, cytochemical stains were the primary method used to differentiate AML from ALL. They remain highly relevant for board exams and as adjunctive diagnostic tools in resource-limited settings.