3.3 Hematologic Malignancies

3.3 Hematologic Malignancies

Hematologic malignancies represent clonal disorders of hematopoietic stem cells or their downstream progeny. The broad classification divides these diseases into leukemias (originating in the bone marrow and circulating in blood) and lymphomas (originating in discrete lymphoid tissue masses). For the MLS exam, the focus is heavily on classifying leukemias and myeloproliferative neoplasms.

Acute vs. Chronic Leukemias

The fundamental difference between acute and chronic leukemia lies in the maturation stage of the malignant clone and the clinical progression.

Acute Leukemias

Acute leukemias involve a block in differentiation; cells proliferate but fail to mature, leading to an accumulation of blasts that crowd out normal marrow elements (causing anemia, bleeding, and infection).

Acute Myeloid Leukemia (AML)

AML is the most common acute leukemia in adults. It involves the malignant proliferation of myeloid blasts (myeloblasts, monoblasts, erythroblasts, or megakaryoblasts).

• Key Morphological Feature: Auer rods. These are needle-like or rod-like inclusions in the cytoplasm of blasts, representing fused primary (azurophilic) granules. Auer rods are pathognomonic for the myeloid lineage; they are NEVER seen in lymphoid blasts.
• Cytochemistry: Positive for Myeloperoxidase (MPO) and Sudan Black B (SBB).
• Important Subtype (APL): Acute Promyelocytic Leukemia (APL) is characterized by a t(15;17) translocation and bundled Auer rods (faggot cells). It frequently causes severe Disseminated Intravascular Coagulation (DIC) and is uniquely treated with all-trans retinoic acid (ATRA).

Acute Lymphoblastic Leukemia (ALL)

ALL is the most common childhood malignancy. It arises from lymphoid precursors.

• Morphology: Lymphoblasts are small to medium-sized with scant cytoplasm, inconspicuous nucleoli, and no granules.
• Classification: Divided into B-ALL and T-ALL. B-ALL accounts for the vast majority. T-ALL often presents in adolescent males as a large mediastinal (thymic) mass.
• Cytochemistry: Negative for MPO and SBB. Positive for Periodic Acid-Schiff (PAS) in block-like patterns, and positive for Terminal Deoxynucleotidyl Transferase (TdT).

Chronic Leukemias

Chronic leukemias involve the proliferation of well-differentiated, mature cells.

Chronic Myeloid Leukemia (CML)

CML is a Myeloproliferative Neoplasm characterized by an extreme overproduction of the granulocytic series.

• Genetics: Defined by the Philadelphia (Ph) chromosome, a reciprocal translocation between chromosomes 9 and 22—t(9;22). This creates the BCR-ABL1 fusion gene, which codes for a constitutively active tyrosine kinase driving unchecked cell division.
• Peripheral Smear: Shows a massive leukocytosis (often >100 x 10^9/L) featuring the entire spectrum of myeloid maturation (from myeloblasts to segmented neutrophils). Basophilia and eosinophilia are prominent and highly suspicious for CML.
• Distinguishing CML from Leukemoid Reaction: A leukemoid reaction (severe infection) mimics CML. To differentiate, CML has a low Leukocyte Alkaline Phosphatase (LAP) score, while a leukemoid reaction has a high LAP score.

Chronic Lymphocytic Leukemia (CLL)

CLL is the most common leukemia in adults in Western countries. It is an indolent neoplasm of mature, functionally incompetent B-lymphocytes.

• Peripheral Smear: Marked absolute lymphocytosis. The cells appear as small, mature lymphocytes with hyper-condensed "soccer ball" chromatin.
• Diagnostic Hallmark: Smudge cells. The neoplastic B-cells are abnormally fragile and rupture during the physical process of making the blood smear. (Note: Adding a drop of albumin to the blood before smearing can prevent this artifact).
• Complications: Often leads to hypogammaglobulinemia (increasing infection risk) or Autoimmune Hemolytic Anemia (AIHA).

Myeloproliferative Neoplasms (MPNs)

MPNs are a group of clonal disorders characterized by the excess proliferation of one or more mature myeloid cell lines (erythrocytes, granulocytes, platelets). CML is a primary member. The others are heavily linked to the JAK2 V617F mutation.

1. Polycythemia Vera (PV): Unregulated proliferation of erythrocytes (high RBC count, high Hgb/Hct), independent of EPO. EPO levels are typically very low. Patients present with hyperviscosity, thrombosis, and intense itching after a hot shower.
2. Essential Thrombocythemia (ET): Proliferation primarily of megakaryocytes leading to extreme thrombocytosis (platelet count often > 1,000 x 10^9/L). Characterized by giant platelets and thrombotic/bleeding complications.
3. Primary Myelofibrosis (PMF): Excessive proliferation of megakaryocytes and granulocytes, which release cytokines (like PDGF) that stimulate fibroblasts to produce massive amounts of collagen in the marrow.
   • Peripheral Smear: Classic teardrop cells (dacrocytes) form as RBCs squeeze through the fibrotic marrow. Leukoerythroblastosis (immature RBCs and WBCs in circulation) is common.