White Blood Cell Neoplasms Overview

Classifying White Cell Neoplasms

Leukemia vs lymphoma. A leukemia consists of malignant cells circulating in the blood and filling the marrow, producing leukocytosis plus marrow failure. A lymphoma is a discrete solid tumor mass in lymph nodes or other tissue. Both arise from lymphoid or myeloid precursors, and the two overlap: a lymphoma can enter a leukemic phase, and CLL and small lymphocytic lymphoma are the same disease in blood and in nodes.

Acute vs chronic. Acute leukemia is defined by 20% or more BLASTS in the marrow. Onset is abrupt, with pancytopenia causing fatigue, infection, and bleeding; ALL is the acute leukemia of children and AML of adults. Chronic leukemias accumulate more MATURE cells and follow an insidious course in older adults (CLL, CML).

Acute Leukemias

Acute lymphoblastic leukemia (ALL). The most common childhood cancer, peaking at 2 to 5 years and associated with Down syndrome. Lymphoblasts are TdT-positive and often CD10-positive (CALLA). TdT (terminal deoxynucleotidyl transferase) is a nuclear DNA polymerase of pre-B and pre-T cells, so it distinguishes lymphoblasts from myeloperoxidase-positive myeloblasts. Most cases are B-lineage; T-ALL classically presents as a mediastinal mass in an adolescent. In children, t(12;21) carries a good prognosis, whereas t(9;22) (Philadelphia-positive ALL) is more common in adults and unfavorable. ALL spreads to the CNS and testes, which therefore require prophylactic therapy.

Acute myeloid leukemia (AML). AML strikes adults, with a median age of about 65. Myeloblasts are myeloperoxidase-positive and may contain Auer rods, crystalline aggregates of azurophilic granules. Risk factors include prior alkylating chemotherapy or radiation, benzene exposure, myelodysplastic syndrome, and Down syndrome.

Acute promyelocytic leukemia (APL, M3). APL carries t(15;17), fusing PML to the retinoic acid receptor-α gene (PML-RARA). The fusion protein arrests maturation at the promyelocyte stage. Procoagulant granule contents (tissue factor), plus annexin II–driven hyperfibrinolysis, can precipitate DIC, the main cause of early death. All-trans retinoic acid (ATRA, a vitamin A derivative) forces the malignant promyelocytes to differentiate, and arsenic trioxide degrades the fusion protein; together they make APL one of the most curable leukemias.

APL is a hematologic emergency: suspect it when AML presents with DIC, and start ATRA before genetic confirmation.

Chronic Leukemias

Chronic lymphocytic leukemia (CLL). The most common adult leukemia in the West, typically in the elderly and often found on a routine blood count. Mature monoclonal B cells (CD5-positive, CD23-positive) produce marked lymphocytosis, and the fragile cells rupture into smudge (basket) cells on the smear. Complications are warm autoimmune hemolytic anemia, hypogammaglobulinemia with recurrent infections, and Richter transformation to diffuse large B-cell lymphoma. The nodal form is small lymphocytic lymphoma.

Chronic myeloid leukemia (CML). The Philadelphia chromosome, t(9;22), fuses BCR to ABL, creating a constitutively active tyrosine kinase that drives unregulated myeloid proliferation. Blood shows marked leukocytosis with the full spectrum of maturing myeloid cells and basophilia, often with splenomegaly; leukocyte alkaline phosphatase (LAP) is LOW. Untreated, the chronic phase progresses to blast crisis, which can resemble AML or ALL. The tyrosine kinase inhibitor imatinib blocks BCR-ABL.

CML vs leukemoid reaction. A very high WBC may be malignant CML or a reactive leukemoid reaction to severe infection or inflammation. CML shows LOW LAP, basophilia, and the Philadelphia chromosome. A leukemoid reaction shows HIGH LAP (activated, mature neutrophils), toxic granulation, Döhle bodies, and a clear trigger, and it resolves when the trigger is treated.

Hodgkin and Non-Hodgkin Lymphoma

Hodgkin lymphoma. Defined by Reed-Sternberg cells: large, binucleate "owl-eye" cells that are CD15- and CD30-positive. They are few, sitting in a background made mostly of reactive lymphocytes and other inflammatory cells. Hodgkin lymphoma has a bimodal age curve (young adults and over 55), spreads in a contiguous nodal pattern, causes B symptoms (fever, night sweats, weight loss), and is EBV-associated. Nodular sclerosis is the most common subtype, typically in young women, with lacunar cells and collagen bands, often involving the mediastinum.

Non-Hodgkin lymphoma (NHL). NHL is more common than Hodgkin, lacks Reed-Sternberg cells, occurs at all ages, arises from B or T cells, and is often multifocal, noncontiguous, and extranodal. Many subtypes are defined by a translocation that places an oncogene next to an active immunoglobulin locus.

Myeloproliferative Neoplasms

JAK2 drives three. Myeloproliferative neoplasms are clonal overproductions of mature myeloid cells; CML is the BCR-ABL member. The JAK2 V617F mutation makes the kinase constitutively active, so cytokine receptor signaling proceeds without growth factor. It is present in nearly all polycythemia vera (~95%) and about half of essential thrombocythemia and primary myelofibrosis. All share thrombosis risk and can transform to acute leukemia.

Polycythemia vera (PV). PV overproduces red cells, plus WBCs and platelets. Clues include aquagenic pruritus (itching after a warm shower), erythromelalgia (burning red hands and feet), facial plethora, headache from hyperviscosity, and thrombosis, including Budd-Chiari syndrome and portal vein thrombosis. Erythropoietin is LOW, because the clone proliferates independently of EPO. In secondary polycythemia, EPO is HIGH, driven by hypoxia (lung disease, high altitude) or an EPO-secreting tumor such as renal cell carcinoma. Treat PV with phlebotomy, hydroxyurea, and low-dose aspirin.

Essential thrombocythemia (ET). Platelets exceed 450,000/μL, often far higher, with both thrombosis and bleeding. ET carries JAK2, CALR, or MPL mutations and a low rate of leukemic transformation; reactive thrombocytosis (iron deficiency, inflammation) must be excluded.

Primary myelofibrosis. Megakaryocytes release PDGF, which stimulates fibroblasts to replace the marrow with fibrosis. Hematopoiesis moves to the spleen and liver (extramedullary hematopoiesis), causing massive splenomegaly. Aspiration yields a dry tap, and the smear is leukoerythroblastic, with teardrop cells (dacrocytes) deformed while squeezing out of the fibrotic marrow. The JAK inhibitor ruxolitinib reduces spleen size and symptoms.