U7 WBC

DISORDERS OF WHITE BLOOD CELLS AND LYMPHOID TISSUES

  • Covering leukocytes, lymphoid tissue, hematopoiesis, hematopoietic growth factors, nonneoplastic and neoplastic disorders of white blood cells, and plasma cell dyscrasias.

Hematopoietic and Lymphoid Tissues

  • Function: Protect the body against invasion by foreign agents.

  • Location of Blood Cell Formation:

    • Blood cells are formed in the myeloid (bone marrow); circulate, mature, and function in lymphoid tissues including: lymph nodes, thymus, and spleen.

  • Development of Blood Cells:

    • Involves interactions among precursor bone marrow cells, growth factors, cytokines (chemical messengers), and gene products like transcription factors

Leukocytes (White Blood Cells)

  • Definition: White blood cells (WBCs) include granulocytes (neutrophils, eosinophils, basophils), monocytes/macrophages, and lymphocytes.

  • Origin of White Blood Cells:

    • Granulocytes and agranular monocytes originate from the myeloid stem cell in the bone marrow, circulate in the blood.

    • T lymphocytes (T-cells) and B lymphocytes (B-cells) originate from lymphoid stem cells in bone marrow, and migrate between the blood and lymphatic system.

      • T Lymphocytes: Mature in the thymus; differentiate into helper T-cells and cytotoxic T-cells.

      • B Lymphocytes: Mature in bone marrow (myeloid) Differentiate into immunoglobulin-producing plasma cells.

  • Natural Killer (NK) Cells: Large granular lymphocytes that do not share specificity with T or B lymphocytes but can lyse target cells

Bone Marrow and Hematopoiesis

  • Hematopoietic System:

    • Arises from a small number of pluripotent stem cells (can-do-anything).

      • Supports development of hematopoietic precursors:

        • Erythroid → RBC

        • Myelocyte → granulocyte and monocyte

        • Lymphocyte → T-cell and B-cell

        • Megakaryocyte → platelets.

  • Unipotent Cells:

    • Progenitors of specific blood cell types.

  • B and T Lymphocyte Development:

    • Begins in bone marrow, ends in peripheral lymphoid structures (lymph nodes, thymus, and spleen); initial immune response via neutrophils lasts 4-5 days

Hematopoietic Growth Factors

  • Function: Control leukopoiesis (production of WBCs).

  • 3 Types of Hematopoietic Growth Factors

  • 1.Specific cell lineage development growth factors.

  • 2.Factors affecting early multipotential progenitor cells.

  • 3. Factors inducing growth factor gene expression in other cells

Leucocyte Developmental Stages

  • Lifespan of WBCs: Short; continuous renewal crucial for normal blood levels.

  • Leucocyte Development: Begins with myeloid / lymphoid stem cells in bone marrow and categorized as blast cells→ immature precursors

  • §Myeloid stem cells → granulocyte and monocyte cell lines

  • lymphoid stem cells → lymphocytes

  • Key Characteristics of WBC Disorders: Conditions can decrease stem cell or hematopoietic growth factor availability leading to lower WBC counts

Lymphoid Tissues

  • Components: Lymphatic system composed of lymphatic vessels, lymphoid tissue, lymph nodes, thymus, and spleen.

  • Development of B and T Lymphocytes: Both start in bone marrow, with:

    • B lymphocytes differentiating into plasma cells, proliferating and producing antibodies in lymph nodes.

    • T lymphocytes become helper T-cells and cytotoxic T-cells in the lymph tissues

  • Lymph Nodes:

    • Organized lymphoid tissue along lymphatic vessels, varying from 1 mm to 1-2 cm in size, with a fibrous structure supporting a delicate reticular network.

    • Parenchyma divided into outer cortex with defined B and T cell domains and a medulla.

    • Lymphomas can arise from lymph nodes and MALT → not incased lymph tissues

Nonneoplastic Disorders of White Blood Cells

  • Physiologic Number of Leukocytes: 5-10,000 cells/µL in peripheral circulation.

  • Types of Disorders:

    • Leukopenia (deficiency of leukocytes)

    • Proliferative disorders with increased leukocyte numbers (leukocytosis).

    • Chemotherapy-induced leukopenia affects neutrophils primarily

Neutropenia (Agranulocytosis) <1000/ul

  • Definition: Decrease in absolute neutrophils, defined as circulating count < 1000/µL.

  • Causes:

    • Can arise from decreased production, accelerated utilization, or shifts from blood to tissue compartments.

  • Key Points: Degree of neutropenia correlates with increased infection risk, especially during severe infections (all used up, can’t make more neuts fast enough).

    • In the absence of infection, neutropenia is associated with immunologic disorders

  • Types:

    • Congenital→ alloimmune neonatal neutropenia

      • Acquired: autoimmune conditions, hematologic malignancies, etc.

  • Severe Cases:

    • Aplastic anemia leads to anemia, thrombocytopenia, and agranulocytosis

    • vSevere neutropenias:

      §Pancytopenia: condition when all the RBCs, WBCs, and platelets are considerably low

      §Agranulocytosis: characterized by the virtual absence of neutrophils

      §In aplastic anemia, the affected individual has a depletion of all the myeloid stem cells → anemia, thrombocytopenia, and agranulocytosis

Infectious Mononucleosis

  • Definition: Self-limiting, lymphoproliferative syndrome caused by acute viral infection of B-lymphocytes.

  • Causative Agent: Epstein-Barr virus (EBV) accounts for 85-90% of IM cases; CMV accounts for the rest.

  • Transmission: Primarily through saliva (“kissing disease”) and other body fluid secretions.

  • Symptomatic IM: Common among adolescents and young adults (ages 15-35), with peak incidence at 15-24 years; rare after 40 but more often caused by CMV.

  • Clinical Manifestations: Pharyngitis, lymphadenopathy, fever; onset of sore throat and fever; classic symptoms of EBV-induced IM include fever lasting 7-10 days, sore throat, cervical lymph node tenderness.

  • Complications:

    • About 50% of cases exhibit splenomegaly x2-3 normal size. Immune mediated hepatitis.

  • Treatment: Usually self-limiting; management is symptomatic

Neoplastic Disorders of Lymphoid and Hematopoietic Origin

  • Overview: Neoplasias of lymphoid origin may arise from B or T cells and encapsulate various stages of development. Major categories being non-Hodgkin lymphomas (NHLs), Hodgkin lymphoma, lymphoid leukemias, and plasma cell dyscrasias.

  • Clinical Features: Determined by cell origin and molecular events driving transformation to malignancy. Neoplasm disseminates from onset d/t blood circulation.

Malignant Lymphomas

  • Definition: Diverse group of solid tumors comprised of neoplastic lymphoid cells.

  • Characteristics:

    • Tumors can arise from primary (thymus/bone marrow) or secondary lymphoid tissue (lymph nodes, spleen, intestinal lymphoid tissues etc.) and vary across genetics and treatment response.

  • Causes: Often initiated by genetic mutations and viral infections, commonly affecting lymph nodes or gastrointestinal lymphoid tissues

  • vTwo (2) major types of malignant lymphomas are Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL)

    §Children are less likely to be diagnosed with NHL

    vLymphoma incidence rates vary with respect to age, assigned-at-birth sex, geographic location, and socioeconomic class

Non-Hodgkin Lymphomas (NHL)

  • NHL Definition: Clinically diverse group arising from B-cells, T-cells, and NK cells,

    • Responsible for approximately 25% of new cancer cases in the US. Highly common in older adults.

  • Incidence: Has significantly increased since the 1970s; variations remain related to environmental and genetic factors.

  • NHL Classification:

    • Divided into B-cell neoplasms (including myelomas)

    • T-cell/NK-cell neoplasms.

  • vNon-Hodgkin lymphomas arise from the lymphocytes

    §Site of origin varies according to their common lymphoid progenitor

    §Exact etiology of the alteration is unknown

    §Linked pathogens: EBV, human T-lymphotropic virus 1, and H. pylori have been linked to specific subtypes

  • Affected Sites: Cervical, axillary, inguinal, and femoral lymphatic chains where painless lymph node swelling and transformation occurs, with systemic manifestations such as night sweats and weight loss. Effects immunosuppressed, older people. Must be confirmed by a lymph node bx.

Mature B-Cell Lymphomas 

  1. Follicular lymphomas:

§Peak incidence, age 60

§↑ risk of secondary malignancies for > 65 y/o at the time of dx 

§Lymph nodes are usually affected

oOther areas of frequent involvement: spleen, bone marrow, peripheral blood, head and neck regions, GI tract, and skin

§Over time, ≈ 33% of follicular lymphomas transform into fast-growing diffuse large B-cell lymphomas

vDiffuse large B-cell lymphomas:

§Heterogeneous group of aggressive germinal or post-germinal center neoplasms

§Occur in all age groups; most prevalent between 60 and 70 years

§Etiology unknown, but may involve EBV or HIV infection

§Rapidly evolving, multifocal, nodal, and extranodular tumors

§Quickly fatal if untreated

  1. Burkitt lymphoma:

§Disorder of germinal B cells

§Fastest-growing human tumor: accounts for 30% of childhood lymphomas worldwide

§Most aggressive and rapidly growing of the NHLs

§Endemic to areas of Africa where both Epstein-Barr virus and malaria are common

Characterized by a rapidly growing tumor primarily affecting adversely the jaw and facial features

Hodgkin Lymphoma (HL)

  • Hodgkin Lymphoma Definition: Specialized lymphoma distinguished by Reed-Sternberg cells

  • Bimodal age distribution peaks in early adults and older adults.

    • §Early adults (15-40 y/o)

      §Older adults ( ≥ 55 y/o)

  • Key Differences From NHL: Presents in a singular node (or chain of nodes) compared to NHL's tendency for extranodal primary sites. Presence of Reed-Sternberg cells is diagnostic→ Characterized by large, atypical, multinucleated tumor cells

  • Etiology: Unknown, but genetic and environmental factors (radiation exposure, viral infections) may contribute

  • Clinical Manifestations: Enlarged, painless lymph nodes above the diaphragm; mediastinal masses common→ cough, dyspnea

  • Systemic symptoms such as intermittent fevers and pruritus can occur, night sweats

    • fatigue→ disease spread

  • Definitive diagnosis via biopsy

  1. Nodular lymphocyte-predominant HL

    §Represents only a small portion of the cases

    §Unique feature: generally exhibits a nodular growth pattern

    oWith or without diffuse areas and rare Reed-Sternberg cells (“popcorn” -- lymphohistiocytic cells)

    §Often localized rather than disseminated at the time of dx

    §Slowly progressive course

    §Survival rate > 80%

  2. Classic HL

    §Clonal proliferation of typical mononuclear Hodgkin cells and multinucleated Reed-Sternberg cells with invariable expression of CD30 (cell surface marker)

    §Four (4) variants of classic HL:

    i. Nodular sclerosis ~ most common and often found in adolescents and young adult assigned-at-birth females, 15-35 y/o

    ii. Mixed cellularity

    iii. Lymphocyte-rich (newly defined entity)

    iv. Lymphocyte-depleted (rarely dx)

Leukemias

  • Leukemia Definition: Malignant neoplasms of cells arising from hematopoietic precursor cells, characterized by unregulated proliferation, leading to overcrowding of bone marrow. Can spill into other organs like liver, spleen, lymph nodes.

  • Types: Classified based on predominant cell of origin (myeloid or lymphoid) and rate of progression (acute or chronic). Four main types include:

    1. Acute lymphocytic leukemia (ALL)

    2. Acute myelogenous leukemia (AML)

    3. Chronic lymphocytic leukemia (CLL)

    4. Chronic myelogenous leukemia (CML)

  • Epidemiology: Higher incidence in males; prevalent in children compared to adults and known to account for a significant number of cancer diagnoses.

  • vLeukemias are the most frequent cancer etiology in children and adolescents

    §Leukemia accounts for 28% of childhood cancers

    §Acute lymphoblastic leukemia (ALL) is the least overall common leukemia type; but the most common leukemia in children (≈ 66% of cases dx before age 20) 

    oLeukemias account for 34% of childhood cancers, and ALL accounts for 78% of new leukemia cases in children

    vLeukemias are dx 10X more frequently in adults than in children

    • Pathogenesis: Unknown etiology; often linked to clonal disorders and genetic predispositions; chromosomal aberrations like the Philadelphia chromosome (translocations between 9 and 22) notable in CML

ACUTE LEUKEMIA

vAcute leukemias:

§Usually have a sudden onset; WBCs are poorly differentiated

§Seen in both at-birth-assigned sexes and in all ages; incidence ↑ dramatically after age 50; affected have a significantly lower survival rate than in chronic leukemias

§Frequent presenting symptomatology: fatigue, fever (low-grade), blurred vision, dyspnea, bone and joint pain, weight loss, pale integument, infections (persistent or frequent), bleeding diathesis (excessive bruising and bleeding)

§Key objective clinical manifestations: low-grade fever and high blast count

§The two (2) most common types of acute leukemias: acute lymphocytic leukemia (ALL); and acute myelogenous leukemia (AML)

  1. Acute lymphocytic leukemia (ALL)

•Rare and aggressive

ü May affect the bone marrow, lymph nodes, spleen, integument, and central nervous system

•Occurs most frequently in children: 75% of all childhood leukemia cases

ü≈ 90% of the affected have numeric and structural changes in the chromosomes of their leukemic cells

•Unexpected manifestations: confusion, ascites, and pleural effusions,

•Frequent symptomatology: persistent flu-like symptoms, lymphadenopathy of unknown etiology, petechiae, minor hemorrhaging (frequent epistaxis, gingivitis)

•≈ 33% of ALL cases occur in adults; account for 80% of adult leukemia deaths

ü30-40% of affected adults achieve remission

  1. Acute myelogenous leukemia (AML)

    •Mainly a dz of older adults, but also seen in children and younger adults

    üAccounts for 25% of cases in children and adolescents

    •Diverse group of neoplasms affecting myeloid precursor cells in the bone marrow

    •Associated pathologies: organomegaly (spleen and liver), central nervous system involvement (headaches, confusion, seizures or cranial nerve palsies)_

    •AML is most associated with acquired genetic alterations inhibiting terminal myeloid differentiation

    üSpecific chromosomal abnormalities, including translocations, are seen in a large number of AMLs

Clinical Manifestations: ALL and AML typically present with similar clinical features, including abrupt onset of symptoms

oFatigue 2°anemia

oLow-grade fever; high blast cell counts

oNight sweats

oWeight loss 2° rapid proliferation and hypermetabolism of the leukemic cells

oBleeding 2°↓ platelet count

oBone pain and tenderness 2° bone marrow expansion

oInfection 2° neutropenia ~ risk ↑ sharply as neutrophil count falls to < 500 cells/microliter

oGeneralized lymphadenopathy, splenomegaly, and hepatomegaly 2° infiltration of leukemic cells ~ more common in ALL

vLeukostasis: circulating blast count becomes markedly elevated, thus ↑ blood viscosity

§Predisposes to lymphoblastic emboli with associated obstruction of small blood vessels in the pulmonary and cerebral circulation

vHyperuricemia: occurs due to the proliferation or ↑  breakdown of purine nucleotides (one of the components of nucleic acids) 2°leukemic cell death resulting from chemotherapy

§Can also occur before or during tx

vDiagnosis:

§Based on blood and bone marrow studies: leukemic cells in the peripheral blood, bone marrow, or extramedullary tissue

§Blood assays reveal the presence of immature WBCs in the circulation and the bone marrow constituting 60-100% of the cells

oAnemia is almost always present

oPlatelet count is ↓

oBlast cells (immature blood cells that develop from stem cells in the bone marrow) are often abnormal and multiply rapidly → ↑ blast cell counts

§Cytogenic studies are used to detect chromosomal abnormalities: among the most powerful prognostic indicators

CHRONIC LEUKEMIA

vChronic leukemias:

§Proliferation of more fully differentiated myeloid and lymphoid cells (than the immature cells found in the acute leukemias)

§Account of the majority of adult leukemias

§Two (2) most common types: chronic lymphocytic leukemia (CLL);  and chronic myelogenous leukemia (CML)

oSeveral forms of CML can occur, depending on the lineage of the malignant cells

§Mostly a disorder of older adults

oIncidence ↑ after age 40: mean age at CML and CLL dx ≈ 70

oRare in those < 40 y/o; infrequent in children

§Chronic leukemic cells are well-differentiated; the dz process advances slowly and insidiously; and affected individuals have a longer life expectancy

§Key clinical manifestations: hx weakness, fatigue, and weight loss

  1. Chronic lymphocytic leukemia (CLL):

•Clonal malignancy of B lymphocytes

•Most common adult leukemia in the Western world

•Number of genomic alterations ↑ throughout the course of the dz

•Immunotyping confirms the dx

•Some affected individuals survive for many years without tx; others have fatal dz despite aggressive tx

oMore aggressive CLL forms experience a more rapid sequence of clinical deterioration characterized by

•↑ lymphadenopathy

•Hepatosplenomegaly

•Fever

•Abdominal pain

•Weight loss

•Progressive anemia

•Thrombocytopenia with a rapid ↑ in the lymphocyte count

vDiagnosis:

§Chronic lymphocytic leukemia (CLL)

oDiagnostic hallmark is isolated lymphocytosis

oWBC is usually > 20,000/µL; may be elevated to several hundred thousand, usually 75-98% are lymphocytes

oHct and lymphocyte counts are usually within defined limits at the time of dx

oAffected individuals may retain normal plasma synthesis and fully differentiated myeloid and lymphoid cells= chronic lymphocytic leukemia

  1. Chronic myelogenous leukemia (CML):

•Disorder of pluripotent hematopoietic progenitor cells

•Characterized by excessive proliferation of marrow granulocytes, erythroid precursors, and megakaryocytes

•CML cells have a distinctive cytogenic abnormality, the Philadelphia chromosome

Clinical Manifestations: Onset is usually slow, with presenting nonspecific symptoms such as weakness, fatigue, and weight loss (for a period of ≥ 6 months)= chronic myelogenous leukemia

üSplenomegaly often → a sensation of abdominal fullness and discomfort

üHepatomegaly is less common

•Lymphadenopathy is relatively uncommon

oAffected individuals can remain in the non-accelerated phase (chronic CML) for years before the dz process accelerates and culminates in a crisis

Diagnosis

oDiagnostic hallmark is an elevated WBC with a median count of 150,000/µL  

•In some cases, WBCs are only moderately elevated

oDz hallmark: the presence of BRC-ABL (breakpoint cluster region-Abelson leukemia virus) gene product (detected in the peripheral blood)

oBone marrow examination is usually not necessary

•Helpful for prognosis and detecting additional chromosomal abnormalities

Plasma Cell Dyscrasias

  • Definition: Characterized by an increase in serum levels of a single monoclonal immunoglobulin or its fragments resulting from expansion of a single clone of immunoglobulin-producing plasma cells.

  • Types: Include multiple myeloma (MM), localized plasmacytoma, lymphoplasmacytic lymphoma, amyloidosis, and monoclonal gammopathy of undetermined significance (MGUS).

    • MGUS is seen as a premalignant condition closely linked to multiple myeloma

Multiple Myeloma (MM)

  • Overview: B-cell malignancy, most frequent and aggressive plasma cell tumor.

  • Etiology: Unknown, but may involve genetic factors and chronic stimuli from environmental sources; prevalence increases with age, with a median age of 71 years for diagnoses.

vPathogenesis:

§Clonal plasma cell cancer characterized by slow proliferation of malignant cells as tumor cell masses scattered throughout the skeletal system and occasionally in soft tissue → bone destruction

  • Abnormal proliferation of plasma marrow cells; and proliferation and activation of osteoclasts

  • Precise etiology: unknown

    oGenetic factors and chronic stimulation of the mononuclear phagocyte system by bacteria, viral agents, and chemicals → agent orange may play a role

    oSlightly more common in assigned-at-birth males than in assigned-at-birth females 

    §Risk factors:

    oModifiable: obesity, exposure to ionizing radiation, occupational exposure to herbicides and pesticides

    oNon-modifiable: chronic immune stimulation, and autoimmune disorders

vMajor clinical manifestations:

§Main sites of involvement: bone and bone marrow

oReported symptoms: bone pain, fatigue

oSigns:

•Hx of bone fractures; bone lesions

•Elevated serum calcium (hypercalcemia)

•Elevated serum creatinine

•Weight loss, anemia, proteinuria

•Recurrent infections 2° suppression of the humoral response

•Renal dz/failure (occurs in ≈ 50% of those affected ~ see Fig. 24.14)

vChemotherapy is the tx of choice