### Detailed Overview: Chapter on Hematopoietic and Lymphoid Systems
#### 1. **Introduction to Hematologic Proliferations**
- Proliferations of white blood cells include neoplasms that are often malignant but
exhibit varying degrees of aggressiveness.
- Modern classification: Based on morphological, immunophenotypic, and genetic
criteria (over 70 entities identified).
#### 2. **HLH (Hyperinflammatory State)**
- **Definition**: Macrophage activation syndrome associated with excessive cytokine
release (e.g., IFN-γ, TNF, IL-6).
- **Causes**:
- Genetic defects affecting cytotoxic lymphocytes (e.g., PRF1 for perforin).
- EBV infection in adolescents with X-linked lymphoproliferative disorders.
- Systemic inflammatory diseases (e.g., lupus).
- Association with peripheral T-cell lymphomas.
- **Morphology**: Bone marrow often shows macrophages actively phagocytosing
red cells, platelets, and nucleated cells.
- **Clinical Presentation**: Fever, splenomegaly, pancytopenia, DIC, ferritin elevation
(>10,000 mg/L), hypertriglyceridemia, low circulating NK cells, and high soluble IL-2
receptor levels.
- **Treatment**: Often ineffective, except hematopoietic stem cell transplantation.
#### 3. **Acute Leukemias**
- Neoplastic proliferations of immature cells replacing normal bone marrow elements.
- **Immunophenotypic Classification**:
- B-ALL (B-cell acute lymphoblastic leukemia).
- T-ALL (T-cell acute lymphoblastic leukemia).
- AML (acute myeloid leukemia).
- **Morphology**:
- **B-ALL and T-ALL**: Lymphoblasts with scant basophilic cytoplasm, finely
stippled chromatin, and small nucleoli.
- **AML**: Myeloblasts are larger, with delicate chromatin, distinct nucleoli, and
azurophilic granules; Auer rods may be present in some subtypes.
- Bone marrow in AML shows >20% blasts, replacing normal elements.
- Specific subtypes like acute promyelocytic leukemia display abnormal
promyelocytes with multiple Auer rods and coarse granules.
- **Clinical Features**: Anemia, fatigue, neutropenia (infections), thrombocytopenia
(bleeding), bone pain from marrow expansion, lymphadenopathy,
hepatosplenomegaly (more common in ALL), CNS involvement (headaches,
vomiting, nerve palsies in ALL).
- **Treatment**:
- Combination chemotherapy.
- Targeted therapies like tyrosine kinase inhibitors (e.g., imatinib for BCR-ABL).
#### 4. **Myelodysplastic Syndromes (MDS)**
- **Definition**: Clonal stem cell disorders with ineffective hematopoiesis.
- **Pathogenesis**:
- Epigenetic mutations (e.g., DNA methylation genes).
- RNA splicing and transcription factor alterations.
- TP53 loss-of-function mutations associated with poor prognosis.
- **Morphology**:
- Dysplastic features in bone marrow include megaloblastoid erythroid precursors,
ring sideroblasts (iron-laden mitochondria), granulocyte precursors with hypolobated
nuclei, and small megakaryocytes with single or multiple nuclei.
- Increased myeloblasts (<20% of cellularity).
- **Clinical Features**:
- Anemia, recurrent infections, thrombocytopenia (bleeding).
- Increased risk of progression to AML (10-40%).
- Precursor condition (CHIP) with normal blood counts but driver mutations.
#### 5. **Myeloproliferative Neoplasms**
- **Common Characteristics**:
- Activating mutations (often tyrosine kinases like JAK2).
- Extramedullary hematopoiesis (enlargement of liver and spleen).
- **Key Entities**:
- **CML (Chronic Myeloid Leukemia)**:
- **Morphology**: Hypercellular marrow with increased granulocytic and
megakaryocytic precursors. Peripheral blood shows elevated white cell counts
(>100,000 cells/μL) with neutrophils, myelocytes, and basophils.
- Splenic red pulp contains extramedullary hematopoiesis.
- **Clinical Features**: Fatigue, weight loss, splenomegaly (abdominal dragging
sensation), progression to blast crisis resembling acute leukemia.
- **Treatment**: BCR-ABL inhibitors.
- **Polycythemia Vera**:
- **Morphology**: Hypercellular marrow with increased erythroid, myeloid, and
megakaryocytic forms. Peripheral blood shows elevated red cell mass, abnormal
large platelets, and basophilia.
- **Clinical Features**: Hypertension, pruritus (histamine release), thrombotic
complications (Budd-Chiari syndrome), bleeding, symptomatic gout from high cell
turnover.
- **Primary Myelofibrosis**:
- **Morphology**: Fibrotic marrow with abnormal megakaryocytes producing
fibrogenic cytokines (TGF-β, PDGF). Peripheral blood shows teardrop-shaped red
cells, nucleated erythroid precursors, and immature myeloid cells
(leukoerythroblastosis).
- Splenomegaly with extramedullary hematopoiesis, infarcts.
- **Clinical Features**: Progressive anemia, fatigue, night sweats, weight loss,
splenomegaly.
#### 6. **Non-Hodgkin Lymphomas and Chronic Lymphoid Leukemias**
- **Classification**: Based on cellular differentiation (CD markers, monoclonal
immunoglobulins).
- **Pathogenesis**:
- Common chromosomal translocations (e.g., t(14;18) in follicular lymphoma).
- Oncogene activation (e.g., MYC in Burkitt lymphoma).
- **Morphology**:
- Follicular lymphoma: Nodular proliferation of centrocytes (small cleaved cells) and
centroblasts (large cells with nucleoli).
- DLBCL: Diffuse sheets of large cells with vesicular chromatin, prominent nucleoli.
- Burkitt lymphoma: Medium-sized cells with basophilic cytoplasm, lipid vacuoles,
and a starry sky pattern due to tingible body macrophages.
- **Clinical Features**:
- Follicular lymphoma: Painless generalized lymphadenopathy, marrow involvement.
- DLBCL: Rapidly enlarging symptomatic masses, common extranodal involvement
(GI tract, CNS).
- Burkitt lymphoma: Jaw tumors (endemic form), abdominal masses (sporadic form),
EBV association in endemic cases.
#### 7. **Hodgkin Lymphoma**
- **Definition**: Characterized by Reed-Sternberg cells in an inflammatory
background.
- **Pathogenesis**: Linked to EBV.
- **Morphology**:
- Reed-Sternberg cells: Large cells with binucleate "owl's eye" nuclei.
- Background varies by subtype (e.g., fibrosis in nodular sclerosis type).
- **Clinical Features**: Localized lymphadenopathy, B symptoms (fever, night sweats,
weight loss), pruritus.
#### 8. **Clinical and Therapeutic Implications**
- **Advances**:
- Targeted immunotherapies (CAR-T).
- Specific kinase and epigenetic inhibitors.
- **Prognosis**: Varies with tumor genetics and therapeutic responses.