Acute Lymphoblastic Leukemia (ALL)

Acute Lymphoblastic Leukemia (ALL)

• Malignant disease of the lymphopoietic system.
• Uncontrolled growth of lymphoid cells in bone marrow, spleen, and lymph nodes.
• Predominantly affects children.
• Most common malignant disease in children aged 2-10 years.

FAB Morphologic Classification

• Type L1: Small cell, homogeneous.
• Type L2: Large cell, heterogeneous.
• Type L3: Burkitt type.

Clinical Manifestations

• Similar to other acute leukemias but with a more sudden onset.
• Prodromal or preleukemic symptoms are often associated.
• Common symptoms include:
• Pancytopenia
• Malaise, fatigue, and pallor
• Bone and joint pains
• Cranial nerve paralysis
• Increased ICP
• Fundic (eye) hemorrhages
• Meningeal infiltration signs
• Lymphadenopathy and hepatosplenomegaly

Laboratory Findings

• Total WBC count elevated (>10 X 10^9/L) in 60% of cases.
• Markedly elevated (>100) in 15% of cases.
• Leukopenic (<5) in 25% of cases.
• (+) leukemic lymphoblast in smears.
• Bone marrow: hypercellular and infiltrated with lymphoid cells.
• Fibrosis: 10-15%.
• Thrombocytopenia.
• Anemia.
• Should be differentiated from:
• Pertussis - lymphoid leukocytosis
• Infectious lymphocytosis
• Infectious mononucleosis (autoimmune anemia and thrombocytosis; (+) heterophil antibody)
• Other viral diseases

Classification of Acute Lymphoblastic Leukemia

• L1: Small cell size, homogenous chromatin, regular nuclear shape with occasional clefting, inconspicuous nucleoli, scanty cytoplasm, slight basophilia, and variable cytoplasmic vacuolization.
• L2: Large, heterogeneous cell size; variable chromatin; irregular nuclear shape with clefting and indentation; one or more prominent nucleoli; moderate cytoplasm; variable basophilia; variable cytoplasmic vacuolization
• L3: Large, homogenous cell size; finely stippled chromatin; regular nuclear shape; prominent nucleoli (one or more, vesicular); moderately abundant cytoplasm; very deep basophilia; often prominent cytoplasmic vacuolization.

Immunologic Markers

• Demonstrate markers on the cell surface.
• Surface Ig (SIg) identifies B cells.
• Sheep Erythrocyte Rosettes identify T cells (non-specific).
• Most ALLs are NON-B and NON-T types.
• CALLA (Common Acute Lymphoblastic Leukemia Antigen): Monoclonal antibody.

CytoChemical Classification

• Myeloperoxidase or Sudan Black: ALL is negative.
• PAS: significant difference between L1 and L2; L1 is strongly positive.
• Acid Phosphatase: positive for all ALL.
• Golgi region is (+) for T-cell type
• Diffuse pattern in myeloid cells
• NSE: focal positivity in T-cells
  • Useful in M5 VS L2 (M5 cytoplasm is diffusely stained).
• Terminal Deoxynucleotidyl Transferase (TdT): an intranuclear enzyme that catalyzes the addition of deoxynucleotides
  • Activity (+) in thymocytes, primitive lymphocytes, and a small type of other cells in the BM.
  • Strong activity in ALL.
  • Useful in CML's lymphoblastic transformations.

Immunologic Markers (Classes)

• Unclassified ALL (UALL): 10% in children, 40% Adults
• Common ALL (CALL): 75% in children, 40% in adults
• T-ALL: 15% in children, 15% in adults
• Pre-T ALL: Has T antigen but lacks sheep erythrocyte receptors
• Pre-B ALL: (+Igs and absence of SIg
• B ALL (Burkitt's Lymphoma/Leukemia): (SIg and B cell antigen)

Classification (table contents)

• Sheep rbc receptors: only present in T-ALL patients
• SIg: present in B ALL/Burkitt's patients only
• Cytoplasmic Ig: present in ALL PRE-B patients
• TdT: present in VALL PRE-T TALL PRE-B patients
• HLA-DR: present in VALL CALL PRE-B patients
• CALLA: present in VALL CALL L1/L2 PRE-B patients
• T antigen: present in PRE-T and TALL patients
• Morphology: the presentation varies

Introduction to Chronic Lymphocytic Leukemia (CLL)

• Heterogenous group from which 3 distinct disease entities have emerged:
• Chronic lymphocytic Leukemia (CLL)
• Prolymphocytic Leukemia (PLL)
• Hairy cell leukemia (HCL)
• Requires different therapeutic approaches.
• Nearly all (99%) are clonal B-lymphocytic disorders (remaining are rare T-cell forms).
• Reduced rate of cell death > Increased rate of cell production.
• Involves malignant equivalents of the different stages of normal lymphocytic development.

Chronic Lymphocytic Leukemia (CLL)

• Most common type of leukemia in the Western hemisphere.
• Is not related to exposure to ionizing radiation

Factors of Chronic Lymphocytic Leukemia (CLL)

• Age
• Gender: Male
• Inherited or acquired immunologic defects.
• Virus - Human T-lymphotrophic virus (HTLV).

Genetic Factors

• B-cell CLL - +12 abnormalities and 11 4q32 (most common 114q32; 11q13).
• Quantitative or qualitative immunoglobulin abnormalities or impaired lymphocyte transformation in response to a phytohemagglutinin (PHA)

Clinical Presentation

• Disease of the elderly (90% >50 years; 65% >65%).
• Male 2x more prone than females.
• An incidental finding.
• Benign to severe.
• 10-15% survive without treatment.
• Median survival = 3-4 years.
• Is less likely to undergo acute exacerbation than the other leukemias.

Physical Signs

• Enlarged lymph nodes.
• Splenomegaly.
• Hepatomegaly.
• Lymphoid infiltration - gonads, skin, prostate, kidney, and walls of the GIT.

Laboratory Findings

• Persistent lymphocytosis (abs count = 10-150 to 1000 X 109/L)
• Lymphocytes appear normal or slightly larger than normal with clumped or condensed chromatin.
• Cleft nuclei - follicular origin.
• (+) smudge cells.
• Neutropenia.
• Anemia. – Increased destruction
• Marrow infiltration
• Autoimmune hemolysis
• Thrombocytopenia – Increased glycogen content in lymphocytes - stain intensely with PA

Prolymphocytic Leukemia (PLL)

• Coined before as a "rare form of CLL."
• The proliferation and accumulation of abnormal lymphoid cells in the spleen, BM and to a lesser extent, the liver account for the S/Sx of PLL.
• Predilection in men of the 6th decade.
• Generally acute in onset (as compared with the classic CLL).
• Associated with hepatosplenomegaly.
• Lymphadenopathy is uncommon.
• Associated with poorer prognosis.

Laboratory Findings (PLL)

• Leukocytosis
• Large Prolymphocytes
• Large
• Mononuclear
• Oval to round nucleus
• Coarse appearing chromatin strands
• One or two large vesicular nuclei
• Perinuclear chromatin condensation
• Basophilic agranular cytoplasm
• Absolute neutrophils low (1 to high 20))
• +/- Absolute monocytosis
• Marrow prolymphocytic infiltration
• Anemia
• Thrombocytopenia

Laboratory Findings (PLL)

• Plasma immunoglobulins - reduced
• BM aspirates - not necessary EXCEPT for those "aleukemic" and "subleukemic" stages
• Marrow lymphocytes = >30%
• Marrow lymphocytosis + peripheral blood lymphocytosis = CLL
• Marrow erythroid cells are megaloblastic
• Increased mast cells

Hairy Cell Leukemia

• A rare neoplasm (2%).
• Characterized by large spleen.
• Presence in the peripheral blood of mononuclear cells with numerous cytoplasmic processes.

Characteristics of Hairy Cell Leukemia

• Large spleen.
• Presence in the peripheral blood of mononuclear cells with numerous cytoplasmic processes.

Other names

• Reticulosis.
• Aleukemic reticuloendotheliosis.
• Reticulum cell leukemia.

Pathophysiology

• Indolent course.
• Mean survival = 5 years.
• Two groups of patients according to complications:
• RELATED TO CYTOPENIAS AND SPLENOMEGALY
• Anemia.
• Infections.
• Bleeding.

Paraneoplastic Complications

• Autoimmune syndromes.
• Paraproteinemia.

Clinical presentation

• Men (4-5:1).
• Median age - 55 years.
• Splenomegaly (consistent).
• Lymphadenopathy and hepatomegaly are more rarer compared to the other CLL.

Laboratory findings

• (+) hairy cells (<50% in peripheral blood) - B cell

Characteristics of a hairy cell

• Scant to abundant, agranular, light grayish blue cytoplasm.
• Hairlike or ruffled cytoplasmic projections.
• Round to oval nucleus which appears bilobed or folded.
• Loose and lazy chromatin.
• One or more nucleoli.

Review of the Immunoglobulins

• PLASMA CELL - a mature B cell capable of synthesizing antibodies.
• ANTIBODIES (IMMUNOGLOBULINS or y GLOBULINS) – are proteins with gamma electrophoretic mobilities that are synthesized in response to an antigen.

Multiple Myeloma

• Most common disease of plasma cells.
• Affects older individuals (50-75 years).
• Etiology: Unknown.

Multiple Myeloma Factors

• Genetics.
• Chronic antigenic stimulation.
• Begins in the bone marrow with lytic bone diseases and osteoporosis.
• Decreased ability to produce normal Igs against a specific antigen although complete Igs or a L-chain subunit (κ or λ)

Laboratory Findings For Multiple Myeloma

• Lgs produced are mostly of the LgG class (50%) or IgA (20%) or L-Chains only (Bence-Jones Protein) (15%) or Amyloid (25%).
• IgD and lgE myelomas - rare.
• IgM - associated with macroglobulinemia.
• Pancytopenia.
• N\N anemia.
• ESR elevated due to increased globulins.
• Rouleaux formation.
• few abnormal plasma cells.
• BM = 10-15% plasmacytes.
• Urinary protein (strip and SSA) - non sensitive due to their specificity to albumin.
• (+) costs - hyaline or tubular epithelial cells.
• Electrophoresis - monoclonal peak.
• Hyperuricemia.
• Hypercalcemia.
• Radiologic exams.

Plasma Cell Leukemia

• Circulating plasma cell levels > 2 X 109/L (0.14-0.20 NV).
• Younger patients.
• Less bone pain.
• Less osteolysis.
• Greater incidence of lymphadenopathy and hepatosplenomegaly.
• Pancytopenia with leukoerythroblastic findings.
• Elevated ESR.
• Abnormal plasma cells are smaller with little cytoplasm and pronounced N:C asynchronism.
• BM infiltration is diffuse (45%).

Waldenstrom Macroglobulinemia

• A lymphoproliferative disorder characterized by large concentrations of monoclonal IgM (>15%)
• The abnormal B lymphocytes arise from the extramedullary nodes and have the ability to differentiate to large plasmacytoid lymphocytes and plasma cells
• Rarely causes osteolytic lesions
• Glomerular lesions caused by deposition of IgM complexes of amyloid
• Affects men >50 years old with hepatosplenomegaly, lymphadenopathy and retinal abnormalities

Laboratory Findings - Waldenstrom Macroglobulinemia

• N/N-hemorrhage, hemodilution from hypovolemia and decreased red cell survival
• Reticulocytes – decreased or normal
• Normal WBC and platelets
• Increased ESR
• BM-plasmacytoid lymphoma
• (+) Mast cells - CLUE!
• Autoimmune hemolytic anemia
• Raynaud's phenomenon (anti-G)
• Cold agglutinin (anti-i)
• Abnormal platelet function
• Thrombocytosis.
• Low fibrinogen
• -Prolonged thrombin time
• Increased plasma viscosity
• Monoclonal IgM with cryoglobulin activity - precipitation or gel formation at 4C
• Electrophoresis - Monoclonal peak in the beta-gammma region (15%)

Heavy Chain Disease

• Rare disease.
• Characterized by abnormal synthesis of Fc fragment of a particular H chain (a, y, u).
• Alpha HCD - infiltration of plasmacytoid lymphocytes into the duodenal and jejunal walls
• In older men and presents with a malignant lymphoma with fever, erythema, lymphadenopathy and hepatosplenomegaly
• Rarest; associated with CLL

Laboratory Findings For Heavy Chain Disease

• Lymphoma Symptoms
• Alpha HCD
• Anemia
• leukocytosis and eosinophilia
  • broad component migrating between alpha 2 and beta regions
  • (+) H-chain
• Gamma HCD
• Anemia
• Leukopenia and eosinophilia
• Marked Thrombocytopenia
• Hypoalbuminemia
• sharp peak (+) anti-HC/ (+) anti L-chain
  • B- ALL

General Amyloidosis Info

• The abnormal proteins (Amyloid) occur through the body
• Primary Amyloidosis (Closely-associated with monoclonal gammopathies i.e. plasma cell myeloma)
• Beta sheets
• Secondary amyloidosis: Associated with chronic illnesses.
• *Need biopsy, electron microscopy, & polarised microscopy with Congo Red stain -> apple green bifringence

Introduction (Lymphoma classification.)

• A group of malignant diseases that originate from the uninhibited growth of cellular elements found in lymphatic tissues.
• Distruption of lymph nodes, hallmark is abnormal enlargement.
• Differs from CLL, don't involve peripheal blood until late.
• Need nodal bx for diagnosis.*

Principal Classification For all Lymphomas

• Traditionally divide into
• Hodgkin lymphoma
• Non-Hodgkin lymphoma

Hodgkin Lymphoma/Disease

• Mores variable and pleomorphic
• Nodal cells are mostly normal
• Involves the so called "Reed-stern berg" all
• Unifocal in oribin
• One LN then methodcally spreads

Non- Hodgkin Lymphoma

• Uniformly composed
• Histologic appearance bears on the prognosis of the disease

Lab Finding - Hodgkin disease (not exhaustive)

• Peripheral blood
• increase in eosinophils and monocytes
• lymphocytopenia = poor prognosis
• increase in lymphos
• positive for plasma cells and red series cell
• N/N Anemla
• Bone marrow - negative unless stage 10- seldomly involved***

Hodgkin Disease (Clinical manifestations)

• Painless LN enlargement
• on the neck
• Mediastinal Mass (CXR)
• Further enlargement -> pain
  • "A" Is Asymptomatic
  • "B" are "B" symptoms (indicate poor prognosis - 3 things) Fever is over 100.4 Weight loss is over 10 percent Night sweats

Other Findings for Hodgkins

• High ESR
• high Hyperuricemia
• Elevated:
• -Copper**

Lymph Node Biopsy: Hodgkin Disease (Gold standard)

• REED-STERNBERG CELL
• 4-8x large the size of lymphcytes -- well demarcated
• Thick - Large eosiniphilic nucleoi distinct halo.
• CD15 and CD30 postive.
• Gold Standard for diagnosis!

RYE Classification for Hodgkin Disease

• Four Histologic Subgroup
• The poorer the lymphocyte the better the prognosis.
• • Two Best Forms**
• Nodular Type-Lymphocyte (AKA popcorn cells) -Sclerosis best form and better prognosis
  • Lymphocyte Depletion
• Divides 4 Histologic Groups
  • Younger and catching the patients earlier yield better prognosis

Ann Arbor staging system (Most Important)

• *Classifies both HD and Hodgkin Lymphoma according to a stage
• Stages - given additional suffux (A or B dependent on symptoms)
• Each Stage-May give e or s subscription E (Extra lypmatic diese) S = Spleen. I Single Lymph node region II Two or more areas on the same diagram III Lymph nodes above a single area and abdomen IV Diffuse involvement of one + or more lymph nodes

N staging and 1/X

• Surgical biopsy - Gold Standard
• Routine lab tests: Platelets, ESR Alk phos, Lfts, Ca, BUN, Creatinine, (Chest Xray)- PA - Biopsy of Illeac Crests, CT Scans.

Non Hodgkin Lymphoma (NHL)

• Types divided to
• Leukemic and Aleukemic
• Studied extensively by Virchow and Galo
• Can tell by size in the filtrates - 1982
• Low intermediate high

Low Grade

The Following Criteria:

• Affeccts patients with low grade.
• Slow growing Lymphonas (LN) are often present.
• Seen at End Stage
• Peripheral blood is un affected.
• Progenosis is 9-14 years
• BM involvement-

Intermediate Grade- NHL

• BM is less affected.
• Like low grade
• Survival 1/2-3 years Extranodal disease, or LN

High Grade

• More rapid lymph node enlargement
• Faster growing malignancies
• Lymphoblastic Lymphoma
• Involves Men in their twenties, and T-cells
• Mediastil mass, and BM

Diagnostic Evaluation

• Histologic (LN) Patterns and the type of cells Small-
• Small Round

Small Cleaved Cels (diagnostic evaluation of LN BIOPSY)

• Same size slightly larger than lymphocyte
• Cytoplasm scanty and some can cause an invasion
• nucleous is densely coarse with prominar clefting.

Non - cleaved B large cells

• B cells 23x size greater than lymphoctye, with chromatin
• Nucleoi is red and large.

Immunoblastic Cells

• 4-5 x the size of normal
• Large red nucleoi, with abundant cytoplasm

Mycosis Fungoides (diagnostic test)

• Skin disorders where lymphocytes are involved Rare, and the main symptom is severe Itchiness"
• Well demarcated reddened plaques, Thickening and desquamation.

Lab Abnormalities for Mycosis fungoids vs Sezary Syndrome

• CD-4 cell with monoclonal or polyclonal increase in globulins.
• Skin Biopsies -Sezary lymph node- (lymphocytes large and contain multi-fold nuclei)
  • Sezary=poorer prognosis compared to Mycosis Fungoide