Lymphocytic Leukemias PDF

Lymphocytic Leukemias MDLS 4226/5226 Hematology II OBJECTIVES: • In accordance with MLS student guidelines, at the completion of this lecture the student is expected to use the information gained to correctly: • Examine ALL, including its clinical manifestations and laboratory findings. • Appraise...

Lymphocytic Leukemias MDLS 4226/5226 Hematology II OBJECTIVES: • In accordance with MLS student guidelines, at the completion of this lecture the student is expected to use the information gained to correctly: • Examine ALL, including its clinical manifestations and laboratory findings. • Appraise the current diagnostic criteria for laboratory evaluation and current treatment of ALL including FAB subtypes. • List the characteristic peripheral blood findings for ALL. • Evaluate findings from an immunologic workup to formulate an immunophenotypic classification for ALL. • Assess the different types of cellular stains in terms of methodology, components, reactions, and diagnostic implications. • Assess the clinical features of chronic lymphocytic leukemia, including its etiology and incidence. • Appraise the current diagnostic criteria for clinical and laboratory evaluation of CLL. OBJECTIVES: • Examine current treatment methodologies for CLL. • Justify criteria for the differential identification of CLL. • Assess the peripheral blood and bone marrow findings of the following chronic leukemias: CLL, prolymphocytic leukemia (PLL) and hairy cell leukemia (HCL). • Predict the identification of cells and corresponding clinical disorders presented in this lecture, using patient history and/or clinical laboratory results. Acute Leukemia • Occurs when massive proliferation of blast cells overwhelm the bone marrow and begin filtrating into the peripheral blood • Cause unknown in most cases, but can be linked to genetics along with drug and environmental causes • Currently believed to rise from multiple genetic mutations influencing the stem cells General ALL Clinical Findings • Normo- normo- anemia, neutropenia, & thrombocytopenia due to bone marrow overcrowding. • Many lymphoblasts observed in majority of patients, but not all! – variable morphologic presentation, depending upon subtype. • Also increased #s smudge cells! ( > 12 / 100 WBCs) • Account for 75% of childhood leukemias • Peak incidence between 2-5 years of age • Rare in adults and have a poor prognosis • Splenomegaly and hepatomegaly possible • Bone pain from infiltration • Lymphoblasts can be observed in CSF • Prognosis has drastically improved but depends upon age, tumor burden, immunophenotype, and genetic mutation ALL Clinical Findings • ALL can be classified as B-ALL or T-ALL Morphology of Lymphoblasts • Lymphoblasts vary in size • Small size is most common with distinct nucleoli • Large type is 2-3 times larger than lymphocyte with distinct nucleoli. • May be confused with myeloblasts Small Lymphoblasts Peripheral Blood Tutor CD-ROM Large Lymphoblasts Immunophenotyping of ALL ALL Subtype Immunophenotype Early (pro/pre-pre) B-ALL CD34, CD 19, cytoplasmic CD22 (cCD22), TdT Intermediate (common)B-ALL CD34, CD19, CD10*, cCD22, TdT Pre-B-ALL CD19, cCD22, TdT (variable) Mature B-ALL CD 19, surface CD22 (sCD22) T-ALL CD2, CD3, CD4, CD5, CD7, CD8, TdT Mature B-ALL – movement of cytoplasmic CD22 to Surface (sCD 22) *CD10 – CALLA (most common) Genetic Findings • Majority of T-ALL have mutations involving the NOTCH1 gene, which alters T cell development. • B-ALL with the t(9;22); BCR-ABL1 mutation (Philadelphia chromosome-positive ALL) has the worst prognosis. • B-ALL with t(12;21);ETV6-RINX1 translocation has an excellent prognosis in children. • Hyperdiploidy is common in B-ALLs with good prognosis in children, bad for adults • Hypodiploidy is rare with bad prognosis in both adults and children T-cell ALL • Poor prognosis. • More common in adult & late teen males. • Frequently seen with mediastinal mass (thymomegaly) in teenaged boys. • Treated with very aggressive chemo. • Pos. for T cell markers: CD2, CD4, CD5, & CD8. • Pos. for acid phosphatase. Treatment options for ALLs • Chemotherapy administered directly into CSF • Methotrexate, vincristine, daunorubicin • Monoclonal antibodies (anti-CD20) are assuming a role in lead therapy • Imatinib, used to treat chronic leukemias • BMT or SCT last line of treatment (but can be curative in some pt. populations) Three Chronic Lymphoproliferative Leukemias • 1. Chronic Lymphocytic Leukemia (CLL) • 2. Prolymphocytic Leukemia (PLL) • 3. Hairy Cell Leukemia (HCL) CLL/SLL Clinical Symptoms: • Onset = insidious, asymptomatic. • Typically, diagnosis made during exam for other problems (fatigue, weight loss, lymphadenopathy, &/or splenomegaly)! • Rarely transforms into acute form. • Even with therapy, median survival 10 yrs. • More common in older pts. & males. • This is THE most common leukemia occurring in elderly patients. CLL/SLL Lab Findings: • Many smudge cells in peripheral blood due to marked cytoplasmic fragility (also seen in ALLs.) • Report smudge cells as # per 100 WBCs diffed • To ↓ # smudge cells & make diff easier, add 2 drops 7% B.B. albumin to 0.5 mL whole anticoagulated blood before making smear (always make a note of this!) • Bone marrow PAS + (for what substance ? _________.) • 95% cases are B-cell; CD 5, 19, 20, & 23 + • 5% cases are T-cell; CD 2, 4, 5, 6, 8 + glycogen Hypermature CLL with “Soccerball” Chromatin Shauna Anderson’s Atlas of Hematology CD-ROM CLL Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) • Most common leukemia/lymphoma in Western Hemisphere. • Malignant, monoclonal proliferation of small lymphoid cells • Mature-looking, but functionally immature, B cells. • Cells are so immature, they don't respond to Ag. • CD5, CD19, CD20, CD23, IgM and IgD+ B-cells CLL/SLL Lab Findings: • Diagnosis based on Monoclonal B-lymphs > 5,000/uL (normal range for ALC in adults = 1,000-4,000/uL.) • SLL involves lymph nodes and organ infiltration • Lymphs usually appear mature & mostly normal • Rarely, look immature & abnormal. • Course chromatin and scant cytoplasm • Appear “hypermature” (some have “soccer-ball appearance”!) CLL Treatment: • Prognosis based upon genetic mutations • Chemotherapy & leukopheresis (to reduce peripheral blood “burden”). • Due to indolent course, use the so-called "watchful waiting” approach. • BMT as last resort. Prolymphocytic Leukemia (PLL) • Rare, mature lymphoid leukemia (both B- and T-cell involvement) • Lymph node involvement is mostly seen with T-cell PLL • Diagnosis requires >55% prolymphocytes • Immature-looking, but functionally intermediate maturity, prolymphocyte B cells in peripheral blood • Large pros, moderately coarse chromatin, 1-2 large nucleoli, agranular & lightly basophilic cytoplasm. • “punched out” nucleolus is characteristic finding • Most common in men in their 60’s. • Very poor prognosis, mean survival ~ 3 years w/ B-cell Prolymphocytic Leukemia (PLL) • Lab Findings: • Absolute lymphocytosis in peripheral blood • ALC = 25,000 - 1,000,000/uL! • Cells will look more mature than lymphoblasts, but yet more immature than a regular “resting lymph”. • CD20, CD19, CD22, and FMC7 • Clinical Symptoms: • Acute onset of common symptoms • Also gross splenomegaly with sweats, & fevers, & weight loss • Presence of sweats & fevers make it important to rule out HIV! Prolymphocytes in PLL (courtesy Keila Poulsen) PLL Hairy Cell Leukemia (HCL) • Malignant, monoclonal proliferation • Atypical-looking, but functionally intermediate to fully mature, B-cells in with “hairy” cytoplasmic projections • Cells usually found in bone marrow or spleen, sometimes found in peripheral blood, rare in lymph nodes • Large lymphs with big nuclei (round, oval, or indented), pale blue cytoplasm with unique, hair-like surface projections • Rare; accounts for only 2% of all leukemias. • More common in middle-aged men. Hairy Cell Leukemia (HCL) • Lab Findings: • Characteristic pancytopenia & “dry tap” on bone marrow aspiration. • Cells contain unusual isoenzyme of acid phosphatase that is not inhibited by tartaric acid: Tartrate-Resistant Acid Phosphatase, or TRAP, thus . . . • Hairy cells are TRAP + • Other lymphoid cells are TRAP neg. • (PAS, SBB, & MPO neg.) • Positive for CD19, CD20, CD22, CD25, and CD103 Hairy Cell Leukemia (HCL) • Clinical Symptoms: • Malaise & fatigue • Hugely enlarged spleen (in 90% patients). • Treatment: . • Considered completely incurable in the past • Now, however, it’s relatively easy to control with chemo. & splenectomy • Good remission rates possible. HCL Hairy Cells in HCL (courtesy Keila Poulsen) TRAP Positivity in HCL (Compare to TRAP pos. cell in Rodak Atlas, p. 200) Shauna Anderson’s Atlas of Hematology CD-ROM HCL