(cls 646) leukemias, lymphomas, & lipid storage disorders

also includes lymphoproliferative disorders

overview of leukemia

progressive, malignant disease of the hematopoietic system characterized by unregulated, clonal proliferation of the hematopoietic stem cells

• malignant cells usually replace normal marrow cells and eventually interfere with normal BM function

• cells may invade other organs; if patient is not treated. leukemic cells eventually cause death

• generally classified according to whether they are acute or chronic diseases, based on the aggressiveness of the illness

overview of acute leukemia

unregulated, immature, undifferentiated or minimally differentiated malignant cells with a gap in the normal maturation stages (i.e., "leukemic hiatus")

• aggressive; abrupt onset of symptoms (fever, hemorrhage, weakness)

• affects all ages

• WBC blasts constitute at least 20% of all nucleated marrow cells

• WBC counts may be elevated, normal, or low

• hallmark signs: anemia, neutropenia, and thrombocytopenia

• mild organomegaly (spleen, liver)

• death within months if treatment is not begun

overview of chronic leukemia

• less aggressive; insidious onset of symptoms (weakness, pallor, severely enlarged spleen & liver)

• dx often made during routine physical following investigation of nonspecific complaints

• adults usually affected

• WBC usually elevated; differential is similar in both the peripheral blood and marrow

• BM infiltrated by increased number of mature cells

• anemia often present, but platelets are normal or increased; thrombocytopenia rare until late in the disease

• all stages of maturation in granulocytic leukemia

• progresses slowly and death occurs years after diagnosis

general classification of acute/chronic leukemias

can each be further subgrouped according to the stem cell from which the abnormal clone of cells differentiated (see table)

• if cells were derived from the CFU-GEMM → myeloid leukemia

• if cells were derived from the CFU-lymphoid → lymphocytic leukemia

etiology/pathophysiology of leukemia

cause is not clear; factors thought to play a role in development of leukemia:

• radiation; drugs/chemicals (chloramphenicol, phenylbutazone, arsenic-containing compounds, sulfonamides, some insecticides)

• genetics; down’s syndrome; fanconis syndrome

• bloom syndrome (chr breakage/rearrangement)

• viruses

***abnormal clone arises from a somatic mutation of one HSC; as that cell proliferates it crowds out the normal cells in BM and begins to spill over into peripheral blood

acute myeloid leukemia (AML) presentation

• pallor, lethargy, fatigue, dyspnea, and weakness from anemia

• bleeding, bruising, and petechial hemorrhages, purpura, epistaxis, and gingival bleeding caused by thrombocytopenia

• infections fail to respond to treatment, fever related to infection caused by neutropenia

• organ infiltration: bone tenderness, splenomegaly, hepatomegaly lymphadenopathy, gum hypertrophy, skin infiltrates, meningeal syndrome (headache, nausea, vomiting)

AML lab findings (rbcs, plts, coag, wbc)

• RBCs

  • Normochromic, normocytic anemia

  • nRBC, aniso, poiks

• Platelets: decreased; hypogranular, giant

• Coagulation: defects may be present

• WBCs: Usually increased

  • Peripheral blood blasts: 15–95%

  • Auer rods may be present

  • Monocytosis; wariable eosino/basophilia

  • Neutropenia with dysplastic neutrophils

AML lab findings (BM, cytogenetics)

• Bone Marrow:

  • Hypercellular with dysplastic cells

  • Blasts >20%

• Cytogenetic abnormalities:

  • Approx 70% have clonal acquired chromosomal abnormalities that can be single, numerical or structural

  • Trisomy 8 common in AML but not diagnostic for a specific type

(characteristics of AML FAB classification) AML-M0

undifferentiated AML

• blasts: >30%

• cytogenetic abnormalities: variable structural and numeric aberrations

• cell markers: HLA-DR+, MPO+, CD13+, 33+

(characteristics of AML FAB classification) AML-M1

AML with minimal maturation

• blasts: >90%; myeloid <10%, monocytic <10%

• cytogenetic abnormalities: same as M0

• cell markers: HLA-DR+, MPO+, CD13+, 33+

(characteristics of AML FAB classification) AML-M2

AML with maturation

• blasts: 30-89%; myeloid >10%, monocytic <20%

• cytogenetic abnormalities: t(8:21)(q22;q22) in 15% of cases

• cell markers: CD19+

(characteristics of AML FAB classification) AML-M3

acute promyelocytic leukemia (APL)

• blasts: <30%; promyelos >50%

• cytogenetic abnormalities: t(15;17)(q22:q11.2) in >90% of cases

• cell markers: HLA-DR-, CD2+

(characteristics of AML FAB classification) AML-M4

acute myelomonocytic leukemia (AMML)

• blasts: >30%; myeloid/monocytic >20%;

  • AML-M4 eo = >5% eos

• cytogenetic abnormalities: abnormal 11q, variable aberrations

  • inv(16)(p32;q22)

  • t(16;16), del(16)(q22)

• cell markers: CD11c+, 14+, 2+

(characteristics of AML FAB classification) AML-M5

acute monocytic leukemia

• blasts

  • M5a >80% ; M5b <80%

• cytogenetic abnormalities:

  • t(9;11)(p22;q23)

  • abnormal 11q t(8:16)

• cell markers: CD11c+, 14+

(characteristics of AML FAB classification) AML-M6

acute erythroid leukemia

• blasts >30%; erythroid >50%

• cytogenetic abnormalities: n/a

• cell markers: glycophorin A+

(characteristics of AML FAB classification) AML-M7

acute megakaryocytic leukemia

• blasts: >30%

• cytogenetic abnormalities: none

• cell markers: CD41+, 61+

(staining patterns of AML) undifferentiated AML (M0)

• MPO/SB ; SE ; NSE -

• PAS +

(staining patterns of AML) AML w minimal maturation (M1)

• MPO/SB +

• SE ; NSE ; PAS -

(staining patterns of AML) AML with maturation (M2)

• MPO/SB ; SE +

• NSE -

• PAS -/diffuse

(staining patterns of AML) acute promyelocytic leukemia (APL; M3)

• MPO/SB ++ ; SE +

• NSE -

• PAS diffuse

(staining patterns of AML) acute myelomonocytic leukemia (M4)

• MPO/SB ; SE ; NSE +

• PAS diffuse

(staining patterns of AML) acute monocytic leukemia (M5)

• MPO/SB +/-

• SE -

• NSE +

• PAS diffuse

(staining patterns of AML) acute erythroid leukemia (M6)

• MPO/SB + (blasts)

• SE / NSE -

• PAS + (rbc precursors)

(staining patterns of AML) acute megakaryocytic leukemia (M7)

• MPO/SB ; SE -

• NSE + (megakaryoblasts)

• PAS +/-

WHO classification of AML

• Emphasizes cytogenetic and molecular features in classifying AML

• Reduced blast threshold from 30% → 20%

  • 20% = threshold that differentiates an acute leukemia from chronic and MDS

AML treatment/prognosis

• Chemotherapy—eradicate all the malignant cells in BM, allowing for repopulation with normal hematopoietic precursors

  • three groups of agents may be used (antimetabolites, alkylating agents, and antibiotics)

    • e.g., cytosine arabinoside, daunorubicin, amsacrine

• Radiotherapy—prevent or eradicate leukemic cells that have infiltrated the meninges

• BM transplant: Highest rate of success in younger (<30 yrs) pts

(acute leukemias) acute lymphoid leukemia (ALL) presentation

symptoms similar to that of AML

lab findings for ALL (wbcs, rbcs, plts)

• WBCs:

  • Increased, normal or decreased

  • Neutropenia ; Lymphoblasts

• RBCs: normochromic, normocytic anemia

• Platelets: thrombocytopenia

lab findings for ALL (BM, cytochemical stains)

• BM: Hypercellular >20% blasts, usually heavily infiltrated

• Cytochemical staining not always effective in determining the cell lineage of undifferentiated cells

  • several monoclonal antibodies have been identified to help determine the specific classification of ALL

useful markers for subclassification of ALL (chart)

distribution of ALL phenotypes

• 65% = Immature B cell

• 20% = Pre-B cell

• 1% = B cell

• 15% = T cell

treatment/pronosis of ALL

usually involves three phases: induction (putting the patient into remission), CNS prophylactic phase, maintenance chemotherapy

• Chemotherapy: Nearly all children and >90% of adults achieve remission in this manner

  • >80% of children who achieve remission and a 2–3-year regimen of maintenance therapy are thought to be cured ; adults have only 20–30% long-term survival rate

• Intrathecal chemotherapy and cranial irradiation: prevent or eradicate leukemic cells that have infiltrated the meninges of the brain

• BM transplant or stem cell transplant

• primary cause of death is infection due to the granulocytopenia; bleeding is the second most common complication

(chronic lymphoproliferative disorders) chronic lymphocytic leukemia (CLL) etiology/pathophysiology

malignant monoclonal proliferation and accumulation of lymphocytes

• generally B-cells (95%) and are immunologically incompetent cells

• primarily disease of the elderly with 90% of patients >50 years; 65% are >60 yrs

• occurs twice as often in men as in women

• In some rare cases the CLL is the result of T-cell proliferation (2–5% of cases)—more likely to have infiltration of epidermal sites and CNS

(chronic lymphoproliferative disorders) CLL presentation

• very insidious onset

• fatigue and reduced exercise tolerance → most frequent presenting symptoms

• dx often made when the patient presents for investigation of some other problem

• enlarged lymph nodes and splenomegaly are common; hepatomegaly develops as the condition progresses

• more advanced disease → marked fatigue, bruising, pallor or jaundice with anemia, fever, recurrent or persistent infection, bone tenderness, weight loss, and edema (from lymph node obstruction)

(chronic lymphoproliferative disorders) CLL lab findings

• Absolute lymphocyte count 10–150x10³/μL common ; can be as high as 1,000x10³/μL

• Lymphs appear to be morphologically normal—somewhat fragile and easily "smudge" when a blood smear is made

  • dense chromatin, nucleoli and agranular cytoplasm

• Autoimmune hemolysis may account for an anemia in 5–10% of patients and may be triggered by viral infections, disease progression, therapeutic agents, or membrane damage by abnormal proteins

• Plasma immunoglobulins may be decreased

• BM sample usually not required

(chronic lymphoproliferative disorders) immunological classification of CLL

lymphocytes in B-CLL appear as mature cells and as such are not identifiable using morphology criteria alone

• Markers Useful in Identifying B-CLL Cells:

  • Surface Immunoglobulin (sIg)

    • almost always express low amounts (one-tenth of normal B-cells)

    • sometimes demonstrate cIg

• CD5 (usually thought of as a T cell marker)

• CD19, 20, 22

(chronic lymphoproliferative disorders) differential dx for CLL

• Reactive lymphocytosis

• Hairy cell leukemia

• Sezary's syndrome

• T-cell CLL

• Prolymphocytic leukemia

• Well-differentiated diffuse lymphoma

• Poorly differentiated lymphoma

(chronic lymphoproliferative disorders) CLL treatment

• chemotherapy: eradicate malignant cells in BM, allowing for repopulation with normal hematopoietic precursors

  • ex: cyclophosphamide or chlorambucil is given singly or in combination with vincristine and prednisone

• Main risk with this treatment is myelosuppression of the bone marrow

• Radiotherapy: treat enlarged lymph nodes and splenomegaly resistant to chemotherapy; does not reduce the number of lymphocytes in the blood and marrow

• Leukapheresis: reduces number of lymphocytes in blood

(chronic lymphoproliferative disorders) CLL prognosis

• clinical course may range from extremely benign to severe with 10—15% of patients living 10–15 years with little or no treatment

• death may come within one year for those with a more aggressive form of the disease—median survival following diagnosis is 3–4 years

• CLL is not as likely to undergo a transformation to an acute form as are other leukemias

• leukemic cells may infiltrate other organs: skin, prostate, gonads, kidney, walls of the gastrointestinal tract

(chronic lymphoproliferative disorders) hairy cell luekemia (HCL) etiology/pathophysiology

distinct clinical entity characterized by pancytopenia, splenomegaly, and presence of a unique cell type ("hair cells") in peripheral blood and tissues and a dry tap bc of marrow fibrosis

• Relatively rare (2% of all leukemias)

• growth and accumulation of the hairy cells in the spleen, blood and marrow account for the complications the patients experience

• men more affected than women (4:1 to 5:1 male: female)

• Median age: 50 yrs—not seen in patients <20 years

(chronic lymphoproliferative disorders) hairy cell leukemia presentation

• indolent course in most patients

• Bleeding, weakness and fatigue, infection and abdominal discomfort

• Splenomegaly seen in 80% of patients

• Lymphadenopathy and hepatomegaly less frequently seen

(chronic lymphoproliferative disorders) hairy cell luekemia (HCL) lab findings

• hairy cells: in peripheral blood of >90% of patients

  • represent <50% of leukocyte differential count

  • Scant to abundant, agranular, light grayish-blue cytoplasm with hair-like or ruffled projections

• Pancytopenia: Granulocytopenia and monocytopenia; normochromic, normocytic anemia

• BM: dry tap due to fibrosis; increased reticulin (fibrosis

• Cytochemistry: TRAP staining (characteristic but not diagnostic) in hairy cells but negative in most other lymphocytes

(chronic lymphoproliferative disorders) immunological classification of HCL

• immunologically, the hairy cells are a mid- to late B-cell with sIg and cytoplasmic immunoglobulin

• useful markers for B-HCL Cells

  • Negative = CD5

  • Positive = CD19, 20, 22, 25, 103, 11c

(chronic lymphoproliferative disorders) hairy cell luekemia (HCL) treatment/prognosis

median survival is 5–7 years

malignant lymphoproliferative disorders (list)

• Hodgkin's Lymphoma

• Non-Hodgkin's Lymphoma

• Multiple Myeloma

• Plasma Cell Leukemia

• Waldenstrom's Macroglobulinemia

(malignant lymphoproliferative disorders) hodgkin’s lymphoma etiology/pathophysiology

• Uncertain cause

• infectious cofactor appears to be operational in the pathogenesis of the disease; probable agent is EBV; CMV & herpesvirus 6 have been implicated

• Incidence:

  • May occur at any age

  • Bimodal distribution: 20–30 yrs then, in patients >50 yrs

  • Most common malignancy of young adults in US and Europe

  • Accounts for 1/3 of newly diagnosed lymphomas in US

(malignant lymphoproliferative disorders) hodgkin’s lymphoma presentation

• Adenopathy and no symptoms, or fever, night sweats, weight loss, malaise

• Unusual complaints → pain in enlarged nodes after alcohol consumption

• Lymph node involvement:

  • Most frequent sites are cervical and supraclavicular lymph nodes

  • Later spreading to contiguous nodal regions, spleen, liver, and BM

• Subclassified into 4 types based on histopathology of involved lymph nodes

(malignant lymphoproliferative disorders) hodgkin’s lymphoma lab findings

• Cytologic hallmark is Reed-Sternberg cell (RS)

• Data favors a lymphocyte origin of RS cell–either B/T-cell

• Dx based upon finding RS cells in the proper cellular, stromal, and clinical setting

• RS-like cells commonly seen in a variety of benign & malignant conditions other than Hodgkin's Disease

• Viral infection (ex: mono); anticonvulsant-induced lymphadenopathy; epithelial & stromal malignancies; melanoma; various lymphomas & leukemias; myeloproliferative disorders

(malignant lymphoproliferative disorders) hodgkin’s lymphoma clinical stages (4)

• Stage I: Tumor in 1 anatomic region or 2 contiguous anatomic regions on same side of diaphragm

• Stage II: Tumor in >2 anatomic regions or 2 noncontiguous regions on same side of diaphragm

• Stage III: Tumor on both sides of diaphragm not extending beyond lymph nodes, spleen, or Waldeyer's ring (includes the palatine, pharyngeal and lingual tonsils that encircle the pharynx)

• Stage IV: Tumor in BM, lung, etc. (any organ site outside of the lymph nodes, spleen, or Waldeyer's ring)

(malignant lymphoproliferative disorders) non-hodgkin’s lymphoma (NHL) etiology/pathophysiology

• Environmental (chemicals, and ionizing radiation, & certain viruses) and inherited genetic abnormalities may participate in the production of irreversible chromosomal alterations that underlie NHL

• Incidence: Freq is age dependent (more common in adults than children); variable worldwide distribution; more common in males than females

(malignant lymphoproliferative disorders) non-hodgkin’s lymphoma (NHL) presentation

• Can be grouped morphologically into small, intermediate, or large size cells with diffuse or follicular (nodular) pattern of growth

• functionally into B-cell, T-cell, and U-cell (undifferentiated cell) disorders

• Clinical setting varies with the type of lymphoma

• Prognosis generally worsens with increasing cell size and mitotic activity

(malignant lymphoproliferative disorders) non-hodgkin’s lymphoma (NHL) lab findings

• Demonstration of surface and/or intracytoplasmic markers of lymphocytes extremely valuable in the classification

• Marker studies can determine the T- or B-cell nature of the cells—utilize flow cytometry and immunoperoxidase techniques

(malignant lymphoproliferative disorders) multiple myeloma etiology/pathophysiology

• Uncontrolled proliferation of malignant plasma cells in BM

• Incidence: Most common form of plasma cell neoplasm

• Males have 50% greater risk than females

• Black individuals have 2x incidence than white individuals

• Risk increases with age

• Environmental factors play clear role for instance, atomic bomb survivors & individuals exposed to radiation have increased risk

(malignant lymphoproliferative disorders) multiple myeloma presentation

• Multiple osteolytic bone lesions

• Tumors develop in hemopoietically active marrow, erode adjacent bone, and may compress the spinal cord or nerve roots emerging from the spinal canal

• Skeletal disease seen in 70% at diagnosis

• Imbalanced immunoglobulin production most frequently yields an excess of light chains that are excreted into urine

(malignant lymphoproliferative disorders) multiple myeloma lab findings

• Monoclonal gammopathy – Incidence: IgG>IgA>IgM>IgD>IgE

• Generalized hypogammaglobulinemia with Bence Jones proteinuria

• Peripheral blood: Rouleaux, increased ESR

• Bone marrow: Varying number of mature and immature plasma cells

  • Cells are frequently enlarged with less chromatin clumping than seen in benign plasma cells

  • Multinucleated cells seen

(malignant lymphoproliferative disorders) plasma cell leukemia

when plasma cells predominate among the circulating leukocytes it is known as leukemia instead of multiple myeloma

• protein abnormalities similar to classic myeloma

• clinical course is generally acute or sub-acute

• No response to chemotherapy observed

(malignant lymphoproliferative disorders) waldenstrom’s macroglobulinemia

plasma cell dyscrasia that secretes monoclonal IgM

• differs from multiple myeloma instead of osteolytic bone lesions there is soft tissue involvement

lipid storage diseases (general)

hereditary conditions in which the macrophages are unable to completely digest phagocytosed material due to a deficiency of lysosomal enzymes needed for the degradation process—undigested substance accumulates in the cell; includes:

• Gaucher & Niemann-Pick Disease

• Sea-blue Histiocytosis Syndrome

• Tay-Sachs & Sandhoff Disease

• Fabry & Wolman's Disease

(lipid storage diseases) gaucher disease etiology/pathophysiology

• Deficiency of B-glucocerebrosidase

• Macrophage unable to digest stroma of ingested cells & glucocerebroside accumulates in cell

• Incidence: autosomal recessive; predominantly in Jewish populations, esp Ashkenazic Jews

(lipid storage diseases) gaucher disease presentation

• Related to accumulation of the lipid in macrophages of lymphoid tissue, spleen, liver, and BM

• Hepatosplenomegaly

• Neurological problems

• Pigmentation of skin (ocher to brown with a yellow or leaden hue); prominent in exposed parts of the body (face, neck, hands, legs)

• Skeletal lesions secondary to marrow involvement; bone pain

(lipid storage diseases) type 1 gaucher disease

adult, chronic non-neurotologic

• Most common of the lipidoses

• Most frequently inherited disorder in Ashkenazi Jewish population

• Average age of onset is between 30–40 yrs; best prognosis

(lipid storage diseases) type 2 gaucher disease

infantile, acute or malignant neuronopathic type

• Very rare; seen in all ethnic groups; uncommon in Jewish population

• Familial intermarriage is frequent in infant's family history

• hallmark is neurologic involvement

• Death usually occurs before age of 2 yrs

(lipid storage diseases) type 3 gaucher disease

juvenile type; subacute neuronopathic

• Onset of symptoms between early childhood to teenage years

• Clinical & physical findings and survivals range between those of Type I and II

• Noted especially in group of children from northern Sweden (offspring of several related intermarriages)

(lipid storage diseases) gaucher disease lab findings

• Peripheral blood: (result from cellular sequestration by an enlarged spleen)

  • Anemia: Normochromic/normocytic

  • Retics: Normal to modest increase

  • WBC: Mild leukopenia

  • Gaucher cells

• Platelets: Slight to marked decrease

• Serum acid phosphatase: Increased

• Mild extravascular hemolysis

(gaucher-disease) guacher cells

• Found in spleen, marrow, liver, lymph nodes; seen most easily in thickest part of the smear

• Cytoplasm appears wrinkled liked crumpled tissue paper

• BM exam alone insufficient for confirming diagnosis since the cells may be present in other disorders

• Cytochemistry: PAS, Oil Red O, Iron, and Sudan Black B are positive; Acid Phosphatase is very positive (tartrate-resistant fraction is what is increased)

psuedo-gaucher cells

found in patients with high cell turnover where the breakdown products cannot be
catalyzed fast enough

• Described in AML, CML, plasma cell myeloma, aplastic anemia, ITP, thalassemia major,
  and RA

• In each of these diseases there is no deficiency of the b-glucocerebrosidase, as there is in Gaucher disease, but rather an over taxation of a normal system

(lipid storage diseases) gaucher disease treatment/prognosis

enzyme replacement therapy has successfully reversed many of the clinical complications of Type I disorder, including correcting blood counts & reducing organomegaly

(lipid storage diseases) niemann-pick disease etiology/pathophysiology

• Deficiency of sphingomyelinase

• Secondary accumulation of unmetabolized lipid sphingomyelin as well as cholesterol

• Incidence: rare autosomal recessive; more commonly seen in Ashkenazic Jewish population

• 5 types (A - E) based on clinical manifestations

(lipid storage diseases) niemann-pick disease lab findings

leukopenia and thrombocytopenia may occur

(lipid storage diseases) niemann-pick disease treatment/prognosis

no treatment ; successful allogeneic BM transplants have been reported for type B