DISEASES OF WHITE BLOOD CELLS DISEASES OF WHITE BLOOD CELLS Premed 3 Premed 3 Dr Roopa Dr Roopa

What Is Leukemia? Cancer of the white blood cells Cancer of the white blood cells Acute or Chronic Acute or Chronic Affects ability to produce normal blood cells Affects ability to produce normal blood cells Bone marrow makes abnormally large number of immature white blood cells called blasts Bone marrow makes abnormally large number of immature white blood cells called blasts

History Means “white blood” in Greek Means “white blood” in Greek Discovered by Dr. Alfred Velpeau in France, 1827 Discovered by Dr. Alfred Velpeau in France, 1827 Named by pathologist Rudolf Virchow in Germany, 1845 Named by pathologist Rudolf Virchow in Germany, 1845

Leukemias ↑ leukocytes ↑ leukocytes Acute leukemias 1. Acute Lymphoblastic Leukemia (ALL) 2. Acute Myelogenous Leukemia (AML) Chronic leukemias 1.Chronic Lymphoblastic Leukemia (CLL) 2. Chronic Myelogenous Leukemia (CML)

Treatment may involve some combination of chemotherapy, radiation therapy, targeted therapy, and bone marrow transplant, in addition to supportive care and palliative care as needed. chemotherapyradiation therapytargeted therapybone marrow transplant supportive care palliative care

The success of treatment depends on the type of leukemia and the age of the person.

Acute Leukemias Blast predominate Blast predominate Child or elder Child or elder Short & drastic course Short & drastic course ALL – Lymphoblasts (pre-B or pre-T) ALL – Lymphoblasts (pre-B or pre-T) AML – Myeloblasts AML – Myeloblasts

Chronic Leukemias More mature cells More mature cells Middle age Middle age Longer & less devastating course Longer & less devastating course CLL – Lymphocytes CLL – Lymphocytes CML – Myeloid stem cells CML – Myeloid stem cells

Acute Leukemias accumulation of blasts in the marrow accumulation of blasts in the marrow

Acute Lymphoblastic Leukemia (ALL) Children Children Lymphoblasts (pre-B or pre-T) Lymphoblasts (pre-B or pre-T) Neoplastic transformation of the Neoplastic transformation of the lymphoid stem cells Progressive accumulation of Lymphoblasts in the bone marrow Progressive accumulation of Lymphoblasts in the bone marrow Suppression of normal hemopoiesis Suppression of normal hemopoiesis

ALL

Primarily a disease of childrenand old age Primarily a disease of childrenand old age B-cell subtype(80%) B-cell subtype(80%) T-cell subtype(20%) T-cell subtype(20%)

ALL - Pathogenesis Etiology unknownEtiology unknown Genetic predisposition (some)Genetic predisposition (some) Down syndrome Translocations (worse prognosis)Translocations (worse prognosis) t(4;11)t(12;21)t(9;22)

Signs &Symptoms Anemia Anemia Infection Infection Bleeding Bleeding Bone pain Bone pain Arthritis Arthritis Splenomegaly Splenomegaly Lymphadenopathy Lymphadenopathy CNS involvement CNS involvement

ALL Prognosis: Age 3-7, pre-B, L1 :Age 3-7, pre-B, L1 : > 90% - CR( 2/3 - cure ) Adults, mature B and T-ALL:Adults, mature B and T-ALL: Less favorable Therapy: Chemotherapy ( w/CNS prophylaxis ), supportive care, BMT

ACUTE MYELOGENOUS LEUKEMIA ( AML ) - Adults - Myeloblasts - monoblasts, eosinoblasts, megakarioblasts, proerythroblasts, basophiloblasts - Auer rods in the cytoplasm of the cells - Very rapidly progressive malignancy

AML

Auer rods in AML

AML - Pathogenesis Environmental factors: High-dose radiation exposure Myelotoxic agents (benzene, alkylating agents) Genetic abnormalities: Down syndrome, Immunodeficiency diseases

Differentiation from ALL may be made by microscopy – presence of Auer Rods. Differentiation from ALL may be made by microscopy – presence of Auer Rods. Clinical features based on Marrow failure –anemia, bleeding, DIC, infection… Marrow failure –anemia, bleeding, DIC, infection… Leukemic infiltration – bone pain, CNS signs, hepatosplenomegaly, lymphadenopathy… Leukemic infiltration – bone pain, CNS signs, hepatosplenomegaly, lymphadenopathy… Constitutional upset -- malaise, fever, weakness, polyarthritis. Constitutional upset -- malaise, fever, weakness, polyarthritis.

Course: Rapidly fatal if untreated (< 2 mo )Rapidly fatal if untreated (< 2 mo ) Median survival - 3 years after chem..Median survival - 3 years after chem.. Adverse prognostic factors:Adverse prognostic factors: Age > 60 t(9;21), Previous chemotherapy Leukocytosis > 100,000 /ul Therapy:Chemotherapy, supportive, BMT

***Remember this*** For Acute leukemias acute leukemias = too many blasts in the marrow acute leukemias = too many blasts in the marrow 2 broad categories: AML vs. ALL 2 broad categories: AML vs. ALL a hematologic urgency a hematologic urgency prognosis is poor in adults; but good in kids with ALL. prognosis is poor in adults; but good in kids with ALL.

CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) A monoclonal lymphoproliferative disorder characterized by lymphocytosis(>4000/cu.mm), lymphadenopathy and splenomegaly B - CLL > 95% T - CLL

CLL Most common adult leukemia inMost common adult leukemia in Western society (30% of all leukemias) Monoclonal proliferation of the small lymphocytes…Monoclonal proliferation of the small lymphocytes… Age > 40M:F / 2:1Age > 40M:F / 2:1

CLL PB and BM

CLL - Pathology Blood: LymphocytosisLymphocytosis ( > 10,000 u/L - diagnostic ) (+) Coombs test (20%)(+) Coombs test (20%) Hypogammaglobulinemia (50-70%)Hypogammaglobulinemia (50-70%) Anemia, thrombocytopenia, neutropeniaAnemia, thrombocytopenia, neutropenia Bone marrow: nodular / interstitial infiltratesnodular / interstitial infiltrates diffuse - obliteration of normal hemopoiesisdiffuse - obliteration of normal hemopoiesis Lymphadenopathy, Hepatosplenomegaly (50-60%)

CLL - Clinical course Initially: asymptomatic Advanced disease: bacterial infections, hemorrhagebacterial infections, hemorrhage Prognostic factors: extent of tumor burdenextent of tumor burden pattern of marrow infiltrationpattern of marrow infiltration chromosomal abnormalitieschromosomal abnormalities Median survival:~ 6 years

Smudge cells - CLL

CLL One more peripheral blood findings in CLL is Presence of Smudge cells One more peripheral blood findings in CLL is Presence of Smudge cells ( parachute cells). ( parachute cells). Along with increased number of normal appearing lymphocytes. Along with increased number of normal appearing lymphocytes.

8/12/ Chronic Myelogenous Leukemia (CML) Excessive development of mature neoplastic granulocytes in the bone marrow Excessive development of mature neoplastic granulocytes in the bone marrow Move into the peripheral blood in massive numbers Move into the peripheral blood in massive numbers Ultimately infiltrate the liver and spleen Ultimately infiltrate the liver and spleen

8/12/ Chronic Myelogenous Leukemia Philadelphia chromosome Philadelphia chromosome 9 and 22 translocation almost specific to CML 9 and 22 translocation almost specific to CML Produces BCR/c-abl fusion oncogene Produces BCR/c-abl fusion oncogene The chromosome abnormality that causes chronic myeloid leukemia (CML) (9 &22) The chromosome abnormality that causes chronic myeloid leukemia (CML) (9 &22)chromosome chronicmyeloidleukemiachromosome chronicmyeloidleukemia Genetic marker Genetic marker Chronic, stable phase followed by acute, aggressive (blastic) phase Chronic, stable phase followed by acute, aggressive (blastic) phase

i.e – mainly uncontrolled proliferation of myeloid cells. i.e – mainly uncontrolled proliferation of myeloid cells. Males more than females Males more than females Splenomegaly – sometimes massive.. Splenomegaly – sometimes massive..

**Philadelphia chromosome** Hybrid chromosome with translocation between the long arm of chr. 9 and long arm of chr t(9:22). Hybrid chromosome with translocation between the long arm of chr. 9 and long arm of chr t(9:22). May be present in granulocyte, RBC or platelet precursors in more than 95% of CML.. May be present in granulocyte, RBC or platelet precursors in more than 95% of CML..

CML - Pathology Bone marrow: Hypercellular / predominant granulocytic hyperplasia Hypercellular / predominant granulocytic hyperplasia Increased megakaryocytes (small forms) Increased megakaryocytes (small forms) Normal to decreased erythroid precursors Normal to decreased erythroid precursors Peripheral blood: Granulocytosis (>25,000/cmm), with immature cells, Granulocytosis (>25,000/cmm), with immature cells, Basophilia, eosinophilia, Basophilia, eosinophilia, Extramedullary hemopoiesis: Spleen, liver, lymph nodes

CML - Clinical Features % of all leukemias; age Symptoms: - non-specific - related to hypermetabolism (high cell turnover) - related to splenomegaly Course: - chronic phase (mean survival, 3-4y) - accelerated phase - blast crisis / myeloid or lymphoid (survival, < 1y) Therapy: chemotherapy; BMT

Hodgkin’s lymphoma a lymphoid neoplastic disorder of B cell origin a lymphoid neoplastic disorder of B cell origin A disease marked by chronic enlargement of the lymph nodes, often local at the onset and later generalized. A disease marked by chronic enlargement of the lymph nodes, often local at the onset and later generalized. characterized by the presence of Reed- Sternberg cells (or variants of RS cells) in the affected tissues characterized by the presence of Reed- Sternberg cells (or variants of RS cells) in the affected tissues Enlargement of the spleen and often of the liver is also present. Enlargement of the spleen and often of the liver is also present.

Reed-Sternberg cells Considered to be a malignant neoplasm of lymphoid cells of uncertain origin. Considered to be a malignant neoplasm of lymphoid cells of uncertain origin. Owl – Eye appearance Owl – Eye appearance These cells have mirror-image nuclei. These cells have mirror-image nuclei. Young adults and elderly Young adults and elderly

Signs & Symptoms Enlarged painless nodes – mostly neck & axilla Enlarged painless nodes – mostly neck & axilla Fever, wt.loss, pruritis & night sweats. Fever, wt.loss, pruritis & night sweats. Pel – Ebstein Fever – fever alternating with long periods (15-28days). Pel – Ebstein Fever – fever alternating with long periods (15-28days). Anemia Anemia Cachexia Cachexia Hepatosplenomegaly Hepatosplenomegaly

Hodgkin’s disease: Summary a lymphoid neoplasm of B cell origin a lymphoid neoplasm of B cell origin characterized histologically by Reed Sternberg cells (or variants) characterized histologically by Reed Sternberg cells (or variants) commonly presents with lymphadenopathy or mediastinal mass in young adults commonly presents with lymphadenopathy or mediastinal mass in young adults treatment modality depends on stage treatment modality depends on stage curable in most curable in most

Non Hodgkin's Lymphoma These include all lymphomas without Reed-Sternberg cells. These include all lymphomas without Reed-Sternberg cells. Most are B-cell proliferations Most are B-cell proliferations Extra nodal involvement is there.. Extra nodal involvement is there..

Signs & Symptoms Often symptomless Often symptomless Lymphadenopathy, wt.loss.. Lymphadenopathy, wt.loss.. Extra nodal spread – skin, bone, gut, CNS, lung.. Extra nodal spread – skin, bone, gut, CNS, lung.. Pancytopenia may be there Pancytopenia may be there Infections are very common. Infections are very common. Fatigue, unexplained fever, sweats Fatigue, unexplained fever, sweats Enlarged Tonsils and adenoids Enlarged Tonsils and adenoids

FOLLICULAR LYMPHOMA Follicular lymphoma’s – most common in US Follicular lymphoma’s – most common in US Derived from B lymphocytes Derived from B lymphocytes t (14:18) t (14:18) Affects middle age Affects middle age Not very aggressive – mean survival 7-10 yrs Not very aggressive – mean survival 7-10 yrs Rarely they may transform in to aggressive type of lymphomas Rarely they may transform in to aggressive type of lymphomas

Burkitt’s Lymphoma A Lymphoblastic lymphoma mainly in African children. A Lymphoblastic lymphoma mainly in African children. Mostly associated with EBV infection. Mostly associated with EBV infection. Involves facial bones ( Jaw), ovaries, and abdominal lymph nodes. Involves facial bones ( Jaw), ovaries, and abdominal lymph nodes. Undifferentiated stem cells with scattered pale macrophages containing nuclear debris. Undifferentiated stem cells with scattered pale macrophages containing nuclear debris. Isolated histiocytes on background of abnormal lymphoblasts (STARRY SKY APPERANCE) Isolated histiocytes on background of abnormal lymphoblasts (STARRY SKY APPERANCE) t (8:14) t (8:14) High incidence in AIDS pt’s High incidence in AIDS pt’s

Burkitts lymphoma