Anaemia 20.04.2012.

Anaemia

SYMPTOMS AND SIGNS OF ANAEMIA
Lassitude Fatigue Breathlessness on exertion Palpitations Throbbing in head and ears Dizziness Tinnitus Headache Dimness of vision Insomnia Paraesthesia in fingers and toes Angina Signs Pallor of Skin Mucous membranes Palms of hands Conjunctivae Tachycardia Cardiac dilatation Systolic flow murmurs Oedema

Specific features of different types of anaemia
Cause of anaemia Specific clinical findings Iron deficiency Megaloblastic anaemia B12 deficiency Haemolytic anaemias Sickle cell disease Thalassaemia Malignancies Leukaemia/lymphoma Myeloma Metastatic cancer Angular stomatitis, painless glossitis, dysphagia due to pharyngeal web (Plummer-Vinson syndrome), koilonychia (spoon shaped nails) Painful glossitis (‘beefy’ red tongue) Peripheral neuropathy, subacute combined degeneration of the cord (damage to corticospinal tracts and dorsal columns) Jaundice, gallstones, splenomegaly, skin ulceration Bone tenderness, osteomyelitis ‘chipmunk face’, poor growth Lymphadenopathy, hepatosplenomegaly, skin nodules, gum hypertrophy, meningism Bone pain and fractures Bone pain and signs of primary malignancy

Initial investigations of anaemia
Full blood count Examination of the blood film Serum ferritin, transferrin Serum B12 Red cell folate Haemolysis screen (if indicated): reticulocyte count, biliburin, lactate dehydrogenase, haptoglobins

Second line investigations of anaemia
Cause of anaemia Appropriate investigations Iron deficiency Low serum B12 Low red cell folate Evidence of haemolysis Oesophagogastroduodenenoscopy (OGD), colonoscopy, gynaecological examination, celiac antibodies Gastric parietal cell antibodies, Schilling test Celiac antibodies and/or duodenal biopsy – if small bowel malabsorption, refer to gastroenterologist Direct Coomb’s tests (DCT) – if DCT Neg: G6PD screen, refer to haematologist

Third line investigations of anaemia
Type of anaemia Investigations Microcytic Normocytic Macrocytic Haemoglobin electrophoresis; search for evidence of underlying infection, inflammatory or neoplastic disorder (blood cultures, ESR, C-reactive protein, ANA,CXR, etc.) Renal function; haemolysis screen (if not already preformed): immunoglobulins and paraprotein screen; search for evidence of underlying infection, inflammatory or neoplastic disorder (see above) Thyroid function tests; liver function tests; haemolysis screen (if not already performed)

The microcytic anaemias (MCV < 80 fl)
Impaired haem synthesis Impaired globin synthesis Iron deficiency Anemia of chronic disease Sideroblastic anaemia Lead poisoning Thalassaemia

Normal iron transport pathways

Laboratory tests to diagnose iron deficiency

The macrocytic anaemias (MCV > 100 fl)
Megaloblastic anaemia (B12 and folate deficiency) Hypothyroidism Liver disease Alcohol Myelodysplasia Anaemias with extreme reticulocytosis

Diagnostic features of a megaloblastic anemia
Investigation Haeglobin Mean cell volume Erythrocyte count Blood film Reticulocyte count Leucocyte count Platelet count Bone marrow Result Often redused, may be very low Usually raised, commanly > 120fl Low for degree of anaemia Oval macrocytosis, poikilocytosis, red cell fragmentation, neutrophil hypersegmentation Low for degree of ananemia Low, normal or redused Increased cellularity, megaloblastic changes in erythroid series, giant metamyelocytes, increased iron in stores, pathological non-ring sideroblasts

Diagnostic features of Addisonian pernicious ananemia
Diagnostic findings Very low serum vitamin B12, often less than 50ng/l Anti-intrinsic factor antibodies in serum (present in 50%) Corroborative findings Macrocytic dysplastic blood picture Megaloblastic marrow Abnormal vitamin B12 absorption test corrected by addition of intrinsic factor (Schilling test)

Hematoligical response to treatment with cobalamin

The normocytic anaemias (MC 80 – 100 fl)
With increased reticulocytes With decreased reticulocytes Bleeding Haemolysis Aplastic anaemia Pure red cell aplasia Anaemia of chronic renal failure Anaemia of chronic disease Myelodysplasia Haematological malignancies Bone narrow metastases

MAIN INDICATIONS FOR BONE MARROW EXAMINATION
Marrow disorders Leukaemias Lymphomas Secondary carcinoma Myeloproliferative disorders Cytopenia(s) Neutropenia Thrombocytopenia Anemia - complex cases or aplasia

Leukemia: history A case of leukaemia was first clearly described in 1845 by John Hughes Bennett and another, 6 weeks later, by Rudolf Virchow These were phenotypic diagnoses at autopsy, the blood being examined microscopically A few years later Virchow was the first to use the term “Leukhemia”

Classification of leukemias
Acute Chronic Myeloid origin Acute Myeloid Leukemia (AML) Chronic Myeloid Leukemia (CML) Lymphoid origin Acute Lymphoblastic Leukemia (ALL) Chronic Lymphocytic Leukemia (CLL)

Leukemia development The development of Leukemia
uncontrolled and accelerated production of progenitors which results in incomplete or defective cell maturation Acute leukemia- rapid proliferation of primitive, undifferentiated stem cells Chronic leukemia- differentiated defective cells

ALL AML Hematopoietic stem cell Neutrophils Eosinophils Basophils
Monocytes Platelets Red cells Myeloid progenitor Lymphoid B-lymphocytes T-lymphocytes Plasma cells germinal center naïve AML

Development of leukemia in the bloodstream
Stage 1- Normal Stage 2- Symptoms Stage 3- Diagnosis Stage 5a- Anemia Stage 5b- Infection Stage 4- Worsening Legend White Cell Red Cell Platelet Blast Germ Sources from Leukemia, by D. Newton and D. Siegel

Causes High level radiation/toxin exposure Viruses Genes Chemicals
Mostly unknown Can’t be caught

Adult acute leukemia usually fatal within weeks to months without
a hematologic urgency usually fatal within weeks to months without chemotherapy with treatment, high mortality due to disease or treatment-related complications (unlike childhood acute leukemia) notify Hematologist promptly if acute leukemia is suspected

Clinical manifestations
marrow failure tissue infiltration leukostasis constitutional symptoms neutropenia (infections, sepsis) anemia (fatigue, pallor) trombocytopenia (bleeding) enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, etc Accumulation of blasts in microcirculation with impaired perfusion Lungs: hupoxemia, pulmonary infiltrates CNS: stroke only seen with WBC >50 x 109/L fever and sweats weight loss

Investigations Complete blood count (CBC):
60% of pts have an elevated WBC. Most are anemic Most are thrombocytopenic 90%have blast in the periphral blood film Electrolytes: Hypo/hyper kalemia Hypomagnesimia Hyperphosphatemia Hypermetabolism: LDH. uric acid Disseminated intravascular coagulation (DIC): Most common with promyelocytic leukemia,small% monocytic leukemia&ALL Bone marrow biopsy and aspirate: 20%or more of all nucleated cells are blast Radiology: CXR:mediastinal mass(T-cell ALL) Osteopenia or lytic lesion 50% of patients with ALL.(itractable pain).

Acute Leukemia Detection and Diagnosis
if 30% blast cells are present, acute leukemia is confirmed a differential diagnosis is made from a staining procedure Immunophenotyping as in ALL establishes diagnosis in 90% of cases

Acute Leukemia Classification/Subtypes:
French-American-British Classification (FAB) based on morphology and cytochemistry World Health Organization Classification based on molecular, morphologic, and clinical features

ALL-Acute Lymphocytic Leukemia-Epidemiology
5/100,000 people affected ALL is the most common pediatric cancer 80% of children with acute leukemia have ALL ALL most commonly a childhood disease Peak incidence between ages 2 and 6 yr old More common in males, whites compared to blacks, and Jews compared to non-Jews

ALL- Acute Lymphocytic Leukemia Prognosis
Complete remission – more then 75%, duration and therefore “cure” are related to a number of factors: age in children < 2 and > 10 poor prognosis, < 1 yr old worst prognosis adult > 50 yrs old very poor prognosis WBC (leukocyte) initial WBC count of < 10,000/mm3 is more favorable than a count of 20,000 to 49,000 a count > 50,000/mm3 is least favorable

L1 - 85% of childhood ALL L2 - Majority of adult ALL L3 - Includes Burkitt’s. < 5% of ALL

ALL-Acute Lymphocytic Leukemia
Staging/classification 25% of patients with ALL are categorized by T-cell, B-cell, or preB-cell markers 70% are classified with null-cell type this null-cell type reacts to antibody to antigen CALLA (common leukemia-associated antigen)

AML-Acute Myelogenous Leukemia
Epidemiology incidence is 5 times greater than ALL Occurs equally at all ages, slightly more common >50 80% of adult leukemia is AML slightly more common in males Etiology Same as for ALL- prior exposure to radiation, benzene, alkylating agents, Fanconi’s anemia, Bloom syndrome (genetic chromosome disorders)

Prognosis Children w/AML have poorer prognosis than w/ALL WBC < 20,000, mm is more favorable the 20-49,000 mm, > 50 worst prognosis Age, tumor burden at time of diagnosis, drug sensitivity of cells are more important prognostic indicators than cell morphology

Clinical Presentation abrupt onset (1-6 month prodromal period) Similar symptoms to ALL-fatigue, flulike, bleeding, petechiae, purpura (hemorrhage under skin), gingival bleeding, GI bleeding, urinary tract bleeding due to decreased platelet count increased susceptibility to infections due to neutropenia Enlarged spleen may be felt

Physical Findings: Fever Splenomegaly Sternal tenderness Multiple bruises Bleeding (gingivae most common) Unexplained infections GI bleed Pulmonary, intracranial, and retinal hemorrhage

Laboratory and Radiographic Work-up: CBC with manual differential Uric Acid level Clotting studies (PT, PTT, D-dimer, fibrinogen) Bone marrow aspirate and biopsy Chest xray Echocardiogram

Acute Leukemia Treatment principles Staging of therapy
Immediate start of treatment after proven diagnosis Principle of oncologic radicalism Strict maintenance of selected chemotherapy scheme Staging of therapy Induction (achievement) of remission Consolidation of remission Supporting therapy

Chronic leukemia Essentials: Most are asymptomatic at presentation
Strikingly elevated WBC Marked left-shift Splenomegaly typical Lymphocytosis

CLL-Chronic Lymphocytic Leukemia
CLL most common leukemia it accounts for 30% of leukemias CLL is 2 X as common as CML incidence increases with age, 65 avg, rare in people under 35 males more common- 2X compared to women equal blacks/whites

Etiology heredity- 3x increased risk if 1st relative has CLL Most notable familial clustering of all leukemias Immunodeficiency syndromes and viruses no conclusive link with radiation exposure or retroviruses Prognostic Indicators stage at time of diagnosis age doubling time of peripheral blood lymphocyte count pattern of bone marrow involvement T-cell variety poorer prognosis

Clinical presentation incidental findings on blood tests lymphocyte counts > 10,000/ mm often asymptomatic night sweats, fatigue, fever, weight loss Lymphadenopathy(?) may be present, spleen almost always enlarged uncomfortable neck masses are common at later stages

Laboratory and Radiographic Work-up: CBC with manual differential Peripheral smear Flow cytometry Chemistry studies to check for organ dysfunction Lymph node biopsy

Hematological Findings: Increased number of lymphocytes on smear smudge cells B-cells with CD 19 and CD 5 on flow cytometry Small lymphocitic lymphoma present in histology of nodal biopsy

Staging/Classification Rai’s staging system (one system) Three major prognostic indicators are: Stage 0- low risk Stages I and II- Intermediate risk Stages III and IV- high risk Stages are based on presence of adenopathy, splenomegaly, anemia, and thrombocytopenia. The majority of patients are in the intermediate risk group

Treatment Techniques no optimal treatment early stage pt- no tx benefit chemo used to treat anemia, thrombocytopenia radiation used to treat palliatively for localized tumors of lymph tissue surgery used to remove spleen because of cytopenia, cells accumulate in the spleen

CML-Chronic Myelogenous Leukemia
CML accounts for 20-30% of all leukemias rare in children uncommon before age 21 peaks mid 40’s males slightly more common

Etiology-unknown linked to radiation, benzene Philadelphia chromosome is present in 95% of CML patients Abnormal Chromosome 22- loss of part of long arm Prognostic Indicators dependent on: spleen size, platelet count, hematocrit (% of erythrocytes in blood volume), gender, % of blood myeloblasts (immature BM cell) Can turn into an acute leukemia after 3 yrs-blast crisis Active phase- 2yr survival

Three Phases: Chronic phase: 3-5 years. Current treatment is with alpha-interferon. Young patients should undergo BMT. Accelerated phase: New nonrandom cytogenic abnormalities in up to 80% of patients. Difficult to control. Development of myelofibrosis. Elevated leukocyte counts. Lasts several months before becoming blastic. Blast phase: > 30% blasts in blood or marrow. Treatment with chemotherapy similar to acute leukemia. Some patients go into remission with treatment, but it is short lived.

Laboratory and Radiographic Work-up: CBC with manual differential Serum Vitamin B12 and B12 binding capacity Leukocyte alkaline phosphatase (decreased) Uric acid level Chromosomal testing - Philadelphia chromosome Bone marrow biopsy

Chronic leukemia Treatment
Chemotherapy Radiotherapy Bone marrow transplantation (CML)

Conceptualizing lymphoma
Neoplasms of lymphoid origin, typically causing lymphadenopathy Leukemia vs lymphoma Lymphomas as clonal expansions of cells at certain developmental stages

B-cell development Bone marrow Lymphoid tissue CLL MM ALL DLBCL,
memory B-cell DLBCL, FL, HL ALL CLL MM stem cell germinal center B-cell mature naive B-cell lymphoid progenitor progenitor-B pre-B immature B-cell plasma cell Bone marrow Lymphoid tissue

Lymphoma classification (2001 WHO)
B-cell neoplasms precursor mature T-cell & NK-cell neoplasms Hodgkin lymphoma Non- Hodgkin Lymphomas

Mechanisms of lymphomagenesis
Genetic alterations Infection Antigen stimulation Immunosuppression

Epidemiology of lymphomas
5th most frequently diagnosed cancer in both sexes males > females incidence NHL increasing Hodgkin lymphoma stable

Risk factors for NHL immunosuppression or immunodeficiency
connective tissue disease family history of lymphoma infectious agents ionizing radiation

Variable severity: asymptomatic to extremely ill time course: evolution over weeks, months, or years Systemic manifestations fever, night sweats, weight loss, anorexia, pruritis Local manifestations lymphadenopathy, splenomegaly most common any tissue potentially can be infiltrated

Other complications of lymphoma
bone marrow failure (infiltration) CNS infiltration immune hemolysis or thrombocytopenia compression of structures (eg spinal cord, ureters) pleural/pericardial effusions, ascites

Diagnosis requires an adequate biopsy
Diagnosis should be biopsy-proven before treatment is initiated Need enough tissue to assess cells and architecture

Staging of lymphoma Stage I Stage II Stage III Stage IV
A: absence of B symptoms B: fever, night sweats, weight loss

Hodgkin lymphoma Cell of origin: germinal centre B-cell
Reed-Sternberg cells (or RS variants) in the affected tissues Most cells in affected lymph node are polyclonal reactive lymphoid cells, not neoplastic cells

Epidemiology Less frequent than non-Hodgkin lymphoma Overall M>F
Peak incidence in 3rd decade

Lymphadenopathy Contiguous spread Extranodal sites relatively uncommon except in advanced disease “B” symptoms

Multiple Myeloma An estimated 20,580 people diagnosed in the United States in 2009 A type of blood cancer in which plasma cells grow uncontrollably, usually inside the bone marrow Associated with bone lesions that cause structural damage and/or fractures from overproduction of myeloma cells Referred to as multiple myeloma because about 90% of patients have multiple bone lesions Solitary plasmacytoma: a mass of myeloma cells in one site in the bone or another organ Extramedullary plasmacytoma: myeloma that begins in other tissues, such as skin, muscle, or lungs

Risk Factors for Multiple Myeloma
Age Race Exposure to radiation and chemicals History of solitary plasmacytoma Monoclonal gammopathy of unknown significance (MGUS): a low level of a protein called monoclonal immunoglobulin (M protein)

Symptoms of Multiple Myeloma
General Weight loss Easy bruising Hazy vision Bleeding gums Bones Pain Fractures Hypercalcemia (high calcium levels in the blood) Nausea and vomiting Increased urination Excessive thirst

Symptoms of Multiple Myeloma
Kidney Failure Nausea and vomiting Fatigue Weakness Amyloidosis (build-up of proteins) Peripheral neuropathy (nerve damage) Edema (swelling caused by build-up of fluid in the body) Enlargement of organs

Diagnosis of Multiple Myeloma
Blood test for anemia, kidney function, and calcium levels Blood and urine tests to measure M protein levels Bone marrow biopsy Diagnosis is confirmed with a bone marrow biopsy X-ray Magnetic resonance imaging (MRI) Computed tomography (CT or CAT) scan Positron emission tomography (PET) scan or PET-CT

Multiple Myeloma Durie-Salmon Staging System
Assesses the extent of the disease or size of the tumor Divided into 3 stages Each stage is classified into A or B depending on kidney function Based on laboratory data including: Red blood cell counts Blood calcium levels M protein levels Amount of bone damage

Multiple Myeloma International Staging System (ISS)
ISS Stage I: B2-M levels are less than 3.5 gm/dl (grams per deciliter) Blood albumin levels are greater than or equal to 3.5 gm/dl ISS Stage II: Criteria for stage II are defined as those that fit neither stage I nor stage III myeloma ISS Stage III: B2-M level greater than 5.5 gm/dl

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Anaemia 20.04.2012.

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