HEMATOLOGY AND NEUROLOGY MULTIPLE CHOICE QUESTIONS

                                                                           

                                                                 NEUROLOGY 

All are true about Creutzfeldt-Jakob Disease, except:

It is a neurodegenerative disease caused by prions

Accumulation in the brain of a normal protease-resistant prion protein

An elevated level of 14-3-3 protein in CSF

It is subacute dementia with rapid clinical progression 

B

What is true about Huntington Disease?:

Life expectancy is 20 years from the time of diagnosis

Multiple abnormal  CAG triplet repeats on chromosome 5

Anticipation is related to less severe disease

Multi9ple abnormal GAA triplet repeats on chromosome 9

A

Patient with Parkinson's Disease, his primary symptom is tremor. Which is the best medication?:

Amantadine

Benztropine

Selegiline

Entacapone

A

Mechanism of action of amantadine?:

A weak non-competitive NMDA receptor antagonist

It blocks the peripheral conversion of levodopa

Anticholinergic

MAO-B inhibitor

A

Mechanism of action of ropinirole and bromocriptine?:

MAO-B inhibitor

COMT inhibitor

Dopamine agonist

Anticholinergic

C

Mechanism of action of Selegiline?:

Anticholinergic

COMT inhibitor

Dopamine agonist

MAO-B inhibitor

D

Mechanism of action of Entacapone and tolcapone?:

Anticholinergic

COMT inhibitor

Dopamine agonist

MAO-B inhibitor

B

Mechanism of action of Benztropine and trihexyphenidyl?:

Anticholinergic

COMT inhibitor

Dopamine agonist

MAO-B inhibitor

A

What is the most often primary cancer in metastatic brain tumors?:

Breast cancer

GI tract cancer

Melanoma

Lung cancer

D

Symptoms of increased intracranial pressure?:

Nausea, vomiting, headache, and confusion

Nausea, vomiting, headache, and diplopia

Fever, weight loss, and headache

Headache, fever, and nuchal rigidity

B

Diagnostic criteria for Neurofibromatosis 1, except:

Café-au-lait spots

Optic glioma

Lisch nodules

Bilateral vestibular schwannomas

D

Patient with a history of Meningioma and neurofibroma. What is the diagnosis?: 

Neurofibromatosis 1

Neurofibromatosis 2

Tuberous Sclerosis

Sturge-Weber disease

B

What structures are included in the limbic system?:

Caudate, putamen, globus pallidus, substantia nigra, and subthalamic nucleus

Habenula, habenular commissure, posterior commissure, and the pineal gland

Subthalamic nucleus, red nucleus, and substantia nigra

Amygdala, hippocampus, fornix, mammillary bodies, cingulate gyrus, and parahippocampal gyrus

D

What structures are included in Basal ganglia?:

Caudate, putamen, globus pallidus, substantia nigra, and subthalamic nucleus

Habenula, habenular commissure, posterior commissure, and the pineal gland

Subthalamic nucleus, red nucleus, and substantia nigra

Amygdala, hippocampus, fornix, mammillary bodies, cingulate gyrus, and parahippocampal gyrus

A

What structures are included in the Epithalamus?:

Caudate, putamen, globus pallidus, substantia nigra, and subthalamic nucleus

Habenula, habenular commissure, posterior commissure, and the pineal gland

Subthalamic nucleus, red nucleus, and substantia nigra

Amygdala, hippocampus, fornix, mammillary bodies, cingulate gyrus, and parahippocampal gyrus

B

What structures are included in the Subthalamus?:

Caudate, putamen, globus pallidus, substantia nigra, and subthalamic nucleus

Habenula, habenular commissure, posterior commissure, and the pineal gland

Subthalamic nucleus, red nucleus, and substantia nigra

Amygdala, hippocampus, fornix, mammillary bodies, cingulate gyrus, and parahippocampal gyrus

C

Pathway in Papez circuit?:

Fornix  hippocampus  mammillary bodies  mammillothalamic tract  anterior nucleus of the thalamus  thalamocingulate radiation  cingulate gyrus  hippocampus

Hippocampus  mammillary bodies  fornix  mammillothalamic tract  anterior nucleus of the thalamus  thalamocingulate radiation  cingulate gyrus  hippocampus

Hippocampus  fornix  mammillary bodies  mammillothalamic tract  anterior nucleus of the thalamus  thalamocingulate radiation  cingulate gyrus  hippocampus

Hippocampus  fornix  mammillary bodies  mammillothalamic tract  anterior nucleus of the thalamus  cingulate gyrus  thalamocingulate radiation hippocampus

C

What is the function of the ventromedial nucleus?:

Satiety 

Hunger

Heat dissipating

Heat conservation

A

What is the function of the anterior hypothalamus?:

Satiety

Hunger

Heat dissipating

Heat conservation

C

What is the function of the posterior hypothalamus?:

Satiety

Hunger

Heat dissipating

Heat conservation

D

What is the function of the lateral area of the hypothalamus?:

Satiety

Hunger

Heat dissipating

Heat conservation

B

What is the function of suprachiasmatic nuclei?:

Heat conservation

Heat dissipating

Circadian rhythms

Synthesis of vasopressin and oxytocin

C

What is the function of supraoptic and paraventricular nuclei?:

Heat conservation

Heat dissipating

Circadian rhythms

Synthesis of vasopressin and oxytocin

D

The classic triad of Wernicke encephalopathy?:

Encephalopathy, ophthalmoplegia, and ataxia

Encephalopathy, ophthalmoplegia, and anterograde amnesia

Encephalopathy, ophthalmoplegia, and retrograde amnesia

Encephalopathy, horizontal nystagmus, and confabulations

A

Signs and symptoms of Korsakoff dementia?:

Encephalopathy, ophthalmoplegia, and ataxia

Encephalopathy, ophthalmoplegia, ataxia, amnesia, and confabulations

Encephalopathy, ophthalmoplegia, ataxia, and tremor

Encephalopathy, ophthalmoplegia, ataxia, and paraplegia

B

Which vitamin deficiency causes Wernicke encephalopathy?:

Vitamin B12

Vitamin B9

Vitamin B3

Vitamin B1

D

Which vitamin deficiency causes peripheral neuropathy?:

Vitamin B12

Vitamin B9

Vitamin B3

Vitamin B1

A

What is the etiology of Closed-Angle Glaucoma?:

Obstruction of drainage pathways by the iris

Decreased drainage due to damaged trabecular meshwork

Macular degeneration

Retinal vascular occlusion

A

What is the etiology of Open-Angle Glaucoma?:

Obstruction of drainage pathways by the iris

Decreased drainage due to damaged trabecular meshwork

Macular degeneration

Retinal vascular occlusion

B

Treatment for Open-Angle Glaucoma?:

Isoproterenol

Timolol

Furosemide

Atropine

B

The lesion in the left optic nerve and defect in the visual field?:

Right anopia

Right homonymous hemianopsia

Left homonymous hemianopsia

Left anopia

D

The lesion in the optic chiasm and defect in visual field?:

Central scotoma

Left hemianopia with macular sparing

Bitemporal hemianopsia

Right homonymous hemianopsia

C

The lesion in the right optic tract and defect in visual field?:

Right homonymous hemianopsia

Left homonymous hemianopsia

Left lower quadrantic  anopsia

Right lower quadrantic anopsia

B

The lesion in left dorsal optic radiation?:

Right lower quadrantic anopsia

Left lower quadrant anopsia

Right upper quadrantic anopsia

Left upper quadrantic anopsia

A

The lesion in right Meyer Loop and defect in the visual field?:

Right lower quadrantic anopsia

Left lower quadrant anopsia

Right upper quadrantic anopsia

Left upper quadrantic anopsia

D

Left PCA infarction and defect in the visual field?:

Left hemianopsia with macular sparing

Right hemianopsia with macular sparing

left lower quadrantic anopsia

right lower quadrantic anopsia

B

Macular degeneration and defect in visual field?:

Hemianopsia with macular sparing

Upper quadrantic anopsia

Lower quadrantic anopsia

Central scotoma

D

What is true about central retinal artery occlusion?:

Swollen optic disc with hemorrhages

Retinal hemorrhages

Cotton-wool spots

Cherry-red spot of the fovea

D

What is true about central retinal vein occlusion?:

Retinal swelling

Bloodless retinal arteries

Cotton-wool spots

Cherry-red spot

C

                                                               HEMATOLOGY

Most common coagulation disorder in Ashkenazi Jews?:

Hemophilia A

Hemophilia B

Hemophilia C

Von Willebrand Disease

C

Mechanism of action of Heparin?:

Inhibits synthesis of vitamin K-dependent coagulation factors

Directly inhibit factor Xa

Inhibits factor II

Activates antithrombin

D

Mechanism of action of Warfarin?:

Inhibits synthesis of vitamin K-dependent coagulation factors

Directly inhibit factor Xa

Inhibits factor II

Activates antithrombin

A

Mechanism of action of Apixaban?:

Inhibits synthesis of vitamin K-dependent coagulation factors

Directly inhibit factor Xa

Inhibits factor II

Activates antithrombin

B

Mechanism of action of Dabigatran?:

Inhibits synthesis of vitamin K-dependent coagulation factors

Directly inhibit factor Xa

Inhibits factor II

Activates antithrombin

D

Mechanism of action of tPA?:

Inhibits synthesis of vitamin K-dependent coagulation factors

Directly inhibit factor Xa

Converts plasminogen into plasmin which breaks down fibrin

Activates antithrombin

C

The best initial test in the diagnosis of Hemophilia?

PTT

Mixing study

Specific factor assays

PT

B

Most accurate test in the diagnosis of Hemophilia?:

PTT

Mixing study

Specific factor assays

PT

C

What is the most common inherited bleeding disorder?:

Von Willebrand Disease

Hemophilia A

Bernard-Soulier syndrome

Glanzmann thrombasthenia

A

What is the most common cause of hereditary thromboembolic disease?:

Antithrombin III deficiency

Protein C deficiency

Factor V Leiden

Protein S deficiency

C

In which condition is seen decreased agglutination on the ristocetin cofactor assay?

Factor V Leiden

Von Willebrand disease

Bernard-Soullier syndrome

Glanzmann thrombasthenia

B

What is the condition caused by a deficiency in GpIIb/IIIa?:

 Factor V Leiden

Von Willebrand disease

Bernard-Soullier syndrome

Glanzmann thrombasthenia

D

What is the condition caused by a deficiency in GpIb?:

Factor V Leiden

Von Willebrand disease

Bernard-Soullier syndrome

Glanzmann thrombasthenia

C

What is the mechanism of action of Clopidogrel and ticlopidine?:

Inhibits ADP receptor

Inhibits GpIIb/IIIa

Inhibits COX 

Inhibits factor II

A

Lab findings in Von Willebrand disease?:

Increased bleeding time

Decreased PTT

Increased PT

Decreased platelet count

A

What is the cause of Idiopathic thrombocytopenic purpura?:

Deficiency of ADAMTS-13

IgG antibodies against patient’s platelets

Depletion of clotting factors and platelets

PF4 antibody 

B

What is the cause of Thrombotic Thrombocytopenic  Purpura?:

Deficiency of ADAMTS-13

IgG antibodies against patient’s platelets

Depletion of clotting factors and platelets

PF4 antibody 

A

What is the cause of Heparin-induced Thrombocytopenia?:

Deficiency of ADAMTS-13

IgG antibodies against patient’s platelets

Depletion of clotting factors and platelets

PF4 antibody 

D

What is the cause of tissue necrosis following warfarin administration?:

Vitamin C and S deficiency

Vitamin K deficiency

Activation of protein C

Activation of protein S

A

Clinical presentation and lab findings in TTP?:

Hemolytic anemia increased creatinine and low platelets without neurologic symptoms

Hemolytic anemia increased creatinine, low platelets, increased TP, increased bleeding time

Hemolytic anemia, increased creatinine, low platelets, seizure, and fever

Hemolytic anemia, increased creatinine, low platelets, retroperitoneal bleeding, and fever

C

Clinical presentation and lab findings in HUS?:

Hemolytic anemia increased creatinine, and low platelets without neurologic symptoms

Hemolytic anemia increased creatinine, low platelets, increased TP, increased bleeding time

Hemolytic anemia, increased creatinine, low platelets, seizure, and fever

Hemolytic anemia, increased creatinine, low platelets, retroperitoneal bleeding, and fever

A

Best initial abortive therapy for Migraine?:

Gabapentin 

Triptans

NSAIDs

Dihydroergotamine 

C

Prophylaxis for Migraine includes, except: 

a) Propanolol

b) Amitriptyline

c) Triptans

d) Topiramate

C

Best initial abortive therapy for Cluster headaches?:

a) 100% O2

b) NSAIDs

c) Triptans

d) Acetaminophen

A

Best prophylactic therapy for Cluster headache?:

a) Valproate

b) Propanolol

c) Amitriptyline

d) Verapamil

D

A 34-year-old patient presents with severe, shooting pain, 6/10, on the right side of his face. It lasts less than one minute and presents several times during the day. He states the pain is worse after chewing or brushing his teeth. He denies fever, changes in his vision, lacrimation, rhinorrhea, nausea, or vomiting. What is the best explanation for his condition?:

a) Migraine

b) Trigeminal neuralgia

c) Cluster headache

d) Temporal arteritis

B

What is the first-line therapy for the condition of the previous patient?:

a) Verapamil

b) Valproate

c) Carbamazepine

d) Steroids

C

 37-year-old female patient presents to ED for severe, constant, pressure-like headache (worst pain of my life), 10/10, that started suddenly this morning while she was exercising. The pain is getting worse, doesn’t alleviate with anything. It is associated with nausea, vomiting, photophobia. The physical exam is remarkable for the presence of the Brudzinski sign. What is the best initial step?:

a) Lumbar puncture and CSF analysis

b) CT scan of the head without contrast

c) CT scan of the head with contrast

d) MRI brain

B

 First-line therapy in children with partial or tonic-clonic seizures?:

a) Levetiracetam

b) Phenytoin

c) Carbamazepine

d) Phenobarbital

D

First-line therapy for Absence seizures?:

a) Valproic acid

b) Levetiracetam

c) Ethosuximide

d) Carbamazepine

C

Which is the best initial therapy in status epilepticus?:

a) Midazolam

b) Phenytoin

c) Phenobarbital

d) Lorazepam

D

A patient is still in status epilepticus after 20 minutes besides the administration of benzodiazepines every 5 minutes, which is the best next step?:

a) Continue benzodiazepine for 20 more minutes

b) Start Phenytoin

c) Start Fosphenytoin

d) Start Phenobarbital

C

When is recommended continuous EEG monitoring?:

a) In convulsive status epilepticus

b) Patient does not wake up after clinically obviously seizures stop

c) During alcohol withdrawal

d) During benzodiazepines withdrawal

B

A 55-year-old patient presents in ED with sudden severe vertigo, nausea, vomiting, and difficulty standing up. He was diagnosed with URI 10 days ago. The physical exam is remarkable for vertical nystagmus and gait unsteadiness. He has a past history of Hypertension, DM T1, and CHF. What is the best initial step?:

a) Diffusion-weighted MRI

b) Start meclizine

c) Start steroids

d) Start NSAIDs

A

In the presentation of Benign Paroxysmal Positional Vertigo, which one is incorrect?:

a) Vertigo lasts < 1 min

b) It is not associated with hearing loss

c) Epley maneuver can resolve the symptoms

d) Meclizine is the best initial therapy

D

In Labyrinthitis, which of the following symptoms is incorrect?:

a) Lacking hearing loss

b) Tinnitus

c) Ear fullness

d) Nausea and vomiting

A

What is correct about Ménière's disease?:

a) Recurrent episodes of vertigo, tinnitus, nausea, vomiting, and hearing loss

b) Acute vertigo, nausea, vomiting, and hearing loss after a recent URI

c) Acute vertigo and nystagmus triggered by changes in head position

d) Acute vertigo, nausea, vomiting without hearing loss after a recent URI

A

What is correct about Vestibular neuritis?:

a) Recurrent episodes of vertigo, tinnitus, nausea, vomiting, and hearing loss

b) Acute vertigo, nausea, vomiting, and hearing loss after a recent URI

c) Acute vertigo and nystagmus triggered by changes in head position

d) Acute vertigo, nausea, vomiting without hearing loss after a recent URI

D

Lab findings in Iron Deficiency Anemia?:

High ferritin, high RDW, high TIBC, low serum iron

Low ferritin, low RDW, high TIBC, low serum iron

Low ferritin, high RDW, high TIBC, low serum iron

Low ferritin, low RDW, low TIBC, low serum iron

C

Lab findings in Anemia of Chronic Disease?:

High ferritin, low serum iron, normocytic anemia

Low ferritin, low serum iron, microcytic anemia

High ferritin, high serum iron, normocytic anemia

Low ferritin, high serum iron, normocytic anemia

A

Lab findings in Megaloblastic Anemia due to B12 deficiency?:

Macrocytic anemia increased MMA and increased homocysteine

Macrocytic anemia, normal MMA, and increased homocysteine

Macrocytic anemia, normal MM, and normal homocysteine

Macrocytic anemia, increased MMA, and normal homocysteine

A

Lab findings in Megaloblastic Anemia due to B9 deficiency?:

Macrocytic anemia increased MMA and increased homocysteine

Macrocytic anemia, normal MMA, and increased homocysteine

Macrocytic anemia, normal MM, and normal homocysteine

Macrocytic anemia, increased MMA, and normal homocysteine

B

What is the most common cause of osteomyelitis in patients with Sickle Cell Disease?:

S aureus

Salmonella

S epidermidis

Shigella

B

What is false about complications in Sickle Cell Disease?:

Splenic sequestration resulting in hypovolemia

Parvovirus B 19 infection resulting in aplastic crisis

Low platelets

Increased PTT

D

What is true about Warm Autoimmune Hemolytic Anemia?:

Presence of IgM antibodies

Presence of IgG antibodies

It is associated with Mycoplasma pneumonia

It is associated with Mononucleosis

B

What is true about Cold Autoimmune Hemolytic Anemia?:

Presence of IgG antibodies to RBC antigens

It is associated with Mycoplasma pneumonia

It is associated with Mononucleosis

It is associated with SLE

D

All are true about Hereditary spherocytosis, except?:

Presence of spherocyte

Positive osmotic fragility tests

Negative direct Coombs test

Positive direct Coombs test

D

What is not a cause of Aplastic Anemia?:

HIV infection

Parvovirus B 19 infection

Sulfa drugs

Ciprofloxacin

D

What is not true about Thalassemia?:

African, Middle Eastern, and Asian descent are mostly affected

Microcytic anemia with normal serum iron

Microcytic anemia with low serum iron

Most patients with Thalassemia do not require treatment

C

What is not present in hyperviscosity syndrome ?:

Easy bruising

Blurred vision

Pruritus after a cold bath

Thrombosis

C

What is the best initial test in the diagnosis of Polycythemia Vera?:

JAK 2 mutation

CBC

CBC with an ABG and EPO level

EPO levels

C

mnemonic of Eosinophilia

mnemonic of Eosinophilia

Blood Histology

Staining of Blood Cells

Blood cells are generally studied in smears or films prepared by spreading a drop of blood in a thin layer on a microscope slide.

.

Blood smears are routinely stained with special mixtures of red (acidic) and blue (basic) dyes. These mixtures also contain azures, dyes that are useful in staining some structures of blood cells known as azurophilics (azure + Gr. philein, to love). Some of these special mixtures (eg, Giemsa, Wright's, Leishman's) are named for the investigators who introduced their own modifications into the original mixture.

Erythrocytes (red blood cells), which are anucleate, are packed with the O2-carrying protein hemoglobin. Under normal conditions, these corpuscles never leave the circulatory system.

Most mammalian erythrocytes are biconcave disks without nuclei .When suspended in an isotonic medium, human erythrocytes are 7.5       m in diameter, 2.6       m thick at the rim, and 0.8       m thick in the center. The biconcave shape provides erythrocytes with a large surface-to-volume ratio, thus facilitating gas exchange.

A decreased number of erythrocytes in the blood is usually associated with anemia. An increased number of erythrocytes (erythrocytosis, or polycythemia) may be a physiological adaptation. It is found, for example, in people who live at high altitudes, where O2 tension is low. Polycythemia (Gr. polys, many, + kytos, cell, + haima, blood), which is often associated with diseases of varying degrees of severity, increases blood viscosity; when severe, it can impair circulation of blood through the capillaries. Polycythemia might be better characterized as an increased hematocrit, ie, an increased volume occupied by erythrocytes.

Red cell formation (erythropoiesis). The process of erythropoiesis is directed towards producing a cell devoid of organelles but packed with haemoglobin. 

The first recognisable erythrocyte precursor is known as the proerythroblast, a large cell with numerous cytoplasmic organelles and no haemoglobin. Further stages of differentiation are characterised by three main features: decreasing cell size and nuclear extrusion 

progressive loss of organelles; the presence of numerous ribosomes at early stages accounts for the marked cytoplasmic basophilia (blue staining) which steadily decreases as the number of ribosomes falls 

progressive increase in the cytoplasmic haemoglobin content; this accounts for the increasing eosinophilia (pink staining) of the cytoplasm towards maturity. 

Reticulocytes

Reticulocytes are immature red blood cells which have shed their nucleus, but still retain residual nuclear material. Reticulocytes are the immature form in which erythrocytes are released into the circulation from the bone marrow.

The rate of release of reticulocytes into the circulation generally equals the rate of removal of spent erythrocytes by the spleen and liver. Since the lifespan of circulating erythrocytes is about 120 days, reticulocytes constitute slightly less than 1% of circulating red blood cells. 

When severe erythrocyte loss occurs, such as after haemorrhage or haemolysis, the rate of erythrocyte production in the bone marrow increases and the proportion of reticulocytes in circulating blood rises (reticulocytosis). Clinically, the reticulocyte percentage is a useful indicator of erythropoiesis. In cases of anaemia, an elevated reticulocyte count indicates normal marrow function, while a decreased count may mean impaired erythropoiesis. 

Clinical:

Failure to maintain an adequate haemoglobin concentration is termed anemia. There are several common causes of anaemia, including lack of factors required to make haemoglobin, (e.g. iron, or vitamins B12 and folic acid), excessive loss or inappropriate destruction of erythrocytes, or failure of bone marrow to manufacture enough cells. Erythrocyte morphology may be altered in certain types of anaemia. Lack of iron leads to cells that are smaller than normal (microcytes) while lack of B12 and folate leads to cells that are larger than normal (macrocytes). Abnormally rounded and fragile erythrocytes (spherocytes) may be caused by mutations in genes coding for proteins in the red cell cytoskeleton

LEUKOCYTES

According to the type of granules in their cytoplasm and the shape of their nuclei, leukocytes are divided into two groups: granulocytes (polymorphonuclear leukocytes) and agranulocytes (mononuclear leukocytes). Both granulocytes and agranulocytes are spherical while suspended in blood plasma, but some become ameboid after leaving the blood vessels and invading the tissues. Their estimated sizes mentioned below refer to blood smears, in which the cells are spread and appear larger than they actually are in the blood.

Granulocytes 

Neutrophils 

Eosinophils 

Basophils 

Mononuclear leucocytes 

Lymphocytes 

Monocytes 

Neutrophils with more than five lobes are called hypersegmented and are typically old cells. Although the maturation of the neutrophil parallels the increase in the number of nuclear lobes under normal conditions, in some pathological conditions, young cells appear with five or more lobes.

PUS:

Dead neutrophils, bacteria, semidigested material, and tissue fluid form a viscous, usually yellow collection of fluid called pus.

Metachromasia is a property that enables certain substances to change the color of some basic dyes (eg, toluidine blue), being stained by the changed color (purple, in this example). Basophils can liberate their granule content in response to certain antigens, as can mast cells .

LYMPHOCYTES

Lymphocytes constitute a family of spherical cells with similar morphological characteristics. They can be classified into several groups according to distinctive surface molecules (markers), which can be distinguished by immunocytochemical methods. They also have diverse functional roles, all related to immune reactions in defending against invading microorganisms, foreign macromolecules, and cancer cells

The cytoplasm of the small lymphocyte is scanty, and in blood smears it appears as a thin rim around the nucleus. It is slightly basophilic, assuming a light blue color in stained smears. It may contain a few azurophilic granules. The cytoplasm of the small lymphocyte has a few mitochondria and a small Golgi complex; it contains free polyribosomes 

The amount of cytoplasm depends upon the state of activity of the lymphocyte, and in circulating blood there is a predominance of 'small' inactive lymphocytes (6-9 μm in diameter). 'Large' lymphocytes (9-15 μm in diameter) make up about 3% of lymphocytes in peripheral blood.

Platelets contain a well-developed cytoskeleton. At the periphery of the cell is a marginal band of microtubules which depolymerise at the onset of platelet aggregation. The cytoplasm is rich in the contractile proteins actin and myosin which are involved in the functions of clot retraction and extrusion of granule contents as part of degranulation. 

Located deep to the marginal band of microtubules and also scattered throughout the cytoplasm is the dense tubular system (DTS) consisting of narrow membranous tubules which contain a homogeneous electron-dense substance. This system is believed to be an intracellular store of calcium which is released into the platelet cytosol following signaling from platelet surface receptors and secondary messengers. 

Platelets contain a system of interconnected membrane channels the surface-connected canalicular system (SCCS) which is in continuity with the external environment via external pits. Alpha granules fuse with the SCCS as part of secretion of their contents

Acute Myeloid Leukemia

Failure of cell maturation

Common age group. is 15 to 45 yrs.

Etiology

Heredity

    trisomy 21  (Down syndrome),  Inherited diseases with defective DNA repair, e.g., Fanconi anemia, Bloom syndrome, ataxia telangiectasia

Radiation - ionizing

Chemical and other occupational exposures

•    Exposure to benzene, 
•    Smoking and exposure to petroleum products, paint, herbicides, and pesticides, 

Drugs

•     Alkylating agents
•     Chloramphenicol, phenylbutazone, and, less commonly, chloroquine

French-American-British (FAB) Classification

M0: Minimally differentiated leukemia,5%

M1:Myeloblastic leukemia without     maturation,20%

M2: Myeloblastic leukemia with maturation,30%

M3: Hypergranular promyelocytic ,10%

M4: Myelomonocytic leukemia, 20%

M4Eo: Variant: Increase in abnormal marrow eosinophils

M5: Monocytic leukemia,10%

M6: Erythroleukemia (DiGuglielmo's disease), 4%

M7: Megakaryoblastic leukemia,1%

Clinical Presentation

Symptoms

Consequence of anemia, leukocytosis, leukopenia or leukocyte dysfunction, or thrombocytopenia. 3 months symptoms

fatigue or weakness, anorexia, weight loss, fever, Signs of abnormal hemostasis (bleeding, easy bruising) 

bone pain, lymphadenopathy, nonspecific cough, headache, or diaphoresis 

a mass lesion located in the soft tissues, breast, uterus, ovary, cranial or spinal dura, gastrointestinal tract, lung, mediastinum, prostate, bone, or other organs. 

The mass lesion represents a tumor of leukemic cells and is called a granulocytic sarcoma, or chloroma. 

Physical Findings

Fever, splenomegaly, hepatomegaly, lymphadenopathy, sternal tenderness, evidence of infection and hemorrhage  

GI bleeding, intrapulmonary hemorrhage, or intracranial hemorrhage  

Retinal hemorrhages, Infiltration of gingivae, skin, soft tissues, or the meninges with leukemic blasts at diagnosis is characteristic of the monocytic subtypes and those with 11q23 chromosomal abnormalities.  

Hematologic Findings

Severe  anemia : normocytic  normochromic

Decreased erythropoiesis often results in a reduced reticulocyte count,accelerated destruction of RBC. 

Active blood loss also contributes to the anemia.

Leukocytosis between 10,000 to 500,000 per cmm.

Leukemic cells in the blood 

Hyperuricemia

renal precipitation of uric acid and the nephropathy 

renal tubular dysfunction

Bone marrow findings

blasts are >20%
cytoplasm often contains primary (nonspecific) granules, and the nucleus shows fine, lacy chromatin with one or more nucleoli characteristic of immature cells.
Abnormal rod-shaped granules called Auer rods


Prognostic Factors

Advancing age is associated with a poorer prognosis,
Patients with t(15;17) have a very good prognosis (approximately 85% cured),

 with t(8;21) and inv(16) a good prognosis (approximately 50% cured

Treatment

Remission induction
    Standard therapy includes a 7-day continuous infusion of cytarabine and a 3-day course of daunorubicin or idarubicin with or without 3 days of etoposide.


Supportive Care

G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF)
Platelet transfusions to maintain a platelet count >20,000/L
RBC transfusions to maintain hemoglobin level >8 g/dL
Prophylactic antibiotics for infection contrl
 Oral nystatin or clotrimazole  to prevent localized candidiasis, acyclovir prophylaxis
Allopurinol – to prevent from tumor lysis syndrome
Consolidation
Patients who achieve complete remission undergo postremission consolidation therapy, including sequential courses of high-dose cytarabine, stem cell transplant (SCT),
Maintenance
prednisolone, vincristine, methotrexate and mercaptopurine

Patients with APL usually receive tretinoin together with anthracycline chemotherapy for remission induction and then consolidation chemotherapy (daunorubicin) followed by maintenance tretinoin, with or without chemotherapy.

Treatment of relapse
Once relapse has occurred, AML is generally curable only by SCT.

CHRONIC MYELOID LEUKEMIA

A clonal expansion of a hematopoietic stem cell possessing a reciprocal translocation between chromosomes 9 and 22. 

This translocation results in the head-to-tail fusion of the breakpoint cluster region (BCR) gene on chromosome 22 with the ABL gene located on chromosome 9. 

Age gp. – 30 to 60 years

Etiology

• No evidence of cytotoxic drugs or a viral etiology. 
• Cigarette smoking accelerated the progression to blast crisis 
• Atomic bomb survivors had an increased incidence;  only large doses of radiation can induce CML.

Three phases

• Chronic phase
• Accelerated  phase
• Blast crisis phase

Clinical Presentation


Signs and Symptoms
 
Fatigue, malaise, and weight loss or  splenic enlargement and symptoms, such as early satiety and left               upper quadrant pain or mass.
 
Granulocyte or platelet dysfunction, such as infections, thrombosis, or bleeding.
 
Severe leukocytosis or thrombosis such as vasoocclusive disease, cerebrovascular accidents, myocardial infarction, venous thrombosis, priapism, visual disturbances, and pulmonary insufficiency.

Unexplained fever, significant weight loss, increasing dose requirement of the drugs controlling the disease, bone and joint pain, bleeding, thrombosis, and infections suggest transformation into accelerated or blastic phases.


Physical Findings

Minimal to moderate splenomegaly; mild hepatomegaly
Lymphadenopathy and myeloid sarcomas are unusual except late in the course of the disease; poor prognosis


Hematologic Findings in chronic phase

Elevated white blood cell counts (WBCs), with increases in both immature and mature granulocytes, are present at diagnosis; 16,000 to 200,00/cmm
Usually less than 5% circulating blasts
Platelet counts elevated or decreased, a mild degree of normocytic normochromic anemia .

Leukocyte alkaline phosphatase is low in CML cells.
Histamine production secondary to basophila is increased in later stages, causing pruritus, diarrhea, and flushing.

Bone marrow cellularity is increased, with an increased myeloid to erythroid ratio. The marrow blast percentage is generally normal to less than 5%

Marrow or blood basophilia, eosinophilia, and monocytosis

Disease acceleration: the development of increasing degrees of anemia or blood or marrow blasts between 10 and 20%, blood or marrow basophils 20%, or platelet count less than 100,000/L.
Blast crisis: Acute leukemia, with blood or marrow blasts 20%.

Chromosomal Findings

The cytogenetic hallmark of CML, is the t(9;22)

 Recognized by the presence of a shortened chromosome 22 (22q-), designated as the Philadelphia chromosome, that arises from the reciprocal t(9;22). Some patients may have complex translocations (designated as variant translocations) involving three, four, or five chromosomes (usually including chromosomes 9 and 22).

Treatment

The goal is complete hematologic, and cytogenetic remission, cure

Complete hematologic remission, WBC less than 10,000/mL, normal blood morphology, hemoglobin and platelet counts, and disappearance of splenomegaly.

Complete cytogenetic remission, no bone marrow metaphases with t(9;22).

Rapid lowering of WBCs, reduction of symptoms,   and reversal of symptomatic splenomegaly.

Imatinib mesylate tyrosine kinase inhibitorinduces apoptosis in cells expressing Bcr/Abl.

Hydroxyurea induces rapid disease control
Busulphan, an alkylating agent  acts on early progenitor
Interferon – if all other options have failed; mechanism is unknown

Autologous SCT

Intensive leukapheresis may control the blood counts in chronic-phase CML
 leukostasis-related complications such as pulmonary failure or cerebrovascular accidents,
Splenectomy for symptomatic relief of painful splenomegaly unresponsive to imatinib or chemotherapy, or for significant anemia or thrombocytopenia associated with hypersplenism. Splenic radiation

Treatment of Blast Crisis
 Only 52% of patients treated with imatinib achieved hematologic remission (21% complete hematologic remission), and the median overall survival was 6.6 months.
 allogeneic SCT with chemotherapy

Allogeneic SCT

The Patient
The Donor
Sex mismatch has an adverse effect on transplantation, with worse outcome associated with a female donor and male recipient. This has been attributed to GVHD against the male histocompatibility Y antigen.

Post-transplantation Treatment

BCR/ABL transcript levels have served as early predictors for hematologic relapse following transplantation.
Imatinib can control CML that has recurred after allogeneic SCT.

Acute lymphoblastic leukemia (ALL)

Clonal proliferation and accumulation of blast cells from lymphoid series in blood, bone marrow and other organs

Disorder  originates in single B or T lymphocyte progenitor 

B cell type – 80%     T cell type – 20%

Common age group – 5 to 15 yrs

Etiology  - unknown 

Acute leukemias - clinical features

1. Bleeding

2. Fever/infection

3. Fatiguability and pallor

4. Hepatomegaly

5. Splenomegaly

6. Lymphadenopathy

7. CNS involvement

8. Testicular involvement in males

Acute leukemias - laboratory findings 

1. Blood examination - anemia, - thrombocytopenia, - variable leukocyte count, usually increased from 10,000 to 500,000/cmm - blood morphology: presence of blast cells 

2. Bone marrow morphology - presence of blast cells (>20%) - suppression of normal hematopoiesis

3. Cytochemical stains

4. Immunophenotyping

5. Cytogenetics

Immune phenotyping

Cytogenetics

Morphologic subtypes of acute lymphoblastic leukemias  (FAB classification)

Subtype           Morphology       Occurrence (%)
L1   Small round blasts              75
clumped chromatin
L2 Pleomorphic larger blasts     20
clefted nuclei, fine chromatin
L3 Large blasts, nucleoli,       5

vacuolated cytoplasm

Chromosomal/molecular abnormalities with prognostic significance in ALL

Better prognosis
- normal karyotype
- hyperdiploidy
Poor prognosis
- t (8; 14)
- t (4; 11)
Very poor prognosis
- t (9; 22); BCR/ABL (+)


 Treatment strategy in ALL

Remission induction therapy in ALL

1. Antineoplastic treatment
a.Drugs: L-asparaginase, Daunorubicin, Prednisolone, Vincristine
    b/Treatment duration: 4-8 weeks
c/ No of courses: 1- 2
2. CNS prophylaxis – Methotrexate (intrathecal)
3. Supportive care

4. Treatment of complications

Consolidation

Drugs – Etoposide, cytarabine, and Daunorubicn, Methotrexate(I.v.)
+/-

Stem Cell transplantation

Maintenance of remission

• Prednisolone, Vincristine, Mercaptopurine and Methotrexate (oral)
• May need to be continued for 2-3 years

Treatment results in ALL 

Adults
Complete remission  (CR) 80-85%
Leukemia-free survival (LFS)            30-40%

Children
Complete remission (CR) 95-99%
Leukemia-free survival (LFS)            70-80%

Cell Markers and Genetic Abnormalities for Hodgkin and Non-Hodgkin Lymphomas

HODGKIN LYMPHOMA

Hodgkin lymphoma with a Reed-Sternberg cell

In the center of the photomicrograph is a classic Reed-Sternberg cell,a binucleate cell with large “owl’s eyes” eosinophilic nucleoli.

Hodgkin lymphoma, nodular sclerosis variant

Note the nodules of lymphocytes and other hematopoietic cells divided by broad fibrous septae.

Hodgkin lymphoma, mixed cellularity variant

Note the Reed-Sternberg cell (arrowhead). The other cell types in this image are reactive (only the Reed-Sternberg cell is neoplastic) and include neutrophils, lymphocytes, and, prominently in this image,eosinophils.

NON-HODGKIN LYMPHOMA

Spleen, non-Hodgkin lymphoma. This spleen exhibits uniform multicentric involvement of the white pulp by a malignant lymphoma. These changes contribute to generalized splenomegaly.

Follicular lymphoma

This lymph node exhibits the characteristic low power features of follicular lymphoma, tightly packed lymphoid follicles of approximately equal size.

Follicular lymphoma involves this hilar lymph node. The black material (arrow) represents normal lymphoid parenchyma with anthracotic pigment displaced 

to one side by the expanding tan lymphomatous process.

Diffuse large B-cell lymphoma

The photomicrograph shows a sheet of monotonous large neoplastic cells with prominent nucleoli.

Burkitt lymphoma

This photomicrograph illustrates the characteristic low power features of Burkitt lymphoma, a sheet of neoplastic cells interspersed with punctate clearings (“starry sky pattern”). The punctate clearings are macrophages engulfing cellular debris. Burkitt lymphoma is an aggressive rapidly growingneoplasm with abundant cellular turnover, hence the presence of the macrophages

Hairy cell leukemia

In the upper left corner is a single neoplastic lymphoid cell. Note the fine hair-like projections from its surface.


General Category Specific Name of Genetic Abnormality of Lymphoma Lymphoma Cell Markers (if associated with one)

Hodgkin lymphoma 

• NS-HL CD 15, 30+ EBV
• MC-HL CD 15, 30+ EBV+
• LP-HL CD 20, EMA + CD 15, 30

Non-Hodgkin lymphoma 

• Follicular lymphoma CD 19,20, and 10+ t(14;18)–bcl-2 surface Ig, bcl-2+ 3q27 abnormalities

• Diffuse large B-cell CD 19,20, and 79a+ t(14;18)–bcl-2 lymphoma Surface Ig+ 3q27 abnormalities

• Burkitt lymphoma CD 10, 19 and 20+ t(8;14)–MYC Bcl-6 and surface Ig+

• Precursor T-cell lymphoblastic Tdt, CD 2 and 7+ Abnormalities of TAL1 leukemia/lymphoma

• Mantle cell lymphoma CD 19,20 and 5+ t(11;14)–cyclin D1 Surface Ig+ CD23

• MALToma CD19, 20 t(1;14)–bcl-10 t(11;18)

• Hairy cell leukemia CD 19, 20, 11c and 103 TRAP+

NS-HL, nodular sclerosis Hodgkin lymphoma; EBV, Epstein-Barr virus; EMA, epithelial membrane antigen; MC-HL, mixed cellularity Hodgkin lymphoma; LPHL,
lymphocyte predominant Hodgkin lymphoma; TRAP, tartrate-resistant acid phosphatase.