Haematological system Flashcards

Question

What are the clinical manifestations of vit b12 or folate deficiency?

Answer 1

* Anemia and jaundice: combined anemia and jaundice (due to hemolysis) * Glossitis/angular cheilitis/mouth ulcers. Glossitis presents with pain, swelling and loss of papillae of the tongue occurs in vit B12 deficiency. Mouth ulcers occurs in folate deficiency * Neuropsychiatric symptoms: presents in both vit B12 and folate deficiency but most of the findings are commonly ascribed in vit b12 deficeincy Subacute combined degeneration of cord * Presents as slowly progressive weakness, sensory ataxia and paresthesias and ultimately spasticity, paraplegia and incontinence. Not all patients with neurologic abnormalities will have anemia or macrocytosis and thus absence of haematological changes cannot be used to exclude dx

Answer 2

* CBC with DC: macrocytic anemiae with MCV>100fL, low reticulocyte count, mild leukopenia or thrombocytopenia * Peripheral blood smear: macroovalocytes, hypersegmented neutrophils * Serum vit b12 level * Serum holotranscobalamin level (better) * Serum and RBC folate level: normal level of serum folate is >4ng/mL * Not routine is methylmalonic acid and homocysteine. Reserved when results for vit B12 and folate levels are borderlines or inconclusive. MMA elevated in vit b12 deficiency but not folate since vit B12 is a cofactor in conversion of methylmalonyl CoA in succinyl CoA * Serum autoantibodies: anti gatric parietal cell antibody, anti intrinsic factor antibody (both have high specificity but low sensitivity) Evidence of hemolysis (premature destruction of developing RBCs in bone marrow (intamedullary hemolysis) and peripheral circulation (hemolysis) * Increased AST * Increased unconjugated bilirubin * Increased LDH level * Increased methemoglobin: oxidized form of Hb inserum which occurs in intravascular hemolysis giving serum a brownish color * Decreased haptoglobini: free hb binds to haptoglobin in which the haemoglobin-haptoglobin complex is rapidly removed by the liver leading to a reduction in plasma haptoglobin

Answer 3

Vit b12 deficiency * Parenteral admin (dont have capacity to absorb oral replacement i.e. pernicious anemia. symptomatic anemia/neurological findings in which absorption is ensured Cyanobalamin 1000mcg 1x/week until deficiency corrected and then 1x/month * Oral admin: cyanobalamin 1000mcg1x/day Treatment of folate deficiency * Oral admin: folic acid 5mg 1x/day for folate deficiency. Usually sufficient even if malabsorption is present it is considerable in excess of the 200mcg recommended dietary allowance. * Folid acid 0.4mg (400mcg) 1x/day for pregnancy

Answer 4

* ANC ≤ 500/ μL (AND) o Single oral temperature ≥ 38.3oC (OR) o Persistent temperature ≥ 38.0oC sustained over ≥ 1 hour

Answer 5

Bacterial pathogens: S. epidermidis is most common. P. aeruginosa also common Viral pathogens: human herpes virus common in high risk patients with chemotherapy induced mucositis * Reactivation of HSV1 and HSV2 (herpes simplex) * Reactivation of VZV (herpes zoster) * Reactivation of CMV/EBV and HHV can also occur in patients as a result of immunosuppression or reciept of blood products or stem cells Fungal pathogens: candida and aspergillus Candida: acquired through GIT colonization and translocation across damaged intestinal epithelail surface Candida albicans: C. glabrata, C. tropicalis account for the remainder Aspergillus species: acquired through inhalation of airborne spores into upper and lower respiratory tract followed by germination and invasive hyphal growth. Aserpgillus common fungal cause in immunocompromised hosts Primarily affects the upper resiratory tract (sinusitis) and pneumonia but also invovles CNS, bones and skin

Answer 6

* Chemotherapy/RT induced mucositis of GIT: mucositis through GIT leading to seeding of endogenous flora in the GIT throughout the bloodstream occurs in majority of cases. Neutropenia usually occurs 10-14 days post CT * Immune defect associated with malignancy * Presence of indwelling catheters * Obstruction: obstruction to lymphatic, biliary tract, bronchial, GI or urinary ssytem. Secondary to tumor or result of surgical procedures

Answer 7

Detailed examination with emphasis on sites most likely infected including skin, oral cavity, lungs, abd, perianal areas, catheter and biopsy sites Vital signs and evidence of sepsis: BP/pulse/ temp/RR/GCS. Ill looking, mental obtundation or decreased oral intake suggests sepsis Specific examination on different organs * IV catheter sites: erythema and tenderness suggesting infection (must exclude line sepsis) * Lungs: signs of pneumonia * Abd: abd tenderness or peritoneal signs may represent neutropenic enterocolitis or C.difficile colitis * Perianal area: erythema, pain and tender hemorrhoids suggesting infection (avoid DRE which can introduce infection by traumatizing the fragile mucosa) * Skin and mucous membranes: evidence of rash or mucositis (ask for diarrhea for potential GI mucositis introducing infection)

Answer 8

* CBC * Electrolyte profile (sepsis) * LFT * RFT * Samples for culture and sensitivity test Blood culture (2 sets from peripheral and central venous catheter if present) Stool for C.difficile antigen detection or PCR Urine/sputum/skin lesions/CSF/ peritoneal fluid Radiological tests * CXR * CT thorax/sinus/abdomen/pelvis Patients with symptoms suggestive of neutropenic enterocolitis or C.difficile colitis should undergo abd CT scan with IV and oral contrast

Answer 9

Environmental precautions: reverse barrier isolation. HSCT recipients should be placed in rooms with positive pressure and high efficiency particular air (HEPA) filtration Neutropenic diet: low bacterial or low microbial diet consisting of well cooked food, often instituted but may not reduce occurence of infection/fever Risk stratification Low risk: expected to be neutropenic <7days and who have no active comorbidities or evidence of hepatic or renal dysfunction High risk: expected to be neutropenic for >7days and have comorbidities or evidence of hepatic or renal dysfunction Duration of therapy Known source = complete standard course of 14 days Unknown source: continue antibiotics until afebrile and ANC >500cells/uL medical treatment Empirical PO for low risk patients: amoxicillin clavualnate + ciprofloxacin/levofloxacin IV for high risk patients (must cover for P. aeruginosa (gram-ve, facultative anaerobe): meropenem/ imipnem/ piperacillin/tazobactam Addition of antifungal agents: should be initated for neutropenic fever after 4-7 days. Liposomal amphotericin B/caspofungin/voriconazole/posaconazole

Answer 10

Widespread activation of coagulation * Intravascular formation of fibrin * Thrombotic occlusions of small vessels * Leads to multiple organ failure Depletion of platelets and clotting factors * Widespread intravascualr coagulation and secondary fibrinolysis * Consumption of clotting factors, inhibitors of coagulation and platelets * Leads to severe bleeding

Answer 11

Principle: precipitating trigger must be eliminated before treatment of DIC is effective. Control of bleeding with frequent monitoring of coagulation screen is essential Platelet and fresh frozen plasma (FFP): supportive therapy Anticoagulants not favaroable Antithrombin concentrate not favorable

Answer 12

Primary ATP: acquired thrombocytoepnia due to autoimmune platelet destruction in the absence of causes or disorders 3 phases * newly diagnosed ITP = within 3 months from dx * Persistent ITP = ongoing ITP between 3-12 months * Chronic ITP = ITP lasting> 12 months Secondary ITP * ITP associated with an underlying condtion most commonly: HIV, HCV, SLE + CLL * Infections: HIV/HCV/ CMV/VZV/H.pylori * Autoimmune: SLE/antiphospholipid syndrome/ evans sydnrome (AIHA +ITP) * Lymphoproliferative disorders = CLL * Vaccination side effects * Common variable immune deficiency (CVID) Drug induced immune thrombocytopenia * Result of drug dependent platelet antibodies that cause platelet destruction * Should be distinguished from drug induced bone marrow suppression which is a non-immune related phenemenon

Answer 13

Congenital platelet disorders Thrombocytipenia (quantitative) * Bernard soulier syndrome * Wiskott aldrich syndrome: considered in young males with thrombocytopenia and small platelets particularly if there is a history of eczema and recurrent infection * Inherited bone marrow failure syndrome. Congenital anasplastic anemia: fanconi anemia, Schwachman-Diamond syndrome, dyskeratosis congenita Platelet function disorder (qualitative) * Defects of adhesion: Bernard Soulier syndrome * Defects of degranulation: grey platelet syndrome/storage pool disease * Defects of aggregation: Glanzmanns thromasthenia Acquired platelet disorders Thrombocytopenia (quantitative) Decreased production from bone marrow * Acquired aplastic anemia * MDS * Bone marrow infiltration: leukemia/lymphoma * Chemotherapy/RT Increased destruction Immune related * ITP * SLE * Drug induced thrombocytopenia Non immune related * TTP (thrombotic thrombocytopenic purpura) * Haemolytic uremic syndrome (HUS) * DIC * Hypersplenism Platelet function disorder (qualitative) * Liver disease * Uremia * Drug induced platelet dysfunctino COX inhibitor: aspirin GP2b/3a inhibitor: abciximab/tirofiban/eptifibatide ADP receptor antagonist: clopidogrel/prasugrel/ticlopidine

Answer 14

Reduced platelet lifespan by antibody mediated destruction Impaired platelet production Inciting events Infection: some cases of ITP associated with a preveding viral infection such as HIV and HCV Immune alteration Alteration in immune haemostasis might induce loss of peripheral tolerance and promote development of self reactive antibodies e.g. SLE and CLL Antibody production: specific IgG autoantibodies produced by patients B cells directed against platelet membrane glycoprotien such as GP2b/3a

Answer 15

Major are asymptomatic Bleeding * Result of thrombocytopenia and typically occurs in skin or mucous membrane * Petechiae: flat, red, discrete lesions that do not blanch under pressure. Occurs in depedent areas of body such as lower legs in ambulatory patients and sacral area in recumbent patients * Purpura: purpura on skin as dry purpura --> not serious. Purpura on mucous membrane are wet purpura and is a predictor of more serious bleeding * Epistaxis: minimal epistaxis occuring during nose blowing is common. Continuous epistaxis that requires intervention is a predictor of more serious bleeding * Hemorrhage: intracranial hemorrhage, overt GI bleeding and haematura is uncommon

Answer 16

Diagnosis of ITP is one of exclusion * Isolated thrombocytopenia (without anemia or leukopenia) without another apparent cause * Presumptive dx of primary ITP when history, PE and lab testing include peripheral blood smear do not reveal with other potential etiology for thrombocytopenia * Presumptive dx of secondary ITP when patient with ITP has underlying associated condition such as HIV, HCV, SLE and CLL

Answer 17

* CBC with DC: thrombocytopenia which varies from mild (100-150x10^9/L) to severe (<10 x10^9/L) Absence of other haematological findings. Evans syndrome = AIHA + ITP * Clotting profile: evaluate for other treatable causes of thrombocytopenia * Peripheral blood smear: required to confirm that thrombocytopenia is not artifactual due to platelet clumping. ITP not characterized by abnormal platelet morphology * Anti platelet antibodies: generally not useful but done in QMH * Serum complements C3/4 levels * Serum autoimmune markres: ANA/RF/antiphospholipid antibodies * Viral serology (HBV/HCV/HIV/EBV) and parvovirus B19/CMV PCR +H.pylori antibody. All patients are tested for HIV and HCV because thrombocytopenia is a common presenting finding for these conditions Bone marrow exam: not routine. Indicated in patients with other unexplained cytopenia, dysplasia on peripheral blood smear Demonstrate normal cellularity, and normal erythropoiesis and myelopoiesis

Answer 18

HPI Bleeding symptoms * Subcutaneous bleeding such as petechiae, purpura, ecchymosis * Mucosal bleeding such as epistaxis, gum bleeding and menorrhagia * Intraaritcular or intramuscular bleeding such as haemarthrosis or muscle haematoma Medical history * HIV + HCV +SLE and CLL * Hypersplenism * Liver diseases * History of platelet or coagulation disorers FH: platelet/coagulation disorders DH: medication that can cause drug induced thrombocytopenia. Heparin induced thrombocytopenia (HIT)

Answer 19

General approach Dx of ITP does not imply therapy is needed Indications to start treatment * Platelet count <10x10^9/L * Clinical evidence of bleeding including mucosal bleed with platelet count 10-30x10^9/L: nose bleeding that cannot be stopped for >15mins, oral mucosal bleeding including gum bleeding or blood retention cyst, GI bleeding * Severe bleeding regardless of platelet count: intracranial hemorrhage (ICH), retinal hemorrhage ITP and surgery: platelet count >50x10^9/L is considered safe for minor procefdures Medical treatment * Platelet transfusion ineffective in ITP (only emergency situation) * IVIG is 1st lin therapy: induces a rapid rise of platelet count within 24-48 hours but effect is transient lasting only for 1-2 weeks. Increases platelet count by interfering with macrophage uptake of autoantibody coated platelets Infuse the drug gradually (5ml/15min; than 10ml/min...) and give it over 1-2 days rather than 4 days * Corticoisteroids is 2nd line therapy for ITP: must perform bone marrow aspirate to rule out leukemia before starting * Anti RH(D): alternative to conventional IVIG for patients whose RBC is Rh (D) +ve * Other treatment options: rituximab, (anti CD20), azathioprine/ cyclosporine/cyclophosphamide/mycophenolate mofetil Surgical treatment * Splenectomy (requires immunization for encapsulated organisms) * Indications: when disease is refractory to steroid, relapse after responding to steroid. High dose of steroids is required for maintenance of safe platelet count.

Answer 20

Lifespan of platelet is normally about 10 days * Reduced to 1 – 2 days in immune thrombocytopenic purpura (ITP)

Answer 21

All causes of bone marrow failure * Acute leukemia * Aplastic anemia * Myelodysplastic syndrome (MDS) * Bone marrow infiltration by neoplastic disease All causes of increased platelet consumption * Hypersplenism * DIC * TTP

Answer 22

Increased megakaryocytes * Suggests a consumptive cause of thrombocytopenia

Answer 23

 Peripheral blood film * Fragmented red cell  Clotting profile * ↑ PT and APTT * ↑ D-dimer * ↓ Fibrinogen level

Answer 24

 Splenectomy is indicated if * Disease is refractory to steroid * Relapse after responding to steroid * High dose of steroids is required for maintenance of safe platelet count

Answer 25

* Thrombotic microangiopathy caused by severely reduced activity of vWF cleaving protease ADAMTS13 * Characterized by small vessel platelet rich thrombi that causes thrombocytopenia, microangiopathic hemolytic anemia and widespread multiorgan thrombosis and injury

Answer 26

hereditary TTP (<5%): also known as Upshaw schulman syndrome. Inherited mutations isn ADAMTS13 Acquired TTP (>95%): autoimmune or immune mediated TTP. Result of development of autoantibodies inhibitors to ADAMTS13. Categorized further into primary (idiopathic) or secondary cause

Answer 27

* Pregnancy (female predominant with median age of 41 years (rare in children)): accounts for 5-25% of all cases of TTP * Connective tissue diseases: SLE, RA, sjogren syndrome * Infections: CMV infection, HIV infection * Drug induced: clopidogrel, ticlopidine, cyclosporine, quinine

Answer 28

* Von willebrand factor (vWF) has multiple ADAMTS13 specific cleavage sites that are susceptible to cleavage by protease when exposed. ADAMTS13 is a metalloprotease that regulates the platelet aggregating activity of vWF by cleaving it at specific sites * Deficiency of von willebrand factor (vWF) cleaving protease ADAMTS13 in TTP Deficiency is due to inherited mutations in the enzymes or autoantibodies against it Results in increased levels of unusually large vWF multimers * Consequences of vWF induced platelet aggregation Thrombocytopenia due to platelet consumption. Microangiopathic haemolytic anemia from mechanical fragmentation or RBCs.

Answer 29

Clinical pentad in 5% of patients: fever, fluctuating neurological symptoms, renal impairment, microangiopathic hemolytic anemia (MAHA), thrombocytoepnia FAT RN = Fever, anaemia (MAHA), thrombocytopenia, renal dysfunction, neurological abnormalities SS of hemolytic anemia: jaundice, pallor, dyspnea, palpitation, fatigue and wewakness SS of thrombocytopenia: subcutaneous bleeding (petechiae, purpura, ecchymosis), mucosal bleeding: epistaxis, gum bleeding, menorrhagia), retinal hemorrhage, intracranial hemorrhage SS of CNS involvement: headache, confusion, focal neurological deficits: weakness, paresthesia, seizure, visual disturbance SS of CVS involvement (MI, arrhythmia, HF): chest pain, orthopnea, paroxysmal nocturnal dyspnea) SS of GI involvement (bowel ischemia): nausea and vomiting, abd pain, diarrhea SS of UG involvement: microscopic or macroscopic haematuria, proteinuria, oliguria/anuria

Answer 30

* CBC: anemia (microangiopathic hemolytic anemia, MAHA), thrombocytopenia (deposition of platelets in microthrombi) * Peripheral blood smear: schizocytes (fragmentation of RBC as RBC passes through platelet rich microthrombi in the microvasculature. Nucleated RBC: normoblasts. Polychromasia * Clotting profile: should be normal * Serum haptoglobin level: decreased haptoglobin (free hb from hemolysis binds to haptoglobin and the complex is rapidly removed by liver) * Serum LDH: increased LDH (reflects both hemolysis and tissue damage due to systemic ischemia) * LFT: hyperbilirubinemia (elevated level of unconjugated bilirubin due to haemolysis) * Urinalysis: dark urine * Direct and indirect antiglobulin (Coombs) test: immune mediated hemolysis typically negative * ADAMTS13 and inhibitor tests: severely reduced ADAMTS13 activity <10% during an acute episodes is a hallmark of acquired TTP. presence of antibodies against ADAMTS13 CT scan: typically normal. May show changes consistent with posterior reversible encephalopathy syndrome (PRES)

Answer 31

TTP is a medical emergency. Platelet transfusion not indicated due to possible exacerbation of thrombosis * Plasma exchange Indicated in patiens with a presumptive dx of TTP Should be initiated within 4-8 hours of clinical dx Should not be delayed while awaiting results of ADAMTS13 activity level Plasma replacement choices: solvent/detergent plasma, fresh frozen plasma. Plasma infusion is not an adequate substitute for plasma exchange in the initial treatment of TTP but can be used as a temporizing measure if an unavoidable delay in plasma exchange is expected * Corticosteroids High dose oral prednisolone 1mg/kg/day IV methylprednisolone 1g/day for 3 days * Rituximab

Answer 32

Well defined hematopoietic neoplasms involving precursor cells committed to myeloid line of cellular development (erythroid, granulocytic, monocytic, megakaryocytic) Characterized by clonal proliferation of myeloid precursor with a reduced capacity to differentiate into more mature cellular elements * Accumulation of leukemic blasts or immature forms in the bone marrow, peripheral blood and other tissues * Decreased production of normal RBC, mature granulocytes (neutrophils) and platelets. * Increased production of malignant cells

Answer 33

Most common acute leukemia in adults and accounts for 80% of cases Acute leukemia is the most common childhood malignancy accounting for 30% ALL accounts for majority of childhood leukemia accounting for 80% AML is much less common than ALL accounting for 15% of all leukemia Disease incidence increases with age. Median age of dx is 65 years.

Answer 34

 Chemical exposure  Radiation exposure  Smoking  Chemotherapy drugs * Alkylating agents (Cyclophosphamide/ Ifosfamide) * Topoisomerase II inhibitors  Genetic abnormalities * Down’s syndrome (Trisomy 21) (15 – 20x increase in risk) * Bloom’s syndrome * Fanconi anemia  Acquired hematopoietic conditions * Myelodysplastic syndrome (MDS) * Myeloproliferative neoplasm (MPN) (particularly CML) * Aplastic anemia * Paroxysmal nocturnal hemoglobinuria

Answer 35

 Anemia * Pallor * Palpitation * Tachypnea * Fatigue * Decreased exercise tolerance (ET)  Neutropenia * Fever * Mucositis * Recurrent infections  Thrombocytopenia * East bruising * Petechiae/ Purpura/ Ecchymosis * Gingival bleeding/ Epistaxis/ Menorrhagia  Constitutional symptoms * Fever * Irritability * Anorexia and weight loss * Fatigue and malaise

Answer 36

Gingival hypertrophy * Especially in monocytic subtypes which has predilection to infiltrate gum and skin Leukemia cutis * Infiltrative lesions suggestive of extramedullary leukemic involvement * Subcutaneous nodules and violaceous/gray blue in color Myeloid sarcoma (chloromas) * Extramedullary tumor of leuekemic cells (deposits of myeloid blasts outside the bone marrow that cause desrtruction or compression in normal tissues * Commonly seen in the orbit and epidural space but can occur anywhere --> associated with t821 Hyperleukocytosis and leukostasis * Presents in 10-20% of patients with newly diagnosed AML * Leukostasis is symptomatic hyperleukocytosis: WBC occluding the microcirculation leading to symptoms of decreased tissue perfusion typically causing neurological and respiratory distress. Resiratory: dyspnea/hypoxia. CNS: visual blurring/headache/dizziness/ tinnitus/confusion/coma/ TOMA * Medical emergency with mortality in 1 week reaching 20-40% left untreated. Cytoreduction with induction chemotherapy, hydroxyurea or leukapheresis. Prophylaxis for tumor lysis syndrome with aggressive hydration and hypouricemic agents including allopurinol or rasburicase. Tumor lysis syndrome * rapidly proliferating and drug sensitive neoplasm * Hyperuricemia, hyperK, hyperphosphatemia, hypocalcemia and raised LDH and metabolic acidosis Disseminated intravascular coagulopathy (DIC) * especially APL. Platelet transfusion and appropriate coagulation factors such as cryoprecipitate for severe hypofibrinogenemia can be considered in select patients

Answer 37

Requires both of the following Evidence of bone marrow infiltration * >20% blasts of the total cells of the peripheral blood or bone marrow aspirate * Leukemia with certain genetic abnormalities such as those with t8;21, inv16 or t15;17 and myeloid sarcom are considerd diagnostic of AML without regard to blast count Leukemic cells must be of myeloid origin * Presence of Auer rods * Cytochemistry positivity for myeloperoxidase * Presence of myeloid markers by immunophenotyping

Answer 38

CBC with DC * Anemia * Leukocytosis * Thrombocytopenia Clotting profile: look for evidence of DIC (PT,aPTT and Ddimer all increased. Decreased fibrinogen) LFT/RFT and CaPO4 level * Look for evidence of tumor lysis syndrome: hyperK, hyperP, hypoCa Serum LDH and uric acid level: signs of TLS Peripheral blood smear * Circulating myeloblasts (95% of cases), Auer rods: pathognomonic of myeloblasts Bone marrow aspirate and trephine biopsy * Hypercellular bone marrow * >20% of blasts: pronormoblast, myeloblast, abnormal promyelocyte, promonocyte, megakaryoblast * Presence of auer rods: pathognomonic of myeloblasts (pink or red like granular structure in cytoplasm)

Answer 39

* Cytochemistry: MPO reaction (are blasts of myeloid lineage) * Immunophenotyping (peripheral blood/BM aspirate and trephine biopsy) Flow cytometry (identification of cell surface antigens) Myeloid lineage: CD117, CD13, CD33 Monocyte lineage: CD11b, CD64,CD14, CD15 * Cytogenetics (BM trephine biopsy) Conventional karyotyping with FISH or RT-PCR Presence of certain cytogenetic abnormalities are sufficient for dx of AML AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 AML with t(15;17) (q22;q12); PML RARA (APL) AML with inv(16)(p13.1q22)(p13.1;q22); CBFB-MYH11

Answer 40

1. Chemotherapy Differences between AML and ALL AML has shorter duration of treatment due to absence of maintenance phase chemotherapy Steroids not used in AML, CNS prophylaxis not indicated in AML Induction (7+3 days): rationale (use of cytotoxic agents to eradicate leukemic cells in bone marrow and in circulation) Outcomes Favorable outcome = complete remission (does not = cure): eradication of all detectable leukemic cells (<5% blasts) from bone marrow and blood. Restoration of normal haematopoiesis (>25% cellularity and normal peripheral blood counts)> patients will relapse within 4-8 months unless given additional cytotoxic therapy Cytarabine + daunorubicin Cytarabaine (antimetabolite): 7 days of continous infusion Daunorubicin/idaraubicin (anthracycline): followed by 3 days Consolidation: must always follow up induction with consolidation regimen. Destroys leukemic cells that survived induction chemotherapy but undetectable by conventional studies * Cytarabine (high dose) * Cytarabaine + daunorubicin: standard consolidation for older adults * Allogenic HSCT: indicated in young adults with unfavorable risk AML. Graft vs tumor effect that decreases relapse rates 2. Allogenic haematopoietic stem cell transplantation always ask for family members such as siblings for potential allogenic HSCT candidates Indicated in young adults with unfavorable risk of AML or risk of relapse cases after complete remission. MOA: T cell in donor graft induce a graft vs leukemia effect against residual disease that has survived the conditioning HLA typing required 3. Supportive care TLS prophyalxsi: hydration and allopurinol/rasburicase. Prevention of uric acid nephropathy or renal failure Antimicrobial prophylaxis Prolonged bone marrow suppression associated with high incident of infections especially S. viridans sepsis and S.viridans shock syndrome as well as fungal infection such as aspergillus infection. Prophylactic antibiotics or G-CSF for bacterial infections. Prophylactic antifungals (fluconazole/itraconazole) for fungal infections

Answer 41

All transretinoic acid (ATRA) + arsenic trioxide (ATO) APL characterized by a gene rearrangement involving the retinoic acid receptor: t(15;17);PML RARa in >95% of cases. Very responsive to ATRA and arsenic trioxide is an effective non cytotoxic therapy Differentiation of APL from other forms of leukemia is important APL associated with higher risk of DIC and life threatning bleeding especially intracranial bleeding APL responds well to initial treatment with all transretinoic acid and chemotherapy APL associated with a good prognosis: best prognosis amongst all AMLs with >90% cure

Answer 42

 Complete remission (CR) achieved in * 70 – 80% in patients < 60 years old * 40 – 50% in patients > 60 years old  Overall survival is variable depending on prognostic factors * Poor prognostic factors include age > 60 years old, unfavorable cytogenetics, poor performance status or antecedent MDS/MPN

Answer 43

 Prior exposure to * Radiation * Chemotherapy * Toxic chemicals  Past history of * Chronic myeloid leukemia (CML) * Myelodysplastic syndrome (MDS) * Myeloproliferative neoplasm (MPN)

Answer 44

 Acute monocytic leukemia * A type of AML * Has a predilection to infiltrate gums and skin

Answer 45

 Morphological examination  Cytochemistry  Immunophenotyping  Cytogenetics  Molecular genetics

Answer 46

 APL is associated with a higher risk of life-threatening bleeding especially intra-cranial bleeding * Require intensive transfusion of platelets and fresh frozen plasma  APL responds well to initial treatment with all-trans retinoic acid and chemotherapy * Responds well to all-trans retinoic acid and arsenate therapy  APL is associated with a good prognosis

Answer 47

 Gram -ve infections (major)  Gram +ve infections * Become increasingly common * Often associated with the use of indwelling central venous catheter  Fungal infection * Prolonged neutropenia is commonly associated with fungal infection

Answer 48

Malignant proliferation of lymphoid cells blocked at an early stage of differentiation Malignancy of lymphoid cells that has primary involvement of blood and bone marrow Leukemia (ALL/CLL): primary involvement of blood and bone marrow Lymphoma: solid tumors of the immune system ALL when >25% blasts in BM Lymphoma preferred term when the process is confined to a mass lesion with minimal or no blood and bone marrow involvement (<25% blasts in BM)

Answer 49

* Occurs more often in males than females * Peak incidence =2-5 years * ChildreN: ALL>AML * Adults: AML?ALL Acute leukemia is the most common childhood malignancy accounting for 30% ALL accounts for majority of childhood leukemia accounting for 80% AML is less common than ALL accounting for 15% of all leukemia Childhood ALL is the 1st disseminated cancer shown to be curable

Answer 50

 Other malignancy with BM involvement * Neuroblastoma * Retinoblastoma * Rhabdomyosarcoma * Ewing sarcoma  Differentiation diagnosis of fever and lymphadenopathy * Infectious mononucleosis  Differentiation diagnosis of fever, bone pain and joint swelling * Juvenile idiopathic arthritis (JIA)  Differential diagnosis of pancytopenia/ failure of single cell line * Immune thrombocytopenia (ITP) * Aplastic anemia

Answer 51

Infiltration is common Lymphadenopathy (50%) * Indicative of extramedullary leukemic spread. LN >1cm in greatest diameter is enlarged except epitrochlear nodes enlarged if >5mm, inguinal nodes >15mm, cervical nodes are >20mm. Lymphadenopathy associated with malignancy is non tender, firm, rubbery and mated which persists or progress despite antibiotic therapy Hepatomegaly: most common finding in association with childhood leukemia Splenomegaly: common in childhood leukemia Bone and joint pain: bone pain particularly in long bone and LL caused by leukemic involvement of periosteum and aseptic osteonecrosis due to malignant cell necrosis in bone marrow. Bone pain can be severe and awake the patient at night (nocturnal pain). Joint swelling and effusion may be present. Differentiation of MSK pain in rheumatological disorders (JIA) and malignancy Morning stiffness and rash occurs more commonly in JIA Nocturnal pain and non articular bony pain occurs more commonly in leukemia

Answer 52

CNS leukemia (more common in ALL than AML since myeloid cells do not travel as extensive than lymphoid cells): headache, nausea and vomiting, neck stiffness, seizures, CN palsy Mediastinal mass: classically seen in T cell-ALL. May compress on trachea and leads to respiratory distress and wheezing. May compresson SVC and leads to SVCO which is manifested as dysphagia, dyspnea and swelling of neck, face and UL Testicular enlargement (testicular leukemia) Tumor lysis syndrome: HyperK, HyperP, Hyperuricemia, HypoCa. Raised LDH and metabolic acidosis

Answer 53

CBC with DC: anemia, leukocytosis (neutropenia), thrombocytopenia Clotting profile LFT/RFT and CaPO4 level: TLS signs Serum LDH and uric acid level: TLS signs Peripheral blood smear: circulating lymphoblasts Bone marrow aspiration and trephine biopsy * Presence of >25% of lymphoblasts (diagnostic) * Hypercellular bone marrow: partial or total replacement of normal cellular components of marrow by immature or undifferentiated cells CSF analysis by lumbar puncture * Included in initial evaluation --> 5-10% of patients have blasts in the CSF. * If lymphoblasts are found and CSF leukocyte count is elevated than overt CNS/meningeal leukemia is present (reflects a worse stage and indicates the need for additional CNS and systemic therapy)

Answer 54

Morphology: absence of granules as seen in myeloid lineage, absence of auer rods Cytochemistry: terminal deoxynucleotidyl transferase positive in 95% of ALL Immunophenotyping * Leukemic cells are classified according to immunophenotyping using an extensive panel of monoclonal antibodies to cell surface "cluster of differentiation": B precursor lineage (70% in children; 75% in adults) T precursor lineage (15% in children; 25% in adults) Flow cytometry B cell: CD10, CD19, CD20, CD22 T cell: CD2, CD3, CD4,CD5, CD7, CD8 * Cytogenetics (BM trephine biopsy) t922 BCR/ABL1 translocation (Ph chromosome): addition of TKI (imatinib) to intensive CT backbone dramatically improves survival t (variable;11q23) t(12;21) ETV6/RUNX1 rearrangeemnt Hyperdiploidy (54-58 chromosomes): present in 20-25% of childhood ALL: associated with a more favorable prognosis

Answer 55

Majority patients achieve remission at the end of induction phase Minimal residual disease: bone marrow aspiration and assesed by PCR or flow cytometry Interim bone marrow aspiration to assess disease response to treatment. Higher levels of MRD at the end of induction suggest a poorer prognosis and higher risk of subsequent release ALL vs AML treatment ALL has longer duration of treatment, steroid is used in ALL treatment, CNS prophylaxis routinely given to all ALL patients Induction (4 weeks): use of cytotoxic agents to eradicate leukemic cells in bone marrow and in circulation Vincristine (weekly) + corticosteroids (daily)+ asparaginase (single dose) Standard induction CT for t(9;22)/BCR ABL1-ve ALL TKI (imatinib) + vincristine + corticosteroids + asparaginase indicated for t(922)/BCR ABL1 +ve ALL Consolidation (4-8 months) Antimetabolite: cytarabine/methotrexate Anthracyclines: daunorubicin/doxorubicin Alkylating agents: cyclophosphamide/ifosfamide Top inhibiotrs: etoposide/etopophosphamide Maintenance (2-3 years) 6-mercaptopurine (6-MP) + methotrexate + vincristine + prednisone 2. Allogenic haematopoietic stem cell transplantation Always ask for family members such as siblings for potential allogenic HSCT candidates Indicated in patients with high risk disease that have an increased incidence of relapse during delayed intensification CT Patient >10 years of old with severe hypodiploidy, patient >1 year of age with 11q23 rearrangements HLA typing required 3. CNS prophylaxis Prevent leukemic meningitis Regimen: triple intrathecal chemotherapy (methotrexate/cytarabine/hydrocortisone) 4. Supportive care TLS prophyalxsi: hydration +allopurinol/rasburicase Antimicrobial prophylaxsi: must receive prophylactic treatment for pneumocystic jiroveci (PCP) with cotrimoxazole (septrin) RBC or platelet transfusion: CT often produces severe myelosuppression requiring transfusion

Answer 56

Cure achieved in 50 – 60% if good prognostic factors but 10 – 30% with poor prognostic factors * Good prognostic factors o Younger age o Early attainment of complete remission (CR) without MRD o WBC < 30,000/ μL o T-cell immunophenotype o Absence of Ph chromosome or t(4:11)

Answer 57

* ALL patients should only receive inactive vaccination during chemotherapy * Live-virus vaccines such as MMR and oral poliovirus are contraindicated

Answer 58

MPN characterized by dysregulated production and uncontrolled proliferation of mature and maturing granulocytes with fairly normal differentiation Occurs more often in males than females Median age of dx is 50 years

Answer 59

BCR ABL1 fusion gene ABL1 gene on ch9 to BCR gene on ch22 BCR-ABL1 protein (tyrosine kinase) is no longer under control by cellular mechanism and causes cell to divide uncontrollably

Answer 60

Splenomegaly (48-76%): can be massive extending to the right iliac fossa depending on when it is dx. Inability to get above the mass and it moves up and down with respiration. Dull on percussion and presence of a notch. Auscultation over massive spleen may reveal a splenic rub.

Answer 61

CBC with DC * Normal/anemia * Leukocytosis >25,000uL (often >100,000uL): virtually all cells of neutrophilic series (myeloblast/promyelocyte/myelocyte/metamyelocyte/band cells/neutrophils) with peaks in myelocytes and segmented neutrophils. Presence of greater percentage of myelocytes than metamyelocytes are known as myelocyte bulge which is a classical CCML finding Other WBC DC * Absolute basophilia is seen in all cases * Absolute eosinophilia is seen in 90% of cases * Absolute monocytosis is not uncommon as well * Normal/thrombocytosis/thrombocytopenia: thrombocytopenia only in blastic crisis when progress into acute leukemai and should alarm reconsideration of other diagnostic possibilities than CML Peripheral blood film * Thrombocytosis * Leukocytosis: virtually all cells of neutrophilic series and basophilia * Presence of blasts: chronic phase <10%, accelerated phase: 10-19%, blastic phase >20% Bone marrow aspiration and trephine biopsy * Hyperplasia of granulocytic series * Increase in reticular fibers and vascularity Special Ix Cytogenetics (BM trephine biopsy) Conventional karyotyping: detection of Ph chromosome (small chromosome 22) FISH: test for BCR-ABL1 fusion gene, actual visualization of t(9;22)by FISH. Overlapping of chromosome 9 and 22 (red and green = yellow) RT-PCR: BCR-ABL1 fusion gene

Answer 62

TKI: curative --> 1st gen: imatinib, 2nd gen: nilotinib/dasatinib/bosutinib Hydroxyurea: only for symptomatic treatment --> not curative Allogenic HSC transplantation: curative treatment option but at the cost of increased potential toxicity and early mortality. Indicated for young patients not responding to TKI treatment and has a suitable donor

Answer 63

Molecular genetics (PCR): most sensitive due to amplification. Measurement of fusion RNA level but not fusion gene or fusion protein. Detect and quantify BCR-ABL1 fusion transcripts by mRNA. mRNA is used instead of DNA because all the introns are spliced and investigator does not have to account for the variability of intron breakage in BCR and ABL1 gene when designing primer. * qRT-PCR * Expression of MRD level = BCR-ABL1/ABL1 Pitfalls of qRT-PCR for MRD (minimal residual disease) monitoring: unable to detect fusion transcript even if CML is present

Answer 64

FISH Interphase: easier to perform since the leukemic cells need not be altered CML due to fusion gene signl In normal cells there should 2 BCR (green) and 2ABL1 (red) genes. Spatial location of the 4 signals should be random as they are located on separate chromosomes. In cells of CML patient a fusion signal is detected as a pair of probe will go together Conventional cytogenetic study: detect normal karyotype which indicates that the presence of BCRABL1 fusion gene in FISH is not due to balanced translocation FISH: fusion gene is caused by insertion instead of translocation. A small fragmetn of ABL1 gene breaks from chromosome 9 and is inserted into BCR gene in chromosome 22 to create a fusion gene. Such breakage is sub-microscopic and hence is not detected by conventional cytogenetic study.

Answer 65

Progressive accumulation of functionally incompetent lymphocytes which are monoclonal in origin Occurs more often in males than femaels Median age of dx is 70 years, never in childhood

Answer 66

Lymphadenopathy (50-90%): generalized or localized. The more generalized the more likely the dx is CLL. Commonly involved LN include cervical, supraclavicular and axillary LN. Enlarged LN are non tener, firm, rounded, discrete and freely mobile on palpation Hepatomegaly (15-25%) Splenomegaly (25-55%) Dermatological system * Leukemia cutis: most commonly involves the face. Nodular and violaceous/gray blue in color. * Can also manifest as macules, papules, nodules, ulcers or blister

Answer 67

Requires both of the following * Absolute B lymphocyte count in periphreal blood >5x 10^9/L with a preponderant population of morphologically mature appearing small lymphocytes * Evidence of clonality of circulating B lymphocytes by flow cytometry of peripheral blood with majority of population expressing the following pattern of monoclonal B cell markers Expression of B cell associated antigens (CD19, CD20,CD23) Expression of T cell assocateid antigens (CD5)

Answer 68

CBC with DC * Anemia: pure red cell aplasia, AIHA * Leukocytosis (major is a diagnostic feature in elderlty) * Thrombocytopenia: autoimmune thrombocytopenia Peripheral blood smear: lymphocytosis (leukemic cells are small, mature appearing lymphocytes with dense nucleus, partially aggregated chromatin and without discernible nucleoli Bone marrow aspiration or trephine biopsy * Not requires for dx of CLL. Presence of lymphocytes for >30% of all nucleated cells LN biopsy * Diffusely effaced nodal architecture with occasional residual naked germinal centers * Infiltrate composed of mature appearing, small lymphocytes with a mixture of prolymphocytes and paraimmunoblasts Serum immunoglobulin level * Hypogammaglobulinemia * Decreased IgG, IgA and IgM Special test: immunophenotyping Flow cytometry B cells: CD10, CD19, CD20, CD22, CD23 T cell: CD2,CD3, CD4, CD5, XD7

Answer 69

General approach: always do chemotherapy (says Kwong sir) Purine analogues: fludrabine/pentostatin Alkylating agents; cyclophosphamide/bendamustine/chlorambucil Monoclonal antibodies: rituximab/ofatumumab/obinutuzumab TKI: ibrutinib HSCT: indicated in young patietns with aggressive disease

Answer 70

Lymphoma are clonal malignancies of lymphoid system Most common site of primary extranodal system is GIT (stomach, duodenum = submucosal) followed by skin. Other rare sites include bone, kidney, bladder, prostate, testis, breast, ovary, orbit, heart Pathological classification by WHO Histological appearance Immunophenotyping (flow cytometry): B cells (85%), T cells (10-15%), NK cells (5%) Cytogenetics/molecular genetics All 3 features are needed for appropriate classifcation of lymphoma

Answer 71

Hodgkin lymphoma: presence of Reed Sternberg cells RS cells are clonal B cells (ALL HL are B cell lymphoma), bilobed nucleus + prominent nucleoli with surrounding clear space Arises from gernal center or post germinal center Bimodal distribution (15-35 years and >50 years old)< less common than non Hodgkinsl ymphoma Mode of spread * Affects superficial (usually cervical or supraclavicular) +/-mediastinal LN * Nodal disease with a tendency to spread in an orderly anatomical fashion to contiguous areas of LN

Answer 72

* Absence of Reed sternberg cells * Consists of a diverse group of malignancy neoplasms derived from precurosr B or T cell, mature B or T cells or NK cells: majority of NHL is still B cells in origin (85%) * Associated conditions Infectious (H.pylori, EBV, HTLV-1) Autoimmune disorders (SLE/RA/Sjogren syndrome) Immunodeficeincy (HIV/post transplant recipients) Median age of dx is 65 years old Mode of spread * Diffuse nodal and/or extranodal spread * Tendency to spread haematogenously with non contigous lymphatic spread unlike in Hodgkins lymphom * More common to have CNS involvement

Answer 73

Bacterial infection: H.pylori (gastric MALT lymphoma) Viral infection * EBV: burkitt lymphoma, NK cell lymphoma (nasal) * HIV: primary lymphoma and primary CNS lymphoma are AID defining malignancies * Human T cell lymphotropic virus (HTLV-1): adult T cell leukemia/lymphoma * Hep C virus: MALT lymphoma Autoimmune disorders * Hashimotos thyroditis * Sjogren syndrome * SLE * RA * Autoimmune hemolytic anemia Immunodeficiency state * Inherited immunodeficiency state * Acquired immunodeficiency state: HIV infection, solid organ or HSCT, immunosuppressants Inflammatory GI diseases: IBD, GI nodular lymphoid hyperplasia

Answer 74

Aggressive lymphoma * Presents acute or subacutely with rapidly growing mass, systemic B symptoms, elevated serum LDH and uric acid * Goal of management = cure since it has a higher chance of cure Indolent lymphoma * Presents insidiously with slow growing lymphadenopathy, hepatomegaly, splenomegaly or cytopenia * Goal of management: symptomatic relief since it is typically incurable

Answer 75

B symptosm (fever+ weight loss +night sweats) Components of B symptoms: fever of unknown region >38C, unexplained weight loss >10% over past 6 months, drenching night sweats Hodgkins lymphoma: Pel Ebstein fever (cyclic fever recurring at variable intervals of days or weeks and lasts for 1-2 weeks before waning), pruritis Non Hodgkins lymphoma: B symptoms may vary between subtypes of NHL Painless lymphadenopathy * Hodgkin lymphoma presents with superficial (usually cervical or supraclavicular)+mediastinal lymphadenopathy * Non Hodgkin lymphoma presents with peripheral lymphadenopathy * Discrete, painless, firm or rubbery * Persists and does not subside over weeks

Answer 76

General exam: skin involvement Lymphoid survey Waldeyers ring: adenoid --> tubal --> palatine --> tonsils * Standard lymph node o Firm or rubbery lymph nodes oCervical --> Supraclavicular--> Axillary --> Epitrochlear --> Inguinal -->Femoral Popliteal lymph node * Abdominal lymph node o Mesenteric lymph node/ Retroperitoneal lymph node * Liver and spleen  Head and neck examination * Nodal and extranodal involvement of H&N is suggested by enlargement of preauricular lymph nodes and tonsillar asymmetry * Primary CNS lymphoma commonly involves the eyes  Chest examination * Mediastinal adenopathy may be detected on clinical examination or chest radiograph * Presents with persistent cough, chest discomfit with an abnormal CXR  Abdominal examination Hepatosplenomegaly is common in indolent lymphoma with intact LFT

Answer 77

* CBC with DC * Peripheral blood smear * LFT * RFT (nephrotoxic CT drugs) * Serum Ca2+ and PO4-: hyperCa due to PTHrP (paraneoplastic syndrome), evaluation of tumor lysis syndrome * Serum LDH level: rapidly growing tumors of NHL such as Burkitt lymphoma * Serum uric acid level * Serum b2-microglobulin level: used in follicular lymphoma and other indolent lymphoma for prognostic purpose * Serum protein electrophoresis. Detection of monoclonal immunoglobulin (M spike). Large M spike associated with lymphoplasmacytic lymphoma. Small M spike associated with small lymphocytic lymphoma/chronic lymphocytic leukemia and extranodal marginal zone lymphoma * HIV serology: systemic non HL and CNS lymphoma are AIDS defining malignancy * HBV and HCV serology: must include HBsAg, anti HBs and anti HBc +-HBV DNA viral load * EBV serology: EBV VCA IgA and EBV EA IgA, EBV DNA viral load * Serum autoantibodies * Evaluation of other tissues: pleural fluid analysis by thoracentesis, peritoneal fluid analysis by paracentesis. CSF fluid by lumbar puncture (indicated in primary CNS lymphoma, lymphomatous meningitis or patients with Burkitt lymphoma which has a high incidence of CNS involvement Radiological tests PET CT scna: staging disease. All nodular lymphoma histology is considered FDG avid except chronic lymphocytic leukemia/small lymphocytic lymphoma, lymphoplasmacytic lymphoma with Waldenstrom macroglobulinemia and marginal zone lymphoma Excisional LN biopsy (sufficient tissue for histologic, immunologic, molecular biologic assessment and classification) LN >1cm diameter should be biopsied LN>2cm has the best diagnostic yield Site of LN: enlarged peripheral LN are generally preferred FNA only for initial screening for peripheral lymphadenopathy to detect benign form of reactive lymphadenopathy (viral/bacterial, non inflammatory) Bone marrow aspirate/trephine biopsy: done prior to initation of treatment as part of the staging evaluation. Typically evaluated for morphology, immunophenotyping, cytogenetics and molecular genetics. Histological exam: pattern of LN involvement (nodular/follicular/diffuse pattern) Immunophenotyping * Flow cytometry: on fresh unfixed single cell suspensions. Detection of surface immunogloblin light chains which is very helpful in determining clonality of B cell proliferation. Superior to IHC as able to etect 2 or more markers simultaneosly, rapid turnaround time, greater quantitative capacity and higher sensitivity for certain markers * Immunohistochemistry: on sections of fixed or fresh frozen tissues. Expression of cell surface lymphoid differentiation antigens are used to distinguish B cell and T cells at various developmental stages Cytogenetics: karyotyping and FISH Molecular genetics: IgH gene rearrangement by PCR, T cell receptor gene rearrangement by PCR

Answer 78

* Cardiac functioning: screening with echocadiogram. Baseline evaluation of cardiac function such as ejection fraction considered if patients likely to be treated with anthracycline (doxorubicin) or mediastinal irradiation * Pulmonary function: CXR/CT thorax, DLCO as pulmonary function considered when patient likely to be treated with bleomycin * HBV/HCV screeing: antiviral prophyalxis required before starting on rituximab

Answer 79

1. Oncological emergency of NHL  CVS: SVCO/ IVCO/ Venous thromboembolic disease/ Pericardial tamponade  Gastrointestinal: Intestinal obstruction/ Hepatic dysfunction  CNS: Spinal cord compression/ Lymphomatous meningitis  Urogenital: Ureteral obstruction/ Hydronephrosis  Respiratory: Acute airway obstruction (mediastinal lymphoma)  Hematology: Hyperleukocytosis (B or T-cell lymphoblastic leukemia/lymphoma)/ Hyperviscosity syndrome (Lymphoplasmacytic lymphoma with Waldenstrom macroglobulinemia)/ Autoimmune hemolytic anemia/ Leukopenia/ Thrombocytopenia  Endocrine: Hypercalcemia/ Hyperuricemia Tumor lysis syndrome Haematological malignancy is highly chemosensitive, high tumor cell proliferation rate. Large tumor burden: bulky disease >10cm in diameter/WBC>50,000uL >2x ULN/organ infiltration or bone marrow involvement Electrolytes Hyperuricemia, hyperP, hypoCa, acute kidney injury Treatment: rasburicase (recombinant urate oxidase) which converts uric acid to solube allantoin Correction of electrolyte abnormalities (especially hyperK), consideration of renal replacement therapy Prevention: IV hydration, hypouricemiac agents. Uric acid lowering agents = allopurinol/febuxostat, recombinant urate oxidase = rasburicase

Answer 80

Malignant causes * Lung cancer Venous obstruction results from extrinsic compression of SVC by either the tumor or enlarged mediastinal LN SCLC: SVCO more common in SCLC accounting for 10% of cases at preentation NSCLC (most common): but overall NSCLC is the most common malignant cause of SVCO because of higher incidence * Lymphoma NHL: diffuse large (DLBCL) and lymphoblastic leukemia are the most common subtypes. SVCO common in patietns with primary mediastinal DLBCL which typically presents with a rapidly enlarging anterior mediastinal mass Hodgkin lymphoma: rarely a cause of SVCO * Others: lymphoma, mesothelioma, primary mediastinal germ cell neopplasm, metastasis to mediastinal LNs (breast cancer) Non malignant causes * Indwelling intravascular devices: SVCO due to thrombosis from devices such as central venous catheter, cardiac pacemaker leads and implantable defibrillator presidposes to SVCO * Fibrosing mediastinitis: excessive host response to prior infection with histoplasma and filariasis * Post radiation fibrosis: patients who recieved prior thoracic RT has increased risk of post radiation local vascular fibrosis

Answer 81

Obstruction of SVC has 2 mechanisms * Intrinsic obstruction due to thrombosis of blood within SVC * External compression or invasion by adjacent pathological processes invovling right lung, LNs and other mediastinal structures Development of venous collaterals * Collateral veins may arise from the azygous, internal mammary, lateral thoracic, paraspinous and esophageal venous systems * CVP remains elevated even when well developed venous collaterals are present Onset of SS depends on rate of SVCO in relation to recruiment of venous collaterals * Patients with malignant SVCO develops within weeks to months since rapid tumor growth and can develop collateral flow * Patients with fibrosing mediastinitis such as due to infection like histoplasmosis may not become symptomatic for years Consequences of SVCO * Edema may narrow the lumen of nasal passages and larynx which can lead to dyspnea, stridor, cough, hoarseness and dysphagia * Edema may lead to cerebral edema and subsequently cerebral ischemia and herniation

Answer 82

 Dyspnea (most common)  Cough  Cyanosis  Stridor/ Wheezing  Dysphagia  Chest pain  Swelling of face, neck and upper extremities  Distension of neck veins and chest veins SS of cerebral edema (may need emergency stenting)  Headache  Dizziness  Syncope  Confusion

Answer 83

* CXR: mediastinal widening and pleural effusion * Duplex USG: cannot directly image the SVC due to acoustic shadowing of overlying ribs. Useful for excluding thrombus in subclavian, axillary and brachiocephalic veins and is the initial imaging for patients with indwelling devices. * Contrast enhanced chest CT is the most diagnostic modality: level and extent of venous blockage, identify and map venous collaterals and permits identification of underlying venous obstructin * Digital subtraction venography: gold standard in dx of SVCO and assess extent of thrombus formation * Biopsy for histopathology Less invasive approach: sputum cytology, superficial/supraclavicular LN biopsy, thoracentesis, transthoracic needle aspiration biopsy under fluoroscopic/CT/USG guidance More invasive approach: bronchoscopy, medinastinoscopy, thoracoscopy, thoracotomy/sternotomy

Answer 84

General mangement: prop up for head elevation, O2 supplement Principle = treatment tailored to specific neoplasm and therefore tissue dx is essential prior to empirical treatment Emphasis on accurate histological dx before starting therapy. Only use stent in last line for rapid relief that can be achieved using RT Medical treatment * Corticosteroids IV dexamethasone 4mg q6h (steroid responsive malignancy including lymphoma and thymoma) patients undergoing RT particularly if laryngeal edema present * Diuretics: frusemide * Anticoagulants only when SVC thrombus is present LMWH preferred over warfarin in malignancy related thrombosis and CrCL>30ml/min. Lower rate of recurrent thromboembolism, less drug interactions with subsequent systemic cancer treatment Surgical and other treatment RT: Symptomatic obstruction is a prolonged process (development of collaterals) and therefore should do diagnostic workup prior to RT (as RT sensitive tumors can be shrunk --> will need to wait for increase in size to confirm dx) except severely symptomatic (Stridor/ increased ICP) Endovascular stenting. Only indicated in patients with severe symptoms who require urgent intervention before tissue dx is avaialble. Recurrent or chronic SVCO following conventional treatment. Stent complications include bleeding, infection, perforation, or rupture of SVC, pulmonary embolism, stent migration and stent failure with reocclusion. Post stenting short term dual antiplatelets (DAPT) for 3 months recommended.

Answer 85

Results from clonal expansion involving pluripotent haematopoietic stem cell (HSC) Production of mature cell which may be normal looking but functionally abnormal Different from MDS in that cells are not dysplastic. Dysplastic cells mean abnormal proliferation of cells which do not mature. Proliferation of all 3 haematopoietic lineages although usually clinically manifests abnormality in 1 lineage only Erythroid lineage, myeloid lineage, megakaryocytic lineage

Answer 86

Classificaiton * Polycythemia vera (PV) * Essential thrombocytosis (ET) * Primary myelofibrosis (PMF) * Chronic myeloid leukemia (CM), BCR-ABL1+ * Chronic neutrophilic leukemia (CNL) * Chronic eosinophilic leukemia, not otherwise specified (NOS) * Myeloproliferative neoplasm, unclassifiable Mutation of MPN as clonal markers and diagnostic tools * JAK2 V617F (Janus kinase): PV = 95%; ET = 50%; PMF = 50% o Gain-of-function mutation in either exon 14 or exon 12 * CALR exon 9 (Calreticulin): ET = 25%; PMF = 35% o Occurs in MPNs without JAK2 or MPL mutations * BCR-ABL1 fusion: ALL cases of CML * MPL/ TET2/ ASXL1: Mutations with lower frequency * CSF3R: CNL = 60% Risk of leukemic transformation in AML Risk of development into myelofibrosis

Answer 87

Chronic MPN which is distinguished from other MPNs by the presence of an elevated RBC mass (erythrocytosis) Increased RBC mass insufficient to establish dx as it is observed in other conditions such as chronic hypoxia and EPO secreting tumors Most frequently caused by GOF mutation in JAK2 V617F in 95% of PV Presents with erythrocytosis often accompanied by leukocytosis and thrombocytosis Associated with increased risk of thromboembolic events and risk of progression into AML and myelofibrosis

Answer 88

JAK2 V617F mutation in exon 14 of JAK2 gene Mutation in exon 12 of JAK2 gene in 4% of patients Secondary causes EPO secreting tumors (most common): RCC, HCC, cerebellar haemangioblastoma, phaeochromocytoma, uterine fibroids Chronic hypoxemia: chronic pulmonary disease, right to left cardiac shunts, red cell defects (methemoglobinemia, carboxyhaemoglobinemia (CO poisoning)

Answer 89

Symptoms * Pruritis: exacerbated by hot bath (aquagenic pruritis) * Vasomortor symptoms: headache, dizziness, light headedness, tinnitis, visual blurring, atypical chest pain. Erythromelalgia (painful burning sensation in extremities accompanied by erythema --> associated with acral paresthesia. Pathognomonic of microvascular thrombotic complications with microvascular ischemia which occurs in both PV and ET0 * Symptoms of thrombosis (hyperviscosity): transient ocular blindness, ocular migraine * Symptoms of bleeding: easy bruising, epistaxis/gum bleeding Signs of PV * Facial plethora * Scratch marks * Hypertension * Hepatomegaly * Splenomegaly * Engorged retinal vein Constitutional symptoms: fever, night sweats, fatigue, weight loss, bone pain

Answer 90

Risk stratification Low risk = age <60 years and no prior thrombosis --> low dose aspirin + phlebotomy to maintain haematocrit <45% High risk = age >60 years old or prior thrombosis --> low dose aspirin + phlebotomy to maintain haematocrit <45% + cytoreductive therapy with hydroxyurea/pegylated IFNa-ruxolitinib Medical treatment Low dose aspirin * Recommended for all patients with PV unless contraindicated to preven thrombosis * Patients with platelet count >1000 x 10^9L should be screened for acquired von Willebrand disease by measuring vWF: ristocetin cofactor activity. Aspirin contraindicated in patients with acquired vWD Hydroxyurea: 1st line cytoreductive agent due to its efficacy, ease of administration, lower cost, long term safety profile and favorable toxicity profile Alternative cytoreductive agents. Pegylated IFNa = associated with high haematological response with limited toxicity (1st line in young patients who may become pregnant) Ruxolinib: JAK1/2 inhibitor indicated for patients who are refractory or intolerabel to hydroxyurea Surgical treatment Phlebotomy (venosection): recommended for all patients with PV to maintain haematocrit <45% Controls polycythemia by producing a state of absolute iron deficiency and hence iron supplementation should not be given Standard one unit of phlebotomy (500ml) should reduce haematocrit by 3% in normal size adult

Answer 91

Median survival with treatment = 13.5 years Associated conditions * Gouty arthritis: increased uric acid due to increased cellular turnover * Peptic ulcer disease (PUD): increased histamine release from basophila * Thrombosis: MI/stroke, peripheral vascular disease/ limb ischemia. Superficial thrombophlebitis/DVT/ PE. Portal/splenic/ mesenteric vein thrombosis. Budd Chiari syndrome

Answer 92

Chronic MPN characterized by excessive clonal platelet production with vasomotor symptoms and a tendency for thrombosis and hemorrhage Mutations associated with ET that have dx and prognostic implications * JAK2 V617F * CALR exon 9 * MPL * 10-15% of patients have negative for all 3 mutations (triple negative patients) Associatedw ith increased risk of thromboembolic events sand risk of progression into AML and myelofibrosis

Answer 93

Normal production of platelets * Thrombopoietin (TPO) binds to MPL (c-Mpl) receptors on megakaryocytes * Induces activation of JAK2 and activating STAT5 signaling pathways * Results in increased megakaryocyte development and thrombopoiesis Mutations associated with ET that have diagnostic and prognostic implications * JAK2 V617F: mutation causes unregulated JAK-STAT signal transduction leading to unregulated myeloproliferation causing megakaryocyte hyperplasia * CALR exon 9 = 25% * MPL mutation = 3-5% * 10-15% of patients are negative for all 3 mutations (triple negative patients)

Answer 94

Dysregulated myeloproliferation = Atypical megakaryocytic hyperplasia and proliferaetion Bone marrow fibrosis = Reactive deposition of fibrous connective tissue (reticulin orcollagen) in the bone marrow often with osteosclerosis o Hallmark of PMF which contributes to ineffective hematopoiesis producing anemia Leukoerythroblastosis = Peripheral blood demonstrates a triad of teardrop-shaped red cells + nucleated red blood cells + early myeloid forms in later fibrotic stages Extramedullary hematopoiesis = Results in hepatomegaly and splenomegaly o Non-functional hematopoiesis with NO significant production of blood cells

Answer 95

* JAK2 V617F (Janus kinase) = 45 – 50% * CALR exon 9 (Calreticulin) = 45 – 50% * MPL (Myeloproliferation leukemia virus oncogene) mutation = 7 – 10% * 1 – 2% of patients are negative for all 3 mutations (triple-negative patients)

Answer 96

CBC with DC * ANemia * Leukopenia/leukocytosis * Thrombocytoepnia/thrombocytosis Peripheral blood smear * Leukoerythroblastic picture: tear drop shaped red cells (dacrocytes): indicates membrane damage from passage through the spleen * Nucleated red blood cells: indicates extramedullary haematopoiesis * Presence of early myeloid forms including myelocytes, promyelocytes and myeloblasts: indicates extramedullary haematopoiesis Anisopoikilocytosis: anisocytosis = variation in RBC size, poikilocytosis= variatio in RBC shape Abnormally large platelets with altered granulation and fragment megakaryocytes Serum LDH level: increased LDH due to ineffective haematopoiesis Serum uric acid level: hyperuricemia due to increased turnover of haematopoietic tissues --> predispose to gouty arthritis and uric acid stones Bone marrow aspiration: difficult to aspirate yielding a dry tap and is not diagnostic even if successful. Bone marrow biopsy: presence of severe extensive reticulin or collagen fibrosis. Reticulin visualized with silver stain, collagen visualized with trichrome stain Decreased erythropoiesis, increased granulocyte proliferation, increased megakaryocytic proliferation and typia Genetic testing JAK2V617F=45-50%, CALR exon9 =45-50%, MPL mutation = 7-10% 1-2% of patients are negative for all 3 mutations

Answer 97

Heterogenous group of clonal disrorders characterized by ineffective haematopoiesis leading to peripheral blood cytopenia and increased risk of transformation to AML Haematological condition characterized by * Increased suspectibility to apoptosis of clonal myeloid progenitors in bone marrow leading to ineffective haematopoisis * Abnormal cells are not released into circulation (pancytopenia): leads to cytopenia despite generally hypercellular bone marrow Risk of leukemic transformation: progression to AML may result from clonal progenitors shifting from apoptosis to proliferation.

Answer 98

AA refers to pancytopenia in association with bone marrow hypoplasia or aplasia without dysplasia, bone marrow infiltrate or bone marrow fibrosis AA may coexist with or evolve into another haematological disorders Paroxsymal nocturnal haemoglobinuria: close relationship between PNH and AA Clonal disorder with acquried somatic mutation of PIG-A gene. Leads to deficiency of GPI anchor for proteins (CD55 and CD59) on the surface of RBCs which normally acts as inhibitors of complement. Presents with haemolytic anemia due to intravascular hemolysis, pancytopenia if overlap with AA or MDS, smooth muscles dystonia and hypercoagulability MDS AML

Answer 99

Bimodal distribution: occurs most commonly in children and young adults aged 10-25 years and adults aged >60 years

Answer 100

Inherited aplastic anemia (15-20%) Fanconi anemia * Most common inherited form of AA * Features: pancytopenia, short stature, microcephaly, absent or hypoplastic thumbs/polydactyly/clinodactyly, gonadal/genital malformations (hypospadias/cryptochordism), developmental delay, VACTREAL-H malformations * Predisposition to malignancy including MDS, AML and SCC of H&N * Diagnostic test: NGS to identify mutations. Chromosomal breakage test with diepoxybutane (DEB) or mitomycin (MMC): hallmark fo FA is defective DNA repair. Addition of DEB leads to chromosomal breakage: normal patient can repair but FA patient cannot Shwachmann Diamond syndrome * Presents in infancy with bone marrow failure, exocrine pancreatic dysfunction and skeletal abnormalities * Dyskeratosis congenita: associated with characteristic skin and nail findings Dyskeratosis cogenita * Associated with characteristic skiin and nail findings (tongue leukoplakia/nail dystrophy/reticular skin pigmentation) Telomere abnormalities * TERT or TERC mutations Acquired aplastic anemia Idiopathic (70-80%) Viral infections * HIV, Hep virus, herpes viridae (VZV,EBV, CMV, HHV-6)< parvovirus B19 (typically causes pure red cell aplasia and isolated anemia) Drug induced: extent and timing of bone marrow suppression to CT and other cytotoxic drugs is generally predictable and not considered AA Drugs assoicated with AA. antibioptics: sulphonamides, anticonvulsants: valproate/ carbamazepine/phenytoin, antithyroid: methimazole/propylthiouracil, NSAID: indomethacin, others: gold Toxins: chemicals, insecticides Ionizing radiation Miscallaneous causes: pregnancy, thymoma, autoimmune disease (SLE, graves), GVHD, post HSCT transplantation

Answer 101

**Anemia**: normocytic normochromic. Causes: bone marrow replacement, kidney damage. Associated symptoms: pallor, fatigue, SOB, tachcyardia, palpitations **Bone pain**: production of osteoclast activating factors by myeloma cells or marrow stoma: receptor activator of NFkB ligand Site: more often in back anad chest, less often in upper and lower extremities Character: induced by movement Associated symptoms: decreased height due to vertebral fracture **Renal disease**: increased serum creatinine causes: hypercalcemica (amjor), light chain myeloma cast nephropathy (major), light chain amyloidosis, light chain deposition disease Hypercalcemia Fatigue Weight loss Others: paresthesia, hepatomegaly, splenomegaly, lymphadenopathy Associated conditions * Infections caused by immune dysfunctions: impaired lymphocyte function, impaired normal plasma cell function * Neurological diseases Radiculopathy: most common neurological complication of MM, usually in thoracic or lumbosacral regions. Caused by compression of nerve by paravertebral plasmacytoma or collapsed bone Cord compression: spinal cord compression from extramedullary plasmacytoma or bone fragment of a fractured vertebral body. Suspected with back pain, weakness or paresthesia of LL, bladder or bowel dysfunction

Answer 102

* Plasmacytoma are tumour composed of plasma cells of variable maturity which are histologically identical to those seen in multiple myeloma o May occur solely in bone and outside in soft tissues (extramedullary plasmacytoma)

Answer 103

* Plasma cell proliferative disorders associated with overproduction of monoclonal light chains * Diagnosis is established by demonstrating amyloid on biopsy of affected tissue such as abdominal fat, bone marrow, rectum or kidney

Answer 104

CBC with DC ESR/CRP Electrolyte profile: hyperCa Serum protien level: hyperproteinemia LFT: normal ALP (meaning osteoblastic acitivity is not increased) RFT and urinanalysis: increased serum creatinine, proteinuria (myeloma cast nephropathy), light chain amyloidosis (usually urinary protien +ve since most of the proteinuria is comprised of albumin (nephrotic syndrome) Peripheral blood smear: rouleaux formation (RBC stack of coins), monoclonal plasma cells (rarely seen in MM), leukopenia (20%): suppressed haematopoiesis, thrombocytopeni (5%): M protein interacts with thrombocytes Bone marrow exam (aspiration and trephine biopsy) * Plasma cell infiltration >10% * Normal mature plasma cells * Myeloam cells: multiple pale bluish white, grape like accumulatin * Immunopheotyping: normal K- λ ratio in bone marrow = 2:1, ratio >4:1 or <1:2 is considerd to be K or λ monoclonality. Significance = differentiate monoclonal gammopathies from reactive plasmacytosis due to autoimmune disease, metastatic carcinoma, chronic liver disease and AIDS Radiological tests Skeletal survey PA view of chest, AP and lateral view of skull, AP view of pelvis, AP and lateral view of cervical, thoracic and lumbar spine, AP and lateral view of femur and humerus Typical features: focal lytic lesions, diffuse osteopenia, pathological fractures, compression fractures of spine Most frequent sites of involvement are sites with active haematopoiesis: skull, vertebral bodies, thoracic cage, pelvix, proximal humerus and femur CT/MRI: routine before making dx of solitary plasmacytoma or smoldering myeloma. MRI can dwetect diffuse and focal bone marrow lesions in patiens with multiple myeloma without osteopenia or focal osteolytic lesions on standard metastatic bone surveys PET/CT scan: FDG correlates with areas of active lytic bone disease Specific test Serum/urine protien electrophoresis and immiunofixation

Answer 105

 Spinal cord compression from vertebral collapse fracture * Leads to acute onset of paraplegia, urinary and bowel incontinence  Urgent decompression spinal surgery or radiotherapy  Amyloidosis  Obstruction of distal renal tubules by protein casts  Toxic effect of light chain on renal tubules  Deposition of light chain in renal glomeruli  Infection  Dehydration  Hypercalcemia  Hyperuricemia

Answer 106

 Impaired B-cell function  Neutropenia

Answer 107

 Heart failure  Bleeding tendency  Dizziness  Somnolence  Coma

Answer 108

 Monoclonal paraprotein in serum  Monoclonal free light chains in urine  Monoclonal plasma cell proliferation in bone marrow  Presence of discrete lytic bone lesions

Answer 109

 Normal ALP level suggests that the underlying cause of hypercalcemia is unlikely due to osteoblastic activity  Multiple myeloma * C: HyperCalcemia * R: Renal insufficiency * A: Anemia * B: Bone lytic lesion  Serum protein electrophoresis  Calculate serum globulin = Total protein – albumin = 58 g/L (high)  B-cells in multiple myeloma produces immunoglobulin which interferes with phosphate during the assay