HemOnc Flashcards

Question

[Platelet Disorders] Immune mediated destruction of platelets 2. Causes of Secondary ITP 3. Causes of neonatal ITP

Answer 1

2. Secondary ITP (non-idiopathic) - viral infections (HIV, CMV, EBV, parvoB19) - vaccinations (MMR, varicella) - immune (DiGeorge, CVID) - autoimmune (Lupus, Crohn's) 3. Neonatal A. Neonatal autoimmune - due to auto-antibodies transferred passively via maternal IgG (if mom has lupus, ITP); treat with IVIG B. mom and baby have different platelet antigens --> maternal antibodies made against fetus antigens and cross placenta; treat with maternal platelets, IVIG

Answer 2

Microangiopathic hemolytic anemia - damaged platelets and RBCs bc of damage to blood vessels 1. TTP - (most commonly acquired) Ab against ADAMTS13, commonly seen in adult females - (AR inherited) deficiency of ADAMTS 13 low ADAMTS13 --> vWF is not cleaved --> ultralarge ULvWF agglutinates leads to abnormal platelet adhesion --> platelet microthrombi 2. HUS - seen in children with E. coli O157:H7 dysentery (Exposure to undercooked beef) --> E. coli verotoxin damages endothelial cells --> platelet microthrombi - also Campylobacter or Shigella 3. Lab findings: - thrombocytopenia with increased bleeding time - normal PT/PTT - schistocytes - increased megakaryocytes on bone marrow biopsy 4. Clinical findings *Pentad* i. skin and mucosal bleeding (due to thrombocytopenia) ii. microangiopathic hemolytic anemia iii. CNS problems - confusion, focal abnormalities *more common in TTP* iv. renal failure (or insufficiency) *more common in HUS* v. fever 5. Treatment A. HUS - supportive, NO antibiotics B. TTP - plasmapheresis (replace ADAMTS13) or corticosteroids (remove circulating antibody)

Answer 3

1. DIC - mixed platelet and coagulation disorder - small blood clot formation in bv everywhere --> use up available coagulation proteins, platelets --> clotting in some places (ischemia and infarction), bleeding in others (mucosal surfaces, IV sites) A. Causes - anything bad enough to kill you (tissue damage) can give you DIC eg drowning, adenocarcinoma, trauma, infection, sepsis, snake bite --> tissue factor/ VII extrinsic clotting cascade B. Lab findings - low platelet count - abnormal + prolonged clotting screens (PT, PTT) - low fibrinogen (used up in making platelet microthrombi) - schistocytes (microangiopathic hemolytic anemia) - fibrin split products eg D dimer (screening test) C. Treatment - treat underlying disease 2. Sequestration - platelets become trapped in spleen --> thrombocytopenia and hypersplenism 3. DD: - liver disease - portal hypertension or thrombosis - infection - Felty's syndrome (lupus) - lyposomal or glycogen storage disorders

Answer 4

1. Bernard-Soulier syndrome A. Cause - genetic (AR inheritance) deficiency of Gp1b (glycoprotein on platelets), which complexes with vWF for platelet adhesion B. Lab - mild thrombocytopenia (platelets don't live as long) with very large platelets ("Big Suckers" created in bone marrow); long clotting times - abnormal ristocetin test (pt platelets + exogenous vWF) C. Clinical - mild to moderate bleeding esp mucosal bleeding (epistaxis, hemoptysis, hematuria) 2. von Willebrand disease - most common inherited clotting disorder / coagulopathy (AD); vWF binds subendothelial collagen and GP1b on platelet; stabilizes VIII (which has short t1/2) A. Cause Type 1 - partial deficiency of vWF (most common) Type 2 - dysfunctional protein; A) improper assembly, B and M) changed binding, N) decreased VIII binding Type 3 - complete deficiency B. Lab - increased PTT (low VIII), VW antigen - abnormal ristocetin test (pt serum + fixed platelets) C. Clinical - easy bruising, menorrhagia, postop bleeding, gingival bleeding, prolonged bleeding after minor cuts

Answer 5

1. Congenital afibrinogenemia - absence of plasma fibrinogen (activated into fibrin, cross-linked by XIII to form hard clot over platelet plug) 2. Glanzmann thrombasthenia - deficiency or defect in GPIIb-IIIa (receptor for fibrinogen) A. Cause - AR; platelets can attach to endothelium but do not aggregate B. Lab - no aggregation with ADP, collagen, epi - only ristocetin (bc it involves Ib, not IIb-IIIa) C. Clinical - mucocutaneous bleeding, risk of platelet allo-immunization

Answer 6

1. Alpha granules - contain proteins e.g. TGFbeta, clotting proteins (vWF) - do not need to know disorders 2. Dense granules - contain chemicals e.g. ADP, ATP, histamine, serotonin, Ca2+ A. Hermansky Pudlak syndrome - AR, common in Puerto Rico, HPS gene mutation --> absence of dense granules B. Storage pool disease - group of disorders with bleeding problems (nosebleeds), easy bruising due to defect in dense granules

Answer 7

``` Hemophilia - X-linked recessive 1. Hemophilia A (80% cases) - Factor VIII deficiency, most common is inversion mutation of short arm of X; increased PTT Hemophilia B (20% cases) - Factor IX deficiency (Christmas disease); increased PTT ``` 2. Clinical - A and B clinically similar, B is much less severe - bleeding into muscles and joints (ankles, knees) and can present in infancy --> joint deformity, disease, debility - other common bleeding spots: soft tissue, iliopsoas, thigh, calf, butt, deltoid, forearm - neck swelling (emergency) - most common cause of death is intracranial hemorrhage 3. Severity A. Mild - up to 50% factor VIII --> bleeding uncommon B. Moderate - up to 5% --> bleed monthly C. Severe - <1% --> bleed weekly, joint disease 4. Treatment - give hemophiliacs factor replacement concentrates prophylactically - some patients develop inhibitors (neutralizing antibodies against the infused factor) --> PTT does not correct when you mix normal plasma with patient's plasma

Answer 8

1. Hemophilia C A. Cause - AR, factor XI deficiency - common in Ashkenazi jewish population B. Clinical - mucocutaneous bleeding (not muscle or joint which is typical hemophilia presentation), clinically mild 2. Factor XIII deficiency A. Cause - AR, v v rare B. Clinical - delayed bleeding (bc XIII has long t1/2), presents in infancy eg bleeding from umbilical stump; normal PT and PTT bc problem is later in clotting process 3. Acquired factor deficiencies A. Vitamin K deficiency - gamma carboxylates factors II, VII, IX, X and is oxidized; reduced back by VKORC to active form; deficiency due to antibiotics, malabsorption, drugs (warfarin/coumadin, rat poison) B. liver disease - decrease in factors II, VII, IX, X; V, fibrinogen *VIII preserved* - decreased platelets - decreased anticoagulants - abnormal bv - esophageal, rectal varices - decreased clearance of activated clotting factors - decreased clearance of clot breakdown products - production of abnormal fibrinogen C. Immune mediated - antibodies against VIII, V, II when immune surveillance is off (cancer, pregnancy, auto-immune disease)

Answer 9

1A. Antithrombin - inhibits serine protease clotting factors IX X, II B. Proteins C and S - inhibit non-serine protease clotting factors V, VIII C. TFPI - tissue factor pathway inhibitor, inactivates VII and X 2. Antiphospholipid syndrome - can be primary or secondary; immune system creates antibody against phospholipid (component of viruses) --> cross-reacts with normal tissues --> activation of coagulation --> causes blood clots in arteries and veins and miscarriage - associated with lupus - prolonged PTT (bc of interference from Ab), even though pt has increased risk of thrombosis 3. Purpura fulminans - severe Protein C deficiency - presents within hours of birth and progresses to DIC - purpuric lesions progress to black eschars (skin necrosis)

Answer 10

1A. Acute - excess myeloblasts or lymphoblasts (immature cells), presents suddenly with short clinical course B. Chronic - mature granulocytes (CML) or lymphocytes (CLL); often present asymptomatic, can take months for diagnosis 2. Acute leukemia - rapidly fatal disease characterized by proliferation and accumulation of abnormal immature hematopoietic cells ("blasts") in bone marrow and other tissues - AML - 85% of acute leukemia in adults - ALL - 85% of acute leukemia in children - acute biphenotypic leukemia (2%) - both lineages 3A. AML: cytoplasmic granules and more cytoplasm, 2-5 nucleoli, Auer rods (red needle-like clumps of azurophilic granules) B. ALL: no cytoplasmic granules and minimal cytoplasm, 1-2 nucleoli

Answer 11

1A. 2 Hit Model - Need 2 types of gene mutations - Class I - proliferative and survival advantage e. g. gain of function mutations of tyrosine kinases - Class II - blocks hematopoietic differentiation --> loss of maturation --> immature cells e. g. loss of function mutations of transcription factors for differentiation 2A. Point mutations - activated RAS oncogene, seen in both AML and ALL B. Translocations - e.g. BCR-ABL in pre-B ALL and CML C. Deletions - of both genes and chromosomes; commonly 5, 7, 11 (v poor prognosis) D. Duplication or gene amplification - trisomy 8 has poor prognosis *PCR is most sensitive diagnostic test for minimal residual disease (MRD)

Answer 12

1A. Flow cytometry AML - CD13, CD33 ALL - (B-ALL) CD 10, 19, 20 (T-ALL) CD2-8 B. Cytohistochemistry AML - myeloperoxidase (+) - seen as Auer rods, Sudan black B (+) ALL - TdT (+) DNA polymerase 2A. Constitutional - weight loss, anorexia, fever, night sweats, hyperkalemia and hyperuricemia B. Marrow replacement (of marrow cells with blasts) --> pancytopenia: i. anemia --> pallor, fatigue, dyspnea ii. thrombocytopenia --> bruising and mucosal bleeding iii. neutropenia (<1,000 neutrophils) --> fever, infections, mouth sores --> neutropenic diet with no fresh fruits, flowers, tap water, rectal exams, or IM injections C. Organ infiltration --> hepatosplenomegaly, gingival hypertrophy - bone pain and lymphadenopathy (more common in ALL)

Answer 13

1A. ALL - mostly in children A. Clinical - abrupt onset - 20% of ALL patients have CNS involvement (headache, vomiting, nerve palsies) - bone marrow failure - bone pain - organ infiltration - hepatosplenomegaly, particularly male testicular swelling - T-ALL usually presents as mediastinal thymic mass in male teenager B. Favorable: low WBC, B-ALL, t(12;21), hyperdiploidy (eg Trisomy 21), ages 2-10 Unfavorable: high WBC (50K+), T-ALL, adult or infant under 2 yrs, t9;22 BCR-ABL, CNS disease C. Treatment: longer than AML (~3 years), but 80% cured - chemo prophylaxis to CNS and scrotum - then 2 years maintenance therapy 2. AML - mostly in adults A. Favorable: younger age (under 50), low WBC, t(8;21) (seen in AML M2), inv16 (seen in AML M4), t15;17 (APML) Unfavorable - older age, poor performance, high WBC, t9;11 (seen in AML M5), prior chemo B. Treatment - conventional chemo with combo cytotoxics, transplant if relapse occurs - no maintenance chemo needed, no CNS prophylaxis

Answer 14

Multiple Myeloma - cancer of plasma cells; most common primary malignancy of bone (MCC overall is metastasis) - increased IL-6 (stimulates plasma cell growth and Ig production) 1. Diagnosis - 10%+ plasma cells in bone marrow - M (monoclonal) spike detected on electrophoresis, usually IgG (more common) or IgA + free light chains - Myeloma-related organ dysfunction (1+) CRAB i. Calcium disorders ii. Renal insufficiency from obstructive Bence Jones light chain proteinuria iii. Anemia - marrow replacement by plasma cells iv. Bone pain - plasma cell activate RANK receptor on osteoclasts --> lytic, punched out lesions --> severe bone pain, fractures - Rouleaux formation of RBCs (stacked on one another due to ↓ charge bw RBCs) 2. Pathogenesis - most common among older patients A. MGUS (monoclonal gammopathy of unknown significance) state - buildup of clonal population of plasma cells in bone marrow - asymptomatic, just observation - need additional mutations to move to next step B. Smoldering state - 10%+ plasma cells in bone marrow - asymptomatic, just observation C. Intramedullary myeloma - 30%+ plasma cells in bone marrow - symptomatic -diagnostic criteria + bone pain - can remiss but eventually relapse D. Extramedullary myeloma - active outside bone marrow 3. Treatment - can treat with: - imids (e.g. thalidomide - unknown etiology but teratogenic) - proteosome inhibitors (bortezomib, carfilzomib) - incurable, 10 year survival rate --> infection MCC of death (esp encapsulated organisms eg Strep pneumo)

Answer 15

1. Cyclophosphamide - nitrogen mustard A. MOA - DNA alkylation --> cross-linking, strand breaks, abnormal base pairing --> inhibits DNA synthesis; most effective in G1 and S phases (replicating cells most susceptible); activated by cyp450 B. Toxicity - dose-related (acute) nausea and vomiting (delayed) - bone marrow depression --> leukopenia, thrombocytopenia 2. Carmustine - nitrosurea A. MOA - DNA alkylation --> inhibits DNA synthesis A. Toxicity - (acute) nausea and vomiting (delayed) myelosuppression, neurotoxicity e.g. ataxia, dizziness - highly lipid soluble (can cross BBB, used for brain tumors) 3. Procarbazine A. MOA - non-classic DNA alkylating agent B. Toxicity - (acute) nausea and vomiting (delayed) high risk of secondary malignancy eg AML - oral administration - acts as MAOI --> Drug interactions with sympathomimetic amines, TCAs, antihistamines, CNS depressants, alcohol

Answer 16

1. Cisplatin A. MOA - DNA alkylating agent; Platinum compound that sticks to DNA strands (also cytoplasmic, nuclear proteins) --> cytotoxic in all stages B. Toxicity - (acute) highly emetogenic (delayed) nephrotoxicity, ototoxicity, irreversible neurotoxicity (peripheral neuropathy in glove and stocking distribution) 2. Bleomycin A. MOA - antitumor antibiotic; binds to DNA and produces free radicals --> causes single and double-stranded DNA breaks --> G2 phase arrest B. Toxicity - skin toxicity (rash), pulmonary toxicity (pneumonitis, infiltrates), alopecia, mucositis + stomatitis 3. Doxorubicin (adriamycin) A. MOA - anthracycline - produces free radicals, intercalates in DNA --> blocks DNA and RNA synthesis B. Toxicity - generates semiquinone free radicals --> Cardiotoxicity - acute - arrhythmias and conduction abnormalities - delayed - dose-dependent dilated cardiomyopathy - give dexrazoxane (iron chelator) to protect the heart against the cardiotoxic side effects of anthracyclines

Answer 17

1. Methotrexate MTX A. MOA - folic acid analog that binds to and irreversibly inhibits DHFR enzyme --> disrupts folate metabolic pathway in thymidine (pyrimidine) synthesis, max effect in S phase - reverse effects with leucovorin (reduced folate) - excretion affected by ASA, penicillin, NSAIDs B. Toxicity - myelosuppression, pancytopenia - megaloblastic anemia - alopecia, mucositis, pulmonary fibrosis, hepatotoxicity - cellular resistance - via decreased drug transport, decreased formation of MTX polyglutamates, increased levels of DHFR 2. 6-Mercaptopurine 6-MP- Purine analogs A. metabolized by HGPRT to become active; deactivated by xanthine oxidase - inhibits enzymes of purine nucleotide synthesis --> blocks synthesis of adenosine and guanine in S phase of cell cycle B. low TPMT enzyme--> toxicity (myelosuppression) - allopurinol (used to treat gout) inhibits xanthine oxidase --> need to reduce 6-MP dose 3. Cladribine - purine analog, can cause myelosuppression - adenosine deaminase inhibitor; treats hairy cell leukemia

Answer 18

1. 5-Fluorouracil 5-FU (inactive) A. MOA - cytotoxic pyrimidine analog, prevents conversion of THF --> DHF in thymidine synthesis - IV administration - catabolized by DPD enzyme (if pt has genetically low DPD levels in liver --> toxicity) B. Toxicity - myelosuppresion, neurotoxicity, cutaneous eg hand foot syndrome (blistering), photosensitivity 2. Capecitabine A. MOA - pro-pro drug of 5-FU - orally available B. Toxicity - hand-foot syndrome, but does not cause alopecia 3. Ironotecan A. MOA - Captothecans - inhibits topoisomerase I - results in S phase arrest; prodrug converted in liver B. Toxicity -serious diarrhea; first line for colorectal cancer (use when you want to preserve nerve function eg violinist)

Answer 19

1. Vincristine A. MOA - Microtubule inhibitors, bind to beta tubulin to inhibit microtubule assembly --> mitotic arrest in Metaphase of cell cycle B. Toxicity - neurotoxicity (peripheral neuropathy), SIADH, autonomic dysfunction (paralytic ileus, orthostatic hypotension) 2. Paclitaxel A. MOA - taxanes - spindle poison that binds directly to microtubules --> enhances polymerization and prevents degradation --> mitotic arrest in Metaphase - metabolized by p450 B. Toxicity --> acute hypersensitivity, nausea, vomiting - delayed - neurotoxicity, alopecia 3. Abraxane A. MOA - Paclitaxel with albumin carrier B. Toxicity - no hypersensitivity ``` 4. Mitomycin C A. MOA - antitumor antibiotic; DNA X-linker - acts on tumors in hypoxic environment - active throughout cell cycle B. Toxicity - HUS ```

Answer 20

1. ATRA (all trans retinoic acid) - used to treat acute promyelocytic leukemia (APML); nuclear receptor A. MOA - allows for differentiation of immature promyelocytic APML cells that had been arrested due to PML-RARa fusion protein --> they spontaneously apoptose (ATRA does not directly kill malignant cells) B. Toxicity - ATRA syndrome with leukocytosis (high neutrophils), capillary leak syndrome (pulmonary edema, respiratory failure), renal failure --> emergency! - treat with steroids, chemo *arsenic is also an approved treatment 2. imatinib (Gleevec) - used to treat chronic myelogenous leukemia (CML) caused by Philadelphia chromosome (BCR-ABL due to 9;22 translocation) A. MOA - binds to ATP binding site of ABL --> inhibits BCR-ABL (constitutively active tyrosine kinase) B. Toxicity - imatinib resistance due to mutations in binding cleft; fluid retention *dasatinib designed to overcome imatinib resistance (also inhibits PDGF-R and c-KIT --> treats GIST GI tumor)

Answer 21

3. trastuzumab (Herceptin) - monoclonal antibody used for HER2+ breast cancer A. MOA - binds to HER2 receptor (type of EGFR tyrosine kinase) --> interferes with HER2 dependent signaling --> antibody-dependent cellular toxicity of tumor cells B. Toxicity - cardiac toxicity (decreased LVEF, heart failure) 4. erlotinib (Tarceva) - tyrosine kinase inhibitor that blocks EGFR; works well on female, non-smoking patients with non small cell lung cancer (NSCLC) - can cause diarrhea, papulopustular acneiform rash 5. cetuximab (Erbitux) - chimeric monoclonal antibody that binds to EGFR tyrosine kinase; niche in head and neck cancer - toxicity - papulopustular acneiform rash; infusion rxn (within 1 hour), serum sickness (within 7-10 days)

Answer 22

6. Crizotinib - targets ALK tyrosine kinase - 4% of NSCLC have translocations with EML4-ALK1 (constitutive kinase activity) - works well on younger, non-smoking patients wild type for EGFR and RAS 7. vemurafenib - inhibits BRAF - V600E tyrosine kinase --> pathognomonic for malignant melanoma - treats melanoma but can cause other skin cancers --> use with MEK inhibitor (to prevent secondary malignancy) * colon cancers with V600E are resistant to vemurafenib (BRAF inhibition leads to EGFR activation) - sorafinib also targets RAF 8. bevacizumab - binds VEGF and prevents interaction with receptor --> inhibits endothelial cell angiogenesis - monoclonal antibody; treats metastatic cancers (lung, colorectal) - added to standard chemo for lung cancer, but causes pulmonary hemorrhage in patients with squamous NSCLC - risk of bleeding, thrombotic events, GI perforation

Answer 23

1. nivolumab (Opdivi) - PD-1 inhibitors bind to programmed death receptor on T cells, prevents T cells from binding and inactivating T cells --> T cells activated and can induce antitumor response - toxicity - ?? - HL, metastatic melanoma (in combo with anti-CTLA-4 inhibitor ipilimumab), NSCLC, RCC, head and neck 2. bortezomib (Velcade) - proteosome inhibitor --> prevents breakdown of proteins that kill cancer cells - treats MM and MCL - toxicity - neuropathy and myelosuppresion 3. rituximab (Rituxan) - chimeric monoclonal antibody against CD20 (transmembrane cell surface protein on B cells) - used to treat B-cell NHL (FL, MCL, MALToma) - other anti-CD20 antibodies are Gazyva and Arzerra (treat CLL but HBV reactivation) - toxicity - infusion rxn (within 1 hour), serum sickness (within 7-10 days)

Answer 24

Lymphoma - begins from one cell that gains survival advantage (tumor cells are clonal / all the same) 1. General features - painless lymph node enlargement (non-tender; tender implies reactive lymphadenitis with real antigen) - immune dysfunction - increased risk infection, devlpt of auto-antibodies (eg against RBCs - hemolytic anemia) 2. diagnosis via histopathology 3. Types A. Indolent - slower growing, harder to catch, no B symptoms --> follicular lymphoma FL, MALToma, mantle cell lymphoma MCL, chronic lymphocytic leukemia CLL B. Rapid growing - present acutely with rapidly growing mass, B symptoms, and high serum LDH and uric acid --> diffuse large B cell DLBCL, Burkitt, anaplastic large T cell lymphoma

Answer 25

1. Follicular lymphoma A. General features - most common indolent lymphoma, mean age at dx is 65 - cells express CD19,20,10, surface Ig, BCL6, and BCL2 B. Pathogenesis - cells of origin are germinal center B cells with 14;18 translocation --> BCL-2 gene under control of Ig heavy chain promoter --> overexpression of BCL2 --> protects cells that should die from apoptosis C. Histopathology - *nodular growth pattern* closely packed follicles overtake lymph node architecture - no light spaces in dark zone of germinal center --> no macrophages bc there are no apoptotic cells - BCL2 expression in the follicular cells in germinal center, whereas in reactive lymphadenitis, BCL2 expression is in the mantle zone cells D. Classic presentation - waxing and waning painless lymphadenopathy - uncommon to have "B symptoms" (fever, weight loss, fatigue) - uncommon to involve other organs/extranodal sites but 80% have bone marrow involvement E. Treatment - no cure, so treatment (rituximab - anti-CD20 Ab) initiated until patients symptomatic, Gazyva if Rituxan resistant - can progress to diffuse large B cell lymphoma (DLBCL)

Answer 26

2. Extranodal marginal zone B cell lymphoma of MALT (mucosal associated lymphoid tissue) type ~ MALToma A. General features - associated with chronic inflammation (H. pylori - gastric MALT | Sjogren's - salivary gland MALT | Borrelia - cutaneous MALT | C psittaci - ocular MALT) B. Pathogenesis - cells of origin are post-germinal center memory B cells in the marginal zone i. chronic inflammation in stomach bc of heliobacter ii. B cell proliferation + gene translocation --> clonal expansion of B cells C. Histopathology - bullseye appearance with a halo (marginal zone) surrounding the darker mantle zone D. Clinical features - peptic ulcer disease/abdominal symptoms, associated auto-immune disease E. Treatment - H. pylori treatment can make lymphoma resolve - can progress to diffuse large B cell lymphoma (DLBCL)

Answer 27

3. Mantle cell lymphoma A. General features - males 50+ B. Pathogenesis - cells of origin are mature, naive pre-germinal center B cells in the mantle zone - region immediately adjacent to the follicle (B cells from original primary follicle that weren't a good fit and got pushed aside) - over-expression of cyclin D1 due to translocation t(11;14) --> phosphorylates and inactivates Rb --> it can no longer inhibit transcription factor E2F --> allows cell cycle to progress from G1 to S --> allows DNA damage to accumulate C. Histopathology - stains positive for cyclin D1 - cells are T cell antigen CD5+ (only other disease is CLL) D. Clinical features - poor prognosis, significant extranodal involvement (spleen, GI, bone marrow) - 1/3 have B symptoms - lymphatomatous polyposis (GI submucosal nodules) E. Treatment - moderately aggressive yet incurable

Answer 28

4. Chronic lymphocytic leukemia CLL A. General features - most common leukemia in adults; if it presents as lymphoma is called small lymphocytic lymphoma SLL; mean age is 72 B. Pathogenesis - cell of origin is mature, naive B cells (mantle cells) - express Ig but have not been exposed to antigen - monoclonal B cell lymphocytosis --> accumulation of functionally incompetent lymphocytes - cells express B cell markers (CD19, 20, 23) and T-cell antigen CD5 (only other B cell condition that expresses CD5 is mantle cell lymphoma) but have low surface Ig - etiology unknown - NOT translocations, but deletions C. Histopathology - increased # of mature lymphocytes in the blood (peripheral smear) - lymph node histology - sheets of small lymphocytes with proliferation center and smudge cells (both are pathognomonic) D. Clinical features - usually asymptomatic - most common sign is lymphadenopathy - cytopenias (immune-mediated via autoantibodies) - hypogammaglobulinemia --> frequent infections (most common cause of death) E. Treatment - treat only when symptomatic - can progress to diffuse large B cell lymphoma (DLBCL) - treat with alemtuzumab (binds CD52)

Answer 29

1. Diffuse large B cell lymphoma DLBCL A. General features - most common lymphoma overall, M>F, mean age 65 B. Pathogenesis - cells of origin are mature germinal center B cells - can be de novo, transformation from low grade (MALT, follicular, CLL), or associated with HIV (75% of HIV patients get DLBCL) - gene translocation or point mutation (more common) --> overexpression of BCL6 (transcriptional repressor)--> inhibits cell differentiation, response to stress/DNA damage C. Histopathology - sheet of large lymphoid cells that replaces lymph node architecture (no nodules) - large cell size with prominent nucleoli - diffuse growth pattern and high growth rate D. Clinical features - most aggressive (rapidly fatal), fast growing symptomatic mass, 1/3 is extranodal (esp to stomach) and 1/3 have B symptoms E. Treatment - 50% survival rate, responsive to aggressive chemo

Answer 30

``` 2. Burkitt lymphoma - A. General features - three forms i. endemic (West Africa)- in young children (4-7), associated with EBV ii. sporadic - mean age 11, seen in USA iii. HIV-associated ``` B. Pathogenesis - cells of origin are mature germinal center B cells - t(8;14) gene translocation --> c-MYC overexpression C. Histopathology - starry sky pattern due to rapid turnover of cells (stars are macrophages eating apoptotic tumor cells) - normal architecture gone - no nodularity, just sheet of cells D. Clinical features i. endemic - jaw tumor ii. sporadic - abdomen with ascites iii. HIV-associated - variable E. Treatment - fastest growing (most mitotically active neoplasm) but curable with aggressive chemo - Ki-67 cell growth fraction ~100% (expressed only in growing cells)

Answer 31

1. Anaplastic large-cell lymphoma (ALK+) A. General features - uncommon tumor of young adults, mean age 30, in males B. Pathogenesis - 2;5 translocation --> ALK positive (normal cells do not express ALK), have better prognosis if so - cells express CD30 C. Histopathology - hallmark cells (large, anaplastic = really atypical, horseshoe shaped nuclei, lots of cytoplasm) D. Clinical features - E. Treatment - 80% cure rate with chemo -- brentuximab vedotin 2. Adult T cell Leukemia/lymphoma (ATLL) - linked to HTLV-1 retrovirus which is endemic in West Africa, Japan, Caribbean - clover leaf mature CD4+ T cells in the bloodstream - lytic bone lesions with hypercalcemia and rash - rapidly progressive, fatal 3. Mycosis fungoides - cutaneous lymphoma of mature CD4+ T cells - malignant CD4+ T cells invade epidermis and form Pautrier microabscesses - rash --> plaque phase --> tumor phase - cells can spread into blood --> Sezary syndrome

Answer 32

Hodgkin's lymphoma 1. General features - 10% of all lymphomas - bimodal age distribution 2. Unique features - All HL originate from germinal center B cells, BUT do not express B cell markers (CD19, CD20) - Reed-Sternberg cell (large, multiple nuclei, prominent "owl eyes" nucleoli) --> reprogram and acquire other cell markers e.g. CD15, CD30--> make inflammatory cytokines to attract other cells (mixed cell infiltrate) - usually involves single group of nodes; distinct pattern of spread (contiguous) - most tumor cells not neoplastic but inflammatory - eosinophilia due to increased IL-5 (produced by RS cells) 3. Pathogenesis - constitutive activation of NF-kappaB (inflammatory response marker) - etiology unknown, risk factors are EBV, immunosuppression; childhood illness protective 4. Clinical presentation - - painless lymphadenopathy in neck (70%), axilla (20%) - 2/3 have mediastinal lymphadenopathy - 1/3 have B symptoms (fever, chills, weight loss) 5. Treatment - good prognosis - more patients due of treatment complications than disease

Answer 33

1. Classical HL - subtypes A. Nodular sclerosis subtype - 70%, most common subtype - young adult females - classically present with mediastinal/neck lymph node - collagenous bands - cellular background of T-cells, eosinophils - 70% present with limited stage, rarely associated with EBV B. mixed cellularity - associated with EBV, older individuals, more advanced, more eosinophils C. lymphocyte rich - T cell infiltrate, best prognosis D. lymphocyte depleted - associated with EBV, rare except in HIV+, worst prognosis 2. Non-classic HL - nodular lymphocyte predominance - young males - variant of Reed-Sternberg cells resembling popcorn - excellent prognosis, not associated with EBV - express B cell markers (CD20, BCL6) and NOT CD15 or CD30

Answer 34

1. CML A. General features - M=F, age is 50; most commonly sporadic origin B. Pathogenesis - cell of origin is hematopoietic stem cell --> all hematopoietic lineages (lymphoid, granulocyte, erythroid, megakaryocytic) will have single molecular abnormality = Philadelphia chromosome t(9;22) --> BCR-ABL fusion protein - blast crisis - rapidly progressing phase where mature neutrophils (chronic form) transform into different immature cells (acute form of disease) --> can lead to AML (2/3) or ALL (1/3) C. Histopathology i. peripheral blood - (chronic) see all stages of WBC forms, from mature neutrophils to blasts, increased basophils --> basophilia - (blast phase) - looks like AML with just blasts (immature WBCs) ii. bone marrow - (chronic) different phases of WBC devlpt; (blast) just blasts D. Clinical features - presents with fatigue, malaise, weight loss, early satiety (splenomegaly), bleeding (platelet dysfunction), chloroma (solid collection of CML cells), but often asymptomatic E. Treatment - imatinib (Gleevec) - specific BCR-ABL tyrosine kinase inhibitor --> binds to ATP site and prevents phosphorylation of substrate - point mutations leads to resistance --> use newer TKIs (nilotinib, dasatinib)

Answer 35

2. Essential thrombocytosis A. General features - platelet count > 450,000 per microliter with no other identifiable cause (normal: 150-450K) - diagnosis of exclusion; DD includes reactive thromboctosis, CML, polycythemia vera, MDS B. Pathogenesis - JAK2 V167F mutation in 50% cases C. Histopathology i. peripheral blood - big platelets, increased # ii. marrow - increased # megakaryocytes D. Clinical features - asymptomatic but can present with thrombosis or bleeding; fatigue, light-headedness - rarely progresses to acute leukemia, marrow fibrosis; no risk of hyperuricemia or gout E. Treatment - prevent ischemic complications of high platelet count (aspirin + hydroxyurea)

Answer 36

3. Polycythemia vera PV A. General features - overproduction of RBCs, granulocytes (50% pts), platelets (50% pts) - rule out causes of secondary erythrocytosis --> familial or renal cell carcinoma (high EPO), responses to hypoxia (low Sa02, high EPO) * EPO in PV is decreased (response to high RBC count) B. Pathogenesis - mutation in JAK2 V617F signaling molecule (constitutively active) --> excess transcription, inhibition of apoptosis, excess hematopoietic cell growth C. Histopathology i. bone marrow - hypercellular marrow (lot of RBC precursors), little fat content D. Clinical features - splenomegaly (75% pts) - dyspnea (viscosity from increased hematocrit), neurologic impairment (blurry vision and headache), thrombosis, burning pain in digits, itching made worse with hot water (histamine release from increased mast cells) - increased risk of hyperuricemia and gout E. Treatment - prevent complications of hyper-viscous blood (phlebotomy, low dose aspirin)

Answer 37

4. Myelofibrosis A. General features - rare; proliferation of mature myeloid cells esp megakaryocytes B. Pathogenesis - JAK2 V167F mutation (50% cases) - megakaryocytes produce PDGF --> marrow cavity becomes fibrosed --> affects hematopoiesis --> anemia (Hb < 10), thrombocytopenia, leukopenia (WBC <4) C. Histopathology i. peripheral blood - tear drop cell (dacrocyte) ii. bone marrow - positive collagen stain D. Clinical features - hepatosplenomegaly (due to extramedullary hematopoiesis) - fatigue and pallor and SOB, bleeding, bruising, fever, bone pain (spleen not able to produce adequate number of platelets, WBCs, RBCs)

Answer 38

5. Mastocytosis = mast cell disease (produce histamine, heparins, tryptase) A. General features - different types - bone marrow biopsy to diagnose; dense infiltrates of MCs in bone marrow or other extracutaneous organs B. Pathogenesis - c-kit oncogene mutations C. Histopathology - spindle-shaped mast cells, heavily granulated D. Clinical features - anaphylaxis, hive-like skin lesions, osteoporosis / lytic lesions (excess heparin weakens bones), diarrhea (excess histamines), anemia, splenomegaly E. Treatment -anti-histamines, anti-leukotrienes

Answer 39

Myelodysplasia - bone marrow failure disorder 1. General features - clonal stem cell disorder occurring in older patients (mean age 65), can transform into AML, classifications based on % myeloblasts B. Pathogenesis - chromosomal abnormalities esp deletions in 5 and 7 --> e.g. 5q- syndrome (anemia but normal WBC, platelets; F>>M) --> problem with maturation of cells - radiation exposures - previous alkylating agent therapy C. Histopathology i. peripheral blood - large, hypernucleated RBC precursor blasts - single nucleated megakaryocytes ii. bone marrow - hypercellular bone marrow due to ineffective hematopoiesis, altered apoptosis --> cytopenia D. Clinical features - pancytopenia - macrocytic anemia - fatigue, SOB - thrombocytopenia --> bruising, bleeding - neutropenia (mild) - leukopenia or leukocytosis (if transforming into AML) E. Treatment - hypomethylating agents (chemo drugs) - not curative - only curative tx is stem cell transplant

Answer 40

1A. ERBB1 - lung cancer, adenocarcinoma, squamous cell carcinoma, epithelial head and neck B. ERBB2 (HER2/NEU) - breast cancer, poorer prognosis but treatment with herceptin 2. Ras - point mutation --> permanent activation --> growth, differentiation, survival signaling - most commonly mutated proto-oncogene in human tumors - pancreatic cancer (90%), colon endometrial thyroid cancers (50%), lung adenocarcinoma and myeloid leukemia (30%)

Answer 41

1. Rb - checkpoint between G1 and S phase: CDK/cyclin levels increase --> phosphorylate Rb --> release it from E2F -- allowing transcription to occur - directly or indirectly inactivated in most cancers, gain of function of CDK4/cyclin D, loss of function of CDK inhibitors - mutations - deletions, point mutations, promoter hypermethylation - germline loss of Rb --> retinoblastoma 2. p53 - genome surveillance, regulates cell response to DNA damage (repair, cell cycle arrest at G1-S, senescence, or apoptosis) - biallelic acquired loss in breast, colon, lung - AD germline mutation in one allele --> Li Fraumeni syndrome (cancer predisposition syndrome) *DNA viruses (HPV, HBV, EBV) bind to both p53 and RB and nullify protective functions 3. Adenomatous polyposis coli (APC) - part of WNT signaling (controls cell polarity, adhesion) - normally APC keeps beta catenin levels low - when APC is gone --> beta catenin goes to nucleus --> transcription factor that promotes growth - somatic loss of both alleles --> sporadic colon cancers - AD inherited single gene mutation --> familial adenomatous polyposis --> colon cancer

Answer 42

1. Mismatch repair A. Mutations in 2 mismatch repair genes discovered (MSH2, MLH1) --> allows mutations to accumulate --> results in Lynch syndrome (AD genetic) --> high risk of colon and other cancers B. Mutations in BRCA1 and 2 (tumor suppressor that repairs breaks in dsDNA)--> increased risk of breast and ovarian cancer i. BRCA1 - early onset, high grade, triple negative (lacks estrogen receptor, progresterone receptor, HER2) --> poor prognosis bc few treatment options 2A. Leukemia - mainly bone marrow and blood involved B. Lymphoma - mainly lymph nodes and solid organs involved; are always clonal

Answer 43

1. Carbohydrate antigen and isohemeagglutinin antibodies A - A antigen, anti-B antibody B - B antigen, ant-A antibody AB - A and B antigens, no antibody O - only H antigen, anti-A and anti-B antibodies N/A - no H antigen *Rare Bombay phenotype* 2. Rh - protein antigen Rh positive - D antigen, no anti-D antibody *more common* Rh negative - no D antigen, no anti-D antibody (only when exposed) 3A. Isohemeagglutinins are IgM antibodies --> pentamers that can cross-link several RBCs + can fix complement --> intravascular hemolysis (breakdown of RBC in blood vessel - hemoglubinemia, hemoglobinuria, cold autoimmune hemolytic anemia) B. Rh have IgG antibodies --> too small to cross-link antigen and fix complement --> extravascular hemolysis - can cross the placenta - warm autoimmune hemolytic anemia

Answer 44

1. Mother is RhD (-) but fetus is RhD (+) --> mother is exposed to RhD antigen at delivery --> memory B cells anti-D antibodies made - second pregnancy with RhD+ fetus --> rapid IgG anti-D produced by mother --> anti-D crosses placenta and attaches to fetal RBCs --> fetal hemolytic anemia --> jaundice, anemia --> hydrops fetalis (fluid in 2+ compartments) --> death 2. Treatment - Rhogam is IgG anti-RhD antibody --> binds to and blocks RhD antigen from activating maternal B cells --> mother does not make any IgG anti-D antibodies 3. ABO hemolytic disease - mother is group O, baby A or B; mother happens to have anti-A, B, or AB IgG antibodies in plasma --> Cross placenta in first pregnancy --> mild hemolytic anemia

Answer 45

1A. Packed red cells - must be ABO compatible, refrigerated - leukodepletion - filter out WBCs - irradiate to kill WBCs (esp T cells) and prevent graft vs host disease B. Platelet concentrate - all ABO acceptable, but donor match recommended; contains WBCs, plasma, RBCs (doesn't create any reactions) - room temp (cold will activate the platelets to stick to vWF - consumed by macrophages) - risk of bacterial contamination and infection C. Fresh frozen plasma - contains all coagulation factors + other proteins (and antibodies) present in blood; must be ABO compatible - frozen, use within 24 hrs when thawed D. Cryoprecipitate - ABO acceptable; contains fibrinogen, factors VIII and XIII, vWF

Answer 46

TR - any adverse signs within 24 hrs, most commonly within 15 minutes 1. febrile, non-hemolytic TR - most common, benign; fever, chills, mild dyspnea --> due to cytokines generated by WBCs that accumulate during storage 2. acute immune-mediated hemolytic TR (IgM-mediated)- within 5-10 min medical emergency! - restlessness with fever, flank pain, SOB, pain at infusion site, diffuse bleeding - intravascular hemolysis - hemoglobinuria, pink plasma, DIC, renal failure - due to ABO incompatibility (error) --> transfused RBCs are being destroyed by patient's IgM (positive direct coombs test) - Tx supportive: give saline --> maintain urine output --> prevent Hb from damaging kidneys 3. delayed immune-mediated hemolytic TR (IgG-mediated)- occurs 3 to 30 days post transfusion - anamnestic antibody response to previously encountered RBC antigen (undetectable on screening) - extravascular hemolysis --> slight fever, mild jaundice, positive direct coombs test) 4. response to massive transfusion - warm the blood to prevent hypothermia, can lead to hypocalcemia (citrate chelates Ca2+), hyperkalemia - can lead to febrile NHTR

Answer 47

5. anaphylactic TR - immediate medical emergency! rapid onset of anaphylaxis (shock, hypotension, respiratory distress) - IgG anti-IgA antibodies in patients who are IgA deficient - can have passive transfer of anaphylaxis to peanuts - give epinephrine 6. urticarial TR - allergenic substance in plasma of donated product reacts with existing IgE --> degranulation --> hives - give benadryl and continue transfusion 7. transfusion-related acute lung injury TRALI - sudden onset respiratory distress during transfusion, due to pulmonary endothelial cell injury (just like ARDS) - pink frothy sputum, ground glass lung infiltrates, SOB (due to hypoxemia), hypotension 8. transfusion-related circulatory overload TACO - most commonly in elderly, give them too much volume or too quickly --> CHF with compromised cardiac function and positive fluid balance (give diuretics) - elevated JVD, elevated PCWP, hypertension (elevated systolic), low EF

Answer 48

1A. Benign - ends in "oma" - well differentiated - neoplastic (irreversible, unregulated monoclonal) cells represent normal equivalents, morphologically and functionally - capsule - slow growing, no vessel invasion or metastases B. Malignant - poorly differentiated - irregular, invasive borders with hemorrhage, necrosis - no encapsulation, increased chromatin and mitoses - rapid growth, vessel invasion and metastases 2A. Anaplasia - loss of differentiation of normal cells (cancer in stem cells) - many mitoses, tumor giant cells - pleomorphism (loss of uniformity) - variable nuclei size and shape B. Dysplasia - disorderly but non-neoplastic proliferation in epithelium (predates cancer) - pleomorphism + hyperchromatic nuclei, increased mitoses

Answer 49

1A. Sarcoma - cancer of mesenchymal cells (e.g. bone --> osteosarcoma); metastasizes via blood vessels (most common sites are liver and lung) B. Carcinoma - cancer of epithelial cells or organ lining; metastasizes via lymphatic system 2. Morphology - from biopsy, fine needle aspiration, or cytologic smears - immunophenotyping - Ab conjugated to cell molecules to assay presence on tumor cells - tumor markers assayed in blood to screen/monitor eg PSA - karyotyping, cytogenic sequencing - molecular profiling of genes 3. Staging: TMN T - invasion, T0-T4 M - metastases, M0-M2 N - lymph node spread, N0-N3