Onc 2.1 Midterm

inheritance patterns of primary immunodeficiencies?

• x-linked → chronic granulomatous disease (&G6PD), wiskott-aldrich, XLA, lymphoproliferative (sapped effect), SCID, hyper IgM (CWALSH)

• autosomal recessive → the remaining

x-linked agammaglobulinemia (XLA) category? etiology? markers? clinical features?

• B cell (humoral) → manifest @ 1st yr of life

• BTK mut. → pre-B cell arrested growth → no light chain/surface marker (IgG/A/M/E/D absent)

• recurrent RT + EC infections, rudimentary germinal centers, absent tonsil, small LN

  • Tx w/ large dose y-globulin infusion

IgA deficiency category? etiology? markers? clinical features?

• B cell (humoral) → manifest @ 1st yr of life

• selective IgA absence (dec. IgA, normal IgG/M, inc. IgE)

• mucosal infections, allergic disease, transfusion rxn, TIG prophylaxis

  • Tx w/ antibiotics

x-linked (B+T) vs autosomal (B) hyper IgM category? etiology? markers?

• B cell (humoral) → manifest @ 1st yr of life

  • CD40L (T) def. → dec. CD40 (B) act.

    • indicated via opp. infection (PCP pneumonia, chronic diarrhea, oral thrush)

  • CD40/AID def. → dec. class switch

• inc. IgM, dec. IgG/A/E/D

x-linked (B+T) and autosomal (B) hyper IgM clinical features? treatment?

• neutropenia (dec. sFcyRIII) → IC bacterial, pyogenic, fungal infections

  • via T cell not binding w/ MO CD40 → dec. cytokines = ineffective granulopoiesis

• poorly organized, lack 2ndary follicle (should have act. B cell) + germinal center

• Tx w/ antibiotics + periodic y-globulin infusion

common variable immunodeficiency (CVI) category? etiology? markers? clinical features?

• B cell (humoral) → manifest @ 1st yr of life

• impaired B cell diff. (dec. IgG/A/M, dec. plasma cell)

• sinopulmonary infections, autoimmunity, giardia

transient hypo y globulinemia (HyG) category? etiology? markers? clinical features?

• B cell (humoral) → manifest @ 1st yr of life

• delayed IgG synth. (placenta) = dec. IgG in infancy

• mild infections, resolves w/ age

x-linked vs autosomal SCID category? etiology? markers? clinical features?

• T cell/combined → manifests early + Tx w/ BMT

  • defective IL2Ry (= T-, B+, NK-)

  • defective ADA, JAK3 (ILRy defect = B+), PNP (B±, NK+), RAG (NK+)

• dec. TREC

• CD3 (T), CD20 (B), CD16 (NK)

x-linked and autosomal SCID clinical features? treatment?

• recurrent viral, bacterial, fungal (strep. pneumocystis, candida) → thrush, otitis media

  • failure to thrive, chronic diarrhea

• absent thymus (only cardiac shadow present), germinal centers, T cells

• omenn syn. (RAG mut.) → erythroderma, hepatosplenomegaly

• Tx w/ antibiotics + Ig (immediate) → BMT (long term)

digeorge syndrome category? etiology? markers? clinical features?

• T cell/combined → manifests early + Tx w/ BMT

• 22q11.2 del. → thymic aplasia

  • dec. T cells, dec. PTH =dec. Ca

• recurrent infections, tetany, tetralogy of fallot

  • dec. LN paracortex development → dec. mature T cells

x-linked WAS category? etiology? markers? clinical features?

• T cell/combined → manifests early + Tx w/ BMT

• WASP mut. → cytoskeleton defect (dec. IgM, inc. IgA/E, dec. platelets)

• eczema, encapsulated bacterial infection

  • Tx w/ BMT

ataxia-telangiectasia category? etiology? markers? clinical features?

• T cell/combined → manifests early + Tx w/ BMT

• ATMK mut. → dec. DNA repair via failure to halt progression

  • = inc. AFP, dec. IgA

• ataxia, telangiectasia (dilated caps), sinopulmonary infections

MHC I vs II deficiency category? etiology? markers? clinical features?

• T cell/combined → manifests early + Tx w/ BMT

  • TAP mut. = dec. CD8 → chronic lung + skin inflammation; viral infection

  • CIITA/RFX mut. = dec. CD4 + IgG/A/M/E/D → SCID-like

x-linked chronic granulomatous disease (CGD) category? etiology? markers? clinical features?

• phagocyte defect

• NADPH oxidase defect (dec. NBT/DHR)

• abscess, granuloma, inc. cat. + infection, -nitroblue

  • G6PD dec.= inc. oxidative injury → heinz bodies + bite cells

leukocyte adhesion deficiency (LAD) category? etiology? markers? clinical features?

• phagocyte defect

• CD18 (B2 integrin) defect (inc. neutrophils, dec. CD18)

• dec. wound healing, no pus, delayed separation of cord (omphalitis)

chediak-higashi syndrome category? etiology? markers? clinical features?

• phagocyte defect

• LYST mut. → dec. vesicle trafficking (giant granules)

• progressive neurodegenerative, lymphoma-like phase, albinism, recurrent pyogenic infections, peripheral neuropathy (PLAIN)

hyper-IgE syndrome (job’s) category? etiology? markers? clinical features?

• phagocyte defect

• STAT3 mut. → dec. Th17 (inc. IgE, eosinophilia)

• eczema, pulm + skin infections, cold abscesses (staph.)

hereditary angioedema (HAE) category? etiology? markers? clinical features?

• complement defect

• dec. C1 esterase inhibitor (C1NH) = dec. C4, inc. bradykinin

  • Type 1 (quantitative def.) or Type 2 (dysfunctional)

• classical path act., edema, epiglottal swelling

  • Tx w/ ruconest, berinert, lanadelumab

C3 vs C5-C9 deficiency category? etiology? markers? clinical features?

• complement defect

  • central opsonin defect = dec. C3 + IgG → recurrent encapsulated bacterial infection (e.g strep)

  • MAC form. defect = dec. term. complement → neisseria infection

origin of leukemias? characteristics? ancillary studies?

• lymphoid or myeloid neoplasm (involves blood + BM)

• tumor cells/WBC in peripheral blood

• immunotyping (flow cytometry or immunochemistry) OR cytogenic analysis (karyotype or FISH)

acute vs chronic leukemia?

• dec. normal hematopoietic act. via marrow replacement → blastocytosis + pancytopenia

  • leukocytosis w/ anemia, thrombocytopenia, neutropenia

  • fatigue bleeding/bruising, infection, bone pain

• inc. clonal hematopoietic act./hypercellular marrow → mature cells w/ preserved function until late

  • cytopenia late

  • fatigue, weight loss, splenomegaly

process of myeloid neoplasms? categorization?

• clonal expansion of hematopoietic progenitors → accumulate in marrow (expansile infiltration) → disrupts normal hematopoiesis + marrow failure → EMH (= splenomegaly)

• acute or chronic (myelodysplastic or myeloproliferative)

acute myeloid leukemia (AML) mechanism? characteristics?

• clonal proliferation of myeloblasts = granular (>20% blasts in periphery) → bone pain, fever, bruising, hepatosplenomegaly

• MOP → auer rods (stain red) + inc. circulating myeloblasts on smear

• ALL + AML = rapid + aggressive vs chronic

acute promyelocytic leukemia (AML)?

• t(15;17) → PML::RARA

  • DIC is common = clotting cascade issue

  • Tx w/ all-trans retinoic acid (vit. A)

• inv (16) (p13;q22) → CFB::MyHII

  • abnormal eosinophils

• t(8;21)(q22;22) → RUNI::RUNXITI

  • granulocytes

myelodysplastic syndrome mechanism? cause? treatment?

• ineffective hematopoiesis (dysplastic precursor) → defective cell maturation/differentiation → clonal cytopenia (anemia common)

  • easy bruise/bleed, fatigue, weight loss/LOA, petechiae, fever, freq. infection, weakness, SOB

• de novo mutation or environmental exposure (benzene, chemo, radiation) → risk of transformation of AML

• Tx w/ allogenic HSC transplant (HLA match), hypomethylating agent/chemo (azacitidine, decitabin), immunosuppressive therapies (ATG, cyclosporine, alemtuzumab)

  • MDS via Chr. 5q del. Tx w/ lenalidomide

myeloproliferative neoplasm mechanism? characteristics? types?

• JAK2/CALR/MPL mut. → mature myeloid clonal proliferation → marrow hypercellularity (cytoses)

• splenomegaly + EHM; middle aged

• chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocytopenia (ET), myelofibrosis

chronic myeloid leukemia (CML) mechanism? smear? progress to? treatment?

• t(9;22) + chimeric fusion BCR-ABL → constitutive oncogene act. → granulocytosis

• spectrum of myeloid maturation (myeloblasts, promyelocytes, neutrophils, basophils, eosinophils) → via defective adhesion of clonal cells to BM = enter blood early

• accelerate/transform to AML (or less common ALL) = “blast crisis”

• Tx w/ imatinib → BCR-ABL TK inhibitor

what is the difference between CML and leukemoid reaction?

• CML = LAP (-), basophilia, t(9;22) → inc. BCR-ABL

• LR = LAP (+), reactive neutrophilia, toxic granulation, dohle bodies, cytoplasmic vacuoles

  • normal eosinophils/basophils

polycythemia vera (PV) mechanism? symptoms? signs of progression? treatment?

• acquired JAK2 mut. = inc. RBC + dec. EPO

• pruritis after shower, erythromelalgia (burning pain in hands/feet + red-blue discoloration via blood clots), hyper viscosity + thrombosis → cardio complications

• conjunctival plethora, granulocytic proliferation, hepatosplenomegaly, medullary fibrosis, panmyelosis, thrombosis

• Tx w/ phlebotomy, hydroxyurea, ruxolitinib (JAK1/2 inhibitor)

essential thrombocytopenia (ET) mechanism? symptoms? treatment?

• massive proliferation of megakaryocytes + platelets

• bleeding + thrombosis, sometimes erythromelalgia

  • paradoxical hemorrhage risk → inc. platelets = inc. vWF = coagulation imbalance = hemorrhage (instead of thrombosis)

• Tx w/ cytoreductive drugs (hydroxyurea or anagrelide)

idiopathic myelofibrosis (IMF) mechanism? characteristics? secondary causes? treatment?

• atypical megakaryocyte hyperplasia (via JAK2 kinase mut.) → inc. TGF-B → inc. fibroblast collagen deposition → inc. obliterative medullary fibrosis → splenomegaly

• associated w/ teardrop poikilocytosis, leucoerythroblastic, splenomegaly, early cell line inc. → late stage pancytopenia

• metastatic carcinoma, lymphomas, granulomatous disorders (TB, histoplasmosis, sarcoidosis)

• Tx w/ ruxolitinib (JAK1/2 inhibitor)

acute monocytic leukemia? acute megakaryoblastic leukemia?

• inc. proliferation of monoblasts; lack MPO

  • infiltrate gums

• inc. proliferation of MK blasts; lack MPO

  • associated w/ DS before 5

lymphoid neoplasm? types?

• derived from B, T, NK cell → Dx w/ flow cytometry (+ supplemental tests)

• lymphoblasts → ALL (B or T)

• mature → CLL/SLL, sezary/ATLL, hairy cell leukemia

acute lymphoblastic leukemia (ALL) markers? diagnosis? types?

• TdT marker (lymphoblast), CD34 (HSC)

• >20% blasts in periphery, common in children (associated w/ DS after 5)

• agranular cytoplasm

  • B-ALL (CD10,19,22) → t(12;21) better prognosis + child vs t(9;22)/Ph+ worse prognosis + adult

  • T-ALL (CD 2-8)→ mediastinal mass (lymphoma) = thymic mass in teen

chronic lymphocytic leukemia (CLL) vs small lymphocytic lymphoma (SLL)? markers? smear?

• mature B cell neoplasm → CLL (marrow, common in adult), SLL (nodal, tissue based)

  • asymptomatic + indolent (turn into aggressive diffuse large B cell lymphoma = richter transformation), AIHA

• CD5, CD20, CD23 (pan-B cell markers)

• smudge cell

• note: also NHL

hairy cell leukemia markers? mechanism? characteristics? treatment?

• mature B cell neoplasm (chronic) → CD103 + B cell markers (CD19,20,22)

• BRAF mut. → filamentous, hairlike projection (fuzzy)

• splenomegaly (pulp engorgement), pancytopenia, marrow fibrosis = dry tap; stains TRAP (+)

  • peripheral LAD uncommon

• Tx w/ purine analogs (cladribine + pentostatin)

• note: also NHL

sezary syndrome characteristics? ATLL?

• CD4 + T cells

  • cut. T cell lymphoma → erythroderma/mycosis fungoides, cerebriform nuclei, LAD

    • CCD4, CCR10

  • peripheral T cell lymphoma → via HTLV-1 (japanese + caribbean) = hypercalcemia, lytic lesions, LAD, HSM, rash

    • flower cells, inc. CD2,3,5 (NOT 7)

non-neoplastic marrow proliferation disorders?

• aplastic anemia

• pure red cell aplasia

• myelopathic anemia

aplastic anemia mechanism? features? types?

• chronic primary hematopoietic failure → dec. blood forming elements → hypocellular marrow w/ lots of fat cells

• pancytopenia, reticulocytopenia, thrombocytopenia, neutropenia, splenomegaly

• acquired (idiopathic, acq. stem cell defect, immune), chemical, physical (while body irradiation, viral infection), inherited (fanconi, telomerase defect)

chemical cause of aplastic anemia?

• dose related → alkylating agents, antimetabolite, benzene, chloramphenicol, inorganic-arsenicals

• idiosyncratic → chloramphenicol, phenylbutazone, organic arsenicals, penicillamine, gold salts, methylphenylethlhydantoin, carbamazepine

pure red cell aplasia mechanism? acquired via?

• diminished erythropoiesis → reticulocytopenia w/ isolated anemia

• neoplasms, drug exposure, autoimmune disorders, infections

• diamond-blackfan → constitutional/congenital disorder via defective erythroid maturation

  • familial/inherited or sporadic, triphalangeal thumbs

myelophthisic anemia mechanism?

• BM wastage → replacement of normal hematopoietic marrow by infiltrative, granulomatous process

• fibrosis, tumor (metastatic), histiocytic expansion (storage or proliferative disorder condition)

• as infiltrative process expands → hematopoietic activity proportionally dec. → pancytopenia

• precursors prematurely enter blood, produce leukoerythroblastosis