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Question

Vitamin K Deficiency definition, dx, tx

Answer 1

Required for factors II, VII, X, & proteins C & S PATHO: infants not supplemented w/ vitamin K after delivery may develop hemorrhagic disease of the newborn (peak incidence @2-5d); increased risk if mother taking anticonvulsants, phenobarbital, phenytoin dx Prolonged PT & PTT Low vitamin K-dependent factors (II, VII, IX, X, proteins C & S) tx SC/IM/IV vitamin K – infants should be treated shortly after birth

Answer 2

MC inherited cause of hypercoagulability (thrombophilia) PATHO: mutated factor V is resistant to breakdown by activated protein C, leading to increased hypercoagulability sx Increased incidence of DVT, PE, hepatic vein, or cerebral vein thrombosis Increased risk of miscarriages during pregnancy dx *activated protein C resistance assay (+) 🡪 confirm w/ DNA testing *DNA testing: mutation analysis tx: indefinite anticoagulation

Answer 3

Proteins C & S are vitamin K-dependent anticoagulant proteins produced by the liver that stimulate fibrinolysis & inactivate factors V & VIII *decreased protein C or S leads to hypercoagulability Etiologies: *inherited: autosomal dominant (C MC) *acquired: ESLD, severe liver disease w/ synthetic dysfunction, early warfarin admin. sx Increased incidence of DVT/PE Warfarin-induced skin necrosis Newborns: purpura fulminans: red purpuric lesions at pressure points, progresses to painful black eschars dx *protein C & S functional assay, plasma protein C & S antigen levels tx Thrombosis: - protein C concentrate - indefinite anticoagulation Warfarin-induced necrosis: - immediate D/C warfarin - admin. IV vitamin K, heparin, protein C concentrate, or FFP

Answer 4

PATHO: antithrombin normally inhibits coagulation by neutralizing the activity of thrombin (factors IIa, IXa, & Xa); decreased levels lead to increased risk of clotting Etiologies: *inherited: autosomal dominant *acquired: liver disease, nephrotic syndrome, DIC, chemo sx: Increased incidence of DVT, PE dx: antithrombin III assays tx Asymptomatic: - anticoagulation only before surgical procedures Thrombosis: - high-dose IV heparin - PO anticoagulation indefinitely

Answer 5

*Derived from astrocytes *Can appear in any part of the brain *MC infratentorial in children Pilocytic Astrocytoma (Grade I): Juvenile Astrocytoma – typically localized; considered “most benign” astrocytoma; MC primary childhood CNS tumor sx Focal deficits: MC – depends on location *Cerebellum: weakness, tremor, ataxia *Visual pathway: visual loss, proptosis, nystagmus *Spinal cord: pain, weakness, gait disturbance General sxs: HA (may be worse in the morning, awaken pt at night, or positional), cranial nerve deficits, AMS changes, neurologic deficits, ataxia, vision changes, weakness ↑ ICP: due to mass effect 🡪 HA, N/V, papilledema, ataxia, drowsiness, stupor dx *CT/MRI w/ contrast: grade I non-enhancing BX: generally form sacs of fluid (cystic), or may be enclosed within a cyst; Rosenthal fibers (eosinophilic corkscrew fibers) tx *surgical excision *post-op radiation if tumor cannot be completely removed; 90% 5y survival rate

Answer 6

*Most common MALIGNANT posterior fossa tumor in children and represents about 20% of all pediatric CNS cancers *METS through CSF Bimodal peak age: 3-4yrs, 8-10yrs sx *vomiting, HA, nausea, visual changes (double vision), unsteady walking or clumsiness DX: MRI, bx tx *surgery, radiation, chemo Long-term survival w/ treatment is 70%

Answer 7

*Ependymal cells line the ventricles & parts of the spinal column; 3rd MC pediatric CNS tumor (10%) *MC in children (mean age @ dx is 6yrs, 30% occur <3y) *MC seen in 4th ventricle, spinal cord, & medulla sx Infants: *increased in head size, irritability, developmental delay *sleeplessness, vomiting Older children/adults: N/V, HA, changes in mood, personality, or concentration; seizures, balance/gait disturbances, spinal cord compression sxs (back pain, loss of bladder/bowel control) dx *CT/MRI w/ contrast: hypointense T1, hyperintense T2 BX: perivascular pseudo rosettes (tumor cells surrounding a blood vessel) tx: surgical resection 🡪 adjuvant radiation

Answer 8

*MC primary intraocular malignancy in childhood *Most diagnosed before 3yo Types: *Non-Heritable: due to somatic mutations in the RB1 gene in the tumor (RB1 is a tumor suppressor gene on chromosome 13) *Heritable: due to germline mutations in the RB1 gene *may develop bilateral retinoblastoma sx *leukocoria (presence of abnormal white reflex instead of the normal red reflex) *may develop strabismus or nystagmus dx *dilated ophthalmologic exam *ocular U/S: intraocular calcified mass *MRI/CT tx *radiation, chemo, &/or enucleation F/U: retinoblastoma can be associated w/ bone neoplasms (Osteosarcoma)

Answer 9

ANC <1000 sx FEVER – earliest & only sign Hx of chemo dx CBC, CMP, blood culture, UA CXR, CT, U/S, LP tx Outpatient: cipro + Augmentin; moxifloxacin Monotherapy *pseudomonas: cefepime, imipenem, Augmentin Dual therapy *unstable: monotherapy + Vanc or flagyl (abd)

Answer 10

HL: malignant lymphoma typically of B-cell origin ▪︎⊕Hodgkin/Reed-Sternberg (HRS) cells: classic RS cells Classical Hodgkin Lymphoma (cHL) * Nodular sclerosis * Mixed cellularity * Lymphocyte rich/depleted o Nodular lymphocyte predominant A 3x ↑ risk in young adults with prior history of serologically confirmed infectious mononucleosis sx “B” symptoms present in approx. 30% of cases. o Fever > 38°C (100.4°F) o Drenching night sweats o Weight loss (>10% of body weight) * Generalized pruritus * Single LN group and spreads to contiguous areas * Late disseminated * Pain in involved lymph nodes immediately after the ingestion of alcohol Diffuse/puffy swelling rather than a discrete mass may be apparent in the supraclavicular, infraclavicular, or anterior chest wall regions * ~70% cervical node involvement dx LABS: CBC, kidney/liver function (CMP), albumin, electrolytes, ESR, HIV testing Imaging: CXR, PET-CT (staging) Confirmatory ⇢ tissue BX: excisional/incisional peripheral lymph node biopsy preferred » ⊕HRS cells (classic RS/variants) Classic Reed-Sternberg cell: ▪︎at least 2 nucleoli in separate nuclear lobes ▪︎characteristic “owl’s eye” appearance tx Limited Stage (I & II): chemo + RT ▪︎MC used chemotherapy ⇢ ABVD » Adriamycin (doxorubicin) » bleomycin » vinblastine » dacarbazine Advanced Stage (III & IV): ▪︎3 possible treatment options ➀ ABVD ➁ Stanford V ➂ BEACOPP (bleomycin, etoposide, Adriamycin, cyclophosphamide, oncovin, procarbazine, prednisone) Refractory/relapse: high-dose chemo, autologous stem cell transplant

Answer 11

▪︎B-cell lymphomas MC (85%) Indolent (slow growing) ➀ Follicular Lymphoma ⇢ MC low-grade lymphoma in adults PATHO: t(14;18) ⇢ IGH/BCL2 fusion gene ⇢ overexpression of BCL2 (blocks apoptosis) causes prolonged cell survival ➁ Hairy Cell Leukemia (HCL) ⇢ MC in middle-aged men PATHO: late, activated memory B-cell w/ a BRAF V600E mutation ➂ Small lymphocytic Lymphoma (SLL): identical to CLL ▪︎CLL ⇢ disease manifests primarily in the blood ➃ Marginal Zone Lymphomas (MZLs) ▪︎post-germinal center memory B cells w/ capacity to differentiate into marginal zone cells & plasma Aggressive ➀ Diffuse Large B-cell (DLBCL) ⇢ MC NHL overall** ▪︎mutations: BCL6 (MC), TP53, BCL2; MYC overexpression ▪︎AIDS-defining malignancy, associated w/ EBV ➁ Mantle Cell Lymphoma (MCL) ⇢ nodal & non-nodal MCL ▪︎express cyclin D1, BCL2, & CD5⊕; CD23⊖ PATHO: t(11;14) ⇢ translocation of CCND1 w/ Ig genes ➂ Burkitt Lymphoma (BL) ⇢ MC in children PATHO: translocation/deregulation of MYC gene

Answer 12

sx S/SXS: MC ⇢ painless lymphadenopathy +/- noncontiguous LNs ▪︎Indolent: insidious, slowly growing or waxing/waning LAD, obstruction ▪︎Aggressive: rapidly growing mass, ⊕B SXS dx LABS: anemia MC +/- lymphocytosis, ⇡ LDH Imaging: CXR, PET-CT (staging) Confirmatory ⇢ tissue BX: excisional/incisional peripheral lymph node biopsy of unfixed tissue ▪︎B-cell lymphomas CD19⊕, CD20⊕, CD79a⊕ ▪︎T-cell lymphomas CD3⊕ Microscopy ⇢ Burkitt lymphoma: “starry sky” ▪︎benign histiocytes (“stars”) w/ abundant clear cytoplasm dispersed throughout neoplastic tumor cells (“sky” tx Indolent: highly treatable, but not reliably curable ▪︎asymptomatic ⇢ monitor ▪︎regional radiation therapy Aggressive: responsive to chemo & often curable ⇢ R-CHOP » rituximab » cyclophosphamide » hydroxydaunorubicin (doxorubicin) » oncovin (vincristine) » prednisone CNS prophylaxis ⇢ MTX Hairy Cell Leukemia: ▪︎cladribine or pentostatin

Answer 13

S/SXS ⇢ sudden symptom onset & rapid progression ▪︎anemia: fatigue, pallor, weakness ▪︎thrombocytopenia: epistaxis, bleeding types Acute Myelogenous Leukemia (AML): ▪︎MC acute leukemia in adults, peak incidence 65yo AML S/SXS: AML w/ minimal granulocyte maturation ▪︎skin infiltration ⇢ leukemia cutis (most often involves the face) M2 AML w/ granulocyte maturation » papules/nodules, may be erythematous, violaceous, gray-blue M3 Acute promyelocytic leukemia (APL) ▪︎M5 (monocytic): gingival infiltration ⇢ gingival hyperplasia » t(15;17), ⊕Auer rods, MPO⊕ ▪︎bone pain & CNS involvement uncommon* Acute Lymphocytic Leukemia (ALL): ▪︎MC childhood malignancy, peak incidence 2-5yo, ♂︎ > ♀︎ B-ALL B-lymphoblastic leukemia (MC, 80-85%) ALL S/SXS: » CD19⊕, CD22⊕, CD79a⊕ ▪︎fever, night sweats, unexplained weight loss, painless LAD T-ALL T-lymphoblastic leukemia (CD3⊕) ▪︎bone pain (limping/refusal to bear weight), hepatosplenomegaly » mediastinal/thymic infiltration ▪︎CNS/meningeal infiltration (common): cranial nerve palsies, HA,

Answer 14

LABS: thrombocytopenia, anemia Tumor lysis syndrome: ⇡ phosphate, ⇡ K, ⇣ calcium, ⇡ uric acid, ⇡ LDH DX: bone marrow aspiration/BX, peripheral smear AML DX: >20% myeloblasts, ⊕Auer rods ▪︎cytogenetic abnormalities: » t(8;21), inv(16), t(16;16), trisomy 8 ▪︎immunophenotype: » MPO⊕, TdT⊖, PAS⊖ » CD13⊕, CD33⊕, CD34⊕, CD117⊕ ▪︎Acute promyelocytic leukemia (APL) » t(15;17)/PML-RARA ALL DX: >20% lymphoblasts, ⊘Auer rods ▪︎cytogenetic abnormalities: » childhood ⇢ t(12;21), high hyperdiploidy » adults ⇢ t(9;22)/BCR-ABL1 (Philadelphia chromosome, Ph⊕) ▪︎immunophenotype: MPO⊖, TdT⊕, PAS⊕ tx Remission: ▪︎<5% blast cells in bone marrow ▪︎ANC >1000/mcL AML TX: ▪︎cytarabine + idarubicin ▪︎APL ⇢ all-trans retinoic acid (ATRA) » matures blasts cells ALL TX: ▪︎doxorubicin, cyclophosphamide ▪︎vincristine, MTX, prednisone ▪︎Ph⊕ ⇢ add TKI (e.g., imatinib) CNS prophylaxis: intrathecal MTX, cytarabine, & hydrocortisone

Answer 15

CML: proliferation of mature myeloid cells ▪︎peak incidence 50-60yo, ♂︎ > ♀︎ PATHO: t(9;22) causes fusion between ABL1 gene (chromosome 9) & BCR gene (chromosome 22) & gives rise to the Philadelphia chromosome (Ph) which inhibits apoptosis & ⇡ miotic rate, resulting in uncontrolled proliferation of mature myeloid cells S/SXS ⇢ 3 phases ➀ Chronic Phase (<10% blasts): MC clinical presentation at diagnosis (85% of patients) ▪︎often asymptomatic early on w/ insidious onset of nonspecific symptoms ▪︎fatigue, weight loss, excessive sweating, bleeding episodes d/t platelet dysfunction ▪︎abdominal fullness, splenomegaly w/ LUQ pain, gouty arthritis (overproduction of uric acid) ➁ Accelerated Phase (10-19% blasts): ▪︎ worsening splenomegaly, worsening cytopenias (anemia, infection/fever) ▪︎genetic instability (e.g., additional chromosomal abnormalities) ➂ Blast Phase/Crisis (≥20% blasts): ▪︎manifests as an acute leukemia, resembles AML (e.g., night sweats, weight loss, bone pain, bleeding) ▪︎leukostasis (hyperleukocytosis): dyspnea, visual changes, HA, tinnitus, priapism, fever dx Peripheral smear: ▪︎leukocytosis, median white count ~100,000/µL ▪︎differentiation ⇢ all cells of neutrophilic series » myeloblasts, myelocytes, mature neutrophils ▪︎LOW leukocyte alkaline phosphatase (LAP) » excludes leukemoid reaction ▪︎basophilia, eosinophilia ▪︎thrombocytosis (platelet count >600,000/µL) Bone marrow BX: granulocytic hyperplasia Confirmatory ⇢ cytogenetic testing: » ⊕Ph chromosome &/or BCR-ABL1 fusion gene TX: tyrosine kinase inhibitors (TKIs) ▪︎imatinib, dasatinib, nilotinib Leukocytosis ⇢ hydroxyurea Allogenic stem cell transplant ▪︎TKI-resistant CML, advanced phases

Answer 16

CLL: proliferative mature B-cell malignancy S/SXS: asymptomatic lymphocytosis MC (B SXS in 5-10%), fatigue ▪︎MC leukemia in adults, median onset 70-72yo ▪︎painless LAD (MC) ⇢ cervical, supraclavicular, axillary ▪︎RF: men, ⇡ age ▪︎splenomegaly (2nd MC), usually painless & nontender to palpation ▪︎leukemia cutis (rare), neutropenia, anemia, thrombocytopenia LABS: ▪︎lymphocytosis >5,000/µL (threshold) » often as high as 100,000/µL ▪︎hypogammaglobulinemia common dx Peripheral smear: ▪︎lymphocytosis (small mature lymphocytes) ▪︎⊕smudge cells ⇢ lymphocytes are mechanically disrupted & smear out when being spread on slide Immunophenotype: ▪︎CD5⊕, CD19⊕, CD20⊕ (dim), CD23⊕, CD10⊖ Markers of good prognosis: ▪︎CD38⊖, ZAP-70⊖ Markers of poor prognosis: ▪︎CD38⊕, ZAP-70⊕, del(11q)⊕, del(17p)⊕ tx Low-risk (Rai 0, Binet A): ▪︎observation w/ regular f/u Intermediate/high-risk, symptomatic or progressive ⇢ chemotherapy ▪︎ibrutinib, rituximab, alemtuzumab ▪︎fludarabine, cyclophosphamide Curative ⇢ allogenic stem cell transplant (not routinely performed)

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