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What is Virchow's triad?
- vessel wall dmg/trauma
- venous stasis
- hypercoagulability (congenital/acquired)
- **remains the paradigm for clot formation**
Who should be further evaluated for congenital causes to hyper coagulability?
- fam hx of VTE
- VTE <45 years old
- recurrent VTE
- VTE in an unusual site
- VTE after "minimal provocation"
What are the general symptoms for a PE?
- chest pain
- bloody sputum
What are the general symptoms for DVT?
- blue-purple discoloration
Broad term for any manifestation of venous clots or emboli including primarily DVT and PE.
- venous thromboembolism (VTE)
- **is often under recognized, under prevented, and under treated**
May be CONSIDERED as a diagnosis for nearly all acute cardiopulmonary presentations (chest pain, dyspnea, limb ischemia, stroke, acute renal failure, etc), esp in the ER or inpatient setting.
- **pulmonary embolus is the archetypal manifestation of the "considered" diagnosis**
Name the inherited conditions that can cause a VTE.
- antithrombin III deficiency
- protein C deficiency
- protein S deficiency
- factor V leiden mutation (heterozygous/homozygous)
- G20210A prothrombin gene mutation
- antiphospholipid antibody syndrome
Name the acquired conditions that can cause a VTE.
- major surgery/trauma
- prior hx of VTE
- antiphospholipid antibody syndrome
- major illness w/ hospitalization in last 3 months
- advanced age
- estrogen therapy (OCPs/HRT)
- infx in past 3 months
- heparin induced thrombocytopenia
- immobilization (prolonged sitting/flight/travel)
This test is primarily valuable for its high negative predictive value in a proper clinical setting for evaluating a possible VTE, and measures the breakdown product of fibrin mesh which indicates an active clotting process if present in the serum.
What imaging study is important for evaluation of a PE?
What are the medications used to treat VTEs?
- factor Xa inhibitors (rivaroxaban, fondaparinux SQ inj)
- direct thrombin inhibitors
What patient history is associated with the "classic" VTE?
- prolonged immobilization: airplane (coach class syndrome), long drives, prolonged hospitalization
- recent surgery/trauma: esp orthopedic (hip & knee replacements)
- illness: hx of cancer
What are the signs and symptoms of a DVT?
- unilateral LE edema, erythema, warmth, tenderness
- difference in calf diameter >2cm
- decreased extremity pulses/cynotic hue
- "heavy legs"
- palpable venous cord
- Homan's sign (unreliable)
What are the signs and symptoms of an acute PE?
- SUDDEN onset SOB
- pleuritic chest pain
- tachypnea (>half the patients)
- ECG findings (MC sinus tach/non specific ST & T wave changes)
- S1-Q3-T3 (massive acute PE & for pulmonale)
70% of patients with PE will have a ___, half of the patients with DVT will have ___ on angiography.
- **always work up pt if you suspect they have both DVT & PE**
What is the initial approach on the physical exam if a patient is suspected to have a DVT?
- special attention to vascular system
- check extremities, chest, heart, abdominal organs and skin
What are the labs ordered when evaluating a pt for DVT?
- CBC w/ platelet
- coags (PT, PTT)
- renal function
- D-dimer: if <500 most likely not VTE
How is the dx of DVT confirmed?
- compression US on LE
- spiral CT w/ contrast for PE
What is the CT based diagnostic strategy used in pts with suspected pulmonary embolism?
What is the recommended acute tx for a DVT?
- LMWH: SQ enoxaparin (lovenox)
- IV UFH: not used often
- factor Xa inhibitor: fondaparinux (arixtra)
- any of the above for 5-7 days with oral coumadin (should overlap at least 5 days)...d/c heparin on day 5-6 once INR is in therapeutic range
What are the risks and benefits to using newer factor Xa inhibitors (rivaroxaban) as acute tx for a DVT?
- benefits: no INR monitoring/daily injections, does not require a coumadin overlap
- RISKS: bleeding since it is an IRREVERSIBLE agent, therefore pt MUST be compliant!
How long should patients with a first episode of a DVT receive anticoagulation therapy? What about recurrent VTE and those with antiphospholipid syndrome?
- 1st episode: at least 6 months
- recurrent VTE: indefinite
- **monitor INR if on coumadin**
What is the initial and subsequent anticoagulation treatment for a patient with a malignancy (which is a hyper coagulable state)?
- initial: LMWH first 3-6 months
- subsequent: LMWH/warfarin indefinitely or until cancer is resolved
What should be tested when screening for inherited thrombophilia? When should pt's be tested?
- test for deficiency: antithrombin, protein C or S
- when: strong fam hx or as part of workup/recommendation at least 2 WEEKS after completion of initial oral anticoag therapy
At what age is routine screening for breast cancer (mammography) recommended?
What is the common recommendation for reducing the risk of colony cancer?
- eat more fiber and less fat
- **however studies show no reduction in risk**
What are the top three all cause mortalities in the United states?
- #1: heart disease
- #2: CANCER!
- #3: chronic lower respiratory diseases
- **mortality is the benchmark of significance**
What are the top three cancer incidences in men? What are the mortality rates from most to least?
- incidence: prostate>lung>CRC
- mortality: lung>prostate>CRC
What are the top three cancer incidences in women? What are the mortality rates from most to least?
- incidence: breast>lung>CRC
- mortality: lung>breast>CRC
How do most cancers develop?
- stepwise fashion
- example- breast cancer: ductal hyperplasia-->ductal carcinoma in situ (DCIS)-->invasive malignancy
What are examples of oncogene mutations that result in certain cancers?
- bcr-abl in CML: d/t 9:22 tanslocation
- C-myc in Burkitt's lymphoma (NHL): d/t 8:14 translocation
- HER-2/neu oncogene in breast cancer
Genes that usually code for or control regulatory proteins that normally suppress cellular proliferation.
tumor suppressor genes
What cancers are defective tumor genes (p53 & APC) associated with?
- p53: lung, colon, breast cancer
- APC: familial adenomatous polyposis (FAP)
Absent or malfunctioning p53 tumor suppressor gene results in the loss of control of what cell functions?
- cell-cycle regulation
- DNA repair
What is the lifetime risk of developing colon cancer in a pt with an autosomal dominant inheritance of a mutated APC gene (causes FAP)?
100% lifetime risk
What is the lifetime risk for breast and ovarian cancer in a pt with a mutated BRCA 1 gene?
What cancers are associated with a mutated BRCA 2 gene?
- male breast
What is the single greatest risk factor for developing any cancer?
What cancers are reliably linked to tobacco use?
- head & neck
Approximately ___ of all cancer deaths and ___ of lung cancer deaths in the US are due to tobacco-related cancers.
What cancers are reliably linked to alcohol use?
- head & neck
- **some data suggests 26% increased risk of breast cancer with ≥1 alcoholic drink/day**
What cancers are reliably linked to radiation exposure?
- several leukemias
- **radiology professionals must adhere to strict measures to protect themselves!**
Name some chemical exposures that can cause cancer and the cancers they cause.
- radon: lung cancer
- vinyl chloride: hepatic angiosarcoma
- benzene: AML, lymphoma
- sunlight (UV): all types of skin cancer
What are the cancers that have a clear increased mortality with obesity?
- women: #1 uterine cancer
- men: #1 liver (hepatocellular) cancer
What are the proposed mechanisms for obesity's contributions to carcinogenesis and mortality?
- insulin resistance
- elevated inflammatory markers
- reduced cancer screening among obese
- reduced cancer screening effectiveness
- decreased cancer treatment effectiveness
What are some infections that can cause cancer and what cancers do they cause?
- EBV: nasopharyngeal carcinoma
- HPV: cervical cancer
- hep B & C: hepatocellular carcinoma
- H. pylori: gastric cancer
- schistosoma haematobium: bladder cancer
- HIV: lymphomas
What are the systemic inflammatory/autoimmune conditions that confer an increased risk of cancer related to chronic inflammation and abnormal immune system function and what cancers do they cause?
- Sjogren's syndrome: lymphoma
- dermatomyositis: multiple types (ovarian CA is most common)
What often influences the necessity and aggressiveness of screening for cancer?
- patient autonomy
- overall health status
What are the common cancers that require screening in primary care?
In addition to initial, pre-treatment staging, what else can PET-CT be used for in evaluating/treating cancer?
- assess response to therapy
- restaging (reassessing cancer's extent of spread after course of therapy is completed)
What is the most widely applied staging system for solid tumors?
TNM (tumor-node-metastasis) system
What is the significance of M1 when using the TNM system to stage a cancer?
implies poor prognosis and coincides with the most advanced stage of dz
What does T1 mean in the TNM system when staging lung cancer?
tumor ≤3 cm surrounded by lung/visceral pleura without invasion
What does T1a and T1b mean in the TNM system when staging lung cancer?
- T1a: tumor ≤2 cm
- T1b: tumor > cm but ≤3 cm
What does T2 mean in the TNM staging system when staging lung cancer?
- tumor >3 cm but ≤7 cm OR...
- tumor that involves main bronchus (≥2 cmdistal to carina)/invades visceral pleura/associated with atelectasis or obstructive pneumonitis that extends to the hilar region (not entire lung)
What does T3 mean in the TNM system when staging lung cancer?
- tumor >7 cm OR...
- directly invades any part of chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, main bronchus <2 cm from carina (not involving carina) OR...
- atelectasis/obstructive pneumonitis of entire lung OR...
- separate tumor nodules in the same lobe
What does T4 mean in the TNM system when staging lung cancer?
- tumor of any size that invades the...
- great vessels
- recurrent laryngeal nerve
- vertebral body
- separate tumor nodules in a different ipsilateral lobe
What does N1 mean in the TNM system when staging lung cancer?
mets in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes & intrapulmonary nodes (incl involvement by direct extension)
What does N2 mean in the TNM system when staging lung cancer?
mets in ipsilateral mediastinal and/or subcarinal lymph nodes
What does N3 mean in the TNM system when staging lung cancer?
mets in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph nodes
What does M1 mean in the TNM system when staging lung cancer?
What does M1a and M1b mean in the TNM system when staging lung cancer?
- M1a: separate tumor nodules in a contralateral lobe; tumor with pleural nodules or malignant pleural or pericardial effusion
- M1b: distant metastasis in extrathoracic organs
Best therapeutic choice when it can be done for potential cure of most solid tumors.
- "debulking" even when not curative sometimes improves survival esp with certain cancer types
What is adjuvant chemotherapy?
chemo given AFTER a primary treatment (surgery/XRT) to improve treatment success
What is neoadjuvant therapy?
chemo given BEFORE a primary treatment (surgery/XRT) to improve treatment success
Usually given in conjunction with chem/surgery when there is a "localized" site of involvement, and is occasionally used to acutely reduce tumor size in oncologic emergencies such as spinal cord compression.
What are some common examples of radiation (XRT) toxicity as manifested in changes in normal tissues surrounding a cancer?
- radiation colitis
- radiation pneumonitis
- hypothyroidism/secondary thyroid cancer
Treatments that take advantage of a cancer's biological characteristics in their effects.
What are some examples of biological/immunological therapy for cancer?
- antiandrogenic therapy for prostate CA (including orchiectomy)
- monoclonal antibody therapy (rituximab for CD20 positive lymphomas, trastuzumab for breast cancer expressing the HER-2/neu oncogene)
What are the tumor markers used for prognosis and assessment of response to treatment for certain cancers?
- alpha fetoprotein (AFP): hepatocellular carcinoma, testicular cancer
- CA 125: ovarian cancer
- CEA (carcinoembryonic antigen): colon cancer
- CA 19-9: pancreatic cancer
Tumor markers are not used for diagnosis or screening for the most part except for which one?
PSA (prostate CA)
Conditions from autosomal dominant inheritance of RET oncogenes that cause tumors to develop in different tissues, mostly endocrine glands.
- multiple endocrine neoplasia syndromes (MEN syndromes)
- endocrine cancer
What is the most common of the MEN syndromes?
MEN 1 (Wermer syndrome)
What are the "P"s of MEN 1?
- hyperParathyroidism (1st clinical sx)
- Pituitary tumors (ie prolactinoma)
- Pancreatic tumors (ie gastrinoma, insulinoma)
- liPomas and facial angiofibromas
What are the manifestations of MEN 2 (Sipple syndrome)?
- medullary thyroid cancer
- 2A: above conditions PLUS hirschsprung dz
- 2B: above conditions PLUS marfan-like habitus, mucosal neuromas, intestinal ganglioneuroma, delayed puberty
What are the broadly classifications of paraneoplastic syndromes ("remote effects of malignancy")?
- endocrine (cushings, SIADH)
- neuromuscular (lambert-eaton myasthenic syndrome)
- dermatologic (acanthosis nigricans)
- hematologic (eosinophilia, anemia, leukocytosis)
What type of cancer is most notoriously associated with the greatest number of potential paraneoplastic syndrome associations?
small-cell lung cancer
Define myeloproliferative, myelodysplasia, myelofibrosis, and myelophthisis.
- myloproliferative: excessive numbers of cells in the MYELOID lines
- myelodysplasia: deformed/ineffective cells
- myelofibrosis: bone marrow fibrosis (scarring)
- myelophthisis: secondary myelofibrosis
Conceptual organization of hematologic malignancies.
The "shared origin" of myeloproliferative disorders may account for the possibility of any of those disorders to do what?
transform to Acute Myelogenous Leukemia (AML)
What conditions are associated with a threat/risk of transformation to AML?
- polycythemia vera: 5% of all cases transform
- essential thrombocytosis: 1-5% transform over 20 yrs
- myelofibrosis: some end-stage myelofibrosis cases terminate in AML
What is the PA's role in primary care as it relates to oncology?
recognition of over proliferation (REFER!)
Treatment that offers the only curative option for some types of cancer, can be a life-saving procedure and works on the basis that hematopoietic stem cells complete restore BM function and formation all blood components, or "re-forms" the immune system.
stem cell transplantation
Where are stem cells for later transplantation collected ("harvested") from?
- peripheral blood via apheresis (MC): admin of filgrastim (G-CSF) mobilizes them from the BM to the blood
- umbilical cord blood via aspiration
- bone marrow
What are the classifications of stem cell transplantation?
- allogeneic: hematopoietic stem cells from donor (matched with HLA loci)
- syngeneic: from identical twin (not may pts have this)
- autologous: hemotpoietic stem cells from pt, has less risk for GVHD but increased chance for tumor contamination
How is an autologous stem cell transplant performed?
- stem cells are collected from pt
- pt receives chemo/radiation
- stem cells are re-infused into pt
Method of stem cell treatment that involves potent chemo and/or radiation with the goal of eradicating the underlying disease AFTER the stem cells are harvested, but results in complicated and prolonged cytopenias from bone marrow toxicity.
Condition in which increased tyrosine kinase activity leads to unregulated cell overproduction.
chronic myeloid leukemia (CML) AKA "philadelphia chromosome"
What is the chromosomal translocation involved with CML (philadelphia chromosome)?
- ABL(abelson)= chromosome 9
- BCR (breakpoint cluster region)= chromosome 22
Leukemia that is diagnosed at a median age of 55, in the early stage (chronic phase) acts like a malignant disease, retains normal BM function, and untreated progresses to an accelerated then acute blast phase which is morphologically identical to acute leukemia.
What are the clinical findings of CML?
- fatigue, anorexia, wt loss
What are the peripheral blood findings of CML?
- elevated WBC count (>25,000)
- elevated platelet count (30-50% of cases)
- reduced leukocyte ALP activity
- all stages of granulocyte differentiation
What are the bone marrow findings of CML?
- hypercellularity, reduced fat content
- increased ratio of myeloid:erythroid cells
- increased numbers of megakaryocytic
- blasts and promyelocytes (<10% of all cells)
What are the general signs and symptoms of CML?
- night sweats
- low grade fever
- elevated WBC count (may be incidental finding)
- rarely pts with WBCs >500,000 will present with blurred vision, respiratory distress, or priapism
What are the symptoms of acceleration of CML?
- fever in the absence of infection
- bone pain
How are the phases of CML disease distinguished?
by the number of blasts present in peripheral blood or BM
What are the different phases of CML?
- chronic (<10% blasts)
- accelerated (15% blasts)
- acute AKA "blast phase" (30% blasts)
What are the treatment options for CML?
- disease control=imatinib (gleevec): inhibits tyrosine kinase activity of bcd-abl gene, very high response rates with excellent clinical tolerance
- potential cure: BM transplant (remains only "curative" therapy), has "graft vs leukemia" effect with recurrence
- pallative therapy: cytotoxic agents
Condition in which RBC overproduction predominates, is pathophysiologically related to increased blood viscosity, 60% of patients are men, pts present at a median age of 60 yrs old.
What are the signs and symptoms of polycythemia vera?
- post shower/bath pruritus (aquagenic)...tingling, tickling, burning
- paradoxical bleeding risk
- thrombotic complications
- burning pain in feet or hands with erythema, pallor or cyanosis (erythromelalgia)
What are the symptoms of polycythemia vera related to?
- expanded blood volume/increased viscosity (HA, dizziness, tinnitus, blurred vision, fatigue)
- histamine release from basophilia (general pruritus esp after shower/bath)
- engorged mucosal blood vessels/abnormal hemostasis/qualitative abnormalities of platelet function (epistaxis)
What are the physical exam findings of polycythemia vera?
- splenomegaly (major finding)
- hepatomegaly (major finding)
- excoriation of skin
- stigmata of prior arterial/venous thrombotic event
- injection of conjunctival small vessels and/or engorgement of veins of optic fundus
- erythema, pallor or cyanosis feet and/or hands
What are the lab findings in a pt with polycythemia vera?
- elevated H&H
- elevated leukocyte ALP level
- low erythropoietin level
- elevated WBC count
- elevated platelet count
What are the major diagnostic criteria for polycythemia vera?
- increase RBC mass (male: ≥36 ml/kg, female: ≥32 ml/kg)
- arterial O2 sat ≥92 percent
What are the minor diagnostic criteria for polycythemia vera?
- PLT count >400,000/microL (in absence of fever/infection)
- WBC count >12,000/microL
- leukocyte ALP score >100
- serum vitamin B12 >900 pg/ml or serum unbound B12 binding capacity >2.200 pg/ml
What are the secondary causes of increased RBC mass that need to be ruled out before diagnosing polycythemia vera?
- spurious: severe volume depletion (heat injury, diuretic use, severe diarrhea, etc)
- hypoxiz driven (erythropoietin dependent): chronic pulmonary dz, high altitude, CO exposure, hypoventilation
- hypoxia independent (pathologic erthropoietin production/supplementation): malignant tumors (esp renal cell carcinoma), PKD, blood doping
What is the prognosis for pts with polycythemia vera who are not treated?
arterial thrombosis is the major cause of morbidity and mortality within 6-18 months
What are the treatment goals for polycythemia vera?
- HCT control via serial phlebotomy (<45% in men, <42% in women)
- pts >60yrs and/or prior thrombosis tx with serial phlebotomy + myelosuppressive agent (hydroxyurea)
- antihistamines, H2 receptor blockers, SSRIs, interferon alpha for severe pruritus
- low dose aspirin for erythromelalgia
- d/c ASA if bleeding occurs, eval for acquired von Willebrand dz
How are pts with polycythemia vera in the low, intermediate and high risk categories treated?
- Low risk...
- <60yrs: phlebotomy +/- low dose ASA
- >60yrs: N/A
- women of childbearing age: phlebotomy alone +/- low dose ASA
- Intermediate risk...
- <60yrs: phlebotomy alone
- >60yrs: N/A
- women of childbearing age: phlebotomy alone
- High risk...
- <60yrs: phlebotomy + hydroxyurea or interferon a + low dose aspirin
- >60yrs: phlebotomy + hydroxyurea + low dose ASA
- women of child bearing age: phlebotomy + interferon a + low dose ASA
What are the "essentials" of diagnosis of essential thrombocytosis (ET) AKA primary thrombocytosis?
- elevated platelet count WITHOUT other cause
- NORMAL rbc mass
- ABSENCE of bcr/abl gene (philadelphia chromosome)
What are the major causes of reactive thrombocytosis?
Condition that has a female preponderance (female to male 2:1), presents at a median age of 60 yrs (20% of female pts may be 40 or younger).
What are the clinical features of essential thrombocytosis?
- half of pts may be asymptomatic @ presentation
- elevated platelet count
- venous thrombosis in unusual sites (mesenteric, hepatic, portal vein)
- transient visual disturbance
- erythromelalgia (painful burning of hands with erythema, pallor/cyanosis, reliably relieved by aspirin)
- livedo reticularis (net-like discoloration of the skin)
How is essential thrombocytosis treated?
- asymptomatic pts: observe
- vasomotor sxs: low dose aspirin 40-100 mg/day
- high risk pts ≥60yrs and/or previous hx of thrombosis: PLT lowering agents (hydroxyurea + low dose ASA), goal is to keep count below 500,000
Condition also known as agnogenic myeloid metaplasia or chronic idiopathic myelofibrosis, and makes up myeloproliferative disorders characterized by bone marrow fibrosis "striking" splenomegaly (hallmark), leukoerythroblastic peripheral blood (huge abnl platelets/megakaryocytes), and "teardrop" poikilocytosis on peripheral smear.
At what age do patients typically present with primary myelofibrosis? What is the nature of the onset (insidious/acute)?
- >50 yrs old
- insidious in onset
What are the common presenting features of primary myelofibrosis?
- fatigue (d/t anemia)
- abdominal fullness (d/t splenomegaly)
- **on exam splenomegaly is commonly MASSIVE, liver is enlarged in >50% of cases**
What are the clinical features of primary myelofibrosis?
- will result in "burnt out" BM and prominent extra medullary hematopoiesis ("dry tap", unable/too difficult to aspirate)
- splenomegaly d/t extramedullary hematopoiesis (prominent spleen, early satiety, may cause severe abdominal pain)
- leukoerythroblastic peripheral blood
- BM failure leads to thrombocytopenia (bleeding)
What are the treatments for primary myelofibrosis?
- allogeneic hematopoietic cell transplant (aloo-HCT): only tx with curative potential
- other tx (mostly palliative): splenectomy, chemo, XRT of spleen for poor surgical candidates, blood transfusion with/without erythropoietin
- drugs: anagrelide, hydroxyurea, thalidomide plus prednisone (fetal deformities!), interferon alfa, etanercept
What are the characteristics of end-stage myelofibrosis?
- generalized asthenia liver failure
- bleeding from thrombocytopenia
- some cases terminate in AML
Heterogeneous clonal malignancies characterized by complex genetic alterations in hematopoietic stem cells, and are distinguished by greater cellular immaturity (blasts) of the over-proliferating cells, esp with acute disease.
What are the effects of the over-proliferation of immature, abnormal cells that account for the majority of the clinical manifestations of leukemia?
- BM "replacement"
- solid organ infiltration
- coagulation activation
What are some know etiologies to acute myelogenous leukemia (AML)?
- radiation exposure (pathologic/therapeutic)
- prior chemo
- marrow toxic drugs like chloramphenicol & chloroquine
- environmental exposure (benzene)
- pre-existing BM disorders
What is the difference between myeloid and lymphoid leukemia?
- myeloid: more closely associated with MPDs
- lymphoid: more closely associated with lymphomas
What are the primary acute & chronic leukemias for adults?
- primary acute: acute myelogenous leukemia (AML)
- primary chronic: chronic lymphocytic leukemia (CLL)
What makes up the majority (80%) of the acute leukemias of childhood?
acute lymphoblastic leukemia (ALL)
The most common acute leukemia in adults with median age of diagnosis ~65yrs, incidence increases with age, male:female ratio ~5:3.
acute myelogenous (myeloid) leukemia (AML)
What are the prominent clinical features of AML?
- general fatigue/easy fatigability (may have this for months)
- bleeding (gingival, ecchymoses, epistaxis, mennorrhagia)
- infections (risk rises as neutrophil count falls, usually <500)
- gum hypertrophy, bone and joint pain
- pale (pallor)
- purpura & petechiae
- fever (d/t infection or just underlying leukemia)
What are the common presentations of infection associated with a low neutrophil count (<500) in a pt with AML?
- perirectal infections (gram neg= e coli, klebsiella, pseudomonas)
What are the hallmark CBC findings in a pt with AML?
- pancytopenia with circulating blasts
- Auer rod (PATHOGNOMONIC)
How should a pt with AML be managed?
- AML is a relative emergency so urgent dx and therapeutic approach is required
- get CBC (look for Auer rods!)
- do bone marrow bx ASAP
What is the treatment plan for pts with AML?
- pts up to age 60 are treated with the objective to cure
- 1st step is obtain complete remission via chemo (remission=normal peripheral smear, BM & clinical status)
- hematologist/oncologist determines this treatment, and the classification and staging so again...REFER!
What are the general treatment concepts for acute myelogenous leukemia?
- induction (induction of remission): very aggressive chemo to completely destroy the leukemic cells, duration of therapy induced cytopenias is prolonged
- post induction: maintenance with less intense chemo than induction chemo
- consolidation: chemo of similar intensity to induction therapy
- intensification: chemo more intense or prolonged than induction therapy
- **goal is complete remission!**
What is considered "complete remission" of AML?
- PLT >100K
- WBC >1K
- BM with <5% blasts
What is post remission therapy for AML?
standard chemo and SCT w/ curative intent
The most common leukemia in Western countries, make up 30% of all leukemias in the US, is more common in men, is mainly a disease of the elderly (incidence rapidly increases with age) with median age at diagnosis being 70 years, but it can occur in younger individuals as well.
chronic lymphocytic leukemia (CLL)
Condition characterized by clonal malignancy of B lymphocytes in which they are immune-incompetent resulting in inadequate antibody production from the abnormal B cells, and is usually an indolent disease.
chronic lymphocytic leukemia (CLL)
What are the clinical manifestations of CLL related to?
- BM failure
- organ infiltration (lymphocytes)
What are the prominent clinical features of CLL?
- MOST pts make an appointment d/t PAINLESS swollen cervical lymph nodes that wax & wane
- can be an incidental finding in asymptomatic pts (CBC reveals absolute lymphocytosis)
- symptoms usually include the typical "B" symptoms
What are the prominent clinical features of CLL on physical exam?
- MOST COMMON is lymphadenopathy: cervical, supraclavicular and axillary (firm, round, non-tender, freely mobile)
- splenomegaly (painless & non tender)
What is the HALLMARK finding of CLL?
- CBC shows ISOLATED lymphocytosis in peripheral blood and BM
- WBC count >20K
- usually 75-98% of circulating cells are lymphocytes
What are the prominent lab findings in a pt with CLL?
- isolated lymphocytosis (hallmark!)
- WBC count >20K, most cells are lymphs
- normal HCT & PLT
- possible neutropenia, anemia & thrombocytopenia at initial dx (usually not severe)
Neutropenia, anemia and thrombocytopenia at the initial dx of CLL can be related to what?
- autoimmune hemolytic anemia
- pure red cell aplasia
- autoimmune thrombocytopenia
What tests are the diagnosis of CLL based on?
- CBC with diff
- peripheral blood smear
- flow cytometry of peripheral blood
- **above tests help determine the immunophenotype of the circulating lymphocytes**
- REFER, REFER, REFER!
What is the treatment plan for CLL?
- standard of care for early stage of dz: observe
- indications for treatment: progressive fatigue, anemia, thrombocytopenia, symptomatic lymphadenopathy, severe "B" symptoms, repeated infection <--(advanced stage disease)
How is CLL treated?
- monoclonal antibodies
- BM transplant
- **choice varies from pt to pt**
What are the second lymphoid malignancies that can develop in some CLL patients (transforms to lymphoproliferative d/o)?
- richter's transformation
- prolymphocytic leukemia
- hodgkins lymphoma
- multiple myeloma
Condition that develops in CLL pt in which an isolated lymph node transforms into an AGGRESSIVE large cell lymphoma resulting in sudden clinical deterioration with a median survival of 5-8 months.
What is the modified Rai clinical staging system for CLL?
How are non-hodgkins lymphoma and hodgkins disease differentiated?
presence of Reed-Sternberg cells (large binucleated cells-"owl eyes") in Hodgkins disease
The most common lymphoma with 85% B-cell origin, may present at any age with a clearly risking prevalence with increasing age.
What are the most common subtypes of non-hodgkin lymphoma?
- follicular lymphoma (indolent/low-grade)
- diffuse large B-cell lymphoma (AGGRESSIVE!! higher grade)
Nearly all etiologic associations for NHL involve chronic inflammation, chronic infection, or immune suppression. What are the conditions that can lead to NHL?
- chronic inflammation: Sjogren's syndrome, RA, celiac sprue
- chronic infx: h. pylori associated chronic gastritis associated with gastric MALT lymphoma, EBV associated with Burkitt lymphoma, human T lymphotrophic virus 1 (HTLV1) associated with T-cell lymphoma, HIV
- immune suppression: organ transplant, HIV
How does a patient with NHL present?
- PAINLESS lymphadenopathy (isolated/widespread or diffuse)
- LAD may be central (retroperitoneum, mesentery, pelvis) or peripheral
- **indolent lymphomas are usually disseminated at the time of diagnosis and BM involvement is frequent**
What are the "B" symptoms of NHL &HD?
- fever >100.4F
- drenching night sweats
- weight loss of >10% in previous 6 months
Which type of NHL manifests with peripheral adenopathy most commonly in the cervical/supraclavicular regions, slow growing lymphadenopathy, BM involvement (cytopenias), and hepatomegaly and/or splenomegaly?
- indolent (follicular subtype)
- **B symptoms uncommon**
Which type of NHL manifests with rapidly progressive adenopathy with a greater likelihood of extra nodal involvement (may dictate clinical presentation), most commonly GI tract, followed by skin (cutaneous T-cell lymphoma), BM, and CNS?
- aggressive (diffuse large B-cell subtype)
- **B symptoms more common**
Lymphoma that presents with an abdominal mass from bulky adenopathy (sporadic variant in the US) that causes abdominal pain/fullness (predilection of dz for the abdomen), can present with a neck or jaw mass in Africa (endemic variant).
How are NHL and HD diagnosed and staged?
biopsy, biopsy, biopsy! (surgical bx preferred over FNA)
During the process of referring ALL pts with lymphoma to a hematologist or oncologist what are some things WE can do?
- baseline labs (CBC, chem panel, LFT, LDH, HIV, hep B&C)
- CBC (anemia is the MOST COMMON initial finding in NHL/HD)
- lactate dehydrogenase (LDH) levels (usually elevated as they reflect tumor proliferation and generally correspond to prognosis)
What are the radiologic studies that are used to establish a dx of NHL & HD?
- CT with contrast of neck, chest, abdomen, and pelvis (serves as baseline study to compare response to tx, also determines disease stage)
- PET scan (detects aggressive NHL), integrated PET/CT imaging best if available
- immunophenotyping and cytogenetics (14:18 translocation MC in NHL, 8:14 translocation MC in Burkitt's lymphoma)
How is staging of NHL & HD done?
- whole body PET/CT scan
- BM biopsy
- pts with high-grade lymphoma/intermediate-grade lymphoma with high-risk features, do a lumber puncture
How are NHL & HD classified according to the WHO?
What are the stages of NHL & HD according to the Ann Arbor staging classification?
- stage I: involvement of single lymph node region or of a single extra lymphatic organ/site
- stage II: involvement of two or more lymph node regions/lymphatic structures on the same side of the diaphragm alone or with involvement of limited, contiguous extra lymphatic organ or tissue
- stage III: involvement of lymph node regions on both sides of the diaphragm which may include the spleen or limited, contiguous extra lymphatic organ or site or both
- stage IV: diffuse/disseminated foci of involvement of one or more extra lymphatic organs or tissues, with or without associated lymphatic involvement
What are the approaches to treatment of NHL?
- chemo: most important tx for pts with aggressive NHL
- immunotherapy: better for indolent NHL (rituximab)
- surgery: rarely a primary therapeutic option except in cases of impending surgical catastrophes (bowel perf with GI lymphomas), or specific situations (orchiectomy for testicular lymphoma)
- **most pts are treated with a combo of modalities**
What is the bimodal age distribution for age at presentation (etiology) of hodgkin lymphoma (HL)?
- first peak in young adults
- second peak in adults >55 yrs
What are the familial factors and infections that increase the risk of developing HL?
- familial factors: same sex siblings of pts with HL carry a 10x greater relative risk
- viral exposure/chronic infection/immune suppression: EBV, HIV, autoimmune disorders (RA, lupus, sarcoidosis)
What are the clinical features of hodgkin's disease?
- asymptomatic LAD: initially painless NECK MASS (localized peripheral LAD), MC nodes affected are cervical, and/or supraclavicular followed by mediastinal
- mediastinal mass on CXR
- B symptoms (1/3 of cases)
- diffuse pruritus
- alcohol induced pain (rare) in involved lymph node...highly specific
How is hodgkin's disease diagnosed?
BIOPSY!! (excision bx preferred, core bx adequate in some cases)
What is identified in all "classical" HD cases?
Reed-Sternberg cells (owls!)
What are the subdivisions of classical HD?
- nodular sclerosis (most common)
- mixed cellularity
- lymphocyte rich
- lymphocyte depleted
How is nodular lymphocyte-predominant HD distinguished from "classical" HD?
is pathologically characterized by large atypical lymphs NOT Reed-Sternberg cells
What are the two classifications of HD?
- nodular lymphocyte predominant
How is HD initially treated based on the stage?
- early stage (I-II) with favorable prognostic factors: short duration chemo + XRT
- early stage (I-II) with unfavorable prognostic factors: standard chemo + XRT
- advanced disease: MOPP (mechlorethamine-vincristine [oncovin]-procarbazine-prednisone); ABVD (doxorubicin [adriamycin]-bleomycin-vinblastine-dacarbazine) <--most commonly used
What are the negative (unfavorable) prognostic factors for HD?
- age >45 yrs
- stage IV dz
- male sex
- WBC >15,000
- total lymph count <600
- albumin lvl <4.0
- Hgb <10.5
How is relapse of classic hodgkin lymphoma initially treated?
high-dose chemo and autologous hematopoietic stem cell transplant (30-50% chance of cure if responsive to chemo)
What is typically seen on peripheral smear in a pt with multiple myeloma?
"rouleaux" formation (stack of chips)
Condition characterized by a neoplastic proliferation of clonal plasma cells (differentiated B-cell lymph) which overproduce a monoclonal protein (M protein) eventually leading to BM replacement by abnormal cells.
Asymptomatic condition that is a premalignant state for MM characterized by limited plasma cell proliferation and absence of end organ damage; BM monoclonal plasma cells <10% in the setting of a paraprotein (serum-M-protein <3 g/dl).
- monoclonal gammopathy of unknown significance (MGUS)
- **most cases of MM arise from MGUS**
What is the key cutoff value that distinguishes MGUS from MM on serum protein electrophoresis (SPEP)?
Epidemiology of this condition shows 3% prevalence among pts >50yrs old, 5% prevalence among pts >70 yrs old, is more frequent in males and african americans (compared to caucasians), and is associated with an estimated risk of progression to MM of about 1% per year.
Epidemiology of this condition shows the median age of diagnosis to be 65 yrs, and is twice as common in african americans than caucasians.
What is the clinical presentation of MM/MGUS?
- bone pain (back, hip, rib)
- organ dmg d/t plasma cells (kidney failure)
- anemia symptoms
- hypercalcemia symptoms
- vertigo, nausea, visual disturbances, AMS
- infection (MM pts prone to strep pneumo and h. influenzae)
- radiculopathy (thoracic/lumbosacral area)
- spinal cord compression
Bone disease d/t stimulation of osteoclasts and inhibition of osteoblasts resulting in pathological fractures (femoral neck/vertebrae) or possible spinal cord compression sxs, can cause plasmacytomas which are isolated tumors composed of clonal plasma cells usually on the ribs or other flat bones, and lytic (not blastic) lesions.
What are the clinical physical exam findings in a pt with MM/MGUS?
- pallor, bone tenderness, soft tissue masses
- signs of neuropathy and spinal cord compression
- fever d/t infection (encapsulated organisms (strep pneumo, h. influenzae)
- renal failure (acute oliguric/nonoliguric due to hypercalcemia, hyperuricemia, light chain cast injury, or primary amyloidosis)
What imagining studies are performed on a pt suspected of having MM/MGUS?
- skeletal survey (plain X-ray head to toe): look for lytic lesions with are most commonly seen in the axial skeleton (skull, spine, proximal long bones, ribs), some pts only have generalized osteoporosis observed
- MRI and PET scans: common practice in eval of these pts
What particular lab findings may indicate the dx of MM/MGUS?
- hypercalcemia (25% of pts at dx)
- anemia (70% of pts at dx, d/t BM replacement by plasma cells)
- rouleaux formation of peripheral smear related to excess proteins
- renal failure
Why is there an increased risk for infection with MM/MGUS?
- abnormal lymphocytes
- encapsulated organisms
What are the initial labs/studies used to look for MM?
- CBC w/ diff and smear
- chem panel
- routine UA & 24hr urine for electrophoresis & immunofixation
- BM biopsy
- metastatic bone survey with plain radiographs (if normal or there are neuro deficits order MRI/CT or PET/CT)
What are the 3 elements required to diagnose MM?
- detectable M protein in serum/urine: SPEP, UPEP (remember to order BOTH tests if MM is suspected!)
- BM aspirate with >10% plasma cells
- end-organ damage from plasma cells (anemia, renal insufficiency, hypercalcemia, bone lesions)
When is "smoldering" multiple myeloma diagnosed?
when lab criteria for MM is met without symptoms or evidence of end-organ damage (i.e. >10% BM plasma cells, detectable M-protein)
What is the treatment for MGUS?
clinical observation with annual lab monitoring or as symptoms require (SPEP/UPEP, CBC, chemistry)
What is the treatment for MM?
chemo followed by autologous BMT
Syndrome of IgM hypergammaglobulinemia that occurs in the setting of a low-grade non-hodgkin lymphoma, B-cells are morphologically a hybrid of lymphocytes and plasma cells which secrete IgM paraprotein, clinical manifestations are related to the macro globulin.
waldenstrom macroglobulinemia (indolent disease)
How do patients with waldenstrom macroglobulinemia present?
- insidious onset
- fatigue (d/t anemia)
- mucosal and GI bleeding (PLT dysfunction/engorged blood vessels)
- nausea, vertigo, visual disturbances
- altered LOC from mild lethargy to stupor to coma
- sxs of cold agglutinin disease (hemolysis), or chronic demyelinating peripheral neuropathy (IgM paraprotein)
What are the physical exam findings of waldenstrom macroglobinemia?
- engorged retinal veins
- purpura may be present
- no bone tenderness
What is the hallmark lab finding for waldenstrom macroglobulinemia?
presence of monoclonal IgM spike seen on SPEP on the globulin region
What is the treatment for waldenstrom macroglobulinemia?
- plasmapheresis: for hyperviscosity syndrome (stupor, coma, pulmonary edema)...its an EMERGENCY!
- chronic tx: periodic plasmapheresis alone/ rituximab/ combo therapy (advanced disease)/ autologous hematopoietic stem cell transplantation reserved for relapsed disease
What is the most common cause of hypercalciemia? What is the key differential?
- PTH vs cancer (20-30% of CA pts have hypercalcemia=predictive of a poor outcome)
What are the most common cancers associated with hypercalcemia?
- lung cancer (esp squamous cell)
- breast cancer
- multiple myeloma
What are the 3 primary mechanisms of hypercalcemia with cancer?
- humoral hypercalcemia of malignancy (HHM)
- local bony destruction from mets
- 1, 25-OH2 vitamin D secretion (associated with lymphomas, may also occur with sarcoidosis/other granulomatous disease)
What is the most common cause of humoral hypercalcemia of malignancy (HHM)?
- parathyroid hormone related protein (PTHrP) secreted from the tumor itself (paraneoplastic syndrome)
- occurs in ~80% of cases
What are the cancers associated with humoral hypercalcemia of malignancy (HHM)?
- SCC (lung, head, neck)
What is the clinical presentation of hypercalcemia?
- stones, bones, abd moans, psychic groans
- AMS (may be more prominent in rapidly growing cancer)
- sxs can be severe with markedly elevated Ca level or acutely elevated level and tend to be "multiple and nonspecific"
What are the early clinical symptoms of hypercalcemia?
What are the late clinical symptoms of hypercalcemia?
- muscular weakness and hyporeflexia
- confusion or AMS (AMS tends to be more prominent in pts with rapidly increasing calcium level as seen with aggressive metastasizing cancer)
What are the cardiac findings associated with hypercalcemia?
- short QT interval
What should you suspect if a pt has unexplained hypercalcemia and LOW PTH with serum calcium elevated greater than 12 mg/dL?
- humoral hypercalcemia of malignancy (HHM)
- **if pt is hypo/hyperalbuminemic serum calcium should be corrected (lab will do it)**
- serum PTHrP will be elevated if present
How is hypercalcemia treated?
- IV fluids
- bisphosphonates (tx of choice when secondary to malignancy): alendronate (pamidronate)/ zolmedronic acid (zometa) preferred
How is mild (Ca <12 mg/dl) hypercalcemia treated?
- hydration (oral)
- avoid thiazide diuretics, volume depletion, prolonged inactivity, high calcium diet, find and treat underlying cause
How is moderate (Ca 12-14 mg/dl) hypercalcemia treated?
- hydration (oral)
- avoid thiazide diuretics, volume depletion, prolonged inactivity, high calcium diets, tx underlying cause
- add saline hydration + bisphosphonate
How is severe (Ca >14 mg/dl) hypercalcemia treated?
- isotonic saline
- bisphosphonate (controls Ca level)
- salmon calcitonin (reduces Ca quickly)
- consider hemodialysis
Treatment of hypercalcemia.
What is the second most common neurological complication cancer (#1 being brain mets)?
- spinal cord compression
- (many pts have evidence of localized back pain for significant time periods prior to developing true spinal cord compression)
What is the presentation for a patient with spinal cord compression?
- back pain: 80% pts have pain at level of tumor mass, aggravated by sneezing, coughing, weight bearing, lying down
- neuro symptoms: progressive weakness, sensory changes, bowel & bladder sxs (incontinence) are late findings
- keep high index of suspicion with back pain/weakness of LEs in a cancer patient
What determines post-treatment neurological function with a spinal cord compression? What is the diagnostic test of choice?
- neurological function at time diagnosis predicts post tx function
- MRI, MRI, MRI is preferred!! (esp in CA pt with new back pain....MRI!)
What is the treatment for pts with spinal cord compression?
- immediate glucocorticoids for ALL patients! (10-100 mg IV followed by 4-6 mg q6 hrs IV/PO)
- pain management
- anticoagulation considered (malignancy is a hypercoag state!)
- radiation/sterotactic body radiotherapy
- neurosurgeon if possible for surgical intervention
Condition that is usually a predictable complication of therapy (7-10 days after chemo) in which a pt with cancer presents with fever d/t a direct effect of the chemo on mucosal barriers and the immune system, or host defense breeches related to underlying malignancy.
- febrile neutropenia
- **can also be primary complication of malignancy esp in cases of acute leukemias or other processes impacting BM directly**
Condition generally defined as an absolute neutrophil count less than 500 with a coexisting fever (>100.4).
How is a pt evaluated for febrile neutropenia?
- targeted hx (sxs of infection)
- PE (emphasis of skin, oral cavity, oropharynx, lungs, abdomen, perianal area)
- labs (CBC, CMP w/ LFT & renal function->baseline then trend)
- blood cultures
- imaging studies if needed
Extremely cautious eval for a fever source needs to be pursued in a pt with febrile neutropenia, even if the pt is non-ill appearing. What exam should you NEVER do and what test should you ALWAYS do for these pts?
- NEVER do rectal if you know pt is neutropenic
- ALWAYS try to get culture data prior to antibiotics if possible
Is febrile neutropenia an emergency? How is it treated?
- YES it is a medical emergency in pts currently undergoing chemo or if they had chemo within 6 weeks!
- tx empirically with broad spectrum abx to cover gram pos, neg, and anaerobes FAST (within 60 mins of presenting for eval)
Patients with neutropenic fever who are at high risk for serious complications.
How are high risk pts with febrile neutropenia treated?
- empiric IV mono therapy with any of the following: cefepime, carbapenem, piperacillin-tazobactam
How are low right pts with febrile neutropenia treated?
- empiric oral antibacterial combo: fluoroquinolone (cipro/levofloxacin) AND beta lactam (amoxicillin-clavulanic acid)
- if pt is already on fluoroquinolone prophylaxis give an IV regimen
- check for allergies! (give clindamycin for PCN allergy instead of augmentin)
Initial management of fever and neutropenia.
Obstruction of blood flow through the SVC caused by invasion or external compression of the SVC by adjacent pathologic processes involving the right lung, lymph nodes, and other mediastinal structures, or by thrombosis of blood within the SVC (both external compression and thrombosis coexist in some cases).
superior vena cava syndrome
What are some the signs and symptoms of superior vena cava syndrome (impaired blood flow return through the SVC d/t tumor compression)?
- facial swelling (plethora)
- upper extremity swelling
If SVC syndrome is unrecognized what can happen?
- acute thrombosis/tumor extends into cardiac chambers with systemic emboli
- complex neurological syndromes related to reduced blood drainage from brain and UEs
What is the SVC syndrome most commonly associated with?
- lung cancer (pancoast syndrome- horner's syndrome of ptosis, mitosis, anhidrosis, and shoulder pain, hand weakness/atrophy)
- can also be seen with lymphoma
What is the most common symptom of SVC syndrome?
How can patients with SVC syndrome present?
- pancoast syndrome
- DYSPNEA (MC)
- HA, facial swelling, head fullness, arm swelling, cough, chest pain, dysphagia
- sxs are worse when pt is supine or bending over
What are the most common PE findings with SVC syndrome?
- facial edema
- venous distention in the neck/chest wall
What imagining are used to identify SVC syndrome?
- chest CT w/ contrast
- venography (contrast) or MRV (magnetic resonance venography) to determine extent/degree of obstruction
How is SVC syndrome treated?
- tx underlying dz: radiation, chemo, corticosteroids if tumor is sensitive
- endovascular stenting: unless tumor resection is feasible and appropriate
When is tumor lysis syndrome most commonly seen?
- following cancer treatment for hematologic malignancies (ALL & Burkitt lymphoma)
- **can develop from any tumor highly sensitive to chemo and rapidly proliferating malignancies**
How does tumor lysis syndrome cause acute renal failure?
- massive release of intracellular contents (potassium and nucleic acids)
- purine nucleic acids metabolize to uric acid resulting in hyperuricemia and uric acid in the renal tubules leading to acute renal failure
What is the significance of intracellular products released with tumor lysis syndrome?
- potassium (hyperkalemia): risks lethal arrhythmias, potassium levels are often further elevated by coexisting renal failure
- phosphorous (hyperphosphatemia): may lead to secondary hypocalcemia from phosphorous binding to calcium leading to tetany, seizures, and arrhythmias, or sudden death
What is the cairo-bishop definition of laboratory tumor lysis syndrome and clinical tumor lysis syndrome?
- uric acid ≥8 mg/dL or 25% increase from baseline
- potassium ≥6 mEq/L or 25% increase from baseline
- phosphorus ≥6.5 mg/dL or 25% increase from baseline
- calcium ≤7 mg/dL or 25% decrease from baseline
- creatinine ≥1.5 times upper limit of normal
- cardiac arrhythmia or sudden death
How is the tumor lysis syndrome treated?
- best treatment is good anticipatory prevention, followed by...
- aggressive hydration prior to, during & after chemo
- allopurinol (prior to planned therapy when appropriate)
- other therapy guided by monitoring chemistries (renal fnx & lytes)
- rasburicase can be used with allopurinol since it also reduces uric acid levels (can't be used with known G6PD deficient pts or preggo/lactating women)
What are the three basic approaches to pain?
- modify the source of pain
- alter the perception of pain
- block the transmission of pain
What are some anticipated complications of pain management?
- reduced mental acuity
- **tolerance (escalating doses) are more likely to develop the longer the pt lives**
What are examples of opioids not always being the answer for all cancer pain?
- bisphosphonates are used for metastatic bone lesions
- NSAIDs for metastatic bone lesions
- neuropathic pain meds (gabapentin, tricyclic antidepressants)
When should you refer a patient to a palliative care expert?
- when pain is not controlled
- **always offer prompt relief to a hurting patient**