Hematology and Oncology

Little Old Lady in No Acute Distress

A 76 year old Caucasian female comes to her primary care physican's office complaining of fatigue and weight loss. This has gotten progressively worse over the past few months. She appears cachectic and pale. Physical exam demonstrates pale conjunctiva and nontender lymphadenopathy in the anterior cervical chain. Labs:WBC 22 (N 4.5 - 11)                         Iron  37  (N  50 - 170)Hemoglobin 8.4  (N 12 - 16)               TIBC 200 (N 250 - 450)Hematocrit  25  (N 35 - 45)                Ferritin 45 (N 10 - 120)MCV 83 (N 80 - 100)                        Saturation 35 (N 15 - 50)Reticulocyte Count 0.5 (N 0.5 - 2.5)Platelets 100 (N 150 - 450)

Little Old Lady in No Acute Distress

What is the most likely cause of LOL's anemia?A. Iron deficiencyB. Lymphoma C. Aplastic anemiaD. Folate deficiencyE. Occult GI bleed

Little Old Lady in No Acute Distress

Answer BA - Iron deficiency anemia is associated with an increase in TIBC and decrease in ferritin unlike LOL. D - Folate presents with megaloblastic anemia and hypersegmented neutrophils. Remember Vit B12 also has neurological symptoms associated with a deficiency.C - In aplastic anemia, the patients bone marrow isn't able to sustain production of all cell lines and should have low blood counts for all cell lines.E - Occult GI bleed would appear similar to iron deficiency in terms of lab values. Although this could be a possible cause, this patient is more likely to have lymphoma based on lab values and physical exam findings.

Anemia Made Easy

 

Anemia Trigger Words

Microcytic:  Target cells - thalassemia  Basophilic stippling - lead poising  Halo/ringed - sideroblastic  Koilonychia - iron deficiency

Normocytic:  AA male, sulfa - G6PD def  osmotic fragility test - spherocytosis  Chloramphenicol, carbamazipine, phenytoin - aplastic  Severe chest pain AA kid - sickle cell  Pigmented gall stones, elevated LDH, shistocytes - autoimmune

Macrocytic:  Diphyllobothriasis, Crohn's - Vit B12 def  Neurologic disorder - Vit B12 def  Palmar erythema, caput medusa, EtOH abuse - cirrhosis  AIDS on HAART - azidothymidine

Little Old Lady in No Acute DistressA lymph node biopsy is performed due to a high suspicion for malignancy. The biopsy results are shown. The most likely diagnosis is?

A. Colon adenocarcinomaB. Multiple myelomaC. Chronic lymphocytic leukemiaD. Burkett's lymphomaE. Hodgkin's lymphoma

Little Old Lady in No Acute DistressAnswer EThe biopsy results demonstrate the typical Reed-Sternberg cells of Hodgkin's lymphoma.  These cells are of B-cell origin and are CD-15 and 30 positive. Typically localized to nodes and move in a contiguous fashion. Multiple myeloma is a monoclonal proliferation of plasma cells producing IgG or IgA to cause M spike on plasma electrophoresis. Roleaux formation of RBCs.  Skull has pepper pot appearance. CLL common leukemia of older individuals with an indolent course. Smear shows smudge cells. Typically do not treat the patients until they have a blast crisis. Burkett's lymphoma typically children and immunosupressed from t(8;14). Africa has jaw lesions but sporadic has abdominal. Starry-sky appearance.

Lymphoma at a Glance

Types of Hodgkin's:Nodular sclerosing (most)    young adults            good prognosis Mixed cellularity (1/4)          lots RS cells           middle prognosisLymphocyte dom (1/10)      young males             good prognosisLymphocyte dep (rare)       older males, tons RS  poor prognosis

Hodgkin's Non-Hodgkin's

Association EBV HIV and immunosupression

Constitutional signs(fever, night sweats, weight loss)

Rare - worsens prognosis Common

Age Bimodal distribiution Peaks 20-40 yo

Spread Localized to single node chain, spreads contigously, rarely etranodal

Diffuse periperhal nodal involemvent, extranodal involvement common

Whitney is Sick

A 2 year old African-American boy is brought to the emergency room because of 2 hours of left-sided abdominal pain and shortness of breath. The patient is hypotensive and tachycardic. Physical exam demonstrated a palpable spleen 8 cm below the costal margin.

Labs:Hemoglobin 5.1Hematocrit 16WBC 4500Platelets 85000

Whitney is Sick

What is most likely causing the presenting signs and symptoms? A. Splenic sequestrationB. Salmonella sepsisC. Congestive heart failureD. Autoimmune hemolytic anemiaE. Aplastic anemia

Whitney is Sick

Answer AWith an enlarged spleen - typical of sicklers prior to autoinfarction and involution of the spleen - blood can be sequestered cause hypovolemia and low platelet counts.B - Salmonella is an important bacteria to remember for sickle cell disease. This is more likely to cause osteomyelitis. Other important bacteria are encapsulated (H. flu, Niesseria, and Strep pneumo.) because after splenic infarction they cannot clear these bacteria from the blood stream.C - The acuity of this presentation rules against CHF. This can however cause hepatosplenomegaly and edema if right-sided.D - Autoimmune hemolytic anemia can present similar to this however, the slide demonstrates sickled cells.E - Aplastic anemia would present with pancytopenia. Also this typically occurs with drugs (see above discussion).

Hemoglobinopathies

Sickle cell: Beta-chain aa 6 G - V. Inherited on Ch 11. Fetus not affected due to no beta-chain production. Treatment with hydroxyurea to increase production of fetal hemoglobin. Vaso-occlusive crisis - stroke, acute chest syndrome, splenic infarction. Prolonged disease cause splenic infarction - cannot clear encapsulated bacteria. Penicillin prophylaxis

Beta-thalasemia: Minor (one chain not produced) and major (no beta chains). Fetal hemoglobin is produced but not adequate. Prevalent in Mediterranean population.

Alpha-thalasemia: 4 alpha genes so can have a mix of disease (1 to 4 with worsening symptoms). Hemoglobin bart (beta-tetromer). Prevalent in Asian and African population.

Oxygen Binding Curve - Questions

Shifts curve to left?Shifts curve to right?Fetal hemoglobin?

Amy L. at the Emergency Department

Amy L. is a 45 year old female who came to the emergency department today because of worsening fatigue, weight loss, and persistent urinary tract infection. She has completed a 5 day course of nitrofurantoin without any improvement. Her vitals are stable, but her labs come back abnormal.  Labs:WBC 36.2 (N 4.5 - 11)                     Blood Smear:Hemoglobin 10.9  (N 12 - 16)           Hematocrit  33 (N 35 - 45)              Platelets 289 (N 150 - 450)               Urine leukocytes >10Leukocyte esterase ++Nitrate ++Bacteria >10,000

Amy L. at the Emergency Department

What is the best treatment option for Amy L.?

A. ImatinibB. Cyclophosphamide, doxyrubicin, vincristine, prednisoneC. CiprofloxacinD. All-trans-retinoic acidE. TrastuzumabF. TamoxifenG. Doxyrubicin, bleomycin, vinblastine, dacarbazine

Amy L. at the Emergency Department

Answer D.The pathology slide shows promyeloblasts with Auer rods. This is M3 of the CML diseases and is treated with all-trans-retinoic acid which cases the cells to mature. A - Imatinib is used to treat CML. This is a direct inhibitor of the bcr-abl tyrosine kinase activity.B - CHOP is the treatment for non-Hodgkin's lymphoma. Cyclophosphamide is an alkylating agent acting at guanine N-7. Causes hemorrhagic cystitis (prevent with N-acetylcysteine. Doxorubicin intercalates with DNA. Causes cardiotoxicity. Vincristine binds to tubulin to prevent polymerization of tubulin. This has neurotoxicity. C - Although this patient is suffering from a urinary tract infection treatment of this will not help her hematologic disorder.E. Traztuzumab is a monoclonal antibody against the HER-2 receptor. This is used for breast cancer.F. Tamoxifen is a selective estrogen receptor that is used to treat breast cancer. This will cause early menopause, and increases the risk for endometrial cancer.G - ABVD is the treatment for Hodgkin's lymphoma. Bleomycin forms free radicals and causes DNA breaks. Side-effect is pulmonary fibrosis. Vinblastine binds tubulin and causes myelosupression.

Amy L. at the Emergency Department

Leukemia - increased number of leukocytes in blood and marrow, can cause anemia and thrombocytopenia   ALL in kids, lymphoblasts with early cell markers, can spread to CNS and sex organs.    AML in adults, trigger word is Auer rods, nine different types but only M3 (one with Auer rods) has special treatment   CLL in older adults, indolent course with smudge cells on slide, can have warm autoantibodies, dont treat until blast crisis   CML Philadelphia chromosome (t(9;22), bcr-abl), increased neutrophils and metamyelocytes. Can tell differrence between this and infection by leukocyte alkaline phosphatase

I Love Me Some ChiliA 23yo caucasian female presents to the Akron City Hospital ED with a painful, swollen right leg. She has just returned from none other than the Nanook Classic Chili Cook-Off in Nanook, Alaska. Further questioning reveals that she takes a daily OCP and smokes 1/2 PPD. Exam reveals a moderately obese female in no apparent distress. The right lower extremity is erythematous and moderately swollen to mid-thigh. On palpation chords are palpated in the right calf. The most likely diagnosis is:    a. CHF    b. DVT    c. Muskuloskeletal Strain    d. Cellulitis     

Deep Vein Thrombosis

IV heparin is started as an inpatient. She is then transitioned to warfarin for outpatient treatment. You see her in your office in follow-up. She is doing very well. After the amazing care she received as an inpatient, she has decided medicine really is "just like Grey's Anatomy." She is now considering a career in medicine. After doing a little reading about DVT and her treatment, she has come up with a few questions.     1. Where in the clotting cascade do warfarin and heparin            work?    2. What is the most common genetic clotting disorder               predisposing to DVT?

Coagulation Cascade

Anticoagulation

Warfarin (PO) -inhibits the vitamin K-dependent synthesis of  clotting factors II, VII, IX and X, as well as the regulatory factors, protein C & S -Significance of inhibition of Protein C&S? -Monitor: PT/INR (Extrinsic)-Teratogenic

Heparin (IV, SC) -binds to antithrombin III which catalyzes the inactivation of thrombin (IIa), IXa, Xa, and XIa

-Monitor: PTT (Intrinsic)-Antidote: Protamine Sulfate-Does not cross placenta

Lipirudin & Bivalrudin- Direct thrombin inhibitors

Test Friendly Genetic Coagulopathies

Factor V Leiden Deficiency    -Factor V is resitant to inhibitory activity of Protein C    -Most common congenital hypercoagulable state    -Heterozygotes often not effected  Hemophilia A&B     -Present with hemarthosis, deep tissue hematoma    -A, Factor VIII Deficiency    -B, Factor IX Deficiency    -Both X-linked (only affects males) Von Willebrand    -Variable inheritance, most common Autosomal Dominant    -Inc Bleeding Time, Inc PTT (because loss of Factor VIII)

 A Routine Check-Up

67yo AA male presents to your office for his annual check-up. Today his only complaint is some mild, low back pain. He also has a history of HTN and hyperlipidemia which are well controlled. As part of your annual screening exam you perform a rectal exam noting an irregular, hard 1.5cm nodule. FMH is (+) for a brother and father with prostate cancer. You refer this patient to a urologist for further evaluation and order a PSA. What do you expect to see with the PSA? You have totally blown off his back pain in lieu of the more serious findings, but could the nodule and back pain be related?

Prostatic AdenocarcinomaAccounts for 33% of all cancers in USA  PSA- increased total, decreased free fraction         - BPH= increased free fraction of PSA Osteoblastic bony metastisis common in late stages    -May present with low back pain     -Increased serum alkaline phosphatase and PSAWhy didn't the patient complain of difficulty urinating or nocturia?    -Most commonly occurs in posterior lobe (25% are in central      zone)

Prostatic Adenocarcinoma

-Infiltrating glands lined by cuboidal epithelium with enlarged nuclei, visible nucleoli, and dark cytoplasm -Absence of outer basal layer.

Prostatic Adenocarcinoma Normal 

Treatment- Surgery & Radiation - Meds     -flutamide- androgen antagonist that blocks the effect of                         testosterone     -leuprolide- GnRH agonist supresses the release of                         luteinizing hormone from pituitary thereby                         suppressing testosterone production

Breast Cancer

A 68 year old woman presents to your office with the CC of a lump in her breast which she noticed while performing her monthly self exam. Being the awesome NEOUCOM student that you are, you dive deeper into her history. She began menses at 10 yoa and menopause at about 53 yoa. She has never been pregnant. Her FMH also reveals a sister who was diagnosed with breast cancer in her mid 40's. On your exam you find an approximately 2cm firm, fixed mass in the upper, outer quadrant of the left breast. No lymphadenopathy is appreciated. You order a mammogram and send her for biopsy.

Normal Breast Histology

Ductal Carcinoma In Situ

-Early malignancy- hasn't made its way through the basement membrane -Can have solid, comedo, cribriform, papillary and clinging types-Nuclear appearance is uniform-Extension causes Paget disease of the nipple -www.webpathology.com

Invasive Ductal Carcinoma

-most common (70-80%); worst and most invasive-Generic term: AKA Carcinoma NOS -microscopically have a diverse appearance

Invasive Lobular Carcinoma

-Signet ring cells (not always, but would be great board image) -2nd most common -Frequently mulitcentric and bilateral (10-20%)

Medullary Carcinoma

-Relatively rare (<1%), good prognosis -Tumor cells grow in clusters or sheets with no evidence of glandular differentiation-Lymphocytic infiltrate is always present

TreatmentSurgery and RadiationPharmacotherapy    DNA Synthesis Inhibitors        Methotrexate- folic acid analog that inhibits dihydrofolate reductase.                      - Myelosuppresion -> Rescue with leucovorin (folinic acid)         Fluouracil- pyrimidine analog bioactivated to 5F-dUMP which complexes                              with folic acid                     - Myelosuppresion-> Rescue with thymidine            DNA Alkylating Agents        Cyclophosphamide- covalently x-link DNA at guanine N-7                     - Hemorrhagic cystitis- partially prevented with mesna

    DNA Intercalating Agents        Doxorubicin-generates free radicals and non-covalently intercalates with                              DNA creating breaks in DNA strand                     - Cardiotoxicity

   

Treatment (cont.)Pharmacotherapy (cont.)     Mitotic Inhibitors        Docetaxel and Paclitaxel- bind to tubulin to hyperstabilize polymerized                                         microtubules preventing mitotic spindles from breaking                                         down (anaphase cannot occur)       Vinblastine and Vincristine- bind to tubulin and blocks polymerization of                                       microtubules so that mitotic spindles cannot form                 - Vincristine can be neurotoxic (arefelxia, peripheral neuritis) and                           cause paralytic ileus                 - "crist" your getting on my nerves, "blast" the immune system    Hormone Antagonist         Anastrozole and Letrozole- aromatase inhibitors preventing the synthesis                                                     of estrogen                     Tamoxifen- estrogen antagonist. Decreases annual recurrence by 30%    Monoclonal Antibodies         Trastuzumab- Ab against HER-2(erb-B2)                              - Cardiotoxicity         

Health Maintenance 

Screening- PSA and DRE offered/discussed with patients at age 50 or age 40 if AA or have family history Breast Cancer Screening: Yearly mammograms and breast exam after 40. 20-39 year old breast exam every 3 years. Mammogram and yearly breast exam 10 years prior to diagnosis of first-degree relative.Colon Cancer Screening: Age 50. Colonoscopy every 10 years (if clear), Flex-sig every 5 years, Barium enema every 5 yearsCervical Cancer Screening: No screening until 21 years old, then every year until 30. They won't ask about this because there is a lot of fuss about the new recommendations.

Citations"Coagulation Cascade." Centipedia. Web. 15 Apr 2011. <http://www.centipedia.com        /images/en/a/a4/Coagulation_ cascade.png>. "Ductal Carcinoma In Situ." WebPathology. Web. 15 Apr 2011.      <http://webpathology.com/image.asp?case=289&n=7>. "Invasive Ductal Carcinoma." WebPathology. Web. 15 Apr 2011.                                      <http://webpathology.com/image.asp?case=290&n=3>. "Invasive Lobular Carcinoma." WebPathology. Web. 15 Apr 2011.      <http://webpathology.com/image.asp?case=292&n=8>. Lee, Margaret. "Pediatric Acute Anemia: Differential Diagnoses & Workup."                   eMedicine. Updated Apr 2009. Accessed Mar 2011.                           <http://emedicine.medscape.com/article/954506-diagnosis>. "Medullary Carcinoma." WebPathology. Web. 15 Apr 2011. <http://webpathology.com       /image.asp?case=298&n=2>.

 

              

Citations (cont.)"Normal Breast Histology." Duke Pathology. Web 15 Apr 2011.                <http://pathology.mc.duke.edu/research/Histo_course/breast1.jpg>. "Normal Prostate." WebPathology. Web. 15 Apr 2011. <http://webpathology.com     /image.asp?case=14&n=2>. "Oxygen Dissociation Curve." Animal Physiology. Web. 15 Apr 2011.      <http://www.bio.davidson.edu/Courses/anphys/1999/Dickens                  /Oxygendissociation.htm>. "Prostatic Adenocarcinoma." WebPathology. Web. 15 Apr 2011.      <http://webpathology.com/image.asp?case=20&n=2>. "Reed-Sternberg Cell". Hematopathology. Web. 15 Apr 2011.      <http://hematopathology.stanford.edu/>.  "Sickle cell Anemia." Pathology Student. Web. 15 Apr 2011.      <http://www.pathologystudent.com/?p=310>.