Hematology and Oncology

1. Hematology and Oncology

2. 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)

3. What is the most likely cause of LOL's anemia? A. Iron deficiency B. Lymphoma C. Aplastic anemia D. Folate deficiency E. Occult GI bleed Little Old Lady in No Acute Distress

4. Little Old Lady in No Acute Distress Answer B A - 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.

5. Anemia Made Easy

6. 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

7. Little Old Lady in No Acute Distress A lymph node biopsy is performed due to a high suspicion for malignancy. The biopsy results are shown. The most likely diagnosis is? A. Colon adenocarcinoma B. Multiple myeloma C. Chronic lymphocytic leukemia D. Burkett's lymphoma E. Hodgkin's lymphoma

8. Little Old Lady in No Acute Distress Answer E The 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.

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

10. 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 5.1 Hematocrit 16 WBC 4500 Platelets 85000

11. Whitney is Sick What is most likely causing the presenting signs and symptoms? A. Splenic sequestration B. Salmonella sepsis C. Congestive heart failure D. Autoimmune hemolytic anemia E. Aplastic anemia

12. Whitney is Sick Answer A With 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).

13. 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.

14. Oxygen Binding Curve - Questions Shifts curve to left? Shifts curve to right? Fetal hemoglobin?

15. 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 >10 Leukocyte esterase ++ Nitrate ++ Bacteria >10,000

16. Amy L. at the Emergency Department What is the best treatment option for Amy L.? A. Imatinib B. Cyclophosphamide, doxyrubicin, vincristine, prednisone C. Ciprofloxacin D. All-trans-retinoic acid E. Trastuzumab F. Tamoxifen G. Doxyrubicin, bleomycin, vinblastine, dacarbazine

17. 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.

18. 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

19. I Love Me Some Chili A 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

20. 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?

21. Coagulation Cascade

22. 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 Anticoagulation Lipirudin & Bivalrudin- Direct thrombin inhibitors

23. 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)

24.  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?

25. Prostatic Adenocarcinoma Accounts 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 PSA Why didn't the patient complain of difficulty urinating or nocturia?     -Most commonly occurs in posterior lobe (25% are in central      zone)

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

27. 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

28. 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.

29. Normal Breast Histology

30. 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

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

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

33. 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

34. Treatment Surgery and Radiation Pharmacotherapy 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

35. 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

36. 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 years Cervical 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.

37. 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>.

38. 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>.