Heme/Onc Core Curriculum - From MKSAP 14/15 (all images from MKSAP 15 unless noted) and Medstudy 12 BACKGROUND ONCOLOGY TOPICS AND ONC EMERGENCIES

1. List the features of a solitary pulmonary nodule (SPN) which would lead you to believe it is malignant. What is the most common benign neoplastic cause of a SPN and what is it’s “classic” appearance on imaging? List other benign causes of a SPN. How do you follow-up solitary pulmonary nodules?

Malignant: Older Age, History of Tobacco, >1cm in size, Irregular, Malignant calcification pattern (lack of “popcorn”) Doubling time <1 year, Low density on CT Scan, Increased uptake on PET Scan Most common benign neoplastic cause is hamartoma. Other benign causes include previous granulomatous infection, tuberculosis, coccidioidomycosis, histoplasmosis or atypical mycobacteria. Other causes include anthracosilicosis, rheumatoid arthritis with fibrosing alveolitis, bronchogenic cysts or sequestration, hemangiomas, lymph node hyperplasia (Castleman’s disease), and rarely pulmonary embolism with infarction or Wegener’s granulomatosis Follow-up should be 3-4 months for first CT scan, 6-8 months for second and third in a year.

2. List malignancies that Metastasize to the Brain. Which cancers metastasize to bone (and differentiate which ones cause Blastic vs Lytic Lesions) Which malignancies commonly metastasize to the Liver? What are the most common causes of metastasis to the Pericardium? What Malignancies Cause Ascites? Brain: Lung, Breast, Melanoma, RCC, Gastric, Thyroid Bone: Breast, Prostate, Lung, Thyroid, Testicular, RCC.

(Lung: Lytic, Prostate: Blastic, Breast: Both) Liver: Colon > Gastric > Pancreas > Breast > Lung Pericardium: Lung > Breast > NHL Ascites: Ovarian, HCC, Gastric, Breast, NHL

3. List the commonly encountered side effects with the listed chemo agents:

Agent Side Effect Cisplatin Nephrotoxic, Acoustic Nerve Vincristine Periph Neuropathy Vinblastine BM Suppression 5-FU Myelosuppression, Mucositis Bleomycin Fibrosis, Hyperpigmentation Etoposide Leukemia, BM Suppression Adriamycin/Doxyrubicin Cardiomyopathy Cyclophosphomide BM Suppression, Hemorrhagic Cystitis

4. List 5 infectious diseases that increase the risk for cancer and the types of cancer they cause.

HIV: Lymphoma (NHL and HD), Cervical Lymphoma, Kaposi’s HHV-8: Kaposi’s Sarcoma, Primary Effusion Lymphoma, Castleman’s Disease HCV/HBV: HCC EBV: Nasopharyngeal Carcinoma HTLV-1: Lymphomas H Pylori: Stomach Cancer, MALTOMA Schistomiasis: Bladder Cancer (SCC) HPV: Cervical Cancer

5. What are the electrolyte disturbances with Tumor Lysis Syndrome? What Tumors are at high risk or developing this consequence? What is the pretreatment in the outpatient setting with lower risk patients? The inpatient setting with high risk patients? What about urine alkalinization? Increased K and Uric Acid and Phos, Decreased Ca with Renal Failure Bulky Tumors, High Grade Lymphomas (ie Burkitt’s), ALL Low Risk: Allopurinol and hydration before chemotherapy High Risk: Fluids and Bicarb, IV rasburicase Urine alkalinization is used, but remains somewhat controversial because it increases the precipitation of calcium phosphate complexes

6. How does superior vena cava syndrome present? What are common causes? What is the treatment? Upper extremity swelling with dyspnea, cough, and dysphagia. Exam reveals venous distention, facial edema, plethora and cyanosis. Causes include lung cancer, Lymphoma and germ cell malignancies. Radiation is the main treatment, and add chemo for chemo-sensitive tumors. Angioplasty and stenting may be needed as well.

7. List Appropriate Cancer Screening Guidelines for the following. When do you stop screening?

Breast >40 annual Mammo, Stop at 70. CBE q3y 20-39, CBE q1y >40 Cervical Pap smears yearly at age 21 or within 3 years of sexual activity. Screen

q3 years when 3 subsequent yearly are negative. Stop at age 70 when 3 negative and no positive in 10 years

Gastric NONE Prostate DRE when 40-50, >50 DRE+ PSA. Age 45 for PSA if African American or

family history. Stop when >70 HCC AFP and U/S q6 months with cirrhosis Colon Annual FOBT when >50, Sigmoid q5y + FOBT, FOBT annually or C-Scope

q10. If 1st degree relative with colon cancer, screen 10 years before their age of diagnosis, or at 40years - whichever comes first

Endometrial Screen only Patients with Lynch/HNPCC with Annual biopsy at 35

BREAST CANCER

8. List At Least 8 Risk factors for Breast Cancer

Age, Oncogenes (BRCA), Use of Estrogens, 1st degree relative, atypical ductal hyperplasia, LCIS, DCIS, early menarche, late menopause, nulliparity, obesity, EtOH

9. When should testing for BRCA1 and BRCA2 be done? What are genetic clues to this?

When there is a personal or family history suggestive of genetic cancer, and when the results will change management. Specific attributes suggest a risk of genetic cancer, and include such features as young onset of breast cancer in first-degree relatives, combination of breast and ovarian cancer, bilateral breast cancer and history of breast cancer in a male relative

10. What are the most effective ways to reduce breast cancer risk? When are they done?

They are prophylactic mastectomy selective estrogen receptor modulators. Prophylactic mastectomy is an option for patients that carry the BRCA mutation to consider Tamoxifen in premenopausal women, and both tamoxifen and raloxifene in postmenopausal women, reduces the risk of breast cancer by up to 50%, when given for 5 years, in women with at least a 1.7% risk of breast cancer. This risk can be calculated by the Gail model (calculator with risk factors included)

11. List the Prognostic pathologic Factors for Breast Cancer. Which is the most important? Which of these factors confers a good prognosis?

Most important is absence of LN Mets. Then Size Her2/neu + -> More aggressive. ER+/PR+ -> More responsive to treatment

12. Compare and Contrast DCIS and LCIS. Which lesion is benign? What is the relation to breast cancer in each condition. What is the treatment of each?

LCIS: Benign, but Increased risk of invasive carcinoma in EITHER breast. Give Tamoxifen to all (increase VTE and Endometrial Cancer) Some opt for Surgical treatment DCIS: Pre-malignant with evolution into Invasive Carcinoma Do Breast Conservation Surgery +/- Radiation then tamoxifen

Tamoxifen alone has no overall effect on survival

13. Describe the Treatment of Breast Cancer: When is Radiation Given? When can you offer Breast Conservation Surgery vs modified radical mastectomy? What about radiation therapy? When do you give Endocrine Therapy? What are your options for endocrine therapy? How is your choice of endocrine therapy affected by menopause? What are their side effects of different types of endocrine therapy? When is Adjuvant Chemo Given? How does your decision to give systemic chemo differ in premenopausal and postmenopausal patients? What are some regimens given? What is Herceptin (Trastuzumab)? When do you use it and what is the side effect?

Can do Breast conservation therapy if the Cancer is <1cm or between 1-4cm. This is usually done with whole-breast radiation (only exception is usually elderly women with small ER+ LN- tumors). Generally, Modified Radical Mastectomy is offered if lesion >4cm (Some offer this if lesion b/w 1-4cm). Radiation is not often given with modified radical mastectomy, unless the mass if very large (>5cm) and there are many positive lymph nodes. Endocrine Treatment only if ER or PR Positive. Premenopausal: Tamoxifen x 5 years Postmenopausal: Aromatase Inhibitors over Tamoxifen Tamoxifen: DVT and Endometrial Cancer Aromatase: Osteoporosis, Post-Menopausal Symptoms and Myalgias Systemic Chemo is usually to be given with positive lymph nodes and/or tumors >1cm (some give chemotherapy to all premenopausal patients, and only to postmenopausal women who are ER/PR Negative). Can Give Cyclophosphamide, Doxorubicin or Taxane for chemotherapy Herceptin for Her2/Neu Positive. It is a EGFR of Tyrosine Kinases. Side effect is Cardiotoxicity. CERVICAL AND OVARIAN CANCER

14. Describe the approach to patients with the Different Cervical Cancer Subtypes: What do you do for a patient with ASCUS? LGSIL? HGSIL? CIN I-III?

ASCUS: Can Treat for BV and recheck in 3 months. If positive again then do Colposcopy and Biopsy OR check HPV and if high risk then Colposcopy and Biopsy

LGSIL or HGSIL: Colposcopy and Biopsy CIN I – No Treatment

CIN II or III: LEEP or Conization

15. What is the staging for Ovarian Cancer. What is treatment based on stage? When is Chemotherapy Given? What are specific treatment options for metastatic ovarian cancer?

I: Ovary Alone II: Pelvis Involvement III: Peritoneal/Liver Spread IV: Metastatic Disease I-III: Debulking Surgery Chemo: Stage I with High Risk (Grade 3 or Clear Cell) and all with Stage II/III Cisplatin for I/II and Cisplatin + paclitaxel for III

Intraperitoneal Chemo can be offered as well

TESTICULAR CANCER

16. List the risk factors for Testicular Cancer. It is the most common solid organ malignancy in what Age Range?

Cryptorchism (esp Abdominal>Inguinal) – even those with orchiopexy have increased risk. Klinefelter’s increases risk. 20-35.

17. Describe the approach to diagnosis and staging of Testicular Cancer. All patients with palpable testicular mass need U/S. Send tumor markers, LDH, CT Abd and Pelvis and CXR. If suggestive of testicular cancer, DO NOT BIOPSY, as orchiectomy is needed for diagnosis.

18. List all the subtypes and classifications of Testicular Cancer. Describe how serum markers help distinguish for each category. How would you approach a patient whose testicular pathology reveals seminoma but the AFP is elevated? When would you expect testicular lymphoma, and what is the marker?

Germ Cell: Either Seminoma or Non-Seminoma Seminomas are ALWAYS AFP Negative. 5-10% are BHCG Positive NS: Embryonal – 50% AFP+, 50% BHCG+ Teratoma – Negative Markers Chorio – ALL BHCG+ Yolk Sac – ALL AFP+ Stromal Cell: Leydig and Sertoli. If seminoma on pathology, but Increased AFP – is has Nonseminomatous components Testicular Lymphoma - Consider in patients >50 or HIV patients. High LDH

19. How do you stage testicular cancer? How do you classify the metastatic stages? What is the treatment of patients with the Seminomatous Subtype? What about Non-Seminomas? Metastatic Dz? What are some side effects of the chemo used for metastatic disease? Staging: Stage I: Testis Stage II: Testis + Retroperitoneal or Periaortic LN Stage III: Spread beyond Retroperitoneal or Periaortic LN Mets are classified as either favorable, intermediate or poor based on histology, markers and location Lesions associated with normal serum tumor markers are classified as S0, whereas tumors associated with increasingly abnormal levels of serum LDH, hCG, and AFP are classified as S1 to S3 Seminoma: Stage I: Orchiectomy and radiation therapy to include the paraaortic lymph nodes and often the ipsilateral ilioinguinal lymph nodes Stage II: Orchiectomy with radiation or cisplatin chemotherapy (in general, radiation for smaller lesions, chemo for larger lesions)

Stage III: Orchiectomy and Bleomycin, etoposide and cisplatin-based chemo Nonseminoma: Stage I: Surgery with close surveillance or surgery with RPLND (Chemo is given to these patients if the RPLN are +, or if markers rise) Stage II: Surgery with RPLND and Cisplatin Chemo Stage III: Surgery with RPLND and Bleomycin, etoposide and cisplatin [Relapsed disease treated with ifosfamide (together with cisplatin), vinblastine, and paclitaxel] Etoposide: Acute Leukemia Bleomycin: Fibrosis and Raynaud’s Cisplatin: Nephrotoxicity and PN PROSTATE CANCER

20. What are the screening guidelines for prostate cancer? How do you screen based on age? When do you proceed with biopsy and when do you proceed with full staging? What tests do you perform to complete staging? When don’t you have to stage patients?

In general only screen if life expectancy is >10 years. If patient is > 50 do DRE+PSA (perform these in african americans at age 45) Usually you do not screen if patient is about 75. If Positive Exam, Elevated PSA or rising PSA: Transrectal U/S and Biopsy. If Positive Bx then do CT Pelvis and Bone Scan. (Note you Don’t have to Stage if the PSA is <10 or a Gleason <7 b/c it is rarely mets)

21. How do you stage and grade Prostate Cancer? Describe the approach to treatment of Prostate Cancer - When is “watchful waiting” appropriate? When do you offer prostatectomy? When do you offer radiation treatment? When do you give hormonal treatment? What are 3 classes of options for hormonal treatment? What medications must be given with these hormonal treatments? What is AIPC and what is the approach to treatment?

Stage:

T1: Not palpable, T2: In Prostate Only, T3: Extended beyond prostate, T4: Fixed N1 is regional lymph nodes. M1 is distant LN spread or other organ spread Grade: By Gleason Score Treatment - one can place patient at risk for metastasis based on Tumor stage, gleason score and PSA. From this, and life expectancy, treatment is determined

Overall: Watchful wait if Early Stage and Low Grade, Older, and Asymptomatic pts with mets Surgery if T1-T2, No mets and >10 year life expectancy. (Side effect is erectile dysfunction and urinary incontinence) Radiation if T1-T3 with no Mets OR T1-T2 with High PSA >20 or Gleason 8-10 (i.e if it is known to be outside the organ or it is highly likely to be outside the organ) - side effect is radiation proctitis and cystitis. Hormonal Treatment when symptomatic with mets, there is increased PSA after initial treatment, or Node positive found after surgery. Can use a GnRH agonist (Leuprolide or Goserelin in combination with bicalutamide. The use of antiandrogen therapy (Flutamide) before, during, and after radiation helps improve survival with high risk or advanced disease. The use of GnRH agonists is as effective as Orchiectomy in metastatic disease. Must give Calcium and Vitamin D to all, and a bisphosphonate if osteopenia or osteoporosis AIPC: Androgen-Independent Prostate Cancer – resistant to hormonal treatment. Can give docetaxel steroids, ketoconazole BLADDER AND RENAL CANCER

22. How does bladder cancer present? diagnosed? Treated? Patients can present with nonspecific findings, including UTI symptoms, and painless hematuria. More advanced cancers cause local obstruction and blank pain. Metastases to bone is common, so bone pain can be present. Diagnose by cystoscopy and biopsy. Urine cytology can be sent Treatment for superficial lesions includes tumor resection and intravesical therapy with bCG or mitomycin C. If this recurs, cystectomy is recommended. Patients with more advanced disease have cystectomy and postop radiation and/or chemo with cisplatin. Metastatic disease treated with gemcitabine-cisplatin.

23. How do you diagnose Renal Cell Carcinoma? What is the treatment?

Diagnose with Imaging (CT or MRI). Do not biopsy Early stage disease treated with partial or radical nephrectomy Locally Advanced and Metastatic Disease is treated with targeted therapy (such as sunitinib, sorafenib, and temsirolimus) HEAD AND NECK ONCOLOGY

24. What is the basic approach to treatment for head and neck cancer? Early Stage Disease - Surgery or radiation with curative intent Advanced Disease - Combination treatment with surgery, radiation and chemotherapy Metastatic Disease - Palliative Chemotherapy GI ONCOLOGY

25. How does Pancreatic Cancer commonly present? How does this affect the stage at diagnose and potential treatments? What are specific treatment options depending on the various stages. What is the Approximate 5-year Survival rate for those that undergo potentially curative surgery? The most common symptom of pancreatic cancer is constant epigastric pain that radiates to the back, especially with cancer of the body and tail. Cancer of the head of the pancreas causes painless jaundice. Weight loss is common at the time of diagnosis, and new-onset diabetes mellitus is present (usually preceding diagnosis by months!) To diagnose - do Pancreatic protocol CT with EUS if needed. Treatment: Less than 20% of presenting patients are candidates for surgery Local: Resection with intent to cure, but 5 year survival 20-25% (Pancreaticoduodenectomy with cancer of the head. Distal pancreaectomy with cancer of body or tail) Adjuvant chemoradiotherapy has been shown to improve patient survival after resection. Note that resection cannot be done with distant metastases, encasement of the superior mesenteric artery or celiac artery, and occlusion of the SMV or portal vein Local but unresectable: Chemo (including 5FU) with radiation Mets: Gemcitabine

26. Describe the Staging of Colon Cancer. What is the Median 5 year survival for each stage? (The Duke Classification is here along with the AJCC staging, although Dukes not used)

Stage 0: Not involving the mucosa Stage I or “A” : Involving the submucosa or muscularis propria Stage IIA or “B1” : Past the muscularis propria but not into nearby organs, no LN Stage IIB or “B2” : Past the muscularis propria and into nearby organs, no LN Stage III or “C” : LN Involvement

Stage IV or “D” : Mets Stage & Relative 5-year Survival Rate: I 92%, II 73%, III 56%, IV 8%

27. Describe the Treatment of Colorectal Cancer. When do you offer Surgery? When do you offer

Chemo? What are some chemotherapy regiment? What are some unique side effects of these chemotherapy regimens? When can you resect hepatic metastases? Briefly describe the mainstay of rectal cancer treatment. What studies do you follow in patients after resection?

Surgery for I (Duke A) or IIA/IIB (Duke B1/B2) Surgery plus Adjuvant Chemo in III (Duke C), controversial for IIB (Duke B2) Chemo for IV (Duke D) Adjuvant Chemo: 5-FU with leucovorin is the standard, but oral capecitabine (a prodrug of 5-FU) is replacing long-term infusional 5-FU. 5FU/LEU + Oxaliplatin (FOLFOX) hase been used with better survival, and FOLFOX can be used as adjuvant chemo in Stage II or III disease Chemo for Mets: Many option exist, including oxaliplatin alone, irinotecan alone (or these in combination with 5-FU as FOLFOX or FOLFIRI. Monclonal antibody therapy (Bevacizumab, Cetuximab) in combination with traditional chemotherapy shows improved survival 5FU: Stomatitis, Anemia, Irinotecan: Diarrhea, watery eyes, increased salivation Oxali: Paresthesias, spasms, Peripheral neuropathy, hepatotoxicity Can resect hepatic metastases if <5 Total Rectal Cancer: Important thing is Radiation therapy: Most give Pre-op Rads or Pre-Op Chemo/Rads with 5-FU or FOLFOX After resection, patients should have CEA performed at regular intervals, follow-up colonoscopy and CT scans if they have more advanced disease

28. What are the historical diagnostic criteria (aka Amsterdam Criteria) for a patient with Lynch Syndrome/HNPCC? How do you diagnose it? What malignancies are commonly seen in these patients?

Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two. Two successive affected generations. One or more colon cancers diagnosed under age 50 years. Familial adenomatous polyposis (FAP) has been excluded

Diagnose with Genetic testing for mutations in DNA mismatch repair genes

80% lifetime risk for colon cancer. Women with HNPCC have a 30-50% lifetime risk of

endometrial cancer. Risk of Gastric and Ovarian Malignancy. Urinary tract cancers (TCC of the ureter and renal pelvis) small bowel cancers occur most commonly in the duodenum and jejunum; the central nervous system tumor most often seen is glioblastoma.

29. List the risk factors for Gastric Cancer including diet, lifestyle and medical conditions. How does it present? How is it diagnosed/worked up? What are treatment options for Early Disease? Metastatic Disease?

Smoking, H. Pylori, Male Gender, Chronic Atrophic Gastritis, Pernicious Anemia, Gastric Polyps, Menetrier’s Disease, FAP, Diet low in fruits and high in smoked foods Usually presents with anemia, abdominal pain, weight loss, and nausea/vomiting Diagnosis with EGD + EUS, followed by CXR and CT (may need PET Scan) Local Disease: Surgery with adjuvant chemotherapy and radiation. If patients can tolerate it, aggressive neoadjuvant chemoradiation (i.e. given before surgery) is given as well. Mets: Palliative chemotherapy, surgery for symptoms. Clinical Trial enrollment is encouraged.

30. How does esophageal cancer present? What is the treatment? Presents with dysphagia (initially liquids then solids), odynophagia, cough, retrosternal pain Surgery with neoadjuvant chemoradiation with early disease, those that cannot undergo surgery receive chemoradiation. Patients with metastatic disease should enroll in a trial. LUNG CANCER

31. What are the 3 broad categories of the presentation for lung cancer. Give examples of each

Local symptoms: New or worsening cough, hemoptysis, dyspnea, fever, chest pain, hoarseness Swelling of face/arm (SVC Syndrome) Pancoast Sybdrome (Shoulder pain, Horner’s [ptosis, miosis, and ipsilateral anhidrosis], arm paresthesias) Pleural Effusions and Post-obstructive pneumonia Paraneoplastic syndromes: Hyponatremia (SIADH) Hypercalcemia (PTH-rp) Acromegaly Cushing's Lambert-Eaton syndrome Limbic Encephalitis Metastatic Presentations: Bone pain, fractures Headache/seizures Hepatomegaly and abdominal pain Pancytopenia Skin nodules

32. List the 4 major subtypes of lung cancer. Describe common locations, epidemiologic background, metastatic spread and paraneoplastic syndromes

NON-SMALL CELL SMALL CELL Squamous Adeno Large Cell Location Central Periphery Periphery Central Paraneoplastic Hypercalcemia HPOA,

Hypercoaguable Rare SIADH/ACTH/LEMS

Malignant? Low-Moderate Moderate Moderate High (mets early) Background Mostly

Smokers Half Smokers and Females

Mostly Smokers

Mostly Smokers

33. Describe the staging of Non-Small Cell Lung Cancer and the Treatment plan based on each stage.

What tests do you perform to stage? Be familiar with the amount of disease-free survival per stage in 5 years. Also, list some common chemotherapy regimens used for initial treatment and recurrent disease. What chemotherapeutic agent is specifically used to treat Lung Adenocarcinoma and can be used in a specific subset of patients?

STAGE DEFINITION TREATMENT Long-Term Disease Free Survival

I Tumor surrounded by lung or pleura, more than 2cm from carina

Surgery and chemo, radiation if cannot undergo surgery

60-70%

II Locally advanced disease without mediastinal involvement

40-50%

IIIA Mediastinal involvement Chemotherapy, Radiation and/or surgery.

5-20%

IIIB Mediastinal involvement with pericardial or pleural effusion

Chemotherapy and/or surgery

5-20%

IV Metastatic Disease Chemotherapy if good performance status. Surgery for solitary brain met.

<5%

Stage with CT and PET Scan Chemotherapy used is cisplatin or carboplatin combined with one of several agents

including paclitaxel, docetaxel, vinorelbine, gemcitabine, irinotecan, or pemetrexed Erlotinib is used in patients that have a mutation in the EGFR gene. Bevacizumab has been used in conjunction with other chemotherapy for advanced nonsquamous cell types

34. How do you stage Small-Cell Lung Cancer? What is the Median Survival In Each Stage? What is the treatment for each stage? What happens if these patients continue to smoke? Limited: Disease limited to one hemithorax, with hilar and mediastinal lymphadenopathy that can be encompassed within one tolerable radiotherapy portal (Median Survival is 16-24 mos) Extensive: Disease does not fit into one port (Median Survival is 8-12 mos). Staging done by CT Scan of chest, MRI/CT of Brain, and bone scan or PET scan. (Note that if disease is extensive, extensive staging beyond CT chest not needed)

Limited Treatment: Cisplatin + Etoposide with cheat radiation Extensive Treatment: Cisplatin + Etoposide or Carboplatin + Etoposide if they have good performance status.

Prophylactic cranial irradiation is also given for patients with small cell lung cancer

Smoking increases risk of a SECOND primary lung cancer

BENIGN HEME

35. Identify each blood smear finding below and the causes of the finding

1 2

3 4

5 6

7 8

9 10

11 12

13 14

15 16

17 18

19 20

21

1 Sickles 2 Target Cells – Thal, Sickle Cell, Liver Dz 3 HS- Hered 4 Spur Cells/Acanthocyte - Cirrhosis 5 Burr Cells/Echinocyte - Uremia 6 Schisto – TTP/HUS/DIC/HTN 7 Microspherocytes - Warm Ab AIHA 8 RBC clumping and aggulitination - Cold Ab AIHA 9 Retic – Blood Loss/Hemolysis 10 Tear Drop - MYelo 11 Rouleaux – IDA, Dehydration, MM 12 Basophilic Stippling – Lead Poision, Sideroblastic 13 Macrocyte – Many Causes 14 Thrombocytosis – Many Causes 15 Bite Cell – Spleen removal of damaged HgB 16 Heinz – G6PD 17 Hgb C Crystals – Hgb C Disease 18 Auer Rods - AML 19 Smudge - CLL 20 Pseudo Pelger-Huet neutrophil - MDS 21 Howell Jolly – usu post splenectomy,

36. List the causes of anemia by both reticulocyte index and MCV. Knowing this, explain the basic approach to the workup of anemia that leads you to a DDx Adequate Reticulocyte Index - Usually from Hemolysis and Blood Loss Low Reticulocyte Index - Problems with production (AOCD, Iron Deficiency, BM Disease) Micro: IDA, AOCD (early), Lead, Sideroblastic Anemia, Thalassemia Normo: Loss, Hemolysis, BM Disease, AOCD (over time) Macro: B12, Folate, Thyroid, Liver Disease

37. List the lab findings to distinguish Iron Deficiency from Anemia of Chronic disease. How can you diagnose iron deficiency anemia in the setting of inflammation? What are the causes of each of these subtypes? What is the treatment of choice for these causes of microcytic anemia? Serum Iron TIBC Iron Saturation Ferritin IRON DEF Low High Low Usually low CHRONIC Low Normal Low-Normal High Iron deficiency with concomitant inflammation raises the ferritin, almost never above 200, and rarely above 100. A ferritin >100 rules out IDA, whereas <15 rules in.

Iron Deficiency: Causes: Pregnancy, blood loss (GI, GU and GYN), malabsorption (celiac disease, inflammatory bowel disease, s/p small bowel resection), chronic hemolysis. Treatment: Iron Sulfate 325md tid without meals. If can't tolerate, take daily. IV iron is given to those with malabsorption issues. Monitor therapy - only takes 3 days for retic count to increase, and about a week to normalize. Hemoglobin takes months to return to normal Anemia of Chronic Disease - Two categories are inflammatory and renal disease Inflammatory: Caused by rheumatic diseases, chronic infections (TB/Osteo), malignancy. Labs: Anemia is initially normocytic, but becomes microcytic over time Treatment: Treat underlying disease. Usually no iron, EPO can be given if the levels are low and the patient is symptomatic, but use with caution Anemia of Renal Disease: Treat with EPO (and iron if iron deficient as well) to target Hgb of 11-12.

38. Distinguish Clinical features, causes and diagnosis of folate and B12 deficiency. What is the treatment of each? Make sure to comment on tests to perform if you are certain a patient has either one of these diseases but levels of B12 and RBC Folate are normal? B12: Cause: Pernicious Anemia, Malabsorption, Dietary (Vegetarians), Infection, Metformin. Clinical: Glossitis, Loss of position and vibratory sense, ataxia, psychosis Testing: Macrocytic anemia with megaloblasts. Many patients also have some degree of leucopenia and thrombocytopenia. Slight elevation of LDH and total bili are not uncommon. Although a B12 Level <200 is usually deficiency, levels 200-400 are not uncommon with true deficiency, and in these patients a homocysteine and methylmalonic acid should be sent (pts with B12 deficiency will have a High Homocysteine and MMA) Treatment: Oral or parental replacement. (If this does not help Hgb in a few months, you should rule out iron deficiency and myelodysplastic syndromes)

Folate: Causes: Decreased intake, EtOH, malabsorption (celiac disease etc), Pregnancy, sickle cell disease, phenytoin Clinical: Fatigue and GI Complaints (no neuro) Testing: Serum folate levels, although RBC folate levels are a better test. If certain, send testing for homocysteine and methylmalonic acid (High Homocysteine, normal MMA) Treament: Daily oral folate (MUST exclude cobalamin deficiency in patients with folate deficiency because supplemental folate can improve the anemia of cobalamin deficiency but not the associated neurologic sequel)

39. What are the causes of microangiopathic hemolytic anemia? What do the labs and blood smear show? Causes include TTP, HUS, HELLP, DIC, Mechanical Heart Valve Shearing, Malignant Hypertension Since this is an intravascular hemolysis, labs reveal a bilirubin that is normal or only slightly elevated. LDH is increased and Haptoglobin is decreased. There is hemoglobinuria, so patients can become iron deficient as well. Blood smear with fragmented cells (schistocytes)

40. What clinical findings are suggestive of TTP/HUS? What distinguishes the two? What does the blood smear show? What test does one send to diagnose classic TTP? How does one treat HUS? What is the only initial treatment that is evidence-based to treat TTP? What about refractory TTP?

MAHA (i.e. hemolysis with schistocytes) and TCP. Renal Failure and Mental Status Changes and Fever are late findings. In general HUS has more renal failure, TTP more neurologic disease - but there is significant overlap in these conditions . HUS is usually in children, though, and occurs from infections (e coli) and familial deficiencies. TTP results from decreased ADAMTS13 PBS with at least "Occasional" Schistocystes. Send ADAMTS13 Level for Classic TTP. Treat HUS with supportive Care. Treat TTP with Plamapheresis (steroids et al are not evidence-based). Can Use Rituximab for refractory cases

41. What are some of the causes of autoimmune hemolytic anemia? Describe the pathophysiology and list potential causes of both warm and cold-antibody mediated hemolytic anemia. What does the smear and lab tests show in each? What is the treatment of each?

General causes are medications, cancer, autoimmune disease, malignancies.

Warm: IgG Mediated - binds to RBC and causes destruction by splenic macrophages Causes: Idiopathic, SLE, Drugs, Leukemia, Lymphoma - especially CLL!!!!!!!!!! Smear with microspherocytes and increased retics. Positive Direct Coombs to IgG Treat with Steroids and if severe can do a splenectomy. If still not responsive, can give agents such as rituximab, cyclosporine, azathioprine Cold: IgM binding to erythrocytes causing C’ fixation and hemolysis Smear with clumping/agglutination. Direct Coombs with Positive C3 Causes: Idiopathic, Mycoplasma, EBV Keep patients from getting cold, can give cyclophosphamide or rituximab

42. What are the features of G6PD deficiency. How is it diagnosed? Patients that get anemia after oxidative stress, such as with infection or from medications. They present with signs of jaundice and "bite cells" on smear. Test with levels in those at risk before giving medications. Once they have the anemia, you must wait 2-3 events to test for G6PD levels

43. What are the clinical manifestations of sickle cell disease in the Musculoskeletal System? Genituurinary? Pulmonary System? Cardiovascular System? GI? CNS? Renal? What are some ID complications of sickle cell disease? Some Hematologic Complications? GI: Splenic Infarction, Cholelithiasis

MS: AVN GU: Priapism CNS: Strokes Renal: Acute Papillary necrosis, CKD CV: Heart Failure Pulm: Chest Syndrome, Pulmonary Embolism, Pulm HTN ID: Osteo, Septic Joint, strep and neisseria infections after autosplenectomy Heme: Vasoocclusive Crisis, Hemolytic Crisis, Aplastic Crisis

(Suspect aplastic crisis and Parvovirus B19 with worsening anemia)

44. How do you diagnose Acute Chest Syndrome and treat it? When do you give exchange transfusion for Chest Syndrome? What are the other indications for exchange transfusion in patients with sickle cell disease?

Exchange transfusion for: Chest Syndrome, Priapism, Stroke, Aplastic Crisis Chest Syndrome : New Pulmonary Infiltrates with any of these: fever, cough, sputum production, dyspnea, or hypoxia. Treat with Cephalosporin/Macrolide, O2. Exchange transfusion when arterial oxygen saturation (SaO2) persistently less than 80% despite aggressive ventilatory support, serial decline in SaO2, unstable &/or worsening vital signs or persistent respiratory rate greater than 30/minute

45. Describe the general treatment of patients with sickle cell disease Hydroxyurea improves mortality. Patients need to keep well hydrated. Need annual pneumococcal and influenza vaccines. Need annual eye exams. Transfuse only when needed, and keep Hgb <10

46. List the cultural epidemiology of both alpha and beta thalassemia. What are the subtypes of each thalassemia and their clinical presentation? How can you use electrophoresis to distinguish the different causes of Beta-Thalassemia? How can you use lab data to distinguish IDA from Beta-Thalassemia minor (which it is commonly confused with)

A: Africa, Mediterranean, Middle East, Asia One deletion – silent carrier Two – Trait – mild anemia with normal erythrocycte count Three – Hemoblobin H disease – Severe Anemia with CHF, Hypoxia Four – Hydrops Fetalis – Fatal in utero B: Mediterranean, Southeast Asia, India and Pakistan

Major: Anemia, Splenomegaly, Pigment gallstones, Iron Overload, Growth Problems, Ineffective hematopoeisis Very Low HgA, High HgA2 and High HgF Minor: Mild Anemia but can get iron overload Low HgA, High HgA2 and Normal HgF

47. What is the best way to screen for hemochromotosis? What about definitive diagnosis? What are the clinical findings? What is the treatment of choice and target goal for treatment? Who gets secondary iron overload and what is the treatment? Iron Sat >60% in Males and >50% in Females. Need Bx for definitive diagnosis. Fatigue, Myalgias, Abdominal Pain, Skin Bronze, CHF, Arrhythmias, Diabetes, Cirrhosis. Treat with phlebotomy to Ferritin of less than 50 Secondary iron overload occurs in those that are heavily transfused, and even in those with thalassemia that do not get transfused. Since patients are usually anemic, phlebotomy usually cannot be done, and iron chelators (deferoxamine and deferasirox) are used.

48. Describe your approach to a patient with abnormal coagulation tests. How would you work up an abnormal PT or PTT? What are the potential causes of an isolated elevated PTT? An isolated elevated PT? A prolonged PTT and PT?

49. Who gets vitamin K deficiency? What do the labs show? Patients with liver disease, chronically ill, malnourished and those on antibiotics. Labs with reduced factor II, VII, IX and X. PT is prolonged initially, but over long-term, the PTT is elevated.

50. How can the physical exam and history help you distinguish from bleeding that is due to platelet disorders or due to coagulopathy? List some common causes of thrombocytopenia. Platelet disorders cause bleeding immediately after injury and reveal petechiea and mucous membrane bleeding. Coagulation disorders manifest as a delay in bleeding, with eccymosis and hemarthroses Increased Destruction (ITP, DIC, TTP, HIT, medications such as sulfas, infection) Decreased Production (Bone marrow - malignancy, chemo/meds, infection) Sequestration (Liver disease)

51. What is the clinical course of HIT? How do you diagnose it? How do you treat it? How do you treat HIT if there is a thrombosis present? Unexplained decrease in platelet counts of at least 50% after 5-10 days of initiating therapy with Heparin or LWMH. Platelets usually b/w 50-70 thousand. Diagnosis is CLINICAL - The criteria for diagnosing HIT include (1) thrombocytopenia (defined as a platelet count <150,000/µL [150 × 109/L] or a 50% decrease in platelet count from baseline, in which case the platelet count may still be within the normal range) in the presence of heparin or its use over the past 3 months; (2) exclusion of other causes of thrombocytopenia; (3) reversal of thrombocytopenia on cessation of heparin; and (4) positive laboratory test results. Use ELISA to test for antibodies to heparin or the Serotonin Release test. Stop all heparin products and start patient on a direct thrombin inhibitor until platelet count returns to baseline. Transition to oral anticoagulant (coumadin) if clot present when platelets are above 100,000 and while patient on direct-thrombin inhibitor

52. What labs are suggestive of DIC? What are the causes? What is the treatment? Elevated PT, PTT with low Fibrinogen, Elevated D-Dimer and Thrombocytopenia (note, that same findings can be present in patients with liver disease!) . PBs can reveal shcistocytes. Causes include infections (esp Gram negative), cancer, and obstetrical complications Treatment with treating underlying cause. FFP is given, as well as possible transfusion of PRBCs and Platelets, Cryoprecipitate given with very low fibrinogen.

53. How does ITP present? What is on the PBS and CBC? What is your diagnostic approach to a patient with ITP? When do you treat patients with ITP? What is the initial treatment of choice? How can you potentially treat refractory disease? Can present from mild bleeding (such as petechiae and epistaxis) to GI or CNS bleeding PBS reveals large platelets, and the CBC is usually otherwise normal Must rule out HIV, HCV and SLE with Tests including ELISA and ANA. Bone Marrow Bx Not required, but done by most to r/o acute leukemia. Some workup for H. Pylori as this has rarely been associated with ITP. Treat when platelets below 30,000 -> Prednisone 1mg/kg/day. Can Give IVIG then try splenectomy if refractory. Last resorts include Danazol, Rituximab and Anti-D

54. What is the clinical presentation of von Willebrand Disease? What are the subtypes? What are the lab abnormalities and confirmatory tests? What is the treatment?

The various types of vWD present with varying degrees of bleeding tendency, usually in the form of easy bruising, nosebleeds and bleeding gums. Women may experience heavy menstrual periods and blood loss during childbirth. Internal bleeding and hemarthrosis are rare except in Type 3 Type I: Quantitative defect Type II: Qualitative Defect, Type III : Marked deficiencies of both VWF and FVIIIc in the plasma Acquired: Rare, can occur from hematologic malignancies Workup with: Increased Bleeding Time (rarely done) or other tests of platelet function (platelet function analyzers) and increased aPTT, Diagnosed by decreased low or variable levels of vWF and decreased ristocetin cofactor activity Minor bleeding problems, such as bruising or a brief nosebleed, may not require specific treatment. For more serious bleeding, desmopressin has become a mainstay of therapy for most patients with mild von Willebrand disease. Can also transfuse other produces that contain vWF, such as cryo or factor concentrates. DAVP can also be used to prepare patients with VWD for surgery. FVIII concentrates contain vWF and are used in severe cases such as subtypes 2 or 3 disease.

55. How does uremia causes bleeding? What is the treatment? Platelet defect in uremia due to toxic effects of uremic plasma, impaired platelet–vessel wall adhesion, and increased production of nitric oxide. Treatment includes dialysis and administration of DDAVP. Conjugated estrogens may be helpful in reducing bleeding. Platelet transfusions are ineffective

56. List 5 causes of acquired AND congenital hypercoaguability. Which of these diseases can cause venous thrombosis? arterial thrombosis? When should you suspect an inherited hypercoaguable state? What is the general workup for secondary causes of thrombosis? Which tests for these diseases can be done at anytime? Which are affected by acute clots? Coumadin therapy? What is the treatment approach for hypercoagulable states?

Acquired: Prior, Obesity, Immobilized, Cancer, Surgery, Estrogens, Stasis, HIT, Nephrotic, Pregnancy, PNH, myeloproliferative diseases, antiphosopholipid Ab syndrome

Congenital Causes include Factor V Leiden, Prothrombin Gene Mutation, ATIII Deficiency, Protein C/S Deficiency. Venous thromboembolism in all listed, Arterial clots can be seen with elevated Homocysteine levels, PNH, HIT, Myeloproliferative diseases and antiphospholipid Antibody Syndrone.

Suspect congenital disease in those with thrombosis in the absence of acquired causes, thrombosis at early age (<40) even in those with acquired causes, Recurrent Thrombosis especially in different sites, Unusual locations or family history of recurrent thrombosis

Lab workup is controversial. Most suggest that workup should be done in those that are young, or have unusual thrombotic events, recurrent events, or a family history. This includes: Factor V Leiden, Protein C and S Activity, AT III deficiency, Prothrombin Gene Mutation, test for antiphospholipid antibodies (Anti-CL and LAC) and Homocysteine, Test for Myeloproliferative Disease and PNH in others when these are suggestive.

57. What are the lab findings with the antiphospholipid antibody syndrome? How is it diagnosed? Labs reveals an elevated PT or PTT (more so PTT) that does not correct with mixing DIAGNOSIS:

58. Describe the use of the following blood products in regards to indications and effects PRBCs - One unit should raise Hgb by 1. Transfuse with symptoms, and in general if Hgb is <7. There is conflicting evidence in the goal Hgb in those with CAD, but in general, it should be between 8-10 Platelets - six pack should increase by 20-25,000. Can transfuse those <20,000 to decrease risk of spontaneous bleeding. For surgery, a count of 50,0000 is generally needed (>100,000 with neurosurgery)

59. List the major types of transfusion reactions, their clinical presentation, and management.

Acute Hemolytic - Inadvertent ABO-incompatible transfusion. Can get Hypotension, AKI and DIC Gives fluids and/or pressors Delayed Hemolytic - Occurs 7-14 days later with fever, anemia and jaundice. Supportive Care TRALI - Dyspnea, hypoxia and infiltrates (similar to ARDS) - usually from plasma, can be delayed. Need ventilation usually for a few days Sepsis - Can occur from bacterial contamination of platelets. Febrile Nonhemolytic - Occurs in <1% of transfusions, and is usually an effect of donor leukocytes or cytokines in donor plasma. Continue transfusion at slower rate. Give antipyretics and leukoreduced products in the future Allergic Reactions - Range from urticaria to bronchospasm. If occurs, give antihistamines If frequent occurance, give washed products Anaphaylaxis - Usually due to IgA deficiency Graft vs Host Disease - Rare, occurs in immunocompromised and presents with disorders of affect the bone marrow, skin, liver, and gastrointestinal tract. Prevent by giving irradiating blood products. APLASTIC DISEASE AND MALIGNANT HEME

60. What is the most common cause of Aplastic Anemia? What are other causes that should be considered/worked up? If these secondary causes are ruled-out then what are available treatment options? Why would you want to limit supportive blood transfusions in patients with aplastic anema? What would you ask the blood bank if a patient with Aplastic Anemia becomes “resistant” to platelet transfusions? What secondary causes should you think of with Pure Red Cell Aplasia and how are they treated?

Causes: Idiopathic(most common). Others are Drugs (esp NSAIDS,Sulfas), Chemicals, Infections (HIV, EBV, CMV,Parvo) and radiation exposure Treat: HSCT if very young (<20 years old) or with acquired forms Most patients get steroids, Cyclosporine, Anti-Thymocyte Globin Limit transfusions to prevent GvHD if given transplant They have antibodies – get “single donor” platelets PRCA: Association with thymoma (treat with surgery), SLE (treat with steroids) and Parvo-B19 (Rx with IVIG)

61. What is the clinical “Triad” of PNH? What other symptoms will patients present with? How is it diagnosed? How is it treated?

Hemolytic anemia, red urine and thrombosis. Pancytopenia results. Men commonly have impotence and patients complain of dysphagia/odynophagia. Diagnosis used to be with the sucrolose/Ham Test but now we do flow cytometry for CD55 and CD59 Treatment is supportive (blood transfusion for anemia, anticoagulation for thrombosis) and the monoclonal antibody eculizumab (Soliris) is used.

62. What is neutropenia? What usually causes it? What is the treatment? ANC <1500 (this is then divided into severity based on number) Many causes exist, but mostly include medications or transient infections Therapy is not needed if the neutropenia is mild and due to a causative agent that can be withdrawn or an infection that is resolving. However, complete cultures and empiric antibiotics that cover staphylococci and enteric pathogens are required when the ANC falls below 1000/µL in a febrile patient. If the neutropenia persists and there is no response to antibiotics after 5 days, empiric antifungal agents are added. If there is still no response to antimicrobial therapy and the patient remains neutropenic and critically ill, G-CSF is added.

63. What are the four histologic subtypes of Hodgkin’s Disease? What is the most common? Best prognosis? Worst Prognosis? What clinical feature distinguishes Hodgkin’s disease from Non-Hodgkin’s Lymphoma? What is the “Characteristic” Cell in Hodgkin’s Disease and draw what it looks like. Nodular Sclerosing (Common), Mixed, Lymphocyte Depleted (worst), Lymphocyte Predominate (best) Disease spread is contiguous, usually beginning in a Cervical LN

64. Describe the staging of Lymphoma in detail. (i.e. what are the stages and how are they defined) What are the 3 “B” symptoms? What is “bulky” disease?

65. What is the treatment depending on each stage in Hodgkins Disease ? What are consequences/side effects of treatment?

I or II that is Non-Bulky and no "B" Symptoms: 2-4 Cycles of Adriamycin, Bleomycin, Vinblastine, Dacarbazine (ABVD) then Radiation Therapy

Bulky I/II or I/II with “B” Symptoms: 6-8 cycles of ABVD then Rads Stage III/IV Disease - ABVD, Stanford V or BEACOPP (Note: early stage lymphocyte predominant disease treated with radiation alone)

Consequence: cardiovascular disease and second malignancies such as acute leukemias, lymphomas, and solid tumors within the radiation therapy field.

66. List some “indolent” Non-Hodgkin’s lymphomas (NHL) and “aggressive” lymphomas. What are the general principals towards prognosis, progression of disease, symptoms and treatment in indolent compared to aggressive NHL?

Indolent: Usually slow growing and stable with no symptoms. Usually harder to cure, one watches and waits. Aggressive has earlier symptoms and extranodal involvement - they are easier to treat but relapse frequently

67. What is the most common Non-Hodgkin’s Lymphoma? How does this commonly present? What is the treatment of choice?

Diffuse Large B-Cell. Present with fast-growing masses and systemic symptoms. R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] is given, and a shorter course of RCHOP can be combined with radiation therapy for early disease.

68. What are the clinical features of follicular lymphoma? What is the common translocation in these patients. What disease do >10% of patients with follicular lymphoma progress to? What is the approach to treatment? What is the treatment for patients with asymptomatic disease? Young patients with symptomatic advanced disease? Older patients with symptomatic advanced disease?

Present in patients older than 50, with diffuse LN disease and usually spleen and bone involvement. Most patients with t (14;18). Progress to Diffuse Large B-Cell Lymphoma. Treatment remains controversial, and is a balance between patient preference (including cosmetic appearance of lymphadenopathy), symptoms and organ involvement Treatment can be watch and wait, radiation therapy and chemotherapy

In general, asymptomatic patients can watch and wait. Those with early stage symptomatic disease are given radiation therapy. Those with more advanced disease can get rituximab alone or combination chemotherapy (R-CVP – Rituximab, Cyclophosphamide, Vincristine and Prednisone)

69. What is the treatment of choice for Low-Grade Gastric MALToma? High Grade Gastric Maltoma? Non-Gastric Maltoma?

Low – H. pylori treatment High - Rituximab +/- CVP [Cyclophosphamide, Vincristine and Prednisone Non-Gastric: Radiation and R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone

70. What hematologic malignancy should be suspected in a patient that presents with chronic eczema or psoriasis that is not responsible to conventional dermatologic treatments? What are some treatment options for this disease? What is the leukemic phase of this disease called and what are the characteristic cells on the Blood Smear? What is the treatment?

Mycosis Fungoides - Topical Steroids, PUVA, Local Radiation, Retinoids Leukemic Phase – Sezary Syndrome with cerebriform nuclei. Treat with systemic chemotherapy.

71. Patients with which Leukemia have a near-normal life span? What is the lymphomatous phase of

this disease called? What symptoms develop later on in the disease course? What are other hematologic lab abnormalities with the disease? When do you treat it, with what and what is the mechanism of action of this drug? What are long-term consequences of the disease CLL. Small Lymphocytic Lymphoma is the other phase. Patients are usually asymptomatic, and diagnosis is found on routine blood work. Most patients have lymphadenopathy and hepatosplenomegaly. Late stage, they develop cytopenias. Patients get AIHA (suspect this when the Hgb in a patient with CLL suddenly drops), Autoimmune thrombocytopenia and Low immunoglobulins leading to infections. Most patients are not treated until symptoms (B symptoms or pain from lyphadenopathy or hepatosplenomegaly) or cytopenias develop. Treatment of choice is Rituximab (anti-CD20), fludarabine and cyclophosphamide. Patients with CLL have a high risk of other malignancies (many solid organ and skin) and transformation into large cell lymphoma (known as Richter syndrome)

72. What disease that is a subtype of CLL gives a “Dry Tap” on bone marrow with characteristic cells on Peripheral Blood Smear? What are the symptoms and common presenting signs of this disease? What is the usual treatment? What are other options for treatment?

Hairy Cell Leukemia. On physical exam, 80–90% of patients display splenomegaly, which can be massive. Peripheral lymphadenopathy (enlarged lymph nodes) is uncommon (less than 5% of patients), but abdominal lymphadenopathy is a relatively common finding on CT scans. Usual treatment with purine analogues (cladribine) – can give rituximab, do splenectomy, give IFN or use fludarabine as well

73. How Does CML Present and what are the 3 different “phases” of the disease? What lab test can

differentiate these phases? What does The Blood Smear Reveal? What is the translocation present? What is the natural history/feared consequence of the disease? What is the treatment of choice, side effects of the Chemotherapy and remission rate achieved? What if patients cannot tolerate this medication – what is the next option? Can present with : 1) Chronic Phase (Splenomegaly and Leukocytosis) – MOST COMMON – they usually otherwise asymptomatic but may have fatigue and weight loss and complaint of early satiety. 10% blasts 2) Accelerated phase - months before the diagnosis of blast crisis. Clinical features in this phase are intermediate between the chronic phase and blast crisis. 20% blasts 3) After an average of 3-5 years, chronic myelogenous leukemia (CML) usually evolves into the blast crisis, which is marked by an increase (30%) in the bone marrow or peripheral blood blast count or by the development of soft-tissue or skin leukemic infiltrates Note that since this is a myeloproliferative disorder, patients with CML can even have elevated platelet counts or Hct at time of diagnosis! Smear with myeloid precursors and Basophils. Patients can get AML or ALL. Translocation is t(9;22). - Philadelphia chromosome. Treat with the tyrosine kinase inhibitor Imatinib (85% success rate) with effects of muscle cramps, nausea, leucopenia, rash, hepatotoxicity and fluid retention. If not tolerable – Hydrea and IFN Therapy used to be used, but now other tyrosine kinase inhibitors are approved (dasatinib and nilotinib)

74. How do the acute leukemias generally present? What are some exam findings? What are risk factors and causes for AML besides the common idiopathic form? What is the characteristic finding on Blood Smear for AML? How is it diagnosed? Describe the treatment plan of a patient diagnosed with AML. What Antibody has been used for treatment in these patients and what is it’s unique side effect? What are the symptoms of acute leukemic crisis and a severely high WBC count and how is it treated?

Presents: Fatigue, bleeding, infections due to defects in the cell lines Exam: Signs of anemia, look for infections, cutaneous nodules/gum hypertrophy, chloromas (firm subcutaneous masses). USUALLY NO Lympadenopathy or HSM Risk: Chemo (Alk Agent/Topoisomerase), Down’s, Radiation/Chemical Exposure, previous myelodysplastic syndromes PBS: Auer Rod and circulating blasts Dx: Bone marrow biopsy with >20% myeloblasts Tx: Induction: Cytarabine + Anthracycline (Daunorubicin or Idarubicin) – this is given for one to two cycles with bone marrow biopsy afterwards. If <5% Blasts no more induction chemo, if >5% repeat chemo. This is followed by consolidation with Cytarabine. Afterwards, some patients can receive allogenic transplants. Gemtuzumab is anti-CD33 – Can get hepatic sinusoidal obstruction. High WBC/Leukostasis (when >50,000): Can get pulmonary infiltrates, AMS, bleeding into the CNS, MI, CVA and priapism. Treat with hydroxyurea and leukopheresis

75. What translocation is present in Acute Promyelocytic Leukemia (APL)? What is a dreaded consequence of APL? What is the treatment of choice for APL and the feared side effect of the treatment? How is this side effect managed?

APL with (t15;17). Patients get DIC. Treat with ATRA (All Trans-retinoic acid) and arsenic trioxide – can get “retinoic acid syndrome” - and ARDS-like picture with fever, volume overload and pulmonary decompensation. This responds to high-dose dexamethasone.

76. What are common clinical features and lab features of ALL? What are some extranodal sites affected? What is the treatment?

Patients present with fevers, cytopenia signs/symptoms, as well as lymphadenopathy (including bulky Mediastinal LAD), And hepatosplenomegaly. It is a lymphoid malignancy so can get extranodal deposits in the CNS, Retina and Testicles. Treat with Induction and Consolidation with Prednisone/Vincristnine/Daunarubicin – patients will likely need Intrathecal treatment and Radiation Therapy. Recently, monoclonal antibodies have been added to the regimen.

77. What are the Four types of Myeloproliferative Syndromes? What mutation is common in all? CML, PCV, ET, MF with JAK2 Mutation

78. What is the presenting feature of essential thrombocythemia? Diagnosed with what and what is the classic finding? What is the treatment? What is the prognosis? Older patients with platelet counts >600,000. Splenomegaly and Hepatomegaly may be seen. Many patients are asymptomatic, and when symptomatic they have erythromelalgia (burning and paresthesias of the extremities that are exacerbated by heat) or central nervous system thrombosis, such as migraine headaches, transient ischemic attacks, scotomas, amaurosis fugax, or seizures. Large-vessel thrombosis, such as renal vein thrombosis or Budd-Chiari syndrome, may also occur. When platelet counts are >1 million, an acquired vWD occurs, and thus hemorrhage can occur. Bone marrow biopsy will show megakaryocytic hyperplasia. When platelet counts are dangerously high, or in the setting of severe symptoms (such as bleeding, stroke, MI) - platelet apheresis and hydrozyurea is given. Other patients get treatment with hydroxyurea, anagrelide, or interferon alfa plus low-dose aspirin. Prognosis is generally good, although patients can transform into the other Myeloproliferative diseases

79. What lab abnormality would lead you to think of polycythemia vera? List Four secondary causes of polycythemia. How do you work up polycythemia?

M with Hct>60 and F with Hct >56 Secondary: High Altitude, Chronic lung Disease, Sleep Apneas, Obesity, Smoking, Cancer (Renal, HCC and Bronchial are most common), RAS, Cirrhosis and Androgen Use. Workup includes EPO level, carboxyhemoglobin level and arterial oxygen saturation

80. What are presenting symptoms of a patient with Polycythemia Vera? What are the major diagnostic criteria for PCV? What are the three major consequences of the disease that cause mortality? What is the treatment plan for all patients? What are other treatment options?

Constitutional symptoms, pruritis after bathing, erythromelalgia, headache and visual changes, plethora. Diagnose with Hct>60 in males and Hct >56 in females. If you think they have the disease, and don't meet these hematocrit criteria, then nuclear medicine testing for RBC Mass should be done. Patients also have low EPO, Normal Saturation, Splenomegaly, JAK2. Complications are bleeding, thromboembolic disease and transformation to AML. Treat with phlebotomy to Hct of 45 in males and <42 in females.

All patients should be on ASA. Add Hydrea, IFN or anagrelide if >70 with history of clot or Plts <400,000.

81. What are the presenting features, physical exam, lab findings and blood smear findings in a patient with Myelofibrosis? What about the bone marrow biopsy? What are specific treatment options?

Patients with myelofibrosis usually have anemia, fever and night sweats. Splenomegaly and Hepatomegaly on exam. Labs reveal a normocytic anemia, and the PBS has teardrop cells and Erythroblasts. the bone marrow aspirate usually gives a "dry tap" but the biopsy will reveal fibrosis. Blood and platelet transfusions are often needed. Patients can be treated with meds (hydrea and IFN) or HSCT

82. What are the clinical features of Multiple Myeloma? How do patients present. Lytic Bone Lesions, Renal Failure, Recurrent Infections, Bleeding/Coagulopathy, Interstitial Nephritis, Polyneuropathy. Remember that the presentation is very non-specific, and usually includes bony back pain, bony chest pain, fatigue and weight loss.

83. What are the lab findings with multiple myeloma. What is the approach to workup? Lab findings include renal failure, hypercalemia, Low/negative anion gap, pseduohyponatremia, rouleux formation, anemia, thrombocytopenia. Send basic labs (as above) serum and protein electrophoresis, serum free light chain analysis, and imaging (bone survey). Do NOT send a bone scan, this is for blastic lesions, not the lytic lesions with myeloma.

84. Describe the diagnostic criteria for multiple myeloma. Note that the WHO Diagnostic requires a minimum of one major criterion and one minor criterion or three minor criteria, which must include bone marrow plasmacytosis of 10%-30% and the presence of a monoclonal protein

85. List the features that distinguish Monoclonal gammopathy of undetermined significance (MGUS) and Smoldering Myeloma from multiple myeloma? What is the natural history of patients with MGUS? MGUS: Less than 10% Plasma Cells with no anemia/bone lesions/renal failure/HyperCa, If serum monoclonal protein is present, it is <3g/dL Smoldering: 10-30% Plasma Cells with no anemia/bone lesions/renal failure/ HyperCa

MGUS: Rate of transformation to myeloma at 1-1.5% per year

86. What are adjunctive treatments for patients with myeloma? Anemia: EPO, even without renal failure Lytic Lesions: Bisphosponates Hypercalcemia: Hydration, steroids, bisphosphonates Recurrent infections: monthly immunoglobulin Preventive measures: influenza and pneumococcal vaccines

87. What treatment approach leads to the best overall survival in patients with Multiple Myeloma? What are the "traditional" treatment options for Multiple Myeloma. What are newer medications what are the side effects of these medications? Best Survival with Response to therapy -> high dose steroids -> Autologous Transplant. Problem with this is that most patients at the time of diagnosis cannot undergo transplant. Traditional treatment with melphalan and prednisone has led to poor response. If they progress on this disease then dexamethasone pulsing alone or in combination with vincristine and doxorubicin are attempted. novel agents: Thalidomide - causes constipation, fatigue, neuropathy and thromboembolism Lenalidomide - less constitutional symptoms then thalidomide, but still causes thromboembolism and increased risk of neutropenia and thrombocytopenia Bortezomib (Velcade), a proteasome inhibitor. This causes neuropathy, Neutropenia, Thrombocytopenia Note that these "novel agents" are used so much now that "traditional" treatment may not be used much longer due to poor response

88. Describe the Clinical and Lab findings in a Patient with Waldenstrom’s Disease. How do you treat this malignancy? Patients with what disease have a higher incidence of Waldenstrom’s? Paraproteinemia of the IgM Type. (Remember Myeloma is usually IgG or IgA). Patients present with BM, Spleen and LN involvement. Commonly have hyperviscosity symptoms (retinopathy, blurring, AMS, CHF). Ophtho exam with engorged retinal vessels. Increased incidence with HCV. Treat hyperviscosity with Plasmapheresis. Rituximab for advancing symptomatic disease. Other chemo used includes chlorambucil, fludarabine or cladribine.

89. What is the presentation of AL amyloidosis. What are the clinical features? How is it diagnosed? What is the treatment? Renal: nephrotic syndrome with progressive worsening of renal function. CV: CHF due to restrictive cardiomyopathy, and an echo with septal hypertrophy / "snowstorm" septum. Low voltage on electrocardiography is found in many patients with AL amyloidosis and often is associated with a pseudoinfarct pattern. GI: Splenomegaly occurs rarely, whereas hepatomegaly occurs commonly and is caused by congestion from right heart failure or by amyloid infiltration. Very high Alk Phos with normal transaminases (infiltrative disease pattern!). Early Satiety Neuro: Very painful peripheral neuropathy, autonomic orthostatic hypotension Skin/Soft-tissue: Macroglossia, submandibular gland enlargement, periorbital purpura Extremities: Carpal Tunnel Syndrome and peripheral edema Diagnose with affected organ biopsy showing apple-green birefringence when stained with Congo red. Abdominal fat pad biopsy can also be performed Treatment with High-dose melphalan and stem cell transplantation for best response, others receive melphalan plus prednisone

90. Which patient population gets Myelodysplastic Syndrome? How do they commonly present and what are characteristic lab abnormalities. Which patients have a favorable prognosis? A Poor Prognosis? What are general treatment options? What nucleoside analog can be used for MDS and what positive affect does it have as far as treatment is concerned? What can you offer a patient with a 5q deletion? What type of BM transplant can be used and when it is offered?

Usually elderly patients. Ineffective production of one or more cell lines, and these cytopenias cause signs and symptoms. The anemia is usually megaloblastic (and hence the reason one must always rule out B12 deficiency in these patients) There can be eventual progression into leukemia (esp AML). Favorable with 5q or 20q deletion. Unfavorable with high amount of blasts or more cell lines down. Treatment is usually supportive with transfusions as needed. Epogen + G-CSF can be given to spare transfusions, and sometimes iron overload occurs needing chelating agents. Steroids can be given for treatment and some use thalidomide. Azacitidine has been used – mostly to stop need for transfusions. 5q deletion – Lenalidomide. Allogenic Transplant if younger and good Performance Status

91. What are the clinical features/treatment of Primary Amyloidosis?

Restrictive CM with Septal Thickening, Proteinuria, Renal Failure, Anemia, Weight Loss, Peripheral Neuropathy, Easy Brusing, Hepatomegaly. Treat with Prednisone and High Dose Melphalan

92. Contrast the types of Hematopoietic stem cell transplantation (HSCT). What are the two major

categories/types of HSCT – describe their specific complications and list at least 5 diseases they are each used to treat.

Autologous: Bone Marrow or Peripheral Blood from self - which harvested, stored and then reinfused after myeloablative chemotherapy - the major problem is tumor relapse. This finding relates to the absence of a graft versus tumor effect (ie, immunologic attack on the tumor by immunocompetent T cells and natural killer cells in the donor graft) and the reinfusion of occult tumor in the graft Can be used for many diseases( Multiple myeloma, Non-Hodgkin lymphoma, Hodgkin disease, Acute myeloid leukemia, Amyloidosis, Neuroblastoma, Germ cell tumors, Autoimmune disorders – Systemic lupus erythematosus (SLE), systemic sclerosis) - but important to note that it prolongs survival in those w ith multiple myeloma and NHL.

Allogeneic:

Cells are harvested from an HLA-matched donor (usually a sibling or unrelated donor) and reinfused after either myeloablative or nonablative chemotherapy. Since nonmyeloablative treatment is used, older patients tolerate it better. However, older patients experience higher transplant-related morbidity and mortality rates due to the need for continuing immunosuppression after the transplantation to prevent the development of graft versus host disease (GVHD). Allogeneic transplants are associated with lower relapse rates compared with autologous transplants because of the graft versus tumor effect

AML, ALL, CML, ALL, MDS, MPD, MM, NHL, HD, Aplastic anemia Pure red cell aplasia, PNH, Fanconi, Thalasemmia major, Sick le cell anemia, SCID, Inborn errors of metabolism