1.
<ul><li>Hematology-High Yield Topics </li></ul><ul><li>For Internal Medicine Boards and Hematology Boards </li></ul><ul><li>Target Audience : Internal Medicine Residents, Family Medicine Residents, Hematology Fellows, Medical Students, IM Board Recertification exam aspirants </li></ul><ul><ul><li>Archer Internal Medicine Board Review </li></ul></ul><ul><ul><li>www.CcsWorkshop.com </li></ul></ul>

2.
<ul><li>Definition: </li></ul><ul><li>Group of lymphoid neoplasms of terminally differentiated B - cells that have in common the expansion of a single clone of immunoglobulin (Ig) - secreting plasma cells and a resultant increase in serum levels of a single homogeneous (monoclonal) Ig or it’s fragments. </li></ul>Plasma Cell Dyscrasias

3.
Plasma Cell <ul><li>Plasma cells : </li></ul><ul><li>Terminally differentiated B-cells </li></ul><ul><li>Not normally found in peripheral blood . </li></ul><ul><li>Account for less than 3.5% of nucleated cells in the bone marrow </li></ul><ul><li>Oval cells with low N:C ratio. Cytoplasm is basophilic blue. Nucleus (30-40% of the cell) is oval or round and typically placed eccentrically (to one side) of the cell. </li></ul><ul><li>A clear, colorless area adjacent to the nucleus contains Golgi apparatus </li></ul><ul><li>Russell bodies : Globules (2-3 μm) of accumulated immunoglobulins in the cytoplasm of plasma cells. Usually round. Russell bodies may be found in normal bone marrow. </li></ul>

4.
Plasma Cell <ul><li>Mott cells </li></ul><ul><li>Plasma cells crowded with Russell bodies. An obstruction blocks the release of Golgi secretions. These cells can be found in any case of chronic plasmacytosis. </li></ul>

5.
Plasma Cell <ul><li>Flame Cells </li></ul><ul><li>Large, multinucleated plasma cells seen in Multiple myeloma. The cytoplasm resembles a red flame . </li></ul>

6.
Plasma Cell Dyscrasias Synonyms

7.
Plasma Cell Dyscrasias

8.
<ul><li>Investigations in any suspected Monoclonal Gammopathy should include to accurately classify the disorder: </li></ul><ul><li>Complete Blood Count ( look for anemia) </li></ul><ul><li>Comprehensive Metabolic panel </li></ul><ul><ul><li>Look for renal insufficiency, hypercalcemia and subtle clues like decreased anion gap </li></ul></ul><ul><ul><li>Total protein and albumin level. Determine Globulin component. Too low globulin ( < 2gm%) or Elevated Globulin ( > 3.5gm%) is concerning : Determine if Polyclonal vs. Monoclonal. Evaluate further with : </li></ul></ul><ul><ul><ul><ul><ul><li>Quantitative Immunoglobulins : Increase in all components usually, polyclonal. Increase in single component with reciprocal decrease of uninvolved globulin usually, may suggest monoclonal . </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Serum Protein Electrophoresis with immunofixation if monoclonal gammopathy is suspected. </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>24HR-Urine protein electrophoresis with urine immunofixation ( Serum Free Light Chain assay ( κ / λ ratio) may be used in place of UPEP} </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Bone marrow biopsy to evaluate % plasma cells if there is monoclonal protein or abnormal UPEP or Light chain assay or if strong clinical picture of myeloma. </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Skeletal survey if monoclonal gammopathy has been established ( Bone scans are usually, negative in MM) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Beta-2 microglobulin and Albumin for staging and prognosis in MM ( once diagnosis is made). </li></ul></ul></ul></ul></ul>Investigations

9.
Serum Protein Electrophoresis <ul><li>Serum Protein Electrophoresis : </li></ul><ul><li>Serum is placed on special paper treated with agarose gel and exposed to an electric current. This separates the serum protein components into five classifications by size and electrical charge : serum albumin, alpha-1 globulins, alpha-2 globulins, beta globulins, and gamma globulins. </li></ul><ul><li>Immunoglobulins ( IgG, IgM, IgA) usually migrate to gamma region but may sometimes extend to beta region. </li></ul><ul><li>SPEP should always be performed in combination with serum immunofixation in order to determine clonality </li></ul>

10.
SPEP <ul><li>SPEP showing Monoclonal Gammopathy </li></ul><ul><li>Shows a tall “narrow” band in gamma region – “M-Spike” </li></ul><ul><li>Also, note reduction in the normal polyclonal gamma band </li></ul>

11.
SPEP <ul><li>SPEP showing Polyclonal Gammopathy </li></ul><ul><li>Shows a broad based peak in gamma region . </li></ul><ul><li>Seen in chronic infections, inflammation, connective tissue disease, lymphoproliferative disease. </li></ul>

12.
Immunofixation <ul><li>More sensitive than SPEP </li></ul><ul><li>Immunofixation is performed when SPEP shows a sharp “peak” or a plasma cell disorder is suspected despite a normal SPEP </li></ul><ul><li>Immunofixation always done to confirm the presence of M-Protein and to determine the type (IgM or IgG etc and the light chain restriction : k or λ ) </li></ul><ul><li>Why do both SPEP and IF ? Why not just IF in initial diagnosis ? </li></ul><ul><ul><li>Unlike SPEP, immunofixation does not give an estimate of the size of the M protein (ie, its serum concentration), and thus should be done in conjunction with electrophoresis. </li></ul></ul>

13.
Constitute Several Disorders Examples :

14.
<ul><li>Denotes presence of an M-protein in a patient without a plasma cell or lymphoproliferative disorder i.e; Undetermined Significance </li></ul>Monoclonal Gammopathy of Undetermined Significance ( MGUS)

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<ul><li>Incidence of MGUS increases with age : </li></ul><ul><ul><ul><li>1% of adults in US </li></ul></ul></ul><ul><ul><ul><li>3% of adults over age 70 years </li></ul></ul></ul><ul><ul><ul><li>11% of adults over age 80 years </li></ul></ul></ul><ul><ul><ul><li>14% of adults over age 90 years </li></ul></ul></ul><ul><li>Significance : Can progress to monoclonal Disease </li></ul><ul><li>IgG or IgA MGUS IgM MGUS </li></ul>Monoclonal Gammopathy of Undetermined Significance ( MGUS)

16.
MGUS - Progression

17.
And it’s Variants

18.
<ul><li>Both criteria should be met : </li></ul><ul><ul><li>Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent </li></ul></ul><ul><ul><li>No end organ damage related to plasma cell dyscrasia (see CRAB) </li></ul></ul><ul><li>Management : </li></ul><ul><ul><li>Does not require any intervention </li></ul></ul><ul><ul><li>Close surveillanace is necessary to ensure stability of the disease ( SPEP, CBC, Creatinine and calcium every 3 to 4 month and Skeletal Survey annually to pick up asymptomatic bone lesions) </li></ul></ul>Smoldering Myeloma

19.
<ul><li>Rare variant : About 1% of Myelomas </li></ul><ul><li>May present with Bone lesions ( most common presenting symptom bone pain) </li></ul><ul><li>No serum or urine monoclonal protein ( diagnosis can be missed if one is not aware of this entity, NSMM). </li></ul><ul><li>Renal failure and hypercalcemia are generally lacking </li></ul><ul><li>Anemia may be present </li></ul><ul><li>Bone marrow biopsy must be performed in suspected cases: Immunostaining for a monoclonal protein on bone marrow sections may establish the diagnosis, Clonal plasma cell population in marrow. </li></ul><ul><li>Must rule out IgD and IgE myeloma </li></ul>Non-Secretory Myeloma

20.
Solitary Plasmacytoma Localized plasma cell tumor • Absence of a plasma cell infiltrate in random marrow biopsies • No evidence of other bone lesions by radiographic examination • Absence of renal failure, hypercalcemia or anemia

21.
<ul><li>Plasma cell tumors that arise outside the bone marrow and no features of Multiple Myeloma </li></ul><ul><li>Most Common Primary Sites - Head and Neck region: Upper air passages and oropharynx (May involve draining lymph nodes. </li></ul><ul><li>Less Common Sites – Lymph nodes (primary), salivary glands, spleen, liver, etc. </li></ul><ul><li>25% have small monoclonal spike </li></ul><ul><li>Rare dissemination, rarer evolution to myeloma </li></ul><ul><li>Management : </li></ul><ul><ul><ul><li>If completely resected during biopsy, no further therapy </li></ul></ul></ul><ul><ul><ul><li>If incompletely resected, radiation therapy locally </li></ul></ul></ul>Extramedullary Plasmacytoma

22.
<ul><li>All three criteria must be met </li></ul><ul><li>Presence of a serum or urinary monoclonal protein </li></ul><ul><li>Presence of 10 percent or more clonal plasma cells in the bone marrow or a plasmacytoma </li></ul><ul><li>Presence of end organ damage felt related to the plasma cell dyscrasia, such as: CRAB : Hyper c alcemia (calcium > 11.5gm%), R enal Insufficiency, A nemia (hgb < 10gm%) or Lytic b one lesions </li></ul>Multiple Myeloma

23.
Multiple Myeloma Bone Lesions : Conventional radiographs (Skeletal Survey) abnormal in 80% of patients who present with multiple myeloma

24.
Multiple Myeloma Anemia: Normochromic /normocytic anemia occurs in 75% patients at diagnosis Defined as less than 10gm% in MM

25.
Multiple Myeloma <ul><li>Major Causes : </li></ul><ul><ul><li>Myeloma cast nephropathy </li></ul></ul><ul><ul><li>Hypercalcemia </li></ul></ul><ul><ul><li>Amyloidosis </li></ul></ul><ul><ul><li>Radiocontrast dye in a patient with myeloma </li></ul></ul>Renal Insufficiency : Serum creatinine increased in > 50% at diagnosis Creatinine >2g/dL in 20% of patients Renal failure may be presenting manifestation

26.
Multiple Myeloma <ul><li>Managed with urgent: </li></ul><ul><li>1. Corticosteroids </li></ul><ul><li>2.Neurosurgical intervention (laminectomy or anterior decompression in pathological #) + radiation therapy to preserve neurological function </li></ul><ul><li>3. Radiation therapy alone ( plasmacytoma) </li></ul>Spinal Cord Compression : An Oncological Emergency Spinal cord compression occurs in 5 % of patients with multiple myeloma ( plasmacytoma or pathological fracture related)

27.
Multiple Myeloma - Cytogenetics Deletion 17p and Abnormalities associated with chromosome 13 carry a particularly unfavorable prognosis & respond poorly to therapy

28.
Multiple Myeloma Staging : International Staging System : Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months

29.
Multiple Myeloma <ul><li>Treatment Decisions : </li></ul><ul><li>Indications for treatment : presence of any of CRAB ( bone lesions can be diffuse osteopenia alone) </li></ul><ul><li>Risk Stratification : </li></ul><ul><ul><li>FISH for detection of t(4;14), t(14;16), and del17p13 </li></ul></ul><ul><ul><li>Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy </li></ul></ul><ul><ul><li>The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment </li></ul></ul>

30.
Current Frontline Options <ul><li>Conventional chemotherapy </li></ul><ul><ul><li>Survival ≤ 3 yrs </li></ul></ul><ul><li>Transplantation </li></ul><ul><ul><li>Prolongs survival 4-5 yrs </li></ul></ul><ul><li>Novel agents targeting stromal interactions and associated signaling pathways have shown promise and improved survival. </li></ul>Chng WJ, et al. Cancer Control. 2005;12:91-104.

31.
MM: INITIAL THERAPY <ul><li>The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation </li></ul>

32.
Initial Approach to Treatment of MM *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest

33.
DETERMINING TRANSPLANT ELIGIBILITY <ul><li>Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy </li></ul><ul><li>All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible </li></ul><ul><li>A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational </li></ul>

34.
NOT Eligible for Autologous HCT <ul><li>Age >77 years </li></ul><ul><li>Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) </li></ul><ul><li>Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis </li></ul><ul><li>Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain </li></ul><ul><li>New York Heart Association functional status Class III or IV </li></ul>

35.
Transplantation vs Conventional Chemotherapy 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test

36.
Autologous Stem Cell Transplantation <ul><ul><li>Mel 200 mg/m 2 standard conditioning regimen </li></ul></ul><ul><ul><li>Sufficient performance score, and adequate liver, pulmonary, cardiac function needed </li></ul></ul><ul><ul><li>Higher PR and CR rates than conventional chemotherapy </li></ul></ul><ul><ul><li>Higher OS and EFS than conventional Rx </li></ul></ul><ul><ul><li>Advanced age and impaired renal function are, by themselves, not contraindications </li></ul></ul>Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010.

37.
Stem Cell Transplantation <ul><li>Key issues </li></ul><ul><li>Efficacy compared with conventional chemotherapy </li></ul><ul><li>Timing: early vs delayed </li></ul><ul><li>Single vs tandem </li></ul><ul><li>Role of allogeneic and miniallogeneic transplantations </li></ul><ul><li>Maintenance post-SCT </li></ul>

38.
Novel Frontline Options <ul><li>Immunomodulatory drugs (IMiDs) </li></ul><ul><ul><li>Thalidomide </li></ul></ul><ul><ul><li>Lenalidomide </li></ul></ul><ul><li>Proteasome inhibitors </li></ul><ul><ul><li>Bortezomib </li></ul></ul><ul><ul><li>Carfilzomib </li></ul></ul>

39.
Proposed Mechanism of Action for Multiple Myeloma Therapies Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved.

40.
Thalidomide: Proposed Mechanism of Action <ul><li>Proposed mechanisms </li></ul><ul><ul><li>Inhibition of TNF-  </li></ul></ul><ul><ul><li>Suppression of angiogenesis </li></ul></ul><ul><ul><li>Increase in cell-mediated cytotoxic effects </li></ul></ul><ul><ul><li>Modulation of adhesion molecule expression </li></ul></ul>Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085.

41.
Lenalidomide <ul><li>Immunomodulatory derivative of thalidomide </li></ul><ul><li>More potent than thalidomide in preclinical models </li></ul><ul><ul><li>Dose-dependent decrease in TNF- α and interleukin-6 </li></ul></ul><ul><ul><li>Directly induces apoptosis, G1 growth arrest </li></ul></ul><ul><ul><li>Enhances activity of dexamethasone </li></ul></ul><ul><li>More favorable toxicity profile than thalidomide </li></ul><ul><li>Difficult to use in renal insufficiency ( dose adjust) </li></ul>Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950.

42.
Lenalidomide Dosing for MM and Impaired Renal Function Lenalidomide [package insert]. Renal Impairment (CrCl) Lenalidomide Dosage Moderate (30 to < 60 mL/min) 10 mg QD Severe (< 30 mL/min, not requiring dialysis) 15 mg Q 48 hrs ESRD (< 30 mL/min, requiring dialysis) 5 mg QD On dialysis days, administer following dialysis

43.
Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2  3  4 b5  6  7 Cross section of  ring Bortezomib <ul><ul><li>Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. </li></ul></ul>B O O OH N N OH Interferes with intracellular pathway that degrades proteins regulating cell cycle, apoptosis,angiogenesis H N N H

44.
Peripheral Neuropathy Following Bortezomib Therapy in Advanced MM <ul><li>Peripheral neuropathy was reported in 90/256 (35%) patients with MM treated with bortezomib in phase II trials </li></ul><ul><li>80% of patients entered these trials with preexisting peripheral neuropathy </li></ul><ul><li>3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathy </li></ul>Richardson PG, et al. ASH 2003. Abstract 512.

45.
Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest

46.
Frontline Therapy in Elderly MM Patients <ul><li>For elderly patients or those who are not suitable candidates for transplantation, MP has been a standard treatment </li></ul><ul><ul><li>ORR: 60% </li></ul></ul><ul><ul><li>Long-term CR: < 5% </li></ul></ul><ul><li>Trials with MP-based combinations reported improved response rates and time to progression </li></ul><ul><ul><li>MPT </li></ul></ul><ul><ul><li>VMP </li></ul></ul>NCCN Practice Guidelines. Myeloma. V.3.2010.

47.
Conclusions <ul><li>In elderly patients, the addition of novel agents to standard MP has provided improved response rates </li></ul><ul><ul><li>MP alone (ORR: 50%; CR: 5%) </li></ul></ul><ul><ul><li>MPR (50% to 95% reduction in myeloma protein in 55.6%) </li></ul></ul><ul><ul><li>VMP (ORR: 86%) </li></ul></ul><ul><li>Care should be taken with IMiD-based therapy to include aspirin prophylaxis for DVT/PE </li></ul><ul><li>Care should be taken with bortezomib-based regimens to include herpes zoster prophylaxis </li></ul>

48.
MM & Skeletal Complications <ul><li>~ 80% of patients with multiple myeloma will have evidence of skeletal involvement on skeletal survey </li></ul><ul><ul><li>Vertebrae: 65% </li></ul></ul><ul><ul><li>Ribs: 45% </li></ul></ul><ul><ul><li>Skull: 40% </li></ul></ul><ul><ul><li>Shoulders: 40% </li></ul></ul><ul><ul><li>Pelvis: 30% </li></ul></ul><ul><ul><li>Long bones: 25% </li></ul></ul>Dimopoulos M, et al. Leukemia. 2009:1-12.

49.
The Central Role of the Osteoclast in Osteolytic Bone Destruction Growth factors Osteoclast differentiation Osteolysis Direct effects on osteoclast differentiation Tumor cells Bone loss Active osteoclast Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.

50.
Mechanism of Bisphosphonate Inhibition of Osteoclast Activity Bisphosphonates inhibit osteoclast activity, and promote osteoclast apoptosis [1] Bisphosphonates are released locally during bone resorption [1] Bisphosphonates are concentrated under osteoclasts [1] Bisphosphonates may modulate signaling from osteoblasts to osteoclasts New bone X Bone <ul><li>Increased OPG production [2] </li></ul><ul><li>Decreased RANKL expression [3] </li></ul>1. Reszka AA, et al. Curr Rheumatol Rep. 2003;5:65-74. 2. Viereck V, et al. Biochem Biophys Res Commun. 2002;291:680-686. 3. Pan B, et al. J Bone Miner Res. 2004;19:147-154.

51.
Recommended Doses and Infusion Times *Consider dose reduction . † 3.5mg (CrCl 50-60 mL/min); 3.3 mg (CrCl 40-49 mL/min); 3.0 mg (CrCl 30-39 mL/min). Kyle R, et al. J Clin Oncol. 2007;25:2464-2472. Drug Dose/Infusion Time Interval Estimated CrCl > 60 mL/min Pamidronate Zoledronic acid 90 mg over 2-3 hrs 4 mg over 15 mins 3-4 wks 3-4 wks Estimated CrCl 30 to < 60 mL/min Pamidronate Zoledronic acid 90 mg over 2-3 hrs* Reduced dosage † 3-4 wks 3-4 wks Estimated CrCl < 30 mL/min Pamidronate Zoledronic acid 90 mg over 4-6 hrs* Not recommended 3-4 wks

52.
Bisphosphonates and Osteonecrosis <ul><li>Uncommon complication causing avascular necrosis of maxilla or mandible </li></ul><ul><li>Suspect with tooth or jaw pain or exposed bone </li></ul><ul><li>May be related to duration of therapy </li></ul><ul><li>True incidence unknown </li></ul><ul><li>Always enquire recent dental therapy or tooth related problems before starting bisphosphonates </li></ul>Papapetrou PD. Hormones (Athens). 2009;8:96-110.

53.
POEMS (Osteosclerotic myeloma)

54.
POEMS (Osteosclerotic myeloma)

55.
Plasma Cell Leukemia <ul><li>>2 X 109/L plasma cells in blood ( seen on peripheral smear) </li></ul><ul><li>Younger age </li></ul><ul><li>Higher incidence of organomegaly and lymphadenopathy </li></ul><ul><li>More extensive bone marrow infiltration </li></ul><ul><li>Renal failure more common </li></ul><ul><li>Less bone pain, fewer lytic lesions </li></ul><ul><li>Poor response to therapy </li></ul><ul><li>Peripheral smear showing Plasma cells </li></ul>

56.
<ul><li>Monoclonal gammopathy - IgM type </li></ul><ul><li>Plasmacytoid lymphoma </li></ul><ul><li>Median age at diagnosis - 60 yrs </li></ul><ul><li>Presentation : </li></ul><ul><ul><ul><li>Hyperviscosity syndrome (15%) : visual impairment, neurologic manifestations </li></ul></ul></ul><ul><ul><ul><li>Bleeding ( Acquired VWD) </li></ul></ul></ul><ul><ul><ul><li>Cryoglobulinaemia </li></ul></ul></ul><ul><ul><ul><li>Organomegaly, lymphadenopathy + (20%-40%) </li></ul></ul></ul><ul><ul><ul><li>Autoimmune hemolysis - common </li></ul></ul></ul><ul><ul><ul><li>Bone marrow involvement 90% </li></ul></ul></ul><ul><ul><ul><li>Lytic bone lesions 2% </li></ul></ul></ul><ul><ul><ul><li>Hypercalcemia 4% </li></ul></ul></ul><ul><li>Management : </li></ul><ul><ul><li>Asymptomatic patients not treated until symptoms develop </li></ul></ul><ul><ul><li>If Hyperviscocity features  urgent Plasmapheresis </li></ul></ul><ul><ul><li>Symptomatic WM : Rituximab based therapy </li></ul></ul>Waldenstrom’s Macroglobulinemia

57.
Amyloidosis

58.
<ul><li>Evaluate for amyloidosis in patients with a monoclonal protein in serum or urine plus : </li></ul><ul><ul><ul><li>Nephrotic syndrome or renal insufficiency </li></ul></ul></ul><ul><ul><ul><li>Congestive heart failure </li></ul></ul></ul><ul><ul><ul><li>Peripheral neuropathy </li></ul></ul></ul><ul><ul><ul><li>Carpal tunnel syndrome </li></ul></ul></ul><ul><ul><ul><li>Hepatomegaly </li></ul></ul></ul><ul><ul><ul><li>Idiopathic malabsorption </li></ul></ul></ul><ul><ul><li>Diagnostic Criteria: </li></ul></ul><ul><ul><ul><ul><li>Tissue biopsy showing typical morphology </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Apple green birefringence under polarized light after Congo Red staining </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Typical fibrillar ultrastructure </li></ul></ul></ul></ul><ul><ul><li>Diagnostic methods and Sensitivity </li></ul></ul><ul><ul><ul><ul><ul><li>Bone marrow examination 56% </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Abdominal fat aspiration 80% </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Combined BM & fat aspirate 89% </li></ul></ul></ul></ul></ul>Amyloidosis

59.
Questions?