Plasma cell dyscrasias

Prepared by Dr Prince

1. Plasma cell dyscrasias By - Dr.Prince Lokwani Guided by – Dr.Kamal Malukani

2. Plasma Cell Dyscrasias Synonyms

3. Plasma cell Dyscrasias / Paraproteinemia Characterized by neoplastic proliferation of plasma cells that typically secrete monoclonal Igs . ( complete or partial). Igs secreted by them, referred to as M protein. 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. Free light chains Heavy chains ( Bence jones protein )

4. Plasma cell dyscrasias can be benign or malgnant (more often). 15 % of all malignant white cell diseases. 1 % of all cancer deaths.

5. M-component can also be detected in – LYMPHOID NEOPLASMS – CLL, some T and B cell neoplasms NON-LYMPHOID NEOPLASMS – CML, Breast Ca, Colon Ca NON NEOPLASTIC CONDITIONS – Cirrhosis, Sarcoidosis , Gaucher’s disease, Parasitic infection AUTOIMMUNE DISEASES – RA, Myasthenia gravis, Cold agglutinin disease SKIN DISEASES – Lichen myxedematous , Necrobiotic xanthogranuloma

6. Classification of Plasma Cell Dyscrasias : Monoclonal Gammopathy of Undetermined Significance (MGUS) ( 62%) Malignant Monoclonal Gammopathies Multiple Myeloma (18%) Variants : Smoldering Myeloma (3%) , Non Secretory Multiple Myeloma, Indolent Myeloma, Light Chain Myeloma Plasmacytoma (2.5%) : Solitary Plasmacytoma of the bone, Extramedullary / Extraosseous Plasmacytoma Plasma cell leukemia IgD myeloma POEMS syndrome ( Osteosclerotic Myeloma) Waldenstrom’s Macroglobulinemia (Lymphoplasmacytic Lymphoma ) Malignant Lymphoproliferative disorders Heavy Chain disease ( Gamma HCD, Mu HCD, Alpha HCD) Immunoglobulin Deposition diseases : Primary Amyloidosis , Systemic light chain and Heavy chain deposition diseases

7. Etiology Unknown Various Predisposing Factors Ionizing radiation Chromosomal translocation ( 11; 14) commonest Other 13q 14 deletion 17p 13 deletion Over expression of MYC or Ras gene Mutation in P53 & Rb-1 gene Exposure to metals (Nickel) Benzene & Petroleum product Silicon, Wood and Leather Industries Infection of marrow macrophages with human herpes virus 8 .

8. Type of Monoclonal Paraproteins Percentage I gG ………………………… ............................. 52 IgA …………………………………………… 21 IgD …………………………………………… 2 IgE …………………………………………….< 0.01 L chains ( K or L) only ……………………. .... 11 H chain (G or A) only …………………….. …. < 1 2 or more monoclonal paraproteins ………… < 1 No monoclonal paraprotein ………………. … 1 IgM …………………………………………….. . 12

9. Pathophysiological effects of paraproteins Raised serum globulin level Hypoalbuminemia Hyponatremia Dilutional anemia Raised ESR Rouleux formation in RBC Hyperviscosity Interference with Platelet function Interference with Coagulation pathway Proteinuria Renal failure Amyloidosis Cryoglobulinemia

10. Investigations in any suspected Monoclonal Gammopathy should include to accurately classify the disorder: Complete Blood Count ( look for anemia) Comprehensive Metabolic Panel Look for renal insufficiency, hypercalcemia and subtle clues like decreased anion gap . 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 : Quantitative Immunoglobulins : Increase in all components usually, polyclonal. Increase in single component with reciprocal decrease of uninvolved globulin usually may suggest monoclonal . Investigations

11. Serum Protein Electrophoresis with immunofixation if monoclonal gammopathy is suspected. 24Hr-Urine protein electrophoresis with urine immunofixation ( Serum Free Light Chain assay ( κ / λ ratio) may be used in place of UPEP} 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. Skeletal survey if monoclonal gammopathy has been established ( Bone scans are usually, negative in MM) Beta-2 microglobulin and Albumin for staging and prognosis in MM ( once diagnosis is made).

12. Serum Protein Electrophoresis Serum Protein Electrophoresis : 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 . Immunoglobulins ( IgG , IgM , IgA) usually migrate to gamma region but may sometimes extend to beta region. SPEP should always be performed in combination with serum immunofixation in order to determine clonality

13. SPEP showing Monoclonal Gammopathy Shows a tall “narrow” band in gamma region – “M-Spike” Also, note reduction in the normal polyclonal gamma band

14. SPEP showing Polyclonal Gammopathy Shows a broad based peak in gamma region . Seen in chronic infections, inflammation, connective tissue disease, lymphoproliferative disease.

15. Immunofixation More sensitive than SPEP Immunofixation is performed when SPEP shows a sharp “peak” or a plasma cell disorder is suspected despite a normal SPEP I mmunofixation 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 ) Why do both SPEP and IF ? Why not just IF in initial diagnosis ? 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.

16. Plasma Cell Disorders Manifest Due to Clonal Immunoglobulin

17. Constitute Several Disorders Examples : Monoclonal Gammopathies

18. And it’s Variants Multiple Myeloma

19. Most common age group > 50 yrs. M>F All three criteria must be met Presence of a serum or urinary monoclonal protein Presence of 10 percent or more clonal plasma cells in the bone marrow or a plasmacytoma 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 Multiple Myeloma

20. Pathogenesis Marrow stromal cells secrete IL-6 Activation of JAK STAT pathway Activation of RAS- MAP kinase pathway Activation of growth factors Inhibition of apoptosis activity Proliferation of Plasma cell Secrete/ express various cytokines.ie TNF α , MIP-1 α , SDF-1, IL-1 β ↑ proliferation & differentiation of osteoclasts Bone resorption and destruction Secrete/ express IL-3, TGF β &HGF Inhibition of osteoblastic activity

21. Osteoclast Osteoblast LYTIC BONE DZ HYPERCALCEMIA Erythropoiesis ANEMIA Ig deposition Cast nephropathy RENAL FAILURE Immune-paresis Hypogamm INFECTION Manifestations of Clonal Plasma Cell Proliferation

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

23. Round lesions filled with a soft reddish material are indicative of foci of myeloma in this section of vertebral bone .

24. The skull demonstrates the characteristic rounded "punched out" lesions of multiple myeloma.

25. PLASMABLAST Diffuse chromatin pattern Nucleus >10 μm Nucleolus greater than 2 μm Concentrically placed nucleus with little or no hof

26. Plasma Cell Plasma cells : Terminally differentiated B-cells Not normally found in peripheral blood . Account for less than 3.5% of nucleated cells in the bone marrow Oval cells with low N:C ratio. Cytoplasm is basophilic blue. N ucleus (30-40% of the cell) is oval or round and typically placed eccentrically (to one side) of the cell. .

27. RUSSELL BODIES Globules (2-3 μm ) of accumulated immunoglobulins in the cytoplasm of plasma cells Usually round May be found in normal bone marrow 1st described by William Russell

28. MOTT CELLS/MORULA CELLS 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

29. Flame Cell Eosinophilic torn cytoplasm Usually associated with IgA myeloma

30. Pathologic rouleaux formation, Multiple myeloma

31. BONE MARROW At low power, the abnormal plasma cells of multiple myeloma fill the marrow.

32. BONE MARROW At high power , the plasma cells of multiple myeloma here are very similar to normal plasma cells, but they may also be poorly differentiated.

33. PATTERNS OF BONE MARROW INVOLVEMENT IN MYELOMA Interstitial Focal Mixed Diffuse

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

35. The rounded "punched out" lesions of multiple myeloma appear as lucent areas with this skull radiograph.

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

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

38. Renal Pathology in MM Light Chain Deposition Disease Light Chain Cast Nephropathy AL Amyloid

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

40. Deletion 17p and Abnormalities associated with chromosome 13 carry a particularly unfavorable prognosis & respond poorly to therapy

41. 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

42. Treatment Decisions : Indications for treatment : presence of any of CRAB ( bone lesions can be diffuse osteopenia alone) Risk Stratification : FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy 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

43. Clinical Features Bone pain : Pathological fracture Hypercalcemia : confusion, constipation, vomiting. Anemia Recurrent infections with bacteria such as S. aureus , S. pneumoniae , and E. coli, resulting from the marked suppression of normal humoral immunity. Renal insufficiency Bleeding manifestations Amyloidosis – resulting in macroglossia

44. Major criteria > 30% bone marrow plasma cells M protein level -Serum IgG > 3.5g/dl or IgA > 2g/dl Urinary κ or λ > 1g/24 hours Biopsy - proven plasmacytoma Minor criteria 10% to 30% bone marrow plasma cells Monoclonal protein present but less than above Decreased normal immunoglobulin levels Lytic bone lesions Diagnosis : One major and one minor criteria or Three minor criteria including 1 and 2 DURIE & SALMON DIAGNOSTIC CRITERIA

45.   1 .Test for Bence Jones Proteinuria

46. 2. Bradshaw’s Test : Layer few ml of urine on to few ml of conc. Hydrochloric acid. BJ proteins is precipitated by acid giving a white ring at junction. Screening test Should confirm by heating test If Bence-Jones proteins present, this test will give positive even after diluting the urine

47. 3. Osgood and Haskin Test : Add 0.5 ml of 50% acetic acid & 1.5 ml of saturated sodium chloride solution to 2.5 ml of urine. A ppt at room temp. appear on adding salt solution is strongly in favour of Bence-Jones proteins. Heat the mixture, note the temp at which any change occur. If BJ proteins present ppt increase in amount at 40 o c , redissolve on boiling. Albumin & globulin usually appear only on heating, and boiling has no effect on the amount of the precipitate.

48. IMMUNOHISTOCHEMISTRY IN PLASMA CELL DYSCRASIAS • Assessment of quantity of plasma cells on bone marrow sections • Identification of a monoclonal plasma cell proliferation • Distinction of myeloma from other neoplasms

49. IMMUNOPHENOTYPE OF PLASMA CELL MYELOMA CD138+ CD10-/+ CD5--/+ Clonal CIg + CD45-/+ CD19--/+ CD38++ HLA-Dr-/+ CD20--/+ CD56+ (most) EMA-/+ CD22--/+ CD79a+ SIg --/+ CD34

50. Monoclonal Gammopathy of Undetermined Significance (MGUS) Asymptomatic monoclonal gammopathy,more common type. Denotes presence of an M-protein in a patient without a plasma cell or lymphoproliferative disorder i.e ; Undetermined Significance Precursor lesion with a tendency to evolve to multiple myeloma. No treatment required . 1/4 with stable levels of M-spike,1/4 M-spike increases but does not show criteria for myeloma,1/4 develop into myeloma,1/4 die of other causes.

51. Incidence of MGUS increases with age : 1% of adults 3% of adults over age 70 years 11% of adults over age 80 years 14% of adults over age 90 years Significance : Can progress to monoclonal Disease IgG or IgA MGUS IgM MGUS

52. DIAGNOSTIC CRITERIA FOR MGUS <10% Plasma cell in bone marrow. M protein present, stable range. levels of M protein/M-spike: IgG < 3g, IgA < 2g ,LC<1g/day in the serum. Normal immunoglobulins - normal levels No Bence -Jones proteinuria No anemia No Renal failure No lytic bone lesion & hypercalcemia (CRAB) Normal β2 microglobulin level

53. Predictors of Progression : S ize of the M-protein at the time of recognition of MGUS - most important predictor of progression IgM & IgA monoclonal proteins have a greater risk of progression than an IgG M-protein. Risk of progression does not go away with time! Risk of progression 1% per year CUMULATIVE RISK 10% at 10 years, 25% at 25 years from diagnosis So, Management : MGUS - Progression

54. Smoldering multiple myeloma M protein present, stable levels of M protein: IgG ≥ 3,0g, IgA ≥ 2g, LC ≥ 1g/day normal immunoglobulins - normal levels marrow plasmacytosis ≥ 10% complete blood count - normal no lytic bone lesions no signs of disease ( SPEP, CBC, Creatinine and calcium every 3 to 4 month and Skeletal Survey annually to pick up asymptomatic bone lesions)

55. INDOLENT MYELOMA M component: IgG <7g/dl, IgA <5g/dl Rare bone lesions (< 3 lytic lesions ), without compression fractures Normal hemoglobin, serum calcium and creatinine No infections

56. NON-SECRETORY MYELOMA <1% of Myelomas • No serum or urine monoclonal protein • Renal failure and hypercalcemia are generally lacking • Immunostaining for a monoclonal protein on bone marrow sections may establish the diagnosis • Rarely there is no monoclonal protein synthesized • Must rule out IgD and IgE myeloma

57. WHO Criteria Monoclonal gammopathy of undetermined significance a Serum monoclonal protein (<3 g/dl) Bone marrow <10% plasma cells No anemia, renal failure, or hypercalcemia (CRAB) Smoldering multiple myeloma a Serum monoclonal protein (=3 g/dl) or =10% marrow plasma cells or aggregates on biopsy, or both No anemia, renal failure, or hypercalcemia attributable to myeloma Multiple myeloma Monoclonal protein present in serum or urine =10% marrow plasma cells on biopsy or histologic evidence of plasmacytoma Plus one or more of the following: Anemia Lytic lesions or osteoporosis and =30% plasma cells in marrow Bone marrow plasma cell labeling index =1% Renal insufficiency Hypercalcemia

58. 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

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

60. POEMS ( Osteosclerotic myeloma)

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

62. Monoclonal gammopathy - IgM type Lymphoplasmacytic lymphoma Median age at diagnosis - 60 yrs Presentation : Hyperviscosity syndrome (15%) : visual impairment, neurologic manifestations Bleeding ( Acquired VWD) Cryoglobulinaemia Organomegaly , lymphadenopathy + (20 %-40 %) Autoimmune hemolysis - common Bone marrow involvement 90% Lytic bone lesions 2% Hypercalcemia 4 % Waldenstrom’s Macroglobulinemia

63. Management : Asymptomatic patients not treated until symptoms develop If Hyperviscocity features  urgent Plasmapheresis Symptomatic WM : Rituximab based therapy

64. R efers to a variety of conditions in which amyloid proteins are abnormally deposited in organs and/or tissues. A protein is described as amyloid if, due to an alteration in its secondary structure, it takes on a particular aggregated insoluble form similar to the beta-pleated sheet FEATURES OF AMYLOIDOSIS : 89% have M protein, 70% lambda 72%serum 73% urine M protein - 7% pts have >3 gm / dl Hypogammaglobulinemia - 20% Median BM plasma cells are 7% ( less than 10%) Myeloma : 20 % of patients have MM Amyloidosis

65. Symptoms are related to Organ involvement. Arrhythmias in cardiac amyloidosis , Renal failure, When the amyloid fibrils and oligomers get to the skin they can cause skin lesions and petechiae . One of the most classic feature is macroglossia

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

67. Diagnostic Approach in Suspected AL Amyloid

68. AMYLOID NODULES

69. Heavy chain disease Neoplastic proliferation of B cells producing only heavy chains. Depending upon the type of heavy chains , these are 3 types α heavy chain disease : commonest type , show predilection for intestine and respiratory tract lymphoid tissue µ heavy chain disease : Rarest, γ heavy chain disese : ( Franklin disease)

70. α Heavy chain disease The most common type of heavy chain disease Younger patients, Mediterranean area Serum electrophoresis: a broad band in the α 2 - β region Hypogammaglobulinemia and decreased level of albumin Immunoelectrophoresis: alpha chains but no light chains No BJ protein Peripheral blood: normal BM: slight/moderate increase in plasma cells Respiratory lymphoplasmacytosis Lymphoma of the small intestine, severe malabsorption syndrome

71. γ Heavy chain disease The second most common type Lymphadenopathy Hepatosplenomegaly in some cases Often normal pr electrophoresis: in serum electrophoresis: the M-band in the gamma or beta regions, M-band reveals more in immunoelectrophoresis Urine electrophoresis mimics the serum immunoelectrophoresis IgA and IgM are not decreased Probability of: lymphocytosis, pancytopenia, atypical lymphocytes, eosinophilia, and plasma cells BM: lymphoplasmacytosis, eosinophils goes up The disease may end up to lymphoma

72. µ Heavy chain disease Parallel with CLL Pr electrophoresis: normal or small spike in the beta region Immunoelectrophoresis: monoclonal M-band BJ Proteinuria, Kappa light chain BM: mimic CLL: 70 to 80% lymphocytes, few plasma cells Amyloidosis and osteoporosis

73. δ Heavy chain disease Very rare disease Similar to Multiple myeloma In serum electrophoresis: M band in the β - γ region No BJ protein BM: plasmacytosis, osteolytic lesions

74. THANK YOU What is Kahler’s Disease? It’s Multiple myeloma. Kahler’s disease is named after an Austrian doctor called Otto Kahler who first investigated and described MM