Plasma cell neoplasmsPlasma cell neoplasmsPlasma cell neoplasms Plasma cell neoplasms

WHO CLASSIFICATION OFWHO CLASSIFICATION OFPLASMA CELL NEOPLASMSPLASMA CELL NEOPLASMS

Pl C ll M lPl C ll M lPlasma Cell MyelomaPlasma Cell MyelomaVariants Variants --

NonNon--secretory myelomasecretory myelomaIndolent myeloma Indolent myeloma yySmoldering myelomaSmoldering myelomaPlasma cell leukemiaPlasma cell leukemiaPlasma cell leukemiaPlasma cell leukemia

PlasmacytomaPlasmacytomaSolitary plasmacytoma of boneSolitary plasmacytoma of boneSolitary plasmacytoma of boneSolitary plasmacytoma of boneExtramedullary plasmacytomaExtramedullary plasmacytoma

Immunoglobulin Deposition DiseasesImmunoglobulin Deposition DiseasesPrimary amyloidosisPrimary amyloidosisPrimary amyloidosisPrimary amyloidosisSystemic light and heavy chain deposition diseasesSystemic light and heavy chain deposition diseases

Osteosclerotic Myeloma (POEMS Syndrome)Osteosclerotic Myeloma (POEMS Syndrome)

L h l ti L hL h l ti L hLymphoplasmacytic LymphomaLymphoplasmacytic Lymphoma(Waldenstrom’s Macroglobulinemia(Waldenstrom’s Macroglobulinemia))(Waldenstrom s Macroglobulinemia(Waldenstrom s Macroglobulinemia))Heavy Chain DiseasesHeavy Chain DiseasesHeavy Chain DiseasesHeavy Chain Diseases

Gamma HCDGamma HCDMu HCDMu HCDAlpha HCDAlpha HCDpp

Multiple MyelomaMultiple Myeloma is is

Malignant proliferation of plasma cellsMalignant proliferation of plasma cells

Accompanied by production of onoclonalimmunoglobulin Accompanied by production of onoclonalimmunoglobulin

Clinical forms:Clinical forms:

multiple myelomamultiple myeloma

solitary plasmacytomasolitary plasmacytoma

l ll l k il ll l k iplasma cell leukemiaplasma cell leukemia

IncidenceIncidenceIncidence Incidence I ithI ithIncreases with ageIncreases with age

Median age Median age –– 68 68 yearsyears<<22% % of patients are < of patients are < 40 40 yearsyears>>4040% % of patients are >of patients are >70 70 yearsyearspp yy

Male >Male > FemalesFemalesBlack >Black > White (White (22::11))Black >Black > White (White (22::11))Incidence is Incidence is

11%% of all malignancies in whiteof all malignancies in white11% % of all malignancies in whiteof all malignancies in white22% % of all malignancies in blackof all malignancies in black

EtiologyEtiologyEtiology Etiology

-- UnknownUnknownVarious Predisposing FactorsVarious Predisposing Factors

-- Ionizing radiationIonizing radiation-- Ionizing radiationIonizing radiation-- Chromosomal translocationChromosomal translocation

& (& (1111; ; 1414) commonest) commonestOtherOther 1313qq 1414 deletiondeletionOther Other 1313q q 14 14 deletiondeletion

1717p p 13 13 deletiondeletion-- Over expression of MYC or Ras geneOver expression of MYC or Ras gene-- Mutation in PMutation in P5353 & Rb& Rb--11 genegeneMutation in PMutation in P53 53 & Rb& Rb 1 1 genegene-- Exposure to metals (Nickel)Exposure to metals (Nickel)

Benzene & Petroleum productBenzene & Petroleum productSilicon, wood and Leather IndustriesSilicon, wood and Leather Industries,,

-- Infection of marrow macrophages Infection of marrow macrophages with human herpes virus with human herpes virus 88

Clinical features of MMClinical features of MMClinical features of MMClinical features of MMBony lesions :Bony lesions :Bony lesions :Bony lesions :--Increased osteoclastic function Increased osteoclastic function Lytic lesionLytic lesionLytic lesionLytic lesionBone pain, pathological fracturesBone pain, pathological fracturesHypercalcemiaHypercalcemiaCord compressionCord compressionOsteoporosisOsteoporosisAnemia :Anemia :Anemia :Anemia :--Bone marrow replacement by tumor cellBone marrow replacement by tumor cellInhibition of HematopoiesisInhibition of HematopoiesisInhibition of HematopoiesisInhibition of HematopoiesisMild HemolysisMild HemolysisFolate, Vit BFolate, Vit B1212, Iron deficiency, Iron deficiency

Renal Failure in MM Renal Failure in MM Interstitial nephritis due to light chain tubularInterstitial nephritis due to light chain tubularInterstitial nephritis due to light chain tubular Interstitial nephritis due to light chain tubular castcastHypercalcemiaHypercalcemiaHypercalcemiaHypercalcemiaAmyloidosisAmyloidosisDirect involvement by Myeloma cellsDirect involvement by Myeloma cellsDirect involvement by Myeloma cells.Direct involvement by Myeloma cells.Light chain deposition in glomerulusLight chain deposition in glomerulusNephrotoxic chemotherapyNephrotoxic chemotherapyNephrotoxic chemotherapyNephrotoxic chemotherapyHyperuricemiaHyperuricemiaNSAIDS for painNSAIDS for painNSAIDS for pain NSAIDS for pain Recurrent infection Recurrent infection Bleeding :Bleeding :--Bleeding :Bleeding :PlateletPlatelet dysfunctiondysfunctionClottingClotting disturbancedisturbance

Neurological Symptoms Neurological Symptoms Hypercalcemia :Hypercalcemia :--

Lethargy depression confusion weaknessLethargy depression confusion weaknessLethargy, depression, confusion, weakness. Lethargy, depression, confusion, weakness. Hyperviscosity :Hyperviscosity :--

Headache, Fatigue, Retinopathy, Visual changesHeadache, Fatigue, Retinopathy, Visual changesHeadache, Fatigue, Retinopathy, Visual changesHeadache, Fatigue, Retinopathy, Visual changesBone disease :Bone disease :--

Cord compression, Radicular painCord compression, Radicular painPeripheral neuropathy :Peripheral neuropathy :--

AmyloidAmyloid

Infections :Infections :--HypogammaglobulinemiaHypogammaglobulinemiaHypogammaglobulinemiaHypogammaglobulinemiaDecreased neutrophil migrationDecreased neutrophil migrationT cell Function NormalT cell Function NormalCommon are Common are

Pneumonia & Pyelonephritis by Capsulated bacteria. Pneumonia & Pyelonephritis by Capsulated bacteria.

PathogenesisPathogenesisPathogenesisPathogenesis

Multiple myeloma is a malignant condition caused by clonal Multiple myeloma is a malignant condition caused by clonal

proliferation of plasma cells .These plasma cells are usually confined proliferation of plasma cells .These plasma cells are usually confined

to BM but may be seen on PB in end stage myelomato BM but may be seen on PB in end stage myeloma

However myeloma cells is a long lived plasma cell which has beenHowever myeloma cells is a long lived plasma cell which has beenHowever myeloma cells is a long lived plasma cell ,which has been However myeloma cells is a long lived plasma cell ,which has been

exposed to antigen having undergone the Bexposed to antigen having undergone the B--cell maturation cell maturation

processesprocessesprocessesprocesses

Maturation of normal B cell precursors to mature plasma cell Maturation of normal B cell precursors to mature plasma cell

involves rearrangement og the Ig genes with subsequent somatic involves rearrangement og the Ig genes with subsequent somatic

mutation of the (V ) region mutation of the (V ) region

11--The myeloma cell is is a post germinal The myeloma cell is is a post germinal center plasma cell which has undergone center plasma cell which has undergone p gp gIg gene recombination ,class switching Ig gene recombination ,class switching and somatic mutation and homes to theand somatic mutation and homes to theand somatic mutation, and homes to the and somatic mutation, and homes to the BM . BM .

22--A chromosomal translocation between the immunoglobulin heavy A chromosomal translocation between the immunoglobulin heavy

chain gene (on the fourteenth chromosome, locus chain gene (on the fourteenth chromosome, locus 1414qq3232) and a ) and a

oncogene (often oncogene (often 1111qq1313, , 44pp1616..33, , 66pp2121, , 1616qq23 23 and and 2020qq1111[[11]) is ]) is g (g ( qq ,, pp ,, pp ,, qq qq [[ ])])

frequently observed in patients with multiple myeloma. This frequently observed in patients with multiple myeloma. This

mutation results in dysregulation of the oncogene which is thoughtmutation results in dysregulation of the oncogene which is thoughtmutation results in dysregulation of the oncogene which is thought mutation results in dysregulation of the oncogene which is thought

to be important initiating event in the pathogenesis of myeloma. to be important initiating event in the pathogenesis of myeloma.

The result is proliferation of a plasma cell clone and genomicThe result is proliferation of a plasma cell clone and genomicThe result is proliferation of a plasma cell clone and genomic The result is proliferation of a plasma cell clone and genomic

instability that leads to further mutations and translocations. The instability that leads to further mutations and translocations. The

hh 1414 b lit i b d i b tb lit i b d i b t 5050% f ll% f llchromosome chromosome 14 14 abnormality is observed in about abnormality is observed in about 5050% of all cases % of all cases

of myeloma. Deletion of (parts of) the thirteenth chromosome is of myeloma. Deletion of (parts of) the thirteenth chromosome is

also observed in about also observed in about 5050% of cases. % of cases.

3-IL-6 is an important cytokine originally identified as B cell3 IL 6 is an important cytokine originally identified as B cell

differentiation Factor that causes proliferation of Plasmap

blastic cells and induces terminal differentiation of B cells

into antibody producing cells. Close cell to cell contact

between Myeloma cell and bone marrow stromal cell

trigger a large amount of IL-6 production by stromal cell.

WHO DIAGNOSTIC CRITERIAWHO DIAGNOSTIC CRITERIAFOR PLASMA CELL MYELOMAFOR PLASMA CELL MYELOMA

Major criteriaMajor criteria

I. Plasmacytoma on tissue biopsyI. Plasmacytoma on tissue biopsy

II B l llII B l ll 3030%%II. Bone marrow plasma cell > II. Bone marrow plasma cell > 3030%%

III. Monoclonal M spike on electrophoresis IgG > III. Monoclonal M spike on electrophoresis IgG > 33,,55g/dl,g/dl,

IgA >IgA > 22g/dl light chain >g/dl light chain > 11g/dl ing/dl in 2424h urine sampleh urine sampleIgA > IgA > 22g/dl, light chain > g/dl, light chain > 11g/dl in g/dl in 2424h urine sampleh urine sample

Minor criteriaMinor criteria

a. Bone marrow plasma cellsa. Bone marrow plasma cells 1010--3030%%a. Bone marrow plasma cells a. Bone marrow plasma cells 1010 3030%%

b. M spike but less than aboveb. M spike but less than above

c. Lytic bone lesionsc. Lytic bone lesionsyy

d. Normal IgM < d. Normal IgM < 5050mg, IgA < mg, IgA < 100100mg, IgG < mg, IgG < 600600mg/dlmg/dl

Major criteriaMajor criteria

I.I. Plasmacytoma on tissue biopsyPlasmacytoma on tissue biopsyDiagnosis:Diagnosis:

**I + b I + c I + dI + b I + c I + d

I.I. Plasmacytoma on tissue biopsyPlasmacytoma on tissue biopsy

II.II. Bone marrow plasma cell > Bone marrow plasma cell > 3030%%

**I + b, I + c, I + dI + b, I + c, I + d

**II + b, II + c, IIII + b, II + c, II

III. Monoclonal M spike on electrophoresis III. Monoclonal M spike on electrophoresis

IgG > IgG > 33,,55g/dl,g/dl,II b, II c, II II b, II c, II + d+ d

**III + a III + c IIII + a III + c I

IgA > IgA > 22g/dl, light chain > g/dl, light chain > 11g/dl in g/dl in 2424h h

urine sampleurine sample**III + a, III + c, I III + a, III + c, I II + dII + d

** + b + +b ++ b + +b +

Minor criteriaMinor criteria

a. Bone marrow plasma cellsa. Bone marrow plasma cells 1010--3030%%**a + b + c, a +b + a + b + c, a +b + dd

a. Bone marrow plasma cells a. Bone marrow plasma cells 1010 3030%%

b. M spike but less than aboveb. M spike but less than above

c. Lytic bone lesionsc. Lytic bone lesions

d. Normal IgM < d. Normal IgM < 5050mg, IgA < mg, IgA < 100100mg, IgG < mg, IgG <

600600mg/dlmg/dl

Diagnosis:Diagnosis:

I + b, I + c, I + d I + b, I + c, I + d , ,, ,II + b, II + c, II + dII + b, II + c, II + d

III + III + I II + dIII + III + I II + dIII + a, III + c, I II + dIII + a, III + c, I II + da + b + c, a +b + da + b + c, a +b + da b c, a b da b c, a b d

Various immunoglobulin in MMVarious immunoglobulin in MMVarious immunoglobulin in MMVarious immunoglobulin in MMIgGIgG 5353% of cases% of casesIgG IgG 5353% of cases % of cases

Slow growth rateSlow growth rateLess Hypercalcemia & AmyloidosisLess Hypercalcemia & Amyloidosis

IgAIgA 2525% of caess% of caessIgA IgA 2525% of caess % of caess HypercalcemiaHypercalcemiaHyperviscosity Hyperviscosity Amyloidosis not commonAmyloidosis not commonAmyloidosis not commonAmyloidosis not common

IgD IgD 11% of cases % of cases HepatosplenomegalyHepatosplenomegalyLAP, Extraosseous lesionsLAP, Extraosseous lesionsLAP, Extraosseous lesionsLAP, Extraosseous lesionsRenal failure, bad prognosisRenal failure, bad prognosis

Light chain disease Light chain disease 2020% of cases % of cases More aggressive courseMore aggressive courseggggRenal failure, lytic lesionRenal failure, lytic lesionHypercalcemiaHypercalcemiaShort survivalShort survival

Myeloma staging systemMyeloma staging system

Clinical stagingClinical staging (Salmon(Salmon--Durie)Durie)

is based on level of haemoglobin, serum calcium, is based on level of haemoglobin, serum calcium, s s d o o og o , s u u ,s s d o o og o , s u u ,

immunoglobulins and presence or not of lytic bone lesionsimmunoglobulins and presence or not of lytic bone lesions

l t ith l b d d il t ith l b d d icorrelates with myeloma burden and prognosiscorrelates with myeloma burden and prognosis

I. Low tumor massI. Low tumor mass

II. Intermediate tumor massII. Intermediate tumor mass

III. High tumor massIII. High tumor mass

subclassificationsubclassification

A A -- creatinine < creatinine < 22mg/dlmg/dl

StageStage CriteriaCriteria Estimated Tumor Burden, x Estimated Tumor Burden, x 10101212 cells/mcells/m²²

II All of the following :All of the following :gg

11. Hemoglobin >. Hemoglobin >100 100 g/L (<g/L (<1010g/dL)g/dL) <<00..6 6 (low)(low)

22. Serum calcium <. Serum calcium <3 3 mmol/L (<mmol/L (<12 12 mg/dL)mg/dL)

33. Normal bone x. Normal bone x--ray or solitary lesion ray or solitary lesion

44. Low M. Low M--component production component production

a. IgG level <a. IgG level <50 50 g/L (<g/L (<5 5 g/dL)g/dL)gg g/ (g/ ( g/ )g/ )

b. IgA level <b. IgA level <30 30 g/L (<g/L (<3 3 g/dL)g/dL)

c. Urine light chain <c. Urine light chain <4 4 g/g/2424hh

II II Fitting neither I nor IIIFitting neither I nor III 00..66--11..20 20 (intermediate) (intermediate)

IIIIII One or more of the following :One or more of the following :

11. Hemoglobin >. Hemoglobin >85 85 g/L (<g/L (<88..55g/dL)g/dL) >>11..20 20 (high)(high)gg g/ (g/ ( g/ )g/ ) ( g )( g )

22. Serum calcium >. Serum calcium >3 3 mmol/L (<mmol/L (<12 12 mg/dL)mg/dL)

33. Advanced lytic bone lesion . Advanced lytic bone lesion

44. High M. High M--component production component production

a. IgG level >a. IgG level >70 70 g/L (>g/L (>7 7 g/dL)g/dL)

b. IgA level >b. IgA level >50 50 g/L (>g/L (>5 5 g/dL)g/dL)gg g/ (g/ ( g/ )g/ )

c. Urine light chain >c. Urine light chain >12 12 g/g/2424hh

Diagnosis of MMDiagnosis of MMDiagnosis of MM Diagnosis of MM The diagnosis of multiple myeloma is often made incidentally The diagnosis of multiple myeloma is often made incidentally g p y yg p y y

during routine blood tests for other conditions. For example, during routine blood tests for other conditions. For example,

th i t f i d hi h t i tth i t f i d hi h t i tthe existence of anemia and a high serum protein may suggest the existence of anemia and a high serum protein may suggest

further testing. further testing.

diagnosis of multiple myeloma is difficult to make on the basis diagnosis of multiple myeloma is difficult to make on the basis

of any single laboratory test result. Accurate diagnosis generally of any single laboratory test result. Accurate diagnosis generally

results from consideration of a number of factors, including results from consideration of a number of factors, including , g, g

physical evaluation, patient history, symptoms, and lab results. physical evaluation, patient history, symptoms, and lab results.

A A number of laboratory tests and medical procedures are number of laboratory tests and medical procedures are used to help confirm a diagnosis of myeloma. These used to help confirm a diagnosis of myeloma. These p g yp g ytests should be conducted on all patients as part of an tests should be conducted on all patients as part of an initial evaluation It is very important for patients toinitial evaluation It is very important for patients toinitial evaluation. It is very important for patients to initial evaluation. It is very important for patients to undergo all appropriate tests, as these tests help undergo all appropriate tests, as these tests help physicians determine treatment options Many of thesephysicians determine treatment options Many of thesephysicians determine treatment options. Many of these physicians determine treatment options. Many of these tests are also used to assess the extent of disease and tests are also used to assess the extent of disease and to plan and monitor treatmentto plan and monitor treatmentto plan and monitor treatment. to plan and monitor treatment.

S d d f di i l i fi i fS d d f di i l i fi i fStandards for diagnosis currently require confirmation of Standards for diagnosis currently require confirmation of 1 1 major major andand one minor criteria one minor criteria oror 3 3 minor criteria in a minor criteria in a patient displaying symptoms of myeloma. patient displaying symptoms of myeloma.

Blood and Urine TestsBlood and Urine Tests

A Complete Blood Count (CBC)A Complete Blood Count (CBC)

measures the number of measures the number of red blood cellsred blood cells, , white blood white blood

cellscells, and , and plateletsplatelets in the blood, as well as the in the blood, as well as the ,, pp ,,

number or relative proportion of the different types number or relative proportion of the different types

f hit bl d ll t t d t t if ff hit bl d ll t t d t t if fof white blood cells present, to detect if any of of white blood cells present, to detect if any of

these are outside the normal range. these are outside the normal range. gg

anaemia, thrombocytopeniaanaemia, thrombocytopenia

rouleaux in peripheral blood smearsrouleaux in peripheral blood smears

ESR >ESR > 100100ESR > ESR > 100100

Chemistry profileChemistry profile checks levels of various blood components such as checks levels of various blood components such as

albuminalbumin blood urea nitrogen (BUN)blood urea nitrogen (BUN) calciumcalcium creatininecreatinine andand lactatelactatealbumin, albumin, blood urea nitrogen (BUN)blood urea nitrogen (BUN), calcium, , calcium, creatininecreatinine, and , and lactate lactate

dehydrogenase (LDH)dehydrogenase (LDH). Increased BUN and creatinine indicate . Increased BUN and creatinine indicate

decreased kidney function while LDH levels help assess tumor celldecreased kidney function while LDH levels help assess tumor celldecreased kidney function, while LDH levels help assess tumor cell decreased kidney function, while LDH levels help assess tumor cell

burden. burden.

Serum levels of betaSerum levels of beta 22 microglobulin (βmicroglobulin (β22 M) reflect the tumor massM) reflect the tumor massSerum levels of betaSerum levels of beta--2 2 microglobulin (βmicroglobulin (β22--M) reflect the tumor mass M) reflect the tumor mass

and are now considered a standard measure of tumor burden.and are now considered a standard measure of tumor burden.

CC--reactive proteinreactive protein is a surrogate marker (meaning it follows the is a surrogate marker (meaning it follows the

same pattern of increased or decreased levels) for ILsame pattern of increased or decreased levels) for IL--66 a growtha growthsame pattern of increased or decreased levels) for ILsame pattern of increased or decreased levels) for IL 66, a growth , a growth

factor for myeloma cells.factor for myeloma cells.

Quantitive immunoglobulins (QIGs) measure the levels of differentQuantitive immunoglobulins (QIGs) measure the levels of differentQuantitive immunoglobulins (QIGs) measure the levels of different Quantitive immunoglobulins (QIGs) measure the levels of different

types of antibodies (IgG, IgA, IgM).types of antibodies (IgG, IgA, IgM).

Electrophoresis (EP)Electrophoresis (EP) measures the levels of variousmeasures the levels of variousElectrophoresis (EP)Electrophoresis (EP) measures the levels of various measures the levels of various proteins in the blood or urine. When performed on proteins in the blood or urine. When performed on blood it is calledblood it is called serum protein electrophoresis (SPEP)serum protein electrophoresis (SPEP)blood, it is called blood, it is called serum protein electrophoresis (SPEP)serum protein electrophoresis (SPEP). . When performed on urine, it is called When performed on urine, it is called urine protein urine protein l t h i (UPEP)l t h i (UPEP) A dditi l t t ll dA dditi l t t ll delectrophoresis (UPEP)electrophoresis (UPEP). An additional test, called an . An additional test, called an

immunoelectrophoresis (IEP)immunoelectrophoresis (IEP) or or immunofixationimmunofixation, may , may l b f d t id ifi i f til b f d t id ifi i f tialso be performed to provide more specific information also be performed to provide more specific information

about the type of abnormal antibody proteins present. about the type of abnormal antibody proteins present. A i h d i f i iA i h d i f i iAssessing changes and proportions of various proteins, Assessing changes and proportions of various proteins, particularly M protein, helps track the progression of particularly M protein, helps track the progression of myeloma disease and response to treatment. Myeloma is myeloma disease and response to treatment. Myeloma is characterized by a large increase in M protein, which characterized by a large increase in M protein, which appears as a "spike" on electrophoresis appears as a "spike" on electrophoresis

24 24 hour urine protein and UPEPhour urine protein and UPEP measure measure the amount of the urine for patientsthe amount of the urine for patientsthe amount of the urine for patients the amount of the urine for patients (about (about 5050%) who show the presence of %) who show the presence of

l t i i th i Thl t i i th i Thmyeloma protein in the urine. These myeloma protein in the urine. These assessments help stage the patient and assessments help stage the patient and assess progression of the disease and assess progression of the disease and response to treatment.response to treatment.response to treatment.response to treatment.

Tests Conducted on the BoneTests Conducted on the BoneXX--rays and other imaging tests can assess changes in rays and other imaging tests can assess changes in y g g gy g g gthe bone structure and determine the number and size the bone structure and determine the number and size of bone lesions. of bone lesions. All patients should have a bone (skeletal) survey, which All patients should have a bone (skeletal) survey, which is a series of xis a series of x--rays of the skull, spine, arms, ribs, pelvis, rays of the skull, spine, arms, ribs, pelvis,

d l (d l ( ))and legs (see xand legs (see x--ray).ray).Some patients may also require:Some patients may also require:

M ti R I i (MRI)M ti R I i (MRI) t h i th tt h i th tMagnetic Resonance Imaging (MRI)Magnetic Resonance Imaging (MRI), a technique that , a technique that uses magnetic energy to provide detailed images of uses magnetic energy to provide detailed images of bone and soft tissuebone and soft tissuebone and soft tissue.bone and soft tissue.Computerized axial tomography (CAT)Computerized axial tomography (CAT), also known as , also known as computed tomography (CT), which uses a computercomputed tomography (CT), which uses a computercomputed tomography (CT), which uses a computer computed tomography (CT), which uses a computer to generate to generate 33--dimensional xdimensional x--ray pictures.ray pictures.

Bone marrow aspirationBone marrow aspiration or or bone marrow bone marrow biopsybiopsybiopsybiopsy

PATTERNS OF BONE MARROWINVOLVEMENT IN MYELOMAINVOLVEMENT IN MYELOMA

• InterstitialFocal• Focal

• Mixed• Diffuse

IMMUNOHISTOCHEMISTRY INIMMUNOHISTOCHEMISTRY INPLASMA CELL DYSCRASIAS• Assessment of quantity of plasma cells onbone marrow sectionsbone marrow sections• Identification of a monoclonal plasma cellproliferation• Distinction of myeloma from other• Distinction of myeloma from other

neoplasms

IMMUNOPHENOTYPE OFPLASMA CELL MYELOMA

CD138+ C D10-/+ CD5--/+CD138+ C D10 /+ CD5 /+Clonal CIg+ CD45-/+ CD19--/+CD38++ HLA-Dr-/+ CD20--/+CD56+ (most) EMA-/+ CD22--/+CD56+ (most) EMA /+ CD22 /+CD79a+ SIg--/+CD34

CYTOGENETICS OF PLASMACELL MYELOMA• ≈ 50% have abnormalities by

conventional cytogenetic studies

• 70% to 100% by FISH

• Hyperdiploidy and complex structural

rearrangements most commong

• Most common involved chromosomes:

• 13 [monosomy or del(13q14)]• 13 [monosomy or del(13q14)]

• 14 [t(11;14)(p13;q32)]

• 1 [duplications of q and deletions of p]• 1 [duplications of q and deletions of p]

• 11,8,6q,5q,7q,12 also common

PROGNOSTIC ASSOCIATIONS OF CYTOGENETICSOF CYTOGENETICS

INMYELOMAINMYELOMAUnfavorable del 13q

hypodiploidy11q11q

More favorable no growth ofmetaphases

DIAGNOSTIC CRITERIA FORMGUS

More common

<10% Plasma cell

M protein presenM protein presentt, , stable stable

l l f M t i I Gl l f M t i I G 33 00 I AI A 22 LCLC 11 /d/dlevels of M protein: IgG < levels of M protein: IgG < 33,,00g IgA < g IgA < 22g LC<g LC<11g/dayg/day

Normal immunoglobulins Normal immunoglobulins -- normal levelsnormal levels

No B nce Jones p oteinNo Bunce-Jones protein

No anemia

No Renal failureNo Renal failure

No lytic lesion & hypercalcemia

Normal β2 microglobulin levelNormal β2 microglobulin level

No treatment required

COURSE OF PATIENTS WITHCOURSE OF PATIENTS WITHMGUS (FOLLOW-UP 22-38 YEARS)

Group DescriptionI N b t ti l i i MCP 12%I No substantial increase in MCP 12%II MCP >3g/dL, but no myeloma or related 10%diseasesIII Died of unrelated causes 52%IV Development of myeloma (68%),

macroglobulinemiag(11%), amyloidosis (13%) 26%or related diseases (8%)or related diseases (8%)

Smoldering multiple myelomaSmoldering multiple myelomaSmoldering multiple myelomaSmoldering multiple myeloma

M protein presenM protein presentt, , stable stable levels of M protein: IgG levels of M protein: IgG ≥≥ 33,,00g IgA g IgA ≥≥ 22g LCg LCp gp g ,, g gg g gg≥≥ 11g/dayg/day

normal immunoglobulinsnormal immunoglobulins -- normal levelsnormal levelsnormal immunoglobulins normal immunoglobulins normal levelsnormal levelsmarrow plasmacytosis marrow plasmacytosis ≥≥ 1010%%complete blood countcomplete blood count normalnormalcomplete blood count complete blood count -- normalnormalno lytic bone lesionsno lytic bone lesionsno signs of diseaseno signs of disease

INDOLENT MYELOMAINDOLENT MYELOMA

M component: IgG <7g/dl, IgA <5g/dl• Rare bone lesions (< 3 lytic lesions)• Rare bone lesions (< 3 lytic lesions),without compression fractures• Normal hemoglobin, serum calcium andcreatininecreatinine• No infections

COMPARISON OF MGUS,INDOLENT AND SMOLDERINGINDOLENT AND SMOLDERING

MYELOMAMGUS SMM IMM

Plasma cells (BM) <10% 10-30% >30%

M component IgG<3.5, IgA <2 IgG>3.5, IgA.>2 IgG 3.5-7, IgA 2-5M component IgG<3.5, IgA <2 IgG>3.5, IgA.>2 IgG 3.5 7, IgA 2 5

Lytic bone lesions None None < 3

Symptoms/infection None None None

PLASMA CELL LEUKEMIAPLASMA CELL LEUKEMIA

2 X 109/L l ll i bl d• >2 X 109/L plasma cells in blood• Younger ageg g• Higher incidence of organomegaly andlymphadenopathylymphadenopathy• More extensive bone marrow infiltration• Renal failure more common• Less bone pain fewer lytic lesions• Less bone pain, fewer lytic lesions• Poor response to therapy

NON-SECRETORYMYELOMA

<1% f M l<1% of Myelomas• No serum or urine monoclonal protein

Renal fail e and h pe calcemia a e• Renal failure and hypercalcemia aregenerally lacking

Immunostaining for a monoclonal protein on• Immunostaining for a monoclonal protein onbone marrow sections may establish thediagnosisdiagnosis• Rarely there is no monoclonal proteinsynthesizedsynthesized• Must rule out IgD and IgE myeloma

PLASMACYTOMASPLASMACYTOMAS

• Solitary Plasmacytoma of Bone• Extramedullary Plasmacytomas• Extramedullary Plasmacytomas

SOLITARY PLASMACYTOMA OFBONE

Localized plasma cell tumor• Absence of a plasma cell infiltrate in randompmarrow biopsies• No evidence of other lesions by radiographic• No evidence of other lesions by radiographicexamination• Absence of renal failure, hypercalcemia,anemia

EXTRAMEDULLARYPLASMACYTOMAS

M t C P i SitMost Common Primary Sites –• Upper air passages and oropharynx(May involve draining lymph nodes)• Less Common Sites –• Lymph nodes (primary), salivary glands,spleen, liver, etc.spleen, liver, etc.• 25% have small monoclonal spike• Rare dissemination rarer evolution to• Rare dissemination, rarer evolution tomyeloma

•

WALDENSTROM’SMACROGLOBULINEMIA(LYMPHOPLASMACYTOID LYMPHOMA)

• Lymphadenopathy or splenomegaly 20%-40%

• Bone marrow involvement 90%

• Lytic bone lesions 2%

H l i 4%• Hypercalcemia 4%

• Hyperviscosity syndrome 15%

Hyperviscosity syndromeHyperviscosity syndromeHyperviscosity syndromeHyperviscosity syndrome

Causes sludging of RBCs in capillaries and Causes sludging of RBCs in capillaries and increased thrombus formation leading to:increased thrombus formation leading to:gg

HeadacheHeadacheDizzinessDizzinessDizzinessDizzinessVertigoVertigoDeafnessDeafnessSeizuresSeizuresBleedingBleeding

TUMOR INFILTRATIONBONE MARROW

LYMPH NODESSPLEEN

MONOCLONAL

MACROGLOBULINEMIA

CIRCULATING IgMTISSUE IgM

NEUROPATHYCIRCULATING IgMHYPERVISCOSITYCRYOGLOBULINEMIACOLD AGGLUTININ ANEMIA

GLOMERULAR DISEASEAMYLOIDOSI

Epidemiology and DemographicsEpidemiology and DemographicsEpidemiology and DemographicsEpidemiology and Demographics

15001500 l di d h i hl di d h i h1500 1500 people diagnosed each year in the people diagnosed each year in the USUSOccurrence is Occurrence is 22x higher in men than in x higher in men than in womenwomenUsually occurs in people > Usually occurs in people > 65 65 More common among caucasiansMore common among caucasiansMore common among caucasiansMore common among caucasiansMean life span after diagnosis is Mean life span after diagnosis is 55--7 7 years years (longer than MM)(longer than MM)1010% of patients attain complete remission% of patients attain complete remission00% o pat e ts atta co p ete e ss o% o pat e ts atta co p ete e ss o

Diagnosis of WMDiagnosis of WMDiagnosis of WMDiagnosis of WM

Good physical exam including :Good physical exam including :fundoscopy to look for “sausage links” in thefundoscopy to look for “sausage links” in thefundoscopy to look for sausage links in the fundoscopy to look for sausage links in the retinaretinaabdominal palpation to look forabdominal palpation to look forabdominal palpation to look for abdominal palpation to look for hepatosplenomegalyhepatosplenomegaly

Se e l diffe ent l b te tSe e l diffe ent l b te tSeveral different lab testsSeveral different lab testsGOLD STANDARD is serum electrophoresisGOLD STANDARD is serum electrophoresispp

LabsLabsLabsLabs

CBC with differentialCBC with differentialHgb is low (mild anemia)Hgb is low (mild anemia)Hgb is low (mild anemia)Hgb is low (mild anemia)WBC count is normal to low WBC count is normal to low Platelet count may be lowPlatelet count may be lowPlatelet count may be lowPlatelet count may be lowBlood smear can show malignant lymphoid Blood smear can show malignant lymphoid

llllcellscellsElevated ESR,Elevated ESR, with rouleauxwith rouleaux

Serum electrophoresisSerum electrophoresisThis will show the overproduction This will show the overproduction of Ig in the serum as an “M spike” of Ig in the serum as an “M spike” in the gamma regionin the gamma regionI l t h iI l t h iImmunoelectrophoresisImmunoelectrophoresis

If a large M spike is seen, If a large M spike is seen, serum immunoelectrophoresis serum immunoelectrophoresis will determine the isotype of the will determine the isotype of the offending macroglobulinoffending macroglobulin

Determining SeverityDetermining SeverityDetermining SeverityDetermining Severity

Test IgM levels in the serumTest IgM levels in the serumThe higher the levels, the more severeThe higher the levels, the more severeThe higher the levels, the more severeThe higher the levels, the more severe

Test serum viscosityTest serum viscosityU i t t i it fU i t t i it fUses a viscometer to measure viscosity of Uses a viscometer to measure viscosity of serum compared to waterserum compared to waterResults are more sensitive than ESRResults are more sensitive than ESRSymptoms will appear when serum viscosity is Symptoms will appear when serum viscosity is y p pp yy p pp y44x normalx normal

Why do we think someone has WM?Why do we think someone has WM?Anemia signs (fatigue, weakness, dyspnea, etc.)Anemia signs (fatigue, weakness, dyspnea, etc.)

Symptoms of hyperviscosity syndromeSymptoms of hyperviscosity syndromey p yp y yy p yp y y

Unexplained weight lossUnexplained weight loss

Unexplained easy bleeding (due to interference withUnexplained easy bleeding (due to interference withUnexplained easy bleeding (due to interference with Unexplained easy bleeding (due to interference with clotting factors clotting factors -- including epistaxis and purpura)including epistaxis and purpura)

Engorgement and narrowing of retinal veinsEngorgement and narrowing of retinal veinsEngorgement and narrowing of retinal veins Engorgement and narrowing of retinal veins

LymphadenopathyLymphadenopathy

P i h l th (d t l ti fP i h l th (d t l ti fPeripheral neuropathy (due to acculumations of Peripheral neuropathy (due to acculumations of paraproteins in perivascular and perineural tissues)paraproteins in perivascular and perineural tissues)

l ll lHepatosplenomegalyHepatosplenomegaly

Increased bacterial infectionsIncreased bacterial infections

OSTEOSCLEROTIC MYELOMA(POEMS SYNDROME)

Polyneuropathy (progressive, demyelinating)Organomegaly (hepatosplenomegalyOrganomegaly (hepatosplenomegaly,lymphadenopathy)Endocrinopathy (hypogonadism,

hypothyroidism)hypothyroidism)Monoclonal gammopathy (usually IgA

lambda o IgG lambda)lambda or IgG lambda)Skin changes (hyperpigmentation)g ( yp p g )

The level of paraprotein in the serum and urine is usually The level of paraprotein in the serum and urine is usually lowlow

Anemia ,hypercalcemia ,renal dysfunction and pathological Anemia ,hypercalcemia ,renal dysfunction and pathological fracture are rarefracture are rarefracture are rare fracture are rare

BM trephine shows a characteristic osteosclerotic BM trephine shows a characteristic osteosclerotic l t hi h i l lti l Thl t hi h i l lti l Thplasmacytoma which may occur singly or multiply .The plasmacytoma which may occur singly or multiply .The

lesion shows thickened trabecular bone with closely lesion shows thickened trabecular bone with closely i t d it b l fib i ith t d li t d it b l fib i ith t d lassociated peritrabecular fibrosis with entrapped plasma associated peritrabecular fibrosis with entrapped plasma

cells ,the rest of the bone marrow away from the lesion is cells ,the rest of the bone marrow away from the lesion is l i l l i h l hl i l l i h l h %% l lll llrelatively normal with les than relatively normal with les than 55% % plasma cells .plasma cells .

Lymph node biopsy shows a follicular proliferation with Lymph node biopsy shows a follicular proliferation with regrssed and reactive follicles and interfollicular plasma cells regrssed and reactive follicles and interfollicular plasma cells accumulation accumulation

IMMUNOGLOBULINDEPOSITION DISEASES

•Primary amyloidosis• Systemic light and heavy• Systemic light and heavy

chain deposition disease

AmyloidosisAmyloidosisDefinitionDefinitionIt is a disorder of protein folding in which It is a disorder of protein folding in which normally soluble protein are deposited in normally soluble protein are deposited in y p py p pthe extracellular space as insoluble fibrils the extracellular space as insoluble fibrils that progressively disrupt tissue structure that progressively disrupt tissue structure p g y pp g y pand function and function AboutAbout 2020 different unrelated proteins candifferent unrelated proteins canAbout About 20 20 different unrelated proteins can different unrelated proteins can form amyloid in vivo form amyloid in vivo The term amyloid is derived from theThe term amyloid is derived from theThe term amyloid is derived from the The term amyloid is derived from the Greek for starch Greek for starch ––like like

Amyloid deposition may be :Amyloid deposition may be :

Systemic or localized Systemic or localized

Hereditary or acquiredHereditary or acquiredHereditary or acquired Hereditary or acquired

Life Life ––threatening or incidental finding threatening or incidental finding

Pathgenesis of amyloidPathgenesis of amyloidg yg y

Amyloidosis breaks the dogma that tertiary Amyloidosis breaks the dogma that tertiary

t t f t i i d t i d l l bt t f t i i d t i d l l bstructures of proteins is dertermined solely by structures of proteins is dertermined solely by

their primary amino acid sequencestheir primary amino acid sequencestheir primary amino acid sequences their primary amino acid sequences

AmyloidAmyloid forming proteins can exist in twoforming proteins can exist in twoAmyloid Amyloid ––forming proteins can exist in two forming proteins can exist in two

completely different stable structurescompletely different stable structurescompletely different stable structures completely different stable structures

The transformation evidently involving massive refolding The transformation evidently involving massive refolding of the native form into one that can autoaggregate in a of the native form into one that can autoaggregate in a highly ordered manner to produce the characteristic highly ordered manner to produce the characteristic predominantly Bpredominantly B--sheet .rigid ,nonsheet .rigid ,non--branching fibrils of branching fibrils of 10 10 –– 15 15 nm in diameter and of indeterminate lengthnm in diameter and of indeterminate length

Acquired biophysical properties common to allAcquired biophysical properties common to allAcquired biophysical properties common to all Acquired biophysical properties common to all

amyloid fibrils include insolubility in physiological solution amyloid fibrils include insolubility in physiological solution relative resistance to proteolysis and ability to bindrelative resistance to proteolysis and ability to bind,relative resistance to proteolysis ,and ability to bind ,relative resistance to proteolysis ,and ability to bind Congo red in an ordered manner that give the the Congo red in an ordered manner that give the the diagnostic green birefringence under crossdiagnostic green birefringence under cross--polarizedpolarizeddiagnostic green birefringence under crossdiagnostic green birefringence under cross--polarized polarized light light

A l id d iti i th i tA l id d iti i th i tAmyloid depoition can occur in three circumstances .Amyloid depoition can occur in three circumstances .

II When there is a sustained abnormally highWhen there is a sustained abnormally highII--When there is a sustained abnormally high When there is a sustained abnormally high

concentration of certain normal protein ,such as concentration of certain normal protein ,such as

amyloid A protein (SAA) in chronic inflammation amyloid A protein (SAA) in chronic inflammation

and Band B22microglobulin in renal failure (ABmicroglobulin in renal failure (AB22M)M)and Band B22microglobulin in renal failure (ABmicroglobulin in renal failure (AB22M)M)

IIII--When there is normal concentration of a normal When there is normal concentration of a normal

,but inherently amyloidogenic ,protein over a very ,but inherently amyloidogenic ,protein over a very

prolonged period such as transthyretin in senileprolonged period such as transthyretin in senileprolonged period ,such as transthyretin in senile prolonged period ,such as transthyretin in senile

amyloidosis (ATTR) and Bamyloidosis (ATTR) and B--protein in Alzheimer’s protein in Alzheimer’s

disease disease

IIIIII--When there is a production of an When there is a production of an acquired or inherited variant protein withacquired or inherited variant protein withacquired or inherited variant protein with acquired or inherited variant protein with and abnormal structure such as and abnormal structure such as amyloidogenic monoclonal Ig light chainamyloidogenic monoclonal Ig light chain,amyloidogenic monoclonal Ig light chain ,amyloidogenic monoclonal Ig light chain

The genetic and environmental factorsThe genetic and environmental factorsThe genetic and environmental factors The genetic and environmental factors that influence individual susceptibility to that influence individual susceptibility to and timing of amyloid deposition areand timing of amyloid deposition areand timing of amyloid deposition are and timing of amyloid deposition are unclear unclear

Systemic AL amyloidosisSystemic AL amyloidosisFormerly known as primary Formerly known as primary Occur in a small proportion of monoclonal BOccur in a small proportion of monoclonal B--cell cell p pp pdyscrasias dyscrasias AL fibrils are derived from monoclonal Ig lightAL fibrils are derived from monoclonal Ig lightAL fibrils are derived from monoclonal Ig light AL fibrils are derived from monoclonal Ig light chain ,which are unique in each patient chain ,which are unique in each patient AL fibrils are more commonly derived fromAL fibrils are more commonly derived fromAL fibrils are more commonly derived from AL fibrils are more commonly derived from lambda than kappa light chain lambda than kappa light chain Vi t ll bi ti fVi t ll bi ti fVirtually any organ or combination of organs Virtually any organ or combination of organs other than the brain may be directly affected other than the brain may be directly affected

l i l di th h tl i l di th h tcommonly including the heart commonly including the heart

Diagnosis and investigation of Diagnosis and investigation of amyloidoisamyloidois

Amyloid should be considered in the DD of :Amyloid should be considered in the DD of :Renal failureRenal failureRenal failure Renal failure NSNSRestrictive cardiomyopathy Restrictive cardiomyopathy Peripheral or autonomic neuropathyPeripheral or autonomic neuropathyPeripheral or autonomic neuropathy Peripheral or autonomic neuropathy Hepatomegaly Hepatomegaly

E l t ftE l t ft ifi difi dEarly symptoms are often very nonEarly symptoms are often very non--specific and specific and insidious insidious

The index of suspicion should be high in patients The index of suspicion should be high in patients known to have clonal Bknown to have clonal B cell dyscrasiascell dyscrasiasknown to have clonal Bknown to have clonal B--cell dyscrasias cell dyscrasias

But in practice the diagnosis of amyliodosis is But in practice the diagnosis of amyliodosis is p g yp g yusually an unexpected finding following biopsy usually an unexpected finding following biopsy of an organ with disturbed functionof an organ with disturbed functionof an organ with disturbed function of an organ with disturbed function

DIAGNOSTIC CRITERIA FOR

PRIMARY AMYLOIDOSIS

• Tissue biopsy showing typical morphologyA l bi f i d l i d• Apple green birefringence under polarized

light after Congo Red stainingg g g• Typical fibrillar ultrastructure

BIOPSY DIAGNOSIS OFAMYLOIDOSIS

Diagnostic %-----------------------------------------------------• Bone marrow examination 56%• Abdominal fat aspiration 80%• Combined BM & fat aspirate 89%• Combined BM & fat aspirate 89%

HEAVY CHAIN DISEASEHEAVY CHAIN DISEASEM l l t i d fMonoclonal protein composed ofincomplete heavy chains devoid of lightchains• Lymphoproliferative disorders - often CLLy p por macroglobulinemia-like picture

• Alpha chain disease• Gamma chain disease• Gamma chain disease• MU chain disease

ALPHA CHAIN DISEASEALPHA CHAIN DISEASE

• Involves GI trackLamina propria is heavily infiltrated withLamina propria is heavily infiltrated withplasma cells• Uniform clinical picture• Bone marrow is normal• Bone marrow is normal

GAMMA CHAIN DISEASEGAMMA CHAIN DISEASEH l b li i dHypogammaglobulinemia andincomplete monoclonal gamma chain

Va iable clinical pict e• Variable clinical picture• ≈ 50% have a lymphoplasmacellularproliferation similar to macroglobulinemiaproliferation similar to macroglobulinemia• ≈ 15% are predominantly plasmacytic

Occasional cases are associated with CLL or• Occasional cases are associated with CLL orlarge cell lymphoma≈ 30% benign appearing or no• ≈ 30% benign-appearing or no

lymphoproliferative disease

MU CHAIN DISEASEMU CHAIN DISEASE

CLL-like picture• More often hepatosplenomegaly• More often hepatosplenomegaly• Less lymphadenopathy• Characteristic vacuolated plasmacellscells• Large amounts of Bence-Jonesprotein

PROBLEMATIC MORPHOLOGICFEATURES IN MYELOMA

• Mature cytology• Pleomorphic cytology• Pleomorphic cytology• Convoluted plasma cell variant• Phagocytosis• Cytoplasmic inclusions• Cytoplasmic inclusions• Plasmablastic myeloma