This document summarizes plasma cell dyscrasias and B-cell development. It discusses the normal development of B-cells from stem cells to plasma cells. It then describes various plasma cell disorders including monoclonal gammopathy of undetermined significance (MGUS), plasma cell myeloma, plasmacytoma, immunoglobulin deposition diseases, and other immunoglobulin secreting neoplasms. It provides details on the morphology, immunophenotyping, classification and diagnostic criteria for these various plasma cell dysrasias.

1. PLASMA CELL DYSCRASIAS
BY EKTA JAJODIA

2. B-CELL DEVELOPMENT
• B lymphocytes arise from lymphoid stem cells
in bone marrow
• Initial development occurs in primary lymphoid
organ (BM) from where B cells migrate to the
secondary lymphoid organs (LN & spleen) and
further differentiation occurs on antigenic
stimulation

3. stem
cell
lymphoid
precursor
progenitor-B
pre-B
immature
B-cell
mature
B-cell
germinal
center
B-cell
memory
B-cell
plasma cell

4. DEVELOPMENT IN
BONE MARROW
Immunoglobulin gene
rearrangement produces
immature B-cells

6. D(H) to J(H) V(H) to DJ(H)
Pre BCR
V(L) to J(L)
BCR

8. ENZYMES REQUIRED
• TdT- (terminal deoxyribonucleotidyl
transferase)
• An enzyme that catalyses heavy chain
rearrangement
• So active in pro-B cell and ceases to be
active in pre b cell stage

9. • RAG-1 and RAG2 –
• An enzyme reqd for both heavy chain and light
chain rearrangement
• So active in both pro B ell and pre b cell stage

10. • BM phase of B cell development ends in
production of an IgM bearing immature B
cells

11. PLASMA CELL DIFFERENTIATION
Immature B cell leave BM and migrate to
secondary lymphoid organs (spleen ,LN)
IgD appears on the surface
Known as naïve/virgin B cells

12. Encounter an antigen
Memory B cells
Plasmablasts
Plasma cells

15. In the spleen – plasma cells
reside in red pulp
In the lymph node plasma
cells reside in the
medullary cords

16. ROLE OF BM MICROENVIRONMENT
• Most important is BM stromal cells (BMSC)
• Data indicate that plasma cells cultured in
presence of BMSC – survived and continued to
secrete antibody for at least 3 weeks
• When cultured withour BMSC – Abs were
detected only for 7 days
• This suggest that BMSC and its secreted factors are
reqd for Plasma cell survival and longevity

17. When plasma cell VLA-4 binds to an unknown
ligand on BMSC (not VCAM-1)
IL-6 mRNA is upregulated in BMSC
So increased IL-6

18. • IL-6 is critical for Plasma cell survival and longevity
• Produced by BMSC
• Not produced by non-malignant plasma cells
• May be produced by myeloma/ malignant plasma
cells

19. • B cell precursors have CXCR4 receptor on their
surface
Binds with CXCL12 on the bone marrow stromal
cells (BMSC)
This binding is responsible for retaining precursor
B cells in the BM

20. But the immature B cells lose expression of CXCR4
Therefore they are no longer retained in BM and
migrate to the secondary lymphoid organs
• Plasma cells also exp CXCR4 which interacts with
BMSC CXCL12
•This is responsible for Plasma cell survival and
localisation in BM

23. MOLECULAR AND
CELLULAR EVENTS OF
PLASMA CELL
DIFFERENTIATION

24. 1. Blimp-1 (B lymphocyte induced maturation
protein 1)
• Is a master regulator of plasma cell differentiation
• Cytokine activation of BCL1 – induces Blimp1
expression
• Expression of blimp- 1 results in concomitant
repression of BCL6 , Pax5, c-myc, CIITA and BCR
signalling markers – Spi-B and Id3
• Conversely Blimp-1 upregulates J-chain exp ( and
thus Ig synthesis) and syndecan-1 protein synthesis

26. 2. XBP-1 (X- box binding protein)
• A transcription factor essential for plasma cell
differentiation
• XBP-1 is sufficient to induce generation of
plasma cells
• Absence of XBP-1 does not affect Blimp-1 exp

27. 3. SYNDECAN-1 (CD138)
• Plasma cells are best distinguished from other
population by their membrane exp of syndecan-1
• Syndecan-1 binds to fibronectin, collagen and
basic fibroblast growth factor
• So reqd for contact with BMSC

28. •Plasma cells are committed to synthesis of antibody
• Their cell surface phenotype differs greatly from
memory B-cells

29. MORPHOLOGY

30. PLASMABLAST
• diffuse chromatin
pattern
• nucleus >10 μm
• nucleolus greater than
2 μm
• concentrically placed
nucleus with little or no
hof

31. • Terminally differentiated B-
cells
• Not normally found in
peripheral blood
• Account for < 3.5% of
nucleated cells in the bone
marrow
PLASMA CELLS

32. • Oval cells with cart-wheel
nucleus
• Cytoplasm is basophilic
blue
• Nucleus is oval or round
and typically placed
eccentrically
• A hof is present adjacent
to the nucleus contains
Golgi apparatus

33. • 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
RUSSELL BODIES

34. 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

35. FLAME CELLS
• Eosinophilic torn
cytoplasm
•Usually associated
with IgA myeloma

36. DUTCHER BODIES
• Immunoglobulin filled
cytoplasm invaginating
into the nucleus creating
the appearance of an
intranuclear inclusion
• PAS +ve
• Identified by Dutcher
and Fahey

37. RHOMBOID CRYSTALLINE INCLUSIONS
intracellular extracellular IHC – lambda chain

38. PLASMA CELL DYSCRASIA
• Plasma cell dyscrasias are disorders of
the plasma cells
• They are produced as a result of abnormal
proliferation of a monoclonal population of
plasma cells that may or may not secrete
detectable levels of a monoclonal
immunoglobulin or immunoglobulin fragment
(paraprotein or M protein)

39. CLASSIFICATION
1. Monoclonal gammopathy of undetermined
significance (MGUS)
2. Plasma cell myeloma
Variants-
a. Asymptomatic(smoldering myeloma)
b. Non-secretory myeloma
c. Plasma cell leukemia
3. Plasmacytoma
a. Solitary plasmacytoma of bone
b. Extraosseous(extramedullary) plasmacytoma

40. 4. Immunoglobulin deposition diseases
a. Primary amyloidosis
b. Systemic light and heavy chain deposition
diseases
5. Osteosclerotic myeloma (POEMS syndrome)

41. OTHER IMMUNOGLOBULIN
SECRETING NEOPLASMS
1. Lymphoplasmacytic lymphoma/ Waldenstrom
macroglobulinemia
2. Heavy chain diseases
• These are classified separately under mature B-cell
neoplasms

42. M-component can also be detected in –
1. LYMPHOID NEOPLASMS – CLL, some T and B cell
neoplasms
2. NON-LYMPHOID NEOPLASMS – CML, Breast Ca,
Colon Ca
3. NON NEOPLASTIC CONDITIONS – Cirrhosis,
sarcoidosis, gaucher’s disease, parasitic infection
4. AUTOIMMUNE DISEASES – RA, Myasthenia
gravis, Cold agglutinin disease
5. SKIN DISEASES – Lichen myxedematous,
necrobiotic xanthogranuloma

43. MGUS
• Monoclonal expansion of Ig secreting plasma cells
but non- neoplastic
• Preneoplastic condition
• 0.5-1% / year of MGUS progress to Multiple myeloma
(MM)

44. Non IgM MGUS
Light chain MGUS
IgM MGUS
• 80% of MM
originates from this
• Primary amyloidosis
• 2% of MM originates from
this
• This usually evolves into
waldenstrom’s or
lymphoplasmacytic lymphoma
Rarely progress to MM
MGUS

45. DIAGNOSTIC CRITERIA
Non IgM MGUS / IgM MGUS –
1.Serum monoclonal protein < 30g/L
2. BM clonal plasma cells / lymphoplasmacytic cells
< 10%
3. Absence of CRAB or amyloidosis

46. Light chain MGUS –
1. Urinary monoclonal protein <500mg/24hrs
2. BM plasma cells <10%
3. Abnormal FLC ratio - >1.65 (in case of increased
kappa light chain)
< 0.26 (in case of
increased lambda light chain )
4. No Ig heavy chain expresion on immunofixation
5. Absence of CRAB or amyloidosis

47. 1) Size and type of M –protein
- M-protein of >25 g/l
-IgM or IgA MGUS- greater risk of progression
2) Detection of DNA aneuploidy and subnormal
levels of polyclonal Igs
Risk factors for progression of
MGUS to plasma cell myeloma

48. • BM aspirate shows median of 3% plasma cells
• Trephine bx- no or minimal increase of plasma
cells
• Plasma cells are mature looking however
occasional cell may have cytoplasmic inclusion or
prominent nucleoli
MORPHOLOGY

49. IMMUNOPHENOTYPING
2 population of plasma cells are seen
CD38 bright +,CD19+ and
CD56 -
This is polyclonal with
normal immunophenotype
• CD19-/CD56-
• CD19-/CD56+
• Weak CD38+
This is monoclonal
population

50. PLASMACYTOMA
CLASSIFICATION-
1.Solitary plasmacytoma of bone
2.Extraosseous (extramedullary)
plasmacytoma

51. 1. Single area of bone/soft tissue destruction due to
clonal plasma cells
2. Normal BM biopsy without clonal disease- ruled
out by B/L iliac crest BM biopsy
3. Normal results on radiologic skeletal survey & MRI
of spine, pelvis, proximal femur & humerus (except
for the primary solitary lesion)
CRITERIA FOR DIAGNOSIS

52. 4. No anemia, hypercalcemia or renal impairment
attributable to myeloma
5. No or low serum or urinary level of monoclonal
protein & preserved levels of uninvolved
immunoglobulins (paraprotein may be seen in
50% cases but usually <2g/dl)

53. • Solitary plasmacytoma with
minimal marrow involvement –
1. One solitary bone lesion
2. BM clonal plasma cells <10%
• If BM clonal plasma cells <10%
with >1 bone lesion – MM
• If BM clonal plasma cells >10%
with solitary plasmacytoma - MM

54. • Long & flat bones, axial skeleton, vertebra
• Dense homogenous PC infiltrate with varying
dysplasia- irregular nuclei with dispersed chromatin,
prominent nucleoli & multinucleation
• 25% cases may show amyloid deposition & foreign
body reaction
SOLITARY PLASMACYTOMA OF BONE

55. Types:
Plasmacytic (WD)- clumped chromatin & little
cytoplasmic dysplasia. Russel & dutcher bodies +ve
Plasmablastic (MD)- dispersed chromatin,
prominent nucleoli & amphophilic cytoplasm
Anaplastic (PD)- nuclear immaturity & dysplasia,
mitosis +ve

56. • Kappa or lambda light chain restriction
• Non monoclonal Ig usually normal with IgG
preponderance in bone & IgA in extramedullary
• 20% cases show B-cell markers CD 79a, CD 19,
CD 20
IMMUNOHISTOCHEMISTRY

57. Adverse prognostic factors
• Persistance of monoclonal protein > 1 yr after Tx
• Predominance of non-IgG class immunoglobulin
• Older patients
• Solitary plasamcytoma >5cm
•They have a higher incidence of progression to MM
• Progression to MM is more in solitary
plasmacytoma of bone compared to extraosseous
plasmacytoma

58. • Localized plasma cell neoplasms that arise in tissues
other than bone
• 80% Extra osseous plasmacytomas occur in URT
• 20% of patients have a small M-protein, most
commonly IgA
EXTRAOSSEOUS PLASMACYTOMA

59. IMMUNOGLOBULIN DEPOSITION
DISEASES
1.Primary amyloidosis
2.Systemic light and heavy chain
deposition disease

60. • Monoclonal plasma cell proliferative disorder
associated with deposition of mostly light
chain(usually lambda) or rarely heavy chain
fragments leading to organ dysfunction
• About 10 % of patient with amyloidosis may also
have MM
• Overtime a small number of patient with MGUS
may eventually develop amyloidosis
PRIMARY AMYLOIDOSIS

61. DIAGNOSIS
• Demonstration of amyloid in abdominal
subcutaneous fat pad ,bone marrow or rectum
• Grossly – waxy or porcelain like
• In H&E – pink amorphous waxy appearing
substance with a characteristic cracking artifact
• Congo red stain- by light microscopy – red to pink
• Under polarised light – apple green birefringence

62. Systemic light and heavy chain
deposition diseases
CLASSIFICATION -
1.Light chain deposition disease
2.Heavy chain deposition disease
3.Light and heavy chain deposition disease

63. • Secrete abnormal light chains or heavy chains or
both which deposit in tissues causing organ
dysfunction
• Most commonly involves – kidneys
• Extrarenal deposition rarely may occur in – heart ,
liver and Peripheral nervous system
• In LCDD – Primary defect – multiple mutations in
Ig light chain variable region
• In HCDD – primary defect – deletion of CH1
constant domain – causes failure to associate with
heavy chain binding protein – results in premature
secretion

64. •Do not form amyloid B-pleated sheets, bind
Congo red or contain amyloid P-component
• LCD usually involves kappa light chains ;
amyloidosis usually involves lambda light
chains
•lambda LCD has a three times worse
prognosis than kappa LCD

65. Morphology – tissue deposits of non-
amyloid, non- fibrillary amorphous refractile
eosinophilic material in glomerular and
tubular basement membrane
•IF – Prominent smooth linear peritubular
deposits along the outer edge of tubular BM
of mostly kappa light chains
• EM – Dense granular non-fibrillary deposits

66. OSTEOSCLEROTIC MYELOMA
(POEMS SYNDROME)
CRITERIA FOR DIAGNOSIS
1. Polyneuropathy
2. Monoclonal plasma cells (almost always
lambda)
3. Any one of the 3 major criteria-
a. Sclerotic bone lesions
b. Castleman’s disease
c. Elevated levels of VEGF

67. 4. Any one of the following 6 minor criteria-
a. Organomegaly (splenomegaly, hepatomegaly,
lymphadenopathy)
b. Extravascular volume overload (edema, pleural
effusion, ascitis)
c. Endocrinopathy
d. Skin changes (hyperpigmentation,
hypertrichosis, glomeruloid hemangiomata,
plethora)
e. Papilledema
f. Thrombocytosis/polycythemia

68. HEAVY CHAIN DISEASE (HCD)
1.Gamma HCD
2.Mu HCD
3.Alpha HCD
Patients secrete a defective heavy chain
immunoglobin

69. 1. Gamma HCD –
• aka franklin’s disease
• Palatal edema (due to involvement of
waldeyer’s ring)
• For diagnosis – Serum M component of IgG
type < 2g/dl
• M- component present in both urine and serum
– usually IgG1 type
• Truncated gamma heavy chain is produced
which lacks light chain binding sites – so cannot
form a complete immunoglobulin molecule

70. Mu HCD –
• Produces a defective Mu heavy chain that lacks
a variable region
• resembles CLL
• High frequency of hepatosplenomegaly and
absence of peripheral lymphadenopathy – these
features distinguish this from CLL
• Presence of vacuoles in malignant lymphocytes
• Excretion of Kappa light chains in urine

71. Alpha HCD –
• aka seligmann’s disease/ mediterranean
lymphoma
• MC HCD
• Also known as IPSID ( immunoproliferative small
intestinal disease) – results in malabsorption and
diarrhoea
• Lymphoplasmacytoid infiltration in the lamina
propria of small intestine that secretes truncated
alpha chains
• Campylobacter jejuni causative organism
• Sometimes reversible by antibiotics but may
progress to DLBCL

72. LYMPHOPLASMACYTIC
LYMPHOMA (LPL)
• Neoplasm of small B lymphocytes, plasmacytoid
lymphocytes and plasma cells
• Does not fulfill criteria for any other small B cell
lymphoid neoplasms that may have plasmacytic
differentiation
• WALDENSTROM MACROGLOBULINEMIA – Found in a
subset of LPL and is defined as LPL with BM involvement
and an IgM monoclonal component of any
concentration

73. • Serum M component – usually 3 g/dl
• Cryoglobulins present – these are Pure M
components ( not mixed cryoglobulins which is
seen in RA that c/o IgM/IgA complexed with IgG
• May sometimes be asociated with HCV
• Hyperviscosity syndrome (15%) : visual
impairment, neurologic manifestations
• In WM – there may be loss of MAG(myelin
associated glycoprotein) – a protein associated with
demyelinating disease of PNS – so WM patients
may develop peripheral neuropathy

74. What is
KAHLER’S
disease
• AKA Multiple
myeloma
• Kahler’s disease is
named after an
Austrian doctor called
Otto Kahler who first
investigated and
described MM

75. What is Randall disease
Monoclonal light and heavy
chain deposition disease

76. What is Crow-Fukase
syndrome
Aka POEMS
syndrome
1st described
by Dr R.S Crow
in 1956 and
then By Dr
M.Fukase in
1968

77. TO BE CONTINUED….