Plasma cell myeloma pathology (1)

Plasma cell disorders
Pathology
Mbbs 2

1. h
.
d.~
Heavy-c a1n 1sease
• Rare disorder
• Bone marrow shows variable increase in plasma cells
• In Heavy chain disease,
there is synthesis and secretion of free H chain
fragments.
•
It is seen in a diverse group of disorders including
• CLUSLL,
• Lymphoplasmacytic lymphoma,
•
An unusual small bowel lymphoma that occurs in malnourished populations.

2. Waldenstrom macroglobulinemia
(Lymphoplasmacytic lymphoma)
• It is rare B cell lymphoproliferative disorder, characterised by
lymphoplasmacytic proliferation in
marrow with secretion of lgM
Monoclonal protein
• Classic features are anemi a, lymphadenopathy, hepatosplenomegaly &
features of hyperviscosity syndrome t,
• WHO classification has grouped it under lymphoplasmacytic lymphoma
• So, WM is lymphoplasmacytic lymphoma with bone marrow involvement &
lgM monoclonal gammopathy.

3. • It inevitably progresses to multiple myeloma, although
progression can
take I O -20 years o► longer.
• Progression
to classic MM is commoner in patients with
solitary osseous plasmacytoma then in extraosseous
plasmacytomas.

4. Solitary Myeloma (Plasmacytoma)
• About 3-5% of plasma cell neoplasms present as a solitary lesion of
either bone or soft tissue.
•
The bony lesions, with single localised collection of plasma cells in
bone, tend to occur in the same lo~tions as in multiple myeloma.
• Extraosseous lesions- in the lungs, oronasopharynx or nasal
sinuses.
• Modest elevations
of M proteins in the blood or urine may be found
in some patients.

5. MGUS
I~
J

6. MGUS Vs Smoldering MM Vs Multiple Myeloma
Investigations MGUS
Bone marrow <10%
plasma cells
M component <30g/L
Lytic lesions
in No bony lesions
bones
Myeloma related Not present
organ damage/
CRAB
Myeloma defining Not present
event
Smoldering
MM
>10-60%
>30g/L
No
bl.'y
lesions
Not present
Not present
Multiple myeloma
>60°/4 clonal or > 10%
clonal plasma cells
with CRAB/
MOE
>35g/L
Present
Present
Present

7. Indolent myeloma
• Have upto 3 lytic bone lesions without bone pain
• Marrow plasmacytosis I 0-30 % ~
• M component at intermediate levels
• No anemia, Normal calcium & creatinine levels

8. Asymptomatic/ Smoldering MM
• It is an intermediate stage between MGUS and MM, (formerly known as
smoldering multiple myeloma). ~
• Clonal bone marrow plasmacytosis: I 0-30%
• Serum M component > 3gm%
• Patients are asymptomatic, without any anemia or lytic bone lesions,
• No
myeloma related end organ damage (CRAB)
• 75% of patients progress to MM ov,er a period of 15 years

9. • Approx I% of patients with MGUS progress to an overt muftipfe
myef oma per year. Therefore, it is considered pre-neopfastic
condition.
• Life long foHow up
with serum M component levef s and Bence Jones
protein
in urine is warranted.

10. Monoclonal Gammopathy of
Undetermined Significance (MGUS)
• MGUS is a relatively benign proliferation of plasma cells resulting in secretion of
Monoclonal proteins
• It is the m/c plasma cell dyscrasia, occurring in about 3-5% of patients > 70 yrs of
age.
• Patients with MGUS have
•
<3 gm/dl of monoclonal protein in the serum
• No Bence Jones proteinuria,
• Clonal BM plasma cells < I 0%,
• Patients r asymptomatic, with
no features of myeloma associated end organ damage,
• No bone lesions on skeletal survey.

11. CLINICAL VARIANTS
• Non-secretory myeloma: rare (I%), myeloma cells synthesize lgs but do not
secrete lgs in plasma, so, lg levels are not increased, therefore M component is absent
• lg
is demonstrated in cytoplasm of myeloma cells by IF or lmmunoperoxidase
studies
• Have
low incidence of renal insufficiency
• Lytic bone
IEt! ons are present, bone marrow reveals increase in plasma cells.
• Plasma cell leukemia: when plasma cells in PBF have a count >2x I 0
9
/L or >20% of
differential count.
-Represent
terminal stage of MM.

12. Treatment
• Despite advancement in therapy of myeloma, it is still incurable disease
• Asymptomatic myeloma patients do
not require therapy
• The main aim
is to have prolonged progression free survival &
symptomatic improvement.
• Treatment
is started if there is evidence of end organ damage (CRAB)
• Melphalan,
~ednisolone
• Bisphosphonates (inhibitors of osteoclast mediated bone resorption)
• Bone marrow stem cell transplantation.

13. Prognosis
• Prognosis is variable; median survival is 4-7 years.
• Patients
with multiple bony lesions, if untreated, rarely survive for more than 6-12
months,
• Translocations involving cyclin
DI are associated with a good outcome,
• Poor prognostic factors are
• Deletions of~3q, I 7p, and the t(4; 14)
• High
tumour load, Higher stage of MM
• Diffuse pattern of marrow involvement
• Raised ~2 microglobulin levels, High
S. creatinine

14. Durie-Salmon staging system
• International staging system, developed over 40 years ago to provide
a practical way to measure MM tumor burden
• Patients are categorized as stage I, II or Ill depending on the degree
of anemia. hypercalcemia. levels of M protein in the serum and urine.
and bone lesions.
~
• In addition, stages are further divided into category A or B if serum
creatinine is <2 mg% or ~2mg%.

15. Diagnosis
• The diagnosis depends on the
• Identification of abnormal monoclonal plasma cells in
the
bone marrow,
• M protein in
the serum or urine on electrophoresis,
• Evidence
of end-organ damage
\.
• Clinical picture consistent with MM

16. Serum protein electrophoresis
Albumin ~ a
2 P
y
A. NORMAL SERUM PATTERN
Polydooal immuooglobolins
('Middle panel')
Albumin ~ ~ p
B. BENIGN POLYCLONAL
GAMMOPATHY
y
Myeloma(M)-band
('Bottom panel')
Albumin ~ <iz
C, MONOCLONAL GAMMOPATHY
(PLASMA CELL MYELOMA)
y

17. -
AL a Cllt
T.,. • -6.AO_._.
A.a. -3_s,
_, -0..23
_, -o.-
• - '.30
,... -o ....
•
~or••Ial Electrophoretic Pattern
•Pe1·formed on serum or urlne
• In this procedure, proteins separated by electrophoresis within gel, are reacted with speclflc antisera.
After extensive washing
of the gel, only proteins that are cross-linked b;v antlsera are retained.
-

18. • Urine examination for presence of Bence Jones proteins.
• Electrophoretic studies on Serum or urine: to screen patient for
presence of monoclonal immunoglobin or M band
• In 99%
of patients, there is increased levels of M lgs in the blood and/or
light chains, i.e. Bence Jones proteins, in the urine
• lmmunofixation: done to confirm the suspected monoclonal lg and classify
it.
The most common serum monoclonal lg is lgG (in 55% of pts), lgA-25%.
• Serum
free light chain assay,
• Imaging studies incluiJng X-rays, MRI, CT Scan to identify bone lesions.

19. Investigations
• PBF:
• Anemia; normocytic normochromic with rouleaux formation
• TLC, DLC is normal, Raised ESR
• Platelet count normal with increased bleeding time
• Bone marrow shows increased number of plasma cells (30-90%),
• Raised
S. calcium due to extensive osteolytic lesions
• Renal function tests are abnormal,
~
• Raised ~2 microglobunn levels indicating high tumour load.

20. Clinical features
• In early stages, patient complains of weakness, fatigue & weight loss,
• Later, various clinical manifestations
are
• Pallor
• Bone pains, pathological
fractures, leading to Hypercalcemia due
to bone resorption,
• Neurological manifestations like confusion, lethargy
~ • Recurrent infections ( due to decreased production of normal lg)
• Bence Jones proteinuria, Renal failure
• Hypergammaglobinemia, Hyperviscosity
in lgM myeloma

21. Clinical features
• Insidious onset
• The clinical features are due to the effects of
• Infiltration of organs, particularly bo~es, by
the neoplastic
plasma cells;
•
Production of excessive immunoglobulins,
•
The suppression of normal humoral immunity.

22. • With progressive disease, plasma cell infiltrate is seen in spleen,
liver, kidneys, lungs, lymph nodes or other soft tissues.

23. • Cytologic variants are d/t abnormal synthesis and
secretion of lg, which leads to intracellular accumulatio
of intact or partially degraded lg. Such variants include
• Flame cells with fiery
red cytoplasm;
•
Mott cells having multiple, blue, grapelike cytoplasmi
droplets;
~
• Russell bodies (have cytopfasmic inclusions) or
• Dutcher bodies (nuclear inclusions)
, I
•

24. • Neoplastic plasma cells like t'eir benign counterpart usually
have a perinuclear clearing
and an eccentrically placed nucleus.
• C. .
• •
•
•

25. • Bone marrow examination reveals increased number of
monoclonal plasma cells, plasmablasts (with vesicular nuclear
chromatin
& a prominent single nucleolus), or bizarre,
multinucleated cells ( I
0-90%).
• Plasma cells infiltrate the marrow diffusely or in sheets that
com lace normal hemato oietic elements.
,, .
•
·-
(. I
!Vo

26. ----------=----------------
• High level of serum M proteins causes red cells in smears of
peripheral blood to appear as a stack of coins, referred to as
rouleaux formation. Although characteristic, it
is not specific.
• Rarely,
tumor cells flood the peripheral blood, giving rise to
Plasma cell leukemia. . ~
3
• -·
;. . ......... ✓~ .
~ -. o<i)
(._r' 0 •
-~ ~

28. Morphology
• MM presents most often as multifocal, destructive bone lesions
composed of plasma cells throughout the skeletal system.
•
Most commonly affects axial skeleton bones & other bones including
• Vertebral Column, Ribs, Skull, Pelvis, Femur, Clavicle
& Scapula.
•
The bone lesions appear radiographically as punched-out defects,
usually 1-4 cm in diameter. ~
~
• Lesions begin in the medullary cavity, erode cancellous bone and
progressively
destroy the bony cortex, often leading to pathologic
fractures.

29. Revised IMWG criteria for diagnosis of Multiple
Myeloma (20 14)
• Out of proposed 3 myeloma defining events (MDEs) one
must be present regardless of presence or absence of CRAB
features.
These are:
• ~60% clonal plasma cells in BM
• Involved/ uninvolved free light chain ratio > I 00
·>I focal lesion on MRI (~Smm in size)

30. Diagnostic criteria for multiple myeloma
(IMVfG 2011)
• Clonal plasma cells ~ I 0% on bone marrow biopsy,
•
Monoclonal protein in serum or urine,
• Evidence
of myeloma related end organ damage (CRAB)
• HyperCalcemia (S. Ca> I I .5mg%)
• Renal insufficiency
(S. Creatinine> I. 9mg%)
~
• Anemia (Hb< I Ogm%)
• Lytic Bone lesions
• In absence
of end organ damage, clonal plasma cells>60%

31. • The proliferation & survival of myeloma cells is dependent on
various cytokines, like IL-6, which is produced by neoplastic plasma
cells and normal stromal cells
in the marrow.
•
IL-6 and MIP-1 a, activate osteoclasts, resulting in bone destruction
(the major pathological feature of MM).
• Other factors released from tumor cells, like modulators of Wnt
pathways, a~ potent inhibitors of osteoblast function.
•
The net effect is a marked increase in bone resorption, which leads
to hypercalcemia and pathologic fractures.

32. Etiology and Pathogenesis
• MM is associated with rearrangements involving lg Heavy chain gene
locus and various proto-oncogenes.
• Translocations involving
chr 14 with oncogene cyclin DI on chr I I q 13
and cyclin D3 on chr 6p2 I.
• Deletions of chromosome 17p (poor outcome).
• Plasma cell w.ukemia (a highly aggressive form of the ds) is associated
with rearrangements involving MYC gene.
• Mutations involving components
of the NF-KB pathway (which supports
B-cell survival).

33. Multiple Myeloma
• Multiple myeloma is a malignant neoplasm of plasma cells; B cell
neoplasm.
• Usually presents as multiple
tumor masses of neoplastic plasma
cells
scattered throughout the skeletal system.
• Accounts
for I% of all malignancies & I 0-20% of all hematologic
malignancits.
• It
is chiefly a disease of the elderly, with a peak age of incidence
around 65-70 years with slight male
preponderence.

34. MULTIPLE MYELOMA

35. ✓ Benign proliferations are important as there is increased risk
of their transformation to MM
✓ Of all the plasma cell dyscrasias, Multiple Myeloma is the
commonest & clinically most important.

36. Plasma cell Neoplasms/ dyscrasias
• Plasma cell dyscrasias are subclassified into 2 groups:
I. Malignant proliferations:
✓ Multiple myeloma
✓ Waldenstrom macroglobulinemia
✓ Solitary Plasmacytoma
✓ Heavy chain disease
2. Relative~ benign proliferations:
✓ Monoclonal Gammopathy of Uncertain Significance (MGUS)
✓ Primary amyloidosis
✓ POEMS syndrome-osteosclerotic myeloma

37. Plasma cell Neoplasms
• Monoclonal lg, or M component refers to structurally homogenous
proteins synthesized by neoplastic plasma cells.
•
These have high MW (~ 1,60,000), so they are restricted to plasma and
extracellular fluid and
are not excreted in urine in absence of glomerular
damage.
•
Neoplastic plasma cells synthesize complete immunoglobulins of same class,
with excess
of light chains or rarely, heavy chains.
•
In contrast, Polyclonal proteins are lgs of different types and are produced
in response to antigenic stimulation by various plasma cell clones during
infections, inflammatory conditions etc.

38. Plasma cell Neoplasms
• In immunoglobulins produced by normal plasma cells, the
production and coupling of heavy (H) and light (L) chains
are tightly balanced, but neoplastic plasma cells usually
synthesize excess of light chains or rarely, ~ chains.
• Light chains produced are either Kappa or Lambda
(never both) & Heavy chains are either alpha, gamma or
mu depending on particular class of immunoglobulins.
• Free light chains are
small in size, so are excreted in
urine. These light chains are known as Bence Jones
Light
Chain
Heavy
Chain

39. Plasma cell Neoplasms
• Normal plasma cells transform into malignant plasma cells
(known
as myeloma cells) and produce large quantities of
an abnormal immunoglobulins called Monoclonal proteins
(M component).
• Collectively, the plasma
cell neoplasms account for about 15%
of the deaths caused by lymphoid neoplasms.

40. Plasma cell Neoplasms
• Plasma cell neoplasmsare abnormal
pro11iferation of plasma cells and represent a
spectrum of diseases called plasma cell
dyscrasias.
• It
is associated with production of
monoclonal immunoglobulins (lgs), which
serve as tumour markers.
• Also known as
monoclonal gammopathy
paraproteinemias, dysproteinemia.
llultiplll,eloN
!lont-

41. Plasma cells
• Plasma cells, also called plasma B cells, are
white blood cells that originate in the bone
marrow and secrete large quantities of proteins
called antib\?ies in response to specific
substances called antigens.
• These cells
are large lymphocytes with abundant
basophilic cytoplasm, an eccentric nucleus,
perinuclear halo with characteristic
cartwheel
or clock face arrangement.
I

42. Blood stem cell
Myeloid stem cell
~
Lymphoid stem cell
Red blood
cells
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t
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Myeloblast Lymphoblast
" B lymphocY-!e JI ~
Granulocytes ~
Baaophll '9JY
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Neutrophll
Eoslnophll
@) ~ I
T lymphocyte killer cell
Plasma cell
Platelets
White blood cells
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43. COMPETENCY 20.1
Describe the features of Plasma Cell Myeloma