Ken's Notes

Plasmacytoma / Plasma Cell Myeloma

(multiple Myeloma)

Epidemiology:

Adults (rare < 30 y)

90% > 50 y
Median 70 y

10-15% of hematologic neoplasms
Black:white = 2:1
3.7 fold higher risk for individuals with a first degree relative with the disease
Chronic antigenic stimulation

Infection
Chronic disease

Risk factors (most have none):

Exposure to specific toxic substances
Radiation exposure

Common sites:

bone marrow
Extramedullary (ex. plasma cell leukemia)

Peripheral blood
Spleen
Liver
Pleural effusion
Ascites
CSF

Gross features:

multiple lytic bone lesions (disseminated BM involvement in most cases)
may be solitary (plasmacytoma)
may be extraosseous (extraosseous plasmacytoma) in advanced disease generally

focal tumoural masses

soft
gelatinous
fish-flesh
hemorrhagic

Histologic / Cytologic features:

plasmacytoid cells

mature forms indistinguishable from normal in some
pleomorphic / immature in some (rarely seen in reactive plasma cells)

more irregular nuclei than normal plasmacytes
multinucleated, polylobated, pleomorphic prominent in some
prominent nucleoli
dispersed nuclear chromatin
higher n:c ratio

plasmablastic (10%)
cytoplasm with:

abundant basophilic cytoplasm and a perinuclear hof (mature forms)
multiple pale blue white grape-like accumulations (Mott cells, Morula cells) maybe
cherry red refractive round bodies (Russell bodies) maybe
vermillion glycogen-rich IgA (flame cells)
overstuffed fibrils (Gaucher-like cells)
crystalline rods

BM:

Clonal plasma cell population

Usually > 10 % of nucleated cells in the marrow but no minimal level is designated
Barely incrased in some
Reactive process rarely reaches 30%

Interstitial clusters, focal nodules, or diffuse sheets

Normal is small clusters around BM arterioles
Tumoural mass displacing normal BM elements is strong evidence

Peripheral blood:

Rouleux formation is most striking
Leukoerythroblastic reaction in some
Small numbers of plasma cells (15%)
Marked plasmacytosis in PCL

Plasma cell leukemia (PCL):

Plasma cells > 2x10⁹/L or 20% of the leukocyte differential
Small plasma cells with relatively little cytoplasm often

May resemble plasmacytoid lymphocytes

Immunophenotype:

Marker:	Sensitivity:	Specificity:
Surface Ig (neg)
Cytoplasmic Ig (G, A, rare D, M, E, or light chain only)	85% of non-secretory
EMA	-/+
CD19, 20, 22 (NEG)	Nearly always CD19- Some may be CD20+
CD79a	usually
CD138		Excellent (rare to see in lymphomas)
CD38
CD56	67-79% (neg in PCL typically)	Excellent (rare to see in lymphomas, normal plasma cells should not stain)
CD45	-/+
HLA-DR	-/+
EMA	-/+
CD43	+/-
CD117	Maybe
CD52	Maybe
CD10	Maybe
Myeloid antigens	Occasionally
Monocytic antigens	Occasionally
Cyclin D1	Those with t(11;14)

Molecular features:

Clonal IgH and IgL gene rearrangements
High load of IGHV gene somatic hypermutation
Ig deletion (some)

JH segments and/or parts or all of chromosome 14 in patients with light chain only or Bence Jones proteinuria

Abnormal karyotype (1/3) (poor prognosis) (this is a gross underestimate of cytogenetic abnormalities in MM, due to low mitotic index in vitro and cryptic IGH rearrangements)

Significant shorter median survival
Higher frequency in PCL
Plasma cells have a low mitotic index in vitro

Complex cytogenetic abnormalities are common

~25% have only 1 or 2 abnormalities

Abnormal FISH (86% using IGH-FGFR3, IGH-MAF, IGH-CCND1, TP53, and 13q in one study) (90% numerical)

54% have abnormal FISH but normal G-banded metaphases

Translocations:

IGH (14q32) most frequently (55-70%) (early event)

t(11;14)(q13;q32) (15-18%)

CCND1-IGH
Good prognosis (also other CCND1 translocations)
Lymphoplasmacytic morphology

MAF (C-MAF) (16q23) (5%) (subtle by karyotype)

Poor prognosis

FGFR3/MMSET (4p16.3) (15%) (cryptic)

Poor prognosis (high risk)

CCND3 (6p21) (3%)

Good prognosis

MAFB (20q11) (2%)

Poor prognosis

IRF4 (6p25)
IRTA1/IRTA2 (1q21)
Others – many are cryptic
Secondary IGH or IGL translocations are associated with progression

MYC (progression)
NMYC (progression)

Gains:

1q (progression)
9q
12q
17q
18
22q

Losses:

-13, 13q or 13q14 deletions (poor prognosis?) (nearly 50%) (early event)
TP53 deletion (poor prognosis) (highest risk of all genetic subsets) (10% by FISH)
1p (progression)
X
6q
8
16
Y

Structural aberrations of:

22q11 (poor prognosis)
16p
16q
1p
1q
11q13
19q13
19p13
6q
17q
7q

3 main cytogenetic patterns:

Hyperdiploid (48-75 chromosomes) (early event) (30-50% of cytogenetically abnormal)

Gains in odd numbered chromosomes (3,5,7,9,11,15,19,21)
Gains in chromosome arms:

9q
15q
11q

Only infrequently have one of the 5 recurrent IGH translocations (9% of these)
-13 in 20% of these

Hypodiploid (20-35 % of cytogenetically abnormal) (poor prognosis)

-13 in 2/3^rd of these
t(14q32) (25 % of these)
-14 (42% of these)
t/del(22q) (34% of these)

pseudodiploid (20-35 % of cytogenetically abnormal

t(14q32) (up to 75%)
-13 (25 % of these)

Upregulation of one of the CCND genes (D1,D2,D3)

Overexpression

TC groups

8 groups based on initiating or early pathogenic events
Based on patterns of translocations (T) and cyclin (C) D overexpression

PCL:

Abnormal karyotype and higher incidence of unfavourable cytogenetics

Mutations:

Activating KRAS or NRAS (30-40%)

Early event in progression maybe
?MGUS to myeloma transition in some

TP53 mutation or deletion

Associated with progression

Mutations of genes resulting in activation of NF-kappa B pathway (progression)
FGFR3

Associated with progression in tumours with t(4;14)

Inactivation of p18^INK4c (progression)
Inactivation of RB (progression)
7 groups by unsupervised clustering by gene expression

Similar but not identical to TC groups
One of the seven groups defined by progression events that lead to increased proliferation

Other features:

Diagnostic criteria:

Symptomatic plasma cell myeloma:

M-protein in serum or urine
Bone marrow clonal plasma cells or plasmacytoma
Related organ or tissue impairment

CRAB:

Hypercalcemia
Renal insufficiency
Anaemia
Bone lesions

Hyperviscosity
Amyloidosis
Recurrent infections

Asymptomatic (smoldering) myeloma

M-protein in serum at myeloma levels (> 30 g/L) AND/OR 10% or more clonal plasma cells in bone marrow
No related organ or tissue impairment (CRAB as above), or myeloma-related symptoms

Median survival 15mo to 5y depending on stage

Progression to symptomatic or amyloidosis:

10% per year for 5 years
3% per year for next 5 years
1% per year for next 10 years

PCL is aggressive with short survival

Staging (Durie-Salmon):

Stage I:

Hgb > 10 g/dL
Ca <= 12 mg/dL
Normal bone X-rays or solitary bone lesion
IgG < 5 g/dL
IgA < 3 g/dL
Urine M-protein < 4 g per 24h

Stage II:

Not stage I or stage III

Stage III: (one or more of)

Hgb > 8.5 g/dL
Ca > 12 mg/dL
Advanced lytic bone lesions
IgG > 7 g/dL
IgA > 5 g/dL
Urine M-protein < 12 g per 24h

Further classified based on serum creatinine

(A) Serum creatinine < 2.0 mg/dL
(B) serum creatinine >= 2.0 mg/dL

Serum and / or urine M-protein (97%) (most cases > 30 g/L)

IgG 50%, IgA 20%, light chain 20%, IgD, IgE, IgM, biclonal < 10%)

Plasma cell leukemia tends ot be light chain only, IgD, or IgE

Decrease in polyclonal Ig (<50% of normal) (90%)
Monoclonal light chains in urine (~70%)

Hyperucicemia (> 50%)
Hypoalbuminemia (~15%)
Plasma cell leukemia:

Clonal PCs in PB exceeds 2x10⁹/L or 20% of the leukocyte count
Aggressive with short survival

Asymptomatic (smoldering) or symptomatic
Symptomatic:

Presence of end-organ damage

CRAB: hyperCalcemia, Renal insufficiency, Anaemia, bone lesions)
Renal failure: tubular damage from monoclonal light chain proteinuria

Osteoporosis
Fractures

Bone pain

Recurrent infections
Anemia due to BM replacement and renal damage with resultant loss of erythropoietin

References:

Swerdlow. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue. 4th ed. WHO Publications; 2008.
Blood. 2005;106: 3553-3558
Heim & Mitelman. Cancer Cytogenetics (2009)