Molecular Imaging in Multiple Myeloma

138 Pages·2019·9.979 MB·English

by  Cristina Nanni, Stefano Fanti, Lucia Zanoni

Molecular Imaging
in Multiple Myeloma
Cristina Nanni
Stefano Fanti
Lucia Zanoni
Editors
123
Molecular Imaging in Multiple Myeloma
Cristina Nanni • Stefano Fanti • Lucia Zanoni
Editors
Molecular Imaging
in Multiple Myeloma
Editors
Cristina Nanni Stefano Fanti
Department of Metropolitan Department of Metropolitan
Nuclear Medicine Nuclear Medicine
Policlinico S.Orsola-Malpighi Policlinico S.Orsola-Malpighi
Bologna Bologna
Italy Italy
Lucia Zanoni
Department of Metropolitan
Nuclear Medicine
Policlinico S.Orsola-Malpighi
Bologna
Italy
ISBN 978-3-030-19018-7 ISBN 978-3-030-19019-4 (eBook)
https://doi.org/10.1007/978-3-030-19019-4
© Springer Nature Switzerland AG 2019
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Contents
Multiple Myeloma: Clinical Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Paola Tacchetti and Michele Cavo
What Does a Clinician Need from New Imaging Procedures? . . . . . . . . . . 15
Elena Zamagni
FDG PET in Multiple Myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Bastien Jamet, Clément Bailly, Thomas Carlier, Anne-Victoire Michaud,
Cyrille Touzeau, Philippe Moreau, Caroline Bodet-Milin, and Françoise
Kraeber-Bodéré
Role of Standard Magnetic Resonance Imaging . . . . . . . . . . . . . . . . . . . . . 39
Eugenio Salizzoni, Alberto Conficoni, and Manuela Coe
Whole Body Diffusion-Weighted Magnetic Resonance Imaging:
A New Era for Whole Body Imaging in Myeloma? . . . . . . . . . . . . . . . . . . . 73
Christina Messiou and Dow-Mu Koh
CXCR4 Imaging in Multiple Myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
M. I. Morales, C. Lapa, and A. K. Buck
PET/CT with Standard Non-FDG Tracers in Multiple Myeloma . . . . . . . 93
Cristina Nanni
The Issue of Interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Cristina Nanni
Clinical Teaching Cases: FDG PET/CT . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Cristina Nanni, Lucia Zanoni, and Stefano Fanti
v
Multiple Myeloma: Clinical Aspects
Paola Tacchetti and Michele Cavo
Definition
Multiple Myeloma (MM) is a plasma cell (PC) disorder characterized by clonal
proliferation of malignant PCs (Fig. 1) in the bone marrow (BM) or, more rarely, in
extramedullary tissues. Neoplastic PCs typically synthesize monoclonal proteins
(M-protein), which can be either intact immunoglobulins (Ig) or free light chains
(FLC).
Fig. 1 Multiple myeloma.
Cytology from aspirate. It
showed an accumulation of
plasma cells, characterized
by the presence of an
abundant basophilic
cytoplasm and a small
eccentric circular core,
with chromatin plates and
arranged radially,
surrounded on the
cytoplasmic side by a less
basophilic area (plasma
arc)
P. Tacchetti · M. Cavo (*)
Seràgnoli Institute of Hematology, S.Orsola-Malpighi University Hospital of Bologna,
University of Bologna, Bologna, Italy
e-mail: [email protected]; [email protected]
© Springer Nature Switzerland AG 2019 1
C. Nanni et al. (eds.), Molecular Imaging in Multiple Myeloma,
https://doi.org/10.1007/978-3-030-19019-4_1
2 P. Tacchetti and M. Cavo
Pathophysiology and Pathogenesis
The original cell of MM has not been yet recognised. The target of the neoplastic
transformation is likely a B-lineage cell and the presence in peripheral blood of B
lymphocytes clonally related to the transformed PCs strongly suggests that the two
types of cells might have a common origin [1]. Both are derived during antigen-
dependent maturation in the follicular germinative centre, which takes place in sec-
ondary lymphoid organs (lymph nodes). Indeed, a common Ig gene somatic
hypermutation pattern can be observed in the two kinds of cell types. Neoplastic
B-lymphocytes subsequently migrate from lymph nodes to BM, where they directly
interact with both stromal cells and extracellular matrix. The presence of adhesion
molecules on B-lymphocytes surface enhances their interaction with receptors on
stromal cells, thus exposing tumor cells to cytokines released from stromal cells and
extracellular-matrix. The most crucial cytokine involved in MM growth – both in
vivo and in vitro – is IL-6. It exerts both a proliferative and an anti-apoptotic activity,
and activates osteocla stogenesis. IL-6 production by BM stromal cells is increased
as a consequence of the direct contact with PCs, which, in turn, are stimulated by
stromal cells to produce other cytokines such as IL-1β, TNF-α and β and
M-CSF. These cytokine signals activate stromal cells, other accessory cells and
osteoclasts. Neoplastic PCs stimulate BM angiogenesis as well, throughout the pro-
duction of VEGF (Vascular Endothelial Growth Factor) and FGF (Fibroblast
Growth Factor).
Karyotyping reveals cytogenetic abnormalities in 20–30% of patients, those
being mainly numerical abnormalities. The introduction of more sensitive tech-
niques as FISH (Fluorescent in Situ Hybridization), CNAs (Copy Number
Alterations) analysis by SNPs (Single Nucleotide Polymorphisms) array and NGS
(Next Generation Sequencing) have improved the resolution of genomic analysis
allowing for the detection of genomic aberrations in virtually all newly diagnosed
patients. As a result, MM is now recognized to be a much more heterogeneous and
complex disease then previously thought, placing the malignancy at the boundary
between solid and haematological tumours.
Primary events are chromosome translocations involving the Ig heavy chain
(IgH) locus, and hyperdiploidy with multiple copies of odd-numbered chromo-
somes. IgH translocations are observed in 40% of cases. Frequently involved part-
ner chromosomes/loci are 4p16 (FGFR3/MMSET) (12–15%), 11q13 (CCND1)
(15–20%), 16q23 (MAF) (3%), 6p21 (CCND3) (5%), and 20q11 (MAFB) (1%).
Hyperdiploidy occurs in 50% of newly diagnosed MM. Trisomies and IgH translo-
cations are considered primary cytogenetic abnormalities. Secondary cytogenetic
abnormalities arise along the course of MM, and include gain(1q) (CKS1B,
ANP32E) (40%), del(1p) (CDKN2C, FAF1, FAM46C) (30%), del(17p) (TP53)
(7%), del (13) (RB1, DIS3) (44%), RAS mutations, and secondary translocations
involving MYC. Both primary and secondary cytogenetic abnormalities can influ-
ence disease course, response to therapy, and prognosis. The International Myeloma
Working Group (IMWG) [2] recommends the use of FISH to define the cytogenetic
Multiple Myeloma: Clinical Aspects 3
risk. According the IMWG consensus statement t(4;14), t(14;16), t(14;20), and
del(17/17p) and any nonhyperdiploid karyotype are high risk cytogenetic abnor-
malities; moreover, gain(1q) is associated with del(1p) carrying poor risk.
Whereas FISH analysis continues to have an important diagnostic role in MM
due to its widespread availability, newer technologies are primarily employed in
clinical research. High throughput sequencing can detect a wider spectrum of
genomic aberrations, including point mutations, gene expression deregulation and
CNAs. Nonetheless, the prognostic significance of these aberrations is still not well
understood, even if it is likely they will eventually be included in genomic markers
of higher-risk disease. One of the more striking observations highlighted as a con-
sequence of the use of high throughput sequencing is the presence of genomically
variable subclones within the same patient within any given disease phase. This
intra-clonal heterogeneity tends to change during the disease course, leading to the
emergence of new clones, which might be different in different phases [3]. These
modifications follow an evolutionary logic, with therapy acting as selective pres-
sure, leading to the selection of the fitter clone, as compared to the less adapted,
which is eliminated. This clonal dynamic has been described also in several solid
tumours, as well as in other haematological malignancies and may be an important
factor underlying therapy resistance and mechanisms for disease progression.
Therefore, the analysis of samples collected in different disease phases is manda-
tory and provides a more complete picture of the patient’s genomic landscape dur-
ing disease progression.
Epidemiology and Etiology
MM accounts for approximately 1% of neoplastic diseases and 13% of hematologic
cancers, accounting for 0.9% of all cancer deaths [4, 5]. In Western countries, the
annual age-adjusted incidence is 5 cases per 100,000 persons. Lifetime risk of being
diagnosed with MM is about 0.7%. The frequency of MM increases with age and
reaches a peak in the 6th–seventh life decades. The median age of the population
affected is about 70 years old, and less than 10% of all patients come to the diagno-
sis between the second and fourth decades of life. The prevalence is higher in males
as compared to females (1.3:1.0) and in black race as compared to the white (ratio
2.0: 1.0). The incidence in the latter population is higher than that observed among
Asians who live in the same geographic areas. Both genetic and environmental fac-
tors are hypothesized to explain racial differences in the incidence of the disease.
The main known risk factors are occupational exposure to pesticides, petroleum and
ionizing radiation.
MM may develop de novo or, most commonly, represents the progression of a
preceding monoclonal gammopathy of undetermined significance (MGUS). This
last evolutionary model is virtually the basis of almost all MM cases, as evidenced
by studies conducted on large series of healthy individuals and with long follow-
up [6].
4 P. Tacchetti and M. Cavo
Clinical Features
MM onset is clinically asymptomatic in 10–20% of cases and is detected by chance
during routine laboratory examinations. In patients with a prior history of MGUS,
the progression is characterized by the increse in serum and/or urinary M-protein,
and medullary plasmacytosis, with consequent transformation in MM. In the
remaining 80–90%, the most common symptoms, for frequency and severity, are
skeletal involvement, renal failure, infectious morbidity, myeloid failure, hypercal-
cemia, neurological complications, hyperviscosity syndrome and amyloidosis.
Regardless of the presence of organ damage, MM is defined as active or symptom-
atic when at least one of the following conditions (defined as CRAB criteria)
(Table 1) are present: hyperCalcemia, Renal failure, Anemia, or Bone lesions.
Recent guidelines identify as myeloma defining events, also biomarkers of malig-
nancy (as markers of early evolution to organ damage, i.e. more than 80% of risk
within 2 years) defined as: high medullary plasmacytosis (≥60%), and/or high
serum FLC (sFLC) ratio (involved/uninvolved ≥100), and/or presence of more than
one focal lesion identifiable with nuclear magnetic resonance (MRI) [7]. MM cah-
racterized by the presence of at least one of CRAB criteria or biomarkers of malig-
nancy, requires the start of treatment. Conversaly, if the diagnostic criteria of MM is
present without CRAB or biomarkers of malignancy, the disease is called smolder-
ing MM. Although smoldering MM represents a disease in neoplastic phase, it does
not require immediate therapy.
Skeletal Involvement
Up to 80% of MM patients present with osteolytic bone lesions at diagnosis and
have an increased risk of skeletal-related events associated with increased morbidity
and mortality. Approximately 60% of myeloma patients will develop a fracture dur-
ing the disease course. The most commonly affected sites are those rich in BM,
including the spine, ribs, pelvis, skull, and long bones. Radiologically, the classical
aspect of osteolysis is that of a round lesion with sharp margins, well-defined, in the
absence of surrounding signs of new bone formation and/or periosteal reaction. In
Table 1 CRAB criteria
C Hypercalcemia (serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of
normal or >2.75 mmol/L (>11 mg/dL)
R Renal impairment (creatinine clearance <40 mL per min (measured or estimated by validated
equations) or serum creatinine >177 μmol/L (>2 mg/dL))a
B Osteolytic lesions, demonstrated with one of the imaging methods available (whole body X
ray, PET/CT, MRI, WBLDCT)
Necessary at least one criterion for the definition of active MM, deserving treatment
aExcluding other causes of kidney failure not related with gammopathy, such as diabetic or cardio-
vascular nephropathy, or others. If a diagnostic dilemma sussists, a kidney biopsy is recommended
Multiple Myeloma: Clinical Aspects 5
the vertebrae one can often find crushing aspects and wedging of the body (vertebral
fractures). Bone disease is the major cause of morbidity in patients. The basis of the
pathogenesis of myeloma-related bone disease is the uncoupling of the bone-
remodeling process. The interaction between myeloma cells and the bone microen-
vironment ultimately leads to the activation of osteoclasts and suppression of
osteoblasts, resulting in bone loss [8]. Studies in transgenic mice have shown that
the enhanced osteoclastic activity is caused by an alteration in the balance between
the production of RANK-L and osteoprotegerin (OPG). RANK (Receptor Activator
of Nuclear factor KB) is a transmembrane receptor, belonging to the superfamily of
TNF receptors, predominantly expressed on osteoclast precursors and mature osteo-
clasts. Its ligand, RANK-L, is produced by several cells in the bone marrow micro-
environment and lymphoid cells. The RANK-RANK-L bond promotes the
differentiation maturation, proliferation, activation of osteoclasts and may inhibit
apoptosis of mature osteoclasts. The activity of RANK is inhibited by OPG, which
acts as a “bait” receptor for RANK, preventing its activation by RANK-L and con-
sequently inhibiting the proliferation and maturation of osteoclasts, as well as their
activity. Many cytokines, growth factors and hormones, including parathyroid hor-
mone, influence the level of RANK-L and OPG, to regulate the activity and differ-
entiation of osteoclasts. In MM, the balance between OPG and RANK-L is altered
by several cytokines, including IL-1ß, IL-6, TNF-α, TGF-ß, which increase the pro-
duction of RANK-L and reduce the production of OPG, inducing osteoclastogene-
sis. Notch signaling pathway is actively implicated in MM-induced
osteoclastogenesis. The net effect of Notch activation is the production of the osteo-
clastogenic factor RANKL by MM cells. At the same time, the osteoblastic activity
is suppressed by inhibition of the differentiation of precursors into functional mature
cells, via inhibition of the transmission of Runx2/Cbfa1 signaling and down-
regulation of genes that encode for the WNT signaling, which is essential for osteo-
blast maturation. Numerous cytokines (IL-3, IL-7, IL-6) and soluble factors
(Dickkopf-1 and secreted frizzle related proteins), produced by the interaction of
PCs with the BM microenvironment, are responsible for inhibition of differentiation
and maturation of osteoblasts.
Kidney Involvement
Renal impairment is the second most common and most severe complication of
MM. It presents in approximately 20% of patients at the time of diagnosis, while
another 20–30% of patients develop renal impairment during the course of their
disease [9]. The pathogenesis of renal failure in MM is multifactorial. First, and
most importantly, it is due to urinary excretion of monoclonal light chains (Bence
Jones proteinuria), that causes damage to tubules and/or glomeruli by three different
mechanisms a) intra-tubular precipitation; b) direct damage of the tubular epithe-
lium by monoclonal light chains or lysosomal enzymes; c) deposition of monoclo-
nal light chains along the basement membrane of the glomeruli and tubules.