Page 1740 - Williams Hematology ( PDFDrive )

1714 Part XI: Malignant Lymphoid Diseases Chapter 105: Plasma Cell Neoplasms: General Considerations 1715

MARROW EXAMINATION varies between 30 and 70 percent, which leads to significant underesti-
Marrow aspirate and biopsy are essential in the workup of PCN. It is mation in diagnosing and staging of patients with myeloma. The skeletal
best not to rely solely on a marrow aspirate. Myeloma cells have the survey does not provide us with a direct image of the tumor cells, but
tendency to form small or large clusters and myeloma is not evenly dis- rather with the consequence of tumor cells being present or having been
tributed throughout the marrow. The marrow may be falsely negative present. Bone lesions in myeloma seldom heal and in most cases, there
in the presence of overt myeloma. In a normal marrow with normal is no healing at all or at the most there is a sclerotic rim around the bone
cellularity, there may be up to 2 percent plasma cells present. However, lesion. Therefore, a skeletal survey is not a good technique to assess
the percentage of plasma cells can be much higher in reactive marrows response to treatment or to diagnose early recurrence of myeloma.
and hypoplastic or aplastic marrows in the absence of PCN. In a normal Much better imaging techniques have become available in the form
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marrow, there can be some clustering of plasma cells around the blood of F-fluorodeoxyglucose positron emission tomography–computed
vessels. However, the presence of larger clusters of plasma cells away tomography (PET/CT) and MRI. When used in combination, PET/CT
from the blood vessels should alert one to the possibility of PCN, espe- scan and MRI were found to have specificity and a positive predictive
cially myeloma. In addition to the morphologic examination, the biopsy value of virtually 100 percent, which is invaluable to clinicians assessing
slides should be stained with a CD138 monoclonal antibody, which is a the efficacy of intensive and expensive treatment approaches with the
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specific immune marker for plasma cells. If the diagnosis of PCN is not goal to cure myeloma.
clear based on morphology and CD138 staining, in situ hybridization
for cytoplasmic κ and λ should be used to evaluate whether the plasma Magnetic Resonance Imaging
cells are clonal (light-chain restricted). Between CT and MRI the latter is the more specific test. A complete
It is customary to perform flow cytometry, metaphase cytogenetics, MRI examination should include a series of sequences to permit iden-
and FISH analysis on myeloma samples. Flow cytometry at diagnosis tification of focal and diffuse marrow involvement, including spin echo
is mainly performed to identify aberrant surface markers on myeloma (T1 and T2 weighted), gradient echo (T2), and short T1 inversion
cells, which can be used subsequently to assess MRD. The identification recovery (STIR) sequences. MRI should include the axial bones with
of an accurate gating strategy is a critical component of a reproducible active hematopoiesis in adults (skull, spine, sternum, shoulders and
and sensitive immunophenotypic analysis. The best gating strategy uses upper humeri, pelvis, and upper femora). In a study from the University
a combination of CD38, CD138, CD45, and light scatter characteristics. of Arkansas for Medical Sciences, using these parameters and includ-
The previously used gating method of CD38 and CD45 decreases the risk ing 611 myeloma patients treated uniformly with tandem transplants,
of contamination with other cells, but excludes the CD45+ cells, which 74 percent had focal myeloma lesions compared with 56 percent on
can constitute the majority of the plasma cells. It is recommended that skeletal survey and 52 percent of patients with negative skeletal sur-
at least a four-color instrument be used, as at least two antigens (CD38 veys had focal lesions on the MRI. Resolution of the MRI focal lesions
and CD138) are required after the initial analysis with CD138, CD38, after treatment occurred slowly, but ultimately was seen in 60 percent
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CD45, and light scatter, to gate plasma cells accurately. When used for of patients and conferred a superior overall survival. MRI should be
MRD, at least 100 neoplastic plasma cell events should be acquired. used routinely for the staging, prognosis and response assessment of
CD56 and CD19 should always be assessed. CD56 is negative on normal patients treated with curative intent.
plasma cells but is positive on myeloma cells, while the opposite is true 18
for CD19. It is also recommended to stain for CD117 and CD20, which F-Fluorodeoxyglucose Positron Emission
are negative on normal plasma cells and can be aberrantly expressed on Tomography–Computed Tomography
myeloma cells. CD28 and CD200 are negative or only weakly expressed One of the major advantages of the PET/CT scan is that it allows assess-
on normal plasma cells, but can be strongly positive on myeloma cells, ing the presence of extramedullary myeloma, which is present in 6 per-
whereas CD27 and CD81 are strongly expressed on normal plasma cells, cent of the patients and associated with a significantly inferior overall
but weak or negative on myeloma cells. It is important to remember survival based on two large studies. In a study of 239 patients receiving
that there is no single marker that can systematically differentiate neo- uniform therapy, the presence of more than three fluorodeoxyglucose
plastic cells from normal plasma cells. Also, the percentage of plasma (FDG)-avid focal lesions was associated with a significantly inferior
cells detected by flow cytometry is typically lower than that found by overall and event-free survival. In contrast, complete FDG suppression
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morphology. The importance of metaphase cytogenetics and FISH prior to the first transplant conferred a significantly better outcome.
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analysis was outlined above in the section Techniques to assess cyto- These data were confirmed in an Italian study including 192 patients.
genetic information. However, metaphase cytogenetic analysis remains A PET-CR occurs earlier than a clinical CR and a MRI-CR happens
important and is the best marker to differentiate between stroma- much later and less frequently.
dependent (early) and stroma-independent (advanced) myeloma. The
metaphases with normal cytogenetics obtained in most patients with OTHER IMPORTANT TESTS
myeloma are derived from the remaining normal hematopoietic ele-
ments and not from the myeloma cells. If myeloma cells are stroma-de- β -Microglobulin
2
pendent, they will die soon after being removed from their supporting The serum β2-microglobulin (β2m) is one of the most important prog-
microenvironment, while stroma-independent myeloma cells are able nostic factors in myeloma; β2m is a small protein that associates with
to grow and divide in the absence of a supporting microenvironment. 148 human leukocyte antigen class I and is almost exclusively catabolized
in the kidneys. Its best-characterized function is to interact with and
stabilize the tertiary structure of major histocompatibility complexn
IMAGING STUDIES (MCH) class α chain. The main source of β2m in the serum is membrane
Bone disease is present in 70 percent of patients with myeloma at diag- turnover. It reflects tumor load and renal function; however, it predicts
nosis. A skeletal X-ray survey has long been considered the gold stan- survival irrespective of renal function and Durie-Salmon stage. The
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dard for assessing bone disease in myeloma. However, the sensitivity exact underlying biologic significance of β2m remains obscure, but
and specificity of a skeletal survey is low. At least 50 to 75 percent of interactions with drug resistance pathways may exist. β2m in high con-
trabecular bone must be lost to see a lytic lesion. The false-negative rate centrations retards the generation of monocyte-derived dendritic cells.
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Kaushansky_chapter 105_p1707-1720.indd 1715 9/18/15 9:45 AM