Diagnostic and clinical considerations in concomitant bone marrow involvement by plasma cell myeloma and chronic lymphocytic leukemia/monoclonal B-cell lymphocytosis: a series of 15 cases and review of literature.
) (or multiple
/my·elo·ma/ () a tumor composed of cells of the type normally found in the bone marrow.
giant cell myeloma see under tumor (1).
) and chronic
n.pr See leukemia, chronic lymphocytic.
1. Chronic lymphocytic leukemia 2. Cholesterol-lowering lipid
) are both common
neoplasms, each constituting about 10% to 11% of all
hematologic malignancies. (1,2) Chronic lymphocytic leukemia/small
lymphocytic lymphoma is the most common type of
Hematology A malignancy of lymphoid and myeloid stem cells. See Chronic lymphocytic leukemia, Chronic myelocytic leukemia.
officially United States of America, republic (2005 est. pop. 295,734,000), 3,539,227 sq mi (9,166,598 sq km), North America. The United States is the world’s third largest country in population and the fourth largest country in area.
and the Western world (annual incidence of 6.75 and 3.65
per 100 000 males and females, respectively) (3) in which the abnormal
cells characteristically express CD5 and CD23 and involve the blood,
bone marrow, and lymph nodes. (4) Monoclonal B-cell
/lym·pho·cy·to·sis/ () an excess of normal lymphocytes in the blood or an effusion.
MBL Movimiento Bolivia Libre
is a recently recognized condition in which low levels of monoclonal B
cells are detected in blood of otherwise normal older adults, and the
incidence of this phenomenon may be at least 100 times higher than that
of CLL. (5-7) Small numbers of clonal B cells may be seen in fewer than
1% of bone marrow specimens from patients without overt lymphoma. (8)
Plasma cell myeloma constitutes about 0.8% of all new cancers worldwide
and also commonly involves the bone marrow. (2) Plasma cell myeloma,
CLL, and MBL all occur predominantly in older adults with a male
preponderance and have a significantly higher incidence in the developed
Despite their origin from mature B cells and similar epidemiology,
CLL and PCM have widely different clinical presentations, pathologic
features, treatment, and outcomes. Chronic lymphocytic leukemia/small
lymphocytic lymphoma has a variable, but typically
1. causing little pain.
2. slow growing.
1. Disinclined to exert oneself; habitually lazy.
ranging from 10 years to more than 25 years. (11,12)
Plasma cell myeloma follows a variable, but generally more aggressive
course, with a median survival of only 3 to 4 years. (2,10) Importantly,
these 2 hematologic neoplasms are treated by entirely different
Even though these 2 hematologic neoplasms are individually quite
common, it is rare to find them together in the same patient,
1. As stated or indicated by; on the authority of:
2. In keeping with:
large clinical series. (15,16) A little more than 50 patients showing
evidence of both CLL and PCM have been described in the
literature written in English since c.1450 by the inhabitants of the British Isles; it was during the 15th cent. that the English language acquired much of its modern form.
, most as case reports (17-44) and only 2 case series. (45,46)
Many prior reports do not address the pathologic
Determination of which one of two or more diseases with similar symptoms is the one from which the patient is suffering. Also called differentiation.
and the clinical implications of this dual involvement are not clear
from individual case reports. We present 15 new cases of concomitant
bone marrow involvement by PCM and CLL or MBL. We have also
comprehensively reviewed clinico-pathologic findings in previously
reported cases. From findings from both sources, we present practical
guidelines for differential diagnosis and the likely clinical outcome in
MATERIALS AND METHODS
After obtaining respective institutional review board approval, the
electronic databases of
A field in anatomical pathology concerned with examination of surgical specimens of tissues removed from living patients for the purpose of diagnosis of disease and guidance in the care of patients.
reports at 4 institutions
were searched, covering a 10-year period between 2000 and 2009, to
identify reports of bone marrow biopsies seen in which
and monotypic plasma cells were both identified. From the cases flagged
by the automated searches, a manual review of pathology reports was
conducted to identify cases of concurrent occurrence of [CD5.sup.+]
monotypic B cells and monotypic plasma cells. All available
and histologic preparations were reviewed along with flow cytometric,
1. pertaining to chromosomes.
2. pertaining to cytogenetics.
pertaining to or originating from the origin and development of the cell.
, and molecular diagnostic data. The available hematology
laboratory data and
adj relating to the process of radiography, the finished product, or its use.
and clinical information were reviewed
from the electronic hospital information systems at the respective
Additional immunohistochemical stains were performed as required.
Five-micron-thick sections of the bone marrow core biopsies were stained
for CD56 (clone TB01, Leica Microsystems, Bannockburn. Illinois) and
) is a city in California that was incorporated on January 23, 1956, from the merger of five smaller communities:
using established labeled polymer immunohistochemical staining
technique. The sections were cut and mounted on
/ad·her·ent/ () sticking or holding fast, or having such qualities.
or , C6H4(CH3)2
, and rehydrated in graded ethanols. Endogenous
/per·ox·i·dase/ () any of a group of iron-porphyrin enzymes that catalyze the oxidation of some organic substrates in the presence of hydrogen peroxide.
activity was blocked by immersion in 0.3% aqueous peroxide
for 15 minutes, followed by 2 washes in 1 x Tris-buffered saline (TBS)
for 5 minutes each. Slides were treated with a cocktail of 10 mmol/L
Tris and 1 mmol/L
see chelating agents.
pH 9.0 and heated in a pressure cooker for 2.5
minutes at 125[degrees]C, followed by a 20 minute cooling period. The
sections were then incubated for 1 hour at room temperature with the
primary antibody diluted in TBS. The negative control consisted of
substitution of the primary antibody in selected cases with mouse
immunoglobulin (Ig) G. This was followed by 2 washes in TBS and then
incubation with anti-mouse
antibody (Envision Plus, Dako Corp,
) for 30
minutes. The bound complexes were visualized by the application of
diaminobenzadine (Dako) containing 0.3%
chemical compound, H2O2, a colorless, syrupy liquid that is a strong oxidizing agent and, in water solution, a weak acid. It is miscible with cold water and is soluble in alcohol and ether.
substrate. After incubation, the sections were washed, lightly
/he·ma·tox·y·lin/ () an acid coloring matter from the heartwood of Haematoxylon campechianum; used as a histologic stain and also as an indicator.
or light green solution, washed again,
dehydrated, cleared, and cover slipped.
The online database PubMed, maintained by National Center for
Biotechnology Information, was searched for
member of the West Germanic group of the Germanic subfamily of the Indo-European family of languages (see Germanic languages). Spoken by about 470 million people throughout the world, English is the official language of about 45 nations.
describing case reports or case series of patients with concurrent or
sequential diagnosis of PCM and CLL. Complete versions of all selected
articles were obtained and the clinical and pathologic information was
abstracted from each and tabulated.
All clinical and pathologic information from the selected cases, as
well as from the published articles, was tabulated with Excel (
). The same software was used to apply
the t test. The Web-based software provided at
http://www.quantitativeskills.com/sisa/index.htm (accessed December 25,
2011) was used to perform the [
n a nonparametric statistic used with discrete data in the form of frequency count (nominal data) or percentages or proportions that can be reduced to frequencies.
] and Fisher exact tests, and
the GraphPad Prism (GraphPad Software, Inc,
, on the Pacific Ocean, S Calif., an uninc. district within the confines of San Diego; founded 1869. The beautiful ocean beaches, in particular La Jolla shores and Black’s Beach, and sea-washed caves attract visitors and
, California) was
used to perform a Kaplan-Meier survival analysis.
Clinical Features and Chronology of Disease Processes
Fifteen cases were identified in which the bone marrow showed
simultaneous presence of monotypic and/or atypical plasma cells and a
[CD5.sup.+]/[CD23.sup.+] monotypic B-cell population. The clinical
features in these patients are summarized in Table 1. There were 13 male
(86.6%) and 2 female patients. The median age was 74 years (range, 56-91
years). In eleven of 15 cases (73.3%), the initial presentation was
related to the
plasma cell dyscrasia
A lymphoproliferative disorder characterized by monoclonal proliferation of plasma cells, with clinical behavior ranging from innocuous extramedullary plasmacytomas to premalignant solitary plasmacytoma of bone to myeloma.
; but in all 11 of these, the first
bone marrow specimen obtained showed the presence of both abnormal
plasma cells and [CD5.sup.+] monotypic B cells. The plasma cell
dyscrasia was further characterized as symptomatic plasma cell myeloma
(PCM) in 8 patients and as smoldering (asymptomatic) myeloma in 3
patients. Among the patients with symptomatic PCM, the primary clinical
findings were related to pathologic fractures/lytic bone lesions in 6,
1. starchlike; amylaceous.
2. the pathologic, extracellular, waxy, amorphous substance deposited in amyloidosis, being composed of fibrils in bundles or in a meshwork of polypeptide
/ne·phrop·a·thy/ () disease of the kidneys.nephropath´ic
/poly·neu·rop·a·thy/ () neuropathy of several peripheral nerves simultaneously.
with weight loss and anemia
were the presenting features in 1 patient each. In 2 patients with
smoldering myeloma, an incidentally detected monoclonal gammopathy
bone marrow examination
, while the third patient had a
14-year history of stable monoclonal gammopathy with more recent
Leukocytosis is a condition characterized by an elevated number of white cells in the blood.
Leukocytosis is a condition that affects all types of white blood cells.
and an increasing level of the monoclonal
/para·pro·tein/ () a normal or abnormal plasma protein appearing in large quantities as a result of a pathological condition; term now largely replaced by M component.
1 patient with symptomatic PCM had a documented 5-year history of
monoclonal gammopathy preceding the diagnosis of PCM. In 4 of 15
patients (26.7%), the initial clinical and pathologic diagnosis was CLL,
preceding the diagnosis of plasma cell dyscrasia by 2 years or longer
(average, 34 months), and the bone marrow examination was performed to
rule out disease progression or to investigate a new finding of
monoclonal paraprotein in serum or urine. In 1 of these 4 patients (case
14), the CLL was in an advanced stage and required treatment, while the
other 3 patients with CLL had not received specific treatment for this
condition. Except for case 14, clinically detectable
/lym·phad·e·nop·a·thy/ () disease of the lymph nodes.
angioimmunoblastic lymphadenopathy , angioimmunoblastic lymphadenopathy with dysproteinemia
not noted in any patient.
Cardiology Blood circulating in the system/body
The peripheral blood findings at the time when the
A procedure in which cellular material is removed from the pelvis or breastbone and examined under a microscope to look for the presence of abnormal blood cells characteristic of specific forms of leukemia and lymphoma.
showed the 2 monotypic processes concomitantly are summarized in
Table 2. Peripheral blood counts are not available for 4 cases (cases 1,
2, 11, and 14) because the bone marrow biopsy was obtained at an outside
institution. For the remaining 11 cases, 6 patients (54.5%) were anemic
at the time of diagnosis. The mean hemoglobin level for the 11 cases was
12.1 g/dL (range, 10.1-15.5 g/dL). The platelet count was largely
unaffected with only 1 case having a platelet count of less than 150
000/[micro]L. Two of 11 patients (18.2%) had a circulating leukocytosis
(cases 8 and 13) with an absolute
see blood; immunity.
Type of leukocyte fundamental to the immune system, regulating and participating in acquired immunity. Each has receptor molecules on its surface that bind to a specific antigen.
count greater than 5000/
[micro]L. One of these patients had a diagnosis of CLL for 3.5 years,
while the other had a stable IgG monoclonal paraprotein for 14 years and
recent lymphocytosis. Three more patients (cases 5, 6, and 7) had
lymphocytosis of greater than 1500/[micro]L. Peripheral blood
was performed in 3 cases, including the 2 cases with greater
than 5000/[micro]L lymphocytosis (cases 8 and 13), which showed 52% and
59% circulating abnormal lymphocytes with the CLL phenotype. The third
case (case 3) showed only 2% abnormal circulating lymphocytes but the
marrow showed 10% abnormal B cells (see below).
Bone Marrow Findings
The salient bone marrow findings are summarized in Table 3. The
bone marrow cellularity varied from 30% to 90% (average, 53%) in the
whole group. The average bone marrow cellularity was similar in those
diagnosed first with PCM (54%) or with CLL (50%). The marrow was
moderately to markedly hypercellular for age in 7 of 15 patients, most
(6) of whom were initially diagnosed with PCM. The proportion of
abnormal plasma cells varied from 2% to 50% of total marrow cells
(average, 23%), while the [CD5.sup.+]/[CD23.sup.+] monotypic B cells
accounted for 0% to 50% of total cells (average, 17%). Neither type of
cells occurred at significantly different proportions when comparing
cases initially diagnosed as plasma cell dyscrasia or CLL. The
proportion of either type of abnormal cells or overall proportion of
abnormal cells did not correlate with marrow cellularity (
, [r.sub.2] < 0.01).
/re·tic·u·lin/ () a scleroprotein from the connective fibers of reticular tissue.
fibrosis was present around
/lym·phoid/ () resembling or pertaining to lymph or tissue of the lymphoid system.
Of or relating to lymph or the lymphatic tissue where lymphocytes are formed.
cells in 5 of 10 cases initially presenting as plasma cell
dyscrasia (reticulin stain was not performed in 1 case), but only in 1
of 4 cases with the initial diagnosis of CLL. Cytogenetics and/or
fluorescence in situ hybridization
A technique for diagnosing DiGeorge syndrome before birth by analyzing cells obtained by amniocentesis with DNA probes. FISH is about 95% accurate.
abnormalities were detected in 7 of
10 patients for whom data were available. Abnormalities including
deletions of 13q or 17p, and numeric abnormalities of chromosomes 11 or
12, were observed in 5 patients, generally in a small proportion of
total cells (3% to 15%). One case showed fusion of cyclin D1 and
IGH Institut de Génétique Humaine
IGH Institute of Gender and Health
IGH Immeuble de Grande Hauteur
IGH Institute for Global Health
gene and 1 patient had deletion of the
n a sex chromosome that in humans and many other species is present only in the male, appearing singly in the normal male. It is carried as a sex determinant by one half of the male gametes. None of the female gametes contain a Y chromosome.
Immunophenotypic Identification of the 2 Abnormal Populations
In every case, the abnormal B cells coexpressed CD5 and CD23,
either by flow cytometry (14 cases) or immunohistochemistry (1 case). In
10 of 15 cases, the abnormal plasma cells were restricted for
immunoglobulin [kappa] light chain and in the remaining 5 for [lambda].
For the [CD5.sup.+]/[CD23.sup.+] abnormal lymphocytes, flow cytometric
characterization of light-chain expression was available for 13
patients, while 1 case had essentially no surface immunoglobulin
light-chain expression and flow cytometry was not performed in 1 case.
The [CD5.sup.+]/[CD23.sup.+] B cells were [kappa] restricted in 8 of 13
cases and [lambda] restricted in 5 of 13. The distribution of
light-chain restriction between the plasma cells and lymphocytes is not
significantly different (P = .29, Fisher exact). In these 13 cases for
which light-chain restriction for both abnormal cell types was known,
the expressed light chains were different for the 2 populations in 6
cases and the same in 7 (both were [kappa] in 6 and [lambda] in 1). Both
immunohistochemistry and flow cytometry results are required for correct
diagnosis when the light-chain restriction by the 2 abnormal populations
is different but CD56 or cyclin D1 are not aberrantly expressed by the
plasma cells, as illustrated in Figure 1, A through H, and Figure 2, A
through D. Cyclin D1 overexpression occurred in the plasma cells in 8 of
14 cases (tissue was exhausted in 1 case and could not be tested). CD56
was aberrantly expressed in the plasma cells in 6 of 12 cases, along
with cyclin D1 expression in all but 1 case. In 4 of 6 cases for which
both abnormal B cells and plasma cells were [kappa] light-chain
restricted, the plasma cells were cyclin D1 positive and a fifth case
1-IGH fusion by fluorescence in situ hybridization in all plasma
cells. In the sixth case, the plasma cells aberrantly expressed CD56.
This immunoreactivity pattern identified the plasma cells as
constituting a plasma cell dyscrasia separate from the [CD5.sup.+]
monotypic B cells. In the case illustrated in Figure 3, A through F, the
abnormal plasma cells and B cells both showed [kappa] light-chain
restriction (not shown), but the 2 hematologic malignancies can be
clearly identified by the distinct
infiltrates of [CD5.sup.+] B
cells and [CD138.sup.+]/cyclin D1+ plasma cells. Overall, in 12 cases
the B cells and plasma cells were shown to be distinct monotypic
populations (6 by virtue of different light-chain restriction and 6 by
virtue of cyclin D1 and/or CD56 expression in plasma cells). In 3 cases,
the additional immunostaining was negative and the light-chain
restriction did not clearly differentiate the plasma cells and B cells
as separate clonal processes. In 1 case, the restriction was concordant
(k) and in 2 cases the B-cell light-chain restriction was unknown. In
these 3 cases, flow cytometric or immunohistochemical demonstration of
the [CD5.sup.+]/[CD23.sup.+] phenotype of the abnormal B cells was
important to rule out other differential diagnostic considerations (see
Five of 15 patients did not receive any specific treatment, 4 of
whom were diagnosed first with plasma cell dyscrasia. For these 4
patients, treatment was withheld per patient request either
Because of; on account of:
prep → ,
advanced age and/or because the disease was clinically stable. Seven of
11 patients who first presented with symptoms related to plasma cell
dyscrasia were treated with myeloma-specific therapy (melphelan,
, sleep-inducing drug found to produce skeletal defects in developing fetuses. The drug was marketed in Europe, especially in West Germany and Britain, from 1957 to 1961, and was thought to be so safe that
, lenalidomide, steroids, or localized radiation
in different combinations), even though [CD5.sup.+] monoclonal B cells
were documented in the marrow. Only 1 patient received additional
therapy directed at the monoclonal B cells (anti-CD20 antibody
rituximab). Two of 11 patients underwent
transplant, 1 with
1. having cell types that are antigenically distinct.
2. in transplantation biology, denoting individuals (or tissues) that are of the same species but antigenically
and one with
/au·tol·o·gous/ () related to self; belonging to the same organism.
cells. Only 1 of 4 patients initially
presenting with CLL received disease-specific treatment
/cy·clo·phos·pha·mide/ () a cytotoxic alkylating agent of the nitrogen mustard group; used as an antineoplastic, as an immunosuppressant to prevent transplant rejection, and to treat some diseases
and fludarabine). In another patient from this group,
anti-PCM treatment was given when abnormal plasma cells were later
detected. Follow-up information was available for 14 patients and
duration of follow-up varied from 1 month to 122 months (median, 6.5
months; average, 27.3 months). Three patients died; for 2, death was
disease related and for the third it was due to a third malignancy
). Eight of 11 patients initially presenting
with PCM and 3 of 4 presenting with CLL had a reduced amount of marrow
disease and/or clinically stable disease at last follow-up.
Plasma cell myeloma and CLL are the 2 most common B-cell
malignancies occurring in the older adult population. (1) Despite
largely overlapping epidemiologic features and origin from mature B
cells, simultaneous occurrence of both diseases in a patient is rare. A
study from the Mayo Clinic, (15) spanning 10 years, found 31 cases of
CLL with a second malignancy, but none of these was PCM. The authors
also conducted a literature review and noted that none of the 107 cases
of a second malignancy found in patients with CLL was PCM. In a large
A study that compares 2 groups of people who are alike except for one factor, such as exposure to a chemical or the presence of a health effect; the investigators try to determine if any factor is associated with the health effect
spanning 38 years and including 54 159 patients with
hematolymphoid malignancies from Sweden, only 3 cases of plasma cell
See lymphocytic leukemia.
were found together. (16) This low
incidence is remarkable because greater than 8000 patients each with
myeloma and lymphoid leukemia were included in this series and the total
number of second malignancies noted was 475 and 659 in myeloma and
lymphoid leukemia, respectively. In a recent German study (47) involving
589 consecutive patients with myeloma seen at a single institution in 11
years, 59 (10%) had a second
or tissue composed of cells that grow in an abnormal way. Normal tissue is growth-limited, i.e., cell reproduction is equal to cell death.
before, during, or after the
diagnosis of myeloma. Of these cases, 5 (0.84%) were CLL, while 6 cases
n See temporomandibular pain-dysfunction syndrome.
1 Maternal deprivation syndrome, see there 2 Myelodysplastic syndrome, see there
and 46 cases of solid tumors were seen in the same cohort. All
CLL cases occurred in males and the condition was diagnosed nearly 2
years before the diagnosis of myeloma. With the recognition of MBL, the
proportion of older adults having detectable monoclonal B cells with
CLL-like phenotype in the blood has dramatically increased (48) but, to
our knowledge, data on actual incidence of concurrent occurrence of PCM
and MBL are not available.
[FIGURE 1 OMITTED]
[FIGURE 2 OMITTED]
We have identified 30 case reports or case series published in the
English language literature describing CLL and PCM together in the same
patient. (17-46) During the span of 50 years covered by these reports,
51 total cases showing the presence of CLL and PCM in the same patient
are described. The salient findings from these studies are summarized in
Table 4. In comparing the published data to our findings, the
demographic profile of patients is similar (most are males in their
sixth or seventh decade of life), but in our series only 4 of 15 (26.7%)
were first diagnosed with CLL and then developed PCM, compared to 31 of
51 such cases (60.8%) in the published literature (P = .02, Fisher
exact). This difference is probably due to the case selection bias: we
selected cases from surgical pathology reports of bone marrow, while
many published reports have selected cases by clinical criteria. The
published literature reports a significantly higher proportion of
abnormal cells in the bone marrow than was observed in our series (46.6%
versus 16.5% CLL cells and 34.1 versus 23.1% plasma cells, P < .001
and P = .08, respectively, t test). Relevant data are missing in 12
published reports for CLL cells and in 7 reports for plasma cells. The
differences in the level of marrow involvement by PCM are difficult to
explain because they are unlikely to be the result of previous
treatment, which was given in a similar proportion of cases in our
series (73.3%) and published reports (66%).
On the other hand, the lower level of marrow involvement by
[CD5.sup.+] B cells seen in our series appears to be a consequence of
the method of case selection and the inclusion of patients with MBL in
our series. In the absence of extramedullary tissue involvement, the
diagnosis of CLL, according to the World Health Organization (WHO)
classification, (4) requires the presence of greater than 5000 monotypic
B cells per [micro]L in the blood, with a [CD5.sup.+] and [CD23.sup.+]
phenotype for at least 3 months. Notably, this definition differs from
earlier definitions that required the presence of 5000 lymphocytes per
[micro]L (rather than monotypic B cells). (49) According to the current
definition, the presence of fewer than 5000 monotypic B cells per
[micro]L is now categorized as MBL, provided there are no clinical or
laboratory features of lymphoma/leukemia.
It is now widely accepted that MBL is an extremely common
occurrence in older adults. (5,6,50) In about 75% of these cases, the
monoclonal B cells have the same phenotype as CLL cells. Only a minority
of MBL cases have absolute lymphocytosis of 1500/[micro]L or greater but
less than 5000/[micro]L and these are designated as “clinical
MBL” (cMBL). The incidence of cMBL is estimated at 0.6% to 0.9% in
persons older than 50 years (which is about 100 times higher than the
incidence of CLL, estimated at 5 to 6 cases per 100 000). Presence of
very low levels of monoclonal B cells (median, 1 monoclonal B cell per
[micro]L) without significant lymphocytosis is much higher, estimated to
affect 20% of otherwise healthy older adults in some European countries
such as Spain. These cases are detected by population screening with
high-sensitivity flow cytometry methods and are designated
“screening MBL.” (7,51) Perhaps all cases of CLL are preceded
by cMBL, but fewer than 1% of cMBL cases progress to CLL. (6) In 1
study, (52) the median level of bone marrow lymphocytes in cMBL was
found to be 20%.
In the 11 patients from our cohort for whom peripheral blood
findings were available, only 2 patients had abnormal B-cell
lymphocytosis at a level sufficient to fulfill the WHO definition of CLL
(cases 8 and 13). In addition to case 13, three other cases involved
patients who were earlier diagnosed with CLL (cases 12, 14, and 15). In
2 patients (cases 1 and 7), the level of [CD5.sup.+] monoclonal B cells
in the marrow was 30% or greater, which is significantly higher than the
of 20% monotypic B cells noted in cMBL, and these cases
also likely represent CLL rather than MBL. Thus, 7 patients in our
cohort appear to have CLL (cases 1, 7, 8, 12, 13, 14, and 15). The
remaining 8 cases are best considered as MBL. However, the actual
distinction between MBL and early-stage CLL may not be clinically
relevant as these 2 conditions are a continuum rather than discrete
entities. (48) Admittedly, the incidence of very-low-level MBL in
patients with PCM cannot be inferred from our study because
high-sensitivity flow cytometric detection of monoclonal B cells in the
blood is not performed routinely in every patient with PCM. Small
numbers of clonal B cells are detected incidentally in the bone marrow
at a low frequency. In a single center
a study in which a search is made for a relationship between one phenomenon or condition and another that occurred in the past (e.g.
, (8) fewer
than 1% of flow cytometry analyses of bone marrow specimens from
patients without a diagnosis of overt lymphoma contained 0.05% to 4.5%
(median, 1.28%) clonal B cells. Of these, fewer than a third had the CLL
phenotype and about a third of the total cohort subsequently developed
non-Hodgkin lymphoma. This rate of progression to overt lymphoma is much
higher than the approximately 1% rate of progression from cMBL to CLL.
(48) This may suggest that subclinical/undetectable lymphoma in
extramedullary locations may exist in a higher proportion of patients
showing low-level clonal B cells in the bone marrow than in those
showing low-level clonal B cells in the blood. Notably, none of the
patients in this study, in whom clonal B cells were incidentally
detected in the marrow, showed plasma cell myeloma in that or subsequent
[FIGURE 3 OMITTED]
While it is probably clinically not very significant to
differentiate cMBL from CLL in patients with concomitant PCM, it is
critical that this rare co-occurrence is correctly differentiated from
other causes of a lymphoplasmacytic infiltration in the bone marrow.
Most patients in published studies, as well as our cohort, required
treatment for PCM, while CLL/MBL was often managed without specific
treatment (Tables 1 and 4). On the other hand, hematologic malignancies
with a lymphoplasmacytic infiltrate may need lymphoma-specific
treatments. The differential diagnoses of a lymphoplasmacytic or
lymphoplasmacytoid infiltration in the bone marrow include at least 3
1. pertaining to a neoplasm.
2. pertaining to neoplasia.
pertaining to neoplasia or a neoplasm.
conditions: lymphoplasmacytic lymphoma (
) (also called
immunocytoma or Waldenstrom
/mac·ro·glob·u·lin·emia/ () increased levels of macroglobulins in the blood.
MZL Minimum Zone Line
) with plasmacytic differentiation, and CLL with plasmacytic
differentiation. The characteristic clinical, morphologic, and
immunophenotypic features useful in this differential diagnosis are
summarized in Table 5.
Deviation from the classic immunophenotype of the lymphoid
neoplasms included in this differential diagnosis may confound the
correct interpretation. While characteristically the small lymphocytes
in LPL are [CD5.sup.-], (53,54) from 5% to 43% of LPL cases may express
CD5, at least partially. (55-57) Asplund et al (58) reported 1 case of
LPL among 26 [CD5.sup.+] B-cell neoplasms with ambiguous
immunophenotype. Some of these [CD5.sup.+] LPL cases may have partial
expression of CD23 but other immunophenotypic features of CLL, such as
dim CD20 and dim surface immunoglobulin, (56,57) are absent and cyclin
D1 is not expressed. (58) The morphologic finding of
An antibody-producing lymphocyte derived from a B cell upon reaction with a specific antigen. Also called plasmacyte.
collections completely separated from the lymphoid collections can
occasionally occur in LPL, (57) which mimics the pattern seen in
concurrent marrow involvement by CLL and PCM (Figure 3, A), but the
plasma cells in LPL do not express cyclin D1 or CD56, (55) in contrast
to PCM cells, which expressed these markers in 53.3% and 42.8% of our
cases, respectively. The presence of an intimate mixture of lymphocytes
and plasma cells, reported in a prior case report of concurrent CLL and
PCM, (59) more closely resembles LPL and needs more careful
n. Abbr. w/u
A thorough medical examination for diagnostic purposes.
(Figure 1). The paraprotein is typically (but not
Not changing or subject to change; constant.
) IgM in
lymphoplasmacytic lymphoma. (56) The paraproteins produced by plasma
cells in our patients were either IgG or IgA, but among the published
reports, several cases include IgM-producing PCM, (26,36,44,45) and
patients with CLL can produce IgM paraprotein at levels overlapping
those of LPL. (60) Thus, the
An antigenic marker that occurs in all members of a subclass of an immunoglobulin class.
of the paraprotein is not a
1. One that discriminates.
2. Electronics A device that converts a property of an input signal, such as frequency or phase, into an amplitude variation, depending on how the signal differs from a
between LPL and concomitant PCM and CLL.
Of the 3 major types of MZLs (
/splen·ic/ () pertaining to the spleen.
Of, in, near, or relating to the spleen.
pertaining to the spleen.
, nodal, and mucosa-associated
splenic marginal zone lymphoma
bone marrow with any regularity, (61,62) but a significant proportion
(21%-74%) may show plasmacytic differentiation. (63,64) Up to 20% of
splenic MZLs can express CD5, (65) leading to difficulty in
distinguishing these cases from CLL; however, splenic MZL typically
shows strong expression of CD20 and surface immunoglobulin, which aids
in the distinction between these 2 entities.
/sple·no·meg·a·ly/ () enlargement of the spleen.
congestive splenomegaly Banti’s disease; splenomegaly secondary to portal hypertension.
can occur in
CLL, as well as splenic MZL, and cannot be used to distinguish the two.
Splenic MZLs lack expression of cyclin D1, (63) which is helpful to
separate them from
A class of proteins that fluctuate in concentration at specific points during the cell cycle and that regulate the cycle by binding to a kinase.
[D1.sub.+] plasma cell neoplasms occurring
concurrently with CLL. Rarely, a monotypic plasma cell proliferation can
occur in marrow involved by splenic MZL, and molecular study may be
necessary to identify the 2 monotypic populations if the light-chain
restriction is the same for both monotypic processes. (64) Chronic
lymphocytic leukemia/small lymphocytic lymphoma itself can show
lymphoplasmacytoid differentiation, but these cases lack true plasma
cells and may appear as “atypical” CLL. True plasmacytic
differentiation in CLL appears to be very rare and may only be seen in
. (66) Clinical and radiographic findings, such as
1. pertaining to lysis or to a lysin.
2. producing lysis.
1. Of, relating to, or causing lysis.
Hypercalcemia is an abnormally high level of calcium in the blood, usually more than 10.5 milligrams per deciliter of blood.
, non-IgM paraprotein, support a diagnosis of
PCM because these features are very rare in the lymphoid malignancies
discussed above (LPL, splenic MZL, and CLL). An erroneous diagnosis of
is a critical diagnostic
1. An unapparent source of trouble or danger; a hidden hazard:
if it is not
realized that the [CD5.sup.+] monoclonal B cells are separate from the
cyclin [D1.sub.+] plasma cells (Figure 3, D and F). Indeed, 1 of our
patients (case 2) was referred for treatment after an outside diagnosis
of mantle cell lymphoma. Conversely, the plasma cells may express CD20
in about 10% of cases (67) and may have a lymphocyte-like “small
cell” morphology in about 3% to 4% of cases. (68) When small plasma
cells express CD20 and CD45, along with cyclin D1 (which is seen in 75%
of “small cell” myelomas), distinction from mantle cell
lymphoma is facilitated by demonstrating the [CD138.sup.+] and
[CD5.sup.-] phenotype of the plasma cells. (68)
Are the [CD5.sup.+] abnormal B cells and monotypic plasma cells
occurring concomitantly in the marrow biologically related and what are
the clinical implications of this rare event? It is generally accepted
that normal plasma cells are terminally differentiated, specialized
cells arising from B cells, (69) and it is theoretically possible that
the monotypic plasma cells are further differentiated or transformed CLL
cells. But the 2 processes may arise independently from the same stem
cell or arise from different B cells purely coincidentally.
Interestingly, only 3 of 51 published reports, (17,44,45) and none of
our cases, show PCM preceding CLL (Table 4). Putative transformation of
CLL cells to plasma cells may be inferred only by showing clonal
identity between the 2 processes. Such clonal identity can be
established definitively by sequencing the rearranged immunoglobulin
heavy-chain genes from pure populations of each of the 2 abnormal cell
types, but these data are not available in most cases. Lacking molecular
data, we can use the well-known property of
in B cells
(70) to estimate clonal relatedness. Caution must be exercised when
interpreting such data, because
1. Not being the same; different.
2. Fraternal, as of twins.
light chains may
occasionally occur in clonal evolution. (24) In our cohort, information
for light-chain restriction of CLL and PCM cells was available for 13
cases: restriction was the same in 7 and different in 6 cases. In the
published reports, excluding the 3 cases first presenting with PCM,
(17,44,45) information for light-chain restriction of CLL and PCM cells
was available for 28 cases and the light-chain restriction was the same
in 15 cases and different in 13. A Kaplan-Meier survival analysis (data
not shown) in which the published cases and our cases were divided on
the basis of same or different light-chain restriction showed
statistically similar disease-specific median survival rates of 22
months and 28 months, respectively. Notably, these survival rates are
shorter than the 36- to 48-month survival seen in
myeloma. (2,10) Whether this apparent shortening of survival reflects a
true change in the biology of PCM occurring on a background of CLL/MBL
needs further study.
In summary, we have presented the clinicopathologic findings in 15
cases in which the bone marrow showed simultaneous presence of
[CD5.sup.+] monoclonal B cells and monotypic plasma cells. We have
compared our results with the 51 cases of concurrent CLL and PCM
previously reported in 30 articles. The distinction between CLL and the
newly described precursor entity “monoclonal B-cell
lymphocytosis” is discussed. Differentiating cases with concomitant
presence of PCM and CLL/MBL from other causes of lymphoplasmacytic or
lymphoplasmacytoid marrow infiltration is crucial for correct treatment.
A careful review of immunophenotype of the B cells and
immunohistochemical staining for CD56 and/or cyclin D1 to identify
abnormal plasma cells will allow separation from conditions such as LPL,
splenic MZL, and CLL with plasmacytic differentiation. Notably, despite
the presence of the 2 abnormal populations, almost all of our patients,
and many patients from published reports, required treatment for myeloma
rather than for CLL.
We thank Steven Conlon, AAS, Photopath Division, Department of
Pathology, Duke University Medical Center, for expert help with the
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Christopher L. Alley, MD; Endi Wang, MD, PhD; Cherie H. Dunphy, MD;
Jerald Z. Gong, MD; Chuanyi M. Lu, MD; Elizabeth L. Boswell, MD; James
Burchette, MT (
American Society of Clinical Pathologists.
); Anand S. Lagoo, MD, PhD
Accepted for publication June 5, 2012.
From the Department of Pathology, Duke University Medical Center,
state in the SE United States. It is bordered by the Atlantic Ocean (E), South Carolina and Georgia (S), Tennessee (W), and Virginia (N).
Facts and Figures
Area, 52,586 sq mi (136,198 sq km). Pop.
(Drs Alley, Wang, and Lagoo and Mr Burchette);
the University of North Carolina,
Chapel Hill, North Carolina
Dunphy and Boswell); Jefferson University Hospital, Philadelphia,
Pennsylvania (Dr Gong); and the
University of California
Affairs Medical Center,
San Francisco, California
The authors have no relevant financial interest in the products or
companies described in this article.
Reprints: Anand S. Lagoo, MD, PhD, Department of Pathology, Box
DUMC Demaree United Methodist Church
, Durham, NC 27710 (e-mail: anand.lagoo@duke. edu).
Table 1. Clinical Findings for Patients Showing Presence of [CD5.sup.+]/[CD23.sup.+] Monotypic B Cells Together With Monotypic Plasma Cells in the Bone Marrow Case Age, Clinical Presentation Initial Treatment No. y/Sex 1 56/M IgG [kappa] paraprotein, Thalidomide, mild anemia, bone dexamethasone, pain, fractures, Velcade, (a) hypercalcemia] autologous stem cell transplant 2 57/M [kappa] Bence Jones Thalidomide, proteinuria on UPEP, dexamethasone, no M protein on SPEP, autologous stem pathologic fractures cell transplant 3 58/M Multiple lytic bone Zometa, (b) lesions, [kappa] free Velcade, (a) light chains dexamethasone, local radiation 4 64/M Diffuse lytic bone lesions Vincristine, and vertebral compression adriamycin, fractures dexamethasone, Velcade, (a) radiation 5 68/M Amyloid nephropathy Revlimid, (c) dexamethasone 6 71/M Chronic lymphopenia/ Observation thrombocytopenia, lytic only (at bone lesions, history of patient's IgG [kappa]M-spike for request) 5 years 7 74/F Anemia, monoclonal Melphalan, gammopathy, lytic bone marrow bone lesion transplant 8 78/M History of IgG monoclonal Melphalan, gammopathy for 14 years, prednisone, elevated total protein Rituxan, (d) levels, elevated white thalidomide, blood cell count Revlimid (c) 9 82/M Renal insufficiency due Observation to renal cysts and RCC, only elevated total protein levels, IgG [kappa] M-spike 10 85/M IgG [lambda] monoclonal Observation gammopathy, anemia, only polyneuropathy, 15-lb weight loss, negative skeletal survey 11 91/M IgA monoclonal protein, Observation negative skeletal survey only 12 63/M History of CLL for 2 Observation years, followed by positive only IgG [kappa] SPEP 13 77/F History of CLL for 3.5 Melphalan, years, renal insufficiency prednisone, with [lambda] Bence Jones Velcade (a) proteinuria 14 77/M History of stage IIIA CLL Cyclophosphamide, for 3 years with recurrence fludarabine 15 80/M History of asymptomatic CLL, Aranespe and positive IgG [lambda] SPEP observation result Case Follow-up, Status at Last Follow-up No. mo 1 122 Persistent marrow involvement by CLL (2%) and PCM (5%) 2 84 Persistent marrow involvement by CLL (15%-20%) and PCM (5%-10%), amyloidosis, nephrotic syndrome, slowly rising free serum [kappa] levels 3 16 Clinically stable but still with multiple lytic bone lesions, currently in remission with no CLL or PCM on follow-up biopsy, preparing for stem cell transplant 4 6 Marrow involvement improvement from 45%-50% to 10% plasma cells, decrease in serum [kappa] free light chains 5 3 Marrow involvement improvement from 20% to 4% CLL and no residual PCM 6 2 Clinically stable but with multiple lytic bone lesions, mildly elevated levels in LFTs 7 48 Clinically stable, persistent minimal residual CLL and PCM seen on follow-up biopsies 8 2 Deceased secondary to metastatic pancreatic adenocarcinoma 9 37 Clinically stable, slight elevation in M-spike 10 1 Deceased secondary to axonal demyelinating polyneuropathy 11 No follow-up 12 3 Asymptomatic with no clinical evidence of disease progression 13 5 Remission from CLL and PCM 14 2 Deceased 15 7 Continual improvement in performance status with improved blood count Abbreviations: CLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; Ig, immunoglobulin; LFTs, liver function tests; PCM, plasma cell myeloma; RCC, renal cell carcinoma; SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis. (a) Velcade, Bortezomib, Millenium Pharmaceuticals, Cambridge, Massachusetts. (b) Zometa, Zoledronic Acid, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey. (c) Revlimid, Lenalidomide, Celgene Corporation, Summit, New Jersey. (d) Rituxan, Rituximab, Genentech, San Francisco, California. (e) Aranesp, Darbepoetin alpha, Amgen Inc, Thousand Oaks, California. Table 2. Peripheral Blood Findings at the Time of Bone Marrow Examination Showing Concomitant Plasma Cell Myeloma and Chronic Lymphocytic Leukemia (CLL)/Monoclonal B-Cell Lymphocytosis Case Hemoglobin, Hematocrit, Mean No. g/dL % Corpuscular Volume, fL 1 NA NA NA 2 NA NA NA 3 10.7 ... 88.4 4 10.1 31 84 5 13.8 39.7 101 6 13.2 38 85 7 12 33.4 100.2 8 10.6 31 101 9 14.2 43 91 10 10.3 33 91 11 NA NA NA 12 15.5 43.2 88 13 10.4 32 104 14 NA NA NA 15 12 36.6 89 Case Red Cell Platelets, White Blood No. Distribution x [10.sup.-3]/ Cells, x Width, % L [10.sup.-3]/L 1 NA NA NA 2 NA NA NA 3 ... 212 6.2 4 16.1 205 5.6 5 14 229 7.7 6 16 99 4.2 7 13.1 309 7.6 8 14.3 154 15.4 9 13.6 236 7.9 10 16.7 237 7.1 11 NA NA NA 12 16 186 4.8 13 13.8 211 33.6 14 NA NA NA 15 14.6 217 6.8 Case Lymphocytes Lymphocytes Peripheral Blood No. >5000/L >1500/L Flow, % Atypical Lymphocytes 1 NA NA NA 2 NA NA NA 3 No No 2 4 No No Not done 5 No Yes Not done 6 No Yes Not done 7 No Yes Not done 8 Yes Yes 52 9 No No Not done 10 No No Not done 11 NA NA NA 12 Untreated Untreated Not done CLL CLL 13 Yes Yes 59 14 Treated Treated NA CLL CLL 15 Untreated Untreated Not done CLL CLL Abbreviation: NA, not available. Table 3. Bone Marrow Findings Case Marrow CLL/MBL PCM No. Cellularity, Cells, Cells, % % % 1 45 40 15 2 55 10 80 3 70 10 2 4 30 15 46 5 40 20 10 6 90 10 10 7 90 30 20 8 60 35 50 9 40 11 10 10 30 3 13 11 40 2 15 12 50 2 15 13 30 50 25 14 70 0 20 15 50 10 15 Case Marrow Fibrosis CLL/MBL PCM No. Light Chain Light Chain 1 None [kappa] [kappa] 2 None [kappa] [kappa] 3 Not performed [kappa] [kappa] 4 Focal mild [lambda] [kappa] fibrosis within lymphoid aggregates 5 No fibrosis [kappa] [lambda] 6 Mild fibrosis [kappa] [kappa] 7 Moderate, focal [lambda] [kappa] 8 Mild fibrosis [kappa] [kappa] within lymphoid aggregates 9 No fibrosis [lambda] [kappa] 10 No fibrosis [lambda] [lambda] 11 Mild to moderate Undetectable [lambda] fibrosis 12 No fibrosis [lambda] [kappa] 13 Mild fibrosis [kappa] [lambda] around lymphoid aggregates 14 No fibrosis [kappa] [kappa] 15 No fibrosis No flow [lambda] cytometry Case Cyclin CD56 FISH/Cytogenetics No. D1 1 Pos Trisomy 12 2 Pos Neg CCND1/IGH fusion 3 Pos Pos 12.5% trisomy 12, 12.5% del(13q14.3) 4 Pos Pos Normal cytogenetics and negative FISH results for TP53, ATM, del(13q), -13, t(11;14), and t(4;14) 5 Neg Neg None noted 6 Pos Neg Normal cytogenetics and negative FISH results for TP53, ATM, del(13q), -13, t(11;14), and t(4;14) 7 Neg Neg None noted 8 Pos Neg 13% del(17p13.1), 12.5% del (13q14.3), 15% trisomy 11 9 Pos Pos 12% del(13q14.3), 3.5% del of both chromosomes 13 10 Neg Neg Normal cytogenetics and negative FISH results for TP53, ATM, del(13q), -13, t(11;14), and t(4;14) 11 Neg Neg None noted 12 Pos Pos None noted 13 Neg Neg 3% monosomy 13 14 Pos Pos del of Y chromosome 15 No No None noted tissue tissue Abbreviations: ATM, ataxia telangiectasia mutated; CCND1, cyclin D1 gene; CLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; del, deletion; FISH, fluorescence in situ hybridization; IGH, immunoglobulin heavy chain gene; MBL, monoclonal B-cell lymphocytosis; Neg, negative; PCM, plasma cell myeloma; Pos, positive. Table 4. Summary of Clinical and Pathologic Findings in Published Cases Case Source, y Age/ Initial Interval No. y/Sex Diseasea (First and Second Disease), mo 1 Vander and 72/M Together 0 Johnson, (34) 1960 2 Naidu and Rosner, 67/M Together 0 (35) 1971 3 Shuster and 54/M CLL 54 Causing, (39) 1971 4 Fitzgerald et 68/F CLL 96 al, (36) 1973 5 Narasimhan et 67/M Together 0 al, (33) 1975 6 Narasimhan et 60/M Together 0 al, (33) 1975 7 Wash U 53/F CLL 44 CPC, (40) 1975 8 Crowley et 80/F Together 0 al, (37) 1977 9 Hoffman and 69/M CLL 24 Rudders, (32) 1977 10 McLaughlin et 77/M Together 0 al, (43) 1978 11 Zawadzki et 48/F CLL 29 al, (38) 1978 12 Pedersen-Bjergaard 78/M CLL 18 et al, (30) 1978 13 Kough and 75/F CLL 72 Makary, (31) 1978 14 Kough and 58/M CLL 144 Makary, (31) 1978 15 Jeha et 64/M Together 0 al, (29) 1981 16 Zalcberg et 69/M PCM 31 al, (44) 1982 17 Kontozoglou and 64/M Together 0 Skinnider, (28) 1983 18 Bassan et al, 52/M Together 0 (27) 1984 19 Pines et al, 42/F CLL 96 (26) 1984 20 Fermand et al, 69/F CLL 120 (25) 1985 21 Brouet et al, 56/M CLL 132 (45) 1985 22 Brouet et al, 63/F CLL 48 (45) 1985 23 Brouet et al, 73/M CLL 24 (45) 1985 24 Brouet et al, 57/M CLL 24 (45) 1985 25 Brouet et al, 76/M Together 0 (45) 1985 26 Brouet et al, 78/F CLL 156 (45) 1985 27 Brouet et al, 65/F CLL 48 (45) 1985 28 Brouet et al, 86/M CLL 132 (45) 1985 29 Brouet et al, 86/M PCM 192 (45) 1985 30 Brouet et al, 74/M Together 0 (45) 1985 31 Brouet et al, 74/M Together 0 (45) 1985 32 Browett et al, 70/F CLL 72 (41) 1988 33 Saltman et al, 52/M Together 0 (24) 1989 34 Novak et al, 50/M CLL 14 (23) 1995 35 Novak et al, 62/M Together 0 (23) 1995 36 Shpilberg et al, 83/M CLL 228 (42) 1995 37 Shpilberg et al, 57/F CLL or MCL 48 (42) 1995 38 Makower et al, 61/M CLL 84 (22) 1996 39 Patriarca et al, 49/M CLL 48 (21) 2000 40 Kaufmann et al, 65/M CLL 24 (20) 2001 41 Kaufmann et al, 76/M CLL 3 (20) 2001 42 Aktan et al, 66/M CLL 72 (19) 2003 43 Chang et al, 68/M Together 0 (18) 2004 44 Chang et al, 45/M CLL 72 (18) 2004 45 Srinivas and 67/F Plasmacytoma 96 Schiffer (17) 2009 46 Srinivas and 60/M CLL 46 Schiffer (17) 2009 47 Pantic et al, 64/M Together 0 (46) 2010 48 Pantic et al, 76/M Together 0 (46) 2010 49 Pantic et al, 73/M CLL 31 (46) 2010 50 Pantic et al, 73/M CLL 54 (46) 2010 51 Pantic et al, 62/M CLL 22 (46) 2010 Case CLL Cells, PCM Cells, CLL Ig No. % of BM % of BM Isotype Cellularity Cellularity 1 60 40 NA 2 46 34 NA 3 13 64 NA 4 60 40 NA 5 46 34 NA 6 40 30 NA 7 30 70 NA 8 NA Sheets sIg negative 9 NA Not given "Different from myeloma" 10 Extensive Occasional NA 11 NA Almost NA complete 12 48 26 [kappa] 13 30 24 NA 14 57 20 NA 15 NA NA IgM k 16 30 later 40 initially, [kappa] 6 when CLL present 17 30 38 NA 18 40 (sheets) 50 [lambda] 19 NA IgM [kappa] 20 Not given Not given IgG1 [kappa] 21 52 46 NA 22 82 9 NA 23 30-60 4-80 [mu]-[kappa] 24 20-60 10-80 IgA 25 62 6 IgM [kappa] 26 25 53 [mu],[kappa] 27 18 20 [mu],[delta],[kappa] 28 37 6 [mu],[delta],[kappa] 29 45 55 [mu],[delta],[kappa] 30 50 50 [mu],[kappa] 31 35 36 [mu],[lambda] 32 Not 32 IgM [kappa] detected 33 40 20 IgM [kappa] 34 10 90 [kappa] 35 NA 22 [kappa] 36 70 25 [kappa] 37 NA NA IgG [kappa] 38 NA NA [kappa] 39 40 30 IgM [lambda], IgD [lambda] 40 Positive 60 [lambda] 41 70 10 NA 42 95 1 NA 43 40 30 [lambda] 44 50 25 [kappa] 45 Sheets 30 [kappa] 46 NA NA [kappa] 47 45 40 Null 48 10 30 [kappa] 49 30 15 [kappa] 50 70 40 [lambda] 51 90 10 [kappa] Case PCM Ig Initial Subsequent No. Isotype Treatment (b) Treatment (b) 1 NA XRT XRT 2 IgA [lambda] Not mentioned Not mentioned 3 IgG CLL-std None 4 IgM [kappa] CLL-std Higher dose CLL-std 5 IgG [lambda] PCM-std 6 IgG [kappa] CLL-std 7 IgG [kappa] CLL-std MM-std, XRT 8 IgA [kappa] Other chemo, XRT 9 "Different None Chemo, XRT from CLL" 10 IgG [kappa] CLL-std after 6 months 11 IgG [kappa] CLL-std PCM-std, XRT 12 [lambda] None Other chemo 13 IgA [kappa] CLL-std PCM-std, CLL-std 14 Not detected Other chemo PCM-std 15 IgG [kappa] CLL-std PCM-std, other chemo, plasma exchange, transfusion 16 IgM [lambda] PCM-std Pleural chemotherapy 17 IgG [kappa] CLL-std 18 IgD [lambda] Not mentioned 19 IgM [kappa] CLL-std XRT 20 IgA [kappa] CLL-std Cyclophosphamide for PCM 21 [kappa] CLL-std, XRT XRT 22 IgA [lambda] CLL-std None 23 IgA [lambda] None CLL-std, PCM-std 24 IgA CLL-std, PCM-std splenectomy 25 IgM [kappa] CLL-std PCM-std 26 [kappa] None PCM-std 27 IgM [kappa] CLL-std Other chemo 28 [alpha], [kappa] Chemo 29 [alpha], [kappa] Chemo 30 IgD [lambda] PCM-std 31 [lambda] CLL-std 32 IgA, no light Not mentioned chain 33 IgA [lambda] Chemo 34 [lambda] None Chemo, transfusions 35 IgG [kappa] Chemo, XRT 36 IgG [kappa] None PCM-std 37 [kappa] None PCM-std, Other chemo 38 IgG [kappa] Leukopheresis Other chemo, PCM-std, for 4 years, PCM-alt then IL-4 39 IgD [kappa] CLL-alt Other chemo, auto SCT 40 IgG [lambda] Not mentioned 41 IgG [lambda] Not mentioned 42 IgG [kappa] CLL-std Other chemo, PCM-std, XRT 43 [kappa] Other chemo PCM-alt, auto SCT 44 [lambda] None Other chemo 45 IgG [kappa] XRT PCM-alt 46 IgG [kappa] CLL-alt PCM-std 47 [kappa] Other chemo, PCM-alt 48 IgG [lambda] None Other chemo 49 IgA [kappa] None PCM-alt 50 IgG [kappa] CLL-alt, other Other chemo chemo, PCM-alt 51 [lambda] None Other chemo, SCT, PCM-alt Case Total Follow-up Clinical Outcome No. After Diagnosis of Second Disease, mo 1 9 Died of PCM 2 Unknown Unknown 3 1 Died of sepsis 4 1 Died 5 24 Partial remission for PCM, no lymphadenopathy 6 2 Developed viral hepatitis and died of liver failure and sepsis 7 48 Died of AML, which developed 3 months prior 8 11 Septicemia 9 <6 Died of PCM 10 18 CLL in remission, PCM paraprotein 11 13 Died of progressive PCM and pneumonia 12 12 Decrease in IgG [lambda] to half, reappearance of IgG [kappa], stable disease 13 21 Died of PCM 14 7 Died of PCM 15 19 Died of progressive and refractory disease 16 1 Died of progressive disease 17 72 Died of PCM 18 Not mentioned Unknown 19 <1 Died of sepsis 20 2 years Progressive disease after PCM 21 4 Died of PCM 22 <1 Died of PCM 23 72 Died suddenly 24 <1 Died of Pl cell leukemia 25 18 Died of PCM 26 24 Died of PCM 27 6 Died of PCM 28 1 Died owing to heart failure 29 <1 Died 30 <1 Died 31 <1 Died 32 Not given Unknown 33 Stable CLL, no evidence of [lambda] paraprotein 34 4 Died of renal failure, septicemia 35 6 Alive, stable disease 36 24 Died of PCM, no CLL 37 Few months Died of PCM 38 34 CLL in complete remission, stable PCM 39 18 after SCT CLL in complete remission, PCM in 40 partial remission 41 42 12 Asymptomatic and progression free 43 [approximately Doing well soon equal to] 24 after BMT 44 [approximately Both CLL and PCM in equal to] 36 partial remission 45 60 CLL in complete remission, PCM in partial remission 46 22 Relapsed disease 47 39 Both diseases stable 48 28 Both CLL and PCM in complete remission, died of AML 49 37 CLL in complete remission, died of PCM 50 7 PCM stable, died of Richter transformation of CLL 51 22 CLL in complete remission, died of PCM Abbreviations: alt, alternative; AML, acute myeloid leukemia; BM, bone marrow; BMT, bone marrow transplant; chemo, chemotherapy; CLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; Ig, immunoglobulin; IL-4, interleukin 4; MCL, Mantle Cell Lymphoma; NA, not applicable; PCM, plasma cell myeloma; SCT, stem cell transplant; sIg, surface immunoglobulin; std, standard; Wash U CPC, Washington University Clinicopathological Conference; XRT, radiation therapy. (a) Together signifies presence of both CLL and PCM at initial diagnosis. (b) The chemotherapies given to these patients are grouped into the following categories: auto SCT = autologous stem cell transplantation; chemo = chemotherapy, no details mentioned; CLL-alt = fludarabine and/ or rituximab and/or bendamustine [+ or -] steroids; CLL-std = chlorambucil or cyclophosphamide [+ or -] steroids; other chemo = vincristine, adriamycin, daunorubicin, triethylenemelamine (singly or in various combinations); PCM-alt = thalidomide and/or lenalidomide and/or bortizomib (Velcade, Millenium Pharmaceuticals, Cambridge, Massachusetts) and/or epirubicin and/or 2-chlorodeoxyadenosine, [+ or -] steroids; PCM-std = melphalan [+ or -] steroids. Table 5. Characteristic Findings Differentiating Concomitant Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL) and Plasma Cell Myeloma (PCM) From Other Monotypic Lymphoplasmacytic Infiltrates in Bone Marrow Condition Clinical Features PCM and CLL, Variable combination of concomitant symptoms: PCM related (bone pain, pathologic fractures, lytic bone lesions, hypercalcemia, renal insufficiency, anemia, and recurrent infections) and CLL related (most are asymptomatic; fatigue, AIHA, organomegaly, or lymphadenopathy) Reactive Underlying condition (viral or plasmacytosis (e) other infection, autoimmune, allergic, etc) Lymphoplasmacytic Anemia, fatigue, lymphoma cryoglobulinemia, neuropathy, coagulopathy, diarrhea; indolent course Splenic marginal zone Splenomegaly, thrombocytopenia, lymphoma with anemia plasmacytic differentiation CLL with Similar to typical CLL lymphoplasmacytoid differentiation Condition Paraprotein PCM and CLL, Usually a single M protein from concomitant PCM cells, IgG (50%), IgA (20%), light chain (20%); a second small M protein may be present from CLL cells, IgM or IgG Reactive Absent ([+ or -] increased polyclonal plasmacytosis (e) free light chains) Lymphoplasmacytic Serum paraprotein, almost always lymphoma IgM Splenic marginal zone One-third have small serum M lymphoma with protein plasmacytic differentiation CLL with Small M protein may be present lymphoplasmacytoid differentiation Condition Morphology PCM and CLL, Two distinct populations: (1) concomitant atypical enlarged plasma cells (unless small cell variant), may be plasmablastic or multinucleated, may contain cytoplasmic or nuclear inclusions, (d) can be in clusters or diffuse; (2) small lymphocytes with clumped chromatin and scant cytoplasm; nodular, interstitial, and/or diffuse infiltrates Reactive May be binucleated; other plasmacytosis (e) features of abnormal plasma cells absent Lymphoplasmacytic Range of cells from small lymphoma lymphocytes to plasmacytoid lymphocytes, and variable number of plasma cells; usually admixed; nodular, interstitial, or diffuse Splenic marginal zone Small to medium-sized lymphoma with lymphocytes with dispersed plasmacytic chromatin and abundant pale differentiation cytoplasm; clusters of plasma CLL with Small lymphocytes with less lymphoplasmacytoid condensed nuclear chromatin differentiation and nuclear irregularities; some lymphocytes are lymphoplasmacytoid Condition Immunophenotype (Intensity or Proportion of Cases Showing Expression) CD5 CD23 CD19 (a) PCM and CLL, Neg Neg Neg (99%) concomitant Pos Pos Pos Reactive Neg Neg Pos plasmacytosis (e) Lymphoplasmacytic Neg (65%-95%) Neg (95%) Neg lymphoma Splenic marginal zone Neg (80%) Neg Pos lymphoma with plasmacytic differentiation CLL with Pos/Neg Pos/Neg Pos lymphoplasmacytoid differentiation Condition Immunophenotype (Intensity or Proportion of Cases Showing Expression) CD20 CD45 CD138 sIg (a) PCM and CLL, Neg (90%) Neg (.95%) Pos Neg (.95%) concomitant Pos (dim) Pos Neg Pos (dim) Reactive Neg Neg Pos Neg plasmacytosis (e) Lymphoplasmacytic Pos Pos Neg Pos (Brt) lymphoma Splenic marginal zone Pos Pos Neg Pos lymphoma with plasmacytic differentiation CLL with Pos (Brt) Pos Neg Pos (Brt) lymphoplasmacytoid differentiation Condition Immunophenotype (Intensity or Proportion of Cases Showing Expression) clg CD56 Cyclin D1 (b) PCM and CLL, Pos (97%) Pos (.60%) Pos (40%) concomitant (c) Neg Neg Neg Reactive Pos Neg Neg plasmacytosis (e) (polyclonal) Lymphoplasmacytic Pos in plasma Neg Neg lymphoma cells (same as sIg) Splenic marginal zone Pos in plasma Neg Neg lymphoma with cells, clonal, plasmacytic same as sIg differentiation CLL with Neg Neg Neg lymphoplasmacytoid differentiation Abbreviations: AIHA, autoimmune hemolytic anemia; Brt, bright; cIg, cytoplasmic immunoglobulin; Ig, immunoglobulin; Neg, negative; Pos, positive; sIg, surface immunoglobulin. (a) These antigens are evaluated by flow cytometry only. (b) This antigen is evaluated by immunohistochemistry only. All other antigens in this list can be evaluated by either flow cytometry or immunohistochemistry. (c) Clonal light chain expression may be the same or different from the sIg detected on B cells. (d) The cytoplasmic inclusions include Russell bodies, crystalloid inclusions, or vacuoles, while nuclear inclusion includes Dutcher body. (e) Reactive plasma cells are present in virtually all adult bone marrows including bone marrows involved by other neoplastic processes (lymphomas, myeloma, or other). Their numbers may be as high as 30% or more in certain conditions.