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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.

Plasma cell myeloma

n.
A malignant plasmacytoma of bone.
 (
PCM

) (or multiple
myeloma
 /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

lymphocytic

 leukemia/small
lymphocytic lymphoma
 Non-Hodgkin’s lymphoma, see there
 (
CLL

abbr.
chronic lymphocytic leukemia


n.pr See leukemia, chronic lymphocytic.


 1. Chronic lymphocytic leukemia 2. Cholesterol-lowering lipid
) are both common

hematologic

 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
chronic leukemia
 Hematology A malignancy of lymphoid and myeloid stem cells. See Chronic lymphocytic leukemia, Chronic myelocytic leukemia.
 in the

United States
 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
lymphocytosis
 /lym·pho·cy·to·sis/ () an excess of normal lymphocytes in the blood or an effusion.


n.
 (
MBL

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
countries. (9,10)

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
indolent
 /in·do·lent/ ()
1. causing little pain.

2. slow growing.


adj.
1. Disinclined to exert oneself; habitually lazy.

2.
 course with

life expectancy

 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

chemotherapy regimens

. (13,14)

Even though these 2 hematologic neoplasms are individually quite
common, it is rare to find them together in the same patient,
according
to


prep.
1. As stated or indicated by; on the authority of:

2. In keeping with:

3.
 large clinical series. (15,16) A little more than 50 patients showing
evidence of both CLL and PCM have been described in the
English
literature

 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
differential diagnosis

n.
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
such cases.

MATERIALS AND METHODS

Case Selection

After obtaining respective institutional review board approval, the
electronic databases of
surgical pathology

n.
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
monotypic

 B cells
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
cytologic

 and histologic preparations were reviewed along with flow cytometric,

cytogenetic
 /cy·to·ge·net·ic/ ()
1. pertaining to chromosomes.

2. pertaining to cytogenetics.


cytogenetic

pertaining to or originating from the origin and development of the cell.
, and molecular diagnostic data. The available hematology
laboratory data and
radiographic
,
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
institutions.

Immunohistochemical Staining

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

cyclin D
   
1 (clone SP4, Thermo
Fisher Scientific

,
Fremont, California
) is a city in California that was incorporated on January 23, 1956, from the merger of five smaller communities:
) by
using established labeled polymer immunohistochemical staining
technique. The sections were cut and mounted on
adherent
 /ad·her·ent/ () sticking or holding fast, or having such qualities.
 glass slides,
dewaxed in
xylene
  or  , C6H4(CH3)2
, and rehydrated in graded ethanols. Endogenous

peroxidase
 /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.


n.
 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
EDTA
 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
horseradish

 peroxidase-labeled secondary
antibody (Envision Plus, Dako Corp,
Carpinteria, California

) for 30
minutes. The bound complexes were visualized by the application of
diaminobenzadine (Dako) containing 0.3%
hydrogen peroxide
 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.
 as a
substrate. After incubation, the sections were washed, lightly
counterstained with
hematoxylin
 /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.

Literature Review

The online database PubMed, maintained by National Center for
Biotechnology Information, was searched for
English language
 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.
 articles
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.

Statistical Analysis

All clinical and pathologic information from the selected cases, as
well as from the published articles, was tabulated with Excel (
Microsoft
Corporation

,
Redmond, Washington

). 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 [
chi square
,
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,
La Jolla
 , 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.

RESULTS

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,
while
amyloid
 /am·y·loid/ ()
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
 
nephropathy
 /ne·phrop·a·thy/ () disease of the kidneys.nephropath´ic


analgesic nephropathy
 and
polyneuropathy
 /poly·neu·rop·a·thy/ () neuropathy of several peripheral nerves simultaneously.


amyloid polyneuropathy
 with weight loss and anemia
were the presenting features in 1 patient each. In 2 patients with
smoldering myeloma, an incidentally detected monoclonal gammopathy
prompted the
bone marrow examination

, while the third patient had a
14-year history of stable monoclonal gammopathy with more recent

leukocytosis
 Definition

Leukocytosis is a condition characterized by an elevated number of white cells in the blood.
Description

Leukocytosis is a condition that affects all types of white blood cells.
 and an increasing level of the monoclonal
paraprotein
 /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.
. Only
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
lymphadenopathy
 /lym·phad·e·nop·a·thy/ () disease of the lymph nodes.


angioimmunoblastic lymphadenopathy , angioimmunoblastic lymphadenopathy with dysproteinemia
 was
not noted in any patient.

Peripheral Blood
 Cardiology Blood circulating in the system/body
 Findings

The peripheral blood findings at the time when the
bone marrow
biopsy


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
lymphocyte
 see blood; immunity.


lymphocyte

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
flow
cytometry


 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 (
linear
regression

, [r.sub.2] < 0.01).
Reticulin
 /re·tic·u·lin/ () a scleroprotein from the connective fibers of reticular tissue.


n.
 fibrosis was present around
the
lymphoid
 /lym·phoid/ () resembling or pertaining to lymph or tissue of the lymphoid system.


adj.
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

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
Y chromosome

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
had
CCND
 
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
nodular

 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
discussion).

Clinical Course

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
owing to

prep.
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,
bortezomib,
thalidomide
 , 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
stem cell

 transplant, 1 with

allogeneic
 /al·lo·ge·ne·ic/ ()
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
autologous
 /au·tol·o·gous/ () related to self; belonging to the same organism.


adj.
1.
 cells. Only 1 of 4 patients initially
presenting with CLL received disease-specific treatment
(
cyclophosphamide
 /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
(pancreatic
adenocarcinoma
 see neoplasm.
). 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.

COMMENT

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

epidemiologic study
 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
myeloma and
lymphoid leukemia

n.
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
neoplasm
 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
of
MDS

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

median value

 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
retrospective study

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
marrow. (8)

[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

neoplastic
 /neo·plas·tic/ ()
1. pertaining to a neoplasm.

2. pertaining to neoplasia.


neoplastic

pertaining to neoplasia or a neoplasm.
 conditions: lymphoplasmacytic lymphoma (
LPL

) (also called
immunocytoma or Waldenstrom
macroglobulinemia
 /mac·ro·glob·u·lin·emia/ () increased levels of macroglobulins in the blood.


Waldenström’s macroglobulinemia
),
marginal zone

 lymphoma
(
MZL

MZL Muzzle
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
plasma cell

n.
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
workup

n. Abbr. w/u
A thorough medical examination for diagnostic purposes.
 (Figure 1). The paraprotein is typically (but not
invariably
  
adj.
Not changing or subject to change; constant.


in·vari·a·bil
) 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
isotype

n.
An antigenic marker that occurs in all members of a subclass of an immunoglobulin class.


i
 of the paraprotein is not a
reliable
discriminator
  
n.
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 (
splenic
 /splen·ic/ () pertaining to the spleen.


adj.
Of, in, near, or relating to the spleen.


splenic

pertaining to the spleen.
, nodal, and mucosa-associated

lymphoid tissue

 type), only
splenic marginal zone lymphoma

 involves the
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.
Splenomegaly
 /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
cyclin
  
n.
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
the
lymph node

. (66) Clinical and radiographic findings, such as
lytic
 /lyt·ic/ ()
1. pertaining to lysis or to a lysin.

2. producing lysis.


adj.
1. Of, relating to, or causing lysis.

2.
 bone lesions,
hypercalcemia
 Definition

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

mantle cell lymphoma

 is a critical diagnostic
pitfall
  
n.
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
allelic exclusion

 in B cells
(70) to estimate clonal relatedness. Caution must be exercised when
interpreting such data, because
nonidentical

adj.
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
de novo

 plasma cell
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
Figures.

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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 (
ASCP
 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,
Durham,
North Carolina
 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

 (Drs
Dunphy and Boswell); Jefferson University Hospital, Philadelphia,
Pennsylvania (Dr Gong); and the
University of California

 & Veterans
Affairs Medical Center,
San Francisco, California
 
 (Dr Lu).

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
3712
DUMC

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.