Central Nervous System Involvement in a Patient with Chronic
Lymphocytic Leukemia and Non-Hodgkin's Lymphoma
(Richter's Syndrome), with Concordant Cell Surface
Immunoglobulin Isotypic and Immunophenotypic Markers
PHILIP K. LANE, M.D., RONALD M. TOWNSEND, M.D., JAY H. BECKSTEAD, M.D., AND LAURENCE CORASH, M.D.
Central nervous system (CNS) involvement in Richter's syndrome has not been previously described. This report describes
a 45-year-old man with the simultaneous occurrence of B-cell
chronic lymphocytic leukemia (CLL), extramedullary large
cell non-Hodgkin's lymphoma (NHL), and malignant lymphoid meningeal involvement. In this case, peripheral blood
lymphocytes, cerebrospinal fluid (CSF) lymphoblasts, and malignant cells in surgical biopsy tissue obtained from a soft tissue mass all stained concordantly for immunoglobulin isotypes
and for B-cell immunophenotypic markers, supporting the hypothesis of a clonal origin for the three malignant cell populations. These observations suggest that the different tumors in
Richter's syndrome (CLL and NHL) may represent the clonal
progression of a common neoplasm rather than independent
neoplastic events. Richter's syndrome and other transformations of lymphoid malignancies (prolymphocytic transformation of CLL, blast crisis of CLL, and blastic transformation of
NHL) may all represent possible routes of progression in the
natural history of a single neoplasm. The present case also
suggests that, in patients with B-cell CLL with CNS symptoms, the possibility of blastic transformation presenting as
CNS lymphoma deserves consideration. (Key words: B-lymphocytes; Cell surface markers; Chronic lymphocytic leukemia; Immunoblastic lymphoma; Immunoenzyme techniques;
Lymphocytic leukemia; Lymphoma; Meningeal neoplasms;
Non-Hodgkin's lymphoma; Richter's syndrome) Am J Clin
Pathol 1988;89:254-259
MENINGEAL LEUKEMIA complicating B-cell
chronic lymphocytic leukemia (CLL) occurs rarely; a
review of the literature reveals four reported cases.13'24'38
However, central nervous system (CNS) involvement
(including meningeal leukemia) in non-Hodgkin's lymphoma (NHL) is distinctly more common; Herman and
associates17 reported an incidence of 5% in a series of
1,039 patients with NHL.
The occurrence of a large cell NHL in the setting of
CLL has been termed Richter's syndrome.16'25'35 A review of the literature fails to reveal reports of Richter's
Received February 24, 1987; received revised manuscript and accepted for publication August 3, 1987.
Address reprint requests to Dr. Corash: Hematology Section, Clinical Laboratories, M-523, University of California, San Francisco, California 94143.
Departments of Laboratory Medicine and Pathology,
University of California, San Francisco, California
syndrome presenting with meningeal or other CNS involvement. In addition, there is controversy whether
this syndrome represents the emergence of a more malignant clone of neoplastic cells ("dedifferentiation,"
"blastic transformation," "clonal progression") or instead represents the chance occurrence of two independent neoplasms. We report an unusual patient who initially presented with the simultaneous occurrence of
blood and bone marrow CLL, a diffuse large cell nonHodgkin's lymphoma at extramedullary sites, and malignant meningeal involvement. Cell surface immunoglobulin isotypic and immunophenotypic marker studies of this patient's cells support the hypothesis of a
clonal origin for all three malignant cell populations.
Richter's syndrome (NHL occurring in a patient with
CLL), prolymphocytic transformation of CLL, 14,20 blast
crisis of CLL,12'21-22'28'43 and blastic transformation of
low-grade NHL 1 ' 7 ' 36 may all represent diverse possible
progressions in the natural history of a single biologic
disease entity.
Report of a Case
A 45-year-old white male presented with a six-month history of
anorexia, fever, night sweats, and weight loss and a three-week history
of a slowly enlarging left knee mass. Two weeks before admission, he
noted the onset of headaches, blurred vision, stiff neck, and intermittent nausea and vomiting. Medical history was remarkable only for
alcohol abuse. On physical examination, the patient was noted to have
meningismus; fundoscopic examination revealed bilateral blurring of
the optic disk margins with absence of venous pulsations. Bilateral
anterior cervical adenopathy, left inguinal adenopathy, and splenomegaly (palpable 5 cm below the left costal margin) were noted. There
was a 10 X 20 cm, nontender, soft tissue mass overlying the left patella.
Abdominal x-ray computed tomography (CT) revealed diffuse abdominal adenopathy and splenomegaly.
Head CT revealed severe hydrocephalus. A lumbar puncture was
performed, which showed a markedly elevated opening pressure (360
mmHjO). The cerebrospinal fluid (CSF) erythrocyte count was 0
254
Vol. 89 • No. 2
SINGLE CASE REPORTS
255
V *4,;^'^<
FIG. 1. A (upper, left). CSF cells, CSF cytocentrifuge preparation. CSF leukocyte population was pleomorphic, varying in size from small
mature-appearing lymphocytes to large cells with a moderate nuclear-cytoplasmic ratio, primitive chromatin, prominent nucleoli, and highly
irregular nuclear borders. Wright's-Giemsa (X1,000). B (upper, right). Lymphoma cells, knee mass biopsy, plastic-embedded section. Lymphoma
cells were large and pleomorphic and had moderate cytoplasm, highly irregular nuclear borders, and prominent nucleoli. Hematoxylin-eosinazure (X 1,000). C (lower, left). Peripheral blood CLL cells, peripheral blood smear. Peripheral blood CLL cells were small mature-appearing
lymphocytes with scanty cytoplasm, mature coarsely clumped chromatin, and slightly irregular nuclear borders. A normal granulocyte is also
present. Wright's-Giemsa (X1,000). D (lower, right). Bone marrow CLL cells, bone marrow biopsy, plastic-embedded section. Bone marrow biopsy
showed a diffuse infiltrate of small lymphocytes with scanty cytoplasm and slightly irregular nuclear borders, as well as remnant normal myeloid
cells including granulocytes and granulocyte precursors. Hematoxylin-eosin-azure (X 1,000).
256
AJ.C.P. • February 1988
LANE ET AL.
Table 1. Immunophenotypic Marker Studies on CSF and Peripheral Blood
Antibody*'f
Cell PhenotypeJ
PB (%)
CSF (%)
Anti-Leu-4 (CD3)
Anti-Leu-5 (CD2)
Anti-Leu-9 (CD7)
Anti-HLA-DR
Anti-CALLA (CD 10)
Anti-Leu-M3
Coulter-Bl
Anti-Leu-12
Anti-SIg
Anti-kappa
Anti-lambda
Anti-Leu-M 1
BA-1 (CD24)
BA-2 (CD9)
My-9
TdTU
T-cells
T-cells (SRBC receptor)
T-cells, T-ALL, T-NHL
B-cells, monocytes (HLA-DR)
Common ALL (CALLA)
Monocytes
B-cells
B-cells
B-cells (surface Ig)
B-cells (kappa light chain)
B-cells (lambda light chain)
Myeloid, monos, Reed-Sternberg cells
B-cells, pre-B, Null-ALL, myeloid
ALL, CLL, early lymphoid, myeloid
Myeloid, monocytic
Early lymphoid
6
7
5
70
0
3
84§
23
97§
92§
13
14
86§
42
10
Neg
65
1
0
47
7
90§
77§
1
4
88§
75§
1
Neg
PB = Percentage of a specified subpopulation of Ficoll-Hypaque purified peripheral blood
mononuclear cells that showed positive staining. The subpopulation analyzed was composed
of small leukocytes (gated on volume as measured by narrow-angle light scatter), constituting
approximately 96% of all peripheral blood mononuclear cells obtained after Ficoll-Hypaque
purification. Excluded 4% subpopulation represented a small number of remnant peripheral
blood granulocytes. CSF = Percentage of cells in CSF (used directly without Ficoll-Hypaque
purification) showing positive staining. The cell population analyzed constituted 100% of CSF
leukocytes (both small and large cells seen in Figure 1 A).
* All markers were studied byfluorescenceactivatedflowcytometry on 10,000 cells, except
(11) nuclear TdT (terminal deoxynucleotidyltransferase) was studied byfluorescencemicroscopy.
t The "clusters of differentiation" (CD) designation of the antibodyreagentas defined by the
Second International Workshop on Human Leukocyte Differentiation Antigens,10 if applicable, is indicated in parentheses.
% Cell types commonly stained (the antigen labeled by the antibody reagent, if known, is
indicated in parentheses).
§ Markers staining 75% or more of cell population (arbitrarily chosen positive cut-off).
X 106/L (0 red blood cells/^L), and the CSF leukocyte count was 1,010
X 106/L (1,010 white blood cells/jtL). CSF cytologic results by cytocentrifuge preparation and Papanicolaou's stain were positive for malignant cells interpreted as consistent with a hematopoietic malignancy; Wright's-Giemsa stain of a CSF cytocentrifuge preparation
showed a pleomorphic cell population ranging in size from small mature-appearing lymphocytes to large cells with a moderate nuclearxytoplasmic ratio, primitive chromatin, prominent nucleoli, and highly
irregular nuclear borders (Fig. \A). Flow cytometry (using a BectonDickinson® "FACS" analyzer) and immunofluorescence (IF) analysis
of this entire cell population (Table 1) characterized it as a single
population of monoclonal B-lymphoid cells; positive markers included
anti-surface immunoglobulin (anti-SIg), antikappa light chain (antikappa), BA-1, and BA-2.'°
At presentation, the peripheral blood hemoglobin concentration was
133 g/L (13.3 g/dL), platelet count 165 X 109/L (165,000/^L), and
white blood cell count 104 X 109/L (104,000/^L), with a differential
count showing 0.9 (90%) mature lymphocytes (Fig. 1C). Flow cytometry and IF analysis of Ficoll-Hypaque® purified peripheral blood
mononuclear cells (Table 1) showed them to be a single population of
monoclonal B-lymphocytes, phenotypically identical to the CSF cell
population. Positive markers on peripheral blood lymphocytes included anti-SIg, anti-kappa, and BA-1. Bone marrow aspiration and
biopsy demonstrated a diffuse infiltrate composed of mature lymphocytes (Fig. ID); these findings were interpreted as consistent with a
diagnosis of CLL, Rai stage II.32 Immunoperoxidase studies of plasticembedded bone marrow biopsy sections4"6 demonstrated that the
lymphoid cell population stained positively with a pan-B-cell marker
("mouse monoclonal anti-B-cell," product #M-708, Dako Corporation, Santa Barbara, CA). The lymphoid cells stained strongly with
antikappa and anti-IgM, weakly with anti-IgD, and did not stain with
antilambda, anti-IgG, or anti-IgA. A stain for the transferrin receptor31
showed only rare cells with positive results.
An excisional biopsy of the knee mass (Fig. IB) revealed a diffuse
large cell lymphoma. Plastic-embedded sections of this tissue demonstrated that the cells stained positively with the same pan-B-cell marker
and stained positively for the same surface immunoglobulin isotypes.
Many cells stained positively for the presence of the transferrin receptor. This lesion was interpreted as consistent with the diagnosis of
high-grade malignant lymphoma, large cell, immunoblastic (IBL) in
the Working Formulation39; B-cell immunoblastic sarcoma in the
Lukes-Collins classification26; and diffuse histiocytic lymphoma in the
Rappaport classification.29,33
The patient was treated aggressively with systemic bleomycin, vincristine, doxorubicin, cyclophosphamide, and dexamethasone and
with whole brain irradiation and intrathecal methotrexate, resulting in
tumor regression and disappearance of peripheral blood lymphocytosis. However, three months after diagnosis, CSF cytologic results
remained positive for malignant cells, despite continuing systemic and
intrathecal chemotherapy, and biopsy of a new nodule at the site of the
original excisional biopsy revealed recurrent lymphoma.
Discussion
Direct involvement of the CNS by acute leukemia has
been extensively documented; 39-56% of patients with
acute lymphocytic leukemia, 19% of patients with acute
nonlymphoid leukemia, and 39% of patients with
chronic granulocytic leukemia in blast crisis will have
clinical or autopsy evidence of CNS involvement.9'42
In contrast, reports of CNS involvement in the usual
B-cell form of CLL are very rare. Getaz and Miller13
reported a case of B-cell CLL in a 65-year-old woman,
who experienced CNS symptoms two years after the
onset of CLL. However, in contradistinction to our
present report, the malignant lymphocytes in the perivascular infiltration found in the spinal cord at autopsy
were morphologically mature. Liepman and Votaw24
reported two similar cases, in which premortem CSF
cytologic results were positive for significant numbers of
Vol. 89 • No. 2
SINGLE CASE REPORTS
mature lymphocytes; B- and T-cell markers were not
studied. Steinberg and associates38 reported a case of
CLL with a meningeal leukemia consisting of mature
lymphocytes, in which both peripheral blood and CNS
lymphocytes had B-cell phenotypic markers. In the rare
T-cell variant of CLL, CNS involvement may be common; Reinherz and associates34 reported three of four
patients with T-cell CLL had evidence of meningeal
leukemia.
CNS involvement in non-Hodgkin's lymphomas is
distinctly more common than in B-cell CLL. Herman
and associates17 reported a CNS involvement rate of 5%
in 1,039 patients with NHL; other case series15'23,27 have
yielded similar results. Histologic subtypes of NHL in
the Rappaport classification at high risk of CNS involvement include nodular histiocytic lymphoma and the
diffuse lymphomas (including histiocytic, lymphoblastic, and undifferentiated), with incidences of CNS involvement ranging from 7 to 54%1723; in the Working
Formulation these subtypes include the intermediate
and high-grade lymphomas. In contrast, all other nonhistiocytic nodular lymphomas as well as diffuse welldifferentiated lymphoma (Rappaport classification),
corresponding to the low-grade lymphomas in the
Working Formulation, have a minimal incidence of
CNS involvement.17'23 Levitt and colleagues23 found 52
cases (11%) of CNS involvement among 592 cases of
non-Hodgkin's lymphoma; in that study, WrightGiemsa-stained CSF cytocentrifuge preparations
showed large pleomorphic cells with highly irregular
nuclear borders that morphologically resembled lymphoblasts rather than mature lymphocytes. Such CNS
spread in NHL carries a grave prognosis; median survival after diagnosis of CNS involvement was eight to
ten weeks.17'27
These observations are consistent with those of the
present case. Although meningeal involvement in
Richter's syndrome (large cell NHL in a patient with
CLL) has not been previously reported, the NHL component of that syndrome may well behave like other
high-grade NHL tumors in their propensity for meningeal spread and in the resultant CSF morphologic characteristics. This suggests that, in patients with B-cell
CLL in whom CNS symptoms develop, the occurrence
of blastic transformation presenting as CNS involvement by NHL may be significantly more likely than the
quite rare possibility of direct spread of CLL to the CNS.
Such a distinction is of substantial prognostic and therapeutic significance, and such patients deserve detailed
evaluation to define the nature of their CNS disease.
In 1928, Richter35 described a 45-year-old man with
simultaneous presentation of a "reticular cell sarcoma"
(large cell lymphoma) and "lymphatic leukemia"
(CLL). Lortholary and colleagues,25 in 1964, first used
257
Richter's name to describe the occurrence of a "reticulum cell sarcoma" in patients with CLL. Most authors
now apply the term "Richter's syndrome" to the occurrence of a NHL (typically a large cell lymphoma, either
intermediate or high grade in the Working Formulation)
in a patient with CLL.2'40 Some would include Hodgkin's disease and Waldenstrom's macroglobulinemia8"
as acceptable lymphoma components of the syndrome.
Estimates of the incidence of Richter's syndrome among
patients with CLL range from 3 to 11%.2-40 Although the
term Richter's syndrome has not been applied to blastic
transformation of other lymphoid malignancies, there is
suspicion that prolymphocytic transformation of
CLL,14'20 blast crisis of CLL,12'21'22'28'43 and blastic transformation of nodular, follicular, or low-grade NHLs to
more malignant intermediate or high-grade varieties''7'36
may also represent closely related manifestations of the
same malignant progression. Estimates of the incidence
of histologic transformation to an intermediate or highgrade lymphoma among patients with low-grade NHL
range from 12 to 23%.I8 Richter's syndrome, as well as
other blastic transformations of lymphoid malignancies,
may therefore represent the evolution of a morphologically "well-differentiated" or "mature" lymphoid neoplasm into a more malignant lesion.
Several observations lend support to this hypothesis.
The concept of "dedifferentiation" or clonal progression
(emergence of a more malignant clone) as the link between CLL and NHL in Richter's syndrome was originally proposed on the basis of the morphologic appearance of "more mature" and "less mature" cells, respectively, in the two lesions. More recently, additional
evidence supporting this link has become available in
the form of cell surface immunoglobulin isotypic and
immunophenotypic marker studies. Delsol and coworkers8 reported a case of Richter's syndrome with
identical surface immunoglobulin isotypes (IgM kappa)
on peripheral CLL lymphocytes and on lymphoma
cells. Harousseau and colleagues16 reported four cases in
which the surface immunoglobulin heavy and light
chain isotypes were identical on lymphoma cells and
CLL cells. Foucar and Rydell" and Bauman and associates3 reported similar findings in three cases and one
case, respectively.
Cytogenetic studies also lend support to the hypothesis of tumor lineage continuity in cases of Richter's
syndrome. Nowell and associates30 reported a patient
with T-cell CLL for ten years who subsequently had
immunoblastic lymphoma develop, in which serial cytogenetic studies on the CLL and lymphoma cells revealed
persistent identical karyotypic abnormalities in both
tumors.
Our findings in this case report of similar cell surface
immunoglobulin isotypic and immunophenotypic
258
LANE ET AL.
markers on peripheral blood and bone marrow CLL
cells, the CSF tumor cells, and the lymphoma biopsy
tissue lend additional support to the hypothesis of tumor
lineage continuity with clonal progression. In addition,
the presence of increased levels of transferrin receptor31
is thought to correlate with higher mitotic activity and a
higher histologic grade in NHL; ourfindingsof low-level
positivity on bone marrow CLL cells but high-level positivity on extramedullary lymphoma cells support the
concept of transformation of CLL into a more malignant lesion in this case.
On the other hand, Splinter and colleagues37 reported
a single patient with simultaneous CLL and diffuse histiocytic (large cell) lymphoma with differing cell surface
immunoglobulin isotypes; the CLL cells carried IgM
lambda, whereas the lymphoma cells carried IgM kappa.
This suggests the possibility that independent clonal origins may occur at least occasionally in Richter's syndrome. It has been known for many years19 that patients
with CLL are at increased risk of second nonlymphoid
malignancies (including colon, skin, breast, and kidney),
so an increased risk of second independent lymphoid
malignancies may also exist.
Most recently, techniques for the characterization of
highly specific immunoglobulin gene rearrangements in
malignant lymphoid cell populations have become
available. Different cell populations arising from a single
precursor clone should share identical immunoglobulin
gene rearrangement patterns (assuming the oncogenic
event occurs late in lymphoid differentiation, at a stage
subsequent to the gene rearrangement process). Van
Dongen and associates41 used these techniques to study
a single patient with CLL and NHL and found different
immunoglobulin heavy chain rearrangements in the
different cell populations, concluding that the two malignancies in that patient were of independent, nonclonal origin. However, in that case, the surface immunoglobulin light chain isotypes also differed; more importantly, the NHL occurred after a 23-year history of
CLL treated with both radiation therapy and chemotherapy, so an independent, therapy-related second malignancy might not be unexpected.
The future application of such precise analytic techniques to material from patients with Richter's syndrome (and from patients with blastic transformations
of other lymphoid malignancies) is likely to provide additional evidence on the question of a clonal origin of
the different malignant cell proliferations.
Acknowledgments. The authors acknowledge the expert assistance of
technologists in the Immunology and Hematology Sections, Clinical
Laboratories, and the Histology Laboratory, Anatomic Pathology,
Moffitt-Long Hospitals, University of California, San Francisco, California. They also thank Thomas McHugh, M.S., MT(ASCP), and
Daniel P. Stites, M.D., for helpful advice and comments, and they
thank Bernice Musante for typing and editing the manuscript.
A.J.C.P. • February 1988
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