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Hypercalcemia May Indicate Richters Syndrome


Report of Four Cases and Review

Johann Beaudreuil, M.D.1


Olivier Lortholary, M.D.1
Antoine Martin, M.D.2
Jean Feuillard, M.D.3
Loic Guillevin, M.D.1
Pierre Lortholary, M.D.3
Martine Raphael, M.D.3
Philippe Casassus, M.D.1

BACKGROUND. Hypercalcemia has rarely been reported in patients with Richters


syndrome (RS). In this article, the authors report four cases with complementary
pathophysiologic examinations.
METHODS. Four patients with hypercalcemia that indicated RS were admitted to
the study unit between 1980 and 1994 with the following diagnoses: transformation

Service de Medecine Interne, Hopital Avicenne, Universite Paris-Nord, Cedex, France.


2

Service dAnatomie et Cytologie Pathologiques, Hopital Avicenne, Universite Paris-Nord,


Cedex, France.
3

Service dHematologie Biologique, Hopital Avicenne, Universite Paris-Nord, Cedex, France.

of mixed follicular lymphoma, Waldenstroms macroglobulinemia, and chronic


lymphocytic leukemia, respectively, in 3 men ages 60 to 73 years, and chronic
lymphocytic leukemia in a woman 73 years of age. Radiologic and histologic features were reported. Circulating levels of parathormone-related peptide (PTHrP),
tumor necrosis factor-alpha (TNF-a), and interleukin-6 (IL-6) were measured.

RESULTS. Radiologic skeletal abnormalities were found in three of three cases:


osteopenia twice and multifocal osteolysis once. All four patients had large cell
lymphoma (LCL). Bone resorption assessed histomorphometrically was elevated
in two of two cases. Serum TNF-a and IL-6 levels were high in three of three and
one of three cases, respectively. Elevated values were also found in four patients
with LCL but without hypercalcemia. The serum PTHrP level was increased in the
only hypercalcemic patient tested and values were normal in the three control
patients.
CONCLUSIONS. Hypercalcemia arising in a patient with a low grade lymphoproliferative disorder may indicate RS. Hypercalcemia is due to increased bone resorption,
which may be caused by the secretion of osteoclast-stimulating factors by the
LCL invading the bone marrow. Independently, TNF-a and/or IL-6 were unlikely
causative factors of hypercalcemia in the patients in this study; however, synergism
with PTHrP was suspected in one case. Cancer 1997;79:12115.
q 1997 American Cancer Society.

KEYWORDS: Richters syndrome, hypercalcemia, bone resorption, cytokines, parathormone-related peptide.

H
The authors thank Janet Jacobson for her careful review of the article.
Address for reprints: Olivier Lortholary, Service
de Medecine Interne, Hopital Avicenne, Universite Paris-Nord, 125, route de Stalingrad,
93009 Bobigny Cedex, France.
Received August 19, 1996; revision received
November 25, 1996; accepted November 25,
1996.

ypercalcemia has been described as arising during the course of


Hodgkins or non-Hodgkins lymphoma,1 and adult T-cell leukemia.1,2 Its pathophysiology is attributed to the production of local
and/or systemic factors, such as cytokines, calcitriol, or parathormone-related peptide (PTHrP).1 3 Richters syndrome (RS) is defined
as a high grade lymphoma occurring during the course of a low grade
lymphoproliferative disease.4 Hypercalcemia has rarely been reported
during RS.5 8 The authors report four cases of such an association,
including complementary examinations undertaken to study hypercalcemia.

PATIENTS AND METHODS


Patients
This study included patients admitted to the Department of Internal
Medicine at Avicenne Hospital between January 1980 and December
1994.

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Lymphoproliferative disorders were diagnosed


based on bone marrow or lymph node biopsy, according to the International Working Formulation.9

Histomorphometry
Bone resorption was histomorphometrically assessed
on decalcified osteomedullar biopsies in Cases 3 and
4, and in one control patient with nonhypercalcemic
RS. Paraffin sections (5-mm thick) were stained with
hematoxylin, eosin, and safran. Eroded surfaces were
defined as the percentage of total trabecular surfaces
on which marks of previous resorption were visible,
whether or not they contained osteoclasts.10 Measurements were made with a semiautomatic image analyzer (Biocom, Les Ulis, France).
Cytokine and PTHrP Assays
Before starting antineoplastic chemotherapy, venous
blood was collected in an ethylenediamine tetraacetic
acid-coated sterile tube from nonfebrile, hypercalcemic cancer patients. Tumor necrosis factor-a (TNF-a)
and interleukin-6 (IL-6) were assayed using immunoradiometric methods (Medgenix, Fleurus, Belgium) in
Cases 2, 3, and 4; normal values were, 0 12 pg/mL
and 6 30 pg/mL, respectively. In Case 4, the PTHrP
level was also evaluated using an immunoradiometric
assay (Nichols Institute, Wijchen, The Netherlands)
before antineoplastic chemotherapy was administered; normal values were 0 1.3 pmol/L. As controls,
four patients with progressive large cell lymphoma
(LCL) without hypercalcemia were also investigated
for cytokines and three were investigated for PTHrP.
Case Reports
Four cases of RS with hypercalcemia have been identified from 34 RS and 304 low grade lymphoma patients
admitted to the study unit during the 15-year study
period.

Case 1
A 65-year-old man was treated monthly with chlorambucil for Waldenstroms macroglobulinemia (WM)
from August 1975 to August 1978. He was then maintained in remission without treatment and had normal
serum calcium levels. The patient was readmitted in
February 1980 for diffuse bone pain. His liver and
spleen were enlarged. Biologic test results were as follows: the serum calcium level was 3.27 mmol/L (normal values 2.06 2.50 mmol/L); serum albumin was
28.2g/L; the leukocyte count was 7.6 1 109/L with 76%
neutrophils and 9% lymphocytes; hemoglobin was 11
g/dL; the platelet count was 390 1 109/L; and immunoglobulin M kappa was 14.4 g/L. Phosphorus level and
kidney function were within normal values. Bone marrow
biopsy showed a diffuse immunoblastic lymphoma,

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which led to the diagnosis of RS. Skeletal radiography


showed diffuse osteopenia without any local lytic bone
lesions. The circulating PTH level was low, as assessed by
radioimmunoassay (carboxy-terminal region). The patient received saline perfusions and mithramycin (1.5 mg
every 3 days) for 6 days. Monthly antineoplastic chemotherapy rapidly resulted in complete remission of the disease. Six months after the diagnosis of RS, the patient died
of septic shock due to Klebsiella pneumoniae, without any
remitting hypercalcemia.

Case 2
A 60-year-old man was treated for an inguinal mixed follicular lymphoma from December 1988 to July 1989, when
a complete remission of the disease was obtained. For a
histologically proven recurrence occurring in September
1991, he received 10 cycles of antineoplastic chemotherapy over the following year until October 1992, when
partial remission of the disease was obtained. At that time,
biologic test results were as follows: the leukocyte count
was 3.4 1 109/L; hemoglobin was 12.1g/dL; the platelet
count was 109 1 109/L; and lactate dehydrogenase (LDH)
was 241 U/L (normal values 100-200 U/L). The serum
calcium level was normal. In November 1992, the patient
was admitted for asthenia, emesis, night sweats, and further enlargement of inguinal adenopathy. The serum calcium level was 4.94 mmol/L; serum albumin was 34
g/L; alkaline reserve was 35 mmol/L (normal values
2029 mmol/L); the leukocyte count was 17.35 1 109/L
with 62% neutrophils and 14% lymphocytes; the hemoglobin level was 12.1 g/dL; the platelet count was 68 1
109/L; and LDH was 930 U/L. Serum creatinine, phosphorus, sodium, and potassium were normal. Chest radiography showed mediastinal adenopathies. Bone marrow biopsy results revealed diffuse immunoblastic lymphoma.
Serum calcitriol measured by radioimmunoassay was below normal values. Serum TNF-a and IL-6 levels were 25
pg/mL and 38 pg/mL, respectively. Hypercalcemia fell
rapidly after treatment with saline perfusions, calcitonin,
and intravenous pamidronate. Nevertheless, the patient
died after receiving 2 monthly cycles of chemotherapy
because of septicemia occurring during profound neutropenia. On the day of death, his serum calcium level was
normal.

Case 3
A 73-year-old woman was treated for B-cell chronic
lymphocytic leukemia (CLL) by monthly chemotherapy from January 1993 to December 1993, when a partial remission of the disease was obtained. At that time,
her leukocyte count, hemoglobin, and serum calcium
levels were normal, but her LDH was 283 U/L, and
hepatosplenomegaly and bone marrow infiltration
persisted. Chlorambucil treatment, 5 days per month,
was started. The patient was readmitted in January

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Richters Syndrome and Hypercalcemia/Beaudreuil et al.

1994 for generalized weakness and confusion. Physical


examination detected enlarged adenopathies. Results
of laboratory analyses were as follows: the serum calcium level was 4.25 mmol/L; serum albumin was 26
g/L; alkaline reserve was 34 mmol/L; and urinary calcium was 7.5 mmol/mmol of creatinine (normal values 0.45). The lymphocyte count was 20 1 109/L;
hemoglobin was 9.7 g/dL; the platelet count was 94 1
109/L; and the LDH was 300 U/L. Other biologic tests
were normal. Skeletal radiography showed diffuse osteopenia. Osteomedullar biopsy showed massive LCL
infiltration leading to the diagnosis of RS and 6.09%
eroded surfaces. Serum calcitriol, as evaluated by radioimmunoassay, was low. Serum TNF-a and IL-6 levels were 64 pg/mL and 15 pg/mL, respectively. Rehydration, calcitonin, and pamidronate associated with
antineoplastic chemotherapy daily for 5 days rapidly
lowered the serum calcium level. Despite clinical improvement, the patient died of septic shock due to
Staphylococcus aureus and Candida albicans in February 1994. At the time of death, her serum calcium level
was 3.51 mmol/L and her disease was in partial remission.

Case 4
A 73-year-old man with a 7-year history of CLL considered to be in remission was admitted in December
1994 for weight loss, weakness, confusion, and pain in
the left ribs. Physical examination revealed generalized
lymphadenopathies. The serum calcium level was 3.52
mmol/L; serum albumin was 34 g/L; the leukocyte
count was 42 1 109/L with 80% blast cells; hemoglobin
was 9.1 g/dL; and the platelet count was 125 1 109/L.
Other biologic tests were normal. Skeletal radiography
revealed multifocal osteolysis in the left ribs, with intense isotope uptake on bone scintigraphic scans.
Bone marrow biopsy showed diffuse LCL infiltration
consistent with a diagnosis of RS and 1.9% eroded
surfaces. Serum intact PTH (1 84) and calcitriol levels
measured by radioimmunoassays were below normal
values. Serum PTHrP was 2.1 pmol/L; TNF-a was 153
pg/mL; and IL-6 was 89 pg/mL. Treatment was comprised of rehydration, intravenous pamidronate, and
methylprednisolone with antineoplastic chemotherapy. The serum calcium level returned to normal
within 48 hours but the patient died of septic shock
after 4 cycles of chemotherapy, 6 months after RS was
diagnosed based on an uncontrollable lymphoma. The
patients serum calcium level was normal at the time
of his death.
None of these patients had a history of taking any
medication that could induce hypercalcemia or clinical, laboratory, or imaging evidence of the presence
of a solid tumor.

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Controls
Eroded surfaces, as assessed on bone marrow paraffin
sections in a 72-year-old male with marrow-infiltrating
nonhypercalcemic RS, were 0.0018%. They appeared
to be much lower than eroded surfaces in Cases 3 and
4. None of the 3 controls in this study had an elevated
PTHrP level. TNF-a levels ranged from 32 to 116 pg/
mL and IL-6 levels ranged from 6 to 106 pg/mL in the
4 controls in the current study.

DISCUSSION
RS has been described as an LCL complicating the
course of a low grade lymphoproliferative disorder.4
RS was first reported in patients with CLL11 but it can
also occur in patients with low grade lymphoma or
WM.4,11,12 Using strict definition criteria, its frequency
is estimated to be between 3 6% of CLL, 4% of WM,
and 12% of non-Hodgkins lymphoma patients.12 15 RS
is characterized by sudden and intense clinical deterioration, resistance to conventional antineoplastic
therapy, and a poor prognosis with a survival time of
usually 5 months. LCL cells may share a common
clonal origin with those of the low grade lymphoma,
but a second malignancy arising from a distinct clone
cannot yet be ruled out.16,17
Herein, the authors describe four cases of RS with
hypercalcemia. This association has been inconsistently noted in the series of patients with RS.4,12 15,18,19
Among series of 17, 39, and 9 transformed CLL, it has
been observed 2, 2, and 1 times respectively.13 15 To
the authors knowledge, until now, only four cases
have been reported in detail (Table 1).5 8 All patients
with RS and associated hypercalcemia initially had
CLL. Bone marrow invasion by LCL was histologically
proven in three cases.5,7,8 Radiologic skeletal abnormalities were also observed three times: diffuse osteopenia twice and multifocal osteolysis once.6 8
These findings strongly suggest that hypercalcemia is
due to bone destruction, which could result from a
local interaction between LCL cells and bone cells.
Furthermore, increased osteoclastic bone resorption
was histomorphometrically assessed in one previously
described patient.6
Hypercalcemia during malignancy is mainly due
to solid tumors.20,21 In the current study cases, there
was no evidence of such malignancies. Moreover,
there was no evidence of drug-induced hypercalcemia
and primary hyperparathyroidism. Indeed, circulating
PTH was low in two patients and metabolic alkalosis
was noted in the remaining two patients, which contrasts with metabolic acidosis usually observed in primary hyperparathyroidism.19 Furthermore, serum
phosphorus levels were normal in the four patients in
the current study. These data are consistent with the
observation that RS-associated hypercalcemia is asso-

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TABLE 1
Clinical, Pathologic, and Evolutive Data for Patients with RS and Hypercalcemia: Previously Reported Cases (n 4) and
Current Study Cases (n 4)

Gender

Initial
disease

Duration
before
RS (mos)

RS
involvement
of BM/bone

59
72
56
82
65
60

Female
Female
Female
Female
Male
Male

CLL
CLL
CLL
CLL
WM
MFL

63
48
0
0
54
47

//0
///
///
0//
///
//

Case 3a

73

Female

CLL

12

///

Case 4a

73

Male

CLL

84

///

Authors

Age
(yrs)

Benvenisti et al.5
Desablens et al.6
Rossi et al.7
Trump et al.8
Case 1a
Case 2a

Metabolic
response

Treatment
Chemotherapy, forced diuresis
Chemotherapy, bisphosphonates
Chemotherapy, calcitonin
Chemo/radiotherapy mithramycin
Chemotherapy, mithramycin
Chemotherapy, bisphosphonates
and calcitonin
Chemotherapy, bisphosphonates
and calcitonin
Chemotherapy, bisphosphonates
and methylprednisolone

Partial
Total

Tumoral
response

Survival after RS and


hypercalcemia (mos)
0.5

None
Partial

Total/relapse
Total
Total

Total
None

6
2
6
2

Total/relapse

Partial

Total

Total/relapse

RS: Richters syndrome; BM: bone marrow; CLL: chronic lymphocytic leukemia; WM: Waldenstroms macroglobulinemia; MFL: mixed follicular lymphoma.
a
Current study.

ciated with increased bone resorption.3 Indeed, bone


radiologic abnormalities were present in three of the
four patients in the current study, one of whom had
high urinary calcium excretion, a biochemical marker
of osteoclast activity.22
Bone resorption, histomorphometrically assessed
as eroded surfaces in osteomedullar biopsies, was dramatically higher in the study cases than in one control
patient with bone marrow-invading RS and a normal
serum calcium level. Bone resorption inhibitors, such
as bisphosphonates, calcitonin, and glucocorticoids,
were effective in lowering serum calcium levels in all
four cases. The particularly low eroded surfaces in the
control case in the current study compared with normal previously reported values, can be explained by
the authors technical conditions.23,24 The biopsies in
the current study were neither transiliac bone biopsy
specimens nor undecalcified.
The increased osteoclast activity observed in the
patients in the current study is likely due to the local
production of stimulating factors by the LCL cells that
invaded the bone marrow in every case. Indeed, bone
marrow involvement by the LCL was only observed in
11 50% of patients with RS without hypercalcemia.4,11,12,18,19 Moreover, bone marrow infiltration in
other lymphoproliferative disorders has been associated with increased histomorphometric bone resorption parameters.23,24 These parameters were particularly elevated when lytic bone lesions or hypercalcemia were present.
High levels of serum TNF-a observed in three patients and IL-6 in one patient may reflect local production in the bone marrow. These cytokines may cause
increased bone resorption but their serum levels were

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also elevated in control patients without hypercalcemia. IL-6 and TNF-a are potent activators of bone
resorption25,26 and elevated serum levels were previously reported in patients with lymphoproliferative
disorders.27 29 Both cytokines may act synergically
with PTHrP to increase bone resorption. Such a complex interaction between TNF-a, PTHrP, and IL-6
could have been responsible for the hypercalcemia
observed in Case 4. Synergism between TNF-a and
PTHrP in the pathogenesis of hypercalcemia in the
other three patients may be postulated but not confirmed herein. PTHrP and TNF-a were reported to induce hypercalcemia in a patient with CLL.30 PTHrP is
responsible for hypercalcemia-complicating carcinomas in the absence of bone metastases,3 but it also
appears to be implicated in some metastatic breast
carcinomas, in adult T-cell leukemia/lymphoma, and
in B-cell lymphoma.31 33 In all these malignancies,
PTHrP may act locally on bone cells.
Other than hypercalcemia, the presentations of the
four patients with RS did not differ from published data
for gender, age, interval between diagnosis of lymphoproliferative disease, and its transformation.4,11,12,18,19 Furthermore, hypercalcemia cannot be considered a factorworsening prognosis, because survival did not appear to
be shorter than that usually observed in patients with RS.
In conclusion, hypercalcemia arising during the
course of a low grade lymphoproliferative disease may
indicate RS. This complication appears to be due to
increased bone resorption. The results of the current
study suggest the involvement of tumoral secretion of
TNF-a, IL-6, and PTHrP in the pathogenesis of increased bone resorption and consequent hypercalcemia in one case (Case 4). The pathogenesis of hyper-

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calcemia in the other three patients remains unknown,


but may include PTHrP secretion by LCL cells. Even
if hypercalcemia appears to be sensitive to bone resorption inhibitors, the LCL remains difficult to control and the prognosis is poor.

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