1211

Hypercalcemia May Indicate Richters SyndromeReport of Four Cases and Review

BACKGROUND. Hypercalcemia has rarely been reported in patients with RichtersJohann Beaudreuil, M.D.1

syndrome (RS). In this article, the authors report four cases with complementaryOlivier Lortholary, M.D.1

pathophysiologic examinations.Antoine Martin, M.D.2METHODS. Four patients with hypercalcemia that indicated RS were admitted toJean Feuillard, M.D.3the study unit between 1980 and 1994 with the following diagnoses: transformationLoic Guillevin, M.D.1of mixed follicular lymphoma, Waldenstroms macroglobulinemia, and chronicPierre Lortholary, M.D.3lymphocytic leukemia, respectively, in 3 men ages 60 to 73 years, and chronicMartine Raphael, M.D.3lymphocytic leukemia in a woman 73 years of age. Radiologic and histologic fea-Philippe Casassus, M.D.1tures were reported. Circulating levels of parathormone-related peptide (PTHrP),

tumor necrosis factor-alpha (TNF-a), and interleukin-6 (IL-6) were measured.1 Service de Medecine Interne, Hopital Avi- RESULTS. Radiologic skeletal abnormalities were found in three of three cases:cenne, Universite Paris-Nord, Cedex, France.

osteopenia twice and multifocal osteolysis once. All four patients had large cell2 Service dAnatomie et Cytologie Patholog- lymphoma (LCL). Bone resorption assessed histomorphometrically was elevatediques, Hopital Avicenne, Universite Paris-Nord, in two of two cases. Serum TNF-a and IL-6 levels were high in three of three andCedex, France.

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 the3 Service dHematologie Biologique, Hopital Avi-cenne, Universite Paris-Nord, Cedex, France. only hypercalcemic patient tested and values were normal in the three control

patients.

CONCLUSIONS. Hypercalcemia arising in a patient with a low grade lymphoprolifer-ative 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, para-thormone-related peptide.

Hypercalcemia has been described as arising during the course ofHodgkins or non-Hodgkins lymphoma,1 and adult T-cell leuke-mia.1,2 Its pathophysiology is attributed to the production of localand/or systemic factors, such as cytokines, calcitriol, or parathor-mone-related peptide (PTHrP).13 Richters syndrome (RS) is definedas a high grade lymphoma occurring during the course of a low gradelymphoproliferative disease.4 Hypercalcemia has rarely been reportedThe authors thank Janet Jacobson for her care-

ful review of the article. during RS.58 The authors report four cases of such an association,including complementary examinations undertaken to study hyper-

Address for reprints: Olivier Lortholary, Service calcemia.de Medecine Interne, Hopital Avicenne, Uni-versite Paris-Nord, 125, route de Stalingrad, PATIENTS AND METHODS93009 Bobigny Cedex, France.

PatientsThis study included patients admitted to the Department of InternalReceived August 19, 1996; revision receivedMedicine at Avicenne Hospital between January 1980 and DecemberNovember 25, 1996; accepted November 25,

1996. 1994.

q 1997 American Cancer Society

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1212 CANCER March 15, 1997 / Volume 79 / Number 6

Lymphoproliferative disorders were diagnosed which led to the diagnosis of RS. Skeletal radiographyshowed diffuse osteopenia without any local lytic bonebased on bone marrow or lymph node biopsy, ac-

cording to the International Working Formulation.9 lesions. The circulating PTH level was low, as assessed byradioimmunoassay (carboxy-terminal region). The pa-tient received saline perfusions and mithramycin (1.5 mgHistomorphometry

Bone resorption was histomorphometrically assessed every 3 days) for 6 days. Monthly antineoplastic chemo-therapy rapidly resulted in complete remission of the dis-on decalcified osteomedullar biopsies in Cases 3 and

4, and in one control patient with nonhypercalcemic ease. Six months after the diagnosis of RS, the patient diedof septic shock due to Klebsiella pneumoniae, without anyRS. Paraffin sections (5-mm thick) were stained with

hematoxylin, eosin, and safran. Eroded surfaces were remitting hypercalcemia.defined as the percentage of total trabecular surfaceson which marks of previous resorption were visible, Case 2

A 60-year-old man was treated for an inguinal mixed fol-whether or not they contained osteoclasts.10 Measure-ments were made with a semiautomatic image ana- licular lymphoma from December 1988 to July 1989, when

a complete remission of the disease was obtained. For alyzer (Biocom, Les Ulis, France).histologically proven recurrence occurring in September1991, he received 10 cycles of antineoplastic chemother-Cytokine and PTHrP Assays

Before starting antineoplastic chemotherapy, venous apy over the following year until October 1992, whenpartial remission of the disease was obtained. At that time,blood was collected in an ethylenediamine tetraacetic

acid-coated sterile tube from nonfebrile, hypercalce- biologic test results were as follows: the leukocyte countwas 3.4 1 109/L; hemoglobin was 12.1g/dL; the plateletmic cancer patients. Tumor necrosis factor-a (TNF-a)

and interleukin-6 (IL-6) were assayed using immunor- count was 1091 109/L; and lactate dehydrogenase (LDH)was 241 U/L (normal values 100-200 U/L). The serumadiometric methods (Medgenix, Fleurus, Belgium) in

Cases 2, 3, and 4; normal values were, 012 pg/mL calcium level was normal. In November 1992, the patientwas admitted for asthenia, emesis, night sweats, and fur-and 630 pg/mL, respectively. In Case 4, the PTHrP

level was also evaluated using an immunoradiometric ther enlargement of inguinal adenopathy. The serum cal-cium level was 4.94 mmol/L; serum albumin was 34assay (Nichols Institute, Wijchen, The Netherlands)

before antineoplastic chemotherapy was adminis- g/L; alkaline reserve was 35 mmol/L (normal values 2029 mmol/L); the leukocyte count was 17.35 1 109/Ltered; normal values were 01.3 pmol/L. As controls,

four patients with progressive large cell lymphoma with 62% neutrophils and 14% lymphocytes; the hemo-globin level was 12.1 g/dL; the platelet count was 68 1(LCL) without hypercalcemia were also investigated

for cytokines and three were investigated for PTHrP. 109/L; and LDH was 930 U/L. Serum creatinine, phospho-rus, sodium, and potassium were normal. Chest radiogra-phy showed mediastinal adenopathies. Bone marrow bi-Case Reports

Four cases of RS with hypercalcemia have been identi- opsy results revealed diffuse immunoblastic lymphoma.Serum calcitriol measured by radioimmunoassay was be-fied from 34 RS and 304 low grade lymphoma patients

admitted to the study unit during the 15-year study low normal values. Serum TNF-a and IL-6 levels were 25pg/mL and 38 pg/mL, respectively. Hypercalcemia fellperiod.rapidly after treatment with saline perfusions, calcitonin,and intravenous pamidronate. Nevertheless, the patientCase 1

A 65-year-old man was treated monthly with chloram- died after receiving 2 monthly cycles of chemotherapybecause of septicemia occurring during profound neutro-bucil for Waldenstroms macroglobulinemia (WM)

from August 1975 to August 1978. He was then main- penia. On the day of death, his serum calcium level wasnormal.tained in remission without treatment and had normal

serum calcium levels. The patient was readmitted inFebruary 1980 for diffuse bone pain. His liver and Case 3

A 73-year-old woman was treated for B-cell chronicspleen were enlarged. Biologic test results were as fol-lows: the serum calcium level was 3.27 mmol/L (nor- lymphocytic leukemia (CLL) by monthly chemother-

apy from January 1993 to December 1993, when a par-mal values 2.062.50 mmol/L); serum albumin was28.2g/L; the leukocyte count was 7.6 1 109/L with 76% tial remission of the disease was obtained. At that time,

her leukocyte count, hemoglobin, and serum calciumneutrophils and 9% lymphocytes; hemoglobin was 11g/dL; the platelet count was 3901 109/L; and immuno- levels were normal, but her LDH was 283 U/L, and

hepatosplenomegaly and bone marrow infiltrationglobulin M kappa was 14.4 g/L. Phosphorus level andkidney function were within normal values. Bone marrow persisted. Chlorambucil treatment, 5 days per month,

was started. The patient was readmitted in Januarybiopsy showed a diffuse immunoblastic lymphoma,

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Richters Syndrome and Hypercalcemia/Beaudreuil et al. 1213

1994 for generalized weakness and confusion. Physical ControlsEroded surfaces, as assessed on bone marrow paraffinexamination detected enlarged adenopathies. Results

of laboratory analyses were as follows: the serum cal- sections in a 72-year-old male with marrow-infiltratingnonhypercalcemic RS, were 0.0018%. They appearedcium level was 4.25 mmol/L; serum albumin was 26

g/L; alkaline reserve was 34 mmol/L; and urinary cal- to be much lower than eroded surfaces in Cases 3 and4. None of the 3 controls in this study had an elevatedcium was 7.5 mmol/mmol of creatinine (normal val-

ues 0.45). The lymphocyte count was 20 1 109/L; PTHrP level. TNF-a levels ranged from 32 to 116 pg/mL and IL-6 levels ranged from 6 to 106 pg/mL in thehemoglobin was 9.7 g/dL; the platelet count was 94 1

109/L; and the LDH was 300 U/L. Other biologic tests 4 controls in the current study.were normal. Skeletal radiography showed diffuse os-teopenia. Osteomedullar biopsy showed massive LCL DISCUSSION

RS has been described as an LCL complicating theinfiltration leading to the diagnosis of RS and 6.09%eroded surfaces. Serum calcitriol, as evaluated by ra- course of a low grade lymphoproliferative disorder.4

RS was first reported in patients with CLL11 but it candioimmunoassay, was low. Serum TNF-a and IL-6 lev-els were 64 pg/mL and 15 pg/mL, respectively. Rehy- also occur in patients with low grade lymphoma or

WM.4,11,12 Using strict definition criteria, its frequencydration, calcitonin, and pamidronate associated withantineoplastic chemotherapy daily for 5 days rapidly is estimated to be between 36% of CLL, 4% of WM,

and 12% of non-Hodgkins lymphoma patients.1215 RSlowered the serum calcium level. Despite clinical im-provement, the patient died of septic shock due to is characterized by sudden and intense clinical deteri-

oration, resistance to conventional antineoplasticStaphylococcus aureus and Candida albicans in Febru-ary 1994. At the time of death, her serum calcium level therapy, and a poor prognosis with a survival time of

usually 5 months. LCL cells may share a commonwas 3.51 mmol/L and her disease was in partial remis-sion. clonal origin with those of the low grade lymphoma,

but a second malignancy arising from a distinct clonecannot yet be ruled out.16,17

Case 4 Herein, the authors describe four cases of RS withA 73-year-old man with a 7-year history of CLL consid- hypercalcemia. This association has been inconsis-ered to be in remission was admitted in December tently noted in the series of patients with RS.4,1215,18,191994 for weight loss, weakness, confusion, and pain in Among series of 17, 39, and 9 transformed CLL, it hasthe left ribs. Physical examination revealed generalized been observed 2, 2, and 1 times respectively.1315 Tolymphadenopathies. The serum calcium level was 3.52 the authors knowledge, until now, only four casesmmol/L; serum albumin was 34 g/L; the leukocyte have been reported in detail (Table 1).58 All patientscount was 421 109/L with 80% blast cells; hemoglobin with RS and associated hypercalcemia initially hadwas 9.1 g/dL; and the platelet count was 125 1 109/L. CLL. Bone marrow invasion by LCL was histologicallyOther biologic tests were normal. Skeletal radiography proven in three cases.5,7,8 Radiologic skeletal abnor-revealed multifocal osteolysis in the left ribs, with in- malities were also observed three times: diffuse os-tense isotope uptake on bone scintigraphic scans. teopenia twice and multifocal osteolysis once.68

Bone marrow biopsy showed diffuse LCL infiltration These findings strongly suggest that hypercalcemia isconsistent with a diagnosis of RS and 1.9% eroded due to bone destruction, which could result from asurfaces. Serum intact PTH (184) and calcitriol levels local interaction between LCL cells and bone cells.measured by radioimmunoassays were below normal Furthermore, increased osteoclastic bone resorptionvalues. Serum PTHrP was 2.1 pmol/L; TNF-a was 153 was histomorphometrically assessed in one previouslypg/mL; and IL-6 was 89 pg/mL. Treatment was com- described patient.6

prised of rehydration, intravenous pamidronate, and Hypercalcemia during malignancy is mainly duemethylprednisolone with antineoplastic chemother- to solid tumors.20,21 In the current study cases, thereapy. The serum calcium level returned to normal was no evidence of such malignancies. Moreover,within 48 hours but the patient died of septic shock there was no evidence of drug-induced hypercalcemiaafter 4 cycles of chemotherapy, 6 months after RS was and primary hyperparathyroidism. Indeed, circulatingdiagnosed based on an uncontrollable lymphoma. The PTH was low in two patients and metabolic alkalosispatients serum calcium level was normal at the time was noted in the remaining two patients, which con-of his death. trasts with metabolic acidosis usually observed in pri-

None of these patients had a history of taking any mary hyperparathyroidism.19 Furthermore, serummedication that could induce hypercalcemia or clini- phosphorus levels were normal in the four patients incal, laboratory, or imaging evidence of the presence the current study. These data are consistent with the

observation that RS-associated hypercalcemia is asso-of a solid tumor.

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1214 CANCER March 15, 1997 / Volume 79 / Number 6

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

Duration RSAge Initial before involvement Metabolic Tumoral Survival after RS and

Authors (yrs) Gender disease RS (mos) of BM/bone Treatment response response hypercalcemia (mos)

Benvenisti et al.5 59 Female CLL 63 //0 Chemotherapy, forced diuresis Partial 0.5Desablens et al.6 72 Female CLL 48 /// Chemotherapy, bisphosphonates Total NoneRossi et al.7 56 Female CLL 0 /// Chemotherapy, calcitonin Partial 6Trump et al.8 82 Female CLL 0 0// Chemo/radiotherapy mithramycin Total/relapse 2Case 1a 65 Male WM 54 /// Chemotherapy, mithramycin Total Total 6Case 2a 60 Male MFL 47 // Chemotherapy, bisphosphonates Total None 2

and calcitoninCase 3a 73 Female CLL 12 /// Chemotherapy, bisphosphonates Total/relapse Partial 2

and calcitoninCase 4a 73 Male CLL 84 /// Chemotherapy, bisphosphonates Total Total/relapse 6

and methylprednisolone

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 also elevated in control patients without hypercalce-mia. IL-6 and TNF-a are potent activators of boneradiologic abnormalities were present in three of the

four patients in the current study, one of whom had resorption25,26 and elevated serum levels were pre-viously reported in patients with lymphoproliferativehigh urinary calcium excretion, a biochemical marker

of osteoclast activity.22 disorders.2729 Both cytokines may act synergicallywith PTHrP to increase bone resorption. Such a com-Bone resorption, histomorphometrically assessed

as eroded surfaces in osteomedullar biopsies, was dra- plex interaction between TNF-a, PTHrP, and IL-6could have been responsible for the hypercalcemiamatically higher in the study cases than in one control

patient with bone marrow-invading RS and a normal observed in Case 4. Synergism between TNF-a andPTHrP in the pathogenesis of hypercalcemia in theserum calcium level. Bone resorption inhibitors, such

as bisphosphonates, calcitonin, and glucocorticoids, other three patients may be postulated but not con-firmed herein. PTHrP and TNF-a were reported to in-were effective in lowering serum calcium levels in all

four cases. The particularly low eroded surfaces in the duce hypercalcemia in a patient with CLL.30 PTHrP isresponsible for hypercalcemia-complicating carcino-control case in the current study compared with nor-

mal previously reported values, can be explained by mas in the absence of bone metastases,3 but it alsoappears to be implicated in some metastatic breastthe authors technical conditions.23,24 The biopsies in

the current study were neither transiliac bone biopsy carcinomas, in adult T-cell leukemia/lymphoma, andin B-cell lymphoma.3133 In all these malignancies,specimens nor undecalcified.

The increased osteoclast activity observed in the PTHrP may act locally on bone cells.Other than hypercalcemia, the presentations of thepatients in the current study is likely due to the local

production of stimulating factors by the LCL cells that four patients with RS did not differ from published datafor gender, age, interval between diagnosis of lympho-invaded the bone marrow in every case. Indeed, bone

marrow involvement by the LCL was only observed in proliferative disease, and its transformation.4,11,12,18,19 Fur-thermore, hypercalcemia cannot be considered a factor-1150% of patients with RS without hypercalce-

mia.4,11,12,18,19 Moreover, bone marrow infiltration in worsening prognosis, because survival did not appear tobe shorter than that usually observed in patients with RS.other lymphoproliferative disorders has been associ-

ated with increased histomorphometric bone resorp- In conclusion, hypercalcemia arising during thecourse of a low grade lymphoproliferative disease maytion parameters.23,24 These parameters were particu-

larly elevated when lytic bone lesions or hypercalce- indicate RS. This complication appears to be due toincreased bone resorption. The results of the currentmia were present.

High levels of serum TNF-a observed in three pa- study suggest the involvement of tumoral secretion ofTNF-a, IL-6, and PTHrP in the pathogenesis of in-tients and IL-6 in one patient may reflect local produc-

tion in the bone marrow. These cytokines may cause creased bone resorption and consequent hypercalce-mia in one case (Case 4). The pathogenesis of hyper-increased bone resorption but their serum levels were

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Richters Syndrome and Hypercalcemia/Beaudreuil et al. 1215

16. Traweek ST, Liu J, Johnson RM, Winberg CD, Rappaport H.calcemia in the other three patients remains unknown,High-grade transformation of chronic lymphocytic leukemiabut may include PTHrP secretion by LCL cells. Evenand low-grade non-Hodgkins lymphoma. Genotypic con-

if hypercalcemia appears to be sensitive to bone re- firmation of clonal identity. Am J Clin Pathol 1993;100:519sorption inhibitors, the LCL remains difficult to con- 26.trol and the prognosis is poor. 17. Matolcsy A, Inghirami G, Knowles DM. Molecular genetic

demonstration of the diverse evolution of Richters syn-REFERENCES drome (chronic lymphocytic leukemia and subsequent large1. Seymour JF, Gagel RF. Calcitriol: the humoral mediator of cell lymphoma). Blood 1994;83:136372.

hypercalcemia in Hodgkins disease and non-Hodgkins 18. Cullen MH, Lister TA, Brearley RL, Shand WS, Stansfeld AG.lymphomas. Blood 1993;82:138394. Histological transformation of non-Hodgkins lymphoma.

2. Kiyokawa T, Yamaguchi K, Takeya M, Takahashi K, Wata- Cancer 1979;44:64551.nabe T, Matsumoto T, et al. Hypercalcemia and osteoclast 19. Foucar K, Rydell RE. Richters syndrome in chronic lympho-proliferation in adult T-cell leukemia. Cancer 1987;59:1187 cytic leukemia. Cancer 1980;46:11834.91. 20. Adami S, Rossini M. Hypercalcemia of malignancy: patho-

3. Mundy GR. Incidence and pathophysiology of hypercalce- physiology and treatment. Bone 1992;13:515.mia. Calcif Tissue Int 1990;(Suppl)46:310. 21. Muggia M. Overview of cancer-related hypercalcemia: epi-

4. Harousseau JL, Flandrin G, Tricot G, Brouet JC, Seligmann demiology and etiology. Semin Oncol 1990;(Suppl)5:39.M, Bernard J. Malignant lymphoma supervening in chronic 22. Nordin BE. Diagnostic procedures in disorders of calciumlymphocytic leukemia and related disorders. Cancer 1981; metabolism. Clin Endocrinol 1978;8:55 67.48:13028. 23. Marcelli C, Chappard D, Rossi JF, Jaubert J, Alexandre C,

5. Benvenisti DS, Sherwood LM, Heineman HO. Hypercalce- Dessauw P, et al. Histologic evidence of an abnormal bonemic crisis in acute leukemia. Am J Med 1969;46:97684. remodeling in B-cell malignancies other than multiple my-

6. Desablens B, Sebert JL, Claisse JF, Fardellonne P, Piprot- eloma. Cancer 1988;62:1163 70.Choffat C, Traulle C. Hypercalcemie revelant la transforma- 24. Rossi JF, Chappard D, Marcelli C, Laplante J, Commes T,tion histologique dune leucemie lymphoide chronique. Pre-

Baldet P, et al. Micro-osteoclast resorption as a characteris-sse Med 1986;15:892.

tic feature of B-cell malignancies other than multiple my-7. Rossi JF, Bataille R, Chappard D, Alexandre C, Janbon C. B

eloma. Br J Haematol 1990;76:46975.cell malignancies presenting with unusual bone involve-

25. Bertolini DR, Nedwin GE, Bringman TS, Smith DD, Mundyment and mimicking multiple myeloma. Am J Med

GR. Stimulation of bone resorption and inhibition of bone1987;83:106.

formation in vitro by human tumor necrosis factors. Nature8. Trump DL, Mann RB, Phelps R, Roberts H, Concley CL. Rich-

1986;319:5168.ters syndrome: diffuse histiocytic lymphoma in patients

26. Rosol TJ, Capen CC. Mechanisms of cancer-induced hyper-with chronic lymphocytic leukemia. Am J Med 1980;68:539calcemia. Lab Invest 1992;67:680702.48.

27. Matsuda K, Yamamoto N, Kaneko T, Iwahashi M, Hashimoto9. The non-Hodgkins lymphomas pathologic classificationS, Araki K. Hypercalcaemia and serum TNF-a in T-cell leu-project. National Cancer Institute sponsored study of classi-kaemia. Lancet 1990;i:1032.fication of non-Hodgkins lymphomas: summary and de-

28. Foa R, Massaia M, Cardona S, Tos AG, Bianchi A, Attisanoscription of a working formulation for clinical usage. CancerC, et al. Production of tumor necrosis factor-alpha by B-cell1982;49:211235.chronic lymphocytic leukemia cells: a possible regulatory10. Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H,role of TNF in the progression of the disease. Blood 1990;Meunier PJ, et al. Bone histomorphometry: standardization76:393400.of nomenclature, symbols and units. J Bone Miner Res

29. Kato H, Kinoshita T, Suzuki S, Nagasaka T, Murate T, Saito1987;2:595610.H, et al. Elevated serum interleukin-6 (IL-6) is derived from11. Lortholary P, Boiron M, Ripault P, Levy JP, Manus A, Bernardneoplastic lymphoid cells in patients with B-cell non-Hodg-J. Leucemie lymphoide chronique secondairement associeekins lymphoma: correlation with extent of IL-6 expressiona` une reticulopathie maligne, syndrome de Richter. Nouvand serum concentration. Br J Haematol 1996;92:101421.Rev Fr Hematol 1964;4:62144.

30. Fain O, MSelmi AE, Dosquet C, Meseur D, Lejeune F, Garel12. Coiffier B, Sebban C, Berger F, Bryon PA, Magaud JP, FfrenchJM, et al. Hypercalcemia in B cell chronic lymphocytic leuke-M, et al. Transformation histologique des syndromesmia. Br J Haematol 1994;87:8568.lympho-proliferatifs de faible malignite. Presse Med 1985;

31. Martin TJ, Grill V. Hypercalcemia in cancer. J Steroid Bio-14:122936.chem Mol Biol 1992;43:1239.13. Armitage JO, Dick FR, Corder MP. Diffuse histiocytic

32. Ikeda K, Ohno H, Hane M, Yokoi H, Okada M, Honma T, etlymphoma complicating chronic lymphocytic leukemia.al. Development of a sensitive two-site immunoradiometricCancer 1978;41:4227.assay for parathyroid hormone-related peptide: evidence for14. Alliot C, Quiquandon I, Demichel M, Claisse JF, Mouillardelevated levels in plasma from patients with adult T-cellP, Desablens B. Syndrome de Richter: 17 cas parmi 401 leu-leukemia/lymphoma and B-cell lymphoma. J Clin Endocri-cemies lymphodes chroniques. Rev Med Interne 1991;nol Metab 1994;79:13227.(Suppl)6:332.

33. Kremer R, Shustik C, Tabak T, Papavasiliou V, Goltzman D.15. Robertson LE, Pugh W, OBrien S, Kantarjian H, Hirsh-Gins-berg C, Cork A, et al. Richters syndrome: a report on 39 Parathyroid-hormone-related peptide in hematologic malig-

nancies. Am J Med 1996;100:40611.patients. J Clin Oncol 1993;11:19859.

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