Hypercalcemia Associated with T-cell Lymphoma-leukemia
BERNARD GROSSMAN, M.D., GERALDINE P. SCHECHTER, M.D., JOHN E. HORTON, M.D., LAWRENCE PIERCE, M.D.,
ELAINE JAFFE, M.D., AND LARRY WAHL, PH.D.
Veterans Administration Medical Center, The Washington
Hospital Center, and the George Washington University
School of Medicine, Washington, D. C, National Cancer
Institute and National Institute of Dental Research, NIH,
Bethesda, Maryland, and Harvard University School of
Dental Medicine, Boston, Massachusetts
Grossman, Bernard, Schechter, Geraldine P., Horton, John
E . , Pierce, Lawrence, Jaffe, Elaine, and Wahl, Larry: Hypercalcemia associated with T-cell lymphoma-leukemia. Am J Clin
Pathol 75: 1 4 9 - 1 5 5 , 1981. Two adults who had T-cell lymphoma-leukemia and recurrent hypercalcemia in the absence of
radiographic evidence of bone disease are described. Bone histopathology showed marked osteoclastic activation. Bone resorbing factors, including both prostaglandin E and a material
produced in the presence of a prostaglandin synthetase inhibitor, were detected in the in-vitro culture fluids of malignant
cells of one of the patients. Serum levels of parathyroid hormone
were not elevated. These findings suggest that hypercalcemia
resulted from in-vitro osteoclast activation by tumor cell produces), one of which may be similar, if not identical, to the
lymphocyte product osteoclast-activating factor. Two other
patients having T-cell lymphoma-leukemia and hypercalcemia
have been identified in the literature: the malignant cells of
one of these patients also released a calcium-mobilizing factor
in vitro. (Key words: T-cell lymphoma; Hypercalcemia; Osteoclast-activating factor.)
Reports of Two Cases
Case I
A 46-year-old black man came to the Washington Veterans Administration Hospital for evaluation of a six-week history of malaise, a
30-pound weight loss, vomiting, constipation, polydypsia. and polyuria. He reported a transient episode called "aplastic anemia" for
which blood tranfusions were given 15 years previously, but confirmation was not possible. On examination, several 1- to 1.5-cm firm
nodes were found in the posterior cervical areas, the right supraclavicular fossa, and both axillae. The liver and spleen were not
palpable. Neurologic examination revealed a mild confusional state.
The skin was normal.
THE occurrence of hypercalcemia associated with
non-Hodgkin's lymphoma is rare. Large series4-24"33
have estimated the frequency of this phenomenon to be
in the order of 2%. In none of the previous studies were
the surface marker characteristics of the malignant cells
known. The predilection for multiple myeloma, for example, to cause hypercalcemia might suggest that
lymphomas of the B-cell type would be more likely to
be associated with this metabolic disorder. It was therefore surprising to document tumor-related hypercalcemia with disseminated T-cell lymphoma. The histopathologic features in both patients were interpreted as
malignant lymphoma: diffuse poorly differentiated
lymphocytic type in one patient and diffuse mixed cell
type in the other. Neither patient had lytic bone lesions
or evidence of excess parathyroid hormone secretion.
In-vitro culture of the leukemic cells of one patient,
but not the other, was associated with release of factors
capable of inducing bone resorption via osteoclast
activation. Bone biopsy specimens from both showed
osteoclast bone resorption.
Received March 31, 1980; accepted for publication April 15, 1980.
Dr. Schechter received support from the Medical Research Service
of the Veterans Administration.
Address reprint request to Dr. Schechter: Hematology Section
(151G), Veterans Administration Medical Center, 50 Irving Street,
N.W., Washington, D. C. 20422.
Laboratory values included a hematocrit of 43% and a leukocyte
count of 16,000//nl with 54% lymphocytes, many with nucleoli and
lobulated nuclei. The serum calcium was 17.3 mg/dl; phosphorous.
1.8 mg/dl: blood urea nitrogen (BUN). 45 mg/dl; creatinine. 3.9 mg/dl;
alkaline phosphatase, 195 mU/ml (normal, less than 80). Serum protein electrophoresis was normal. Shortening of the QT interval
was noted on the electrocardiogram. The serum level of parathyroid hormone, determined by radioimmunoassay (Metpath®),
was 100 jul Eq/ml (normal, less than 300). A bone scan showed increased but uniform uptake in bone adjacent to large joints, as well as
in the greater trochanteric areas of both femurs and the skull, consistent with increased bone turnover due to metabolic causes. Roentgenograms of the chest, hands, skull, and lower extremities were normal.
A liver-spleen scan was also normal. The bone marrow could not be
aspirated, but a touch preparation of the biopsy specimen showed
infiltration with lymphoid cells similar to those seen in the peripheral
blood, as well as many osteoblasts and osteoclasts. The marrow
biopsy was normocellular and showed focal infiltrates of atypical
large lymphoid cells with irregular nuclear contours. The lymphoid
infiltrates were not paratrabecular, but within the marrow space. A
right cervical lymph node biopsy was performed and showed diffuse
infiltration by atypical lymphoid cells that varied in size. Larger cells
had open nuclear chromatin and small nucleoli, whereas small cells
had condensed nuclear chromatin and inconspicuous nucleoli. Many
cells had irregular nuclear contours. The lymph node contained
numerous small venules (post-capillary venules) whose walls were
also infiltrated by the atypical lymphoid cells (Fig. 1). The pathologic
diagnosis was malignant lymphoma, diffuse poorly differentiated
lymphocytic type. Surface marker studies of the peripheral blood and
lymph node lymphocytes showed the abnormal lymphocytes to have
membrane characteristics of T cells (see below and Table 1). The
0002-9173/81/0200/0149 $00.85 © American Society of Clinical Pathologists
149
150
A.J.C.P. • February 1981
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Vol. 75 . No. 2
T-CELL LYMPHOMA-LEUKEMIA AND HYPERCALCEMIA
15 1
FIG. 1 (upper, left). Lymph node biopsy specimen from Patient 1. Lymph node is diffusely replaced by atypical lymphoid cells.
The postcapillary venule is infiltrated by tumor cells (arrow). Hematoxylin and eosin. x375.
FIG. 2 (upper, right; center, right). Peripheral blood smear from Patient 2. Atypical lymphoid cells with multilobulated,
hyperchromatic nuclei, Wright's stain. x950.
FIG. 3 (lower). Bone marrow biopsy specimen from Patient 2. Marked osteoclastic activity is seen. Marrow is mildly hypercellular:
no tumor is identified. Hematoxylin and eosin. x250.
<
peripheral blood lymphoid cells did not contain terminal transferase
activity.*
The patient's hypercalcemia was resistant to saline infusion, furosemide, oral phosphorus, and calcitonin. After the institution of
chemotherapy that included cyclophosphamide, hydroxyldaunomycin, vincristine, and prednisone (CHOP), 1 " the serum calcium fell
from a pretreatment level of 13.7 mg/dl to 8.5 mg/dl within 48 hours
and reached a nadir of 6.6 mg/dl on the third day. One week postchemotherapy, the lymph nodes disappeared, the leukocyte count
dropped to 900/p\, and abnormal lymphoid cells were no longer evident in the peripheral blood. The patient's serum calcium and leukocyte cell count rose to normal by the second week, and he was able to
be discharged.
He remained in clinical remission under treatment with CHOP for
five months before lymphadenopathy recurred. Six weeks later, he
had a simultaneous recurrence of hypercalcemia (calcium, 16.8 mg/
dl; phosphate, 3.5 mg/dl) and infiltration of the peripheral blood,
with a leukocyte count of 19,000//xl with 90% lymphoid cells. During
the last two months of his life, he was treated with bleomycin,
CCNU, VP16, and cis-platinum, and appeared to have no, or at best
transient, response to these agents. Recurrent episodes of hypercalcemia, often associated with marked lymphocytosis, responded to
mithramycin and prednisone. Phosphorous levels at the time of
hypercalcemia varied from 2.5 to 4.9 mg/dl. Although the final hypercalcemia episode also responded to mithramycin (serum calcium
fell from 20.8 to 5.7 mg/dl), the patient remained comatose and died
of an undiagnosed pulmonary infiltrative process. Permission for an
autopsy was not granted.
Case 2
A 43-year-old black woman was hospitalized at the Washington
Hospital Center after a two-month history of fever, chills, night
sweats, anorexia with a 15-pound weight loss, conjunctivitis, rhinitis,
* Assay kindly performed by the laboratory of Dr. R. C. Gallo,
National Cancer Institute, National Institutes of Health.
pharyngitis, hoarseness, and an exfoliative rash of the palms and
soles. Inguinal and cervical node enlargement occurred one week
before admission, and oral ampicillin and penicillin failed to arrest
her symptomatology. Positive physical findings included dry pigmented scaling of skin of the palms and soles, 1-cm generalized
adenopathy in all superficial nodal chains, uveitis, conjunctivitis,
dry mouth, metacarpal-phalangeal joint swelling and tenderness, and
an enlarged spleen palpated 3 cm beneath the left costal margin.
Initial laboratory values revealed a hematocrit of 44% and a leukocyte count of 26,000/til with 20%-30% atypical lymphocytes containing multilobulated, hyperchromatic nuclei (Fig. 2). The platelet
count, BUN, creatinine, liver function tests, hepatitis B antigen,
fluorescent antinuclear antibody, uric acid, and serum protein electrophoresis were normal, but the serum calcium was 12.8 and phosphorus 2.8 mg/dl. The chest roentgenogram was normal, as were the
liver-spleen, salivary gland, and bone scans. A serum parathyroid
hormone level (Herner Analytics®) was 0.6 pg/ml (normal, 0-1.5 pg/
ml) when serum calcium was 13.8 mg/dl. The serum calcium persisted
in the range of 10.9-14 mg/dl despite hydration and treatment with
calcitonin, but returned to normal with parenteral prednisone therapy.
A biopsy of the involved skin showed an intraepidermal pustule
and was considered nondiagnostic. The lymphoid cells were small,
with condensed nuclear chromatin and markedly irregular or cerebriform nuclei. A liver biopsy did not show tumor. Bone marrow aspirate
and biopsy were hypercellular with a single lymphoid nodule: increased osteoblasts and osteoclasts were also present. An axillary
node biopsy revealed a paracortical proliferation of small irregular
lymphocytes and large immunoblasts. Although a lymphoproliferative disease was thought likely, a precise diagnosis was not established; therefore, diagnostic splenectomy with liver and abdominal
node biopsies was performed. The spleen weighed 650 g. It was
beefy-red in color with blurring of the demarcation between the red
and white pulp. Histologic sections showed expansion of the white
pulp, in particular the periarteriolar lymphoid sheaths or thymicdependent zones. Follicles were present, often containing atrophic
hyalinized germinal centers. A mixed population of atypical lymphoid cells infiltrated the involved white pulp. Some cells were extremely large, with irregular vesicular nuclei and prominent nucleoli.
Table I. Surface Marker Studies of Peripheral Blood and Lymph Node Lymphocytes
from Two Patients with T-cell Lymphoma-leukemia
% T
% B
Untreated Sheep
Erythrocytes
AET-treated Sheep
Erythrocytes*
SIg Assay
Complementreceptor Assay
Patient 1
Blood mononuclear cells
Lymph node cells
—
—
81
76
6
5
II
8
Patient 2
Blood mononuclear cellst
5
55
10
9
* AET, 2-aminoethylisothiouronium bromide.
t % binding neuraminidase-treated sheep erythrocytes was 20%.
GROSSMAN ET AL.
152
A.J.C.P. • February 1981
FIG. 4. E-rosetted peripheral blood leukemic cells from Patient 1. The pleomorphic
nature of the nuclear size and chromatin,
and cytoplasmic vacuolization are evident.
There was a broad morphologic spectrum, with smaller cells having a
condensed nuclear chromatin and markedly hyperconvoluted nuclei.
The red pulp was diffusely infiltrated by the smaller cell component.
Lymph nodes showed paracortical infiltration by an infiltrate cytologically similar to that in the spleen; follicular sparing was present.
Surface membrane studies of the peripheral blood mononuclear leukocytes showed them to be T cells with low-affinity receptors for
sheep erythrocytes (Table 1). The histologic diagnosis was malignant
lymphoma, diffuse, mixed cell type (T-cell lymphoma). Terminal
transferase activity was not present.t
The patient made an uneventful postoperative recovery and received an initial course of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP). 6 She was discharged improved with a
normal serum calcium, only to be readmitted ten days later with
increasing somnolence, respiratory distress, and hypotension. A
chest roentgenogram revealed bilateral patchy infiltrates. The serum
calcium and phosphorus were 18.6 and 6.1 mg/dl, respectively, and
creatinine was 0.8 mg/dl. Despite treatment with steroids, hydration
with saline and furosemide, pressors, and antibiotics, the patient died
shortly after admission.
Autopsy confirmed the presence of a T-cell lymphoma with cutaneous and visceral involvement. Sections of clinically involved skin
(palms and soles) showed an atypical dermal and epidermal infiltrate
composed of hyperchromatic and hyperconvoluted lymphoid cells.
Numerous Pautrier microabscesses were present. Extracutaneous
involvement was found in the lymph nodes, lungs, liver, kidneys,
and bone marrow. Increased numbers of osteoclasts and osteoblasts
with peritrabecular fibrosis were again present in the marrow (Fig. 3).
Other findings included marked pulmonary edema and metastatic
calcification of the myocardium and renal tubules. The parathyroid
glands were small and histologically normal, containing 50% fat.
Special Procedures
Membrane Surface Marker Studies of Lymphoid Cells
Blood mononuclear leukocytes were isolated by centrifugation on Hypaque-Ficoll®. Lymph node cells
t Kindly assayed by Dr. Jerome Donlon, National Institutes of
Health.
were obtained by mincing nodes in tissue culture medium (TC 199, GIBCO). The percentage of T cells was
determined by using untreated 2 or 2-aminoethylisothiouronium bromide (AET)-treated sheep erythrocytes. 13
Cytocentrifuge preparations of the rosetted cells were
stained with Wright-Giemsa and examined by light
microscopy (x 1,500). Membrane surface immunoglobulin was detected by using antiimmunoglobulin antisera (Meloy) and flourescence phase microscopy. 1
Lymphocytes bearing complement receptors were detected by using fluoresceinated complement-coated
salmonellae. 8
Assay of Leukocyte Supernatants
Bone Resorbing Activity
for
Blood mononuclear leukocytes were isolated as
above and cultured in BGJ b medium (GIBCO) and 0.5%
autologous plasma at a cell concentration of 1-1.5
x 106 cells/ml. In selected instances, indomethacin
(10 - 5 M) was also added to the cultures. After 24 hours
of incubation at 37 C, the supernatant medium was
removed and frozen at - 4 0 C until it was assayed for
bone resorbing activity. The organ culture technic to
assay resorption from bone explants has been described. 23 Briefly, paired shafts of the radius and ulna
from 19-day rat fetuses radiolabeled by injection of the
mother with 250 /u.Ci of 45Ca (New England Nuclear) on
the previous day were incubated at 37 C in BGJ b medium supplemented with bovine serum albumin, Lglutamine, penicillin, and streptomycin. After 24'hours
of incubation to remove exchangeable 45 Ca, the bone
shafts were transferred to a culture vessel containing
test medium (leukocyte culture supernatant at a 1:4
dilution) or control medium, and cultured for as long as
T-CELL LYMPHOMA-LEUKEMIA AND HYPERCALCEMIA
Vol. 75 • No. 2
153
Table 2. Bone Resorbing Activity in Leukocyte Culture Fluids*
" C a Release Ratiot
Leukocyte Source
No
Additive
Indomethacin
(10- 5 M)
PGEt
(mol/l)
Patient 1
a. Untreated, serum calcium 15.5 mg/dl
b. With calcitonin, serum calcium 13.7 mg/dl
c. 7 Months later, relapsed, sefum calcium 16.8 mg/dl
d. With mithramycin, serum calcium 6.8 mg/dl
1.26
2.05
1.83
4.96
0.09
0.08
0.08
0.42
—
1.4 x 10-°
0.7 x I0~9
1.48 ± 0.07
1.96 ± 0.10
1.2 x 10"8
Patient 2
a. Untreated
1.26 ± 0-09
1.07 ± 0.03
1.6 x 10"9
Normal controls
1. Simultaneous with Patient 1 (b)
2. Simultaneous with Patient 1 (d)
3. Simultaneous with Patient 2 (a)
1.33 ± 0.09
1.57 ± 0.07
1.26 ± 0.09
1.52 ± 0.04
1.08 ± 0.04
±
±
±
±
1.6 x 10~9
3.0 x 10-"
* Culture conditions for mononuclear leukocytes for 24 hours after which supernatant
fluid was removed and tested for bone resorbing activity.
+ Values for test/control ratio in this series: 1.26 or greater are significantly greater than
I at P < 0.05: 1.48 or greater, at P < 0.01. Parathyroid hormone at 2.8 ill/ml resulted
in ratio of 7.57 ± 0.94.
t PGE. prostaglandin E.
48 hours. Supernatant fluids from the organ cultures
were assayed for the amount of 45Ca released from the
labeled bones by liquid scintillation counting. The data
are expressed as the mean ratio of radioactivity released
(test/control) from the bone cultures. Student's r-test
was used to determine the statistical significance of
replicate data. Certain organ cultures'were also incubated with parathyroid hormone, 2.8 U/ml (Inolex), for
comparison.
Prostaglandin-E (PGE) activity was detected in the
leukocyte supernatants by using a previously described
radioimmunoassay sensitive to both PGE, and PGE 2 . 32
and the single study from Patient 2, only modest levels,
which were not greater than levels found in our normal
peripheral blood controls, were found. Incubating the
cultured cells at 4 C abolished detection of the bone
resorbing activity, which suggests that metabolic activity by the cells was required for its release (data not
shown). Upon hypercalcemic relapse, the in-vitro release of the bone resorbing activity was found to be
partially inhibited by the addition of indomethacin.
Analysis of these leukocyte culture fluids revealed that
the levels of PGE 2 were lower than those reported able
to cause bone resorption in the bioassay used, 20 except
in one set of cultures (Table 2, Id). The cells cujtured in
Id contained a higher concentration of monocytes
(30%) than previously noted (8%).
Results
Surface Marker Studies
The peripheral blood of both patients contained atypical lymphoid cells with receptor characteristics of T
cells (Table 1). The E-rosetted lymphoid cells from both
the blood and the lymph node of Patient 1 had markedly
atypical morphologic features with convoluted and immature-appearing nuclei (Fig. 4). The initial use of untreated sheep erythrocytes in Patient 2 suggested that
the leukemia was of null type, until the studies were
repeated with AET-sheep erythrocytes, a reagent with
increased sensitivity for a subpopulation of T cells with
low-affinity receptors for sheep erythrocytes.
Bone Resorbing
Activity
In two of four studies, culture fluids of peripheral
blood mononuclear cells from Patient 1 contained bone
resorbing activity at levels considerably higher than
those found in culture fluids from normal controls
(Table 2). In two other culture studies from Patient 1
Discussion
Hypercalcemia is an uncommon event, during the
course of lymphoma. In large series of lymphoma patients, its frequency has ranged from 0.3% to 2.8%.4-24'33
The occurrence of hypercalcemia in lymphoma has
been noted in both histiocytic and lymphocytic lymphoma and with and without radiographic evidence of
bone disease. Using the Rappaport classification, our
cases were classified as malignant lymphomas, diffuse
poorly differentiated lymphocytic and mixed cell types,
respectively. However, these two T-cell lymphomas
were characterized by a broad range of maturation.that
does not lend itself readily to that classification. In
Patient 2, features histologically characteristic of
mycosis fungoides were present in the skin; however,
clinically we feel the process is better classified as a
T-cell lymphoma, with cutaneous and visceral involvement. The characteristic indolent history of mycosis
154
GROSSMAN ET AL.
fungoides with a prolonged cutaneous phase was not
present.
The large series cited above and a number of isolated
case reports14'26-28 calling attention to the association
between hypercalcemia and lymphoma for the most
part antedate methods currently available to study cell
surface markers and thereby characterize the origin of
the malignant lymphoid cell. In the present report, this
association was found in two adult patients who had Tcell lymphomas without radiographic evidence of localized skeletal destruction. T-cell lymphoma-leukemias
are more frequently being identified now, but compared
with B-cell malignancies they remain relatively uncommon in adults. In our review of the patients reported to
have T-cell lymphoma-leukemia, two other patients
who had hypercalcemia were identified.12-30 In one of
these patients, evidence for release of a calcium-mobilizing factor by the leukemic cells was also presented.12
Until cell surface markers in a larger series of patients
who have lymphoma and hypercalcemia are characterized, we cannot state whether the association found is
fortuitous or whether it implies certain activities of
a subset of malignant T cells.
Recently, interest has been renewed in mechanisms
underlying the association of hypercalcemia with
lymphocytic and plasma cell malignancies.3-2"-21 This
was initiated by the demonstration that cultures of
normal human mononuclear leukocytes stimulated
with mitogen or antigen contain a bone resorbing factor
termed osteoclast-activating factor (OAF)." Subsequent studies indicated that both activated T- and Blymphocytes were associated with its release.510 This
bone resorbing agent appears to be a protein in the
molecular weight range of 9- 13,000 and has been distinguished from other known stimulators of bone resorption, such as parathyroid hormone, prostaglandins,
and vitamin-D metabolites.'*-1"-17 OAF-like material has
been found in culture fluids of lymphoid cell lines of Tand B-cell types, myeloma cell lines, and also freshly
isolated myeloma cells,7-1"-2"'-2'25 which suggested a
mechanism for the lysis of bone in myeloma. A recent
report described a patient with hypercalcemia and
lymphosarcoma cell leukemia whose leukemic cells in
culture also secreted a bone resorbing agent similar to
OAF.21 However, the cell type of this patient was not
reported.
In our studies of the patients described herein, release of OAF-like material was detected in two of four
cultures of peripheral blood mononuclear leukocytes
derived from Patient 1 while he was leukemic. The
level of bone resorbing activity was markedly greater
than that found in cultured leukocytes from normal
subjects. In the remaining studies and a single study of
A.J.C.P. • February 1981
Patient 2, a more minimal level of bone resorbing activity was found, which did not differ from that in cultures
of normal unstimulated leukocytes. In this laboratory
(G.P.S.), minimal levels of bone resorbing activity are
occasionally found in cultures of unstimulated normal
leukocytes.
Our evidence that the material released by lymphoma
cells and responsible for the bone resorption in vitro is
OAF or OAF-like is indirect. The bone abnormalities
in the patients were consistent in that osteoclastic bone
resorption was prominent. Yet, other materials, including prostaglandins and parathyroid hormone, both
of which have been suggested to be involved in the
production of hypercalcemia,27-31 may account for similar resorption of bone.
Prostaglandins are of particular interest because they
have also been detected in human leukocyte cultures,
and have been shown to be predominantly a product of
monocytes.15 Since mixtures of lymphocytes and
monocytes were cultured in our studies, prostaglandins
could account for part of the bone resorbing activity
observed. Indeed, levels of PGE (the bone resorbing
prostaglandins) in one set of cultures from Patient 1
reached those required for bone resorption to occur in
the bioassay used. However, indomethacin used in
concentrations that inhibit PGE synthesis only partially
inhibited the release of bone resorbing factor, suggesting that a bone resorbing material other than PGE was
present. It is of interest that PGE has recently been
reported to be. a requirement for OAF production in
cultures of human leukocytes.34
Ectopic parathyroid hormone production would appear to be an unlikely candidate in that serum parathyroid hormone levels in both patients were low. In
Patient 1 the serum phosphorous levels were transiently
low only during the first episode of hypercalcemia;
thereafter, the levels were normal.
In vitro, the effect of OAF on bone has been shown
to be highly sensitive to low concentrations of hydrocortisone.21-2" Clinically, the hypercalcemia of lymphoma, similar to that of myeloma, usually responds
rapidly to treatment with corticosteroids. This effect
was amply demonstrated in our patients. While we concede that this result may also be due to a direct lympholytic effect by steroids, it also supports the concept that
hypercalcemia in lymphoma is due to an excess production by malignant lymphoid cells of a lymphocyte product that stimulates the resorption of bone and whose
effect on bone may be modified with steroids.
Now ndclecl in proof: Since this manuscript was submitted the
authors have observed three other adult patients in whom severe
hypercalcemia was one of the initial manifestations of T-cell
lymphoma.
Vol. 75 • No. 2
T-CELL LYMPHOMA-LEUKEMIA AND HYPERCALCEMIA
References
1. Aisenberg AC, Bloch KJ, Long JC: Cell surface immunoglobulins in chronic lymphocytic leukemia and allied disorders.
Am J Med 55:184-191, 1973
2. Bentwich Z, Douglas SD, Siegal FP, et al: Human lymphocyte
sheep erythrocyte rosette formation: some characteristics of
the interaction. Clin Immunol Immunopathol 1:511-522, 1973
3. Brewer HB: Osteoclastic bone resorption and the hypercalcemia
of cancer (editorial). N Engl J Med 291:1081-1082, 1974
4. Canellos GP: Hypercalcemia in malignant lymphoma and leukemia. Ann NY Acad Sci 230:240-246, 1974
5. Chen P, Trummel C, Horton J, et al: Production of osteoclast
activating factor by normal human peripheral blood resetting
and non-rosetting lymphocytes. Eur J Immunol 6:732-736,
1976
6. DeVita VP, Serpick AA, Carbone PO: Combination chemotherapy in the treatment of advanced Hodgkin's disease. Ann
Intern Med 73:881-895, 1970
7. Durie BGM, Salmon SE; Mundy GR: Multiple myeloma: clinical
staging and role of osteoclast activating factor in localized
bone loss. Proceedings, mechanisms of localized bone loss.
Edited by JE Horton, TM Tarpley, WF Davis. Washington
D. C , and London, Information Retrieval Inc., 1978, pp
319-329
8. Gelfand JA, Fauci AS, Green I, et al: A simple method for the
determination of complement receptor-bearing mononuclear
cells. J Immunol 116:595-599, 1976
9. Horton JE, Koopman WJ, Farrar JJ, et al: Partial purification of
a bone resorbing factor elaborated from human allogeneic
cultures. Cell Immunol 43:1-10, 1979
10. Horton JE, Oppenheim JJ, Mergenhagen SE, et al: Macrophage
lymphocyte synergy in the production of osteoclast activating
factor. J Immunol 113:1278-1287, 1974
11. Horton JE, Raisz LG, Simons HA, et al: Bone resorbing activity
in supernatant fluid from human cultured peripheral blood
leukocytes. Science 177:793-795, 1972
12. Ishihara H, Higashi J, Eto K, et al: A case of adult T-cell leukemia associated with hypercalcemia. Jpn J Clin Oncol 8:187194, 1978
13. Kaplan M, Clark C: An improved rosetting assay for detection
of T lymphocytes. J Immunol Methods 5:131-135, 1974
14. Kippen DA, Freeman JB: Isolated histiocytic lymphoma of the
spleen causing fever and hypercalcemia. Arch Surg 112:12331234, 1977
15. Kurland JI, Bockman R: Prostaglandin E production by human
blood monocytes and mouse peritoneal macrophages. J Exp
Med 147:952-957, 1978
16. Luben RA: Purification of a lymphokine: osteoclast activating
factor from human tonsil lymphocytes. Biochem Biophys Res
Commun 84:15-22, 1978
17. Luben RA, Mundy GR, Trummel CL, et al: Partial purification
of osteoclast activating factor from phytohemagglutinin-
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
155
stimulated human leukocytes. J Clin Invest 53:1473-1480,
1974
McKelvey EM, Gottleib JA, Wilson HE, et al: Hydroxyldaunomycin (adriamycin) combination chemotherapy in malignant
lymphoma. Cancer 38:1484-1493, 1976
Mundy GR, Luben RA, Raisz LG, et al: Bone-resorbing activity
in supernatants frb'm lymphoid cell'lines. N Engl J Med 290:
867-871, 1974
Mundy GR, Rajsz LG, Cooper RA, et al: Evidence for the secretion of an osteoclast stimulating factor in myeloma. N Engl
J Med 291:1041-1046, 1974
Mundy GR, Rick ME, Turcotte R, et al; Pathogenesis of
hypercalcemia in lymphosarcoma cell leukemia. Am J Med
65:600-606, 1978
Neiders ME. Horton JE, Kim J, et al: Bone resorbing activity in
supernatant fluids from established lymphoid tumor cell lines.
J Dent Res 57 (Spec. Issue A): 145, 1978
Raisz LG: Bone resorption in tissue culture: factors influencing
the response to parathyroid hormone. J Clin Invest 44:103116, 1965
Rosenberg SA, Diamond HD. Jaslowitz B. et al: Lymphosarcoma: a review of 1,269 cases. Medicine (Baltimore) 40:3184, 1961
Schechter GP, Horton JE, Wahl L: In vitro bone resorption by
human myeloma cells, Progress in myeloma. Edited by M
Potter. Amsterdam, Elsevier, 1980, pp 67-80
Schott GR: Hypercalcemia stupor as a presentation of lymphosarcoma. J Neurol Neurosurg Psych 38:382-385. 1973
Seyberth HW, Segre GV, Morgan JL, et al: Prostaglandins as
mediators of hypercalcemia associated with certain types of
cancer. N Engl J Med 293:1278-1283, 1975
Singer FT. Powell D, Minkin C. et al: Hypercalcemia in reticulum cell sarcoma without hyper-parathyroidism or skeletal
metastases. Ann Intern Med 78:365-369, 1973
Strumpf M, Kowalski MA, Mundy GR: Effects of glucocorticoids on osteoclast activating factor. J Lab Clin Med 92:
772-778, 1978
Stryckmans PA, Debusscher L, Heyder-Bruckner C, et al:
Clonal origin of a T cell lymphoproliferative malignancy.
Blood 52:69-76, 1978
Tashjian AH: Tumor humors and the hypercalcemias of cancer.
N Engl J Med 290:905-906, 1974
Wahl LM, Olsen CE, Wahl SM. et al: Prostaglandin regulated
macrophage collagenase, Proceedings, mechanisms of localized bone loss. Edited by JE Horton, TM Tarpley, WG Davis.
Washington, D. C . and London. Information Retrieval Inc..
1978, pp 181-190
Walker IR: Lymphoma with hypercalcemia. CMA Journal 111:
928-930, 1974
Yondea T, Mundy GR: Prostaglandins are necessary for osteoclast activating factor production by activated peripheral
blood leukocytes. J Exp Med 149:279-283! 1979