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ARTICLE

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Parathyroid Hormone-Related Protein as a Cause of Hypercalcemia in a B-cell Type Malignant Lymphoma Seiki Wada, Hideyuki Kitamura, Yoshifusa Matsuura*, Yasuyuki Katayama, Hidenori Ohkawa, Nobuo Kugai, Kazuo Motoyoshi, Yusuke Fuse* and Naokazu Nagata Hypercalcemia occurred in a patient with non-Hodgkin's (B-cell type) lymphoma when generalized lymphadenopathy developed. Despite low normal plasma parathyroid hormone (PTH), nephrogenous CAMP (NcAMP) was not suppressed, and serum and urine PTH-related protein (PTH-rP) levels were elevated. The plasma level of 1,25(OH)2D was within normal range. The combined chemotherapies successfully reduced the tumor size, serum Ca, PTH-rP, and lactic dehydrogenase. Serum osteocalcin was suppressed while the patient was hypercalcemic, and increased after chemotherapy. In the extract of the tumor tissue obtained post mortem, bioactivity stimulating the production of CAMP in osteoblasts was demonstrated along with the immunoreactive PTH-rP. This is the first report of a B-cell lymphoma producing PTH-rP and its association with humoral hypercalcemia of malignancy. (Internal Medicine 31: 968-972, 1992) Key words: malignancy associated hypercalcemia, osteocalcin (bone GLA protein: BGP), hydroxypro line

Introduction lymphoma: ATLL) are frequently complicated with hyper calcemia and have been demonstrated to produce PTH-rP Hypercalcemia often occurs patients malignancy. (7, 8). However, as far as weinare able towith ascertain, never Its pathophysiology is heterogeneous and is commonly has a B-cell lymphoma produced such results. separated Here we report into three the first categories: case of ahumoral B-cell lymphoma hypercalcemia pro of malignancy ducing immunologically (HHM) ; hypercalcemia detectable PTH-rP associated withwith biological localized osteolytic disease (LOH); and associated activity. We also examined thehypercalcemia changes of indices of Cawith hematologic metabolism,malignancies i.e., PTH-rP, (1). osteocalcin (bone ^-carboxy HHM is a pathological condition in which tumorglutamic-acid-containing protein: and hydroxy produced hormone-like factors areBGP), responsible for the proline during the clinical course. hypercalcemia (1); parathyroid hormone (PTH)-related Subjects and Methods protein (PTH-rP) is well recognized as the most important causative factor in HHM, increasing osteoclastic bone resorption and renal Ca reabsorption like PTH (2, 3). Subject Among The subject the hematologic of this study malignancies, was a 40-year lymphomas old male, who of various had hadtypes non-Hodgkin's also develop follicular hypercalcemia, medium and sizedmultiple cell type mechanisms lymphoma for have seven beenyears, discussed and had as the undergone causes of many hypercalcemia. A lymphoma has been demonstrated to convert courses of combined chemotherapy (cyclophosphamide, 25-hydroxyvitamin D to 1,25 dihydroxyvitamin hydroxydaunomycin, vincristine, prednisolone: D CHOP). He [1 ,25(OH)2D] (4); elevated serum 1,25(OH)2D concentrawas admitted in January 1991 because of generalized tions have been observed in some lymphoma cases lymphadenopathy and hypercalcemia. Serum lacticwith de hypercalcemia (5, 6).was However, the(normal production of hydrogenase (LDH) 2349 U/l 100-225), 1,25(OH)2D is not the rule in most lymphoma cases (1). alkaline phosphatase (ALP) 181 U/lT-cell (normal 30-110), T-cell lymphomas (especially, adult leukemia/ serum creatinine 1.7 mg/dl (normal 0.7-1.3), and From the Third Department of Internal Medicine and *the Second Department of Pathology, National Defense Medical College, Tokoro Received for publication January 13, 1992; Accepted for publication April 23, 1992 Reprint requests should be addressed to Dr. Seiki Wada, the Third Department of Internal Medicine, National Defense Medical College 3-2, Namiki, Tokorozawa-shi, Saitama 359, Japan 968 Internal Medicine Vol. 31, No. 8 (August 1992)

PTH-rP and Hypercalcemia Table

1. Laboratory

S e ru m C a (m g / d l) U rin e C a (m g / g -c rea ) T m P O 4/ G F R (m g / d l) N c A M P (n m o l/ d lG F) H S -P T H (p g / m l) C - P T H (p g / m l)

Data for Ca Metabolism J a n . 12 1 4 .9 124 3 .2 2 .1 210 200

F eb .22 18 .2 1 12 0 1 .6 2 .8 10 0 300

N orm al (8 .5 - 10 .2 ) (< 120) (2 .3 - 4 .5 ) (0 .8 - 2 .8 ) (1 6 0 - 2 50 ) ォ 500)

of B-Lymphoma

(CD5), J5 (CD10), B-l (CD20), and I a (HLA-DR) (Becton Dickinson, San Joe, CA) (15). Results

Change in the chemical data during hospitalization is demonstrated in Fig. 1. After the first course of VIPP (etoposide, ifosfamide, prednisolone, procarbazine), the s er u m P T H -rP (p m o l/ 1) 307 3 10 (2 1 .8 - 4 4 .8 ) serum Ca was successfully controlled to 9 mg/dl for two u rin e P T H -rP (p m o l/ g -c re a) 1350 13 6 0 (3 2 0 - 7 80 ) B G P (n g / m l) < 1.0 < 1 .0 (2 .0 - 5 .2 ) weeks along with reduction of the tumor size, LDH, and H y d ro x y p ro lin e (m g / g *c re a) 33 58 (2 3 - 4 8) PTH-rP. With the recurrence of general lymphadenopathy, 2 5 (O H )D (n g /m l) 10 (1 0 - 5 5) serum Ca and PTH-rP again began to increase in parallel, 1 ,2 5 (O H )2D (p g / m l) 41 (2 0 - 7 0 ) and the second course of VIPP achieved only a minimal TmPO4: transport maximum of phosphate reabsorption, GFR: and transient effect. Another combined chemotherapy glomerular filtration rate, NcAMP: nephrogenous cyclic adenosine (enocitabin, acrarubicin, etoposide, prednisolone: ABEP) mono-phosphate, GF: glomerular filtrate, 25(OH)D: 25 hydroxyvitamin along with pamidronate did reduce the tumor size and serum D, 1 ,25(OH)2D: 1,25 dihydroxyvitamin D, crea: creatinine. Ca, and a surge of LDH and PTH-rP, probably was related to tumor-lysis, occurred. However, bone marrow suppres glomerular filtration rate (GFR) 51.3 ml/min. The sion, pneumonia, heart failure, and renal failure ensued, laboratory data of Ca metabolism on admission is shown and the patient died on the April 8, 1991. The serum BGP in Table 1. Lytic bone lesions were found at the right level was not detectable when the serum levels of Ca and scapula and humerus, and abnormal accumulation was PTH-rP were high, but was detectable when both were Autopsy revealed generalized lymph node invasion of demonstrated in the thoracic and lumbar vertebrae by controlled (Fig. 1, lower panel). in the retroperitoneum and malignant lymphoma, especially 99mTc diphosphonate scanning. Ma terials Fasting sera and second urine in the morning were stored at -80°C before measurement of PTH-rP, BGP, and hydroxyproline. Tumor tissue obtained at autopsy was extracted with acid/urea followed by ethanol/NaCl frac tionation according to Burtis et al (9), and was also examined for cellular surface antigens. Meth ods PTH-rP in the serum, urine, and tumor extract were measured by C-terminal region specific radioimmunoassay for human PTH-rP (109-141) (Daiichi Radioisotope Laboratories, Ltd. Tokyo) (10). BGP in the blood was measured by BGP immunoradiometric assay (IRMA) kit (Mitsubishiyuka Co., Ltd. Tokyo). Urine hydroxyproline and creatinine were measured according to the methods of Kivirikko et al (ll), and Bosnes and Taussky (12), respectively, and the concentration of urine hydroxyproline was expressed per gram of urine creatinine. PTH-like adenylate cyclase-stimulating activity was examined by measuring CAMP production in an osteoblastic cell MC3T3E1? as previously reported (13). Cyclic AMP was measured by radioimmunoassay (Yamasa Shoyu Co., Chiba). PTH (mid-region assay) and vitamin D were commercially measured by SRL Inc, Tokyo. All serum Ca The surface the tumor examined by albumin values wereantigens correctedofbased on thewere respective serum indirect immunoalkaline-phosphatase method using level according to Payne et al (14). monoclonal antibodies: Leu 1 (cluster of differentiation Internal

Medicine

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1992)

pelvic cavity. Histopathologically, lymphoma cells and an

DAYS AFTER ADMISSION Fig. 1. Clinical course. After successful combined chemotherapies, serum Ca, LDH, and PTH-rP decreased, while serum BGP increased. APD: pamidronate, crea: creatinine, Ccr: creatinine clearance, HYP: hy droxyproline. Normal values in our laboratory: BGP, 2.0-5.2 ng/ml; hydroxypro line, 23-48 mg/g. creatinine. 969

Wada et al increased number of osteoclasts were demonstrated in the vertebral bones (Fig. 2). PTH-rP (109-141) immunologically detected was 10 pmol in 1 g of wet tissue (Fig. 3). The tumor extract in creased CAMP production in MC3T3EJ cells dose dependency, and the dose response relationship was essentially equal to that of human PTH-rP (1-34) (Table 2).On immunological characterization, the tumor cells were positive for CD10, CD20 (pan B antigen), and HLA-DR, and negative for CD5 (pan T antigen), indicating the tumor originated from B lymphocytes. Discussion The case presented here is the first case of a B cell Fig. 2. Histopathological demonstration of vertebral bone resected lymphoma producing PTH-rP, and causing hypercalcemia post mortem. Note increased number of osteoclasts and large resorptive through the mechanism of HHM. In malignant lymphoma, pits on the bone. (HE stain, x200) Canellos reported that hypercalcemia occurs in 1.8% of cases, sometimes during the clinical course (16). Although a special type of T cell lymphoma (ATLL) has been reported to produce PTH-rP (7, 8), a non-Hodgkin's B-cell lymphoma hss never been confirmed to produce PTH-rP, even hypercalcemic In thisincase, high levels conditions. of serum and urine PTH-rP were detected immunologically, and the values decreased in response to effective combined chemotherapies in parallel with other tumor markers such as tumor size, LDH, and Ca. In the extract of this tumor, PTH-rP was detectable immunologically by RIA, and biologically by the stimula tion of CAMP production in MC3T3E! cells. These results indicate that this B-cell lymphoma produced PTH-rP. Using the C-terminal PTH-rP radioimmunoassay, we also examined the serum levels in some cases of HHM (un Fig. 3. Immunological PTH-rP in the tumor extract (A). PTH-rP published data), including esophageal cancer, squamous cell cancer, and ATLL. In those patients, the serum levels was assayed by radioimmunoassay using antibody against the C lung terminal of PTH-rP (1-141) (#). of PTH-rP ranged from 120 to 1300 pmol/1, comparable to the present case. Similar values have been reported by Watanabe et al (17) and Bando et al (18), employing the Table 2. The Effect of the Tumor Extract and same assay kit. The tissue C-terminal PTH-rP level in this PTH-rP on CAMP Production in MC3T3E1 Cells case was 10 pmol in 1 g of wet tissue. We previously measured the content of PTH-rP in leiomyosarcoma and CA M P p ro ductio n (p m oles/m l) breast cancer associated with HHM, using antibody raised V eh icle 6.2 + 0 .3 1 against PTH-rP (1-34). The levels of PTH-rP (1-34) in T u m o r extract these tumors were 5.7 pmol and 9.7 pmol in 1 g of wet 0 .06 m g/m 1 7.9 ア 0 .40 The level of NcAMP in this case was not as high as that 0 .18 m g/m 1 14.7 ア 1 .2* tissue, respectively (19, 20). 0 .54 m g/m 1 17.6 ア 1 .4 * generally reported in HHM patients (21). This fact may 1.62 m g/m 1 2 2.3 ア 4 .3* indicate that the measurement of serum PTH-rP is more P T H -rP sensitive in the diagnosis of HHM compared to NcAMP i(r lOM 12 .2 + 2 .2 * 1(T 9M 36.4 + 5.3* which may be influenced by various factors such as renal function or coexisting tumor products. Regarding the *p

Parathyroid hormone-related protein as a cause of hypercalcemia in a B-cell type malignant lymphoma.

Hypercalcemia occurred in a patient with non-Hodgkin's (B-cell type) lymphoma when generalized lymphadenopathy developed. Despite low normal plasma pa...
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