Hypercalcemia in malignancies is a frequent complication, mostly affecting patients with solid tumors or multiple myeloma. Calcium elevation is induced by direct bone infiltration of a tumor mass or through calcium liberation from the skeleton by a humoral mediator. The latter mechanism is referred to as humoral hypercalcemia of malignancy (HHM). Frequent mediators of HHM are parathyroid hormone-related peptides (PTHrP). We report a patient with chronic lymphocytic leukemia and hypercalcemia induced by PTHrP. In contrast to solid tumors and myeloma, PTHrP-induced HHM is very rare in low-grad lymphoma including chronic lymphocytic leukemia. Therapeutical approaches consist of cytoreductive treatment and calcium-lowering therapy with bisphosphonates.

Keywords:
Chronic lymphocytic leukemia, Hypercalcemia, Lymphoma, Malignancy, Parathyroid hormone-related peptide
1.
Grill V, Maring TJ: Hypercalcemia of malignancy. Rev Endocr Metab Disord 2000;1:253–263.
2.
Mundy GR, Guise TA: Hypercalcemia of malignancy. Am J Med 1997;103:134–145.
3.
Rankin W, Grill V, Martin TJ: Parathyroid hormone-related protein and hypercalcemia. Cancer 1997;80:1564–1571.
4.
Firkin F, Seymour JF, Watson A, Grill V, Martin TJ: Parathyroid hormone-related protein in hypercalcemia associated with hematological malignancy. Br J Haematol 1996;94:468–492.
5.
Majumdar G: Incidence and prognostic significance of hypercalcemia in B-cell non-Hodgkin’s lymphoma. J Clin Pathol 2002;55:637–638.
6.
Seymour JF, Gagel RF: Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin’s disease and non-Hodgkin’s lymphomas. Blood 1993;85:1383–1394.
7.
Clines GA, Guise TA: Hypercalcemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone. Endocr Relat Cancer 2005;12:549–583.
8.
Beaudreuil J, Lortholary O, Martin A, Feuillard J, Guillevin L, Raphael M, Casassus P: Hypercalcemia may indicate Richter’s syndrome. Cancer 1997;79:1211–1215.
9.
Minina E, Wenzel HM, Kreschel C, Karp S, Gaffield W, McMahon AP, Vortkamp A: BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation. Development 2001;128:4523–4534.
10.
Wysolmerski JJ, Broadus AE, Zhou J, Fuchs E, Milstone LM, Philbrick WM: Overexpression of parathyroid hormone-related protein in the skin of transgenic mice interferes with hair follicle development. Proc Natl Acad Sci USA 1994;91:1133–1137.
11.
Wysolmerski JJ, Philbrick WM, Dunbar ME, Lanske B, Kronenberg H, Broadus AE: Rescue of the parathyroid hormone-related protein knockout mouse demonstrates that parathyroid hormone-related protein is essential for mammary gland development. Development 1998;125:1285–1294.
12.
Schilling T, Pecherstorfer M, Blind E, Leidig G, Ziegler R, Raue F: Parathyroid hormone-related protein (PTHrP) does not regulate 1,25-dihydroxyvitamin D serum levels in hypercalcemia of malignancy. J Clin Endocrinol Metab 1993;76:801–803.
13.
Southby J, Kissin MW, Danks JA, Haymann JA, Moseley JM, Henderson MA: Immunhistochemical localization of parathyroid hormone-related protein in human breast cancer. Cancer Res 1990;50:7710–7716.
14.
Sato K, Fujii Y, Kasono K, Ozawa M, Imamura H, Kanaji Y, Kurosawa H, Tsushima T, Shizume K: Parathyroid hormone-related protein and interleukin-1 alpha synergistically stimulate bone resorption in vitro and increase the serum calcium concentration in mice in vivo. Endocrinology 1989;124:2172–2178.
15.
Guise TA, Yoneda T, Yates AJP, Mundy GR: The combined effect of tumor-produced parathyroid hormone-related peptide and transforming growth factor enhance hypercalcemia in vivo and bone resorption in vitro. J Clin Endocrinol Metab 1993;77:40–45.
16.
Fukumoto S, Matsumoto T, Ikeda K, Yamashita T, Watanabe T, Yamaguchi K, Kiyokawa T, Takatsuki K, Shibuya N, Ogata E: Clinical evaluation of calcium metabolism in adult T-cell leukemia/lymphoma. Arch Intern Med 1988;148:921–925.
17.
Watanabe T, Yamaguchi K, Takatsuki K, Osame M, Yoshida M: Constitutive expression of parathyroid hormone-related protein gene by the human T-cell leukemia virus type 1 (HTLV-1) tax and HTLV-2 tax proteins. Blood 1993;81:1017–1024.
18.
Fain O, el M’Selmi A, Dosquet C, Meseure D, Lejeune F, Garel JM, Thomas M: Hypercalcemia in B cell chronic lymphocytic leukemia. Br J Haematol 1994;87:856–858.
19.
Lemer D, Esteves C, De Oliveira MS: B-CLL in PLL transformation associated with hypercalcemia. Leuk Lymphoma 1994;12:231–235.
20.
Vlasfeld LT, Pauwels T, Ermens AA, Aarnoudse WH, Ooms HW, Haak HR: Parathyroid-hormone-related protein (PTH-rP) associated hypercalcemia in a patient with an atypical chronic lymphocytic leukaemia. Neth J Med 1999;54:21–26.
21.
Seymour JF, Keating MJ: Parathyroid-hormone-related protein in hypercalcaemia in CLL. Br J Haematol 1995;89:685–686.
22.
Davies SV, Vora J, Wardrop CAJ: Parathyroid hormone related protein (PTHrP) in hypercalcaemia of lymphoproliferative disease. J Clin Pathol 1993;46:188–191.
23.
Schoevaerdts D, Mineur P, Hennaux V, Sibille C: Hypercalcemia, chronic lymphocytic leukaemia and multiple myeloma: uncommon association. Acta Clin Belg 1999;54:217–219.
24.
Schöttker B, Heinz W, Weissinger F, Sözener K, Eck M, Seufen J: Parathyroid hormone-related protein-associated hypercalcemia in a patient with CLL type low grade leukemic B-cell lymphoma. Hematologica 2006;91(suppl 12):ECR45.
25.
Sato K, Onuma E, Yocum RC, Ogata E: Treatment of malignancy-associated hypercalcemia and cachexia with humanized anti-parathyroid hormone-related protein antibody. Semin Oncol 2003;5(suppl 16):167–173.
26.
Vassilopoulou-Sellin R, Newman BM, Tylor SH, Ensor JE, Guinee VF: Hypercalcemia of malignancy: incidence in a comprehensive cancer centre. Proc Am Soc Clin Oncol 1991;10:131.
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2010
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