DOI: 10.1359/jbmr.2003.18.3.579. Vitamin D-Mediated Hypercalcemia in Lymphoma: Evidence for Hormone Production by Tumor-Adjacent Macrophages

Vitamin D-Mediated Hypercalcemia in Lymphoma: Evidence for Hormone Production by Tumor-Adjacent Macrophages

10.1359/jbmr.2003.18.3.579

Crossref journal-article

Oxford University Press (OUP)

Journal of Bone and Mineral Research (286)

Abstract

Abstract Nearly one-half of all hypercalcemic patients with lymphoma present with inappropriately elevated circulating concentrations of the active vitamin D metabolite 1,25-dihydroxyvitamin D (1,25(OH)2D3). However, the cellular source of the vitamin D hormone in lymphomas remains unclear. To address this, we report the case of a 75-year-old man with hypercalcemia associated with raised circulating concentrations of 1,25(OH)2D3 and suppressed parathyroid hormone (PTH) levels. Positron emission tomographic (PET) and computed tomographic (CT) imaging revealed the presence of a large lymphoma that was confined to the spleen; subsequent pathological analysis showed that this was an intermediate grade B-cell lymphoma. After surgical removal of the spleen, serum calcium and 1,25(OH)2D3 levels became normalized within 24 h. Immunolocalization of the vitamin D-activating enzyme 25-hydroxyvitamin D3-1α-hydroxylase (1α-hydroxylase) in sections of resected spleen showed that staining was negative in the lymphoma cells but positive in neighboring macrophages. This case study indicates that the hypercalcemia associated with lymphomas may be due, in some instances, to excessive extrarenal production of 1,25(OH)2D3. Furthermore, by using immunohistochemistry to assess the distribution of 1α-hydroxylase, we have been able to show for the first time that tissue macrophages, rather than actual tumor cells, are the most likely ectopic source of this enzyme. Based on this case study, we propose that the abnormal synthesis of 1,25(OH)2D3 associated with some lymphomas is because of paracrine regulation of tumor-associated macrophages.

Bibliography

Hewison, M., Kantorovich, V., Liker, H. R., Van Herle, A. J., Cohan, P., Zehnder, D., & Adams, J. S. (2003). Vitamin D-Mediated Hypercalcemia in Lymphoma: Evidence for Hormone Production by Tumor-Adjacent Macrophages. Journal of Bone and Mineral Research, 18(3), 579â582.

Authors 7

Martin Hewison (first)
Vitaly Kantorovich (additional)
Harley R Liker (additional)
Andre J Van Herle (additional)
Pejman Cohan (additional)
Daniel Zehnder (additional)
John S Adams (additional)

References 25 Referenced 106

10.1001/archsurg.1980.01380060012004 / Arch Surg / Incidence of hypercalcemia and malignant neoplasm by Burt (1980)
10.3109/10428199809050909 / Leuk Lymphoma / Parathyroid hormone-related protein in hypercalcemia associated with hematological malignancy by Firkin (1998)
{'key': '2024013019160119500_bib3', 'first-page': '903', 'volume-title': 'Vitamin D', 'author': 'Adams', 'year': '1997'} / Vitamin D by Adams (1997)
10.1016/S0140-6736(85)92864-8 / Lancet / Abnormal vitamin D metabolism in Hodgkin's lymphoma by Davies (1985)
10.1126/science.277.5333.1827 / Science / 25-hydroxyvitamin D3 1α-hydroxylase and vitamin D synthesis by Takeyama (1997)
{'key': '2024013019160119500_bib6', 'first-page': '1961', 'article-title': 'Cloning of human 25-hydroxyvitamin D-1α-hydroxylase and mutations causing vitamin D-dependent Rickets Type I', 'volume': '11', 'author': 'Fu', 'year': '1997', 'journal-title': 'Mol Endocrinol'} / Mol Endocrinol / Cloning of human 25-hydroxyvitamin D-1α-hydroxylase and mutations causing vitamin D-dependent Rickets Type I by Fu (1997)
10.1359/jbmr.1997.12.10.1552 / J Bone Miner Res / The 25-hydroxyvitamin D 1-alpha-hydroxylase gene maps to the pseudovitamin D deficiency rickets (PDDR) disease locus by St-Arnaud (1997)
10.1006/bbrc.1997.7508 / Biochem Biophys Res Commun / Molecular cloning of cDNA and genomic DNA for human 25-hydroxyvitamin D3 1α-hydroxylase by Monkawa (1997)
10.1210/endo.140.5.6683 / Endocrinology / Constitutive expression of 25-hydroxyvitamin D-1α-hydroxylase in a transformed human proximal tubule cell line: Evidence for direct regulation of vitamin D metabolism by calcium by Bland (1999)
10.1681/ASN.V10122465 / J Am Soc Nephrol / Expression of 25-hydroxyvitamin D3-1α-hydroxylase in the human kidney by Zehnder (1999)
{'key': '2024013019160119500_bib11', 'first-page': '888', 'article-title': 'Extra-renal expression of 25-hydroxyvitamin D3-1α-hydroxylase', 'volume': '86', 'author': 'Zehnder', 'year': '2001', 'journal-title': 'J Clin Endocrinol Metab'} / J Clin Endocrinol Metab / Extra-renal expression of 25-hydroxyvitamin D3-1α-hydroxylase by Zehnder (2001)
{'key': '2024013019160119500_bib12', 'first-page': '1202', 'article-title': 'Abnormal synthesis of 1, 25-dihydroxyvitamin D in patients with malignant lymphoma', 'volume': '78', 'author': 'Davies', 'year': '1994', 'journal-title': 'J Clin Endocrinol Metab'} / J Clin Endocrinol Metab / Abnormal synthesis of 1, 25-dihydroxyvitamin D in patients with malignant lymphoma by Davies (1994)
10.1136/pgmj.66.779.757 / Postgrad Med J / Intermittent hypercalcaemia and vitamin D sensitivity in Hodgkin's disease by Karmali (1990)
10.1016/0002-9343(88)90028-9 / Am J Med / Recurrent hypercalcemia and elevated 1, 25-dihydroxyvitamin D levels in Hodgkin's disease by Mercier (1988)
10.1002/1097-0142(19870501)59:9<1543::AID-CNCR2820590902>3.0.CO;2-L / Cancer / Ectopic production of 1, 25-dihydroxyvitamin D by B-cell lymphoma as a cause of hypercalcemia by Mudde (1987)
10.1210/jcem-60-1-29 / J Clin Endocrinol Metab / Elevation in circulating 1, 25-dihydroxyvitamin D in three patients with lymphoma-associated hypercalcemia by Rosenthal (1985)
10.1001/archinte.1985.00360010197037 / Arch Intern Med / Humoral hypercalcemia in Hodgkin's disease. Association with elevated 1, 25-dihydroxycholecalciferol levels and subperiostal bone resorption by Zaloga (1985)
10.7326/0003-4819-100-1-1 / Ann Intern Med / Hypercalemia associated with increased serum calcitriol levels in three patients with lymphoma by Breslau (1984)
10.1007/s002770050393 / Ann Hematol / Hypercalcemia associated with parathyroid hormone-related protein produced by B-cell type primary malignant lymphoma of the kidney by Uno (1998)
10.1046/j.1365-2141.1996.d01-1819.x / Br J Haematol / Parathyroid hormone-related protein in hypercalcaemia associated with haematological malignancy by Firkin (1996)
10.1016/0960-0760(92)90196-P / J Steroid Biochem Mol Biol / Hypercalcemia in cancer by Martin (1992)
10.1056/NEJM200008033430506 / N Engl J Med / Innate immunity by Medzhitov (2000)
10.1038/35047207 / Nature / A toll for DNA vaccines by Modlin (2000)
10.1046/j.1365-2567.2000.00093.x / Immunology / Toll-like receptors: Molecular mechanisms of the mammalian immune response by Brightbill (2000)
10.1359/jbmr.1999.14.5.730 / J Bone Miner Res / Novel mutations in the 1 alpha-hydroxylase (P450cl) gene in three families with pseudovitamin D-deficiency rickets resulting in loss of functional enzyme activity in blood-derived macrophages by Smith (1999)

Dates

Type	When
Created	19 years, 4 months ago (April 27, 2006, 1:20 a.m.)
Deposited	1 year, 5 months ago (March 13, 2024, 11:06 a.m.)
Indexed	4 days, 7 hours ago (Aug. 28, 2025, 8:04 a.m.)
Issued	22 years, 6 months ago (March 1, 2003)
Published	22 years, 6 months ago (March 1, 2003)
Published Online	15 years, 8 months ago (Dec. 2, 2009)
Published Print	22 years, 6 months ago (March 1, 2003)

Funders 0

None

BibTeX

@article{Hewison_2003, title={Vitamin D-Mediated Hypercalcemia in Lymphoma: Evidence for Hormone Production by Tumor-Adjacent Macrophages}, volume={18}, ISSN={1523-4681}, url={http://dx.doi.org/10.1359/jbmr.2003.18.3.579}, DOI={10.1359/jbmr.2003.18.3.579}, number={3}, journal={Journal of Bone and Mineral Research}, publisher={Oxford University Press (OUP)}, author={Hewison, Martin and Kantorovich, Vitaly and Liker, Harley R and Van Herle, Andre J and Cohan, Pejman and Zehnder, Daniel and Adams, John S}, year={2003}, month=mar, pages={579–582} }

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