Skip to main content

Advertisement

SpringerLink
Log in

Hypercalcemia in non-Hodgkin’s lymphoma due to cosecretion of PTHrP and 1,25-dihydroxyvitamin D

  • Case Report
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Hypercalcemia occurs in up to 30% of patients with malignancies and can be due to osteolysis by metastases, parathyroid hormone-related protein (PTHrP), excess 1,25-dihydroxyvitamin D (1,25(OH)2D) production or, rarely, ectopic parathyroid hormone (PTH) secretion. Hypercalcemia in non-Hodgkin’s lymphoma has been described with elevations in PTHrP or, more commonly, excess 1,25(OH)2D production. We present the first case of a patient with new diagnosis of non-Hodgkin’s lymphoma and severe hypercalcemia who was found to have concurrently elevated PTHrP and 1,25(OH)2D. In human studies, PTHrP has shown limited ability to stimulate 1,25(OH)2D production. To demonstrate that both PTHrP and 1,25(OH)2D were of tumor origin in our patient, tissue from her tumor underwent histochemical staining, demonstrating expression of both PTHrP and CYP27B1, indicating the presence of 1,25(OH)2D production in the tumor tissue. Our case illustrates the complexity of hypercalcemia in patients with underlying malignancy and highlights the importance of a thorough diagnostic workup for achievement of a successful therapeutic approach. In our patient, definitive chemotherapeutic treatment resulted in achievement and maintenance of normal calcium, PTHrP and 1,25(OH)2D levels 18 months after initial diagnosis.

Summary

Hypercalcemia occurs in up to 30% of malignancies and can be due to several mechanisms. We present the first case of cosecretion of parathyroid hormone related peptide (PTHrP) and 1,25-dihydroxyvitamin D (1,25(OH)2D) in a patient with non-Hodgkin’s lymphoma and demonstrate that both PTHrP and 1,25(OH)2D were of tumor origin by immunohistochemical staining.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Stewart AF (2005 Jan 27) Clinical practice. Hypercalcemia associated with cancer. N Engl J Med 352(4):373–379

    Article  CAS  Google Scholar 

  2. Ralston SH, Gallacher SJ, Patel U, Campbell J, Boyle IT (1990 Apr 1) Cancer-associated hypercalcemia: morbidity and mortality. Clinical experience in 126 treated patients. Ann Intern Med 112(7):499–504

    Article  CAS  Google Scholar 

  3. Francini G, Petrioli R, Maioli E, Gonnelli S, Marsili S, Aquino A, Bruni S (1993 Sep) Hypercalcemia in breast cancer. Clin Exp Metastasis 11(5):359–367

    Article  CAS  Google Scholar 

  4. Roodman GD (2004 Apr 15) Mechanisms of bone metastasis. N Engl J Med 350(16):1655–1664

    Article  CAS  Google Scholar 

  5. Firkin F, Schneider H, Grill V (1998 May) Parathyroid hormone-related protein in hypercalcemia associated with hematological malignancy. Leuk Lymphoma 29(5-6):499–506

    Article  CAS  Google Scholar 

  6. Horwitz MJ, Tedesco MB, Sereika SM, Syed MA, Garcia-Ocana A, Bisello A et al (2005 Oct) Continuous PTH and PTHrP infusion causes suppression of bone formation and discordant effects on 1,25(OH)2 vitamin D. J Bone Miner Res 20(10):1792–1803

    Article  CAS  Google Scholar 

  7. Seymour JF, Gagel RF (1993 Sep 1) Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin's disease and non-Hodgkin's lymphomas. Blood. 82(5):1383–1394

    Article  CAS  Google Scholar 

  8. Hibi M, Hara F, Tomishige H, Nishida Y, Kato T, Okumura N et al (2008 Jan-Feb) 1,25-dihydroxyvitamin D-mediated hypercalcemia in ovarian dysgerminoma. Pediatr Hematol Oncol 25(1):73–78

    Article  Google Scholar 

  9. Zhu V, de Las MA, Janicek M, Hartshorn K (2014 Aug) Hypercalcemia from metastatic pancreatic neuroendocrine tumor secreting 1,25-dihydroxyvitamin D. J Gastrointest Oncol 5(4):E84–E87

    PubMed  PubMed Central  Google Scholar 

  10. Akai PS, Wong T, Chang-Poon V, Green F, Whitelaw WA, Hanley DA (1989 Jun) Resectable bronchogenic carcinoma presenting with hypercalcemia: tumor-associated granulomatous reaction and probable production of 1,25-dihydroxyvitamin D. Clin Invest Med 12(3):212–216

    CAS  PubMed  Google Scholar 

  11. Fraher LJ, Hodsman AB, Jonas K, Saunders D, Rose CI, Henderson JE et al (1992 Aug) A comparison of the in vivo biochemical responses to exogenous parathyroid hormone-(1-34) [PTH-(1-34)] and PTH-related peptide-(1-34) in man. J Clin Endocrinol Metab 75(2):417–423

    CAS  PubMed  Google Scholar 

  12. Syed MA, Horwitz MJ, Tedesco MB, Garcia-Ocana A, Wisniewski SR, Stewart AF (2001 Apr) Parathyroid hormone-related protein-(1--36) stimulates renal tubular calcium reabsorption in normal human volunteers: implications for the pathogenesis of humoral hypercalcemia of malignancy. J Clin Endocrinol Metab 86(4):1525–1531

    CAS  PubMed  Google Scholar 

  13. Nakayama K, Fukumoto S, Takeda S, Takeuchi Y, Ishikawa T, Miura M, Hata K, Hane M, Tamura Y, Tanaka Y, Kitaoka M, Obara T, Ogata E, Matsumoto T (1996 Feb) Differences in bone and vitamin D metabolism between primary hyperparathyroidism and malignancy-associated hypercalcemia. J Clin Endocrinol Metab 81(2):607–611

    CAS  PubMed  Google Scholar 

  14. Walker AT, Stewart AF, Korn EA, Shiratori T, Mitnick MA, Carpenter TO (1990 Feb) Effect of parathyroid hormone-like peptides on 25-hydroxyvitamin D-1 alpha-hydroxylase activity in rodents. Am J Phys 258(2 Pt 1):E297–E303

    CAS  Google Scholar 

  15. Broadus AE, Mangin M, Ikeda K, Insogna KL et al (1988 Sep 1) Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide. N Engl J Med 319(9):556–563

    Article  CAS  Google Scholar 

  16. Budayr AA, Zysset E, Jenzer A, Thiebaud D, Ammann P, Rizzoli R et al (1994 Apr) Effects of treatment of malignancy-associated hypercalcemia on serum parathyroid hormone-related protein. J Bone Miner Res 9(4):521–526

    Article  CAS  Google Scholar 

  17. Fukumoto S, Matsumoto T, Yamoto H, Kawashima H, Ueyama Y, Tamaoki N et al (1989 May) Suppression of serum 1,25-dihydroxyvitamin D in humoral hypercalcemia of malignancy is caused by elaboration of a factor that inhibits renal 1,25-dihydroxyvitamin D3 production. Endocrinology. 124(5):2057–2062

    Article  CAS  Google Scholar 

  18. Seymour JF, Gagel RF, Hagemeister FB, Dimopoulos MA, Cabanillas F (1994 Nov 1) Calcitriol production in hypercalcemic and normocalcemic patients with non-Hodgkin lymphoma. Ann Intern Med 121(9):633–640

    Article  CAS  Google Scholar 

  19. Shallis RM, Rome RS, Reagan JL (2018 Feb) Mechanisms of Hypercalcemia in Non-Hodgkin Lymphoma and Associated Outcomes: A Retrospective Review. Clin Lymphoma Myeloma Leuk 18(2):e123–e129

    Article  Google Scholar 

  20. Davies M, Hayes ME, Yin JA, Berry JL, Mawer EB (1994 May) Abnormal synthesis of 1,25-dihydroxyvitamin D in patients with malignant lymphoma. J Clin Endocrinol Metab 78(5):1202–1207

    CAS  PubMed  Google Scholar 

  21. Hewison M, Kantorovich V, Liker HR, Van Herle AJ, Cohan P, Zehnder D et al (2003 Mar) Vitamin D-mediated hypercalcemia in lymphoma: evidence for hormone production by tumor-adjacent macrophages. J Bone Miner Res 18(3):579–582

    Article  Google Scholar 

  22. Hoekman K, Tjandra YI, Papapoulos SE (1991 Aug 1) The role of 1,25-dihydroxyvitamin D in the maintenance of hypercalcemia in a patient with an ovarian carcinoma producing parathyroid hormone-related protein. Cancer. 68(3):642–647

    Article  CAS  Google Scholar 

  23. Rodriguez-Gutierrez R, Zapata-Rivera MA, Quintanilla-Flores DL, Camara-Lemarroy CR, Lavalle-Gonzalez FJ, Gonzalez-Gonzalez JG et al (2014) 1,25-dihydroxyvitamin D and PTHrP mediated malignant hypercalcemia in a seminoma. BMC Endocr Disord 14:32,6823–3214-32

    Article  Google Scholar 

  24. Shivnani SB, Shelton JM, Richardson JA, Maalouf NM (2009 Apr) Hypercalcemia of malignancy with simultaneous elevation in serum parathyroid hormone--related peptide and 1,25-dihydroxyvitamin D in a patient with metastatic renal cell carcinoma. Endocr Pract 15(3):234–239

    Article  Google Scholar 

  25. Van den Eynden GG, Neyret A, Fumey G, Rizk-Rabin M, Vermeulen PB, Bouizar Z et al (2007 Apr) PTHrP, calcitonin and calcitriol in a case of severe, protracted and refractory hypercalcemia due to a pancreatic neuroendocrine tumor. Bone. 40(4):1166–1171

    Article  Google Scholar 

  26. Johnston SR, Hammond PJ (1992 Sep) Elevated serum parathyroid hormone related protein and 1,25-dihydroxycholecalciferol in hypercalcaemia associated with adult T-cell leukaemia-lymphoma. Postgrad Med J 68(803):753–755

    Article  CAS  Google Scholar 

  27. Ogawa T, Miyata J, Fukunaga K, Kawana A, Inoue T (2020) Successful Treatment for Hypercalcemia due to Cosecretion of Parathyroid Hormone-Related Protein and 1,25-Dihydroxyvitamin D 3 in Non-Small-Cell Lung Cancer: A Case Report and Literature Review. Case Rep Pulmonol 2020:2475725

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Endocrinology, Yale New Haven Health NEMG, Fairfield, CT, USA

    A.R. Gonciulea

  2. Department of Medicine, University of California San Francisco, San Francisco, USA

    Y. Wang & D.D. Bikle

  3. Department of Medicine, San Francisco VA Medical Center, San Francisco, CA, USA

    D.D. Bikle

  4. Division of Endocrinology, Gerontology and Metabolism, Stanford University School of Medicine, 300 Pasteur Dr. M/C 5103, Palo Alto, CA, 94305, USA

    D.E. Sellmeyer

Authors
  1. A.R. Gonciulea
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D.D. Bikle
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D.E. Sellmeyer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D.E. Sellmeyer.

Ethics declarations

Conflict of interest

None.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gonciulea, A., Wang, Y., Bikle, D. et al. Hypercalcemia in non-Hodgkin’s lymphoma due to cosecretion of PTHrP and 1,25-dihydroxyvitamin D. Osteoporos Int 32, 2587–2592 (2021). https://doi.org/10.1007/s00198-021-06054-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-021-06054-7

Keywords

Search

Navigation