Abstract
Ameloblastoma is a rare odontogenic tumor which may be complicated by hypercalcemia in advanced disease. Tumoral parathyroid hormone-related peptide (PTHrP) production and local osteolysis from paracrine factors have been proposed as mechanisms. Mitogen-activated protein kinase (MAPK) inhibitors have been successfully used in ameloblastomas with BRAF V600E mutation to reduce symptoms and decrease tumor burden. Serum calcium has been observed to normalize following treatment with MAPK inhibitors; however, the response of PTHrP and markers of bone turnover has not been reported. We describe a case of a 55-year-old female with PTHrP-mediated hypercalcemia secondary to BRAF V600E-positive ameloblastoma with pulmonary metastases. Following treatment with dabrafenib and trametinib, the patient experienced the regression of pulmonary lesions and normalization of serum calcium, PTHrP, and markers of bone turnover. Tissue samples of ameloblastoma carrying BRAF V600E mutation are more likely to express PTHrP than tissue samples carrying wild-type BRAF. In our case, resolution of PTHrP-mediated hypercalcemia following initiation of BRAF/MEK inhibition provides additional evidence that the MAPK pathway contributes to PTHrP synthesis. It also raises the question of whether MAPK inhibitors would be effective in treating PTHrP-mediated hypercalcemia associated with other malignancies harboring BRAF V600E mutation.
Similar content being viewed by others
References
Lo TEN, Villafuerte CV, Acampado LT (2014) Overwhelming hypercalcemia in mandibular ameloblastoma. BMJ Case Rep 2014:bcr2014205491. https://doi.org/10.1136/bcr-2014-205491
Kurppa KJ, Catón J, Morgan PR, Ristimäki A, Ruhin B, Kellokoski J, Elenius K, Heikinheimo K (2014) High frequency of BRAF V600E mutations in ameloblastoma. J Pathol 232(5):492–493. https://doi.org/10.1002/path.4317
Abramson Z, Dayton OL, Drane WE, Mendenhall WM, Kaye FJ (2022) Managing stage 4 ameloblastoma with dual BRAF/MEK inhibition: a case report with 8-year clinical follow-up. Oral Oncol 128:10585410. https://doi.org/10.1016/j.oraloncology.2022.105854
Kaye FJ, Ivey AM, Drane WE, Mendenhall WM, Allan RW (2014) Clinical and radiographic response with combined BRAF-targeted therapy in stage 4 ameloblastoma. J Natl Cancer Inst 107(1):378. https://doi.org/10.1093/jnci/dju378
Abdelsayed RA, Vartanian RK, Smith KK, Ibrahim NA (2004) Parathyroid hormone-related protein (PTHrP) expression in ameloblastoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 97:208–219. https://doi.org/10.1016/j.tripleo.2003.10.003
Donovan PJ, Sundac L, Pretorius CJ, d’Emden MC, McLeod DS (2013) Calcitriol-mediated hypercalcemia: causes and course in 101 patients. J Clin Endocrinol Metab 98(10):4023–4029. https://doi.org/10.1210/jc.2013-2016
Horwitz MJ, Tedesco MB, Gundberg C, Garcia-Ocana A, Stewart AF (2003) Short-term, high-dose parathyroid hormone-related protein as a skeletal anabolic agent for the treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab 88(2):569–575. https://doi.org/10.1210/jc.2002-021122
Horwitz MJ, Tedesco MB, Sereika SM, Syed MA, Garcia-Ocaña A, Bisello A, Hollis BW, Rosen CJ, Wysolmerski JJ, Dann P, Gundberg C, Stewart AF (2005) Continuous PTH and PTHrP infusion causes suppression of bone formation and discordant effects on 1,25(OH)2vitamin D. J Bone Miner Res 20(10):1792–1803. https://doi.org/10.1359/JBMR.050602
Donovan PJ, Achong N, Griffin K, Galligan J, Pretorius CJ, McLeod DSA (2015) PTHrP-mediated hypercalcemia: causes and survival in 138 patients. J Clin Endocrinol Metab 100(5):2024–2029. https://doi.org/10.1210/jc.2014-4250
Asonitis N, Kassi E, Kokkinos M, Giovanopoulos I, Petychaki F, Gogas H (2017) Hypercalcemia of malignancy treated with cinacalcet. Endocrinol Diabetes Metab Case Rep 2017:17–0118. https://doi.org/10.1530/EDM-17-0118
Broudic-Guibert M, Blay JY, Vazquez L, Evrard A, Karanian M, Taïeb S, Hoog-Labouret N, Oukhatar CMA, Boustany-Grenier R, Arnaud A (2019) Persistent response to vemurafenib in metastatic ameloblastoma with BRAF mutation: a case report. J Med Case Rep 13(1):245. https://doi.org/10.1186/s13256-019-2140-6
Fregnani ER, Perez DEdC, Paes de Almeida O, Fonseca FP, Soares FA, Castro-Junior G, Alves FA (2017) BRAF-V600E expression correlates with ameloblastoma aggressiveness. Histopathology 70(3):473–484. https://doi.org/10.1111/his.13095
Cheung CHY, Cheng CK, Lau KM, Ip RKL, Chan NCN, Tam THC, Wong RSM, Raghupathy R, Chan NPH, Ng MHL (2018) Prevalence and clinicopathologic significance of BRAF V600E mutation in chinese multiple myeloma patients. Clin Lymphoma Myeloma Leuk 18(7):315–325. https://doi.org/10.1016/j.clml.2018.05.008
Garnett M, Marais R (2004) Guilty as charged: B-RAF is a human oncogene. Cancer Cell 6(4):313–319. https://doi.org/10.1016/j.ccr.2004.09.022
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Kathryn Corbett, Dean Ruether, and Gregory Kline declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
The patient provided informed and written consent for publication of the case details and images.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Corbett, K., Ruether, D., Seiden-Long, I. et al. Resolution of PTHrP-Mediated Hypercalcemia Following Treatment with Dual BRAF/MEK Inhibition for BRAFV600E-Positive Metastatic Ameloblastoma. Calcif Tissue Int 114, 444–449 (2024). https://doi.org/10.1007/s00223-023-01177-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00223-023-01177-x