Case Reports in Pulmonology

Case Reports in Pulmonology / 2020 / Article

Case Report | Open Access

Volume 2020 |Article ID 2475725 | https://doi.org/10.1155/2020/2475725

Takunori Ogawa, Jun Miyata, Koichi Fukunaga, Akihiko Kawana, Takashi Inoue, "Successful Treatment for Hypercalcemia due to Cosecretion of Parathyroid Hormone-Related Protein and 1,25-Dihydroxyvitamin D3 in Non-Small-Cell Lung Cancer: A Case Report and Literature Review", Case Reports in Pulmonology, vol. 2020, Article ID 2475725, 6 pages, 2020. https://doi.org/10.1155/2020/2475725

Successful Treatment for Hypercalcemia due to Cosecretion of Parathyroid Hormone-Related Protein and 1,25-Dihydroxyvitamin D3 in Non-Small-Cell Lung Cancer: A Case Report and Literature Review

Academic Editor: Takeshi Terashima
Received06 Oct 2019
Accepted11 Dec 2019
Published03 Jan 2020

Abstract

Hypercalcemia of malignancy frequently manifests as paraneoplastic syndrome in patients with solid tumors. A 71-year-old man was diagnosed with stage IIIB lung squamous cell carcinoma. Laboratory examination revealed high serum calcium concentration with elevated serum parathyroid hormone-related protein (PTHrP) and 1,25-dihydroxyvitamin D3 levels. As the patient did not respond to the initial treatment with calcitonin, extracellular fluid infusion, and chemotherapy, systemic prednisolone was administered additionally. Thus, the levels of serum calcium normalized and PTHrP and 1,25-dihydroxyvitamin D3 decreased simultaneously. To our knowledge, this is the first case report on the successful treatment of hypercalcemia of malignancy caused by PTHrP and 1,25-dihydroxyvitamin D3 cosecretion in a patient with lung cancer.

1. Introduction

Hypercalcemia is a relatively common finding in cases of paraneoplastic syndrome. Hypercalcemia of malignancy (HCM) occurs in up to 20 to 30% of patients with cancer [1]. It can be classified into the following four types: caused by local osteolytic hypercalcemia, secretion of parathyroid hormone- (PTH-) related protein (PTHrP), secretion of 1,25-dihydroxyvitamin D3 (calcitriol), and ectopic hyperparathyroidism. PTHrP derived from solid tumors, especially squamous cell carcinoma, is a well-known mediator of HCM. However, calcitriol is rarely secreted from these tumors. Only few previous reports have described elevated levels of both blood serum PTHrP and calcitriol in patients with solid tumors [26]. Here, we report the case of a patient with squamous cell lung cancer, who developed hypercalcemia caused by cosecretion of PTHrP and calcitriol, which was improved by corticosteroids.

2. Case Presentation

The patient was a 71-year-old man who presented with nausea, fatigue, and anorexia. He was referred to our hospital for investigation of these symptoms and abnormalities; as such, chest radiography was performed (Figure 1(a)). Laboratory examination revealed an elevated blood serum calcium level (12.3 mg/dL, serum albumin level 3.2 g/dL) and normal creatinine level, which did not indicate dehydration and renal dysfunction (Table 1). He did not take any hypercalcemia-inducing agents such as thiazide diuretics, theophylline, lithium, osteoporosis therapeutic drugs, and vitamin D supplements. Serum PTHrP level was elevated (11.7 pmol/L ()), although the intact PTH level was low (7 pg/mL (reference value 10-65 pg/mL)). Surprisingly, the serum calcitriol level was elevated (105 pg/mL (reference value 20-40 pg/mL)) although 25-OH vitamin D3 level was low (16 ng/mL ()). Integrated computed tomography and 18F-2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET/CT) showed uptake of FDG by a left pulmonary hilar lesion and both ipsilateral mediastinal and subcarinal lymph nodes, because of which lung cancer with metastasis to the lymph nodes was highly suspected (Figures 1(b)1(d)). No other organs, including the bone, liver, and bilateral adrenal glands, showed FDG uptake. Head magnetic resonance imaging revealed no metastatic lesions. Based on the results of a bronchoscopic examination showing proliferation of large polygonal atypical cells with intercellular bridges in the bronchial submucosa (Figure 2), the patient was diagnosed with stage IIIB lung squamous cell carcinoma (55% of tumor cells were positive for programmed cell death-ligand 1 expression). Lymphoma, granulomatous disease, and mycobacterial or fungal infections were ruled out based on the results of histopathological analysis. Pembrolizumab (200 mg/body every 3 weeks) was administered as the first-line treatment. In addition to anticancer treatment, calcitonin and intravenous 0.9% normal saline were first administered. Despite initial treatment for HCM, hypercalcemia did not improve. On day 28 from the initial treatment of HCM, systemic prednisolone (40 mg/day) was additively administered. Serum calcium level rapidly decreased thereafter and normalized (serum calcium 8.5 mg/dL, serum albumin 3.1 g/dL) on day 31. Serum PTHrP and calcitriol levels decreased simultaneously (PTHrP: 5.4 pmol/L; calcitriol: 65.4 pg/mL) in response to systemic prednisolone. Serum intact PTH levels were elevated to the normal range (47 pg/mL), indicating improvement of the negative feedback circuit to regulate serum calcium levels. However, lung cancer gradually progressed during two cycles of pembrolizumab, suggesting an inadequate therapeutic response to this immunotherapy. Respiratory failure developed, and the patient died on day 58. Figure 3 shows the clinical course of this patient.


ValueReference value

Peripheral blood
 White blood cells11,900/μL3,900-9,800
 Neutrophils85.8%
 Lymphocytes8.5%
 Basophils0.5%
 Eosinophils0.8%
 Monocytes4.4%
 Hemoglobin11.8g/dL13.5-17.6
 Hematocrit36.8%39.8-51.8
 Platelets413,000/μL131,000-362,000
Blood biochemistry
 Total bilirubin0.59mg/dL0.2-1.2
 Aspartate transaminase25U/L9.0-30
 Alanine transaminase17U/L4.0-35
 Lactate dehydrogenase197U/L80-260
 Alkaline phosphatase282U/L106-345
γ-Glutamyl transpeptidase59U/L16-84
 Total protein7.5g/dL6.5-8.2
 Albumin3.2g/dL3.9-4.9
 Urea nitrogen16.4mg/dL8.0-20
 Creatinine0.94mg/dL0.6-1.1
 Sodium143mEq/L132-148
 Potassium4.2mEq/L3.6-5.0
 Chloride105mEq/L96-110
 Calcium12.3mg/dL8.2-10.2
 Phosphorus2.6mg/dL2.3-4.3
 Intact PTH7pg/mL10-65
 PTHrP11.7pmol/L<1.1
 Calcitriol105pg/mL20-40
 25-OH vitamin D316ng/mL>20
Urine
 pH5.55.0-9.0
 Occult blood(-)
 Sugar(-)
 Protein(-)
 Urea nitrogen312mg/dL650-1,300
 Creatinine69.9mg/dL50-150
 Sodium38mEq/L70-250
 Potassium37.7mEq/L25-100
 Chloride41mEq/L70-250
 Calcium22.2mg/dL50-300
 Phosphorus36.8mg/dL<500

PTH: parathyroid hormone; PTHrP: parathyroid hormone-related protein; calcitriol: 1,25-dihydroxyvitamin D3.

3. Discussion

To our knowledge, this is a rare case with cosecretion of PTHrP and calcitriol in lung cancer. There are only five previous reports of the cosecretion of PTHrP and calcitriol in cases of solid tumors including ovarian carcinoma, pancreatic neuroendocrine tumor, renal cell carcinoma, seminoma, and lung cancer [26], which are summarized in Table 2. In the previous report on lung cancer, the histological type was squamous cell carcinoma [6], as in our case. The patient could not receive systemic prednisolone because of rapid tumor progression with no improvement of hypercalcemia. However, systemic prednisolone could be effective for HCM induced by cosecretion of PTHrP and calcitriol in other cases with solid tumors. In summary, this is the first report of the successful treatment of HCM caused by cosecretion of PTHrP and calcitriol in a patient with lung cancer.


AuthorAgeSexPrimary tumorHistological typeTx of HCMSxCTxRTxCourse of the tumorOutcome of HCMEffective Tx of HCM

Hoekman et al. [2]70FOvarian carcinomaAdenocarcinomaPamidronateYesNoNoResectionImprovementOperation
Hydrocortisone
Van den Eynden et al. [3]59MPancreatic neuroendocrine tumorNeuroendocrine tumorPamidronateYesYesNoReductionImprovementChemotherapy
Zoledronic acid
Shivnani et al. [4]57MRenal cell carcinomaClear cellPamidronateNoYesNoProgressionImprovementPrednisolone
Prednisolone
Rodriguez-Gutierrez et al. [5]35MSeminomaSeminomaCalcitoninNoYesNoReductionImprovementChemotherapy
Nemr et al. [6]60MLung cancerSquamousCalcitoninNoNoNoProgressionNo improvementNone
Zoledronic acid
Furosemide
Ogawaa71MLung cancerSquamousPrednisoloneNoYesNoProgressionImprovementPrednisolone
Calcitonin

CTx: chemotherapy; HCM: hypercalcemia of malignancy; RTx: radiation therapy; Sx: surgery; Tx: treatment. aPresent case.

The mechanism of independently elevated PTHrP and calcitriol productions remains poorly understood. PTHrP secreted from solid tumors binds to the PTH-1 receptor causing hypercalcemia [7]. However, unlike PTH, it does not elicit calcitriol synthesis [8]. 1-α-Hydroxylase, an enzyme converting 25-OH vitamin D3 to calcitriol, normally expresses in the kidney. Previous report demonstrated that its expression in alveolar macrophages was higher in the lung cancer patients than in the healthy group [9]. Additionally, a human small cell lung cancer cell line constitutively expressed this enzyme [10]. These findings might explain the possible mechanism of PTHrP and calcitriol cosecretion in patients with lung cancer.

Hypercalcemia with an elevated calcitriol level has been reported in patients with some granulomatous diseases including sarcoidosis, tuberculosis, fungal infection, and lymphoma [11]. In our case, histopathological examination suggested no complications with these diseases. Thus, we concluded lung cancer as the cause of elevated serum calcitriol.

Treatment using extracellular fluid infusion, calcitonin, and chemotherapy was initially introduced in our case. Previous reports indicated that combined extracellular fluid infusion and calcitonin worked rapidly (within several hours) in some cases [12]. However, this therapy was not effective without responsiveness of the lung cancer to chemotherapy, which strongly suggested the necessity of an additive therapeutic drug.

In a case of metastatic renal cell carcinoma, prednisolone was chosen for the treatment of HCM, with beneficial effects [4]. Similarly, in our case, hypercalcemia showed a good response to systemic prednisolone as an add-on agent, possibly through steroid-mediated suppressive effects on the expression of enzymes necessary for PTHrP and calcitriol synthesis.

In four previous reports, bisphosphonates were selected for treating HCM due to cosecretion of PTHrP and calcitriol [24, 6], although hypercalcemia was not unaltered in the patients. Bisphosphonates were consequently unnecessary in our case because prednisolone therapy in addition to calcitonin and extracellular fluid infusion was sufficient to normalize the serum calcium levels. However, recurrence of HCM might be observed during initial therapy using prednisolone, though long-term observation was impossible due to the rapid tumor progression. Bisphosphonates could possibly be beneficial as additive agents in this situation [13, 14].

In summary, caution must be exercised by clinicians when patients with lung cancer show hypercalcemia with elevated serum levels of both PTHrP and calcitriol. Early introduction of prednisolone as an optimal therapeutic strategy should be recommended for patients with HCM induced by cosecretion of PTHrP and calcitriol.

Conflicts of Interest

The authors have no conflicts of interest to report.

References

  1. A. F. Stewart, “Clinical practice. Hypercalcemia associated with cancer,” New England Journal of Medicine, vol. 352, no. 4, pp. 373–379, 2005. View at: Publisher Site | Google Scholar
  2. K. Hoekman, Y. I. Tjandra, and S. E. Papapoulos, “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, vol. 68, no. 3, pp. 642–647, 1991. View at: Publisher Site | Google Scholar
  3. G. G. Van den Eynden, A. Neyret, G. Fumey et al., “PTHrP, calcitonin and calcitriol in a case of severe, protracted and refractory hypercalcemia due to a pancreatic neuroendocrine tumor,” Bone, vol. 40, no. 4, pp. 1166–1171, 2007. View at: Publisher Site | Google Scholar
  4. S. B. Shivnani, J. M. Shelton, J. A. Richardson, and N. M. Maalouf, “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,” Endocrine Practice, vol. 15, no. 3, pp. 234–239, 2009. View at: Publisher Site | Google Scholar
  5. R. Rodríguez-Gutiérrez, M. A. Zapata-Rivera, D. L. Quintanilla-Flores et al., “1,25-dihydroxyvitamin D and PTHrP mediated malignant hypercalcemia in a seminoma,” BMC Endocrine Disorders, vol. 14, no. 1, 2014. View at: Publisher Site | Google Scholar
  6. S. Nemr, S. Alluri, D. Sundaramurthy, D. Landry, and G. Braden, “Hypercalcemia in lung cancer due to simultaneously elevated PTHrP and ectopic calcitriol production: first case report,” Case Reports in Oncological Medicine, vol. 2017, Article ID 2583217, 3 pages, 2017. View at: Publisher Site | Google Scholar
  7. P. Esbrit and J. Egido, “The emerging role of parathyroid hormone-related protein as a renal regulating factor,” Nephrology, Dialysis, Transplantation, vol. 15, no. 8, pp. 1109–1111, 2000. View at: Publisher Site | Google Scholar
  8. M. J. Horwitz, M. B. Tedesco, S. M. Sereika, B. W. Hollis, A. Garcia-Ocaña, and A. F. Stewart, “Direct comparison of sustained infusion of human parathyroid hormone-related protein-(1-36) [hPTHrP-(1-36)] versus hPTH-(1-34) on serum calcium, plasma 1,25-dihydroxyvitamin D concentrations, and fractional calcium excretion in healthy human volunteers,” The Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 4, pp. 1603–1609, 2003. View at: Publisher Site | Google Scholar
  9. K. Yokomura, T. Suda, S. Sasaki, N. Inui, K. Chida, and H. Nakamura, “Increased expression of the 25-hydroxyvitamin D3-1α-hydroxylase gene in alveolar macrophages of patients with lung cancer,” The Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 12, pp. 5704–5709, 2003. View at: Publisher Site | Google Scholar
  10. E. B. Mawer, M. E. Hayes, S. E. Heys et al., “Constitutive synthesis of 1,25-dihydroxyvitamin D3 by a human small cell lung cancer cell line,” The Journal of Clinical Endocrinology and Metabolism, vol. 79, no. 2, pp. 554–560, 1994. View at: Publisher Site | Google Scholar
  11. P. J. Tebben, R. J. Singh, and R. Kumar, “Vitamin D-mediated hypercalcemia: mechanisms, diagnosis, and treatment,” Endocrine Reviews, vol. 37, no. 5, pp. 521–547, 2016. View at: Publisher Site | Google Scholar
  12. J. D. Maier and S. N. Levine, “Hypercalcemia in the intensive care unit: a review of pathophysiology, diagnosis, and modern therapy,” Journal of Intensive Care Medicine, vol. 30, no. 5, pp. 235–252, 2013. View at: Publisher Site | Google Scholar
  13. A. O. Hoff, B. B. Toth, K. Altundag et al., “Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates,” Journal of Bone and Mineral Research, vol. 23, no. 6, pp. 826–836, 2008. View at: Publisher Site | Google Scholar
  14. R. Mhaskar, A. Kumar, B. Miladinovic, and B. Djulbegovic, “Bisphosphonates in multiple myeloma: an updated network meta-analysis,” Cochrane Database of Systematic Reviews, no. 12, article CD003188, 2017. View at: Publisher Site | Google Scholar

Copyright © 2020 Takunori Ogawa et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder
Views538
Downloads300
Citations

Related articles

We are committed to sharing findings related to COVID-19 as quickly as possible. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. Review articles are excluded from this waiver policy. Sign up here as a reviewer to help fast-track new submissions.