Severe hypercalcemia requiring emergency hemodialysis and multidrug therapy in a case of diffuse large B-cell lymphoma with multiple bone lesions

Abstract

Background

Severe hypercalcemia is a rare but serious complication observed in patients with diffuse large B-cell lymphoma (DLBCL) with multiple bone lesions. Currently, no standard therapy has been established for this life-threatening condition.

Case presentation

A 54-year-old Japanese woman with severe hypercalcemia (serum total calcium concentration of 23.0 mg/dL) was referred to our hospital. Initial management included multiple sessions of emergency hemodialysis, aggressive hydration, and administration of calcitonin. Although these interventions temporarily improved her condition, her serum calcium levels soon rebounded. The addition of bisphosphonates did not induce a prompt or sufficient reduction in serum calcium levels. Computed tomography revealed osteolytic lesions, strongly suggestive of malignancy. Given that the pathological condition was attributed to bone lesions, denosumab was administered, leading to a marked reduction in serum calcium levels and sustained control. A definitive diagnosis of DLBCL was established through bone biopsy and bone marrow aspiration. Based on these findings, severe hypercalcemia was determined to be secondary to DLBCL with multiple bone lesions. Following the initiation of chemotherapy, her serum calcium levels remained stable during follow-up.

Conclusions

Severe hypercalcemia in this case was caused by DLBCL with multiple bone lesions. Successful management was achieved through a combination of emergency hemodialysis, aggressive hydration, and a multi-drug regimen, including calcitonin, bisphosphonates, and denosumab.

Background

Hypercalcemia develops in approximately 25% of malignancy cases [1] and is most frequently observed in lung cancer, multiple myeloma, and renal cell carcinoma [2]. It can also occur in DLBCL; however, severe cases, defined as a serum total calcium concentration exceeding 12 mg/dL, are uncommon [3]. Although there have been reports of severe hypercalcemia in DLBCL with multiple bone lesions [4], such cases are considered rare. Due to its rarity, no well-established consensus exists on the optimal management of severe hypercalcemia in DLBCL with multiple bone lesions.

The standard initial treatment for hypercalcemia involves aggressive saline hydration to promote urinary calcium excretion. Additional therapeutic options include the administration of calcitonin and bisphosphonates [5]. Hemodialysis is typically considered particularly effective in severe cases, especially when serum total calcium levels exceed 18–20 mg/dL and/or when accompanied by neurological symptoms [5]. Denosumab, a monoclonal antibody targeting the receptor activator of nuclear factor-kappa B ligand (RANKL), has also been shown to be effective in malignancy-associated hypercalcemia that is refractory to bisphosphonate therapy [6].

Here, we present a case of severe hypercalcemia in a patient with DLBCL with multiple bone lesions. The condition was successfully managed with a combination of emergency hemodialysis, aggressive hydration, and administration of calcitonin, bisphosphonates, and denosumab.

Case presentation

The patient was a 54-year-old Japanese woman with a four-year history of type 2 diabetes mellitus; however, she had discontinued her treatment on her own. She developed back pain and a progressive loss of appetite two weeks before hospitalization. Her husband found her having difficulty moving and called for emergency medical assistance. At a regional hospital, she was diagnosed with severe hypercalcemia (serum total calcium concentration of 23.0 mg/dL). Due to the need for urgent treatment, she was transferred to the emergency department of a secondary hospital on the same day.

At the time of admission, her vital signs included a blood pressure of 89/72 mmHg, a heart rate of 81 beats per minute, and a respiratory rate of 18 breaths per minute. She was in a deep coma. Laboratory tests revealed an extremely high total serum adjusted calcium concentration (21.4 mg/dL), and ionized calcium (2.85 mmol/L). Her serum blood urea nitrogen (BUN) level was markedly elevated (83 mg/dL), whereas the increase in serum creatinine was mild (1.06 mg/dL). Blood glucose (580 mg/dL) and hemoglobin A1c (13.9%) were both significantly elevated. Alkaline phosphatase (192 IU/L) was mildly above the normal range. Other blood test results are shown in Table 1. Chest X-ray showed no pleural effusion or abnormal mass. Given her critical condition, the attending physician initiated aggressive hydration, emergency hemodialysis, and calcitonin administration under strict monitoring. Additionally, insulin therapy was started for hyperglycemia. Although her serum total calcium concentration decreased to 13.9 mg/dL (ionized calcium 1.76 mmol/L) and her level of consciousness improved, albeit incompletely, a new issue emerged: bilateral pleural effusions detected on computed tomography (CT). CT also revealed multiple osteolytic lesions; however, their significance was unclear at that time. As further detailed evaluation and specialized treatment were deemed necessary, she was transferred to our hospital, the highest-level medical institution in the region, on hospital day 2. (The clinical course of the patient before and after the transfer is summarized in Fig. 1 in this section.)

Table 1.

Patient’s laboratory results

Examination	Patient’s level	Reference range
Blood tests
Total protein (g/dL)	6.4	6.4–8.2
Albumin (g/dL)	3.0	3.9–5.1
Sodium (mEq/L)	153	138–145
Potassium (mEq/L)	2.9	3.6–4.8
Chloride (mEq/L)	109	100–110
Calcium (mg/dL)	20.4	8.6–10.1
Adjusted calcium (mg/dL)	21.4	8.6–10.1
Phosphate (mg/dL)	1.6	2.7–4.6
Magnesium (mg/dL)	1.5	1.8–2.4
Blood urea nitrogen (mg/dL)	83	8–20
Creatinine (mg/dL)	1.06	0.65–1.07
eGFR (mL/min/1.73 m2)	42.8	≥ 60
Blood glucose (mg/dL)	580	70–100
HbA1c (%)	13.9	4.6–6.2
Alkaline phosphatase (IU/L)	192	38–113
IgG (mg/dL)	951	870–1700
IgA (mg/dL)	290	110–410
IgM (mg/dL)	99	33–190
Immunofixation Electrophoresis	-	-
Free light chains kappa/lambda ratio	1.14	0.26–1.65
PTH-INTACT (pg/mL)	20	10–65
PTHrP (pmoL/L)	< 1.0	0–1.0
Anti-thyroid peroxidase antibody (IU/mL)	≤ 3.0	≤ 3.0
Anti-thyroglobulin antibody (IU/mL)	≤ 5.0	≤ 5.0
Thyrotrophin receptor antibody (IU/L)	0.9	< 2.0
1,25 dihydroxy vitamin D3 (pg/mL)	14	20–60
25 hydroxy vitamin D (ng/mL)	8.6	≥ 30.0
Adrenocorticotropic Hormone (pg/mL)	53.5	7.2–63.3
Cortisol (µg/dL)	25.3	4.4–21.1
HTLV-1 antibody	-	-
Soluble interleukin-2 receptor (U/mL)	1883	157–474

Abbreviations: eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; PTH, Parathyroid hormone; PTHrP, parathyroid hormone-related peptide; HTLV-1, Human T-cell Leukemia Virus type I

Note: eGFR was calculated using a modified version of the Modification of Diet in Renal Disease formula of the Japanese Society of Nephrology: eGFR (mL/min/1.73 m²) = 194 × ^−0.287 × serum creatinine^− 1.094 (× 0.739 for women). Adjusted calcium = calcium + [4 − albumin])

Fig. 1.

Patient’s clinical course. The horizontal axis represents the number of days since admission, while the vertical axis represents eGFR and adjusted calcium levels. Pola-R-CHP is a chemotherapy regimen consisting of polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisolone. Adjusted calcium levels decreased following hemodialysis and denosumab administration. Abbreviations: eGFR, estimated glomerular filtration rate. Pola-R-CHP, polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisolone

Upon her transfer to our hospital, her vital signs were as follows: blood pressure of 151/84 mmHg, heart rate of 63 beats per minute, and respiratory rate of 15 breaths per minute. Her level of consciousness was assessed as 14 on the Glasgow Coma Scale. Serum total calcium concentration initially remained stable, and she was monitored without additional treatment. However, on hospital day 7, her serum total calcium concentration unexpectedly began to rise again. She was administered intravenous zoledronic acid, but her serum calcium levels continued to rise, and her level of consciousness deteriorated once more. By that time, blood analysis related to hypercalcemia had been completed. Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) levels were within normal ranges, while both 1,25-dihydroxy vitamin D₃ and 25-hydroxy vitamin D levels were decreased. These results suggested that her severe hypercalcemia was not due to hyperparathyroidism or vitamin D-producing diseases such as tuberculosis or sarcoidosis. CT revealed osteolytic lesions in the right humerus, left second rib, skull, and pelvis (Fig. 2). Based on these findings, osteolytic changes due to malignancy were suspected as the underlying cause of her severe hypercalcemia. On hospital day 9, subcutaneous denosumab was administered. At that time, the adjusted calcium level was 17.4 mg/dL, and the ionized calcium level was 1.97 mmol/L. Additionally, two further sessions of hemodialysis were performed. With these additional treatments, her hypercalcemia improved dramatically, and her level of consciousness recovered.

Fig. 2.

Contrast-enhanced computed tomography. Contrast-enhanced computed tomography revealed osteolytic lesions in (a) the pelvis, (b) the skull, (c) the right humerus, and the left second rib

In collaboration with a hematologist, the cause of osteolysis was investigated. Immunoelectrophoresis results were normal, and no abnormalities were detected on gastrointestinal endoscopy. A bone biopsy of the right humerus was performed on hospital day 17, revealing diffuse proliferation of atypical lymphoid cells on histological analysis (Fig. 3a). Bone marrow aspiration, conducted on hospital day 23, showed similar findings (Fig. 3b), leading to a confirmed diagnosis of stage IV diffuse large B-cell lymphoma (DLBCL). Subsequently, the hematologist initiated pola-R-CHP chemotherapy, consisting of polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisolone. Since then, her serum total calcium concentration has remained consistently stable.

Fig. 3.

Microscopic findings. Microscopic examination revealed (a) bone and (b) bone marrow composed of atypical lymphoid cells

Discussion and conclusions

Approximately 90% of hypercalcemia cases are caused by primary hyperparathyroidism or malignancy [5]. Recently, hypercalcemia has been reported as a relatively common complication in DLBCL [7]with an average serum total calcium concentration ranging from 10.5 to 12.0 mg/dL³. This level is generally not considered life-threatening and can be managed with standard treatment. In contrast, our case involved severe hypercalcemia (serum total calcium concentration of 23 mg/dL) associated with DLBCL with multiple bone lesions, as confirmed by bone biopsy and bone marrow aspiration. The occurrence of such severe hypercalcemia as a complication of DLBCL is rare. Clinicians should be aware that DLBCL with multiple bone lesions can present with severe hypercalcemia, requiring prompt recognition and intervention.

The pathogenesis of hypercalcemia in malignancies can generally be categorized into humoral hypercalcemia of malignancy (HHM) and local osteolytic hypercalcemia (LOH) [8]. HHM is primarily driven by PTHrP secreted by malignant tumors and is commonly associated with squamous cell carcinoma of the lung, head and neck tumors, urothelial carcinomas, and breast cancer. It is also a complication in more than 70% of adult T-cell leukemia cases [9, 10]. In contrast, LOH is typically observed in patients with bone metastases from breast cancer or multiple myeloma. It has been reported that increased expression of RANKL plays a key role in LOH [11]. The activation of osteoclasts and subsequent bone resorption, driven by RANKL overexpression, contribute to hypercalcemia [11]. A much rarer mechanism, accounting for less than 1% of cases and not typically explained by HHM or LOH, involves tumor overproduction of 1,25-dihydroxy vitamin D. This form of hypercalcemia is most commonly seen in Hodgkin’s disease and non-Hodgkin’s lymphomas [12]. It is not particularly rare for DLBCL to be associated with hypercalcemia. However, there are only limited reports that delve into the underlying mechanisms and treatment approaches. To the best of our knowledge, there have been five reported cases of DLBCL in which the mechanisms, treatment strategies, and outcomes of hypercalcemia were discussed. Among the five cases, two were attributed to LOH. An increase in RANKL levels was investigated in only one case, and the elevation was confirmed. Most cases achieved good control with hydration, hemodialysis, diuretics, calcitonin, and bisphosphonates. This mini-review is presented in Table 2. In our case, plasma PTHrP concentration was normal, and serum 1,25-dihydroxy vitamin D concentration was low. Multiple osteolytic lesions were detected on CT imaging. Based on these findings, we suspected that LOH due to DLBCL was the primary mechanism underlying the severe hypercalcemia. Chen et al. have reported a case of DLBCL with multiple bone lesions causing hypercalcemia through increased RANKL expression [4], suggesting that the clinical features of hypercalcemia in such cases resemble those commonly observed in multiple myeloma. Additionally, Shibata et al. demonstrated in vitro that RANKL expression is upregulated in certain B-cell lymphomas [16]. Thus, it is possible that severe hypercalcemia in DLBCL may occur through RANKL activation. In our case, it remains unclear whether RANKL expression played a role in the pathogenesis.

Table 2.

Literature review: hypercalcemia in DLBCL [1, 4, 13–15]

Author	Age	Gender	Peak serum calcium concentration (mg/dL)	Pathogenesis	Treatment	Outcome
Alpha Oumar Diallo et al. [1]	76	Male	16.7	PTHrP mediated HHM	Aggressive hydration Calcitonin Bisphosphonates Hemodialysis	Decreased serum calcium concentration. The patient succumbed to the underlying disease.
Gabriella A. Conte et al. [13]	69	Male	16.1	PTHrP mediated HHM	Aggressive hydration Calcitonin Bisphosphonates Diuretic	Decreased serum calcium concentration.
Arafat Shabbir et al. [14]	71	Male	13.5	LOH	Aggressive hydration Calcitonin Prednisolone	Decreased serum calcium concentration.
Ping Chen et al. [4]	58	Female	15.6	LOH (Increased expression of RANKL) PTHrP mediated HHM	Aggressive hydration Calcitonin Bisphosphonates Diuretic	Decreased serum calcium concentration.
Yasser Hegazy et al. [15]	60	Female	12.5	Overproduction of 1,25-dihydroxy vitamin D	Bisphosphonates	Decreased serum calcium concentration.

Abbreviations: PTHrP, parathyroid hormone-related protein; HHM, humoral hypercalcemia of malignancy; LOH, local osteolytic hypercalcemia; RANKL, receptor activator of nuclear factor-kappa B ligand

The first-line treatment for hypercalcemia involves aggressive hydration, which promotes urinary calcium excretion and addresses hypovolemia, a common comorbidity of hypercalcemia [17]. Intravenous bisphosphonates, such as zoledronic acid, are often administered alongside hydration to achieve longer-term control of hypercalcemia [5]. Calcitonin is effective in rapidly lowering serum calcium levels, particularly in severe cases, and combination therapy with bisphosphonates is advantageous since calcitonin acts within hours, whereas bisphosphonates require 1–2 days to exert their effect [5]. Emergency hemodialysis is typically reserved for severe and refractory hypercalcemia [5]. It is a rapid and effective method for reducing serum total calcium concentration in emergency settings [18]. In our case, aggressive hydration, emergency hemodialysis, and calcitonin were initiated at the patient’s previous hospital to treat severe hypercalcemia. After transfer to our hospital, serum total calcium concentration was initially well controlled but subsequently increased again. Although intravenous zoledronic acid was administered, serum calcium levels remained inadequately controlled. In response, we resumed hemodialysis and introduced denosumab. Denosumab is a potent therapeutic option for hypercalcemia associated with malignancy, particularly when refractory to bisphosphonates [6, 9]. In our case, we strongly suspected a malignant etiology due to the presence of osteolysis on CT. After denosumab administration, serum total calcium concentration decreased significantly and remained well controlled thereafter. This suggests that targeting RANKL may have been the key to treatment in our case.

However, several limitations should be noted. Although zoledronic acid typically begins to exert its effects within approximately one week, denosumab was administered shortly thereafter due to the urgency of the clinical situation. As a result, the observed reduction in serum calcium levels may have been partially influenced by the prior administration of zoledronic acid, making it difficult to attribute the effect solely to denosumab. Additionally, although ionized calcium is the preferred measurement in cases of hypercalcemia, it was measured at our institution only intermittently. In our case, adjusted calcium levels calculated based on serum albumin (adjusted calcium = total calcium + [4.0 − serum albumin]) were used. However, due to the presence of underlying DLBCL, serum albumin levels may have been unreliable, potentially compromising the accuracy of the adjusted calcium values. This limitation should be acknowledged in the present study. Furthermore, since the mechanism of hypercalcemia was thought to involve LOH, measuring metabolic bone markers such as bone-specific alkaline phosphatase, osteocalcin, and C-terminal telopeptide of type I collagen would likely have provided useful information. However, under the current Japanese national health insurance system, these tests are not covered and therefore were not performed in this case.

In conclusion, we report a rare case of severe hypercalcemia caused by DLBCL with multiple bone lesions. The severe hypercalcemia was successfully managed with a combination of aggressive hydration, hemodialysis, calcitonin, bisphosphonates, and denosumab.

Abbreviations

DLBCL

DIFFUSE large B-cell lymphoma

PTHrP

Parathyroid hormone-related protein

CT

Computed tomography

HHM

Humoral hypercalcemia of malignancy

LOH

Local osteolytic hypercalcemia

RANKL

Receptor activator of nuclear factor-kappa B ligand

Pola-R-CHP

Polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisolone

Author contributions

Rinka Yamamoto, Toshiaki Ogishi, Sachika Okamoto, and Kosuke Yuyama diagnosed the patient. Shohei Kaneko supervised the case report. Yusaku Watanabe wrote the manuscript. Akari Matsuoka, Yuhei Nakamura, and Shiori Ando reviewed and edited the manuscript. Susumu Ookawara, Kiyonori Ito, Keiji Hirai made critical revisions. Yoshiyuki Morishita approved the final version. All authors read and approved the manuscript.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethical approval and consent to participate

All procedures performed in studies involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committee, as well as the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Consent for publication

Informed consent was obtained from the patient for the publication of this case report.

Note

In this manuscript, “aggressive hydration” is defined as fluid management involving careful monitoring of fluid input and output, aimed at safely providing the maximum tolerable volume.

Authors’ information

We thank Akari Matsuoka and Yuhei Nakamura, Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan, and Shiori Ando, Department of Diagnostic Pathology, Saitama Medical Center, Jichi Medical University, Saitama, Japan, for helpful discussions on the manuscript.

Competing interests

The authors declare no competing interests.