Introduction

Hypercalcemia occurs in 10–20 % of patients with malignant diseases [1]. The primary causes of hypercalcemia are humoral hypercalcemia of malignancy (HHM), wherein the parathyroid hormone-related protein (PTHrP) plays a central role, and local osteolytic hypercalcemia due to bone destruction by primary or metastatic tumors [2]. Up to 80 % of cases of hypercalcemia in patients with malignancies are due to HHM [3]. HHM most commonly occurs in squamous cell carcinoma, including lung, esophagus, and head and neck cancers. Other tumors that cause HHM are breast cancer, renal cancer and adult T cell leukemia.

However, HHM rarely occurs in patients with gastric cancer. In all previous cases, gastric cancer was diagnosed after the appearance of hypercalcemia. Here, we report a case of HHM due to gastric cancer during chemotherapy. We surveyed all previous cases and our case to investigate the characteristics of HHM associated with gastric cancer.

Case report

A 61-year-old male visited our hospital because he was checked up by gastric cancer screening using barium radiography. Endoscopy revealed a friable mass in the antrum of the stomach (Fig. 1a, b). The tumor was diagnosed as a poorly differentiated adenocarcinoma and signet ring cell carcinoma (human epidermal growth factor receptor 2-negative) by biopsy (Fig. 2a). Computed tomography (CT) of the abdomen showed extensive metastatic lymph nodes. The patient was treated with a combination therapy of S-1 (tegafur, gimeracil and potassium oxonate) and cisplatin. S-1 (100 mg) was administered orally for 3 weeks, followed by 2 drug-free weeks, and cisplatin (90 mg) was administered intravenously on day 8. After two courses of the therapy, reduction of the swollen lymph nodes was observed by CT. After finishing six courses of the therapy, CT revealed stable disease and laboratory examination revealed no adverse effects including serum levels of calcium, while tumor markers were slightly increased. Therefore, another course of the same chemotherapy was started. However, 2 weeks later, the patient presented with severe fatigue, nausea and anorexia, and the laboratory examination revealed hypercalcemia (Table 1). After hospitalization, we started intensive care to improve the general condition and hypercalcemia; this included intravenous hydration and zoledronic acid and calcitonin administration. CT showed swollen lymph nodes and ascites suggesting the extent of metastasis (Fig. 3a, b). None of the bone metastases, ectopic hyperparathyroid lesions or parathyroid nodule was found by CT. Although the patient's serum calcium level decreased to the normal range, he died of multiorgan failure and disseminated intravascular coagulation syndrome (DIC) on the 14th day after admission. The serum level of PTHrP was 6.2 pmol/l (normal range, <1.1), and the intact PTH level was less than 4 pg/ml (normal range, 10–65 pmol/ml). The biopsy specimen at the time of diagnosis revealed that cancer cells were immunohistochemically positive for PTHrP (Fig. 2b). Therefore, the patient was diagnosed with HHM because of hypersecretion of PTHrP by gastric cancer.

Fig. 1
figure 1

Endoscopic image of a friable mass in the antrum of the stomach (a) and the mass after spreading indigocarmine (b)

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Fig. 2
figure 2

a Gastric tumor was poorly differentiated adenocarcinoma. b Tumor cells were stained positive for PTHrP by immunohistochemistry

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Table 1 Laboratory date on admission
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Fig. 3
figure 3

At the time of admission, CT revealed enlarged metastatic lymph nodes (arrow) (a) and ascites (b)

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Discussion

HHM rarely occurs in patients with undifferentiated gastric cancer with rapid growth even when receiving chemotherapy. In previous reports, PTHrP expression in gastric cancer was not associated with hypercalcemia [4]. Alipov et al. found that PTHrP was expressed in 77.2 % of gastric carcinomas without humoral hypercalcemia and particularly expressed in 100 % of poorly differentiated carcinoma [5]. PTHrP expression is not rare in gastric cancer, while HHM due to hypersecretion of PTHrP by gastric cancer is rare. Dens et al. revealed no correlation between serum calcium levels and PTHrP levels and described that whether PTHrP expression alone is sufficient to cause hypercalcemia in patients with gastric cancer is unclear [6].

In the present case, the patient showed serum hypercalcemia and DIC during chemotherapy. Although the chemotherapy was effective on the CT image before admission, the tumor markers were increasing. The patient denied second line chemotherapy because of the general condition and efficacy of the first line chemotherapy on the CT image. Indeed, the same course of chemotherapy seemed ineffective because the CT image after admission suggested rapid growth of the tumor. Previous cases showed hypercalcemia before the diagnosis of gastric cancer at the end stage. All of these cases were diagnosed as undifferentiated adenocarcinoma and revealed hypercalcemia in progressed cancer or in the end stage. Alipov et al. suggested that PTHrP was expressed by human gastric epithelium in association with malignant transformation [5]. The mechanism of the increase in serum PTHrP in patients with gastric cancer has not been elucidated. In this case, one possible mechanism is that gastric cancer cells had malignant transformation and acquired the ability to produce PTHrP during chemotherapy. Another possibility is that tumor lysis by the chemotherapy led to the release of PTHrP into the blood. Although hypocalcemia is generally observed in tumor lysis syndrome, the release of PTHrP from gastric cancer cells might cause hypercalcemia. The former explanation seems to be more likely than the latter because the serum level of Ca was within normal limits during chemotherapy.

To date, only seven cases of hypercalcemia in PTHrP-producing gastric cancer have been reported [7–13]. We surveyed these seven cases and our case to investigate the characteristics of gastric cancer associated with HHM (Table 2). The median age of the patients was 65 years (range, 50–70 years), and 87 % of the patients were men. Most patients were diagnosed as poorly differentiated carcinoma, while none of the patients had well-differentiated carcinomas. None of the patients received chemotherapy before being diagnosed with HHM. In all the previous seven cases, PTHrP expression was investigated by immunohistochemistry after hypercalcemia was confirmed. The mean prognosis was 52 days after the diagnosis of HHM. All the patients showed high calcium levels and elevated serum levels of PTHrP. Intact PTHrP levels were measured in five patients, four of whom showed suppressed PTH levels. The mean serum calcium level was 15.2 ± 2.4 mg/dl, and the mean serum level of albumin-corrected calcium (4-albumin concentration + calcium concentration) was 16.2 ± 2.4 mg/dl. All eight cases showed distant metastasis when hypercalcemia was diagnosed. Three cases were diagnosed as gastric cancer according to autopsy results, whereas five cases were diagnosed by gastroduodenal endoscopy. Of the five patients, after hypercalcemia was diagnosed, three received chemotherapy, whereas our patient and another did not receive chemotherapy because of their deteriorated condition. Although the prognosis was poor, only one patient who responded to chemotherapy (cisplatin, epirubicin and etoposide) survived for more than 4 months [12].

Table 2 Reported cases of gastric cancer associated with HHM due to PTHrP secretion
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In conclusion, HHM due to PTHrP secretion by gastric cancer is rare and associated with poor prognosis. In cases of undifferentiated gastric cancer, the possibility of HHM should be considered even during chemotherapy.