Background

Malignant tumors occasionally secrete hormonal factors that can cause some types of paraneoplastic symptoms [1–3]. Hypercalcemia is a relatively common paraneoplastic syndrome, and recent studies have demonstrated that parathyroid hormone-related protein (PTHrP) secreted by tumor cells can cause hypercalcemia in patients with malignant tumors [4, 5], while leukocytosis is a paraneoplastic syndrome caused by tumor-derived granulocyte colony-stimulating factor (G-CSF) [6]. However, the paraneoplastic production of both PTHrP and G-CSF by cancer cells is extremely rare. In this case report, we present a patient with tongue squamous cell carcinoma presenting with hypercalcemia and leukocytosis caused by tumor-derived PTHrP and G-CSF.

Case presentation

A 57-year-old man was referred to the Department of Oral and Maxillofacial Surgery, Kyushu University, with a chief complaint of a painful ulcerative lesion on the left lateral border of his tongue (Fig. 1a). Magnetic resonance imaging (MRI) revealed a tumorous mass occupying half of the tongue on the left side, extending to the lingual septum, and partially invading into the internal pterygoid muscle (Fig. 1b). No metastatic lymph nodes were found in the bilateral neck by palpation, ultrasonography, or computed tomography (CT). The patient had a medical history of diabetes mellitus. Pathological diagnosis of an incisional biopsy specimen indicated a moderately differentiated squamous cell carcinoma (SCC) (cT4aN0M0, stage IV). Planning CT was carried out followed by preoperative chemoradiotherapy including external beam irradiation to the primary tumor and neck in daily fractions of 2 Gy, five times weekly for 3 weeks, and oral administration of S-1 (120 mg/day) started 1 week prior to radiotherapy and continued throughout the radiotherapy period. One month after completing the preoperative chemoradiotherapy, the tumor was resected by subtotal glossectomy and segmental mandibulectomy under general anesthesia. Modified radical neck dissection and reconstruction using a rectus abdominis myocutaneous flap were performed simultaneously with tumor resection. Pathologically, four metastatic lymph nodes were identified: one in level I, one in level II, and two in level III. The histopathological response of the primary tumor to preoperative chemoradiotherapy was poor, and many residual carcinoma cells were noted in the muscular tissues in the resected specimens, though the surgical margin was tumor-free. Locoregional recurrence was detected by CT imaging 3 months after surgery, and the patient received further chemoradiotherapy (S-1, 120 mg/day; external beam irradiation in daily fractions of 2 Gy, five times weekly for 7 weeks). However, after completion of the chemoradiotherapy, the patient developed hypercalcemia (maximum serum calcium level, 16.3 mg/dL) and leukocytosis (maximum white blood cell count, 22.7 × 103/μL). The serum levels of PTHrP and G-CSF increased in parallel with progression of his hypercalcemia and leukocytosis (Figs. 2 and 3). Immunohistochemical staining revealed expression of PTHrP and G-CSF in the residual cancer cells (Fig. 4a, b). Interleukin (IL)-6 expression was also detected in the cancer cells (Fig. 4c). Based on these clinical and pathological findings, the patient was diagnosed with hypercalcemia and leukocytosis associated with malignancy. He was subsequently managed with intravenous fluids, furosemide, prednisolone, elcatonin, and pamidronate. However, an F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scan disclosed multiple metastatic regions, including the pelvis, lung, femur, adrenal gland, sternal bone, and inguinal nodes, and he progressed to respiratory failure and died of carcinomatous pleuritis 1 month later.

Fig. 1
figure 1

Intraoral and MRI findings. a Tumorous mass with ulcerative lesion on the left lateral border of the tongue. b Contrast-enhanced MRI findings. White arrow indicates tumorous mass

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Fig. 2
figure 2

Time course of serum levels of calcium and PTHrP. Serum levels of calcium and PTHrP gradually increased in parallel after the completion of chemoradiotherapy for locoregional recurrence

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Fig. 3
figure 3

Time course of white blood cell count and serum G-CSF level. The number of white blood cells and G-CSF level gradually increased in parallel

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Fig. 4
figure 4

Immunohistochemical staining for PTHrP, G-CSF, and IL-6 in residual cancer cells. (×400). a PTHrP. b G-CSF. c IL-6

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Conclusions

We present a very rare case of a patient with tongue squamous cell carcinoma presenting with hypercalcemia and leukocytosis. The serum levels of PTHrP and G-CFS were markedly elevated in the patient, in line with progression of his hypercalcemia and leukocytosis. Furthermore, immunohistological staining revealed PTHrP and G-CSF expression in the residual carcinoma cells. These findings suggested that hypercalcemia and leukocytosis in this patient were associated with tumor-derived PTHrP and G-CSF.

Yoneda et al. reported only five cases (2.2 %) presenting with both hypercalcemia and leukocytosis among 225 oral malignancies [7], though they did not demonstrate if the hypercalcemia and leukocytosis were caused by tumor-derived PTHrP and G-CSF. To the best of our knowledge, there have been only 13 recorded cases of head and neck tumors that produced both PTHrP and G-CSF, including the current case (Table 1) [8–16], in all of which patients presented with both hypercalcemia and leukocytosis. Pathologically, squamous cell carcinoma was the most frequent type of tumor (10 cases, 76.9 %), but only three cases of tongue squamous cell carcinoma have been reported [11, 12]. Furthermore, except for a patient with a benign ameloblastoma, 11 of the 12 previous cases had a poor prognosis. In the patient with hypopharyngeal carcinoma, the serum levels of both PTHrP and G-CSF were remarkably decreased after radical resection and the patient was rescued [16]. The present and previous findings thus suggest that increased serum levels of both PTHrP and G-CSF are indicative of a poor prognosis in patients with head and neck tumors.

Table 1 Case reports of head and neck tumors producing both PTHrP and G-CSF
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Hypercalcemia can be categorized as humoral hypercalcemia of malignancy (HHM) or local osteolytic hypercalcemia (LOH) [17]. HHM is caused by tumor-derived PTHrP, while LOH is mainly caused by osteolysis associated with bone metastasis. The present patient demonstrated multiple bone metastases on FDG-PET with elevated serum PTHrP levels, suggesting the existence of both HHM and LOH in this case. The clinical manifestations of hypercalcemia affect the neuromuscular, renal, gastrointestinal, skeletal, and cardiovascular systems [18], and anti-hypercalcemic therapy should therefore be initiated as soon as possible to avoid hypercalcemic crisis [19]. In this patient, saline infusion (2000–3000 mL/day) with concomitant loop diuretics (furosemide) was administered to increase calcium excretion and reduce serum levels as rapidly as possible. We also administered calcitonin (a naturally occurring peptide hormone that inhibits bone resorption and increases renal calcium excretion) and a bisphosphonate (alendronate) to treat the hypercalcemia [20]. Bisphosphonates are effective therapeutic agents for hypercalcemia that inhibit osteoclast differentiation and function [21]. We also used prednisolone to reduce gastrointestinal calcium absorption [22]. However, although the patient’s calcium levels were normalized by this therapy, subsequent hypercalcemic exacerbation developed. Yamazaki et al. demonstrated an average survival period of 39.0 days from the diagnosis of hypercalcemia in patients with oral cancer treated with bisphosphonates or calcitonin, compared with 19.5 days in untreated patients [11]. These results suggest that the prognosis of patients with tumor-derived PTHrP and G-CSF is extremely unfavorable, though anti-hypercalcemic therapy may slightly improve life expectancy.

Numerous previous studies have shown that G-CSF is responsible for paraneoplastic leukocytosis [6, 7, 23–25]. However, the mechanisms responsible for the production of these hormonal factors by tumor cells remain unknown. Recent studies have suggested that some inflammatory cytokines, including IL-6, may be associated with G-CSF production by malignant cells [26]. Moreover, hypercalcemia has been associated with cosecretion of PTHrP and IL-6 [27]. We previously showed that increased IL-6 expression in cancer cells predicted a poor response to chemoradiotherapy and an unfavorable prognosis in patients with oral SCC [28]. The current patient demonstrated a poor histological response to preoperative chemoradiotherapy and strong IL-6 expression in the residual cancer cells. These results suggested that IL-6 may play a key role in resistance to chemoradiotherapy and production of PTHrP and G-CSF in the cancer cells. However, further in vitro and in vivo studies are needed to clarify the association between IL-6 expression in oral squamous cell carcinoma and the production of PTHrP and G-CSF.

Abbreviations

FDG-PET, F-18 fluorodeoxyglucose positron emission tomography; G-CSF, granulocyte colony-stimulating factor; HHM, humoral hypercalcemia of malignancy; IL-6, interleukin 6; LOH, local osteolytic hypercalcemia; PTHrP, parathyroid hormone-related protein; SCC, squamous cell carcinoma