- Case report
- Open Access
Tongue squamous cell carcinoma producing both parathyroid hormone-related protein and granulocyte colony-stimulating factor: a case report and literature review
© The Author(s). 2016
Received: 24 November 2015
Accepted: 15 June 2016
Published: 17 June 2016
The Erratum to this article has been published in World Journal of Surgical Oncology 2016 14:187
Paraneoplastic syndrome generally results from tumor-derived hormones or peptides that cause metabolic derangements. Common metabolic conditions include hyponatremia, hypercalcemia, hypoglycemia, and Cushing’s syndrome. Herein, we report a very rare case of tongue carcinoma presenting with leukocytosis and hypercalcemia.
A 57-year-old man was admitted to our hospital with tongue squamous cell carcinoma (cT4aN0M0, stage IV). He underwent radical resection following preoperative chemoradiotherapy, but locoregional recurrence was detected 2 months after surgery. He presented with marked leukocytosis and hypercalcemia with elevated serum levels of granulocyte colony-stimulating factor (G-CSF) and parathyroid hormone-related protein (PTHrP). He was therefore managed with intravenous fluids, furosemide, prednisolone, elcatonin, and pamidronate. However, the patient died 1 month later of carcinomatous pleuritis following distant metastasis to the lung. Immunohistochemical analyses of the resected specimens revealed positive staining for PTHrP and G-CSF in the cancer cells.
In this case, it was considered that tumor-derived G-CSF and PTHrP caused leukocytosis and hypercalcemia.
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) . 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.
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.
Case reports of head and neck tumors producing both PTHrP and G-CSF
Serum PTHrP (pmol/L) (normal range)
Serum G-CSF (pg/mL) (normal range)
Cervix, lung, liver
Cervix, lung, liver,
Follicular and papillary carcinoma
Lung, liver, pancreas
3109 (<16) [pg/mL]
285 (<20) (pleural fluid)
Cervix, lung, liver, bone, kidney, skin
Cervix, lung, bone, femur, adrenal gland, groin
Hypercalcemia can be categorized as humoral hypercalcemia of malignancy (HHM) or local osteolytic hypercalcemia (LOH) . 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 , and anti-hypercalcemic therapy should therefore be initiated as soon as possible to avoid hypercalcemic crisis . 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 . Bisphosphonates are effective therapeutic agents for hypercalcemia that inhibit osteoclast differentiation and function . We also used prednisolone to reduce gastrointestinal calcium absorption . 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 . 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 . Moreover, hypercalcemia has been associated with cosecretion of PTHrP and IL-6 . 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 . 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.
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
We are very thankful to our patient for providing his informed consent for publication of this case report.
This work was supported by a Grant-in-Aid (26463014, 60615798, 26670869) from the Japanese Ministry of Education, Culture, Sports, Science and Technology.
Availability of data and materials
The authors do not wish to share their data. They respect the patient’s rights to privacy and to protect his identity. The authors presented all the necessary information about their case report in the manuscript. Raw data regarding our patient are managed strictly. However, about the literature review, all used literature is referenced appropriately in the “References” section.
SK, MI, and SN contributed to the treatment of the patient. NK, YM, and TH collected the clinical data. RM, YG, and TJ prepared and analyzed the pathological data. NK and SK drafted the manuscript. RM, YG, TJ, YM, TS, TH, and SN helped in the manuscript drafting. All authors have read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.
Ethics approval and consent to participate
This report was approved by the Ethics Committee of Kyushu University, and written informed consent was obtained from all of the patients (IRB serial number: 27-362).
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Robinson WA. Granulocytosis in neoplasia. Ann NY Acad Sci. 1974;230:212–8.View ArticlePubMedGoogle Scholar
- Broadus AE, Mangin M, Ikeda K, Insogna KL, Weir EC, Burtis WJ, et al. Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide. N Engl J Med. 1988;319:556–63.View ArticlePubMedGoogle Scholar
- Isidori AM, Kaltsas GA, Pozza C, Frajese V, Newell-Price J, Reznek RH, et al. The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up. J Clin Endocrinol Metab. 2006;91:371–7.View ArticlePubMedGoogle Scholar
- Suva LJ, Winslow GA, Wettenhall RE, Hammonds RG, Moseley JM, Diefenbach-Jagger H, et al. A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science. 1987;237:893–6.View ArticlePubMedGoogle Scholar
- Mangin M, Ikeda K, Dreyer BE, Broadus AE. Isolation and characterization of the human parathyroid hormone-like peptide gene. Proc Natl Acad Sci U S A. 1989;86:2408–12.View ArticlePubMedPubMed CentralGoogle Scholar
- Asano S, Urabe A, Okabe T, Sato N, Kondo Y. Demonstration of granulopoietic factor(s) in the plasma of nude mice transplanted with a human lung cancer and in the tumor tissue. Blood. 1977;49:845–52.PubMedGoogle Scholar
- Yoneda T, Nishimura R, Kato I, Masatoshi O, Masaaki T, Masayoshi S. Frequency of the hypercalcemia-leukocytosis syndrome in oral malignancy. Cancer. 1991;68:617–22.View ArticlePubMedGoogle Scholar
- Yazawa S, Toshimori H, Nakatsuru K, Katakami H, Takemura J, Matsukura S. Thyroid anaplastic carcinoma producing granulocyte-colony-stimulating factor and parathyroid hormone-related protein. Intern Med. 1995;34:584–8.View ArticlePubMedGoogle Scholar
- Murao T, Takaba S, Fujita T. A case of squamous cell carcinoma of the tonsil with high concentration of serum granulocyte colony stimulating factor and parathyroid hormone-related protein. J Okayama Surg Pathol Assoc. 1997;34:9–12.Google Scholar
- Kunisue H, Tanaka K, Sonoo H, Kurebayashi J, Shimozuma K, Mikami Y. Transformation to undifferentiated from differentiated thyroid cancer associated with remarkable leukocytosis and hypercalcemia: report of a case. J Japanese Surg Assoc. 2000;61:886–9.View ArticleGoogle Scholar
- Yamazaki H, Ota Y, Karakida K, Sekiya R, Mizusawa N, GOTO J. Hypercalcemia in patients with oral cancer. Japan Soc Head Neck Cancer. 2000;26:95–100.View ArticleGoogle Scholar
- Obara S, Yoshimura Y. A case of tongue carcinoma showing leukocytosis and hypercalcemia with the production of G-CSF and PTHrP. Jpn J Oral Maxillofac Surg. 2001;47:22–4.View ArticleGoogle Scholar
- Tanaka K, Nibu K. Laryngeal squamous cell carcinoma with ectopic production of granulocyte colony-stimulating factor and parathyroid hormone-related protein. Int J Clin Oncol. 2005;10:195–7.View ArticlePubMedGoogle Scholar
- Tamura K, Yoshinaga T, Tanino M, Kimura T, Yamada N, Nishimura M, et al. Hypopharyngeal squamous cell carcinoma producing both granulocyte colony-stimulating factor and parathyroid hormone-related protein. Pathol Int. 2008;58:652–6.View ArticlePubMedGoogle Scholar
- Ota Y, Aoki T, Otsuru M, Hirabayashi K, Nakamura N, Tsukinoki K. Huge ameloblastoma associated with hypercalcemia, leukocytosis, and elevated tumor markers via production of parathyroid hormone-related protein and granulocyte colony-stimulating factor. J Oral Maxillofac Surg. 2011;70:1380–5.View ArticlePubMedGoogle Scholar
- Matsuo M, Rikimaru F, Higaki Y, Masuda M. A case of G-CSF producing hypopharyngeal carcinoma. Japanese J Head Neck Cancer. 2013;39:60–5.Google Scholar
- Rosol TJ, Capen CC. Biology of disease: mechanisms of cancer-induced hypercalcemia. Lab Invest. 1992;67:680–702.PubMedGoogle Scholar
- Bajorunas DR. Clinical manifestations of cancer-related hypercalcemia. Semin Oncol. 1990;17:16–25.PubMedGoogle Scholar
- Iwase M, Takemi T, Manabe M, Nagumo M. Hypercalcemic complication in patients with oral squamous cell carcinoma. Int J Oral Maxillofac Surg. 2003;32:174–80.View ArticlePubMedGoogle Scholar
- Hosking DJ, Gilson D. Comparison of the renal and skeletal actions of calcitonin in the treatment of severe hypercalcemia of malignancy. Q J Med. 1984;211:359–68.Google Scholar
- Watters J, Gerrard G, Dodwell D. The management of malignant hypercalcemia. Drugs. 1996;52:837–48.View ArticlePubMedGoogle Scholar
- Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc. 2010;85:838–54.View ArticlePubMedPubMed CentralGoogle Scholar
- Horii A, Shimamura K, Honjo Y, Mitani K, Miki T, Takashima S, et al. Granulocyte colony stimulating factor-producing tongue carcinoma. Head Neck. 1997;19:351–6.View ArticlePubMedGoogle Scholar
- Ito T, Shimamura K, Shoji K, Akatsuka A, Kiryu Y, Tamaoki N, et al. Urinary bladder carcinoma producing granulocyte colony stimulating factor (G-CSF): a case report with immunohistochemistry. Virchows Archiv A Pathol Anat. 1993;422:487–90.View ArticleGoogle Scholar
- Ota S, Kato A, Kobayashi H, Yonezumi M, Yamaguchi J, Musashi M, et al. Monoclonal origin of an esophageal carcinosarcoma producing granulocyte-colony stimulating factor. Cancer. 1998;82:2102–11.View ArticlePubMedGoogle Scholar
- Inoue M, Minami M, Fujii Y, Matsuda H, Shirakura R, Kido T. Granulocyte colony-stimulating factor and interleukin-6-producing lung cancer cell line. LCAM J Surg Oncol. 1997;64:347–50.View ArticlePubMedGoogle Scholar
- Asanuma N, Hagiwara K, Matsumoto I, Matsuda M, Nakamura F, Kouhara H, et al. PTHrP-producing tumor: squamous cell carcinoma of the liver accompanied by humoral hypercalcemia of malignancy, increased IL-6 and leukocytosis. Intern Med. 2002;41:371–6.View ArticlePubMedGoogle Scholar
- Jinno T, Kawano S, Maruse Y, Matsubara R, Goto Y, Sakamoto T, et al. Increased expression of interleukin-6 predicts poor response to chemoradiotherapy and unfavorable prognosis in oral squamous cell carcinoma. Oncol Rep. 2015;33:2161–8.PubMedPubMed CentralGoogle Scholar