Yen-Hung Yao
1
, Sung-Hua Chuang
1
, Wu-Chang Yang
1
, Ng Yee-Yung
1
1
Division of Nephrology, Department of Medicine
Running title: Small cell lung cancer and hypercalcemia
Correspondence should be addressed to:
Yee-Yung Ng, MD.
Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital
No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan
Tel: 886-2-2871-2121 ext 2993; Fax: 886-2-28204735
E-mail: yyng@vghtpe.gov.tw
Adress for reprint requests:
Taipei Veterans General Hospital No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan
1

高血鈣常見於乳癌、鳞狀細胞肺癌、及多發性骨髓瘤等病患，但少見於小
細胞肺癌。各種細胞型態的肺癌，包括小細胞肺癌，均有相當高比例會分泌副甲
狀腺荷爾蒙相關蛋白（Parathyroid hormone-related protein, PTHrP）。不同細
胞型態的肺癌合併高血鈣的發生率各異，這可能與 PTHrP 的分泌型態或速度不
同有關。文獻報告小細胞肺癌引發高血鈣的機會與腫瘤大小有關。此外，我們回
顧有關小細胞肺癌合併高血鈣（>12mg/dL）的個案報告，發現病患均有骨轉移。
本文報導一位小細胞肺癌病患，腫瘤迅速擴大且合併骨轉移，於住院中發生高血
鈣與急性腎衰竭，最後過世。雖然小細胞肺癌患者甚少發生高血鈣，若腫瘤體積
較大或合併骨轉移時，臨床醫師仍需追蹤血鈣濃度，以及早診斷高血鈣並預防其
併發症。
關鍵字：小細胞肺癌，高血鈣，骨轉移
2

Hypercalcemia is relatively common in patients with malignancies, especially breast cancer, squamous cell lung cancer and multiple myeloma, but uncommon in patients with small cell lung cancer. Actually all types of lung cancer have high incidence of abnormal parathyroid hormone-related protein (PTHrP) secretion, including small cell lung cancer. The different incidence of hypercalcemia between squamous cell and small cell lung cancers may result from different patterns or rates of PTHrP secretion.
Besides, patients of small cell lung cancer with serum calcium level greater than 12mg/dL usually had concurrent bone metastasis or larger tumor burden. We report a patient of small cell lung cancer with large tumor burden and extensive bone metastases. The patient suffered from hypercalcemia with acute renal failure and was expired soon after the diagnosis was made.
In summary, although hypercalcemia is uncommon among patients with small cell lung cancer, this complication should be kept in mind whenever we encounter acute renal failure in these patients. Serum calcium should be monitored regularly in who have large tumor burdens or bony metastases in order to discover hypercalcemia early as well as prevent related acute renal failure and other complications.
Key words: small cell lung cancer, hypercalcemia, bone metastasis
3

Hypercalcemia is a relatively common paraneoplastic syndrome in patients with breast cancer, squamous cell lung cancer, or multiple myeloma, but uncommon in patients with small cell lung cancer. We present a case of small cell lung cancer complicated with hypercalcemia and acute renal failure, and review the literatures about hypercalcemia in small cell lung cancer.
Case Report
A 35 year-old male patient was found to have a right lung mass by a chest plain film in March 2008. He was admitted in July 2008 due to progressive low back pain for 3 months. On admission, his vital signs were stable, and physical examinations revealed knocking pain over the lower back. Blood tests disclosed: white blood cell count 10100 /mm
3
, hemoglobin 13.4 g/dL, platelet count 251000 /mm
3
, blood urea nitrogen (BUN) 18 mg/dL, creatinine (Cr) 0.96 mg/dL, albumin 3.8 g/dL, calcium
10.6 mg/dL, phosphate 4.6 mg/dL. The chest plain film demonstrated a 6.3 cm x 6.1 cm mass over right lower lung field (Figure 1A), and the chest computed tomography
(CT) showed a 6.2 x 6.1cm mass lesion at the right lower lobe of lung with encasement of right lower lung bronchus, mediastinal lymphadenopathy and bone metastases. The CT scan of lumbar spine revealed diffuse bony metastases at vertebra,
4

right sacrum, and left iliac bones, with pathologic fracture of the third lumbar vertebra body (Figure 2). Therefore, he underwent total laminectomy of T10 and L3 as well as internal fixation over T9-11 and L2-5 levels to relieve bone pain and spinal cord compression. The pathologic exam of specimen from his vertebra and surrounding soft tissue showed metastatic small cell carcinoma. One week after operation, serum
BUN and Cr levels were elevated (BUN 45 mg/dL, Cr 2.08 mg/d), and the tumor mass was enlarged to 8.3 cm in diameter in the chest plain film (Figure 1B). Five days later, consciousness drowsiness was noted. The results of blood tests were as follows: albumin 3.4 g/dL, calcium 21 mg/dL, phosphate 4.4 mg/dL, alkaline phosphatase 541
U/L, BUN 79 mg/dL and Cr 5.28 mg/dL. Serum level of intact PTH was 2.71 pg/mL
(normal range < 50 pg/mL).
After hydration with intravenous isotonic saline and 3 courses of hemodialysis, the patient’s serum calcium level decreased to 11.1 mg/dL, and consciousness recovered. Unfortunately, the patient died from massive upper gastrointestinal bleeding three weeks later.
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Hypercalcemia is a common paraneoplastic syndrome, which occurs in about 20
% of patients with cancer.
1
The most common malignancies that cause paraneoplastic hypercalcemia are breast cancer, squamous cell lung cancer, and multiple myeloma.
1,2
Generally, there are three mechanisms
1
of hypercalcemia in patients with cancer.
Firstly, osteolytic metastases release local cytokines, such as tumor necrosis factor, interleukin-1, and osteoclast activating factors. Secondly, some tumor cells secrete calcitriol. The final and most important mechanism is parathyroid hormone-related protein (PTHrP)
3,4
secreted by tumor cells themselves. PTHrP is undoubtedly the most common cause of hypercalcemia in patients with nonmetastatic solid tumors
(so-called humoral hypercalcemia of malignancy, HHM), and accounts for about 80% of malignancy-associated hypercalcemia.
3
Tumor-derived PTHrP stimulates osteoclastic resorption, with release of bone-derived growth factors (ex: TGF -β) which accelerate tumor growth and subsequent PTHrP expression. This processes become a vicious circle.
3,4
It’s well-known that humoral hypercalcemia of malignancy is common in patients with squamous cell lung cancer, but rare in those with adenocarcinoma or small cell lung cancer, despite the fact that incidences of PTHrP secretion and lytic bone metastases were high in both cancers.
5-10
In fact, according to the study of L. A.
6

Davidson et al,
9
the majority of lung cancers have PTHrP expressed in the tumor tissues (100% in squamous cell carcinoma, 95% in adenocarcinoma, 84% in small cell lung cancer, and 93% in carcinoid). What mechanisms lead to different incidences of hypercalcemia among different types of lung cancer? The reasons why some malignancies cause elevated PTHrP secretion but not hypercalcemia include: peptide levels not high enough to raise serum calcium, increased rate of peptide breakdown, or peptide without appropriate biological activity. In addition, PTHrP may need synergestic effects of other tumor-derived growth factors or cytokines to cause hypercalcemia, and there may be some counter-regulatory substances involved in this process.
5
Furthermore, tumor specific posttranslational modification of PTHrP may be important in the synthesis of specific molecular forms of PTHrP with hypercalcemic activity.
5,11
In brief, one or more abovementioned mechanisms might lead to heterogeneity of PTHrP effects among different cells types of lung cancer, which have different ability to alter calcium metabolism. Serum PTHrP level was not checked in this case, because this measurement is usually not necessary for diagnosis considering most patients have clinically apparent malignancy, especially if other factors predisposing hypercalcemia could be excluded, such as dehydration or use of thiazide diuretics.
We made a search in Pubmed and collect case reports of patients with concurrent
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small cell lung cancer and hypercalcemia (greater than 12.0 mg/dL). (Table 1)
12-17
Including our patient, there are twelve patients reported, and all of them had bone metastasis. In contrast, Bender RA’s report
10
pointed out that osseous involvement was detected only in 66% of patients of small cell lung cancer with normal calcium level. The serum calcium level of case 5 (Table 1) was 10.8 mg/dL initially while there was no bone metastasis; the level roe to 12.0 mg/dL six months later when bone metastases occurred. Hence, in addition to humoral mechanism, multiple lytic bone metastases might contribute to the hypercalcmeia and acute renal failure in our patient.
The tumor in this patient grew rapidly from 6 cm to 8cm in diameter among two weeks, at the same time hypercalcemia was developing. This is compatible with previous report that hypercalcemia was usually associated with larger tumor burdens and shorter survival.
18
Although hypercalcemia was corrected, our patient died within three weeks.
In this presented case, hypercalcemia with acute renal failure occurred soon after the orthopaedic surgery for spinal compression and pathologic fracture. It is not clear if there is any association between hypercalcemia and orthopaedic surgery.
Prophylactic surgical correction of bone metastases is indicated for impending fracture of weight-bearing bones,
2
and there is no report of hypercalcemia associated with surgical management of spinal metastasis. Hence, hypercalcemia of this case is
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not likely to be related to the decompressive operation.
In summary, hypercalcemia in patients with small cell lung cancer is related to multifaceted factors such as PTHrP, bony metastasis and tumor size. In this case, serum calcium was not followed until his consciousness changed. Therefore, this case reminds us to monitor serum calcium frequently in patients with huge small cell lung cancer and bony metastasis in order to discover hypercalcemia early and to prevent associated acute renal failure or neurologic manifestation.
Conflict of interest statement . None declared.
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Reference
1.
Andrew F. Stewart: Hypercalcemia associated with cancer. N Engl J Med 2005;
352: 373-379.
2.
G A Clines, T A Guise : Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone.
Endocrine-Related Cancer 2005; 12: 549-583
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Dominic A. Solimando: Overview of hypercalcemia of malignancy. Am J
Health-Syst Pharm. 2001; 58(3): S4-7
4.
Gregory R. Mundy, James R. Edwards: PTH-Related Peptide (PTHrP) in
Hypercalcemia. J Am Soc Nephrol 2008; 19: 672-675
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Asa SL, Henderson J, Goltzman D, Drucker DJ: Parathyroid hormone-like peptide in normal and neoplastic human endocrine tissues. J Clin Endocrinol
Metub 1990;71: 1112-1118.
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Iguchi H. A: PTHrP-producing cell line derived from human small cell lung carcinoma. Hum Cell 1996; 9(1): 75-78.
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Brandt DW, Burton DW, Gazdar AF, Oie HE, Deftos L: All major lung cancer cell types produce parathyroid hormone-like protein: heterogeneity assessed by high performance liquid chromatography. J. Endocrinology 1991; 129(5):
2466-2470
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8.
Deftos LJ, Gazdar AF, Ikeda K, Broadus AE: The parathyroid hormone-related protein associated with malignancy is secreted by neuroendocrine tumors. Mol
Endocrinol. 1989 Mar; 3(3): 503-508.
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L. A. Davidson, M. Black, F. A. Carey, F. Logue, A. M. Mcnicol: Lung tumors immunoreactive for parathyroid hormone related peptide: analysis of serum calcium levels and tumor type. Journal of Pathology 1996; 178: 398-401.
10.
Bender RA, Hansen H: Hypercalcemia in bronchogenic carcinoma. A prospective study of 200 patients. Ann Intern Med. 1974 Feb; 80(2): 205-208.
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Dunne FP, Lee S, Ratcliffe WA, Hutchesson AC, Bundred NJ, Heath DA:
Parathyroid hormone-related protein (PTHrP) gene expression in solid tumors associated with normocalcaemia and hypercalcaemia. J Patho. 1993; 171(3):
215-221
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Dainer Paul: Octreotide acetate therapy for hypercalcemia complicating small cell carcinoma of the lung. South Med J. 1991; 84(10): 1250-1254
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15.
Stuart-Harris R, Ahern V, Danks JA, Gurney H, Martin TJ: Hypercalcaemia in small cell lung cancer. Report of a case associated with PTHrP. Eur J Cancer.
1993; 29A(11): 1601-1604.
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Noriko Hidaka, Motoko Nishimura, Koichi Nagao: Establishment of two human small cell lung cancer cell lines: the evidence of accelerated production of parathyroid hormone-related protein with tumor progression. Cancer Letters
1998; 125: 149–155
17.
Yoshimoto K, Yamasaki R, Sakai H, Tezuka U, Takahashi M, Iizuka M, et al:
Ectopic production of parathyroid hormone by small cell lung cancer in a patient with hypercalcemia. J Clin Endocrinol Metab. 1989; 68(5): 976-981
18.
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Table 1. Clinical manifestations of patients with small cell lung cancer and serum calcium level greater than 12mg/dL
Year Case Age/gender Location of tumor in lung Serum Ca* (mg/dL) Serum IP (mg/dL) Metastasis at time of Other features
(reference)
1975 (12)
1981 (13)
1
2
3
4
5
38/M
64/M
46/M
56/M
43/M
LUL
Left main bronchus
Left hilum
LUL
LUL, hilum
13.7
15.3
15.6
12.6
10.8
5.0
1.4
4.2
4.6
2.5 hypercalcemia
T and L spine, mediastinum, right scapula, adrenal galnds,
Liver, bone spleen, LNs
T8-12, right femur, liver, LNs
Coincidental primary hyperparathyroidism
Bone marrow
Antemortem Ca 13.9 mg/dL, with
Bone marrow widespread mets
Antemortem Ca 12 mg/dL, with bone, BM, liver, brain mets
6
7
8
1991 (14) 9
54/F
53/M
64/M
67/F
Right hilum
LUL
Left hilum
LUL
16
12.1
13.2
14
5.1
-
2.6
Decreased
T 9-12 spine, LN
-
Bone, liver, brain
L3-4, left sacral ala, left diaphragm, liver, LNs, brain
Bone pain; suspecious bone mets
1993 (15) 10
1998 (16) 11
67/M
32/F
LUL
Not mentioned
14.7
17.5
-
-
Bone marrow, liver
Not mentioned
PTHrP was localized in the tumor specimen; low tubular IP threshold
High serum PTHrP;
PTHrP transcription and secretion increased at late stage.
Acute renal failure; ectopic PTH production
1989 (17) 12 70/M RLL 19.3 -
L spine, liver, lung, LNs, adrenals, prostate
2009 13 37/M RLL 21.48 4.4 T9-11, L2-5 Acute renal failure
* Serum calcium level was corrected according to albumin level, if data is available.
Abbreviation: Ca, calcium; F, female; IP, inorganic phosphate; L, lumbar; LN, lymph nodes; LUL, left upper lobe; M, male; Mets, metastases;
PTH, parathyroid hormone; PTHrP, parathyroid horomone-related protein; T, thoracic
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Figures legend
Figure 1. A) Chest X-ray showed: a 6.3 x 6.1 cm mass lesion at right lower lung field.
B) The mass enlarged into 8.3 x 6.3 cm 2 weeks later.
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Figure 2. Computed tomography scan showed A) multiple radiolucent bony lesion at
T12 ~L5 vertebra, soft tissue mass with bony destruction and about 40% collapse in
L3 vertebral body with extradural compression, and B) bony destruction at right sacrum and left iliac bones.
15