Lung Cancer (2004) 43, 301—307

Hypercalcemia—leukocytosis syndrome associated

with lung cancer
Akio Hiraki a,*, Hiroshi Ueoka a , Ichiro Takata b , Kenichi Gemba a ,
Akihiro Bessho a , Yoshihiko Segawa b , Katsuyuki Kiura a , Kenji Eguchi b ,
Toshiyuki Yoneda c,d , Mitsune Tanimoto a , Mine Harada a

a
Department of Medicine (II), Okayama University Medical School, Okayama, Japan
b
Department of Medicine, National Shikoku Cancer Center, Matsuyama, Ehime, Japan
c
Department of Biochemistry, Faculty of Dentistry, Osaka University, Suita, Osaka, Japan
d
Department of Medicine, Division of Endocrinology and Metabolism, The University of
Texas Health Science Center at San Antonio, San Antonio, TX, USA
Received 24 March 2003 ; received in revised form 26 August 2003; accepted 2 September 2003

KEYWORDS Summary Hypercalcemia and leukocytosis are two of the most common paraneoplas-
Paraneoplastic tic syndromes associated with various malignancies. Of note, concomitant manifesta-
syndrome; tion of hypercalcemia and leukocytosis are occasionally observed in the same cancer
Lung cancer; patients. However, the relationship between these two paraneoplastic syndromes and
Hypercalcemia;
clinical outcome is unclear. In the present study, we retrospectively investigated the
occurrence of hypercalcemia (≥10.2 mg/dl after adjustment for serum albumin con-
Leukocytosis;
centration), leukocytosis (≥14,000/mm3 with no evidence of infection) or both in lung
Prognosis
cancer patients (1149 cases). There were 65 cases (5.7%) of hypercalcemia, 16 cases
(1.4%) of leukocytosis and six cases (0.5%) of both hypercalcemia and leukocytosis
at the time of first presentation. The occurrence of these two distinct paraneoplas-
tic syndromes in the same patients was more frequent than could have been ex-
pected by chance alone (P < 0.001). There was a significant correlation between the
hypercalcemia—leukocytosis syndrome and performance status (P = 0.002). Survivals
of patients with hypercalcemia alone (median survival time: MST 3.8 months, n = 59),
leukocytosis alone (MST 1.9 months, n = 10), and the hypercalcemia—leukocytosis
syndrome (MST 1.5 months, n = 6) were significantly shorter than those without
them (MST 9.5 months, n = 1074; P < 0.001). Moreover, survival of patients with the
hypercalcemia—leukocytosis syndrome was significantly shorter than that of patients
with hypercalcemia alone (P = 0.013). On the other hand, there was no significant
difference in survival between the hypercalcemia—leukocytosis syndrome and leuko-
cytosis alone (P = 0.47). Multivariate analysis of prognostic factors using the Cox pro-
portional hazards model could not demonstrate that the hypercalcemia—leukocytosis
syndrome had independent prognostic significance. In conclusion, our results sug-
gest that the hypercalcemia—leukocytosis syndrome is an additional clinical entity of

* Corresponding author. Present address: Department of Respiratory Medicine and Clinical Research, National Sanyo Hospital,

Respiratory Disease Center, 685 Higashi-kiwa, Ube, Yamaguchi 755-0241, Japan. Tel.: +81-836-58-2300; fax: +81-836-58-5219.
E-mail address: [email protected] (A. Hiraki).

0169-5002/$ – see front matter © 2003 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.lungcan.2003.09.006
302 A. Hiraki et al.

paraneoplastic syndrome and is an indicator for poorer outcome in lung cancer pa-
tients, although the frequency of the combined syndrome is very rare (0.5% of cases
over a 10 year interval.
© 2003 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Center Hospital between 1986 and 1996. These

patients were composed of 871 men and 278
Paraneoplastic syndromes are systemic and non- women, with a median age of 66 years (ranges,
metastatic manifestations that cause increased 20—92). Histologically, there were 442, 324, 55
morbidity and possibly mortality in patients with and 294 patients with adenocarcinoma, squa-
a variety type of cancers [1—5]. Among these mous cell carcinoma, large cell carcinoma and
paraneoplastic syndromes, hypercalcemia is rel- small-cell carcinoma, respectively. Patients with
atively common in patients with lung cancer [1]. laboratory or clinical evidence for infection were
The frequency of hypercalcemia has been reported excluded.
to range between 10 and 25% (2). Leukocyto-
sis is another common paraneoplastic syndrome, 2.2. Diagnostic definition for hypercalcemia
ranging between 16 and 30%, in patients with
and leukocytosis
lung cancer [3—5]. Of note, recent studies have
reported that hypercalcemia and leukocytosis si-
Hypercalcemia was defined as a serum calcium
multaneously occur in patients with lung cancer
(Ca) concentration greater than 10.2 mg/dl. When
[3—6] and other carcinomas [7—10]. We have
serum albumin concentrations were lower than
described that patients with oral cancers occa-
4.0 g/dl, Ca values were adjusted according to
sionally manifest both hypercalcemia and leuko-
the formula, adjusted Ca concentration (g/dl)
cytosis and that there is a statistically significant
= measured Ca concentration + 4.0 − albumin con-
correlation between the occurrence of hypercal-
centration. Leukocytosis was defined as a white
cemia and leukocytosis [11]. From these observa-
blood cell count exceeding 14,000 ␮l−1 .
tions, we proposed that concomitant occurrence
of hypercalcemia and leukocytosis could be cat-
egorized as the hypercalcemia—leukocytosis syn- 2.3. Evaluation of bone metastases
drome [11]. However, it is unknown whether the
hypercalcemia—leukocytosis syndrome is a spe- All the patients with lung cancer were examined
cific clinical entity for oral cancers or general for bone metastases at the time of their first visit
one for other malignancies. More importantly, using 99 mTc-MDP. When the presence of bone
it is also unclear whether cancer patients with metastases was suspected, further examination by
both hypercalcemia and leukocytosis exhibit dif- X-ray, computed tomography (CT) and magnetic
ferent clinical outcome from patients with hy- resonance imaging (MRI) was conducted to verify
percalcemia or leukocytosis alone. To determine bone metastases.
this, we performed an extensive examination of
the clinical records of 1149 lung cancer patients 2.4. Statistical analysis
for the occurrence of hypercalcemia, leukocy-
tosis or both in a retrospective manner. Our re- The Chi-square test was used to evaluate cor-
sults show that lung cancer patients manifest the relations between hypercalcemia alone, leuko-
hypercalcemia—leukocytosis syndrome as well and cytosis alone, and simultaneous occurrence of
suggest that the hypercalcemia—leukocytosis syn- them (hypercalcemia—leukocytosis syndrome).
drome is an indicator for poorer outcome in these The Chi-square test or trend test was used to
patients. evaluate correlations between hypercalcemia—
leukocytosis syndrome and several categorical
variables. Probabilities of survival were esti-
2. Patients and methods mated using the Kaplan—Meier method, and dif-
ferences between patient groups were evaluated
2.1. Patients by the log-rank test. Prognostic factors were an-
alyzed using the Cox proportional hazard model.
This study included 1149 consecutive patients with All reported P-values are two-sided. A level
lung cancer who were admitted to the Okayama of P < 0.05 was accepted as statistically
University Hospital and National Shikoku Cancer significant.
Hypercalcemia—leukocytosis syndrome associated with lung cancer 303

Table 1 Patient characteristics

Total Hypercalcemia Leukocytosis Hypercalcemia—
leukocytosis syndrome
No. evaluated 1149 65 16 6
Median age 66 67 58 63
Range 92—20 92—45 75—45 49—75
Sex
Male 871 59 13 6
Female 278 6 3 0
Performance status
0 332 4 2 1
1 561 23 2 0
2 122 12 5 1
3 88 17 3 2
4 46 9 4 2
Histology
NSCLC 835 54 15 6
Adenocarcinoma 442 14 8 2
Squamous cell carcinoma 324 33 5 3
Large cell carcinoma 55 5 1 0
Adenosquamous cell carcinoma 14 2 1 1
SCLC 294 10 1 0
Others 20 1 0 0
Stage
I 151 4 1 0
II 77 4 0 0
IIIA 178 8 0 0
IIIB 266 22 2 1
IV 477 27 13 5

NSCLC: non-small cell lung cancer; SCLC: small cell lung cancer.

3. Results ical stage IV in and one at IIIB. Serum Ca levels

in patients with hypercalcemia—leukocytosis syn-
3.1. Incidence of hypercalcemia and drome ranged between 10.3 and 14.6 mg/dl (mean,
leukocytosis 11.8 mg/dl). The average white blood cell count
(WBC) in patients with the syndrome was 24,166
Patient characteristics are presented in Table 1. mm−3 (range, 14,300—45,500 mm−3 ). The average
Sixty-five (5.7%) patients developed hypercal- WBC in the whole patients involved in this study
cemia and 16 (1.4%) showed leukocytosis at first was 7446.9 mm−3 (median, 6800 mm−3 ).
visit. Among these patients, six cases (0.5%)
manifested both hypercalcemia and leukocyto- 3.2. Relationship between
sis. Concomitant manifestation of hypercalcemia hypercalcemia—leukocytosis syndrome and
and leukocytosis was not due to by chance, clinicopathologic factors
since there was a statistically significant cor-
relation between the occurrence of hypercal- The relationship between hypercalcemia—leuko-
cemia and leukocytosis by chi-square test cytosis syndrome and clinicopathologic factors is
(P < 0.001). shown in Table 3. A statistically significant cor-
Patients with hypercalcemia—leukocytosis syn- relation was observed between hypercalcemia—
drome are listed in Table 2. All of these six patients leukocytosis syndrome and performance status (PS)
were male and their median age was 63. Three (P = 0.002). However, hypercalcemia—leukocytosis
of them were with squamous cell carcinoma, two syndrome was not correlated with clinical stage
with adenocarcinoma, and one with adenosqua- (P = 0.095), gender (P = 0.345), histology (P =
mous cell carcinoma. Five patients were at clin- 0.347), and bone metastasis (P = 0.104).
 304
Table 2 Patients with hypercalcemia—leukocytosis syndrome in 1149 lung cancer
Patient Age/sex Histology Clinical PS Invasion Treatment Serum Ca Leukocyte CRP Survival
no. stage of bone for lung (mg/dl) (mm3 ) (mg/dl) (months)
cancer
1 64/M AC IV 3 + Paliative 10.3 25000 9.3 1.45
2 64/M SCC IV 3 + Paliative 10.6 14300 5.0 1.48
3 59/M ASCC IV 2 + VDS + CDDP 10.7 45500 6.1 1.58
4 75/M SCC IV 4 − CBDCA + ETP 14.6 14700 3.7 0.43
5 49/M ASCC IV 4 + IFO + VDS 12.4 14700 5.8 1.38
6 62/M SCC IIIB 0 − Paliative 12.2 30800 6.0 3.55

AC: adenocarcinoma; SCC: squamous cell carcinoma; ASCC: adenosquamous cell carcinoma; PS: performance status; CRP: C-reactive protein; VDS: vindesine;
CDDP: cisplatin; CBDCA: carboplatin; ETP: etoposide; IFO: ifosfomide.

A. Hiraki et al.
Hypercalcemia—leukocytosis syndrome associated with lung cancer 305

Table 3 Relationship between hypercalcemia—leu- Cox proportional hazards model revealed that
kocytosis syndrome and clinicopathologic factors hypercalcemia—leukocytosis syndrome had no in-
dependent prognostic significance.
Factor Hypercalcemia— Non- P
leukocytosis hypercalcemia—
syndrome leukocytosis 4. Discussion
syndrome
Sex Hypercalcemia and leukocytosis are two of the
Male 6 871 0.345 most common paraneoplastic syndromes that occur
Female 0 278 in the advanced stages of the illness [3—11]. In the
Performance status present study, we retrospectively examined 1149
0—2 2 1013 0.002 patients with lung cancer for manifestation of hy-
3—4 4 130 percalcemia and/or leukocytosis at their first visit.
Our results showed that 65 (5.7%) patients man-
Histology
ifested hypercalcemia alone, 16 patients (1.4%)
NSCLC 6 835 0.347
leukocytosis alone and six patients (0.5%) both hy-
SCLC 0 314
percalcemia and leukocytosis. Statistical analysis
Stage demonstrates that the concomitant occurrence of
I—II 0 406 0.096 hypercalcemia and leukocytosis in these six pa-
III—IV 6 737 tients is more frequent than could have been ex-
Bone metastasis pected by chance alone (P < 0.001) and thus sug-
Present 3 232 0.104 gests that these two paraneoplastic syndromes are
Absent 3 911 closely correlated with each other. These results
suggest that the hypercalcemia—leukocytosis syn-
NSCLC: non-small cell lung cancer; SCLC: small cell
drome we previously proposed in oral malignancies
lung cancer. The Chi-square test or trend test was used
to evaluate correlations between hypercalcemia—
[11] is also an independent clinical entity in lung
leukocytosis syndrome and several categorical vari- cancer.
ables. All reported P-values are two-sided. A level of It has been long recognized that paraneoplastic
P < 0.05 was accepted as statistically significant. syndromes such as hypercalcemia and leukocyto-
sis are indicators of poor prognosis in the various
types of malignancies [2,5]. Consistent with this,
our study confirmed that survival of patients with
3.3. Relationship between survival and either hypercalcemia or leukocytosis alone was
hypercalcemia, leukocytosis or both significantly shorter than that of those without
these syndromes. On the other hand, the prog-
Fig. 1 shows survival curves of lung cancer pa- nostic value of the hypercalcemia—leukocytosis
tients with hypercalcemia, leukocytosis or both. syndrome has not been determined to date. Our
Survival in patients with hypercalcemia alone data clearly showed that survival of patients with
(median survival time: MST 3.8 months, n = 59), the hypercalcemia—leukocytosis syndrome was
leukocytosis alone (MST 1.9 months, n = 10), significantly shorter than that of patients with
and hypercalcemia—leukocytosis syndrome (MST hypercalcemia alone. To our knowledge, this is
1.5 months, n = 6), was significantly shorter the first demonstration that suggests that the
than those in patients without hypercalcemia hypercalcemia—leukocytosis syndrome is an indica-
and leukocytosis (MST 9.5 months, n = 1074; tor for poorer outcome than hypercalcemia alone
P < 0.001). Of note, survival in patients with in lung cancer patients. However, our results did
hypercalcemia—leukocytosis syndrome was signif- not prove that the hypercalcemia—leukocytosis
icantly shorter than that in patients with hyper- syndrome has independent prognostic significance.
calcemia alone (P = 0.013). On the other hand, Our results also suggest that hypercalcemia and
there was no significant difference in survival be- leukocytosis can be caused through a common
tween hypercalcemia—leukocytosis syndrome and mechanism. Recent studies have reported that
leukocytosis alone (P = 0.47). long-term exposure to granulocyte-colony stim-
Multivariate analysis of prognostic factors includ- ulating factor (G-CSF) results in a stimulation of
ing hypercalcemia—leukocytosis syndrome age, PS, osteoclastic bone resorption in patients with con-
clinical stage, gender, serum Ca concentrations, genital neutropenia [12,13] and in normal rodents
serum albumin concentrations, serum lactate de- [14,15]. Purton et al. described an increase of os-
hydrogenase concentrations and WBC using the teoclast progenitors in G-CSF-mobilized peripheral
306 A. Hiraki et al.

Non-Hypercalcemia and leukocytosis

1 (MST; 9.5 months, n=1074)
* **
Hypercalcemia alone (MST; 3.8 months, n=59)
0.8
Leukocytosis alone (MST; 1.9 months, n=10)
Survivsal Probability

*** ****
Hypercalcemia-leukocytosis syndrome
0.6 (MST; 1.5 months, n=6)

*, ** P < 0.001, *** P = 0.47, **** P = 0.013

0.4

0.2

0 5 10 15
Time (Years)
Fig. 1 Kaplan—Meier curve for overall survival in patients with hypercalcemia, leukocytosis or both.

blood mononuclear cells from normal human donors pendent clinical entity that indicates poorer out-
[16]. Increased osteoclastic bone resorption is one come in lung cancer patients. These findings should
of the major causes of hypercalcemia [1]. There- deepen our understandings of the pathophysiol-
fore, G-CSF secreted from cancer cells may cause ogy of hypercalcemia and leukocytosis and, more
not only leukocytosis but also hypercalcemia by importantly, improve the management of cancer
promoting proliferation and differentiation of the patients with these paraneoplastic syndromes.
common hematopoietic progenitors of granulocytes
and osteoclasts. This might be one of the mech-
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