Open Access Maced J Med Sci electronic publication ahead of print,

published on November 24, 2018 as https://doi.org/10.3889/oamjms.2018.421

ID Design Press, Skopje, Republic of Macedonia

Open Access Macedonian Journal of Medical Sciences.
https://doi.org/10.3889/oamjms.2018.421
eISSN: 1857-9655
Clinical Science

Procalcitonin Level in Non-Small Cell Lung Cancer Patients

among Indonesian Population

1* 1 1 1 1
Noni Novisari Soeroso , Muhammad Faiz Tanjung , Dina Afiani , Andika Pradana , Setia Putra Tarigan , Arlinda Sari
2
Wahyuni

1
Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, University of Sumatera Utara, University of
2
Sumatera Utara Hospital, Jl. Dr. Mansyur No.66 Medan 20154, Sumatera Utara, Indonesia; Department of Public Health,
Faculty of Medicine, University of Sumatera Utara, Jl. Dr. Mansyur No.66 Medan 20154, Sumatera Utara, Indonesia

Abstract
Citation: Soeroso NN, Tanjung MF, Afiani D, Pradana A, BACKGROUND: Serum Procalcitonin (PCT) is a biomarker that is frequently used to diagnose an infection. In
Tarigan SP, Wahyuni AS. Procalcitonin Level in Non-
Small Cell Lung Cancer Patients among Indonesian
some cases of thoracic malignancy, procalcitonin level appears to increase. However, the role of procalcitonin to
Population. Open Access Maced J Med Sci. diagnose malignancy is not certain yet, and the causes have not been known.
https://doi.org/10.3889/oamjms.2018.421
Keywords: Procalcitonin; Non-small cell lung cancer; AIM: This study aimed to investigate procalcitonin levels in non-small cell lung cancer patients.
Adenocarcinoma; Lung cancer
*Correspondence: Noni Novisari Soeroso. Department of METHODS: This was an observational study with a cross-sectional design. All lung cancer patients did not
Pulmonology and Respiratory Medicine, Faculty of diagnose based on cytology/histopathology results with no evidence nor were signs and symptoms of infection
Medicine, University of Sumatera Utara, University of
Sumatera Utara Hospital, Jl. Dr Mansyur No.66 Medan
recruited through consecutive sampling. The subtypes of lung cancer include adenocarcinoma, squamous cell
20154, Sumatera Utara, Indonesia. E-mail: carcinoma, and large cell carcinoma, staged III and IV. The procalcitonin levels were analysed from blood using
noni@usu.ac.id immunofluorescent assay. Data were then analysed with the Chi-Square test by Epi Info™ 7 programs in which p-
Received: 08-Aug-2018; Revised: 18-Oct-2018; value < 0.05 was considered statistically significant.
Accepted: 21-Oct-2018; Online first: 24-Nov-2018
Copyright: © 2018 Noni Novisari Soeroso, Muhammad RESULTS: A total of 68 lung cancer patients fulfilled the criteria of this study, 55 men (80.9%) and 13 women
Faiz Tanjung, Dina Afiani, Andika Pradana, Setia Putra
Tarigan, Arlinda Sari Wahyuni. This is an open-access
(19.1%). The highest percentage of cytology/histopathology type found was adenocarcinoma (80.9%), and 60.3%
article distributed under the terms of the Creative of those were diagnosed in stage IV. An increased procalcitonin level (greater than 0.01 ng/mL) occurred in
Commons Attribution-NonCommercial 4.0 International 80.9% of Non-Small Cell Lung Cancer (NSCLC) patients. It appears that the higher the stage of lung cancer, the
License (CC BY-NC 4.0)
lower procalcitonin levels would be, although it was not statistically significant. There was no association between
Funding: This research did not receive any financial
support lung cancer subtype with procalcitonin levels.
Competing Interests: The authors have declared that no
competing interests exist
CONCLUSION: An increased level of procalcitonin may be an indication not only for infection but also for Non-
Small Cell Lung Cancer.

Introduction importance of distinguishing the diagnosis of cancer

patients with clinical symptoms of fever and increased
levels of CRP [5], [6]. On the other hand, recent
Procalcitonin (PCT) is a derivate of calcitonin studies showed PCT concentrations at the right level
hormones. It is produced primarily in the liver by with sepsis in patients with an advanced stage of
macrophages (Kupffer cells) or neuroendocrine cells cancer [7]. This raises doubts about the role of
which are involved in systemic reactions in response procalcitonin in diagnosing infections in cancer
to endotoxin circulation and inflammatory cytokine patients.
produced during bacterial or fungal infections [1], [2] Patients with malignant diagnoses have a
[3]. The plasma level is associated with the severity of high risk of developing infections which are non-
the infection [4]. In healthy individuals, PCT levels are specific clinical signs and the sign of several different
very low (< 0.1 ng/ml). Procalcitonin has shown the clinical outcomes, such as drug reactions, actual
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infections, or paraneoplastic syndromes commonly determined, in which levels above 0.01 ng/ml was
known as 'neoplastic fever' [7]. The PCT values rise considered high [10].
rapidly at 2-4 hours from the bacterial infection onset.
To assess the relationship between gender,
PCT has a half-life of 22-24 hours; therefore, this
age, and the Brinkman index with procalcitonin levels
concentration can be halved when the infection is
in non-small cell lung cancer patients, the Chi-Square
cured [8]. Although PCT in patients with oncology
test was performed. While the procalcitonin levels
neutropenia fever has been investigated in several
based on the cytologic/histopathologic subtypes
studies, recent meta-analysis studies failed to define
cancer stage were analysed with Mann-Whitney and
its role. Also, Shomalli et al., [9] studied the role of
Kruskal Wallis test, data were analysed using Epi
PCT as a biomarker to distinguish fever due to
Info™ 7 programs in which p-value of < 0.05 was
infection and non-infectious fever in non-neutropenia
considered statistically significant.
patients with solid tumours and hematologic
malignancy. They also argued that the increase in
PCT levels and C-Reactive Protein could also
increase in malignancy. Several malignancies usually
show false positive for PCT. Results
Information about the values and
characteristics of PCT are limited to lung cancer
incidence [10]. Based on the above description, this Based on the characteristics of the subjects, it
study aimed to investigate the procalcitonin levels in was found that the highest number of gender in lung
non-small cell lung cancer patients. cancer incidence was male (80.9%). The average age
dominant with lung cancer was 40–60 years (51.5%).
All subjects were smokers and mostly categorised as
heavy smoker based on Brinkman index (75%). The
most common subtype of lung cancer was
Material and Methods adenocarcinoma type (80.9%). The data can be seen
in Table 1.

This was an observational study with a cross- Table 1: Demographic characteristics of the study subjects
sectional design to investigate the characteristics of Characteristics n %
Male 55 80.9
procalcitonin levels in non-small cell lung cancer Gender
Female 13 19.1
patients among Indonesia population. The study was Under 40 years-old 3 4.4
Age 40-60 years-old 35 51.5
conducted in Adam Malik General Hospital for 3 Over 60 years old 30 44.1
Active smoker 68 100.0
months. Data were collected through the medical Smoking status
Non smoker 0 0.0
records of Adam Malik General Hospital from Type of cigarettes
Clove cigarettes (kretek) 44 64.7
Filter cigarettes (white) 24 35.3
November 2016 to June 2017. Severe 51 75.0
Brinkman Index Moderate 14 20.6
Subjects were recruited through consecutive Mild
Adenocarcinoma
3
55
4.4
80.9
sampling based on cytology/histopathology result. Cytology/histopathology Squamous Cell Carcinoma 12 17.6
Large Cell Carcinoma 1 1.5
Patients diagnosed with tumour mediastinum and lung I 8 11.8
tumour metastasis were excluded from this study. pTNM
II
III
10
9
14.7
13.2
Smoking status was also recorded. Patients IV 41 60.3
Increased (> 0.01 ng/ml) 55 80.9
categorised as active smokers if they have a smoking Procalcitonin levels
Normal ( 0.01 ng/ml) 13 19.1
history of ≥ 100 cigarettes throughout their lives [11],
passive smoker (a person who inhales cigarette
smoke from a smoker). Type of cigarettes includes The association between procalcitonin levels
clove cigarettes (kretek) and filter (white) cigarettes. and gender, age and Brinkman index on Non-Small
The Brinkman Index value was obtained from the Cell Lung Cancer patients were displayed in table 2.
multiplication of the average number of cigarettes
Table 2: The association between demographic factors and the
smoked a day and multiplied by the duration of levels of procalcitonin
smoking (years). The value of Brinkman Index (IB) is
Procalcitonin level
mild if 0-199, moderate if 200-599, and severe if > 600 Variables Increased Normal p-value
[12]. n % n %
Male 44 80.0 11 84.6
Sex 0.702a
Female 11 20.0 2 15.4
First, 4 ml of peripheral venous blood were Under 40 years-old 2 3.6 1 7.7
taken and then inserted into the EDTA tube. Next, the Age 40-60 years-old 30 54.5 5 38.5 0.53a
Over 60 years old 23 41.8 7 53.8
serum was isolated. The procalcitonin values were Severe 40 72.7 11 84.6
Brinkman Index Moderate 13 23.6 1 7.7 0.38a
determined by immunofluorescence using BRAHMS Mild 2 3.6 1 7.7
procalcitonin sensitive Kryptor automated system Total 55 100.0 13 100.0
a) Chi-Square test.
(Thermo Scientific, Brahms, Henningsdorf, Germany)
[10]. The values of serum procalcitonin were

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 Soeroso et al. Procalcitonin Level in Non-Small Cell Lung Cancer Patients Among Indonesian Population
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Table 3 showed that there was no difference 20% were moderate smokers, and the other 4.3%
in the levels of procalcitonin between were light smokers. A similar result was also found by
adenocarcinoma, squamous cell carcinoma, and large Soeroso et al., [15], [16] in which 52.9% of their
cell carcinoma. It appears that the higher the stage of research participants were categorised as heavy
lung cancer, the lower procalcitonin levels would be. smokers. Also, this study was to evaluated nicotine
However, this correlation was not observed in stage dependence based on the Fagerstrom Tolerance
IV cancer patients, and thus it was not statistically Questionnaire (mFTQ), and the results showed that
significant. 65% of Fagerstrom scores were very high.
Epidemiologic studies suggest that smoking is the
Table 3: The comparison of procalcitonin levels based on leading cause of lung cancer. Smokers are 22 times
tumour diagnosis more likely to die of lung cancer than nonsmokers [1].
Variables n
Procalcitonin levels Smoking has a role in lung cancer at various levels.
mean ± SD median (min-max) p value
Adenocarcinoma (n = 55) 1.02 ± 2.06 0.34 (0.02 - 11.9) Smoking can cause mutations of genes that leads cell
Cytology/ Squamous Cell
histopathology Carcinoma and large (n = 13) 0.91 ± 1.24 0.48 (0.14 - 4.2)
0.206 a to be oncogenic. One of the mutations is a p53
cell mutation found in more than 53% in smokers [2].
Stage I (n = 8) 1.21 ± 2.23 0.44 (0.02 - 6.71)
II (n = 10) 0.84 ± 0.45 0.90 (0.14 - 1.47) Furthermore, smoking can also influence adverse
0.12 b
III (n = 9) 0.63 ± 1.04 0.17 (0.04 - 2.86) effects during therapy, either chemotherapy or
IV (n = 41) 1.07 ± 2.24 0.25 (0.02 - 11.9)
a) Mann-Whitney test; b) Kruskal Wallis test. radiotherapy [2].
Lung cancer is one of the leading causes of
Generally, it can be concluded that there was death around the world, particularly in Indonesia. In
no effect of the cancer cell types nor cancer stage on 2014, WHO stated that the mortality rate due to lung
serum procalcitonin levels. cancer reached 21.8% for men and 9.1% for a woman
in Indonesia [17]. The most common type of cancer
found in this study was adenocarcinoma (80.9%).
Although previous studies found that squamous cell
carcinoma as the most common type found, new
Discussion paradigm depicted that adenocarcinoma was the most
common type of cancer. This is probably because the
type of cigarettes favoured by Indonesians is clove
The sample of this research was 68 cases of cigarettes. This study found that the most common
lung cancer patients who have been diagnosed type of lung cancer found in Batak tribe in Indonesia
definitively (cytology/histopathology). Based on the was adenocarcinoma (92.9%), and the most
gender of the subjects, there were 55 male patients consumed cigarette type was clove cigarettes. Clove
(80.9%) whereas there were 13 female patients cigarettes contain clove that will make smokers suck
(19.1%). The same situation was also reflected in in more deeply; thus, smokes containing carcinogenic
other parts of the world. Aareleid conducted substances eventually enter the peripheral respiratory
epidemiological studies of lung cancer from 1985 to tract [16], [18]. Syahruddin et al., [19] found that the
2014. According to that study, 18,399 cases (80.3%) EGFR mutations rate among Indonesian population
were male patients whereas 4491 cases (19.7%) were reached 57.1% common mutations (exon 19 ins/dels,
female patients [13]. In Indonesia, specifically in Adam L858r) and about 29% uncommon mutations (G719X,
Malik General Hospital, Medan, the highest number of exon 20 ins, T790M, L861Q).
patients based on gender was male with 85.62%
compared to a female with 24 patients (24.37%) [3]. In this study, most of the patients have
entered the stage IV of cancer (60%), and the patients
In this study, the number of patients between in stage III were 14.3%. This is slightly different from
the age of 40-60 years were predominant with 36 the results found by Soeroso in 2010-2012 in which
patients (51.4%), followed by the age group of over 60 most of the cases were in stage III with 56 cases
years with 30 patients (42.9%). An epidemiological (33.54%) from a total of 167 patients [3]. However,
study conducted by Ridge in 2015 also suggested that there is a trend found that lung cancer is generally
about 60% of lung cancer cases were suffered by diagnosed when it has entered an advanced stage.
patients aged 50-60 years old [14]. In his study, he There are some factors that may cause late diagnosis.
also stated that the prevention of cigarettes was a top One of them is the absence of accurate screening to
priority for public health. Globally, cigarettes are one date [4].
of the biggest death factors with a 1:10 ratio in adults
and a mortality rate of about 5 million people per year The results showed that serum procalcitonin
[14]. Similarly, a study conducted by Soeroso in 2018 based on histopathology (adenocarcinoma, squamous
showed that 60% of lung cancer cases suffered by cell, and large cell) in this study did not show a
patients aged 55-64 years [15], [16]. significant difference in the Kruskal-Wallis test (p >
0.05). This study also showed that the values of
Brinkman index is used to assess the severity procalcitonin increased in 55 samples (80.9%). This
level of smoking. The Brinkman index in this study contrasts with Avrillon’s findings that 42% of 89
found that 75.7% of subjects were heavy smokers, samples experienced an increase in procalcitonin
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levels [10]. Procalcitonin is not a substance commonly Acknowledgement

used as a diagnostic tool for cancer, but recent
research conducted by Vincenzi et al., [5] showed an
increased in procalcitonin levels with cancerous The authors would like to thank Haji Adam
conditions. The study also stated that during an Malik Hospital Medan, Indonesia for the opportunity
advanced stage of cancer, the production of and place provided for conducting this research.
inflammatory cytokines is more active than usual
leading to procalcitoninemia conditions [5].
Ghillani et al., [20] found an increased level of
procalcitonin compared with healthy subjects by
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