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Abstract

BACKGROUND:

Laryngeal cancer is one of the most common malignancies in the head and neck. Activated platelets play a critical role in cancer development and progression. Altered mean platelet volume (MPV) and platelet distribution width (PDW) have been found in various types of cancer. The purpose of the current study was to investigate the association of platelet indices with laryngeal cancer.

STUDY DESIGN:

The study included 216 patients with laryngeal cancer, 189 subjects with benign laryngeal disease, and 213 control subjects between January 2015 and December 2015. All participants’ clinical and laboratory characteristics at initial diagnosis were collected.

RESULT:

MPV was significantly lower and PDW was markedly higher in laryngeal cancer patients compared with control subjects and patients with benign laryngeal disease. A significant correlation between MPV and lymph node metastasis was found. The prevalence of laryngeal cancer increased as MPV quartiles decreased and PDW quartiles increased. Furthermore, MPV and PDW were independent risk factors for distinguishing laryngeal cancer from benign laryngeal disease.

CONCLUSIONS:

The patients with laryngeal cancer have reduced MPV and increased PDW compared to the subjects without laryngeal cancer. In addition, MPV and PDW play different roles in laryngeal cancer from benign laryngeal disease.

Keywords

Laryngeal cancer mean platelet volume platelet distribution width diagnosis

1. Introduction

Laryngeal cancer is one of the most common malignancies in the head and neck. There are approximately 40% of patients in advanced stage when first evaluated [1]. Therefore, it is extremely necessary to identify new biomarkers to detect patients with laryngeal cancer in early stage.

Platelets play an essential role in cancer progression and metastases. Platelets form aggregates with tumor cells. Furthermore, activated platelets interact with cancer cells through paracrine signaling and direct contact, promoting tumor cell growth and survival [2]. A growing body of evidence has showed that elevated platelets are associated with a poor prognosis in various types of cancer, such as pancreatic cancer, gastric cancer, colorectal cancer, endometrial cancer, and ovarian cancer [3, 4, 5, 6, 7]. However, platelet count is determined by the balance between the rate of production and consumption of platelets. A normal platelet count could conceal the presence of highly hypercoagulative and pro-inflammatory cancer phenotypes in the presence of efficient compensatory mechanisms [8]. Mean platelet volume (MPV) is an index of activated platelets and is linked to different inflammatory conditions [9]. Considerable evidence reported that MPV changed in gastric cancer, ovarian cancer, lung cancer, colon cancer, and breast cancer [10, 11, 12, 13, 14]. Platelet distribution width (PDW), another platelet index, indicates variation in platelet size [15].

However, only limited data are available in the literature with regard to the relationship between platelet indices and laryngeal cancer. The purpose of the current study was to investigate the association of platelet indices with laryngeal cancer.

2. Materials and methods

The study included 216 patients with laryngeal cancer (mean age 57.7 $\pm$ 8.5 years, range 40–80 years), 189 subjects with benign laryngeal disease (mean age 54.6 $\pm$ 9.7 years, range 30–80 years), and 213 control subjects (mean age 56.2 $\pm$ 3.8 years, range 50–72 years) between January 2015 and December 2015. The patients were recruited from clinic and had surgery done at Harbin Medical University Cancer Hospital. None of them had ever received radiotherapy or chemotherapy before surgery. The exclusion criteria included hematological disorders, hypertension, diabetes mellitus, and medical treatment with anticoagulant, statins, and acetylic salicylic acid. The control subjects were recruited from Harbin Medical University Cancer Hospital.

This study was approved by the Institutional Review Board of Harbin Medical University Cancer Hospital and written informed consent was obtained from the subjects.

2.1 Clinical examination and biochemical measurements

All the subjects underwent physical examination. Clinical data including smoking status, medical history and medication use were recorded for each subject. Venous blood samples after a 10-hour overnight fasting were collected from the individuals within 1 week prior to surgery. White blood cell (WBC), haemoglobin, and platelet indices were measured by an autoanalyzer (Sysmex XE-2100, Kobe, Japan). The whole blood samples were collected in EDTA-containing tubes, and all samples were processed within 30 minutes after blood collection.

2.2 Statistics

All data were expressed as means $\pm$ SD or median (inter-quartile range) or percentage. Significance differences of continuous variables between two groups were determined with the Student’s t test or Mann-Whitney U test. When the characteristics among three groups were compared, normally distributed continuous variables were compared with the one-way ANOVA and skewed-distributed with Kruskal-Wallis H test. The Chi-square test was used for categorical variables. Post hoc analyses using a two-tailed Tukey HSD test were conducted to compare differences in normally distributed data between the groups. Logistic regression analysis was performed to evaluate the risk factors for distinguishing laryngeal cancer from benign laryngeal disease. All participants were classified into quartiles by their MPV and PDW levels. The prevalence of laryngeal cancer is calculated by the quartiles of MPV and PDW levels. $P<$ 0.05 was considered to indicate a statistically significant difference. All data analyses were performed using SPSS Statistics version 22.0 (SPSS Inc., Chicago, IL, USA).

3. Results

The study consisted of 216 patients with laryngeal cancer, 189 subjects with benign laryngeal disease, and 213 control subjects between January 2015 and December 2015. Of the 618 participants enrolled, 489 (79.1%) were men and 129 (20.9%) were women.

Table 1
The characteristics of the participants according to laryngeal cancer status

Variables	Control subjects	Benign disease	Laryngeal cancer	p-value
N	213	189	216
Age (years)	57.2 $\pm$ 3.5	54.6 (9.7)	57.7 $\pm$ 8.5	$<$ 0.001
Sex (male, %)	164 (77.0)	148 (78.3)	177 (81.9)	0.172
Smoker (n, %)	192 (90.1)	164 (86.8)	188 (87.0)	0.167
BMI (kg/m ${}^{2}$ )	22.6 $\pm$ 3.1	23.6 $\pm$ 3.7	22.3 $\pm$ 3.5	0.001
FPG (mmol/L)	5.20 (4.80–5.68)	5.20 (4.75–5.80)	5.10 (4.80–5.70)	0.800
WBC ( $\times$ 10 ${}^{9}$ /L)	6.79 $\pm$ 1.75	7.15 $\pm$ 1.76	7.16 $\pm$ 2.10	0.077
Haemoglobin (g/dl)	146.0 $\pm$ 13.6	149.0 $\pm$ 13.7	145.1 $\pm$ 16.0	0.018
Platelet ( $\times$ 10 ${}^{9}$ /L)	225.9 $\pm$ 57.4	219.0 $\pm$ 48.9	220.9 $\pm$ 59.6	0.435
MPV (fL)	9.5 $\pm$ 0.7	9.7 $\pm$ 1.5	8.9 $\pm$ 1.3	$<$ 0.001
PDW (%)	14.9 $\pm$ 2.0	15.2 $\pm$ 2.1	16.9 $\pm$ 1.1	$<$ 0.001

Values are shown as mean $\pm$ standard deviation or median (IQR) or percentage. BMI, body mass index; FPG, fasting plasma glucose; WBC, white blood cell; MPV, mean platelet volume; PDW, platelet distribution width.

Figure 1.

MPV levels in laryngeal cancer, benign laryngeal disease, and control group.

Figure 2.

PDW levels in laryngeal cancer, benign laryngeal disease, and control group.

The characteristics of the patients with laryngeal cancer and benign laryngeal disease, and control subjects are reported in Table 1. One-way ANOVA analysis showed a significant group difference in age, BMI, MPV, PDW, and haemoglobin levels. However, there are no markedly difference in FPG, platelet count, white blood cell, and the percentage of male and current smokers among three groups.

MPV and PDW levels in laryngeal cancer, benign laryngeal disease, and normal control group are shown in Figs 1 and 2. MPV levels were increased both in normal control subjects and in patients with benign laryngeal disease compared to those in cancer patients (normal control vs. laryngeal cancer, $p<$ 0.001; benign laryngeal disease vs. laryngeal cancer, $p<$ 0.001, pos hoc Tukey test). PDW levels were reduced both in normal control subjects and in patients with benign laryngeal disease compared to those in cancer patients (normal control vs. laryngeal cancer, $p<$ 0.001; benign laryngeal disease vs. laryngeal cancer, $p<$ 0.001, post hoc Tukey test). However, there was no significant difference in platelet indices between patients with benign laryngeal disease and normal control subjects.

Correlations between clinicopathological characteristics and platelet indices in laryngeal cancer are summarized in Table 2. A significant correlation between MPV and lymph node metastasis was observed. However, there were no correlations between platelet indices and tumor size, tumor depth, tumor differentiation, and tumor stage.

Table 2

Correlations between clinicopathological features and pre-operative platelet indices in laryngeal cancer

Variables	N	Platelet ( $\times$ 10 ${}^{9}$ /L)	p-value	MPV (fL)	p-value	PDW (%)	p-value
Age (years)			0.116		0.229		0.468
$<$ 60	142	224.5 (59.2)		8.7 (1.3)		16.9 (1.1)
$\geqslant$ 60	74	214.2 (60.2)		9.0 (1.4)		17.0 (1.0)
Gender			0.126		0.015		0.870
Male	177	218.0 (57.0)		8.7 (1.3)		17.0 (1.1)
Female	39	234.2 (69.4)		9.3 (1.3)		16.9 (0.9)
Smoking			0.146		0.495		0.171
Nonsmokers	28	205.6 (50.1)		9.0 (1.4)		16.9 (1.0)
Current smokers	188	223.2 (60.6)		8.8 (1.3)		17.2 (1.2)
Tumor site			0.164		0.500		0.989
Supraglottic	124	216.6 (51.8)		8.9 (1.3)		16.9 (0.9)
Glottic	57	233.8 (77.3)		8.7 (1.2)		16.9 (0.8)
Subglotti	35	215.3 (50.2)		9.0 (1.7)		17.0 (1.7)
Tumor differentiation			0.337		0.770		0.604
Well	55	208.2 (56.0)		8.9 (1.3)		17.0 (1.1)
Modera	127	224.4 (58.6)		8.9 (1.3)		17.0 (1.0)
Poor	34	228.3 (67.8)		8.7 (1.5)		16.8 (1.3)
Tumor depth			0.945		0.483		0.915
T1 $+$ T2	152	220.8 (61.3)		8.8 (1.3)		16.9 (0.9)
T3 $+$ T4	64	221.4 (55.8)		8.9 (1.5)		17.0 (1.4)
Lymph node metastasis			0.143		0.024		0.057
Negative	175	218.1 (56.0)		8.9 (1.3)		17.0 (1.0)
Positive	41	233.2 (72.4)		8.4 (1.3)		16.7 (1.3)
Tumor stage			0.262		0.500		0.755
I/II	141	217.6 (55.4)		8.9 (1.3)		17.0 (0.9)
III/IV	75	227.2 (66.7)		8.8 (1.5)		16.9 (1.3)

Figure 3.

Prevalence rate of laryngeal cancer in the subjects with different quartiles of mean platelet volume.

Figure 4.

Prevalence rate of laryngeal cancer in the subjects with different quartiles of platelet distribution width.

To understand the relationship between MPV and PDW levels and the prevalence of laryngeal cancer, the participants with laryngeal cancer and control subjects were classified into quartiles by their MPV and PDW levels. The prevalence of laryngeal cancer in the participants with different quartile levels of MPV and PDW was analyzed (Figs 3 and 4). For MPV, quartile 1 (Q1) was $\leqslant$ 8.5 fl, quartile 2 (Q2) was 8.6–9.3 fl, quartile 3 (Q3) was 9.4–9.8 fl, and quartile 4 (Q4) was $\geqslant$ 9.9 fl. The prevalence rate of laryngeal cancer in Q1, Q2, Q3, and Q4 was 82.1% (96/117), 53.9% (62/115), 22.1% (23/104), and 37.6% (35/93), respectively. For PDW, quartile 1 (Q1) was $\leqslant$ 14.5%, quartile 2 (Q2) was 14.6–16.3%, quartile 3 (Q3) was 16.4–16.8%, and quartile 4 (Q4) was $\geqslant$ 16.9%. The prevalence rate of laryngeal cancer in Q1, Q2, Q3, and Q4 was 0.9% (1/108), 68.4% (80/117), 49.5% (51/103), and 83.2% (84/101), respectively. The results indicated that prevalence of laryngeal cancer increased as MPV quartiles decreased and PDW quartiles increased ( $p_{\text{trend}}<$ 0.001).

Table 3

MPV and PDW levels in the different pathological types of laryngeal cancer and benign laryngeal disease

	N	Platelet count	MPV (fL)	PDW(%)
Benign laryngeal disease
Hyperplasia	115	221.4 (52.7)	9.6 (1.4)	15.1 (2.1)
Papilloma	16	217.4 (33.3)	9.3 (1.4)	15.4 (2.0)
Polyp	47	212.7 (43.0)	10.2 (1.6)	15.5 (1.9)
Others	11	223.7 (53.6)	9.5 (1.1)	15.5 (1.7)
P value		0.765	0.066	0.626
Laryngeal cancer
Squamous cell	205	220.8 (59.6)	8.8 (1.3)	16.9 (1.1)
carcinoma
Others	11	223.4 (62.2)	8.9 (0.9)	17.0 (0.7)
P value		0.890	0.845	0.795

MPV, mean platelet volume; PDW, platelet distribution width.

Table 4

Multiple logistic regression analysis of factors used for differentiating benign laryngeal disease from laryngeal cancer

Variables	$\beta$	OR (95% CI)	$p$ -value
Age (years)	0.035	1.035 (1.007–1.064)	0.014
BMI (kg/m ${}^{2}$ )	$-$ 0.121	0.886 (0.823–0.954)	0.001
Haemoglobin (g/dl)	$-$ 0.005	0.995 (0.977–1.012)	0.539
MPV (fL)	$-$ 0.555	0.574 (0.469–0.704)	$<$ 0.001
PDW (%)	1.066	2.904 (2.113–3.992)	$<$ 0.001

Data are presented as means (SD) or median (interquartile range) or percentage. BMI, body mass index; MPV, mean platelet volume; PDW, platelet distribution width.

We evaluated the levels of platelet indices in laryngeal cancer and benign laryngeal disease of various pathological types (Table 3). Platelet count, MPV and PDW levels were not markedly different in different pathological types of benign laryngeal disease and laryngeal cancer.

Logistic regression analysis was performed to evaluate the risk factors for distinguishing laryngeal cancer from benign laryngeal disease. The risk factors found to be significantly associated with differentiation in the regression analysis included age, BMI, MPV, and PDW (Table 4).

4. Discussion

In this study, we provided evidence that platelets are activated in laryngeal cancer using a simple, relatively inexpensive, almost universally obtained test. The patients with laryngeal cancer have reduced MPV and increased PDW compared to the controls.

The prevalence of laryngeal cancer increased as MPV quartiles decreased and PDW quartiles increased. Furthermore, MPV and PDW are independent risk factors for distinguishing laryngeal cancer from benign laryngeal disease.

Platelets play a critical role in the development and progression of different cancers by promoting cancer cell proliferation, survival, angiogenesis, and metastasis. Several studies revealed that thrombocytosis is associated with poor prognosis in patients with various tumor types, such as lung cancer, ovary cancer, endometrium cancer, rectum cancer, renal cell cancer, gastric cancer, pancreas cancer, and breast cancer. Several clinical reports confirmed that the altered parameters of platelet activation, such as soluble P-selectin, CD40 ligand, and $\beta$ -thromboglobulin ( $\beta$ -TG) in patients with cancer [16, 17, 18]. However, these indicators reflecting activated platelets were expensive and not routinely evaluated in clinical practice. MPV and PDW are not difficult to test and involve no added costs. Therefore, MPV and PDW might be suitable to apply in clinical screening.

The molecular mechanism underlying the association of reduced MPV and increased PDW with laryngeal cancer has yet to be fully defined. Decreased MPV may be related to inflammation. There is a strong linkage between inflammation and cancer [19]. Furthermore, platelet plays a key role in inflammation and cancer. MPV was an early indicator of activated platelets. Reduced MPV could come from an enhanced consumption of large platelets in inflammatory states [9]. Moreover, recent studies confirmed that low levels of MPV are associated with high-grade inflammatory diseases and reverse in the course of anti-inflammatory therapy [19].

Another possible mechanism is that platelets play a crucial role in promoting the hypercoagulable state in cancer. Activated platelets create a procoagulant micro-environment that enables the tumor cells to cover themselves with platelets and evade the host immune system [20]. Multifactorial complex interactions between platelets, endothelial cells and leukocytes further stimulate production of proinflammatory cytokines [21]. The mentioned above were just suggested based on theory. More experiments need to be carried out to explore the molecular mechanism for the change of MPV and PDW in laryngeal cancer.

Several lines of evidence supports the association between platelets and laryngeal cancer in clinical studies [22]. Our previous study found that higher PDW predicts poor prognosis in laryngeal cancer [23]. In this study, we confirmed the association between activated platelets and laryngeal cancer using simple and inexpensive biomarkers.

Our study has several limitations. First of all, we analyzed the subjects cross-sectionally, and this type of study fails to indicate causal relationship between MPV and PDW and laryngeal cancer. Secondly, this is a study carried out in a single hospital. Therefore, larger prospective studies are required to confirm these preliminary studies.

In summary, the patients with laryngeal cancer have reduced MPV and increased PDW compared to the subjects without laryngeal cancer. In addition, MPV and PDW play different roles in laryngeal cancer and benign laryngeal disease. Further studies on the involvement of MPV and PDW in laryngeal cancer are warranted.

Footnotes

Conflict of interest

All authors declare that they have no conflict of interest.

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