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doi:10.1111/jgh.12498

GASTROENTEROLOGY

Stathmin overexpression identifies high risk for lymphatic

metastatic recurrence in pN0 esophageal squamous cell
carcinoma patients
Javed Akhtar, Zhou Wang, Wen Peng Jiang, Ming Ming Bi and Zhi Ping Zhang
Department of Thoracic Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China

Key words
esophageal squamous cell carcinoma,
lymphatic metastatic recurrence, stathmin-1.
Accepted for publication 12 December 2013.
Correspondence
Professor Zhou Wang, Department of
Thoracic Surgery, Provincial Hospital Affiliated
to Shandong University, Jinan, Shandong
250021, China. Email:
wz620226@hotmail.com
Conflict of interest: The authors declare that
they have no competing interests.

Abstract
Background and Aim: Common patterns of the operative failure after Ivor-Lewis
esophagectomy in esophageal squamous cell carcinoma (ESCC) patients are locoregional
lymph node metastasis. It is clinically significant to investigate the biological markers to
predict the subset of patients who are at higher risk of lymphatic metastatic recurrence. Our
research aimed to investigate the association between the Stathmin (STMN-1) gene expression and lymphatic metastatic recurrence in pN0 ESCC patients after surgery.
Methods: One hundred seventy-four patients who suffered from mid-thoracic ESCC and
completely resected with Ivor-Lewis esophagectomy were enrolled in our study. The entire
patients were restricted to pN0 ESCC. Tissue specimens were examined for STMN-1
expression levels by immunohistochemistry and Western blotting methods. The correlation
of STMN-1 levels with clinicopathological variables, prognosis, and metastatic potential
was analyzed.
Results: One hundred patients had STMN-1 protein overexpression (57.47%), and the
patients with overexpression were accompanied by significantly higher rate of lymphatic
metastatic recurrence as compared with patients who had low STMN-1 expression
(P = 0.003). Multivariable Cox regression analysis revealed that the STMN-1 protein
expression and T classification were independent factors to predict the lymphatic metastatic recurrence (P = 0.007, P = 0.000, respectively).
Conclusions: Even pN0 ESCC are a potential to lymphatic metastatic recurrence.
Stathmin overexpression can be used as a marker to identify those patients who are at high
risk for lymphatic metastatic recurrence in pN0 ESCC after an Ivor-Lewis esophagectomy.

Introduction
Esophageal squamous cell carcinoma (ESCC) is the leading cause
of cancer death worldwide. More than half of global esophageal
cancers occur in China, which is one of the areas showing the
highest incidence rate of ESCC, a major histological type of
esophageal cancer.1 Surgery is the best option for curing patients in
the early stages of this disease. It remains the superior therapeutic
modality for control in patients with locally advanced disease.
Despite advances in treatment, the benefits of surgical resection
combined with chemotherapy or radiotherapy is not satisfactory.
The prognosis of ESCC patients still remains poor. More than half
of all ESCC patients die from tumor relapse or metastasis. Some
reports show that the main reason for the failure of these operations is the lymphatic metastatic recurrence. Therefore, to improve
the long-term survival rate of esophageal cancer, the key is to
control lymph node metastatic recurrence. According to the
National Comprehensive Cancer Network (NCCN) guidelines,
patients with ESCC who undergo complete resections are not
944

candidates for adjuvant therapy. However, our previous study

found that the pattern of first recurrence was lymphatic metastasis,
even in pN0 ESSC patients.2 In our opinion, it is necessary to
identify the patients who are at high risk for lymphatic metastatic
recurrence in pN0 ESCC patients. These patients may get benefits
from adjuvant therapy. Clinically, lymph node metastasis of the
ESCC patients is predictive by means of the TNM staging system,
while lymph node metastasis is a strong adverse factor of lymphatic metastatic recurrence in ESCC patients who underwent
esophagectomy. Usually the probability of lymphatic metastatic
recurrence can be estimated with T descriptor but sometimes its
not sensitive enough. Therefore it is important to search for a
biological marker to predict patient survival in addition to the T
descriptor in patients with pN0 ESCC.
Stathmin-1 (STMN-1), also known as p17, p18, p19, 19 K,
metablastin, oncoprotein 18, LAP 18, and Op18, is a 19 kDa
cytosolic protein. Its function as an important regulatory protein of
microtubule dynamics has been well characterized.3 STMN-1
likely plays an important role in cell cycle progression and cell

Journal of Gastroenterology and Hepatology 29 (2014) 944950

2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

J Akhtar et al.

Stathmin expression in esophageal cancer

Table 1 Correlations of stathmin gene expression and lymphatic metastatic recurrence with clinicopathological characteristics in esophageal
squamous cell carcinoma patients
Characteristics

Age
< 50
50
Gender
Male
Female
Tumor size
< 3 cm
35 cm
> 5 cm
Differentiation
Low
Mid-high
T status
T1
T2
T3
STMN-1 overexpression
Yes
No

No. of patients
n = 174

Low (n = 74)

STMN-1 expression
High (n = 100)

37
137

16
58

21
79

134
40

58
16

76
24

58
68
48

27
31
16

31
37
32

49
125

20
54

29
71

12
70
92

6
33
35

6
37
57

Recurrence rate

0.921

0.649
16 (43.2%)
61 (44.5%)

0.712

0.110
63 (47.0%)
14 (35.0%)

0.006

0.013
16 (27.6%)
34 (50.0%)
27 (56.3%)

0.775

0.171
24 (49.0%)
53 (42.4%)

0.016

100
74

0.000
3 (25.0%)
18 (25.7%)
56 (60.9%)
0.003
52 (52.0%)
25 (33.8%)

Chi-square test or test. Logrank test.

2

migration. It has been reported that STMN-1 is overexpressed in

many human malignancies, such as leukemia, lymphoma, neuroblastoma, and ovarian, prostatic, breast, and lung cancers.4
Our previous study showed that stathmin is overexpressed in
gastric cancer,5 and the modulation of its expression correlates
with invasion and metastasis. There are some reports that STMN-1
gene expression is associated with lymph node metastasis.6 Previous research showed that stathmin expression is a predictor of
survival in ESCC,7but presently there are no reports showing
whether STMN-1 overexpression is associated with lymphatic
metastasis in ESCC.
In this study, we compared STMN-1 expression with antihuman STMN-1 polyclonal antibodies in pN0 patient samples,
and investigated the relationship between the STMN-1 gene
expressions with lymph node metastasis in patients who had
undergone the Ivor-Lewis esophagectomy. We aimed to explore
whether the STMN-1 gene can predict lymphatic metastasis
recurrence or not.

Methods

All of the patients in this study were completely resected. This

group of 174 cases included 134 males and 40, with a mean age
of 59.8 years old (clinical data are shown in Table 1). All of
these patients were resected using the Ivor Lewis esophagogastrectomy with two-field lymph node dissection for midthoracic ESCC.
The inclusion criteria during this study were as follows:
1 We followed the guidelines in the 2009 The Union for International Cancer Control (UICC) standard for mid-thoracic ESCC,
Ivor-Lewis esophagogastrectomy with two-field lymph node
dissection, to achieve complete tumor resection (R0). Pathological examination of the esophagus after surgery revealed
a cancer-free surgical margin and a lateral margin without
residual foci. Average lymph node dissection was more than 12.
2 All of the patients included in the study were restaged according
to the 2009 UICC TNM staging guidelines for esophageal
cancer. Patients staged pathologically after surgery with stage
I-IIA (pT1,2,3N0M0) were included.
3 Adjuvant chemotherapy was not administered prior to surgery,
nor was radiotherapy administered after surgery. Recurrence of
the tumor was not followed by systemic chemotherapy or radiotherapy. Patients who died perioperatively were not included in
the study. The surgical procedure was the same as was mentioned in our previous study.7

Ethics statement. The study protocol was approved by the

ethics committee of Provincial Hospital Affiliated to Shandong
University. All the participants provided their written informed
consent for inclusion in the data analysis and manuscript publication. Data were analyzed anonymously.

This study was approved by the hospitals ethics committee, and

patient consent was obtained.

Patients. From January 2002 through January 2006, the full

clinical records of 174 enrolled patients, who were part of our
study in the Department of Thoracic Surgery, were retrospectively
studied.

Immunohistochemistry (IHC). Formalin-fixed and

paraffin-embedded sections were dewaxed in xylene, rehydrated
through graded alcohol, and placed in an endogenous peroxide

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Stathmin expression in esophageal cancer

J Akhtar et al.

block for 10 min. Antigen retrieval was performed using microwaves in 10 mM of citrate buffer for 15 min and processed
using immunohistochemical streptavidin peroxidase conjugate
method. Rabbit anti-STMN-1 polyclonal antibodies were purchased from Abcam (Cambridge, MA, USA). As for the negative
control, the primary antibody was replaced by the phosphatebuffered saline (PBS). All sections were examined by two independent pathologists who were blinded to the clinical data. The
immunohistochemical score (IHS) was calculated by combining
the proportion score (percentage of positive stained cells) with the
staining intensity score. The proportion score ranged from 0 to 4,
as follows: 0 (< 5%), 1 (524%), 2 (2549%), 3 (5074%), and
4 ( 75%). The staining intensity was scored as follows: 0 (negative), 1(weak), 2 (moderate), and 3(strong). The proportion score
and staining intensities score were then multiplied to generate
the IHS for each case. The case with IHS 4 was considered to be
positive expression (same as our previous study).7
Protein extraction and Western blotting. We prepared tissue extracts in RIPA lysis buffer (25 mM Tris pH 7.5, 1%
Triton X-100, 0.5% sodium deoxycholate, 5 mM EDTA, 150 mM
NaCl) containing a cocktail of protease inhibitors (Sigma, St.
Louis, MO, USA). Protein concentrations were determined using
the Bradford method. The Bio-Rad protein assay reagent (Bio-Rad,
Bio-Rad Laboratories, Richmond, CA, USA) and 2040 mg of
protein mixed with loading buffer was loaded per lane, separated by
12% sodium dodecylsulfate -polyacrylamide gel electrophoresis
(SDS-PAGE). Proteins were transferred to polyvinylidene fluoride
(PVDF) membrane filters (Millipore, Billerica, MA, USA). Nonspecific binding was blocked by incubation in PBS containing 0.1%
Tween 20 (PBS-T) and 5% skim milk. PVDF membranes were
blocked with 5% dry milk for 1 h at 4C. Membranes were
incubated in STMN-1 primary antibody (1:1000) overnight at
4C. The membranes were then incubated with the corresponding
secondary antibody (1:2000, horseradish peroxidase-conjugated
anti-rabbit) in TBST-5% nonfat milk for 1 h at room temperature,
and the immunoreactive bands were visualized using EZ ECL
Chemiluminescence Detection Kit for HRP (Biological Industries
Ltd, Kibbutz Beit Haemek, Israel). Images were acquired using
the LAS3000 Imager (Fujifilm, Fuji, Edison, NJ, USA).
Membranes were reprobed for beta-actin as a loading control.

rate was analyzed with the logrank test. P < 0.05 was considered
statistically significant. Risk factors of lymph node metastasis after
surgery were analyzed with Cox regression model. All statistical
analysis was performed using IBM SPSS version 21.0 (IBM
Corp., Armonk, NY, USA).

Results
Tumor metastatic recurrence and prognosis. Of the
enrolled one hundred seventy four patients, 98 patients (56.32%)
experienced the recurrence and metastatic disease. The median
disease free interval was 25.5 1.1 months (Fig. 1). The mode of
first recurrence of the tumor included lymphatic metastatic recurrence in 54 cases, hematogenous metastasis in 21 cases, lymphatic
metastatic recurrence and blood born metastasis in 23 cases. Lymphatic metastatic recurrence in pN0 Esophageal Squamous cell
Carcinoma Patients after Ivor-Lewis Esophagectomy is shown in
Figure 2. The 5-year survival probability in this group of patients
is shown in survival curves (Fig. 3).
STMN-1 protein expression analysis in tumor
tissue specimen. Immunohistochemical analysis of 174
ESCC specimens revealed that 100 patients (57.47%) showed
STMN-1 protein overexpression, as shown in Figure 4b,c.
STMN-1 protein expression was low or undetected in normal
esophageal tissue (Fig. 4a). In ESCC specimens, STMN-1 protein
expression was higher than in normal esophageal tissues.
Relationship between STMN-1 expression and
lymphatic metastatic recurrence. Based on the immunohistochemical analysis of STMN-1 protein expression, in 100
patients with STMN-1 protein overexpression, 52 (52.00%) of
our cases had lymphatic metastatic recurrence, while of 74 patients

Follow-up after surgery and the diagnosis of

lymph node metastasis. After surgery, patients were regularly reexamined every 36 months. The checkup included a thorough physical examination, chest and upper abdomen computed
tomography scan, and abdominal ultrasound. Some of the patients
underwent Positron Emission Tomography and Computed Tomography (PET-CT) scan examination. We compared the PET-CT
examination with preoperative imaging data; if there was progressive lymph node enlargement; we used the clinical basis to diagnose lymphatic metastatic recurrence. Some patients diagnoses
were based on biopsies. If new lesions appeared in the other
organs, we excluded the primary tumor and clinically diagnosed
them as metastatic cancers. The study follow-up ended in January
2011; the longest follow-up period was 6 years, an average of
48.4 1.3 months.
Statistical analysis. Recurrence rates were calculated by
the KaplanMeier method, and the difference of the recurrence

946

Figure 1 Overall recurrence rate of esophageal squamous cell

carcinoma patients after surgery.

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J Akhtar et al.

Stathmin expression in esophageal cancer

Figure 2 Imaging diagnosis of lymphatic

metastatic recurrence in pN0 esophageal
squamous cell carcinoma patients after IvorLewis esophagectomy. (a, b, and c) Computed tomography scan showing lymphatic
metastatic recurrence, and (d) PET-CT
showing diagnosis of lymphatic metastatic
recurrence after surgery.

the lymphatic recurrence rate was higher than in patients with low
STMN-1 expression.
Based on both types of protein assay, the patients with higher
STMN-1 protein expression were accompanied by higher lymphatic metastatic recurrence.
Multivariate Cox regression analysis of lymphatic
metastatic recurrence. We performed multivariate Cox
regression analysis to identify variables that closely related to the
lymphatic metastatic recurrence in pN0 ESCC patients. Results
showed that tumor T stage and STMN-1 overexpression are independent factors of lymphatic metastatic recurrence in pN0 ESCC
(Table 2).

Discussion

Figure 3 Overall survival curve of esophageal squamous cell

carcinoma patients.

with lower or normal STMN-1 protein expression, only 25

(33.8%) cases had lymphatic metastasis. There was a statistically
significant difference in lymphatic metastatic recurrence in low
STMN-1 expression and overexpression patients (Fig. 5).
Based on the Western blotting analysis of STMN-1 proteins
expression, in the recurrence-free group, STMN-1 protein level
was 0.0982 0.0234, while in the lymphatic recurrence group
STMN-1 protein level was 0.9799 0.0532. Statistical results
showed that in patients with high levels of STMN-1 expression,

ESCC is a malignant tumor with strong invasion and high frequency of lymph node metastasis. There are still about 40% of
them that are found to be lymph node micro-metastasis by IHC
and molecular biological methods.8 The long-term survival of
patients with mid-thoracic ESCC remains poor because of the high
incidence of lymph node metastases and early recurrence even
after curative surgery.911 The embryological structure of the
esophagus is different from other digestive tracts, especially in
presence of lymph-vessels in muscularis mucosae. Lymph node
metastasis of esophageal cancer can occur when the primary tumor
is very small. The lymphatic drainage of the esophagus is complex
with a rich lymphatic network, and lymph node metastasis may
present as regional metastasis, skipping metastasis, or distant
metastasis.1214 The middle thoracic ESCC has bidirectional metastasis trend, including upward spread to neck and upper mediastinum, and downward to thoracic lower mediastinum abdomen.15
All of the above likely contribute to the high rate of local and
regional lymph node recurrence after resection.

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Stathmin expression in esophageal cancer

J Akhtar et al.

Figure 4 Expression
analysis
of
the
stathmin (STMN-1) protein by immunohistochemistry in esophagus and esophageal squamous cell carcinoma (ESCC) specimens. (a)
Normal esophageal tissue shows no STMN-1
protein expression. Original magnification,
400. (b) Strong STMN-1 protein expression
in ESCC specimen, STMN-1 expression was
mainly localized within cytoplasm. Original
magnification, 400. (c) Moderate STMN-1
expression in ESCC specimen. Original magnification, 400. (d) Low STMN-1 expression
in ESCC specimen. Original magnification,
400.

Figure 5 Lymphatic metastatic recurrence curve for patients with

stathmin (STMN-1) protein expression. , STMN-1 overexpression;
, Low STMN-1 expression.

A complete surgical resection is considered to be first-line treatment for individuals with localized ESCC1618 and remains the
superior therapeutic modality for patient with locally advanced
disease. On the basis of oncology, McKeown (three-incision)
esophagogastrectomy with three-field lymphadenectomy is
regarded as the best approach for mid-thoracic ESCC. However,
this procedure has been criticized because it is very invasive and
has a high incidence of complications.1922 Whether three-field
lymph node dissection should be performed in all patients with
948

thoracic esophageal carcinoma remains controversial.23,24 There

are different surgical approaches for mid-thoracic esophageal
cancer worldwide. There is no single widely accepted standard
approach. In our department, we usually perform the Ivor-Lewis
procedure to treat mid-thoracic ESCC. Compared with three-field
lymph node dissection, the biggest drawback of Ivor-Lewis
esophagectomy is that cervical lymph node metastatic lesions
would be out of reach. Some studies showed that locoregional
lymph nodes recurrence was the main pattern of tumor recurrence
after Ivor-Lewis esophagectomy with two-field lymph node dissection. Dresner and Griffin reported a 5.7% of cervical node
recurrence25 after Ivor-Lewis esophagectomy, and we reported
about 15% incidence in our previous study,26 which was slightly
higher than that after the three-field lymph node dissection.
Despite the development of advanced surgical techniques and
multimodality treatment for ESCC patients, patient outcomes
remain unsatisfactory. In spite of the complete resection of esophageal cancer, one third of patients will experience lymphatic metastatic recurrence within 23 years.2729 The probability of 5-year
survival is less than 50%, even after complete surgical resection.
This means that about half of the patients will have tumor relapse
after the surgery. Some reports showed that locoregional relapse
(lymphatic metastatic recurrence) was the main pattern of relapse
of disease.11 Our previous study also showed that locoregional
lymph node recurrence was the main pattern of tumor recurrence
after Ivor-Lewis esophagectomy with two-field lymph node dissection26,30 Many of the patients with postoperative locoregional
recurrence died within 1 year, so controlling locoregional recurrence might be an important measure to improve prognosis of
patients with esophageal carcinoma, There is consensus on the
adjuvant radiotherapy effectiveness to prevent the lymphatic metastatic recurrence, although there are some debates as to whether it
can increase overall survival or not. It is of clinical importance to
predict lymphatic metastatic recurrence early and to take adjuvant

Journal of Gastroenterology and Hepatology 29 (2014) 944950

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J Akhtar et al.

Table 2
surgery

Stathmin expression in esophageal cancer

Multivariate Cox regression analysis for risk factor of lymphatic metastatic recurrence in esophageal squamous cell carcinoma patients after

Risk factors

SE

Wald

d.f.

Sig.

Exp (B)

95.0% confidence
interval for exp (B)
Lower
Upper

Age
Gender
Size
T descriptor
Differentiation
STMN-1

0.269
0.468
0.112
0.924
0.235
0.661

0.287
0.308
0.171
0.250
0.257
0.247

0.878
2.306
0.426
13.671
0.837
7.160

1
1
1
1
1
1

0.349
0.129
0.514
0.000
0.360
0.007

1.309
1.597
1.118
2.519
1.265
1.936

0.745
0.873
0.799
1.544
0.765
1.193

treatment in time. There are few reports about molecular indicators

to tentatively predict lymphatic metastatic recurrence.2,30
Stathmin-1 (STMN-1), also known as p17, p18, p19, 19 K,
metablastin, oncoprotein 18, LAP 18, and Op18, is a 19 kDa
cytosolic protein, functions as an important regulatory protein of
microtubule dynamics, and has been well characterized.3 It has
been reported that STMN-1 is overexpressed in many human
malignancies, such as leukemia, lymphoma, neuroblastoma, and
ovarian, prostatic, breast, and lung cancers,4 and the modulation of
its expression correlates with invasion and metastasis. The protein
expression of STMN-1 has been explored and found to correlate to
clinicopathological factors and poor prognosis in several cancers
in different tissues, such as brain,31 oral mucosa,32 breast,28,33,34
urothelial,35 as well as ovarian36 and uterine cervix.37 Our previous
study showed that stathmin is overexpressed in gastric cancer5
Recently, some reports showed that STMN-1 is also related to
lymph node metastasis.6 Our previous research suggested
STMN-1 gene expression is a predictor of prognosis in stage IIA
ESCC. But there are no data about STMN-1 association with
lymphatic metastatic recurrence in ESCC.
Currently, the NCCN guidelines do not recommend postoperative adjuvant chemo or radiotherapy in pN0 after complete
resection of ESCC. In our present study, we validated the
overexpression of STMN-1 gene and its association with lymphatic metastatic recurrence. Our data show that the patients with
STMN-1 overexpression are at higher risk of lymphatic metastatic
recurrence of the disease. These high-risk patients should be followed by chemo or radiotherapy to prevent relapse of the malignant disease. Our previous studies have shown that adjuvant
radiation treatment can significantly reduce the incidence of
esophageal cancer lymphatic metastatic recurrence after IvorLewis surgery.29,30 This research suggested that the overexpression
STMN-1 is closely associated with lymphatic metastatic recurrence in pN0 ESCC. Therefore, STMN-1 might become a reference index for clinical assessment of lymphatic metastatic
recurrence. Although previous reports and our research showed
that the STMN-1 is associated with lymph node and lymphatic
metastatic recurrence, the underlying mechanism is unclear.
Several researchers have shown that p53 and p27Kip1 are cell
cycle regulatory proteins and differentially expressed in different
cancers. For the purpose of determining possible underlying
mechanisms of lymphatic metastatic recurrence in ESCC subtype
of patient with high stathmin expression, we are performing laboratory research on p53, p27Kip1, and PI3K pathway to understand
the possible relationships between these regulatory proteins and

2.297
2.921
1.565
4.112
2.093
3.14

their influence on stathmin. We suspect that coordinated changes

in STMN-1 and p27 expression in ESCC may be significant for at
least two reasons. First, STMN-1 expression in ESCC could be
interpreted as direct evidence of cell cycle entry, and this event
likely follows a release of p27-mediated restrictions on cell proliferation. Second, p27 has been shown to directly bind to and
inhibit STMN-1 in the context of cell migration. Microtubule
dynamics are important not only for mitosis but also for cell
motility. p27 appears to interfere with STMN-1s depolymerizing
ability, thus impairing the cytoskeletal remodeling required for cell
movement. Loss of p27-mediated regulation may potentiate aberrant cell proliferation, migration, and/or loss of polarity during
early tumorigenesis. P53-mediated negative regulation of
stathmin/Op18 also plays an important role in cell-cycle control.
To disclose possible interconnection and mechanism, we will continue research on a molecular basis.
In conclusion, surgery still remains the mainstay for midthoracic ESCC in China. Even patients with pN0 ESCC who are
completely resected will experience lymphatic metastatic recurrence. Our research demonstrates that the patients with STMN-1
overexpression in ESCC are at higher risk of lymphatic metastatic
recurrence. The overexpression of STMN-1 gene in tumor tissues
can be used to predict lymphatic metastatic recurrence in pN0
ESCC as a molecular reference indictor.
We strongly suggest that prospective study in ESCC subset
of patient with STMN-1 gene overexpression should be done.
Perhaps this subset of patient can benefit from postoperative
adjuvant radiotherapy.

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Journal of Gastroenterology and Hepatology 29 (2014) 944950

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