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Int J Clin Oncol
DOI 10.1007/s10147-017-1201-3
ORIGINAL ARTICLE
Esophageal squamous cell neoplasia is an independent negative
prognostic factor for head and neck cancer patients
Yasuhiko Hamada1 · Toshiro Mizuno2 · Kyosuke Tanaka1 · Masaki Katsurahara1 ·
Noriyuki Horiki1 · Reiko Yamada3 · Hiroyuki Inoue3 · Yoshiyuki Takei3 ·
Naoyuki Katayama2 Received: 30 April 2017 / Accepted: 7 October 2017
© Japan Society of Clinical Oncology 2017
Abstract Background Patients with head and neck cancer (HNC)
have a high incidence of esophageal squamous cell neoplasms (ESCN). ESCN also has a negative impact on the
survival of HNC patients. However, recent endoscopic
advances enable the early detection of ESCN, and novel
treatments may lead to improving survival rates for HNC
patients with ESCN.
Methods HNC patients who underwent magnifying esophagogastroduodenoscopy (EGDS) from 2005 to 2012 were
included in this study (n = 226). We analyzed the prevalence
and prognostic value of ESCN in HNC patients and the difference in overall survival between HNC patients with and
without ESCN.
Results Thirty-four patients (15%) developed an ESCN
during their clinical course. Of the 34 patients, 10 patients
underwent endoscopic resection for ESCN and 10 patients
underwent simultaneous chemoradiation therapy for HNC
and ESCN. The 3-year survival rates in HNC patients with
and without ESCN were 53% and 70%, respectively. Multivariate analysis identified the advanced clinical stage of the
HNC [hazard ratio (HR) = 2.15; 95% confidence interval
(CI) = 1.18–3.93; p = 0.012] and the presence of ESCN (HR
= 1.73; 95% CI = 1.00–2.97; p = 0.049) as significant and
independent determinants of overall survival.
* Yasuhiko Hamada
y‑hamada@clin.medic.mie‑u.ac.jp
1
Department of Endoscopic Medicine, Mie University
Hospital, 2‑174 Edobashi, Tsu, Mie 514‑8507, Japan
2
Department of Hematology and Oncology, Mie University
Graduate School of Medicine, Tsu, Japan
3
Department of Gastroenterology and Hepatology, Mie
University Graduate School of Medicine, Tsu, Japan
Conclusions Our study suggests that although the survival
of HNC patients with ESCN may be improved by routine
EGDS during tumor surveys and by advances in endoscopy,
the presence of ESCN still remains an independent negative
prognostic factor for HNC patients.
Keywords Head and neck cancer · Esophageal
neoplasia · Prognostic factor
Introduction
Head and neck cancer (HNC) is the seventh most common
cancer worldwide, with more than 600,000 patients diagnosed with HNC annually [1]. HNC is associated with a
high likelihood of second primary malignancies. The most
common site for this type of cancer is an aerodigestive site,
including the lungs and esophagus [2, 3]. Epidemiological
studies have suggested an increased risk for the development
of HNC is associated with smoking and alcohol drinking
habits; these risk factors overlap those related to such aerodigestive malignancies [4, 5].
Patients with HNC have shown a high prevalence of
esophageal squamous cell neoplasia (ESCN). Specifically,
from 5% to 15% of patients with HNC ultimately develop
synchronous or metachronous ESCN [6–8]. A screening
esophagogastroduodenoscopy (EGDS) to conduct a tumor
survey is routinely recommended for patients with HNC
[9–11].
Moreover, ESCN was found to have a significantly negative impact on the survival of HNC patients. Studies have
shown the 3-year overall survival rate to be between 0% and
15% in HNC patients [12–14]. However, recent advances
in endoscopy have enabled the early detection of esophageal neoplasia [8]. Therefore, in HNC patients today, the
13
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incidence of advanced ESCN may be lower and the present
overall survival rate may have improved from those of past
reports.
The objective of this study was to investigate the prevalence of ESCN and the impact on the overall survival rate of
HNC patients in recent years. We retrospectively examined
such questions using the medical data of the HNC patients
who had undergone EGDS at our institute.
Patients and methods
Patients
We retrospectively reviewed the medical records of HCN
patients who had undergone EGDS at our institute between
October 2005 and September 2012. Patients were selected
for this study according to the following criteria:
i. At the time of an HCN diagnosis, patients underwent
staging workups, including oral cavity inspection,
endoscopic examination of the pharynx and larynx,
computed tomography (CT) and/or magnetic resonance imaging of the head and neck, and whole-body
fluorodeoxyglucose–positron emission tomography.
ii. For those patients with HCN who underwent EGDS,
EGDS were performed with an upper gastrointestinal
high-resolution magnifying endoscope (GIF-Q240Z,
GIF-H260Z; Olympus Medical Systems, Tokyo,
Japan).
iii. After treatment for HCN, CT and EGDS were performed annually to check for the recurrence of disease
and to survey for ESCN.
Int J Clin Oncol
consumption was estimated as the average number of grams
of pure ethanol ingested per drinking day. Smoking was calculated according to the Brinkman index (the number of
cigarettes smoked per day multiplied by the number of total
smoking years). The primary tumor was grouped by location
(oral cavity, epipharynx, oropharynx, hypopharynx, larynx).
Tumor stage was classified according to TNM classification
of the Union for International Cancer Control, 6th edition
[15].
Statistical analysis
Continuous variables were described by medians and ranges;
categorical variables were described by counts and percentages. All patient data were compared based on whether
patients had ESCN. Continuous variables were compared
using the Wilcoxon rank-sum test. Categorical variables
were compared with the chi-square test when appropriate;
otherwise, a Fisher’s exact test was used. Cumulative incidences of overall survival of HNC patients, with or without
ESCN, were calculated by the Kaplan–Meier method, with
the date of the first EGDS at our institute as the starting
point, and differences were assessed with the log-rank test.
The prognostic factors that were shown to be significant in
a univariate Cox regression analysis were also tested with a
multivariate Cox regression analysis. We used the analysis
to examine hazard ratio (HR) of the HNC patients, with the
95% confidence interval (CI). We conducted all statistical
analyses using SPSS version 20 (SPSS, Chicago, IL, USA).
All statistical tests were two tailed, and significance was
defined as p < 0.05. This study was approved by the institutional review board of Mie University Hospital.
Study design
Results
We analyzed the prevalence of ESCN in HNC patients, its
association with patient baseline characteristics (sex, age,
toxic habits such as smoking and alcohol drinking, location of HNC, staging of HNC, location of second primary
malignancies, initial treatment for HNC), the difference in
therapeutic outcomes of HNC patients with and without
ESCN, and the prognostic value of the presence of ESCN
in HNC patients.
The data of HNC patients with ESCN were divided into
two groups, depending on whether patients had synchronous
or metachronous ESCN. Synchronous ESCN was defined
as developing at the same time, or within 6 months before
and after a diagnosis of HNC. For development before and
after 6 months, the ESCN was considered metachronous. In
cases of HNC with multiple ESCNs, the ESCN stage was
defined according to the most advanced lesion. Alcohol
Baseline characteristics of patients with HNC
13
During the study period, a total of 226 patients fulfilled
the eligibility criteria for this study (Table 1). Of the 226
patients, 194 (85.8%) were male; the median age was 68
years (range, 33–89 years). The median amount of daily
alcohol intake was 22 g (range, 0–220 g) and the median
Brinkman index was 606 (range, 0–2560). Considering
the location of the HNC, 40 lesions (17.7%) were found
in the oral cavity, 12 lesions (5.3%) in the epipharynx, 42
lesions (18.6%) in the oropharynx, 74 lesions (32.7%) in the
hypopharynx, and 58 lesions (25.7%) in the larynx. Sixtyseven patients (29.6%) had localized disease (stage I, II),
and 159 patients (70.4%) had locally advanced or metastatic
disease (stage III, IV). Twenty-three patients (10.2%) had
second primary malignancies other than ESCN (gastric
Int J Clin Oncol
Table 1 Patient background and comparison between those with and without ESCN
Characteristics
Total (n = 226)
Without ESCN (n = 192)
With ESCN (n = 34)
p*
Sex (male), n (%)
Age, median, year (range)
Alcohol intake, median, g/day (range)a
Brinkman index, median (range)
Location of primary tumor, n (%)
Oral cavity
Epipharynx
Oropharynx
Hypopharynx
Larynx
Clinical stage, n (%)
Stage I
Stage II
Stage III
Stage IV
Second primary tumor except ESCN, n (%)
Initial treatment for HNC
Surgery
Radiotherapy
Chemoradiation therapy
Chemotherapy
Other
194 (85.8)
68 (33–89)
22 (0–220)
606 (0–2560)
161 (83.9)
68 (33–89)
20 (0–220)
520 (0–2560)
33 (97.1)
68 (51–88)
44 (0–220)
880 (0–1480)
0.06
0.98
0.007
0.26
40 (17.7)
12 (5.3)
42 (18.6)
74 (32.7)
58 (25.7)
38 (19.8)
12 (6.3)
33 (17.2)
55 (28.6)
54 (28.1)
2 (5.9)
0 (0.0)
9 (26.4)
19 (55.9)
4 (11.8)
0.053
0.22
0.23
0.003
0.050
24 (10.6)
43 (19.0)
36 (15.9)
123 (54.5)
23 (10.2)
19 (9.9)
38 (19.8)
32 (16.7)
103 (53.6)
19 (9.9)
5 (14.7)
5 (14.7)
3 (8.8)
21 (61.8)
4 (11.8)
0.37
0.64
0.31
0.38
0.76
73 (32.3)
21 (9.3)
104 (46.0)
18 (8.0)
10 (4.4)
68 (35.4)
17 (8.9)
83 (43.2)
16 (8.3)
8 (4.2)
5 (14.7)
4 (11.8)
21 (61.7)
2 (5.9)
2 (5.9)
0.030
0.53
0.061
1.00
0.65
ESCN esophageal squamous cell neoplasia, HNC head and neck cancer
* Chi-square or Fisher’s exact tests were used for sex, site of primary tumor, clinical stage, second primary tumor except ESCN, and initial treatment for HNC; Wilcoxon rank-sum tests were used for age, alcohol intake, and Brinkman index
a
Amount of alcohol intake converted to ethanol value
cancer, lung cancer, colon cancer, hepatocellular carcinoma,
and prostate cancer).
For HNC treatment, radiotherapy fields included the
lesion; the daily fractional radiation dose was 2 gray (Gy),
administered 5 days per week, for all patients. The standard
total radiation dose for HNC was 70 Gy. Chemotherapy for
HNC consisted of cisplatin only, 5-fluorouracil plus cisplatin, or S-1 only. One hundred and four patients (46.0%)
had undergone chemoradiation therapy as initial treatment
for HNC.
Comparison with characteristics of HNC patients
with or without ESCN
There were 192 patients with HNC without ESCN (85.0%)
and 34 patients with HNC and with ESCN (15.0%) (Table 1).
Comparing the characteristics of HNC patients, the amount
of alcohol intake (44 vs. 20 g, p = 0.007) and location of
cancer in the hypopharynx (55.9% vs. 28.6%, p = 0.003)
were significantly greater in patients with ESCN compared
to those without ESCN. On the other hand, use of surgical
treatment for HNC was significantly lower in patients with
ESCN (14.7% vs. 35.0%, p = 0.030).
Characteristics of ESCN lesions
The characteristics of ESCN lesions are shown in Table 2.
Thirty-eight ESCNs were detected in 34 patients: 30 patients
had 1 lesion, and 4 patients had 2 lesions each. Thirty-three
synchronous and 5 metachronous ESCNs were diagnosed in
this study. Of the 38 ESCN lesions, 31 (81.6%) were early
ESCN (stage 0, I). These results demonstrated that ESCNs
were likely to be an earlier-stage neoplasia than HNC.
Treatment characteristics for patients with ESCN
Treatments for HNC patients with ESCN are shown in
Table 3. Of 34 patients with ESCN, 10 patients (29.4%)
underwent endoscopic resection for ESCN and 10 patients
(29.4%) underwent simultaneous chemoradiation therapy.
Radiotherapy fields for ESCN included the lesion. The daily
fractional radiation dose was 2 Gy, administered 5 days per
week to all patients. The standard total radiation dose for
13
Int J Clin Oncol
Table 2 Characteristics of esophageal squamous cell neoplasia
(ESCN)
No. of ESCN (%)
Single/double
Single
Double
Synchronous/metachronous
Synchronous
Methacronous
Clinical stage of ESCN (UICC 6th)
Stage 0
Stage I
Stage II
Stage III
Stage IV
30 (78.9)
8 (21.1)
33 (86.8)
5 (13.2)
11 (29.0)
20 (52.6)
5 (13.2)
1 (2.6)
1 (2.6)
ESCN esophageal squamous cell neoplasia, UICC Union for International Cancer Control
ESCN was 60 Gy. Chemotherapy for ESCN consisted of
5-fluorouracil plus cisplatin.
Impact of ESCN on survival outcome
To evaluate the actual magnitude of the impact of ESCN on
survival, the overall survival of HNC patients with or without a prognostic factor [age: <68 years vs. ≥68 years; sex:
female vs. male; Brinkman index: <1000 vs. ≥1000; amount
of daily alcohol intake: <33 vs. ≥33 g; clinical stage: I, II
vs. III, VI; hypopharyngeal cancer: absence vs. presence;
ESCN: absence vs. presence; primary second malignancies
except ESCN: absence vs. presence; initial treatment of
HNC: local therapy (surgery, radiotherapy, other) vs. systemic therapy (chemotherapy and chemoradiation therapy);
and chemoradiation therapy: absence vs. presence] was
compared.
Table 3 Types of treatments
for tumors in patients with
esophageal squamous cell
neoplasia (n = 34)
13
The median follow-up period was 29.8 months (range,
0–98.0 months). During the follow-up period, 17 (50.0%) of
HNC patients with ESCN and 57 (29.7%) of HNC patients
without ESCN died. Figure 1 shows the overall survival
curves of HNC patients without or with ESCN. The median
survival period for HNC patients without ESCN was not
reached; that for those with ESCN was 45 months. The
3-year survival rates for HNC patients with or without
ESCN were 53% and 70%, respectively. Kaplan–Meier curve
analysis using a log-rank test showed that the presence of
ESCN (p = 0.029) was associated with a greater probability
of a shorter overall survival period.
We conducted univariate and multivariate analyses using
a Cox regression analysis with a time-dependent covariate
(Table 4). This analysis also identified a more advanced
clinical stage (HR = 2.15; 95% CI = 1.18–3.93; p = 0.012)
and the presence of ESCN (HR = 1.73; 95% CI = 1.00–2.97;
p = 0.049) as significant and independent determinants of
the overall survival period.
Discussion
The high incidence of ESCN in HCN patients is illustrated
by the concept of the “field cancerization” rule. Carcinogens
such as tobacco and alcohol elevate the risk of epithelial
cancer developing in the upper aerodigestive tract. In our
study, however, the incidence of ESCN in HCN patients was
at a higher rate than those of previous reports [6, 7]. Reasons
include the undertaking of routine EGDS in HNC patients as
well as endoscopic advances that are increasing the detection rates. In particular, endoscopic advances, such as highresolution endoscopy with magnification and narrow-band
imaging system, may contribute to the earlier detection of
lesions [16, 17].
In our study, the 3-year survival rate of HNC patients
with ESCN was more than 50%, which was an improvement
compared to that in past reports [12–14]. The contributing
Treatment
Head and neck cancer n (%)
Esophageal
neoplasia n
(%)
Surgical resection
Radiotherapy
Chemoradiation therapy
Chemotherapy and surgical resection
Radiotherapy and surgical resection
Chemoradiation therapy and surgical resection
Endoscopic resection
No treatment
Simultaneous chemoradiation therapy
3 (8.8)
3 (8.8)
21 (61.8)
2 (5.9)
1 (2.9)
2 (5.9)
0 (0.0)
2 (5.9)
10 (29.4)
1 (2.9)
0 (0.0)
12 (35.3)
2 (5.9)
0 (0.0)
0 (0.0)
10 (29.4)
9 (26.5)
Int J Clin Oncol
Fig. 1 Kaplan-Meier survival curves comparing head and neck cancer patients (HNC) with or without esophageal squamous cell neoplasia (ESCN). p = 0.029 for a comparison between the groups by a
log-rank test
reasons include not only advances in anticancer therapies,
such as new surgical and radiotherapy techniques as well as
new anticancer drugs, but also the improved ability to detect
earlier ESCN lesions. In fact, the early detection of ESCN
Table 4 Cox regression
analyses for risk factors in
overall survival rates
Risk factors
in HCN patients is critical to improving the prognosis [18];
most ESCNs in our study were detected at an early clinical
stage.
The development of ESCN, however, remained one of the
poor prognostic factors found for the overall survival rate
among the HNC patients in our study. The reasons for this
remain undetermined, but our data suggest several possibilities. First, the rate of hypopharyngeal cancer patients with
ESCN was significantly higher than that of hypopharyngeal
cancer patients without ESCN. In our study, hypopharyngeal cancer was not a significantly poorer prognostic factor associated with overall survival of HNC patients. The
prognosis for patients with hypopharyngeal cancer, however,
has been relatively poor among patients with head and neck
cancers [19]. Therefore, it may affect the overall survival
of all patients with ESCN. Second, another possible explanation for the shorter survival period in ESCN patients is
the adverse effect of simultaneous chemoradiation therapy
(CRT). The efficacy and feasibility of simultaneous CRT for
patients with HNC and ESCN have been reported [20–23].
Shinoto et al. showed that median survival was 19 months
and that the 2-year survival rate was 44% in patients with
synchronous HNC and esophageal tumors who received
simultaneous CRT; therapy was found to be feasible and
effective [23]. Simultaneous CRT, however, increased the
Levels
n
Univariate analysis
HR
Age (years)
Sex
Brinkman index
Daily alcohol intake
Clinical stage
Hypopharyngeal cancer
ESCN
Second primary tumor
except ESCN
Initial ­treatmenta
Chemoradiation therapy
<68
≥68
Female
Male
<1000
>1000
<33 g
>33 g
I, II
III, IV
Absence
Presence
Absence
Presence
Absence
Presence
Local treatment
Systemic treatment
Absence
Presence
103
123
32
194
160
66
130
96
67
159
152
74
192
34
203
23
104
122
122
104
1
1.31
1
0.77
1
0.67
1
1.08
1
2.21
1
1.09
1
1.81
1
1.18
1
1.51
1
1.39
95% CI
Multivariate analysis
p
HR
95% CI
p
1
2.15
1.18–3.93 0.012
1
1.73
1.00–2.97 0.049
0.82–2.08 0.26
0.37–1.61 0.49
0.39–1.16 0.15
0.68–1.71 0.75
1.21–4.03 0.010
0.66–1.76 0.75
1.05–3.11 0.033
0.59–2.36 0.65
0.94–2.42 0.085
0.88–2.20 0.15
HR hazard ratio, CI confidence interval, ESCN esophageal squamous cell neoplasia
a
Local treatment; surgery, radiotherapy, and other; systemic treatment: chemotherapy and chemoradiation
therapy
13
radiation field of the lung and the adverse effects, resulting
in a reduced survival rate [24, 25]. In our series, the majority of HNC patients with synchronous ESCN underwent
simultaneous chemoradiation therapy. Of the HNC patients
with synchronous ESCN, a definite CRT-related death was
observed in a patient with radiation pneumonitis; moreover,
the late complications of CRT were hidden as HNC-related
deaths. In fact, ESCN patients who received simultaneous
CRT tended to show a shorter overall survival period after
analysis using a log-rank test in our study (p = 0.10; data
not shown).
The present study had several limitations. First, patients
were enrolled in a single center. The findings reported here
should be confirmed in a multicenter study. A second limitation was that the study design was retrospective: we relied
on medical records for patient data. Furthermore, the choice
of treatment regimen depended on the managing physicians.
The foregoing factors would have contributed to biases in
the present study.
In conclusion, ESCN is associated with a high incidence
of HNC patients so that screening for EGDS is crucial for
such patients. The presence of ESCN is one of the poor
prognostic factors in HNC patients, possibly because of the
presence of comorbid hypopharyngeal cancer and undergoing simultaneous CRT.
Compliance with ethical standards Conflict of interest The authors declare that they have no conflict
of interest.
Int J Clin Oncol
8.
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10.
11.
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13.
14.
15.
16.
17.
18.
19.
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