Introduction
Multiple squamous cell carcinomas (SCCs) frequently arise in the upper aerodigestive
tract [1]
[2]. This phenomenon can be explained by the field cancerization theory, which suggests
that the entire epithelial surface of the upper aerodigestive tract is at increased
risk of developing cancers because of its repeated exposure to carcinogens such as
alcohol and through smoking [3]
[4]. Surveillance of the aerodigestive tract in patients with head and neck (H&N) and
esophageal SCCs is therefore recommended based on this theory, and periodic endoscopic
examinations in these patients may facilitate the early detection of SCCs in this
area [5]. Early detection of cancers may be associated with a better prognosis and increased
possibility of minimally invasive treatment, including endoscopic resection [6]
[7]
[8].
Although previous studies have reported on the use of surveillance endoscopic examinations
in patients with esophageal cancer [9]
[10]
[11], they have only included small numbers of patients, and no detailed information
on the second primary H&N cancers was provided. However, detailed analyses of second
primary H&N cancers may help to elucidate the characteristics of cancers caused by
the field cancerization effect, and thus help to establish effective surveillance
methods for patients with esophageal cancer. In this study, we therefore investigated
the incidence, primary sites, and stages of second primary H&N SCCs detected in patients
with esophageal SCC.
Patients and methods
Patients
A total of 818 patients underwent endoscopic resection for superficial esophageal
cancer at Osaka Medical Center for Cancer and Cardiovascular Diseases between January
2006 and December 2013. We prospectively collected baseline clinical data for these
patients, including treatment date, age, sex, past medical history, and lesion characteristics,
such as location, size, histology, and depth of invasion. From this database, we identified
439 patients who met the following inclusion criteria: (1) histologically proven esophageal
SCC; (2) mucosal or submucosal esophageal SCC; (3) no prior radiotherapy, chemotherapy,
or surgery for esophageal SCC; (4) no prior diagnosis or treatment of H&N SCC; (5)
no history of other incurable cancer before endoscopic resection; and (6) followed
up with upper gastrointestinal endoscopy in our hospital for more than 6 months ([Fig. 1])
Fig. 1 Flowchart of patients.
In this study, multiple H&N cancers detected after endoscopic resection were classified
as metachronous. The incidences and characteristics of metachronous H&N cancers were
obtained from electronic medical records. All the lesions were histologically confirmed
as SCC according to World Health Organization criteria [12]. The lesions were also diagnosed as cancerous based on obvious cytological abnormalities
of the squamous epithelium, even when the abnormalities were confined to the lower
half of the squamous epithelium [13]. This study was approved by the ethics committee at Osaka Medical Center for Cancer
and Cardiovascular Diseases.
Follow up
Patients were followed up at our hospital or by the referring physicians after treatment.
In this study, we only analyzed second primary H&N cancers in patients who were followed
up for more than 6 months in our hospital, to ensure the quality of endoscopic examination.
Surveillance of H&N cancers was conducted by upper gastrointestinal endoscopy and
pharyngolaryngoscopy. Upper gastrointestinal endoscopy was generally conducted by
gastroenterologists at 2 months after endoscopic resection, and annually thereafter.
Most endoscopic examinations were carried out using a magnifying endoscope with narrow-band
imaging (NBI) (GIF-Q240Z or GIF-H260Z; Olympus Optical Co Ltd, Tokyo, Japan) fitted
with a soft black hood attachment (MB-162 for GIF-Q240Z, or MB-46 for GIF-H260Z; Olympus)
on its top. Pharyngolaryngoscopy by otorhinolaryngologist was conducted annually or
as dictated by symptoms such as hoarseness or discomfort in swallowing. During endoscopic
examination, we observed the oropharynx, hypopharynx, and oral cavity. If a well-demarcated
brownish area and microvascular irregularities were observed with NBI, the lesion
was diagnosed as endoscopically suspected superficial SCC [14], and biopsy samples were taken.
General treatment principles of H&N cancer
All detected H&N cancers were treated at our hospital based on a strategy determined
by otorhinolaryngologists and gastroenterologists. Lesions that fulfilled the following
criteria were treated by minimally invasive treatment, such as transoral surgical
mucosectomy or endoscopic resection: (1) cancers limited to the epithelium or invading
into the surface part of the subepithelial layer; (2) cancers with no spread into
the pharyngeal space bilaterally; and (3) no lymph node or distant metastasis visible
by computed tomography. Because lesions in the oral cavity and superior wall of the
oropharynx can be accessed easily by a surgical device, transoral surgical mucosectomy
was carried out by otorhinolaryngologists. However, if a transoral direct approach
was difficult, endoscopic resection was performed by gastrointestinal endoscopists.
If the detected lesion did not meet the indication criteria for minimally invasive
treatment as mentioned above, radical surgery, radiotherapy, or chemoradiotherapy
was considered.
Statistical analysis
The cumulative incidence rates of metachronous H&N cancers were plotted using the
Kaplan-Meier method. The observation period was measured from the date of endoscopic
resection to the date of detection of metachronous multiple cancers, or the latest
endoscopic examination in patients in whom multiple cancers were not found. Categorical
variables were compared using Yates χ2 tests. For all analyses, a two-sided P value < 0.05 was considered statistically significant. Statistical analyses were
performed using JMP version 10.0 (SAS Institute, Cary, NC, USA).
Results
The characteristics of the 439 patients and the esophageal lesions are listed in [Table 1]. For patients with synchronous multiple esophageal SCCs, data for the deepest or
largest lesion are shown. The patients included 370 men and 69 women, with a median
age of 68 years (range 41 – 83). Eighteen patients had submucosal cancer with lymphovascular
involvement, 42 had submucosal cancer without lymphovascular involvement, and 23 had
mucosal cancer with lymphovascular involvement. Of these 83 patients, additional treatment
was performed in 71 patients (63 chemoradiotherapy, 7 surgery, and 1 chemotherapy)
to reduce the risk of lymph node metastasis. The remaining 12 patients did not receive
the additional treatment because of patient refusal in 11 cases and liver cirrhosis
in 1 case.
Table 1
Characteristics of patients and lesions.
|
Gender, male/female, n
|
370/69
|
|
Age, median (range), y
|
68 (41 – 83)
|
|
Lesion location, n
|
|
|
Cervical esophagus
|
51
|
|
Upper thoracic esophagus
|
115
|
|
Middle thoracic esophagus
|
197
|
|
Lower thoracic esophagus
|
76
|
|
Lesion size, median (range), mm
|
12 (2 – 80)
|
|
Tumor depth, n
|
|
|
EP
|
118
|
|
LPM
|
171
|
|
MM
|
90
|
|
SM
|
60
|
|
Lymphovascular involvement, n
|
|
|
Positive
|
41
|
|
Negative
|
398
|
EP, epithelium; LPM, lamina propria; MM, muscularis mucosa; SM, submucosa.
Among all the patients, 98 % (428/439) received follow-up examinations at 1 year,
79 % (346/439) at 2 years, 60 % (264/439) at 3 years, 44 % (191/439) at 4 years, and
28 % (123/439) at 5 years. A total of 53 metachronous H&N cancers developed in 40
patients after median follow-up of 46 months (range 9 – 109), with cumulative incidence
rates of metachronous H&N cancers at 3, 5, and 7 years of 5.3 %, 9.7 %, and 17.2 %,
respectively ([Fig. 2]). The characteristics of the metachronous H&N cancers are listed in [Table 2]. Thirty-five lesions were located in the hypopharynx, 9 in the oropharynx, 4 in
the oral cavity, and 5 in the larynx. Four lesions were detected by otorhinolaryngologists
(1 lateral wall of oropharynx, 2 oral floor, and 1 glottis), and all of the remaining
lesions were detected by gastroenterologists. Among all the subsites in the H&N region,
70 % of lesions were located at the pyriform sinus (47 %, 25/53) or posterior wall
of the pharynx (23 %, 12 /53). The median size of the detected lesions was 17 mm (range
2 – 45 mm). Minimally invasive treatment such as endoscopic resection or transoral
surgical mucosectomy was conducted for 39 of the 53 lesions (74 %). [Table 3] shows the T and N stages of the detected cancers (no distant metastasis was detected
in any of the lesions). Most of the lesions (70 %, 37/53) were classified as Tis/T1N0,
although 4 lesions had lymph node metastasis when their primary sites were detected
(1 postcricoid area, 2 posterior wall of hypopharynx, and 1 lateral wall of oropharynx).
Three of 5 protruded lesions and 1 of 46 flat lesions had lymph node metastasis. There
was a significant association (P = 0.0002) between endoscopic appearance (protruded or flat) and N stage (N0 or N1 – 2).
Fig. 2 Cumulative incidence of metachronous head and neck cancers after endoscopic resection
of esophageal squamous cell carcinoma.
Table 2
Characteristics of metachronous head and neck cancers.
|
Patients, n (%)
|
40 (9.1)
|
|
Lesions, n
|
53
|
|
Lesion location, n
|
|
|
Hypopharynx
|
|
|
Left pyriform sinus
|
10
|
|
Right pyriform sinus
|
15
|
|
Postcricoid area
|
3
|
|
Posterior wall
|
7
|
|
Oropharynx
|
|
|
Superior wall
|
3
|
|
Posterior wall
|
5
|
|
Lateral wall
|
1
|
|
Oral cavity
|
|
|
Oral floor
|
2
|
|
Buccal mucosa
|
2
|
|
Larynx
|
|
|
Supraglottis
|
4
|
|
Glottis
|
1
|
|
Lesion size, median (range), mm
|
17 (2 – 45)
|
|
Macroscopic appearance, n[1]
|
|
|
Flat
|
46
|
|
Protruded
|
5
|
|
Treatment, n
|
|
|
Endoscopic resection
|
31
|
|
Transoral surgical mucosectomy
|
8
|
|
Radical surgery
|
3
|
|
Radiotherapy
|
4
|
|
Chemoradiotherapy
|
3
|
|
Endoscopic resection & radiotherapy
|
1
|
|
Surgery & radiotherapy
|
1
|
|
Surgery & chemoradiotherapy
|
1
|
|
Observation[2]
|
1
|
1 Macroscopic types of 2 lesions were not recorded
2 Lesions were not recorded 2because of other incurable cancer
Table 3
T and N stages of metachronous head and neck cancers.
|
TN stage, n
|
|
Lesion location
|
Tis/T1N0
|
T2N0
|
T3N0
|
TanyN1 – 2
|
|
Hypopharynx
|
|
|
|
|
|
Pyriform sinus
|
17
|
7
|
1
|
0
|
|
Postcricoid area
|
2
|
0
|
0
|
1
|
|
Posterior wall
|
5
|
0
|
0
|
2
|
|
Oropharynx
|
|
|
|
|
|
Superior wall
|
2
|
1
|
0
|
0
|
|
Posterior wall
|
4
|
1
|
0
|
0
|
|
Lateral wall
|
0
|
0
|
0
|
1
|
|
Oral cavity
|
2
|
2
|
0
|
0
|
|
Larynx
|
5
|
0
|
0
|
0
|
Discussion
In this study, we demonstrated a cumulative 5-year incidence rate of 9.7 % for metachronous
H&N SCC in patients with esophageal SCC. The pyriform sinus and posterior wall of
the pharynx were the most common sites for the development of metachronous SCCs. Most
of the lesions were detected at an early stage and were completely removed by minimally
invasive treatment, such as transoral surgical mucosectomy or endoscopic resection.
However, some lesions in the postcricoid area and posterior wall of the hypopharynx
were initially diagnosed at an advanced stage.
In Japan, the age-specific annual incidence rate for oral and pharyngeal cancer in
65- to 69-year-olds was 30.6 per 100,000 in 2008 [15]. Compared with the general population, our study demonstrated that patients with
esophageal cancer were at extremely high risk of developing H&N cancers, with an incidence
of approximately 2000 per 100,000 patients. We also previously reported that metachronous
esophageal cancer frequently developed in patients who had undergone endoscopic resection
for esophageal cancer (cumulative incidence rate at 5 years of 20.6 %) [16]. These studies demonstrate that the entire epithelial surface of the upper digestive
tract is at increased risk of cancer in patients with esophageal cancer, thus supporting
the field cancerization theory.
According to the H&N cancer registry in Japan, a total of 3899 H&N cancers were newly
diagnosed in 2012, 840 of which (22 %) were classified as Tis/T1N0, and 249 (6.4 %)
of which were treated by minimally invasive methods, such as transoral surgical mucosectomy
or endoscopic resection [17]. In this study using periodic endoscopic surveillance with NBI, 70 % (37/53) of
lesions were detected as Tis/T1N0 cancers, and 39 of the 53 lesions (74 %) were treated
by minimally invasive procedures. These results indicate that periodic endoscopic
surveillance facilitates the early detection of H&N cancers, and suggest that NBI
may also be relevant [18].
Effective surveillance requires an understanding of the detailed features, such as
the annual incidence and common sites of H&N cancers. Katada et al. reported the prevalence
of superficial H&N cancers in patients with esophageal cancer, but not their annual
incidence [10]. Hori et al. investigated the annual incidence of H&N cancers, but the number of
lesions was relatively small and their detailed locations were not reported [9]. The H&N cancer registry in Japan shows the detailed locations of the cancers, but
most cancers included in the registry are advanced cases [17]. The current study is thus the largest to demonstrate the incidence of superficial
H&N cancers in patients with esophageal cancer, with detailed information on the locations
and stages of the lesions. Although this study was conducted in patients with esophageal
cancer, the findings regarding cancer location might be applied to cancers arising
based on the field cancerization theory.
In this study, H&N cancers were frequently located at the pyriform sinus or posterior
wall of the pharynx (70 %, 37/53 lesions). Because the structure of the H&N region
is complex and it is difficult to view the region thoroughly, information on the most
common sites of H&N cancers may help effective surveillance. Although we detected
most H&N lesions at an early phase, some lesions in the postcricoid area and posterior
wall of the hypopharynx already had lymph node metastasis when their primary sites
were discovered. These anatomically adjacent sites in the hypopharynx constitute a
closed space, which disturbs us to notice subtile changes in the muscosa during endoscopic
observation ([Fig. 3]). Methods to open this closed space, such as the Valsalva maneuver, would facilitate
detection of these lesions, and such methods should thus be included as a part of
the routine surveillance program.
Fig. 3 Number (prevalence [%]) of cancers in each subsite. a left pyriform sinus. b right pyriform sinus. c postcricoid area and posterior wall of the hypopharynx. d posterior wall of the oropharynx. Number (prevalence [%]) with a red background indicates
cancers with lymph node metastasis.
Our study was limited by its retrospective, single-center design, and by the large
number of patients (115 patients) who were lost to follow up. However, conducting
a multicenter study would be difficult given that there is currently no established
surveillance program for H&N cancer. Furthermore, limiting the patients who were followed
up at our hospital allowed us to maintain similar surveillance intervals and similar
qualities of endoscopic examinations for H&N cancer. Despite the limitations, the
results of this study will thus contribute to the development of future surveillance
programs.
In conclusion, the 5-year incidence of metachronous H&N SCC in patients with esophageal
SCC was 9.7 %, with the pyriform sinus and posterior wall of the pharynx being the
most common sites. A standardized surveillance program for H&N SCC should be developed
for patients with esophageal SCC.
