Narrow band imaging for detecting superficial squamous cell carcinoma of the head and neck in patients with esophageal squamous cell carcinoma

• Introduction
• Patients and methods
• Results
• Patient characteristics
• Detection of superficial SCCHN
• Treatment and course
• Discussion
• References

Background and study aims: Narrow band imaging combined with magnifying endoscopy (NBI-ME) is useful for the detection of superficial squamous cell carcinoma (SCC) within the oropharynx, hypopharynx, and oral cavity. The risk of a second primary SCC of the head and neck is very high in patients with esophageal SCC. This prospective study evaluated the detection rate of superficial SCC within the head and neck region (superficial SCCHN) with NBI-ME in patients with esophageal SCC.

Patients and methods: Between March 2006 and February 2008, 112 patients with a current or previous diagnosis of esophageal SCC were enrolled. All patients underwent endoscopic screening of the head and neck by NBI-ME. The primary end point was the detection rate for superficial SCCHN. Secondary end points were to compare demographic characteristics between patients with and without superficial SCCHN and to assess the clinical course of patients with superficial SCCHN.

Results: The detection rate for superficial SCCHN was 13 % (15/112). The prevalence of multiple Lugol-voiding lesions, observed endoscopically throughout the esophageal mucosa after application of Lugol dye solution, was significantly higher in patients with superficial SCCHN than in those without (100 % vs. 24 %, P < 0.0001). Minimally invasive curative treatment with organ preservation was feasible without severe complications in patients with superficial SCCHN after curative treatment of esophageal SCC.

Conclusions: In patients with esophageal SCC, NBI-ME is useful for detecting superficial SCCHN, thereby facilitating minimally invasive treatment.

Introduction

Gastrointestinal endoscopy is an essential technique for the diagnosis of esophageal and gastrointestinal lesions. Narrow band imaging (NBI) is a novel optical technique that enhances the diagnostic capability of gastrointestinal endoscopy by highlighting the intraepithelial papillary capillary loops of the squamous cell mucosa by means of light passed through filters that narrow the spectral bandwidths, incorporated into a red–green–blue sequential illumination system [1]. It has previously been reported that NBI combined with magnifying endoscopy (NBI-ME) could detect superficial squamous cell carcinoma (superficial SCC) within the oropharynx, hypopharynx, and oral cavity [2] [3] [4] [5]. Muto et al. reported that NBI-ME had higher rates for both detection and diagnostic accuracy for superficial SCC within the head and neck region (superficial SCCHN) than did conventional white light observation with magnifying endoscopy on back-to-back endoscopic examination [6].

Since in patients with esophageal cancer the most common site for synchronous and metachronous second primary malignancies is the head and neck [7] [8] [9], we prospectively studied the ability of NBI-ME to detect superficial SCCHN in patients with a current or previous diagnosis of esophageal SCC.

Patients and methods

Between March 2006 and February 2008, 112 patients were enrolled who met the following criteria: (i) a current or previous diagnosis of esophageal SCC; (ii) age of at least 20 years; (iii) no history of head and neck cancer; (iv) no symptoms of the head and neck; (v) no previous surgical treatment or radiotherapy of the head and neck; and (vi) no previous endoscopic screening of the head and neck by NBI-ME. The study protocol and informed consent form were approved by our institutional review board in February 2006. Written informed consent was obtained from all patients.

The patients underwent endoscopic screening of the head and neck by NBI-ME. In this study, we performed NBI using a high definition video endoscopy system (CV-260SL, processor, CLV-260SL light source; Olympus Optical Co., Tokyo, Japan) and an optical magnifying endoscope with a system that could magnify objects up to 80 times (GIF Q240Z video endoscope; Olympus). The diameter of the GIF Q240Z video endoscope was 10.2 mm, and the flexibility was similar to that of a conventional gastrointestinal endoscope. Screening was done in the following order: (i) observation with shifting of the tongue to create sufficient space for screening the oral cavity without mouth gear, and (ii) observation with vocal exercise to create sufficient space for screening the oropharyngeal, hypopharyngeal, and laryngeal regions with mouth gear.

The primary end point was the detection rate of superficial SCCHN by endoscopic screening using NBI-ME in patients with a current or previous diagnosis of esophageal SCC. Secondary end points were: (i) to compare demographic characteristics between patients with and those without superficial SCCHN, and (ii) to assess the clinical course of patients with superficial SCCHN.

Because prospective studies assessing the ability of NBI to detect early, superficial SCCHN have not been reported previously, it was difficult to estimate the required sample size. We therefore set the study period at 2 years, during which we estimated that at least 100 patients could be enrolled.

Only superficial cancers, that is, microinvasive SCC and high grade intraepithelial neoplasia as defined by the World Health Organization classification of tumors, were studied [10]. An NBI diagnosis of superficial SCC required the presence of both (i) a well-demarcated brownish area, and (ii) an irregular microvascular pattern [2] [3] [4]. Examples of superficial SCC in the left piriform sinus, the left superior wall of the oropharynx, and the left side of the tongue are shown in [Figs. 1 3]. Conventional white light observation showed a slightly reddish area with mild mucosal irregularity ([Figs. 1 a], [2 a], and [3 a]). NBI showed a well-demarcated brownish area ([Figs. 1 b], [2 b], and [3 b]). NBI combined with maximum magnification ( × 80) showed an irregular microvascular pattern ([Figs. 1 c], [2 c], and [3 c]).

Biopsy specimens were taken after the completion of screening for all superficial cancers in the head and neck region. Before biopsy in the laryngeal region, 4 % lidocaine solution was sprayed through the endoscope to attenuate the gag reflex. Resected specimens, biopsy specimens, or both, were evaluated histopathologically. The histological characteristics of neoplasms were classified according to the World Health Organization criteria for esophageal tumors [10]. We used the histological diagnosis as the gold standard diagnosis. Although the results of endoscopy were not blinded, the histological diagnosis was confirmed by two gastrointestinal pathologists.

Lugol chromoendoscopy of the esophageal mucosa was carried out in all patients, using the Lugol dye staining method [11]. A 1.5 % solution of Lugol dye was used in this study. Multiple Lugol-voiding lesions (LVLs) were defined to be numerous, well-defined, irregularly shaped lesions that appeared throughout the entire esophageal mucosa after the application of Lugol dye solution [12] [13].

Because the oral cavity and superior wall of the oropharynx could easily be accessed by a surgical device, transoral surgical mucosectomy (TSM) of lesions in such regions was done by a head and neck surgeon, with the patient under general anesthesia. Lesions were removed using an electric surgical knife or carbon dioxide laser, without injecting saline beneath the epithelium to lift the lesion above the surrounding mucosa [4]. If a transoral direct surgical approach was difficult, endoscopic mucosal resection (EMR) was performed by a gastrointestinal endoscopist with the patient under general anesthesia; lesions were removed using a transparent, soft plastic cap [2] [14]. We used an orotracheal route for intubation at the time of EMR. However, in patients who underwent TSM because a transoral direct surgical approach was possible, a nasotracheal route was used for intubation to secure a good operative field.

In patients with superficial SCCHN treated with curative intent, follow-up examinations by NBI-ME and computed tomography (CT) examination were repeated at least every 6 months after treatment. The duration of follow-up was longer than 1 year in this study.

All statistical analyses were carried out using the StatView software package for Macintosh (Version 5; Abacus Concepts, Inc., Berkeley, California, USA). The significance of differences was assessed with Fisher’s exact test. P values of < 0.05 were considered to indicate statistical significance.

Results

Patient characteristics

Patient characteristics are shown in [Table 1]. The study group comprised 100 men (89 %) and 12 women (11 %), with a mean age (± SD) of 67 ± 7.5 years. The clinical stage of esophageal cancer was stage I in 42 patients (38 %), stage II in 26 (23 %), stage III in 32 (29 %), and stage IV in 12 (11 %).

Of the patients, 80 (71 %) had a current diagnosis of esophageal SCC and it had been previously diagnosed in 32 (29 %). There was a history of cancer in other organs in 12 patients (11 %): gastric cancer in 7 (6 %), lung cancer in 2 (2 %), liver cancer in 1 (1 %), bladder cancer in 1 (1 %), and leukemia in 1 (1 %). The remaining 100 patients (89 %) had no history of cancer in other organs.

Habitual alcohol use was reported by 101 patients (90 %), and 98 (88 %) were smokers. Multiple LVLs of esophageal mucosa were found in 38 patients (34 %).

Detection of superficial SCCHN

The detection rate for superficial SCCHN was 13 % (15/112), with 16 lesions detected in 15 patients. One patient had two lesions, 1 each in oropharyngeal and hypopharyngeal mucosal sites. No advanced cancer was detected. The 16 lesions comprised 3 (19 %) detected in the oral cavity, 4 (25 %) in the oropharynx, and 9 (56 %) in the hypopharynx ([Table 2]); no laryngeal cancer was detected. For 8 of the 16 lesions, biopsy specimen and resection specimens were available for histological evaluation; for the remaining 8 lesions, only biopsy specimens were available since these patients were treated with techniques other than surgical or endoscopic resection. All 16 superficial SCCHNs were diagnosed endoscopically and confirmed histopathologically.

The characteristics of patients with and without superficial SCCHN are compared in [Table 3]. The prevalence of multiple LVLs of the background esophageal mucosa was significantly higher in patients with superficial SCCHN (100 % vs. 24 %, P < 0.0001). Other characteristics did not differ significantly between the groups.

Treatment and course

In the 15 patients with superficial SCCHN, their esophageal cancer had been previously diagnosed in 3 and had been currently (at the time of the present study) diagnosed in 12. Because 10 patients were transiently disease-free after treatment for esophageal cancer, their superficial SCCHNs were treated with curative intent.

[Fig. 4] summarizes the clinical courses of the ten patients in whom 11 superficial SCCHNs were treated with curative intent. Of the 11 lesions, 8 were resected (TSM 4, EMR 4; see below for further details); 2 lesions arising in the piriform sinus were treated by chemoradiotherapy [15]; and another 1 lesion in the piriform sinus by radiotherapy. The patient receiving radiotherapy for this hypopharyngeal SCCHN had two lesions and underwent TSM for an oropharyngeal lesion.

All of these patients were followed up every 6 months for at least 1 year. The average follow-up period (± SD) was 25 ± 6.3 months (range 14 – 33), and the average number of examinations per patient (± SD) was 4.8 ± 1 (range 3 – 6). No recurrent or newly diagnosed superficial SCCHN was detected during follow up.

One patient had synchronous advanced esophageal cancer and superficial SCC of the oral cavity, which were treated by chemoradiotherapy and TSM, respectively. However, this patient died because of recurrence of the esophageal cancer. The superficial SCC of the oral cavity was unrelated to the cause of death. With a median follow-up period of 29 months (range 14 – 33), all of the other patients have remained disease-free without severe complications.

Resections. Regarding the 8 resected superficial SCCHNs, 2 lesions arose in the oral cavity, and 2 in the oropharynx, and these were removed by TSM; the remaining 4, in the hypopharynx, were all removed by EMR.

The average resected tumor size (± SD) was 18 ± 5 mm (range 10 – 25). No lesion was < 10 mm in diameter, 3 were ≥ 10 to < 20 mm in diameter, and 5 were ≥ 20 to < 30 mm in diameter.

Histologically, 4 of these lesions were high grade intraepithelial neoplasia, and 4 were microinvasive SCC. Two of the microinvasive SCCs were treated by EMR, and the deep resection margins in both patients were free of tumor. Lymphatic or vessel invasion was not found in any resected specimen.

In two patients with hypopharyngeal lesions, laryngeal edema developed during the EMR procedure. This complication was treated by temporary tracheotomy. No patient had bleeding, stenosis, or perforation as a complication of resection. The median follow-up period was 27 months (range, 14 – 33 months), and, as noted above, 1 of the 8 patients died of recurrent esophageal cancer.

Discussion

Annually, about 50 000 cases of SCCHN are newly diagnosed worldwide annually. Tumors of the hypopharynx are particularly problematic because they are usually are diagnosed at an advanced stage and carry a poor prognosis [16] [17] [18] [19]. Recent studies have reported that NBI-ME is useful for the detection of superficial SCCHN [2] [3] [4] [5]. In patients with esophageal cancer, synchronous and metachronous second primary malignancies most commonly arise in the upper aerodigestive organs, including the head and neck, stomach, and lung [7] [8] [9] [20] [21] [22]. An exceptionally strong association of esophageal cancer with head and neck cancer has been reported [7] [8] [9] [23] [24]. Matsubara et al. reported that the risk of head and neck cancer markedly increases after esophagectomy (relative risk 34.9; 95 %CI 24.3 – 48.6). The 5-year cumulative risk of developing head and neck cancer was estimated to be 7 % [9]. Consistent with these results, the detection rate of a second head and neck cancer in patients who had previously had esophageal cancer was 9 % (3/32) in our study. These findings suggest that endoscopic screening of the head and neck region by NBI-ME may substantially contribute to the early detection of head and neck cancer in patients with esophageal SCC. In the future, large prospective follow-up studies are needed to establish the optimal interval for surveillance by NBI-ME after treatment for esophageal SCC.

In the esophagus and head and neck region, the development of multiple primary SCCs and widespread epithelial oncogenic alterations, including carcinoma in situ, dysplasia, and hyperkeratosis, have long been a recognized phenomenon [25]. Clinically, Lugol chromoendoscopy can be used to visualize epithelial changes such as multiple LVLs, since dysplastic or hyperkeratotic epithelium does not stain with Lugol iodine solution and appears white or pink, whereas normal epithelium is stained brown [11] [12]. Multiple LVLs of esophageal mucosa are considered precursors for a second primary esophageal cancer in patients with head and neck cancer [12], and have also been associated with a very high risk of multiple cancers in the esophagus, as well as the head and neck [13] [26] [27]. In our study, the prevalence of multiple LVLs of esophageal mucosa was significantly increased in patients with superficial SCCHN. The presence of multiple LVLs of esophageal mucosa may therefore be a powerful biomarker for detecting a second primary superficial SCCHN. The Lugol dye staining method cannot be used in the head and neck region because it causes severe mucosal irritation, leading to pain and discomfort; the dye solution may even be aspirated into the airway. Therefore, patients with esophageal cancer who have multiple LVLs of the esophageal mucosa should undergo careful endoscopic screening of the head and neck by NBI-ME.

Effective treatment of superficial SCCHN is considered essential for cure in patients with esophageal SCC, but definitive studies are lacking. The safety and efficacy of follow-up treatment for superficial SCC thus remains unclear. In our series, curative treatment of superficial SCCHN was possible without severe complications in all patients in whom the esophageal SCC was successfully treated. Although 2 of 4 patients (50 %) had laryngeal edema during the EMR procedure, which was treated by temporary tracheotomy, the incidence of laryngeal edema can be lowered by minimizing mechanical stimulation caused by contact with surgical devices and chemical stimulation caused by Lugol dye solution on the laryngeal and hypopharyngeal regions at the time of treatment. All patients who underwent curative treatment remained disease-free and retained their larynx. Our results suggest that minimally invasive curative treatment with organ preservation is possible in patients with superficial SCCHN. Since EMR or TSM of head and neck region is less invasive than chemoradiotherapy or radiotherapy, expected benefits should be weighed against potential risks when selecting the treatment strategy. If superficial SCCHN is detected in patients with esophageal SCC, our results may suggest important clues for disease management. In the future, more definitive studies are needed to clarify the safety and efficacy of follow-up treatment for superficial SCCHN.

In conclusion, our results suggest that endoscopic screening by NBI-ME is useful for the detection of superficial SCCHN in patients with esophageal SCC. In particular, patients with multiple LVLs of the esophageal mucosa should be closely monitored to facilitate early detection of superficial SCCHN and permit minimally invasive curative treatment with organ preservation.

Competing interests: None

References

• 1 Gono K, Obi T, Yamaguchi M. et al . Appearance of enhanced tissue feature in narrow-band endoscopic imaging.  J Biomed Opt. 2004;  9 568-577
  CrossrefPubMedSearch in Google Scholar
• 2 Muto M, Nakane M, Katada C. et al . Squamous cell carcinoma in situ at oropharyngeal and hypopharyngeal mucosal sites.  Cancer. 2004;  101 1375-1381
  CrossrefPubMedSearch in Google Scholar
• 3 Muto M, Katada C, Yasushi S. et al . Narrow band imaging: a new diagnostic approach to visualize angiogenesis in superficial neoplasia.  Clin Gastroenterol Hepatol. 2005;  3 16-20
  CrossrefPubMedSearch in Google Scholar
• 4 Katada C, Nakayama M, Tanabe S. et al . Narrow band imaging for detecting superficial oral squamous cell carcinoma.  Laryngoscope. 2007;  117 1596-1599
  CrossrefPubMedSearch in Google Scholar
• 5 Nonaka S, Saito Y. Endoscopic diagnosis of pharyngeal carcinoma by NBI.  Endoscopy. 2008;  40 347-351
  Thieme ConnectPubMedSearch in Google Scholar
• 6 Muto M, Saito Y, Ohmori T. et al . Multicenter prospective randomized controlled study on the detection and diagnosis of superficial squamous cell carcinoma by back-to-back endoscopic examination of narrow band imaging and white light observation.  Gastrointest Endosc. 2007;  65 AB110-0
  PubMedSearch in Google Scholar
• 7 Shibuya H, Wakita T, Nakagawa T. et al . The relation between an esophageal cancer and associated cancers in adjacent organs.  Cancer. 1995;  76 101-105
  CrossrefPubMedSearch in Google Scholar
• 8 Begg C B, Zhang Z F, Sun M. et al . Methodology for evaluating the incidence of second primary cancers with application to smoking-related cancers from the surveillance, epidemiology, and end results (SEER) program.  Am J Epidemiol. 1995;  142 653-665
  PubMedSearch in Google Scholar
• 9 Matsubara T, Yamada K, Nakagawa A. Risk of second primary malignancy after esophagectomy for squamous cell carcinoma of the thoracic esophagus.  J Clin Oncol. 2003;  21 4336-4341
  CrossrefPubMedSearch in Google Scholar
• 10 Hamilton S R, Aaltonen L A. World Health Organization classification of tumors. Pathology and genetics of tumors of the digestive system. Lyon; IARC Press 2000: 9-30
  PubMedSearch in Google Scholar
• 11 Inoue H, Rey J F, Lightdale C. Lugol chromoendoscopy for esophageal squamous cell cancer.  Endoscopy. 2001;  33 75-79
  Search in Google Scholar
• 12 Muto M, Hironaka S, Nakane M. et al . Association of multiple Lugol-voiding lesions with synchronous and metachronous esophageal squamous cell carcinoma in patients with head and neck cancer.  Gastrointest Endosc. 2002;  56 517-521
  CrossrefPubMedSearch in Google Scholar
• 13 Muto M, Takahashi M, Ohtsu A. et al . Risk of multiple squamous cell carcinomas both in the esophagus and the head and neck region.  Carcinogenesis. 2005;  26 1008-1012
  PubMedSearch in Google Scholar
• 14 Inoue H, Endo M, Takeshita K. et al . A new simplified technique of endoscopic mucosal resection using a capfitted panendoscope (EMRC).  Surg Endosc. 1992;  6 264-265
  CrossrefPubMedSearch in Google Scholar
• 15 Ohtsu A, Yoshida S, Boku N. et al . Concurrent chemotherapy and radiation therapy for locally advanced carcinoma of the esophagus.  Jpn J Clin Oncol. 1995;  25 261-266
  PubMedSearch in Google Scholar
• 16 Kraus D H, Zelefsky M J, Brock H A. et al . Combined surgery and radiation therapy for squamous cell carcinoma of the hypopharynx.  Otolaryngol Head Neck Surg. 1997;  116 637-641
  CrossrefPubMedSearch in Google Scholar
• 17 Wahlberg P C, Andersson K E, Biorklund A T. et al . Carcinoma of the hypopharynx: analysis of incidence and survival in Sweden over a 30-year period.  Head Neck. 1998;  20 714-719
  CrossrefPubMedSearch in Google Scholar
• 18 Johansen L V, Grau C, Overgaard J. Hypopharyngeal squamous cell carcinoma – treatment results in 138 consecutively admitted patients.  Acta Oncol. 2000;  39 529-536
  CrossrefPubMedSearch in Google Scholar
• 19 Eckel H E, Staar S, Volling P. et al . Surgical treatment for hypopharynx carcinoma: feasibility, mortality, and results.  Otolaryngol Head Neck Surg. 2001;  124 561-569
  CrossrefPubMedSearch in Google Scholar
• 20 Poon R TP, Law S YK, Chu K M. et al . Multiple primary cancers in esophageal squamous cell carcinoma: Incidence and implications.  Ann Thorac Surg. 1998;  65 1529-1534
  CrossrefPubMedSearch in Google Scholar
• 21 Hoar S K, Wilson J, Blot W J. et al . Second cancer following cancer of the digestive system in Connecticut, 1935–82.  Natl Cancer Inst Monogr. 1985;  68 49-82
  PubMedSearch in Google Scholar
• 22 Fogel T D, Harrison L B, Son Y H. Subsequent upper aerodigestive malignancies following treatment of esophageal cancer.  Cancer. 1985;  55 1882-1885
  CrossrefPubMedSearch in Google Scholar
• 23 Petit T, Georges C, Jung G M. et al . Systematic esophageal endoscopy screening in patients previously treated for head and neck squamous-cell carcinoma.  Ann Oncol. 2001;  12 643-646
  CrossrefPubMedSearch in Google Scholar
• 24 Dubuc J, Legoux J L, Winnock M. et al . Endoscopic screening for esophageal squamous-cell carcinoma in high risk patients: a prospective study conducted in 62 French endoscopy centers.  Endoscopy. 2006;  38 690-695
  Thieme ConnectPubMedSearch in Google Scholar
• 25 Slaughter D P, Southwick H W, Smejkal W. Field cancerization in oral stratified squamous epithelium: clinical implications of multicentric origin.  Cancer. 1953;  6 963-968
  CrossrefPubMedSearch in Google Scholar
• 26 Shimizu Y, Tsukagoshi H, Fujita M. et al . Head and neck cancer arising after endoscopic mucosal resection for squamous cell carcinoma of the esophagus.  Endoscopy. 2003;  35 322-626
  Thieme ConnectPubMedSearch in Google Scholar
• 27 Urabe Y, Hiyama T, Tanaka S. et al . Metachronous multiple esophageal squamous cell carcinomas and Lugol-voiding lesions after endoscopic mucosal resection.  Endoscopy. 2009;  41 304-309
  Thieme ConnectPubMedSearch in Google Scholar

C. KatadaMD 

Department of Gastroenterology
Kitasato University School of Medicine

1-15-1 Kitasato
Sagamihara 228-8555, Japan

Fax: +81-42-7498690

Email: ckatada@med.kitasato-u.ac.jp

References

• 1 Gono K, Obi T, Yamaguchi M. et al . Appearance of enhanced tissue feature in narrow-band endoscopic imaging.  J Biomed Opt. 2004;  9 568-577
  CrossrefPubMedSearch in Google Scholar
• 2 Muto M, Nakane M, Katada C. et al . Squamous cell carcinoma in situ at oropharyngeal and hypopharyngeal mucosal sites.  Cancer. 2004;  101 1375-1381
  CrossrefPubMedSearch in Google Scholar
• 3 Muto M, Katada C, Yasushi S. et al . Narrow band imaging: a new diagnostic approach to visualize angiogenesis in superficial neoplasia.  Clin Gastroenterol Hepatol. 2005;  3 16-20
  CrossrefPubMedSearch in Google Scholar
• 4 Katada C, Nakayama M, Tanabe S. et al . Narrow band imaging for detecting superficial oral squamous cell carcinoma.  Laryngoscope. 2007;  117 1596-1599
  CrossrefPubMedSearch in Google Scholar
• 5 Nonaka S, Saito Y. Endoscopic diagnosis of pharyngeal carcinoma by NBI.  Endoscopy. 2008;  40 347-351
  Thieme ConnectPubMedSearch in Google Scholar
• 6 Muto M, Saito Y, Ohmori T. et al . Multicenter prospective randomized controlled study on the detection and diagnosis of superficial squamous cell carcinoma by back-to-back endoscopic examination of narrow band imaging and white light observation.  Gastrointest Endosc. 2007;  65 AB110-0
  PubMedSearch in Google Scholar
• 7 Shibuya H, Wakita T, Nakagawa T. et al . The relation between an esophageal cancer and associated cancers in adjacent organs.  Cancer. 1995;  76 101-105
  CrossrefPubMedSearch in Google Scholar
• 8 Begg C B, Zhang Z F, Sun M. et al . Methodology for evaluating the incidence of second primary cancers with application to smoking-related cancers from the surveillance, epidemiology, and end results (SEER) program.  Am J Epidemiol. 1995;  142 653-665
  PubMedSearch in Google Scholar
• 9 Matsubara T, Yamada K, Nakagawa A. Risk of second primary malignancy after esophagectomy for squamous cell carcinoma of the thoracic esophagus.  J Clin Oncol. 2003;  21 4336-4341
  CrossrefPubMedSearch in Google Scholar
• 10 Hamilton S R, Aaltonen L A. World Health Organization classification of tumors. Pathology and genetics of tumors of the digestive system. Lyon; IARC Press 2000: 9-30
  PubMedSearch in Google Scholar
• 11 Inoue H, Rey J F, Lightdale C. Lugol chromoendoscopy for esophageal squamous cell cancer.  Endoscopy. 2001;  33 75-79
  Search in Google Scholar
• 12 Muto M, Hironaka S, Nakane M. et al . Association of multiple Lugol-voiding lesions with synchronous and metachronous esophageal squamous cell carcinoma in patients with head and neck cancer.  Gastrointest Endosc. 2002;  56 517-521
  CrossrefPubMedSearch in Google Scholar
• 13 Muto M, Takahashi M, Ohtsu A. et al . Risk of multiple squamous cell carcinomas both in the esophagus and the head and neck region.  Carcinogenesis. 2005;  26 1008-1012
  PubMedSearch in Google Scholar
• 14 Inoue H, Endo M, Takeshita K. et al . A new simplified technique of endoscopic mucosal resection using a capfitted panendoscope (EMRC).  Surg Endosc. 1992;  6 264-265
  CrossrefPubMedSearch in Google Scholar
• 15 Ohtsu A, Yoshida S, Boku N. et al . Concurrent chemotherapy and radiation therapy for locally advanced carcinoma of the esophagus.  Jpn J Clin Oncol. 1995;  25 261-266
  PubMedSearch in Google Scholar
• 16 Kraus D H, Zelefsky M J, Brock H A. et al . Combined surgery and radiation therapy for squamous cell carcinoma of the hypopharynx.  Otolaryngol Head Neck Surg. 1997;  116 637-641
  CrossrefPubMedSearch in Google Scholar
• 17 Wahlberg P C, Andersson K E, Biorklund A T. et al . Carcinoma of the hypopharynx: analysis of incidence and survival in Sweden over a 30-year period.  Head Neck. 1998;  20 714-719
  CrossrefPubMedSearch in Google Scholar
• 18 Johansen L V, Grau C, Overgaard J. Hypopharyngeal squamous cell carcinoma – treatment results in 138 consecutively admitted patients.  Acta Oncol. 2000;  39 529-536
  CrossrefPubMedSearch in Google Scholar
• 19 Eckel H E, Staar S, Volling P. et al . Surgical treatment for hypopharynx carcinoma: feasibility, mortality, and results.  Otolaryngol Head Neck Surg. 2001;  124 561-569
  CrossrefPubMedSearch in Google Scholar
• 20 Poon R TP, Law S YK, Chu K M. et al . Multiple primary cancers in esophageal squamous cell carcinoma: Incidence and implications.  Ann Thorac Surg. 1998;  65 1529-1534
  CrossrefPubMedSearch in Google Scholar
• 21 Hoar S K, Wilson J, Blot W J. et al . Second cancer following cancer of the digestive system in Connecticut, 1935–82.  Natl Cancer Inst Monogr. 1985;  68 49-82
  PubMedSearch in Google Scholar
• 22 Fogel T D, Harrison L B, Son Y H. Subsequent upper aerodigestive malignancies following treatment of esophageal cancer.  Cancer. 1985;  55 1882-1885
  CrossrefPubMedSearch in Google Scholar
• 23 Petit T, Georges C, Jung G M. et al . Systematic esophageal endoscopy screening in patients previously treated for head and neck squamous-cell carcinoma.  Ann Oncol. 2001;  12 643-646
  CrossrefPubMedSearch in Google Scholar
• 24 Dubuc J, Legoux J L, Winnock M. et al . Endoscopic screening for esophageal squamous-cell carcinoma in high risk patients: a prospective study conducted in 62 French endoscopy centers.  Endoscopy. 2006;  38 690-695
  Thieme ConnectPubMedSearch in Google Scholar
• 25 Slaughter D P, Southwick H W, Smejkal W. Field cancerization in oral stratified squamous epithelium: clinical implications of multicentric origin.  Cancer. 1953;  6 963-968
  CrossrefPubMedSearch in Google Scholar
• 26 Shimizu Y, Tsukagoshi H, Fujita M. et al . Head and neck cancer arising after endoscopic mucosal resection for squamous cell carcinoma of the esophagus.  Endoscopy. 2003;  35 322-626
  Thieme ConnectPubMedSearch in Google Scholar
• 27 Urabe Y, Hiyama T, Tanaka S. et al . Metachronous multiple esophageal squamous cell carcinomas and Lugol-voiding lesions after endoscopic mucosal resection.  Endoscopy. 2009;  41 304-309
  Thieme ConnectPubMedSearch in Google Scholar

C. KatadaMD 

Department of Gastroenterology
Kitasato University School of Medicine

1-15-1 Kitasato
Sagamihara 228-8555, Japan

Fax: +81-42-7498690

Email: ckatada@med.kitasato-u.ac.jp