Images of Early Cancer: Esophageal Squamous-Cell Carcinoma

Introduction

Despite the widespread use of upper gastrointestinal endoscopy, the proportion of superficial esophageal squamous-cell carcinomas (SCCs) detected in Western countries is poor [1]. In a European enquiry, 51 such cases were found among 902 207 upper digestive endoscopy procedures. According to the registry in Burgundy, T1 cancer represents 4 % of the total number of esophageal SCCs, and T1 cancer limited to the mucosa only makes up 0.8 % of cases in France. By contrast, the rate of T1 esophageal SCC is five times higher in Japanese reports. The rates of T1 and T1 mucosal cancer reported by the National Cancer Center in Tokyo are 42 % and 18 %, respectively. These differences between Japan and Western countries may be explained by differences in histological interpretation, but it is likely that Japanese authors are more aware of the diagnosis of superficial cancer and pay more attention to it in general, and especially during endoscopy procedures. The failure of endoscopy to provide an early diagnosis of SCC in Western countries, despite a higher incidence of the condition than in Japan, shows that there is insufficient knowledge in the West of the macroscopic patterns of early carcinoma and that there is a tendency to carry out a cursory examination of the esophagus and to use chromoendoscopy to only a very limited extent.

Adequate examination of the esophagus involves slow and complete analysis of the mucosa in order to detect any raised areas and - more importantly - any abnormalities in color, as alterations in color can reflect differences in the vascular pattern between tumor tissue and normal tissue. The superficial lesions frequently have an erythroplastic appearance if they are flat, or whitish if they are slightly elevated. The examiner also needs to focus on peristalsis transmission along the esophagus; a fixed area may be explained by the presence of a flat but already invasive carcinoma.

Chromoendoscopy with vital staining is carried out between the initial precise examination and the taking of biopsies. In Europe, chromoendoscopy is not a widely used procedure, as it is regarded as being of little interest, difficult to perform, and above all, time-consuming and expensive. It must be emphasized that chromoscopy is mandatory in relation to esophageal squamous-cell carcinoma; in certain circumstances, not performing it must be regarded as an error.

The first expert approach section published in Endoscopy, in 2001, was concerned with Lugol staining [2]. The cases presented in the picture gallery here illustrate the high sensitivity and specificity of this method for diagnosing SCC. Toluidine blue is also capable of revealing occult dysplasia or unsuspected SCC in conventional esophagoscopy, but the technique required is more difficult and prolonged than Lugol staining, and it has a higher rate of false-negative results. Of all the chromoendoscopy methods available, Lugol staining at least should be recommended in Europe.

Which patients should undergo Lugol staining? There are several theoretical goals in chromoendoscopy:

To increase the number of dysplasias or SCCs diagnosed by detecting lesions that are not normally visible in at-risk mucosa - i. e., screening. To help determine the nature of a macroscopic lesion (whether or not it is malignant) - i. e., characterization. To delineate the lesion before endoscopic or surgical treatment, while looking for multiple SCCs - i. e., staging.

Screening [1] [3] [4]. In-situ or intramucosal SCCs are still mainly asymptomatic, and the diagnosis is based on screening in high-risk patients. Patients exposed to tobacco and those with alcohol abuse and nutritional deficiencies are more likely to develop multiple primary malignancies. Prospective studies have demonstrated that in heavy alcohol drinkers and smokers, systematic upper gastrointestinal endoscopy with chromoscopy allows SCC to be detected in only 3 - 4 % of cases - a rate that is too low to allow mass screening. The incidence of an associated esophageal SCC in patients with a primary carcinoma in the head and neck region ranges from 2 % to 13 %. The variability of the rates reported results from several factors, including whether or not the study is prospective, the accuracy of the follow-up, difficulties in distinguishing between metachronous tumors and metastases, and whether or not optimal diagnostic methods are used. A recent French study (in press), including more than 1000 patients, found a superficial esophageal cancer rate of 6 %.

It is usually recommended that panendoscopy (bronchoscopy, pharyngoesophagoscopy, and laryngoscopy) should be carried out in patients with ear, nose, and throat (ENT) carcinomas. However, esophageal endoscopy is rarely conducted in optimal conditions in such cases, using a video endoscope and systematic chromoscopy. The reasons for the lack of interest include inadequate collaboration with ENT surgeons, the severity of the initial ENT cancers, and the usually poor general condition in these patients, who frequently have other severe diseases or present with side effects of alcoholism. However, a careful examination of the esophagus using chromoscopy should be encouraged in patients with ENT carcinoma, particularly when surgery or chemoradiotherapy is being considered, or in patients who have been cured of ENT cancer. Other etiological factors are rare in Western countries: genetic factors (tylosis), achalasia, caustic lesions, sequelae of radiotherapy, and the small numbers of cases do not allow screening evaluation.

Characterization. When mucosal abnormalities are observed, Lugol staining has a high specificity for SCC. The initially yellow mucosal surface of the carcinoma becomes slightly pink, and this pink color within the dark brown normal surface is highly specific. Lugol staining does not, of course, preclude subsequent biopsies.

Staging. When SCC is found, several tumor-related criteria need to be taken into account before the decision is taken to carry out surgical treatment, endoscopic mucosal resection, endoscopic destruction, and/or chemoradiotherapy: location, lateral spread, and depth of invasion. Depth of invasion is of course the main factor to be assessed. As the images presented in this gallery show, the Japanese classification of superficial digestive carcinoma, based on macroscopic patterns in the lesion, can help predict the depth of invasion even before an endoscopic ultrasound (EUS) examination. The lateral spread also needs to be assessed accurately to allow a choice to be made between endoscopic mucosal resection with smaller lesions and endoscopic destruction (argon plasma coagulation, Nd:YAG laser therapy, or photodynamic therapy) or surgery with larger lesions. In relation to surgery in patients with T1 submucosal tumors, evaluation of the lateral spread is mandatory in order to detect the upper limit for resection. Even if the lesion is well-delineated macroscopically, one cannot rely on video endoscopy alone to determine the exact margins of the dysplastic or carcinomatous area. The lateral spread can be very large and completely flat, and chromoendoscopy is therefore necessary to assess it. In addition, SCC on the esophageal mucosa is frequently multifocal, and some sites only become visible after Lugol staining. Chromoendoscopy is also very useful for assessing the results of resection. After endoscopic mucosal resection, we would recommend spraying a small amount of Lugol solution to allow any residual unstained areas along the resection margins to be detected. We also spray the specimen itself after it has been fixed on the cork support, to check that there is an adequate safety margin around the lesion. Of course, histological analysis is the ultimate gold standard for confirming that the resection is complete both at the sides and at the base of the lesion.

Finally, repeated chromoendoscopy examinations need to be scheduled during the follow-up, so that recurrences or other lesions in the esophagus can be detected after surgical or endoscopic treatment.

References

• 1 Papazian A, Descombes P, Capron J P. et al . Incidence of esophageal cancer synchronous with upper aerodigestive tract cancers (100 cases): value of vital staining with Lugol and toluidine blue [in French].  Gastroenterol Clin Biol. 1985;  9 16-22
• 2 Inoue H, Rey J F, Lightdale C. Lugol chromoendoscopy for esophageal squamous-cell carcinoma.  Endoscopy. 2001;  33 75-79
• 3 Fagundes R B, de Barros S GS, Putten A CK. et al . Occult dysplasia is disclosed by Lugol chromoendoscopy in alcoholics at high risk for squamous-cell carcinoma of the esophagus.  Endoscopy. 1999;  31 281-285
• 4 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