Ⅵ Gastrointestinal Diseases

Esophageal Disorders

JMAJ 47(10): 451–457, 2004

Teruo KOUZU

Professor, Department of Endoscopic Diagnostic and Therapeutics, Chiba University School of Medicine

Abstract: Recent trends of esophageal disorders in Japan are described. Diag- nosis of at early stages has come to be practiced extensively by means of endoscopic mucosal resection, which contributed greatly to improve the benefit of patients. As severity classification of gastroesophageal reflux disease has now been established, main study subjects of the disease are shifting to diagnosis of Barrett’s , and diagnosis and treatment of resulting early carcinoma. In addition, is increasingly treated first by means of balloon dilatation, followed by laparoscopic surgery in case of no improvement by balloon dilatation. Progress in the endoscopic ultrasonography has now devel- oped to the EUS-guided fine-needle aspiration (EUS-FNA), contributing to diag- nosis and treatment.

Key words: Early esophageal carcinoma; EMR; GERD; Barrett’s esophagus; Achalasia

This paper will report recent trends in the treatment such as endoscopic mucosal resec- diagnosis, treatment, and care of disorders of tion (EMR) to surgical dissection in three the esophagus. The esophagus of approximately regions, namely thoracic, abdominal, and cer- 27 cm in length is susceptible to various disor- vical regions. Of particular note is that patients ders. First, esophageal cancer will be discussed. with mucosal cancer, a superficial carcinoma of the esophagus, who are in the early stages of Esophageal Cancer cancer with no lymph node metastasis, are encountered at most medical institutions every There is no other disease in which the resec- year. This fact has recently been verified by the tion treatment has broader variations in inva- five-yearly report of the Japanese Society for siveness than the esophageal cancer. Briefly, Esophageal Diseases. the extent of resection varies from endoscopic In the past ten years, for instance, the inci-

This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol. 129, No. 4, 2003, pages 452–456). The Japanese text is a transcript of a lecture originally aired on November 4, 2002, by the Nihon Shortwave Broadcasting Co., Ltd., in its regular program “Special Course in Medicine”.

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dence of mucosal cancer has increased rapidly 2. Treatment from 21 to 43.8% while that of submucosal can- Based on the pre-operative diagnosis of the cer has decreased from 79 to 56.2%. This shift invasion depth of the cancer, EMR is selected is largely due to the widespread use of upper for the treatment of mucosal cancer. Esophag- gastrointestinal endoscopy with dye-spraying. ectomy and surgical dissection in the cervical, The detection rate for esophageal cancer by thoracic, and abdominal regions are the stan- mass X-ray examination is 0.008%, or 1/13 the dard treatment for patients diagnosed with detection rate for gastric carcinoma. In con- cancer deeper than sm1. In regard to esoph- trast, the detection rate for esophageal cancer agectomy, there is a consensus that the more in the initial mass screening by endoscopy is recent approach of thoracoscopic and laparo- 0.1%. In mass screenings by endoscopy with scopic surgery is as radical as conventional iodine dye in high-risk groups such as alco- open chest surgery. In patients with very ad- holics, the detection rate is 3.6%. In addition, vanced cancer, radiotherapy and chemotherapy approximately 10% of patients with cancer in may be attempted in order to arrest the prog- the head and neck regions also have esoph- ress of the disease. However, the therapeutic ageal cancer. Based on morbidity rates, this effect of these treatments is controversial. means that for every ten cases of gastric car- cinoma detected by endoscopy, one case of 3. Course and prognosis esophageal cancer will be missed unless further According to Japanese national data for testing is performed. 2002, the overall ten-year survival rate for At the 56th meeting of the Japanese Society patients who underwent esophagectomy for for Esophageal Diseases in June 2002, a gen- esophageal cancer was 25.5%. Of course, the eral guideline on the treatment of esophageal prognosis varies depending on the staging, as cancer was presented. It should be noted that determined by invasion depth, extent of lymph a clear guideline does not currently exist in node metastasis, and organ metastasis. In terms Western countries. This guideline will be dis- of invasion depth, the most recent ten-year cussed in the following sections, beginning with survival rates for pTis (m1), pT1 (sm), pT2 the diagnosis of esophageal cancer. (mp), pT3 (a1-2), and pT4 (a3) were 54.4, 36.7, 26.9, 20.2, and 9.0, respectively. A study of 1. Diagnosis lymph node metastasis emphasized that the With the widespread use of EMR today, number of metastases is closely reflected in the there is a demand for an accurate diagnosis of prognosis. Briefly, the most recent eight-year the invasion depth of cancer in the esophageal survival rates for patients with no metastases, mucosa and submucosa. A detailed dynamic one to three metastases, four to seven meta- diagnosis using dye-spraying endoscopy is use- stases, and eight or more metastases was 57.5, ful for distinguishing between m1 and 2 cancers 36.6, 19.3, and 8.8%, respectively. Thus, accu- and between m3 and sm1 cancers. For the diag- rate staging prior to surgery is being increas- nosis of sm2 and 3 cancers, neoplasms can be ingly demanded. objectively visualized by high frequency ultra- sound probe sonography. CT and MRI are Reflux suited to diagnose adventitial invasion. The lymph nodes can be effectively visualized by Reflux esophagitis, a concept which is linked endoscopic ultrasonography (EUS), CT, or to gastroesophageal reflux disease (GERD), MRI, with metastasis being correctly diagnosed refers to damage of the esophageal mucosa due in 80% or more of cases. to reflux of an acidic or alkaline substance. The severity of the damage is classified according to

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Table 1 Los Angeles Classification of Reflux Esophagitis (revised by Hoshibara et al.)

Grade N No endoscopic change.

stomach Grade M Color-change type (minimal change)

stomach Grade A Mucosal break: Mucosal break5mm in length and an area of white scar confined to mucosal folds. or erythema clearly stomach demarcated from Grade B adjacent normal- At least 1 mucosal breakͧ5mm in length; appearing mucosa mucosal breaks which are not connected to stomach mucosal breaks in adjacent mucosal folds. Grade C At least 1 mucosal break which extends across 2 or more adjacent mucosal folds, stomach but is not circumferential. Grade D Circumferential mucosal break.

stomach Note: Presence of , esophageal ulceration, and Barrett’s esophagus.

the extent and depth of lesions. unexpectedly have deep ulceration in the From an epidemiological perspective, the middle region of the esophagus. Ulceration incidence of patients endoscopically diagnosed associated with Barrett’s esophagus, a disorder with reflux esophagitis has increased from 5 to acquired as a result of long-standing reflux 17% in the past 30 years. While there may be esophagitis, is treated in the same way as for problems with the selection of the data set and gastric ulcers. Although ulcers even at a depth regional differences, the number of patients of U1 IV respond rapidly to proton pump with reflux esophagitis is definitely increasing. inhibitors (PPI), they typically recur on dis- Men aged in their 30s to 50s are most com- continuation of treatment. monly afflicted whereas there is a marked increase in the incidence among women aged 1. Classification of reflux esophagitis 60 or more. The main classifications of reflux esophagitis Endoscopic findings of reflux esophagitis are in current use are a severity classification and a characterized by inflammation which becomes stage classification which aim to evaluate thera- increasingly mild with increasing distance from peutic effect. According to the classification of the gastroesophageal junction. Briefly, it is usual the Japanese Society for Esophageal Diseases, for patients with severe reflux esophagitis to the disease was traditionally classified as “color- have deep ulceration and stricture at the gas- change type”, “erosion/ulceration type”, and troesophageal junction and erosion and ery- “protruding thick type”. However, since most thema toward the mouth side. The exception is patients fall in the category of the “erosion/ stooped and/or bed-ridden patients who may ulceration type”, the system was not practical

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Table 2 The 1996 Classification of Reflux Esophagitis of the Japanese Society for Esophageal Diseases (Tokyo classification)

Grade 0 No evidence of esophagitis. Grade 1 Grade 1 Grade 3 Grade 3 ͧ  Red or white turbidity observed. cm Erosion/ulcers 5cm and 10cm cm 10 from gastroesophageal junction; 10 5 evident but not 5 circumferential. 0 0

Grade 2 Grade 2 Grade 4 Grade 4 Erosion ulcers5cm from Erosion ulcersͧ10cm from cm / cm / 10 gastroesophageal junction; 10 gastroesophageal junction; no adhesion. 5 adhesion evident and 5 circumferential. 0 0

Notes: 1. Barrett’s esophagus: Description of the length of columnar epithelium of esophagus. 2. Stricture: Description of the approximate diameter.

Note: ᕃFilamentous unstained band which is first seen with iodine stain is also included in Grade 1. ᕄEsophagogastric junction refers to the mucosal junction (squamo-columnar junction). ᕅ2 parallel, continuous lesions are called “adhesion”. The majority of lesions without adhesions are filamentous or point-like erosions.

(Source: Kouzu, T.: Dictionary of Gastrointestinal Terminology, Igaku Shoin, 2002; p. 206. (in Japanese))

in the actual classification of patients. Sub- it is important to distinguish whether the sequently, the Los Angeles (LA) classification mucosa at the lower end of the stricture is system which uses the concept of “mucosal columnar or squamous epithelium. In the for- break” (an area of white scar or erythema mer case, some erythema and erosion, etc. are clearly demarcated from adjacent normal- observed at the upper end in most patients, appearing mucosa) was reported in Western making a diagnosis of reflux esophagitis pos- countries. Although the LA system was used sible. In the latter case, the presence of local- widely throughout Japan, it was difficult to ized or circumferential esophageal cancer or distinguish between gradings A and B in the unexplained chronic benign stricture must be system and a modified version (Table 1) was considered in a differential diagnosis. Today, developed in Japan which took into account understanding the pathological state of an the therapeutic effect. At about the same time, esophageal stricture at the lower end is facili- the Japanese Society for Esophageal Diseases tated by balloon dilatation of stenotic regions proposed a new classification, called the Tokyo as small as a pinhole, providing a guidewire can Classification (Table 2), based on the extent be inserted endoscopically. and length of lesions. Both the modified LA and Tokyo Classification systems are currently 3. Treatment used. A third classification system shows the The drug of first choice for esophageal ulcers therapeutic effect in a single lesion and uses a and esophagitis, disorders caused by GERD, is similar stage classification as in the healing PPIs. As maintenance therapy, PPIs should be process of gastric ulcers (Table 3). administered at a half-dose. In patients who still complain of nocturnal reflux symptoms 2. Differential diagnosis despite PPI treatment and in whom nocturnal In patients with severe esophageal stricture, acid breakthrough (NAB) is evident based on

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Table 3 Stage Classification of Esophagitis

Stage Endoscopic findings Stain findings Thick white scar Stains to ulcer margin with iodine. A1 Peripheral edema Periphery may stain randomly. Raised margin Erosion surface stains reddish violet with toluidine blue. Active White scar Stains to ulcer margin with iodine Edema disappeared A Fluff-like densely stained appearance (small amount). 2 Regenerated epithelium Erosion surface stains reddish violet with toluidine blue. (small amount) White scar reduced White scarstains blue with toluidine blue. Regenerated epithelium H Regenerated epithelium does not stain. 1 (increased) Margin has fluff-like densely stained appearance. Gentle margin Healing White scar further reduced Margin has increased fluff-like densely stained H2 Ulceration virtually covered appearance. by regenerated epithelium

Regression of ulceration Slightly puckeredwith fluff-like densely stained S1 Slightly raised and puckered with erythema appearance. Scarred Disappearence of densely stained. Slightly puckered but S Almost uniformly stained. 2 no color change Partly non-uniformly stained.

(Source: Makuuchi, H. et al.: Endoscopic findings. Reflux Esophagitis, Bunkodo, 1988; pp. 129Ð135. (in Japanese))

24-hour esophageal pH monitoring, adminis- thelium is classified as short-segment Barrett’s tration of a H2-blocker before bed is effective epithelium (SSBE) or long-segment Barrett’s in some cases. epithelium (LSBE) based on the boundary of Esophageal stricture and Barrett’s esopha- the esophageal columnar epithelium of 3 cm. gus are acquired as a result of long-standing At present, difference, if any, in the incidence reflux esophagitis. Most patients who present of canceration between the two types, what with esophageal stricture are elderly and aggres- mucosal changes are useful in the diagnosis of sive surgery is not an option favored by either early cancer and how tumor suppressor genes, the physician or patient. With early diagnosis of cancer genes, and growth factors are involved the disease, drug therapy and endoscopic dila- in the metaplasia-dysplasia-carcinoma-sequence, tation of the stenosis are currently a satisfac- are unknown. Understanding the clinical course tory treatment. from inflammation to carcinogenesis will be the There is a consensus that Barrett’s esopha- direction of future research. gus is the end stage of reflux esophagitis. It is While the number of cases is limited, EMR defined by the Japanese Society for Esophageal has started to be used in the treatment of early Diseases as “the presence of columnar epi- cancer. Prior to a definite diagnosis of malig- thelium continuing from the stomach to the nancy, photodynamic therapy (PDT) of pre- esophagus”. In light of the rapid increase in cancerous foci and deciduation of Barrett’s esophageal adenocarcinoma arising from Bar- epithelium by argon plasma coagulation (APC) rett’s esophagus and the increasing tendency in are performed, and PPI therapy aimed at reflux esophagitis in Japan, there is an urgent decreasing squamous epithelium is also being need to clarify the various canceration pro- investigated. cesses of Barrett’s epithelium. Barrett’s epi- In the case of mucosal cancer patients with

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squamous epithelium carcinomas, a two- to Submucosal Cancer three-year study of follow-up patients would be quite feasible. However, in the case of carci- Advances in EUS have simplified the biopsy nomas in Barrett’s esophagus, there is little and identification of the primary lesion in sub- opportunity to conduct follow-up observations mucosal cancers of the esophagus. Differenti- and future studies on the morphological ating between benign and malignant myogenic changes which occur in the disease over time tumors based on ultrasound images alone, are warranted. however, is still difficult. The recent develop- ment of EUS-guided aspiration biopsy has Esophageal Achalasia enabled a tissue sample to be safely collected from within a tumor based on an ultrasound Esophageal achalasia is frequently accom- image with color Doppler function obtained panied by esophageal cancer, with the inci- via the insertion point of the aspiration needle. dence of both diseases occurring simultane- Endoscopic extirpation of tumors following ously being about 3.5 to 4.5%. A treatment biopsy can also be safely performed. which minimizes the period of and remedies it early in the course of the disease is Other Esophageal Disorders demanded. Previously, various types of abdom- inal and open-chest surgery have been reported In the past ten years, the most common for- and there are many reports of techniques eign object in the esophagus was a two-sided which aim to prevent post-operative reflux bridge prosthesis. Recently, tablets in press- esophagitis. through packaging continue to be common Given the young age of patients recently, foreign objects. The incidence of fish bones and treatment tends to be drug therapy to reduce pieces of meat also tends to be high. The instru- the lower esophageal sphincter (LES) pressure ments used to remove a foreign object depend and therapy using latest high-precision bal- on the type of the object and the instrument loons. If there is no improvement, laparoscopic needed is usually determined after an endo- surgery is performed. There is a tendency for scopic examination. an increasing number of patients to recover The key to removal of a foreign object is to after one or two dilatation treatments. It is not make every effort to prevent damage to the known whether this increase in the recovery mucosal surface of lesions also and damage to rate is due to the greater precision of dilatation the cardia and cervix in the esophagus. To this balloons in recent years. Surgery is reserved for end, the following instruments must be at hand: patients who fail to respond to repeated dilata- ᕃlarge EMR grasping forceps, ᕄa polypec- tions. These patients tend to be very nervous tomy snare, ᕅa mesh-covered polypectomy because of their poor response to previous snare, ᕆan endoscopic variceal ligation (EVL) treatment. Given this background, the dura- overtube, ᕇan EMR overtube for esophageal tion of the illness and morphological findings mucosal resection, and ᕈa tip-mount trans- on X-ray both play a role. parent hood. Most foreign objects can now be A recent trend in the treatment of achalasia removed without complications. is direct injection of botulinum toxin into the LES muscle by EUS. While this procedure and Perforation offers promise of reducing LES pressure by blocking cholinergic receptors, it has not yet The causes of esophageal perforation are been approved in Japan. classified as follows: ᕃinadvertent ingestion of foreign object, ᕄiatrogenic, ᕅtrauma, and

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ᕆ idiopathic esophageal rupture, etc. With the REFERENCES widespread use of endoscopic treatments, there is a tendency for iatrogenic causes to increase 1) The Japanese Society for Esophageal Dis- and an awareness of the perforation during eases: Guideline (draft) on the Treatment of Esophageal Cancer, 2001. (in Japanese) treatment is critical. 2) The Japanese Society for Esophageal Disease The treatment of esophageal perforation de- (eds): Comprehensive Registry of Esophageal pends on whether or not the mediastinal pleura Cancer in Japan (1995, 1996, 1997), 3rd Edi- is ruptured. Depending on the extent of the tion. 2002. perforation and the amount of time that has 3) Kouzu, T. et al.: Gastroesophageal reflux dis- elapsed, mediastinal emphysema progresses ease: Endoscopic diagnosis. Clinic All-Round to subcutaneous emphysema of the cervical 2001; 50: 2046–2050. (in Japanese) region, periesophagitis, mediastinitis, medias- 4) Kouzu, T., Miyazaki, N., Yoshimura, S. et al.: tinal abscess, pneumothorax, retention of pleu- Barrett’s esophagus and reflux esophagitis. Endoscopia Digestiva 1997; 9: 911–917. (in ral fluid, and empyema. Therefore, it should be Japanese) borne in mind that early diagnosis of this 5) Kouzu, T.: Barrett’s esophagus: recent find- condition is critical. ings. Surgical Diagnosis and Treatment 1996; This paper has focused on recent trends in 38: 197–201. (in Japanese) esophageal disorders. 6) Aogi, T.: Report of the investigative commit- tee on the definition of Barrett’s esophagus (epithelium). Activity Report of The Japanese Society for Esophageal Diseases Committee 1998; pp.15–20. (in Japanese)

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