Esophageal cancer

Japanese: 食道癌

Definition/Concept : Malignant epithelial tumors that occur in the esophagus. There are primary esophageal cancer and metastatic esophageal cancer.
Classification
1) Location:
The site of the primary tumor is defined as follows:
a) Cervical esophagus (Ce): From the entrance of the esophagus to the upper edge of the sternum.
b) Thoracic esophagus (Te):
i) Upper thoracic esophagus (Ut): From the upper edge of the sternum to the lower edge of the tracheal carina.
ii) Middle thoracic esophagus (Mt): The upper half of the esophagus, divided into two equal parts from the lower edge of the tracheal carina to the esophagogastric junction.
iii) Lower thoracic esophagus (Lt): The intrathoracic esophagus in the lower half of the esophageal cavity, which is divided into two equal parts from the lower edge of the tracheal carina to the esophagogastric junction.
c) Abdominal esophagus (Ae): From the upper edge of the esophageal hiatus to the esophagogastric junction.
2) X-ray, endoscopic and macroscopic classification:
The following is a quote from the 10th edition of the Guidelines for the Treatment of Esophageal Cancer (April 2007) (Table 8-3-4). Superficial type is when the depth of invasion is estimated to be up to the submucosal layer. Lesions estimated to have extended deeper than the muscularis propria are considered advanced type.
3) Depth of wall invasion classification, lymph node metastasis classification, and progression classification:
The following is a quote from the Guidelines for the Treatment of Esophageal Cancer, 10th Edition (April 2007) (Table 8-3-5). Esophageal cancer in which the primary focus is confined to the mucosa is called "early carcinoma of the esophagus", while cancer that is confined to the submucosa is called "superficial carcinoma". In either case, there is no need to worry about the presence or absence of lymph node metastasis. Lymph node group classification is divided into groups 1 to 4 according to the location of the primary focus and the extent of metastasis to the lymph nodes in the neck, chest, and abdomen. The stage is classified according to three factors: depth of wall invasion (T), extent of lymph node metastasis (N), and metastasis to other organs (M). The treatment plan, as described below, is determined according to the stage.
Causes and pathogenesis: Alcohol consumption and smoking are important risk factors for esophageal squamous cell carcinoma. Other risk factors include burnt meat or fish containing nitro compounds, wild vegetables (bracken), food additives (preservatives, colorants), diet (eating hot foods, poor nutritional status, vitamin deficiency), and radiation. Conversely, green and yellow vegetables and fruits are considered to be preventive factors. In adenocarcinoma, Barrett's epithelium, which is caused by persistent inflammation of the lower esophagus due to gastroesophageal reflux disease (GERD), is known to be the developmental site.
Epidemiology: According to estimates in 2007, the incidence rate (crude incidence rate) of esophageal cancer was 27.3 per 100,000 population in men and 4.6 per 100,000 population in women (based on statistics from the National Cancer Center's Cancer Control Information Center). The age-adjusted incidence rate has been increasing for men, but has not shown any increase or decrease in recent years for women. According to the Ministry of Health, Labor and Welfare's Vital Statistics Survey, the number of deaths from esophageal cancer in 2011 was 11,970, accounting for 3.4% of all deaths from malignant neoplasms.
The histological classification of esophageal cancer is shown in Table 8-3-6. Squamous cell carcinoma accounts for more than 90% of cases. Adenocarcinoma accounts for approximately 3%, and Barrett's esophageal cancer is rare in Japan.
Pathophysiology: Esophageal cancer occurs most frequently in the mid thoracic esophagus, followed by the lower thoracic esophagus. Characteristically, it often occurs multiple times and may have intraepithelial spread or intramural metastasis. Additionally, there are many cases of overlapping cancers such as head and neck cancer and gastric cancer. Even at the superficial cancer stage, lymph node metastasis occurs easily, and more than 40% of submucosal cancers result in lymph node metastasis. In advanced cancer, it invades surrounding important organs (trachea, aorta) and often causes distant metastasis to the liver, lungs, and bones, making treatment difficult.
Clinical manifestations
1) Symptoms:
Symptoms include difficulty swallowing, chest pain, and hoarseness. In the relatively early stages, patients may complain of a tingling sensation in the chest when swallowing or heartburn, but generally there are few subjective symptoms until the disease progresses. Hoarseness occurs when the cancer invades the recurrent laryngeal nerve.
2) Objective symptoms:
Weight loss, increased intake of liquid substances, and preference for soft, easily passed foods.
diagnosis
1) Diagnosis of cancer lesions:
a) Screening: X ^- ray imaging, endoscopy, FDG-PET ( ^18F fluorodeoxyglucose-positron emission tomography), tumor markers (SCC, CEA, CYFRA).
b) Local diagnosis of the esophagus: X-ray, endoscopy, biopsy, endoscopic ultrasound (EUS), CT, MRI, FDG-PET.
c) Diagnosis of metastatic lesions: ultrasound, EUS, CT, MRI, bone scintigraphy, FDG-PET, etc.
2) Diagnosis of overall condition:
a) Heart, lung, liver, kidney, and central nervous system function tests b) Metabolic diseases such as diabetes, etc. c) Diagnosis of multiple cancers in other organs:
i) Head and neck cancer, gastric cancer, colon cancer, others ii) Otorhinolaryngological examination, upper and lower endoscopy, others Upper gastrointestinal endoscopy is useful for detecting esophageal cancer, and a definitive diagnosis is made by histopathological diagnosis by biopsy. Chromoendoscopy and image-enhanced endoscopy using iodine staining are useful for detecting and identifying the extent of the lesion (Figures 8-3-16, 8-3-17). The stratified squamous epithelium of the normal esophagus contains glycogen, which reacts with iodine and stains brown. Cancer cells are poor in glycogen and are not stained, appearing white. Image-enhanced endoscopy includes digital methods such as FICE (flexible spectral imaging color enhancement) and optical digital methods such as NBI (narrow band imaging), which improve the visibility of lesions and enable detailed observation of surface fine structures and microvessels by changing the spectral characteristics and using computer processing. When used in combination with magnifying observation, it is possible to observe microvessels (intra-epithelial papillary capillary loops: IPCLs), and it is expected that the quality of endoscopic diagnosis will improve (Figure 8-3-17). For superficial cancers, endoscopy, magnifying endoscopy, and EUS are useful for diagnosing the depth of wall invasion, while X-ray imaging (Figure 8-3-18), CT, and MRI are useful for advanced cancers. EUS, CT, and FDG-PET are useful for diagnosing lymph node metastasis and distant metastasis.
Differential diagnosis
1) Gastroesophageal reflux disease:
There are cases where erosions and ulcers localized at the esophagogastric junction are difficult to differentiate from other types of cancer, and care must be taken because some cases are mistaken for cancer even in pathological diagnoses of tissue biopsies.
2) Benign tumors:
Large papillomas and granular cell tumors are morphologically similar to undifferentiated carcinoma and adenoid cystic carcinoma. Pathological diagnosis of tissue biopsy is useful for differential diagnosis.
3) Esophageal ulcer:
These include drug-induced ulcers and burn ulcers.
4) Esophageal stenosis:
Although it is often easy to distinguish between reflux esophagitis and esophageal achalasia based on clinical symptoms, there are some cases where this is difficult.
complications
1) Esophageal airway fistula:
Cancer invades the trachea and bronchi, forming fistulas. Patients may experience coughing and bloody sputum. Airway narrowing may also occur.
2) Pneumonia:
If digestive contents enter the airway through the fistula, it can cause pneumonia. In addition, esophageal stenosis or recurrent laryngeal nerve paralysis can lead to aspiration, resulting in aspiration pneumonia.
3) Bleeding:
Cancer invasion can cause bleeding from the bronchial arteries, brachiocephalic artery, and proper esophageal artery. Bleeding from the aorta can cause sudden death due to massive bleeding.
4) Mediastinitis/abscess:
When esophageal cancer penetrates the mediastinum, it can cause mediastinitis and form an abscess.
Course and prognosis: According to a survey of the Japan Esophageal Society's nationwide esophageal cancer registry, the five-year survival rate for cases in 2003 was 46.6% for surgical resection, 80% for endoscopic treatment, and 21.9% for definitive chemoradiotherapy. These results cannot be compared directly because the disease stages targeted by each treatment are different.
TreatmentThe treatment method for esophageal cancer is selected according to the stage of progression (Figure 8-3-19). The main treatments are endoscopic treatment, surgery, radiation therapy, chemotherapy, and chemoradiotherapy.
1) Endoscopic treatment:
There are two types of endoscopic resection: endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). In recent years, ESD, which allows en bloc resection of large lesions, has rapidly become more common.
2) Surgical treatment:
Surgical treatment varies depending on the location of the tumor, whether or not there has been metastasis, and the patient's overall condition. Surgical treatment is highly invasive and has a high incidence of complications.
a) Surgery for cervical esophageal cancer: Depending on the extent of the lesion, cervical esophageal cancer may require a combined pharynx and larynx resection, in which case a permanent tracheostomy will be created. Lymph node metastasis is relatively limited to the neck, and in many cases radical surgery is appropriate.
b) Surgery for thoracic esophageal cancer: Thoracic esophageal cancer easily causes lymph node metastasis in three regions: the neck, chest, and abdomen. Therefore, a right thoracotomy is performed to remove the primary tumor and dissect the mediastinal lymph nodes. In some cases, lymph node dissection in three regions, including the neck and abdomen, is also required. The stomach is the first choice of reconstructed organ, followed by the colon and jejunum. Reconstruction routes include the anterior chest wall route, the retrosternal route, and the posterior mediastinal route, but recently the posterior mediastinal route has become more commonly used.
c) Surgery for abdominal esophageal cancer: In esophageal cancer limited to the abdominal esophagus and cardia, there is little significance in dissecting the cervical and upper mediastinal lymph nodes, so a lower esophageal and cardia-proximal gastrectomy or a total lower esophageal and gastrectomy is performed via a left thoracotomy/laparotomy or a succession of left thoracic and abdominal incisions. d) Other surgical treatments: i) Non-thoracic esophagectomy: A method in which the esophagus is removed and resected without opening the thorax via the esophageal hiatus during laparotomy, but dissection of the mediastinal lymph nodes is insufficient.
ii) Esophageal resection and reconstruction using a laparoscope: Currently, research is being conducted on the minimally invasive, curative, and long-term treatment outcomes of this technique. Thoracoscope- and laparoscopic esophageal resection and reconstruction, as well as endoscopically assisted transesophageal hiatal non-thoracic esophagectomy using a mediastinoscope and laparoscope, are being performed.
3) Radiation therapy:
Chemotherapy is often used in combination. Radiation alone is administered by external beam radiation therapy at 2 Gy/day, 5 fractions/week, for a total of 60 Gy or more.
4) Chemotherapy:
For cases of distant metastasis, chemotherapy is used alone or as adjuvant therapy before or after surgery. Multidrug chemotherapy is the mainstream, and the combination of cisplatin and 5-FU is the standard.
5) Chemoradiotherapy:
This is the standard treatment for non-surgical treatment. It is generally performed in combination with cisplatin and 5-FU with a radiation dose of 50 to 60 Gy. [Tatsuya Miyazaki and Hiroyuki Kuwano]
■References <br /> Edited by the Japan Esophageal Society: Clinical and Pathological Guidelines for the Treatment of Esophageal Cancer, 10th Edition, Kanehara Publishing, Tokyo, 2007. Edited by the Japan Esophageal Society: Esophageal Cancer Diagnosis and Treatment Guidelines, April 2012 Edition, Kanehara Publishing, Tokyo, 2012. Takubo Kaiyo: Pathology of the Esophagus, 2nd Edition, Sogo Igakusha, Tokyo, 1996.

Table 8-3-4
X-ray, endoscopic and macroscopic classification of esophageal cancer (cited from the 10th edition of the Guidelines for the Treatment of Esophageal Cancer (April 2007))

Table 8-3-4

Table 8-3-5
Wall invasion depth classification (quoted from the esophageal cancer handling regulations 10th edition (April 2007))

Table 8-3-5

Table 8-3-6
Histological classification of esophageal cancer ">

Table 8-3-6

Fig. 8-3-19
Esophageal cancer treatment algorithm

Fig. 8-3-19

Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information

Japanese:

定義・概念
　食道に発生する上皮性の悪性腫瘍である．原発性食道癌と転移性食道癌がある．
分類
1）占居部位：
原発巣の占居部位は下記のように定義されている．
　a）頸部食道（cervical esophagus：Ce）：食道入口部より胸骨上縁まで．
　b）胸部食道（thoracic esophagus：Te）：
　ⅰ）胸部上部食道（upper thoracic esophagus：Ut）：胸骨上縁より気管分岐部下縁まで．
　ⅱ）胸部中部食道（middle thoracic esophagus：Mt）：気管分岐部下縁より食道胃接合部までを2等分した上半分．
　ⅲ）胸部下部食道（lower thoracic esophagus：Lt）：気管分岐部下縁より食道胃接合部までを2等分した下半分の中の胸腔内食道．
　c）腹部食道（abdominal esophagus：Ae）：食道裂孔上縁から食道胃接合部まで．
2） X線・内視鏡・肉眼型分類：
食道癌取扱い規約第10版（2007年4月）から引用して示す（表8-3-4）．表在型は深達度が粘膜下層までと推定されているものである．固有筋層以深に及んでいると推定される病変を進行型とする．
3）壁深達度分類・リンパ節転移分類・進行度分類：
食道癌取扱い規約第10版（2007年4月）から引用する（表8-3-5）．癌腫の原発巣が粘膜内にとどまる食道癌を｢早期食道癌（early carcinoma of the esophagus）｣，粘膜下層までにとどまるものを「表在癌（superficial carcinoma）」とよぶ．いずれもリンパ節転移の有無を問わない．　リンパ節群分類は原発巣の占居部位によって頸部・胸部・腹部のリンパ節の転移範囲で1群から4群に分けられる．進行度（ステージ）は壁深達度（T），リンパ節転移の範囲（N）および他臓器への転移（M）の3つの因子にて分類されている．進行度によって下記に述べる治療方針が決定される．
原因・病因
　食道扁平上皮癌では飲酒および喫煙が危険因子として重要である．ニトロ化合物を含む肉や魚のコゲ，山菜（ワラビ），食品添加物（防腐剤，色素剤），食生活（熱い食物摂取，栄養状態低下，ビタミン欠乏），放射線などが危険因子とされる．逆に緑黄色野菜や果物は予防因子とされる．腺癌では胃食道逆流症（gastroesophageal reflux disease：GERD）による下部食道の持続的な炎症に起因するBarrett上皮がその発生母地として知られている．
疫学
　食道癌の罹患率（粗罹患率）は2007年の推計によると男性が27.3人（人口10万人対），女性が4.6人（人口10万人対）であった（国立がん研究センターがん対策情報センターの集計による）．年齢調整罹患率は男性は増加傾向にあり，女性は近年は増減の傾向はない．厚生労働省の人口動態調査によると2011年の食道癌死亡者数は11970人であり，全悪性新生物の死亡者数の3.4％に相当する．
病理
　食道癌の組織型分類は表8-3-6のとおりである．頻度として扁平上皮癌が90％以上を占める．腺癌は3％程度であり，わが国ではBarrett食道癌は少ない．
病態生理
　食道癌は胸部中部食道に好発し，ついで胸部下部食道に多い．特徴として多発することが多く上皮内進展や壁内転移を有することがある．また，頭頸部癌や胃癌などとの重複癌が多い．表在癌の段階で容易にリンパ節転移をきたし粘膜下層癌では40％以上にリンパ節転移をきたす．進行癌では周囲の重要臓器（気管，大動脈）に浸潤し，肝・肺・骨に遠隔転移をきたし治療困難となることが少なくない．
臨床症状
1）自覚症状：
嚥下困難，胸部痛，嗄声などがある．比較的初期の段階では嚥下時に起こる胸がしみる感じや胸やけ感などの症状を訴えることがあるが，一般的には進行するまでは自覚症状に乏しい．反回神経に浸潤すると嗄声となる．
2）他覚症状：
体重減少，水様物を多く摂取し，やわらかい，通りやすい食事を好む．
診断
1）癌病巣に関する診断：
　a）スクリーニング：X線造影，内視鏡，FDG-PET（¹⁸F fluorodeoxyglucose-positron emission tomography），腫瘍マーカー（SCC，CEA，CYFRA）．
　b）食道局所の診断：X線造影，内視鏡，生検，超音波内視鏡（EUS），CT，MRI，FDG-PET．
　c）転移病巣の診断：超音波，EUS，CT，MRI，骨シンチグラフィ，FDG-PET，その他．
2）全身状態の診断：
　a）心，肺，肝，腎，中枢神経機能検査
　b）糖尿病などの代謝性疾患，その他
　c）他臓器重複癌の診断：
ⅰ）頭頸部癌，胃癌，大腸癌，その他
ⅱ）耳鼻科的診察，上部・下部内視鏡検査，その他　食道癌の発見は上部消化管内視鏡検査が有用でありその確定診断は生検による病理組織診断でなされる．発見，病変範囲の同定にヨード染色を用いた色素内視鏡や画像強調内視鏡が有用である（図8-3-16，8-3-17）．正常食道の重層扁平上皮にはグリコーゲンが含まれていて，ヨードと反応して褐色に染色される．癌細胞はグリコーゲンが乏しいため染色されずに白色を呈する．画像強調内視鏡は画像強調内視鏡にはデジタル法のFICE（flexible spectral imaging color enhancement）や光デジタル法のNBI（narrow band imaging）などがあり，分光特性を変化させたりコンピューター処理をすることで病変の視認性向上や詳細な表面微細構造，微小血管観察が可能になった．拡大観察と併用することで微細血管（上皮内乳頭内ループ状血管，　intra-epithelial papillary capillary loop：IPCL）を観察することができ，内視鏡診断の質的向上が期待されている（図8-3-17）．壁深達度診断として表在癌は内視鏡，拡大内視鏡，EUSが有用であり，進行癌はX線造影（図8-3-18），CT，MRIが有用である．リンパ節転移診断・遠隔転移診断としてEUS，CT，FDG-PETが有用である．
鑑別診断
1）逆流性食道炎：
食道胃接合部に限局するびらんや潰瘍で鑑別困難な症例があり，組織生検の病理診断でも癌と誤るものがあるため注意が必要である．
2）良性腫瘍：
大きな乳頭腫や顆粒細胞腫は，形態的に未分化癌や腺様囊胞癌と類似している．組織生検の病理診断が鑑別に有用である．
3）食道潰瘍：
薬剤性潰瘍や熱傷性潰瘍などがある．
4）食道狭窄：
逆流性食道炎の狭窄や食道アカラシアとの鑑別は臨床症状から容易なことが多いが，一部に難しいものがある．
合併症
1）食道気道瘻：
癌が気管・気管支に浸潤し，瘻孔を形成する．咳や血痰が出現する．気道の狭窄をきたすこともある．
2）肺炎：
上記の瘻孔から消化管内容物が気道に流入すると肺炎を生じる．また，食道の狭窄や反回神経麻痺により誤嚥し嚥下性肺炎をきたす．
3）出血：
癌の浸潤により気管支動脈，腕頭動脈，食道固有動脈から出血をきたす．大動脈からの出血の場合大量出血により頓死することがある．
4）縦隔炎・膿瘍：
食道癌が縦隔に穿通すると縦隔炎を併発し，膿瘍を形成する．
経過・予後
　日本食道学会の全国食道がん登録の調査によると2003年の症例を対象として手術切除症例の5年生存率は46.6％，内視鏡治療の5年生存率は80％，根治的化学放射線治療の5年生存率は21.9％であった．これらの成績は各治療の対象となる病期が異なるため直接比較はできない．
治療
　食道癌の治療法はその進行度により選択される（図8-3-19）．おもに内視鏡治療，外科手術，放射線療法，化学療法，化学放射線療法が行われる．
1）内視鏡的治療：
内視鏡的切除術には内視鏡的粘膜切除術（endoscopic mucosal resection：EMR）と内視鏡的粘膜下層剥離術（endoscopic submucosal dissection：ESD）の方法がある．近年，大きな病変の一括切除が可能なESDが急速に広まっている．
2）外科治療：
占居部位や転移の有無，患者の全身状態により外科治療の内容も多様である．侵襲が高く合併症発生率が高い．
　a）頸部食道癌に対する手術：頸部食道癌はその病変範囲によっては咽頭喉頭を合併切除する必要があり，その際には永久気管孔を造設する．リンパ節転移が比較的頸部に限局しており，根治手術の適応になる症例が多い．
　b）胸部食道癌に対する手術：胸部食道癌は頸部・胸部・腹部の3領域にリンパ節転移を容易にきたすため，右開胸で原発巣の切除と縦隔リンパ節の郭清を行うとともに，頸部と腹部を含めた3領域のリンパ節郭清が必要なこともある．再建臓器は胃が第一選択で用いられ，ついで，結腸，空腸が用いられる．再建経路は胸壁前経路，胸骨後経路，後縦隔経路があるが，最近は後縦隔経路がよく用いられる．
　c）腹部食道癌に対する手術：腹部食道から噴門に限局する食道癌では，頸部，上縦隔リンパ節の郭清意義が少ないため左開胸・開腹法や左胸腹連続切開法で下部食道噴門側胃切除や下部食道胃全摘術が行われる．　d）その他の外科治療： ⅰ）非開胸食道切除術：開腹下に食道裂孔を介して開胸せず食道を抜去切除する方法で縦隔のリンパ節郭清が不十分である．
　ⅱ）体腔鏡を用いた食道切除・再建術：低侵襲性，根治性，遠隔治療成績などに関して現時点では研究段階である．胸腔鏡，腹腔鏡下食道切除再建術や，縦隔鏡，腹腔鏡を用いた内視鏡補助下経食道裂孔的非開胸食道抜去術などが行われている．
3）放射線療法：
化学療法を併用することが多い．放射線単独では体外照射法で2 Gy/日，5回/週，合計60 Gy以上を照射する．
4）化学療法：
遠隔転移症例に対しては単独で，手術前後に補助療法として化学療法が行われる．多剤併用化学療法が主流でありシスプラチンと5-FUの組み合わせが標準的である．
5）化学放射線療法：
非外科的治療を行う場合の標準的な治療として施行される．シスプラチン・5-FUに放射線照射量は50〜60 Gyを併用する方法が一般的である．［宮崎達也・桑野博行］
■文献
日本食道学会編：臨床・病理．食道癌取扱い規約第10版，金原出版，東京，2007．日本食道学会編：食道癌診断・治療ガイドライン2012年4月版，金原出版，東京，2012.田久保海誉：食道の病理，第2版，総合医学社，東京，1996．

表8-3-4
食道癌のX 線・内視鏡・肉眼型分類（食道癌取扱い規約第10 版（2007 年4 月）から引用）">

表8-3-4

表8-3-5
壁深達度分類（食道癌取扱い規約第10 版（2007 年4 月）から引用）">

表8-3-5

表8-3-6
食道癌の組織型分類">

表8-3-6

図8-3-19
食道癌治療のアルゴリズム">

図8-3-19

出典　内科学第10版内科学第10版について　情報

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