Japanese Classification of Esophageal Cancer, 11th Edition: part II and III

2:1:2. Tumor location ......................................................................................................................................................... 39 2:1:3. Macroscopic tumor type .......................................................................................................................................... 42 2:1:4. Depth of tumor invasion (T).................................................................................................................................... 44 2.2. Metastatic lesions from esophageal cancer ............................................................................................................... 44 2:2:1. Lymph node metastasis............................................................................................................................................ 44 2:2:1:1. Naming and numbers of lymph node stations...........................................................................................44 2:2:1:2. Lymph node groups .....................................................................................................................................49 2.4. Multiple primary cancers ........................................................................................................................................... 49 3:4:3. Lymph node dissection ............................................................................................................................................ 49 3:4:3:1. Types of lymph node dissection .................................................................................................................49 3.7. Curativity (Cur) .......................................................................................................................................................... 49 4:2:1. Histological classification ........................................................................................................................................ 49 4:2:1:1. Benign epithelial neoplasms........................................................................................................................49 4:2:1:2. Intraepithelial neoplasias .............................................................................................................................50 4:2:1:3. Malignant epithelial neoplasms...................................................................................................................51 4:2:1:4. Non-epithelial tumors ..................................................................................................................................56 4:2:1:5. Lymphoid tumors.........................................................................................................................................57 4:2:1:6. Other malignant tumors ...............................................................................................................................57 4:2:2. Depth of tumor invasion (pT).................................................................................................................................. 57 4:2:9. Pathological criteria for the effects of radiation and/or chemotherapy ................................................................. 57


Principles of description and methods of abbreviation
General findings are often described as findings. In such cases, the ''f'' representing general findings may be omitted, and a description such as ''MtLt, 10 cm, Type 2, T2, N0, M0, Stage II'' is acceptable. When clinical findings need to be distinguished from pathological findings, descriptions such as ''Although surgery was performed based on a preoperative finding of cT2,cN0, the pathological finding was pT3,pN1'' are acceptable.
2.1 Description of primary tumor 2.1.1. The number and size of the lesions needs to be described; if multiple peripheral tumors are present, the location, size, tumor type, and depth of invasion should be described for each lesion. In cases with multiple lesions, the major lesion is the deepest lesion (or the lesion with the largest dimension if the depth of tumor invasion is equal). In cases where evaluation using X-ray or endoscopy is only possible in one direction, the largest dimension measured should be described as the clinical finding.

Tumor location
[Diagnostic criteria for cancer located at the esophagogastric junction] The esophagogastric junction (EGJ) should be defined systematically in accordance with the criteria listed below. It is important that a diagnosis be made before the initiation of treatment. Endoscopic findings should be prioritized over findings obtained using other diagnostic modalities. Cancer at the EGJ means that the tumor center is located between 2 cm proximal to and distal from the EGJ. When the tumor size or tumor invasion makes it difficult to define the EGJ, the location of the EGJ should be comprehensively identified based on general findings. In such instances, the tumor location should be described with an acknowledgement that the diagnosis was not based on strict diagnostic criteria for EGJ cancer.

Endoscopic findings
The EGJ is defined as the lower margin of palisading small vessels ( Fig. 2-1a-c).
If the palisading small vessels cannot be clearly identified, the oral margin of the longitudinal folds of the greater curvature of the stomach can be defined as the EGJ (Fig. 2-1d).
j Commentary: Esophageal sphincters are located at both the proximal and distal ends of the esophagus and are referred to as the upper esophageal sphincter (UES) and the lower esophageal sphincter (LES), respectively. The propria mucosa layer of these two loci contains palisading small vessels that penetrate the muscularis mucosa layer after branching from submucosal vessels. Since the sphincter muscles are considered to be a feature of the esophagus, the esophagus is defined as the tract between the upper margin of the UES and the lower margin of the LES. Because the lower margin of the LES is defined as the EGJ, the level of the EGJ can be defined as the level of the lower margin of the lower palisading vessels. With this interpretation in mind, the majority of Japanese experts define the EGJ endoscopically as the lower margin of the lower palisading vessels. The endoscopic observation of palisading small vessels should be performed under a condition in which the lower esophagus is adequately stretched after suctioning the air from inside the stomach and the examinee has inhaled deeply. The lower margin of the palisading small vessels and the oral margin of the longitudinal folds of the greater curvature of the stomach are both clearly visible and coincident at the same level. In such cases, this site of coincidence is defined as the EGJ and is nearly identical to the SCJ. b The lower margin of the palisading small vessels and the oral margin of the longitudinal folds of the greater curvature of the stomach are both clearly visible and coincident at the same level. In such cases, this site of coincidence is defined as the EGJ (black arrows). The gap between the SCJ and the EGJ is diagnosed as Barrett esophagus. c The palisading small vessels are visible, but the longitudinal folds are unclear. The lower margin of the palisading small vessels is defined as the EGJ (black arrows). The gap between the SCJ and the EGJ is diagnosed as Barrett esophagus. d The longitudinal folds are visible, but the lower margin of the palisading vessels is unclear. The upper oral margin of the longitudinal fold is defined as the EGJ (black arrows). The gap between the SCJ and the EGJ is diagnosed as Barrett esophagus Esophagus (2017) 14:37-65 39 The palisading small vessels may be difficult to distinguish in endoscopic examinations of cases with gastroesophageal reflux disease or long segment Barrett esophagus (LSBE). Also, constant esophageal stretching cannot be attained by a deep inhalation if the patient has been sedated. The majority of Western experts have long used the criterion that the EGJ be defined as the upper end of the longitudinal folds of the stomach. The EGJ is defined as the upper end of the longitudinal folds of the stomach in the Prague C&M Classification, developed by the International Working Group for the Classification of Oesophagitis (IWGCO) in 2006. Endoscopic observation of the upper end of the longitudinal folds should be performed with optimal decompression of the stomach through suction; however, ''optimal decompression'' has not been strictly defined. The oral margin of the longitudinal folds of the stomach cannot be reliably defined if the amount of air inside the stomach varies. Thus, the diagnostic concordance rate is not very high for the detection of short segment Barrett esophagus (SSBE) extending for lengths smaller than 1 cm. Moreover, the gastric folds tend to be smaller in the presence of atrophic gastritis, which is more common in Japan, and the upper end of the longitudinal folds cannot be reliably observed if the amount of gas inside the stomach varies. With these points in mind, the upper end of the longitudinal folds can be difficult to define in some cases.
In making a diagnosis, the EGJ should be defined with a comprehensive interpretation of both the palisading small vessels and the longitudinal folds. In Japan, LSBE is less common and atrophic gastritis is more common. Therefore, in the Japanese Classification of Esophageal Cancer, the lower margin of the palisading vessels is primarily used to define the EGJ. The upper end of the longitudinal folds is used as a secondary criterion in cases where the palisading vessels are difficult to distinguish.

X-ray: Upper gastrointestinal series
• The EGJ is defined as the narrowest locus of the lower esophagus ( Fig. 2-2). • In cases with a sliding hiatal hernia, the EGJ should be identified as the oral margin of the longitudinal folds ( Fig. 2-3). • In the presence of Barrett esophagus, the SCJ is located on the oral side of the EGJ, and Barrett mucosa appears as mucosa containing reticular structures in a doublecontrast study ( Fig. 2-4). The EGJ is identified as the oral margin of the longitudinal folds.
j Commentary: In a barium contrast series, the esophagus can be divided into two segments of tubular and vestibule (or saccular) esophagus with a junction called the tubulovestibular junction, where the lumen of the esophagus gradually narrows. The Angle of His designates the angle formed by the esophagus and the fornix of the stomach. In healthy subjects, the Angle of His is acute, and the EGJ is identical to the narrowest part of the lower esophageal lumen. A muscular fiber lies between the left side of the esophagus and the entry of the stomach, resulting in the acuteness of the Angle of His. This fiber is located inside the propria muscle of the stomach and is called the ''sling fiber''. In healthy subjects, the level of the EGJ is nearly identical to the level of the SCJ. j Commentary: In cases with a hiatal hernia, a circular ''neck'' of the esophageal lumen is observed close to the hiatus or at the lower level of the pleural cavity during a barium contrast study, and this neck is referred to as a mucosal ring (B ring) or ''Z-line''. Although this neck is referred to as a ''ring'', the ring is not formed by a circular fiber of the muscular propria. Instead, the ''ring'' is presumably formed by the sling fiber and is prominent on the left side, or the fornix side, of the esophagus. In cases with a hiatal hernia, the EGJ is usually imaged as the oral margin of the longitudinal folds of the stomach. j Commentary: The ''circular neck'' of the esophagus accompanying a hiatal hernia is often obscured in the presence of Barrett mucosa. Therefore, the EGJ is usually defined as ''the oral margin of the longitudinal folds of the stomach'' in subjects with Barrett mucosa.

Pathological study
Macroscopic definition: The EGJ should be defined macroscopically as the point at which the luminal caliber changes in the area where the tubular esophagus is connected to the vestibule lumen of the stomach. Microscopic definition: For a mucosal layer with intact structures, the EGJ should be defined as follows: 1. Non-Barrett esophagus: The EGJ is defined as the squamocolumnar junction.
2. Barrett esophagus: Histological structures such as proper esophageal glands and their ducts, a double-layer muscularis mucosa, or palisading small vessels should be included in the microscopic definition of the EGJ. For a non-intact mucosal layer, the EGJ should be defined based on the macroscopic findings of the surgical specimen, and the EGJ should be presumed based on the presence of histological structures associated with the esophagus or stomach. j Commentary: To define the EGJ, the surgical specimen must be fully extended and optimally fixed. The histological structures must be examined using a full section of the whole specimen. If the palisading small vessels are visible in a fresh specimen, the anal margin of the vessels should be marked before the histological inspection. The EGJ is defined as ''the borderline between the muscular structures of the esophagus and the stomach''; however, histological discrimination of the muscular structures of each area is difficult. The EGJ is also often histologically unclear. Therefore, the histological definition of the EGJ depends on the macroscopic findings or the histological features of the mucosal or submucosal layer.
The definition of the histological EGJ should be given individually for non-Barrett esophagus and Barrett esophagus cases.
À Non-Barrett esophagus The SCJ is identical to the level of the lumen where the esophagus connects to the stomach and the macroscopic luminal caliber changes; this location is approximately identical to the EGJ. The SCJ can be visualized using Lugol staining, appearing as a linear or slightly curved borderline between squamous and columnar epithelium. In cases with a hiatal hernia, the luminal caliber change tends to be obscured, but the EGJ can often be defined after a closer inspection. Barrett esophagus The SCJ is not identical to the EGJ.
(a) Non-circular Barrett esophagus The line of the SCJ adjacent to the non-Barrett epithelium is identical to the EGJ.

(b) Circular Barrett esophagus
The EGJ can be defined as the most anal level of the lumen where any of the following histological features are observed: Presence of proper esophageal glands or esophageal gland tubules beneath the columnar epithelium Presence of squamous islands in the columnar epithelium Presence of a double-layer muscularis mucosae beneath the columnar epithelium Palisading vessels The level of the luminal caliber change is included in the definition of the EGJ.
[Cancer at the EGJ] Since the pattern of lymph node metastasis for EGJ cancer differs from that of carcinomas of the lower esophagus or the upper stomach, special attention should be paid to the surgical procedure. Consequently, EGJ cancer is dealt with separately in the Japanese Classification. Previously, Nishi's classification was used for the definition of EGJ cancer. According to this classification, EGJ cancer includes lesions with a tumor center located between 2 cm proximal to and distal from the EGJ, irrespective of histology ( Fig. 2-5). Accordingly, cancer of the abdominal esophagus is included in EGJ cancer. In Western countries, Siewert's classification is commonly used. According to Siewert's classification, cancer at the EGJ is defined as adenocarcinoma with a tumor center located within 1 cm distal from and 2 cm proximal to the EGJ (Fig. 2-6). EGJ cancer corresponds to Siewert Type II-True cardia cancer.
Adenocarcinoma in Barrett esophagus cannot be excluded from a diagnosis of EGJ cancer located in the abdominal esophagus.
Note 1: In cancers located at the EGJ, the oral and anal portions of the EGJ are described as ''E'' and ''G'', respectively. As shown in Fig. 2-3, the terms ''E, EG, E=G, GE, and G'' can be used depending on the tumor location. Note 2: In cases with adenocarcinoma in Barrett esophagus, the disease should be described. Note 3: Siewert's classification Types I, II and III ( Fig. 2-6) should also be described for adenocarcinoma located in the lower esophagus or at the EGJ ( Fig. 2-7). [References] ( Type 0 Superficial type: Tumor invasion is limited to the submucosa. Type 1 Protruding type: localized protruding lesion. The definitely protruding lesion which commonly has an erosive surface. However, the lesion is occasionally covered by intact squamous epithelium continuing from surroundings. Type 2 Ulcerative and localized type: The ulcerative lesion has a well-demarcated surrounding ridge. Type 3 Ulcerative and infiltrative type: The ulcerative lesion has an ill-demarcated surrounding ridge circumferentially or semi-circumferentially. Type 4 Diffusely infiltrative type: Lesion with wide intra-mural invasion, and generally without conspicuous ulcer or protrusion. Even if the lesion has ulcerative and/or protruding components, it is defined as type 4.     This was judged to be advanced cancer based on its size, mobility (or cut cross section). b Type 1: this protruding type lesion with a clearly demarcated border has lobules or a papillary appearance on its surface. c Type 1: most of the surface of the protrusion is covered by non-cancerous epithelium. This was judged to be advanced cancer based on its size and immobility. d Type 2: this lesion is a deep ulcer with a well-demarcated surrounding ridge. Macroscopic findings: advanced type (Types 1-5). e Type 3: this lesion is a deep ulcer surrounded by a poorly demarcated ridge. The lesion extended circumferentially causing luminal stenosis. f Type 4: this diffusely invasive lesion with no clear margin makes the esophageal wall thick and hard, and causes luminal stenosis. No distinct ulcer can be seen. g Type 4: the thickening of the esophageal wall and the edematous changes of the mucosa suggest diffuse intramural extension of the lesion, but there is no finding of hardening or stenosis, and no finding of ulcer formation. h Combined type: this cancer showed mixed morphology of advanced Type 1 and Type 2 (0-IIc Type extension can be seen in part). i Type 5a: the macroscopic appearance is extremely complex with Type 1, and Type 2 and others, and it is difficult to categorize. j Type 5b: this macroscopic tumor (Type 5b) cannot be categorized because of preoperative chemoradiotherapy. i Type 5a: the macroscopic appearance is extremely complex with Type 1, and Type 2 and others, and it is difficult to categorize. j Type 5b: This macroscopic tumor (Type 5b) cannot be categorized because of preoperative chemoradiotherapy Type 0-I Superficial and protruding type: definitely protruding lesion diagnosed as superficial cancer, based on findings of size, height and a relatively narrow basis. Type 0-Ip Pedunculated: lesion with a peduncle or semipeduncle, and generally the height is more conspicuous than the horizontal spread of the base. Type 0-Is Sessile (broad based): lesion without a peduncle, and generally the horizontal spread of the base is more conspicuous than the height. Types of 0-Ipl and 0-Isep in the 9th edition of the Japanese Classification are included in this type. Type 0-II Superficial and flat type: the lesion without definite protrusion or depression.
Type 0-IIa Slightly elevated type: lesion with a slight elevation (up to about 1 mm in height). Type 0-IIb Flat type: the lesion without macroscopic elevation or depression. This cancerous lesion can occasionally be recognized only by iodine staining. Type 0-IIc Superficial and depressed type: lesion with a slight depression, commonly accompanied with mucosal reddening. The degree of depression is equivalent to erosion.
Type 0-III Superficial and depressed type: lesion showing more distinct depression than the 0-IIc type, and bottom of the depression appears to extend beyond the muscularis mucosae ( Fig. 2-14).
In endoscopically resected specimens, lesions located within 200 lm of the muscularis mucosae are identified as T1b-SM1, and lesions invading beyond this range are identified as T1b-SM2.

Lymph node metastasis
In Japan, regional lymph nodes are classified as ''compartment 1 to 3'' according to tumor location, while distant lymph nodes are categorized as ''compartment 4''. Based on this lymph node grading classification, the degree of lymph node metastasis (N classification) is defined as N0-N4. On the other hand, the UICC (International Union Against Cancer) TNM classification defines lymph nodes located in the defined area as ''regional lymph nodes'' regardless of the tumor location. The degree of lymph node metastasis is described as N0-N3 based on number of lymph node metastases. Metastasis to lymph nodes other than regional lymph nodes is categorized as M1.
2.2.1.1 Naming, number, range and boundary of regional lymph node (1) Cervical lymph nodes  No.100 Superficial lymph nodes of the neck The cervical lymph nodes except for the deep cervical nodes according to the General Rules for Clinical Studies on Head and Neck Cancer No.100spf Superficial cervical lymph nodes: Lymph nodes located along the external jugular veins and anterior jugular veins beneath the superficial cervical fascia. No.100sm Submandibular lymph nodes: Lymph nodes located around the submandibular glands and parotid glands, and anterior to the mylohyoid muscle. No.100tr Cervical pretracheal lymph nodes: Lymph nodes located in the pretracheal fatty tissue, extending from the hyoid bone superiorly, to the left brachiocephalic vein inferiorly, including the prethyroidal lymph nodes and the prelaryngeal lymph nodes.
No.100ac Accessory nerve lymph nodes: Lymph nodes located along the accessory nerve(s), and anterior to the trapezius muscle.
No.101 Cervical paraesophageal lymph nodes Lymph nodes located around the cervical esophagus, including lymph nodes located along the recurrent laryngeal nerve and the cervical paratracheal lymph nodes. The lateral boundary is the medial border of the carotid sheath. A distinction between left and right must be included.

No.102 Deep cervical lymph nodes
Lymph nodes located around the internal jugular vein and the common carotid artery. No.102up Upper deep cervical lymph nodes: Lymph nodes located from the caudal border of the digastric muscle superior to the carotid artery bifurcation. No.102mid Middle deep cervical lymph nodes: Lymph nodes located from the carotid artery bifurcation superiorly to the lower border of the cricoid cartilage inferiorly.

No.103 Peripharyngeal lymph nodes
Lymph node located medial to the carotid sheath, extending from the caudal border of the digastric muscle b Fig. 2-11 Macroscopic findings: superficial type (0 type). a Type 0-Ip (superficial and protruding type, pedunculated): The tumor is well demarcated and has a narrow base. b Type 0-Ip (superficial and protruding type, pedunculated): The well-demarcated, protruding tumor has an irregular and nodular surface. c Type 0-Is (superficial and protruding type, sessile): the surface of this ill-demarcated tumor is mostly covered by the normal epithelium. d Type 0-IIa (slightly elevated type): the tumor is only slightly elevated from the mucosa. Its color is generally white. e Type 0-IIb (flat type): there are only minute irregularities and no macroscopic abnormal features. f Type 0-IIb (flat type) (iodine-stained view of e) the superficial tumor can now be seen unstained by iodine. g Type IIc (slightly depressed type): the superficial depressed lesion has no clear margin and a finely granular surface. h (iodine-stained view of g): the superficial tumor is unstained by iodine. i Type 0-IIc (slightly depressed type): the superficial depressed lesion has an irregular margin. j Type 0-III (superficial and depressed type): the deeply depressed lesion with a slightly elevated margin suggests invasion beyond the muscularis mucosae. k Type 0-IIc?''0-IIa'' (superficial spreading type): the widespread slightly depressed red lesion (0-IIc) has a slightly elevated lesion (0-IIa) in its center, suggesting invasion into the submucosal layer. The lesion, more than 5 cm in length, is defined as the superficial spreading type. l Type 0-IIc?''0-IIa'' (superficial spreading type) (iodine-stained view of k): the reddish depressed lesion is not stained with iodine solution. m Type 0-IIc ? ''0-Ip'': the welldemarcated protruding tumor with a narrow base (0-Ip) has a slightly depressed lesion (0-IIc) in the surrounding area. This macroscopic appearance is characterized as carcinosarcoma Esophagus (2017)   No.112 Posterior mediastinal lymph nodes: Lymph nodes located in the area surrounded by the descending aorta, inferior pulmonary vein and pericardium. These lymph nodes are divided into the following subgroups.
No.112aoA Anterior thoracic paraaortic lymph nodes: Among lymph nodes located around the descending aorta, lymph nodes existing on the same side of the esophagus, including lymph nodes along the thoracic duct.
No.112aoP Posterior thoracic paraaortic lymph nodes: Among lymph nodes located around the descending aorta, lymph nodes existing on the opposite side of the esophagus.
No.112pul pulmonary ligament lymph nodes: Lymph nodes located in the pulmonary ligament(s), including lymph nodes adjacent to the pericardium b Fig. 2-13 Endoscopic findings: superficial type. a Type 0-Ip, superficial and protruding type, pedunculated (cT1b-SM2-3): a welldemarcated protruding and pedunculated tumor shows an irregular and nodular surface. b Type 0-Is, superficial and protruding type, sessile (pT1b-SM2): a well-demarcated protruding and sessile tumor. c Type 0-Is, superficial and protruding type, sessile (pT1b-SM2): À Conventional endoscopy: an ill-demarcated protruding tumor covered by normal esophageal mucosa suggests a tumor mass in the submucosa.`Iodine staining: the mucosa covering the tumor is stained brown, and an unstained area at the top suggests exposed tumor tissue. d Type 0-IIa, slightly elevated type (pT1a-MM): a plaque-like, slightly elevated white tumor. Tumor invasion of the white area remained within the lamina propria, while a tiny protrusion at the distal margin of the tumor had invaded the muscularis mucosae. e Type 0-IIa, slightly elevated type (pT1a-EP): a slightly elevated tumor with well-demarcated reddening (the height of a type 0-IIa lesion is less than 1 mm). f Type 0-IIb flat type (pT1a-EP): À Conventional endoscopy: a conventional observation could not detect the lesion.`Narrow band imaging shows a brownish area.´Iodine staining: a completely flat lesion was identified as a well-demarcated, unstained area using iodine staining. g Type 0-IIc, slightly depressed type (pT1a-LPM). À Conventional endoscopy: an irregularly shaped mucosal reddening with a slight depression is visible.`Narrow band imaging: the lesion is also visible as a brownish area.´Iodine staining: a well-demarcated, unstained area is visible using iodine staining. h Type 0-IIc, slightly depressed type (pT1b-SM1): À Conventional endoscopy: an area of mucosal reddening with a slight depression and marginal elevation is visible.`Narrow band imaging: a brownish area suggesting a hypervascular lesion is visible. i Type 0-III, superficial and excavated type (cT1b-SM2-3). À Conventional endoscopy,`narrow band imaging (cT1b-SM2-3): a distinctly depressed lesion with a surrounding elevated area is visible using conventional observations, suggesting an ulcer reaching the muscularis mucosa. j Combined type 0-IIc ? ''0-Is'' (pT1b-SM2): À Conventional endoscopy: a distinct elevation with a wide base is visible. A slightly depressed lesion was also noted close to the distal margin of the lesion.`Narrow band imaging: a lesion with a welldemarcated margin is visible. k Combined type 0-Is ? 0-IIc (pT1b-SM2): À Conventional endoscopy: a distinctly protruding lesion with a wide base and irregular, nodular changes is visible. Reddening of the esophageal mucosa close to the lesion with an ill-defined margin was suspected.`Iodine staining: The margins of the mucosal changes were identified as well-demarcated, unstained areas Esophagus (2017)    [References] (1)     Note: There are two types of intraepithelial neoplasia; intraepithelial neoplasia of the squamous epithelium and intraepithelial neoplasia of the columnar epithelium in Barrett esophagus. The details of the intraepithelial neoplasia of the squamous epithelium are explained below. Intraepithelial neoplasia of columnar epithelium is described in the section on esophageal adenoma. Explanation 1. Intraepithelial neoplasia is a neoplastic lesion that exhibits structural and cytological abnormalities but does not include carcinoma. Previously, this lesion was formally known as dysplasia, but it has been referred to as intraepithelial neoplasia since the publication of the WHO classification (2000) and the 10th edition of the Japanese classification (2008). Intraepithelial neoplasia has been classified into two groups: low grade and high grade. In the 10th edition, high-grade intraepithelial neoplasia included lesions that could be diagnosed as squamous cell carcinoma in situ in Japan. Since the 11th edition includes the diagnosis of squamous cell carcinoma in situ, the previous two-tier subclassification of low grade and high grade has been abolished. 2. Of note, a peculiar type of squamous cell carcinoma in situ mimicking a ''low-grade intraepithelial neoplasia'' according to the diagnostic criteria of the 10th edition has been reported. Although such tumor cells differentiate towards the epithelial surface, the cell density (cellularity) is increased and the cell arrangement (polarity) is irregular in the basal and parabasal layers of the epithelium. Cellularity in the epithelial surface is also increased, compared with non-neoplastic lesions. The nuclei of the tumor cells are uniform. However, they are occasionally large. Iodineunstained lesions more than 10 mm in diameter mimicking low-grade intraepithelial neoplasia should be suspected as being a carcinoma in situ.
Note: Differential diagnoses of intraepithelial neoplasia include lesions that exhibit reactive atypism as a result of inflammation and regeneration. For instance, regenerative squamous epithelium in cases with reflux esophagitis sometimes exhibits atypical basal or parabasal cells, but these lesions should not be diagnosed as intraepithelial neoplasia. Lesions in which the differentiation of neoplasm from reactive changes is difficult should be diagnosed as ''atypical epithelium'' or ''atypical epithelium, indefinite for neoplasia''.

Malignant epithelial neoplasms
Histological subtyping should be done based on the predominant histological features of the tumor.  Keratinization, stratification, and intercellular bridges are frequently observed. A few tubules and a small amount of epithelial mucus may exist in the tumor; these features should be noted, if present.
Note: Squamous cell carcinoma in situ can be diagnosed based on structural and cytological atypia. Structural atypia includes cellular density (cellularity), cell differentiation, loss of polarity at the basal layer, etc. Cytological atypia includes variations in nuclear size and shape, hyperchromasia, loss of polarity, prominent nucleoli, an increased nuclear/cytoplasmic ratio, and mitoses. There is no need to describe the degree of differentiation in squamous cell carcinoma in situ. Invasive squamous cell carcinoma is subclassified into three groups based on squamous differentiation: well differentiated, moderately differentiated, and poorly differentiated. Verrucous carcinoma, a type of very well differentiated squamous cell carcinoma with papillary growth, is a rare tumor in the esophagus (Fig. 2-31).
Poorly differentiated squamous cell carcinoma can be composed of spindle-shaped cells and may resemble 2. Basaloid (-squamous) carcinoma ( Fig. 2-32) Basaloid (-squamous) carcinoma consists of relatively small cells that resemble basal cells and that grow in a solid or trabecular pattern, occasionally forming irregular adenoid or small cystic structures. This entity is also characterized by hyalinization both within and outside tumor nests, and the hyaline material is the same as that in the basement membrane. Duct-like structures may be High magnification. The tumor shows mild nuclear atypia with low cellular density and a regular arrangement of the basal layer. c Histology of biopsy specimen. The lesion is visible as an iodine-stained tan area measuring 5 mm in size. Histopathologically, a mildly thickened epithelium exhibits atypical cell proliferation in the lower two-thirds of the epithelium, but nuclear atypia is mild and the basal layer has a regular arrangement  observed. Squamous cell carcinoma frequently coexists with basaloid squamous carcinoma in the intraepithelial area and is occasionally present in invasive areas.
Note: In adenocarcinoma located predominantly in the lower esophagus, if the tumor is considered to be gastric cancer with esophageal invasion, its possible origin should be noted in the pathological diagnosis.
5. Adenosquamous carcinoma (Fig. 2-35) Adenosquamous carcinoma has both components of adenocarcinoma and squamous cell carcinoma, each component of which can be easily recognized. When either of the two components is limited to a very small area (less than 20%), the tumor should be classified as a major component, with an additive note regarding the minor component (e.g. squamous cell carcinoma with an adenocarcinoma component).
6. Mucoepidermoid carcinoma (Fig. 2-36) Mucus-containing cells (adenocarcinoma cells) are present within nests of squamous cell carcinoma. There are usually no distinct tubular structures. The mucus-containing cells may be goblet or signet ring cell type. Mucus is occasionally discharged into the stroma and intercellular spaces.
7. Adenoid cystic carcinoma (Fig. 2-37) Adenoid cystic carcinoma is a very rare tumor with the same histological appearance as a salivary gland. Small cells with scanty cytoplasm form cribriform structures, solid nests or trabecular structures. Mucus within small  cystic spaces inside and outside the tumor nests stains light blue with Alcian blue-PAS. There is no epithelial mucus production in the cribriform areas, unlike in adenocarcinoma with a cribriform pattern. A pattern of small duct-like structures is occasionally seen in which ducts consist of tumor cells aligned in a double layer containing epithelial mucus. This tumor should be carefully distinguished from basaloid squamous carcinoma.
8. Neuroendocrine cell tumor (Fig. 2-38) Neuroendocrine cell tumors include both neuroendocrine tumors (formerly known as carcinoid tumors) and neuroendocrine carcinoma (formerly known as endocrine cell carcinoma). Neuroendocrine tumors of the esophagus are very rare and have the same histological appearance as neuroendocrine tumors located in other organs. Neuroendocrine carcinoma forms nests of tumor cells in various sizes and occasionally shows a trabecular or ribbon-like growth pattern or rosette formation. This tumor can be classified into two types: small cell type and non-small cell type (mixed type of small and large cells). Definitive diagnosis needs immunohistochemical positivity of endocrine markers such as chromogranin A, synaptophysin, and CD56 (N-CAM).
Note: Tumors exhibiting neuroendocrine differentiation were formerly diagnosed as undifferentiated carcinoma. Neuroendocrine carcinoma can be distinguished from undifferentiated carcinoma by the presence of neuroendocrine differentiation.
9. Undifferentiated carcinoma This tumor shows medullary growth pattern consisting of small and large tumor cells, lacking particular cell and structural differentiation. Various histopathological methods fail to reveal any particular cell differentiation.

Others
This category includes malignant epithelial tumors that cannot be classified in any of the above groups. Differentiation between benign and malignant tumor is based on the cellularity, nuclear pleomorphism, and mitosis. Fig. 2-37 Adenoid cystic carcinoma. a A tumor with duct-like structures and a cribriform pattern has invaded downwards. b The histology of esophageal adenoid cystic carcinoma is almost the same as that with a salivary gland origin. Nuclear atypia is more prominent in the esophageal tumor than in the salivary gland tumor 2. Gastrointestinal stromal tumor (GIST) (Fig. 2-40) This tumor shows histologic findings similar to a smooth muscle tumor. It is occasionally difficult to differentiate GIST from smooth muscle tumor without immunohistochemical staining. GIST is defined as a mesenchymal tumor that immunohistochemically exhibits KIT (CD117) and/or DOG1 positivity. CD34 is positive in about 80% of GISTs.
Note: Risk assessment follows the Guidelines for the Diagnosis and Treatment of GIST.
3. Granular cell tumor ( Fig. 2-41) Granular cell tumors, which are composed of large round cells with eosinophilic granules in abundant cytoplasm, form solid nests of various sizes and grow predominantly in the lamina propria mucosae or submucosa. Stratified squamous epithelium commonly covers these tumors, and they occasionally exhibit pseudoepitheliomatous hyperplasia.

Lymphoid tumors
There have been a few case reports of B cell lymphoma of the esophagus. The latest version of the WHO classification is used for esophageal malignant lymphoma.
4.2.1.6. Other malignant tumors 1. Malignant melanoma  In order to make a diagnosis of primary malignant melanoma, histological identification of junctional activity that tumor cells producing melanin granules proliferate in the basal layer of the epithelium is needed.

Others
Choriocarcinoma has been reported in the esophagus.

Depth of tumor invasion (pT)
If the layers of the esophagus are destroyed by preoperative treatment, the depth of tumor invasion should be described based on the deepest layer where the primary tumor is considered to have been present before preoperative treatment.

Pathological criteria for the effects of radiation and/ or chemotherapy
Some of the findings regarded as therapeutic effect due to radiation and chemotherapy are described below . Preoperative chemoradiotherapy was performed for a Type 2 advanced cancer. In the resected specimen, only mild stricture and wall thickening (arrow) are observed in the lower esophagus.
Serial sectioning was performed for pathological examinations. Histologically, fibrosis was observed in the stricture, which can be regarded as the extent of the preexisting tumor.   According to global changes from the WHO to the ''Response Evaluation Criteria in Solid Tumors (RECIST)'' criteria, JSCO has already adopted these criteria, which has led JES to the same decision. The response evaluation criteria for the primary site of the esophageal cancer are included in this revised version.
Concerning adapting RECIST into the present criteria, the policy of RECIST is described to ensure its proper use. Both the WHO and RECIST criteria are targeted to evaluate the effect of antitumor agents on tumor shrinkage. Their purposes are to estimate the response 'as a surrogate end point in clinical trials'. RECIST can be used in daily clinical practice; however, it is not intended for making any decisions on treatment strategy. Achieving a ''partial response (PR)'' with 50% reduction in tumor size does not mean giving a definite advantage to the patient. ''Clinical improvement'' may not correspond to ''objective tumor response'' in daily practice. The RECIST guidelines clearly state that ''the defined criteria are not necessarily developed further to be applicable or complete in such a context''. Physicians who are using the present criteria should recognize that the RECIST criteria are only for evaluating antitumor activity as a surrogate end point in clinical trials.
The present criteria added the evaluation criteria for primary tumor of the esophagus. These additional descriptions are needed to define complete response (CR) for the primary tumor, since the CR rate was more correlated with prognosis after definitive chemoradiotherapy or radiotherapy than response rate 2) . It should be noted that these criteria are indicative not for pathological response but for clinical response as a surrogate end point related to prognosis. These criteria are defined for ''evaluating tumor reduction as an end point in clinical trials'' and do not attempt to determine the value of esophagography as an evaluation tool in daily clinical practice. Although the value of ''PR'' is not confirmed, this definition is described in ''Notes'' since it may be used in cases of preoperative therapy. The development of new imaging modalities, such as positron-emission tomography (PET), may allow the proposal of new criteria in the future.

Subjects
Subjects evaluated by the present criteria are patients with esophageal cancer and treated with chemotherapy and/or radiotherapy.

Methods for response evaluation
1. Because it is difficult to accurately measure the primary site of the esophagus, it is defined as a ''non-measurable lesion''. Evaluation of reduction in tumor size of the primary site should be done by esophagoscopy (including biopsy, see 5.) in accordance with the definition of ''non-target lesion''. 2. Either measurable or non-measurable lesions apart from the primary esophageal lesion should be evaluated according to the RECIST criteria. 3. Basically the same methods as used in baseline evaluation should be adopted. 4. All measurements should be recorded in metric notation.

Response evaluation criteria for target lesions
Evaluation of the target lesions should be done for up to 5 lesions greatest in dimension per organ and classified according to the following criteria. Rates of decrease or increase in the sum of the greatest dimensions are calculated by the following formula.
Rates of decrease of the greatest dimensions = {(sum of the greatest dimensions at baseline -sum of the greatest dimensions at evaluation)/sum of the greatest dimensions at baseline)} 9 100% Increasing rate of the greatest dimensions = {(sum of the greatest dimensions at evaluation -smallest sum of the greatest dimensions since the treatment started)/smallest sum of the greatest dimensions since the treatment started} 9 100% 3.1. Complete response (CR) The disappearance of all target lesions as well as secondary changes associated with the tumors.
Note: In case of lymph node metastasis, CR is declared if the size decreases to normal size or less.

Partial response (PR)
At least a 30% decrease in the sum of the greatest dimensions of target lesions, taking as reference the baseline sum of greatest dimensions.

Progressive disease (PD)
At least a 20% increase in the sum of greatest dimensions of target lesions, taking as reference the smallest sum of greatest dimensions recorded since the treatment started.

Stable disease (SD)
Neither PR nor PD.

Complete response (CR)
The disappearance of all non-target lesions and normalization of tumor marker level. In addition, the response of the primary lesion must meet criterion 5.1: complete disappearance of primary lesion on endoscopy.

Incomplete response/stable disease (IR/SD)
The persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker level above the normal limits. In addition, the response of the primary lesion meets criterion 5.2, incomplete response/stable disease of primary lesion by endoscopy.

Progressive disease (PD)
The appearance of one or more new lesions and/or unequivocal progression in existing non-target lesion(s). In addition, the response of the primary lesion meets criterion 5.3, progressive disease of the primary lesion on endoscopy.
5. Response evaluation criteria for primary lesion using endoscopy

Complete response of primary lesion (primary lesion CR)
When conditions satisfy all of 1 to 4, the response is judged as CR.
1. Disappearance of endoscopic findings suggesting the presence of a tumor The findings noted below should be judged as possible tumor lesions and should not be judged as a CR.
Eroding changes of the mucosa with an irregular surface Ulcerative lesions Distinctly protruded changes (including protrusions suggestive of a submucosal tumor) The findings noted below should not be judged as possible tumor lesions and should be judged as a CR.

Overall response
Overall responses for all possible combinations of tumor responses in target and non-target lesions with or without the appearance of new lesions. If there is no target lesion and only non-target lesions are available (e.g. primary esophageal cancer without lymph node metastasis), overall response is determined only by the responses of the non-target lesions.  Cancer tissue is probably exposed on the top and distal half of the tumor. b The exposed tumor was identified as a brownish area with a central white coating using narrow band imaging  Overall response of CR in serial assessments at an interval of 4 weeks or more.

Partial response (PR)
Overall response of PR or better response (CR or PR) in serial assessments at an interval of 4 weeks or more. Endoscopic findings for IR/SD cases 7.3. Stable disease (SD) When one of the following criteria is met. 1. Best overall response CR or PR was obtained, but duration was less than 4 weeks. 2. Stable disease or better response in serial assessments at an interval of 4 weeks or more, at 4 weeks or more after the start of treatment. (If the first assessment is SD, and the second assessment is of PD, it should be judged as PD.) Note: If there is no target lesion (e.g. esophageal cancer without metastasis), IR/SD is used as a description in place of PD or SD.

Progressive disease (PD)
When none of above conditions is met.
Note: In phase II studies in which response rates are used as end points, confirmation should be made with an interval of 4 weeks or more. In phase III, studies in which survival is used as the end point, the best overall response without confirming response can be used.
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