ESOPHAGEAL SQUAMOUS CELL CARCINOMA : diagnosis and treatment.

Preface
Contents
1: Epidemiology of Esophageal Squamous Cell Carcinoma
	1.1	 Esophageal Cancer in the World and Japan
		1.1.1	 Esophageal Cancer in the World: Burden, Geographical Difference, and Trends
			1.1.1.1	 Global Burden and Geographical Difference (Global Cancer Observatory, https://gco.iarc.fr/)
			1.1.1.2	 Histological Type [1]
		1.1.2	 Esophageal Cancer in Japan (Cancer Information Service, https://ganjoho.jp)
	1.2	 Risk Factors
		1.2.1	 Tobacco Smoking and Alcohol Consumption
		1.2.2	 Genetic Susceptibility to Tobacco Smoking and Alcohol Drinking
		1.2.3	 Fruit and Vegetable Intake
		1.2.4	 Mate and Hot Beverages
		1.2.5	 Causes of Esophageal Cancer in Japan
	References
2: Pathology of Esophageal Squamous Cell Carcinoma
	2.1	 Definitions
	2.2	 Macroscopic Features
		2.2.1	 Handling of Specimens
		2.2.2	 General Features
		2.2.3	 Superficial Esophageal Cancer
		2.2.4	 Advanced Esophageal Cancer
		2.2.5	 Multicentric Squamous Cell Carcinoma (Field Cancerization)
		2.2.6	 Risk Factors
	2.3	 Microscopic Features
	2.4	 Tumor Spread
		2.4.1	 Superficial Esophageal Cancer
			2.4.1.1	 Ductal/Glandular Involvement
			2.4.1.2	 Diffuse Pagetoid Spread
		2.4.2	 Lymph Node Metastasis in Patients with Superficial Esophageal Cancer
		2.4.3	 Advanced Esophageal Cancer
			2.4.3.1	 Intramural Metastasis
			2.4.3.2	 Prognostic Factors
	2.5	 Precursor Lesion (Squamous Dysplasia/Intraepithelial Neoplasia)
	2.6	 Tumor Response to Neoadjuvant Therapy
	2.7	 Variants
		2.7.1	 Basaloid Squamous Cell Carcinoma
		2.7.2	 Carcinosarcoma/Spindle Cell Squamous Cell Carcinoma/Sarcomatoid Carcinoma
		2.7.3	 Adenosquamous Carcinoma
		2.7.4	 Verrucous Carcinoma
	References
3: Diagnostic Imaging of the Esophageal Cancer
	3.1	 Introduction
	3.2	 Anatomy of the Esophagus
		3.2.1	 Divisions of the Esophagus
		3.2.2	 Zonal Anatomy of the Esophageal Wall
	3.3	 T Staging by Imaging
		3.3.1	 Barium Esophagography
		3.3.2	 EUS
		3.3.3	 CT
			3.3.3.1	 CT Study Protocol and Optimal Phase for the Evaluation
			3.3.3.2	 Diagnostic Criteria of the Esophageal Cancer
			3.3.3.3	 Diagnostic Criteria for Tumor Invasion to the Adjacent Structures
		3.3.4	 MRI
		3.3.5	 PET
	3.4	 N Staging by Imaging
	3.5	 M Staging by Imaging
	3.6	 Follow-Up
	References
4: Diagnostic Imaging: PET/CT(PET)
	4.1	 PET/CT(PET)
	4.2	 N Staging by Imaging
	4.3	 M Staging by Imaging
	4.4	 Follow-up
		4.4.1	 Response Assessment
		4.4.2	 Surveillance
	References
5: Endoscopic Diagnosis of Squamous Cell Carcinoma of the Esophagus
	5.1	 Endoscopic Imaging of the Esophagus and ESCC
	5.2	 Endoscopic Detection and Differential Diagnosis of Superficial ESCC
		5.2.1	 Conventional White Light Imaging (WLI)
		5.2.2	 Lugol Chromoendoscopy
		5.2.3	 Equipment-Based Image-Enhanced Endoscopy (IEE)
	5.3	 Estimation of the Depth of Invasion of Superficial ESCC
		5.3.1	 Conventional WLI
		5.3.2	 Lugol Chromoendoscopy
		5.3.3	 Equipment-Based IEE
		5.3.4	 Endoscopic Ultrasound
		5.3.5	 Optical Coherence Tomography
	5.4	 Endoscopic Diagnosis of Advanced ESCC
	5.5	 Differential Diagnosis of Squamous Cell Carcinoma and Adenocarcinoma
	5.6	 Histological Confirmation by Biopsy
	5.7	 Virtual Biopsy
	References
6: Stage Classifications: UICC/AJCC Classifications and the Japanese Classification
	6.1	 Introduction
	6.2	 Historical Overview
		6.2.1	 History of the UICC and the TNM Classification (Fig. 6.1) [1–8]
		6.2.2	 History of the AJC/AJCC and the AJCC Cancer Staging Manual (Fig. 6.1) [9, 11–17]
		6.2.3	 History of the JSED/JES and the Japanese Classification (Fig. 6.1) [10, 24–38]
	6.3	 Anatomical Subsites: Esophagus and Esophagogastric Junction
		6.3.1	 The TNM Classification
			6.3.1.1	 Anatomical Subsites [4, 14]
			6.3.1.2	 Definition of the Esophagogastric Junction (C16.0) in the Seventh Edition (UICC, 2009) [7]
			6.3.1.3	 Definition of Esophagogastric Junction (C16.0) in the Eighth Edition (UICC, 2017) [8]
		6.3.2	 The AJCC Cancer Staging Manual
		6.3.3	 The Japanese Classification
			6.3.3.1	 Definition of the Esophagogastric Junction (EGJ) [26–28]
			6.3.3.2	 Definition of the Zone of the EGJ [26–28]
	6.4	 T Category: Primary Tumor
		6.4.1	 The TNM Classification
		6.4.2	 The AJCC Cancer Staging Manual
		6.4.3	 The Japanese Classification
			6.4.3.1	 Histological T Categories [29]
	6.5	 N Category—Lymph Node Metastasis
		6.5.1	 TNM Classification
		6.5.2	 The AJCC Cancer Staging Manual
		6.5.3	 The Japanese Classification
	6.6	 M Category: Distant Metastasis
		6.6.1	 The TNM Classification
		6.6.2	 The AJCC Cancer Staging Manual
		6.6.3	 The Japanese Classification
	6.7	 Stage Groups
		6.7.1	 The TNM Classification
		6.7.2	 The AJCC Cancer Staging Manual
		6.7.3	 The Japanese Classification
	6.8	 Other Classifications
		6.8.1	 The TNM Classification/AJCC Cancer Staging Manual
			6.8.1.1	 G: Histopathological Grading [8, 12]
			6.8.1.2	 Residual Tumor (R) Classification [8, 12]
			6.8.1.3	 y Symbol: Post-Therapy Classification [8, 12]
		6.8.2	 The Japanese Classification
			6.8.2.1	 Macroscopic Tumor Type [24, 25]
			6.8.2.2	 Extent of Lymph Node Dissection (D) [26–28]
			6.8.2.3	 Curativity (Cur) [26–28]
	6.9	 Discussions
		6.9.1	 Definition of Cancer at the Esophagogastric Junction
		6.9.2	 N Category
		6.9.3	 M1-Lym Category
		6.9.4	 Anatomical Staging and Prognostic Staging
	References
7: Comprehensive Registry in Japan
	7.1	 Introduction
	7.2	 History of the Registry of Esophageal Cancer Cases in Japan
	7.3	 Attempts to Resume the Registration Project
		7.3.1	 Handling of Personal Information
		7.3.2	 Hash Function
		7.3.3	 Certification of the Registration Project
		7.3.4	 Preparation of Registration Sheets
		7.3.5	 Trial of the New Registration Project
	7.4	 Resumption of the Registration Project
	7.5	 Publication of the Resumed Reports
	7.6	 Next Year Registration
	7.7	 Problems Arising During the First Two Years
	7.8	 Summary of the Comprehensive Registry of Esophageal Cancer in Japan, 2001–2012
	7.9	 New Registry System
	7.10	 Significance of the Registration Project
	References
8: Esophageal Cancer Practice Guidelines in Japan
	8.1	 Method of Development of the Esophageal Cancer Practice Guidelines [1]
		8.1.1	 On the Methodology of Preparation of the Guidelines
		8.1.2	 Preparation of Clinical Questions and Search of the Literature
		8.1.3	 Systematic Review Procedure
		8.1.4	 Determination of the Strength of Recommendations
	8.2	 Treatment Algorithm for cStage 0 and I Esophageal Cancer (Fig. 8.1) [1]
	8.3	 Treatment Algorithm for cStage II and III Esophageal Cancer (Fig. 8.2) [1]
	8.4	 Treatment Algorithm for cStage IV Esophageal Cancer (Fig. 8.3) [1]
	8.5	 Endoscopic Treatment [2]
	8.6	 Surgical Treatment [2]
		8.6.1	 Surgery for Cervical Esophageal Carcinoma
		8.6.2	 Surgery for Thoracic Esophageal Carcinoma
		8.6.3	 Surgery for Carcinoma of the Esophagogastric Junction (Abdominal Esophageal Carcinoma)
	8.7	 Perioperative Management and Clinical Path [2]
	8.8	 Chemotherapy for Unresectable Advanced or Recurrent Esophageal Cancer [2]
	8.9	 Radiotherapy [2]
	8.10	 Multidisciplinary Treatment [2]
		8.10.1	 Pre- and Postoperative Adjuvant Therapy
		8.10.2	 Chemoradiotherapy
	8.11	 Follow-Up after Treatment of Esophageal Cancer [2]
	8.12	 Treatment of Recurrent Esophageal Cancer [2]
	8.13	 Palliative Care [2]
	8.14	 Diagnosis and Treatment of Barrett’s Esophagus and Barrett’s Carcinoma [2]
	8.15	 Future Perspectives
	References
9: Endoscopic Treatment: EMR and ESD
	9.1	 Introduction
	9.2	 Indication of Endoscopic Resection
	9.3	 Endoscopic Mucosal Resection
	9.4	 Endoscopic Submucosal Dissection
		9.4.1	 Details of Practical Skill
	9.5	 Management of Complications
		9.5.1	 Bleeding
		9.5.2	 Perforation
		9.5.3	 Postoperative Stricture
	9.6	 Outcomes of ESD for Esophageal Squamous Cell Carcinoma
		9.6.1	 Short-Term Outcomes
		9.6.2	 Long-Term Outcomes
	9.7	 Summary
	References
10: Surgery Transthoracic Esophagectomy
	10.1	 Introduction
	10.2	 Surgery for SCC of Thoracic Esophagus
		10.2.1	 Esophagectomy
		10.2.2	 Regional Extent of Lymphadenectomy
			10.2.2.1	 Upper Thoracic Esophageal Carcinoma
			10.2.2.2	 Middle Thoracic Esophageal Carcinoma
			10.2.2.3	 Lower Thoracic Esophageal Carcinoma
	10.3	 Surgical Procedure
		10.3.1	 Surgical Approach
		10.3.2	 Upper Mediastinal Procedure
		10.3.3	 Middle and Lower Mediastinal Procedure
		10.3.4	 Abdominal Procedures
	10.4	 Mortality and Morbidity after Esophagectomy
		10.4.1	 Mortality
		10.4.2	 Morbidity
			10.4.2.1	 Pulmonary Complications
			10.4.2.2	 Cardiovascular Complications
			10.4.2.3	 Recurrent Laryngeal Nerve Injury
			10.4.2.4	 Chylothorax
	10.5	 Discussion on the Three-Field Lymphadenectomy
	10.6	 Future Perspectives
	References
11: Surgery: Minimally Invasive Esophagectomy
	11.1	 Introduction
	11.2	 Overview of MIE
		11.2.1	 Terminology of MIE
		11.2.2	 VATS Esophagectomy
			11.2.2.1	 History
			11.2.2.2	 Indication
			11.2.2.3	 Positioning
			11.2.2.4	 Lymph Node Dissection
			11.2.2.5	 Reconstruction Procedures
			11.2.2.6	 Our Procedures
		11.2.3	 Short-Term Outcomes of VATS Esophagectomy
		11.2.4	 Long-Term Outcomes of VATS Esophagectomy
		11.2.5	 Robotically-Assisted Esophagectomy
		11.2.6	 Laparoscopy/Mediastinoscopy-Assisted Esophagectomy
	11.3	 Discussion
	References
12: Surgery: Esophageal Reconstruction
	12.1	 Introduction
	12.2	 Thoracic Esophageal Cancer
		12.2.1	 Stomach
			12.2.1.1	 Operative Technique
			12.2.1.2	 Esophagogastric Anastomosis
		12.2.2	 Colon
			12.2.2.1	 Operative Technique
		12.2.3	 Jejunum
			12.2.3.1	 Operative Technique of Jejunal Roux-en-Y Reconstruction with Vascular Anastomoses for Supercharge and Superdrainage
		12.2.4	 Reconstruction Route
	12.3	 Cervical Esophageal Cancer
		12.3.1	 Free Jejunal Transfer
			12.3.1.1	 Operative Technique
	References
13: Perioperative Nutritional Management of Esophageal Cancer Surgery
	13.1	 Introduction
	13.2	 Nutritional Assessments
		13.2.1	 CONUT
		13.2.2	 Geriatric Nutritional Risk Index
		13.2.3	 Prognostic Nutritional Index
		13.2.4	 Skeletal Muscle Index
		13.2.5	 Nutritional Risk Screening
	13.3	 Nutritional Management of Patients with Esophageal Cancer
		13.3.1	 Early Enteral Nutrition
		13.3.2	 The Starting Timing of Enteral Nutrition After Esophagectomy
		13.3.3	 Advancement Schedule of Immediate Enteral Feeding
		13.3.4	 Immunonutrition
		13.3.5	 Immunonutrition in the Multidisciplinary Treatments for Esophageal Cancer
		13.3.6	 Enhanced Recovery After Surgery (ERAS)
		13.3.7	 A Practicable Example of the ERAS Program
		13.3.8	 Immediate Oral Intake Following Esophagectomy
	References
14: Neoadjuvant and Adjuvant Therapy
	14.1	 Introduction
	14.2	 Adjuvant and Neoadjuvant Therapy for ESCC in Japan
		14.2.1	 Historical Changes in Surgical Adjuvant Therapy of ESCC in Japan
			14.2.1.1	 Preoperative and Postoperative Radiotherapy
			14.2.1.2	 Postoperative Chemotherapy (Adjuvant Chemotherapy  aCT)
				Postoperative Radiotherapy Versus Postoperative Chemotherapy
				Additive Effect on Survival of Postoperative Adjuvant Chemotherapy over Surgery Alone
			14.2.1.3	 Preoperative Chemotherapy (Neoadjuvant Chemotherapy  nCT)
		14.2.2	 Future Candidates for Surgical Adjuvant Therapy for ESCC in Japan
	14.3	 Adjuvant and Neoadjuvant Therapy for ESCC out of Japan
		14.3.1	 Adjuvant Therapy for ESCC
		14.3.2	 Neoadjuvant Therapy for ESCC
			14.3.2.1	 Neoadjuvant Chemotherapy (nCT) for ESCC
			14.3.2.2	 Neoadjuvant Chemoradiotherapy (nCRT) for ESCC
	14.4	 Future Perspective of Adjuvant and Neoadjuvant Therapeutic Modality
	References
15: Chemotherapy and Chemoradiotherapy
	15.1	 Purpose and Evaluation of Chemotherapy
	15.2	 Chemotherapeutic Agents Used for Esophageal Squamous Cell Carcinoma
		15.2.1	 Bleomycin
		15.2.2	 Fluoropyrimidine
			15.2.2.1	 5-Fluorouracil
			15.2.2.2	 S-1
		15.2.3	 Platinum Agents
			15.2.3.1	 Cisplatin
			15.2.3.2	 Carboplatin
			15.2.3.3	 Oxaliplatin
			15.2.3.4	 Nedaplatin
		15.2.4	 Taxanes
			15.2.4.1	 Paclitaxel
			15.2.4.2	 Docetaxel
		15.2.5	 Vinca Alkaloids
			15.2.5.1	 Vindesine
			15.2.5.2	 Vinorelbine
		15.2.6	 Topoisomerase Inhibitors
			15.2.6.1	 Etoposide
			15.2.6.2	 Irinotecan
		15.2.7	 Others
	15.3	 Combination Chemotherapy
		15.3.1	 Combination with Platinum Agents
			15.3.1.1	 CDDP and Fluoropyrimidine
			15.3.1.2	 CDDP and Vinorelbine
			15.3.1.3	 CDDP and Gemcitabine
			15.3.1.4	 Oxaliplatin and Fluoropyrimidine
			15.3.1.5	 Nedaplatin and Fluoropyrimidine
		15.3.2	 Combination with Taxanes
			15.3.2.1	 Paclitaxel and Platinum
			15.3.2.2	 Paclitaxel and Fluoropyrimidine
			15.3.2.3	 Docetaxel and CDDP
		15.3.3	 Triplet Combinations
			15.3.3.1	 5-FU, CDDP, and Paclitaxel
			15.3.3.2	 5-FU, CDDP, and Docetaxel
			15.3.3.3	 5-FU, CDDP, and Doxorubicin
	15.4	 Chemoradiotherapy
		15.4.1	 Definitive Chemoradiotherapy for Resectable Esophageal Cancer
			15.4.1.1	 Chemoradiotherapy with CDDP and 5-FU
			15.4.1.2	 Chemoradiotherapy with Carboplatin and Paclitaxel
			15.4.1.3	 Chemoradiotherapy with Oxaliplatin and 5-FU
		15.4.2	 Chemoradiotherapy for Unresectable Locally Advanced Esophageal Cancer
			15.4.2.1	 Chemoradiotherapy with CDDP and 5-FU
			15.4.2.2	 Chemoradiotherapy with Triplet of CDDP, 5-FU, and Docetaxel
			15.4.2.3	 Induction Chemotherapy Followed by Definitive Chemoradiotherapy
	15.5	 Chemotherapy or Chemoradiotherapy with Targeted Agents
		15.5.1	 Antihuman Epidermal Growth Factor Receptor Inhibitors
			15.5.1.1	 Gefitinib and Erlotinib
			15.5.1.2	 Anti-EGFR Antibody
			15.5.1.3	 Other Antihuman Epidermal Growth Factor Receptor Inhibitors
		15.5.2	 Immune-Checkpoint Inhibitors
			15.5.2.1	 Nivolumab
			15.5.2.2	 Pembrolizumab
			15.5.2.3	 Combination of Immune-Checkpoint Inhibitors
		15.5.3	 Other Potential Molecular Targets
	15.6	 Future Directions
	References
16: Radiation Therapy for Esophageal Squamous Cell Carcinoma
	16.1	 Indications of Radiotherapy
	16.2	 Radiation Therapy Techniques
		16.2.1	 Simulation
		16.2.2	 Treatment Planning
			16.2.2.1	 Target Volume Delineation
				Gross Tumor Volumes (GTV)
				Clinical Target Volume (CTV)
				Planning Target Volume (PTV)
			16.2.2.2	 Field Design
			16.2.2.3	 Dose and Fractionation
			16.2.2.4	 Dose Constraints
		16.2.3	 Brachytherapy
	16.3	 Treatment Results
		16.3.1	 Radiotherapy Alone
		16.3.2	 Chemoradiotherapy
			16.3.2.1	 Chemoradiotherapy for Unresectable Locally Advanced Esophageal Cancer
			16.3.2.2	 Chemoradiotherapy for Resectable Esophageal Cancer
			16.3.2.3	 Prophylactic Chemoradiotherapy
			16.3.2.4	 Neoadjuvant Chemoradiotherapy
		16.3.3	 Palliative Therapy
	16.4	 Toxicity of Radiotherapy
	16.5	 New Radiation Treatment Modalities
	References
17: Hong Kong Experiences of the Treatment of Esophageal Squamous Cell Carcinoma
	17.1	 Introduction
	17.2	 Diagnosis
	17.3	 Investigations
		17.3.1	 Staging
		17.3.2	 Patient Pre-treatment Evaluation
		17.3.3	 Patient Pre-habilitation and Preparation for Surgery
	17.4	 Treatment
		17.4.1	 Endoscopic Treatment for Early Cancer
		17.4.2	 Neoadjuvant or Adjuvant Treatment
		17.4.3	 Surgery
			17.4.3.1	 Cervical Esophageal Cancer
			17.4.3.2	 Intra-thoracic Esophageal Cancer
				The Approach to Resection
				Extent of Resection and Lymphadenectomy
				Reconstruction
		17.4.4	 Postoperaive Management
		17.4.5	 Other Morbidities and Mortality
	17.5	 Palliation
	17.6	 Summary
	References
18: Squamous Cell Carcinoma of the Esophagus: The Indian Experience
	18.1	 Introduction
	18.2	 Epidemiology, Etiology, Diagnosis, and Staging of Squamous Esophageal Cancer in India
		18.2.1	 Epidemiology of Esophageal Cancer in India
		18.2.2	 Etiology
			18.2.2.1	 Tobacco Consumption
			18.2.2.2	 Alcohol
			18.2.2.3	 Dietary Factors
			18.2.2.4	 Low Socio-economic Status
			18.2.2.5	 Genetic Factors
			18.2.2.6	 Role of Human Papilloma Virus (HPV)
		18.2.3	 Diagnosis
			18.2.3.1	 Barium Swallow
			18.2.3.2	 Endoscopy
			18.2.3.3	 Endoscopic Ultrasonography
			18.2.3.4	 Contrast Enhanced Computed Tomography (CECT) Scan of the Thorax and Upper Abdomen
			18.2.3.5	 Positron Emission Tomography (PET/PET-CT)
		18.2.4	 Staging
		18.2.5	 The Tata Memorial Centre Experience
	18.3	 Treatment of Squamous Esophageal Cancer in India
		18.3.1	 Treatment
			18.3.1.1	 Patient Evaluation
			18.3.1.2	 Principles of Management
		18.3.2	 Surgery
			18.3.2.1	 Approach
			18.3.2.2	 Lymphadenectomy
			18.3.2.3	 Minimally Invasive Surgery
			18.3.2.4	 Reconstruction
		18.3.3	 Multi-modality Management
		18.3.4	 Chemoradiotherapy
		18.3.5	 Palliative Therapy
		18.3.6	 The Tata Memorial Centre Experience
	18.4	 Research in Esophageal Cancer in India
		18.4.1	 Epidemiology Research
		18.4.2	 Primary Treatment
		18.4.3	 Neoadjuvant Therapy
		18.4.4	 Surgical Trials
			18.4.4.1	 Anastomotic Technique
			18.4.4.2	 Peri-operative Management
		18.4.5	 Palliative Treatment
		18.4.6	 Ongoing Research
	18.5	 Future Directions
	References
19: Korean Experiences of the Treatment of Esophageal Squamous Cell Carcinoma
	19.1	 Esophageal Cancer in Korea
	19.2	 Diagnosis and Staging
	19.3	 Endoscopic Treatment for Superficial Esophageal Cancer
	19.4	 Surgery
		19.4.1	 Analysis of Surgical Treatment Based on Health Insurance Review and Assessment Service Data
		19.4.2	 Approach, Extent of Resection, and Lymphadenectomy
			19.4.2.1	 Extent of Resection and Lymphadenectomy
		19.4.3	 Reconstruction
		19.4.4	 Minimally Invasive Esophagectomy (MIE) Series in Korea
	19.5	 Definitive Chemoradiation and Other Treatments
	19.6	 Neoadjuvant and Adjuvant Therapy
	19.7	 Summary
	References
20: Chinese Experiences of the Treatment of Esophageal Squamous Cell Carcinoma
	20.1	 Introduction
	20.2	 Epidemiology
	20.3	 Endoscopic Resection
	20.4	 Surgery
		20.4.1	 Surgical Approach
		20.4.2	 Anastomotic Techniques
		20.4.3	 Extent of Lymphadenectomy
	20.5	 Perioperative Therapy
	20.6	 Targeted Therapy and Immunotherapy
	References
Index