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Section 3 Clinical Presentation/
Diagnosis
Clinical Presentation/Diagnosis
Esophageal squamous cell carcinoma frequently presents in the
middle or proximal esophagus. Despite different histology,
patients with both adenocarcinoma and ESCC located in the
thoracic part of the esophagus have similar clinical presentation. Only a minority group of patients (6–10%) is asymptomatic at the time of diagnosis (Cavallin 2018).
Signs and Symptoms
At an early stage of the disease, symptoms can be non-specific
such as minor change in sensation when swallowing or dyspepsia. When the tumor progresses, this is usually followed by
impairment of the ability to swallow (dysphagia) and/or pain
on swallowing (odynophagia). Meat and bread are often the
first type of foods that give to dysphagia or regurgitation, often
progressing over weeks to dysphagia for semi-solids and liquids. Some patients present with dribbling saliva (sialorrhea),
when even water cannot be swallowed.
Patients with locally advanced tumors often present with
weight loss caused by dysphagia, which occurs if the tumor causes
reduction of the esophageal diameter. Also cancer-related
anorexia may contribute to weight loss. Patients can experience
pain in the epigastric or retrosternal area. Pain in other body
parts, such as bone structures, may indicate metastatic disease.
Some patients have obscure gastro-intestinal blood loss as a
sign of underlying ESCC, which can result in iron deficiency
anemia (Schatz and Rockey 2017). Melena or hematemesis can
occur especially in patients that take NSAIDs or oral anticoagulants. Acute severe gastro-intestinal bleeding due to tumor
invasion into the aorta or pulmonary arteries is rare.
Respiratory symptoms, such as persistent cough and recurrent pneumonia, can be caused by aspiration of undigested
food or direct invasion of the tumor in the tracheobronchial
three (tracheobronchial fistula) which is a late phenomenon of
tumor progression. A small number of patients will present
with chest infection or a lung abscess.
Section 4 Clinical Staging
Clinical Staging
Clinical staging is performed to estimate the extent of
the disease and to decide which treatment is indicated.
Two staging classification systems are commonly used.
The 8th edition of the Union for International Cancer
Control (UICC)/American Joint Committee on Cancer
(AJCC) TNM cancer staging and the Japanese
Classification of esophageal cancer (JES) (Kitagawa
2019; Rice 2017). There are some differences between
the two staging systems. UICC defines the N-category
according to the number of the metastatic regional
lymph nodes only and supraclavicular nodes are
excluded (Udagawa and Ueno 2018). In JES system,
regional nodes are divided into five different patterns
according to the primary tumor location, and supraclavicular nodes are defined as regional nodes for thoracic
esophageal cancer (Table 2 and Figure 1). The most
commonly used staging groups according to the 8th
edition of the AJCC/UICC are illustrated in Table 1.
102
upR
100
102
R
104
R
106
8p
12
Figure 1 Station numbers of regional lymph nodes.
8a
5
13
17
103
101
R
114
106
pre
105
106
tbR tbL
107
109
R
108
112
110
111
20
16
7
9
3b
14
14
6
15
102
100
102
L
101
106
reel
109
L
112
1
3a
V
A
L
106
112
112
113
2
11p
104
L
4sa
19
11d
18
4d
10
4sb
Table 1
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Cancer staging categories for ESCC (Adapted from Rice et al. 2017).
Category Criteria
T category T category
TX Tumor cannot be assessed
T0 No evidence of primary tumor
Tis High-grade dysplasia, defined as malignant cells confined by the basement membrane
T1 Tumor invades the lamina propria, muscularis mucosae, or submucosa
Tis Tumor invades the lamina propria, muscularis mucosae, or submucosa
T1a* Tumor invades the lamina propria or muscularis mucosae
T1b* Tumor invades the submucosa
T2 Tumor invades the muscularis propria
T3 Tumor invades adventitia
T4 Tumor invades adjacent structures
T4a* Tumor invades the pleura, pericardium, azygos vein, diaphragm, or peritoneum
T4b* Tumor invades other adjacent structures, such as aorta, vertebral body, or trachea
N category
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in 1–2 regional lymph nodes
N2 Metastasis in 3–6 regional lymph nodes
N3 Metastasis in 7 or more regional lymph nodes
M category
M0 No distant metastasis
M1 Distant metastasis
Table 2 Lymph node groups according to tumor location (JES classification).
Category Criteria
T category T category
TX Depth of tumor invasion cannot be assessed
T0 No evidence of primary tumor
T1a Tumor invades mucosa
T1a-EP Carcinoma in situ (Tis)
T1a-LPM Tumor invades lamina propria/mucosae
T1a-MM Tumor invades muscularis mucosae
T1b Tumor invades submucosa (SM)
T1b-SM1 Tumor invades the upper third of the submucosal layer
T1b-SM2 Tumor invades the middle third of the submucosal layer
T1b-SM3 Tumor invades the lower third of the submucosal layer
T2 Tumor invades muscularis propria
T3 Tumor invades adventitia
T4
T4a
T4b
Tumor invades adjacent structures
Pleura, pericardium, diaphragm, lung, thoracic duct, azygos vein, nerve
Aorta (great artery), trachea, bronchus, pulmonary vein, pulmonary artery, vertebral body
(Continued)
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Table 2
(Continued)
N category
Tumor location Group 1 (N1) Group 2 (N2) Group 3 (N3)
Cervical Ce 101, 106rec
Upper thoracic Ut 101, 105, 106rec 104, 106tbL, 107, 108, 109 102mid, 106pre, 106tbR, 110, 112aoA,
Middle thoracic Mt 106rec, 108, 1, 2, 3a 101, 104, 105, 107, 109, 110, 112aoA, 112pul, 7, 9, 20 106tbL
Lower thoracic Lt 110, 1, 2, 3a, 7, 20 101, 106rec, 107, 108, 109, 112aoA, 112pul, 9 104, 105, 106tbL, 111, 8a, 11p
Abdominal Ae 110, 1, 2, 3a, 7, 20 111, 112aoA, 112pul, 8a, 9, 11p, 19 106rec, 107, 108, 109, 11d
Nodes other than N1 through N3 are expressed as N4
a
Limited to the area which can be dissected from the cervical incision
M category
Mx Distant organ metastasis cannot be assessed
M0
M1
a
No distant organ metastasis
Distant organ metastasis
102, 104, 105
Routine Clinical Staging
Since 2017, esophagogastroduodenoscopy (EGD) with biopsies,
endoscopic ultrasonography (EUS) with fine-needle aspiration
(FNA) of suspected lymph nodes and
tomography/computed tomography (FDG-PET/CT) are mainstays
in clinical staging of esophageal cancer or cancer of the esophagogastric junction (EGJ) (Rice 2017). This is in accordance with
the National Comprehensive Cancer Network (NCCN) guideline
(Ajani 2019). The order in which these diagnostic modalities are
used can vary, depending on physician preference, costs, and availability. In general, there are two common strategies. The first consists of EGD with biopsies, EUS, and EUS-FNA to determine clinical
18
F-FDG positron emission
a
100
112pul, 1, 2, 3a, 7, 20
the upper and lower border of the tumor, the location of the Z-line,
gastric folds, and diaphragm. Biopsies are taken from all suspected
areas to confirm pathological diagnosis of ESCC.
Computed Tomography (CT)
CT should include the neck, thorax, and abdomen, and be performed with oral and intravenous contrast agents to evaluate Nand M-stage. With the advent of multi-detector CT, more accurate
staging of esophageal cancer is possible (Kim etal. 2009). The
high definition of scans now also allows more accurate primary
tumor and nodal staging, although these parameters may be more
accurately defined by endoscopic ultrasound.
T- and N-stage followed by FDG-PET/CT for additional clinical
N-stage and detection of distant metastases (M-stage). This strategy
is efficient because all clinical staging categories are determined, but
is also costly. An endoscopic submucosal dissection (ESD) can be
performed for an early cancer when no (lymph node) metastases are
present. The second strategy begins with FDG-PET/CT to determine clinical M-stage and therefore in case of cM1 stage it can be
considered that no additional diagnostics are required. This second
strategy is cost- effective, but, does not cover the entire TNM-stage.
Endoscopic Ultrasound (EUS)
Endoscopic ultrasound is considered to be the best tool to distinguish T1 lesions from T2-T4 lesions and for estimating the
depth of ESCC invasion into the esophageal wall with a high
sensitivity and specificity of 81–92% and 94–97%, respectively
(Puli etal. 2008; Quint and Bogot 2008). For cT1 cancers, EUS
overestimates the depth of invasion in 20–30% of patients
(Gotink 2017). In these patients, endoscopic judgment is the
Endoscopy with Biopsy
In the developed world esophageal cancer is usually diagnosed at
upper endoscopy with biopsy. Occasionally a barium swallow is the
first investigation but it must be followed by endoscopic biopsy to
confirm the diagnosis when abnormalities are seen. During endoscopy, anatomical landmarks are mapped, as well as the location –
for ESCC often proximal or mid esophagus – and circumferential
extent of the tumor (Rustgi and El-Serag 2014). These landmarks
are the distance from the incisors to the upper esophageal sphincter,
mainstay to assess if a cT1 esophageal cancer may be endoscopic
resectable. EUS uses high-resolution probes which provides
multi-layered echo structures of the esophageal wall. Linear
EUS with FNA of suspected lymph nodes on indication should
be carried out to evaluate lymph node involvement. Accurate
staging of the primary tumor and locoregional lymph nodes by
EUS can be used to inform decisions on curative therapy,
including primary chemoradiotherapy, neoadjuvant therapy
followed by surgery or surgery alone. Despite the high accuracy
of EUS for ESCC staging, lymph node metastasis in the neck or
5 ESOPHAGEAL SQUAMOUS CELL CARCINOMA 87
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abdominal field are difficult to detect by EUS and thus a PET/
CT of the neck should be performed.
Positron Emission Tomography/Computed
Tomography (PET/CT)
Positron emission tomography (PET) is a unique imaging
modality using the radiopharmaceutical
2-deoxy-D-glucose) for the detection of high rate glucose metabolism within carcinomas. FDG-PET in esophageal cancer plays
an important role in clinical staging (detection of suspicious
lymph nodes, distant metastasis) but is also of value as diagnostic
evaluation modality after (chemo)radiotherapy or in early detection of recurrent disease (surveillance).
PET/CT has great advantage as not only FDG uptake but also
tumor size by CT part could be measured simultaneously. The
detection rate of esophageal cancer (i.e. FDG uptake) is 0% in
pT1a where the tumor confined in the mucosal layer, and 20%
in pT1b up to the submucosal layer, and 100% when depth
reached pT2 or more (Kato 2005). Also, PET/CT shows additional value, as it improves specificity over morphological
image to assess locoregional lymph node metastases (Miyazaki
2014; Van Westreenen etal. 2004). Where microscopic metastasis sometimes causes false negative results, inflammatory diseases such as pneumonia and sarcoidosis could explain false
positive results as well as esophagitis at the level of the primary
tumor. In these circumstances, shape and size of lymph nodes
are helpful to distinguish infection from lymphadenopathy due
to cancer involvement. Finally, PET/CT is particularly useful in
advanced cancer with high possibility of distant metastases,
since high contrast of PET enables to detect lesions that are
missed by CT-scan. In case brain metastases are suspected
based on clinical symptoms, an MRI is essential to exclude or
diagnose brain metastases, but is not part of standard staging.
18
F-FDG (2[18F]-fluoro-
Other Staging Techniques
In addition to the diagnostic modalities already described, a
variety of specific diagnostic and imaging modalities may be
recommended by the multidisciplinary tumor board (MTB)
for tumor staging depending on the presentation, site of the
primary tumor or suspicion of metastatic disease.
diagnostic modality for esophageal tumors located at or above
the level of the carina, because of the high incidence of airway
involvement (Carreiro 2013; Riedel 2000).
Endobronchial Ultrasonography (EBUS)
During endobronchial ultrasonography a radial probe or balloonprobe is passed through the working channel of the bronchoscope. While the balloon probe requires inflation of the balloon
for ultrasonographic visualization, the radial probe requires direct
apposition to the airway wall. Endobronchial ultrasonography
allows the pulmonologist take fine needle aspirations of lymph
nodes not accessible with EUS or to take biopsies from lesions
suspicious or tumor infiltration in the trachea. Finally, EBUS
could also improve tumor staging, by determining the depth and
extent of tumor into the tracheobronchial wall.
MRI-scan
Magnetic resonance imaging (MRI) is a non-irradiating and noninvasive promising technique because it provides excellent softtissue contrast which allows us to better assess morphological
differences between the normal and pathologic esophagus.
Nevertheless, MRI does not have a role in routine clinical staging
yet because of its low availability and technical limitations (e.g.
motion artifacts). Some studies on high-resolution T2-weighted
and diffusion-weighted MRI showed that MRI could clearly
depict the different layers of the esophageal wall (Wei 2017;
Yamada 2014). The T2-weighted technique showed high accuracy to distinguish tumor stage T2 and T3, but it tends to over
stage T1 tumors. A recent meta-analysis of 11 trials showed a
pooled sensitivity of 92% (95% CI 82–96) and specificity of 67%
(95% CI 51–81) for MRI used to distinguish T0 and T1 tumor
stages, and sensitivity and specificity of respectively 86% (95% CI
76–92) and 86% (95% CI 75–93) for differentiation between T2
or lower disease and T3 and higher disease (Lee 2021). Recent
studies focused on the performance of MRI for lymph node
assessment showed pooled sensitivity of 71% (95% CI 60–80) and
specificity of 72% (95% CI 64–79). To conclude, MRI has a good
sensitivity for T-staging in esophageal cancer and to discriminate
between metastatic and non-metastatic lymph nodes, which is
promising for the future role of MRI in routine clinical staging.
Bronchoscopy
The proximal part of the intrathoracic esophagus is located between the trachea and the vertebral column. When esophageal
cancer is located beyond the level of the carina, tracheobronchial invasion (T4b) may be present which often is associated
with palliative care. Because of the therapeutic consequences of
tracheobronchial invasion, patients with these proximal esophageal tumors should therefore undergo pretreatment bronchoscopy (with biopsy on indication) when CT-scan or EUS
suggests airway invasion (Allum 2002; Omloo 2008). Other
studies even suggest to include bronchoscopy as routine
Diagnostic Laparoscopy
Most staging algorithms also include laparoscopy in the
assessment of tumors of the distal esophagus. Laparoscopy
could provide more accurate information about local invasion
of the tumor, lymph node metastases and distant metastases
and allows the surgeon to take biopsies of small peritoneal or
liver surface metastases which may not be apparent on PET/
CT. It also allows direct anesthetic assessment of patients who
may be recommended to have surgical resection as part of
definitive treatment. Similarly, staging thoracoscopy and mediastinoscopy are sometimes recommended.
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Summary
1 The 8th edition of UICC/AJCC TNM and the Japanese classification
system JES are commonly used to stage esophageal cancer.
2 Routine clinical staging consists of upper endoscopy with biopsies,
endoscopic ultrasonography with fine-needle aspiration and
18
F-FDG PET/CT.
3 Depending on clinical presentation, site of the primary tumor or
clinical suspicion, additional tests including bronchoscopy, EBUS,
MRI-scan or diagnostic laparoscopy/thoracoscopy may be indicated.
Section 5 Histopathological Staging
Handling of Specimens
Accurate pathological staging requires careful examination of
the gross specimen for cancer location, size, configuration,
margins, invasion depth, and nodal status.
1. Endoscopic Resection Specimen
Endoscopic submucosal dissection (ESD) has been recognized
as a modality for both diagnosis and treatment of early-stage
ESCC. (Kumarasinghe 2020; Marginean 2020). Compared
to endoscopic mucosal resection, ESD provides larger and
intact specimens with submucosal tissue for accurate pathological assessment of tumor grade, invasion depth and lymphovascular invasion. Specimens should be pinned out on
a board in order to avoid the intern tendency to curl and
fixed in 10% buffered formalin (for half a day or more often
overnight). According to the guideline of Japan Esophageal
Society (JES), the esophageal mucosa can be treated with a
relatively low concentration (0.1–0.5%) of iodine solution
to increase the contrast between lesions and normal areas.
(Japanese Esopahgeal Society 2017) After inking the margins,
the specimen should be serially cut in a 2- to 4-mm interval
and entirely submitted for pathological assessment.
2. Esophagectomy Specimen
Patients with ESCC are often treated with chemotherapy and
radiation therapy prior to resection. The main tumor mass may
be absent with only a shallow ulcer, mucosal erosion, or
depressed fibrotic lesion at its former site. The specimen should
be opened longitudinally, preferably form the left side, with the
size of esophagus and stomach measured and recorded. The
size of any identified lesion and its distance to margins should
be recorded. After inking the margins, the specimen should be
pinned out on a board and fixed in 10% buffered formalin
overnight. A superficial lesion should be serially cut longitudinally and entirely submitted for pathological sections. For an
advanced lesion, representative sections including one with the
deepest invasion should be taken. Surgical margins should be
evaluated both macroscopically and microscopically. Lymph
nodes submitted as separate specimens should also be documented in the pathology report.
Esophageal Dysplasia
The precursor of ESCC is dysplasia of squamous epithelium.
Unlike invasive carcinoma, disoriented proliferation of epithelial cells in squamous dysplasia is limited to the basal membrane.
On white-light endoscopy, neoplastic disease appears as a flat,
slightly depressed lesion with mild redness. In pathological sections, squamous dysplasia displays both cytological atypia and
architectural distortion. Cytological atypia is characterized by
nuclear abnormalities, including enlargement, pleomorphism,
hyperchromasia, loss of polarity, and overlapping. Architectural
distortion is characterized by impaired epithelial maturation.
The grading system for squamous dysplasia has been controversial throughout the years and different systems were used
in Eastern and Western practices. Since 2000, the WHO introduced a two-tier system (low-grade vs. high-grade dysplasia).
This has been the sole recommended classification system by
the WHO Classification in 2019. (WHO Editorial Board 2019)
The term “squamous cell carcinoma in situ” frequently used
in Japan and some other parts of Asia has been classified as
“high-grade dysplasia,” when more than half of the epithelium is involved or when severe cytological atypia is present
(regardless of the extent of epithelial involvement) (Figure 2a).
Low grade is defined as dysplasia with mild cytological atypia,
involving only half of the epithelium (Figure 2b).
Esophageal Squamous Cell Carcinoma
Invasive ESCC is defined as invasion of neoplastic squamous cells
through the basal membrane into the lamina propria and deeper
layers. When better differentiated, it is associated with keratinization. Macroscopically, it often presents at an advanced pathological stage with an ulcerative mass. A macroscopic classification has
been provided by the JES (Japanese Esopahgeal Society 2017).
ESCC is graded by the degree of cytological atypia, mitotic
activity and the presence of keratinization. A three-tiered system
Figure 2a High-grade squamous dysplasia.
5 ESOPHAGEAL SQUAMOUS CELL CARCINOMA 89
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Figure 2b Low-grade squamous dysplasia.
consisting well, moderately or poorly differentiated SCC is commonly applied. However, since the distinction between “well” and
“moderately” is highly observer dependent, a two-tiered system
(well, moderately vs poorly) may be clinically more relevant.
1
Well differentiated (Figure 3a) = Grade 1: enlarged cells with
eosinophilic cytoplasm, intercellular bridges, and keratin pearls
formation. Cytological atypia is minimal and the mitotic rate is low.
The invasive margin is pushing and the cells remain well ordered.
Moderately differentiated (Figure 3b) = Grade 2: more disor-
2
ganized cells with evident cytological atypia. Mitotic figures are
easily identified. There is usually surface parakeratosis, but keratin pearl formation is infrequent.
3
Poorly differentiated (Figure 3c) = Grade 3: predominantly
basal-like cells forming nests, which may show central necrosis.
The tumor nests consist of sheets or pavement-like arrangements
of tumor cells with occasional parakeratotic or keratinizing cells.
Pathological Assessment
There are two different staging systems for ESCC. The most
widely accepted system from the American Joint Committee on
Cancer (AJCC)/Union for International Cancer Control (UICC)
Figure 3b Moderately differentiated squamous cell carcinoma of the
esophagus.
Figure 3c Poorly differentiated squamous cell carcinoma of the
esophagus.
is based on the TNM descriptor published its 8th edition in 2017
(James 2017). In addition to the AJCC system, Japan has its own
ESCC staging system (Japanese Esophageal Society 2017). The
8th edition of AJCC/UICC demonstrated that simple sharing of
stage groups among classifications was not possible due to
marked survival differences and unique pathologic stage groups
with (ypTNM) or without preoperative treatment (pTNM).
Today, the clinical relevance of pathologic staging remains relevant for early-stage cancers, as the most accurate reflection of
cancer facts and as a survival reference point, but depends greatly
on neoadjuvant therapy for advanced-stage cancers.
Figure 3a Well-differentiated squamous cell carcinoma of the
esophagus.
Pathological Staging of Squamous Cell
Carcinoma
The most commonly used staging groups are the classifications
according to the 8th edition of the AJCC/UICC, as illustrated
in Table 3. The alternative Japanese staging manual is discussed
in the previous section (Table 4 and Figure 1).
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Table 3 Pathologic stage groups for ESCC (Adapted from Rice et al. 2017).
pStage group pT pN pM pGrade pLocation
0 Tis N0 M0 N/A Any
IA T1a N0 M0 G1, X Any
IB T1b N0 M0 G1, X Any
T1 N0 M0 G2-3 Any
T2 N0 M0 G1 Any
IIA T2 N0 M0 G2-3, X Any
T3 N0 M0 Any Lower
T3 N0 M0 G1 Upper/middle
IIB T3 N0 M0 G2–3 Upper/middle
T3 N0 M0 X Any
T3 N0 M0 Any X
T1 N1 M0 Any Any
IIIA T1 N2 M0 Any Any
T2 N1 M0 Any Any
IIIB T4a N0-1 M0 Any Any
T3 N1 M0 Any Any
T2-3 N2 M0 Any Any
IVa T4a N2 M0 Any Any
T4b N0-2 M0 Any Any
T1-4 N3 M0 Any Any
IVb T1-4 N0-3 M1 Any Any
N/A, not applicable; X, not defined.
Table 4
Morbidity after esophagectomy in cornerstone trials.
Open
MIRO-trial 30% 7% – 6%
TIME-trial 34% 7% 14% 2%
ROBOT-trial (open thoracotomy) 58% 20% 11% 2%–
Minimally invasive
Hybrid (MIRO-trial) 18% 11% \– 4%
MIE (TIME-trial) 12% 12% 2% 3%
Robot-assisted MIE (ROBOT-trial) 32% 24% 9% 9%
Abbreviations: MIE: minimally invasive esophagectomy
Pulmonary complications Anastomotic leakage Laryngeal nerve injury Postoperative mortality
Pathological Staging of Superficial Squamous
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Cell Carcinoma
According to JES, esophageal superficial SCC can be subtyped
based on the depth of tumor invasion. The mucosal layer T1a is
divided into three layers (T1a-EP, T1a-LPM, and T1a-MM), and
the submucosal layer T1b is also divided into three layers
(T1b-SM1, T1b-SM2, and T1b-SM3). In endoscopically resected
specimens, lesions located in the submucosa within 200 μm of
the muscularis mucosae are identified as T1b-SM1, and lesions
invading beyond this range are identified as T1b-SM2.
Pathological Staging after Neoadjuvant
Therapy
5 ESOPHAGEAL SQUAMOUS CELL CARCINOMA 91
Chemo- and/or radiotherapy is frequently given before surgery
and induces changes in both tumor cells and surrounding
tissue. While new lesions usually arise from the mucosa, recurrent lesions after chemoradiotherapy could develop in relatively
deep areas of the esophagus without concomitant intraepithelial squamous lesions. Endoscopic biopsy of such deep lesions
could be challenging.
Epithelial cell changes such as nuclear enlargement or shrinkage,
nuclear vacuolation, apoptosis, and necrosis are seen in tumor cells.
Dying cells may release keratin and undergo dystrophic calcification and elicit a surrounding giant cell reaction. Other histologic
responses to therapy include neutrophilic or chronic inflammation.
Stromal changes such as fibrosis and sometimes stromal elastosis
could be present and regional vessels typically show intimal proliferation, endarteritis obliterans, telagiectasia, or organizing thrombi.
Lymph nodes may show fibrosis, necrosis, calcification and keratin
with giant cell reaction. Lymph nodes with these changes, and
without any viable cancer cells, should be considered negative for
metastasis (ypN0). On the other hand, particularly in the mediastinal lymph nodes, fibrotic changes can occur independently from
cytotoxic treatment. Immunohistochemical stains such as -keratin
AE1/AE3 may be used to confirm the presence of rare residual cancer cells and. – should be always interpreted in conjunction with
morphologic findings.
A tumor regression grade (TRG) is used to classify the extent
of tumor regression and is an important prognostic factor.
(Figure 4a/b and 5a/b)The first applied method was the
Mandard system, graded by comparing the amount of residual
tumor versus the amount of therapy-induced fibrosis. (Mandard
1994) Another concept is an estimation of the amount of
residual tumor (%) in relation to the tumor bed, where complete
regression or < 10% residual tumor is related to a good prognosis. (Becker 2003) The Japanese version proposed by the JES
with cutoff value of 1/3 and 2/3 for residual tumor, is also widely
used in ESCC (JES 2017). In a Delphi survey that could represent an international standard for histopathologic TRG grading
of gastroesophageal carcinomas, the expert panel recommended
a four-tiered TRG system for assessing the primary tumor
combined with a three-tiered system for grading therapeutic
response in metastatic lymph nodes (Saliba 2021):
Figure 4a Depressed fibrotic lesion of the esophagus after neoadjuvant
chemoradiotherapy without residual tumor visible (complete
histopathological tumor regression).
Figure 4b Cross section of Figure 4a, with only fibrosis and no tumor visible.
Figure 5a Residual ulcerative tumor of the esophagus after neoadjuvant
chemoradiotherapy.
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Figure 5b Cross section of Figure 4b, with visible tumor residual.
1 Tumor: grade 1: No residual tumor (complete histopathologic
tumor regression)
2
Tumor: grade 2: less than 10% residual tumor (near-complete
regression)
Tumor: grade 3: 10–50% residual tumor (partial regression)
3
4 Tumor: grade 4: greater than 50% residual tumor (minimal/
no regression),
5 Lymph node: grade a: no residual tumor (complete histopathologic TRG)
6
Lymph node: grade b: partial regression (tumor cells and
regression)
Lymph node: grade c: no regression (no sign of tumor response).
7
Prognostic Values of Pathological Staging
Systems
The prognostic values of the pTNM-staging system have
been validated extensively in literature for many tumor types
treated with surgery alone. The Worldwide Esophageal Cancer
Collaboration reported survival discrepancies between different
stages of ESCC using data from 33 institutions from 6 continents
(Figure 6) (Rice 2016a). New to the eighth edition is stage grouping of patients with ESCC who have undergone neoadjuvant
therapy and had pathological review of the resection specimen
(Figure 7) (Rice 2017). The pathological stage groups are identical for both adenocarcinoma and SCC (Figure 8) (Rice 2016b).
Summary
1 The 8th edition of UICC/AJCC TNM and the Japanese classification
system JES are used for pathological staging of ESCC.
2 The precursor of ESCC is squamous dysplasia and is commonly
divided into low- and high- grade dysplasia. ESCC is divided into
well, moderately, and poorly differentiated.
3 Compared to the AJCC system, the Japanese classification differs
in lymph node mapping as this is based on location of lymph nodes
according to tumor location.
4 After neoadjuvant CRT, a tumor regression grade is an important
prognostic factor.
Section 6 Curative Treatment Part I
Endoscopic Treatment
For intramucosal esophageal cancers (EC), endoscopic resection (ER) is the standard treatment. The principle of ER is
based on the fact that the chance of lymph node metastasis is
very small when neoplasia is confined to the mucosal layer of
the esophagus, ER can be curative for these tumors. For ESCC
invading the muscularis mucosa (T1am3) and those with
minimal invasion to the submucosal layer (< 200μm below the
muscularis mucosa, T1b), the incidence of lymph node metastasis was 9.3% and 19.6%, respectively (Fujishiro M 2009). The
risk of lymph node metastasis of early stage ESCC is also significantly higher compared to adenocarcinoma, thus only selected
cases of T1am3 (muscularis mucosae involvement) and T1b are
eligible for ER.
The two main types of ER are endoscopic mucosal resection
(EMR) and endoscopic submucosal dissection (ESD). Multiple
studies showed a higher curative resection rate of ESD than
EMR for superficial ESCC and is thereby the most recommended for low- and high-grade intraepithelial neoplasia and
superficial mucosal cancer (Noordzij 2019). When performing
an ESD, an en-bloc resection with continuous dissection along
the submucosal plane is performed.
The rate of complication after ER is discrepant throughout
the literature, with acute intra-procedural bleeding ranking
from 0.9–24% and perforations from 1.8–6.95%. (Noordzij
2019). One of the main late complications is stricture formation
(3.6–49.7%), however most cases can be adequately treated by
dilatation. There have been novel insights in the prevention of
stricture such as steroid injection therapy and oral steroid
administration, tissue shielding methods with polyglycolic acid
sheet, autologous oral mucosal epithelial sheet transplantation,
and stent placement, but further studies in this research field
are needed (Hikichi 2020). Treatment related mortality was
0.2% with a major complication rate of 1.5% in a large series of
1000 EC patients in which ER was performed (Pech 2014).
Although ER is performed with curative intent, curative ER
is not always possible. Lesions that are limited to the lamina
propria or muscularis mucosae, in the absence of lymphovascular invasion and poor differentiation, don’t need additional
therapy. Incomplete tumor resection, however, is a criterion for
is
Survival (%)
90
100
Survival (%)
Survival (%)
Years
https://t.me/medicina_free
80
70
5 ESOPHAGEAL SQUAMOUS CELL CARCINOMA 93
60
50
40
30
20
10
0
0
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
02
2
pT
pT1
pT2
pT3
pT4a
pN3
pN0
pN1
pN2
8
pM1
100
pM0
2
4
Years
4
Years
4
6810
6
6810
Figure 6 Survival stratified by pT, pN, and pM categories for ESCC.
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