Anatomic Pathology / ESOPHAGEAL CARCINOMAS AFTER CHEMORADIATION

Histopathologic Examination and Reporting of Esophageal

Carcinomas Following Preoperative Neoadjuvant Therapy
Practical Guidelines and Current Issues
Fuju Chang, MD, PhD, Harriet Deere, MBBS, MRCPath, Ula Mahadeva, MBBS, MRCPath,
and Simi George, MBBS, MRCPath
Key Words: Esophagus; Residual carcinoma; Neoadjuvant chemoradiotherapy; Tumor regression grading; Histopathology
DOI: 10.1309/CCR3QN4874YJDJJ7

Abstract
Neoadjuvant chemoradiotherapy is being
increasingly offered to patients with invasive
esophageal carcinoma in an effort to downstage the
tumor and consequently increase the rate of curative
resection. A substantial amount of data has suggested
that pathologic tumor regression following neoadjuvant
therapy is an important predictor of local recurrence
and long-term survival in esophageal cancer. Therefore,
it is important that these posttreatment resection
specimens are handled in a standardized manner and a
reproducible method of tumor regression grading is
used. Pathologic examination of such specimens is not
straightforward, and, in fact, it presents a particular
challenge to pathologists, especially when a good
response to neoadjuvant therapy has been achieved and
little or no residual tumor remains. We provide some
guidelines for handling and reporting such specimens
and outline the commonly used tumor regression
grading systems for posttreatment esophagectomy
specimens.

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Esophageal carcinoma ranks among the 10 most frequent

malignancies worldwide.1,2 The 5-year survival rate from diagnosis for these patients is low, about 10%.2-5 In the past decade,
the incidence of adenocarcinoma of the lower esophagus and
gastroesophageal junction has risen markedly, and it is now
more common than squamous cell carcinoma in the United
Kingdom and United States.6,7 Attempts have been made to use
preoperative chemoradiotherapy to downstage the primary
tumor and destroy occult lymph node metastases to increase the
possibility of a successful complete resection and to decrease
the rate of tumor recurrence.8-18 Meta-analyses of randomized
trials of neoadjuvant treatment in patients with esophageal cancer to date have shown that the degree of benefit is substantial
and highly comparable with the benefits of neoadjuvant treatment in other cancers, such as breast, colorectal, and lung.19-21
At present, there is no clinical imaging modality that can
accurately gauge tumor response to chemoradiation, and
pathologic examination of the posttreatment resection specimen remains the gold standard for evaluation of tumor
response.22 There has been accumulating evidence to suggest
that pathologic responses in the tumor to primary therapy are
important predictors of local recurrence and long-term survival.23-29 Therefore, preoperative neoadjuvant therapy has
been used increasingly in the management of this group of
patients, and many esophageal carcinoma resection specimens
arrive at the laboratory already modified by chemoradiation.
Pathologic examination of such specimens may be difficult,
particularly if there has been a good response to preoperative
neoadjuvant therapy; even the site of the cancer may be difficult to identify macroscopically and microscopically.
We present a brief review of the literature on morphologic changes associated with preoperative neoadjuvant therapy
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and outline the most commonly used tumor regression grading (TRG) systems. Special issues regarding specimen processing and histopathologic examination of posttreatment
esophagectomy specimens are also discussed.

Chemoradiotherapy-Induced Morphologic
Changes
It is well known that chemoradiotherapy causes a number
of histopathologic changes in the tumor and its adjacent tissue
Table 1.23-30
Changes in Tumor Cells
Marked cytoplasmic eosinophilia and vacuolation are
commonly seen Image 1. There is often associated nuclear
atypia without apparent mitotic activity.30 When little residual

tumor remains, carcinoma cells are often dissociated and

arranged singly, in short lines or tubules in a fibrotic stroma.
Carcinoma cells may have very large nuclei, often bizarrely
shaped and multilobated. Nuclear chromatin in tumor cells
tends to be vesicular with large eosinophilic single or multiple
nucleoli. The culmination of these changes is often upgrading
of the tumor to a poorly differentiated carcinoma.
The percentage of tumor cells with neuroendocrine differentiation seems to increase in posttreatment resection specimens Image 2. Morphologically, this can encompass the full
range of the neuroendocrine spectrum, from large cells with
abundant granular eosinophilic cytoplasm to poorly differentiated small round carcinoma cells resembling small cell carcinoma, but immunophenotypic expression of neuroendocrine markers is required for confirmation. Neuroendocrine change was
found in 52% of residual adenocarcinomas after preoperative

Table 1
Neoadjuvant TherapyInduced Morphologic Changes in Tumor Cells and Nonneoplastic Tissue
Morphologic Changes
In tumor cells
Architecture
Nucleus
Cytoplasm
In nonneoplastic tissue
Blood vessels
Stroma
Epithelial changes

Description

Dissociated tubules, short lines, or single cells in a fibrotic stroma; discohesive cells, often suspended in pools
of mucin in mucinous tumors
Nuclear membrane irregularities; chromatin clumping, including pyknosis, karyorrhexis, and formation of
apoptotic bodies; may have large and bizarrely shaped nuclei with multiple lobes and popcorn-like
appearance; fewer mitotic figures; large, often multiple nucleoli
Dense, granular and eosinophilic, or vacuolated; may have merging of cytoplasm of adjacent cells
Intimal proliferation, telangiectasia, organizing thrombi and endarteritis obliterans; atypical endothelial
proliferation also possibly present
Transmural fibrosis and elastosis with a lymphoplasmacytic chronic inflammatory cell infiltrate, bizarre
fibroblasts, foreign body reaction
Esophageal mucosa: may show squamous metaplasia and atrophy of submucosal glands; villiform change
of squamous mucosa; gastric mucosa: may show atrophy of specialized glands and increased numbers
of apoptotic bodies

Image 1 Chemoradiotherapy-induced morphologic changes. Scattered pyknotic carcinoma cells are present in an inflammatory
fibrous stroma. Carcinoma cells show cytoplasmic eosinophilia and vacuolization (H&E, A, 200; B, 400).

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neoadjuvant therapy, whereas such change was seen in only

38% of the paired pretreatment biopsy specimens.31 Notably,
the neuroendocrine component seems to be more resistant to
preoperative neoadjuvant therapy than tumors without such
differentiation, and the presence of neuroendocrine differentiation in residual esophageal carcinomas has been associated
with a worse clinical outcome.31
Stromal and Vascular Changes
Tumor regression in posttreatment specimens seems to be
mostly in the form of fibrosis or fibroinflammatory changes
replacing tumor cells (Image 1).30 Mucinous substance in
fibrotic areas should not be considered as vital residual tumor
but rather a sign of therapeutic success. Bizarre stromal
fibroblasts are often present. There are large, atypical endothelial cells in granulation tissue underlying ulcerated tumor.
Vascular changes such as telangiectasia, organizing thrombi,
myxohyaline intimal proliferation of vessels, and endarteritis
obliterans are common. Giant cell reaction around ghost cells
and keratin may be seen in squamous cell carcinoma.
Nonneoplastic Epithelial Changes
Chemoradiotherapy does not exclusively target the tumor
cells; it also has some effect on nonneoplastic tissues. The morphologic alterations seen, such as an increase in nuclear/cytoplasmic ratio, nuclear pleomorphism, clumping of chromatin,
and the presence of prominent, multiple, and irregular nucleoli,
may cause confusion with dysplasia and carcinoma.
Acanthosis of squamous epithelium away from tumor,
with exaggeration of surface folds giving a serrated appearance, may be present. Esophageal submucosal mucous glands
show acinar atrophy and squamous metaplasia. Squamous

epithelium adjacent to tumor may show spongiosis, focal

acantholysis, ballooning, and cystic degeneration of keratinocytes. Specialized gastric mucosa shows focal gland
atrophy, flattening of epithelium, and nuclear atypia.
Apoptotic bodies may be seen in the parietal and chief cells.
Gland lumina frequently contain neutrophils and cell debris.
There is often a pronounced lymphoplasmacytic infiltrate in
the adjacent esophageal and gastric mucosa.

Tumor Regression Grading

On gross examination, posttreatment resection specimens
can be roughly divided into 3 macroscopic groups. In the first
group, there is bulky residual tumor with no evidence of gross
response to preoperative neoadjuvant therapy. In the second
group, apparent tumor regression is present. No macroscopic
residual tumor is seen but a scar (tumor bed) is found instead.
The third group includes partial-response cases in which
fibrosis and a variable amount of residual tumor are grossly
present. However, accurate TRG relies on the microscopic
assessment. So far, several classification systems have been
used to assess the pathologic response to preoperative neoadjuvant therapy Table 2,30,32-37 none of which has become universally accepted.
The TRG system described by Mandard et al30 seems to
be the most widely used. This system estimates the percentage
of residual carcinoma in relation to the total tumor area,
including the amount of radiation-induced tissue injury. This
method distinguishes 5 tumor regression grades. TRG1 is
defined as the absence of residual tumor and fibrosis extending through the different layers of the esophageal wall. TRG2

Image 2 Neuroendocrine differentiation in residual esophageal carcinoma. A, Poorly differentiated carcinoma cells arranged in
cords and nests showing hyperchromatic nuclei and nuclear molding (H&E, 200). B, Tumor cells are positive for CD56 (400).

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Table 2
Tumor Regression Grading (TRG) Systems Commonly Used
in Gastroesophageal Carcinomas
5-tiered grading system proposed by Mandard et al30
TRG 1, absence of residual cancer and extensive fibrosis
TRG 2, rare residual cancer cells scattered through the fibrosis
TRG 3, increased residual cancer cells but fibrosis still predominating
TRG 4, residual cancer outgrowing fibrosis
TRG 5, absence of regressive changes
4-tiered grading system advocated by Chirieac et al,32 Brucher et
al,25 Swisher et al,33 and Wu et al34
TRG 1, no residual carcinoma
TRG 2, 1%-10% residual carcinoma
TRG 3, 11%-50% residual carcinoma
TRG 4, >50% residual carcinoma
3-tiered grading system advocated by Swisher et al,33 Malaisrie et
al,27 and Wu et al34
P0, 0% residual tumor
P1, 1%-50% residual tumor
P2, >50% residual tumor

is characterized by rare residual cancer cells scattered

throughout the fibrosis. TRG3 has more residual tumor cells,
but fibrosis still predominates. In TRG4, residual cancer cells
predominate in the fibrosis, and in TRG5, the tumor shows no
signs of regression.
This TRG system has been shown to be reproducible by
several authors.23,37 Esophagectomy specimens histologically
graded as TRG1 or TRG2 have been associated with a statistically significant survival benefit compared with other regression classes. However, no statistically significant difference
could be detected between pathologic complete remission
(TRG1) and microscopic residual disease (TRG2) in patients
with esophageal cancer.30 Because the separation of TRG1
from TRG2 tumors is dependent on the diligence of the
pathologist in searching for scanty residual tumor cells, this
statistical nonsignificance may be false.
In a large retrospective review of 235 cases carried out by
Chirieac et al,32 a 4-tiered classification scheme Image 3 for
extent of residual carcinoma was used: 0% residual carcinoma, 1% to 10% residual carcinoma, 11% to 50% residual carcinoma, and more than 50% (gross residual carcinoma).
Overall survival was best for patients with no residual carcinoma and worst for patients with more than 50% residual carcinoma, but there was no statistical difference in survival
between patients with 1% to 10% and 11% to 50% residual
carcinoma, who were in an intermediate prognostic category.
On the basis of these results, Wu et al34 proposed a 3tiered classification as P0 (0% residual carcinoma), P1 (1%50% residual carcinoma), and P2 (>50% residual carcinoma)
to reflect the status of tumor response to chemoradiation. The
4- and 3-tiered grading systems were tested in 60 coded cases
of esophageal adenocarcinomas treated with preoperative
chemoradiation followed by esophagectomy. The cases were
reviewed by 6 pathologists from 4 institutions for extent of
residual carcinoma and pathologic TNM stage. Their results

suggested that the interobserver agreement for extent of residual carcinoma is excellent when using a 3-tiered classification
scheme (all scores >0.75). Patients with 0% residual carcinoma (P0) had significantly better overall survival than
patients with 1% to 50% residual carcinoma (P1) and patients
with more than 50% residual carcinoma (P2). Further subdividing the pathologic response in the P1 group into 1% to 10%
residual carcinoma and 11% to 50% residual carcinoma was
not highly reproducible and could achieve at best only good
agreement among pathologists ( = 0.62 for 1%-10% residual
carcinoma; = 0.50 for 11%-50% residual carcinoma).
Therefore, this 3-tiered grading system seems to be more easily implemented and more reproducible and yields similar
quality prognostic information.
Pathologic complete response rates have been reported in up
to 30% of patients.23-37 Most patients experience at least a partial
response after preoperative neoadjuvant therapy. Although different neoadjuvant therapy regimens have been used for preoperative treatment of different carcinoma types, data have suggested
that the TRG classifications could be equally applicable to squamous cell carcinoma and adenocarcinoma.26

Special Issues in Specimen Examination

and Reporting
As for conventional cancer resection specimens, all posttreatment esophagectomy specimens should be examined by
experienced surgical pathologists according to standardized
protocols (eg, College of American Pathologists Cancer
Protocols and the Royal College of Pathologists Minimum
Dataset) that include World Health Organization tumor classification, tumor differentiation, lymph node involvement,
resection margin status, and TNM staging. The y symbol
should be used for staging following neoadjuvant chemoradiotherapy.38 The ypTNM categorizes the extent of residual
tumor in posttreatment resection specimens; it is not an estimate of tumor before initiation of neoadjuvant therapy.38
Macroscopic Examination
Specimens should be sent immediately to the pathology
laboratory, ideally in the fresh state. If this is not possible, the
specimen should be fixed in formalin of a volume at least
twice that of the specimen. The specimen should be accompanied by full clinical information, including the tumor site; the
tumor type and grade if biopsied before neoadjuvant therapy;
the type of neoadjuvant therapy; and the radiologic and clinical
assessments of the response to neoadjuvant therapy. Owing to
neoadjuvant therapyinduced fibrosis, the esophagectomy
specimens may be of suboptimal quality and any tears or
defects in the esophageal adventitia or muscularis propria
need to be carefully documented.
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Specimens should be well fixed. The issue of whether the

esophagus should be opened longitudinally and pinned or left
intact in the region of the tumor and the lumen stuffed with a

3-Tiered

4-Tiered

P0
(0%)

TRG1
(0%)

tissue paper wick is a contentious one.39 It is our opinion that

as long as the circumferential resection margin is inked before
cutting through it, a flexible approach should be adopted, with

TRG2
(1-10%)

P1
(1-50%)

TRG3
(11-50%)

P2
(>50%)

TRG4
(>50%)

Image 3 Schematic diagram and representative illustrations for assessment of residual esophageal carcinoma in
posttreatment resection specimens. In the 4-tiered tumor regression grading (TRG) system, the extent of residual carcinoma is
classified as 0% residual carcinoma (TRG1), 1% to 10% residual carcinoma (TRG2) (arrows), 11% to 50% residual carcinoma
(TRG3), and >50% residual carcinoma (TRG4). The modified 3-tiered system is devised by combining TRG2 and TRG3 to form a
single category. (Modified from Wu et al.34)

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noncircumferential and impalpable tumors best pinned and

bulky circumferential tumors best left intact.
The sampling technique and the number of blocks taken
are clearly dependent on the size of the residual tumor. In many
institutions, including ours, the fixed specimen is cut into complete transverse slices encompassing the entire area of tumor
Image 4. Orientation of the sliced sections can be achieved by
inking the quadrants of circumferential resection margin in different colors. If the lesion remains macroscopically visible, the
specimen can be handled as a specimen not having received
preoperative therapy. A minimum of 4 paraffin blocks should
be taken from the tumor, including samples from its closest
point to the nearest margin to enable microscopic assessment.
In approximately one third of cases, the tumors may have complete or near complete response to preoperative therapy.
Macroscopic assessment of these specimens can be difficult.
The tumor may be ill-defined and impossible to distinguish
from fibrous stromal tissue. In these cases, it is important to
identify the tumor bed. Characteristically, this is a central,
sometimes somewhat edematous-appearing area of fibrosis
Image 5. Pathologic complete response is the gold standard
for many of the ongoing clinical trials and is recognized to be a
good prognostic factor for patients; pathologists must, therefore, sample widely to confirm that there is indeed no pathologically detectable disease. If the tumor bed cannot be identified
macroscopically, the entire area of macroscopic abnormality
may need to be blocked.
The Siewert classification of junctional adenocarcinoma
is used, as for tumors resected without previous neoadjuvant
therapy.40,41 Accordingly, adenocarcinoma of the distal esophagus with the center of the tumor lying 1 to 5 cm above the

gastroesophageal junction is designated as Siewert type 1,

with the center of the tumor lying between 1 cm above and 2
cm below the gastroesophageal junction is designated as
Siewert type 2, and with the center of the tumor lying between
2 and 5 cm below the gastroesophageal junction is designated
as Siewert type 3. This classification determines which
ypTNM system should be used: Siewert type 1 adenocarcinomas are considered as esophageal primary tumors, whereas
type 2 and type 3 adenocarcinomas are regarded as gastric primary tumors. Notably, carcinomas of the squamous, small
cell, and undifferentiated types located at the gastroesophageal junction (topographically equivalent to Siewert
type 2 tumors) are classified as esophageal primary tumors. In
cases with complete pathologic response, the location of the
tumor bed determines the Siewert typing.
The use of large (mega) blocks Image 6, if available, can
be valuable in determining the distribution of residual tumor
foci, when present. If only patchy residual disease is present
and tumor is no longer contiguous, this can be identified particularly clearly in such large blocks.
The documentation of the size, location, and gross
appearance of the tumor as digital images is often useful in the
reporting of the specimen and discussion of the case in correlation with radiologic images at multidisciplinary meetings.
Microscopic Examination
A histologic complete pathologic response is defined by
the inability of the pathologist to demonstrate any viable (nonnecrotic) tumor cells within the specimen. Microscopic evidence of a tumor bed must be identified, and this is mandatory for assessment of complete response. Histologically, the

Image 4 A, An example of macroscopic examination of partial esophagogastrectomy specimen containing a Siewert type 2
tumor at the gastroesophageal junction. B, After fixation, the specimen is transversely sectioned and the slices are laid out for
inspection and blocking.

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Image 5 Complete pathologic response. A, A tumor bed

(arrow) with surface ulceration and transmural fibrosis is
present, but no visible tumor is seen on macroscopic
examination. B, This area is composed of fibrous tissue
infiltrated by inflammatory cells (H&E, 100). C, Note the blood
vessels showing intimal hyperplasia (H&E, 200).

Image 6 An example of a mega block section of esophageal carcinoma. A, A transversely sectioned slice revealing bulky
residual tumor on macroscopic examination. B, The tumor apparently infiltrates into esophageal adventitial fibrofatty tissue and
lies very close to the circumferential resection margin.

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tumor bed is characterized by abnormal fibroblastic stroma

that is devoid of the normal layers of the esophageal wall and
contains foamy macrophages and a moderate number of
fibroblasts and mononuclear inflammatory cells (Image 5). In
these areas, there may be edema or mucinous or myxoid
change of the stroma or even areas of necrosis.
The presence of mucin lakes without associated malignant cells should be defined as a pathologic complete response
Image 7. Similarly, necrotic areas (Image 7) and keratin
flakes without identifiable viable cancer cells should be
defined as a pathologic complete response.

When there is diagnostic uncertainty, step-sections and

further staining procedures such as mucin staining (alcian
blueperiodic acidSchiff) and immunohistochemical analysis for pancytokeratin (MNF116 or AE1/AE3) may be helpful
in distinguishing individual tumor cells from treatment-related bizarre fibroblasts and foreign body giant cells Image 8.
Lymph Node Handling
The use of chemoradiotherapy seems to cause lymph
nodes to undergo regression and atrophy to such an extent that
they may become impalpable macroscopically. Therefore, the

Image 7 The presence of necrotic areas (A, H&E, 200) and mucin lakes (B, H&E, 400) without identifiable viable carcinoma
cells should be defined as a pathologic complete response.
A

Image 8 Good response to preoperative treatment is evident in this specimen. A, Only occasional residual carcinoma cells are
seen, and a confident diagnosis is obscured by the presence of chemoradiation-induced bizarre fibroblasts and histiocytic
multinucleated giant cells (H&E, 400). B, Immunohistochemical analysis for pancytokeratin (MNF116) highlights the residual
carcinoma cells (400).

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number of lymph nodes found following preoperative therapy

is generally low. Careful searching for lymph nodes is essential. In addition, random sampling of adventitial fat often
yields only microscopically identifiable lymph nodes.
On microscopic examination, the lymph nodes usually
display considerable lymphoid depletion, sinus histiocytosis, accumulation of hemosiderin-laden macrophages, fibrosis, hyalinization, and acellular mucin lakes. As for the primary tumor, these changes are regarded as negative for
residual tumor unless viable cancer cells can be demonstrated. The residual metastatic carcinoma cells may show cytologic changes similar to those seen in the primary tumor.
When little residual tumor remains, it may be impossible to
demonstrate carcinoma cells in H&E-stained slides. The use
of immunohistochemical analysis for broad-spectrum
cytokeratins, such as MNF116 and AE1/AE3, may be helpful in these cases Image 9. However, false-positive results
may occur, and assessment must be based on the correlation
of such immunohistochemical findings with morphologic
features.

involvement of the resection margins, vascular and perineural invasion, and lymph node involvement.
Preoperatively treated esophageal tumors are graded
using the same criteria as nontreated carcinomas.20-30 It is
important to note that histologic grading of these treated
tumors may be affected by therapy-induced morphologic
changes. As discussed in the preceding sections, preoperative
neoadjuvant therapy causes a number of architectural and
cytologic changes. These include increased percentage of
tumor cells with neuroendocrine differentiation and increased
nuclear atypia of residual cancer cells.30,31 The culmination of
these changes could lead to upgrading of the tumor to a poorly differentiated carcinoma. Further evaluation of neoadjuvant
therapyinduced tumor morphologic changes and their possible effects on tumor differentiation would be helpful in defining more accurate tumor grading systems for preoperatively
treated esophageal carcinomas.

Pathology Report
In addition to comment on the pathologic response to preoperative neoadjuvant therapy (ie, tumor regression grade),
the histopathology report for posttreatment esophagectomy
specimens should also include the principal prognostic factors
already being used for nontreated esophageal cancer specimens. These have been detailed in the CAP Cancer Protocols
(available at http://www.cap.org) and the Royal College of
Pathologists Minimum Dataset (available at http://www.
rcpath.org). Briefly, a report should include comments on the
type and differentiation of the tumor, depth of invasion, TRG,

A substantial amount of data has been accumulated to

suggest that TRG and pathologic ypTNM staging are important prognostic factors in esophageal cancer.23-37 Although
response to therapy has been evaluated using various radiologic imaging techniques, currently, there is no clinical imaging
modality that can accurately gauge tumor response to
chemoradiation,22,42 and pathologic examination of the resected specimen remains the gold standard for tumor response
assessment.23-37 Therefore, it is important that these posttreatment resection specimens are handled in a standardized manner, and a reproducible TRG method must be used.

Conclusions and Future Direction

Image 9 A, A lymph node shows extensive fibrosis (H&E, 100). B, Scattered carcinoma cells are identified by
immunostaining for pancytokeratin (MNF116) (100).

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There is significant variability in the histopathologic

response of tumors to neoadjuvant chemotherapy. Approximately
15% to 30% of patients experience a complete response,
whereas up to 70% of patients have an incomplete or no
response to the neoadjuvant regimen. The identification of
factors that predict a response would be of considerable clinical benefit. The underlying mechanism for this variability is
unknown, and, currently, there are no reliable predictors of
response based on standard pathologic assessment and
immunohistochemical analysis of biopsy specimens.43
Contributing factors may include the diverse genetic
alterations involved in growth factor receptors, chemokines of
angiogenesis, tumor suppressor genes, cell cycle regulators
and enzymes involved in the DNA repair system, apoptosis,
and the degradation of extracellular matrix.43-48 Preliminary
reports indicate that gene expression profiles and polymorphisms seem to allow prediction of sensitivity to specific
chemotherapy and radiotherapy regimens44,48 and, thus, may
allow rational and individualized treatment approaches for
gastroesophageal carcinomas.
From the Department of Histopathology, St Thomas Hospital,
Guys and St Thomas NHS Foundation Trust, London, England.
Address correspondence to Dr Chang: Dept of
Histopathology, St Thomas Hospital, Guys and St Thomas NHS
Foundation Trust, Lambeth Palace Rd, London SE1 7EH, England.
Acknowledgment: The skillful technical assistance of K.
Marsden, FIBMS, and R. Cumming, FIBMS, is gratefully
acknowledged.

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