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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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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
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).
DOI: 10.1309/CCR3QN4874YJDJJ7
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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
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
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3-Tiered
4-Tiered
P0
(0%)
TRG1
(0%)
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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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 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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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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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,
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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