Download Pathologic Assessment of Tumor Regression after Preoperative

2680
Pathologic Assessment of
Tumor Regression after
Preoperative Chemoradiotherapy
of Esophageal Carcinoma
Clinicopa thologic Correlations
Anne-Marie Mandard, M.D.,* Frldlric Dalibard, M.D.,?
Jean-Claude Mandard, M.D.,t Jacques Marnay, M.A.,* Michel Henry-Amar, M.D.,$
Jean-Frangois Pefiot, Ph.D.,§ Alain Roussel, M.D., ( 1 Jacques-Henry Jacob, M.D.,B
Philippe Segol, M.D.,# Guy Samama, M.D.,# Jean-Marie Ollivier, M.D.,**
Sylvie Bonvalot, M.D.,# and Marc Gignoux, M.D.#
Background. The benefits of preoperative chemotherapy and radiation for esophageal carcinoma are under investigation. A pilot study was undertaken to determine if pathologic assessment of tumor regression correlated with disease free survival.
Methods. Ninety-three resected specimens from patients treated with cis-dichloro-diamino cisplatin and irradiation before surgery were examined on semiserial
sections. Patients selected for surgery were all Status 1
according to the World Health Organization (WHO) classification. Histologic typing was based on the WHO classification. Tumor regression grade (TRG) was quantitated
in five grades: TRG 1 (complete regression) showed absence of residual cancer and fibrosis extending through
the different layers of the esophageal wall; TRG 2 was
characterized by the presence of rare residual cancer
Presented in part at the 19th International Congress of the International Academy of Pathology, Madrid, Spain, October 19-23,
1992.
From the Departments of *Pathology, $Clinical Research, (IRadiotherapy, lIGastroenterology, and **Surgery, Centre Francois
Baclesse, Caen; the Departments of tPathology and #Surgery, Centre
Hospitalo-Universitaire, Caen; and the @StatisticsDepartment, Institut Universitairede Technologie, Universit; de Haute Bretagne, Vannes, France.
Supported by funds from the FCdbration Nationale des Groupements des Entreprises Francaises dans la Lutte Contre le Cancer.
The authors thank D. Potier, A. Baudron, D. Bonnet, P. Herlin,
M. Joret, P. Petit, H. Quintard, and M. Michel for their technical assistance; M. Blonde1for her help in documentation and for typing the
manuscript; M. Shore for the English translation; and W. V. Bogomoletz for reviewing the manuscript.
Address for reprints: Anne-Marie Mandard, M.D., Department
of Pathology, Centre FranFois Baclesse,F- 14021 Caen, Cedex, France.
Accepted for publication January 18, 1994.
cells scattered through the fibrosis; TRG 3 was characterized by an increase in the number of residual cancer cells,
but fibrosis still predominated; TRG 4 showed residual
cancer outgrowing fibrosis; and TRG 5 was characterized
by absence of regressive changes.
Survival curves were estimated according to the
Kaplan-Meier method. A quantification of the relationship between treatment failure and confounding variables (age, tumor location, tumor size, esophageal wall
involvement by residual cancer and/or regressive
changes, histology, treatment, adequacy of surgery,
pathologic lymph node status, and tumor regression
grade) was done using Cox’s proportional hazards model.
Resulfs. Forty-two percent of specimens were TGR
1-2;20%, TGR 3;and 33%, TGR 4-5. Univariate analysis
found that tumor size, pathologic lymph node status, tumor regression grade, and esophageal wall involvement
were highly correlated with disease free survival (P <
0.05). After multivariate analysis, only tumor regression
(i-e., TRG 1-3 versus TRG 4-5) remained a significant (P
< 0.001)predictor of disease free survival.
Conclusions. This study highlights the importance of
tumor regression in the survival of patients with esophageal carcinoma treated with preoperative chemoradiotherapy. These findings suggest that tumor regression
grade should be considered when evaluating therapeutic
results. Cancer 1994:73:2680-6.
Key words: esophageal carcinoma, preoperative chemoradiotherapy, tumor regression grade, survival, prognostic factors, multivariate analysis.
The benefits of preoperative chemotherapy and radiation for esophageal carcinoma are under investigation.
Esophageal Carcinoma Regression/Mandard et al.
2681
Those benefits remain to be assessed in prospective randomized trials comparing surgery alone with combined-modality therapy. Several reports on single-arm
uncontrolled trials have been p~blished.'-~
We present
here a detailed pathologic study of the changes of
esophageal carcinoma after preoperative chemoradiotherapy.
The current study was performed as part of a pilot
study to assess the feasibility and tolerance of a new
preoperative regimen and its consequences on the primary tumor in a resected specimen.4r5The aim of the
current study was to investigate the features of regression of esophageal cancer after preoperative chemoradiotherapy to assess quantitatively this regression and
to determine whether this assessment would correlate
with the patient's survival.
the cases were T1; 52%, T2; and 16%, T3. Initial tumor
size was less than 5 cm of the esophageal length in 32
patients (37% of the cases) and more than 5 cm of the
esophageal length in 55 patients (63% of the cases). The
initial tumor size could not be determined in six patients. The regional lymph node status reported was a
postsurgical histopathologic classification (pN): 58% of
the cases were pN- and 42% of the cases were pN+.
Histology was performed according to the World
Health Organization classification of esophageal carcinoma.' The histologic types were squamous cell carcinoma in 84% of patients, undifferentiated carcinoma in
8%, adenosquamous carcinoma in 3%, and unspecified
in 5%.
Patients and Methods
Pathologic examination of all surgical specimens was
performed as described previo~sly.~
After gross examination and dye test, semiserial sectioning of the entire
specimen was performed and sections were numbered
on a one-to-one scale diagram showing all the gross lesions. All the sections were examined microscopically,
and the lesions identified were recorded on the diagram. Cancer resection was considered adequate when
there was no tumor involvement of all surgical margins
(upper and lower margins as well as the adventitia).
When one surgical margin or more were involved, surgery was considered inadequate. In situ carcinoma,
when present, was regarded as distant from the primary
tumor only when separated from the latter by at least
0.5 cm of uninvolved tissue." Lymph nodes were dissected separately, except for periesophageal nodes, the
latter being included in the esophageal sections. The
lymph nodes identified were the periesophageal nodes,
lesser omentum and greater omentum nodes, and those
of the mediastinum or other sites, which may have been
dissected directly by the surgeon.
Gross examination. Specimens were divided into
three macroscopic groups. In the first group, there was
obvious residual tumor with ulcerating, fungating, or
infiltrative features. In the second group, apparent tumor regression had occurred and a scar was found instead. The third group included doubtful cases.
Histology. Cases were separated into two histologic groups. In the first group, the tumor showed no
regressive changes. The second group included all those
cases in which regressive changes were noted. Regressive changes included the following:
Between October 1985 and March 1989, 93 resected
specimens of esophageal carcinoma from patients who
had received preoperative chemoradiotherapy were examined in the Department of Pathology of the Centre
Franqois Baclesse and the Centre Hospitalo-Universitaire, Caen, France. Eighty-eight of the patients were
men and five were women. The age range was 37-74
years (mean age, 58 years).
The tumor was located in the upper third in 14% of
the patients, in the middle third in 58%, and in the
lower third in 28%. The initial performance status of all
patients selected for this treatment was 1 according to
the World Health Organization classification.6
The treatment protocol of the current pilot study
included radiotherapy delivered in two courses of 18.5
Gy for 5 days (3.7 Gy X 5), with a total dose 37 Gy,
separated by a rest period of 15 days. Radiation used
were photon beams of 10-25 MV with portals 5 cm
above and below the tumor edges and 2 cm laterally
by either four oblique fields or one posterior and two
oblique posterior fields. Cis-dichloro-diamino-cisplatin
(80-100 mg/m2) was given in a single dose 1-5 days
before each course of radiation. Surgery was performed
2-3 weeks after the second radiation course. Seventytwo patients (77%) were given the complete treatment
as specified in the protocol. The remaining 21 patients
(23%) received incomplete treatment: 13 patients were
given one cycle of chemotherapy, 3 patients received a
total dose of chemotherapy lower than 80 mg/m2, and
5 patients received a total dose of radiation lower than
37 Gy.
The initial clinical assessment of the esophageal tumor was appraised according to the TNM classification
of the International Union Against Cancer for esophageal car~inoma.~
According to this classification, 32% of
Pathologic Examination
1. Cytologically, cancer cells showed cytoplasmic vacuolization and/or eosinophilia, nuclear pyknosis,
and necrosis (Fig. 1).
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CANCER June 1,2994, Volume 73,No. 11
still predominated. Grade 4 showed residual cancer
outgrowing fibrosis. Grade 5 was characterized by the
absence of regressive changes.
The same grading system was used for assessing tumor regression in metastatic lymph nodes. In the latter,
”complete regression” corresponded to the presence of
keratin plugs or neoplastic squamous ghost cells scattered in dense fibrosis. The above definition enabled us
to confirm the nature of regressed metastatic lymph
node.
Esophageal wall involvement. Assessment of
esophageal wall involvement by residual cancer and/
or regressive changes was performed. Esophageal specimens were divided into two groups. In the first group,
residual cancer and/or regressive changes extended
only in the mucosa and submucosa. In the second
group, residual cancer and/or regressive changes ex-
Figure 1. Inflammatory fibrosis (F) and cytologic changes of residual
cancer cells: pyknosis and cytoplasmic eosinophilia creating an
appearance of differentiated squamous cell (SQ).(H & E, original
magnification X20).
2. Stromal changes included fibrosis, with or without
inflammatory infiltrate, including giant cell granuloma around ghost cells and keratin (Figs. 2 and 3).
The fibrosis was either dense with much collagen or
edematous.
Tumor regression grade. On the basis of these
changes, primary tumor regression was classified into
five histologic tumor regression grades (Fig. 4). Grade 1
(complete regression) showed absence of histologically
identifiable residual cancer and fibrosis extending
through the different layers of the esophageal wall,
with or without granuloma (Fig. 5). Grade 2 was characterized by the presence of rare residual cancer cells
an inscattered through the fibrosis. Grade
crease in the number of residual cancer cells, but fibrosis
Figure 2. Esophageal wall scar (S) and giant cell granuloma (G)
(H & E, original magnification XS).
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Esophageal Carcinoma Regression/Mandard et al.
Figure 3. Fibrosis (F) with inflammatory infiltrate including giant cell
granuloma (GC) around keratin plug (K) (H & E, original
magnification X51).
tended within the muscularis propria or beyond, to the
adventitia.
Figure 5. Histologic findings: complete regression of an esophageal
carcinoma with preoperative chemoradiotherapy. Scar (S)and
inflammatory granuloma at the initial tumor site (H & E, original
magnification X 1). (m) mucosa; (sm) submucosa; (mp) muscularis
propria; (pe) periesophageal tissue.
that was diagnosed synchronously (i.e., within 12
months of the esophageal carcinoma).
Associated Carcinomas
Statistical Analysis
Of the 93 patients, 15 (16%) presented an associated
carcinoma, which was located in the upper digestive
tract for 10 patients. Of these 15 patients, 8 were excluded from the prognostic study on the following
grounds: 2 patients had been treated previously for another cancer and 6 patients had associated neoplasm
Comparison between proportions was made using the
Fisher's exact test. The time at risk for progression or
relapse (disease free survival) was computed from the
date of first examination to the date of diagnosis of
treatment failure, the date of death, the date of last
known status, or April 1, 1992, whichever came first.
The contribution to the risk of treatment failure of age,
tumor location, histologic typing, tumor size, esophageal wall involvement, lymph node metastasis (pN),
type of treatment (i.e., complete or incomplete), surgical
excision (adequate or inadequate) and grade of tumor
regression was estimated by two methods. In the first,
univariate analysis selected those parameters that correlated significantly with disease free survival. Survival
curves were estimated by the Kaplan-Meier method."
The 95% confidence limits (CL) were obtained by the
method of Greenwood.'* Comparisons were made using the log-rank test.I3In the second method, a quantification of the relationship between the time of occurrence of treatment failure and confounding variables,
such as age, tumor location, tumor size, pN, histology,
treatment, surgical excision, grade of tumor regression,
and esophageal wall involvement was calculated using
Cox's proportional hazards model.'* The Statxact and
Stata statistical packages were
\
-
TRGl
TRG 3
Fibrosisoutgrowing
residual cancer
outgrwving fibrosis
regresswe changes
Results
RESIDUAL CANCER CELLS
SCAR
Figure 4.Esophageal carcinoma: tumor regression grade.
Pathologic Findings
The results of tumor regression grading for the 93 patients are shown in Table l. Tumor regression grades
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CANCER June 1,1994, Volume 73,No. 11
Table 1.Esophageal Carcinoma: Tumor Regression
Grade-93 Patients
Grade
1
20
3
4
5
Unspecified
Total
No.
20
19
19
22
8
5
93
Table 2. Prognostic Study: Univariate Analysis of
Disease Free Survival-85 Eligible Patients
%
22
20
20
24
9
5
100
1 and 2 were seen in 42% of the resected specimens.
Correlations between gross findings and tumor regression grade showed that, in some cases, gross examination did not give accurate assessment of the presence
of residual cancer. The assessment of esophageal wall
involvement by residual cancer and/or regressive
changes showed that they remained in the mucosa and
submucosa in 13 specimens (14% of the cases). In 77
specimens (86% of the cases), residual cancer and/or
regressive changes extended within the muscularis propria or, beyond, to the adventitia. There was a correlation between initial tumor size and esophageal wall involvement by residual cancer and/or regressive
changes (P < 0.001).
An analysis of relation between tumor regression
grade and initial tumor size showed that tumor regression grade decreased with an increase in tumor size (P =
0.017) and that tumor regression grade decreased when
lymph node metastases were present (P = 0.009). These
two relations remained significant when made with
stratification on pN (P = 0.007) or tumor size (P =
0.012).
A more detailed analysis of 36 cases with lymph
node metastases (pN+) and known tumor regression
grade suggested that regression of lymph node metastases paralleled tumor regression ( P < 0.0002).
Examination of the whole esophageal mucosa
showed varying degrees of esophagitis, and distant in
situ carcinoma was seen in two specimens (2%).
Surgical excision was considered adequate in 67
cases (72%) and inadequate in 26 cases (28%).
Survival
The overall survival rate was 31% (95% CL, 21-41%)
at 3 years and 25% (95% CL, 15-35%) at 4 years. Disease free survival was 34% (95% CL, 23-44%) at 3
years and 27% (95% CL, 17-38%) at 4 years. Fifty-nine
patients died, of whom 48 died of their cancer, 5 of
other causes, and 6 of unknown causes. Fifty-four of
the 55 patients who presented with recurrences died.
Variable
No. of
uatients
P value
Age
< 60 yr
60 yr
Localization
Upper third
Middle third
Lower third
Unspecified
Tumor size
<5cm
r5cm
Unspecified
Histology
Squamous cell carcinoma
Undifferentiated carcinoma
Adenosquamous carcinoma
Unspecified
Treatment
Complete
Incomplete
Surgical excision
Adequate
Inadequate
2
PN
-
+
Tumor regression grade
1
2
3
4-5
Unspecified
Esophageal wall involvement
Mucosa and submucosa
Muscularis propria or beyond
Unspecified
47
38
10
49
25
1
29
51
5
78
3
1
3
0.07
0.33
0.0007
0.71
67
18
0.84
61
24
0.05
50
35
0.014
18
19
18
26
4
12
70
3
0.001
0.02
The average interval between the first postoperative recurrence and death was 59 days (0-409 days). Two patients died postoperatively.
Prognostic Study
In the analysis of prognostic factors, disease free survival was used as the end point. Univariate analysis of
disease free survival was performed with the parameters of age, tumor location, initial tumor size, esophageal wall involvement, pathologic lymph node status
(pN), histologic typing, treatment (complete or incomplete), surgical excision (adequate or inadequate),
and tumor regression grade. The results are shown in
Table 2.
Esophageal Carcinoma Regression/Mandard et al.
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(u
L
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36
Time since Diagnosis, i n months
Figure 6. Esophageal carcinoma: disease free survival according to
tumor regression grade (TRG): 81 patients eligible (P < 0.0001). TGR
1 = 18, TGR 2 = 19, TGR 3 = 18, TGR 4 = 19, TGR 5 = 7.
Tumor size and pN, tumor regression grade (tumor
regression grade 1-2 and 3 versus tumor regression
grade 4 and 5) and esophageal wall involvement correlated highly with disease free survival, whereas adequacy of excision and age were borderline significant.
Disease free survival according to tumor regression is
shown in Figure 6.
The above parameters that correlated with disease
free survival in univariate analysis were included in the
multivariate analysis. Using Cox’s regression analysis,
tumor regression grade correlated highly (relative risk,
2.87; P < 0.001) with disease free survival, whereas tumor size (relative risk, 1.93; P = 0.07) and age (relative
risk, 1.60;P = 0.11) were borderline significant.
Discussion
We have described the gross and histologic features of
tumor regression seen after preoperative chemoradiotherapy in 93 cases of esophageal carcinoma. This regression was assessed by comparing the proportion of
residual carcinoma to scarring, and our results were
found to correlate with patients’ survival. The preliminary assessment was performed using a tumor regression grading of five grades. Multivariate analysis
showed two groups of tumor regression grade that were
prognostically relevant: Grades 1, 2, and 3 versus
Grades 4 and 5.
We believed that our method of assessment was
simple and reproducible. We initially used semiserial
sections, but this was time consuming in terms of the
preparation and study of slides.’ We found with experience that the procedure could be simplified to facilitate
wider application. In the presence of tumor regression
corresponding to scarring on gross examination, the
esophagectomy specimen could be examined in toto in
five to eight longitudinal section^,'^ or the histologic
sampling used to assess tumor regression could be limited to sections of the whole scar lesion.
Tumor regression of squamous cell carcinoma of
the esophagus after radiotherapy was studied by Akakura et al. in 117 patients.’* Their gross findings appeared to be identical to ours. However, the microscopic
criteria that they used for evaluation of response to radiotherapy were essentially cytologic and did not include an exact quantitative approach. We found that
their cytologic criteria correlated with our assessment of
tumor regression but were not totally reproducible in
our material, possibly due to the difference in preoperative treatment.
Several clinical studies on preoperative chemoradiotherapy of carcinoma of the es~phagus’~’~-’~
have
assessed survival as a function of the presence or absence of residual cancer in the surgical specimen. However, none of those provided a detailed pathologic study
of regression of tumor and lymph node metastases.
A quantitative study comparable to ours was conducted by Braun et al.’3 on tumor regression after chemoradiotherapy of head and neck tumors. They reported a statistically significant correlation between
grade of tumor regression and survival. Sulfaro et al.24
presented a study of regression of carcinoma of the
head and neck after intraarterial chemotherapy. The cytologic and stromal damage of the carcinoma after treatment were comparable to those we described after chemoradiotherapy. These authors used the TNM classification” to assess the different types of regression. We
found that the gross diagnosis was not always sufficiently reliable for us to use this classification in our
study.
A noteworthy feature in our series was the low incidence of in situ carcinomas distant to the invasive carcinoma. These were found in 14% of cases in a previous
study of esophagectomy specimens from patients who
had not received preoperative treatment.” In the current study, this percentage was only 2%, suggesting a
possible regression of in situ carcinoma secondary to the
preoperative treatment.
It was not within the scope of the current pilot study
to evaluate the benefits of preoperative chemoradiotherapy regarding survival of patients with esophageal
carcinoma, because this could only be done in a comparative therapeutic trial. Such a trial is actually in progress (European Organization for Research and Treatment of Cancer protocol No. 40881). However, our results indicate that there is a correlation between
response to preoperative treatment and disease free sur-
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CANCER June 1,1994, Volume 73,No. 11
viva1 and that this should be considered along with
other known prognostic indicators in the evaluation of
therapeutic results in esophageal cancer.
11.
Addendum
12.
Since the present study first was submitted, Darnton et
a].” have shown that in 12 patients with squamous cell
carcinoma of the esophagus, quantitative study of tumor regression after chemotherapy, particularly in relation to the proportion of tumor to stroma, is a simple
and accurate technique to evaluate objectively the effect
of chemotherapy on squamous cell carcinoma of the
esophagus.
13.
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