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Signet-Ring Cell or Mucinous Histology after Preoperative
Chemoradiation and Survival in Patients with Esophageal
or Esophagogastric Junction Adenocarcinoma
Lucian R. Chirieac,1 Stephen G. Swisher,2
Arlene M. Correa,2 Jaffer A. Ajani,3
Ritsuko R. Komaki,4 Asif Rashid,1
Stanley R. Hamilton,1 and Tsung-Teh Wu1
Departments of 1Pathology, 2Thoracic and Cardiovascular Surgery,3GastrointestinalMedical Oncology and 4Division of Radiation Oncology,University of Texas M.D. Anderson Cancer Center, Houston, Texas
ABSTRACT
Purpose: The survival of patients with local-regional
adenocarcinoma of the esophagus or esophagogastric junction
(EGJ) treated with preoperative chemoradiation is much
better in patients with pathologic complete response than
those with residual tumor. Some adenocarcinomas havemixed
patterns, including signet-ring cell and mucinous histology,
but the clinical significance of these subtypes is unknown.
Experimental Design: We studied 412 consecutive
patients with esophageal or EGJ adenocarcinoma treated
with chemoradiation followed by esophagectomy (193
patients) or surgery alone (219 patients). We evaluated
signet-ring cell and mucinous histology in the resection and
pretherapy biopsy specimens and compared clinicopathologic
features with overall survival.
Results: The fraction of signet-ring cell and mucinous
histology was similar in evaluated specimens of patients
treated with preoperative chemoradiation or surgery alone
(17% and 18%, respectively). The overall survival rate at 5
years of patients treated with preoperative chemoradiation
was significantly better if residual signet-ring cell or
mucinous histology was present in the esophagectomy
specimen (63% versus 28%; P = 0.02). All 13 patients with
acellular mucin pools and no residual carcinoma are still alive
after an average follow-up time of 36 months. By contrast, in
patients treated with surgery alone, overall survival rate was
significantly worse if signet-ring cell or mucinous histology
was present (14% versus 30%; P = 0.05). In multivariate
analysis, overall survival was independently predicted by
presence of signet-ring cell or mucinous histology (P = 0.04).
Conclusions: Our study showed that patients with
esophageal or EGJ adenocarcinoma who have signet-ring
cell or mucinous histology benefited substantially from
preoperative chemoradiation and esophagectomy.
INTRODUCTION
Adenocarcinoma of the esophagus and esophagogastric
junction (EGJ) is aggressive and has a poor prognosis (1–6).
Esophagectomy has been the main approach for localized
esophageal carcinoma, although multimodality strategies, in-
cluding preoperative chemoradiation followed by esophagec-
tomy, are accepted modalities of treatment (7). When surgical
resection is the primary therapy, the best predictor of overall
survival is pathologic stage (8–12). The outcome of patients
after preoperative chemoradiation is much better if no residual
carcinoma (stage 0) is found in the resected specimen,
representing a pathologic complete response (13–21). However,
pathologic complete response occurs in <30% of patients who
undergo surgery following preoperative chemoradiation (13).
A subset of adenocarcinomas has mixed histologic patterns,
including signet-ring cell and mucinous histology. Signet-ring
cell carcinoma is a unique subtype of mucin-producing
adenocarcinoma characterized by abundant intracellular mucin
accumulation and a compressed nucleus displaced toward one
extremity of the cell. Mucinous carcinoma has abundant
extracellular mucin. These two histologic morphologies com-
monly occur together. In general, the prognosis of patients with
signet-ring cell carcinoma of any organ site is poor (22–25).
However, in patients treated with chemoradiation therapy
followed by esophagectomy, it remains unclear whether these
particular histologic patterns indicate worse overall survival.
Furthermore, acellular mucin pools with no evidence of residual
carcinoma cell are identified in a subset of surgical resection
specimens of patients with local-regional carcinoma of the
esophagus and EGJ. No report currently exists about the
presence of acellular mucin pools predicting overall survival
for patients who have no residual carcinoma cell in the resected
specimen after preoperative therapy.
We have observed that patients with acellular mucin pools
with no evidence of residual carcinoma cell in resected
specimens have long-term survival after esophagectomy. There-
fore, we hypothesized that patients with local-regional adeno-
carcinoma of the esophagus and EGJ with signet-ring cell or
mucinous histology represents a subset of patients who have the
highest benefit from preoperative neoadjuvant chemoradiation.
We also postulated that presence of residual acellular mucin
pools in the resection specimen of patients treated with
preoperative neoadjuvant chemoradiation is associated with a
better prognosis. We therefore studied the clinical significance of
signet-ring cell and mucinous histology in 412 patients with
adenocarcinoma of the esophagus and EGJ and related the
findings to survival.
Received 9/10/04; revised 12/8/04; accepted 12/15/04.The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby markedadvertisement in accordance with 18 U.S.C. Section 1734 solely toindicate this fact.Note: L. R. Chirieac is presently at the Department of Pathology,Brigham and Women’s Hospital and Harvard Medical School, Boston,Massachusetts.Requests for reprints: Tsung-Teh Wu, Department of Pathology,University of Texas M.D. Anderson Cancer Center, Unit 085, 1515Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-4977; Fax:713-792-4049; E-mail: [email protected].
D2005 American Association for Cancer Research.
Vol. 11, 2229–2236, March 15, 2005 Clinical Cancer Research 2229
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MATERIALS AND METHODS
Patient Characteristics. This study included 412 consec-
utive patients at the University of Texas M.D. Anderson Cancer
Center who had histologically confirmed adenocarcinoma of the
esophagus or EGJ treated with chemoradiation followed by
esophagectomy or surgery alone between 1985 and 2003 and had
their pathology specimens available for review (Table 1). The
study was approved by the institutional review board.
The first group of 193 patients was treated with chemo-
radiation followed by esophagectomy. The mean age was
59.7 years (range, 32-79 years). There were 180 men and
13 women. The vast majority of cancers (98%) were in the distal
esophagus or EGJ with only 2% in the middle or upper
esophagus. Patients with clinical stage I or IVB disease
(systemic metastases) were not eligible for preoperative chemo-
radiation. Pretreatment clinical stage was determined by barium
swallow esophagogram, computed tomographic scan, endo-
scopic ultrasonography, and positron emission tomography. The
pretreatment clinical stage was II in 54% of patients, III in
39%, and IVA with celiac lymph node involvement in 6%.
Three agents were used for preoperative chemotherapy:
fluorouracil, cisplatin, and a taxane. All patients underwent
computed tomographic simulation for radiation therapy. Clinical
target volume was defined as the gross tumor volume plus a 5-cm
margin superior to the highest extension and inferior to the
lowest extension of the carcinoma with a 2-cm radial margin.
Planning target volume was defined as the clinical target volume
plus a 5-mm margin. The total dose of radiation therapy was
45 Gy in 25 fractions or 50.4 Gy in 28 fractions prescribed to
cover at least 95% of the planning target volume. Radiation
therapy was given with megavoltage (>6 MV) equipment with
anterior and posterior fields for 20 to 22 fractions followed by
oblique or lateral fields for the remaining fractions to spare the
spinal cord. Four to 6 weeks after completing preoperative
therapy, patients underwent a radical en bloc esophagectomy.
The surgical approaches used were Ivor-Lewis esophagectomy
(abdominal-right thoracic approach) in 114 (59%) patients, three-
field McKeown esophagectomy (right thoracic abdominal-
cervical approach) in 25 (13%) patients, and transhiatal
esophagectomy (abdominal-cervical approach) in 53 (28%)
patients (26, 27). One (1%) patient underwent two-stage
esophagectomy (Table 1).
The second group was treated with surgery alone. Patients
with clinical stage I and IVB were excluded to serve as a control
group to patients treated with chemoradiation followed by
esophagectomy, leaving 219 patients for study. The mean age
was 62.5 years (range, 28-84 years). There were 194 men and
25 women. The majority of cancers (93%) were in the distal
esophagus or EGJ with 7% in the middle or upper esophagus.
The pretreatment clinical stage was II in 83% of patients, III
in 15%, and IVA with celiac lymph node involvement in 2%.
Assessment of Esophageal Adenocarcinoma Specimens.
H&E-stained slides from each case were reviewed with no
knowledge of the previous diagnosis, staging, or outcome for
each case. Patients who were treated with chemoradiation
followed by esophagectomy had both the post-therapy surgical
specimen and the pre-chemoradiation biopsy specimen evaluated
for comparison of the results in the two types of specimens with
greatly different sampling. Patients who were treated with
surgery alone had surgical resection specimen evaluated. Speci-
mens remained encoded for the entire histopathologic evalua-
tion. In patients treated with chemoradiation followed by
esophagectomy, residual carcinoma status was determined in
each surgical specimen. These patients had either complete
pathologic response or residual carcinoma present in fibrotic
tissue or in acellular mucin pools at the primary site. If residual
carcinoma was identified grossly, tumor was sampled for
histologic evaluation in an average of 15 slides (95% confidence
interval, 11.8-18.6). If no residual carcinoma was identified
grossly, areas with ulcer or scar indicating the therapy field were
submitted completely for histologic examination and generated
an average of 17 slides (95% confidence interval, 15.4-18.6).
Each esophagectomy specimen was evaluated for depth of
invasion, margin status, and lymph node metastasis and staged
according to the sixth edition of the American Joint Committee
on Cancer system for esophageal carcinoma (9).
Definition of Signet-Ring Cell and Mucinous Histology.
The tumors in this study were divided into two categories:
adenocarcinomas with signet-ring cell or mucinous histology and
adenocarcinomas of the usual type. Adenocarcinomas with
signet-ring cell or mucinous histology included mucinous
adenocarcinomas, carcinomas with mucinous features, signet-
ring cell carcinomas, carcinomas with signet-ring cell, and
adenocarcinomas with mixed signet-ring cell and mucinous
histology. The remainder of the cases was carcinomas without
mucinous differentiation or presence of signet-ring cell. For
adenocarcinomas treated with preoperative chemoradiation,
presence of mucin pools, irrespective of presence or absence of
residual tumor cells, was classified as adenocarcinoma with
signet-ring cell or mucinous histology (Fig. 1).
Definition of Residual Carcinoma Status. Residual
cancer status in patients treated with preoperative chemo-
radiation was determined in esophagogastrectomy specimens.
Extent of residual carcinoma was assessed semiquantitatively
irrespective of lymph node status based on estimated percentage
of residual carcinoma in relation to total carcinoma area,
including amount of radiation-induced tissue injury, in mural
Table 1 Characteristics of the patients according to the therapy group
Chemoradiationfollowed by surgery
Surgeryalone
Characteristics (n = 193) (n = 219)
Gender, n (%)Male 180 (93.3) 194 (88.6)Female 13 (6.7) 25 (11.4)
Age (y)Mean 59.68 62.54Median (range) 60 (32-79) 65 (28-84)
Primary location, n (%)Cervical/upper/middle 3 (1.6) 15 (6.8)Lower/EGJ 190 (98.4) 204 (93.2)
Type of esophagogastrectomy, n (%)Transthoracic (Ivor-Lewis) 114 (59.1) 105 (47.9)Transhiatal 53 (27.5) 86 (39.3)Total (three-field technique) 25 (13.0) 16 (7.3)Two-stage procedure 1 (0.5) 12 (5.5)
Positive margin, n (%)* 16 (8.3) 80 (36.5)
NOTE. Because of rounding, not all percentages total 100.*A specimen with at least one of the proximal, radial, or distal
resection margins involved by carcinoma.
Signet-Ring Cells or Mucin in Esophageal Carcinoma2230
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histologic sections (28). Extent of residual carcinoma in the
esophagectomy specimen was assigned to one of four categories:
no residual carcinoma (Fig. 1C), 1% to 10% residual carcinoma
(Figs. 1A and B and 2C), 11% to 50% residual carcinoma, and
>50% residual carcinoma, as modified from selected published
grading systems for esophageal and gastric carcinomas (28, 29).
The extent of residual carcinoma in regional lymph nodes was
not assessed.
Statistical Analysis. v2 or Fisher’s exact tests were used
to compare categorical data. Overall survival was calculated
from time of surgery to time of death from any cause or to time
of last follow-up, at which point the data were censored. Overall
survival curves were constructed using the Kaplan-Meier
method, and log-rank test was used to evaluate the statistical
significance of differences.
The prognostic significance of clinical and pathologic
characteristics was determined using univariate Cox regression
analysis. Cox proportional hazards models were fitted for
multivariate analysis. After interactions between variables were
examined, a backward stepwise procedure was used to derive the
best-fitting model.
Statistical analysis was done using SPSS software (version
11.5.2.1 for Windows, SPSS, Chicago, IL). Kaplan-Meier
survival curves were drawn with GraphPad Prism (version 4
for Windows, GraphPad Software, San Diego, CA). We used
two-sided significance level of 0.05 and power of 0.90 for all
statistical analyses.
RESULTS
Prevalence of Signet-Ring Cell or Mucinous Histology
in Patients with Esophageal or Esophagogastric Junction
Adenocarcinoma. In patients with esophagus and EGJ
adenocarcinoma treated with surgery alone, 40 (18.2%) had
signet-ring cell or mucinous histology and 179 (81.7%) had
adenocarcinoma of the usual type (Table 2). There were no
significant differences in gender, tumor location, and pathology
stage between patients with adenocarcinoma of the usual type
and those with signet-ring cell or mucinous histology. Patients
with adenocarcinoma of the usual type were slightly older and
had less positive margins (Table 2).
The post-treatment surgical specimens of patients with
esophagus and EGJ adenocarcinoma treated with chemoradiation
followed by surgery included 33 (17.1%) cases with signet-ring
cell or mucinous histology and 160 (82.9%) cases with
adenocarcinoma of the usual type (Table 3). Of the 33 cancers
with signet-ring cell or mucinous histology in the post-treatment
surgical specimen, 13 (39.4%) were classified as stage 0 (only
Fig. 1 Histopathology of adenocarcinoma of esophagus and EGJtreated with chemoradiation followed by esophagogastrectomy. Thetreated primary site has signet-ring cell and mucinous histology. A andB, residual carcinoma characterized by rare individual carcinoma cellwith signet-ring features present in mucin pools at the primary site. C,acellular mucin pools extending through the layers of the esophagealwall without residual carcinoma.
Clinical Cancer Research 2231
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acellular mucin pools without residual tumor cells were present),
1 (3%) as stage I, 12 (36.3%) as stage II, 5 (1.5%) as stage III,
and 2 (6%) as stage IV. Acellular mucin pools were present in 13
(23.2%) cases of 56 patients with complete pathologic response
(no residual tumor); mucin extended into adventitia in nine
cases, in muscularis propria in one case, and in submucosa only
in three cases. Mucin with neoplastic usual cell or signet-ring
cell was present in 12 cases with 1% to 10% residual tumor, 4
cases with 11% to 50% residual tumor, and 4 cases with >51%
residual tumor (Table 3). In the cases where the extent of residual
tumor was 1% to 10%, mucin extended into adventitia in eight
cases, in muscularis propria in one case, and in submucosa in
three cases. Overall, the pathologic stages were 0 (29%), I
(10.9%), II (33.7%), III (21.2%), and IV (5.2%). The
clinicopathologic features of the two subgroups were similar,
except for a slightly higher proportion of patients with positive
margins in the group with signet-ring cell or mucinous histology
(P = 0.04; Table 3).
The pretreatment biopsy specimen of patients with
esophagus and EGJ adenocarcinoma treated with chemoradiation
followed by surgery had 32 (16.6%) cases with signet-ring cell
or mucinous histology and 161 (83.4%) with adenocarcinoma of
the usual type (Table 3). We found no significant differences in
the evaluated clinicopathologic features between patients with
adenocarcinoma of the usual type and those with signet-ring cell
or mucinous histology in the biopsy specimens (Table 3).
Correlation of Tumor Histology between Post-treatment
Resection Specimen and Pretreatment Biopsy Specimen in
Patients Treated with Chemoradiation Followed by Surgery.
Although the findings in the pretreatment biopsies were slightly
different from the findings in the surgical specimens, the
concordance for each patient was extremely high (P = 0.67;
Table 4). For 136 (90.6%) patients, the biopsy classification was
identical to the findings in the surgical specimens. Eight patients
with a diagnosis of adenocarcinoma of the usual type in the
biopsy revealed signet-ring cell or mucinous histology in the
subsequent post-treatment surgical specimen (five had complete
pathologic response and three had 1-10% residual tumor). We
believe that these findings represent sampling error due to the
limited nature of the tissue to be examined in the biopsy. On the
other hand, six patients with presence of signet-ring cell in
the biopsy specimens had adenocarcinoma of the usual type
in the post-treatment surgical specimen (five had gross residual
tumor and one had 1-10% residual tumor).
Survival Analysis. The mean potential follow-up time
using censored data was 79.2 months. Univariate Cox regression
analysis showed that pathologic stage, and presence of signet-
ring cell or mucinous histology in the resection specimen were
Table 2 Characteristics of the patients with adenocarcinoma of theesophagus treated with surgery alone according to the presence of
signet-ring cell or mucinous histology
Characteristics
Adenocarcinomawith signet-ring cellor mucin (n = 40)
Adenocarcinomaof the regulartype (n = 179) P
Gender, n (%)Male 34 (85.0) 160 (89.4) 0.42Female 6 (15.0) 19 (10.6)
Age (y)Mean 59.38 63.25 0.04Median (range) 62 (32-81) 65 (28-84)
Tumor location, n (%)Cervical/upper/middle 1 (2.5) 14 (7.8) 0.32Lower/EGJ 39 (97.5) 165 (92.2)
Pathologic stage, n (%)I 3 (7.5) 33 (18.4) 0.10II 9 (22.5) 52 (29.1)III 19 (47.5) 74 (41.3)IV 9 (22.5) 20 (11.2)
Positive margin, n (%)*Radial, proximal, distal 21 (51.2) 60 (33.5) 0.03
NOTE. Because of rounding, not all percentages total 100.*A specimen with at least one of the proximal, radial, or distal
resection margins involved by carcinoma.
Fig. 2 Kaplan-Meier curves of overall survival among patients with carcinoma of the esophagus and EGJ treated with surgery alone and patientstreated with preoperative neoadjuvant chemoradiation followed by esophagectomy. A, patients treated with surgery alone who had adenocarcinoma ofthe usual type in the esophagus or EGJ have a better overall survival than patients with signet-ring cell or mucinous histology in the post-treatmentsurgical specimens. B, in contrast to the patients treated with surgery alone, the overall survival rate for the patients treated with chemoradiationfollowed by surgery was significantly worse for patients who had adenocarcinoma of the usual type than it was for patients with signet-ring cell ormucinous histology in the post-treatment surgical specimens.
Signet-Ring Cells or Mucin in Esophageal Carcinoma2232
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prognostic indicators for overall survival for both patients treated
with surgery alone and those treated with preoperative neo-
adjuvant chemoradiation (Table 5).
The overall survival rate for the patients treated with surgery
alone was significantly better for patients who had adenocarci-
noma of the usual type in the esophagus or EGJ (median overall
survival, 22.9 months) than patients with signet-ring cell or
mucinous histology (median overall survival, 17.5 months; P =
0.05; Fig. 2A). Because patients who had signet-ring cell or
mucinous histology had higher positive margin rate than patients
who had adenocarcinoma of the usual type, we included patients
with only negative margins in a separate analysis, and the overall
survival rate for the patients treated with surgery alone remained
significantly better for patients who had adenocarcinoma of the
usual type in the esophagus or EGJ (median overall survival, 39.6
months) than patients with signet-ring cell or mucinous histology
(median overall survival, 16.2 months; P = 0.02).
In contrast to the patients treated with surgery alone, the
overall survival rate for the patients treated with chemoradiation
followed by surgery was significantly worse for patients who
had adenocarcinoma of the usual type (median overall survival,
42.3 months) than it was for patients with signet-ring cell or
mucinous histology in the resection post-therapy specimen
(median survival time was not reached; P = 0.02; Fig. 2B). The
same trend was present if signet-ring cell or mucinous histology
was present in the pretreatment mucosal biopsy specimen. The
overall survival rate for the patients treated with chemoradiation
followed by surgery was worse for patients who had adenocar-
cinoma of the usual type (median overall survival, 31.6 months)
than it was for patients with signet-ring cell or mucinous
histology present in the pretreatment mucosal biopsy specimens
(median survival time was not reached; P = 0.06).
After adjusting for significant variables, we found that
presence of signet-ring cell or mucinous histology (P = 0.04)
was an independent predictor of overall survival (Table 6).
Presence of Acellular Mucin Pools in Patients Treated
with Chemoradiation Followed by Surgery. Within the group
of patients treated with chemoradiation followed by surgery, we
found a group of 56 patients with complete pathologic response.
We identified two categories based on the presence or absence of
acellular mucin pools at the treatment site (Fig. 3). Among these
patients, 13 (23%) had acellular mucin pools and 43 (73%) had no
Table 3 Characteristics of the patients with adenocarcinoma of the esophagus treated with chemoradiation followed by surgery according to thepresence of signet-ring cell or mucinous histology
Pretreatment biopsy Post-treatment surgical specimen
Characteristics
Carcinoma withsignet-ring cell
or mucin (n = 32)
Carcinoma of theregular type(n = 161) P
Carcinoma withsignet-ring cell
or mucin (n = 33)
Carcinoma of theregular type(n = 160) P
Gender, n (%)Male 30 (93.7) 150 (93.1) 1.00 30 (90.9) 150 (93.7) 0.47Female 2 (6.2) 11 (6.8) 3 (9.1) 10 (6.2)
Age (y)Mean 61.22 59.38 0.34 61.30 59.35 0.30Median (range) 64 (37-79) 59 (32-79) 64 (37-79) 59 (32-79)
Tumor location, n (%)Cervical/upper/middle 0 (0) 3 (1.8) 1.00 0 (0) 3 (1.8) 1.00Lower/EGJ 32 (100) 158 (98.1) 33 (100) 157 (98.1)
Pathologic stage, n (%)0 9 (28.1) 47 (29.1) 0.84 13 (39.3) 43 (26.8) 0.32I 2 (6.2) 19 (11.8) 1 (3.0) 20 (12.5)II 13 (40.6) 52 (32.2) 12 (36.3) 53 (33.1)III 6 (18.7) 35 (21.7) 5 (15.1) 36 (22.5)IVA 2 (6.2) 8 (4.9) 2 (6.0) 8 (5)
Residual carcinoma, n (%)0% 9 (28.1) 53 (32.9) 0.61 13 (39.3) 49 (30.6) 0.191-10% 10 (31.2) 42 (26.0) 12 (36.3) 40 (25)11-50% 4 (12.5) 32 (19.8) 4 (12.1) 32 (20)>50% 9 (28.1) 34 (21.1) 4 (12.1) 39 (24.3)
Positive margin, n (%)* 5 (15.6) 11 (6.8) 0.15 6 (18.1) 10 (6.2) 0.04
*A specimen with at least one of the proximal, radial, or distal resection margins involved by carcinoma.
Table 4 Correlation between pretreatment biopsy and post-treatment specimen evaluation in patients treated with chemoradiation followed by surgery
Post-treatment specimen findings, n (%)*
Biopsy findingsCarcinoma with signet-ring cell
or mucin (n = 33)zCarcinoma of the regular type
(n = 117) Py
Carcinoma with signet-ring cell or mucinous histology 25 (80.6) 6 (19.4) 0.67Carcinoma of the regular type 8 (6.7) 111 (93.2)
*All 43 cases with no residual tumor and no mucin pools (complete pathologic response) were excluded from the correlation because there is noinformation available regarding the cell type (signet-ring or regular).
yWilcoxon matched-pairs signed-rank test for paired comparison between pretreatment biopsy and post-treatment specimen findings.zThis group includes 13 patients with complete pathologic response and presence of acellular mucin pools in the resected pathology specimen.
Clinical Cancer Research 2233
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mucin. There were no differences in age, sex, tumor location, type
of treatment, and clinical stage between the two groups. The
overall survival was significantly better in patients with complete
pathologic response and presence of acellular mucin pools than
patients with complete response without acellular mucin pools
(P = 0.02; Fig. 3A). All 13 patients with acellular mucin pools are
still alive after an average follow-up time of 36 months (range,
1.4-70.2 months). In contrast, there was no difference in overall
survival between patients with presence or absence of mucin pools
when residual carcinoma was present (Fig. 3B and C).
DISCUSSION
Primary signet-ring cell carcinoma of the esophagus and EGJ
is infrequent (30–32). Signet-ring cell carcinoma may arise in
various organs, including the stomach, colon, urinary bladder,
prostate, and breast. In general, the prognosis of patients with
signet-ring cell carcinoma of any site is poor (22–25). This dismal
outcome has been attributed to the diffusely infiltrating nature of
the neoplasm, leading to widespread metastases before being
clinically apparent (33). In the present study, we confirmed that
patients with adenocarcinoma of the esophagus and EGJ with
signet-ring cell or mucinous histology have a slightly worse
prognosis than gland-forming adenocarcinoma if treated with
surgery alone.
Multimodality strategies, including preoperative chemo-
radiation followed by esophagectomy, are accepted therapy
approaches. The prognostic significance of histopathologic
variants of adenocarcinomas treated with neoadjuvant chemo-
radiation in different tumor types has not been fully characterized.
Several phase II studies have indicated that preoperative treatment
with a combination of chemotherapy and irradiation (chemo-
radiotherapy) followed by esophagectomy produced a complete
response as determined pathologically in f30% of patients (13,
34–37). Such combination treatment thus offers the prospect of
improved survival (38). Our data on 193 patients treated with
preoperative chemoradiation and esophagectomy showed that the
extent of residual carcinoma predicted overall survival and
confirmed the findings in previous reports that patients who had
no residual carcinoma in the esophagus or EGJ had a considerable
Table 5 Univariate analysis of overall survival in relation to pathologic characteristics
Chemoradiation followed by surgery Surgery alone
CharacteristicsPatients, n (%)*
(n = 193)Hazard ratio
(95% confidence interval) PPatients, n (%)*
(n = 219)Hazard ratio
(95% confidence interval) P
Age 193 (100) 1.018 (1.00-1.04) 0.10 219 (100) 1.002 (0.99-1.02) 0.83Pathologic tumor-node-metastasis stage
0y (reference) 56 (29) 1 <0.001 — — <0.001I 21 (11) 1.30 (0.56-3.04) 0.55 36 (16) 1 —II 65 (34) 2.31 (1.24-4.32) 0.01 61 (28) 2.99 (1.44-6.20) 0.003III 41 (21) 4.37 (2.36-8.11) <0.001 93 (42) 9.19 (4.59-18.42) <0.001IV 10 (5) 4.44 (1.82-10.86) 0.001 29 (13) 10.96 (5.09-23.60) <0.001
Residual carcinoma0% (reference) 62 (32) 1 <0.001-10% 52 (27) 2.10 (1.14-3.90) 0.0211-50% 36 (19) 2.26 (1.14-4.46) 0.02>50% 43 (22) 4.50 (2.49-8.16) <0.001
Signet-ring cell or mucinous histology in surgery specimenNo (reference) 160 (83) 1 0.02 179 (82) 1 0.04Yes 33 (17) 0.45 (0.23-0.90) 40 (18) 1.45 (1.00-2.12)
Signet-ring cell or mucinous histology in biopsy specimenNo (reference) 161 (83) 1Yes 32 (17) 0.53 (0.27-1.03) 0.06
*Because of rounding, not all percentages total 100.yDashes denote that patients treated with surgery alone had at least stage I disease.
Table 6 Results of multivariate Cox regression analysis of overall survival among the 193 patients with carcinoma of the esophagus and EGJ treatedwith chemoradiation followed by surgery
Characteristic Patients, n (%) Hazard ratio (95% confidence interval) P
Mean age (y) 59.68 1.029 (1.01-1.05) 0.02Pathologic tumor-node-metastasis stage
0 56 (29) 1 0.03I 21 (11) 0.46 (0.08-2.50) 0.37II 65 (34) 1.01 (0.23-4.42) 0.99III 41 (21) 1.59 (0.33-7.70) 0.56IV 10 (5) 2.25 (0.40-12.50) 0.36
Residual carcinoma0% (reference) 62 (32) 1 0.191-10% 52 (27) 2.36 (0.53-10.43) 0.2611-50% 36 (19) 1.95 (0.43-8.79) 0.39>50% 43 (22) 3.32 (0.76-14.54) 0.11
Signet-ring cell or mucin in surgery specimen 33 (17) 0.479 (0.23-0.98) 0.04
Signet-Ring Cells or Mucin in Esophageal Carcinoma2234
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survival advantage over those who had residual carcinoma
remaining in their resection specimen (13, 17, 18, 39). Although
patients included in this study were not treated uniformly with one
regimen or one esophagectomy technique, therapeutic modality
did not play a significant role in disease-free and overall survival
(data not shown). These findings indicate that the outcome of
patients treated with preoperative therapy is not determined by the
regimens used.
It was unclear if the subset of patients where adenocarci-
nomas had mixed histologic patterns, including signet-ring cell
and mucinous histology, treated with chemoradiation therapy
followed by esophagectomy also had poorer overall survival as
patients treated with esophagectomy alone. Our results suggest
that patients with signet-ring cell or mucinous tumors have the
greatest benefit from preoperative neoadjuvant chemoradiation.
In addition, acellular mucin pools without residual tumor present
in the surgical specimens of patients with a complete pathologic
response and no evidence of residual carcinoma was associated
with excellent overall survival (Fig. 3). Data on the presence of
acellular mucin pools in the esophagus and other gastrointestinal
organs have been limited. Although few published reports
describing the prognostic significance of acellular mucin pools in
adenocarcinomas treated with neoadjuvant chemoradiation in
other tumor types found no survival advantage of patients with
adenocarcinoma of the rectum (40), results on a limited number
of patients with adenocarcinoma of esophagus and EGJ show
that presence of acellular mucin pools is a rare finding and may
represent a better survival (41). We have also shown that these
patients have clinicopathologic characteristics similar to those
who had complete response but no mucin, and differences in
overall survival are more likely attributed to presence of acellular
mucin pools than to other demographic or pathologic variables.
This survival advantage disappeared in patients with presence of
residual tumor in the esophagectomy specimen (Fig. 3B and C).
The explanation on finding that patients with acellular mucin
pools in tumors with complete response after preoperative
chemoradiation have the best prognosis is unknown. Our results
suggest that therapy may have a selective effect on these
particular cancers (Figs. 2 and 3). Although we did not attempt to
make a distinction between these tumors according to the extent
of mucinous or signet-ring cell component, we showed that even
focal features were associated with benefit.
The survival advantage of patients with signet-ring cell or
mucinous histology was present when we evaluated the post-
treatment surgical specimens. Although we found a trend of
survival advantage for patients with signet-ring cell or mucinous
histology present in the pretreatment mucosal biopsy specimens
(P = 0.06), we believe that the analysis did not reach significance
due to the limited size of the sample. We have shown strong
concordance in the pretherapy and post-therapy histology
findings (Table 4) despite the marked differences in amount of
tissue sampled and the location within the esophageal wall.
Therefore, biopsy fragments seem to be useful in predicting
response to preoperative neoadjuvant chemoradiation.
Our study provides support for the concept of tumor
heterogeneity and different responses to various therapy
approaches in adenocarcinoma of the esophagus and EGJ.
Therefore, our findings suggest that adenocarcinoma of the
esophagus and EGJ with signet-ring cell and mucinous features
represents a distinct subgroup of cancer with characteristic
pathologic and clinical features and a favorable response to
chemoradiation therapy.
REFERENCES
1. Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med 2003;349:2241–52.
2. Medical Research Council Oesophageal Cancer Working Group.Surgical resection with or without preoperative chemotherapy in oeso-phageal cancer: a randomised controlled trial. Lancet 2002;359:1727–33.
Fig. 3 Kaplan-Meier curves of overall survival among patients withcarcinoma of the esophagus and EGJ treated with preoperativeneoadjuvant chemoradiation followed by esophagectomy. A, patientswith acellular mucin pools have a better overall survival in specimenswith no residual carcinoma. B and C, mucin pools in the post-treatmentsurgical specimens do not confer a survival advantage in the group with1-10% residual carcinoma or the group with 11-50% residual carcinoma.
Clinical Cancer Research 2235
Research. on October 8, 2020. © 2005 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
3. Orringer MB, Marshall B, Iannettoni MD. Transhiatal esoph-agectomy: clinical experience and refinements. Ann Surg 1999;230:392–400.
4. Altorki N, Kent M, Ferrara C, Port J. Three-field lymph nodedissection for squamous cell and adenocarcinoma of the esophagus. AnnSurg 2002;236:177–83.
5. Akiyama H, Tsurumaru M, Udagawa H, Kajiyama Y. Radical lymphnode dissection for cancer of the thoracic esophagus. Ann Surg 1994;220:364–72.
6. Lerut T, De Leyn P, Coosemans W, Van Raemdonck D,Scheys I, LeSaffre E. Surgical strategies in esophageal carcinomawith emphasis on radical lymphadenectomy. Ann Surg 1992;216:583–90.
7. Coia LR, Minsky BD, Berkey BA, et al. Outcome of patientsreceiving radiation for cancer of the esophagus: results of the 1992-1994Patterns of Care Study. J Clin Oncol 2000;18:455–62.
8. Ando N, Ozawa S, Kitagawa Y, Shinozawa Y, Kitajima M.Improvement in the results of surgical treatment of advanced squamousesophageal carcinoma during 15 consecutive years. Ann Surg 2000;232:225–32.
9. Greene FL, Page DL, Fleming ID, et al. AJCC cancer staging manual.6th ed. New York (NY): Springer; 2002. p. 91–8.
10. Holscher AH, Bollschweiler E, Bumm R, Bartels H, Hofler H,Siewert JR. Prognostic factors of resected adenocarcinoma of theesophagus. Surgery 1995;118:845–55.
11. Korst RJ, Rusch VW, Venkatraman E, et al. Proposed revision of thestaging classification for esophageal cancer. J Thorac Cardiovasc Surg1998;115:660–9.
12. Steup WH, De Leyn P, Deneffe G, Van Raemdonck D, CoosemansW, Lerut T. Tumors of the esophagogastric junction. Long-term survivalin relation to the pattern of lymph node metastasis and a critical analysisof the accuracy or inaccuracy of pTNM classification. J ThoracCardiovasc Surg 1996;111:85–94.
13. Heath EI, Burtness BA, Heitmiller RF, et al. Phase II evaluation ofpreoperative chemoradiation and postoperative adjuvant chemotherapyfor squamous cell and adenocarcinoma of the esophagus. J Clin Oncol2000;18:868–76.
14. Forastiere AA, Orringer MB, Perez-Tamayo C, et al. Concurrentchemotherapy and radiation therapy followed by transhiatal esophagec-tomy for local-regional cancer of the esophagus. J Clin Oncol 1990;8:119–27.
15. Ajani JA, Faust J, Yao J, et al. Irinotecan/cisplatin followed by 5-FU/paclitaxel/radiotherapy and surgery in esophageal cancer. Oncology2003;17:20–2.
16. Malthaner R, Fenlon D. Preoperative chemotherapy for resectablethoracic esophageal cancer. Cochrane Database Syst Rev 2003:CD001556.
17. Darnton SJ, Archer VR, Stocken DD, Mulholland PJ, Casson AG,Ferry DR. Preoperative mitomycin, ifosfamide, and cisplatin followed byesophagectomy in squamous cell carcinoma of the esophagus: pathologiccomplete response induced by chemotherapy leads to long-term survival.J Clin Oncol 2003;21:4009–15.
18. Meluch AA, Greco FA, Gray JR, et al. Preoperative therapy withconcurrent paclitaxel/carboplatin/infusional 5-FU and radiation therapyin locoregional esophageal cancer: final results of a Minnie Pearl CancerResearch Network phase II trial. Cancer J 2003;9:251–60.
19. Leichman L, Steiger Z, Seydel HG, et al. Preoperative chemotherapyand radiation therapy for patients with cancer of the esophagus: apotentially curative approach. J Clin Oncol 1984;2:75–9.
20. Poplin E, Fleming T, Leichman L, et al. Combined therapies forsquamous-cell carcinoma of the esophagus, a Southwest OncologyGroup Study (SWOG-8037). J Clin Oncol 1987;5:622–8.
21. Ellis FH Jr, Heatley GJ, Krasna MJ, Williamson WA, Balogh K.Esophagogastrectomy for carcinoma of the esophagus and cardia: acomparison of findings and results after standard resection in three
consecutive eight-year intervals with improved staging criteria. J ThoracCardiovasc Surg 1997;113:836–46.
22. Frost AR, Terahata S, Yeh IT, Siegel RS, Overmoyer B, SilverbergSG. The significance of signet ring cells in infiltrating lobular carcinomaof the breast. Arch Pathol Lab Med 1995;119:64–8.
23. Kitamura H, Sumikawa T, Fukuoka H, Kanisawa M. Primary signet-ring cell carcinoma of the urinary bladder. Report of two cases withhistochemical studies. Acta Pathol Jpn 1985;35:675–86.
24. Merchant SH, Amin MB, Tamboli P, et al. Primary signet-ring cellcarcinoma of lung: immunohistochemical study and comparison withnon-pulmonary signet-ring cell carcinomas. Am J Surg Pathol 2001;25:1515–9.
25. Yamashina M. A variant of early gastric carcinoma. Histologic andhistochemical studies of early signet ring cell carcinomas discoveredbeneath preserved surface epithelium. Cancer 1986;58:1333–9.
26. KitajimaM,KitagawaY. Surgical treatment of esophageal cancer– theadvent of the era of individualization. N Engl J Med 2002;347:1705–9.
27. Hulscher JB, van Sandick JW, de Boer AG, et al. Extendedtransthoracic resection compared with limited transhiatal resection foradenocarcinoma of the esophagus. N Engl J Med 2002;347:1662–9.
28. Mandard AM, Dalibard F, Mandard JC, et al. Pathologic assessmentof tumor regression after preoperative chemoradiotherapy of esophagealcarcinoma. Clinicopathologic correlations. Cancer 1994;73:2680–6.
29. Becker K, Mueller JD, Schulmacher C, et al. Histomorphology andgrading of regression in gastric carcinoma treated with neoadjuvantchemotherapy. Cancer 2003;98:1521–30.
30. Takubo K, Takai A, Yamashita K, Onda M. Carcinoma with signetring cells of the esophagus. Acta Pathol Jpn 1987;37:989–95.
31. Rubio CA, Lagergren J. Histological features pertinent to localtumour progression in Barrett’s adenocarcinoma. Anticancer Res 2003;23:3015–8.
32. Paraf F, Flejou JF, Pignon JP, Fekete F, Potet F. Surgical pathologyof adenocarcinoma arising in Barrett’s esophagus. Analysis of 67 cases.Am J Surg Pathol 1995;19:183–91.
33. Tung SY, Wu CS, Chen PC. Primary signet ring cell carcinoma ofcolorectum: an age- and sex-matched controlled study. Am J Gastro-enterol 1996;91:2195–9.
34. Bosset JF, Gignoux M, Triboulet JP, et al. Chemoradiotherapyfollowed by surgery compared with surgery alone in squamous-cellcancer of the esophagus. N Engl J Med 1997;337:161–7.
35. Ilson DH, Forastiere A, Arquette M, et al. A phase II trial ofpaclitaxel and cisplatin in patients with advanced carcinoma of theesophagus. Cancer J 2000;6:316–23.
36. Kelsen DP, Ginsberg R, Pajak TF, et al. Chemotherapy followed bysurgery compared with surgery alone for localized esophageal cancer.N Engl J Med 1998;339:1979–84.
37. Webb A, Cunningham D, Scarffe JH, et al. Randomized trialcomparing epirubicin, cisplatin, and fluorouracil versus fluorouracil,doxorubicin, and methotrexate in advanced esophagogastric cancer. J ClinOncol 1997;15:261–7.
38. Fink U, Stein HJ, Bochtler H, Roder JD, Wilke HJ, Siewert JR.Neoadjuvant therapy for squamous cell esophageal carcinoma. AnnOncol 1994;5 Suppl 3:17–26.
39. Urba SG, Orringer MB, Turrisi A, Iannettoni M, Forastiere A,Strawderman M. Randomized trial of preoperative chemoradiationversus surgery alone in patients with locoregional esophageal carcinoma.J Clin Oncol 2001;19:305–13.
40. Shia J, Guillem JG, Moore HG, et al. Patterns of morphologicalteration in residual rectal carcinoma following preoperative chemo-radiation and their association with long-term outcome. Am J Surg Pathol2004;28:215–23.
41. Hornick JL, Farraye FA, Wang HH, Odze RD. Prevalence andsignificance of acellular mucin pools in the esophagus post neoadjuvantchemoradiotherapy for Barrett’s associated adenocarcinoma. Mod Pathol2003;16:121–2A.
Signet-Ring Cells or Mucin in Esophageal Carcinoma2236
Research. on October 8, 2020. © 2005 American Association for Cancerclincancerres.aacrjournals.org Downloaded from
2005;11:2229-2236. Clin Cancer Res Lucian R. Chirieac, Stephen G. Swisher, Arlene M. Correa, et al. Esophagogastric Junction AdenocarcinomaChemoradiation and Survival in Patients with Esophageal or Signet-Ring Cell or Mucinous Histology after Preoperative
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