signet-ring cell or mucinous histology after preoperative ... · signet-ring cell or mucinous...

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



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



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.




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.




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




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.




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.




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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