Signet-Ring Cell Or Mucinous Histology After Preoperative Chemoradiation and Survival in Patients with Esophageal Or Esophagogastric Junction Adenocarcinoma

Vol. 11, 2229–2236, March 15, 2005 Clinical Cancer Research 2229

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 Conclusions: Our study showed that patients with Arlene M. Correa,2 Jaffer A. Ajani,3 esophageal or EGJ adenocarcinoma who have signet-ring cell or mucinous histology benefited substantially from Ritsuko R. Komaki,4 Asif Rashid,1 preoperative chemoradiation and esophagectomy. Stanley R. Hamilton,1 and Tsung-Teh Wu1 Departments of 1Pathology, 2Thoracic and Cardiovascular Surgery, 3Gastrointestinal Medical Oncology and 4Division of Radiation Oncology, INTRODUCTION University of Texas M.D. Anderson Cancer Center, Houston, Texas 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 ABSTRACT esophageal carcinoma, although multimodality strategies, in- Purpose: The survival of patients with local-regional cluding preoperative chemoradiation followed by esophagec- adenocarcinoma of the esophagus or esophagogastric junction tomy, are accepted modalities of treatment (7). When surgical (EGJ) treated with preoperative chemoradiation is much resection is the primary therapy, the best predictor of overall better in patients with pathologic complete response than survival is pathologic stage (8–12). The outcome of patients those with residual tumor. Some adenocarcinomas have mixed after preoperative chemoradiation is much better if no residual patterns, including signet-ring cell and mucinous histology, carcinoma (stage 0) is found in the resected specimen, but the clinical significance of these subtypes is unknown. representing a pathologic complete response (13–21). However, Experimental Design: We studied 412 consecutive pathologic complete response occurs in <30% of patients who patients with esophageal or EGJ adenocarcinoma treated undergo surgery following preoperative chemoradiation (13). with chemoradiation followed by esophagectomy (193 A subset of adenocarcinomas has mixed histologic patterns, patients) or surgery alone (219 patients). We evaluated including signet-ring cell and mucinous histology. Signet-ring signet-ring cell and mucinous histology in the resection and cell carcinoma is a unique subtype of mucin-producing pretherapy biopsy specimens and compared clinicopathologic adenocarcinoma characterized by abundant intracellular mucin features with overall survival. accumulation and a compressed nucleus displaced toward one Results: The fraction of signet-ring cell and mucinous extremity of the cell. Mucinous carcinoma has abundant histology was similar in evaluated specimens of patients extracellular mucin. These two histologic morphologies com- treated with preoperative chemoradiation or surgery alone monly occur together. In general, the prognosis of patients with (17% and 18%, respectively). The overall survival rate at 5 signet-ring cell carcinoma of any organ site is poor (22–25). years of patients treated with preoperative chemoradiation However, in patients treated with chemoradiation therapy was significantly better if residual signet-ring cell or followed by esophagectomy, it remains unclear whether these mucinous histology was present in the esophagectomy particular histologic patterns indicate worse overall survival. specimen (63% versus 28%; P = 0.02). All 13 patients with Furthermore, acellular mucin pools with no evidence of residual acellular mucin pools and no residual carcinoma are still alive carcinoma cell are identified in a subset of surgical resection after an average follow-up time of 36 months. By contrast, in specimens of patients with local-regional carcinoma of the patients treated with surgery alone, overall survival rate was esophagus and EGJ. No report currently exists about the significantly worse if signet-ring cell or mucinous histology presence of acellular mucin pools predicting overall survival was present (14% versus 30%; P = 0.05). In multivariate for patients who have no residual carcinoma cell in the resected analysis, overall survival was independently predicted by specimen after preoperative therapy. presence of signet-ring cell or mucinous histology (P = 0.04). 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- Received 9/10/04; revised 12/8/04; accepted 12/15/04. fore, we hypothesized that patients with local-regional adeno- The costs of publication of this article were defrayed in part by the carcinoma of the esophagus and EGJ with signet-ring cell or payment of page charges. This article must therefore be hereby marked mucinous histology represents a subset of patients who have the advertisement in accordance with 18 U.S.C. Section 1734 solely to highest benefit from preoperative neoadjuvant chemoradiation. indicate this fact. Note: L. R. Chirieac is presently at the Department of Pathology, We also postulated that presence of residual acellular mucin Brigham and Women’s Hospital and Harvard Medical School, Boston, pools in the resection specimen of patients treated with Massachusetts. preoperative neoadjuvant chemoradiation is associated with a Requests for reprints: Tsung-Teh Wu, Department of Pathology, better prognosis. We therefore studied the clinical significance of University of Texas M.D. Anderson Cancer Center, Unit 085, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-4977; Fax: signet-ring cell and mucinous histology in 412 patients with 713-792-4049; E-mail: [email protected]. adenocarcinoma of the esophagus and EGJ and related the D2005 American Association for Cancer Research. findings to survival.

MATERIALS AND METHODS cervical approach) in 25 (13%) patients, and transhiatal Patient Characteristics. This study included 412 consec- esophagectomy (abdominal-cervical approach) in 53 (28%) utive patients at the University of Texas M.D. Anderson Cancer patients (26, 27). One (1%) patient underwent two-stage Center who had histologically confirmed adenocarcinoma of the esophagectomy (Table 1). esophagus or EGJ treated with chemoradiation followed by The second group was treated with surgery alone. Patients esophagectomy or surgery alone between 1985 and 2003 and had with clinical stage I and IVB were excluded to serve as a control their pathology specimens available for review (Table 1). The group to patients treated with chemoradiation followed by study was approved by the institutional review board. esophagectomy, leaving 219 patients for study. The mean age The first group of 193 patients was treated with chemo- was 62.5 years (range, 28-84 years). There were 194 men and radiation followed by esophagectomy. The mean age was 25 women. The majority of cancers (93%) were in the distal 59.7 years (range, 32-79 years). There were 180 men and esophagus or EGJ with 7% in the middle or upper esophagus. 13 women. The vast majority of cancers (98%) were in the distal The pretreatment clinical stage was II in 83% of patients, III esophagus or EGJ with only 2% in the middle or upper in 15%, and IVA with celiac lymph node involvement in 2%. esophagus. Patients with clinical stage I or IVB disease Assessment of Esophageal Adenocarcinoma Specimens. (systemic metastases) were not eligible for preoperative chemo- H&E-stained slides from each case were reviewed with no radiation. Pretreatment clinical stage was determined by barium knowledge of the previous diagnosis, staging, or outcome for swallow esophagogram, computed tomographic scan, endo- each case. Patients who were treated with chemoradiation scopic ultrasonography, and positron emission tomography. The followed by esophagectomy had both the post-therapy surgical pretreatment clinical stage was II in 54% of patients, III in specimen and the pre-chemoradiation biopsy specimen evaluated 39%, and IVA with celiac lymph node involvement in 6%. for comparison of the results in the two types of specimens with Three agents were used for preoperative chemotherapy: greatly different sampling. Patients who were treated with fluorouracil, cisplatin, and a taxane. All patients underwent surgery alone had surgical resection specimen evaluated. Speci- computed tomographic simulation for radiation therapy. Clinical mens remained encoded for the entire histopathologic evalua- target volume was defined as the gross tumor volume plus a 5-cm tion. In patients treated with chemoradiation followed by margin superior to the highest extension and inferior to the esophagectomy, residual carcinoma status was determined in lowest extension of the carcinoma with a 2-cm radial margin. each surgical specimen. These patients had either complete Planning target volume was defined as the clinical target volume pathologic response or residual carcinoma present in fibrotic plus a 5-mm margin. The total dose of radiation therapy was tissue or in acellular mucin pools at the primary site. If residual 45 Gy in 25 fractions or 50.4 Gy in 28 fractions prescribed to carcinoma was identified grossly, tumor was sampled for cover at least 95% of the planning target volume. Radiation histologic evaluation in an average of 15 slides (95% confidence therapy was given with megavoltage (>6 MV) equipment with interval, 11.8-18.6). If no residual carcinoma was identified anterior and posterior fields for 20 to 22 fractions followed by grossly, areas with ulcer or scar indicating the therapy field were oblique or lateral fields for the remaining fractions to spare the submitted completely for histologic examination and generated spinal cord. Four to 6 weeks after completing preoperative an average of 17 slides (95% confidence interval, 15.4-18.6). therapy, patients underwent a radical en bloc esophagectomy. Each esophagectomy specimen was evaluated for depth of The surgical approaches used were Ivor-Lewis esophagectomy invasion, margin status, and lymph node metastasis and staged (abdominal-right thoracic approach) in 114 (59%) patients, three- according to the sixth edition of the American Joint Committee field McKeown esophagectomy (right thoracic abdominal- 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: Table 1 Characteristics of the patients according to the therapy group adenocarcinomas with signet-ring cell or mucinous histology and Chemoradiation Surgery adenocarcinomas of the usual type. Adenocarcinomas with followed by surgery alone signet-ring cell or mucinous histology included mucinous Characteristics (n = 193) (n = 219) adenocarcinomas, carcinomas with mucinous features, signet- Gender, n (%) ring cell carcinomas, carcinomas with signet-ring cell, and Male 180 (93.3) 194 (88.6) Female 13 (6.7) 25 (11.4) adenocarcinomas with mixed signet-ring cell and mucinous Age (y) histology. The remainder of the cases was carcinomas without Mean 59.68 62.54 mucinous differentiation or presence of signet-ring cell. For Median (range) 60 (32-79) 65 (28-84) adenocarcinomas treated with preoperative chemoradiation, Primary location, n (%) presence of mucin pools, irrespective of presence or absence of Cervical/upper/middle 3 (1.6) 15 (6.8) Lower/EGJ 190 (98.4) 204 (93.2) residual tumor cells, was classified as adenocarcinoma with Type of esophagogastrectomy, n (%) signet-ring cell or mucinous histology (Fig. 1). Transthoracic (Ivor-Lewis) 114 (59.1) 105 (47.9) Definition of Residual Carcinoma Status. Residual Transhiatal 53 (27.5) 86 (39.3) cancer status in patients treated with preoperative chemo- Total (three-field technique) 25 (13.0) 16 (7.3) Two-stage procedure 1 (0.5) 12 (5.5) radiation was determined in esophagogastrectomy specimens. Positive margin, n (%)* 16 (8.3) 80 (36.5) Extent of residual carcinoma was assessed semiquantitatively NOTE. Because of rounding, not all percentages total 100. irrespective of lymph node status based on estimated percentage *A specimen with at least one of the proximal, radial, or distal of residual carcinoma in relation to total carcinoma area, resection margins involved by carcinoma. including amount of radiation-induced tissue injury, in mural

histologic sections (28). Extent of residual carcinoma in the for Windows, GraphPad Software, San Diego, CA). We used esophagectomy specimen was assigned to one of four categories: two-sided significance level of 0.05 and power of 0.90 for all no residual carcinoma (Fig. 1C), 1% to 10% residual carcinoma statistical analyses. (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). RESULTS The extent of residual carcinoma in regional lymph nodes was Prevalence of Signet-Ring Cell or Mucinous Histology not assessed. in Patients with Esophageal or Esophagogastric Junction Statistical Analysis. v2 or Fisher’s exact tests were used Adenocarcinoma. In patients with esophagus and EGJ to compare categorical data. Overall survival was calculated adenocarcinoma treated with surgery alone, 40 (18.2%) had from time of surgery to time of death from any cause or to time signet-ring cell or mucinous histology and 179 (81.7%) had of last follow-up, at which point the data were censored. Overall adenocarcinoma of the usual type (Table 2). There were no survival curves were constructed using the Kaplan-Meier significant differences in gender, tumor location, and pathology method, and log-rank test was used to evaluate the statistical stage between patients with adenocarcinoma of the usual type significance of differences. and those with signet-ring cell or mucinous histology. Patients The prognostic significance of clinical and pathologic with adenocarcinoma of the usual type were slightly older and characteristics was determined using univariate Cox regression had less positive margins (Table 2). analysis. Cox proportional hazards models were fitted for The post-treatment surgical specimens of patients with multivariate analysis. After interactions between variables were esophagus and EGJ adenocarcinoma treated with chemoradiation examined, a backward stepwise procedure was used to derive the followed by surgery included 33 (17.1%) cases with signet-ring best-fitting model. cell or mucinous histology and 160 (82.9%) cases with Statistical analysis was done using SPSS software (version adenocarcinoma of the usual type (Table 3). Of the 33 cancers 11.5.2.1 for Windows, SPSS, Chicago, IL). Kaplan-Meier with signet-ring cell or mucinous histology in the post-treatment survival curves were drawn with GraphPad Prism (version 4 surgical specimen, 13 (39.4%) were classified as stage 0 (only

Fig. 1 Histopathology of adenocarcinoma of esophagus and EGJ treated with chemoradiation followed by esophagogastrectomy. The treated primary site has signet-ring cell and mucinous histology. A and B, residual carcinoma characterized by rare individual carcinoma cell with signet-ring features present in mucin pools at the primary site. C, acellular mucin pools extending through the layers of the esophageal wall without residual carcinoma.

Fig. 2 Kaplan-Meier curves of overall survival among patients with carcinoma of the esophagus and EGJ treated with surgery alone and patients treated with preoperative neoadjuvant chemoradiation followed by esophagectomy. A, patients treated with surgery alone who had adenocarcinoma of the usual type in the esophagus or EGJ have a better overall survival than patients with signet-ring cell or mucinous histology in the post-treatment surgical specimens. B, 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 than it was for patients with signet-ring cell or mucinous histology in the post-treatment surgical specimens.

acellular mucin pools without residual tumor cells were present), three cases. Overall, the pathologic stages were 0 (29%), I 1 (3%) as stage I, 12 (36.3%) as stage II, 5 (1.5%) as stage III, (10.9%), II (33.7%), III (21.2%), and IV (5.2%). The and 2 (6%) as stage IV. Acellular mucin pools were present in 13 clinicopathologic features of the two subgroups were similar, (23.2%) cases of 56 patients with complete pathologic response except for a slightly higher proportion of patients with positive (no residual tumor); mucin extended into adventitia in nine margins in the group with signet-ring cell or mucinous histology cases, in muscularis propria in one case, and in submucosa only (P = 0.04; Table 3). in three cases. Mucin with neoplastic usual cell or signet-ring The pretreatment biopsy specimen of patients with cell was present in 12 cases with 1% to 10% residual tumor, 4 esophagus and EGJ adenocarcinoma treated with chemoradiation cases with 11% to 50% residual tumor, and 4 cases with >51% followed by surgery had 32 (16.6%) cases with signet-ring cell residual tumor (Table 3). In the cases where the extent of residual or mucinous histology and 161 (83.4%) with adenocarcinoma of tumor was 1% to 10%, mucin extended into adventitia in eight the usual type (Table 3). We found no significant differences in cases, in muscularis propria in one case, and in submucosa 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). Table 2 Characteristics of the patients with adenocarcinoma of the Correlation of Tumor Histology between Post-treatment esophagus treated with surgery alone according to the presence of Resection Specimen and Pretreatment Biopsy Specimen in signet-ring cell or mucinous histology Patients Treated with Chemoradiation Followed by Surgery. Adenocarcinoma Adenocarcinoma Although the findings in the pretreatment biopsies were slightly with signet-ring cell of the regular different from the findings in the surgical specimens, the Characteristics or mucin (n = 40) type (n = 179) P concordance for each patient was extremely high (P = 0.67; Gender, n (%) Table 4). For 136 (90.6%) patients, the biopsy classification was Male 34 (85.0) 160 (89.4) 0.42 identical to the findings in the surgical specimens. Eight patients Female 6 (15.0) 19 (10.6) Age (y) with a diagnosis of adenocarcinoma of the usual type in the Mean 59.38 63.25 0.04 biopsy revealed signet-ring cell or mucinous histology in the Median (range) 62 (32-81) 65 (28-84) subsequent post-treatment surgical specimen (five had complete Tumor location, n (%) pathologic response and three had 1-10% residual tumor). We Cervical/upper/middle 1 (2.5) 14 (7.8) 0.32 believe that these findings represent sampling error due to the Lower/EGJ 39 (97.5) 165 (92.2) Pathologic stage, n (%) limited nature of the tissue to be examined in the biopsy. On the I 3 (7.5) 33 (18.4) 0.10 other hand, six patients with presence of signet-ring cell in II 9 (22.5) 52 (29.1) the biopsy specimens had adenocarcinoma of the usual type III 19 (47.5) 74 (41.3) in the post-treatment surgical specimen (five had gross residual IV 9 (22.5) 20 (11.2) Positive margin, n (%)* tumor and one had 1-10% residual tumor). Radial, proximal, distal 21 (51.2) 60 (33.5) 0.03 Survival Analysis. The mean potential follow-up time using censored data was 79.2 months. Univariate Cox regression NOTE. Because of rounding, not all percentages total 100. *A specimen with at least one of the proximal, radial, or distal analysis showed that pathologic stage, and presence of signet- resection margins involved by carcinoma. ring cell or mucinous histology in the resection specimen were

Table 3 Characteristics of the patients with adenocarcinoma of the esophagus treated with chemoradiation followed by surgery according to the presence of signet-ring cell or mucinous histology Pretreatment biopsy Post-treatment surgical specimen Carcinoma with Carcinoma of the Carcinoma with Carcinoma of the signet-ring cell regular type signet-ring cell regular type Characteristics or mucin (n = 32) (n = 161) P or mucin (n = 33) (n = 160) P Gender, n (%) Male 30 (93.7) 150 (93.1) 1.00 30 (90.9) 150 (93.7) 0.47 Female 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 0.30 Median (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) 1.00 Lower/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) 0.32 I 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) 0.19 1-10% 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. prognostic indicators for overall survival for both patients treated 42.3 months) than it was for patients with signet-ring cell or with surgery alone and those treated with preoperative neo- mucinous histology in the resection post-therapy specimen adjuvant chemoradiation (Table 5). (median survival time was not reached; P = 0.02; Fig. 2B). The The overall survival rate for the patients treated with surgery same trend was present if signet-ring cell or mucinous histology alone was significantly better for patients who had adenocarci- was present in the pretreatment mucosal biopsy specimen. The noma of the usual type in the esophagus or EGJ (median overall overall survival rate for the patients treated with chemoradiation survival, 22.9 months) than patients with signet-ring cell or followed by surgery was worse for patients who had adenocar- mucinous histology (median overall survival, 17.5 months; P = cinoma of the usual type (median overall survival, 31.6 months) 0.05; Fig. 2A). Because patients who had signet-ring cell or than it was for patients with signet-ring cell or mucinous mucinous histology had higher positive margin rate than patients histology present in the pretreatment mucosal biopsy specimens who had adenocarcinoma of the usual type, we included patients (median survival time was not reached; P = 0.06). with only negative margins in a separate analysis, and the overall After adjusting for significant variables, we found that survival rate for the patients treated with surgery alone remained presence of signet-ring cell or mucinous histology (P = 0.04) significantly better for patients who had adenocarcinoma of the was an independent predictor of overall survival (Table 6). usual type in the esophagus or EGJ (median overall survival, 39.6 Presence of Acellular Mucin Pools in Patients Treated months) than patients with signet-ring cell or mucinous histology with Chemoradiation Followed by Surgery. Within the group (median overall survival, 16.2 months; P = 0.02). of patients treated with chemoradiation followed by surgery, we In contrast to the patients treated with surgery alone, the found a group of 56 patients with complete pathologic response. overall survival rate for the patients treated with chemoradiation We identified two categories based on the presence or absence of followed by surgery was significantly worse for patients who acellular mucin pools at the treatment site (Fig. 3). Among these had adenocarcinoma of the usual type (median overall survival, patients, 13 (23%) had acellular mucin pools and 43 (73%) had no

Table 4 Correlation between pretreatment biopsy and post-treatment specimen evaluation in patients treated with chemoradiation followed by surgery Post-treatment specimen findings, n (%)* Carcinoma with signet-ring cell Carcinoma of the regular type Biopsy findings or mucin (n = 33)z (n = 117) Py Carcinoma with signet-ring cell or mucinous histology 25 (80.6) 6 (19.4) 0.67 Carcinoma 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 no information 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.

Table 5 Univariate analysis of overall survival in relation to pathologic characteristics Chemoradiation followed by surgery Surgery alone Patients, n (%)* Hazard ratio Patients, n (%)* Hazard ratio Characteristics (n = 193) (95% confidence interval) P (n = 219) (95% confidence interval) P Age 193 (100) 1.018 (1.00-1.04) 0.10 219 (100) 1.002 (0.99-1.02) 0.83 Pathologic tumor-node-metastasis stage 0y (reference) 56 (29) 1 <0.001 — — <0.001 I 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) 0.003 III 41 (21) 4.37 (2.36-8.11) <0.001 93 (42) 9.19 (4.59-18.42) <0.001 IV 10 (5) 4.44 (1.82-10.86) 0.001 29 (13) 10.96 (5.09-23.60) <0.001 Residual carcinoma 0% (reference) 62 (32) 1 <0.00 1-10% 52 (27) 2.10 (1.14-3.90) 0.02 11-50% 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 specimen No (reference) 160 (83) 1 0.02 179 (82) 1 0.04 Yes 33 (17) 0.45 (0.23-0.90) 40 (18) 1.45 (1.00-2.12) Signet-ring cell or mucinous histology in biopsy specimen No (reference) 161 (83) 1 Yes 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.

mucin. There were no differences in age, sex, tumor location, type clinically apparent (33). In the present study, we confirmed that of treatment, and clinical stage between the two groups. The patients with adenocarcinoma of the esophagus and EGJ with overall survival was significantly better in patients with complete signet-ring cell or mucinous histology have a slightly worse pathologic response and presence of acellular mucin pools than prognosis than gland-forming adenocarcinoma if treated with patients with complete response without acellular mucin pools surgery alone. (P = 0.02; Fig. 3A). All 13 patients with acellular mucin pools are Multimodality strategies, including preoperative chemo- still alive after an average follow-up time of 36 months (range, radiation followed by esophagectomy, are accepted therapy 1.4-70.2 months). In contrast, there was no difference in overall approaches. The prognostic significance of histopathologic survival between patients with presence or absence of mucin pools variants of adenocarcinomas treated with neoadjuvant chemo- when residual carcinoma was present (Fig. 3B and C). 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- DISCUSSION radiotherapy) followed by esophagectomy produced a complete Primary signet-ring cell carcinoma of the esophagus and EGJ response as determined pathologically in f30% of patients (13, is infrequent (30–32). Signet-ring cell carcinoma may arise in 34–37). Such combination treatment thus offers the prospect of various organs, including the stomach, colon, urinary bladder, improved survival (38). Our data on 193 patients treated with prostate, and breast. In general, the prognosis of patients with preoperative chemoradiation and esophagectomy showed that the signet-ring cell carcinoma of any site is poor (22–25). This dismal extent of residual carcinoma predicted overall survival and outcome has been attributed to the diffusely infiltrating nature of confirmed the findings in previous reports that patients who had the neoplasm, leading to widespread metastases before being no residual carcinoma in the esophagus or EGJ had a considerable

Table 6 Results of multivariate Cox regression analysis of overall survival among the 193 patients with carcinoma of the esophagus and EGJ treated with chemoradiation followed by surgery Characteristic Patients, n (%) Hazard ratio (95% confidence interval) P Mean age (y) 59.68 1.029 (1.01-1.05) 0.02 Pathologic tumor-node-metastasis stage 0 56 (29) 1 0.03 I 21 (11) 0.46 (0.08-2.50) 0.37 II 65 (34) 1.01 (0.23-4.42) 0.99 III 41 (21) 1.59 (0.33-7.70) 0.56 IV 10 (5) 2.25 (0.40-12.50) 0.36 Residual carcinoma 0% (reference) 62 (32) 1 0.19 1-10% 52 (27) 2.36 (0.53-10.43) 0.26 11-50% 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

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. Fig. 3 Kaplan-Meier curves of overall survival among patients with Therefore, biopsy fragments seem to be useful in predicting carcinoma of the esophagus and EGJ treated with preoperative response to preoperative neoadjuvant chemoradiation. neoadjuvant chemoradiation followed by esophagectomy. A, patients with acellular mucin pools have a better overall survival in specimens Our study provides support for the concept of tumor with no residual carcinoma. B and C, mucin pools in the post-treatment heterogeneity and different responses to various therapy surgical specimens do not confer a survival advantage in the group with approaches in adenocarcinoma of the esophagus and EGJ. 1-10% residual carcinoma or the group with 11-50% residual carcinoma. Therefore, our findings suggest that adenocarcinoma of the esophagus and EGJ with signet-ring cell and mucinous features survival advantage over those who had residual carcinoma represents a distinct subgroup of cancer with characteristic remaining in their resection specimen (13, 17, 18, 39). Although pathologic and clinical features and a favorable response to patients included in this study were not treated uniformly with one chemoradiation therapy. regimen or one esophagectomy technique, therapeutic modality did not play a significant role in disease-free and overall survival REFERENCES (data not shown). These findings indicate that the outcome of 1. Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med 2003; patients treated with preoperative therapy is not determined by the 349:2241–52. regimens used. 2. Medical Research Council Oesophageal Cancer Working Group. It was unclear if the subset of patients where adenocarci- Surgical resection with or without preoperative chemotherapy in oeso- nomas had mixed histologic patterns, including signet-ring cell phageal cancer: a randomised controlled trial. Lancet 2002;359:1727–33.

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