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

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, including preoperative chemoradiation followed by esophagectomy, 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 commonly 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. Therefore, we hypothesized that patients with local-regional adenocarcinoma 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.

MATERIALS AND METHODS

Patient Characteristics. This study included 412 consecutive 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 chemoradiation 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 chemoradiation. Pretreatment clinical stage was determined by barium swallow esophagogram, computed tomographic scan, endoscopic 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. Specimens remained encoded for the entire histopathologic evaluation. 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).

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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.

Definition of Residual Carcinoma Status. Residual cancer status in patients treated with preoperative chemoradiation 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 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.

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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.

Statistical Analysis. χ² 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 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 prognostic indicators for overall survival for both patients treated with surgery alone and those treated with preoperative neoadjuvant chemoradiation (Table 5).

The overall survival rate for the patients treated with surgery alone was significantly better for patients who had adenocarcinoma 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 adenocarcinoma 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 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).

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Fig. 3

Kaplan-Meier curves of overall survival among patients with carcinoma of the esophagus and EGJ treated with preoperative neoadjuvant chemoradiation followed by esophagectomy. A, patients with acellular mucin pools have a better overall survival in specimens with no residual carcinoma. B and C, mucin pools in the post-treatment surgical specimens do not confer a survival advantage in the group with 1-10% residual carcinoma or the group with 11-50% residual carcinoma.

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 chemoradiation followed by esophagectomy, are accepted therapy approaches. The prognostic significance of histopathologic variants of adenocarcinomas treated with neoadjuvant chemoradiation 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 (chemoradiotherapy) followed by esophagectomy produced a complete response as determined pathologically in ∼30% 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 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 adenocarcinomas 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.