Impact of Different Histopathological Factors on Recurrence and Survival in Operated Carcinoma Esophagus

Introduction

Even with the recent advances in the diagnosis and treatment, esophageal cancer still has significantly high mortality. The mean survival for squamous cell carcinoma (SCC) is 13.95 ± SD 11.2 months and for esophageal adenocarcinoma (EA) is 13.22 ± SD 10.23 months.^[1–3] Prognostic factors linked to the patient and with the disease are numerous and not well investigated. Defining these factors will help in a better classification of high-risk groups.^[4,5]

Esophageal cancer is a frequent cancer world over, leading to more than 400,000 deaths every year.^[6] In the treatment protocols of esophageal carcinoma in early stage, surgical resection is commonly recommended. Nevertheless, the overall 5-year survival rate after esophagectomy remains ~25%.^[7] Such unfavorable results are due to the high rate of recurrences following resection of the primary tumor. Loco-regional recurrences and distant organ metastases are identified in 50% of patients, usually in 2 to 3 years post-surgery.^[8–11] Current advances in adjuvant therapy techniques may specifically benefit patients with a high risk of recurrence after surgical resection. In fact, recurrent disease sometimes has superior response to chemotherapy and radiation treatment, and those patients can achieve relatively longer overall survival. Despite radical surgery for esophageal carcinoma, a considerable number of patients develop recurrence. The objective of our current study was to evaluate the impact of diverse histopathological factors as a guide to identify recurrence and survival in postoperative patients of carcinoma esophagus.

Materials and Methods

This retrospective study was conducted at the Gujarat Cancer and Research Institute, Ahmedabad, India. The study was officially approved by the Ethics Committee of the Institute, and 182 patients treated with surgery between January 2011 and December 2016 were enrolled. All tumors were confirmed, as either squamous cell carcinoma (SCC) or adenocarcinoma by endoscopy and guided biopsy.

Results

Among these 182 patients included in the study, only 74 (40.66%) patients were alive at the time of final analysis; the rest 108 (59.33%) died of various causes. The most common cause of death was disease recurrence seen in 51 patients, followed by death due to complications related to cardio-pulmonary systems. The cause of death was not known in 13 patients. Patient’s demographic and histopathological features are enumerated in Table 1.

Impact of different prognostic factors on DFS and OS

The impact of multiple prognostic factors on DFS and OS was calculated using the Kaplan–Meier survival curve [Figures 1–3]. As the minimal follow-up period in our study was 12 months, only 1-year DFS and OS was calculated. Patients with PNI-positive disease had statistically significant lower DFS and OS than PNI-negative disease with a p-value < 0.05. Patients with adenocarcinoma histology had statistically significant lower DFS than SCC with a p-value < 0.05, but the impact of histology on OS was non-significant with a p-value > 0.05. Patients with poorly differentiated tumor had statistically significant lower DFS and OS than moderately to well-differentiated tumor with a p-value < 0.05. Patients with lymph node-positive disease on final histopathology had statistically significant lower DFS and OS than node-negative disease with a p-value < 0.05. Patients with stage III disease on final histopathology had statistically significant lower DFS and OS with a p-value < 0.05. LVI had a statistically nonsignificant impact on both DFS and OS with a p-value > 0.05. Patients with the ENE-positive disease had lower 1-year DFS and OS than ENE-negative disease with a p-value of < 0.05, which was statistically significant [Table 2].

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Figure 1

(A) Impact of PNI on DFS and OS. (B) Impact of histology on DFS and OS.

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Figure 2

(A) Impact of grade of differentiation on DFS and OS. (B) Impact of node-positive status on DFS and OS.

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Figure 3

(A) Impact of histopathological stage on DFS and OS. (B) Impact of ENE on DFS and OS.

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Table 2 Impact of different variables on DFS and OS (1 year) on univariate analysis.

Variables	Impact on DFS			Impact on OS
	Chi square test	p-value	Significance	Chi-square test	p-value	Significance
LVI	0.74	0.38	No	1.55	0.21	No
PNI	8.93	0.003	Yes	6.5	0.01	Yes
ENE	9.02	0.003	Yes	4.81	0.028	Yes
Histology	6.22	0.013	Yes	1.64	0.2	No
Grade	16.72	0.000	Yes	9.09	0.003	Yes
Node (+)ve	11.47	0.001	Yes	10.51	0.001	Yes
Stage	19.48	0.000	Yes	17.0	0.001	Yes

Discussion

Radical surgery in form of esophagectomy with radical lymph node dissection is the principal modality in the treatment for esophageal cancer. Yet, the rich lymphatic capillary network in the esophageal mucosa and submucosa leads to a high incidence of local recurrences or distant metastases after surgery. It has been identified that within 2 to 3 years after the surgery, more than half of esophageal cancer patients develop recurrence or metastases.^[8,9] Mariette et al^[10] have reported that 90% of recurrence occur within 38 months after surgery.

Neoadjuvant chemoradiotherapy has been found to improve local regional control and extend the survival in patients with locally advanced esophageal cancer. Recurrence at locoregional sites is still reported in 13 to 22% of patients considered to have a pathological complete response following neoadjuvant therapy.^[12,13] In the present study, 35.87% (33/92) developed recurrences in the upfront surgery settings, whereas 24.44% (22/90) developed in the combined modality group, which is similar to the findings in other studies.

Systemic recurrences were found to have adverse impact on prognosis. with most frequent sites of hematogenous metastases being liver, lungs, and bones.^[8,10,14] In Su et al’s study, the most common sites for distant recurrence were still the lungs, liver, and bones, accounting for 81.8% of all metastases.^[15] The present study also confirmed the above findings with the liver, lungs, and bones accounting for greater than 58.90% (21/36) of distant recurrences.

Out of 55 patients who developed recurrences, 16 took some form of treatment for recurrence in the form of chemotherapy alone, radiotherapy alone, and chemo-radiotherapy. In our study, none of these patients were taken for metastasectomy. Post recurrence average survival in these patients who took treatment was 7.25 months versus 5.95 months for those who did not take treatment for recurrences.

Schoppmann et al have reported that “both the 5-year OS (14% vs. 60%, p < 0.001) and the 5-year DFS (14% vs. 49%, p < 0.001) were significantly reduced in patients with positive LVI.”^[16] Chen et al. have also reported that “SCC patients with PNI-negative tumors had a 1.7- fold increase in the 5-year recurrence-free survival over the 5-year DFS or with patients with PNI positive tumors.”^[17] As for ECI, d’Annoville reported that the “proportion of ECI detected in N1, N2, and N3 patients was 28% (21 of 73 patients), 51% (21 of 41 patients), and 70% (17 of 24 patients), respectively. The presence of ECI seems to have a negative additive impact on DFS, regardless of the pN stage.”^[18] ECI (extra capsular invasion)/ENE identified after preoperative chemoradiation has been reported to be coupled with a very poor prognosis. In D’Journo’s study, the 5-year DFS rates were 46% in N0 patients, 36% in N+ with intracapsular invasion patients, and 11%, in N+ with ECI/ENE patients.^[19]

In the present study, SCC histology was associated with superior 1-year % DFS and OS compared with adenocarcinoma histology, i.e., 55.59 (48.82–62.35 with 95% CI) versus 25.65 (17.94–33.36 with 95% CI) for DFS and 68.64 (62.52- 74.77 with 95% CI) vs. 40.32 (32.67–47.97 with 95% CI) for OS. Similarly, nodal positivity was associated with inferior 1-year DFS and OS compared with node-negative disease, i.e., 38.70% (29.75–47.66 with 95% CI) vs. 60.03% (52.47–67.58 with 95% CI) for DFS and 55.64% (46.49–64.79 with 95% CI) vs. 74.48% (68.16–80.79 with 95% CI) for OS [Table 3].

Patients with poorly differentiated histology (Grade III) had inferior 1-year DFS and OS compared with moderately to well-differentiated histology, i.e., 21.15% (13.19–29.17 with 95% CI) vs. 56.79% (50.21–63.36 with 95% CI) and 34.87% (26.32–43.41 with 95% CI) vs. 70.60% (64.79–76.41 with 95% CI). LVI-positive disease on histology was associated with inferior 1-year DFS and OS compared with LVI-negative disease, i.e., 38.52% (28.61–48.43 with 95% CI) vs. 52.51%(45.65–59.37 with 95% CI) for DFS and 49.52% (39.94–59.10 with 95% CI) vs. 68.54% (62.39–74.68 with 95% CI) for OS [Table 3].

PNI-negative disease had a superior 1-year DFS and OS compared with PNI-positive disease. Corresponding survival values were 53.42% (47.22–59.61 with 95% CI) vs. 19.35% (4.88–33.83 with 95% CI) for DFS and 68.41% (62.84–73.98 with 95% CI) vs. 35.42% (17.89–52.96 with 95% CI) for OS. ENE-negative disease had superior 1-year DFS and OS compared with ENE-positive disease, i.e., 53.98% (47.63–60.34 with 95% CI) vs. 11.50% (7.03–15.06 with 95% CI) for DFS and 68.70% (62.99–74.47 with 95% CI) vs. 20.95% (15.24–26.67 with 95% CI) for OS [Table 3].

On multivariate analysis, lymph node-positive status, higher stage, poor differentiation, and PNI had statistically significant poor 1-year DFS and OS. ENE was found to have a statistical significance on DFS alone. LVI had no statistically significant impact on DFS and OS. In the multivariate analysis, the histology of the tumor was kept as a constant parameter and analysis was performed for other histopathological variables.

There were several limitations in our analysis, including retrospective nature, the impact of various treatment regimes not analyzed separately, only 1-year DFS and OS could be calculated to shorter duration of follow-up. Adjuvant treatment protocols in this study used dissimilar doses and schedules, so optimal treatment regimen could not be established.

Conclusion

Our study documented that recurrence is frequent following surgical management of carcinoma esophagus. More common are the systemic recurrences in comparison to locoregional recurrence. Adenocarcinoma, particularly has a significantly higher rate of systemic recurrence in comparison to squamous cell carcinoma. PNI, ENE, grade, nodal positivity, and final stage had statistically significant negative impact on both DFS and OS, whereas histology had a significant effect on OS alone, LVI had no impact on DFS and OS.