Relationship of lymphovascular invasion with lymph node metastasis and prognosis in superficial esophageal carcinoma: systematic review and meta-analysis

Superficial esophageal carcinoma (SEC) can be classified as submucosal (T1b), mucosal (T1a), or intraepithelial (Tis) irrespective of lymph node metastasis (LNM). Patients suffering from SEC have a better chance of survival after esophagectomy compared to those with advanced esophageal carcinoma (EC). According to the Japanese criteria, the depth of tumor invasion is subclassified into six layers. The mucosa is subdivided into the intraepithelial (m1) region, lamina propria (m2), and muscularis mucosa (m3) while the submucosa is homogeneously classified into three sections: inner (sm1), middle (sm2), and deep submucosa (sm3) [1]. The prognostic factors for EC include the histology type, tumor size, grade category, invasion depth, blood vessel and lymphatic vessel permeation, as well as LNM and distant metastasis [2]. EC patients with LNM frequently have an adverse prognosis. Therefore, the impact of LVI on LNM and prognosis requires attention.

The development of tumor cells inside the lymphatics or blood vessels is known as lymphovascular invasion (LVI). Lymphatic vessels are believed to play a crucial role in LNM and their presence increases the micro-metastatic risk in locoregional malignancy [3]. Though lymph node metastasis via LVI or lymphatic vessels has not been confirmed [4], lymphatic vessels are known to provide entry for the penetration of tumor cells [5]. Some studies have provided evidence of an association between LVI and LNM in SEC. Nonetheless, the impact of LVI on OS and LNM in SEC requires investigation. Thus, we conducted a meta-analysis to obtain additional insight into the correlation between LVI, LNM, and prognosis in SEC.

Our study demonstrated that SEC patients with LVI have a poor OS (HR = 1.85, 95% CI: 1.10–3.11, P = 0.02; I² = 54.6%, P = 0.085). LVI significantly reduces OS in patients with SEC. This conclusion should be clarified with caution due to medium heterogeneity. Additionally, LVI and LNM are strongly correlated (univariate: OR = 4.94, 95% CI: 3.74–6.53, P < 0.0001, I² = 0.9%, P = 0.422; multivariate: OR = 5.72, 95% CI: 4.38–7.4, P < 0.0001; I² = 0%, P = 0.926) in patients suffering from SEC. These results suggest that LVI is an important prognostic factor for patients with SEC with regard to predicting LNM and survival.

SEC is similar to the esophageal tumors, which are limited to the mucosal layer (T1, T0) and include high-grade dysplasia, intramucosal cancer (T1a), and tumors infiltrating the submucosa (T1b) [30]. .Reports state that patients with T0 (0% chance) or T1a (1–2% chance) esophageal cancer have a minimal risk of local LNM [31]. There is no specific standard available for the detection of LVI. However, the identification of tumor cells in the lymphatic vessels, arteries, or veins during pathological evaluation of specimens indicates LVI. The condition is an independent prognostic factor of LNM in malignant tumors causing lung, prostate, breast, and esophageal cancer. However, the role of LVI in SEC has not been clarified to date. Additionally, the impact of LVI in SEC on OS and LNM has not been assessed using meta-analysis in the past. Therefore, we conducted this study by analyzing data for 4854 patients reported in 24 eligible articles retrieved from PubMed and other relevant sources. We demonstrated LVI relevance in LNM and the prognosis for patients with SEC. According to a literature review, our work is the first systematic review and meta-analysis on LVI relevance in LNM and prognosis in patients with SEC.

During the early stage of esophageal cancer, LVI is regarded as a potential prognostic factor in predicting LNM. Current research has demonstrated that patients with T1b esophageal cancers without LVI have a significantly higher survival rate up to 5 years higher those with LVI [32]. A larger cohort study revealed that LVI has a significant effect on the prognosis after resection for ESCC [33]. Our study shows that SEC patients with LVI have a poor OS (HR = 1.62, 95% CI: 1.17–2.26, P = 0.004, I² = 0.0%), and LVI significantly increases the risk of LNM in SEC (univariate: OR = 5.26, 95% CI: 4–6.91, P < 0.0001, I² = 30.2%; multivariate: OR = 5.7, 95% CI:4.43–7.33, P < 0.0001; I² = 16%). Reports describing the relationship between LVI, LNM, and OS in SEC indicate that LVI raises the possibility of LNM, leading to a poor OS.

Esophagectomy and other non-surgical options including chemotherapy and radiotherapy are the mainstream treatments for esophageal cancer. However, endoscopic resection (ER) is the diagnostic and radical choice for the treatment of SEC with a low possibility of LNM. The Japan Esophageal Society published a guideline in 2014 recommending ER as the best treatment option for T0 and T1a lesions located within the limits of the mucosal layer and not associated with LNM. The treatment can still be applied for lesions that infiltrate the muscularis mucosae or the inner submucosa (T1b-SM1) but the risk of LNM exists for these cases. Hence, other classifications for superficial carcinomas (T1b-SM2 and T1b-SM3) should not be treated with endoscopy alone due to the high rates of metastasis [34]. ER can be classified as endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). All visible neoplasms are removed by EMR for definitive histopathological staging. However, EMR is ineffective compared to ESD in terms of en bloc resection of large lesions. The largest lesion amenable to en bloc resection with the EMR device is approximately 15 mm [35, 36] whereas en bloc resection can be achieved with ESD regardless of the size of neoplastic lesions [36]. Furthermore, several studies have reported that ESD has a higher R0 resection rate and a lower local recurrence rate compared to EMR. Therefore, ESD is considered the standard for ER treatment of ESCC [37‐39]. Esophagectomy, the main surgical treatment for EC, was compared with ER treatment and the results revealed that T1b lesions were managed endoscopically with no impact on survival [40‐42]. Therefore, ER is preferable to surgery and also appears to be an optimal first-line treatment for early esophageal cancer.

This study does have some limitations. First, we used only studies published in English for our meta-analysis. Consequently, studies reporting negative results may have been overlooked. Next, the stages, treatment, staining method, and adjuvant therapy differed for each study. In addition, the heterogeneity of OS was medium. The subgroup analysis was unable to carry out due to limited studies. Few studies provided Kaplan-Meier curves and we calculated the HR and 95% CI where necessary. Therefore, we strongly recommend interpreting the results with caution.

SEC patients with positive LVI indicated poor prognosis compared with patients without LVI. Therefore, the association between LVI and LNM in SEC patients was close.