The pattern of lymph node metastases in microsatellite unstable gastric cancer

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Abstract

Background

Microsatellite instability (MSI) is one of the new groups of molecular divisions of gastric cancer (GC). The aim of this study was to investigate the pattern of lymph node metastasis according to MSI status.

Methods

MSI analysis of 361 GC patients with information about lymph node stations was performed using 5 quasimonomorphic mononucleotide repeats. The metastasis rates for each lymphatic station was analyzed, combined with clinicopathologic characteristics. Stations were divided into compartments 1–3 on the basis of Japanese Classification. A median number (interquartile range, IQR) of 33 (18–50) lymph nodes were removed and analyzed.

Results

N0 status was observed in 53.7% MSI patients, and in 29.7% microsatellite stable (MSS) (p < 0.001).The median value of involved nodes was 1 in MSI vs. 5 in MSS (p < 0.001). Furthermore, the number of involved node stations was significantly lower in the MSI group (p < 0.001). MSS tumors showed a higher propensity to spread to second and third compartment nodes. In absence of lymphovascular invasion only 3.2% cases demonstrated positive nodes beyond the first compartment. Skip metastases were seen in 6.1% MSS patients and 0% MSI (p = 0.011). No difference in the 10-year cancer related survival among MSI and MSS patients was found, for both those with 1st compartment (p = 0.223) and with 2nd compartment involvement (p = 0.814).

Conclusions

MSI GC shows a high rate of N0 stage, a lower number of lymph node metastases, and a less extensive spread to lymph node stations than MSS tumors. These data indicate that tailored lymphadenectomy may be investigated for these patients.

Introduction

One of the most important factors associated with gastric cancer (GC) prognosis is metastasis to lymph nodes. There is an ongoing debate among surgeons in terms of proposing a tailored approach to the extent of lymphadenectomy, with an attempt to individualize the treatment based on different clinical and pathological features.

More extensive lymphadenectomy is still considered beneficial for an improvement in local control and overall survival (OS) by many surgeons [1]. Currently, D2 lymphadenectomy for gastric cancer is a standard procedure, but some surgeons advocate for less aggressive lymphadenectomy in cases of early gastric cancer and more extensive lymphadenectomy for advanced cases, especially those with unfavorable pathology [1], [2], [3], [4], [5]. The Japanese Gastric Cancer Association produced their guidelines of GC surgical treatment for clinical stage taking into account early versus advanced GC [6], [7].

Anatomical and physiological studies have demonstrated that gastric lymphatic drainage shows different pathways that are connected with regions of the stomach [8], [9]. In some studies, the nodal metastasis incidence was analyzed [10], [11].

For many years, the extent of lymphadenectomy based on tumor stage has been under discussion. Proper lymph node dissection is of the highest importance for accurate staging, and currently the International Union Against Cancer/American Joint Cancer Committee (UICC/AJCC) tumor node metastasis (TNM) classification uses the number of resected lymph nodes as a marker of adequate lymphadenectomy. Although the number of positive nodes is currently used for N staging, knowledge of the anatomic extent of metastases may help in clinical staging and in surgical planning.

In the new age of modern drugs, individualized treatment of patients, and modern surgical approach, like minimally invasive surgery or image guided surgery, we also have to change our point of view of pathological reports [12], [13], [14], [15], [16]. Some months ago, Cancer Genome Atlas Research Network et al., and later Cristescu et al., proposed a new molecular division of GC into four groups [15], [16]. Both classifications considered microsatellite instability (MSI) as an individual subgroup. In GC, many studies about the clinical and pathological characteristic of MSI GC have been reported. The majority of MSI GCs are observed in older patients, mostly female, in the distal third of the stomach, with intestinal pathology, lower pTNM stage, and with a lower number of mLNs [17], [18]. However, studies based on the topographic pattern of mLNs are rare in countries outside East Asia; the Japanese topographic classification of lymph nodes has been used in our department since 1995, and each lymph node station has been routinely classified and examined separately.

The aim of this study was to investigate the pattern of lymph node metastasis according to MSI status in a large series of patients submitted to gastrectomy and lymphadenectomy.

Section snippets

Patients

We analyzed data from the database of patients with primary GC surgically resected in the Division of Surgical Oncology, University of Siena, Italy, between January 1995 and December 2011, and whose specimens were available in a frozen tissue bank. Clinical, pathological, and follow-up data were prospectively collected and stored in the database. Patients without full lymph node mapping were excluded; as such, a final number of 361 patients with full information were analyzed.

Skip metastasis

Results

General clinical and pathological characteristics of patients are presented in Table 1. MSI were seen in 22.7% of all patients. Statistically significant MSI were more commonly observed in females (64.6% vs. 34.8%, p < 0.001). Most cases in both MSS and MSI groups were in advanced pT stage (T3/T4 represented 72% of cases in MSS and 75.6% in MSI group).

N0 status was observed in 53.7% of the MSI patients, and in 29.7% of MSS patients (p < 0.001). The median value of involved nodes was 1 in MSI

Discussion

This analysis is one of the largest available for a series of MSI GC patients. The experience of our group in translational research, performance of extended lymphadenectomy in GC, and above all mapping of lymph node stations in the resected specimen after gastrectomy are all important factors indicating the weight this research can have on the subject.

Conclusions

MSI GC shows a high rate of N0 stage, a lower number of lymph node metastases, and a less extensive spread to lymph node stations than MSS tumor.

A definitive conclusion could not be made because of the study limitations. However, we can speculate that according to the presented data, which have to be confirmed in prospective studies and also validated in endoscopic biopsy, we could tailor the extension of lymphadenectomy according to MSI status and additional clinical and pathological factors.

Acknowledgments

Source of Funding: This study was funded by Istituto Toscano Tumori (ITT) grant entitled Gene expression profiles and therapy of gastric cancer- (Grant No. ITT-2007). No other conflicts of interest.

The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7) GastricGlycoExplorer under grant agreement n° [316929] (Karol Polom, Franco Roviello).

Role of the funding source: No involvement in the study design, in the collection, analysis and

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