The pattern of lymph node metastases in microsatellite unstable gastric cancer
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
References (31)
- et al.
Super-extended (D3) lymphadenectomy in advanced gastric cancer
Eur J Surg Oncol
(2010) - et al.
Appropriate lymph node dissection for early gastric cancer based on lymph node metastases
Surgery
(2001) - et al.
Impact of super-extended lymphadenectomy on relapse in advanced gastric cancer
Eur J Surg Oncol
(2015) - et al.
Lymph node involvement in gastric cancer for different tumor sites and T stage: Italian Research Group for Gastric Cancer (IRGGC) experience
J Gastrointest Surg
(2007) - et al.
Biological effects and equivalent doses in radiotherapy: a software solution
Rep Pract Oncol Radiother
(2014) - et al.
Microsatellite instability at multiple loci in gastric carcinoma: clinicopathologic implications and prognosis
Gastroenterology
(1996) - et al.
Clinical significance of skip lymph node metastasis in gastric cancer patients
Eur J Sur Oncol
(2015) - et al.
Surgical treatment of gastric cancer: 15-year follow-up results of the randomised nationwide Dutch D1D2 trial
Lancet Oncol
(2010 May) - et al.
D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer
N Engl J Med
(2008) - et al.
Neoadjuvant chemotherapy with S-1 and cisplatin followed by D2 gastrectomy with para-aortic lymph node dissection for gastric cancer with extensive lymph node metastasis
Br J Surg
(2014 May)
Japanese classification of gastric carcinoma: 3rd English edition
Gastric Cancer
Japanese gastric cancer treatment guidelines 2014 (ver. 4)
Gastric Cancer
Le drainage lymphatique de l’estomac
Anat Clin
Type-oriented therapy for gastric cancer effective for lymph node metastasis: management of lymph node metastasis using activated carbon particles adsorbing an anticancer agent
Seminars Surg Oncol
Lymph node metastases of gastric cancer. General pattern in 1931 patients
Ann Surg
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