Introduction

Microscopic involvement after apparently radical resection of gastric cancer (RLI) is observed in 2.8–20% of gastric resections [1, 2] and it is always considered a difficult situation to manage. Although several retrospective studies and a number of reviews have focused on this problem, there are still no definitive guidelines for treatment because of the few cases considered and the obvious lack of perspective studies or randomized trials carried out in this area.

In recent years, several endoscopic studies have evaluated RLI in early gastric cancer (EGC), some focusing on large patient populations with long follow-up. Also many surgical reports on this topic exist. However, to our knowledge, no studies dealing with both endoscopic and surgical point of views have been published to date. Whilst endoscopists only consider surgical options for some cases of incomplete resection, proposing follow-up strategies in the remaining patients, surgical studies generally propose re-resection for early-stage gastric cancer. The issue of new surgical resection in advanced gastric cancer patients when RLI is confirmed in the definitive pathology report is still debated. The aim of the present review is to report all the existing evidences on the management of RLI after endoscopic or surgical treatment for gastric cancer and to assess the optimal strategy to be adopted in this challenging situation in different clinical scenarios.

Literature search

We performed a literature search in PubMed for English-language studies published from January 2000 to July 2015 using the key words: gastric or stomach cancer, or carcinoma; gastrectomy and positive margins; surgical margins or resection line or endoscopic margin involvement; and R1 resection. Fifty-three studies were considered pertinent to the study. Eighty studies were collected of which 3 were review articles. Twenty-four were excluded because they did not completely focus on RLI. Fifty-three studies were considered pertinent to the subject matter, 15 studies were of relevant endoscopic interest, and 38 were written by surgeons. All the articles were discussed by the authors to determine their suitability for inclusion. We also examined the studies referred to in the three reviews identified [3,4,5] and took into account the conclusions of a Web Round Table organized before the 10th International Gastric Cancer Congress (IGCC) held in Verona in 2013 involving endoscopists and surgeons. Information about the conclusions of the Web Round Table is reported in Gastric Cancer [6].

Risk factors for resection line involvement

Endoscopists frequently reported a higher incidence of RLI when criteria for indication to endoscopic resection were not completely fulfilled. Non-differentiated cancer, size, T stage and lesion sites with technical problems were reported as risk factors for resection line involvement in multivariate analyses (Table 1). Of note, risk factors for RLI were similar also after surgical resection (Table 2). However, Bissolati et al. differentiated risk factors in relation to Lauren’s classification [26]; they found that in locally advanced gastric cancer with Lauren intestinal histology, serosal invasion, cardia location, and a margin distance of < 3 cm were independent risk factors, while in diffuse/mixed tumor types, lymphatic infiltration, tumor diameter > 4 cm, esophagogastric junction location and serosal invasion were significantly associated with a high RLI risk.

Table 1 Multivariate analysis of risk factors for RLI in endoscopic patients
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Table 2 Risk factors for RLI in surgical patients
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Indications for safe resection margins in gastric cancer treatment

When endoscopic criteria for resection were met, endoscopists generally consider a distance of 5–10 mm from the lesion as adequate resection margins. With regard to surgical resection, guidelines differ from country to country; the definition of correct margins range from 2 to 8 cm from the tumor [27,28,29,30], chosen on the basis of cancer stage and pathological and gross type (Table 3).

Table 3 National guidelines on resection margins
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Indications for frozen section

When the distance from the margin did not respect guidelines and/or risk factors for RLI are present, i.e., serosal or lymphatic invasion, esophagogastric junction location, diffuse type, and size > 4 cm (complete list is reported at Table 2), frozen sections are always indicated if a new, wider resection is immediately achievable [38, 39]. However, false negatives were reported [24], especially in diffuse or mixed tumors.

Resection line as a prognostic risk factor

None of the studies by endoscopists in early gastric cancer considered incomplete endoscopic resection as a significant prognostic factor; an endoscopic re-resection or surgery is indicated without doubt only in patients with vertical or massive lateral margin involvement [18, 29]. Close follow-up is indicated in cases of limited lateral margin involvement without any other risk factor for nodal metastases [8]. This differs greatly from surgical studies. Indeed, all but two [40, 41] of the studies evaluating prognostic impact of RLI after surgery for gastric cancer considered it as a negative prognostic factor even in early stages of disease (Table 4). Specifically, for early lesions (pT1 or pT2), a very poor prognosis is generally reported in case of RLI compared to cases with pathologically clear resection margins [10, 12]. Only few authors reported good survival rates for R1 EGC patients who were not re-resected [49, 50]. Nagata found that approximately 70% of EGC patients with histologically positive margins (R1) did not develop recurrence [18]. In case of more advanced tumors, although RLI was generally recognized as a significant risk factor at univariable analysis in surgical studies, it sometimes lost significance in multivariable analyses (Table 4). Moreover, some authors reported that a further intraoperative resection after a positive frozen section did not always change patient’s prognosis. In detail, Squires et al., considering R0 patients submitted immediately to a new resection after a positive frozen section, observed an improvement in the local recurrence rate but the same poor outcome of R1 RLI patients [24]. Bissolati et al. also reported an unfavorable outcome for 35 patients even after re-operation [26]. Conversely, only one study showed a better outcome in this patient subset [19].

Table 4 RLI as prognostic factor of overall survival
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Indications for re-resection in early gastric cancer

The studies in which residual cancer was found in surgical specimen of patients previously treated with not radical endoscopic resection are reported in Table 5. The frequency of the residual cancer varied between 6.7 and 84% in relation to the characteristics of margin involvement after endoscopic resection.

Table 5 Incidence of residual cancer on surgical specimen in endoscopically resected patients with RLI
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The low incidence of residual tumor found in patients with only partial lateral margin involvement and no other risk factors for lymph node metastases led endoscopists to manage these patients with close follow-up strategy performing endoscopic re-resection if new lesions were detected (Table 6). Relapse in this subgroup varied between 14% [8] and 36% [60].

Table 6 Lateral margin involvement after endoscopic resection
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A surgical resection was generally proposed in patients with massive lateral margin involvement, i.e, > 6 mm, or with lesions > 2 cm [60], in those with lateral margin involvement > 1 cm [58], or when vertical margins were involved (Table 7) because of the high incidence of residual disease and the risk of lymph node metastases.

Table 7 Vertical margin involvement after endoscopic resection
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Indications for re-treatment in previously surgically treated early gastric cancer are shown in Table 8. Surgeons frequently advised re-operation but few authors reported data on re-resected patients.

Table 8 Indications for surgical treatment in T1 RLI
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Indications for re-resection in cases of locally advanced gastric cancer with RLI

In case of locally advanced gastric cancer with RLI, when a radical resection is achievable trough a new surgical treatment, the indication for re-operation is generally evaluated on the basis of nodal stage (Table 9). However, it is not clear how surgeons identified radically re-resected patients given that none reported information on peritoneal cytology status and only in very few series an adequate lymphadenectomy was performed. Cascinu et al. proposed to re-resect node negative patients, but all the patients in their study were submitted to D1 lymphatic dissection [11]. Such limited dissection could not provide adequate information on nodal diffusion and on prognosis of patients. Kim et al. observed that microscopic RLI lost its prognostic impact in multivariate analysis in all but in patients with less than five positive nodes disease when D2 or D3 lymphadectomy was performed and thus hypothesized re-resection for such patients [12].

Table 9 Indications for surgical treatment in ≥ T2 RLI
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Squires et al. re-treated 48 RLI-positive patients, achieving an R0 resection [24]. This population showed a lower incidence of local relapse but similar survival of non re-resected RLI patients. In 2015, Bissolati et al. also reported very low survival rates for 32 re-resected patients who showed a survival similar to that of not re-treated RLI advanced cancer [26].

RLI in mini-invasive surgery

Sarela et al. described a high incidence of margin infiltration (50%) in T3 cancer cases submitted to laparoscopic gastrectomy [62]. Nozaki et al. observed an RLI incidence of 9% after surgical wedge resection of EGC [63]. According to Nagata et al., the increasing use of the stapler will make it harder to identify the correct margin, creating even more problems in this already complex area [18].

Recurrence in non re-resected RLI patients

In patients with RLI that did not receive additional resection, only 20–30% of recurrences involved local sites and anastomosis (Table 10). In Woo et al.’s study on 1536 patients, local recurrence was more frequent in the negative margin group than in patients with RLI (27.1 vs. 14.3%) [25]. Overall, there was a higher incidence of distant and peritoneal metastases and metastatic relapse occurred earlier than local recurrence. Moreover, a high number of patients had associated metastases, thus precluding further treatment.

Table 10 Sites of recurrence
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Indications for re-resection in cases of duodenal margin involvement

The indications for surgical re-resection in case of RLI that are reported above based on tumor stage are mainly focused on proximal margin infiltration. Indeed, in case of duodenal involvement the issue is even more challenging and only the surgeon who performed the first resection can decide whether a new resection is feasible [64]. When duodenal involvement is > 4 cm, radical treatment may not be possible [65]. Pancreaticoduodenectomy is rarely proposed to achieve radical resection. A meta-analysis of a small number of heterogeneous studies carried out by Roberts et al. in 2012 revealed higher post-operative morbidity when there was substantial duodenal involvement [66]. The authors found not possible the identification of a subset of patients who could benefit from pancreaticoduodenectomy.

Is it advisable to extend lymphadenectomy in cases of surgical re-resection for RLI?

Achieving a more extended lymphadenectomy in all RLI patients may be technically demanding and increase the morbidity of patients because of scar tissue, adhesions and risk of bleeding. None of the examined studies reported detailed information on this point. Whilst a new resection and wide lymphadenectomy could theoretically reduce local recurrence, the question is whether local recurrence actually impacts on the prognosis of patients with RLI. Our search of the literature revealed that few patients showed isolated local recurrence (Table 10).

Can a multimodal treatment be proposed?

Regarding radiochemotherapy as treatment option for RLI, according to the National Comprehensive Cancer Network (NCCN) American guidelines [37], some conflicting data exist (Table 11). Stiekema et al. showed that 30 R1 patients with RLI only submitted to radiochemotherapy did not show a worse prognosis than the R0 group [41]. Conversely, Canyilmaz et al. [47] and Schoenfeld et al. [48], analyzing 30 and 19 positive margin patients, respectively, submitted to multimodal treatment, confirmed worse survival rates [48].

Table 11 Multimodal treatment
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Conclusions

Management of patients with RLI after endoscopic or surgical treatment for gastric cancer is challenging. For endoscopically treated early gastric cancer RLI includes a specific subset of patients who frequently show good prognosis even when not re-resected. In case of early gastric cancer with RLI after surgery, surgically re-resection to achieve radicality is generally indicated, but some authors, considering good results also in not re resected EGC, propose a new surgical resection only in patients without comorbidity.

In advanced gastric cancer, frozen sections must be performed not only when the distance from surgical margins is lower than that proposed by guidelines, but also when risk factors for RLI are present, e.g., non differentiated cancer, large tumor size or advanced T stage. Frozen sections can help to reduce the possibility of margin involvement but false negatives are sometimes observed and this technique cannot be relied upon to completely eliminate the problem. Indications for re-resection in advanced gastric cancer are limited to cases with very confined nodal involvement, namely those with less than five pathologically positive nodes.

Multimodal treatment such as additive radiochemotherapy may improve survival in these patients and should then be considered as alternative to surgery, especially if a re-resection is technically challenging.