The risk of LVI was similar to that of LN metastasis. LVI was associated with the histological type, size, depth of invasion, and lymphadenopathy on CT scans (P < .05). However, unlike LN metastasis, the existence of anemia was related to LVI (P = .023). LVI was present in 37.9% (189/498 cases) of differentiated cancers, 60% (39/65 cases) of poorly differentiated cancers, 24.2% (22/91 cases) of SRCs, 19.2% (5/26 cases) of poorly differentiated types with SRC components, 63.4% (26/41 cases) of mixed types, 50% (5/10 cases) of medullary types, and 40.6% (37/91 cases) of poorly cohesive carcinomas other than SRC. LVI was present in 14 of 432 (3.2%) patients with M cancer, 54.6% (47/86 cases) of patients with SM1 cancer, 84.4% (130/154) of patients with SM2 cancer, and 88% (132/150 cases) of patients with SM3 cancer (Table 3).
In the multivariate analysis, LN metastasis was associated with tumoral size, LVI, and lymphadenopathy on CT scans. As compared to EGC lesions smaller than 1 cm, the OR for LN metastasis was 2.663 for EGC lesions between 1 and 2 cm (P = .222), and it was 2.835 for EGC lesions between 2 and 3 cm (P = .197). Only EGC lesions larger than 3 cm showed a statistically significant OR (5.782, P = .026). Compared to patients with no LVI, the OR for LN metastasis in patients with LVI was 290.7 (P = .000). In cases of positive lymphadenopathy on CT scans, the OR was 2.572 (P = .008). In the logistic regression, the histological type and depth of invasion did not show a significant difference (Table 4).
LVI was related to the histological type, size, and depth of invasion in the multivariate analysis (Table 5). Compared to differentiated carcinomas, the ORs for poorly differentiated carcinomas, mixed types, and poorly cohesive carcinomas other than SRCs were significant (P = .008 and .014). The OR for SRCs was 1.969 (0.745–5.206, P = .172). The existence of anemia and lymphadenopathy on a CT scan were not associated with LVI in the logistic regression.
In 91 cases with SRCs, only 5 cases showed LN metastasis. All the lesions in the patients with LN metastasis were greater than 3 cm. LN metastasis was present in 1.5% (1/66 cases) of M cancer with SRCs, 20% (2/10 cases) of SM2 cancers, and 28.6% (2/7 cases) of SM3 cancers. Eight cases of SM1 cancer with SRCs showed no LN metastasis (Table 6). Six of 253 cases (2.4%) of EGC lesions smaller than 1 cm with differentiated cancer and 2 of 81 cases (2.5%) of M cancer with differentiated cancer showed LN metastasis. Compared with differentiated carcinomas, SRCs did not exhibit aggressive behavior (i.e., LN metastasis and LVI).
Follow-up observation of 767 patients’ results showed death in 20 patients, and cancer recurrence occurred in 7 patients (0.9%). Only 2 cases of death were related to cancer recurrence. Other causes included different cancer (6 patients), pneumonia (4 patients), cerebrovascular accidents (3 patients), sudden cardiac death (2 patients), sepsis (1 patient), suicide (1 patient), and postgastrectomy complications (1 patient). Cancer recurrence was related to histology, LN metastasis, and LVI (P < .05, χ2 test.). Three cases of differentiated cancer (3/485, 0.6%), 1 case of poorly differentiated cancer (1/61, 1.6%), and 3 cases of mixed histology (3/41, 7.3%) showed cancer recurrence. One patient with mixed histology showed metachronous recurrence at the remnant stomach, and 1 patient with differentiated cancer showed nodal and hepatic metastasis. Other 5 cases were nodal metastases.
Previous studies of the prognosis of SRCs reported conflicting results.[5–10,13–21] Several studies strongly suggested a poor prognosis in cases of SRC, including a French study, which also suggested that the prognostic predictors in SRC differed from those in non-SRC. According to the French study, SRC histology was a poor prognostic factor. Several case reports also expressed concerns about the risk of SRCs in EGC. Kobayashi reported 39 cases of overt bone metastasis in patients with EGC, most of whom had SRCs and poorly differentiated carcinomas. Our team also reported overt bone marrow metastasis from small SRCs in EGC. Another French study also showed a poor prognosis in SRC of the stomach, although that study had several limitations, including a relatively small number of patients (n = 215) and a low number of EGC cases (only 20% of the total patient population in the study).
Recent studies of the prognosis in SRC cases reported a favorable prognosis in EGC but a poor or similar prognosis for SRC in advanced gastric cancer.[17–21] Many studies reported less LN metastasis and a favorable prognosis for SRC in EGC.[5–10,17,19–21] In those studies, SRCs which is confined to mucosal layer without LVI and below 2 cm were mostly free from LN metastasis. The risk factors for LN metastasis in those studies were the depth of invasion, LVI, and tumor's size. SRC histology itself was not a risk factor of LN metastasis. The results of the present study were in accordance with those in the literature, as shown by the univariate analysis. Although LN metastasis was most prevalent in the mixed types in the present study, this finding was not statistically significant in the multivariate analysis. The findings of the present study are also is in line with those of a previous Japanese study, which suggested that undifferentiated types and predominantly mixed types of gastric cancer with SM invasion were risk factors for LN metastasis. In addition, a Korean study reported that EGC lesions with mixed SRC histology showed aggressive behavior. In that study, SRC was associated with M cancer and lower LN metastasis, but SRCs with mixed histology showed more SM invasion, larger size, and higher LN metastasis. The findings of these 2 studies and the results of the present study strongly suggest that mixed histology is associated with the risk of invasion and metastasis. Follow-up data suggest that mixed histology was related to cancer recurrence after gastrectomy. No recurrence occurred in patients with SRC.
LVI is an important determinant of the possibility of endoscopic treatment. As mentioned above, the lymphatic system of the stomach is located in the deep mucosal layer, and many physicians are concerned about potential LVI because an SRC is easily separated from the main lesion. The literature on the risk factors for LVI is scarce. In the present study, according to the univariate analysis, LVI was associated with histology, tumoral size, depth of invasion, existence of anemia, and lymphadenopathy on a CT scan. Poorly differentiated types with SRC components showed the lowest LVI, and SRCs exhibited the second lowest LVI. As shown by the logistic regression analysis, compared with differentiated carcinomas, the OR of SRC was 1.969 (P = .172). Both the tumoral size and depth of invasion were risk factors for LVI in the multivariate analysis. Mixed histology showed the highest OR (6.098, P = .008).
In a Korean study of 448 patients with EGC with SRCs, LN metastasis was present in 10.7% of cases, and LVI was present in 5.6% of cases. Six SRCs less than 2 cm in EGC were associated with LN metastasis, with the smallest SRC being 0.9 cm. In the same study, 5.9% of M cancer in SRC cases showed LN metastasis, which was similar to that observed for differentiated types. The authors recommended gastrectomy for SRCs in EGC because LN metastases from small SRCs were not uncommon. In the present study, SRCs smaller than 3 cm showed no LN metastasis, but 2 cases of M cancer and 2 cases of EGC lesions smaller than 1 cm showed LVI (16.7%). Small or mucosal SRCs may have LVI. In this respect, determining ESD indication for SRCs in cases of EGC should be performed very carefully.
There are several barriers to ESD for SRCs in cases of EGC. The first problem relates to the accurate estimation of the size and margin of the lesions. One study of endoscopic treatment for SRCs in EGC reported underestimations of 30.2% in lesional sizes. In that study, an EGC lesion larger than 2 cm was considered a risk factor for underestimation. However, most studies of the prognosis of SRCs in EGC have been based on data from pathological findings rather than endoscopic data.[5–10,13–21] When determining endoscopic treatment, endoscopist should be aware that the actual lesion could be larger than endoscopic measurements and that it may be risky to treat EGC lesions larger than 2 cm endoscopically. The second problem is the oncological safety of endoscopic treatment. LN dissection is impossible with endoscopic treatment. In some cases, SRCs in EGC may spread to distant organs.[14,15] However, several studies of the outcome of endoscopic treatment for EGC lesions with undifferentiated or poorly differentiated histology, including SRCs, showed no distant metastasis and little LN recurrence.[26–29] In one study in Japan, recurrence in EGC after surgical resection was not associated with the histology of the lesion. The third and final problem is the low complete resection rate. In studies, curative resection was 50% to 60% in cases of undifferentiated histology, and lateral margin involvement was common in SRCs.[26–29] Endoscopic treatment for SRCs in EGC can be increased only after these problems are overcome.
The present study has several limitations. First, it was a retrospective study based on medical records. Second, it consisted of a relatively small number of patients enrolled in a single center. Finally, EGC treated with endoscopic treatment was not evaluated. Approximately 200 to 250 patients with EGC receive endoscopic treatment in our center each year. LN metastasis in EGC lesions smaller than 2 cm with differentiated histology is rare. LN metastasis from differentiated EGC lesions may be overestimated because the data were based on pathological findings after surgical resection. However, as 253 cases of mucosal cancer with differentiated histology were included in the present study, we expect only a small gap between present data and real world.
There are also several strong points in the present study. Unlike other studies, the lesions were classified into a detailed category of histological types. SRCs were distinguished from other poorly cohesive carcinomas. Poorly cohesive carcinoma other than SRC showed more aggressive behavior in our study. We also found risk factors for LVI. As mentioned above, LVI is a very important factor in endoscopic treatment for SRC.
In conclusion, endoscopic resection may be considered as a treatment option for small mucosal gastric SRCs. However, due to limited studies, it should only be performed under strict indications. Also, additional researches are necessary to assess the safety of endoscopic resection for SRC.
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Keywords:Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
endoscopic treatment; lymph node; signer ring cell carcinoma; stomach