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Frequency and predictive factors related to lymphatic metastasis in early gastric cancer

Abstracts

BACKGROUND: The standard treatment of gastric cancer still has high morbidity and mortality in western populations. Groups of patients with negligible risk of lymph node metastasis may benefit from less invasive treatments. Data regarding the frequency and predictive factors related to lymphatic metastasis in early gastric cancer are rare. AIM: To perform the analysis of frequency and predictive factors related to lymphatic metastasis in patients with early gastric cancer treated in a tertiary center in Brazil. METHODS: Nine hundred and twenty three patients underwent gastrectomy for gastric adenocarcinoma at the hospital. Of these, 126 had early tumors and were included in the analysis. Clinical and pathological related findings and lymphatic metastasis were evaluated. RESULTS: Lymph node metastases were observed in 7.8% of patients with mucosal tumors and 22.6% of submucosal tumors. The presence of ulceration, Lauren histologic type, tumors larger than 50 mm, submucosal invasion, and presence of lymphatic or vascular invasion were significant factors in univariate analysis. The presence of ulceration, lesions larger than 50 mm, infiltration of the submucosal layer and lymphatic invasion were factors independently related to lymphatic metastasis in multivariate analysis. CONCLUSION: Ulceration, lesions larger than 50 mm, infiltration of the submucosal layer and lymphatic invasion are independent risk factors related to lymphatic metastasis in early gastric cancer.

Stomach neoplasms; Lymphatic metastasis; Adenocarcinoma; Predictive value


RACIONAL: O tratamento padrão do câncer gástrico ainda apresenta alta morbidade e mortalidade em populações ocidentais. Grupos de pacientes com risco negligenciável de metástase linfonodal podem se beneficiar de tratamentos menos invasivos. Dados referentes à frequência e fatores preditivos relacionados a metástase linfática em câncer gástrico precoce são raros. OBJETIVOS: Realizar a análise de frequência e fatores preditivos relacionados à metástase linfática em pacientes com câncer gástrico precoce tratados em centro terciário do Brasil. MÉTODOS: Novecentos e vinte e três pacientes foram submetidos à gastrectomias por adenocarcinoma gástrico. Destes, 126 tinham tumores precoces e foram avaliadas características clínicas e patológicas relacionadas e metástases linfáticas. RESULTADOS: Metástases linfonodais foram observadas em 7,8% dos pacientes com tumores mucosos e 22,6% dos tumores submucosos. A presença de ulceração, tipo histológico de Lauren, tumores maiores que 50 mm, invasão de submucosa e presença de invasão linfática ou vascular foram fatores significativos em análise univariada. A presença de ulceração, lesões maiores que 50 mm, infiltração da camada submucosa e invasão linfática foram fatores independentemente relacionados à metástase linfática em análise multivariada. CONCLUSÃO: Ulceração, lesões maiores que 50 mm, infiltração da camada submucosa e invasão linfática são fatores de risco independentes relacionados à metástase linfática em câncer gástrico precoce.

Neoplasias gástricas; Metástase linfática; Adenocarcinoma; Valor preditivo


ORIGINAL ARTICLE

Frequency and predictive factors related to lymphatic metastasis in early gastric cancer

Leonardo Medeiros MilhomemI; Daniela Medeiros Milhomem CardosoI; Eliane Duarte MotaI; Ailton Cabral Fraga-JúniorI; Edésio MartinsII; Orlando Milhomem da MotaI

ICancer Hospital Araújo Jorge

IICatholic University of Goiás, Goiânia, GO, Brazil

Correspondence

ABSTRACT

BACKGROUND: The standard treatment of gastric cancer still has high morbidity and mortality in western populations. Groups of patients with negligible risk of lymph node metastasis may benefit from less invasive treatments. Data regarding the frequency and predictive factors related to lymphatic metastasis in early gastric cancer are rare.

AIM: To perform the analysis of frequency and predictive factors related to lymphatic metastasis in patients with early gastric cancer treated in a tertiary center in Brazil.

METHODS: Nine hundred and twenty three patients underwent gastrectomy for gastric adenocarcinoma at the hospital. Of these, 126 had early tumors and were included in the analysis. Clinical and pathological related findings and lymphatic metastasis were evaluated.

RESULTS: Lymph node metastases were observed in 7.8% of patients with mucosal tumors and 22.6% of submucosal tumors. The presence of ulceration, Lauren histologic type, tumors larger than 50 mm, submucosal invasion, and presence of lymphatic or vascular invasion were significant factors in univariate analysis. The presence of ulceration, lesions larger than 50 mm, infiltration of the submucosal layer and lymphatic invasion were factors independently related to lymphatic metastasis in multivariate analysis.

CONCLUSION: Ulceration, lesions larger than 50 mm, infiltration of the submucosal layer and lymphatic invasion are independent risk factors related to lymphatic metastasis in early gastric cancer.

Headings: Stomach neoplasms. Lymphatic metastasis. Adenocarcinoma. Predictive value.

INTRODUCTION

Gastric cancer is the second cause of cancer death in the world today. It is observed decrease in incidence in several countries related to reducing the prevalence of risk factors, improvement of basic sanitation, food changes and reduction of smoking32. However, gastric cancer is still diagnosed in advanced stages. The early gastric cancer, which represents the lesions limited to the mucosa and submucosa layers, independent of lymph node metastases12, corresponds in our country about 15% of cases of this disease11,19 Similar rates are observed in European countries and China3. In other Asian countries like Japan and Korea about 50-60% of cases of gastric cancer are diagnosed in the early stages22.

The early lesions, unlike advanced lesions, have a favorable prognosis, with survival rates at five years over 90%26,29. The operation associated with radical lymphadenectomy remains the gold standard treatment in cases of gastric cancer, even in early stages. However, therapeutic modality is associated with high morbidity and mortality in Western countries4,28.

Less invasive therapeutic methods and associated lower morbidity and mortality, such as endoscopic resection, can be used in specific groups of patients with negligible risk of lymph node metastases,; the oncological results are similar to standard treatment, avoiding unnecessary radical treatments in these situations.

Data related to the frequency and factors associated with lymph node metastasis in early gastric cancer are rare in Western countries.

The aim of this study was to perform frequency analysis and predictive factors related to lymph node metastasis in patients with early gastric cancer treated at a tertiary center in the Central-Western Brazil.

METHODS

This study was approved by the Research Ethics Committee of the Cancer Association in Goiás with Protocol No 035/2011.

Variables analyzed included macroscopic characteristics such as size of lesions, presence of ulceration, histological factors (Lauren classification), grade of differentiation, depth of invasion, presence of lymphatic and vascular invasion, associated with Helicobacter pylori infection and the presence of lymph node involvement.

The macroscopic appearance of the lesions was determined according to criteria of the Japanese Society for Research in Gastric Cancer (Japanese Research Society for Gastric Cancer)12.

The Helicobacter pylori infection was diagnosed by histological method. The size of each lesion was determined by measurement according to the largest diameter, performed by a pathologist and divided into three groups: lesions less than 20 mm, between 20 and 50 mm and larger than 50 mm. The depth of invasion was measured according to the finding of malignant cells at the point of greatest penetration into the layers of the gastric wall. In cases of multifocal tumors deeper lesion was considered for analysis. All dissected lymph nodes were analyzed for the presence of metastatic disease.

Poorly differentiated tumors, carcinomas with signet ring cell and mucinous adenocarcinomas were classified as undifferentiated tumors. Tubular papillary adenocarcinomas and tumors were classified as differentiated. Histological evaluation by classifying Lauren was also performed.

The data were compiled in a database with the program Microsoft Excel 2007. Statistical analysis was performed using SPSS for Windows version 18.0. The chi-square test was used to compare variables. Multivariate analysis was performed using logistic regression method of Mantel-Hansell. P values <0.05 were considered statistically significant.

RESULTS

From January 1998 to December 2010, 923 patients underwent gastrectomies with curative or palliative intent for gastric adenocarcinoma in Araújo Jorge Hospital Cancer of Goiás. Of these, a total of 126 patients (13.65%) with tumors restricted to gastric mucosa and submucosa layers were included in the analysis. The mean age was 60.73 years (28-93), with 66 men (52.38%) and 60 women (47.61%). Clinical characteristics and information pertaining to the treatment are shown in Table 1.

Of the 126 patients with early gastric cancer, 21 (16.6%) had lymph node metastases, 17 cases N1 and four N2 (3.17%). Of the 51 patients with lesions restricted to the mucosal layer four (7.8%) had lymph node metastases and among 75 patients with submucosal lesions, 17 (22.6%) had lymph node metastases.

The association between the variables and the presence of lymph node metastasis is exposed in Table 2.

Infection with Helicobacter pylori, endoscopic classification of lesions and degree of differentiation were not factors associated with metastasis.

Regarding the diameter of lesions was observed that the probability of lymph node metastases lesions was greater in lesions more than 50 mm (p = 0.01). The presence of ulceration was also a significant factor, with 6.5% of cases without ulceration presenting lymph node metastases and 23.9% with ulceration had lymph node metastases (p = 0.01).

The depth of lesions, diffuse type of Lauren and the presence of lymphatic and vascular invasion were also factors associated with lymph node metastasis.

Was conducted multivariate analysis of the variables associated with lymph node metastasis. Were independent factors associated with lymph node metastases: the presence of ulceration (OR 4.035, 95% CI 1.085 to 15.023, p = 0.03), lesion size greater than 50 mm (OR 5.22, 95% CI, 1.18 to 23 , 02, p = 0.02), invasion of the submucosal layer (OR 3.45, 95% CI, 1.08 to 11.03, p = 0.03) and lymphovascular invasion (OR 11.08, 95% CI, 1.4 - 87.77, p = 0.02) (Table 3). The presence of vascular invasion showed no association with lymph node metastases in multivariate analysis

DISCUSSION

Although epidemiological studies show decreasing worldwide incidence of gastric cancer, this disease still represents one of the cancers with highest incidence rates and mortality worldwide32. In Brazil are estimated for the year 2012 about 12,670 new cases, representing mostly the lesions classified as advanced lesions5. It stands out among the prognostic factors of this tumor to lymph node metastases10,16,27,31, considered as the only independent prognostic factor in multivariate analyzes9,20,25.

The early gastric carcinomas correspond to lesions limited to the mucosa and submucosa independent of lymph node metastases12, representing in our country in about 15% of cases1,19. It is observed in these lesions probability of incidence of lymph node metastases ranging from 2.6% to 23.6% according to the level of invasion of the primary tumor8. Among the lesions restricted to the mucosal layer this probability varies between 2.6% to 4.8%, and between the submucosal from 16.5% to 23.6%, according to retrospective Eastern and Western studies14,26.

In the present study, the incidence of lymph node metastasis in mucosal lesions was 7.84% of cases, incidence greater than that observed in other series. The incidence of lymph node metastasis in submucosal tumors was 22.66%, similar to other published reports. The incidence of lymph node metastases in lymph nodes N2 was found in about 2-3% of patients with early gastric cancer16, and was 3.17% in this study.

The gold standard treatment of gastric cancer with curative intent is radical operation generally associated with D2 lymphadenectomy13. This treatment has a high success rate in early cases, but is associated with not negligible morbidity and mortality4,28. Certain groups of patients with early gastric cancer have negligible risk of lymph node metastases, allowing these situations to adopt less invasive treatment strategies7,33. In general, currently available imaging methods have low diagnostic accuracy for the presence of lymph node metastases, because they are based on parameters of low reliability8,33. Retrospective studies conducted in Eastern countries, concerning the analysis of predictive factors, clinical and pathological features associated with lymph node metastasis in early gastric cancer, led to the adoption of criteria widely used today in the indication of endoscopic surgeries in these populations4,7,28,34. The application of the same criteria in Western populations remains uncertain and questionable.

Among the clinical and pathological factors assessed in this study, the presence of ulceration, tumors of the diffuse type of Lauren, lesions with a diameter greater than 50 mm, depth of invasion in the submucosal layer, and the presence of vascular or lymphatic invasion, showed association with lymphatic metastasis in univariate analysis. Multivariate analysis of these factors showed that independent predictors associated with lymph node metastasis in early gastric cancer were ulceration, tumors larger than 50 mm, the submucosal layer invasion and lymphatic invasion.

The presence of ulceration is questionable factor15,18,37, depending on the natural history of these lesions and the criteria for determining the presence of ulceration. Studies show that up to a third of them may undergo gross changes and even healing, plus a large inter-observer variation. In a previous study of Gotoda et al.6, with a significant number of patients, the presence of ulceration was an independent factor associated with lymph node metastases. Recent studies indicate not only the presence of ulceration as a biomarker for lymph node metastases, but also the diameter of ulceration35,36.

The depth of invasion of the lesion proved to be an important factor, a finding similar to other studies, and accepted by many researchers as the main factor associated with the presence of regional lymph node metastases1,6,18,24.

The diameter of the lesions was found to be an independent factor related to regional lymph node metastases. In this study the difference between the larger and smaller lesions than 50 mm was statistically significant. Other reports in the literature show that the diameter greater than 20 mm is an independent predictor of lymph node metastases2,17,23,34, parameter currently used as a criteria for indication of endoscopic resection13.

The presence of lymphovascular invasion was also confirmed as an important predictor of lymph node metastases, a finding similar to descriptions of several other authors2,6,34.

The selection of patients, performing less invasive therapeutic modalities, endoscopic or surgical, respecting oncological security is difficult. The determination of predictive factors related to regional lymph node metastasis established the criteria currently used in the therapeutic application of these methods in oriental populations. Its acceptance is still low and questionable in the West, where the number of studies on the subject is limited.

CONCLUSION

Ulceration, lesions larger than 50 mm, infiltration of the submucosal layer and lymphatic invasion are independent risk factors related to lymph node metastasis in early gastric cancer.

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  • Endereço para correspondência:
    Leonardo Medeiros Milhomem,
    e-mail:
  • Publication Dates

    • Publication in this collection
      07 Feb 2013
    • Date of issue
      Dec 2012

    History

    • Received
      09 June 2012
    • Accepted
      10 Sept 2012
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