The N-classification for esophageal cancer staging: should it be based on number, distance, or extent of the lymph node metastasis?

BACKGROUND: The recently published AJCC-TNM staging system for esophageal carcinoma made an obvious modification on N-classification based on the number of metastatic regional lymph nodes (LN). However, this classification might ignore the site at which these LNs occur, a factor that might be even more important in reflecting patients' prognosis. METHODS: A retrospective study of 236 patients with carcinoma of thoracic esophagus who underwent esophagectomy between 1984 and 1989 with each at least six LNs removed was conducted, with a 10-year follow-up rate of 92.4%. The proposed scheme for N-classification according to the number (0, 1-2, 3-6, ≥7; N0-3), distance (0, 1, 2, 3 stations; S0-3), or extent (0, 1, and 2 fields; F0-2) of LN involvement was evaluated by univariate and multivariate survival analysis. RESULTS: The LN metastasis was identified in 112 patients, revealing a poorer 5-year survival in this patient group when compared to patients without node involvement. Cox regression analysis revealed that the number and distance of LN metastases and the number of metastasis fields were factors significantly influencing survival. When these factors were further analyzed by univariate log-rank test, no significant difference in survival existed between N2 and N3 patients, or among S1, S2, and S3 patients. When patients were grouped according to the extent of LN metastasis, significant differences in survival were observed overall and between each subgroup. CONCLUSIONS: Refining the current N-classification for esophageal cancer according to the extent of LN metastasis, rather than by number alone, might be a better means of staging that could subgroup patients more effectively and result in different rates of survival.

[Analysis of the survival in patients after surgical resection of thoracic esophageal cancer].

OBJECTIVE: To investigate the prognostic factors and influence of the number of lymph node metastases on survival and UICC-TNM classification in patients with thoracic esophageal cancer after curative resection. METHODS: From 1985 to 1990, 1224 patients were surgically treated for thoracic esophageal cancer. The patients who died within 30 days after operation were not included in this study. Fifteen factors possibly influencing survival of these patients were selected and analyzed. A multivariate analysis of these individual variables was performed by Cox proportional hazard model. According to the number of lymph node metastases (0, 1 and > or = 2), a new modification of the TNM classification was suggested: stage IIa (T2N0M0 and T3N0M0), stage IIb [T1N1M0 and T2N1(1)M0], stage IIIa [T2N1 (2)M0 and T3N1 (1) M0] and stage IIIb [T3N1 (2) M0 and T4N any M0]. RESULTS: According to multivariate analysis, lymph node metastases, depth of invasion, location of tumor, histological classification and length of the tumor were of prognostic significance (P < 0.01). There was obvious correlation between the rate of lymph node metastasis and the depth of invasion, length of tumor and grade of differentiation. The 5-year survival rate of the patients with 0, 1 and > or = 2 positive metastatic lymph nodes was 59.1%, 32.0% and 8. 9%, respectively. The 5-year survival rate of the patients with stage T2N1 M0 and stage T3N1 M0 was significantly higher in those with only one lymph node involved than in those with two or more lymph nodes involved (43.1% vs. 18.0% and 28.0% vs. 9.6%, P < 0.01). The 5-year survival rate of the modified stage IIa, IIb, IIIa and IIIb was 56.5%, 43.9%, 25.6% and 11.1%, respectively, with a statistically significant difference among different stages (P < 0.01). CONCLUSION: The lymph node metastasis is the most important prognostic factor for thoracic esophageal cancer after resection. The major influencing factors of lymph node metastasis are the depth of invasion, length of tumor and grade of differentiation. Therefore, the lymphadenectomy along with esophagectomy and subsequently combined modality therapy against lymph node metastasis is necessary to improve the 5-year survival rate. Our proposed new classification based on number of lymph node metastases (0, 1, > or = 2 positive nodes) is more applicable because it can well reflect the correlation between lymph node metastasis and the survival, and provides evidence for the modification of the currently used UICC TNM staging system for surgically treated thoracic esophageal cancer.

[Prevention and treatment of complications after surgical resection for esophageal and gastric cardiac cancers].

OBJECTIVE: To summarize the experience in surgical resection for esophageal and gastric cardiac cancers so as to put forward countermeasures to prevent the post-operative complications. METHODS: From September 1952 to December 2005, 20,796 patients with esophageal and gastric cardiac cancers underwent surgical operation. The category and incidence of the complications in different decades were retrospectively analyzed. RESULTS: (1) 18,772 of the 20 796 patients with esophageal and gastric cardiac cancers underwent surgical resection. Operative complications occurred in 1741 patients (9.27%), death occurred in 433 of which (24.87%). (2) The complication rate was 39.77% in 1950s, and decreased to 4.10% in 2000s. The mortality rate of complication was 44.29% in 1950s, and decreased to 15.42% in 2000s. (3) The incidence and mortality rates of closely-surgery-related complications declined obviously over the period of study. The incidence and mortality rates of anastomotic leakage were 4.55% and 50.00% respectively in 1950s, and then decreased to 1.21% and 3.33% respectively in 2000s. The incidence and the mortality rates of empyema were 7.39% and 38.46% respectively in 1950s, and decreased to 0.36% and 5.56% respectively in 2000s. The incidence and the mortality rates of chylothorax was 0.16% and 0% recently. (4) The incidence of non-surgical-related complications declined slightly but the mortality rate was still very high over the period of study. The mortality rates of pulmonary and cardiovascular complication were 27.42% and 25.00% respectively recently. CONCLUSION: (1) One of the advantages of surgical treatment for esophagus and gastric cardiac cancers is the obvious decline of the incidence and the mortality rates of complications. (2) In order to reduce the incidence of systemic complication, especially pulmonary complication, active and corresponding preoperative preparation should be improved along with the expansion of the scope of surgical indication. (3) The key for prevention of post-operative complications is consummate surgery techniques. Prevention and treatment of anastomotic leakage, gastric wall necrosis, and intrathoracic and intraabdominal bleeding are still the focal points.

[Cox proportional hazard model analysis of prognosis in patients with carcinoma of esophagus and gastric cardia after radical resection].

OBJECTIVE: To investigate the factors affecting the long-term survival of patients with carcinoma of esophagus and gastric cardia after curative resection. METHODS: The clinical data of 906 patients with carcinoma of esophagus and gastric cardia treated by radical resection in 1996 - 2004 were analyzed retrospectively. Twelve clinicopathological factors possibly influencing survival were encoded and assessed by Cox regression analysis. RESULTS: The 1-, 3- and 5-year cumulative survival rates were 89.8%, 75.4% and 71.7%, respectively. The univariate analysis showed that age, length of tumor, pathological differentiation, number of metastatic lymph nodes, depth of invasion, involvement of adjacent organs and the TNM stage influenced the prognosis significantly (P < 0.01). However, multivariate analysis showed that pathologic differentiation, number of metastatic lymph nodes, involvement of adjacent organs and TNM stage were independent prognostic factors (P < 0.05). CONCLUSION: The independent prognostic factors of the patients with carcinoma of esophagus and gastric cardia are pathologic differentiation, TNM stage, number of metastatic lymph nodes, and involvement of adjacent organs. The other factors influencing survival are age, length of tumor and depth of invasion. Furthermore, invasion of adjacent organs suggests worse prognosis, and should be followed-up closely.

[Establishment of obliterative bronchiolitis in allo-trachea transplant model of rat and detection of its pathogenesis preliminarily].

OBJECTIVE: To establish an animal model of obliterative bronchiolitis (OB) after lung transplantation and investigate the pathogenesis preliminarily. METHODS: Tracheal segments (5 cartilaginous rings each) were transplanted from SD rats to SD rats (Group I) or to Wistar rats (Group II and III). Grafts were implanted into an abdominal cavity and wrapped in the omentum. Animals in Group I and II did not receive CsA, animals in Group III received CsA daily by gastro-tube at 10 mg.kg(-1).d(-1) from beginning to end. Grafts were harvested on day 3, 14, 28 after transplantation as representative time points for 3 phases of injury in the evolution of allograft airway obliteration, then examined histological changes and gene expression of T-helper 1-and T-helper 2-type cytokines [Th1: interleukin-2 (IL-2), interferon-gamma (IFN-gamma); Th2: interleukin-4 (IL-4), interleukin-10 (IL-10)] in grafts. At the same time, effects of CsA were observed on the above-mentioned indices. RESULTS: There was no significant difference in histological changes on day 3 after transplantation among 3 groups (P > 0.05). Tracheas in Group I approached to normal morphology on day 14 after transplantation. Airway epithelium of Group II and III almost lost completely on day 14 after transplantation. There was no significant difference between Group II and Group III (P > 0.05), but there were significant differences between Group I and Group II or Group III. The cross-sectional area of the tracheal lumen was narrowed by approximately (5.0 +/- 1.2)%, (28.5 +/- 5.0)% and (19.4 +/- 2.9)% respectively on day 14 after transplantation in Group I, II and III, there were significant differences among 3 groups. On day 14 after transplantation, tracheas in Group I revealed few lymphocytic infiltration, but it showed dense lymphocytic infiltration in Group II. Tracheas in Group III have much more lymphocyte infiltration than that in Group I, but much less than that in Group II. There were significant differences among 3 groups, too (P < 0.01). The tracheal lumen revealed almost total luminal obstruction (94.8 +/- 3.6)% on day 28 after transplantation in Group II. The cross-sectional area of the tracheal lumen was narrowed by approximately (3.7 +/- 0.8)% and (36.6 +/- 7.6)% respectively in Group I and III on day 28. There were significant differences among 3 groups (P < 0.01). Compared with that on day 14, lymphocytic infiltration had decreased gradually on day 28 in Group II and III. There were significant differences among 3 groups all the same (P < 0.01). In Group II, expression of IL-2, IFN-gamma, IL-4, and IL-10 were much higher than that in Group I. Expression of Th1 cytokines was increased to a greater extent than that of Th2 cytokines in Group II compared with Group I. Allografts in Group III expressed significantly less IL-2 gene transcripts than that in Group II over all the points. There was no significant difference between Group II and III in IFN-gamma, IL-4, and IL-10 gene expression. CONCLUSIONS: Compared with isografts, allografts have more obvious changes, such as epithelial damage, fibroproliferation and lymphocytic infiltration. Th1 and Th2 lymphocyte subtypes contribute to the development of obliterative bronchiolitis in heterotopic trachea transplant model of rat, and changes of their cytokines gene expression may be involved in the pathogenesis. CsA could reduce the development of fibroproliferation and lymphocyte infiltration markedly, but it could not protect airway epithelium. CsA inhibits IL-2 gene transcripts, so it can reduce development of the pathologic lesion of obliterative bronchiolitis to a certain degree.

[Influence of number of removed lymph nodes on the TNM staging and survival in advanced esophageal carcinoma].

OBJECTIVE: To evaluate the impact of total number of removed regional lymph nodes (LN) during esophagectomy on TNM staging and long-term survival. METHODS: Between 1984 and 1989, a total of 1098 patients with advanced squamous cell carcinoma of the thoracic esophagus were surgically treated, and the data were retrospectively analyzed. The survival was analyzed by Kaplan-Meier method. Multivariate and univariate analysis were performed using Cox proportional hazard model and Log-rank test respectively in order to compare the survival difference and the impact of <6 or > or =6 removed LN on TNM staging and survival. RESULTS: The shortest follow-up time was 10 years with a follow-up rate of 91.4%. Of these 1098 patients, 378 patients were found to have regional LN metastases with a LN metastasis rate of 34.4%. Totally, 4157 LN were removed and tumor spreading into the lymph node was documented in 800 with a lymph node metastasis degree of 19.2%. The mean number of removed LN in each esophgectomy was 3.8. According to the number of total removed LN, patients were divided into group A (removed LN <6, N=825) and group B (removed LN > or =6, N=273). The survival of group A was worse than that of group B. The depth of tumor invasion, degree of lymph node metastasis, tumor location, and tumor residual status were the most important prognostic factors. Even though the lymphatic metastasis rate in group A was significantly lower than that in group B (30.3% vs. 46.9% P < 0.001), the LN metastasis degree was higher in group A than that in group B (21.2% vs. 17.5% P = 0.002) due to less number of removed LN in group A than in group B. With the stratification analysis according to the number of involved lymph nodes, for patients without LN spreading, the survival in group A was significantly worse than that in group B (P = 0.003), but in the patients with only one or > or =2 positive nodes, the survival was similar (P = 0.919 and 0.182, respectively). When stratified patients according to TNM stage, for stage IIa patients (T2N0M0, T3N0M0), the survival in group A was significantly worse than that in group B (P = 0.006), while such difference did not exist in patients with stage IIb or stage lIII(P = 0.302 and 0.108, respectively). CONCLUSION: A large series of retrospective study on advanced squamous cell carcinoma of the thoracic esophagus demonstrates that the number of metastatic LN is an important prognostic factor, therefore, it should be considered when refining UICC-TNM classification for esophageal cancer. If the total number of LN removed during each esophagectomy is less than 6, the occult positive regional LN might be missed, resulting in an inaccurate N classification and incorrect staging. Removal of > or = LN for each esophageal cancer patient during esophagectomy recommended by UICC is rational and should be complied with.

DHPLC is superior to SSCP in screening p53 mutations in esophageal cancer tissues.

Mutations of the p53 tumor-suppressor gene universally occur on exons 5-8 in human cancer. We analyzed these mutations in esophageal cancer tissue from 207 patients in China using 2 methods, single-strand conformation polymorphism (SSCP), one of the most frequently used methods, and the recently developed denaturing high-performance liquid chromatography (DHPLC), and compared their sensitivity and efficiency. Exons 5-8 of p53 were amplified from esophageal cancer tissue genomes, screened for fragments of mutations and polymorphisms by SSCP and DHPLC in a blind study and confirmed by direct sequencing to detect the mutations and polymorphisms. The numbers detected by DHPLC were greater than those detected by SSCP, though the rate of mutations and polymorphisms was lower in SSCP than in DHPLC, which appeared to detect smaller mutations (substitutions and 1 bp insertions/deletions). Of the mutations with substitutions detected by DHPLC but not by SSCP, 50% substituted adenosine for other nucleotides, suggesting that these mutations are often missed when SSCP is used. According to these data, the sensitivity of SSCP and DHPLC was 81% and 97%, respectively, and the specificity was 97% and 85%, respectively. Our results suggest that DHPLC may be recommended over SSCP when screening gene mutations. Thus, rates of p53 mutations and polymorphisms in esophageal cancer tissue in Chinese patients were 49% and 41% by DHPLC and SSCP, respectively.