Non-regional Lymph Node Metastasis Research Articles

Evaluation of different lymph node (LN) variables as prognostic markers in patients undergoing radical cystectomy and extended LN dissection to the level of the inferior mesenteric artery

To evaluate the prognostic impact of lymph node (LN) variables in patients undergoing radical cystectomy (RC) and extended LN dissection. From January 2004 to January 2009, 167 patients with bladder cancer underwent RC and extended LN dissection to the level of the inferior mesenteric artery in a surgery-only series with no neoadjuvant or adjuvant chemotherapy. Correlation to prognosis of different LN variables according to presence of LN metastasis, number, localization, extracapsular extension (ECE), size, volume, LN density and N-stage according to two different Tumour-Node-Metastasis (TNM) classifications were analysed. In all, 43 patients (26%) had LN metastases. In univariate analysis, gender, T-stage and several different LN variables stratified by presence of LN metastasis, number of positive LNs, anatomical localisation, ECE, LN density, size and volume of positive LNs, were significant prognostic predictors. Female gender, advanced T-stage, presence of LN metastasis, non-regional LN metastases (M-positive) and number of positive LNs (1 vs >1) were significant adverse prognostic predictors in multivariate analysis, whereas the other LN variables were not. Inclusion of the common iliac LNs in the regional LNs as suggested in the seventh edition of the TNM classification was relevant regarding prognosis. However, subclassification based on location was not correlated to prognosis. The new N3 category therefore seems superfluous. LN-positive patients have a poor prognosis, especially if >1 positive LN is present. Despite several different suggestions of new LN-dependent prognostic factors, none of the tested variables were independently significant in the present series.

Glasgow Prognostic Score is a Predictor of Perioperative and Long-term Outcome in Patients with only Surgically Treated Esophageal Cancer

Systemic inflammation (SI) plays a pivotal role in cancer. C-reactive protein (CRP) and albumin as parameters of SI form the Glasgow Prognostic Score (GPS). The purpose of the study was to evaluate the potential prognostic role of GPS in a homogeneous population of esophageal cancer (EC) patients undergoing only resection. GPS was evaluated on the basis of admission blood sample taken before surgery. Patients with a CRP<10mg/L and albumin>35g/L were allocated to GPS0 group. If only CRP was increased or albumin decreased patients were allocated to the GPS1 and patients in whom CRP was ≥10mg/L and albumin level ≤35g/L were classified as GPS2. GPS was correlated to clinicopathological parameters and clinical outcome. Increasing GPS significantly correlated with more aggressive tumor biology in terms of tumor size (P<0.001), presence of regional (P=0.01) and nonregional lymph node metastasis (P=0.02), and higher tumor recurrence rate (P<0.001). Furthermore, GPS was identified as an independent prognosticator of perioperative morbidity (odds ratio 1.9; P=0.03). In addition, a gradual decrease in disease-free and overall survival was evident between the three GPS subgroups. Survival differences between the GPS groups remained apparent even after stratification of the study population to underlying tumor type and nodal status. GPS was identified as a strong prognosticator of tumor recurrence (hazard ratio 2.5; P<0.001) and survival (hazard ratio 3.0; P<0.001) in EC. GPS represents a strong prognosticator of perioperative morbidity and long-term outcome in resected EC patients without neoadjuvant or adjuvant treatment.

Distant nodal metastases from intrathoracic esophageal squamous cell carcinoma: Characteristics of long‐term survivors after chemoradiotherapy

Non-regional lymph node metastasis in intrathoracic esophageal cancer is classified as M1 lesion with poor prognosis following surgery alone. We studied the controversial question of whether chemoradiotherapy (CRT) improves survival of these patients. A cohort of patients with clinically overt nodal M1 disease, which could be encompassed by a tolerable radiation therapy port, was selected from the database of the Chang Gung Memorial Hospital. From 1994 to 2005, 54 nodal stage IV intrathoracic esophageal squamous cell carcinoma (SCC) patients received neoadjuvant CRT. Significant response occurred in 24 patients. Scheduled esophagectomy was performed in 26 patients. The 3-year overall survival (OS) and disease-free survival (DFS) for the whole group were 27% (median: 14.2 months) and 22% (median: 14.7 months), respectively. Multivariate analysis identified pretherapy lymph nodes classified as M1a and R0 resection after CRT as independent favorable prognosticators. Median survival reached 36.9 months in the pretherapy M1a subgroup as opposed to 12.5 months in the M1b subgroup (3-year-DFS: 40% vs. 10%, P = 0.0117). Scheduled surgery after CRT benefits only after R0 resection (3-year-DFS: 36%, median survival: 45 months). The group with incomplete resection had a high surgical risk and dismal survival compared to the non-surgery group (3-year-DFS: 0% vs. 9%, 9.5 vs. 10.5 months). Pretherapy M1a disease had a significantly better survival than nodal M1b disease after CRT in SCC. Aggressive surgical treatment after CRT is reserved for cases when complete resection is anticipated.

Super-extended (D3) lymphadenectomy in advanced gastric cancer

Purpose To analyze our experience with D3 lymphadenectomy in the treatment of advanced GC with specific reference to post-operative morbidity and mortality, incidence of para-aortic node (PAN) metastases, and long-term prognosis. Methods Short- and long-term results of D3 lymphadenectomy were analyzed in 286 patients with advanced GC. Results PAN metastases were demonstrated in 37 patients. PAN involvement was significantly higher in upper third tumours (29%) compared to middle and lower third (7%; P < 0.001). Eighty patients developed post-operative complications, being pulmonary disorders (6%), abdominal abscesses (4.5%) and pancreatic fistulas (3%) the most frequently observed. In-hospital mortality was 2%. Overall 5-year survival rate for R0 pT2-4 patients was 52%. When considering survival in relation to nodal involvement, both pN3 and non-regional lymph node metastases (M1a) patients showed a chance of long-term survival: 5-year survival was 31% for pN3 and 17% for M1a cases. Furthermore, the 5-year survival rate was remarkably high (about 60%) even in pN2 and pN3 subsets when no serosal invasion (pT2) was demonstrated. Conclusions D3 lymphadenectomy could be further explored in specialized centers for curative surgery of advanced GC, especially for upper third tumours, providing that an acceptable morbidity and no increase in mortality can be offered.

Abstract B1: Heme oxygenase-1 transcription controlling GTn repeat polymorphism has contrary prognostic value in squamous cell carcinoma and adenocarcinoma of the esophagus

Abstract Purpose: The regulation of basal transcription of heme oxygenase-1 (HO-1) is dependent upon a GTn repeat polymorphism (GTn) in the promoter of the heme oxygenase-1 gene (HMOX-1). Here, we evaluate the role of GTn in surgically resected esophageal cancer patients without neoadjuvant or adjuvant treatment. Patients and Methods: Genomic DNA was extracted from peripheral blood leucocytes of 297 patients. To determine the number of the GTn repeats DNA was amplified by RT-PCR and sequenced. The results were correlated with clinicopathological parameters, disseminated tumor cells (DTC) and clinical outcome. Results: Three genotypes (SS, SL and LL) were defined based on cut-off points for short allele (“S”) with GTn repeats &amp;lt;25 and ≥25 as long allele (“L”). Throughout all analyses a contrary role of GTn was evident in squamous cell carcinoma (SCC) and adenocarcinoma (AC) patients. In SCC patients the SS genotype patients presented with less aggressive tumors in terms of tumor size, presence of regional and non-regional lymph node metastases, DTC and lower relapse rate compared to SL and LL genotype patients. In contrast, in AC patients the SS genotype patients displayed more aggressive tumor biology with bigger tumors, a higher rate of lymph node metastases, DTC as well as tumor recurrence compared to LL and SL genotype patients. The disease-free and overall survival in SCC patients was markedly reduced in LL genotypes compared to SL and SS genotypes. To the contrary, in AC the SS genotype patients displayed the worst disease-free and overall survival. Conclusion: GTn was identified as an independent prognostic factor with contrary prognostic value for tumor recurrence and death in the two subtypes of esophageal cancer, SCC and AC. Citation Information: Clin Cancer Res 2010;16(7 Suppl):B1

Is pancreatectomy with arterial reconstruction a safe and useful procedure for locally advanced pancreatic cancer?

We often encounter unresectable pancreatic cancer due to invasions of the major vessels. Vascular resection for locally advanced pancreatic cancers has an advantage in en block local resection. There are potential cases in which good outcomes can be achieved by arterial resection. Pancreatectomy (including total pancreatectomy in 15 cases, pancreatoduodenectomy in 7 cases and distal pancreatectomy in one case) was performed in 23 cases of invasive ductal carcinoma of the pancreas, in combination with resection and reconstruction of the hepatic artery in 15 cases, the superior mesenteric artery in 12 cases (there are overlaps) and the portal vein in 20 cases. The median operating time was 686 min (416-1,190 min) and the median blood loss was 2,830 ml (440-19,800 ml). This shows that the surgery was highly-invasive. The operative mortality rate was 4.3%. On the basis of the UICC classification, there were 2 cases of Stage IIa, 4 cases of Stage IIb, 9 cases of Stage III, 8 cases of Stage IV, while there were 18 cases (78.3%) of R0 resection. On the other hand, the final histological findings showed that there were 8 cases (34.8%) of M1 (liver and non-regional lymph node metastases), so it is thought that decisions on operative indications should be not be made slightly. As for the overall survival rate, the 1-year survival rate was 51.2% and the 3-year survival rate was 23.1% while the median survival time (MST) was 12 months. As for 15 cases of M0, the 1-year survival rate was 61.9% and the 4-year survival rate was 38.7% while the MST was 16 months. On the other hand, the MST was poor (10 months) in 8 cases of M1, showing that a statistically significant difference was observed depending upon the degree of metastasis (log-rank P = 0.0409). In 18 cases of R0, the 1-year survival rate was 67.2%, the 4-year survival rate 30.2% and the MST 13 months, respectively, while in 5 cases of R1 and R2, the MST was 6 months, showing that there was a statistically significant difference between R0 cases and R1, R2 cases (log-rank P = 0.0002). Further discussion is required concerning surgical indications and significance. However, it is thought that resection is useful only when surgery of R0 has taken place for selected locally advanced pancreatic cancer (M0).

Predictors of Long-Term Survival After Resection of Esophageal Carcinoma With Nonregional Nodal Metastases

Patients with esophageal carcinoma and celiac, cervical, or other nonregional nodal metastases generally have a poor prognosis after surgical resection. Factors predicting long-term survival are unclear. The goal of this study was to analyze factors predicting long-term survival in this subset of patients. We conducted a retrospective review of a prospective database over a 20-year period to identify patients with resected esophageal carcinoma with nonregional lymph node metastases. Medical records were reviewed and risk factors were analyzed. Sixty-seven patients underwent esophagectomy for M1a or M1b disease from 1987 to 2007. Esophagectomy was transthoracic in 62 patients and transhiatal in 5. The median number of lymph nodes harvested was 36. Sites of nodal metastases were the following: recurrent nodal chain in 42 patients, celiac in 20, both recurrent and celiac in 4, and paratracheal in 1. Median length of follow-up was 66 months. The 5-year overall survival for the entire cohort was 25%. The 5-year overall survival was significantly higher with earlier T-status, (pathologic tumor [pT]1/T2 vs pT3/T4; 62% vs 15%, p = 0.006). Thirteen patients who had nonregional nodal metastases without involvement of regional nodes (pN0) had a significant improvement in 5-year survival (67% vs 15%; p < 0.001). Patients with squamous cell carcinomas had higher 5-year survival compared with those with adenocarcinomas (42% vs 14%; p = 0.009). Patients treated with induction chemotherapy had prolonged 5-year survival (41%, p = 0.06) compared with those treated with adjuvant chemotherapy (11%) or no therapy (20%). Multivariate analysis demonstrated that chemotherapy treatment, squamous cell type, and early T stage (pT1/T2) are significant positive predictors of survival. Surgical resection for patients with esophageal cancer associated with nonregional nodal metastases results in 25% survival at five years. Squamous histology, earlier T status, and perioperative chemotherapy are independent positive predictors of long-term survival.

Positron Emission Tomography–Computed Tomography in Predicting Locoregional Invasion in Esophageal Squamous Cell Carcinoma

In order to clarify the role of positron emission tomography-computed tomography (PET/CT) in thoracic esophageal squamous cell carcinoma we investigated its value in predicting locoregional invasion. Forty-five patients receiving curative esophagectomy and lymph node dissection were included. The relationship between PET/CT findings and pathology results were studied. Correlation between nodal uptake and the modified lymph node staging, which is based on number of involved nodes (N0 = no nodes; N1 = 1 to 3 nodes; N2 = more than 3 nodes), was evaluated. The mean maximal standardized uptake value (SUV(max)) was 5.09 +/- 4.00 in T1, 14.17 +/- 2.46 in T2, 13.32 +/- 3.96 in T3, and 10.37 +/- 1.94 in T4 primary tumor. The SUV(max) was significantly lower in stage T1 tumors than in stage T2 and T3 tumors. For regional nodal involvement, PET/CT findings significantly correlated with pathology results. However, the sensitivity, specificity, and accuracy of PET/CT were only 57.1%, 83.3%, and 71.1%, respectively, and even lower for detecting nonregional lymph node metastasis. When stratified by the modified staging system, the mean SUV(max) was 0.64 +/- 1.60 in N0, 1.43 +/- 2.08 in N1, and 4.67 +/- 4.32 in N2 regional lymph node metastases, and was significantly higher in patients with N2 metastasis than in patients with N0 and N1 metastases. Locoregional invasion in esophageal cancer can be predicted by PET/CT. The SUV(max) of the primary tumor helped identify T1 tumor, and the SUV(max) of the regional lymph nodes correlated with the severity of nodal involvement.

Prognostic Variables in Thoracic Esophageal Squamous Cell Carcinoma

Thoracic esophageal squamous cell carcinoma (TESCC) is an aggressive malignancy with a poor prognosis. The current American Joint Committee on Cancer (AJCC) TNM cancer staging system focusing on the effect of regional (N1) and nonregional lymph node (M1a and M1b) metastasis may need reappraisal. We investigated the role of the number of dissected and positive nodes in TESCC patients. A total of 109 TESCC patients (97 men; mean age of 62.3 years) who underwent surgical resection were retrospectively analyzed. The current AJCC TNM system and other lymph node classifications were used to subgroup these patients and analyze survival differences. Previously reported prognostic factors were evaluated. Patients with positive lymph node metastasis had a poor prognosis (p < 0.001). There was a significant difference in survival among the 67 node-positive patients subdivided into subgroups with 1 to 3 and 4 or more positive nodes (p = 0.004). Multivariable Cox proportional hazard regression analysis identified four independent prognostic factors: difficulty in swallowing (p = 0.024), cigarette smoking (p = 0.003), number of positive lymph nodes (0, 1 to 3, and > or = 4; p < 0.001), and gastric cardia invasion (p = 0.012). Total dissection of at least 20 lymph nodes was the minimal requirement to achieve accurate nodal staging. Dissection of more than 20 lymph nodes is mandatory in TESCC patients to achieve accurate staging. Positive lymph node metastasis of 4 or higher is a significant independent prognostic factor.

Value of Dilation in the EUS Staging of Obstructing Esophageal Cancer

Introduction: Endoscopic ultrasound (EUS) staging of esophageal cancer is often limited by a tumor stricture preventing passage of the endosonoscope, and thus evaluation of potential distal metastatic lesions. It remains controversial whether dilation should be performed to allow complete EUS examination in these cases. The objective of this study was to assess the benefit and safety this approach. Patients and Methods: 114 consecutive patients underwent EUS staging of esophageal cancer at our institution from 2004-2007. Data were retrospectively obtained regarding need for and success of dilation, cancer staging, sampling of lesions distal to the stricture, complications, type of endosonoscope used, and treatment recommendations. Results: 114 patients underwent EUS staging of esophageal cancer. 56 patients (49%) had strictures that prevented endosonoscope passage. Of those, 52 patients underwent dilation, which allowed successful passage of the echoendoscope in 41 (79% success rate). Dilation was performed to a median diameter of 15 mm (range 10-18 mm) with a balloon (n = 5), Savary dilators (n = 45) or both (n = 2). Cases with an obstructing stricture were more often staged T3 or greater than those without an obstructing stricture (93% vs. 59%, p < 0.001). Biopsy of additional structures distal to the stricture was performed in 14 of the 41 cases (34%) where distal endosonoscope passage was possible after dilation, and demonstrated M1a (n = 7) or M1b disease (n = 2) in 9 cases (22%). This altered the therapeutic recommendations in 8 patients (20%). Perforation occurred in 2 patients who underwent dilation and in one patient who did not undergo dilation. All perforations were managed conservatively. Conclusions: A tumor stricture requiring dilation for endosonoscope passage is a strong indicator of T3 disease or greater. Dilation provides the opportunity for identification of metastatic involvement which can justify the small risk of perforation. Detection of M1a and M1b status distal to the stricture altered management in most of our cases. However, this may be different at other institutions since treatment recommendations for patients with non-regional lymph node metastases are not uniform.

Capecitabine and Cisplatin Chemotherapy (XP) Alone or Sequentially Combined Chemoradiotherapy Containing XP Regimen in Patients with Three Different Settings of Stage IV Esophageal Cancer

The 1997 staging system for esophageal carcinoma subdivided distant metastatic disease (M1) into nonregional lymph node metastases (M1a) and other metastases (M1b). To determine the relevance of this classification system, we investigated the efficacy and toxicity of capecitabine/cisplatin (XP) chemotherapy alone or in combination with radiotherapy. We identified 74 patients with M1 disease treated at Asan Medical Center from January 2003 to December 2005. Of these patients, 19 (25.7%) were classified as M1a, 29 (39.2%) as M1b (nonvisceral lymph node metastases), and 26 (35.1%) as M1b (visceral metastases). All patients were treated with first two cycles of XP induction chemotherapy, consisting of capecitabine 1000 mg/m(2) twice daily on days 1-14, and i.v. cisplatin 60 mg/m(2) on day 1, every 3 weeks. Patients classified as M1a and M1b (nonvisceral lymph node metastases) were treated with 54 Gy of radiotherapy, concurrently with weekly capecitabine 800 mg/m(2) twice daily on days 1-5 and i.v. cisplatin 30 mg/m(2) on day 1 during radiation. Patients classified as M1b (visceral metastases) were treated with chemotherapy only until disease progression or intolerance to chemotherapy. In response to the first two cycles of chemotherapy, 3/18 (16.7%) M1a nonregional lymph node (LN), 4/27 (14.8%) M1b nonvisceral LN metastases and 5/25 (20%) M1b visceral metastases patients attained partial responses. After definitive chemoradiation in the setting of M1a, M1b nonvisceral LN metastases and maximum cycles of chemotherapy in the M1b visceral metastases setting, the response rates were 77.8, 62.9 and 36.0% respectively. With median follow-up of 12.5 months (range 0.5-22.8), 50 of 74 patients (67.5%) died. The median time to progression (TTP) was 7.8 months (95% CI, 6.0-9.5 months) and the median overall survival (OS) was 12.0 months (95% CI, 9.0-15.0 months). Median TTP in the M1a, M1b nonvisceral LN metastases and M1b visceral metastases were 10.3, 6.5 and 5.9 months, respectively (P = 0.087), whereas median OS in these groups was 13.8, 13.8, and 8.2 months, respectively (P = 0.134). Median TTP was 8.4 months (95% CI, 5.5-11.3 months) in the 48 patients with M1a and M1b nonvisceral LN metastases and 5.9 months (95% CI, 2.7-9.0 months) in the 26 patients with M1b visceral metastases (P = 0.03), and median OS in these two groups was 13.8 months (95% CI, 10.4-17.3 months) and 8.2 months (95% CI, 5.7-10.7 months), respectively (P = 0.04). The similar OS in patients with M1a and M1b nonvisceral LN metastases suggests that concurrent chemoradiotherapy might contribute in the latter. Our findings indicate that sequentially combined chemoradiotherapy containing XP regimen was active and well tolerated as first-line treatment for M1a as well as M1b esophageal cancer.

M1a/M1b esophageal carcinoma: Clinical relevance

Objective: The 1997 staging system for esophageal carcinoma subdivides distant metastatic disease (M1) into M1a (nonregional lymph node metastases) and M1b (other metastases). This study evaluates the relevance of this classification. Methods: One hundred forty patients were identified with M1 disease, 36 (26%) M1a and 104 (74%) M1b. The histologic type was adenocarcinoma in 118 (84%), squamous cell in 18 (13%), and adenosquamous in 4 (3%), with a similar distribution for M1a and M1b (P = .3). Forty-five underwent surgery, 28 (78%) with M1a disease and 17 (16%) with M1b disease (P < .001). Chemotherapy and/or radiation therapy was given to 33 (73%) surgical patients and 63 (66%) nonsurgical patients (P = .4), 28 (78%) with M1a disease and 68 (66%) with M1b disease (P = .17). Results: Median and 5-year survivals were 11 months and 6% in patients with M1a disease and 5 months and 2% in those with M1b disease (P = .001). Surgery provided no advantage in M1b (P = .6) or M1a disease (P = .2). Multivariable analysis demonstrated that patients with M1b disease had 1.8 times the mortality risk of those with M1a disease (CI 1.2-2.7, P = .004), and patients without chemotherapy and/or radiotherapy had 2.2 times the mortality risk of those with chemotherapy and/or radiotherapy (CI 1.5-3.2, P < .001). Despite the prevalence of surgery in patients with M1a disease, the analysis suggests that M1a and use of chemotherapy and/or radiotherapy, rather than surgery, account for the small, clinically unimportant differences in survival. Conclusions: We conclude that (1) although there are statistically significant survival differences between M1a and M1b disease, these differences are not clinically important; (2) chemotherapy and/or radiotherapy is associated with a modest survival benefit; and (3) surgery offers no survival advantage. (J Thorac Cardiovasc Surg 1999;118:900-7)

Prognosis of Patients with Prostate Carcinoma Presenting as Nonregional Lymph Node Metastases

Objective: The mode of progression in patients with prostate cancer with metastasis to nonregional lymph nodes was examined in order to know whether the site of metastasis effects the prognosis of prostate cancer. Methods: From 1986 to 1995 at the Chiba University Hospital, 205 cases of prostatic cancer with distant metastases were experienced. In 17 of them, nonregional lymph node metastases were observed at the diagnosis, of whom 10 also had bone metastases. Results: There was no statistical difference in prognosis between 17 patients with nonregional lymph node metastases and remaining 188 patients with metastatic prostate cancer. In all patients metastasized to nonregional lymph nodes, serum prostate-specific antigen and/or prostatic acid phosphatase levels were elevated. Anti-androgen therapy was effective in 15 cases and 5-year survival rate was 45.8%. Patients without bone metastases at the initial diagnosis could survive longer than those with metastases to bone (p < 0.05). Conclusions: From these observations, endocrine therapy was effective even in patients with distant lymph node metastases.

Carcinoma of the prostate presenting as non-regional superficial lymph node metastasis

The objective of this study is to evaluate the prognosis of carcinoma of the prostate presenting as non-regional superficial lymphnode metastasis. From 1986 to 1996 at the Chiba University Hospital, 205 cases of prostatic cancer with distant metastasis were experienced. In nine of them, non-regional lymphnode metastasis was observed at the diagnosis. In all of them, serum prostate specific antigen and/or prostate acid phosphatase levels were elevated. In eight of nine cases, cancer nodule was detected by digital rectal examination. Anti-androgen therapy was effective in eight cases and five year survival rate was 56%. From these observations, prostate cancer should be considered when superficial lymphnode was enlarged.