Original Article
Prognostic Value of Immunohistochemically Identifiable Tumor Cells in Lymph Nodes of Patients with Completely Resected Esophageal Cancer
N Engl J Med 1997; 337:1188-1194October 23, 1997
- Abstract
Background
Current methods of disease staging often fail to detect small numbers of tumor cells in lymph nodes. Metastatic relapse may arise from these few cells.
Methods
We studied 1308 lymph nodes from 68 patients with esophageal cancer without overt metastases who had undergone radical en bloc esophagectomy. A total of 399 lymph nodes obtained from 68 patients were found to be free of tumor by routine histopathological analysis and were studied further for isolated tumor cells by immunohistochemical analysis with the monoclonal anti–epithelial-cell antibody Ber-EP4. This antibody did not stain lymph nodes from 24 control patients without carcinoma.
Results
Of the 399 “tumor free” lymph nodes, 67 (17 percent), obtained from 42 of the 68 patients, contained Ber-EP4–positive tumor cells. Fifteen of 30 patients who were considered free of lymph-node metastases by histopathological analysis had such cells in their lymph nodes, and 5 of the 15 had small primary tumors. Ber-EP4–positive cells found in “tumor free” nodes were independently predictive of significantly reduced relapse-free survival (P = 0.008) and overall survival (P = 0.03). They predicted relapse both in patients without nodal metastases (P = 0.01) and in those with regional lymph-node involvement (P = 0.007). All 12 patients whose lymph nodes were negative on both histopathological and immunohistochemical analysis and who were available for follow-up survived without recurrence. The presence of micrometastatic tumor cells in bone marrow had no additional prognostic value.
Conclusions
Immunohistochemical examination of lymph nodes may improve the pathological staging of esophageal cancer.
Media in This Article
Figure 1
Detection of Ber-EP4–Positive Tumor Cells by Immunohistochemical Analysis.Figure 2
Kaplan–Meier Survival Curves for Patients with and without Ber-EP4–Positive Tumor Cells in Their Lymph Nodes.Article Activity
- Article
Esophageal cancer is an aggressive carcinoma with a poor prognosis. Although postoperative mortality has declined and rates of complete resection have improved considerably, reported rates of survival five years after surgery range from 20 to 36 percent.1-5 Early metastatic relapse after the complete resection of an apparently localized primary lesion6-8 indicates that disseminated tumor cells, undetectable by current methods, may already have been present at the time of surgery.
Monoclonal antibodies against tumor-associated antigens or epithelial-cell proteins can be used to detect individual epithelial tumor cells in lymph nodes that are free of metastases on routine histopathological examination.9-12 The clinical significance of these immunohistochemical assays is controversial, however,13-21 and they have not been used in patients with esophageal cancer. In view of the critical role of lymph-node metastases in such patients,2,6,11,22-24 we prospectively studied the clinical implication of immunohistochemically identifiable tumor cells in lymph nodes of patients with completely resected esophageal cancer.
Methods
Patients and Study Design
This study was approved by the ethics committee of the chamber of physicians in Hamburg. Informed consent was obtained from all the patients before their inclusion in the study. Tumor samples, lymph nodes, and bone marrow aspirates of the upper iliac crest were collected from 71 consecutive patients with resectable esophageal cancer who had undergone radical en bloc esophagectomy between April 1992 and July 1995 and had tumor-free resection margins on microscopical examination of the surgical specimen. In each patient reconstruction was performed with a gastric tube with a cervical esophagogastric anastomosis. Tumor stage and grade were classified according to the fourth edition of the tumor–node–metastasis classification of the International Union against Cancer16 by investigators unaware of the immunohistochemical findings in the lymph nodes and bone marrow. Three patients were excluded from the study because they had evidence of liver metastases at surgery; thus, 68 patients were included. None received neoadjuvant or adjuvant therapy.
The patients were examined again on an outpatient basis every three months after esophagectomy for two years and at six-month intervals thereafter by physicians who had no knowledge of the immunohistochemical findings. These evaluations included a physical examination, plain chest radiography, endoscopy, endosonography, computed tomography of the chest and abdomen, abdominal ultrasonography, studies of tumor markers (squamous-cell carcinoma antigen, carcinoembryonic antigen, and CA 19-9), and bone scanning. All 68 study patients were available for follow-up. Five patients (three patients with no nodal involvement [pN0] and two patients with regional nodal involvement [pN1]) were excluded from the analyses of survival because they died in the hospital within 90 days after surgery (mortality rate, 7 percent).
Tissue Preparation and Immunohistochemical Analysis
Of 1308 resected lymph nodes, 680 were judged to be tumor-free by the surgeons. These nodes were systematically sampled during lymphadenectomy from lymph nodes in five locations (regional mediastinal lymph nodes both in the vicinity of the tumor and distant from it, perigastric lymph nodes, common hepatic lymph nodes, and lymph nodes at the celiac trunk). No tumor cells were found on routine histopathological examination in 399 of these 680 lymph nodes. All the nodes were mapped by the surgeon according to the scheme of the American Thoracic Society17 as modified by Casson et al.18
Each of the lymph nodes sampled was divided into two parts. One part was embedded in paraffin for routine histopathological staging and stained with hematoxylin and eosin; the other part and a representative sample of the primary tumor were snap-frozen in liquid nitrogen within three hours after their removal and stored at -80°C until use. Lymph nodes from patients in whom there was no evidence of nodal metastasis on routine histopathological examination were screened by immunohistochemical analysis with the anti–epithelial-cell monoclonal antibody Ber-EP4 (IgG1; Dako, Hamburg, Germany), which can be used on snap-frozen or paraffin-embedded material to detect isolated tumor cells, as described previously.10 Ber-EP4 is an antibody against two glycopolypeptides of 34 and 49 kd on the surface and in the cytoplasm of all epithelial cells (except parietal cells, hepatocytes, and the superficial layers of squamous epithelium). The antibody does not react with mesenchymal tissue, including lymphoid tissue.12,19 Cryostat sections 6 to 8 μm thick were cut at three different levels in each node and transferred onto glass slides treated with 3-triethoxysilylpropylamin (Merck, Darmstadt, Germany). One section of the sample obtained at each level was stained by the alkaline phosphatase–antialkaline phosphatase technique.10 We have found that lymph nodes from 24 control patients with nonepithelial tumors or inflammatory diseases consistently stained negative.10 Sections of normal colonic mucosa served as positive staining controls, and isotype-matched, irrelevant murine monoclonal antibodies served as negative controls (purified immunoglobulin mouse myeloma protein for IgG1; Sigma, Deisenhofen, Germany).
Aspirates of 4 to 8 ml of bone marrow from the iliac crest were obtained from all the patients before surgery and were processed as previously described.20 The specimens were collected in heparin, and mononuclear cells, isolated by density-gradient centrifugation through Ficoll–Hypaque (Pharmacia, Freiburg, Germany) at 400×g for 30 minutes, were deposited onto glass slides by cytocentrifugation at 150×g for 3 minutes. To detect tumor cells in bone marrow, we used the monoclonal antibody A45-B/B3 (IgG1; Micromet, Munich, Germany), which detects an epitope on a variety of cytokeratin components, including cytokeratins 8, 18, and 19.21 The antibody reaction was developed with the alkaline phosphatase–antialkaline phosphatase technique combined with the new fuchsin stain (Sena, Heidelberg, Germany) for the visualization of alkaline phosphatase bound to the antibody.20
The slides stained with hematoxylin and eosin and the immunostained slides were evaluated in a blinded fashion by two observers working independently. For 90 percent of the slides, the observers' evaluations were identical; the remaining slides were reevaluated, and consensus decisions were made. Minimal tumor-cell involvement in a lymph node that was considered to be tumor-free by routine histopathological staining was defined as the presence of one to three Ber-EP4–positive cells in the body of the node (Figure 1AFigure 1
Detection of Ber-EP4–Positive Tumor Cells by Immunohistochemical Analysis. and Figure 1B). In the 42 patients who had Ber-EP4–positive cells in histopathologically “tumor free” lymph nodes, two lymph-node sections adjacent to the one that contained the immunostained cells were prepared, stained with hematoxylin and eosin, and evaluated by a pathologist with no knowledge of the initial results.Statistical Analysis
Associations between categorical variables were assessed by Fisher's exact test. The Kaplan–Meier method was used to estimate overall survival and survival free of local recurrence, distant metastases, and relapse. Point and interval estimates of the survival rates at 24 months were calculated. For comparison purposes, log-rank tests and exact stratified log-rank tests were performed. Cox proportional-hazards models were fitted for multivariate analysis.25 Differences between groups were considered statistically significant if the P values were less than 0.05 in a two-tailed test. The follow-up times were calculated according to the method proposed by Schemper and Smith.26
Results
The material used in the study was obtained from 68 patients with esophageal cancer (Table 1Table 1
Characteristics of the Patients and Tumors.). The mean age was 57 years (range, 34 to 76). There were 14 women and 54 men. The location of the primary tumor was supracarinal in 30 patients (44 percent) and infracarinal in 38 (56 percent). Forty-nine tumors (72 percent) were classified as squamous-cell carcinoma, and 19 (28 percent) as adenocarcinoma (Table 1); in 12 of these 19 patients, the adenocarcinoma arose from Barrett's mucosa. The prevalence of squamous-cell carcinomas was slightly higher in our study than in others, in which such carcinomas accounted for about 60 percent of all tumors.27-30 The immunohistochemical assay was used to screen cryostat sections of all the primary tumors and 399 lymph nodes obtained from the 68 patients. All these nodes were “tumor free” on conventional histopathological analysis. Sixty-five of the 68 primary tumors (96 percent) showed homogeneous staining with the Ber-EP4 antibody, and the remaining 3 (4 percent) had heterogeneous staining patterns. To study whether the Ber-EP4 antigen was lost from metastatic cells, lymph nodes from the first 25 consecutive patients who had regional nodal involvement that was classified as metastatic on routine staining with hematoxylin and eosin were stained with the Ber-EP4 antibody. A homogeneous staining pattern was found in all these specimens, indicating that metastatic cells retain the antigen bound by Ber-EP4.
Table 1 shows that in 42 of the 68 patients Ber-EP4–positive cells were found in lymph nodes that were considered to be tumor-free according to standard criteria. These Ber-EP4–positive cells or cell clusters (containing up to three cells) were found in the sinuses, the lymphoid interstitium, or both in 67 lymph nodes from the 42 patients. Immunostaining revealed tumor cells at one or two lymph-node levels in 24 patients and at more than two levels in 16. Four patients with histologically negative but Ber-EP4–positive lymph nodes had small primary tumors (Table 1), and one patient in this group had a carcinoma in situ. Table 1 indicates the tumor-staging nomenclature.
To compare immunostaining with conventional staining, two sections adjacent to the Ber-EP4–positive sections were stained with hematoxylin and eosin. In none of these sections were tumor cells detected by staining with hematoxylin and eosin, suggesting that greater sensitivity of the analysis rather than sampling error accounted for the higher rate of detection of tumor cells by the immunohistochemical method.
There was no correlation between the detection of Ber-EP4–positive cells in lymph nodes and other factors we studied, such as primary-tumor stage (T stage), pathological stage, tumor type, presence or absence of lymphovascular invasion, or histopathological grade (Table 1). All 25 patients who had isolated tumor cells in their bone marrow, as revealed by immunostaining with monoclonal antibody A45-B/B3 against cytokeratins, also had Ber-EP4–positive tumor cells in their lymph nodes (Table 1). However, lymph-node involvement was found with the Ber-EP4 antibody in 17 of the 43 patients who had negative bone marrow findings (Table 1).
The mode of spread of the Ber-EP4–positive cells into lymph nodes was erratic. Spatial progression of micrometastasis throughout the regional node levels was seen in only 50 percent of patients with Ber-EP4–positive cells. In the remaining patients, the micrometastases appeared to skip one or more lymph-node levels (data not shown).
After a median observation period of 21 months (range, 2 to 51) the presence of Ber-EP4–positive tumor cells in lymph nodes was associated with significantly reduced disease-free survival. The rate of relapse-free survival at two years was 68 percent in patients without Ber-EP4–positive cells and 25 percent in patients with such cells (P<0.001) (Table 2Table 2
Prognostic Value of Ber-EP4 –Positive Tumor Cells in Lymph Nodes. and Figure 2AFigure 2Kaplan–Meier Survival Curves for Patients with and without Ber-EP4–Positive Tumor Cells in Their Lymph Nodes.). Stratification according to pathological stage showed that the presence of Ber-EP4–positive lymph nodes predicted early relapse in both patients with no nodal involvement (P = 0.01) and those with regional nodal involvement (P = 0.007) (Table 2). A subgroup analysis of the prognostic influence of Ber-EP4–positive cells in patients with no nodal involvement, adjusted for tumor stage and grade by exact stratified log-rank tests for relapse-free survival, yielded results identical to those of the unstratified analyses (P = 0.01), indicating that Ber-EP4 status is an independent prognostic variable in patients without nodal involvement. Nevertheless, the small number of patients in this subgroup analysis is an argument for cautious interpretation.Ber-EP4–positive cells also had significant predictive value with regard to overall survival. The rate of overall survival was 68 percent in patients without Ber-EP4–positive tumor cells in their lymph nodes, as compared with 25 percent in patients with such cells (P<0.001) (Table 2 and Figure 2B).
There was a significant relation between the presence of Ber-EP4–positive tumor cells in lymph nodes and relapse with distant metastases, but not between the presence of such cells and local recurrence. Distant metastases occurred in 25 of 41 patients with Ber-EP4–positive tumor cells and 4 of 22 without these cells (P<0.001) (Table 2). The additional presence of A45-B/B3–positive tumor cells in bone marrow had no further influence on relapse-free survival (P = 0.66 by the log-rank test) or overall survival (P = 0.28) (data not shown).
Cox regression analysis showed that Ber-EP4–positive cells in lymph nodes had independent prognostic importance for relapse-free survival (relative risk, 3.76; 95 percent confidence interval, 1.40 to 10.07; P = 0.008) and overall survival (relative risk, 3.0; 95 percent confidence interval, 1.04 to 8.67; P = 0.03). As expected, histopathological lymph-node stage was a strong independent prognostic factor for both clinical end points (P<0.001). Histologic tumor grade and lymphovascular invasion were also independent predictors of relapse-free survival (P = 0.01) and overall survival (P = 0.04) (Table 3Table 3
Multivariate Cox Regression Analyses of the 63 Patients Who Survived More than 90 Days after Surgery.). Primary-tumor stage and tumor type had no independent prognostic influence (Table 3).None of the 12 patients without nodal involvement, as determined by both histopathological and immunohistochemical analysis, had tumor recurrences during the study period (Table 2). Four of the 12 patients had invasion of the adventitia, 3 had invasion of the muscularis propria, 4 had invasion of the submucosa, and 1 had a carcinoma in situ. The median observation period for these 12 patients was 21 months (range, 2 to 51), as compared with 19 months (range, 2 to 49) in the patients with immunohistochemical involvement and 26 months (range, 2 to 26) in those who were positive by both methods (P not significant).
Discussion
Lymph-node metastasis identified on histopathological examination is the most important prognostic factor in patients with esophageal cancer.2,6,11,22-24 Our study provides evidence that isolated tumor cells or small clusters of cells, which can be detected in lymph nodes by immunohistochemical analysis, are independent prognostic factors in esophageal cancer. Remarkably, all the patients who were found to be free of nodal tumor involvement by both histopathological and immunohistochemical analysis survived the median observation period of 21 months without recurrence. In contrast, patients in whom no lymph-node metastases were found by conventional means but who had immunostained tumor cells in their lymph nodes had outcomes similar to those of patients with histopathologically proved lymph-node metastases. Moreover, patients with regional nodal involvement who had immunostained tumor cells in other lymph nodes that were found to be tumor-free by standard analyses had shorter relapse-free and overall survival than similar patients without such cells. This surprising finding may be explained by the total load of residual tumor cells, a potential source of subsequent metastatic relapse.
The predisposition to have distant metastases among patients with Ber-EP4–positive tumor cells in their lymph nodes suggests that these cells are the consequence of advanced tumors, rather than indicators of sites of subsequent relapse. According to Paget's seed-and-soil hypothesis, the growth of disseminated tumor cells into overt metastases is influenced by the environment into which the cells have been seeded. The presence of growth factors in the local environment and the capacity of isolated tumor cells to respond to them may determine the pattern of relapse.31 In this context, it is interesting that lymphovascular infiltration did not correlate with the detection of Ber-EP4–positive tumor cells in the lymph nodes, which suggests that not all tumor cells that gain access to lymphatic vessels become established in the draining lymph nodes. Squamous-cell carcinoma and adenocarcinoma have different biologic features, but both have a similar potential for dissemination into secondary organs.10
Lymph-node micrometastasis has been assessed in breast cancer by the histopathological examination of numerous consecutive sections.32 This time-consuming method is not practical as a routine procedure. Recently, our group showed that immunohistochemical analysis with monoclonal antibody Ber-EP4 is a sensitive and specific method for detecting isolated lung-cancer cells or clusters of cells in lymph nodes.10 In the present study, sections were cut from only three levels of the lymph node, which could introduce a sampling error. Analyzing more than three sections, however, would not be routinely feasible. The positive correlation between the result of our assay and the prognosis of patients indicates that examining three levels is sufficient.
Immunohistochemical assessment of tumor-cell dissemination into bone marrow33 may be useful before preoperative chemotherapy or radiotherapy. Immunocytochemical assays with the monoclonal and anti-cytokeratin antibody A45-B/B3 are more sensitive than flow-cytometric analysis with monoclonal antibody CK2 against cytokeratin 18, which is not frequently expressed in esophageal-cancer cells.33,34 Our data suggest that there is dissemination of tumor cells into lymph nodes before blood-borne spread, because only 60 percent of the patients we studied who had Ber-EP4–positive tumor cells in their lymph nodes also had immunohistochemically identifiable tumor cells in their bone marrow. The lack of a significant difference in relapse-free survival between patients with only Ber-EP4–positive lymph nodes and those with involvement of both lymph nodes and bone marrow suggests that the main prognostic factor in esophageal cancer is the spread of tumor to the lymph nodes; hematogenous spread may be a secondary event.
Our data indicate that immunohistochemical assessment of lymph nodes can be used to refine the staging system for esophageal cancer and help identify patients who will not be cured by surgery alone. The value of adjuvant therapy in patients with small primary tumors who are thought to have no nodal involvement is unknown, but patients with a minimal amount of residual tumor may respond better to such therapy than patients with more advanced disease.
Supported by grants from the Deutsche Krebshilfe, Dr. Mildred Scheel Stiftung, Bonn, and the Friedrich Bauer Stiftung, Munich, Germany.
Source Information
From the Abteilung f ür Allgemeinchirurgie, Universitätskrankenhaus Eppendorf (J.R.I., S.B.H., A.R., C.B., B.P., C.E.B.), the Abteilung f ür Mathematik in der Medizin (U.P.), and the Institut für Pathologie (A.N.), Universität Hamburg, Hamburg; and the Institut für Immunologie, Ludwig-Maximilians-Universität, Munich (K.P.) — all in Germany.
Address reprint requests to Dr. Izbicki at the Abt. für Allgemeinchirurgie, Universitätskrankenhaus Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany.
- References
References
1
Lerut T ,De Leyn P ,Coosemans W ,Van Raemdonck D ,Scheys I ,LeSaffre E . Surgical strategies in esophageal carcinoma with emphasis on radical lymphadenectomy. Ann Surg 1992;216:583-590
CrossRef | Web of Science | Medline2
Siewert JR ,Bartels H ,Bollschweiler E , et al. Plattenepithelcarcinom des Oesophagus: Behandlungskonzept der Chirurgischen Klinik der Technischen Universität Munchen. Chirurg 1992;63:693-700
Web of Science | Medline3
Watanabe H . Plattenepithelcarcinom des Oesophagus. Chirurg 1992;63:689-692
Web of Science | Medline4
Earlam R. Epidemiology of esophageal cancer from the European point of view. In: Siewert JR, Hölscher AH, eds. Diseases of the esophagus. Berlin, Germany: Springer-Verlag, 1988:11-7.
5
Goldminc M ,Maddern G ,Le Prise E ,Meunier B ,Campion JP ,Launois B . Oesophagectomy by a transhiatal approach or thoracotomy: a prospective randomized trial. Br J Surg 1993;80:367-370
CrossRef | Web of Science | Medline6
Hennessy TPJ . Lymph node dissection. World J Surg 1994;18:367-372
CrossRef | Web of Science | Medline7
Morita M ,Kuwano H ,Ohno S ,Furusawa M ,Sugimachi K . Characteristics and sequence of the recurrent patterns after curative esophagectomy for squamous cell carcinoma. Surgery 1994;116:1-7
Web of Science | Medline8
Abe S ,Tachibana M ,Shiraishi M ,Nakamura T . Lymph node metastasis in resectable esophageal cancer. J Thorac Cardiovasc Surg 1990;100:287-291
Web of Science | Medline9
Byrne J ,Waldron R ,McAvinchey D ,Dervan P . The use of monoclonal antibodies for the histopathological detection of mammary axillary micrometastases. Eur J Surg Oncol 1987;13:409-411
Web of Science | Medline10
Passlick B ,Izbicki JR ,Kubuschok B , et al. Immunohistochemical assessment of individual tumor cells in lymph nodes of patients with non-small-cell lung cancer. J Clin Oncol 1994;12:1827-1832
Web of Science | Medline11
Raymond WA ,Leong AL . Immunoperoxidase staining in the detection of lymph node metastases in stage I breast cancer. Pathology 1989;21:11-15
CrossRef | Web of Science | Medline12
Latza U ,Niedobitek G ,Schwarting R ,Nekarda N ,Stein H . Ber-EP4: new monoclonal antibody which distinguishes epithelia from mesothelia. J Clin Pathol 1990;43:213-219
CrossRef | Web of Science | Medline13
Bussolati G ,Gugliotta P ,Morra I ,Pietribiasi F ,Berardengo E . The immunohistochemical detection of lymph node metastases from infiltrating lobular carcinoma of the breast. Br J Cancer 1986;54:631-636
CrossRef | Web of Science | Medline14
Chen ZL ,Perez S ,Holmes CE , et al. Frequency and distribution of occult micrometastasis in lymph nodes of patients with non-small-cell lung carcinoma. J Natl Cancer Inst 1993;85:493-498
CrossRef | Web of Science | Medline15
de Mascarel I ,Bonichon F ,Coindre JM ,Trojani M . Prognostic significance of breast cancer axillary lymph node micrometastases assessed by two special techniques: reevaluation with longer follow-up. Br J Cancer 1992;66:523-527
CrossRef | Web of Science | Medline16
Hermanek P, Sobin LH. TNM classification of malignant tumours. 4th ed. New York: Springer, 1992.
17
Martini N ,Flehinger BJ ,Zaman MB ,Beattie EJ Jr . Results of resection in non-oat cell carcinoma of the lung with mediastinal lymph node metastases. Ann Surg 1983;198:386-397
CrossRef | Web of Science | Medline18
Casson AG ,Rusch VW ,Ginsberg RJ ,Zankowicz N ,Finley RJ . Lymph node mapping of esophageal cancer. Ann Thorac Surg 1994;58:1569-1570
CrossRef | Web of Science | Medline19
Momburg F ,Moldenhauer G ,Hammerling GJ ,Moller P . Immunohistochemical study of the expression of a Mr 34,000 human epithelium-specific surface glycoprotein in normal and malignant tissues. Cancer Res 1987;47:2883-2891
Web of Science | Medline20
Pantel K ,Schlimok G ,Angstwurm M , et al. Methodological analysis of immunocytochemical screening for disseminated epithelial tumor cells in bone marrow. J Hematother 1994;3:165-173
CrossRef | Medline21
Kasper M ,Stosiek P ,Typlt H ,Karsten U . Histological evaluation of three new monoclonal anti-cytokeratin antibodies. 1. Normal tissues. Eur J Cancer Clin Oncol 1987;23:137-147
CrossRef | Medline22
Vogel SB ,Mendenhall WM ,Sombeck MD ,Marsh R ,Woodward ER . Downstaging of esophageal cancer after preoperative radiation and chemotherapy. Ann Surg 1995;221:685-693
CrossRef | Web of Science | Medline23
Lerut TE ,de Leyn P ,Coosemans W ,Van Raemdonck D ,Cuypers P ,Van Cleynenbreughel B . Advanced esophageal carcinoma. World J Surg 1994;18:379-387
CrossRef | Web of Science | Medline24
Jauch KW ,Bacha EA ,Denecke H ,Anthuber M ,Schildberg FW . Esophageal carcinoma: prognostic features and comparison between blunt transhiatal dissection and transthoracic resection. Eur J Surg Oncol 1992;18:553-562
Medline25
Cox DR . Regression models and life-tables. J R Stat Soc [B] 1972;34:187-22026
Schemper M, Smith TL. A note on quantifying follow-up studies of failure time. Control Clin Trials 1996;17:343-6.
27
Millikan KW ,Silverstein J ,Hart V , et al. A 15-year review of esophagectomy for carcinoma of the esophagus and cardia. Arch Surg 1995;130:617-624
Web of Science | Medline28
Daly JM ,Karnell LH ,Menck HR . National Cancer Data Base report on esophageal carcinoma. Cancer 1996;78:1820-1828
CrossRef | Web of Science | Medline29
Blot WJ ,Devesa SS ,Kneller RW ,Fraumeni JF Jr . Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 1991;265:1287-1289
CrossRef | Web of Science | Medline30
Chen MYM ,Ott DJ ,Gelfand DW . More evidence for the increasing prevalence of adenocarcinoma of the esophagus over an 18-year period. J Clin Gastroenterol 1995;21:254-255
CrossRef | Web of Science | Medline31
Paget S . The distribution of secondary growths in cancer of the breast. Lancet 1889;1:571-573
CrossRef32
International (Ludwig) Breast Cancer Study Group
Web of Science | Medline33
O'Sullivan GC ,Collins JK ,O'Brien F , et al. Micrometastases in bone marrow of patients undergoing “curative“ surgery for gastrointestinal cancer. Gastroenterology 1995;109:1535-1540
CrossRef | Web of Science | Medline34
Thorban S ,Roder JD ,Nekarda H ,Funk A ,Siewert JR ,Pantel K . Immunocytochemical detection of disseminated tumor cells in the bone marrow of patients with esophageal carcinoma. J Natl Cancer Inst 1996;88:1222-1227
CrossRef | Web of Science | Medline
- Citing Articles (137)
Citing Articles
1
K.L. Prenzel, A.H. Hölscher, U. Drebber, M. Agavonova, C.A. Gutschow, E. Bollschweiler. (2012) Prognostic impact of nodal micrometastasis in early esophageal cancer. European Journal of Surgical Oncology (EJSO)
CrossRef2
Matthias Reeh, Michael F. Nentwich, Katharina von Loga, Julia Schade, Faik G. Uzunoglu, Alexandra M. Koenig, Maximilian Bockhorn, Thomas Rosch, Jakob R. Izbicki, Dean Bogoevski. (2012) An Attempt at Validation of the Seventh Edition of the Classification by the International Union Against Cancer for Esophageal Carcinoma. The Annals of Thoracic Surgery
CrossRef3
C. Mariette, G. Piessen. (2012) Oesophageal cancer: How radical should surgery be?. European Journal of Surgical Oncology (EJSO)
CrossRef4
Masaki Hata, Junji Machi, Jonathan Mamou, Eugene T. Yanagihara, Emi Saegusa-Beecroft, Gregory K. Kobayashi, Clifford C. M. Wong, Conway Fung, Ernest J. Feleppa, Kazuhiro Sakamoto. (2011) Entire-volume Serial Histological Examination for Detection of Micrometastases in Lymph Nodes of Colorectal Cancers. Pathology & Oncology Research 17:4, 835-841
CrossRef5
Yanan Xu, Mengjia Fei, Jiadong Wang, Luying Zheng, Yiming Chen, Qiang Liu. (2011) Clinical significance of micrometastases in lymph nodes from laryngeal squamous cell carcinoma. American Journal of Otolaryngology
CrossRef6
B. Kayani, E. Zacharakis, K. Ahmed, G.B. Hanna. (2011) Lymph node metastases and prognosis in oesophageal carcinoma – A systematic review. European Journal of Surgical Oncology (EJSO) 37:9, 747-753
CrossRef7
Vivi Andasari, Alf Gerisch, Georgios Lolas, Andrew P. South, Mark A. J. Chaplain. (2011) Mathematical modeling of cancer cell invasion of tissue: biological insight from mathematical analysis and computational simulation. Journal of Mathematical Biology 63:1, 141-171
CrossRef8
Ines Gockel, George Sgourakis, Orestis Lyros, Ursula Polotzek, Carl Christoph Schimanski, Hauke Lang, Toshitaka Hoppo, Blair A Jobe. (2011) Risk of lymph node metastasis in submucosal esophageal cancer: a review of surgically resected patients. Expert Review of Gastroenterology & Hepatology 5:3, 371-384
CrossRef9
Sarah K. Thompson, Dylan Bartholomeusz, Peter G. Devitt, Peter J. Lamb, Andrew R. Ruszkiewicz, Glyn G. Jamieson. (2011) Feasibility study of sentinel lymph node biopsy in esophageal cancer with conservative lymphadenectomy. Surgical Endoscopy 25:3, 817-825
CrossRef10
Goran Marjanovic, Markus Schricker, Axel Walch, Axel zur Hausen, Ulrich T. Hopt, Andreas Imdahl, Frank Makowiec. (2011) Detection of Lymph Node Involvement by Cytokeratin Immunohistochemistry is an Independent Prognostic Factor After Curative Resection of Esophageal Cancer. Journal of Gastrointestinal Surgery 15:1, 29-37
CrossRef11
Brechtje A. Grotenhuis, Mark van Heijl, Bas P. L. Wijnhoven, Mark I. van Berge Henegouwen, Katharina Biermann, Fiebo J. W. ten Kate, Olivier R. C. Busch, Winand N. M. Dinjens, Hugo W. Tilanus, J. Jan B. van Lanschot. (2010) Lymphatic micrometastases in patients with early esophageal adenocarcinoma. Journal of Surgical Oncology 102:7, 863-867
CrossRef12
Takeo Fukagawa, Mitsuru Sasako, Seiji Ito, Hayao Nakanishi, Hisae Iinuma, Shoji Natsugoe, Hitoshi Katai, Tadakazu Shimoda. (2010) The prognostic significance of isolated tumor cells in the lymph nodes of gastric cancer patients. Gastric Cancer 13:3, 191-196
CrossRef13
Sarah K. Thompson, Andrew R. Ruszkiewicz, Glyn G. Jamieson, Thomas R. Sullivan, Peter G. Devitt. (2010) Isolated Tumor Cells in Esophageal Cancer. Annals of Surgery 252:2, 299-306
CrossRef14
X. Zhang, S.-B. Chen, J.-X. Chen, J. Wen, H. Yang, M.-R. Xie, Y. Zhang, Y.-Z. Hu, P. Lin. (2010) CK19 mRNA expression in the bone marrow of patients with esophageal squamous cell carcinoma and its clinical significance. Diseases of the Esophagus
CrossRef15
Zhi-Yong Wu, Jun-Cai Yu, Li-Yan Xu, Jin-Hui Shen, Jian-Zhong Wu, Shao-Hong Wang, Jun-Hui Fu, Yang-Hang Fan, Bin-Na Yang, Zhong-Ying Shen, Qiao Huang, En-Min Li. (2010) Prognostic significance of perigastric lymph nodes metastases on survival in patients with thoracic esophageal cancer. Diseases of the Esophagus 23:1, 40-45
CrossRef16
M. Micev, M. Cosic-Micev. (2010) Pathology and pathobiology of the oesophageal carcinoma. Acta chirurgica iugoslavica 57:2, 15-26
CrossRef17
Jin-Cheng Lu, Hua Tao, Zhen-Zhang Chen, Pu-Dong Qian. (2009) Prognostic factors of radiotherapy in patients with node-positive thoracic esophageal squamous cell carcinoma after radical surgery. Diseases of the Esophagus 22:6, 490-495
CrossRef18
Brechtje A. Grotenhuis, Bas P.L. Wijnhoven, Ronald van Marion, Herman van Dekken, Wim C. Hop, Hugo W. Tilanus, J. Jan B. van Lanschot, Casper H.J. van Eijck. (2009) The sentinel node concept in adenocarcinomas of the distal esophagus and gastroesophageal junction. The Journal of Thoracic and Cardiovascular Surgery 138:3, 608-612
CrossRef19
Glyn G. Jamieson, Peter J. Lamb, Sarah K. Thompson. (2009) The Role of Lymphadenectomy in Esophageal Cancer. Annals of Surgery 250:2, 206-209
CrossRef20
Klaus Pantel, Catherine Alix-Panabières, Sabine Riethdorf. (2009) Cancer micrometastases. Nature Reviews Clinical Oncology 6:6, 339-351
CrossRef21
U. Zingg, M. Montani, M. Busch, U. Metzger, P. Went, D. Oertli. (2009) Prognostic influence of immunohistochemically detected lymph node micrometastasis and histological subtype in pN0 oesophageal cancer. European Journal of Surgical Oncology (EJSO) 35:6, 593-599
CrossRef22
Alexandra M. Koenig, Klaus L. Prenzel, Dean Bogoevski, Emre F. Yekebas, Michael Bubenheim, Lucia Faithova, Yogesh K. Vashist, Karim A. Gawad, Stephan E. Baldus, Klaus Pantel, Paul M. Schneider, Arnulf H. Hölscher, Jakob R. Izbicki. (2009) Strong Impact of Micrometastatic Tumor Cell Load in Patients with Esophageal Carcinoma. Annals of Surgical Oncology 16:2, 454-462
CrossRef23
Peter Scheunemann, Nikolas H. Stoecklein, Kai Hermann, Alexander Rehders, Claus F. Eisenberger, Wolfram T. Knoefel, Stefan B. Hosch. (2009) Occult disseminated tumor cells in lymph nodes of patients with gastric carcinoma. A critical appraisal of assessment and relevance. Langenbeck's Archives of Surgery 394:1, 105-113
CrossRef24
G. G. Jamieson, S. K. Thompson. (2009) Detection of lymph node metastases in oesophageal cancer. British Journal of Surgery 96:1, 21-25
CrossRef25
Ljiljana Radosevic-Jelic, V. Stankovic, T. Josifovski, V. Nikolic, I. Popov, P. Pesko. (2009) Preoperative chemoradiotherapy in locally advanced esophageal cancer. Acta chirurgica iugoslavica 56:4, 83-89
CrossRef26
Dean Bogoevski, Hassan Chayeb, Guell Cataldegirmen, Paulus G. Schurr, Jussuf T. Kaifi, Oliver Mann, Emre F. Yekebas, Jakob R. Izbicki. (2008) Nodal Microinvolvement in Patients with Carcinoma of the Papilla of Vater Receiving No Adjuvant Chemotherapy. Journal of Gastrointestinal Surgery 12:11, 1830-1838
CrossRef27
D. Bogoevski, T. Strate, E. F. Yekebas, J. R. Izbicki. (2008) Pancreatic cancer: a generalized disease—prognostic impact of cancer cell dissemination. Langenbeck's Archives of Surgery 393:6, 911-917
CrossRef28
Andreas-Claudius Hoffmann, Ryutaro Mori, Daniel Vallbohmer, Jan Brabender, Uta Drebber, Stephan E. Baldus, Ellen Klein, Mizutomo Azuma, Ralf Metzger, Christina Hoffmann, Arnulf H. Hoelscher, Kathleen D. Danenberg, Klaus L. Prenzel, Peter V. Danenberg. (2008) High Expression of Heparanase is Significantly Associated with Dedifferentiation and Lymph Node Metastasis in Patients with Pancreatic Ductal Adenocarcinomas and Correlated to PDGFA and Via HIF1a to HB-EGF and bFGF. Journal of Gastrointestinal Surgery 12:10, 1674-1682
CrossRef29
J.-C. Lu, H. Tao, Y.-Q. Zhang, W.-W. Zha, P.-D. Qian, F. Li, K.-X. Xu. (2008) Extent of prophylactic postoperative radiotherapy after radical surgery of thoracic esophageal squamous cell carcinoma. Diseases of the Esophagus 21:6, 502-507
CrossRef30
C. J. Buskens, F. J. W. Ten Kate, H. Obertop, J. R. Izbicki, J. J. B. van Lanschot. (2008) Analysis of micrometastatic disease in histologically negative lymph nodes of patients with adenocarcinoma of the distal esophagus or gastric cardia. Diseases of the Esophagus 21:6, 488-495
CrossRef31
Y DELPECH, C COUTANT, E DARAI, E BARRANGER. (2008) Sentinel lymph node evaluation in endometrial cancer and the importance of micrometastases. Surgical Oncology 17:3, 237-245
CrossRef32
D. M. Schewe, J. A. Aguirre-Ghiso. (2008) ATF6 -Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo. Proceedings of the National Academy of Sciences 105:30, 10519-10524
CrossRef33
Q. Liu, B. Liu, X. Song, Q. Zhao. (2008) Deficient expression of human leukocyte antigen class I antigen-processing machinery components in human esophageal squamous cell carcinoma�THIS ARTICLE HAS BEEN RETRACTED. Diseases of the Esophagus
CrossRef34
HEIKE ALLGAYER, JULIO A. AGUIRRE-GHISO. (2008) The urokinase receptor (u-PAR)-a link between tumor cell dormancy and minimal residual disease in bone marrow? . APMIS 116:7-8, 602-614
CrossRef35
Peter Scheunemann, Nikolas H. Stoecklein, Alexander Rehders, Minu Bidde, Sylvia Metz, Matthias Peiper, Claus F. Eisenberger, Jan Schulte am Esch, Wolfram T. Knoefel, Stefan B. Hosch. (2008) Occult tumor cells in lymph nodes as a predictor for tumor relapse in pancreatic adenocarcinoma. Langenbeck's Archives of Surgery 393:3, 359-365
CrossRef36
Nikolas H. Stoecklein, Stefan B. Hosch, Martin Bezler, Franziska Stern, Claudia H. Hartmann, Christian Vay, Annika Siegmund, Peter Scheunemann, Paulus Schurr, Wolfram T. Knoefel, Pablo E. Verde, Uta Reichelt, Andreas Erbersdobler, Roger Grau, Axel Ullrich, Jakob R. Izbicki, Christoph A. Klein. (2008) Direct Genetic Analysis of Single Disseminated Cancer Cells for Prediction of Outcome and Therapy Selection in Esophageal Cancer. Cancer Cell 13:5, 441-453
CrossRef37
Dean Bogoevski, Florian Onken, Alexandra Koenig, Jussuf T. Kaifi, Paulus Schurr, Guido Sauter, Jakob R. Izbicki, Emre F. Yekebas. (2008) Is It Time for a New TNM Classification in Esophageal Carcinoma?. Annals of Surgery 247:4, 633-641
CrossRef38
Christian G. Peyre, Jeffrey A. Hagen, Steven R. DeMeester, Nasser K. Altorki, Ermanno Ancona, S Michael Griffin, Arnulf Hölscher, Toni Lerut, Simon Law, Thomas W. Rice, Alberto Ruol, Jan J.B. van Lanschot, John Wong, Tom R. DeMeester. (2008) The Number of Lymph Nodes Removed Predicts Survival in Esophageal Cancer: An International Study on the Impact of Extent of Surgical Resection. Transactions of the ... Meeting of the American Surgical Association 126, 190-197
CrossRef39
Zimin Qin, Bing Li, Wenguang Wang. (2007) Effect of immune function on lymph node micrometastasis in esophageal cancer patients. The Chinese-German Journal of Clinical Oncology 6:6, 546-548
CrossRef40
C. Milsmann, L. Füzesi, E. Heinmöller, P. Krause, C. Werner, H. Becker, O. Horstmann. (2007) Morphological and immunohistochemical characterization of isolated tumor cells by p53 status in gastrointestinal tumors. Langenbeck's Archives of Surgery 393:1, 49-58
CrossRef41
Jussuf T Kaifi, Uta Reichelt, Alexander Quaas, Paulus G Schurr, Robin Wachowiak, Emre F Yekebas, Tim Strate, Claus Schneider, Klaus Pantel, Melitta Schachner, Guido Sauter, Jakob R Izbicki. (2007) L1 is associated with micrometastatic spread and poor outcome in colorectal cancer. Modern Pathology 20:11, 1183-1190
CrossRef42
Hiroyuki Saito, Tatsuo Sato, Masaru Miyazaki. (2007) Extramural lymphatic drainage from the thoracic esophagus based on minute cadaveric dissections: fundamentals for the sentinel node navigation surgery for the thoracic esophageal cancers. Surgical and Radiologic Anatomy 29:7, 531-542
CrossRef43
M. Schenck, F. Dorp, C. Boergermann, Y. Busch, A. Carpinteiro, B. Wilker, S. Keitsch, K.W. Schmid, M. Groneberg, M. Stuschke, H. Ruebben, E. Gulbins. (2007) Gründung einer Arbeitsgruppe „Lymphknotenmetastasierung“ am Westdeutschen Tumorzentrum (WTZE), Universitätsklinikum Essen. Der Urologe 46:9, 1257-1260
CrossRef44
J. Wind, S.M. Lagarde, F.J.W. ten Kate, D.T. Ubbink, W.A. Bemelman, J.J.B. van Lanschot. (2007) A systematic review on the significance of extracapsular lymph node involvement in gastrointestinal malignancies. European Journal of Surgical Oncology (EJSO) 33:4, 401-408
CrossRef45
Koshi Mimori, Yoshimasa Kosaka, Shigeo Hirasaki, Yoshiaki Kita, Noriyuki Moriyama, Masaki Mori. (2007) Disseminated isolated tumor cells in bone marrow of esophageal cancer cases. Esophagus 4:1, 29-33
CrossRef46
Yutaka Shimada, Fumiaki Sato. (2007) Molecular factors related to metastasis of esophageal squamous cell carcinoma. Esophagus 4:1, 7-18
CrossRef47
Shoji Natsugoe, Masaki Mori. (2007) Isolated tumor cells in esophageal cancer. Esophagus 4:1, 1-5
CrossRef48
Alexander Rehders, Stefan Benedikt Hosch, Nikolaus H. Stoecklein, Peter Scheunemann, Matthias Peiper, Wolfram Trudo Knoefel. (2007) Metastatic Phenotype of Disseminated Nodal Tumor Cells in Esophageal Cancer. Polish Journal of Surgery 79:3, 173-181
CrossRef49
Klaus L. Prenzel, Alexandra König, Paul M. Schneider, Christian Schnickmann, Stephan E. Baldus, Wolfgang Schröder, Elfriede Bollschweiler, Hans P. Dienes, Rolf P. Mueller, Jakob R. Izbicki, Arnulf H. Hölscher. (2007) Reduced Incidence of Nodal Micrometastasis after Major Response to Neoadjuvant Chemoradiation in Locally Advanced Esophageal Cancer. Annals of Surgical Oncology 14:2, 954-959
CrossRef50
Paulus G. Schurr, Sophia Behnke, Jussuf T. Kaifi, Dean Bogoevski, Bjoern Link, Oliver Mann, Tim Strate, Klaus Pantel, Jakob R. Izbicki, Emre Yekebas. (2007) Central Mesenteric Lymph Node BER-Ep4+ Cells in Colorectal Cancer: Challenge to Sentinel Node Concept?. Digestive Surgery 24:1, 19-27
CrossRef51
S. Natsugoe, H. Okumura, M. Matsumoto, Y. Uchikado, T. Setoyama, N. Yokomakura, S. Ishigami, T. Owaki, T. Aikou. (2006) Randomized controlled study on preoperative chemoradiotherapy followed by surgery versus surgery alone for esophageal squamous cell cancer in a single institution. Diseases of the Esophagus 19:6, 468-472
CrossRef52
S. Gretschel, A. Bembenek, T. Schulze, W. Kemmner, P. M. Schlag. (2006) Minimalresiduale Tumorerkrankung bei gastrointestinalen Karzinomen. Der Chirurg 77:12, 1104-1117
CrossRef53
Paulus G. Schurr, Emre F. Yekebas, Jussuf T. Kaifi, Steffi Lasch, Tim Strate, Asad Kutup, Guel Cataldegirmen, Michael Bubenheim, Klaus Pantel, Jakob R. Izbicki. (2006) Lymphatic spread and microinvolvement in adenocarcinoma of the esophago-gastric junction. Journal of Surgical Oncology 94:4, 307-315
CrossRef54
Hideaki Shimada, Shin-ichi Okazumi, Hisahiro Matsubara, Yoshihiro Nabeya, Tooru Shiratori, Kiyohiko Shuto, Takanori Shimizu, Yasunori Akutsu, Yutaka Tanizawa, Hideki Hayashi, Takenori Ochiai. (2006) Location and clinical impact of solitary lymph node metastasis in patients with thoracic esophageal carcinoma. The American Journal of Surgery 192:3, 306-310
CrossRef55
Shoji Natsugoe, Hiroshi Okumura, Masataka Matsumoto, Yasuto Uchikado, Tetsuro Setoyama, Naoya Yokomakura, Yoshikazu Uenosono, Sumiya Ishigami, Tetsuhiro Owaki, Takashi Aikou. (2006) Individualization of lymphadenectomy in superficial esophageal squamous cell cancer. Esophagus 3:2, 41-45
CrossRef56
Eiji Sasaki, Masato Nagino, Tomoki Ebata, Koji Oda, Toshiyuki Arai, Hideki Nishio, Yuji Nimura. (2006) Immunohistochemically Demonstrated Lymph Node Micrometastasis and Prognosis in Patients With Gallbladder Carcinoma. Annals of Surgery 244:1, 99-105
CrossRef57
Eiko Sakata, Yoshio Shirai, Naoyuki Yokoyama, Toshifumi Wakai, Jun Sakata, Katsuyoshi Hatakeyama. (2006) Clinical Significance of Lymph Node Micrometastasis in Ampullary Carcinoma. World Journal of Surgery 30:6, 985-991
CrossRef58
Emre F. Yekebas, Paulus G. Schurr, Jussuf T. Kaifi, Bjoern C. Link, Asad Kutup, Oliver Mann, Lars Wolfram, Jakob R. Izbicki. (2006) Effectiveness of radical en-bloc-esophagectomy compared to transhiatal esophagectomy in squamous cell cancer of the esophagus is influenced by nodal micrometastases. Journal of Surgical Oncology 93:7, 541-549
CrossRef59
Hiroshi Miyata, Masahiko Yano, Yuichiro Doki, Takushi Yasuda, Setsuko Yoshioka, Yurika Sugita, Shuji Takiguchi, Yoshiyuki Fujiwara, Morito Monden. (2006) A prospective trial for avoiding cervical lymph node dissection for thoracic esophageal cancers, based on intra-operative genetic diagnosis of micrometastasis in recurrent laryngeal nerve chain nodes. Journal of Surgical Oncology 93:6, 477-484
CrossRef60
Stefan Thorban, Robert Rosenberg, Matthias Maak, Jan Friederichs, Ralf Gertler, Jörg-Rüdiger Siewert. (2006) Impact of disseminated tumor cells in gastrointestinal cancer. Expert Review of Molecular Diagnostics 6:3, 333-343
CrossRef61
L Tao, M Lefèvre, S Ricci, P Saintigny, P Callard, S Périé, R Lacave, J-F Bernaudin, J Lacau St Guily. (2006) Detection of occult carcinomatous diffusion in lymph nodes from head and neck squamous cell carcinoma using real-time RT–PCR detection of cytokeratin 19 mRNA. British Journal of Cancer 94:8, 1164-1169
CrossRef62
K. Taniguchi, M. Tabata, T. Iida, T. Hori, S. Yagi, S. Uemoto. (2006) Significance of lymph node micrometastasis in pN0 hilar bile duct carcinoma. European Journal of Surgical Oncology (EJSO) 32:2, 208-212
CrossRef63
M. Al-Haddad, M. B. Wallace. (2006) Molecular diagnostics of non-small cell lung cancer using mediastinal lymph nodes sampled by endoscopic ultrasound-guided needle aspiration. Cytopathology 17:1, 3-9
CrossRef64
J. T. Kaifi, E. F. Yekebas, P. Schurr, D. Obonyo, R. Wachowiak, P. Busch, A. Heinecke, K. Pantel, J. R. Izbicki. (2005) Tumor-Cell Homing to Lymph Nodes and Bone Marrow and CXCR4 Expression in Esophageal Cancer. JNCI Journal of the National Cancer Institute 97:24, 1840-1847
CrossRef65
C. Milsmann, L. Füzesi, C. Werner, H. Becker, O. Horstmann. (2005) Okkulte lymphatische Tumorzelldisseminierung beim Pankreaskarzinom. Der Chirurg 76:11, 1064-1072
CrossRef66
Dianne Pulte, Eric Li, Bernard K. Crawford, Elliot Newman, Alice Alexander, David C. Mustalish, Daniel R. Jacobson. (2005) Sentinel lymph node mapping and molecular staging in nonsmall cell lung carcinoma. Cancer 104:7, 1453-1461
CrossRef67
Yutaka Yamazaki, Itsuo Chiba, Atsuko Hirai, Chiharu Satoh, Noriyuki Sakakibara, Ken-ichi Notani, Tadashi Iizuka, Yasunori Totsuka. (2005) Clinical value of genetically diagnosed lymph node micrometastasis for patients with oral squamous cell carcinoma. Head & Neck 27:8, 676-681
CrossRef68
M. Schenck, G. Lümmen, M. Stuschke, K. W. Schmid, H. Rübben. (2005) Prinzipielle Probleme der Lymphknotenchirurgie. Der Urologe, Ausgabe A 44:6, 605-607
CrossRef69
Jan Friederichs, Ralf Gertler, Robert Rosenberg, Jörg Nahrig, Katrin Führer, Bernhard Holzmann, Hans-Joachim Dittler, Michael Dahm, Stefan Thorban, Hjalmar Nekarda, Jörg Rüdiger Siewer. (2005) Prognostic Impact of CK-20-positive Cells in Peripheral Venous Blood of Patients with Gastrointestinal Carcinoma. World Journal of Surgery 29:4, 422-428
CrossRef70
P.A.M. Heeren, W. Kelder, I. Blondeel, H.L. van Westreenen, H. Hollema, J.Th. Plukker. (2005) Prognostic value of nodal micrometastases in patients with cancer of the gastro-oesophageal junction. European Journal of Surgical Oncology (EJSO) 31:3, 270-276
CrossRef71
Shoji Natsugoe, Masataka Matsumoto, Hiroshi Okumura, Saburo Nakashima, Hiroshi Higashi, Yoshikazu Uenosono, Katsuhiko Ehi, Sumiya Ishigami, Sonshin Takao, Takashi Aikou. (2005) Initial metastatic, including micrometastatic, sites of lymph nodes in esophageal squamous cell carcinoma. Journal of Surgical Oncology 89:1, 6-11
CrossRef72
B. M. K
nzli, H. Friess, J. Kleeff, E. Yekebas, O. Mann, J. R. Izbicki, M. W. B
CrossRef73
Dean Bogoevski, Emre F. Yekebas, Paulus Schurr, Jussuf T. Kaifi, Asad Kutup, Andreas Erbersdobler, Klaus Pantel, Jakob R. Izbicki. (2004) Mode of Spread in the Early Phase of Lymphatic Metastasis in Pancreatic Ductal Adenocarcinoma. Annals of Surgery 240:6, 993-1001
CrossRef74
Olaf Horstmann, Laszlo F
CrossRef75
Yoshio Ishibashi, Tomoe Matsumoto, Mikio Niwa, Yutaka Suzuki, Nobuo Omura, Nobuyoshi Hanyu, Koji Nakada, Katsuhiko Yanaga, Kyosuke Yamada, Kiyoshi Ohkawa, Makio Kawakami, Mitsuyoshi Urashima. (2004) CD147 and matrix metalloproteinase-2 protein expression as significant prognostic factors in esophageal squamous cell carcinoma. Cancer 101:9, 1994-2000
CrossRef76
Tara A. Waterman, Jeffrey A. Hagen, Jeffrey H. Peters, Steven R. DeMeester, Clive R. Taylor, Tom R. DeMeester. (2004) The Prognostic Importance of Immunohistochemically Detected Node Metastases in Resected Esophageal Adenocarcinoma. The Annals of Thoracic Surgery 78:4, 1161-1169
CrossRef77
Jesus Gonzalez Bosquet, Gary L Keeney, Andrea Mariani, Maurice J Webb, William A Cliby. (2003) Cytokeratin staining of resected lymph nodes may improve the sensitivity of surgical staging for endometrial cancer
. Gynecologic Oncology 91:3, 518-525
CrossRef78
T Lerut, W Coosemans, G Decker, P De Leyn, N Ectors, S Fieuws, J Moons, P Nafteux, D Van Raemdonck. (2003) Extracapsular lymph node involvement is a negative prognostic factor in T3 adenocarcinoma of the distal esophagus and gastroesophageal junction. The Journal of Thoracic and Cardiovascular Surgery 126:4, 1121-1127
CrossRef79
Steven R. DeMeester. (2003) Lymph node involvement in esophageal adenocarcinoma: if you see one, have you seen them all?. The Journal of Thoracic and Cardiovascular Surgery 126:4, 947-949
CrossRef80
Y. Shimada, F. Sato, M. Maeda, G. Watanabe, S. Nagatani, J. Kaganoi, Y. Hashimoto, T. Kan, Z. Li, M. Imamura. (2003) Validity of intraoperative pathological diagnosis of paratracheal lymph node as a strategy for selection of patients for cervical lymph node dissection during esophagectomy. Diseases of the Esophagus 16:3, 246-251
CrossRef81
Peter C Wu, Mitchell C Posner. (2003) The role of surgery in the management of oesophageal cancer. The Lancet Oncology 4:8, 481-488
CrossRef82
Robert Macadam, Abeezar Sarela, Jonathan Wilson, Kenneth MacLennan, Pierre Guillou. (2003) Bone marrow micrometastases predict early post-operative recurrence following surgical resection of oesophageal and gastric carcinoma. European Journal of Surgical Oncology (EJSO) 29:5, 450-454
CrossRef83
M. Matsumoto, S. Natsugoe, S. Ishigami, Y. Uenosono, S. Takao, T. Aikou. (2003) Rapid immunohistochemical detection of lymph node micrometastasis during operation for upper gastrointestinal carcinoma. British Journal of Surgery 90:5, 563-566
CrossRef84
Tadashi Tanabe, Tadashi Nishimaki, Hidenobu Watanabe, Yoichi Ajioka, Kohei Akazawa, Shintaro Komukai, Katsuyoshi Hatakeyama. (2003) Immunohistochemically detected micrometastasis in lymph nodes from superficial esophageal squamous cell carcinoma. Journal of Surgical Oncology 82:3, 153-159
CrossRef85
Yuichiro Tojima, Masato Nagino, Tomoki Ebata, Katsuhiko Uesaka, Junichi Kamiya, Yuji Nimura. (2003) Immunohistochemically Demonstrated Lymph Node Micrometastasis and Prognosis in Patients With Otherwise Node-Negative Hilar Cholangiocarcinoma. Annals of Surgery 237:2, 201-207
CrossRef86
Xiao-wei Xiao. (2002) Relationship between lymph node metastases in esophageal carcinoma and its prognosis. Chinese Journal of Cancer Research 14:4, 297-301
CrossRef87
Yoichi Tabira, Masahiro Yasunaga, Tomonori Sakaguchi, Yuji Yamaguchi, Toshiyuki Okuma, Michio Kawasuji. (2002) Outcome of histologically node-negative esophageal squamous cell carcinoma. World Journal of Surgery 26:12, 1446-1451
CrossRef88
Y. Tsuchiya, M. Onda, K. Sasajima, K. Yamashita, T. Nomura, H. Makino, H. Maruyama, N. Hagiwara, K. Takubo, M. Miyashita. (2002) Effects of preoperative chemotherapy on metastatic lymph nodes in esophageal squamous cell carcinoma. Diseases of the Esophagus 15:3, 226-231
CrossRef89
W. Schröder, S. P. Mönig, S. E. Baldus, C. Gutschow, P. M. Schneider, A. H. Hölscher. (2002) Frequency of nodal metastases to the upper mediastinum in Barrett's cancer. Annals of Surgical Oncology 9:8, 807-811
CrossRef90
Shoji Natsugoe, Saburo Nakashima, Masataka Matsumoto, Hironori Sakita, Fuminori Sakamoto, Hiroshi Okumura, Masamichi Baba, Heiji Yoshinaka, Sonshin Takao, Takashi Aikou. (2002) Biologic and imaging diagnosis of lymph node metastasis in esophageal carcinoma. Journal of Surgical Oncology 81:1, 25-32
CrossRef91
Christoph A Klein, Thomas JF Blankenstein, Oleg Schmidt-Kittler, Marco Petronio, Bernhard Polzer, Nikolas H Stoecklein, Gert Riethmüller. (2002) Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. The Lancet 360:9334, 683-689
CrossRef92
Yutaka Shimada, Masayuki Imamura, Fumiaki Sato, Masato Maeda, Jun-ichi Kaganoi, Yosuke Hashimoto, Takatsugu Kan, Shiro Nagatani, Zhigang Li. (2002) Indications for abdominal para-aortic lymph node dissection in patients with esophageal squamous cell carcinoma. Surgery 132:1, 93-99
CrossRef93
Xiaolong Jiao, Mark J. Krasna. (2002) Clinical significance of micrometastasis in lung and esophageal cancer: a new paradigm in thoracic oncology. The Annals of Thoracic Surgery 74:1, 278-284
CrossRef94
Christine L Lau, Mary-Beth H Moore, Kelly R Brooks, Thomas A D'Amico, David H Harpole. (2002) Molecular staging of lung and esophageal cancer. Surgical Clinics of North America 82:3, 497-523
CrossRef95
Eungseok Lee, Yangseok Chae, Insun Kim, Jongsang Choi, Bomwoo Yeom, Anthony S.-Y. Leong. (2002) Prognostic relevance of immunohistochemically detected lymph node micrometastasis in patients with gastric carcinoma. Cancer 94:11, 2867-2873
CrossRef96
Tsutomu Nakamura, Hiroko Ide, Reiki Eguchi, Kazuhiko Hayashi, Masaho Ota, Ken Takasaki. (2002) Clinical implications of lymph node micrometastasis in patients with histologically node-negative (pN0) esophageal carcinoma. Journal of Surgical Oncology 79:4, 224-229
CrossRef97
John W.C Entwistle, Melvyn Goldberg. (2002) Multimodality therapy for resectable cancer of the thoracic esophagus. The Annals of Thoracic Surgery 73:3, 1009-1015
CrossRef98
S. Komukai, T. Nishimaki, T. Suzuki, T. Kanda, S. Kuwabara, K. Hatakeyama. (2002) Significance of immunohistochemical nodal micrometastasis as a prognostic indicator in potentially curable oesophageal carcinoma. British Journal of Surgery 89:2, 213-219
CrossRef99
Jakob R Izbicki, Klaus Pantel, Stefan B Hosch. (2002) Micrometastasis in solid epithelial tumors: Impact on surgical oncology. Surgery 131:1, 1-5
CrossRef100
N.T van Heek, M Tascilar, J.L van Beekveld, P Drillenburg, G.J.A Offerhaus, D.J Gouma. (2001) Micrometastases in bone marrow of patients with suspected pancreatic and ampullary cancer. European Journal of Surgical Oncology (EJSO) 27:8, 740-745
CrossRef101
Jeffrey A. Hagen, Tom R. DeMeester. (2001) Esophageal adenocarcinoma. The Annals of Thoracic Surgery 72:4, 1430-1432
CrossRef102
Jean-Marie Collard, Jean-Bernard Otte, René Fiasse, Pierre-François Laterre, Marc De Kock, Jacques Longueville, David Glineur, Renato Romagnoli, Marc Reynaert, Paul-Jacques Kestens. (2001) Skeletonizing En Bloc Esophagectomy for Cancer. Annals of Surgery 234:1, 25-32
CrossRef103
Jeannine Lacroix, Magnus von Knebel Doeberitz. (2001) Technical aspects of minimal residual disease detection in carcinoma patients. Seminars in Surgical Oncology 20:4, 252-264
CrossRef104
Stefan B. Hosch, Peter Scheunemann, Jakob R. Izbicki. (2001) Minimal residual disease in non-small-cell lung cancer. Seminars in Surgical Oncology 20:4, 278-281
CrossRef105
Peter Kienle, Moritz Koch. (2001) Minimal residual disease in gastrointestinal cancer. Seminars in Surgical Oncology 20:4, 282-293
CrossRef106
Stefan B. Hosch, Stephan Braun, Klaus Pantel. (2001) Characterization of disseminated tumor cells. Seminars in Surgical Oncology 20:4, 265-271
CrossRef107
Stephan Braun, Robert Rosenberg, Stefan Thorban, Nadia Harbeck. (2001) Implications of occult metastatic cells for systemic cancer treatment in patients with breast or gastrointestinal cancer. Seminars in Surgical Oncology 20:4, 334-346
CrossRef108
P. Scheuemann, S. B. Hosch, J. R. Izbicki. (2001) Cytokeratins and other sensitive markers for esophageal cancer and metastases*. Diseases of the Esophagus 14:2, 85-90
CrossRef109
S. W. Qubain, S. Natsugoe, M. Matsumoto, S. Nakashima, M. Baba, S. Takao, T. Aikou. (2001) Micrometastases in the cervical lymph nodes in esophageal squamous cell carcinoma. Diseases of the Esophagus 14:2, 143-148
CrossRef110
Jean-Marie Collard. (2001) Exclusive radical surgery for esophageal adenocarcinoma. Cancer 91:6, 1098-1104
CrossRef111
Luigi Bonavina, Davide Soligo, Nadia Quirici, Patrizia Bossolasco, Bruno Cesana, Giorgio Lambertenghi Deliliers, Alberto Peracchia. (2001) Bone marrow—disseminated tumor cells in patients with carcinoma of the esophagus or cardia. Surgery 129:1, 15-22
CrossRef112
Sharon A. Keene, Michael J. Demeure. (2001) The clinical significance of micrometastases and molecular metastases. Surgery 129:1, 1-5
CrossRef113
Tsutomu Nomura, Masahiko Onda, Masao Miyashita, Hiroshi Makino, Hiroshi Maruyama, Shigenao Nagasawa, Ryouhei Futami, Kiyohiko Yamashita, Kaiyo Takubo, Koji Sasajima. (2001) Wide-spread Distribution of Sentinel Lymph nodes in Esophageal Cancer. Journal of Nippon Medical School 68:5, 393-396
CrossRef114
S Natsugoe. (2000) Effect of neoadjuvant chemotherapy for lymph node micrometastasis and tumor cell microinvolvement in the patients with esophageal carcinoma. Cancer Letters 159:2, 119-125
CrossRef115
Giorgio Cortesina, Tiziana Martone, Emanuela Galeazzi, Martina Olivero, Antonella De Stefani, Mario Bussi, Guido Valente, Paolo M. Comoglio, M. Flavia Di Renzo. (2000) Staging of head and neck squamous cell carcinoma using theMET oncogene product as marker of tumor cells in lymph node metastases. International Journal of Cancer 89:3, 286-292
CrossRef116
Hitoshi Shiozaki, Yuichiro Doki, Kensyu Kawanishi, Awad Shamma, Masahiko Yano, Masatoshi Inoue, Morito Monden. (2000) Clinical application of malignancy potential grading as a prognostic factor of human esophageal cancers. Surgery 127:5, 552-561
CrossRef117
Masataka Matsumoto, Shoji Natsugoe, Saburo Nakashima, Fuminori Sakamoto, Hiroshi Okumura, Hironori Sakita, Masamichi Baba, Sonshin Takao, Takashi Aikou. (2000) Clinical significance of lymph node micrometastasis of pN0 esophageal squamous cell carcinoma. Cancer Letters 153:1-2, 189-197
CrossRef118
Carolyn Compton, Cecilia M. Fenoglio-Preiser, Norman Pettigrew, L. Peter Fielding. (2000) American Joint Committee on Cancer prognostic factors consensus conference. Cancer 88:7, 1739-1757
CrossRef119
Andrea Mariani, Maurice J. Webb, Laura Galli, Karl C. Podratz. (2000) Potential Therapeutic Role of Para-aortic Lymphadenectomy in Node-Positive Endometrial Cancer. Gynecologic Oncology 76:3, 348-356
CrossRef120
Lawrence E. Harrison, Jiw K. Choe, Marsha Goldstein, Ara Meridian, Steve H. Kim, Kevin Clarke. (2000) Prognostic significance of immunohistochemical micrometastases in node negative gastric cancer patients. Journal of Surgical Oncology 73:3, 153-157
CrossRef121
Shintaro Komukai, Tadashi Nishimaki, Hidenobu Watanabe, Yoichi Ajioka, Tsutomu Suzuki, Katsuyoshi Hatakeyama. (2000) Significance of immunohistochemically demonstrated micrometastases to lymph nodes in esophageal cancer with histologically negative nodes. Surgery 127:1, 40-46
CrossRef122
Thanos Sioris, Heikki Helin, Ritva. (2000) Immunostaining for Detecting Lymph Node Metastases in Non-small Cell Lung Cancer. Scandinavian Cardiovascular Journal 34:5, 536-540
CrossRef123
Klaus Pantel, Magnus von Knebel Doeberitz. (2000) Detection and clinical relevance of micrometastatic cancer cells. Current Opinion in Oncology 12:1, 95-101
CrossRef124
Paul Hermanek, Robert V. P. Hutter, Leslie H. Sobin, Christian Wittekind. (1999) Classification of isolated tumor cells and micrometastasis. Cancer 86:12, 2668-2673
CrossRef125
Bernward Passlick, Boris Kubuschok, Jakob R Izbicki, Olaf Thetter, Klaus Pantel. (1999) Isolated tumor cells in bone marrow predict reduced survival in node-negative non-small cell lung cancer. The Annals of Thoracic Surgery 68:6, 2053-2058
CrossRef126
RJ Cote, H Fpeterson, B Chaiwun, RD Gelber, A Goldhirsch, M Castiglione-Gertsch, B Gusterson, AM Neville. (1999) Role of immunohistochemical detection of lymph-node metastases in management of breast cancer. The Lancet 354:9182, 896-900
CrossRef127
M KRASNA. (1999) The role of thoracoscopic staging of esophageal cancer patients*1. European Journal of Cardio-Thoracic Surgery 16, S31-S33
CrossRef128
K. Pantel, R. J. Cote, O. Fodstad. (1999) Detection and Clinical Importance of Micrometastatic Disease. JNCI Journal of the National Cancer Institute 91:13, 1113-1124
CrossRef129
Scheunemann, Peter, Izbicki, Jakob Robert, Pantel, Klaus, . (1999) Tumorigenic Potential of Apparently Tumor-Free Lymph Nodes. New England Journal of Medicine 340:21, 1687-1687
Full Text130
Jonathan N. Glickman, Carlos Torres, Helen H. Wang, Jerrold R. Turner, Aliakbar Shahsafaei, William G. Richards, David J. Sugarbaker, Robert D. Odze. (1999) The prognostic significance of lymph node micrometastasis in patients with esophageal carcinoma. Cancer 85:4, 769-778
CrossRef131
Peter L. Fielding. (1999) Invited editorial. Diseases of the Colon & Rectum 42:2, 154-158
CrossRef132
Michael J Demeure, Kara M Doffek, Richard A Komorowski, Philip N Redlich, Yong-ran Zhu, Beth A Erickson, Paul S Ritch, Henry A Pitt, Stuart D Wilson. (1998) Molecular metastases in stage I pancreatic cancer: Improved survival with adjuvant chemoradiation. Surgery 124:4, 663-669
CrossRef133
Shoji Natsugoe, James Mueller, Hubert J. Stein, Marcus Feith, Heinz H
CrossRef134
Liefers, Gerrit-Jan, Cleton-Jansen, Anne-Marie, van de Velde, Cornelis J.H., Hermans, Jo, van Krieken, Johannes H.J.M., Cornelisse, Cees J., Tollenaar, Rob A.E.M., . (1998) Micrometastases and Survival in Stage II Colorectal Cancer. New England Journal of Medicine 339:4, 223-228
Full Text135
L.A. McDonald, D.M. Walker, J.R. Gibbins. (1998) Cervical lymph node involvement in head and neck cancer detectable as expression of a spliced transcript of type II keratin K5. Oral Oncology 34:4, 276-283
CrossRef136
(1998) Cryptic Tumor Cells in Lymph Nodes of Patients with Esophageal Cancer. New England Journal of Medicine 338:8, 550-551
Full Text137
P. Fuentes, P. Thomas, R. Giudicelli. (1998) Place de la cytoponction échoendoscopiquement guidée dans le bilan d’extension ganglionnaire des cancers de l’œsophage. Acta Endoscopica 28:1, 21-26
CrossRef
- Letters
