Ann Thorac Surg 2002;74:278-284
© 2002 The Society of Thoracic Surgeons
Review
Clinical significance of micrometastasis in lung and esophageal cancer: a new paradigm in thoracic oncology
Xiaolong Jiao, MDa*,
Mark J. Krasna, MDa
a Division of Thoracic Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
* Address reprint requests to Dr Jiao, Division of Thoracic Surgery, University of Maryland Medical System, Rm N4E35, 22 S Greene St, Baltimore, MD 21201 USA
e-mail: xjiao{at}smail.umaryland.edu
 |
Abstract
|
|---|
In the past decade, detection of micrometastatic disease in different clinical samples including pleural lavage, lymph node, bone marrow, and blood has become a rapidly growing area of interest in research of non-small cell lung cancer and esophageal cancer. The results of these studies support the concept that, just as in many other solid malignancies, systemic spread may happen at an early stage in non-small cell lung cancer and esophageal cancer. Such systemic spread is often occult (micrometastases) at the time of primary diagnosis, which may have adverse effects on survival. Improved staging can be expected with information on micrometastases, and a subgroup of patients who will benefit most from adjuvant therapy might be identified. Although reliable and standard methods need to be developed before detection of micrometastasis is incorporated in the routine clinical practice, we suggest that it be considered an important correlate in clinical trials in non-small cell lung cancer and esophageal cancer.
|
Introduction
|
|---|
Non-small cell lung cancer (NSCLC) and esophageal cancer (EC) are the most common intrathoracic malignancies treated by thoracic surgeons. Surgical intervention remains the gold standard treatment for locoregional disease. With the recent progress in surgical technique, mortality has been linked increasingly to early metastasis, which is often occult at the time of primary diagnosis. The early detection of such tumor dissemination might be a promising approach to assess recurrence risk and to identify specific patients who would benefit from adjuvant or neoadjuvant treatment. Clinical imaging techniques such as computed tomography, positron emission tomography, magnetic resonance imaging, or ultrasound can detect only lesions larger than approximately 1 g or 1 cm3. Detection of metastatic sites smaller than about 109 tumor cells has been clinically impossible thus far [1]. In the last decade, new immunologic and molecular analytic techniques have been developed to diagnose and characterize these occult disseminated tumor cells. This review summarizes the recent literature on detection of micrometastasis in NSCLC and EC.
|
Definition of micrometastasis
|
|---|
In this review, we have defined "micrometastasis" as a metastasis from a nonhematopoietic malignancy that is not detected with conventional clinicopathologic methods of staging. This has different meanings based on the location involved (pleural cavity, lymph node, blood, and bone marrow) [2]. "Occult pleural dissemination" of tumor cells is defined as tumor cells found by pleural lavage cytology (PLC) during surgical intervention in patients with EC or NSCLC who have no clinical or radiologic evidence of pleural effusion before the operation. "Lymph node micrometastasis" (LNM) refers to a small metastatic lesion (a cluster of five or fewer tumor cells) in a lymph node that is not detected with conventional histologic examination. "Bone marrow micrometastasis" (BMM) is defined as tumor cells detected by cytologic or immunologic technique in a bone marrow aspirate or biopsy in patients with no clinical or radiologic evidence of distant or bone marrow metastasis. "Circulating tumor cells" (CTCs) refers to any detectable circulating tumor cells in peripheral blood.
|
Methods of detecting micrometastasis
|
|---|
Cytology
Cytology is an old but useful tool in the diagnosis of cancer. Peritoneal lavage cytology has been found to be a useful staging procedure during operations for gastric cancer and malignant ovarian neoplasms. In recent years, PLC has been used to identify occult disseminated tumor cells in the chest for NSCLC and EC during surgical intervention.
Immunocytochemistry and immunohistochemistry
Detection of occult epithelial tumor cells in lymph node, bone marrow, and blood relies on methods that distinguish cells with different origins (eg, hematopoietic cells versus epithelial cells), a concept introduced by investigators at the Royal Marsden Hospital and the Ludwig Institute 20 years ago [3]. Currently, most studies that show an association between the success of a cancer patient’s treatment and the presence of occult micrometastases have used immunohistochemistry or immunocytochemical methods to detect extrinsic epithelial tumor cells. These methods are very sensitive and can detect as few as one to two tumor cells in 106 bone marrow mononuclear cells. With enrichment methods, the sensitivity can be increased by at least one order of magnitude [4, 5].
Polymerase chain reaction
More recently, techniques for the identification of nucleic acid-based biomarkers have been developed. Tumor DNA and mRNA can be amplified and detected by polymerase chain reaction (PCR) and reverse transcriptase PCR, respectively. These techniques permit the specific and sensitive detection of as few as 1 to 10 cancer cells in up to 107 normal nucleated cells in bone marrow aspirate or peripheral blood samples, in lymph node biopsies, sputum, urine, and other clinical specimens [1]. The additional advantage of reverse transcriptase PCR is that, because of the extremely labile nature of mRNA in the extracellular environment, its presence in tissue or fluid is strongly indicative of the presence of a tumor [6].
Culture techniques
Another method for detection of micrometastasis is the use of the tumor clonogenic assay. This technique, which was first reported by Salmon and colleagues [7], was developed in an attempt to identify patients with poor prognosis by analyzing tumor colony growth in vitro. This method has been shown to be more effective than routine analysis at identifying tumor contamination of bone marrow specimens from patients with breast carcinoma and lymphoma. It was also used to verify the viability of micrometastasis tumor cells in NSCLC and EC.
|
Sites for detection of micrometastases in EC and NSCLC
|
|---|
Pleural cavity
Like the peritoneal cavity, the pleural cavity is a good place for tumor cell transplant of intrathoracic malignancies. Pleural lavage cytology has been applied to detect occult pleural dissemination in the past. In addition to cytology, the reverse transcriptase PCR technique has been used for detection of peritoneal dissemination of gastric and ovarian cancers, and the technique was proved to be more sensitive [8]. However, there are few reports on the application of such new molecular analysis methods in pleural lavage study.
Lymph node
The presence or absence of metastases to regional lymph nodes is the single most important standard risk factor for patients with most solid tumors when there is no evidence of systemic metastases. However, routine histopathologic examination of lymph nodes will underestimate the prevalence of such metastases; in fact, it has been calculated that a pathologist has only a 1% chance of identifying a small (three-cell diameter) metastatic focus of cancer [9]. The detection of occult metastases in the lymph nodes of patients with node-negative cancer has been shown to be prognostically important in an increasing number of studies on many types of cancer, including NSCLC and EC. These results emphasize the importance of verifying the lymph node status, which may improve tumor staging and may provide additional criteria for administering adjuvant therapy.
Bone marrow
For epithelial tumors, which tend to have skeletal metastases, individual tumor cells are easily detected among bone marrow cells aspirated from the iliac crest. The medullary space of the iliac crest is a site of particularly intensive exchange of cells between blood and the mesenchymal interstitium. Occult tumor cells are even detected in the bone marrow of patients who have cancers that generally do not metastasize to the bone (eg, colon cancer), indicating that the bone marrow is a particularly good site for the detection of occult tumor cells. Some studies have also demonstrated that rib segment resection is superior to iliac crest aspirate for detection of micrometastasis in patients with NSCLC and EC [10, 11]. Not only do these results suggest that the more marrow available for analysis, the greater the probability of finding BMM, but they also indicate that isolated tumor cells may spread preferentially to chest bones rather than to distant bone sites.
Blood
Tumors release a large number of cells into the circulation, only a small proportion of which have metastatic potential. Overall, the risk for relapses rises with increasing numbers of residual tumor cells and their time or persistence. Identification of such cells in the blood may indicate increased risk of future disease recurrence. However, in contrast to lymph node and bone marrow, detection of occult tumor cells in the peripheral blood of patients with early-stage cancer is much more difficult because of the low frequency of these cells. The clinical relevance of CTCs at this time remains questionable [12, 13]. Blood may thus be a suboptimal source for the detection of occult tumor cells despite its obvious ease of sampling. Recent developments in methods of enrichment of tumor cells may improve the utility of this technique [4, 5].
|
Clinical results
|
|---|
Pleural lavage cytology in NSCLC and EC
In recent years, several reports have been published on the prognostic value of PLC in NSCLC patients without a pleural effusion who are undergoing surgical resection [14–21]. The positive rate of PLC for NSCLC varied widely, from 3.7% to 38.6%, a difference that might be attributable to different stages of patients enrolled and different techniques or diagnostic standards used (Table 1).
Although the results of the relationship between positive PLC and clinicopathologic factors such as invasion of the visceral pleura, T stage, N stage, TNM stage, and histologic type remain controversial, most authors have suggested that for surgically treated NSCLC patients, positive PLC might be a prognostic indicator of more aggressive tumor biology, high risk of recurrence, and poorer survival rate [14, 15, 17, 19, 23]. Some authors advocate adding PLC to the TNM staging system for NSCLC in order to stratify patients more accurately [17, 19, 22, 23].
Contrary to the enthusiastic studies on PLC for NSCLC, there are few reports on PLC for EC. The first case report of pleural lavage in EC was published as a letter to the editor in 1974 [24]. The patient was found to have positive pleural lavage incidentally. Natsugoe and colleagues [25] reported their results on PLC in a series of 78 EC patients in 1999; however, they did not find any positive tumor cells in preresection pleural lavage. On the contrary, we found a high positive rate (18.8%) for pleural lavage cytology before resection in a group of 48 EC patients with the squamous cell carcinoma as the dominant histologic type [26]. Its clinical significance, however, remains to be elucidated with further study.
The source of the malignant cells in the pleura is still unclear. There are two ways to explain positive PLC of NSCLC patients: exfoliation and lymphatic spread. Three reports from Japan found an association with pleural invasion, possibly suggesting cell exfoliation [15, 17, 22]. Higashiyama and colleagues [17] and Kondo and colleagues [22] also reported an association between positive cytology and lymphatic permeation as well as vascular involvement, suggesting the existence of lymphatic spread. This was further supported by Buhr and colleagues [19], who performed tissue cultures for lung parenchyma around NSCLC that was initially tumor free and found tumor cells in lymphatic vessels after incubation. Preformed stomas that connect subpleural lymphatics with the pleural space could account for tumor cell dissemination [27, 28]. Exfoliation and lymphatic spread are also two plausible mechanisms to explain the etiology of positive PLC of EC, considering its locally invasive properties and rich lymphatic drainage.
Lymph node micrometastasis in NSCLC and EC
Quite a few studies on LNM in NSCLC and EC have been reported [29–35]. Immunohistochemistry staining of anticytokeratin has been the most common method used (Tables 2 and 3).
Reverse transcriptase PCR has also been used in some studies to detect carcinoma embryonic antigen (CEA) mRNA; p53 and k-ras mutations; and surfactant protein A, B, C, and D genes or mucin (MUC1) mRNA in lymph nodes [30–34]. A novel human lung-specific gene can also be a target for detection micrometastases in lymph nodes in NSCLC [47].
View this table:
[in this window]
[in a new window]
|
Table 2. Detection and Clinical Significance of Lymph Node Micrometastasis (LNM) in Patients With Non-Small Cell Lung Cancer
|
|
In patients with NSCLC whose disease was diagnosed as N0 according to conventional pathologic findings, a wide spectrum in the incidence of nodal microdissemination has been reported (10.4% to 80%). This range is partly attributable to differences in the antibody, type of tissue (fresh tissue versus paraffin-embedded tissue), and technique used. Generally, LNM was found to be a poor prognosticator [29, 36, 38–40], although there remains some controversy [37].
Similar results have also been found in EC patients. Most authors have reported that LNM is associated with higher risk of recurrence and poorer survival [31, 41, 42, 44–46], but Glickman and colleagues [43] did not demonstrate a correlation between LNM and poor survival. The inconsistencies between the different series may be caused by the different methods used to detect LNM, patient selection bias, patients with different histology, and different data analysis methods [48]. An important finding of Pantel’s group from Germany (Hosch and colleagues [49]) is that they established tumor cell lines from an immunohistochemically positive lymph node and demonstrated the tumorigenicity and metastatic potential of the cell lines in immunodeficient mice. Their results provide direct evidence of the malignant potential of micrometastatic cancer cells in lymph node from EC patients.
Bone marrow micrometastasis in NSCLC and EC
Since Sloane and coworkers [50] first reported their results using an immunocytochemical approach for the detection of disseminated carcinoma cells in bone marrow aspirates of breast cancer patients in 1980, a number of studies have been conducted to evaluate the prognostic impact of BMM in a variety of epithelial tumors, including NSCLC and EC. In some studies on breast cancer, colorectal cancer, and gastric cancer, positive BMM status has been identified as an indicator of poor prognosis. Recently, BMM status has gained increasing clinical interest to identify high-risk node-negative patients for conventional adjuvant therapy and to monitor chemotherapeutic response; however, a recent metaanalysis of studies on BMM suggested cautious interpretation of BMM as a prognostic indicator for a variety of tumor types, strengthening the necessity of defining a consensus on methodology and standards for the design of further studies [51].
Studies on NSCLC showed that cytokeratin-positive epithelial tumor cells in bone marrow are present in 40% to 70% of patients with localized NSCLC (Table 4).
Positive BMM is associated with higher risk of earlier recurrence, particularly blood-borne metastases, in most studies [52–54]. Nevertheless, one recent report failed to demonstrate its prognostic value [56]. Passlick and colleagues [55] recently reported their long-term follow-up data of patients with completely resected node-negative NSCLC who had BMM. They found that BMM is an independent prognostic factor for overall survival. The postoperative persistence of BMM or reappearance of BMM in some patients indicates that these are not simply shed cells but rather represent true micrometastasis. They also found that the detection of isolated tumor cells in bone marrow does not predict the occurrence of later bone metastases. This result suggests that BMM might indicate the disseminatory capacity of the individual tumor. Because a considerable part of the tumor cells in bone marrow are nonproliferating cells [57], it is conceivable that bone marrow is a reservoir for these tumor cells and that they may subsequently travel through the blood stream to other, secondary organs where they encounter a more accommodating growth milieu.
There are fewer reports on BMM in EC. Thorban and colleagues [58] found a positive BMM rate of 41.1% in EC patients, and BMM related to higher recurrence and shorter survival. O’Sullivan and coworkers [10] reported that rib biopsy can increase the detection rate above that provided by iliac crest aspiration in EC patients. They also demonstrated the viability and tumorigenicity of the metastatic cells from rib marrow by culture and xenograft.
Circulating tumor cells in NSCLC and EC
Circulating tumor cells in NSCLC are usually detected by amplification of cytokeratin 19, although the specificity of cytokeratin 19 is questionable [59–61]. Carcinoma embryonic antigen mRNA is an alternative marker [62]. Cytokeratin 20 is not a good candidate target because of its low expression in NSCLC [63]. The rate of positive findings varies from 12.5% to 80% depending on the stage of the disease (Table 5).
False-positive rates from 1.6% to 46.2% have also been reported [59–61]. A modified method for blood sample collection may avoid epidermal cell contamination and decrease the false-positive rate [61]. Circulating tumor cells were found to correlate with the TNM stage, tumor burden, and treatment response, as well as distant metastasis [61, 62, 64]. The prognostic value of CTCs remains unknown.
View this table:
[in this window]
[in a new window]
|
Table 5. Detection of Circulating Tumor Cells (CTCs) in Peripheral Blood and Its Clinical Significance in Non-Small Cell Lung Cancer
|
|
Detection of CTCs is also a useful tool for clinical research. Using reverse transcriptase PCR technique to detect CEA mRNA in peripheral blood taken before, during, and after operation, Kurusu and coworkers [65] demonstrated that ligating the pulmonary vein first may lessen intraoperative hematogenous dissemination better than ligating the pulmonary artery first in lung cancer resection. With the same technique, they found that video-assisted lobectomy was associated with a higher risk of seeding tumor cells into the circulation during operation than was open lobectomy [66].
We could find no systematic work on CTCs in EC patients reported to date. Only one study, which was focused on gastric carcinoma, colorectal carcinoma, and breast carcinoma, included eight cases of EC [67]. In this report, 1 EC patient with stage I disease who had positive CEA mRNA developed lung metastasis. The clinical significance of CTCs in EC is unknown.
|
General considerations and future directions
|
|---|
The presence of metastases at the time of diagnosis of a primary tumor is a well-established poor prognostic indicator. The impact of micrometastases on outcome is less clear in most solid tumors. Nevertheless, there is increasing evidence to suggest that, in NSCLC and EC, the presence of LNM and BMM on presentation indicates a more biologically aggressive tumor, as evidenced by the verification of viability of micrometastasis tumor cells and, most important, by increased locoregional and distant recurrence and reduced survival. Pleural lavage cytology can find occult disseminated tumor cells in the pleural cavity for both NSCLC and EC. The findings of PLC might be a poorer prognosticator for patients with NSCLC, whereas its effect on EC is unknown. Studies on CTCs in both lung carcinoma and EC are few, and there are no survival data available so far. The clinical significance of CTCs in NSCLC and EC remains less clear and needs further study. With advances of molecular analysis, the ability to identify, enrich, and characterize true disseminated tumor cells will ideally be improved. A modification of the TNM classification system that includes the detection of micrometastasis has been proposed for evaluation and treatment of patients with NSCLC [68]. However, there are still many problems in the study of micrometastases. Controversial results have been reported, with different rates of detection and different findings regarding the clinical relevance of micrometastasis. False-positive results have also been found in some reports. Thus, standard and reliable detection methods need to be developed to provide true information on tumor dissemination. Although quantitative assays such as immunohistochemistry and PCR have provided some prognostic information, there is still a need for further improvement in assessing the prognostic value of micrometastasis testing. The most recent qualitative tests on micrometastatic tumor cells may provide this additional information. Some preliminary work has been done on the expression of gene products in micrometastatic cells to evaluate the viability and growth potential of these cells and their invasive capacity. Such studies may identify the factors influencing the survival, dormancy, and growth of disseminated tumor cells and help to find new approaches to control metastatic lesions. One question that remains unanswered is whether simultaneous detection of micrometastases at different sites (pleural cavity, lymph node, bone marrow, and blood) in individual patients can provide more accurate staging information. Pilot work needs be done in this field.
In conclusion, the results of current studies suggest that micrometastases may happen at an early stage in NSCLC and EC. These results support the concept that NSCLC and EC are systemic rather than local-regional diseases. Improved staging can be expected with the information of micrometastases, and a subgroup of patients who will benefit most from adjuvant therapy might be identified. Although reliable and standard methods need to be developed before detection of micrometastasis is incorporated into the routine clinical practice, we suggest that it be considered an important correlate in clinical trials in NSCLC and EC.
|
Acknowledgments
|
|---|
The authors thank Dr Stephen J. Meltzer for reviewing the manuscript.
|
References
|
|---|
- Doeberitz M.K., Lacroix J. Nucleic acid based techniques for the detection of rare cancer cells in clinical samples. Cancer Metastasis Rev 1999;18:43-64.[Medline]
- Pelkey T.J., Frierson H.F., Bruns D.E. Molecular and immunological detection of circulating tumor cells and micrometastases from solid tumors. Clin Chem 1996;42:1369-1381.[Abstract/Free Full Text]
- Dearnaley D.P., Sloane J.P., Ormerod M.G., et al. Increased detection of mammary carcinoma cells in marrow smears using antisera to epithelial membrane antigen. Br J Cancer 1981;44:85-90.[Medline]
- Naume B., Borgen E., Beiske K., et al. Immunomagnetic techniques for the enrichment and detection of isolated breast carcinoma cells in bone marrow and peripheral blood. J Hematother 1997;6:103-114.[Medline]
- Racila E., Euhus D., Weiss A.J., et al. Detection and characterization of carcinoma cells in the blood. Proc Natl Acad Sci USA 1998;95:4589-4594.[Abstract/Free Full Text]
- Dorudi S., Kinrade E., Marshall N.C., et al. Genetic detection of lymph node micrometastases in patients with colorectal cancer. Br J Surg 1998;85:98-100.[Medline]
- Salmon S.E., Hamburger A.W., Soehnlen B., Durie B.G.M., Alberts D.S., Moon T.E. Quantitation of differential sensitivity of human-tumor stem cells to anticancer drugs. N Engl J Med 1978;298:1321.[Abstract]
- Nakanishi H., Kodera Y., Yamamura Y., et al. Molecular diagnostic detection of free cancer cells in the peritoneal cavity of patients with gastrointestinal and gynecologic malignancies. Cancer Chemother Pharmacol 1999;43(Suppl):S32-S36.
- Gusterson B., Ott R. Occult axillary lymph-node micrometastases in breast cancer. Lancet 1990;336:434-435.[Medline]
- O’Sullivan G.C., Sheehan D., Clarke A., et al. Micrometastases in esophageogastric cancer: high detection rate in resected rib segments. Gastroenterology 1999;116:543-548.[Medline]
- Mattioli S., D’Ovidio F., Tazzari P., et al. Iliac crest biopsy versus rib segment resection for the detection of bone marrow isolated tumor cells from lung and esophageal cancer. Eur J Cardiothorac Surg 2001;19:576-579.[Abstract/Free Full Text]
- Soeth E., Bogel I., Roder C., et al. Comparative analysis of bone marrow and venous blood isolates from gastrointestinal cancer patients for the detection of disseminated tumor cells using reverse transcription PCR. Cancer Res 1997;57:3106-3110.[Abstract/Free Full Text]
- Wyld D.K., Selby P., Perren T.J., et al. Detection of colorectal cancer cells in peripheral blood by reverse-transcriptase polymerase chain reaction for cytokeratin 20. Int J Cancer 1998;79:288-293.[Medline]
- Kondo H., Naruke T., Tsuchiya R., et al. Pleural lavage cytology immediately after thoracotomy as a prognostic factor for patients with lung cancer. Jpn J Cancer Res 1989;80:233-237.[Medline]
- Okumura M., Ohshima S., Kotake Y., Morino H., Kikui M., Yasumitsu T. Intraoperative pleural lavage cytology in lung cancer patients. Ann Thorac Surg 1991;51:599-605.[Abstract]
- Arnau Obrer A., Canto Armengod A., Martin Diaz E., et al. Prognostic value of positive cytology found in pleural lavage of patients with cancer of the lung: prospective study. Arch Bronconeumol 1996;32:321-326.[Medline]
- Higashiyama M., Doi O., Kodama K., et al. Pleural lavage cytology immediately after thoracotomy and before closure of the thoracic cavity for lung cancer without pleural effusion and dissemination: clinicopathologic and prognostic analysis. Ann Surg Oncol 1997;4:409-415.[Medline]
- Kjellberg S.I., Dresler C.M., Goldberg M. Pleural cytologies in lung cancer without pleural effusions. Ann Thorac Surg 1997;64:941-944.[Abstract/Free Full Text]
- Buhr J., Berghauser K.H., Gonner S., Kelm C., Burkhardt E.A., Padberg W.M. The prognostic significance of tumor cell detection in intraoperative pleural lavage and lung tissue cultures for patients with lung cancer. J Thorac Cardiovasc Surg 1997;113:683-690.[Abstract/Free Full Text]
- Hillerdal G., Dernevik L., Almgren S.O., Kling P.A., Gustafsson G. Prognostic value of malignant cells in pleural lavage at thoracotomy for bronchial carcinoma. Lung Cancer 1998;21:47-52.[Medline]
- Okada M., Tsubota N., Yoshimura M., Miyamoto Y., Maniwa Y. Role of pleural lavage cytology before resection for primary lung carcinoma. Ann Surg 1999;229:579-584.[Medline]
- Kondo H., Asamura H., Suemasu K., et al. Prognostic significance of pleural lavage cytology immediately after thoracotomy in patients with lung cancer. J Thorac Cardiovasc Surg 1993;106:1092-1097.[Abstract]
- Dresler C.M., Fratelli C., Babb J. Prognostic value of positive pleural lavage in patients with lung cancer resection. Ann Thorac Surg 1999;67:1435-1439.[Abstract/Free Full Text]
- Berson D. Pleural lavage in carcinoma of the esophagus. N Engl J Med 1974;291:530.
- Natsugoe S., Shimada M., Nakashima S., et al. Intraoperative pleural lavage in esophageal carcinoma. Ann Surg Oncol 1999;6:305-307.[Medline]
- Jiao X., Zhang M., Wen Z., Krasna M.J. Pleural lavage cytology in esophageal cancer without pleural effusions: clinicopathologic analysis. Eur J Cardiothorac Surg 2000;17:575-579.[Abstract/Free Full Text]
- Wang N.S. The preformed stomas connecting the pleural cavity and the lymphatics in the parietal pleura. Am Rev Respir Dis 1975;112:12-20.
- Kanazawa K. Exchange through the pleura. In: Chretien J., Bigmom J., Hirsch A., eds. The pleura in health and disease. New York: Marcel Dekker, 1985:195-231.
- Dobashi K., Sugio K., Osaki T., Oka T., Yasumoto K. Micrometastatic p53-positive cells in the lymph nodes of non-small cell lung cancer: prognostic significance. J Thorac Cardiovasc Surg 1997;114:339-346.[Abstract/Free Full Text]
- Kajiyama Y., Kanno H., Ueno M., et al. P53 gene mutation in 150 dissected lymph nodes in a patient with esophageal cancer. Dis Esophagus 1998;11:279-283.[Medline]
- Luketich J.D., Kassis E.S., Shriver S.P., et al. Detection of micrometastases in histologically negative lymph nodes in esophageal cancer. Ann Thorac Surg 1998;66:1715-1718.[Abstract/Free Full Text]
- Krasna M.J., Mao Y.S., Sonett J.R., et al. p53 gene protein overexpression predicts results of trimodality therapy in esophageal cancer patients. Ann Thorac Surg 1999;68:2021-2025.[Abstract/Free Full Text]
- Betz C., Papadopoulos T., Buchwald J., Dammrich J., Muller-Hermelink H.K. Surfactant protein gene expression in metastatic and micrometastatic pulmonary adenocarcinomas and other non-small cell lung carcinomas: detection by reverse transcriptase-polymerase chain reaction. Cancer Res 1995;55:4283-4286.[Abstract/Free Full Text]
- Salerno C.T., Frizelle S., Niehans G.A., et al. Detection of occult micrometastases in non-small cell lung carcinoma by reverse transcriptase-polymerase chain reaction. Chest 1998;113:1526-1532.[Abstract/Free Full Text]
- Maruyama R., Maruyama R., Sugio K., et al. Evaluation of p53 alterations in occult lymph node metastases. J Surg Oncol 2000;73:143-147.[Medline]
- Chen Z.L., Perez S., Holmes E.C., et al. Frequency and distribution of occult micrometastases in lymph nodes of patients with non-small-cell lung cancer. J Natl Cancer Inst 1993;85:493-498.[Abstract/Free Full Text]
- Nicholson A.G., Graham A.N., Pezzella F., Agneta G., Goldstraw P., Pastorino U. Does the use of immunohistochemistry to identify micrometastases provide useful information in the staging of node-negative non-small cell lung carcinomas?. Lung Cancer 1997;18:231-240.[Medline]
- Kubuschok B., Passlick B., Izbicki J.R., Thetter O., Pantel K. Disseminated tumor cells in lymph nodes as a determinant for survival in surgically resected non-small-cell lung cancer. J Clin Oncol 1999;17:19-24.[Abstract/Free Full Text]
- Ohta Y., Nozawa H., Tanaka Y., Oda M., Watanabe Y. Increased vascular endothelial growth factor and vascular endothelial growth factor-c and decreased nm23 expression associated with microdissemination in the lymph nodes in stage I non-small cell lung cancer. J Thorac Cardiovasc Surg 2000;119:804-813.[Abstract/Free Full Text]
- Hashimoto T., Kobayashi Y., Ishikawa Y., et al. Prognostic value of genetically diagnosed lymph node micrometastasis in non-small cell lung carcinoma cases. Cancer Res 2000;60:6472-6478.[Abstract/Free Full Text]
- Izbicki J.R., Hosch S.B., Pichlmeier U., et al. Prognostic value of immunohistochemically identifiable tumor cells in lymph nodes of patients with completely resected esophageal cancer. N Engl J Med 1997;337:1188-1194.[Abstract/Free Full Text]
- Bonavina L., Ferrero S., Midolo V., Buffa R., Cesana B., Peracchia A. Lymph node micrometastases in patients with adenocarcinoma of the esophageogastric junction. J Gastrointest Surg 1999;3:468-476.[Medline]
- Glickman J.N., Torres C., Wang H.H., et al. The prognostic significance of lymph node micrometastasis in patients with esophageal carcinoma. Cancer 1999;85:769-778.[Medline]
- Komukai S., Nishimaki T., Watanabe H., Ajioka Y., Suzuki T., Hatakeyama K. Significance of immunohistochemically demonstrated micrometastases to lymph nodes in esophageal cancer with histologically negative nodes. Surgery 2000;127:40-46.[Medline]
- Matsumoto M., Natsugoe S., Nakashima S., et al. Clinical significance of lymph node micrometastasis of pN0 esophageal squamous cell carcinoma. Cancer Lett 2000;153:189-197.[Medline]
- Kijima F., Natsugoe S., Takao S., et al. Detection and clinical significance of lymph node micrometastasis determined by reverse transcription-polymerase chain reaction in patients with esophageal carcinoma. Oncology 2000;58:38-44.[Medline]
- Iwao K., Tatanabe T., Fujiwara Y., et al. Isolation of a novel human lung-specific gene, LUNX, a potential molecular marker for detection of micrometastasis in non-small-cell lung cancer. Int J Cancer 2001;91:433-437.[Medline]
- Mueller J.D., Stein H.J., Oyang R., et al. Frequency and clinical impact of lymph node micrometastasis and tumor cell microinvolvement in patients with adenocarcinoma of the esophageogastric junction. Cancer 2000;89:1874-1882.[Medline]
- Hosch S., Kraus J., Scheunemann P., et al. Malignant potential and cytogenetic characteristics of occult disseminated tumor cells in esophageal cancer. Cancer Res 2000;60:6836-6840.[Abstract/Free Full Text]
- Sloane J.P., Ormerod M.G., Neville A.M. Potential pathological application of immunocytochemical methods to the detection of micrometastases. Cancer Res 1980;40:3079-3082.[Abstract/Free Full Text]
- Funke I., Schraut W. Meta-analyses of studies on bone marrow micrometastases: an independent prognostic impact remains to be substantiated. J Clin Oncol 1998;16:557-566.[Abstract]
- Cote R.J., Beattie E.J., Chaiwun B., et al. Detection of occult bone marrow micrometastases in patients with operable lung carcinoma. Ann Surg 1995;222:415-423.[Medline]
- Pantel K., Izbicki J., Passlick B., et al. Frequency and prognostic significance of isolated tumour cells in bone marrow of patients with non-small-cell lung cancer without overt metastases. Lancet 1996;347:649-653.[Medline]
- Ohgami A., Mitsudomi T., Sugio K., et al. Micrometastatic tumor cells in the bone marrow of patients with non-small cell lung cancer. Ann Thorac Surg 1997;64:363-367.[Abstract/Free Full Text]
- Passlick B., Kubuschok B., Izbicki J.R., Thetter O., Pantel K. Isolated tumor cells in bone marrow predict reduced survival in node-negative non-small cell lung cancer. Ann Thorac Surg 1999;68:2053-2058.[Abstract/Free Full Text]
- Hsu CP S.L., Chen C.Y., Kwang P.C., Miao J., Hsia J.Y., Shai S.E. Bone-marrow microinvolvement in non-small cell lung cancer is not a reliable indicator of tumour recurrence and prognosis. Eur J Surg Oncol 2000;26:691-695.[Medline]
- Pantel K., Schilimok G., Braun S., et al. Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl Cancer Inst 1993;85:1419-1424.[Abstract/Free Full Text]
- Thorban S., Roder J.D., Nekarda H., Funk A., Siewert J.R., 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.[Abstract/Free Full Text]
- Dingemans A.M., Brakenhoff R.H., Postmus P.E., Giaccone G. Detection of cytokeratin-19 transcripts by reverse transcriptase-polymerase chain reaction in lung cancer cell lines and blood of lung cancer patients. Lab Invest 1997;77:213-220.[Medline]
- Krismann M., Todt B., Schroder J., et al. Low specificity of cytokeratin 19 reverse transcriptase-polymerase chain reaction analyses for detection of hematogenous lung cancer dissemination. J Clin Oncol 1995;13:2769-2775.[Abstract]
- Peck K., Sher Y.P., Shih J.Y., Roffler S.R., Wu C.W., Yang P.C. Detection and quantitation of circulating cancer cells in the peripheral blood of lung cancer patients. Cancer Res 1998;58:2761-2765.[Abstract/Free Full Text]
- Castaldo G., Tomaiuolo R., Sanduzzi A., et al. Lung cancer metastatic cells detected in blood by reverse transcriptase-polymerase chain reaction and dot-blot analysis. J Clin Oncol 1997;15:3388-3393.[Abstract/Free Full Text]
- Chausovsky G., Luchansky M., Figer A., et al. Expression of cytokeratin 20 in the blood of patients with disseminated carcinoma of the pancreas, colon, stomach, and lung. Cancer 1999;86:2398-2405.[Medline]
- Kurusu Y., Yamashita J., Ogawa M. Detection of circulating tumor cells by reverse transcriptase-polymerase chain reaction in patients with resectable non-small-cell lung cancer. Surgery 1999;126:820-826.[Medline]
- Kurusu Y., Yamashita J., Hayashi N., Mita S., Fujino N., Ogawa M. The sequence of vessel ligation affects tumor release into the circulation. J Thorac Cardiovasc Surg 1998;116:107-113.[Abstract/Free Full Text]
- Yamashita J., Kurusu Y., Fujino N., Saisyoji T., Ogawa M. Detection of circulating tumor cells in patients with non-small cell lung cancer undergoing lobectomy by video-assisted thoracic surgery: a potential hazard for intraoperative hematogenous tumor cell dissemination. J Thorac Cardiovasc Surg 2000;119:899-905.[Abstract/Free Full Text]
- Mori M., Mimori K., Ueo H., et al. Clinical significance of molecular detection of carcinoma cells in lymph nodes and peripheral blood by reverse transcription-polymerase chain reaction in patients with gastrointestinal or breast carcinomas. J Clin Oncol 1998;16:128-132.[Abstract/Free Full Text]
- Cote R.J., Hawes D., Chaiwun B., Beattie E.J. Detection of occult metastases in lung carcinomas: progress and implications for lung cancer staging. J Surg Oncol 1998;69:265-274.[Medline]
This article has been cited by other articles:
|
|
|
|
 
M. Riquet, P. Bagan, F. Le Pimpec Barthes, E. Banu, F. Scotte, C. Foucault, A. Dujon, and C. Danel
Completely Resected Non-Small Cell Lung Cancer: Reconsidering Prognostic Value and Significance of N2 Metastases
Ann. Thorac. Surg.,
December 1, 2007;
84(6):
1818 - 1824.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Schwartz and D. E. Henson
Diagnostic Surgical Pathology in Lung Cancer: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)
Chest,
September 1, 2007;
132(3_suppl):
78S - 93S.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. A. Silvestri, M. K. Gould, M. L. Margolis, L. T. Tanoue, D. McCrory, E. Toloza, and F. Detterbeck
Noninvasive Staging of Non-small Cell Lung Cancer: ACCP Evidenced-Based Clinical Practice Guidelines (2nd Edition)
Chest,
September 1, 2007;
132(3_suppl):
178S - 201S.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Nwogu, G. Fischer, D. Tan, M. Glinianski, D. Lamonica, and T. Demmy
Radioguided Detection of Lymph Node Metastasis in Non-Small Cell Lung Cancer
Ann. Thorac. Surg.,
November 1, 2006;
82(5):
1815 - 1820.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F.-Y. Liu, J. T. Chang, H.-M. Wang, C.-T. Liao, C.-J. Kang, S.-K. Ng, S.-C. Chan, and T.-C. Yen
[18F]Fluorodeoxyglucose Positron Emission Tomography Is More Sensitive Than Skeletal Scintigraphy for Detecting Bone Metastasis in Endemic Nasopharyngeal Carcinoma at Initial Staging
J. Clin. Oncol.,
February 1, 2006;
24(4):
599 - 604.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Kim, W. Ryu, S. J. Cho, J. Kim, and S. Park
Touch print cytology shows higher sensitivity than pleural lavage cytology for pleural micro-metastasis in lung cancer
Interactive CardioVascular and Thoracic Surgery,
February 1, 2005;
4(1):
70 - 74.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. M. Spence, A. N. J. Graham, K. Mulholland, P. Maxwell, W. G. McCluggage, J. M. Sloan, and J. A. McGuigan
Bone Marrow Micrometastases and Markers of Angiogenesis in Esophageal Cancer
Ann. Thorac. Surg.,
December 1, 2004;
78(6):
1944 - 1949.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. B. Faries, R. J. Bleicher, X. Ye, R. Essner, and D. L. Morton
Lymphatic Mapping and Sentinel Lymphadenectomy for Primary and Metastatic Pulmonary Malignant Neoplasms
Arch Surg,
August 1, 2004;
139(8):
870 - 877.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Lim, A. Ali, P. Theodorou, A. G. Nicholson, G. Ladas, and P. Goldstraw
Intraoperative pleural lavage cytology is an independent prognostic indicator for staging non-small cell lung cancer
J. Thorac. Cardiovasc. Surg.,
April 1, 2004;
127(4):
1113 - 1118.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Jiao, A. Eslami, O. Ioffe, K. F. Kwong, M. Henry, Q. Zeng, Y. Refaely, W. Burrows, Z. Gamliel, and M. J. Krasna
Immunohistochemistry analysis of micrometastasis in pretreatment lymph nodes from patients with esophageal cancer
Ann. Thorac. Surg.,
October 1, 2003;
76(4):
996 - 1000.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Skuladottir and J. H. Olsen
Conditional Survival of Patients With the Four Major Histologic Subgroups of Lung Cancer in Denmark
J. Clin. Oncol.,
August 15, 2003;
21(16):
3035 - 3040.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
