Interact CardioVasc Thorac Surg 2009;9:659-661. doi:10.1510/icvts.2009.214197
© 2009 European Association of Cardio-Thoracic Surgery
Institutional report - Pulmonary |
Sentinel node mapping and micrometastasis in patients with clinical stage IA non-small cell lung cancer
Takashi Onoa,
Yoshihiro Minamiyaa,*,
Manabu Itoa,
Hajime Saitoa,
Satoru Motoyamaa,
Hiroshi Nanjob and
Junichi Ogawaa
a Division of Thoracic Surgery, Department of Surgery, Akita University School of Medicine, 1-1-1 Hondo Akita City 010-8543, Japan
b Division of Clinical Pathology, Akita University Hospital, 1-1-1 Hondo Akita City 010-8543, Japan
Received 9 June 2009;
received in revised form 15 July 2009;
accepted 15 July 2009
*Corresponding author. Tel.: +81 18 884 6132; fax: +81 18 836 2615.
E-mail address: minamiya{at}med.akita-u.ac.jp (Y. Minamiya).
 |
Abstract
|
|---|
Many evidences suggest that prognosis of non-small cell lung cancer (NSCLC) with lymph node micrometastases (LNMM) is poor compared with those without LNMM. Therefore, it is better to evaluate LNMM through immunohistochemistry (IHC) of serial sectioning of all dissected lymph nodes. However, this labor-intensive approach is impossible in a practical setting. Therefore, we examined whether we are able to efficiently diagnose LNMM using the sentinel node (SN) mapping. Fifty-one patients with clinical T1N0M0 NSCLC were enrolled in this study. SNs were then detected intraoperatively. After SN mapping, lobectomy and hilar and mediastinal lymph node dissection were performed. Metastases of all dissected lymph nodes were examined by hematoxylin and eosin (H&E) staining and immunohistochemical cytokeratin staining. SN detection rate was 80.4% (41/51). Average number of SNs was 1.8±1.1 in a patient. Lymph node metastases were diagnosed in two patients using H&E staining. LNMM were found only in SNs of two patients. On the other hand, micrometastasis was not found in non-SN. According to these results, two patients with clinical T1N0M0 NSCLC migrated to T1N1M0. Evaluation of micrometastases of all dissected lymph nodes may be substituted by evaluating micrometastases of SNs. We believe that further studies are warranted to determine the most useful clinical applications.
Key Words: Sentinel node; Micrometastasis; Lung cancer
|
1. Introduction
|
|---|
The presence or absence of lymph node metastasis is a key prognostic indicator in malignant disease and lymph node dissection is an effective therapeutic procedure when carried out in patients with nodal metastasis. On the other hand, lymph node dissection is not therapeutic and may even be harmful for patients without lymph node metastasis. The sentinel node (SN) concept is that the lymphatic flux from a primary tumor first flows into the SN before flowing into more distal lymph nodes. If this concept is correct, then when metastasis is not found in a SN, it most likely will not be present in more distal nodes. SN mapping has been done in recent years as a way to avoid the complications of lymph node dissection, and has become a common procedure in the treatment of breast cancer [1] and melanoma [2]. Moreover, evidences of the existence of SNs in non-small cell lung cancer (NSCLC) are accumulated [3–6].
Many investigators studied lymph node micrometastases (LNMM) and demonstrated that survival rates of the patients with LNMM are poor compared with those without micrometastasis in pathological node negative patients [7–11]. LNMM were detected mainly by two kinds of methods, reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC). According to those investigations, the rate of micrometastases was found to range from 16.0% to 27.8% of pathological node negative patients with NSCLC [7–12]. When the number of sectioning of the specimen increased, the detection rates of micrometas-tases increased. Therefore, to diagnose micrometastases precisely, serial lymph node sectioning IHC of all dissected lymph nodes are required. However, this labor-intensive approach is impractical outside of the research setting.
In the current study, we applied SN concept to detect micrometastases to avoid serial sectioning IHC of all dissected lymph nodes. According to SN concept, when micrometastasis is not found in SNs, micrometastasis will not be detected in more distal nodes. If this method is applicable, it is enough to determine micrometastases with a serial sectioning IHC only in SNs to select node micrometastasis positive patients after SN mapping and lymph dissection with lung resection; otherwise we need serial sectioning IHC of all dissected lymph nodes.
|
2. Patients and methods
|
|---|
2.1. Patients
This study was approved by the Institutional Review Boards at Akita University School of Medicine and University Hospital. Fifty-one patients diagnosed cT1N0M0 peripheral NSCLC were enrolled in the study between May 2003 and October 2007 after obtaining written informed consent. Patients who underwent lobectomy via video-assisted thoracic surgery (VATS) with small access ports (<3 cm) or segmentectomy were excluded. After preoperative evaluation, the patients were taken to an operating room, and the standard preparations were made for a thoracotomy and lung resection. None of the patients received preoperative chemotherapy or radiotherapy.
2.2. SN mapping
Method for SN mapping using magnetic force has been described previously [4]. Briefly, 1.6 ml of ferucarbotran (Resovist, Schering, Tokyo, Japan) was injected around the tumor after thoracotomy. To avoid surgical destruction of the lymphatic system of the pleura and along the bronchi and vessels, we waited 15 min after injecting the tracer before proceeding. The lymph node stations were based on the classification by Naruke et al. [13]. During the operation, the magnetic force within lymph nodes was measured in vivo using a highly sensitive, hand-held magnetometer developed at our institute. After completing the SN mapping, lobectomy and hilar, and mediastinal lymph node dissection was performed.
2.3. Histopathological evaluation
Samples from all dissected lymph nodes were sectioned and conventionally examined using hematoxylin and eosin (H&E) staining. In addition, one section of the maximum cut surface of each lymph node was immunohistochemically labeled with an anti-CK AE1/AE3 antibody cocktail (DAKO Corporation Carpinteria, CA) was used to detect the presence of micrometastases. A result was considered positive if positive cell clusters or individual cells with the appropriate tumor cell morphology were recognized. As proposed by the new AJCC Cancer Staging Manual [14], isolated tumor cells were not considered as positive in this study.
|
3. Results
|
|---|
Patient characteristics are summarized in Table 1. All patients received lobectomy. Twenty-six of the 51 patients were resected via VATS with a 7 cm window and one port. Twenty-five of the 51 patients were resected via standard thoracotomy (open). Table 2 summarizes results of SN mapping. Detection rate was 80.1%. Accuracy, sensitivity, and false negative rates were 97.6%, 75.0%, and 2.4%, respectively. Micrometastases were detected with immunohistochemical staining using anti-cytokeratin antibody. Table 3 summarizes the status of nodal metastases. All patients were diagnosed no-node metastasis under determination of computed tomography (clinical T1N0M0). Three metastatic nodes were found under determination of H&E stained section. Two micrometastatic nodes were found in only SN. However, micrometastasis was not found in any non-SN. According to the status of micrometastases, pathological stage of two patients migrated from stage IA to stage IIA (Table 4).
|
4. Discussion
|
|---|
In this study, we identified SNs and dissected hilar and mediastinal lymph nodes in 51 patients with clinical T1N0M0 NSCLC. Then, micrometastases were detected in all dissected lymph nodes using cytokeratin-staining. Micrometastases were detected only in SNs. However, no micrometastasis was found in non-SN. According to the results, evaluation of micrometastases of all dissected lymph nodes may be substituted by evaluating micrometastases of SNs.
In this study, micrometastases were found in only two SNs and two patients upstaged from stage IA to stage IIA. On the other hand, according to the previous reports, the incidence of stage migration ranged from 16.0% to 27.8% of pathological node negative patients [7–12]. Our value is lower than previous reports. This difference may be explained by the number of sections examined with IHC. We examined only one slice of the maximum cut surface of each lymph node. If we increased the number of serial sectioning of lymph node, more micrometastases may have been found. When our concept that we demonstrated in this study is accepted and applicable, we can limit the pathological examination to SNs instead of examination of all dissected lymph nodes. Then, we can examine serial sectioning of SNs using IHC in detail as a practical procedure.
Although some studies indicated that the presence of LNMM does not affect long-term disease [12, 15], many investigators demonstrated that survival rates of the patients with LNMM are poor compared with those without micrometastasis in pathological node negative patients [7–11]. These investigations applied many methods and criterion, including IHC of cytokeratin, and RT-PCR of tumor marker to detect micrometastasis. To solve the controversy on this issue, we hope that future, larger, multi-center studies on micrometastases of patients with NSCLC need to use categories of micrometastasis according to the current AJCC Cancer staging criteria. Isolated tumor cells were smaller than 0.2 mm, while pN1mi and pN2mi measured 0.2–2 mm [14]. As proposed by the new AJCC Cancer Staging Manual [14], isolated tumor cells were not considered as positive in this study.
There are four reports from three institutes on micrometastasis and SN [3, 5, 6]. Sugi et al. carried out SN mapping and examined micrometastases of all dissected lymph nodes like this study [5]. Their data also demonstrated that all lymph nodes positive for micrometastasis were SNs in the patients with pN0 and support our result.
In conclusion, evaluation of micrometastases of all dissected lymph nodes may be substituted by evaluating micrometastases of SNs. Although we examined a limited number of patients in this study, further studies are warranted to determine the most useful clinical applications.
|
References
|
|---|
- Edwards MJ, Whitworth P, Tafra L, McMasters KM. The details of successful sentinel lymph node staging for breast cancer. Am J Surg 2000;180:257–261.[CrossRef][Medline]
- Chao C, McMasters KM. Update on the use of sentinel node biopsy in patients with melanoma: who and how. Curr Opin Oncol 2002;14:217–220.[CrossRef][Medline]
- Liptay MJ, Grondin SC, Fry WA, Pozdol C, Carson D, Knop C, Masters GA, Perlman RM, Watkin W. Intraoperative sentinel lymph node mapping in non-small-cell lung cancer improves detection of micrometastases. J Clin Oncol 2002;20:1984–1988.[Abstract/Free Full Text]
- Minamiya Y, Ito M, Katayose Y, Saito H, Imai K, Sato Y, Ogawa J. Intraoperative sentinel lymph node mapping using a new sterilizable magnetometer in patients with non-small cell lung cancer. Ann Thorac Surg 2006;81:327–330.[Abstract/Free Full Text]
- Sugi K, Kobayashi S, Yagi R, Matsuoka T. Usefulness of sentinel lymph node biopsy for the detection of lymph node micrometastasis in early lung cancer. Interact CardioVasc Thorac Surg 2008;7:913–915.[Abstract/Free Full Text]
- Melfi FM, Lucchi M, Davini F, Viti A, Fontanini G, Boldrini L, Boni G, Mussi A. Intraoperative sentinel lymph node mapping in stage I non-small cell lung cancer: detection of micrometastases by polymerase chain reaction. Eur J Cardiothorac Surg 2008;34:181–186.[Abstract/Free Full Text]
- Li SH, Wang Z, Liu XY, Liu FY. Gene diagnosis and prognostic significance of lymph node micrometastasis after complete resection of histologically node-negative non-small cell lung cancer. World J Surg 2008;32:1651–1656.[CrossRef][Medline]
- Wang Z, Liu XY, Liu FY. Gene diagnosis and prognostic significance of lymph node micrometastasis after complete resection of histologically node-negative non-small cell lung cancer. World J Surg 2008;32:1651–1656.[CrossRef][Medline]
- Tezel C, Ersev AA, Kiral H, Urek S, Kosar A, Keles M, Dudu C, Arman B. The impact of immunohistochemical detection of positive lymph nodes in early stage lung cancer. Thorac Cardiovasc Surg 2006;54:124–128.[CrossRef][Medline]
- Nosotti M, Falleni M, Palleschi A, Pellegrini C, Alessi F, Bosari S, Santambrogio L. Quantitative real-time polymerase chain reaction detection of lymph node lung cancer micrometastasis using carcinoembryonic antigen marker. Chest 2005;128:1539–1544.[Abstract/Free Full Text]
- Osaki T, Oyama T, Gu CD, Yamashita T, So T, Takenoyama M, Sugio K, Yasumoto K. Prognostic impact of micrometastatic tumor cells in the lymph nodes and bone marrow of patients with completely resected stage I non-small-cell lung cancer. J Clin Oncol 2002;20:2930–2936.[Abstract/Free Full Text]
- Rena O, Carsana L, Cristina S, Papalia E, Massera F, Errico L, Bozzola C, Casadio C. Lymph node isolated tumor cells and micrometastases in pathological stage I non-small cell lung cancer: prognostic significance. Eur J Cardiothorac Surg 2007;32:863–867.[Abstract/Free Full Text]
- Naruke T, Suemasu K, Ishikawa S. Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg 1978;76:832–839.[Abstract]
- American Joint Committee on Cancer, AJCC cancer staging manual, (6th edition), Springer, New York. 2002.
- Marchevsky AM, Qiao JH, Krajisnik S, Mirocha JM, McKenna RJ. The prognostic significance of intranodal isolated tumor cells and micrometastases in patients with non-small cell carcinoma of the lung. J Thorac Cardiovasc Surg 2003;126:551–557.[Abstract/Free Full Text]
|
|
Top
Abstract
1. Introduction