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Ann Thorac Surg 1997;64:363-367
© 1997 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Micrometastatic Tumor Cells in the Bone Marrow of Patients With Non–Small Cell Lung Cancer

Department of Surgery II and Institute of Ecological Sciences, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan

Accepted for publication March 10, 1997.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. This study was designed to evaluate the incidence and clinical implications of detection of micrometastatic cancer cells in bone marrow aspirates of patients with operable non–small cell lung cancer. The relationship between micrometastatic cells and p53 overexpression in the primary tumor was also assessed.

Methods. Thirty-nine patients with stages I through III non–small cell lung cancer who underwent curative resection were entered into this study. Immunohistochemistry with monoclonal antibody to cytokeratin 18 was used to detect tumor cells in bone marrow. Immunostaining of p53 protein in the corresponding primary tumors was also done.

Results. Cytokeratin 18–positive cells were detected in 15 (39%) of the 39 patients. Overexpression of p53 was associated with positivity of the tumor cells in the bone marrow at borderline significance (14/29 versus 1/10; p = 0.0574). The patients with cytokeratin 18–positive cells in bone marrow demonstrated a significantly earlier recurrence than those without such cells (p = 0.0083, log-rank test).

Conclusions. Micrometastatic cancer cells were frequently present in bone marrow of patients with operable non–small cell lung cancer and may be a significant predictor of early recurrence. Further evaluation of this method may be useful in identifying patients with non–small cell lung cancer who are most likely to benefit from adjuvant chemotherapy.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
See also page 367.

Lung cancer is the leading cause of cancer-related deaths in North America, and it is expected to soon become the leading cause also in Japan [1, 2]. Lung cancer is divided into two morphologic types: small cell lung cancer and non–small cell lung cancer (NSCLC) [2]. About 30% of patients with NSCLC have localized disease, and successful surgical management with long-term disease control is generally restricted to this group of early-stage patients [2]. However, even after a "curative" resection for stage I disease, ie, tumors with no invasion of the adjacent structures and no metastases to the regional lymph nodes or distant organs, about 30% of patients have recurrence and eventually die of the disease [2, 3]. About two thirds of such recurrences are in distant organs such as the brain, contralateral lung, and bone as a result of the hematogenous spread of cancer cells [3, 4]. In other words, recurrence of the cancer is simply a clinical manifestation of metastatic disease that is present but occult and undetected at the time of surgical intervention. Therefore, it is of great importance to develop a technique for detecting these micrometastatic cancer cells that are missed by conventional diagnostic methods to be able to provide a more precise prognosis.

Over the past 10 years, several attempts have been made to detect micrometastatic cells in lymph nodes [5], bone marrow (BM) [6–9], or peripheral blood [10, 11] by immunohistochemistry or a polymerase chain reaction–based assay for various types of human cancers. In about 30% to 50% of patients with operable cancer of the breast [8], colon [12], or lung [13–15], occult metastatic cells are detected in BM. Most investigators [8, 12–15] report that the detection of these micrometastatic cells is a poor prognostic indicator.

In this study, we examined the incidence and prognostic implications of micrometastatic cancer cells in the iliac BM of 39 patients with stages I through III NSCLC. We took advantage of immunohistochemical staining of cytokeratin 18 (CK18) as a panepithelial marker [14–16]. We also examined primary tumors for any abnormal accumulation of p53 protein to see if a mutation of this protein is related to the detection of micrometastatic cancer cells in the BM, as we [17, 18] have found that a mutation of the p53 tumor suppressor gene is associated with a poor prognosis in these patients.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Thirty-nine patients with histologically proven NSCLC who underwent a potentially curative pulmonary resection at the Department of Surgery II, University of Occupational and Environmental Health University Hospital, form the study group. Twenty-two patients had adenocarcinoma, 16 had squamous cell carcinoma, and 1 patient had large cell carcinoma. After extensive diagnostic procedures, including chest roentgenography, computed tomography of the chest and brain, ultrasonography of the abdomen, and a bone scan, clinical stages were determined according to the TNM classification of the International Union Against Cancer (modified in 1986) [19]. Twenty-two patients had stage I disease, 4 had stage II, 9 had stage IIIA, and 4 had stage IIIB. As negative controls, we studied 5 patients who were suspected of having lung cancer preoperatively but later benign lung disease (tuberculosis in 4 and pulmonary abscess in 1) was diagnosed pathologically.

For the postoperative follow-up, the patients were asked to visit our clinic to undergo chest roentgenography and tumor marker examinations every month for the first year, every other month for the second year, and every 3 months thereafter. Computed tomographic scanning and a bone scintiscan were performed every 6 months postoperatively. The median follow-up was 140 days (range, 30 to 910 days).

Specimens
Informed consent was obtained from all patients. Approximately 5 mL of BM aspirate was obtained from one site in the upper iliac crest within a week before operation and yielded an average of 1.0 x 10⁷ nucleated cells. Mononuclear cells were isolated by density centrifugation with FICOLL-HYPAQUE (Mono-Poly Resolving Medium; Dainippon Pharmaceutical Co, Ltd, Osaka, Japan). The interface cells were washed by centrifugation and then resuspended in phosphate-buffered saline solution. Finally, the cells were cytocentrifuged at 1,300 rpm on glass slides in a cytocentrifuge (Auto Smear; Sakura Seiki Co, Tokyo, Japan) after the number of cells was counted (average number of cells per slide, 3.6 x 10⁵). The slides were either stained immediately or stored at -80°C after overnight air-drying and 4% paraformaldehyde–acetone fixation for 90 seconds. Five slides were routinely examined for each patient.

Resected lung cancer specimens were fixed in 20% formalin for 3 days and embedded in paraffin. For the histologic study, sections were stained with hematoxylin and eosin. As a positive control in 17 patients, touch preparations of malignant cells for staining of CK18 were made by lightly pressing the cut surface of a block of fresh tissue to the slide.

Immunohistochemistry of BM Aspirates or Touch Preparations for CK18
The slides of the BM aspirates or touch preparations were stained for CK18 with the alkaline phosphatase–anti–alkaline phosphatase method using a commercially available kit (DAKO, Tokyo, Japan). The primary antibody was CK2 (Boehringer Mannheim Biochemica, Mannheim, Germany), 2.0 µg/mL, raised against CK18. Staining was done according to the procedures recommended by the manufacturer. Counterstaining was briefly performed with Mayer's hematoxylin.

Immunohistochemistry of Primary Tumors for p53 Protein
Immunohistochemistry for p53 protein was performed as described previously [18]. Briefly, the sections were immersed in a citrate buffer and irradiated five times for 5 minutes each in a domestic microwave oven for antigen retrieval. They were then stained with the mouse monoclonal antibody DO-1 (Oncogene Science Inc, Cambridge, MA) against the p53 protein using a Labeled Streptavidin Biotin kit (DAKO). The sections were subsequently examined for nuclear staining under a light microscope. Five hundred tumor cells in the primary section were examined to estimate the percentage of p53-positive cells.

Statistical Analysis
A comparison of the proportion was done using the two-tailed Fisher's exact test. The Kaplan-Meier method was used to estimate the probability of survival as a function of time, and survival differences were analyzed by the log-rank test. For patients with lung cancer recurrence, the time to the first recurrence was calculated as the number of days from pulmonary resection to first documentation of recurrence.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Detection of CK18–Positive Cells in BM
Cytokeratin 18–positive cells were detected in densities ranging from 1/3.0 x 10⁶ nucleated cells to 1/1.4 x 10⁵ nucleated cells in BM aspirates from 15 (39%) of the 39 patients with NSCLC. None of the 5 patients with benign lung disease had any CK18–positive cells in their BM. All 17 touch preparations of the primary lung cancer specimens were positive for CK18.

Table 1 summarizes the relationships between the presence of CK18–positive cells in BM and various clinical features. No association was found between the detection of CK18–positive cells and age, sex, histology or stage of disease. However, it was noteworthy that 6 (27%) of 22 patients with stage I disease had CK18–positive cells in iliac BM. Cytokeratin 18–positive cells were also detected in BM of 2 of 4 patients in stage II and 7 (54%) of 13 in stage III. Moreover, the incidence of CK18–positive cells in BM aspirates tended to be associated with the N factor. In patients with N0 disease, the incidence was 6 (26%) of 23 versus 9 (56%) of 16 patients with N1 through N3 disease (p = 0.0944).

Prognostic Significance of Detection of CK18–Positive Cells
We then analyzed the prognostic significance of the detection of CK18–positive cells. The patients who had CK18 cells in BM demonstrated recurrent disease significantly earlier than those who were free from these cells (p = 0.0083) (Fig 1A). In the subset of 26 patients with apparently earlier disease (stage I and II), the presence of occult CK18–positive cells in BM was also associated with earlier recurrence (p = 0.0335) (Fig 1B). However, in this cohort, p53 overexpression was not predictive of earlier recurrence (p = 0.2634) (Fig 1C). We also noted that the presence of CK18 cells in BM was predictive of the pattern of recurrence. Four patients with recurrence through hematogenous spread (contralateral lung in 2, brain in 1, and bone in 1) had CK18–positive cells in BM, whereas 2 patients who had regional lymph node recurrence were CK18 negative. The remaining patient (CK18–positive cells in BM) showed an abnormal elevation of the tumor marker (carcinoembryonic antigen) after operation, and we thus regarded that as recurrence, although the evidence had not yet been revealed by other methods.

View larger version (21K): [in this window] [in a new window]   Fig 1. . Disease-free interval in patients with non–small cell lung cancer who underwent pulmonary resection. (A) Detection of cytokeratin 18 ( CK)–positive cells in bone marrow (BM) (stage I through stage III). (B) Detection of CK18–positive cells in BM (stages I and II). (C) Overexpression of p53 protein in primary tumor. (N.S. = not significant.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

We detected micrometastatic cancer cells in patients with apparently localized lung cancer who were thus candidates for a potentially curative resection. In this study, 8 (31%) of the 26 patients in stages I and II had micrometastatic cancer cells in BM compared with 7 (54%) of 13 patients in stage III. Cote and associates [13] reported similar results in that micrometastatic cells in BM were detected in 5 (29%) of 17 patients with stage I or II NSCLC and in 12 (46%) of 26 with stage III disease. The incidence of micrometastatic cell detection in BM appears to be dependent on extension of the tumor. Concerning lymph node involvement, the incidence of CK18–positive cells was lower in patients with N0 disease (6/23, 26%) than in those with N1 through N3 disease (9/16, 56%) in our study. However, Pantel and colleagues [20] found no correlation between the detection of CK18 cells in BM and lymph node involvement (54% in N0 versus 65% in N1 or N2). They speculated that different mechanisms exist for the homing of tumor cells to BM tissue compared with lymphoid tissue.

Another important question is whether or not the detection of these micrometastatic cancer cells in the BM is predictive of early disease recurrence or poor survival of the patient. We found that patients who had CK18–positive cells in iliac BM had a significantly shorter disease-free interval and that this was also the case in the subset of patients in stages I and II; this finding is in accordance with previous reports showing that patients with NSCLC who display cytokeratin-positive cells in BM demonstrate a significantly shorter disease-free interval. However, Heiss and associates [21] reported that the detection of micrometastatic cells alone was not a poor prognostic sign but that an increasing number of such cells by serial BM aspirates, accompanied with an expression of urokinase-type plasminogen activator receptor, was significantly correlated with a poor survival.

In CK18–positive patients in our study, the pattern of recurrence seemed to be hematogenous, and only 1 patient of 4 patients with recurrence through hematogenous spread had bone metastasis as an initial site of failure. The existence of micrometastatic cells in BM may not directly represent a very early phase of bone metastasis, but CK18 cells in BM may be a predictor of distant metastases. It is known that the metastatic process consists of several stages (ie, invasion into the vessels, migration, adhesion to the endothelium, extravasation, and colonization), all of which are indispensable for the development of clinically overt metastases. The detection of CK18–positive cells in BM may indicate that some micrometastatic cancer cells have escaped from the primary tumor and are circulating systemically. Further study is needed concerning the qualitative evaluation of micrometastatic cancer cells with respect to metastatic potential, eg, the expression of oncogene product.

It is now clear that human cancer develops and progresses through an accumulation of multiple genetic changes. In NSCLC, alterations in various oncogenes or tumor suppressor genes such as ras, my, p53, rib, p16, and p15 have been reported [22]. We [17, 18] have shown that the mutation of the p53 gene or overexpression of the p53 protein is associated with a poor prognosis in a subset of patients with NSCLC, although other investigators [23, 24] report opposite results. Overexpression of the p53 protein is not considered to be associated with stage of the disease determined by conventional methods [17, 18, 25], and therefore the mechanism or mechanisms through which the overexpression of p53 contributes to the poor outcome remains to be clarified. In this study, patients with tumors showing p53 overexpression had a tendency toward a higher incidence of micrometastatic cancer cells in BM (48% versus 10%; p = 0.0574). This may at least partially account for the effect of p53 mutation on patient survival.

In conclusion, micrometastatic cancer cells in iliac BM were found in a significant proportion of patients with operable NSCLC. The detection of these cells in the BM appeared to be predictive of early recurrence, particularly bloodborne metastases, and thus of a poor prognostic outcome as well. Overexpression of the p53 protein in primary tumors appeared to be correlated with an increased incidence of these micrometastatic cells in the BM. The use of systemic chemotherapy after operation has been shown to be of limited usefulness in the treatment of NSCLC [26]. However, by monitoring the micrometastatic cancer cells in BM, it would be possible to select patients who might benefit from adjuvant chemotherapy. To determine the treatment of the patient with lung cancer, the micrometastatic status as well as the conventional TNM system would be considered. For example, adjuvant therapy for stage I CK18–positive patients or aggressive surgical resection in stages IIIA and IIIB CK18–negative patients should be advocated.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This work was supported in part by grants-in-aid for scientific research (no. 07457300 and no. 08877216) from the Ministry of Education, Science and Culture, Japan.

We thank Dr Tetsuo Hamada and the staff of the Department of Surgical Pathology, University of Occupational and Environmental Health, University Hospital, for their technical advice and assistance.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Ohgami, Department of Surgery II, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807, Japan (e-mail: gamisan{at}med.uoeh-u.ac.jp).

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

1. Statistics and Information Department. Vital statistics 1990 Japan. Tokyo, Japan: Ministry of Health and Welfare, 1991:96–7.
2. Minna JD, Pass H, Glatstein E, Ihde DC. Cancer of the lung. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. Philadelphia: JB Lippincott, 1989:591–705.
3. Little AG, DeMeester TR, Ferguson MK, et al. Modified stage I (T1N0M0, T2N0M0), nonsmall cell lung cancer: treatment results, recurrence patterns, and adjuvant immunotherapy. Surgery 1986;100:621–7.[Medline]
4. Martini N, Bains MS, Burt ME, et al. Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 1995;109:120–9.[Abstract/Free Full Text]
5. Chen ZL, Perez S, Holmes EC, et al. Frequency and distribution of occult micrometastasis in lymph nodes of patients with non small cell lung carcinoma. J Natl Cancer Inst 1993;85:493–7.[Abstract/Free Full Text]
6. Schlimok G, Funke I, Holzmann B, et al. Micrometastatic cancer cells in bone marrow: in vitro detection with anti-cytokeratin and in vivo labeling with anti-17-1A. Proc Natl Acad Sci USA 1987;84:8672–6.[Abstract/Free Full Text]
7. Schlimok G, Funke I, Pantel K, et al. Micrometastatic tumor cells in bone marrow of patients with gastric cancer: methodological aspects of detection and prognostic significance. Eur J Cancer 1991;27:1461–5.[Medline]
8. Redding HW, Coombes RC, Monaghan P. Detection of micrometastases in patients with primary breast cancer. Lancet 1983;2:1271–4.[Medline]
9. Pantel K, Schlimok G, Braun S, et al. Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl Cancer Inst 1993;85:1419–24.[Abstract/Free Full Text]
10. Burchill SA, Bradbury MF, Pittman K, et al. Detection of epithelial cancer cells in peripheral blood by reverse transcriptase–polymerase chain reaction. Br J Cancer 1995;71:278–81.[Medline]
11. Moreno JG, Croce CM, Fischer R, et al. Detection of hematogenous micrometastasis in patients with prostate cancer. Cancer Res 1992;52:6110–2.[Abstract/Free Full Text]
12. Lindemann F, Schlimok G, Dirschedl P, Witte J, Riethmuller G. Prognostic significance of micrometastatic tumour cells in bone marrow of colorectal cancer patients. Lancet 1992;340:685–9.[Medline]
13. Cote RJ, Beattie EJ, Chaiwun B, et al. Detection of occult bone marrow micrometastases in patients with operable lung carcinoma. Ann Surg 1995;222:415–25.[Medline]
14. Pantel K, Izbicki JR, Angstwurm M, et al. Immunocytological detection of bone marrow micrometastasis in operable non–small cell lung cancer. Cancer Res 1993;53:1027–31.[Abstract/Free Full Text]
15. Pantel K, Dickmanns A, Zippelius A, et al. Establishment of micrometastatic carcinoma cell lines: a novel source of tumor cell vaccines. J Natl Cancer Inst 1995;87:1162–8.[Abstract/Free Full Text]
16. Pantel K, Schlimok G, Angstwurm M, et al. Methodological analysis of immunocytochemical screening for disseminated epithelial tumor cells in bone marrow. J Hematother 1994;3:165–73.[Medline]
17. Mitsudomi T, Oyama T, Kusano T, et al. p53 Gene mutations as a predictor of poor prognosis in patients with non–small cell lung cancer. J Natl Cancer Inst 1993;85:2018–23.[Abstract/Free Full Text]
18. Mitsudomi T, Oyama T, Nishida K, et al. p53 Nuclear immunostaining and gene mutations in non–small cell lung cancer and their effect on patient survival. Ann Oncol 1995;6(Suppl 3):S9–13.
19. Mountain CF. A new international staging system for lung cancer. Chest 1986;89(Suppl):225S–33S.
20. 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;347:649–53.[Medline]
21. Heiss MM, Alligayer H, Gruetzner KU, et al. Individual development and uPA-receptor expression of disseminated tumour cells in bone marrow. Nature Med 1995;1:1035–9.[Medline]
22. Minna JD. The molecular biology of lung cancer pathogenesis. Chest 1993;103:445S–56S.[Medline]
23. Lee JS, Yoon A, Kalapurakal SK, et al. Expression of p53 oncoprotein in non-small-cell lung cancer: a favorable prognostic factor. J Clin Oncol 1995;13:1893–903.[Abstract/Free Full Text]
24. Passlick B, Izbicki JR, Haussinger K, Thetter O, Pantel K. Immunohistochemical detection of P53 protein is not associated with a poor prognosis in non-small-cell lung cancer. J Thorac Cardiovasc Surg 1995;109:1205–11.[Abstract/Free Full Text]
25. Nishio M, Koshikawa T, Kuroishi T, et al. Prognostic significance of abnormal p53 accumulation in primary, resected non-small-cell lung cancers. J Clin Oncol 1996;14:497–502.[Abstract/Free Full Text]
26. Non–Small Cell Lung Cancer Collaborative Group. Chemotherapy in non–small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995;311:899–909.[Abstract/Free Full Text]

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Akira Ohgami Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ohgami, A. Articles by Yasumoto, K. Search for Related Content PubMed PubMed Citation Articles by Ohgami, A. Articles by Yasumoto, K. Related Collections Related Article