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Ann Thorac Surg 1999;68:2053-2058
© 1999 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Isolated tumor cells in bone marrow predict reduced survival in node-negative non-small cell lung cancer

^a Division of Thoracic Surgery, University of Munich, Munich, Germany
^b Department of Surgery, Klinikum Innenstadt, University of Munich, Munich, Germany
^c Institute of Immunology, Division of Tumor Immunology, University of Munich, Munich, Germany

Address reprint requests to Dr Passlick, Department of Surgery, University of Munich, Klinikum Innenstadt, Nussbaumstr 20, 80336 Munich, Germany
e-mail: passlick{at}lrz.uni-muenchen.de

Abstract

Background. It recently became evident that isolated tumor cells undetectable by conventional tumor staging are frequently present in bone marrow of patients with apparently localized non-small cell lung cancer (NSCLC). The clinical relevance of this minimal hematogenous tumor cell dissemination is under vigorous debate.

Methods. For tumor cell detection in the bone marrow, we used monoclonal antibody CK2 against the epithelial intermediate filament protein cytokeratin 18. The influence of a positive bone marrow finding on clinical outcome was studied in 139 patients with NSCLC postoperatively staged as pT_1–4, pN_0–2, M₀, and R₀ after a median follow-up of 66 months (range 48 to 74 months).

Results. Cytokeratin-18-positive cells in bone marrow were demonstrated in 83 (59.7%) patients at the time of primary surgery and in 6 of 12 representative patients analyzed twice 3 to 18 months after surgery. In patients without histopathological lymph node metastases (pN₀; n = 66), the occurrence of 2 or more tumor cells in bone marrow at primary surgery was a strong and independent predictor for overall survival (p = 0.007) in univariate analysis. The multivariate analysis showed a 2.8 times increased risk for shorter survival in patients with disseminated tumor cells versus patients without such cells. Four of the 6 patients with a positive cytokeratin status after surgery developed a tumor recurrence 11 to 44 months after the operation, while none of the patients with a negative bone marrow at all time intervals showed a tumor relapse.

Conclusions. Minimal residual bone marrow involvement is an independent prognostic factor for overall survival in patients with node-negative NSCLC, which may help to identify patients in need of an adjuvant systemic therapy. The postoperative persistence or reappearance of tumor cells in bone marrow indicates that these are not only shedded cells but rather represent true micrometastasis.

In non-small cell lung cancer (NSCLC), the occult hematogenous and lymphatic spread of tumor cells can arise before diagnosis of apparently localized primary tumors [1–4]. This finding is consistent with the unsatisfactory outcome of surgical treatment, ie, a 5-year survival rate of only 60%, even in early tumor stages [5]. To improve the diagnosis of this occult stage of early metastasis, several groups, including ours, have developed sensitive immunocytochemical or molecular techniques that facilitate the detection of isolated lung carcinoma cells in distant (eg, bone marrow or lymph nodes) organs [1–3, 6, 7]. The prominent role of bone marrow in the investigation of hematogenous tumor cell dissemination is due to the fact that, in contrast to other distant organs, it can be is easily probed by needle aspiration. Although there is evidence that cytokeratin-positive, epithelial tumor cells are present in 40% to 60% of patients with localized NSCLC [1–3], the clinical relevance of this minimal hematogenous dissemination is still controversially discussed [8]. So far, no data exist available on the impact of such bone marrow tumor cells on overall survival. Herein, we present evidence that minimal residual bone marrow involvement is a strong and independent predictor for long-term survival of patients with completely resected, node-negative NSCLC (pT_1–3, N₀, M₀, R₀). This finding, together with the observation that tumor cells are detectable in bone marrow months after surgical resection of the primary tumor, underscores the malignant character of immunocytochemical identifiable cells in bone marrow.

Patients and methods

Patients and follow-up
At the time of surgery, tumor samples and bone marrow aspirates were collected from 139 consecutive patients with operable NSCLC who had been treated by lobectomy or pneumectomy in combination with systematic mediastinal lymphadenectomy between October 1989 and December 1991. Tumor stage and grading were initially determined according to the 4th edition of the International Union Against Cancer (1987) [9] and reclassified using the new international staging system [10]. Only patients in stage M₀ (ie, no diagnostic sign for distant metastasis) with completely resected (R₀) primary tumors as assessed by histopathological examination were admitted to the study. All participants gave informed consent. Most patients received no adjuvant therapy, excepting patients with pT₃ or pT₄ primary tumors who underwent postoperatively percutaneous radiation (50 Gy) of the tumor bed, and patients with pN₂ disease who had percutaneous radiation (50 Gy) of the entire mediastinum.

After primary surgery, patients were reexamined every 3 months over 2 years and thereafter at 6-months intervals. The evaluation included physical examination, plain chest radiography, bronchoscopy with peribronchial or intraluminal biopsies, computed tomography of thorax and abdomen, abdominal ultrasound, and bone scan. Complete information on tumor relapse and survival was obtained from 128 of the 139 NSCLC patients. The remaining 11 patients had to be excluded because of death not related to cancer (n = 7), or an unclear status of relapse (n = 4). The median observation period was 66 months (range 48 to 74 months).

A follow-up bone marrow analysis was performed twice in 12 patients. The first bone marrow aspiration was done 3 to 7 months (median 6 months) after surgery, and the second 10 to 18 months (median 12 months) postoperatively. For all follow-up bone marrow analysis, one iliac crest was punctured under local anaesthesia in the outpatient clinic. For comparison of the bone marrow status at primary surgery and postoperatively, only one iliac crest aspirate was considered.

Tissue preparation
At the primary operation, two to four bone marrow aspirates from both sites of the iliac crest and at least one of the ribs were taken through an aspiration needle. By Ficoll Hypaque density gradient, between 5 x 10⁶ and 6 x 10⁷ (mean 2.5 x 10⁷) mononuclear cells could be isolated out of 2 to 10 mL (mean 5 mL) volume of the aspirates. A defined number of these cells (8 x 10⁴) were then put on glass slides by cytocentrifugation (150 g for 5 minutes) and dried overnight for immediate staining or storage at -80°C.

Immunocytochemistry and evaluation
The bone marrow preparations and the primary tumor were stained by the monoclonal antibody CK2 (IgG₁, 2.5 µg/mL; Boehringer Mannheim, Mannheim, Germany) directed to cytokeratin polypeptide 18 (CK18). CK2 reacts with simple epithelia and tumors derived thereof, as well as most squamous cell lung carcinomas [11]. In our recent immunohistochemical investigation, CK18 expression was observed on 95.5% (84 of 88) of lung tumors [12]. The high sensitivity of CK2 for detection of disseminated tumor cells in bone marrow were demonstrated in our previous study [3]. There were only 2.8% positive findings in bone marrow aspirates from 215 patients with benign epithelial tumors, nonepithelial neoplasms, and inflammatory diseases or mesenchymal malignancies.

In all experiments, an isotype-matched, irrelevant murine monoclonal antibody (MOPC 21, IgG₁; Sigma, Deisenhofen, Germany) serves as negative control. For visualization of antibody binding, the alkaline phosphatase anti-alkaline phophatase (APAAP) technique combined with the Neufuchsin method was employed as previously reported [3]. Briefly, after incubation with CK2, the polyvalent rabbit anti-mouse immunoglobulin antiserum (30 minutes, Z259; Dako, Heidelberg, Germany) and preformed complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase antibodies (30 minutes, D651; Dako) were applied at the appropriate dilutions.

From each bone marrow aspirate, five cytospin slides were screened (4 x 10⁵ cells per slide). All slides were examined by two independent observers. In about 90% of specimens, both observers gave the same result; the slides with discrepant evaluations were reevaluated and a consensus was reached.

Statistical analysis
For statistical analysis, all variables were dichotomized. Age as the only continuous variable was dichotomized at the median (60 years) to limit the leverage of outlying values and to fulfill the assumption of multivariate analysis. Kaplan-Meier survival curves were calculated and the observed differences in survival was compared by log-rank test. The Cox proportional hazard models were applied for multivariate analysis using the SPSS statistical software package (SPSS Software, Munich, Germany).

Results

Frequency of CK18⁺ tumor cells in bone marrow at primary surgery
The immunocytochemical staining with the monoclonal antibody CK2 (against cytokeratin 18) revealed disseminated epithelial cells in 83 (59.7%) of 139 patients with resectable NSCLC (Fig 1). Frequencies of CK18⁺ cells were very similar in the different tumor stages (Table 1). In patients with pT1, pN0 disease (n = 15) -disseminated tumor cells in the bone marrow were detected in 9 (60%) patients, in pT2, pN0 patients (n = 47) in 23 (48.9%) cases, and 6 (75%) of the 8 pT3, pN0 patients displayed a positive bone marrow status (p = 0.346, ² test). The CK18⁺ cells predominantly occurred as isolated cells. Tumor cell clusters were only seen in few cases (10.1% of NSCLC patients) [3]. The median number of CK18⁺ cells per 4 x 10⁵ mononuclear cells was 2 (range 1 to 531) (Fig 2). With regard to the total bone marrow, this would be an estimated tumor load of 4 x 10⁶ to 2 x 10⁹ cells [13].

View larger version (136K): [in this window] [in a new window]   Fig 1. Isolated CK18+ cell in the bone marrow of a patient with a resectable NSCLC (adenocarcinoma; pT1, pN0, M0). Alkaline phosphate-anti-alkaline phosphatase (APAAP) staining using monoclonal antibody CK2 against CK18; in order to facilitate the detection of immunocytochemical positive cells, no counter staining was done.

View larger version (11K): [in this window] [in a new window]   Fig 2. Frequency of CK18+ tumor cells in bone marrow of patients with completely resected NSCLC.

View larger version (10K): [in this window] [in a new window]   Fig 3. Overall survival (Kaplan-Meier analysis) in pN0 patients (n = 66) with surgically resected NSCLC depending on the presence (thick line) or absence (thin line) of immunocytochemically CK18+ tumor cells ( 2 cells per 4 x 105) in bone marrow. The difference is significant: p = 0.007 by log-rank test.

Comment

This study was performed to substantiate the prognostic significance of single, disseminated tumor cells in the bone marrow of patients with completely resected NSCLC (pT_1–4, pN_0–2, M₀). As shown by a profound methodological analysis [14] and confirmed by different other groups [1, 15, 16], the immunocytochemical assay now used offers a well-established method of detecting even one epithelial cell in a given number (10⁶) of mononuclear bone marrow cells. In various tumor entities, the malignant nature of isolated, epithelial cells in bone marrow was corroborated by overexpression of the erbB2 oncogene, downregulation of major histocompatibility complex class I antigens, as well as by their growth potential in cell cultures [17, 18].

In a multivariate analysis, the present investigation clearly demonstrates that the detection of disseminated, epithelial tumor cells in bone marrow of patients with node-negative NSCLC is correlated with an increased rate of tumor relapse and cancer-related death after long-term follow-up. This study in NSCLC shows an independent prognostic significance of such a minimal tumor load in bone marrow for overall survival. The predictive value of the isolated bone marrow tumor cells for shorter survival is of similar importance as the predictive value of pathological T stage.

Interestingly, the detection of isolated tumor cells in bone marrow does not predict the occurrence of later bone metastases, as shown by the low frequency of bone metastases in CK18⁺ patients. Rather, they indicate the disseminatory capacity of the individual tumor. Previous studies indicate that a considerable part of the tumor cells in bone marrow are nonproliferating cells [17]. Thus, it is conceivable that bone marrow is a reservoir for these tumor cells, and that they may subsequently travel via the blood stream to other secondary organs where they encounter a more appropriate growth milieu. An important factor in forming resident metastases seems to be the expression of urokinase-type plasminogen activator, which enables the cell to degrade matrix proteins and establish tumor stroma [19].

Our preliminary follow-up bone marrow analysis revealed that in two-thirds of the patients with a positive bone marrow status at the time of primary surgery CK18⁺ cells can also be detected 3 to 18 months postoperatively. In most of these patients, a postoperative positive bone marrow status was associated with a clinically evident tumor recurrence later on. Although this association needs to be confirmed in larger studies, our data provide evidence that NSCLC cells persist in bone marrow after surgical resection of the primary tumor. Thus, these cells appear to be viable micrometastases rather than shed tumor cells with a limited life span. This finding contrasts the data of Mansi and associates in breast cancer, who demonstrated a lack of tumor cells in most of their postoperative bone marrow aspirations [20].

As previously shown, the detection of tumor cells in the bone marrow was not associated with an early lymphatic tumor cell spread [4], indicating that early hematogenous and early lymphatic tumor cell dissemination might be differentially regulated. This assumption is supported by the observation that primary tumors from patients with an early tumor cell spread to lymph nodes, as detected by sensitive immunohistochemical methods, show a deficient expression of major histocompatibility complex class I and ICAM-1 molecules, while the expression of these immunoregulatory molecules is not altered in primary tumors from patents with bone marrow micrometastases [21].

In view of the prognostic importance of disseminated tumor cells in bone marrow, a number of attempts have been undertaken to improve the sensitivity of current detection assays. Flow cytometric analysis has so far not been proven to be superior to immunocytological techniques [22], but the progress in this method is promising [23]. More recently, molecular approaches using the reverse-transcriptase polymerase chain reaction (RT-PCR) technique have been developed, which screen for tumor-associated and/or organ specific mRNA expression in bone marrow and blood. However, a disadvantage of the RT-PCR approach is that the origin of positive findings can not be traced back to an intact and viable tumor cell. Thus, illegitimate (ie, non-tissue-specific) expression of small amounts of tumor associated mRNA species (CK18, 19, EGP-40, MUC1, or CEA) in bone marrow cells can be detected if the amplification of the transcribed cDNA is extensive [24].

In conclusion, the immunocytochemical detection of tumor cells in bone marrow provides the means for the diagnosis of otherwise occult minimal systemic disease and can consequently lead to a more accurate identification of patients with unfavorable prognosis. These findings provide further support for the suggestion of the standardization committee of the International Union Against Cancer (UICC) to introduce this early stage of metastatic disease as the category pM1(i) into the existing tumor classification [25]. Whether the identified patients may benefit from an adjuvant therapy has to be evaluated in further studies.

Acknowledgments

This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 469), Bonn, the K.L. Weigand-Stiftung, Munich, and the MMW-Herausgeberstiftung, Munich, Germany. We thank Simone Baier and Tanja Hoffmann for excellent technical assistance.

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This Article Abstract Full Text (PDF) 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): Jakob R. Izbicki Olaf Thetter Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Passlick, B. Articles by Pantel, K. Search for Related Content PubMed PubMed Citation Articles by Passlick, B. Articles by Pantel, K.