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Micrometastases of Bone Marrow in Localized Prostate Cancer: Correlation With Established Risk Factors

From the Urologische Klinik and II Medizinische Klinik, Zentralklinikum Augsburg, Augsburg, and Institut für Immunologie der Universität München, Munich, Germany.

Address reprint requests to Dorothea Weckermann, MD, Urologische Klinik, Zentralklinikum Augsburg, Stenglinstr 2, 86156 Augsburg, Germany

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: The presence of cytokeratin 18–positive cells in bone marrow correlates with conventional risk factors in many tumors. We examined whether this was also valid for localized or lymphatically spread prostate cancer.

PATIENTS AND METHODS: Immediately before radical prostatectomy, bone marrow aspirates from both sides of the iliac crest were taken from 287 patients. The presence of cells containing cytokeratin 18 was interpreted as micrometastasis.

RESULTS: In patients with negative lymph nodes (n = 219), conventional risk factors (Gleason score, pathologic stage, ploidy, and preoperative prostate-specific antigen) did not correlate with the preoperative detection of cells containing cytokeratin 18. There was also no correlation with lymph node metastases. Furthermore, there was no interdependency between the preoperatively detected number of cells and the established risk factors.

CONCLUSION: We assume the presence of epithelial cells in bone marrow to be an independent parameter, the clinical importance of which must be substantiated by further studies.

	INTRODUCTION

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DISSEMINATED micrometastases at the time of surgery are a major problem in terms of a curative therapy. Because novel imaging is not able to detect tumor cells far away from the primary tumor, immunohistochemical and immunocytochemical methods have been developed.

Because cells containing cytokeratin 18 do not normally occur in bone marrow, their presence in patients with clinically localized epithelial tumors is regarded as micrometastatic spread.¹ In various tumors, epithelial cells are seen in bone marrow at the time of primary surgery, whereby, depending on the tumor type, the incidence of cells correlates with conventional risk factors or, respectively, is a prognostic factor itself. We have examined whether this is also valid for localized or lymphatically spread prostate cancer.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The study group comprised 287 patients who had undergone a radical prostatectomy between October 1992 and December 1997. The patients' ages ranged between 48 and 78 years (median, 66 years). All patients had an adenocarcinoma of the prostate, and 48 patients had lymph node metastases. Before surgery, bone marrow aspirates from both sides of the iliac crest were taken from every patient after informed consent was given. On an average, 1 to 2 x 10⁶ mononuclear cells were evaluated per patient. The period between preoperative diagnostic tests (prostate biopsies, transurethral resection) and bone marrow aspiration was 4 to 6 weeks.

The correlation between cytokeratin (CK) 18–positive cells and conventional risk factors (Gleason score, pathologic stage, lymph node metastasis, ploidy, and preoperative prostate-specific antigen [PSA]) was examined. Moreover, we verified whether the amount of cells was of any importance.

Bone Marrow Aspiration, Preparation, and Immunostaining
The bone marrow aspiration was carried out immediately before surgery. Six to 8 mL of bone marrow aspirate from both sides of the iliac crest were extracted in syringes containing 1,000 U heparin/mL marrow. Marrow fat was separated by centrifugation, and the RBCs remaining in the suspension were lysated by the addition of a buffer solution. Mononuclear cells were collected from the interphase after density centrifugation through Ficoll-Paque (Seromed, Berlin, Germany). The total number of marrow cells was then determined using Neubauer's counting chamber. The nonvital cells were marked by means of trypan blue staining. An average number of 1 x 10⁶ bone marrow cells were centrifugated on glass slides in a cytocentrifuge. After overnight air drying, the slides were either immediately fixated and stained or stored at a minimum temperature of -80°C. The staining took place under humid room conditions at room temperature, using phosphate-buffered saline (pH 7.6; our own production) as a medium for incubation. Nonspecific bonding sites were blocked by the addition of a 10% antibody serum (Biotest, Dreieich, Germany).

For immunostaining, the monoclonal antibody against CK 18 was used at a concentration of 0.05 µg/mL (Klon CK2; Boehringer Mannheim, Mannheim, Germany). Subsequently, the antibody reaction was developed with alkaline phosphatase with a polyvalent rabbit anti-mouse immunoglobulin antiserum (Dako, Hamburg, Germany) and preformed complexes of alkaline phosphatase and monoclonal anti–alkaline phosphatase antibodies (APAAP-Komplexe; Dako), according to the technique described by Cordell et al.² Cells containing CK18 were stained red by using neofuchsin and naphtol-AS-biphosphate after inhibition of endogenous phosphatase by preincubation with levamisole. The cells were washed three times between each of the steps.

Negative Controls. One isotype control per side of the iliac crest was carried out with each staining in order to exclude nonspecific reactions. This was achieved by inhibiting the CK18-bonding locations with mouse immunoglobulin G1 (MOPC 21). The negative control procedure, with respect to the existence of epithelial cells in bone marrow, was carried out in marrows of patients with no underlying malignant disease. Nine patients had urolithiasis, and one patient had impaired micturition. Four of these patients were female and six were male. Their ages ranged between 27 and 46 years (median, 34 years).

Positive Controls. A cell line of colorectal adenocarcinoma, the cells of which express CK18, served as the positive control. The positive control procedure, with respect to the existence of epithelial cells in the bone marrow, was performed with marrows of patients who had prostate cancer with bone metastasis (n = 43).

Histologic Examination and Flow Cytometry
Radical prostatectomy was performed using a suprapubic incision. The specimens were inked and fixed in formalin. The apical and caudal margins, the seminal vesicles, the transitional regions between seminal vesicles and prostate, and the margins of the spermatic ducts were analyzed separately. The prostate was cut into 3- to 4-mm slices. Each lobe was examined separately. Lymph nodes and surrounding adipose tissue were processed. Samples were stained with hematoxylin and eosin. Immunohistochemical examinations were performed when no tumor could be found or in unclear cases.

The ploidy was determined by means of flow cytometry. A distinction was made between diploid and tetraploid/aneuploid tumors. Tetraploid and aneuploid tumors were dealt with as one group.

Statistical Analysis
The correlation between the preoperative detection of CK18-positive cells in bone marrow and the prognostic factors, ie, Gleason score, pathologic stage, lymph node metastases, perineural invasion, and ploidy, was evaluated by means of the ² test or the Fisher's exact test. The interdependency between the marrow findings and the preoperative PSA level was determined with the Mann-Whitney test. The level of significance was 5%. To determine the differences in the distribution of the PSA levels within the groups with negative bone marrow findings, one CK-positive cell, two CK-positive cells, and three or more cells containing CK18, the Kruskal-Wallis, Median, and Jonckheere-Terpstra tests were applied.

	RESULTS

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Of all of the study samples (from 287 patients), 21 puncture specimens (7.3%) were not assessable. Of the 266 assessable puncture specimens, 76.3% were CK18-negative and 23.7% were CK18-positive. In patients with negative pelvic lymph nodes (n = 219), 75.8% of the preoperative bone marrow specimens were CK18-negative and 24.2% were CK18-positive. In the majority of patients, the number of CK18-positive cells was one to two cells per 1 to 2 x 10⁶ marrow cells. Rarely were there more than two cells or cell clusters (Table 1).

Patients with negative lymph nodes (n = 219) did not show any correlation between the Gleason score and the CK findings in the marrow. In tumors with a Gleason score of 2 to 4, 12.5% were CK-positive; in tumors with a Gleason score of 5 or 6, positive specimens could be found in 23.1%. In tumors with a Gleason score of 7, 23.5% of specimens were CK-positive, and in tumors with a Gleason score of 8 to 10, 26.8% were CK-positive (Fig 1A). Also, the number of cells had no correlation with the Gleason score, indicating that patients with undifferentiated tumors did not have larger numbers of cells than those with a lower tumor grade (Fig 1B) (212 patients were evaluated; In seven patients, no Gleason score was available).

View larger version (38K): [in this window] [in a new window]   Fig 1. (A) Distribution of CK18-negative () and CK18-positive () bone marrow specimens among the prostate cancers with Gleason scores of 2 to 4, 5 + 6, 7, and 8 to 10 (pN0, n = 219). (B) Distribution of CK 18-negative () and CK18-positive bone marrow specimens containing one () and two or more () cells among prostate tumors with Gleason scores of 2 to 4, 5 + 6, 7, and 8 to 10 (pN0, n = 219).

The pathologic stage also did not correlate with the detection of CK18-positive cells: 28.3% of patients (39 of 138) with organ-confined tumors (pT1/2) had CK18-positive marrow cells. In patients with specimen-confined tumors (pT3a, negative margins), CK18-positive cells were detected in 50% (one of two). Two (9.1%) of 22 patients with positive margins had positive marrow findings, whereas CK18-positive marrow cells were detected in 21.1% (seven of 33) of those patients with seminal vesicle invasion (pT3b). The number of cells did not correlate with tumor stage.

Twenty-four of the patients with negative lymph nodes had a lymphatic invasion; 16.7% were CK18-positive. The lymphatic invasion did not correlate with positive bone marrow findings or the preoperatively detected number of cells.

Despite the fact that perineural invasion is not considered an established prognostic factor, we investigated whether this finding correlates with a higher detection rate of CK18-positive bone marrow cells in patients with negative lymph nodes. Twenty-seven percent of the patients had perineural invasion and 13.6% were CK18-positive. Again, there was no correlation between the number of CK-positive cells and perineural invasion.

Forty-seven of the assessable patients had lymph node metastases. A connection between these findings and the proof of CK18-positive cells in the marrow or the number of these cells could not be established.

The ploidy of the tumor material was determined in 58 patients: 45 patients had diploid tumors and 13 patients had tetraploid or aneuploid tumors (DNA index 1.17 to 2.21). Of the 44 lymph node–negative patients, 37 had a diploid tumor and seven had a tetraploid/aneuploid tumor (DNA index 1.17 to 2.21). Of patients with aneuploid tumors, 23.1% had positive bone marrow findings, as did 17.8% of patients with diploid tumors. This difference was not significant, and the number of cells did not correlate with the ploidy.

The preoperative PSA level had no impact on the marrow findings: In both groups of patients (positive and negative marrow findings), the PSA levels were evenly distributed (Fig 2A). Additionally, there was no correlation between the number of CK18-positive cells and the preoperative PSA level (Fig 2B) (preoperative PSA levels were available for 215 patients).

View larger version (31K): [in this window] [in a new window]   Fig 2. (A) Distribution of the PSA levels in the patient groups with negative () and positive () bone marrow specimens. (B) Distribution of the PSA levels in the patient group with negative () and positive bone marrow specimens with one (), two, and three or more CK18-positive cells ().

Within the control group (n = 10), one bone marrow specimen was not assessable. Eight specimens were CK18-negative and one specimen was CK18-positive (one CK18-positive cell/1 x 10⁶ mononuclear cells).

	DISCUSSION

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Therapies with a curative intent are to be questioned if disseminated micrometastasis can be proven at the time of surgery. Since, in 1980, Sloane et al³ succeeded in proving the existence of disseminated tumor cells in the marrow of breast cancer patients, numerous studies have followed that correlate the proof of epithelial cells in bone marrow with conventional risk factors and/or follow-up data, thereby arriving at the statement that these cells are of prognostic relevance for different types of tumors.^4-8 Most of these studies refer to breast cancer in which the prevalence of micrometastases in bone marrow is between 2% and 48% and in which a mostly positive correlation with the proof of axillary lymph node metastases is found.^9-11 Some of the studies additionally describe a correlation with the pathologic tumor stage, the size of the tumor, and vessel invasion.^9,11 These examinations led to studies on micrometastasis of gastrointestinal and lung tumors and carcinomas of the head, neck, and pancreas, which also tend to metastasize in approximately 38.5% of patients.¹² It is remarkable that micrometastases with a similarly high prevalence were found in all carcinomas and that epithelial cells in the marrow are always proven in cases of solid tumor. This supports the thesis that these cells indicate an early state of dissemination but that there is not necessarily a further development to metastasis of the skeleton. This is substantiated by the fact that gastrointestinal tumors have a similarly high rate of micrometastasis, although metastases of the skeleton do not occur at the same frequency. Furthermore, micrometastases of various tumors differ from each other morphologically and phenotypically.^13-18

In patients with breast and gastrointestinal cancer, Pantel et al¹⁵ found a loss of HLA class I antigen on CK-positive cells of the bone marrow in 9% to 50% of patients; this loss was correlated with the grade of the primary tumor.

To prove the oncogenic capacity of the CK18-positive cells in the marrow, various proliferation markers were examined by means of double staining. Ki67 could be found only on a small portion of CK-positive cells.^8,16,19 Thus, it is concluded that most CK18-positive cells are in a "dormant" state.

In 78 patients with curatively resected stomach cancer, Allgayer et al^20,21 demonstrated that the expression of the urokinase plasminogen activator receptor on CK18-positive cells in the marrow correlated with an increased relapse rate.

As for localized prostate cancer, only studies that refer to a relatively small number of patients are available. In these studies, the prevalence of bone marrow micrometastases varies between 33% and 54.5%.^14,22,23 Investigations by Oberneder et al¹⁴ and Leißner et al²² revealed a correlation between the immunologic proof of CK18-positive bone marrow cells and the histopathologic tumor stage and the grade of prostate cancer, respectively. In contrast, Pantel et al²³ were unable to prove a correlation with tumor volume, grading, and preoperative PSA.

Thus, our objective was to examine the prevalence of CK18-positive cells and the correlation between micrometastasis and conventional risk factors, especially for localized and lymphatically spread prostate cancer. In those patients with negative lymph nodes, there was no correlation between Gleason score, pathologic stage, and preoperative PSA and the preoperative proof of CK18-positive cells in the marrow. Remarkably, patients with tetraploid and aneuploid tumors showed a higher rate of bone marrow micrometastases compared with diploid tumors. However, this difference was not statistically significant. Furthermore, we saw no more CK18-positive cells in patients with positive lymph nodes than we did in those with negative lymph nodes. We investigated whether the pathologic tumor stage or other prognostic parameters (ploidy, preoperative PSA, and lymph node metastases) showed any correlation with the number of CK18-positive cells before radical prostatectomy. We did not see a correlation between these parameters and the number of cells detected preoperatively.

Riesenberg et al¹⁸ were able to prove the origin of the CK18-positive cells in bone marrow of patients with prostatic carcinoma. They succeeded by using double staining versus CK18 and PSA, whereby a coexpression occurred in five of 13 patients. Pallavicini et al²⁴ found chromosomal anomalies in bone marrow micrometastases of prostate cancer and correlated these with findings in the primary tumor.

Long-term investigations regarding the impact of CK18-positive cells on the course of disease after radical prostatectomy are not yet available. Our own investigations of 169 patients with organ-confined prostate cancer did not show a higher biochemical relapse rate (PSA 0.5 ng/mL) in patients with positive preoperative bone marrow findings versus those with negative preoperative marrow findings after a median observation period of 32 months. Remarkably, patients with a larger number of cells (three CK18-positive cells/1 to 2 x 10⁶ mononuclear cells) had a poorer prognosis than those with fewer CK18-positive cells or with negative marrow findings. However, this difference was not significant, probably because of the small number of patients.²⁵

Results from a large patient study group are available with respect to the specificity of the immunocytochemical detection of CK18-positive cells in the marrow.⁷ In this study, only six (2.8%) of 215 patients without evidence of malignant tumor had one CK18-positive cell. As for our own control group, only one patient had one CK18-positive cell. One reason for false-positive results is the expression (although rare) of CK18 on nonepithelial bone marrow cells (eg, plasma cells). Furthermore, CK18 is not specific for prostate cancer; thus, any occult carcinoma may lead to bone marrow micrometastases. In contrast, 22 (55%) of 40 patients with prostate cancer and metastasis of the skeleton had CK18-positive marrow, which showed tremendous numbers of cells (one to 1,000 cells/1 to 2 x 10⁶ mononuclear cells) or cell clusters.

Results from a large study with respect to the sensitivity of the immunocytochemical detection of CK18-positive cells in bone marrow are not available. We are dealing with a rather low sensitivity in cases of small amounts of CK18-positive cells, since it should be difficult to find one CK18-positive cell in a pool of one to two million cells. Another reason for false-negative results is the downregulation of CK18 in bone marrow micrometastases.¹⁷

Thus, it is to be concluded that the available investigations of the immunocytochemical detection of CK18-positive bone marrow cells in prostate cancer are somewhat contradictory and not comparable, since these data derive from studies with heterogeneous patient groups. The results of the bone marrow examination depend on the applied monoclonal antibody, the number and volume of bone marrow aspirates, and the number of evaluated marrow cells per aspirate. Presently, we can state that CK18-positive bone marrow cells are detectable in 24.2% (our own data) to 54.5% of patients with localized prostate cancer and that these results are reproducible. The CK-positive cells derive, at least in part, from the prostate and correlate with the findings of the primary tumor. In localized prostate cancer, it is not possible to identify patients with a poor prognosis by immunocytochemical detection of CK18-positive bone marrow cells, since the sensitivity and specificity of this method are too low and preliminary results do not show a correlation between positive marrow findings and established risk factors or a higher biochemical relapse rate. As, however, CK18-positive cells are tumor cells, at least in part, future investigations ought to aim at a closer characterization of these cells, to show that relevant metastases may develop from these cells. On the other hand, it is necessary to initiate further examinations on a control group with CK18-positive cells, in order to find out whether these results are false-positive or whether CK18-positive cells really are tumor cells derived from a clinically occult carcinoma.

	ACKNOWLEDGMENTS

 
We thank Waltrand Werdecker, Dr Dorothea Wantia, and our local urologic colleagues for the valuable help in acquiring and evaluating the data and Karlheinz Haude for excellent statistical analysis.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted October 28, 1998; accepted July 8, 1999.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Weckermann, D. Articles by Schlimok, G. Search for Related Content PubMed PubMed Citation Articles by Weckermann, D. Articles by Schlimok, G. Social Bookmarking                            What's this?