Bone marrow is among the most frequent site for metastasis of lung cancer, but pathologic studies on bone metastatic disease or on the metastatic tissues are surprisingly rare in the literature. Proper diagnosis of bone marrow involvement should have an influence on decision making as regards to therapeutic strategy and surgical approach in order to achieve better prognosis in these patients with this bad prognostic factor that upgrades the primary lesion to stage IIIA.
The current study indicates that micrometastases detected with IHC are lower than PCR but not statistically significant. Also, we have found that a total of 14 of the 41 (34%) surgically treated patients with NSCLC, mainly Stage IIIa, present with bone marrow micrometastasis (BMM) at the time of surgery. In addition, our data revealed that iliac bone marrow aspiration failed to demonstrate BMM among lung cancer patients. In previous studies, the frequencies of BMM in patients with NSCLC have varied between 22% and 70%.[4
] This considerable variation could be explained by the use of different assays (immunocytochemistry and flow cytometry) and detection markers with varying specificity and sensitivity, but also the number of bone marrow harvest sites varied between reports. Thus, the two studies reporting the highest frequencies (60% and 70%) both included multiple bone marrow aspiration sites, which have been shown to contribute to increased sensitivity of tumor cell detection.[10
In the present study, no significant differences in BMM frequency were observed between patients with early (stages I-IIb, n = 23) and advanced stage disease (stages III, n = 17). Interestingly, in this group of mainly early stage disease, the frequency of detected BMM was in the mid-range of previously reported results from almost exclusively early stage patients. Our results are similar to other studies[11
] revealing that BMM is independent of disease stage. This may support the hypothesis that systemic spread may occur early during tumor development in patients with NSCLC.[11
With respect to the prognostic significance of BMM in NSCLC, no consensus may be derived from the published literature, illustrated by a 2004 review in which four of the seven included studies found that BMM could predict poor prognosis, while the three remaining studies reported the opposite conclusion.[13
] Our study may, however, not have been ideally designed to assess the prognostic significance of BMM in NSCLC, since most of the examined patients had failure to follow up. Therefore, we have no data on patient's survival.
These findings suggest that in this selected group of long-term survivors, it is unclear whether the presence of tumor cells in BM could influence patient survival, which could indicate that tumor cells may have entered into a non-proliferative or dormant stage. Metastatic cells can remain dormant indefinitely or may begin to proliferate after variable periods of dormancy due to factors that are not well understood.[14
] It has previously been reported that cancer vaccines can induce and maintain dormancy in tumor cells, presumably through immune-mediated mechanisms,[15
] which could help explain the observed continued presence of BMM without detectable clinical progression in the study of Brunsvij et al
] One study suggests that the presence of micrometastatic cells in a sanctuary site has no major impact on the prognosis and survival of patients with operable NSCLC. Therefore, embarking on adjuvant therapies for early-stage NSCLC-based solely on the finding of bone marrow micrometastatic cells seems not justified at this point (62).[4
In contrast to our study, other reports confirmed a trend for higher prevalence of BMM with increased cancer staging. However, when predictor variables such as age, sex, histology, tumor location, smoking, or weight loss are analyzed, no correlation can be found between micrometastasis prevalence and any of those variables.