4. Discussion
To our knowledge, this systematic review is the first to describe the incidence of metastatic BM disease with and without the presence of additional metastatic disease in newly diagnosed ES patients, as well as report the testing characteristics of FDG-PET scans in the diagnosis of metastatic BM disease in this population.
Our results indicate a pooled incidence of BM metastasis of 4.8% in all patients with newly diagnosed ES and 17.5% in patients with other clinically or radiographically apparent metastatic disease. Further, 8.8% of patients with known lung metastasis were reported to have BM but not bone metastasis. FDG-PET scan demonstrates a sensitivity and specificity of 100% and 96%, and a PPV and NPV of 75% and 100% to detect BM metastatic disease compared to BMBA. Given these findings, we have modified our local practice as follows. During initial workup in patients with newly diagnosed ES presenting with clinical or radiographic (including FDG-PET scan) evidence of metastatic disease, we obtain BMBA as this information may provide information relevant to prognosis, response assessment, and understanding potential delays due to slow blood count recovery. In the specific setting of isolated pulmonary metastasis on staging studies obtained prior to BMBA, the incidence of detecting BM metastatic disease appears high enough and the prognostic impact of a positive finding great enough to make this a particularly important population to evaluate by BMBA. On the converse, one may reasonably conclude that detecting BM metastasis in patients with known bone metastasis provides only modest additional prognostic information. Our local practice nevertheless still includes BMBA for such patients to obtain full extent of disease at baseline, which may inform response, toxicity assessment, and prognosis. In patients with no evidence of metastases including no BM uptake on FDG-PET scan, we now omit BMBA as part of routine staging, unless there are clinical concerns (e.g., findings on peripheral complete blood count) or clinical trial requirements. This latter approach is consistent with conclusions drawn by several studies included in this review.[21,24,26,29] While some studies reported an association of BM metastasis disease with primary tumors of the pelvis, [24,27] it is not clear if this finding represents sampling of primary tumor tissue during BMBA procedure. Based upon the available evidence, we do not recommend bone marrow sampling in the setting of a primary pelvic tumor if diagnostic workup reveals no concern for metastatic lesions.
Though rare, we identified 18 reported cases of newly diagnosed ES patients with isolated BM metastasis.[24,25,27,36,37] In eight cases, location of the primary tumor was provided, with 63% (5/8) reporting location in the appendicular skeleton.[24,25,27] On review of these individual cases, no significant associations to aid in their identification was observed. In 16 of 18 cases, staging workup was reported. All 16 cases included MRI of the primary site, CT scan of the chest as well as bone scan to evaluate the presence/absence of metastatic disease. FDG-PET scans, a relatively newer technology, were not reported during initial workup.
We acknowledge that our approach to omit BMBA at initial staging in patients without other metastasis may miss this very rare subgroup of patients with isolated BM metastasis. However, the available data support a role for using FDG-PET scan as a screening tool for assessment for BM disease. We found no reported cases of false negative findings of BM metastatic disease by use of FDG-PET scan (sensitivity and NPV of 100%). Thus, when FDG-PET scan is negative for BM metastasis or other metastasis, omission of BMBA seems reasonable. When FDG-PET scan demonstrates BM metastasis by imaging, the decision to perform a confirmatory BMBA may be based upon the overall clinical context. For example, an FDG-PET scan demonstrating a positive BM signal in the context of widespread bone metastasis would likely be viewed differently from an FDG-PET scan demonstrating only a positive BM signal in a patient with otherwise localized disease. Given the major prognostic implications in the latter case, a confirmatory BMBA may be particularly important clinically. Of note, our review found one reported false positive case by FDG-PET scan with negative BMBA. However, this assumes BMBA as the gold standard for diagnosing BM metastasis, but given the possibility of BM involvement being patchy, this finding may represent a false negative BMBA.
The role of BM investigation by either a BMB or BMA or by a unilateral vs bilateral procedure were discussed in several reports. One study concluded that completing only a BMB or a BMA was inadequate as they noted BM involvement to be focal in several patients resulting in frequent discrepancies between aspirates and biopsies at the various sites explored.[27] A second study analyzing the ability of BMB vs BMA and unilateral vs bilateral approach in detection of BM metastatic disease found BMB and bilateral approach, respectively, were superior in detecting BM metastases.[21] Based upon these findings, when indicated, we obtain bilateral evaluation with bone aspirate and biopsy.
From this systematic review of the literature, the incidence of BM metastasis is 4.8% in all patients with newly diagnosed ES and 17.5% in patients with clinically apparent metastatic ES. Based upon the testing characteristics of FDG-PET scans in the diagnosis of metastatic BM disease in newly diagnosed ES, we now obtain BMBA at initial staging according to the algorithm in Figure 2. In the absence of specific extenuating circumstances, we omit staging BMBA in newly diagnosed patients with no evidence of metastases on other staging studies. In patients with newly diagnosed ES who have metastatic disease detected by other staging studies that include an FDG-PET scan, we obtain baseline BMBA.
Conflict of Interest Statement: SGD reports travel expenses from Loxo Oncology, Roche, and Salarius and consulting fee from Bayer and Loxo Oncology.
Grant Support: NIH T32 CA136432-08 (KC) and Alex’s Lemonade Stand Foundation (KC & DS).