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).