3. Results
3.1. Study selection
The initial search identified 11,110 titles reviewed (PubMed: 8,324;
Google Scholar: 1,208; Cochrane library: 1,578). Reviewer 1 read 330
abstracts, from which 97 articles (including 17 articles screened from
references) were flagged for Reviewer 2 (Fig. 1). Seventy-five articles
were identified for full-text review. Of these, 37 were deemed
ineligible for inclusion due to the following reasons: 18 did not report
incidence of BM metastasis; 7 did not utilize FDG-PET scans to assess
for BM metastasis; 6 had missing data on diagnostic testing used for
metastatic disease; 4 were not in English; 2 involved patients with
diseases other than ES.
3.2 Quantitative analysis: Incidence of BM metastasis
We identified 10 studies providing quantitative data describing the
incidence of BM metastasis in all unselected patients with newly
diagnosed ES (Table 1).[21,23-31] These studies ranged in year of
publication from 1995 – 2020. Eight studies were completed in a
retrospective manner, one was a phase 3 clinical trial and one was a
pilot trial. Combined, they comprise 1,663 patients (median 75
patients/study; range 17 – 647 patients).
Of the total of 1,663 patients, 79 had BM metastasis, for an incidence
of 4.8% in this unselected group of patients. Among the 450 patients
with any metastatic disease, the incidence of BM disease was 17.5%
(79/450). Three studies reported the presence or absence of isolated BM
metastases, with 1.2% (8/692) of patients with isolated BM
metastasis.[24,25,27] Ten additional patients with isolated BM
metastatic disease were identified in the literature for a total of 18.
Eight of these 18 cases reported the location of the primary tumor:
three pelvic primary tumors and five located in the appendicular
skeleton.
We identified an additional 8 studies for which inclusion was restricted
to newly diagnosed ES patients with metastatic disease only or a
specific subset of metastatic ES. Five of these studies reported the
incidence of BM metastasis in a selected population of ES patients
(Table 2).[2,32-35] Of these, three excluded patients with newly
diagnosed localized ES and reported on 934 total patients with newly
diagnosed metastatic ES. Of these, 19.0% were reported to have BM
metastasis. Two other studies describe further subsets of metastatic ES
patients. One excluded patients with lung only metastatic disease and
reported an incidence of BM metastasis of 43.8% (123/281).[2] A
second study limited its inclusion to patients with metastatic bone ES
and reported an incidence of BM metastasis of 23.7% (23/97).[35]
Two additional studies in patients with metastatic disease reported
patients with isolated BM metastatic disease without providing an
incidence of any BM metastasis. One study reported 7% (8/110) of
patients with newly diagnosed metastatic ES to present with isolated BM
metastasis,[36] another reported 3.3% (2/60) incidence of isolated
BM metastatic disease.[37]
Patients with isolated lung metastasis have superior outcomes compared
to patients with other metastasis.[3] Since detecting BM metastasis
in patients who might otherwise have a more favorable outcome may
provide important prognostic information, we also assessed the frequency
of BM metastases in patients with lung metastasis but lacking bone
metastases. We evaluated all studies included in Tables 1 2. Six of the
15 studies analyzed reported relevant data, with 8.8% (20/225) of
patients with reported lung metastatic disease also having BM metastasis
but not bone metastasis.
3.3 Quantitative analysis: FDG-PET scan vs. BMBA
Four studies (Table 3) were identified which utilized FDG-PET scans for
staging of BM metastasis in newly diagnosed ES
patients.[21,29,38,39] Data from these studies were aggregated for
quantitative analysis to define testing characteristics of FDG-PET scans
compared to BMBA. The studies ranged in publication year from 2013 -
2019 and all were completed in a retrospective manner. Combined, these
studies comprised 142 patients (median 23 patients/study; range 16-80
patients).
Pooled patient level data were used to construct a contingency table to
determine sensitivity, specificity, PPV and NPV. Results revealed
FDG-PET scans to have a sensitivity of 100% (3/3) and specificity of
96% (96/100) to detect BM metastasis. Compared to BM biopsy, the PPV of
a positive FDG-PET scan was found to be 75% (3/4) and the NPV of a
negative FDG-PET scan was 100% (106/106). The patient with a negative
BMBA but positive FDG-PET scan was identified by Kasalek et al on
FDG-PET scan to have BM metastatic lesions involving bilateral posterior
iliac crest and extensive BM involvement elsewhere in the axial and
appendicular skeleton. [38]
3.4 Qualitative analysis
Several studies were selected for inclusion in our review based upon
qualitative analysis or descriptive findings contributing to the
understanding of the incidence of BM disease at presentation in ES as
well as the advantages and disadvantages to BMBA and FDG-PET scan in
assessment of BM metastatic disease.
The most common reported association for patients with BM metastasis was
the presence of other metastatic lesions, and specifically bone
metastasis. Kopp et al found BMBA to be positive in 41.9% (13/31) of
patients with the presence of other metastatic but 0% (0/85) in ES
patients with non-metastatic disease.[26] A positive association of
the number of bone metastatic lesions and presence of BM metastasis was
reported by Inagaki et al. Of 26 patients with newly diagnosed ES, 100%
(3/3) of patients with BM metastasis had bone metastases and 4.3%
(1/23) patients without BM metastases had bone metastases.[29]
Newman et al reported 0 of 91 ES patients with BM metastases in cases
without osseous metastatic disease.[21] Khan et al reported that
45.5% (5/11) of patients with BM mets had concurrent bone metastatic
disease.[25]
Additionally, BM metastasis was reported to be associated with primary
tumors of the pelvis, large tumor size, and presentation with fever
and/or elevated lactate dehydrogenase (LDH) level. Two studies reported
that pelvic primary site was significantly associated with BM metastatic
disease at diagnosis. One reported a risk of BM involvement three times
higher in patients with pelvic lesions compared with other primary
sites; the second reported BM involvement in 22% (13/59) of patients
with pelvic primary disease.[24,27] Tumor diameter (≥80mm) and LDH
level at diagnosis (> x ULN) were reported to be factors
significantly related to BM involvement by Inagaki et al.[29]
Oberlin et al reported fever at diagnosis was significantly associated
with the presence of BM metastasis.[27]
One study analyzed the concordance between BM aspirate (BMA) and BM
biopsy (BMB). Among 59 patients with bilateral BMA and 62 patients with
bilateral BMB, concordance rates between sides were 97% and 98%,
respectively. BMB was concluded to be more sensitive to detect
metastatic disease than BMA as 100% (4/4) cases of positive BMA were
also found to have positive BMB, three positive BMB procedures had
negative ipsilateral BMA.[21] In a study including adult patients
with various types of sarcoma, discrepancies in findings of metastatic
disease between bilateral samples by morphologic evaluation were found
in 29% of (27/94) of cases.[40]