Bone metastases from breast cancer: associations between morphologic CT patterns and glycolytic activity on PET and bone scintigraphy as well as explorative search for influential factors
Bone metastases from breast cancer: associations between morphologic CT patterns and glycolytic activity on PET and bone scintigraphy as well as explorative search for influential factors
Tsutomu Sugihara 0 1 2 3 4 5 6
Mitsuru Koizumi 0 1 2 3 4 5 6
Masamichi Koyama 0 1 2 3 4 5 6
Takashi Terauchi 0 1 2 3 4 5 6
Naoya Gomi 0 1 2 3 4 5 6
Yoshinori Ito 0 1 2 3 4 5 6
Kiyohiko Hatake 0 1 2 3 4 5 6
Naohiro Sata 0 1 2 3 4 5 6
0 Department of Nuclear Medicine, Cancer Institute Hospital , 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 , Japan
1 Department of Breast Oncology, Yasugi Daiichi Hospital , 899-1 Yasugi, Yasugi, Shimane 692-011 , Japan
2 & Mitsuru Koizumi
3 Department of Gastrointestinal Surgery, Jichi Medical University , 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498 , Japan
4 Department of Hematology Oncology, Cancer Institute Hospital , 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 , Japan
5 Department of Breast Medical Oncology, Cancer Institute Hospital , 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 , Japan
6 Department of Diagnostic Radiology, Cancer Institute Hospital , 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 , Japan
Background This study aimed to compare the detection of bone metastases from breast cancer on F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) and bone scintigraphy (BS). An explorative search for factors influencing the sensitivity or uptake of BS and FDG-PET was also performed. Methods Eighty-eight patients with bone metastases from breast cancer were eligible for this study. Histological confirmation of bone metastases was obtained in 31 patients. The bone metastases were visually classified into four types based on their computed tomography (CT) appearance: osteoblastic, osteolytic, mixed, and negative. The sensitivity of BS and FDG-PET were obtained regarding CT type, adjuvant therapy, and the primary tumor characteristics. The FDG maximum standardized uptake value (SUVmax) was analyzed.
Bone metastases; FDG-PET scintigraphy; Breast cancer
The bone is the most common site for distant metastases in
patients with breast cancer, accounting for about 65% of
patients with distant metastases and representing the first
site of metastasis in 50% of patients [
bone scintigraphy (BS) has been widely used to search for
bone metastases, and it is undoubtedly useful because of its
ability to evaluate the entire skeleton at a relatively low
cost . However, in some cases, it has low specificity and
produces false-positive results due to uptake by benign
lesions, such as osteoarthritis, fractures, and inflammation.
Consequently, even experienced nuclear physicians often
have difficulty in distinguishing bone metastases from
benign disease [
F-18 Fluorodeoxyglucose positron emission
tomography (FDG-PET) is useful for staging cancer, detecting
recurrences, and evaluating treatment effectiveness, and it
is reportedly of particular value when searching for bone
metastases from breast cancer [
]. Multiple authors
have concluded that FDG-PET/computed tomography
(CT) is more sensitive for the detection of lytic bone
metastases in patients with breast cancer, while BS is
more sensitive for the detection of osteoblastic bone
]. A meta-analysis in 2008 showed no
conclusive evidence regarding the superiority of BS or
FDG-PET . Since then, PET machines have been
equipped with CT. A more recent meta-analysis in 2013
concluded that FDG-PET/CT is superior to BS in
diagnosing bone metastases from breast cancer [
these previous studies did not discuss the tumor
characteristics of breast cancer. In another study, non-FDG-avid
osteoblastic bone metastases were more common in
patients with invasive lobular carcinoma than in those
with invasive ductal carcinoma [
In the present study, we further extended this
investigation by directly comparing FDG-PET and BS for the
detection of bone metastases from breast cancer. Each bone
lesion was classified as the osteoblastic, osteolytic, mixed,
or negative type based on its CT findings. We also
performed an extensive search for factors influencing the
sensitivity or uptake of BS and FDG-PET. We attempted to
clarify the pitfalls of using FDG-PET for the detection of
Patients and methods
This single-institution retrospective study included
consecutive patients with suspected bone metastases from
histologically proven breast cancer treated at our hospital
from February 2013 to December 2016. Patients who were
suspected to have bone metastases on BS were pooled
during this period, and those with definite bone metastases
and FDG-PET/CT studies within 1 month were enrolled in
this study. Bone involvement was histologically confirmed
by biopsy, especially in cases of oligo bone metastases. If
biopsy was difficult to perform or multiple bone lesions
were present, the diagnosis was established clinically:
confirmation was performed by other imaging modalities
such as CT and magnetic resonance imaging, and by
The primary tumor characteristics as histological
subtypes, tumor nuclear grades (NG), estrogen receptor (ER)
status, and human epidermal growth factor receptor type 2
(HER2) status were recorded. We also investigated the
effect of chemotherapy or hormone therapy on the
diagnosis of bone metastases. The patients were divided into no
treatment at the diagnosis of bone metastases, adjuvant
hormone therapy, or adjuvant chemotherapy.
This study was done in accordance with ethical standard
laid down in the 1964 Declaration of Helsinki and its later
amendments, and this study was approved by our local
ethical committee. Informed consent was waived for this
type of study.
BS, FDG-PET/CT, and CT
BS was performed approximately 3 h after an intravenous
injection of 740 MBq technetium-99m methylene
diphosphonate (99mTc-MDP, Fujifilm RI Pharma Co. Ltd.,
Tokyo, Japan). Whole-body images were obtained using
three different gamma cameras (ADAC Forte, Toshiba
ECAM, and GE Infinia) equipped with low energy
highresolution parallel-hole collimators. The matrix size was
256 9 1024. The energy peak was centered at 140 keV
with a 15% window. Scan speed of whole body was
20 cm per min.
Patients fasted for at least 6 h before being injected
with 4 MBq/kg FDG and then whole-body image
acquisition started at 60 min later from the top of the
skull to the mid-thigh using an Aquiduo PET/CT scanner
(Toshiba, Japan) or Discovery 600 PET/CT scanner (GE,
USA). Emission data were acquired for 2–3 min per bed
position. The PET images were reconstructed using an
iterative algorithm (attenuation-weighted ordered subset
expectation maximization: 4 iterations, 14 subsets) with
an 8-mm Gaussian filter, a 128 9 128 matrix (3.9 mm/
pixel) and 81 slices (2 mm/slice). Whole-body CT
scanning proceeded under the following parameters:
120 kV; auto exposure control system (noise level: SD
10); 512 9 512 matrix; beam pitch, 0.94; 2 mm 9
16row mode. Maximum of standardized uptake value
(SUVmax) was measured from the representative bone
metastatic lesion: biopsied site or representative site.
Each patient had one SUVmax.
CT studies were performed by a multi-detector
GEdiscovery 750 HD (64 rows, GE Healthcare Japan, Hino,
Tokyo, Japan). CT scans were reconstructed with a 2-mm
thickness at 5-mm intervals. Lesions of bone metastases on
CT scan were visually classified by multi-slice CT based
on the degree of osteoblastic and osteolytic change into
four types: osteoblastic, osteolytic, mixed and negative (not
detectable). FDG-PET, BS and CT images were evaluated
Fig. 1 A 51-year-old female had right breast cancer surgery 10 years
ago. She showed a tumor marker elevation (carcinoembryonic
antigen), and bone scintigraphy (BS) was performed. A hot spot
was shown in her left femur (around lesser trochanter) on BS (a).
However, following CT could not demonstrate the lesion (b coronal,
independently by two nuclear medicine physicians. The
discordant number was 2/88 in BS, 7/88 in CT, and 2/88 in
FDG results. The discrepant cases were discussed by two
nuclear physicians, and the final version was decided.
Analysis and statistical methods
Step 1: The sensitivities of BS and FDG-PET were
calculated with the CT four types of bone metastases on all
patients. The contingency table analysis was performed
using Fisher’s exact test.
Step 2: The sensitivity of BS and FDG-PET were
calculated with respect to CT type, systemic therapy, and the
primary tumor characteristics at the time of initial
treatment. A contingency table analysis was performed using
Fisher’s exact test.
Step 3: The FDG SUVmax of the bone metastases were
compared with respect to factors showing a statistically
significant difference in the above analysis and influential
factors. Data were statistically analyzed using the Mann–
Whitney U test.
Multivariate analysis was not applied because the
number of patients was too small. Statistical analysis
software (SPSS version 24; IBM Corp., Armonk, NY,
c axial). Therefore, FDG-PET/CT study was carried out, and an
intense FDG uptake was noticed on her left femur (d whole-body
FDG image, e fusion axial image). CT-guided bone biopsy revealed
the lesion as metastasis pathologically
USA) was used. A P value of P \ 0.05 was considered to
indicate statistical significance.
Suspected bone metastases from breast cancer were present
in 149 patients, 88 of whom had definite bone metastases
and had undergone both BS and FDG-PET studies within
1 month. The median patient age at diagnosis was 60 years
(range 31–85 years). Thirty-five of the 88 patients
underwent biopsy or surgery for the suspected bone metastases,
and histological confirmation was obtained in 31 patients.
The other 57 patients were clinically diagnosed with bone
metastases by their imaging findings and clinical course.
Bone metastases were classified according to their CT
findings as osteoblastic in 16 patients, osteolytic in 31,
mixed in 21, and negative in 20. The final diagnosis of
CTnegative patients was made as follows: 6 patients were
confirmed by bone biopsy, 4 by MRI, and 10 by later
studies (CT appearance turned to be evident). Figure 1
shows a CT-negative patient. A hot spot was shown in the
left femur (around the lesser trochanter) on BS; however,
CT study did not detect any abnormality (CT negative).
Therefore, FDG-PET/CT study was carried out to evaluate
the left femur lesion, and intense FDG uptake was detected.
Then, CT-guided biopsy confirmed the lesion as metastasis
The patients’ demographic characteristics are shown in
The sensitivities of the three imaging modalities (CT,
BS, and FDG-PET) were 77% (68/88), 89% (78/88), and
94% (83/88), respectively. The sensitivities of BS and
FDG-PET for the four CT-based types are shown in
Table 2. The sensitivity of BS was 94% (15/16) for the
osteoblastic type, 90% (28/31) for osteolytic, 100% (21/21)
for mixed, and 70% (14/20) for negative. The sensitivity of
FDG-PET was 69% (11/16) for the osteoblastic type, and
100% for the other three types. The sensitivity of
FDGPET for the osteoblastic type was significantly lower than
that for the other types (P \ 0.001). The sensitivity of BS
for the negative type (70%, 14/20) was significantly lower
than that for the other types (P = 0.008). There was no
significant difference in the sensitivities of BS and
FDGPET with respect to the histological type, ER status, HER2
status, or systemic adjuvant therapy. A significant
difference in the sensitivity of FDG-PET was observed between
NG1 and NG2–3 (P = 0.032).
Numbers in parentheses indicate (positive patient number/patient
Total CT sensitivity: 77% (68/88)
BS bone scintigraphy, FDG F-18 fluorodeoxyglucose, CT computed
The patients’ SUVmax are shown in Table 3. The
SUVmax was available in 77 of 88 patients. The CT type
(osteoblastic vs. others) and NG (NG1 vs. NG 2–3) were
chosen because they showed statistically significant
differences in the preceding analysis (contingency table
analysis). The histological type (invasive ductal cancer vs.
invasive lobular cancer) was also included because it was
one of the main investigation themes of this study. The
SUVmax of the osteoblastic type was significantly lower
than that of the other types (P = 0.009). The SUVmax of
NG1 was significantly lower than that of NG2–3
(P = 0011). The median SUVmax of invasive lobular
cancer was lower than that of invasive ductal cancer
(median, 4.5 and 6.7, respectively); however, these values were
not statistically different (P = 0.103) (Table 4).
The diagnostic accuracy of FDG-PET and BS for bone
metastases in patients with breast cancer has been
exclusively compared and studied, but whether FDG-PET or BS
is superior in detecting bone metastases remained
inconclusive in a 2008 meta-analysis [
]. However, in a 2013
meta-analysis, FDG PET/CT had higher sensitivity and
accuracy than BS for detection of bone metastases in
patients with breast cancer [
]. Earlier reports suggested
that FDG-PET, while highly sensitive for detecting
osteolytic type bone metastases as shown on CT, had a lower
detection ratio for osteoblastic-type metastases [
The decreased FDG uptake in osteoblastic bone metastases
might be explained by the following scenario: osteoblastic
proliferation in osteoblastic metastases results in an
increased bone matrix and relatively decreased cell density;
this leads to lower FDG accumulation because FDG uptake
in tissue reflects the underlying glucose metabolism and
cell density [
]. In the present study, the SUVmax and
sensitivity of FDG-PET for CT osteoblastic-type
a Number of patients
BS bone scintigraphy, FDG F-18 fluorodeoxyglucose, CT computed tomography, ER estrogen receptor,
HER2 human epidermal growth factor receptor type 2, NG nuclear grade
metastases were significantly lower than those for other CT
types. Our study also showed that the sensitivity of BS was
low for the CT-negative type. PET machines have recently
been equipped with CT, and the FDG PET/CT results can
be comprehensively evaluated using both FDG
accumulation and CT features. Therefore, FDG-PET/CT allowed for
detection of all bone metastases in our study.
Another factor that might influence on FDG uptake is
histological differences. Previous studies have suggested
that the FDG avidity of primary breast cancer is lower in
patients with invasive lobular carcinoma than invasive
ductal carcinoma [
]. The lower FDG avidity of
invasive lobular carcinoma could be explained by the lower
cellular density, proliferation rate, and number of GLUT
glucose transporters in this breast cancer histology than in
more common histologies [
]. However, few studies
have investigated the relationship between breast cancer
histology and FDG avidity in patients with bone
metastases. Dashevsky et al. [
] compared the histology of
breast cancer and the FDG avidity in bone metastases from
breast cancer. They reported that non-FDG-avid sclerotic
osseous metastases were more common in invasive lobular
cancer than in invasive ductal cancer. The present study
results are not in agreement with their findings. All bone
metastases in our patients with invasive lobular cancer
were FDG avid (7/7). Of the seven patients, three patients
were the CT-negative type and the other four were the
CTosteolytic type. The median FDG SUVmax of invasive
lobular cancer was lower, but not statistically significant;
the median FDG SUVmax of invasive lobular and ductal
cancers were 4.5 and 6.7, respectively, but there was no
statistically significant difference (P = 0.103). The reason
for this discrepancy might be the small patient number in
our study (n = 7). Another factor that differed between the
present study and that by Dashevsky et al. [
] is that our
bone metastases were newly diagnosed, but some patients
received adjuvant therapy. Among seven patients with
invasive lobular cancer, five did not receive adjuvant
therapy, but two were diagnosed with bone metastases
during adjuvant hormone therapy. Further investigation is
needed to clarify the relationship between the histology of
breast cancer and FDG avidity in bone metastases.
We identified a relationship between the NG of breast
cancer and FDG avidity. Specifically, FDG avidity (both
sensitivity and SUVmax) of bone metastases in patients with
NG1 cancer was significantly lower than that in patients
with NG2–3 cancer. In other words, FDG uptake in bone
metastases from primary tumors with a mild NG was lower
than that from primary tumors with a more aggressive NG.
This finding is unique but needs to be clarified in other
studies because the number of patients was not enough in
the present study. We found no significant correlation
between the NG grade and CT type (data were not shown).
The limitations of the present study are its retrospective
design and rather small number of patients, especially in
the subgroups. The small number of patients prevented us
from performing a multivariate analysis. Another limitation
of the present study was that 31 of 88 patients were
confirmed histologically as having bone metastasis, which
means 57 patients were diagnosed clinically. We
experienced difficulty in clinical diagnosis of bone metastasis in
CT-negative (intertrabecular type) patients. There were 20
patients with CT-negative results. The final diagnosis of
CT-negative patients was made as follows: 6 patients were
confirmed by bone biopsy, 4 by MRI and follow-up, and 10
by later studies (CT appearance turned to be evident).
The development of single photon emission computed
tomography with CT (SPECT/CT) made the planar bone
scintigraphy as an old modality, although bone scan is still
actively used in clinical practice. The computer-aided
diagnosis such as Bone Navi made the old modality
(bone scintigraphy) as a modern diagnostic tool. We
hoped to conduct the study using bone SPECT/CT,
however, bone SPECT/CT was not performed in any
patients. This prevents us from performing the study
using bone SPECT/CT.
In conclusion, the diagnostic performance of BS and
FDG-PET was re-evaluated in patients with bone
metastases from breast cancer, and histological confirmation of
bone metastases was obtained in 31 of 88 patients. We
considered that CT morphological type was an important
factor for the diagnostic performance. The negative type
often showed negative BS results, and the osteoblastic type
often showed negative FDG-PET results. FDG-PET/CT
has potential to serve as an excellent imaging modality
because both FDG and CT data can be obtained in a single
study, and each imaging modality compensates for the
other’s weak points. We further performed the analysis of
various factors influencing FDG accumulation.
Significantly low FDG uptake was seen in osteoblastic-type bone
metastases and bone metastases from primary breast cancer
with a low NG. Other factors including the histological
type showed no significant difference. These results would
be of use when interpreting bone metastases.
Acknowledgements We thank Ms. Hiromi Ito for editing this
Compliance with ethical standards
Conflict of interest No potential conflicts of interest were disclosed.
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