Introduction
According to the 2017 data of the American Cancer Society,
breast cancer is the most common cancer in women. Breast cancer ranks second in cancer-related deaths after
lung cancer.[] Early diagnosis, more accurate and
non-intervention staging, follow-up of treatment, and
prognosis are the most important processes in determining the approach to breast cancer.[] About 50-70%
of breast cancers are invasive ductal carcinoma (IDC),
5-15% are invasive lobular cancer (ILC), 1-6% are mucinous
carcinoma, and 1-2% are tubular carcinoma.[]
The diagnosis and staging of ILC is more difficult than
IDC because of the characteristic growth pattern.[] The
tumor does not produce a stromal reaction and therefore
tissue thickening occurs more than a mass formation
and microcalcification, which is the most important
clinical finding in early diagnosis that is rarely seen.[,]
Although 18F-fluorodeoxyglucose ([18F] FDG)
positron emission tomography (PET) imaging has
high sensitivity and specificity in showing malignant
lesions, its sensitivity in breast cancer is limited. In a
meta-analysis, the overall sensitivity and specificity of
[18F] FDG PET/CT in detecting primary breast cancer
were found to be 64-96% and 73-100%, respectively.[]
While the sensitivity of [18F]FDG PET/CT is 57% in
tumors <1 cm in diameter, it exceeds 90% in tumors
larger than 1 cm.[] Glut-1 and hexokinase expression,
number of viable tumor cells, histological subgroup,
microvascular density, and presence of inflammatory
cells are the major factors affecting [18F] FDG uptake
in breast cancer.[] It is known that estrogen and progesterone
receptor negative, human epidermal growth
factor receptor 2 (HER-2) expression positive tumors
show higher [18F] FDG uptake than receptor-positive
and HER-2-negative tumors.[] Furthermore, [18F]
FDG PET/CT imaging is less sensitive in ILC than IDC
because of low [18F] FDG uptake. It is reported that
the clinical systemic contribution of PET/CT is low
due to the low [18F] FDG affinity in mucinous (1-6%)
and tubular (1-2%) cancers, which are less common
with ILC, which constitutes 10-15% of breast cancers.
[,] The main factors that explain low [18F] FDG
uptake in ILCs are lower tumor cell density, diffuse infiltration
in the surrounding tissue, low Glut-1 expression,
and low proliferation rate.[] For these reasons,
the influence of [18F] FDG PET/CT to IDC was mostly
assessed in the studies and the ILC could be included
in a limited number of studies or was not included because
of low sensitivity.[,]
It is known that the continued accumulation of
[18F] FDG is due to the low concentration of glucose-
6-phosphatase enzyme in the tumor cell, and it is
known that imaging quality will be optimal as long as
the radiopharmaceutical half-life allows and that imaging
may contribute to the diagnosis in malignancies.
[] There are many studies reporting that late image
on [18F] FDG PET/CT significantly increases sensitivity
and specificity in breast cancer.[-]
Last decade, the importance of measuring tumor
heterogeneity is identified to solve the inability of current
therapies. The tumor heterogeneity is not fully understood
with invasive techniques, such as biopsy, and
also non-invasive imaging techniques such as PET/CT
which could give the information of genotypic and phenotypic
tumor variations. Many techniques have been
proposed to use tumor heterogeneity as a biomarker.
There are some mathematical methods to define tumor
heterogeneity. One of these is the term "texture analysis."
This analysis specifies the various quantification of
the spatial distribution of voxel intensities in images.
The advantages of using imaging techniques to define
heterogeneity are the account of the whole tumor, intratumoral
heterogeneity in very small spatial scales,
and non-invasiveness.[] However, in daily practice,
these methods are barely used.
In this retrospective study, we aimed to investigate
the effect of late imaging and textural analysis on diagnosis
in pre-operative [18F] FDG PET/CT of ILC.
Methods
Patients
Between May 2007 and December 2018, 20 patients
referred for [18F] FDG PET/CT for the staging of an
invasive lobular breast cancer to the department of nuclear
medicine and molecular imaging were included
in this study.
Image Acquisition
About 50-70 min after intravenous 5-9 mCi [18F]FDG,
standard 7-9 bed length between vertex and mid-crus
and after 160-200 min, neck and thorax 2-bed area late
imaging were taken Discovery IQ 5 ring (General Electric
Corp., Milwaukee, WI, USA) PET/CT device.
Images Analysis
All primary tumors of standard and late [18F] FDG
PET/CT images were delineated with 40% of SUV
maximum value method to create volumes of interest
(VOI). The texture analysis results were recorded
with s-prefix for standard images and l-prefix for late
images. In each VOI, standard PET quantitative measures
were evaluated by conventional indices (SUVmax,
SUVmin, SUVmean, SUVstd, SUVpeak, and
TLG), indices from histogram (skewness and kurtosis)
and shape (MTV, sphericity, and capacity) and 32
textural indices were recorded using LIFEx software
(Fig. 1). The subtraction of these textural indicis was
created by calculating four different matrices for each VOI: The Gray-Level Cooccurrence Matrix (GLCM),
the Gray-Level Run Length Matrix (GLRLM), the
Neighborhood Gray-Level Dependence Matrix
(NGLDM), and the Gray-Level Zone, Length Matrix
(GLZLM). GLCM represents that voxel pairs with
specific SUV values can be found in a certain direction
and at a certain distance. It is calculated using
1 voxel and 13 directions. GLRLM gives the size of
homogeneous runs for each gray level using 13 directions,
while NGLDM is calculated by calculating
the gray level difference between a voxel and its 26
neighbors in three directions. GLZLM gives the size
of homogeneous regions for each gray level in three
dimensions. For the textural indices to be calculated
software, there must be a VOI equal to or greater than
64 voxels that only contain one cluster, corresponding
to a minimum volume of 2.12 ml (voxel size of
4.07×4.07×2 mm). Preferences for VOI with multiple
clusters were manually selected by the operator.[20]
Fig 1: Right breast upper-inner quadrant invasive lobular cancer; primary malignancy area of interest (blue arrow).
S: Standard image, L: late image.
Clinical and Histopathological Variables
T and N stages, histological and nuclear grades, estrogen
receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67
values of histopathological results are recorded of mastectomy
(8 patients) or breast-conserving surgery (12
patients). Eight patients in the T1 stage and 12 patients
in the T2 stage were included in the study. N1 and N2
patients are classified as N positive.
The objective study outcome was to evaluate the
relationship between texture analysis findings of [18F]
FDG PET/CT both standard and late images, T and
N stages, and histopathological results (histologic and
nuclear grades, presence of ER, PR and HER-2, and Ki-
67 level). In lobular breast cancer imaging, which has
a relatively low level of FDG uptake, it is aimed to contribute
to the diagnosis with the change of background
activity in late images.
Statistical Analysis
The data were evaluated with the SPSS 25.0 (IBM, NY,
USA) program. Comparison of standard and late images
was evaluated with the Wilcoxon test, and the
characteristics of tumor heterogeneity were evaluated
with the Mann-Whitney U-test. Significant p<0.05 was
considered.
Results
Table 1 presents the demographic and histopathological
characteristics of 20 ILC patients that we included
in the study. Twelve breast-conserving surgery (60%),
eight mastectomies (40%) were performed in median
32 days (1-56 days). Eight of the cases were pT1, 12
were pT2. The N stage of 8 ILC patients was N (-), the
others were N (+).
Table 1: Patients characteristics
The correlations between the textural analysis findings
with standard and late imaging results of primary
tumor are shown in Table 2.
Table 2: Comparison level and median values of textural indices between standard and late imaging
Table 2: Cont.
SUV mean, max, Q1, Q2, Q3, peak 0.5 ml and
peak 1 ml, histo-skewness, kurtosis, excess kurtosis,
entropy log10, entropy log 2, GLCM homogeneity, energy,
contrast, and dissimilarity, GLRLM LRE, SRLG
and LRHGE, NGLDM contrast and busyness, GLZLM
HGZE, SZHGE, ZLNU, and ZP values of late imaging
were statistically higher than standard imaging (p<0.05).
When histopathological features were examined,
significantly higher values were found in both standard
and late images, especially in the ER-negative group
(Tables 3, 4).
Table 3: Significantly correlated texture indicis between standard imaging and histopathological features
Table 4: Significantly correlated texture indicis between late imaging and histopathological features
Table 4: Cont.
Discussion
ILC has the lowest sensitivity and specificity in diagnosis
with conventional imaging methods due to growth
pattern in invasive breast cancers.[] According to
the diagnosis of primary malignancy, lymph node and
hematogenous metastasis diagnosis sensitivity and
specificity are better, but the rates are still around 80%.
Due to the primary local diagnosis difficulties in ILC,
it is likely that the case will be in the metastatic process
at the time of diagnosis. In addition, compared to IDC,
the probability of metastasis is higher, and the possibility
of unexpected metastasis such as GIS, peritoneum,
skin, and gynecological organs is also high.[]
Therefore, in this study, we assumed that in addition
to the management of malignancy in patients with ILC
who have not previously been studied, the combination
of [18F] FDG PET/CT late imaging and texture analysis
may contribute to the diagnosis and/or better correlate
with histopathological information. Actually, [18F]
FDG PET/CT is not a routine examination for diagnosis
in ILC because of the low [18F] FDG uptake due to
low tumor cell density, diffuse infiltration in surrounding
tissue, low Glut-1 expression, and low proliferation
rate. Many different metabolic parameters such as SUV,
MTV, TLG, and late imaging information have been
used to increase sensitivity and specificity in breast tumors.[] However, nearly all the studies constitute the
more common IDC in the majority of cases. In seven
studies investigating the contribution of late imaging
with [18F] FDG PET/CT in invasive breast cancer, only
2/53, 3/66, 13/86, 2/53, 8/48, and 2/38 ILC patients
were included in the studies, respectively.[,,]
In 86 invasive breast cancer cases, 13 of which were
ILC with suspicion of local recurrence and distant
metastasis, Garcia-Vicente et al.[] shared that more
malignancy could be detected by decreasing background
activity in late images. In our study, especially
the visualization of metastatic lymph node was seen in
the late image of an ILC patient (Fig. 2).
Fig 2: 18F-fluorodeoxyglucose ([18F] FDG) positron emission tomography/CT standard and late images; right breast
lower-inner quadrant invasive lobular cancer area of interest (red arrow), [18F] FDG uptake in the right central
axillary metastatic lymph node visualized in late image (blue arrow).
S: Standard image, L: Late image.
Tumor heterogeneity with aggressive malignancy has
been shown in many tumors. The techniques are proposed
to define tumor heterogeneity for differentiation
between tumor types, tumor grading, response monitoring,
and outcome prediction in imaging. However, measuring
tumor heterogeneity is not simple, information
obtained from biopsy tissues are invasive and do not
represent the whole tumor. Since intratumoral heterogeneity
can be formed at very small areas, many studies
have been designed to understand the heterogeneity of
tumor with texture analysis information obtained from
imaging which is non-invasive. Analysis methods for
defining tumor heterogeneity are divided into four categories as a category consisting of non-spatial methods,
local spatial distribution methods, fractal analysis, and
filters. Transformations in PET, magnetic resonance
imaging, computed tomography, single photon emission
computed tomography, and ultrasonography. However,
due to limited software, lack of validation, and standardization,
it cannot be assessed in routine practice.[]
Tumor heterogeneity is also taking into account of
[18F] FDG uptake.[] The calculation of spatial heterogeneity
with histogram-based features relied on the
global computation of tumor heterogeneity only of the
SUV values and not the spatial relations between voxels
within the tumor.
Lee et al.[] reported that late imaging showed a
more significant correlation with prognostic factors in
38 invasive breast cancer cases. In addition, it was reported
that a similar correlation was observed even in
cases where the late image was taken earlier (100 min).
In our study, we found higher number of correlated
texture indicis in late imaging.
Dual time point application in [18F] FDG PET/
CT has been previously studied to evaluate variation of SUV-based parameters.[] We found that 36 of
64 textural indices measuring tumor heterogeneity
showed significant increases in late imaging compared
to standard PET/CT acquisition. Tumor heterogeneity
changes have been reported in 40.8% of tumors in delayed
imaging using the gradient segmentation method
using dual time point [18F] FDG PET/CT in patients
with pancreatic adenocarcinoma.[]
Larger tumors may have larger connected regions
and provide larger values of the LRM-based variables.
[] In our study, statistically significant correlations
found 15 in the standard image and 36 in the late image,
and it was noteworthy that LRM-based texture indices
have a significant correlation only in late images.
ER status is the determinant of the hormone therapy
alternative and provides the most important prognostic
information in breast cancer.[] In our study,
eight texture indicis correlations in standard image and
24 in late images were resulted of ER status.
The correlation between conventional quantitative
FDG PET parameters and prognostic histopathological
information in breast cancer has been described. It is remarkable that in our study, especially GLRM
and GLZLM-based texture indices also had this correlation.
The studies can be performed with a high
number of cases, early screening of cancer metastasis
will be possible.
To the best of our knowledge, there are no studies
evaluating the heterogeneity in ILC compared with
histopathological variables in double time point PET/
CT. In addition, limited patient numbers and inconsistencies
in the literature suggest that further analysis of
heterogeneity in ILC is required. The major limitation
of the study is the low number of patients and retrospective
analysis. In our study, we aimed to investigate
the correlation with prognostic histopathological information
according to FDG affinity of ILC in standard
and late images. Sensitivity and specificity values could
not be given because there is no accepted threshold
level for FDG uptake in breast lesions and it is not possible
to perform a ROC analysis in which we can reach
significant sensitivity and specificity levels with our
existing patient number. ILC is not a common breast
cancer, and FDG PET is not used much in staging. The
lack of validation of the textural analysis has not been
concluded and PET/CT spatial resolution cannot provide
a clear conclusion about the small volume of tumors
and questions of interpretation.
Conclusion
ILC shows relatively low uptake in [18F] FDG PET/
CT compared to IDC due to tumor characteristics. In
our study, GLRM-based, GLZLM-based, and conventional/
discretized indices have more correlation than
other texture values. In addition, in late image, especially
in the ER status, these correlations occur in much
higher (15 vs. 36) in late image. For this method to be
put into clinical practice, prospective and case-controlled
studies are needed.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved
by the Koc University Ethics Committee (No: 2019.359.
IRB2.119, Date: 26/11/2019).
Financial Support: None declared.
Authorship contributions: Concept - F.O.F.; Design -
F.O.F., H.S.; Supervision - F.O.F.; Funding - None; Materials
- None; Data collection and/or processing - F.O.F.; Data
analysis and/or interpretation - F.O.F., H.S.; Literature search
- F.O.F., H.S.; Writing - F.O.F.; Critical review - F.O.F., H.S.
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