DOI:10.2214/AJR.05.0696
AJR 2006; 187:297-306
© American Roentgen Ray Society
Correlation Between Numeric Gadolinium-Enhanced Dynamic MRI Ratios and Prognostic Factors and Histologic Type of Breast Carcinoma
Hiroyuki Narisada1,
Takatoshi Aoki1,
Takakazu Sasaguri2,
Hiroshi Hashimoto3,
Tetsumi Konishi4,
Masaru Morita5 and
Yukunori Korogi1
1 Department of Radiology, University of Occupational and Environmental Health,
School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu-shi, 807-8555
Japan.
2 Department of Pathology and Cell Biology, University of Occupational and
Environmental Health, School of Medicine, Kitakyushu-shi, Japan.
3 Department of Pathology and Oncology, University of Occupational and
Environmental Health, School of Medicine, Kitakyushu-shi, Japan.
4 First Department of Surgery, University of Occupational and Environmental
Health, School of Medicine, Kitakyushu-shi, Japan.
5 Second Department of Surgery, University of Occupational and Environmental
Health, School of Medicine, Kitakyushu-shi, Japan.
Received April 24, 2005;
accepted after revision November 3, 2005.
Address correspondence to H. Narisada.
Abstract
OBJECTIVE. The purpose of this study was to assess the usefulness of
numeric ratios from dynamic contrast-enhanced MRI in predicting histologic
type of breast carcinoma and three histologic prognostic factors for invasive
ductal carcinoma.
MATERIALS AND METHODS. A total of 104 patients with breast carcinoma
were included in the study. Dynamic contrast-enhanced MR images were obtained
every 30 seconds during the first 4.5 minutes after administration of contrast
material, and peripheral contrast enhancement ratio and central contrast
enhancement ratio were calculated in the early phase (1 minute after contract
injection) and in the delayed phase (4 minutes after injection). Four contrast
enhancement ratios were used for quantitative analysis of the following
numeric ratios: early peripheral/early central, delayed peripheral/delayed
central, delayed peripheral/early peripheral, and delayed central/early
central. The four ratios were compared with histologic type. For invasive
ductal carcinoma, the ratios were then compared with modified
Scarff-Bloom-Richardson histologic grade, microvessel density, and fibrotic
focus.
RESULTS. Mucinous carcinoma had significantly higher mean early
peripheral/early central and delayed central/early central ratios than other
types of tumors (p< 0.0001). For invasive ductal carcinoma, the
mean early peripheral/early central ratio was significantly lower for modified
Scarff-Bloom-Richardson grade 1 tumors than for grades 2 and 3 tumors
(p < 0.0001). Early peripheral/early central ratio had a
significant correlation with the ratio of peripheral to central mean
microvessel density (p < 0.0001). There was also a significant
difference in early peripheral/early central ratio (p < 0.0001)
between tumors with a fibrotic focus and those without a fibrotic focus.
CONCLUSION. Numeric ratios obtained on gadolinium-enhanced dynamic
MRI of the breast may be useful in predicting histologic type of breast
carcinoma and three histologic prognostic factors for invasive ductal
carcinoma: modified Scarff-Bloom-Richardson grade, microvessel density, and
fibrotic focus.
Keywords: breast cancer • dynamic MRI • MRI
Introduction
Dynamic contrast-enhanced MRI has been an effective method in the diagnosis
of breast abnormalities. Its main uses have been to differentiate malignant
tumors from benign lesions and to determine the extent of spread of carcinoma
within the breast
[1-5].
Results have shown that early peripheral enhancement can be seen in breast
carcinoma on dynamic contrast-enhanced MRI
[5-10].
Although some reports conflict with this subjective assessment, peripheral
enhancement has been identified as a specific indicator of breast carcinoma in
up to 87% of cases.
A few reports have documented the relation between dynamic
contrast-enhanced MRI enhancement characteristics and histologic prognostic
factors for breast carcinoma. In those studies time-intensity curve profiles
were compared with histologic prognostic factors
[11-13].
However, the reports varied considerably in their results, and the efficiency
of dynamic MRI in histologic prognosis of breast carcinoma continues to be
controversial.
In this study, we assessed the difference in contrast enhancement ratio
between the peripheral and central regions of the breast carcinomas and
analyzed changes in contrast enhancement ratios over time. We used the data to
calculate four numeric ratios and compared the results with breast cancer
histologic type and three histologic prognostic factors for invasive ductal
carcinoma.
Materials and Methods
Hospital institutional review board approval was obtained for this
retrospective study. Informed consent was not required.
Patients
We retrospectively reviewed 3D dynamic contrast-enhanced MR images of 108
women with breast carcinoma. Of the 108 patients, four patients with diffusely
spreading lesions (two invasive ductal carcinomas and two ductal carcinomas in
situ) were excluded from this study because we did not identify a dominant
lesion for analysis. The dominant lesion was defined as the largest lesion
when there were multifocal lesions.
A total of 104 patients were included in the study. The age range was 33-84
years (mean, 55.3 years). All patients underwent preoperative MRI between
April 2000 and March 2003, and the tumors were excised at our institution.
Initial lesion detection was by physical examination, mammography, or
sonography. None of the patients had a history of breast cancer on the side
studied. One patient had a history of cancer in the opposite breast. All
breast carcinomas were confirmed at histopathologic examination of the
surgical specimen. The results are shown in
Table 1. We identified the
pathologic subtype of mucinous carcinoma: Four lesions were pure type of
mucinous carcinoma, and two lesions were mixed type. Each lesion of the
mixed-type tumors contained invasive ductal carcinoma constituting less than
30% of the tumor at histopathologic evaluation. Tumor size ranged from 0.8 to
7.0 cm (mean, 2.3 cm).
MRI
All MR images were acquired with a 1.5-T MR system (Signa Advantage, GE
Healthcare). Each patient was examined in the prone position with a dedicated
breast coil on the affected side. Before administration of contrast material,
we obtained transverse T2-weighted fast spin-echo images (TR/TE, 4,000/102)
with a 30-cm field of view, 4- or 5-mm section thickness, no intersection gap,
and a 256 x 224 matrix size. Sagittal T2-weighted images (4,100/102)
were acquired with fast spin-echo technique with fat saturation and a 17-cm
field of view with 4- or 5-mm section thickness, no gap, and a 256 x 192
matrix size. Sagittal dynamic imaging was performed with a fat-suppressed 3D
fast spoiled gradient-echo sequence (25/1.3) with a flip angle of 15°,
18-cm field of view, 3- to 6-mm section thickness, no gap, and a 256 x
160 matrix size. Before the examination, an IV line was established in either
antecubital vein. After the initial reference image was acquired, a 0.1-mmol
bolus of gadopentetate dimeglumine (Magnevist, Schering) was administered at a
rate of 3 mL/sec through an MR-compatible automatic injector and followed by a
20-mL saline flush. The initial section of the dynamic study was obtained in
the sagittal plane at 30-second intervals for 4.5 minutes. After the dynamic
study, sagittal T1-weighted fast spin-echo images (400/14) with fat saturation
were obtained with a 17-cm field of view, 5- or 6-mm section thickness, no
gap, and a 256 x 192 matrix size.
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Fig. 1 —Scheme illustrates central and peripheral regions of interest
(ROIs) in tumor. Center ROI measuring 8 mm2 is large square.
Vertical and horizontal crosshairs form target at center of square. Four
peripheral ROIs measuring 2 mm2 are small squares just within
periphery of each tumor on each crosshair radial.
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Image Analysis
The following procedure was performed for all tumors. We set an
8-mm2 region of interest (ROI) in the center of the tumor, targeted
its center with vertical and horizontal crosshairs, and set four
2-mm2 ROIs just within the periphery of each tumor on each of the
four crosshair radials (for a total of five ROIs)
(Fig. 1). In the case of
multifocal disease, only the dominant lesion was examined. We defined contrast
enhancement ratio as (SIpost - SIpre)
/ SIpre, where SIpre = signal
intensity before administration of contrast medium and
SIpost = signal intensity after contrast medium
administration.
Although contrast enhancement ratios were measured every 30 seconds, we
used the ratios at 1 and 4 minutes for this study. The following four contrast
enhancement ratios were acquired: early peripheral contrast enhancement ratio,
delayed peripheral contrast enhancement ratio, early central contrast
enhancement ratio, and delayed central contrast enhancement ratio. For
example, the early peripheral contrast enhancement ratio was an average of the
four ROI signal intensities in the peripheral region 1 minute after contrast
administration. On the basis of these four contrast enhancement ratios, we
calculated the following four numeric ratios: early peripheral/early central,
delayed peripheral/delayed central, delayed peripheral/early peripheral, and
delayed central/early central.
Histopathologic Analysis
All of the histopathologic specimens were reviewed for this study by a
breast pathologist who did not know the MRI findings. Specimens were stained
with H and E. Histologic types of the tumors were assigned in accordance with
World Health Organization histopathologic standards. Histologic grade was
classified according to modified Scarff-Bloom-Richardson histologic grading
criteria [14].
Table 2 shows a listing of
modified Scarff-Bloom-Richardson gradings.
The presence of a fibrotic focus was evaluated according to the definitions
by Hasebe et al. [15] (Figs.
2A,
2B,
2C, and
2D). A fibrotic focus is
defined as a scarlike area in the center of a breast carcinoma. It appears as
a radially expanding fibrosclerotic core made up of loose, dense, or
hyalinized collagen bundles and a variable number of fibroblasts. Fibrotic
foci < 3 mm in diameter do not contain carcinoma cells, but larger fibrotic
foci sometimes do. All cases were processed for immunohistologic analysis to
determine the microvessel density in paraffin-embedded sections. Small blood
vessels were visualized by staining of endothelial cells for CD31
(clone JC/70A, Dako). Microvessels were counted in five fields at x200
magnification in each peripheral portion of each lesion (total, 20 peripheral
fields); the mean counts were used as peripheral microvessel density. In the
central portion of each lesion, microvessels were counted in 10 fields at
x200 magnification, and the mean counts of the fields were recorded as
central microvessel density. The ratio of peripheral to central microvessel
density was calculated for each lesion
(Fig. 3).
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Fig. 2D —52-year-old woman with tumor classified as modified
Scarff-Bloom-Richardson histologic grade 3. Photomicrograph of histologic
specimen shows central large scarlike area composed of dense or loose collagen
bundles (arrows), indicating fibrotic focus. Early peripheral/early
central ratio, 1.26; delayed peripheral/delayed central, 1.08; delayed
peripheral/early peripheral, 0.74; delayed central/early central, 0.86. (H and
E, x3)
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Fig. 3 —Scheme illustrates method of counting microvessels in
peripheral and central regions of tumor. Microvessels were counted in five
fields in each peripheral portion of each lesion (total, 20 peripheral
fields). In central portion of each lesion, microvessels were counted in 10
fields.
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Fig. 4 —Graph shows plots of early peripheral/early central values.
Dots represent means, and lines through dots represent SD. Early
peripheral/early central ratio for mucinous carcinoma was significantly higher
than for invasive ductal carcinoma (IDC) (p < 0.0001) and ductal
carcinoma in situ (DCIS) (p < 0.0001). Mucinous = mucinous
carcinoma, IL = invasive lobular carcinoma. EP/EC = ratio of peripheral
contrast enhancement ratio 1 minute after contrast administration to central
contrast enhancement ratio 1 minute after contrast administration.
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Fig. 5 —Graph shows plot of delayed central/early central values.
Dots represent means, and lines through dots represent SD. Delayed
central/early central ratio for mucinous carcinoma was significantly higher
than for invasive ductal carcinoma (IDC) (p < 0.0001) and ductal
carcinoma in situ (DCIS) (p < 0.0001). Delayed central/early
central ratio for invasive lobular (IL) carcinoma was significantly higher
than for invasive ductal carcinoma (p = 0.0005) and ductal carcinoma
in situ (p = 0.0003). Mucinous = mucinous carcinoma, DC/EC = ratio of
central contrast enhancement ratio 4 minutes after contrast administration to
central contrast enhancement ratio 1 minute after contrast administration.
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Statistical Methods
Normal distributions of the numeric ratios were evaluated with the
Shapiro-Wilk test. Because only the continuous variable of delayed
peripheral/delayed central ratio was normally distributed, nonparametric
methods were used. Association of the four numeric ratios with histologic type
was analyzed by Kruskal-Wallis test. We first looked for differences between
histopathologic types regarding the four numeric ratios based on findings on
dynamic contrast-enhanced MRI. If the Kruskal-Wallis test results were
positive, we applied the Bonferroni correction to determine whether
differences between two specific histopathologic types existed. Using the same
method, we analyzed the relation between the four numeric ratios and modified
Scarff-Bloom-Richardson histologic grade.
The Mann-Whitney U test was used for statistical analysis of
correlations between the four numeric ratios and the presence or absence of
fibrotic focus. Statistical analysis was performed for correlation between the
four numeric ratios and the ratios of peripheral to central microvessel
density by Spearman's rank correlation coefficient (Spearman's r).
For all tests except the Bonferroni correction, a p value of less
than 0.01 was used to indicate significance. Because three and four groups
have three and six possible pairwise comparisons, the level of significance
for each comparison was set at 0.0033 (0.01/3) for three groups (modified
Scarff-Bloom-Richardson histologic grade) and at 0.0017 (0.01/6) for four
groups (histologic type) as a result of the Bonferroni correction.
The Shapiro-Wilk test was performed with statistical software (JMP version
5.0.1, SAS Institute). All other statistical analyses were performed with
Microsoft Windows StatView 5.0 (SAS Institute).
Results
The results of the Kruskal-Wallis test indicated statistically significant
differences between different histologic types for all four ratios
(Table 3). After the Bonferroni
correction was applied to the early peripheral/early central ratio, mucinous
carcinomas showed a significantly higher mean early peripheral/early central
value than invasive ductal carcinoma (p < 0.0001) and ductal
carcinoma in situ (p < 0.0001)
(Fig. 4). In the case of the
delayed peripheral/delayed central ratio, however, only mucinous carcinoma had
a significantly higher mean value than invasive ductal carcinoma (p =
0.0005). No significant difference was seen in the delayed peripheral/early
peripheral ratio. In the case of the delayed central/early central ratio
(Fig. 5), mucinous carcinoma
and invasive lobular carcinoma had significantly higher mean values than
invasive ductal carcinoma (p < 0.0001 and p = 0.0005,
respectively) and ductal carcinoma in situ (p < 0.0001 and
p = 0.0003, respectively) (Table
4).
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TABLE 3: Relation Between Numeric Ratios on Gadolinium-Enhanced Dynamic MR Images
and Histopathologic Types and Between Numeric Ratio and Histologic Prognostic
Factors
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Modified Scarff-Bloom-Richardson histologic grades were available for
invasive ductal carcinoma: 29 (33.7%) of the tumors were grade 1; 39 (45.3%),
grade 2; and 18 (20.9%), grade 3. The relation between numeric ratio and
histologic prognostic factors (modified Scarff-Bloom-Richardson histologic
grades and fibrotic focus) are summarized in
Table 3. When the
Kruskal-Wallis test was applied to the relation between the four numeric
ratios and modified Scarff-Bloom-Richardson histologic grade, only the early
peripheral/early central ratio showed a significant difference (p
< 0.0001). After the Bonferroni correction was applied to the early
peripheral/early central ratio, grade 1 tumors (Figs.
6A,
6B,
6C, and
6D) showed a significantly
lower mean value of early peripheral/early central ratio than either grade 2
(p < 0.01) or grade 3 (p < 0.0001) (Figs.
7A,
7B,
7C, and
7D) tumors. The mean values of
early peripheral/early central and delayed central/early central ratios were
significantly higher for the tumors with positive fibrotic focus than for
those without fibrotic focus (p < 0.0001). There was a significant
positive correlation between the ratio of peripheral to central microvessel
density and early peripheral/early central ratio (r = 0.62,
p < 0.0001) (Fig.
8), whereas delayed peripheral/delayed central ratio showed a
positive but low correlation (r = 0.39, p = 0.0003). There
was no significant correlation between ratio of peripheral to central
microvessel density and delayed peripheral/early peripheral ratio or delayed
central/early central ratio. Fibrotic focus was found more frequently in
tumors with a higher modified Scarff-Bloom-Richardson histologic grade
(p = 0.0005) (Table
5).
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Fig. 6D —54-year-old woman with tumor classified as modified
Scarff-Bloom-Richardson histologic grade 1. Photomicrograph of histologic
specimen of tumor shows cellular growth pattern without fibrotic focus. Early
peripheral/early central ratio, 0.72; delayed peripheral/delayed central,
0.74; delayed peripheral/early peripheral, 0.77; delayed central/early
central, 0.75. (H and E, x3)
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Fig. 7D —62-year-old woman with tumor classified as modified
Scarff-Bloom-Richardson histologic grade 3. Photomicrograph of histologic
specimen of tumor shows peripheral cellular growth (arrows) with
central fibrotic focus (arrowheads). Early peripheral/early central
ratio, 1.77; delayed peripheral/delayed central, 0.68; delayed
peripheral/early peripheral, 0.79; delayed central/early central, 1.26. (H and
E, x3)
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Fig. 8 —Scatterplot of early peripheral/early central ratio versus
ratio of peripheral to central microvessel density shows statistically
significant correlation (r = 0.62, p < 0.0001). EP/EC =
ratio of peripheral contrast enhancement ratio 1 minute after contrast
administration to central contrast enhancement ratio 1 minute after contrast
administration.
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Discussion
Dynamic contrast-enhanced MRI has proved to be a good tool in the diagnosis
of breast carcinoma and in differentiating malignant from benign tumors
[1,
3-5].
Contrast enhancement ratio or time-intensity curve profiles have been used in
many studies to show the efficacy of dynamic contrast-enhanced MRI in the
assessment of breast abnormalities
[3,
4,
7]. Although breast carcinoma
generally shows faster and stronger enhancement than most benign lesions after
bolus injection of a gadolinium-based contrast agent, overlap in benign and
malignant findings has been seen in a number of cases, making it difficult to
differentiate the two types
[16]. The reported specificity
in differentiating fibroadenoma from malignant lesions has varied greatly,
from 37% to 93%
[16-19].
The capillary density of breast carcinoma is not uniform between the
peripheral and central regions
[20,
21]. Capillary density usually
is greatest in the tumor periphery
[10,
22]. It has been reported that
changes in peripheral enhancement of breast carcinoma are useful in
differentiating malignant tumors from benign lesions
[6-11].
Improvement in MR technology has made it possible to acquire detailed
morphologic information about tumors and the extent of cancer. Several reports
have described the relation between dynamic MR enhancement characteristics and
histopathologic prognostic factors for breast carcinoma
[11-13].
Mussurakis et al. [12] found
significant differences between enhancement ratios and axillary lymph node
status and between enhancement ratios and tumor histologic grade. Other
investigators, however, did not find a significant relation between histologic
and dynamic MRI findings. Stomper et al.
[11] found that histologic
grade 3 tumors were not significantly associated with greater enhancement
amplitude or rate compared with lower-grade tumors. Fischer et al.
[13] concluded that the signal
behavior of contrast-enhanced MR mammography was not related to established
histopathologic prognostic parameters, such as tumor grade and the presence of
axillary lymph node metastasis. Thus, the relation between histologic type and
dynamic MR enhancement characteristics has yet to be studied sufficiently.
Mucinous carcinoma of the breast has a less aggressive growth pattern and a
better prognosis than invasive ductal carcinoma
[23,
24]. Mucinous carcinoma
usually consists of a central region of mucin intersected and surrounded by
fibrous tissues that contain small and large blood vessels. Andre et al.
[24] studied 82 cases and
reported that in all cases of mucinous carcinoma, extracellular mucin
accounted for more than 50% of the total tumor volume. In our study, the mean
values of both early peripheral/early central ratio and delayed
peripheral/delayed central ratio were significantly higher for mucinous
carcinoma than for invasive ductal carcinoma. In other words, in comparison
with invasive ductal carcinoma, the peripheral region of mucinous carcinoma
was more strongly enhanced than the central region both 1 and 4 minutes after
contrast medium injection. Mucinous carcinoma had significantly higher mean
values of delayed central/early central ratio than did invasive ductal
carcinoma. These results concurred with those in two cases described by Buadu
et al. [9], in which mucinous
carcinoma was enhanced in the periphery during the early phase and peripheral
enhancement persisted during the delayed phase. We speculated that mucin in
the center of mucinous carcinoma delays diffusion of contrast material and
hence leads to greater ratios between the peripheral and the central regions
relative to other tumor types. Therefore, we believe that numeric ratios on
dynamic MRI help in the diagnosis of mucinous carcinoma.
Modified Scarff-Bloom-Richardson histologic grade is widely used because of
its excellent reproducibility. Its components such as tubule formation,
nuclear size (pleomorphism), and mitotic counts also provide important
information about prognosis
[14,
25]. Therefore, we chose
modified Scarff-Bloom-Richardson histologic grade as one of three histologic
prognostic factors for invasive ductal breast carcinoma. The relation between
modified Scarff-Bloom-Richardson histologic grade and the prognosis of
invasive ductal breast carcinoma has been reported extensively. Elston and
Ellis [25] assessed 1,831
patients and reported that modified Scarff-Bloom-Richardson histologic grade
provided important prognostic information. Patients with grade 1 tumors had a
significantly better survival rate that those with grade 2 or 3 tumors.
Histologic grade is also a strong predictive factor of response to induction
chemotherapy [26,
27]. Because in our study
grade 1 tumors had a significantly lower mean value of early peripheral/early
central ratio than did either grade 2 or 3 tumors, the use of dynamic
contrast-enhanced MRI may allow preoperative prediction of tumor behavior and
effectiveness of chemotherapy.
Jitsuiki et al. [22]
reported that fibrotic focus occupied various percentages of the tumor and
that the tumors with fibrotic focus had significantly higher microvessel
counts in the periphery than those without fibrotic focus. Similarly, Colpaert
et al. [28] documented that
the presence and size of fibrotic focus correlated significantly with
microvessel counts. Colpaert et al.
[28,
29] also found that central
fibrotic focus, necrosis, or both were observed more frequently with tumors of
higher histologic grade than with tumors of low histologic grade. Our results
concur with theirs. We found that the relation between modified
Scarff-Bloom-Richardson histologic grade and fibrotic focus strongly indicated
a significant positive correlation.
A few researchers have reported correlation between rim enhancement on
dynamic contrast-enhanced MRI and peripheral microvessel density in breast
carcinoma. Matsubayashi et al.
[6] found that a high ratio of
peripheral to central microvessel density correlated significantly with
depiction of early rim enhancement. Furthermore, peripheral enhancement in
invasive carcinoma correlated with high peripheral and low central microvessel
densities [9,
10]. In our study, the early
peripheral/early central ratio for invasive ductal carcinoma showed
significant correlation with the ratio of peripheral to central mean
microvessel density. We also found that tumors with central fibrotic focus had
significantly higher mean values of early peripheral/early central ratio than
those without fibrotic focus. It thus seems reasonable that there was
significant correlation between early peripheral/early central ratio and
peripheral to central microvessel density as well as correlation between early
peripheral/early central ratio and central fibrotic focus. In our study,
fibrotic focus was observed most frequently in tumors of high modified
Scarff-Bloom-Richardson histologic grade. This result concurs with the results
reported by Colpaert et al.
[28,
29]. We speculate that the
presence of fibrotic focus in the center of invasive ductal carcinoma is a
significant factor in the strong correlation between early peripheral/early
central ratio and histologic grade.
This study had limitations. First, in this retrospective study the number
of cases of each tumor type was small except for invasive ductal carcinoma.
Although mucinous carcinoma had significantly higher mean values of early
peripheral/early central ratio and delayed central/early central ratio than
other tumor types, further studies with more cases are necessary to determine
a cutoff value for differentiating mucinous carcinoma from other tumors.
Second, diffusely spreading types of tumors were not included in this study
because it was impossible to place ROIs in these tumors. Third, unavoidable
and essential limitations occur with the use of ROI in this type of study. An
automated ROI selection method would overcome the problems related to
subjective ROI placement. Finally, we did not evaluate the time-intensity
curve profiles of dynamic contrast enhancement, which have been generally
accepted as useful information for differentiation of breast tumors. We also
did not consider the morphologic characteristics of the lesions. In
conjunction with the dynamic curve patterns and morphologic characteristics,
including lesion margins and internal characteristics, the numeric ratios
might have led to more accurate prediction of histologic type of and the
histologic prognostic factors for breast carcinoma.
In conclusion, we found a strong correlation between numeric ratios from
gadolinium-enhanced dynamic MRI and histologic type and between the ratios and
histologic prognostic factors (modified Scarff-Bloom-Richardson histologic
grade, microvessel density, and fibrotic focus). The numeric ratios obtained
from gadolinium-enhanced dynamic MRI of the breast have the potential for
assisting in treatment planning with regard to the required extent of surgery
and the need for adjuvant or neoadjuvant therapy.
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Abstract
Introduction
