ABSTRACT

Objectives:

This study investigates the relationship between ¹⁸fluoride-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) parameters and histopathological features in patients with early-stage invasive ductal breast carcinoma (IDBC).

Methods:

Patients with early-stage IDBC who underwent ¹⁸F-FDG PET/CT scan for staging were included in this retrospective study. The status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2, Ki-67 proliferative index, and grades of tumors were recorded. The conventional metabolic parameters [maximum standard uptake value (SUV_max) and average standard uptake value] and volume-based parameters [metabolic tumor volume (MTV) and total lesion glycolysis] of the primary tumor were obtained from the ¹⁸F-FDG PET/CT images. The associations and correlations between the ¹⁸F-FDG PET/CT parameters and histopathological features were assessed.

Results:

One hundred forty-three patients were included. ¹⁸F-FDG PET/CT parameters, other than MTV, were significantly associated with the ER and PR status and Ki-67 index, while T-staging was significantly associated with all ¹⁸F-FDG PET/CT parameters. In the axillary lymph node (ALN) involvement, no significant difference was found in the ¹⁸F-FDG PET/CT parameters. In terms of the pathological stage, a significant difference was found in all ¹⁸F-FDG PET/CT parameters. ¹⁸F-FDG PET/CT parameters, other than MTV, were significantly higher in non-luminal breast tumors than luminal tumors and in high-grade tumors than low-grade ones. Triple-negative tumors had the highest ¹⁸F-FDG PET/CT parameter, but the difference was insignificant for MTV. The SUV_max had the strongest correlation with Ki-67 proliferative index.

Conclusion:

Tumors with aggressive histopathological features had higher ¹⁸F-FDG PET/CT parameter values. This study suggests that ¹⁸F-FDG PET/CT may provide prognostic information in patients with early-stage IDBC.

Introduction

Breast cancer (BC) is the most widely diagnosed form of cancer and the second cause of cancer-related death in women (1). The most common pathological subtype is invasive ductal breast carcinoma (IDBC), which is associated with different prognostic behaviors concerning molecular subtypes (2). The size and grade of tumors, hormonal receptor status, human epidermal growth factor receptor-2 (HER-2) expression, Ki-67 proliferative index, axillary lymph node (ALN) involvement, and distant metastasis are important for the prognosis and treatment of IDBC (3,4).

¹⁸Fluoride-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) has been widely used for the staging, restaging, assessment of treatment response, and prediction of prognosis in BC (5). Several studies have previously evaluated the relationship between the maximum standard uptake value (SUV_max) and clinicopathological factors in BC (6,7,8,9,10,11), while the metabolic tumor volume (MTV) or total lesion glycolysis (TLG), called volume-based PET parameters, shows the total tumor burden and tumor metabolism. The prognostic value of these parameters was significantly associated with BC subtypes and prognosis in many studies (12,13,14,15,16,17).

This study aimed to evaluate the relationship between the ¹⁸F-FDG PET/CT parameters [SUV_max, average standard uptake value (SUV_avg), MTV, and TLG] and histopathological features (pathologic T size, pathological stage, ALN involvement, hormone receptor expressions, HER-2 receptor expression, Ki-67 proliferative index, and molecular subtypes) in IDBC.

Materials and Methods

The Local Ethics Committee of KTO Karatay University Faculty of Medicine approved this study under the decision number: 2020/10. Written informed consent was obtained from all patients. The data of patients with histopathologically documented and surgically excised IDBC, who underwent a preoperative ¹⁸F-FDG PET/CT between July 2013 and December 2019, were analyzed. Patients with the following features were excluded from the study: Multifocal or multicentric tumors; bilateral breast tumors; chest wall, surrounding muscle, or skin tissue involvement; distant metastasis; missing clinical data; those with a history of any therapeutic intervention before surgery (e.g., chemotherapy, radiotherapy, and hormone therapy). Moreover, in this study, the largest diameter of the evaluated lesions required to be larger than 10 mm to decrease the partial volume effect.

Results

One hundred forty-three female patients with IDBC and a mean age of 52.43±11.79 years (range: 29-81 years) were included. Table 1 shows the characteristics of the patients. Table 2 shows the relationship between the histopathological features and ¹⁸F-FDG PET/CT parameters.

Table 1

Table 2

Fifty-nine (41.3%) tumors were stage T1c, and 84 (58.7%) tumors were stage T2. The median values of all ¹⁸F-FDG PET/CT parameters were higher in the T2 group than the T1c group (p<0.001 for all comparisons).

All ¹⁸F-FDG PET/CT parameters were almost similar across ALN states. The SUV_max, SUV_avg, and TLG were higher in high-grade tumors (p<0.001 for all comparisons). Moreover, high-grade tumors had higher MTV, but the difference was insignificant.

The SUV_max, TLG, and SUV_avg were higher in hormone-receptor-negative tumors compared with the positive ones. The MTV was also higher in hormone-receptor-negative tumors compared with the positive ones, but the differences were insignificant. HER-2-positive tumors had higher SUV_avg and SUV_max than the negative ones (p=0.046 and p=0.04, respectively). The TLG and MTV were higher in HER-2-positive tumors compared with the negative ones, but the differences were insignificant.

Figure 1 shows the transaxial slice of PET/CT images of a patient with IDBC (histologic grade 3; ER-positive, PR-positive, and HER-2-positive).

Figure 1

Luminal A was found in 33 patients (23.1%); luminal B HER-2-negative, 61 patients (42.7%); luminal B HER-2-positive, 28 patients (19.6%); HER-2-positive, 10 patients (7.0%); TN, 11 patients (7.7%). The SUV_max, SUV_avg, and TLG were different among the five molecular subtypes (p<0.001, p<0.001, and p=0.010, respectively). Although MTV varied among the molecular subtypes, the difference was insignificant. All ¹⁸F-FDG PET/CT parameters were the highest in TN groups in terms of the molecular subtypes. In the post-hoc analysis, the luminal A group had a significantly lower SUV_max (p=0.026 and p<0.001, respectively) and SUV_avg (p=0.016 and p<0.001, respectively) than the HER-2-positive and TN groups. The luminal B HER-2-negative group had a significantly lower SUV_max (p=0.006) and SUV_avg (p=0.007) than the TN group. TLG was significantly lower in the luminal A group compared with the TN group (p=0.015).

Among the ¹⁸F-FDG PET/CT parameters, TLG had the strongest correlation with the tumor’s diameter (r=0.679; p<0.001). Moreover, SUV_avg had a modest correlation with Ki-67 (r=0.472; p<0.001). The group with Ki-67 ≥14% had a significantly higher SUV_avg, SUV_max, and TLG compared with that with Ki-67 <14% (p<0.001, p<0.001, and p=0.002, respectively). The MTV was higher in the group with Ki-67 ≥14% compared with that with Ki-67 <14%, but the difference was statistically insignificant.

There was a difference in the volumetric parameters (MTV and TLG) in the pathological stage (p<0.001 for both comparisons). Other PET parameters also varied significantly (SUV_max and SUV_avg; p=0.013 and p=0.028, respectively). In the post-hoc analysis, stage-I and stage-II tumors showed differences in terms of SUV_max (p=0.01), SUV_avg (p=0.026), MTV (p<0.001), and TLG (p<0.001), and stage-I and stage-III tumors showed differences in terms of MTV (p=0.008) and TLG (p=0.001).

Table 3 shows the comparison of the area-under-the-curve (AUC) values of ¹⁸F-FDG PET/CT parameters for the histopathological. The AUC values were similar in all tested features except for MTV. Of note, the AUC of SUV_avg was the largest for ER and PR status, Ki-67 index, and molecular group. Considering the HER-2 status, TLG had the largest AUC.

Table 3

Discussion

IDBC is a heterogeneous group of tumors (21). Several studies have reported a correlation between the parameters of ¹⁸F-FDG PET/CT and the histopathological features of BC (12,22,23,24). However, most of them evaluated different histological subtypes of BC and reported highly variable results. This study showed that tumors with aggressive histopathological features are associated with high ¹⁸F-FDG PET/CT parameters in IDBC.

An independent prognostic factor for BC is the tumor’s size. Moreover, poor histopathological differentiation and larger tumor size are related to an increased metastasis risk in BC (25). While some studies reported the correlation between the tumor’s size and ¹⁸F-FDG PET/CT parameters (9,23,26,27,28), others did not report such an association (8,10,29). In this study, the T-stage groups were associated with all ¹⁸F-FDG PET/CT parameters. Our patient population was predominantly composed of individuals with pathological T2-stage tumors, and there were no T3 tumors in this series.

Studies showed that the negative ER status was associated with higher ¹⁸F-FDG PET/CT parameters (12,24,26). In line with these studies, we found significantly higher ¹⁸F-FDG PET/CT parameters in ER-negative patients than ER-positive patients, but the difference was statistically insignificant for MTV. According to the studies by Kajáry et al. (12) and Groheux et al. (24), a negative PR status was associated with higher SUV_max, MTV, and TLG. Conversely, according to the study by Kaida et al. (23), there was no association between PR status and any volumetric parameters (MTV and TLG). In the present study, there was a significant association between the ER or PR status and the ¹⁸F-FDG PET/CT parameters, except for MTV. Some studies (12,30) have reported significant associations between HER-2 status and ¹⁸F-FDG PET/CT parameters, but others did not report such an association (24,29). All ¹⁸F-FDG PET/CT parameters were higher in HER-2-positive tumors than the negative ones, but significant associations were observed only for SUV_max and SUV_avg in the present study. A higher histological grade is associated with aggressive behavior (24). Several studies have demonstrated a significant relationship between the histological grade and ¹⁸F-FDG PET/CT parameters (9,10,12,26,31,32,33). Similarly, in the present study, there was a significant association between tumor’s grade and all ¹⁸F-FDG PET/CT parameters, except for MTV. Several studies have demonstrated a positive correlation between the Ki-67 index levels and ¹⁸F-FDG PET/CT parameters (9,26,29,32). Similarly, in our study, a positive correlation was observed between the Ki-67 levels and SUV_max, SUV_avg, and TLG. When the patients were grouped for their Ki-67 levels, the higher-level group had a significantly higher SUV_max, SUV_avg, and TLG. Our results showed that, among the ¹⁸F-FDG PET/CT parameters, SUV_max had the strongest correlation with Ki-67.

Studies have reported that molecular subtypes are associated with a variable prognosis, for example, the worst for TN and HER-2-positive and the best for luminal A (12,26,34). Concerning the molecular subtypes, Kajáry et al. (12), Groheux et al. (24), and Önner et al. (26) reported significant associations with SUV_max, SUV_avg, and TLG. Similarly, in our study, there was a significant relationship between the molecular subtypes and ¹⁸F-FDG PET/CT parameters, except for MTV. In the luminal A subtype, cellular proliferation genes are expressed at low levels. Conversely, the HER-2 gene promotes both cancer growth and progression, and the rates of recurrence and mortality are higher in the HER-2-positive subtype (35). TN BC is the most aggressive subtype and is associated with a worse prognosis (36). In this study, the lowest SUV_max, SUV_avg, and TLG were observed in the luminal A group, while the highest was in the TN group. In this line, Önner et al. (26) and Kajáry et al. (12) observed the lowest SUV_max, SUV_avg, MTV, and TLG in the luminal A group and the highest SUV_max, MTV, and TLG in the TN group. In this study, SUV_max, SUV_avg, and TLG were significantly higher in the non-luminal group. Regarding MTV, the median values of MTV were similar in both groups. Similarly, previous studies reported that ¹⁸F-FDG parameters were significantly higher in the non-luminal groups (12,24,26).

We performed receiver operating characteristic analyses to find which ¹⁸F-FDG PET/CT parameters reflected the pathological features better. The AUC values of SUV_max, SUV_avg, and TLG were high in all pathological variables (ER, PR, and HER-2 status, Ki-67 index, and molecular subtypes). The largest AUC value was seen for SUV_avg in terms of the ER and PR status, Ki-67 index, and molecular groups and for TLG in terms of the HER-2 status. This was incompatible with some recent studies (12,23). We think that these differences are due to different SUV_max threshold values used in MTV calculation. Kaida et al. (23) used a threshold of 50% of peak SUV within the lesions for calculating MTV and reported that TLG reflected the tumor metabolism with histopathological features better than SUV_max or MTV. However, in another study using 2.5 as the SUV_max threshold value in MTV calculation, a high AUC value could not be achieved with MTV. There is a lack of consensus on methods for calculating the volumetric parameters in the literature (12,23#*#ref,24#*#,26,37,38). In solid tumors such as BC, some authors recommend using 42% of tumor SUV_max as a threshold to represent the glycolytic activity (37,38). So, we used 42% as the threshold for the present study.

Conclusion

The findings of this study showed that tumors with aggressive histopathological features are associated with high ¹⁸F-FDG PET/CT parameters, and therefore, ¹⁸F-FDG PET/CT imaging can be used as an aid in predicting the prognosis in early-stage IDBC.

Imaging and Analysis of ¹⁸F-FDG PET/CT

Before the ¹⁸F-FDG injection, the patients were fasted for at least six hours to ensure that the blood glucose levels were below 150 mg/dL. The scan was performed 60 min after the intravenous injection. The region of interest (ROI) around the primary tumor was drawn by manual adjustment to exclude structures showing physiological ¹⁸F-FDG uptake around the tumor. The tumor was completely covered in three planes. SUV_max was obtained by manually drawing the ROI from the slice with the highest uptake of ¹⁸F-FDG in the primary tumor. MTV was obtained using a 42% threshold of SUV_max. TLG was calculated by multiplying SUV_avg by MTV.

Histopathological Analysis and Molecular Subtypes

Patients included in this study underwent surgery or ALN dissection. The pathological data of the tumors, such as size, grade, pathological stage, and other prognostic parameters, were obtained from the records. The tumor has been graded according to the Bloom-Richardson grading system updated by Elston and Ellis (18). The pathological prognostic staging was performed according to the eighth edition of the American Joint Committee on Cancer’s Staging Manual (19). The status of the estrogen receptor (ER), progesterone receptor (PR), and HER-2 expression and the Ki-67 proliferative index were evaluated immunohistochemically. The fluorescence in situ hybridization method was used to confirm the presence of HER-2 expression, when the scores were 2+ (20). The molecular subtypes of the ER, PR, and HER-2 expression status were determined. The proliferative index was considered high when the Ki-67 was ≥14% and low when it was <14%. The subjects were classified according to the molecular subtypes as recommended in the 12^th International Breast Conference (2). The molecular subtypes were divided into two groups: Luminal (luminal A, luminal B HER-2-negative, and luminal B HER-2-positive subtypes) and non-luminal [HER-2-positive and triple-negative (TN) subtypes].

Statistical Analysis

The statistical analyses were performed using IBM SPSS Statistics for Windows (ver. 21, IBM Corp., Armonk, NY). The normality of the distribution of the continuous data was evaluated. The continuous data were expressed as medians or mean ± standard deviations, where appropriate. The categorical data were shown as frequencies and percentages. For comparing continuous data, non-parametric tests were used. The relationship between the continuous data was evaluated using a Spearman correlation test. A p value less than 0.05 was considered statistically significant.

Study Limitations

The limitations of this study include being retrospective and having low patients in the groups. Moreover, we cannot predict the findings of this study in patients with advanced IDBC.

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Evaluation of the Histopathological Features of Early-stage Invasive Ductal Breast Carcinoma by 18Fluoride-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography