Both diffusing MR imaging and FDG PET/CT can provide important functional information for IDC with high cellularity. Diffusion MR imaging can provide information about the random water motion in tissues, and have a potential roles in the characterization of malignancy, including determination of lesion aggressiveness and monitoring response to therapy [
5,
7‐
10]. PET/CT visualizes the metabolic activities of tissue and provides information about the rate of glucose metabolism [
2]. FDG PET/CT can detect enhanced glycolysis of breast cancer cells and can be used for diagnosing, staging, detecting recurrence, and assessing response to therapy [
1,
2]. Both diffusion MR imaging and FDG PET/CT may be related to tumor cellularity. Areas of high cellularity have more structures and cell membranes resulting in impedance of water motion, and have increased cellular proliferation. Therefore, ADC values are low and FDG uptake gets higher in high cellular tumors [
11]. In contrast, areas with low cellularity are less resistant to water diffusion resulting in higher ADC value; scarce proliferative activity resulting in lower FDG uptake [
11].
Correlation between ADC value and prognostic factors
We studied the correlation between mean ADC value and prognostic factors such as tumor size, LN metastasis, histologic grade, age, and expression levels of ER, PR, HER2, EGFR, and Ki-67. Significant associations were noted between mean ADC and positive ER status (
P = 0.009) and negative HER2 status (
P = 0.016), which is similar to the results reported by Jeh
et al. [
6]. The ADC value is useful for the differentiation of malignant masses from benign masses or normal breast tissue, as malignant tumors have lower ADC values compared to benign masses [
7,
12‐
15]. Hatakenaka
et al. [
8] reported that the ADC value differed significantly between invasive and non-invasive ductal cancer. ER expression is associated with a favorable prognosis [
16‐
18]. Tumors that display positive ER and PR expression respond well to adjuvant and palliative hormone therapy [
4]. Ludovini
et al. [
19] explained that the reason for the lower ADC values observed in the ER-positive group as compared to the ER-negative group is that ER blocks the angiogenic pathway and reduces perfusion, which in turn affects the ADC value. Notably, HER2 is similar in structure to the human epidermal growth factor receptor (EGFR). When overexpressed, it inhibits the control mechanisms in normal cells, accelerates cell growth and division and can cause cancer. HER2-positive cells that are more likely to exhibit a malignant phenotype, accompanied by cell proliferation, invasion and metastasis [
4,
6]. In addition to cell growth, HER2 induces angiogenesis; thus, blood flow increases in tumors that are HER2 positive and hormone receptor negative [
16]. Reduced perfusion in the HER2-negative group may explain the observed reduction in ADC values. Kim
et al. [
4] reported that ADC values were higher in tumors with increased HER2 expression, although there was no significant correlation between HER2 expression and ADC values.
There was no correlation between mean ADC value and histologic grade as determined by Ki-67 expression. Notably, one of the important indices of histologic tumor grade is tumor cellularity [
6,
14]. Ki-67 is a marker of tumor cellularity and is a benign nuclear antigen found in proliferative-phase cells [
6,
14]. Tumor grade and Ki-67 expression are also related to other proliferative diseases and recurrences [
17], and cancer of lower cellularity is associated with improved prognosis [
20]. Diffusion is difficult in areas of dense tumor cellularity because of the effective motion of water molecules [
13]. There are some reports of a negative correlation between ADC values and tumor cellularity [
7,
8,
15,
21]. Woodhams
et al. [
21] reported that DWI is a unique marker of tumor cellularity. However, Yoshikawa
et al. [
22] and Kim
et al. [
4] reported that ADC value and tumor cellularity are not correlated. Previous reports found no correlation between Ki-67 expression and ADC value [
6].
ADC mean was not correlated with LN metastasis. Breast cancer with ipsilateral axillary lymph node metastasis is the most important predictor of long-term survival [
23,
24]. In the case of LN metastasis, the prognosis is poor, with the prognosis worsening as the number of LN metastases increases [
7]. The presence of LN metastasis is most important in conjunction with the expression of hormone receptors in the decision to proceed with conservative therapy [
7]. Some authors have reported a correlation between LN metastasis and ADC value; the ADC value can help in avoiding unnecessary surgical staging of axillary LN [
1,
7]. However, Kim
et al. [
4] found no association between ADC and LN metastasis, which is similar to our results.
ADC values and tumor size were not correlated (
P = 0.185). Tumor size is a very important factor in the future prognosis of breast cancer [
7]. As tumor size increases, the likelihood of metastasis increases, and the overall survival rate decreases [
7]. Although Kim
et al. [
4] and Nakajo
et al. [
1] stated that ADC and tumor size are not correlated, Kuroki-Suzuki
et al. [
9] stated that there is a significant correlation among ADC, pT1 and pT2-4. Razek
et al. [
7] also reported a correlation between tumor size and ADC. Based on a hypothesis that small lesions of less than 1 cm are difficult to detect in DWI, Razek
et al. excluded lesions less than 1 cm in size. Because lesions less than 1 cm in size were not excluded in this study, which resulted in a difference in mean tumor size, comparison with the results obtained by Razek
et al. [
7] is difficult (in this study, the mean was 2.8 ± 2.2 cm; in the study by Razek
et al., the mean was 3.9 ± 2.0 cm).
Correlation between ADC mean and SUVmax
Mean ADC and SUVmax were not correlated (
P = 0.786). There were reports of ADC values decreasing due to the fact that water diffusion becomes difficult in regions of high tumor cellularity. Furthermore, ADC and tumor cellularity are inversely proportional [
7,
8,
15,
21]. Several authors have reported that FDG uptake and cellularity are positively correlated [
26,
27]. Because SUVmax and ADC were expected to be inversely proportional to each other, the existence of any correlation between the results obtained with both modalities is currently being investigated further. Nakajo
et al. [
1] reported that the SUV values and ADC values were inversely proportional in the context of malignancy. Ho
et al. [
5] stated in their study of primary cervical cancer that SUVmax and ADC mean were not correlated. Our study used a larger sample size than that used by Nakajo
et al. [
1] and Ho
et al. [
5]. In contrast to the study performed by Nakajo
et al. [
1], our study did not separate the prognostic group into a ‘better’ group and a ‘worse’ group. In contrast to Nakajo
et al. [
1], who included only DCIS, our study only used IDC as subjects. Because the study by Ho
et al. [
5] investigated cervical cancer, the subjects differed from those included in the present study. The accurate identification of a clinical correlation between DWI and PET/CT requires further evaluations involving a variety of subjects. For now, the two modalities cannot be considered as interchangeable.
This study has some limitations. First, because there were many cases in which ADC values were difficult to measure for non-mass lesions, 24 lesions were excluded due to inaccuracy of the ROI measurement. Due to the variation in histologic values, this exclusion of lesions may have introduced variability to the study. Second, although detecting lesions less than 1 cm was considered difficult with DWI, this study included all such small lesions; however, ACD values were not measured in these small lesions. Third, there was no correlation established between the histologic prognostic factors and the actual clinical prognosis follow-up. Further evaluations that complement these limitations are necessary.