Early SUV_max is the best predictor of axillary lymph node metastasis in stage III breast cancers

Introduction

Breast cancer is the most common malignant tumor in women worldwide (1,2), and the incidence of breast cancer is increasing each year in China (3,4). Lymphatic metastasis is the most common type of metastasis (5,6), and the axillary lymph node is the first site of breast cancer metastasis, which compresses the axillary vein and results in edema of the upper limb on the affected side. Edema then extends to the clavicle and the internal mammary lymph node, which leads to metastasis of the lung, pleura, bone, liver, brain, kidney and other areas, and may result in direct invasion of the surrounding tissue of the chest wall. Moreover, different pathological types of metastasis vary in associated symptoms and signs. As breast cancer progresses, deterioration occurs. The later the disease progression, the greater the possibility of systemic metastasis and the more difficult it is to treat. Recalcitrant disease is associated with reduced patient quality of life and increased mortality. Regional lymph node metastasis plays an important role in treatment planning and prognosis prediction. Axillary lymph node dissection (ALND) is a routine, but highly invasive surgery to determine the lymph node stage of breast cancer. Recently, sentinel lymph node biopsy (SLNB) has been developed, through which ALND can be avoided if the sentinel lymph node is negative. However, surgical trauma is still associated with SLNB, and traditional imaging methods, such as ultrasonography, magnetic resonance imaging (MRI), and computed tomography (CT) have limited effectiveness in evaluating lymph node metastasis (7,8).

Positron emission tomography (PET) is a kind of imaging technology that displays biological activity in vivo, at the molecular level. PET mainly uses fluorine-18 (¹⁸F) and other positron nuclides to label various biomolecules. This labeling allows the biological characteristics and functions of the marker molecules to remain intact, while permitting objective display of biological processes in vivo, revealing genetic, metabolic, and functional changes that are occurring due to the disease, and providing a scientific basis for early detection. Because of the high sensitivity and specificity of PET, this imaging method provides the possibility for non-invasive diagnosis of breast cancer and axillary lymph node metastasis, providing a basis for treatment selection and allowing dynamic observation of response to treatment. Although fluorine-18-labeled 2-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (¹⁸F-FDG PET/CT) imaging has been used in the study of lymph node metastasis in breast cancer (9-11), dual-time imaging studies in this area are still rare.

The axillary lymph node is the first site of breast cancer metastasis, and early detection of metastasis to this site is critical. Therefore, we retrospectively analyzed dual-phase ¹⁸F-FDG PET/CT imaging findings, in which the change in SUV_max values was calculated and compared between metastatic and non-metastatic lymph nodes, as well as among subgroups of metastatic lymph nodes. Furthermore, differences in SUV_max values were evaluated for predictive capacity in the preoperative detection of axillary lymph node metastasis in patients with stage III breast cancer.

Methods

Participants

Clinical data from 40 women with breast cancer who underwent ¹⁸F-FDG PET/CT examinations from December 2016 to December 2019 in our hospital were retrospectively analyzed (Table S1). All patients had the following characteristics: unilateral lesions without distant metastasis; no second primary tumor; no cancer-related treatment; no current pregnancy or lactation; and dual-phase PET/CT imaging 1–2 weeks before surgery. The patients were divided into two groups based on their average age (55.6 years, ranged from 33 to 72 years) for further analysis. According to histopathological assessment, all 40 patients had stage III (N2) disease, including 31 patients with invasive ductal carcinoma and 9 patients with invasive lobular carcinoma. Patients were divided into two groups according to the average diameter of tumor (2.58 cm, ranged from 0.8 to 5.7 cm) for further analysis. A total of 398 axillary lymph nodes were resected, including 176 metastatic lymph nodes and 222 non-metastatic lymph nodes. A total of 209 lymph nodes were matched with the lymph nodes on PET/CT images, including 97 metastatic lymph nodes and 112 non-metastatic lymph nodes. Ethical approval was obtained from the institutional review boards and the requirement of informed consent was waived due to the retrospective nature of this study.

Dual-time point ¹⁸F-FDG PET/CT imaging

The ¹⁸F-FDG was provided by Shanghai Atomic Kexing Pharmaceutical Co., Ltd., China. The PET/CT imaging instrument was a 64-slice Siemens Biograph mCT with a ring consisting of 52 detectors. The patients fasted for at least 4–6 h and had a fasting blood sugar level of 4.0–8.2 mmol/L. After an intravenous injection of ¹⁸F-FDG at a dose of 4.81 MBq/kg body mass, the patients were instructed to lie down in the dark for 60–70 min. The bladder was emptied before the early scan, which ranged from the skull base to the middle of the upper femur. Plain CT scan was performed, first with a current of 170 mA, voltage of 120 kV, scanning time of 18.66–21.94 s, pitch of 0.8, rotational speed of 0.5 s/rot and scanning thickness of 3 mm and then a PET scan, a total of 6–7 body positions (via changing the bed position) were imaged at a scanning rate of 2 min/position (early SUV_max). The bladder was emptied again 120 to 150 min after FDG injection, delayed scan was acquired at a scanning rate of 4 min/position (delayed SUV_max), ranging from the skull base to the middle of the upper femur (6–7 body positions). The images were reconstructed after attenuation correction, and fusion images of the transverse, coronal, and sagittal views of PET, CT, and PET/CT scans with 5 mm thickness were obtained.

Image analysis

The PET/CT images were assessed by two experienced radiologists. A region of interest (ROI) was used to determine the maximum standardized uptake value (SUV_max) of the matched lymph nodes on the PET/CT fusion images, and the SUV_max values at the early and delayed stages were calculated accordingly. The change in SUV_max was determined using the following equation:

Delta SUV_max (ΔSUV_max) = (delayed SUV_max− early SUV_max)/early SUV_max

The short-axis lymph node diameters were measured on plain CT sections. There was a limitation on scanning thickness and it was difficult to accurately delineate the ROIs, therefore lymph nodes with a short-axis diameter of less than 4 mm were excluded. During the operation, the matched lymph nodes on PET/CT were located and labeled according to the lymph node size, shape, direction, and the distance from the primary breast cancer. The lymph nodes were identified as metastatic lymph nodes by optical microscopy.

Statistical analysis

Data were analyzed using SPSS 20.0 and MedCalc 12.7 software. Continuous data were expressed as mean ± standard deviation. Correlation of lymph nodes with clinicopathological parameters was assessed using the χ² test. One-way ANOVA was used to compare subgroups of metastatic lymph nodes. Comparison between groups was performed using the two-sample t-test or the paired t-test. The diagnostic efficacy and diagnostic threshold in three types of values (early, delayed phases and Delta SUV_max) were analyzed using receiver operating characteristic (ROC) curves, and ROC curves between every two types were compared using the Delong test. P<0.05 was considered statistically significant.

Results

Clinical characteristics of the patients

In the resected lymph nodes, metastasis and non-metastasis were not related to age, pathological type, location, molecular subtype, Scarff-Bloom-Richardson (SBR), or size of primary focus (P values were 0.534, 0.595, 0.496, 0.524, 0.525 and 0.658, respectively). The matching of lymph nodes with PET/CT data showed no correlation with clinical characteristics (P values were 0.260, 0.765, 0.532, 0.788, 0.883 and 0.516, respectively). The short-axis diameters were not significantly different between the metastatic and non-metastatic lymph nodes (t=1.56, P=0.121). The SUV_max values for contralateral normal axillary region on the delayed scans were not significantly higher compared with the early scans (t=1.65, P=0.107).The SUV_max values for tumors on the delayed scans were significantly higher compared with the early scans (t=25.89, P<0.001; Table 1) (Figures 1,2). There was no significant difference in SUV_max of the early and delayed phases between the invasive ductal carcinoma and invasive lobular carcinoma (t=1.40 and 0.58, P =0.164 and 0.565, respectively). However, we analyzed the I, II and III grades of SBR, and found that the worse the degree of differentiation, the greater the SUV_max, and the difference was statistically significant (F=30.57 and 16.33, respectively, P<0.001; Table 2).

Table 1 Clinical characteristics of the patients
Full table

Figure 1 ¹⁸F-FDG PET/CT imaging and pathology of right breast outer upper quadrant invasive ductal carcinoma (A-F, female, 37 years old). Red arrow shows primary breast cancer. White arrow shows that the short diameter of lymph node is 6.35 mm, the SUV_max values on the early scan (1.58) and delayed scan (1.65), but no metastasis is found in postoperative pathology. Yellow arrow shows that the short diameter of lymph node is 6.51 mm, the SUV_max values on the early scan (4.21) and delayed scan (4.87). Green arrow shows that the short diameter of lymph node is 7.23 mm, the SUV_max values on the early scan (6.56) and delayed scan (7.98). These two lymph nodes can be seen with pathological metastasis after operation (F, HE×10).

Figure 2 ¹⁸F-FDG PET/CT imaging and pathology of left breast invasive ductal carcinoma (A-F, female, 71 years old). Red arrow shows primary breast cancer. White arrow shows that the short diameter of lymph node is 6.03 mm, the SUV_max values on the early scan (1.51) and delayed scan (1.59), but no metastasis is found in postoperative pathology (F, HE×10).

Table 2 Comparison of the dual-phase SUV_max values in histologic subtypes of matched metastatic lymph nodes
Full table

Comparison of the SUV_max of metastatic and non-metastatic lymph nodes

The SUV_max of metastatic lymph nodes from the delayed scan images was significantly higher compared with the early scan images (t=−4.96, P<0.001), and the ΔSUV_max on the dual-phase images was 0.08±0.21. The SUV_max value of non-metastatic lymph nodes from the delayed scan images was higher compared with the early scan images (t=−0.30, P=0.766). Table 3 reveals that the SUV_max values from the early and delayed scan images were each significantly different between the metastatic and non-metastatic lymph nodes (P<0.001) (Figure 3).

Table 3 Comparison of the SUV_max values of dual-phase images between the metastatic and non-metastatic group in matched lymph nodes
Full table

Figure 3 ¹⁸F-FDG PET/CT image of another patient with invasive ductal carcinoma of the right upper outer quadrant of the breast (A-F, female, 53 years old). Red arrow shows primary breast cancer. White arrow shows that the short diameter of lymph node is 5.45 mm, the SUV_max values on the early (1.43) and delayed scan (1.51), and no metastasis is found in postoperative pathology. Yellow arrow shows that the short diameter of lymph node is 6.56 mm, the SUV_max values on the early scan (3.82) and delayed scan (4.49), but metastasis is found in postoperative pathology (F, HE×10).

Comparison SUV_max in metastatic lymph node subgroups

The SUV_max values were not significantly different in the subgroup with short diameters of >4.00 and ≤6.00 mm when comparing early and delayed scans (t=1.96, P=0.06). The SUV_max value from the delayed scan was higher compared with the early scan in the subgroup with short diameters of >6.00 and ≤8.00 mm, as well as in the subgroup with short diameters of >8.00 and ≤10.00 mm; both of these differences were significant (t=9.67 and 17.34, respectively, P<0.001; Table 4).

Table 4 Comparison of the dual-phase SUV_max values in subgroups of matched metastatic lymph nodes
Full table

Comparison of the change in SUV_max

The ΔSUV_max values were significantly different between metastatic and non-metastatic lymph nodes (t=3.46, P=0.001; Table 3). The differences in ΔSUV_max values among the three metastatic subgroups (4.00mm< short diameter ≤6.00 mm, 6.00 mm < short diameter ≤8.00 mm and 8.00 mm < short diameter ≤10.00 mm) were statistically significant (F=78.98, P<0.001), and the differences between every two subgroups were statistically significant (P<0.001; Table 4).

Analysis and comparison of ROC curves

ROC curve analysis showed that the AUC of SUV_max in the early phase was 0.961 (P=0.013, 95% CI: 0.925–0.983), and the diagnostic threshold was 4.29. The sensitivity and specificity for diagnosing metastatic lymph nodes were 82.5% and 100%, respectively. The AUC of SUV_max in the delayed phase was 0.897 (P=0.022, 95% CI: 0.847–0.934), and the diagnostic threshold was 4.33. The sensitivity and specificity for diagnosing metastatic lymph nodes were 73.2% and 100%, respectively. The AUC of the ΔSUV_max was 0.602 (P=0.043, 95% CI: 0.532–0.669), and the diagnostic threshold was 0.18. The sensitivity and specificity for diagnosing metastatic lymph nodes were 39.2% and 100%, respectively (Table 5, Figure 4).

Table 5 Analysis of ROC curves for three types of values
Full table

Figure 4 ROC curve of the SUV_max and ΔSUV_max values on dual-phase images for diagnosing metastatic lymph nodes. The sensitivity in delayed phase and ΔSUV_max were lower than that in early phase. (A) AUC of early phase was 0.961; (B) AUC of delayed phase was 0.897; (C) AUC of ΔSUV_max was 0.602.

The sensitivities in the delayed phase and ΔSUV_max were lower than that in the early phase. The difference of AUC between the early and delayed phases was statistically significant (z=4.46, P<0.001). Furthermore, the AUC of ΔSUV_max was significantly lower than the early and delayed scans (z=8.95 and 9.13, respectively, P<0.001) (Table 6).

Table 6 Comparison of ROC curves between every two types of values
Full table

Discussion

Breast cancer cells are prone to shedding into the lymphatic system or blood, leading to metastasis and posing a greater risk of death (12). The lymphatic system is one of the most common routes of cancer cell dispersal; therefore, lymph node metastasis plays a critical role in staging, treatment planning, and establishing a prognosis for breast cancer (13-15). With improvements in the diagnosis and treatment of breast cancer, there is an urgent need to, clarify the stage of breast cancer accurately and effectively by evaluating lymph node metastasis. Traditional imaging methods, such as CT, MRI, and ultrasonography, play a role in evaluating axillary lymph node morphology (16). However, small or irregular lymph node metastases can be easily overlooked when using these methods during diagnosis (17,18). Some studies have shown that ¹⁸F-FDG PET/CT detection of lymph node metastasis may allow patients to avoid SLNB (19). The use of ¹⁸F-FDG PET/CT in the evaluation of lymph node metastasis in breast cancer has also been described (9,20-24). However, few comparative analyses have assessed the preoperative and postoperative regional lymph node metastasis of breast cancer by dual-phase imaging. In this study, an ROC curve was used to analyze the diagnostic efficacy and determine the optimal SUV_max threshold for diagnosing metastatic lymph nodes.

Some studies have found difficulties in the differential diagnosis of some inflammatory or infectious lesions and malignant lesions with PET/CT dual-phase imaging (25). Other studies have suggested that the FDG uptake in tumor cells increases over time, while mononuclear uptake due to inflammation and other major factors decreases over time (26). The uptake of ¹⁸F-FDG in the lesions may be underestimated by a single imaging around 1 hour after the imaging agent injection. Dual-phase imaging and delayed imaging can improve the diagnostic efficacy in differentiating benign and malignant lesions (27). In the present study, we showed that metastatic lymph nodes had a significantly higher SUV_max value on delayed scans compared with early scans, and primary breast cancer had a significantly higher SUV_max value on delayed scans compared with early scans as well. Moreover, non-metastatic lymph nodes had a slightly higher SUV_max value on delayed scans compared with early scans, although the difference was not statistically significant. These findings were consistent with the above-mentioned reports. The SUV_max values from the delayed and early scans of metastatic lymph nodes were significantly higher compared with the non-metastatic lymph nodes, suggesting that dual-phase and delayed phase imaging could improve visualization of lymph node metastases in breast cancer, which is an outcome of immense diagnostic value. An SUV_max that was increased on the delayed image of the lymph node suggested that the lymph node had a tendency towards metastasis, which could be attributed to the uptake peak of ¹⁸F-FDG by tumor cells occurring at 3–4 h after injection, whereas the uptake peak of inflammatory lesions occurs at approximately 1 h after injection (28,29).There were also some studies supporting the view that the peak value of SUV_max for inflammatory or infectious diseases was longer (30). In this study, early imaging at 60–70 min after the injection captured the peak uptake time of non-metastatic lymph nodes, whereas the SUV_max value of non-metastatic lymph nodes was lower compared with the metastatic lymph nodes during the non-peak uptake time. After a 120–150 min delay of imaging, the uptake of ¹⁸F-FDG in the tumor cells was still increasing. However, few studies have investigated the diagnostic value of PET/CT in different pathological types of breast cancer at home and abroad (31).

In this study, the SUV_max values of metastatic lymph nodes and non-metastatic lymph nodes in patients with breast cancer were 5.45±1.35 and 2.79±0.72, respectively, which were different from those in a previously reported study (32). Such a discrepancy may reflect that the determination of SUV is affected not only by physiological factors, such as patient body weight and blood glucose concentration, but also by the software and hardware involved in imaging and analysis, including acquisition modes of different equipment, attenuation correction methods, and reconstruction algorithms (33,34). Therefore, there may be substantial differences in the SUV_max values of benign and malignant tumors determined by various PET centers. Further ROC curve analyses showed that the AUC of early imaging was 0.961, and the sensitivity and specificity of a SUV_max >4.29 for diagnosing metastatic lymph nodes were 82.5% and 100%, respectively. The AUC of delayed imaging was 0.897, and the sensitivity and specificity of a SUV_max >4.33 for diagnosing metastatic lymph nodes were 73.2% and 100%, respectively. The AUC of the ΔSUV_max was 0.602. The difference in AUC between the early and delayed scans was statistically significant (P<0.001), and the AUC of the ΔSUV_max was significantly lower for the early compared with the delayed scans (P<0.001), suggesting that the increase in SUVmax upon delayed imaging predicts a tendency towards lymph node metastasis, albeit with decreased sensitivity. Therefore, the early SUV_max offers the best value in predicting axillary lymph node metastasis in stage III (N2) breast cancers. The size of SUV_max was not only related to the degree of malignancy of the tumor, but also related to the size of the lesion. The metastatic lymph nodes were further divided into three subgroups. The results showed that the SUV_max values of some small metastatic lymph nodes (4.00< short diameter ≤6.00 mm) were not significantly increased, and even slightly decreased, between the early and delayed scans. This made the overlap between the SUV_max values on the delayed image for non-metastatic lymph nodes wider than that on the early image for non-metastatic lymph nodes. This study suggested that FDG uptake peaks occurred earlier than anticipated in some small metastatic lymph nodes, an effect that may be related to tumor heterogeneity (35), and may contribute to missed diagnoses with both single- and dual-phase imaging for small metastatic lymph nodes. We believe that the smaller the lymph node is, the greater the diagnostic value of SUV_max in the early phase, and SUV_max in the delayed phase can be used as supplementary diagnostic information. However, some studies suggested that some inflammatory or infectious lesions reduced the diagnostic efficiency of dual phase imaging (36). Therefore, it is necessary to perform further research with larger sample sizes.

Ma et al. (37) found that the standard attributes indicating lymph node metastasis were different depending on the sites, e.g., the short-axis diameter of the ipsilateral retropharyngeal lymph node >5 mm, the short diameter of the middle lymph node >11 mm, and the short diameter of other parts >10 mm. Lymph nodes with a short diameter of <1 cm on CT images cannot be excluded from the possibility of metastasis (38). In this study, the average short diameter of 97 metastatic lymph nodes was 6.25±1.25 mm, which was consistent with the results of the above-mentioned studies. The average short diameter of 112 non-metastatic lymph nodes was 6.02±0.79 mm, which was smaller than that of the metastatic lymph nodes, although the difference was not significant. We selected as few cases of stage N2 lymph node metastases as possible and excluded some cases of lymph node fusion or stage N2 metastases to accurately match the preoperative PET/CT findings of lymph nodes with the postoperative pathology, which may contribute to the lack of significance in diameter variation.

The present study has several limitations. First, the number of cases was relatively small, and all included cases featured high ¹⁸F-FDG uptake in the primary lesion, which failed to allow interpretation that accounts for the heterogeneity of pathological types and differentiation. Second, there was selection bias. Some cases of metastases higher than stage N2 or lymph node fusion were excluded during case selection to accurately match the pathological lymph node results with the preoperative PET/CT findings. Third, this was a retrospective study, and although only cases with axillary lymph node metastasis below stage N2 were included, some matching errors may remain. Finally, at present, we still face the problem of low sensitivity of small lesions in the absence of SLNB. Therefore, the differential diagnosis between small metastatic lymph nodes and other lesions should be more cautious.

Conclusions

Lymph node size had limited value in the diagnosis of axillary lymph node metastasis of breast cancer. In contrast, dual-phase ¹⁸F-FDGPET/CT imaging had great value in evaluating axillary lymph node metastasis of stage III breast cancer. An SUV_max that continuously increased in a lymph node suggested metastasis, and early SUV_max offers the best value in predicting axillary lymph node metastasis in stage III breast cancers.

Acknowledgments

Funding: The authors would like to thank the national natural science foundation of China (No. 81671743), clinical key diseases diagnosis and therapy special foundation of Suzhou City (Grant number LCZX201801), and high-level health talent project of Jiangsu Province (Grant number LGY2016035).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-20-423). The authors have no conflicts of interest to declare.

Ethical Statement: Ethical approval was obtained from the institutional review boards and the requirement of informed consent was waived due to the retrospective nature of this study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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