FDG uptake reflects breast cancer immunological features: the PD-L1 expression and degree of TILs in primary breast cancer.

BACKGROUND: High F18-fluorodeoxyglucose (FDG) uptake has been reported to be a predictor of poor prognosis in patients with breast cancer. We investigated the relationship between FDG uptake and immunological factors, including the data of programmed cell death-ligand 1 (PD-L1), CD8, and tumor-infiltrating lymphocytes (TILs). METHODS: Breast cancer tissues of 97 patients who underwent surgery without preoperative therapy were examined. The grade of stromal TILs was immunohistochemically evaluated using the criteria of the International TILs Working Group in breast cancer. PD-L1 positivity and CD8 positivity were immunohistochemically evaluated. The FDG uptakes were evaluated based on the standardized uptake value max (SUVmax). The relationships between SUVmax and TIL grade and expression of PD-L1 and CD8 were investigated. RESULTS: Among the 97 patients, 41 (42.3%) had a high SUVmax in their primary tumor, based on the SUVmax cut-off value 3 yielded by receiver operating characteristic curves. PD-L1 was positive in 17 patients (17.5%). Our analyses revealed that large tumor size, high nuclear grade, high degree of TILs and positive expression of PD-L1 were significantly associated with high SUVmax in the primary tumor. There were significant associations between SUVmax and the degree of TILs (r = 0.428, p < 0.001) and between SUVmax and the PD-L1 positivity (r = 0.413, p < 0.001). All cases with a high degree of TILs showed high CD8 expression. CONCLUSION: Our results indicate that the FDG uptake may be predictive of immunological features including TILs and PD-L1 expression in breast cancer patients. Additional research is necessary to further evaluate FDG-PET as a biomarker of immune checkpoint therapy in breast cancer.

ß2-Adrenergic receptor expression is associated with biomarkers of tumor immunity and predicts poor prognosis in estrogen receptor-negative breast cancer.

PURPOSE: Antitumor immunity plays an important role in the progression of breast cancer. ß2-adrenergic receptor (ß2AR) was found to regulate the antitumor immune response and breast cancer progression in preclinical studies. To understand the clinical role of ß2AR in cancer progression, we investigated the clinicopathological and prognostic significance of ß2AR expression in invasive breast cancer. METHODS: ß2AR levels in breast tumors were evaluated by immunohistochemistry in a well-characterized patient cohort with long-term follow-up (n = 278). We evaluated the relationship of ß2AR expression to patient survival and clinicopathological factors, including immune biomarkers such as tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression. Breast cancer-specific survival was compared between high- and low-ß2AR expression groups. RESULTS: Although ß2AR was not related to clinicopathological factors across the whole cohort, high ß2AR was significantly related to PD-L1 negativity in estrogen receptor (ER)-negative patients. Tumors with high ß2AR tended to have low TIL grade, and high ß2AR was an independent prognostic factor for reduced survival in ER-negative patients. CONCLUSIONS: ß2AR is an independent poor prognostic factor in ER-negative breast cancer. The findings suggest that tumor ß2AR regulates immune checkpoint activity, which may have therapeutic implications for patients with ER-negative breast cancer.

Prognostic value of extracapsular invasion of axillary lymph nodes combined with peritumoral vascular invasion in patients with breast cancer.

BACKGROUND: Extracapsular invasion (ECI) of metastatic axillary lymph nodes has been associated with aggressive nodal disease but its prognostic role in breast cancer is unclear. The present study evaluated nodal ECI as a predictor of breast cancer recurrence. METHODS: We evaluated 154 women with histologically proven node-positive breast cancer who were diagnosed with invasive ductal carcinoma, and investigated the relationships between ECI and recurrences and other clinicopathological factors, particularly vascular invasion and the number of lymph node metastases. RESULTS: The presence of ECI at positive nodes was significantly associated with the number of positive nodes, and with disease recurrence and survival in univariate (but not multivariate) analysis. Interestingly, all ECI(+) patients with distant metastases in our series had peritumoral vascular invasion (PVI), which may have reflected systemic disease; ECI with PVI of the primary tumor strongly predicted recurrent disease and shorter survival. CONCLUSION: ECI of axillary metastases combined with PVI indicates high tumor aggressiveness. Patients with ECI and PVI may be considered for stronger adjuvant therapies because of their high risk for distant recurrences.

Clinicopathological significance of decreased galectin-3 expression and the long-term prognosis in patients with breast cancer.

PURPOSE: Galectin-3 expression is modulated in cancer cells, and that finding has led to the recognition of galectin-3 as a diagnostic or prognostic marker for various cancers, including breast cancer. This study investigated the correlation between galectin-3 expression and the clinicopathological features in patients with breast cancer, in order to determine the relevance and role of galectin-3 in breast cancer progression. METHODS: Galectin-3 expression was investigated immunohistochemically in 116 patients with breast cancer, and a statistical analysis was performed. RESULTS: Galectin-3 expression in breast cancer was significantly associated with tumor vascular invasion. However, galectin-3 expression was not associated with Ki-67 expression, which reflects tumor proliferation. Disease-free survival and long-term overall survival were significantly shorter for patients with reduced galectin-3 expression. CONCLUSIONS: This study demonstrated that the galectin-3 expression was associated with tumor vascular invasion and metastasis, suggesting that galectin-3 plays a critical role in tumor progression via an invasive mechanism but not via proliferation in breast cancer. Furthermore, reduced expression of galectin-3 is useful for predicting a long-term poor prognosis in patients with breast cancer.

Accuracy of intraoperative macroscopic diagnosis of sentinel node metastases in breast cancer: is accurate prediction possible?

BACKGROUND: Accurate intraoperative diagnosis of sentinel lymph node (SLN) metastases enables the selection of patients who require axillary lymph node dissection, thus avoiding an additional operation. In this study we investigated the accuracy of intraoperative macroscopic diagnosis of SLN metastases in patients with breast cancer. METHODS: SLNs from 276 breast cancer patients with clinically negative nodes were analyzed by macroscopic examination. The results of intraoperative macroscopic diagnosis were compared with those of frozen section analysis. RESULTS: The sensitivity, specificity, overall accuracy, and false negative rate of SLN biopsy in the assessment of node status were 82.1%, 100%, 96.4%, and 17.9%, respectively, for frozen section analysis, and 57.1%, 95.5%, 87.7%, and 42.9%, respectively, for macroscopic evaluation. Even in patients with node metastasis >7 mm, the false negative rate of macroscopic evaluation was 11.1%. CONCLUSIONS: Our results suggest that macroscopic diagnosis is less effective in predicting lymph node status in breast cancer than frozen section analysis. These findings imply that intraoperative macroscopic evaluation of sentinel nodes is never predictive of the final pathology.

Implication of extracapsular invasion of sentinel lymph nodes in breast cancer: prediction of nonsentinel lymph node metastasis.

BACKGROUND: Accurate intraoperative diagnosis of sentinel lymph node (SLN) metastases enables the selection of patients who require axillary lymph node dissection (ALND). However, many patients with positive SLN do not show metastasis to other axillary lymph nodes. In this study, we investigated the factors that may determine the likelihood of additional positive nodes in the axilla when metastasis is found in the SLN. METHODS: SLN biopsy was performed on 276 patients with breast cancer with clinically negative nodes, of which 46 (16.6%) had positive SLNs and underwent ALND. Eleven (23.9%) of these 46 cases had additional metastasis in nonsentinel lymph nodes (NSLN). The clinical and pathological features of these cases were reviewed and statistical analysis was performed. RESULTS: All cases of positive nodes in NSLN in our series had extracapsular invasion (ECI) at the metastatic SLNs. Furthermore, the absence of ECI of SLN was significantly associated with the absence of metastasis in the NSLN (P < 0.001). As contributing factors, the absence of lymphatic invasion at the primary tumor, primary tumor size (<2 cm) and foci size in the metastatic SLN fell short of reaching statistical significance. Other factors, including histological type, pathological grade, estrogen receptor status, HER2 status, and age, were not significantly associated with metastatic involvement of NSLN. CONCLUSIONS: Our results suggest that the presence of ECI at metastatic SLNs is a strong predictor for residual disease in the axilla. These findings imply the possibility that ALND might be foregone in the treatment of patients with breast cancer without ECI at metastatic SLNs.

VEGF-A Is Associated With the Degree of TILs and PD-L1 Expression in Primary Breast Cancer.

BACKGROUND/AIM: Vascular endothelial growth factor-A (VEGF-A), an important angiogenic factor, has been reported to effect cancer growth and development. Recent reports indicated that anti-VEGF therapy has an important effect of enhancing anti-tumor immunity in various cancers. In the current study, we investigated the relationship between VEGF-A expression and immunological factors, including programmed cell death ligand 1 (PD-L1) and the degrees of stromal tumor-infiltrating lymphocytes (TILs) in breast cancer. PATIENTS AND METHODS: This study enrolled 97 cases with invasive breast cancer who had undergone surgery without preoperative therapy. The grades of stromal-TILs were evaluated using the criteria of the International Working Group for TILs in breast cancer: low, intermediate, and high. VEGF-A and PD-L1 positivity were evaluated by immunohistochemistry. The relationship between VEGF-A expression and the expression of PD-L1 and TILs was investigated. RESULTS: Among the 97 cases, 37 (38.1%) had positive VEGF-A expression in the breast tumor. We divided the cases in two groups based on the VEGF-A expression levels. The analysis revealed that PD-L1 positivity was significantly associated with VEGF-A expression in the breast tumor (29.7% vs. 10.0%, p=0.014). Among the cases with positive PD-L1, 36.7% of VEGF-positive cases and none of VEGF-negative cases had low TILs in the breast tumor. CONCLUSION: VEGF-A expression in breast cancer may reflect PD-L1 expression in the tumor. VEGF-A may act as a negative biomarker of TILs in PD-L1-positive breast cancer. Our results suggest that VEGF-A may be predictive of immunological features and may serve as a useful biomarker for immuno-targeting therapy in patients with breast cancer.

Relationship Between FDG Uptake and Neutrophil/Lymphocyte Ratio in Patients with Invasive Ductal Breast Cancer.

BACKGROUND: 18F-Fluorodeoxyglucose-positron-emission tomography (FDG-PET) is used to evaluate the glucose metabolic rates of tumors. Several studies have reported that high FDG uptake is predictive of poor prognosis and aggressive features in patients with breast cancer. FDG uptake is influenced by many factors, including inflammation. In this study, the relationship between FDG uptake and neutrophil/lymphocyte ratio (NLR), which is an indicator of systemic inflammation, was investigated. PATIENTS AND METHODS: A retrospective investigation of the cases of 143 consecutive patients with invasive ductal carcinoma who had undergone surgery and FDG-PET preoperatively. PET was evaluated using standardized uptake value max (SUVmax). The median SUVmax was 2.5 (range=0-10.5). The cases were divided into two groups based on the value of SUVmax: low (<2.5) and high (≥2.5). The relationships between SUVmax and clinicopathological features, including NLR, were investigated. RESULTS: Among the 143 patients, 73 (51.0%) had high SUVmax in the primary tumor. The analysis revealed that large tumor size (p<0.001), high nuclear grade (p<0.001), the presence of lymphovascular invasion (p<0.001), high C-reactive protein (p=0.046) and high NLR (p<0.001) were significantly associated with high SUVmax in the primary tumor. SUVmax and NLR were significantly positively correlated (r=0.323, p<0.001). Among the 70 cases with low SUVmax, there was no recurrent disease, while out of the 73 cases with high SUVmax had disease recurrence. It is interesting to note that the group with high SUVmax and low NLR had no recurrent disease. CONCLUSION: The present study demonstrated that the finding of high preoperative FDG uptake in breast cancer may be reflective of poor prognosis and that a high NLR may be predictive of aggressive features among patients with breast cancer. On the other hand, among patients with breast cancer with high SUVmax in the primary tumor, it will be useful to identify those with a low NLR in order to improve prognostic accuracy.

Clinicopathological Features of Ductal Carcinoma In Situ from 18F-FDG-PET Findings.

AIM: The presence of ductal carcinoma in situ (DCIS) can increase the risk of developing an invasive ductal carcinoma (IDC), but it is difficult to predict what will occur if a DCIS is left untreated. We reported the usefulness of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for DCIS, and that the presence of FDG uptake in the tumor could be considered a predictor of invasive potential in patients with DCIS. In this study, we retrospectively evaluated the clinicopathological features of DCIS by using FDG-PET findings, and we evaluated the possibility of using FDG-PET in DCIS cases as a biomarker of which lesions will go on to become invasive. PATIENTS AND METHODS: We investigated the cases of 185 consecutive patients with primary breast cancer who were diagnosed as having DCIS or IDC and underwent FDG-PET preoperatively. RESULTS: We divided the cases into two groups on the basis of histology; DCIS vs. IDC (n=171). The DCIS cases were divided into two groups on the basis of FDG uptake in the primary tumor. Fourteen of the 185 patients (7.4%) were revealed to have a DCIS. The analysis revealed that the SUVmax and the number of cases not detected by FDG-PET were significantly different between the DICS and IDC groups. The extent of the primary tumor was not significantly different between the two groups. In six cases (42.9%) of the 14 DCIS cases, no FDG uptake was detected by FDG-PET. The extent of tumor did not significantly differ between the two groups. In addition, all six cases without FDG uptake were of the diffuse-spread type, without mass formation. All eight cases with mass formation had FDG uptake. CONCLUSION: Our present findings suggest that the FDG-PET uptake reflects tumor burden or tumor density, which should be considered to be associated with the presence of invasion.

Impact of vascular invasion of a primary tumor as a strong risk factor for disease recurrence in patients with node-positive breast cancer.

The presence of lymph node metastasis is considered to be the most significant indicator of prognosis. However, in some cases with node-positive breast cancer, cancer cell dissemination is localized to the lymphatic systems. It is, therefore, important to develop selection criteria for strong adjuvant therapy in patients with node-positive breast cancer. This study was undertaken to evaluate the presence of vascular invasion that may reflect systemic disease as a predictor of disease recurrence in node-positive breast cancer. We retrospectively evaluated the cases of 134 consecutive female patients with breast cancer with lymph node metastasis who underwent radical breast operations. We examined the relationship between recurrence and clinicopathological factors, particularly vascular invasion. The presence of vascular invasion was found to be significant in a univariate analysis. The presence of vascular invasion was the independent risk factor in a multivariate analysis. Among the 66 patients without vascular invasion, four (6.1%) had disease recurrence. On the other hand, among the 68 patients with vascular invasion, 15 (22.1%) had a recurrence. It is interesting to note that despite the presence of lymph node metastasis, the group without vascular invasion had few patients with distant metastases. Our results suggest that the presence of vascular invasion could be an indicator of high biological aggressiveness and may be a strong prognostic factor for node-positive breast cancer.

Extracapsular invasion of sentinel lymph nodes is not associated with disease recurrence in breast cancer.

The purpose of this study was to evaluate the presence of extracapsular invasion (ECI) in positive sentinel lymph nodes (SLNs) as a predictor of disease recurrence in breast cancer. SLN biopsy was performed on 318 breasts of 316 breast cancer patients, of which 50 (15.7%) had positive SLNs. Six (12.0%) of these 50 cases had disease recurrence. The clinicopathologic features of these cases were reviewed. The ECI at SLNs was not significantly associated with disease recurrence. The recurrence-free interval by Kaplan-Meier curves did not differ significantly among patients with and without ECI at SLNs. On the other hand, metastasis at non-SLNs was observed in 12 cases (24.0%) among the 50 cases with positive SLNs, and in the non-SLN metastasis group there were 7 patients with ECI at non-SLNs. Three of 7 cases with ECI at non-SLNs had disease recurrence and none of those 5 without ECI at non-SLNs had disease recurrence. Our current study suggests that the presence of ECI at metastatic SLNs is not associated with recurrent disease in breast cancer. Our results also imply that patients with ECI at positive non-SLNs have a high risk of disease recurrence.

Impact of the prognostic value of vascular invasion, but not lymphatic invasion, of the primary tumor in patients with breast cancer.

BACKGROUND: The prognostic value of lymphovascular invasion (LVI) in patients with breast cancer is unclear. Lymphatic invasion may mainly represent the selective affinity of breast cancer cells for lymph nodes. This study was undertaken to evaluate the presence of vascular invasion that may reflect systemic disease as a predictor of disease recurrence in breast cancer, separate from lymphatic invasion of the primary tumor. PATIENTS AND METHODS: We retrospectively evaluated the cases of 263 consecutive female patients with primary breast cancer who underwent a radical breast operation. We examined the relationship between recurrence and the prognostic significance of clinico-pathological factors, particularly lymphatic (Iy) and vascular invasion (v). RESULTS: The presence of lymphatic invasion and that of vascular invasion were significant in univariate analysis. The presence of vascular invasion was an independent prognostic factor, but lymphatic invasion lost its prognostic significance in multivariate analysis. Among the 91 patients in the ly-/v- group, 5 (5.5%) had disease recurrence, and among the 73 patients in the ly+/v- group, 5 (6.8%) had disease recurrence. On the other hand, among the 95 patients in the ly+/v+ group, 19 (20.0%) had a recurrence, and among the 3 patients in the ly-/v+ group, one had a recurrence. It is interesting to note that despite the presence of lymphatic invasion, the group without vascular invasion (ly+/v-) had a few patients with distant metastases, a result which is similar to that of the ly-/v- group. CONCLUSION: The presence of vascular invasion, but not lymphatic invasion, could be an indicator of high biological aggressiveness and may be a valid prognostic factor for breast cancer.

Early predictive value of non-response to docetaxel in neoadjuvant chemotherapy in breast cancer using 18F-FDG-PET.

BACKGROUND: The aim of this prospective study of patients with breast cancer was to identify non-responders to docetaxel in neoadjuvant chemotherapy (NCT) using fluorine-18-fluorodeoxyglucose positron-emission tomography ((18)F-FDG-PET). PATIENTS AND METHODS: We analyzed the maximum standardized uptake value (SUVmax) of (18)F-FDG-PET before and after the first course and the reduction rate in tumor size shown by magnetic resonance imaging (MRI) before the first and after the fourth course of docetaxel. RESULTS: None of the eight patients (0%) whose SUVmax decrease was less than 18% revealed a clinical partial response or clinical complete response; Seven out of the sixteen patients (44%) with an SUVmax decrease over 45% achieved a complete response. CONCLUSION: An SUVmax reduction rate less than 18% is observed in patients with breast cancer after the first course of docetaxel in NCT and may be indicator of non-response to docetaxel.

Single-incision laparoscopic surgery for a small-intestinal gastrointestinal stromal tumor: report of a case.

Our report concerns a 64-year-old man with a small-intestinal gastrointestinal stromal tumor (GIST), which was successfully treated with single-incision laparoscopic surgery (SILS). Small-bowel endoscopy detected a submucosal tumor located approximately 10 cm from the ligament of Treitz in the wall of the proximal jejunum. Contrast-enhanced computed tomography revealed a tumor (diameter, 4 cm) containing high- and low-density areas in the proximal jejunum. On 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET), the tumor demonstrated intense FDG uptake (maximum standard uptake value, 3.82), whereas it displayed high signal intensity on diffusion-weighted magnetic resonance images. No metastatic lesions were observed. The patient was diagnosed with a jejunal GIST. Wedge resection of the jejunum was performed using the SILS procedure. The tumor was histopathologically diagnosed as a low-grade malignant GIST. SILS is a useful resection technique for small-intestinal GIST.

The detection of pCR after PST by contrast-enhanced ultrasonography for breast cancer.

BACKGROUND: Primary systemic therapy (PST; such as chemotherapy) has been approved as the standard therapy. Breast-conserving surgery is involved in 60-70% of breast cancer operations, and cancer can spread in the period between the initial treatment and preoperative chemotherapy. To reduce the residual tumor in persistent disease of breast tissue, determining the margin including normal tissue when removing the tumor is very difficult. With the development of the color Doppler method, contrast-enhanced ultrasonography (CEUS) allows visualization of the tumor bloodstream. The availability and efficacy of CEUS for setting the resection margin in breast-conserving surgery were examined and compared with MRI imaging as tools for making decisions for breast-conserving surgery. METHODS: One hundred seventy patients underwent breast cancer operations: 59 were PST(+) and 111 PST(-). Imaging studies, ultrasonography and MRI, to measure the size of the tumor were performed twice, before and after chemotherapy, for PST patients. This was carried out not only to measure the residual tumor size after PST, but also to detect whether pathologically complete response (pCR) had been achieved or not. Fifty-nine patients received CEUS after PST, and we determined the precision of CEUS and conventional US. RESULTS: The sensitivity of CEUS for pCR was 80.0% (95% CI 0.571-0.88), specificity 98.0% (95% CI 0.933-0.996), positive predictive value 88.9% (95% CI 0.635-0.978) and negative predictive value 96.0% (95% CI 0.914-0.976). The difference between the pathological examination and ultrasonography, conventional ultrasonography and CEUS was -4.455 ± 2.02 and 2.582 ± 2.298 cm (95% CI -13.11 to -0.96, p = 0.0235); CEUS was near the diameter of the actual pathological examination. CONCLUSION: Contrast-enhanced ultrasonography is suitable for the preoperative examination, especially after PST, to determine the resection margin before breast-conserving surgery and detects pCR, which can help to avoid surgical procedures in the future.