Discoidin Domain Receptor 2 (DDR2) is a receptor tyrosine kinase for collagen, stimulating epithelial-mesenchymal transition and stiffness in breast cancer. Here, we investigated levels of DDR2 in breast tumor cells in relation to vascular invasion, TIL subsets, macrophages, molecular tumor subtypes, modes of detection and prognosis. This retrospective, population-based series of invasive breast carcinomas from the Norwegian Screening Program in Vestfold County (Norway), period 2004-2009, included 200 screening patients and 82 cases detected in screening intervals. DDR2 was examined on core needle biopsies using a semi-quantitative, immunohistochemical staining index and dichotomized as low or high DDR2 expression. Counts of macrophages and TIL subsets were dichotomized based on immunohistochemistry using TMA. We also recorded blood or lymphatic vessel invasion (BVI or LVI) as present or absent by immunohistochemistry. High expression of DDR2 in tumor cells showed significant relation with high counts of CD163+ macrophages (p < 0.001) and FOXP3 TILs (p = 0.011), presence of BVI (p = 0.028), high tumor cell proliferation by Ki67 (p = 0.033), ER negativity (p = 0.001), triple-negative cases (p = 0.038), basal-like features (p < 0.001) as well as interval detection (p < 0.001). By multivariate analysis, high DDR2 expression was related to reduced recurrence-free survival (HR, 2.3, p = 0.017), when examined together with histologic grading, lymph node assessment, tumor diameter, BVI, and molecular tumor subtype. This study supports a link between high DDR2 expression, high counts of macrophages by CD163 (tumor associated) and regulatory T cells by FOXP3 together with the presence of BVI, possibly indicating increased tumor motility and intravasation in aggressive breast tumors.

UNASSIGNED: The presence of lymph-vascular space invasion is a powerful predictor of lymph node metastasis. However, most studies do not distinguish lymph vessel invasion (LVI) and blood vessel invasion (BVI). The aim of this study was to distinguish the role of LVI and BVI in lymphatic metastasis and recurrence in patients with endometrial cancer.
UNASSIGNED: We examined 171 patients with endometrial cancer. Immunohistochemical double staining was used to distinguish lymphatic invasion and vascular invasion. First, the relationship between lymphatic/vascular invasion and clinicopathological features and lymphatic metastasis was studied. Then, the expression of D2-40/LVI and CD31/BVI in patients with recurrence was analyzed.
UNASSIGNED: Pathological grading (G3) and D2-40/LVI were independent high-risk factors for lymph node metastasis of endometrial cancer. The area under the receiver operating characteristic curve values for predicting lymphatic metastasis using pathological grading (G3) or D2-40/LVI alone were .642 and .680, respectively, and the area under the curve value for the combined detection of pathological grading (G3) and D2-40/LVI was .726, which was greater than the values obtained for the abovementioned independent variables. Among the 15 recurrent patients, 5 (33.3%) were D2-40/LVI positive, 2 (13.3%) were CD31/BVI positive, and 8 (53.3%) were both D2-40/LVI and CD31/BVI positive.
UNASSIGNED: D2-40/LVI combined with G3 can effectively predict lymph node metastasis of endometrial carcinoma.

BACKGROUND: Lymphovascular invasion, including lymphatic-vessel invasion and blood-vessel invasion, plays an important role in distant metastases. The metastatic pattern of blood-vessel invasion may differ from that of lymphatic-vessel invasion. However, its prognostic significance in breast cancer remains controversial. We evaluated the role of blood-vessel invasion in the prognosis of operable breast-cancer patients and its association with clinicopathological characteristics.
METHODS: We systematically searched EMBASE, PubMed, the Cochrane Library and Web of Science for studies in English through December 2020. Disease-free survival, overall survival and cancer-specific survival were the primary outcomes. Pooled hazard ratios and 95% confidence intervals were assessed using a random-effects model.
RESULTS: Twenty-seven studies involving 7954 patients were included. Blood-vessel invasion occurred in 20.4% of tumor samples. Pooled results showed significant associations of blood-vessel invasion with worse disease-free survival (hazard ratio = 1.82; 95% confidence interval = 1.43-2.31) and overall survival (hazard ratio = 1.86; 95% confidence interval = 1.16-2.99) in multivariate analyses. The results of the univariate analyses were similar. Among the clinicopathological factors, blood-vessel invasion was associated with larger tumor size, lymph-node metastasis, nonspecific invasive type, higher histological grade, estrogen receptor-negative breast cancer, human epidermal growth factor receptor 2-positive breast cancer and lymphatic-vessel invasion. In the lymph-node-negative subgroup analyses, the presence of blood-vessel invasion led to poorer disease-free survival (hazard ratio = 2.46; 95%confidence interval = 1.64-3.70) and overall survival (hazard ratio = 2.94; 95%confidence interval = 1.80-4.80).
CONCLUSIONS: We concluded that blood-vessel invasion is an independent predictor of poor prognosis in operable breast cancer and is associated with aggressive clinicopathological features. Breast-cancer patients with blood-vessel invasion require more aggressive treatments after surgery.

OBJECTIVE: Recent studies have shown that blood vessel invasion (V1) influences the long-term survival of patients with Non-Small Cell Lung Cancer (NSCLC). The aim of the present study was to emphasize V1 as an independent risk factor. We evaluated the effects of V1 on the survival of NSCLC patients with UICC stages I, II, and III after surgery.
METHODS: This retrospective study includes 747 consecutive patients with NSCLC who underwent anatomic resection and radical lymphadenectomy at our institution between January 2012 and December 2020. V1- were compared to V0-patients (no blood vessel invasion). All patients received adjuvant therapy according to European guidelines when indicated. After excluding patients with detection of lymphangiosis carcinomatosa, tumor-cells at the resection margin, distant metastases and those, that received neoadjuvant therapy, 1-, 3- and 5- year survival rates were assessed by Kaplan-Meier method. To proof V1 as an independent risk factor, a propensity score matched (PSM) analysis was performed regarding age, gender, UICC-stage, lymph-node involvement, and comorbidities.
RESULTS: A total of 461 patients (V0: 440; V1: 21) were included in this analysis. Baseline characteristics did not show any significant difference. Mean age in V0-group was 65.7 ± 10.5 years and 64.1 ± 8.6 years in V1-group (p-value = 0.5). In the V0-group 54.8% were male, whereas in the V1-group this number was 66.7% (p-value = 0.37). Mean survival in V1-group was significantly shorter compared to V0-group (V1: 45.8 ± 9.3 months; V0: 81.1 ± 1.1 months; p-value<0.001). This was confirmed after applying a propensity score matched analysis (V0: 99.9 ± 4.9 months; V1: 45.8 ± 9.3 months; p-value<0.001) - V1 is a prognostic marker independent of UICC stage. The 1-, 3- and 5-year survival rates were significantly shorter for V1-patients (1-year: V0: 100%; V1: 70.6%; p-value = 0.012) (3-year: V0: 95.2%; V1: 46.2%; p-value = 0.002) (5-year: V0: 90.5%; V1: 36.4%; p-value = 0.003).
CONCLUSIONS: As we have shown with our investigations, V1 has a major impact on long-term survival in NSCLC patients and furthermore, acts as an independent risk factor. Due to our small but specified sample size, our statement should be confirmed by a multicenter study. In the meantime, we suggest making the implementation of the V0/V1 specification mandatory in the tumor classification.

Lung cancer is the most frequent cause of cancer-related death worldwide. The patient’s outcome depends on tumor size, lymph node involvement and metastatic spread at the time of diagnosis. The prognostic value of lymph and blood vessel invasion, however, is still insufficiently investigated. We retrospectively examined the invasion of lymph vessels and blood vessels separately as two possible prognostic factors in 160 patients who underwent a video-assisted thoracoscopic lobectomy for non-small-cell lung cancer at our institution between 2014 and 2019. Lymph vessel invasion was significantly associated with the UICC stage, lymph node involvement, tumor dedifferentiation, blood vessel invasion and recurrence. Blood vessel invasion tended to be negative prognostic, but missed the level of significance (p = 0.108). Lymph vessel invasion, on the other hand, proved to be a prognostic factor for both histological subtypes, adenocarcinoma (p < 0.001) as well as squamous cell carcinoma (p = 0.018). After multivariate analysis apart from the UICC stage, only lymph vessel invasion remained independently prognostic (p = 0.018). Remarkably, we found analogue survival curve progressions of patients with stage I, with lymph vessel invasion, compared to stage II non-small-cell lung cancer. After further validation in prospective studies, lymph vessel invasion might be considered as an upstaging factor in resectable lung cancer. Especially in the early-stage of the disease, it might represent an additional risk factor to consider adjuvant therapy after surgical resection.

Numerous studies analyzed lymphovascular invasion (LVI) in various malignant diseases, however, little is known about the role of lymphatic invasion (LI) as well as vascular invasion (VI) in oral squamous cell carcinoma (OSCC). The aim of this study is to illuminate the role of LI and VI in a population-based cohort study.
We retrospectively analyzed 745 primarily resected OSCC patients in Eastern Bavaria for histopathologically verified LI and VI. Overall survival (OS) and recurrence-free survival (RFS) were calculated, whereas analysis was performed by uni- and multivariate statistics. Mean follow-up time was 7.4 years.
LI was found in 115 patients (15.4%), VI was diagnosed in 23 cases (3.1%). LI correlated significantly with distinct anatomical sites (p = 0.004), increasing pT-classification (p < 0.001), lymph node involvement (p < 0.001), higher grading (p < 0.001), advanced UICC-stages (p < 0.001) and adjuvant therapies (p < 0.001). Similar results were found for VI. Survival analysis resulted in a significantly decreased five-year OS and RFS in patients with diagnosed LI (OS: 41.1%, RFS: 38.3%) in contrast to LI-negative cases (OS: 66.8%, RFS: 59.7.7%, p < 0.001). Analogous outcomes were seen for patients with VI. Additionally, LI was identified as a predictive parameter, indicating individual patients\' response to adjuvant therapies.
This population-based cohort study underlines the unfavorable aspect of LI and VI on outcome in OSCC. Including LI and VI in existing staging systems could help to stratify patients\' risk for adverse outcome and consecutively determine adjuvant treatment in malignant disease.

The purpose of this study was to analyze the influencing factors of BVI in advanced gastric cancer and explore the factors affecting the prognosis of advanced gastric cancer, so as to accurately evaluate the disease status and enable patients to receive effective treatment. We retrospectively analyzed 622 cases with complete data and successful follow-up. BVI was found in 144 of the 622 patients with advanced gastric cancer, with a detection rate of 23.15%. BVI was closely related to the differentiation degree, infiltration depth and lymph node metastasis of advanced gastric cancer, (P <  0.05). Gender, age, tumor location, tumor size, Lauren classification, tumor M stage, and clinical TNM stage were not the influencing factors of BVI in patients with advanced gastric cancer (P >  0.05). The 5-year survival rate of patients in the positive group of BVI was 34.72%. The 5-year survival rate of patients with advanced gastric cancer was correlated with BVI, Lauren classification, depth of invasion, lymph node metastasis, and clinical TNM staging, (P <  0.05). The 5-year survival rate was independent of gender, age, tumor location, tumor size, tumor tissue differentiation, and M stage (P >  0.05). The results of multi-factor analysis showed that BVI, N stage and clinical TNM stage were independent predictors of prognosis in patients with advanced radical gastric cancer. By analyzing the stage and related prognostic factors of resectable advanced gastric cancer, we found that BVI was not only closely related to lymph node metastasis, but also an independent predictor of prognosis of advanced gastric cancer. As this study was only a single-center retrospective study, there may be a selective bias in clinical data. So large-scale and multi-center collaboration is needed to further explore the influencing factors of BVI in the progression of gastric cancer.

The prognostic significance of blood and lymphatic vessel invasion in the 8th edition of the Tumor, Node, Metastasis (TNM) classification remains unclear. Therefore, this study aimed to evaluate the prognostic significance of blood and lymphatic vessel invasion in p-stage IA lung adenocarcinoma in the 8th edition of the TNM classification.
We retrospectively examined patients with p-Stage 0-IA lung adenocarcinoma, reclassified according to the 8th edition of the TNM classification. Blood and lymphatic vessel invasion were evaluated using hematoxylin-eosin and Elastica van Gieson and hematoxylin-eosin and anti-podoplanin antibody staining, respectively. Combined blood and lymphatic vessel invasion constituted tumor vessel invasion (TVI).
Overall, 306 patients were evaluated. The median follow-up period was 98.0 (range: 10-216) months. The 5-year recurrence-free survival differed significantly among patients with and without TVI in p-stage IA1 (TVI-: 100%, TVI+: 88.9%, P = 0.007) and IA2 (TVI-: 94.6%, TVI+: 80.8%, P = 0.012) but not in p-stage IA3 (TVI-: 66.7%, TVI+: 75.0%, P = 0.598). The 5-year lung cancer-specific survival also differed significantly among those with and without TVI in p-stage IA1 (TVI-: 100%, TVI+: 88.9%, P < 0.001) and IA2 (TVI-: 98.2%, TVI+: 88.7%, P = 0.043) but not in p-Stage IA3 (TVI-: 66.7%, TVI+: 75.0%, P = 0.858). No recurrence and lung cancer-specific deaths occurred in p-stage IA1 patients without TVI. On multivariate analysis, the presence of TVI was independently associated with recurrence and lung cancer-specific death in patients with p-stage IA1-2 lung adenocarcinoma. TVI did not affect the prognosis of those with p-stage IA3 adenocarcinoma.
TVI is a prognostic factor in patients with p-stage IA1-2 lung adenocarcinoma. P-stage IA1 lung adenocarcinoma without TVI may therefore be classified as minimally invasive.

Giant cell tumor of bone is a rare but aggressive benign tumor that arises at the end of long tubular bones. The tumor rarely metastasizes; however, we report a case in which a giant cell tumor of bone presented with progressive pulmonary metastases. There has been no clear pathologic evidence of the definitive cause or route of metastasis. In our case, the primary tumor site was located in the left femur with pathological evidence of blood vessel invasion. The histological and pathological features of this entity are discussed in this letter to the editor.

OBJECTIVE: Lymphatic and blood vessel invasion are important independent prognostic factors in colorectal cancer, but identification of the separate components remains difficult. The aim of the present study was to compare routine hematoxylin and eosin (H&E) and elastica staining with immunohistochemistry using D2-40 and CD31.
METHODS: A total of 75 surgical specimens of colorectal cancer were examined for blood and lymphatic vessel invasion, by comparing stains.
RESULTS: The minimum clinical follow-up of survivors was 5 years. During that time, 45 patients died, 34 from their cancer. Lymphatic invasion by H&E was found in 19% compared to 40% detected with D2-40 (p<0.001). Lymphatic invasion was not associated with T-stage (H&E, p=0.923; D2-40, p=0.724) but was significantly associated with N-stage, (H&E, p=0.001; D2-40, p<0.001). No significant association between lymphatic invasion (H&E or D2-40) and cancer-specific survival was found on univariate analysis. Blood vessel invasion by elastic detection was detected in 53% compared to 32% detected with CD31 (p=0.090). Blood vessel invasion was associated with T-stage, (elastica, p=0.028; CD31, p=0.839) but was not associated with N-stage (elastica, p=0.377; CD31, p=0.519). On univariate analysis of blood vessel invasion was associated with cancer-specific survival (elastica, p=0.009) when detected by elastica, but not when detected by CD31, (p=0.611). Lymphatic invasion (D2-40) was associated with blood vessel invasion (elastic) (p=0.019). On multivariate analysis, blood vessel invasion with elastica had independent prognostic value (hazard ratio=2.55, 95% confidence interval=1.23-5.28; p=0.012).
CONCLUSIONS: The results of the present study indicate that immunohistochemistry using D2-40 improves the identification of lymphatic invasion compared to use of H&E staining only; however, its prognostic value was limited. Elastica staining improves the detection rate of blood vessel invasion (compared to CD31) and venous invasion detected with elastica had independent prognostic value in patients undergoing curative resection for colorectal cancer.